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Microbial Interventions to Control and Reduce Blood Pressure in Australia (MICRoBIA): rationale and design of a double-blinded randomized cross-over placebo controlled trial (STEPHEN MAYER)

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Microbial Interventions to Control and Reduce Blood Pressure in Australia (MICRoBIA): rationale and design of a double-blinded randomized cross-over placebo controlled trial (STEPHEN MAYER)

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Hypertension, or high blood pressure, is a prevalent chronic disease that affects many people worldwide. It is not well controlled due to poor diets and lack of medicine compliance. This clinical study’s goal is to validate their hypothesis that the microbiota of the gut plays an integral role in the maintenance of blood pressure, along with environmental and genetic factors. Microbiota populations that generate short-chain fatty acids (propionate, acetate, and butyrate) are found in prebiotic fiber rich diets and is thought to be the key when attempting to ameliorate inflammatory diseases. This study will assess the use of an acetylated and butyrylated high amylose maize starch (HAMSAB) as treatment for hypertension. Lots of pre-clinical trials have supported that HAMSAB has beneficial outcomes associated with cardiovascular disease.

This study has not yet published its data as it is still currently recruiting as of last summer. I chose this article because it shows a great example of active work being done in the field and how to think outside of the box. This study is important as it relates to nutritional sciences because curing CVD through diet and creating buy in will save many lives around the world. This study will present data for the first time on the combination use of both pre- and post-biotics to lower BP in humans.

Rhys-Jones, D., Climie, R. E., Gill, P. A., Jama, H. A., Head, G. A., Gibson, P. R., Kaye, D. M., Muir, J. G., & Marques, F. Z. (2021). Microbial Interventions to Control and Reduce Blood Pressure in Australia (MICRoBIA): rationale and design of a double-blinded randomised cross-over placebo controlled trial. Trials, 22(1), 496. https://doi.org/10.1186/s13063-021-05468-2

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Randomized Controlled Trial

doi: 10.1186/s13063-021-05468-2.

Affiliations

¹ Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 25 Rainforest Walk, Clayton, Victoria, 3800, Australia.

² Department of Gastroenterology, Central Clinical School, Monash University, Melbourne, Australia.

³ Sports Cardiology, Baker Heart and Diabetes Institute, Melbourne, Australia.

⁴ Menzies Institute for Medical Research, University of Tasmanian, Hobart, Australia.

⁵ Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.

⁶ Department of Pharmacology, Monash University, Melbourne, Australia.

⁷ Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia.

⁸ Central Clinical School, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Australia.

⁹ Department of Cardiology, Alfred Hospital, Melbourne, Australia.

¹⁰ Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 25 Rainforest Walk, Clayton, Victoria, 3800, Australia. Francine.marques@monash.edu.

¹¹ Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia. Francine.marques@monash.edu.

Free PMC article

Randomized Controlled Trial

Free PMC article

doi: 10.1186/s13063-021-05468-2.

Affiliations

¹ Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 25 Rainforest Walk, Clayton, Victoria, 3800, Australia.

² Department of Gastroenterology, Central Clinical School, Monash University, Melbourne, Australia.

³ Sports Cardiology, Baker Heart and Diabetes Institute, Melbourne, Australia.

⁴ Menzies Institute for Medical Research, University of Tasmanian, Hobart, Australia.

⁵ Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.

⁶ Department of Pharmacology, Monash University, Melbourne, Australia.

⁷ Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia.

⁸ Central Clinical School, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Australia.

⁹ Department of Cardiology, Alfred Hospital, Melbourne, Australia.

¹⁰ Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 25 Rainforest Walk, Clayton, Victoria, 3800, Australia. Francine.marques@monash.edu.

¹¹ Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia. Francine.marques@monash.edu.

Abstract

Background: Hypertension is a prevalent chronic disease worldwide that remains poorly controlled. Recent studies support the concept that the gut microbiota is involved in the development of hypertension and that dietary fibre intake may act through the gut microbiota to lower blood pressure (BP). Resistant starch is a type of prebiotic fibre which is metabolised by commensal bacteria in the colon to produce short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate. Previous work in pre-clinical models provides strong evidence that both prebiotic fibre as well as SCFAs (i.e. postbiotics) can prevent the development of hypertension. The aim of this clinical trial is to determine if acetylated and butyrylated modified resistant starch can decrease BP of hypertensive individuals via the modulation of the gut microbiota and release of high levels of SCFAs.

Methods: This is a phase IIa double-blinded, randomised, cross-over, placebo controlled trial. Participants are randomly allocated to receive either a diet containing 40 g/day of the modified resistant starch or placebo (corn starch or regular flour) for 3 weeks on each diet, with a 3-week washout period between the two diets. BP is measured in the office, at home, and using a 24-h ambulatory device. Arterial stiffness is measured using carotid-to-femoral pulse wave velocity. Our primary endpoint is a reduction in ambulatory daytime systolic BP. Secondary endpoints include changes to circulating cytokines, immune markers, and modulation to the gut microbiome.

Discussion: The findings of this study will provide the first evidence for the use of a combination of pre- and postbiotics to lower BP in humans. The results are expected at the end of 2021.

Trial registration: Australia and New Zealand Clinical Trial Registry ACTRN12619000916145 . Registered on 1 July 2019.

Keywords: Blood pressure; Diet; Fibre; Hypertension; Postbiotics; Prebiotics.

Conflict of interest statement

J. Muir works in a department that financially benefits from the sales of a digital application, booklets, and a food certification program on the low-Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols diet. Funds raised from these activities contribute to research of the Department of Gastroenterology and to the University. J. Muir receives no personal remuneration.

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Habitual dietary fibre intake influences gut microbiota response to an inulin-type fructan prebiotic: a randomised, double-blind, placebo-controlled, cross-over, human intervention study.

Healey G, Murphy R, Butts C, Brough L, Whelan K, Coad J. Healey G, et al. Br J Nutr. 2018 Jan;119(2):176-189. doi: 10.1017/S0007114517003440. Epub 2018 Jan 8. Br J Nutr. 2018. PMID: 29307330 Clinical Trial.

References

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Vrijens B, Antoniou S, Burnier M, de la Sierra A, Volpe M. Current situation of medication adherence in hypertension. Front Pharmacol. 2017;8:100. doi: 10.3389/fphar.2017.00100. - DOI - PMC - PubMed

Burnier M, Egan BM. Adherence in hypertension. Circ Res. 2019;124(7):1124-1140. doi: 10.1161/CIRCRESAHA.118.313220. - DOI - PubMed

Marques FZ, Mackay CR, Kaye DM. Beyond gut feelings: how the gut microbiota regulates blood pressure. Nat Rev Cardiol. 2018;15(1):20-32. doi: 10.1038/nrcardio.2017.120. - DOI - PubMed

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national center for biotechnology information

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Microbial Interventions to Control and Reduce Blood Pressure in Australia (MICRoBIA): rationale and design of a double-blinded randomised cross-over placebo controlled trial - PubMed

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Randomized Controlled Trial doi: 10.1186/s13063-021-05468-2. 1 Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 25 Rainforest Walk, Clayton, Victoria, 3800, Australia. 2 Department of Gastroenterology, Central Clinical School, Monash University, Melbourne, Australia. 3 Sports Cardiology, Baker Heart and Diabetes Institute, Melbourne, Australia.

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Julie Rees - https://jamanetwork.com/journals/jama/article-abstract/184309

Determining the main drivers in hypertension is important for treatments to have the greatest impact. This paper looked at 83,882 women without CVD, diabetes, cancer, or high blood pressure then evaluated them again after 14 years to see who developed hypertension.  They identified 6 lifestyle factors to determine which was the greatest predictor for development of hypertension.  A high body mass index increased the likelihood of developing high blood pressure with a BMI>31 causing a sixfold increase.  They did however find that low-risk factors like DASH diet and low alcohol consumption, decreased risk in both normal and over women but not obese.

This study tells us that maintaining health weight is a major factor in preventing hypertension.  Diet and exercise not only reduce weight but also contribute benefits to blood pressure for those not trying to lose weight.

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Diet and Lifestyle Risk Factors Associated With Incident Hypertension in Women

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Context Hypertension is an important preventable risk factor for death among women. While several modifiable risk factors have been identified, their combined risk and distribution in the population have not been assessed.Objective To estimate the hypothetical fraction of hypertension incidence...

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Fruit Intake to Prevent and Control Hypertension and Diabetes

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Fruit Intake to Prevent and Control Hypertension and Diabetes

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Park, H. A. (2021). Fruit Intake to Prevent and Control Hypertension and Diabetes. Korean Journal of Family Medicine, 42(1), 9.
-Clarisa Williams
This article published through the Korean Journal of Family Medicine is a meta-analysis that reviewed the evaluated and summarized evidence that fruit intake for the prevention and control of hypertension along with diabetes mellitus. The authors reviewed articles addressing the relationship between fruit intake and incident hypertension. A fruit intake of up to 530g - 600g per day was concluded to protect against incident hypertension. The meta-analysis of two longitudinal studies involving increased showed a less likelihood of developing hypertension and even a decreased diastolic and systolic pressure with consistent increased fruit intake. The use of fruit as a control for these studies isolate the effects that nutrition has on the health. Clinicians can utilize this information as a mean for preventative care for individuals with higher risk of developing hypertension. Clinicians can also include elevated fruit intake in the nutritional intervention for someone with hypertension as a way manage symptoms.

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Beating Hypertension- the Silent Killer - Dierra Doaks

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Beating Hypertension- the Silent Killer - Dierra Doaks

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The article that I chose for this week is about how lifestyle changes can help hypertension. The article discusses how many people with high blood pressure do not even know that they have it.  Hypertension is treated with medications in about 7 out of 10 adults in the United States. However, lifestyle changes can be as effective as medications to control hypertension. Lifestyle changes can also help prevent hypertension. Limiting sodium intake is one of the changes discussed in this article. According to the study, close to 58,000 cardiovascular deaths per year were related to high sodium intake. Another lifestyle change discussed was incorporating potassium-rich foods into one's diet. This can reduce the negative effects of dietary sodium and lower blood pressure. The potassium helps the body excrete sodium and helps relax blood vessel walls. One can incorporate greens, fruits, legumes, and fish to have more potassium in their diet. This study relates to nutritional sciences because it is important for people to understand how their diet can impact their risk for diseases.

“Beating Hypertension- the ‘Silent Killer.’” Tufts University health & nutrition letter 37.3 (2019): 4–5. Print.

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The Double-Edged Sword Effects of Maternal Nutrition in the Developmental Programming of Hypertension

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The Double-Edged Sword Effects of Maternal Nutrition in the Developmental Programming of Hypertension

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Ellen Reusch

For this week's wall post, I found this article published in Nutrients in 2018. I think it actually goes pretty well with another article I saw posted to this wall for the week, regarding maternal-fetal nutrition and how that can impact one's development of hypertension in the future. This particular article discusses developmental programming and how maternal nutrition can affect that of a fetus. Maternal nutrition is known to have long-term health implications on the health of the offspring, which can include the development of hypertension and other medical conditions. A study referenced in this article documented that poorer maternal nutrition could result in increased risk or rate for preterm birth, which is a risk factor for hypertension later in life. Additionally, short-term breastfeeding and macronutrient intake deficiencies have been shown to correlate with elevation of blood pressure in the offspring.

The article also discusses some specifics supporting the hypothesis that maternal nutrition affects development. In animal models, nutritional deficiencies towards the end of pregnancies have been demonstrated to  result in lower nephron numbers (and renal development continues until near-birth in rodents). These nutritional deficiencies ranged from iron deficiency, high-salt diet, low-protein diet, and vitamin A deficiency to name a few.

Furthermore, the renin-angiotensin system is important in controlling blood pressure. If RAS is dysregulated, lower nephron numbers can result within the kidneys. Studies have shown that there is a correlation between certain nutritional deficiencies and dysregulation of RAS.

I found this article extremely interesting. I also liked how the researchers referred to maternal nutrition as a "double-edged sword", because that term seems to be relevant to quite a few concepts within the medical community. It is important for clinicians to understand the information presented in this article, especially if they are taking care of pregnant or nursing patients. Maternal nutrition is known to be important for fetal development, but many people don't understand the ins and outs specifically of WHY. Also, I think it might be beneficial for clinicians to know certain nutritional recommendations for women who have a family history of a certain health condition. If these women decided to have children, but were concerned about their child's development of hypertension (for example) in the future, their clinicians could potentially suggest certain ways that they could help reduce their child's risk of developing it later on!

Hsu, Chien-Ning, & Tain, You-Lin. The Double-Edged Sword Effects of Maternal Nutrition in the Developmental Programming of Hypertension. Nutrients. 2018. 10(12), 1917. https://www.mdpi.com/2072-6643/10/12/1917/htm

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Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan

School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

Author to whom correspondence should be addressed.

Received: 20 October 2018 / Revised: 22 November 2018 / Accepted: 30 November 2018 / Published: 4 December 2018

Hypertension is a growing global epidemic. Developmental programming resulting in hypertension can begin in early life. Maternal nutrition status has important implications as a double-edged sword in the developmental programming of hypertension. Imbalanced maternal nutrition causes offspring's hypertension, while specific nutritional interventions during pregnancy and lactation may serve as reprogramming strategies to reverse programming processes and prevent the development of hypertension. In this review, we first summarize the human and animal data supporting the link between maternal nutrition and developmental programming of hypertension. This review also presents common mechanisms underlying nutritional programming-induced hypertension. This will be followed by studies documenting nutritional interventions as reprogramming strategies to protect against hypertension from developmental origins. The identification of ideal nutritional interventions for the prevention of hypertension development that begins early in life will have a lifelong impact, with profound savings in the global burden of hypertension.

1. Introduction

Hypertension remains an important public health challenge, despite treatment advances over the past decades. However, hypertension is a disease of multifactorial origins that can be treated to prevent more related disorders if found early. Although hypertension is more common in adults, it can occur at any age. Indeed, adult-onset hypertension can originate in early life [ 1]. Maternal nutrition during pregnancy and lactation has important implications for optimal fetal development and long-term health of the offspring. Imbalanced maternal nutrition produces fetal programming that permanently alters the body's morphology and function and leads to many adult diseases, including hypertension [ 2]. This notion is framed as the developmental origins of health and disease (DOHaD) [ 3]. Conversely, the DOHaD concept leads to a shift in the therapeutic approach from adult life to early stage, before hypertension is evident. This strategy reversing the programming processes in fetal and infantile life is known as reprogramming [ 4]. Nutrition interventions have recently started to gain importance as a reprogramming strategy to prevent hypertension of developmental origins [ 4, 5, 6].

According to the two aspects of the DOHaD concept, maternal nutrition may play an important role as a double-edged sword in developmental programming of hypertension. This review will first present the clinical and experimental evidence for how maternal undernutrition and overnutrition trigger the programming mechanisms leading to programmed hypertension. This will be followed by potential nutritional interventions that may serve as a reprogramming strategy to halt the growing epidemic of hypertension. A schematic summarizing the links between maternal nutrition, early-life insults, and mechanisms underlying programming of hypertension is presented in Figure 1.

2. Evidence for Programming of Hypertension Related to Maternal Nutrition Status in Humans

Nevertheless, these cohorts cannot per se directly establish a causal relationship between the maternal nutrition status and hypertension phenotype in offspring. Also, these cohorts do not illuminate molecular mechanisms by which the hypertension phenotype is created. As a consequence of ethical considerations concerning what is feasible or not in human studies, animal models are of great importance. It is obvious that much of our knowledge comes from animal models, which identify that specific types of nutrients may program hypertension phenotypes. The developmental window is critical for nutritional programming, and specific nutrition interventions can be used as reprogramming strategies.

3. Animal Models of Programmed Hypertension Induced by Imbalanced Maternal Nutrition

Dietary nutrients can be divided to macronutrients, micronutrients, and non-essential nutrients. Macronutrients, which provide energy, include carbohydrates, proteins, and fats. Restriction of calories to various degrees (ranging from 30% to 70%) in pregnant dams has been reported to cause hypertension in their adult offspring [ 20, 21, 22, 23]. Offspring exposed to a more severe degree of caloric restriction are likely to develop hypertension earlier. Rodent models of low protein feeding have been extensively used to study the mechanisms of nutritional programming. Similar to caloric restriction, a greater degree of protein restriction causes an earlier development of hypertension in offspring [ 24, 25, 26, 27, 28]. However, a previous study showed that two divergent low-protein (9%) diet manipulations in rat pregnancy provoked different programming effects on the offspring's BP [ 49]. Of note, the balance of protein and other nutrients may be a critical determinant of the long-term effects of maternal low-protein diet on programming of hypertension. Pregnant women are now recommended to eat methyl donor food to reduce adverse birth outcomes [ 50]. Such methyl donor nutrients include methionine, choline, folic acid, and vitamins B2, B6, and B12. However, we recently found that pregnant rats fed with high methyl-donor diet or methyl-deficient diet resulted in programmed hypertension in their male adult offspring [ 29].

Besides, sodium, potassium, calcium, magnesium, and other ions are listed with macronutrients as they are required in large quantities. Interestingly, both low- and high-salt diet exposure during pregnancy and lactation have been reported to cause elevated BP in male adult offspring [ 41]. Maternal calcium-deficient diet increased BP in adult offspring [ 42], while magnesium-deficient diet did not [ 43].

Additionally, deficiencies in micronutrients, including trace elements and vitamins, in pregnant mothers are associated with the development of hypertension in their adult offspring [ 44, 45, 46, 47]. These micronutrients include iron [ 44, 45], vitamin D [ 46], and zinc [ 47]. Although vitamin C, E, B6, flavonoids, and coenzyme Q-10 have been shown to lower BP [ 57], whether deficiencies of these micronutrients on pregnant mothers leading to programmed hypertension in their offspring is still largely unknown. Besides, no studies have been conducted examining the role of deficient non-essential nutrients on programming of hypertension. In the current review, limited information is available about the use of large animals to study nutritional programming induced offspring hypertension. Two reports in cows and sheep showed that maternal undernutrition causes elevation of BP in adult offspring [ 58, 59].

4. Common Mechanisms Underlie Nutritional Programming of Hypertension

Since various nutritional manipulations in gestation and lactation generate very similar outcomes with respect to hypertension in adult offspring in different species, these observations suggest the existence of common mechanisms that may contribute to the pathogenesis of hypertension of developmental origin. So far, programming of hypertension has been attributed to several mechanisms [ 4, 60, 61, 62, 63, 64]. Some of these mechanisms that have been previously linked to nutritional programming include low nephron number, oxidative stress, activation of the renin-angiotensin system (RAS), nutrient-sensing signals, gut microbiota, and sex differences. Each will be discussed in turn.

4.1. Low Nephron Number

The kidneys are known to play a decisive role in regulation of BP. There is an increasing body of literature demonstrating the relationship between low nephron number and hypertension, as reviewed elsewhere [ 65, 66]. Renal development in rodents, unlike in humans, continues up to postnatal week 1-2. Therefore, nutritional insults during last third of pregnancy and early lactation periods have been reported to impair nephrogenesis, leading to a reduction in nephron number [ 61]. As we reviewed elsewhere [ 67], these nutritional factors include caloric restriction [ 22], low-protein diet [ 25, 68], high-salt diet [ 41], low-salt diet [ 41], vitamin A deficiency [ 69], and iron deficiency [ 70]. Maternal protein restriction resulted in reduced nephron number and elevation of BP in adult male offspring, which is related to renal hyperfiltration and activation of the renin-angiotensin system (RAS) [ 25]. Additionally, maternal iron and zinc deficiencies have also been found to reduce nephron number and increase systolic BP in adult offspring [ 66]. Conversely, nephron endowment can be unaltered [ 71], or even increased in response to nutritional programming [ 72]. These findings suggest that the nutritional programming of hypertension might be not specific to a single factor (i.e., low nephron endowment) and other mechanisms demands further exploration.

4.2. Oxidative Stress

Oxidative stress is an oxidative shift characterized by an imbalance between pro-oxidant molecules and antioxidant defenses. Nitric oxide (NO), a vasodilator and a free radical, is involved in BP control and oxidative stress. NO plays an important role in placental and fetal growth [ 73]. Early-life redox imbalance may lead to lifelong effects in vulnerable organs leading to hypertension in later life [ 74]. Offspring born to dams with NO deficiency develop hypertension [ 75], while restoration of the balance between NO and reactive oxygen species (ROS) was considered as a reprogramming strategy to prevent hypertension of developmental origins [ 76]. Numerous nutritional interventions have been reported to result in programmed hypertension related to oxidative stress, including caloric restriction [ 21, 22], low protein diet [ 26], methyl-donor diet [ 29] high fat intake [ 30, 32, 33], high-fructose diet [ 36], and zinc deficiency diet [ 47]. Although oxidative stress is unlikely to be attributed to the sole mechanism that increases the vulnerability to later hypertension, it is required to elucidate its interplay with other mechanisms of nutritional programming in determining its impact on hypertension.

4.3. Renin-Angiotensin System

RAS is broadly involved in control of BP and pharmacological blockade of the RAS has been clinically used to treat hypertension. Inactivation of RAS components cause the reduction of nephron number [ 77]. Several nutritional insults during early life leading to predisposition toward dysregulation of RAS have been reported, including low-protein diet [ 25, 28], high-fat diet [ 33], high-sucrose diet [ 34], and high-fructose diet [ 37]. Conversely, early blockade of the RAS has been reported to reprogram inappropriate activation of the RAS to prevent the developmental programming of hypertension [ 37, 78, 79]. These observations support the notion that RAS might be a common mechanism that underlies hypertension of developmental origins. It is noteworthy that blockade of the RAS to prevent the programmed hypertension cannot start as early as two weeks after birth in the rodent models for two reasons. First, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated during pregnancy because of their teratogenic effects. Second, blockade of the RAS impairs nephrogenesis and nephrogenesis completes in postnatal weeks 1-2 in rodents.

4.4. Nutrient-Sensing Signals

Nutrient-sensing signaling pathways influence fetal metabolism and development according to maternal nutritional status. Cyclic adenosine monophosphate (AMP)-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs) are well-known nutrient-sensing signals [ 80]. The interplay between AMPK and other nutrient-sensing signals, driven by maternal nutritional interventions were found to regulate PPARs and their target genes, thereby generating programming of hypertension [ 81]. Several genes involved in oxidative stress are PPAR target genes, such as Nos2, Nos3, Sod2, and Nrf2 [ 82]. Additionally, PPARγ has been reported to stimulate renin gene expression [ 83]. Given that the RAS cascade starts with the release of renin from the kidney, it is possible that programmed hypertension is attributed to these PPAR target genes induced oxidative stress and RAS activation. Furthermore, PPARγ can increase several sodium transporters to increase sodium reabsorption, leading to programmed hypertension [ 84]. Therefore, nutritional insults could affect PPARs and their target genes to induce renal programming leading to programmed hypertension.

Conversely, pharmacological interventions targeting AMPK signaling has been considered as reprogramming strategies to prevent programmed hypertension [ 85]. Detailed mechanisms that underlie the interactions between maternal nutrition and nutrient-sensing signals and their roles in the programming process toward hypertension of developmental origins, however, remain unclear.

4.5. Gut Microbiota

Gut is the first organ in contact with dietary nutrients. Maternal nutritional insults may cause a microbial imbalance, namely dysbiosis [ 86]. Dysbiosis in early life has negative effects and may have long-term consequences leading to many adult diseases, including hypertension [ 86]. Emerging evidence shows that the development of hypertension is correlated with gut microbiota dysbiosis in animal models of hypertension [ 87, 88, 89]. Several possible mechanisms have been identified linking the dysbiosis and hypertension, including alterations of microbial metabolite short-chain fatty acids and their receptors, increases of microbiota-derived metabolite trimethylamine-N-oxide, increased sympathetic activity, activation of the RAS, and inhibition of NO as well as hydrogen sulfide [ 89]. In addition to macro- and micro-nutrients, non-essential nutrients are substances within foods that can have a significant impact on health, for example, dietary fiber. It is noteworthy that consumption of dietary fiber has become one dietary strategy for modulating the microbiota. Our recent report showed that modulation of gut microbiota by prebiotics (i.e., a special form of dietary fiber) or probiotics (i.e., beneficial bacteria in the gut) can prevent maternal high-fructose consumption induced programmed hypertension [ 90]. Despite recent studies demonstrating that microbiota-targeted therapies can be applied to a variety of diseases [ 91], their roles on programmed hypertension remain to be identified.

4.6. Sex Differences

There now is a substantial literature indicating that sex differences exist in the developmental programming of hypertension [ 92, 93], showing that males are more prone to hypertension than females. Besides, several above-mentioned mechanisms of renal programming, such as oxidative stress [ 94] and inappropriate activation of the RAS [ 95] have been reported to respond to early-life insults in a sex-specific manner. The long-term effects of the same nutritional insult, such as maternal caloric restriction [ 23], high-fat diet [ 33], or high-fructose diet [ 37], can induce various phenotypes on male and female offspring. This difference has led many researchers to target their efforts entirely to one sex, especially to males [ 22, 25, 26, 29, 30, 31, 34, 35, 38, 39, 40, 41, 47]. Nevertheless, only few studies have investigated the programming response to maternal diet focused on transcriptome profiles of the offspring kidney [ 96]. In a maternal high-fructose diet model [ 37], we found renal transcriptome is sex-specific and female offspring are more fructose-sensitive. This is in accord with a report revealing that more genes in the placenta were affected in females than in males under different maternal diets [ 97]. A previous study has shown that sex-specific placental adaptations are often associated with male offspring developing adult disease while females are minimally affected [ 98]. However, whether higher sensitivity to nutritional insults is beneficial or harmful for programming effects in female offspring awaits further evaluation.

5. Nutritional Interventions as Reprogramming Strategies to Prevent Programmed Hypertension

Reprogramming strategies can be created based on the above-mentioned mechanisms leading to programmed hypertension. The reduced nephron number was restored by citrulline supplementation in the caloric restriction model [ 22]. The beneficial effects of citrulline [ 22, 75], micronutrients [ 21], conjugated linoleic acid [ 106], and folic acid [ 107] on hypertension are related to reduction of oxidative stress. On the other hand, branched-chain amino acid supplementation prevented hypertension related to regulation of the RAS in the caloric restriction model [ 104]. Furthermore, maternal administration of inulin prevented adult rat offspring against high-fructose diet-induced programmed hypertension associated with nutrient-sensing signals [ 90].

Moreover, growing evidence from animal studies suggests that sex differences in the kidney could be a key factor in the developmental programming of hypertension [ 92, 93]. Further work is warranted to recognize the influences of sex differences on programmed hypertension that will aid in developing novel sex-specific strategies to prevent hypertension of developmental origin in both sexes.

6. Conclusions

Maternal nutrition is like a double-edged sword. A growing body of evidence suggest that supplementation with specific macro- and micro-nutrients, and even non-essential nutrients in pregnancy and lactation protect adult offspring against hypertension in a variety of models of developmental origins. Yet, at the same time, it needs to be aware that unbalanced maternal nutrition not only affects maternal health, it also has an impact on fetal programming leading to programmed hypertension. Nutritional intervention as a reprogramming strategy against the development of hypertension is a great opportunity and will become even more crucial with the growing epidemic of hypertension and related disorders. These strategies have been proven effective in animal models, as shown earlier. A better understanding of mechanisms underlying nutritional programming is urgently needed before these interventions are implemented in humans.

Author Contributions

C.-N.H.: contributed to concept generation, data interpretation, drafting of the manuscript, critical revision of the manuscript, and approval of the article; Y.-L.T.: contributed to concept generation, data interpretation, drafting of the manuscript, critical revision of the manuscript, and approval of the article.

Funding

This research was supported by grant MOST 107-2314-B-182-045-MY3 from the Ministry of Science and Technology, Taiwan, and the grants CMRPG8G0672 and CMRPG8F0023 from Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Sengupta, P. The Laboratory Rat: Relating Its Age with Human's. Int. J. Prev. Med. 2013, 4, 624-630. [Google Scholar]

2. Tain, Y.L.; Huang, L.T.; Lee, C.T.; Chan, J.Y.; Hsu, C.N. Maternal citrulline supplementation prevents prenatal NG-nitro-l-arginine-methyl ester (L-NAME)-induced programmed hypertension in rats. Biol. Reprod. 2015, 92, 7. [Google Scholar] [CrossRef]

3. Thaeomor, A.; Teangphuck, P.; Chaisakul, J.; Seanthaweesuk, S.; Somparn, N.; Roysommuti, S. Perinatal Taurine Supplementation Prevents Metabolic and Cardiovascular Effects of Maternal Diabetes in Adult Rat Offspring. Adv. Exp. Med. Biol. 2017, 975, 295-305. [Google Scholar]

Cohort Study

Offspring, n

Age Range, Year

Country

Risk Factors

Animal Models

Intervention Period

Species/Gender

Age at Measure (Week)

Higher than Control

Reference

Macronutrients

20% w/v sucrose in drinking water

Pregnancy

SD/M

90

Yes

[ 34]

10% w/v fructose plus 4% NaCl in drinking water

4 weeks before conception and throughout pregnancy and lactation

SD/M

9

Yes

[ 35]

High-fructose diet, 60%

Pregnancy and lactation

SD/M+F

12

Yes

[ 36, 37]

10% w/v fructose in drinking water

Pregnancy and lactation

C57BL6J mice/M

52

Yes

[ 39]

Micronutrients

Nutritional Interventions

Animal Models

Intervention Period

Species/Gender

Age at Measure (Week)

Lower BP?

Ref.

Macronutrients

Micronutrients

Non-essential nutrients

# data[].attributes.attachment_link.title
The Double-Edged Sword Effects of Maternal Nutrition in the Developmental Programming of Hypertension

# data[].attributes.attachment_link.description
Hypertension is a growing global epidemic. Developmental programming resulting in hypertension can begin in early life. Maternal nutrition status has important implications as a double-edged sword in the developmental programming of hypertension. Imbalanced maternal nutrition causes offspring’s hypertension, while specific nutritional interventions during pregnancy and lactation may serve as reprogramming strategies to reverse programming processes and prevent the development of hypertension.

# data[].attributes.headline
Katelyn Spain: Hypertension and Its Associations with Dental Status: Data from the Dental, Oral, Medical Epidemiological (DOME) Nationwide Records-Based Study

# data[].attributes.subject
Katelyn Spain: Hypertension and Its Associations with Dental Status: Data from the Dental, Oral, Medical Epidemiological (DOME) Nationwide Records-Based Study

# data[].attributes.body
The purpose of this study was to determine the association between dental status and hypertension in young to middle-aged adults. It was found that the prevalence of hypertension in this study was 2.5%. It was found that hypertension in these patients was positively associated with obesity, diabetes mellitus, and presence of fatty liver. Further analysis of this population of patients, found that patients diagnosed with hypertension could contribute to a dental inflammation score. A dental inflammation score is a model that creates a score based on the prevalence of periodontal disease, number of teeth requiring crowns, and missing teeth. They found that patients being diagnosed with hypertension was not statistically significant enough to increase their dental inflammation scores. However, patients diagnosed with both  hypertension and diabetes presented with a higher dental inflammation score. The clinical implications of this article are for dental providers to talk to their patients about the higher risk factors that can contribute to both hypertension and dental health issues, such as smoking and obesity.
Almoznino, G., Zini, A., Kedem, R., Protter, N. E., Zur, D., & Abramovitz, I. (2021). Hypertension and Its Associations with Dental Status: Data from the Dental, Oral, Medical Epidemiological (DOME) Nationwide Records-Based Study. Journal of clinical medicine, 10(2), 176. https://doi.org/10.3390/jcm10020176

# data[].attributes.attachment_link.readable_text
Abstract

Conflicting results have been published regarding the associations between dental status and hypertension. This study aims to explore whether or not hypertension is associated with dental status among young to middle-aged adults. To that end, data from the Dental, Oral, Medical Epidemiological (DOME) study were analyzed. The DOME is a cross-sectional records-based study that combines comprehensive socio-demographic, medical, and dental databases of a nationally representative sample of military personnel. Included were 132,529 subjects aged 18-50 years who attended the military dental clinics for one year. The prevalence of hypertension in the study population was 2.5% (3363/132,529). Following multivariate analysis, the associations between hypertension and dental parameters were lost and hypertension retained a positive association with obesity (Odds ratio (OR) = 4.2 (3.7-4.9)), diabetes mellitus (OR = 4.0 (2.9-5.7)), birth country of Western Europe vs. Israeli birth country (OR = 1.9 (1.6-2.2)), male sex (OR = 1.9 (1.6-2.2)), cardiovascular disease (OR = 1.9 (1.6-2.3)), presence of fatty liver (OR = 1.8 (1.5-2.3)), the birth country Asia vs. Israeli birth country (OR = 1.6 (1.1-2.3)), smoking (OR = 1.2 (1.05-1.4)), and older age (OR = 1.05 (1.04-1.06)). Further analysis among an age-, smoking- and sex matched sub-population ( N = 13,452) also revealed that the dental parameters lost their statistically significant association with hypertension following multivariate analysis, and hypertension retained a positive association with diabetes (OR = 4.08 (2.6-6.1)), obesity (OR = 2.7 (2.4-3.2)), birth country of Western Europe vs. Israel (OR = 1.9 (1.6-2.3)), cardiovascular disease (OR = 1.8 (1.5-2.2)), fatty liver (OR = 1.7 (1.3-2.3)), high school education vs. academic (OR = 1.5 (1.3-1.8)), and low socio-economic status (SES) vs. high (OR = 1.4 (1.03-1.8)). We analyzed the associations between C-reactive protein (CRP) and dental parameters and combined the statistically significant variables to create a dental inflammation score (DIS). This crated a final model with the appropriate weights written as follows: DIS = (periodontal disease × 14) + (the number of teeth that required crowns × 11) + (missing teeth × 75). The mean DIS was 10.106 ± 25.184, and it exhibited a weak positive association with hypertension in the univariate analysis (OR = 1.011 (1.010-1.012)). Receiver operating characteristic (ROC) analysis of the DIS against hypertension produced a failed area under the curve (AUC) result (0.57 (0.56-0.58)). Moreover, the DIS also lost its statistical significance association with hypertension following multivariate analysis. We conclude that hypertension had no statistically significant nor clinically significant association with dental status. The study established a profile of the "patient vulnerable to hypertension", which retained well-known risk factors for hypertension such as older age, male sex, smoking, diabetes, obesity, and fatty liver but not dental parameters.

Keywords: hypertension, dental, caries, decayed teeth, metabolic syndrome, diabetes mellitus, hyperlipidemia, C-reactive protein, obesity, electronic medical record, electronic dental record

1. Introduction

Hypertension is a chronic disease that is often dubbed the "silent killer" as it rarely causes symptoms, but simultaneously it is an independent risk factor for coronary heart disease, stroke, renal disease, peripheral arterial disease, and vascular cognitive impairment [ 1, 2]. Hypertension is one of the components of metabolic syndrome (MetS), along with diabetes mellitus, hyperlipidemia, abdominal obesity, and fatty liver [ 3].

The global prevalence of hypertension was estimated at 1.3 billion in 2015 [ 4, 5]. The data indicate that hypertension among young adults is more common than what was frequently thought. Among men aged 18-39, there was a higher prevalence of 15-20% in men and 12-15% in women, which was even higher among overweight people [ 6, 7]. In addition, younger adults have significantly higher rates of under-diagnosis of hypertension [ 6, 7], and lower rates of blood pressure control [ 8, 9] than the rates among those aged 40 and older.

Associations between dental problems, hypertension and cardiovascular diseases (CVD) have been previously investigated. A recent consensus report updated the existing epidemiological evidence for significant associations between periodontitis and cardiovascular diseases, although a causal relationship has not been established [ 10]. The proposed mechanisms include bacteremia and the associated systemic inflammatory sequelae, including elevations in C-reactive protein (CRP) and oxidative stress [ 11]. Given that endodontic infections share several characteristics with periodontitis, including altered microbiota and pro-inflammatory mediators, their role in CVD has also been investigated [ 12]. Indeed, oral infections in childhood appear to be associated with the subclinical carotid atherosclerosis seen in adulthood [ 13]. The consensus report concluded that there is now a significant body of evidence to support independent associations between severe periodontitis and several non-communicable diseases including diabetes, cardiovascular disease, chronic obstructive pulmonary disease and chronic kidney disease, and even with all-cause and cardiovascular mortality in several populations [ 10]. These associations had not been established specifically in hypertension, however considering that hypertension is part of the metabolic syndrome, there is a need for large-scale epidemiological studies that will assess the inflammatory theorem in the context of hypertension, by studying the association between hypertension, dental morbidities and markers for systemic inflammation, such as CRP. Indeed, when assessing the association between dental parameters and hypertension, the studies should distinguish between cases with hypertension as a sole diagnosis, vis-à-vis cases where hypertension exists as part of the metabolic syndrome cluster.

Moreover, while some studies support the association of hypertension with caries [ 14, 15], other studies did not find a significant association between carious teeth and hypertension [ 16, 17]. These conflicting results could be attributed to the limitations of the published studies, such as heterogeneity in the definitions of dental and systemic diseases and the presence of possible confounders that were not always considered. For example, there are well-known common risk factors [ 18] for many chronic diseases, including dental caries and hypertension [ 19, 20, 21]. Among the common risks are increased age, socioeconomic status, smoking, alcohol consumption, and obesity [ 22, 23].

Considering these limitations, there is a need for large-scale studies with a rigorous protocol regarding dental and medical disease definitions, which take into account the existence of many possible confounders. In particular, it is important to assess the associations between dental status and hypertension among young and middle-aged adults due to the relatively high prevalence of hypertension, as well as the lower rates of diagnosis in these age groups.

To address the gap in the literature, the primary objective of this study was to analyze the association of hypertension with dental status among young and middle-aged adults. To that end, the current study used data from the "The Dental, Oral, Medical Epidemiological (DOME)" study [ 24]. The DOME is a cross-sectional records-based study that combines comprehensive socio-demographic, medical, and dental databases of a nationally representative sample of military personnel from the Israel Defense Forces (IDF) [ 24]. The methods of data collection of the DOME study were described in detail previously [ 17, 24, 25, 26]. An unusual opportunity exists in Israel to study these associations using this comprehensive information collected in the military databases and captured in the DOME repository. The military population in Israel is large and comprises a credible data source for epidemiological studies among young and middle-aged adults. This is partly since conscription exists in Israel for all Jewish, Druze, or Circassian citizens over the age of 18 [ 17]. Importantly, service in the IDF includes medically complex individuals, except for those who are unfit for service for health reasons (physical or mental), and even for those subjects, there is an option to apply for volunteering [ 27, 28]. Dental services are part of the comprehensive medical care, and the IDF military personnel do not incur any medical and/or dental expenses [ 29, 30].

In our recent publications, we coined the term "SOS teeth" to represent teeth that need to be treated first due to advanced caries reaching the pulp or the presence of decayed root fragments [ 17, 26]. Using the DOME database, we have previously shown that teeth with advanced caries termed "SOS teeth" had no statistically significant association with metabolic syndrome [ 17]. In this study, we focused on hypertension and further explored its association with dental treatment needs and actual dental treatments. Specifically, we assessed the associations of hypertension with the prevalence of the following dental treatment needs and actual dental procedures: (1) fillings, (2) endodontic treatments, (3) post fabrications, (4) crowns, (5) extractions, (6) periodontal disease and (7) missing teeth. Assessment of other dental parameters beyond these dental parameters is beyond the scope of this paper. To assess possible confounders, we also analyzed the associations of hypertension with socio-demographic parameters, health-related risk habits, medical and dental attendance patterns, and medical diagnoses of the subject. This will enable us to establish a profile of the "patient vulnerable to hypertension", and to see if following the multivariate analysis, the profile will still include dental parameters. Furthermore, in order to assess the inflammatory theorem presented above, another objective of this study was to analyze the associations between CRP and the dental conditions, combine the statistically significant variables to create a dental inflammation score (DIS), assign weights according to their importance, and use the DIS as a predictor for hypertension.

The main research hypothesis is that poor dental status, reflected by a higher prevalence of dental treatment needs, will be the predictor of the outcome of hypertension. Nevertheless, we hypothesized that these associations and correlations may be explained by shared risk factors, and therefore will be lost after controlling for socio-demographics, common health-related habits, and other systemic morbidities. This hypothesis was based on our prior evidence when analyzing the associations between metabolic syndrome and periodontal disease, as well as SOS teeth [ 17, 31].

2. Methods

2.1. Study Population

The study included data from the DOME study [ 24], which captures the socio-demographic, medical and dental records of all IDF military personnel, over the age of 18 years and of both sexes, who attended military dental clinics of the Israel Defense Forces (IDF) between January 1st, 2015 and January 1st, 2016, for which there are records in the DPR (dental patient Record) database [ 24]. Excluded were subjects with an absence of data in these databases.

2.2. Data Collection

A full description of the data collection, protocols, and methods of the DOME study had been previously published [ 24]. In brief, the DOME is a structured repository that captures three military electronic databases [ 17, 26]: (a) DPR, dental patient record-this electronic dental record (EDR) system stores the dental records of all military dental attendees; (b) MPR, medical patient record-this is a comprehensive electronic medical record (EMR) system that stores the general medical records of all military personnel [ 32]; (c) the IDF's central demographic database keeps the personal socio-demographic profiles of the military population [ 24, 33].

2.3. Study Variables

We analyzed the associations and correlations between hypertension as a dependent variable and independent variables. Definitions of the variables available in the DOME repository have been detailed in the DOME protocol and methods paper previously [ 24], and will be described briefly below.

2.3.1. Definitions of Dental Parameters

Standardized codes for dental procedures in the dental patient record (DPR). Standardized uniform codes are employed in the DPR for each dental procedure [ 24]. As described in the protocol of the DOME [ 24], the DOME repository includes uniform codes for dental procedures employed in the DPR that are equivalent to the nomenclature used by the American Dental Association's (ADA) Current Dental Terminology (CDT) [ 34]. Each dental code was drawn from the computerized database twice: once as the treatment plan needs value (assigned as "required"), and secondly as the value of the treatments that were actually performed for the specific parameter (assigned as "performed"). Definitions of the included dental treatment needs and actual dental procedures and their equivalent ADA-CDT codes are as follows:

In addition to procedures, the DPR data include records of the presence of periodontal disease and a count of missing teeth for any reason (excluding wisdom teeth) [ 24]. The standardization process as well as definitions of standardized diagnostic criteria for all dental parameters were described in detail previously in the DOME methods paper [ 24]. In brief, examinations were performed according to the guidelines of the Dental Department of the IDF medical corps, in an indoor setting, using a pair of vertical bilateral bitewings for the molar and premolar areas for all subjects, and periapical radiographs for deep caries, endodontically treated teeth, and periodontal disease [ 24]. To ensure standardization administrative as well as clinical workup, all military dentists complete routine training wherein the guidelines and protocols are reviewed, and there are regular quality assessment (QA) audits [ 24].

2.3.2. Definitions and Measurement of the Socio-Demographic Predictors

The definitions and measurement of the socio-demographic parameters were described in detail previously in the DOME methods paper [ 24]. In brief, the socio-demographic variables drawn from the IDF's central demographic database included the following [ 24]: age, sex (men/women), service duration (months), education (high school/technical college/academic), locality of residence (urban Jewish, urban non-Jewish, rural), socio-economic status (SES) (drawn from the records of the Israeli Ministry of the Interior (low (1st-4th deciles), medium (5th-7th), and high (8th-10th)), rings of a city/town (midtown/suburbs), and countries of birth [ 33, 35, 36] (Western Europe, Former Soviet Union (FSU), Asia, Ethiopia, Africa, North America, South America, Israel) [ 24].

2.3.3. Definitions of Health-Related Habits

Current smoking and alcohol as depicted in the MPR records, based on self-reported consumption status (yes/no) [ 17, 24].

Health-related habits derived from the DPR included assessment of the following (yes/no): (a) Teeth brushing at least once a day; (b) Consumption of cariogenic diet (the use of snacks and/or sweets between meals or instead of meals); (c) Sweetened beverages (exposure to sweet drinks over one cup a day) [ 24].

2.3.4. Definitions of Medical and Dental Attendance Patterns

Assessment of health care utilization during the study period included the total number of appointments with a general physician, the total number with a dentist, and the number of non-attendance to scheduled dental appointments [ 24].

2.3.5. Definitions of General Health Status Parameters

The general health status parameters that were obtained from the MPR included the following medical diagnoses, as was detailed previously [ 17, 24]:

2.4. Statistical Methods

Data were tabulated, and statistical analyses were performed using SPSS software version 25.0 (IBM, Chicago, IL, USA).

2.4.1. Descriptive Statistics

Continuous variables are presented as means and standard deviations. Categorical variables are presented as frequencies and percentages.

2.4.2. Explanatory Statistics-Univariate Analysis

The associations between hypertension and independent variables were examined with Pearson Chi-Square test or likelihood ratio test (for categorical parameters), and with a non-paired t-test for independent samples (for continuous variables). The assessment of normal distributions of all the continuous parameters was performed and revealed a lack of normal distribution. Therefore, we also used the non-parametric Mann-Whitney test, which does not require the assumption of normal distributions to analyze the association between hypertension diagnosis and the independent continuous variables. Due to the large sample size, and since there were no differences in the statistical significance between the t-test results and the Mann-Whitney test results, we present the t-test results for all the correlations between hypertension diagnosis and the independent continuous parameters in this study.

2.4.3. Calculations of Odds Ratios (OR)

OR were calculated for the continuous variables using linear regression analysis, and for categorical variables, the calculation was performed using binary logistic regression analysis.

2.4.4. Addressing the Large Sample Size and Possible Confounders

Following the univariate analyses, a multivariate analysis was performed using multivariate logistic regression analysis for hypertension diagnosis as the dependent variable. The criteria for independent variables to enter the multivariate analysis were as follows:

A statistically significant association with hypertension diagnosis in the univariate analysis. Due to the large sample size, a p value of <0.01 (2-tailed) in the univariate analysis was considered statistically significant to enter the multivariate analysis;

Multicollinearity tests-before entering a statistically significant variable in the univariate analysis into the multivariate model, the collinearity of the independent variables was examined. If two or more variables were found highly collinear, only one of them was included in the model, and it was decided by the context which of the variables will be included in the analysis. A p value of <0.01 level (2-tailed) was also considered significant for the multicollinearity tests. The multicollinearity tests between the variables comprising the DOME repository have been previously published [ 24]. A linear regression analysis was performed to assess collinearity between the independent variables. The variance inflation factors (VIFs), which are 1/Tolerance, are presented in the linear regression analysis. The results ruled out collinearity (VIF < 2.5). Although values of VIF below 10 are usually regarded as indicating multicollinearity, in weaker models values above 2.5 may be a cause for concern. Therefore, the cutoff of VIF in the present study was 2.5.

Multivariate analysis-Finally, the multivariate logistic regression analysis was used as a statistical model, by including in the analysis simultaneously all the variables fulfilling the criteria as described above. Due to the large sample size, a p value of <0.01 (2-tailed) was also considered statistically significant in the multivariate analysis.

3. Results

3.1. Description of the Study Population and the Prevalence of Hypertension

The study included 132,529 records of patients who met the eligibility criteria of the study. The mean age of the whole study population 21.88 ± 6.02 years, the age range was 18-50 and the median age was 20 years. The prevalence of hypertension in the study population was 2.5% (3363/132,529). Among the study population, the mean number of decayed teeth was 2.10 ± 2.8 and the mean number of missing teeth was 0.58 ± 1.3. Men compared to women exhibited higher mean number of both decayed (2.1 ± 2.8 vs. 1.9 ± 2.6, p < 0.001) and missing teeth (0.6 ± 1.3 vs. 0.52 ± 1.1, p < 0.001). The number of filling teeth is not included in the DOME repository.

All analyses were performed twice:

Comparison to those without hypertension using the whole study population ( N = 132,529 subjects; of those, 3363 with hypertension and 129,166 without hypertension) (presented on the left side of the Tables);

Comparison to age-, sex- and smoking-matched group without hypertension, which is three times larger than the hypertension group ( N = 13,452 subjects: of those, 3363 with hypertension and 10,089 without hypertension) (presented on the right side of the Tables).

To create the age-, sex- and smoking-matched group, we stratified the data according to sex (male/female), smoking (smoker/no smoker) and age, the latter of which was dichotomized into younger (<30 years) (the ~mean age of the hypertension group) and older (≥30 years). This resulted in eight possible strata, as can be seen in Table A1 in the appendix. We created a "control group without hypertension" that was three times larger than the hypertension group, according to the weight on each strata. As can be seen in Table A1 , the likelihood ratio analysis of the "Strata" variable against "hypertension" revealed p = 1.0.

3.2. The Associations between Socio-Demographic Parameters and Hypertension

Table 1 presents the associations between socio-demographic parameters and hypertension among the study population.

Comparison to those without hypertension among the whole study population: Compared to those without hypertension, hypertension was statistically significantly positively associated with male sex (OR men/women 2.8 (2.5-3.2)), technical education (OR technical/academics 1.3 (1.2-1.5)), medium vs. high SES (OR for medium/high 1.1 (1.0-1.2)), living in the peripheral rings of a city/town (OR periphery/central city rings 1.2 (1.1-1.3)), age (OR = 1.1 (1.1-1.1)), time in service (OR = 1.1 (1.1-1.1)), and the following countries of birth compared to native Israelis (from the highest to the lowest OR): Asia (OR = 2.3 (1.6-3.3)), Africa (OR = 2.2 (1.4-3.6)), and Western Europe (OR = 1.9 (1.8-2.2)) (see Table 1 ).

Compared to those without hypertension, the hypertension group had a statistically significant negative association (i.e., had a lower prevalence of hypertension) with the following variables: Urban Jewish (OR = 0.3 (0.2-0.4)) and Urban non-Jewish (OR = 0.2 (0.1-0.3)) localities compared to the rural locality, immigrants from Ethiopia (OR = 0.5 (0.4-0.8)) and North Americaa (OR = 0.5 (0.3-0.7)) birth countries (see Table 1 ).

The comparison to the age-, sex- and smoking-matched group without hypertension revealed similar trends except for age, sex and time in service, which were matched.

3.3. The Associations of Hypertension with Patient Health-Related Habits, and Attendance Patterns

Table 2 presents the associations of hypertension diagnosis with patient health-related habits, as well as the medical and dental attendance patterns.

The health-related habits of the patient. Hypertension was positively associated with smoking (OR = 5.6 (5.1-6.1)), alcohol consumption (OR = 3.6 (2.0-6.3)) and with brushing teeth less than once a day (OR = 1.5 (1.4-1.7)) ( Table 2 ). Hypertension was inversely associated with the consumption of a cariogenic diet (OR = 0.7 (0.6-0.8)) and the consumption of sweetened beverages (OR = 0.8 (0.7-0.9)) ( Table 2 ).

Attendance patterns. Those with hypertension had more appointments with a general physician (OR = 1.027 (1.024-1.029), had more dental appointments (OR = 1.025 (1.023-1.027)), and were more likely to not attend to scheduled dental appointments (OR = 1.060 (1.052-1.068)) ( Table 2 ).

The comparison to the age-, sex- and smoking-matched group without hypertension revealed similar trends regarding attendance patterns; however, health-related habits were not statistically significant, except for alcohol consumption.

3.4. General Health Status Parameters and Periodontal Disease According to Hypertension Diagnosis

Table 3 presents the general health status parameters and periodontal disease according to hypertension diagnosis among the study population. Hypertension was positively associated with the following conditions: hyperlipidemia (OR = 6.1 (5.0-7.3)), diabetes mellitus [OR = 27.6 (22.2-34.4)], impaired glucose tolerance (OR = 6.3 (3.8-10.4)), obesity (OR = 12.7 (11.8-13.6)), cardiovascular disease (OR = 6.0 (5.4-6.7)), fatty liver (OR = 14.5 (12.5-16.9)), obstructive sleep apnea (OR = 8.7 (6.5-11.6)), anemia (OR = 1.7 (1.5-1.9)) and periodontal disease (OR = 1.4 (1.2-1.6)) ( Table 3 ). Osteoporosis, Stroke, TIA (transient ischemic attack), DVT (deep vein thrombosis) and PVD (peripheral vascular disease) each had an extremely low prevalence among the hypertensive group. Therefore, we do not present in the table the results of their analyses against hypertension as a dependent variable, since these can be misleading.

The comparison to the age-, sex- and smoking-matched group without hypertension revealed similar trends, except for IGT, anemia and periodontal disease, which did not have a statistically significant association with hypertension in the sub-population analysis.

3.5. Dental Status According to Hypertension Diagnosis

Table 4 presents the requirements and performance of dental procedures according to hypertension diagnosis among the study population. Hypertension diagnosis had a weak statistically significant negative association with the following: the number of teeth that required one surface amalgam filling (OR = 0.9 (0.9-0.9)), the number of teeth where one surface amalgam filling was performed (OR = 0.9 (0.9-1.0)), and the number of teeth that required amalgam fillings on two surfaces (OR = 0.9 (0.8-0.9)).

There was no statistically significant association between hypertension and the number of teeth on which one surface amalgam filling was performed (0.9 (0.9-1.0)).

All other requirements, and the performance of the dental procedures that are presented in Table 4 , had weak statistically significant positive associations with a hypertension diagnosis.

In the comparison to the age-, sex- and smoking-matched group without hypertension, hypertension had a weak positive association with the number of teeth that required one surface amalgam filling (OR = 1.043 (1.008-1.079), the total number of teeth that required fillings (OR = 1.021 (1.004-1.039)), the total number of teeth that required endodontic treatment (OR = 1.113 (1.017-1.219)), the total number of teeth whereon endodontic treatment was performed (OR = 1.112 (1.019-1.214)), the number of teeth whereon prefabricated (direct, post and core) was performed (OR = 1.117 (1.048-1.191)), the number of teeth whereon extractions were performed (OR = 1.084 (1.023-1.150)), and missing teeth (OR = 1.043 (1.009-1.078)).

3.6. Multivariate Analysis

3.6.1. Multivariate Analysis of the Whole Study Population (N = 132,529)

Following the univariate analyses, a linear regression analysis was performed to assess the collinearity between the independent variables among the whole study population ( N = 132,529) ( Table 5 ). The results ruled out collinearity (VIF < 2.5). Following this, a multivariate logistic regression analysis was performed for hypertension diagnosis as the dependent variable ( Table 5 ).

Table 5

Parameter

B

Standard Error

p Value

Exp(B) and 95% Confidence Interval for Exp (B)

Collinearity Statistics *

Tolerance

VIF

The parameters were entered simultaneously into the analysis. The parameters that retained a statistically positive association with hypertension in the multivariate analysis presented in Table 5 were (from the highest to the lowest OR) as follows: obesity (OR = 4.2 (3.7 −4.9)), the presence of diabetes mellitus (OR = 4.0 (2.9-5.7)), birth country of Western Europe vs. Israeli birth country (OR = 1. 9 (1.6-2.2)), male sex (OR = 1.9 (1.6-2.2)), cardiovascular disease (OR = 1.9 (1.6-2.3)), presence of fatty liver (OR = 1.8 (1.5-2.3)), the birth country Asia vs. Israeli birth country (OR = 1.6 (1.1-2.3)), smoking (OR = 1.2 (1.05-1.4)), and older age (OR = 1.05 (1.04-1.06)) ( Table 5 ).

3.6.2. Multivariate Analysis among the Age-, Sex- and Smoking-Matched Subjects

Following the univariate analyses, a linear regression analysis was performed to assess the collinearity among the sub-population of age-, sex- and smoking-matched subjects ( N = 13,452) ( Table 6 ). The results ruled out collinearity (VIF < 2.5). Following this, a multivariate logistic regression analysis was performed for hypertension diagnosis as the dependent variable in this sub-population ( Table 6 ).

Table 6

Parameter

B

Standard Error

p Value

Exp(B) and 95% Wald Confidence Interval for Exp (B)

Collinearity Statistics *

Tolerance

VIF

(Intercept)

1.6

0.6

0.01

The parameters were entered simultaneously into the analysis. The parameters that retained a statistically positive association with hypertension in the multivariate analysis of the age-, sex- and smoking-matched sub-population that are presented in Table 6 were (from the highest to the lowest OR) as follows: the presence of diabetes mellitus (OR = 4.08 (2.6-6.1)), obesity (OR = 2.7 (2.4-3.2)), birth country of Western Europe vs. Israeli birth country (OR = 1.9 (1.6-2.3)), cardiovascular disease (OR = 1.8 (1.5-2.2)), presence of fatty liver [OR = 1.7 (1.3-2.3)], high school education vs. academic (OR = 1.5 (1.3-1.8)), and low SES vs. high (OR = 1.4 (1.03-1.8)) ( Table 6 ).

3.6.3. Dental Inflammation Score

To build a systemic inflammation theorem and explore how oral infection can contribute to it, we created a "dental inflammation score" (DIS) using CRP as a dependent variable. We used a method similar to the method employed by Janket et al. for the creation of the "asymptotic dental score" [ 37]. The CRP test was performed in 30,418 subjects from the total population (of those, 1387 were subjects with hypertension and 29,031 were subjects without hypertension), and the mean CRP test result was 3.7 ± 10.1 mg/L, the median was 1.1 mg/L, and the mode was 0.4 mg/L. Patients with hypertension exhibited statistically significantly higher CRP levels compared to those without hypertension (5.1 ± 11.7 vs. 3.7 ± 10.1, p < 0.001, OR = 1.009 (1.005-1.012)).

In the first step to create the "dental inflammation score", we used a general linear model (GLM) to analyze the association between CRP level as the dependent variable and all the dental variables as predictors, and we chose only significant variables ( Table 7 ). We used the likelihood ratio Chi-square from the Omnibus test results to determine the weight of each statistically significant variable. The only dental variables that had a statistically significant association with CRP were periodontal disease (likelihood ratio Chi-square: 6.77), the number of teeth that required crowns (likelihood ratio Chi-square: 5.24), and missing teeth (likelihood ratio Chi-square: 36.91) (see Table 7 ). We combined the likelihood ratio scores of the statistically significant variables (48.93), and for each variable, we computed the weight of this variable in the score as the likelihood ratio, then determined the weight of each variable as the likelihood ratio of each variable out of the total × 100 ( Table 7 ). The DIS was calculated by summing these values. This created the final model with the appropriate weights, written as follows: Dental inflammation score (DIS) = (periodontal disease × 14) + (the number of teeth that required crowns × 11) + (missing teeth × 75). Each of the variables were entered into this model as dichotomized variables (presence of the dental condition: yes/no). The mean dental inflammation score (DIS) was 10.106 ± 25.184, median = 0.0, minimum = 0, maximum = 100. The hypertension group had a statistically significantly higher DIS compared to those without hypertension (19.13 ± 32.57 vs. 9.87 ± 24.91; p < 0.001; GLM: OR = 1.011 (1.010-1.012)).

Table 7

OR 95% CI

p Value

Omnibus Test *

Likelihood Ratio of Each Variable Out of Total × 100

Likelihood Ratio Chi Square

p Value

A receiver operating characteristic (ROC) analysis was performed on the DIS as the predictor of hypertension ( Figure 1 ), and the area under the curve (AUC) was 0.57 (0.56-0.58), which is a fail result.

Finally, we ran a multivariate regression analysis with hypertension diagnosis as a dependent variable and all the statistically significant study variables, but instead of using the statistically significant dental variables we included the DIS. The multivariate analysis was performed among the whole study population as well as among the age-, sex- and smoking-matched sub-population. In both multivariate analyses the DIS lost its statistically significant association with hypertension, and the variables which retained statistically significant associations with hypertension were as follows:

Multivariate analysis among the whole study population: The parameters that retained statistical significance with hypertension were, from the highest to the lowest OR, obesity (OR = 4.5 (4.06-5.0)), cardiovascular disease (OR = 1. 8 (1.6-2.1)), birth country of Western Europe vs. Israeli birth country (OR = 1. 7 (1.5-1.9)), sex (OR = 1.6 (1.5-1.8)), hyperlipidemia (OR = 1. 4 (1.1-1.7)) and age (OR = 1.04 (1.03-1.05)). The DIS lost its statically significant association with hypertension (OR = 1.0 (1.0-1.0));

Multivariate analysis among the age-, sex- and smoking-matched sub population: The parameters that retained statistical significance with hypertension were, from the highest to the lowest OR, diabetes (OR = 4.3 (3.1-6.0)), obesity (OR = 2.7 (2.4-3.0)), fatty liver (OR = 1. 6 (1.3-2.0)), high school vs. academic education (OR = 1. 4 (1.3-1.6)), low SES vs. high (OR = 1. 3(1.1-1.6)), and technician vs. academic education (OR = 1.2(1.08-1.4)). The DIS lost its statically significant association with hypertension (OR = 1.0 (0.99-1.0)).

4. Discussion

The present study demonstrated that hypertension had no statistically significant or clinically significant association with dental status. Data were analyzed twice, among the whole study population as well as among an age-, sex- and smoking-matched sub-group, and in both analyses the dental parameters lost their statistically significant association with hypertension following multivariate analysis, which reflects a consistent trend. We computed a dental inflammation score (DIS) based on dental variables that had a statistically significant association with CRP. Although the DIS had a statistically significant association with hypertension in the univariate analysis, the DIS also lost its statistical significance association with hypertension following multivariate analysis. Moreover, the ROC analysis of the DIS against hypertension produced a fail AUC result (0.57). This records-based study assesses the association between hypertension and dental morbidities, combining comprehensive socio-demographic, dental and medical databases, which include dental treatment needs and actual procedures performed, socio-demographic data, medical diagnoses, health-related habits, and attendance patterns. This allowed the analysis of many confounders and mediators at the same time that were not considered concomitant previously in the medical and dental literature. The study established a profile of the "patient vulnerable to hypertension", which retained well-known risk factors for hypertension such as older age, male sex, immigrant status, low education and low socio-economic status, smoking, diabetes, cardiovascular disease, obesity and fatty liver, but not dental parameters.

4.1. Dental Status and Hypertension

The associations between hypertension and dental parameters found in the univariate analysis should be interpreted with utmost caution. This is due to the large sample size, which enables us to detect even weak statistical associations that may be clinically insignificant. Indeed, in the univariate analyses, the odds ratios for some of the parameters were close to 1, suggesting a weak statistical association (see Table 4 ). Moreover, although the differences regarding the dental parameters between those with and without hypertension were statistically significant in the univariate analysis, the differences in the mean scores were small and clinically non-significant. For this reason, data were analyzed also among an age-, sex- and smoking-matched sub-population. The analysis of the sub-population not only reduced the huge sample size, but also controlled for important well-known confounders of age, sex and smoking. Following multivariate analysis, these weak statistical associations between hypertension and the dental parameters were lost both in the analyses of the whole population as well as among the age-, sex- and smoking-matched sub-population. These consistent results in both analyses lead us to conclude that hypertension had no statistically significant or clinically significant association with dental status.

Separately, both hypertension and dental parameters were positively associated with CRP; however, the present study could not establish a systemic inflammation theorem wherein oral infection contributes to hypertension, due to the failure to establish an association between CRP, hypertension and dental parameters, using the DIS. This could result from the weak associations between the dental parameters and hypertension. It should also be kept in mind that although patients with hypertension and with the dental pathologies comprising the DIS exhibited significantly higher CRP levels, CRP tests are not routinely performed to monitor either dental pathologies or hypertension, and the cross-sectional study design cannot address the causality between these parameters.

Instead of the systemic inflammation theorem, the findings of the present study are in line with the common risk factors approach, stating that many chronic conditions share common risk factors, and therefore changing a few risk factors can positively impact numerous diseases [ 18]. Genetic and environmental factors such as increased age, smoking, and lifestyle are well-known major risk factors for many chronic diseases, including metabolic syndrome, hypertension, hyperlipidemia, diabetes type 2, as well as cardiovascular disease [ 19, 20, 21], and have also been related to oral health status [ 18, 38, 39]. This common risk factors approach is in line with the WHO Global policy for the improvement of oral health in the 21st century, which concluded that because health risks are linked, preventable, and related to lifestyle, oral and general health promotion should be integrated [ 40]. In line with our findings, other authors also demonstrated that the significant association between edentulousness and hypertension became non-significant and was attenuated after adjustment of the potential confounders [ 41].

Interestingly, another possible explanation of the results could be the lower perception of pain in spontaneous or experimentally induced high blood pressure, termed "blood pressure-related hypoalgesia" [ 42]. The phenomenon was first described in Israel [ 43, 44]. Since the first publication, it has been further described in the literature in many other research papers [ 45, 46, 47, 48, 49, 50, 51]. A possible hypothesis is that higher pain thresholds could account for higher rates of non-attendance to visits in the dental office, which consequently leads to more teeth with advanced carious lesions. Indeed, in the present study, patients with hypertension had a higher mean number of non-attendances to scheduled dental appointments, and had slightly more dental treatment needs, which supports this hypothesis. Unfortunately, measurements of pain thresholds were not included in this study, which excludes our ability to test this hypothesis. It is recommended that future studies will test this hypothesis by including pain thresholds as co-variants.

4.2. Patient Profile Positively Associated with a Hypertension Diagnosis

The study established a profile of the "patient vulnerable to hypertension", which retained well-known risk factors for hypertension that include age, sex, birth country of Western Europe vs. native Israeli, technical education vs. academic education, the presence of diabetes mellitus, obesity, and the presence of fatty liver.

4.3. Socio-Demographicparameters and Hypertension

In line with our findings, previous studies have demonstrated that blood pressure progressively increases with age [ 52], and is more common in men [ 53]. Although in recent years there has been an increase in the prevalence of hypertension across all demographics, there were greater increases among men compared with women [ 53]. However, the prevalence of hypertension remains lower in women until menopause [ 54], and we can attribute the higher prevalence of hypertension among men in the present study to the inclusion of subjects aged 18-50.

The lower SES and education found in patients with hypertension in the current study is in line with the results of a meta-analysis that demonstrated that low SES is associated with higher blood pressure, and this association is particularly evident in those with a lower level of education [ 55]. Moreover, our finding of a positive association between hypertension and rural locality is in line with that of others, who also demonstrated that hypertension prevalence, detection, and medication use among rural adults are all significantly lower than among urban adults [ 56].

Regarding birth countries, the present results show that some immigrant populations have a higher prevalence of hypertension compared to native Israelis, and according to the multivariate analysis, particularly those from Western Europe and Asia. Interestingly, the 2010-2016 US National Health Interview Survey (NHIS) demonstrated that immigrants from Russia and Southeast Asia had the highest hypertension prevalence [ 57]. In particular, a high salt intake among Asian-born persons such as the Chinese population may make them prone to hypertension [ 58]. Understanding the distribution of hypertension risk factors among immigrants is an essential area in epidemiology because of current trends in migration, particularly in Israel, which is an immigrant state. Previous epidemiological studies have shown that immigrants to the US typically have better health when they arrive from their home countries than the US-born population; however, this advantage is lost with increasing years of residence in the US [ 59]. This phenomenon is referred to as the "healthy immigrant effect", and is attributed to changes in the socio-economic, physical, and cultural environment [ 60]. The healthy immigrant effect, in the context of cardiovascular health and hypertension, may differ for particular immigrant groups, and the apparent advantage may be short-lived [ 57], which may explain our results. Future longitudinal studies that combine genetic and environmental assessments should further explore these observational findings.

4.4. Health-Related Habits and Hypertension

In the present study, smoking retained a positive association with hypertension even following multivariate analysis. Smoking is a common risk factor for both hypertension and dental/oral diseases [ 18]. Indeed, tobacco use is a leading cause of preventable death globally [ 61]. Shared risk factors, such as smoking, may account for the associations found in the univariate analysis between hypertension and dental parameters. This emphasizes the need for an appropriate risk factors management approach that should be adopted by both dental and general health clinicians, in order to control high-risk behaviors, such as smoking. While current smoking was assessed in this study, a history of past smoking was not included. Past smokers are at a higher risk of cardiovascular disease and hypertension, and relative to never-smokers, their cardiovascular risk remained significantly elevated beyond 5 years after smoking cessation [ 62]. Therefore, past smoking should be taken into account as a co-variant in future studies.

A sugar-sweetened diet and carbonated beverages are also risk factors for both dental caries and systemic morbidity, including hypertension [ 63]. In the current study, hypertension was negatively associated with cariogenic diet and with sweetened beverages consumption among the whole study population, and had no statistically significant association with hypertension in the age-, sex- and smoking-matched group. This could be attributed to the nutritional restrictions that patients with hypertension must follow. The interpretation of these parameters should be done with the utmost caution, considering that these are the only self-reported parameters in this records-based study and may be underreported.

4.5. The Association of Hypertension with the Systemic Morbidity of the Subject

Regarding the systemic morbidity of the subject, we found a positive association between hypertension and diseases comprising metabolic syndromes (i.e., diabetes, fatty liver, obesity), which were independently associated with hypertension. This is to be expected considering that hypertension is a part of the metabolic syndrome. Indeed, previous studies in the adult population with hypertension demonstrated higher rates of a positive parental history of hypertension [ 64]. The association between the triad of diabetes, fatty liver and obesity was highlighted in a recent study that showed that weight gain and the re-emergence of diabetes were associated with an increase in liver-derived plasma triglyceride, the re-accumulation of fat within the pancreas, and the recurrence of beta cell dysfunction [ 65]. Medical societies now recognize obesity as a chronic progressive disease [ 66, 67], and "Diabesity" is considered a world epidemic. Not all studies that assessed the association between dental parameters and hypertension distinguished between cases with hypertension as a sole diagnosis and cases wherein hypertension exists as part of the metabolic syndrome cluster. Dental parameters may be associated with diseases comprising the metabolic cluster other than hypertension. Therefore, adjustment for other diseases comprising the metabolic syndrome is crucial so as to understand the association between hypertension and dental parameters.

Anemia was positively associated with hypertension in the univariate analysis of the whole study population, but not among the age-, sex- and smoking-matched sub-population. This may reflect the differences in hemoglobin levels across age, sex and smoking that were lost following matching. Another interesting explanation for the association between hypertension and anemia can be attributed to anemia of inflammation, also known as anemia of chronic disease, which is prevalent in patients with diseases that cause prolonged immune activation, including infection, autoimmune diseases, and cancer [ 68]. More recently, the list has grown to include aging, obesity, diabetes mellitus and pulmonary arterial hypertension, chronic liver disease, and advanced atherosclerosis, with its sequelae of coronary artery disease and stroke [ 68].

The lack of adjustment for these important parameters leads to a failure to address the complexity of the clinical scenario, and it may explain why previous studies reported on epidemiological associations between hypertension and dental problems, which might have been lost following multivariate analysis.

4.6. Strengths and Limitations of the Study

The main strengths of the present study are the large sample size (132,529 records) and the strict protocol for utilizing the comprehensive socio-demographic, medical, and dental databases as part of a structured study termed the DOME study [ 24]. Since Israel is an immigrant country, multiple ethnicities were included, which may enhance the generalizability of the results. The IDF socio-demographic, medical, and dental systems are homogenous, with standardized uniform administrative, medical and dental clinical workup and training programs for dentists and physicians regarding diagnostic and treatment protocols, as well as the uniform computerized codes. Dental examinations in the IDF are accessible and free. However, there are cases of refusal, missed examinations, or treatments in civilian dental clinics, which might cause under-documentation.

Many possible confounders were taken into account; however, due to the complexities of the topic, and the limited ability of one paper to address all possible parameters, there are other contributing factors which were not included, such as medications use, physical activity, level of control of hypertension (systemic parameters), as well as the assessment of periapical area, reasons and diagnoses for endodontic treatments and extractions, and specific numbers of teeth (dental parameters). Future studies should assess these parameters. Although most parameters are records-based and were coded by authorized professionals (socio-demographics, dental, and medical data), there are some self-reported parameters, such as health-related behaviors, which are reported by the patients, and are therefore subjected to recall bias. Due to the cross-sectional study design, we cannot assume causality, and therefore this study can only address associations and correlations between the variables. The limitations of the study include the convenience sample, which may limit the generalizability of the results. Additional studies, including long-term longitudinal population-based epidemiological surveys in other settings and populations, would help address these issues.

5. Conclusions

The present study demonstrated that hypertension had no statistically significant or clinically significant association with dental status. The study established a profile of the "patient vulnerable to hypertension", which retained well-known risk factors for hypertension such as older age, male sex, smoking, diabetes, obesity, and fatty liver, but not dental parameters.

The present study analyzed the associations between CRP and dental conditions, and combined the statistically significant variables to create a dental inflammation score (DIS). The ROC analysis and multivariate analyses produced "fail" statistical associations between DIS and hypertension, thus the results could not support an inflammation theorem wherein dental status contributes to systemic inflammation and hypertension. The associations in the univariate analysis between hypertension and dental status may be explained by a shared common profile, and risk factors such as demographics and smoking. An appropriate risk factors management approach should be adopted by both dental and general health clinicians and health authorities, in order to control for common high-risk behaviors such as smoking, and to promote a healthy lifestyle to reduce chronic disease occurrence.

Acknowledgments

The authors declare the self-funding of the research.

Abbreviations

BMI

Body mass index

MPR

Medical patient record

CRP

C-reactive protein

CVD

Cardiovascular disease

DMF

Decayed, missed, filled teeth

DPR

Dental patient record

HDL

High-density lipoprotein

IDF

Israeli Defense Force

MetS

Metabolic syndrome

OSA

Obstructive sleep apnea

PD

Periodontal disease

SES

Socio-economic status

TIA

Transient ischemic attack

VLDL

Very low-density lipoprotein

Appendix

Table A1

Strata

Hypertension Diagnosis

Total N (%)

No N (%)

Yes N (%)

Author Contributions

Conceptualization, G.A. and I.A.; data curation, D.Z.; formal analysis, R.K. and G.A.; investigation, G.A., A.Z., N.E.P. and I.A.; methodology, G.A., A.Z., R.K. and I.A.; project administration, G.A.; software, G.A., R.K. and D.Z.; supervision, G.A.; validation, G.A., R.K. and D.Z.; visualization, G.A. and I.A.; writing-original draft, G.A.; writing-review and editing A.Z., R.K., N.E.P., D.Z. and I.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was approved by the Medical Corps Institutional Review Board (protocol code IDF-1281-2013).

Informed Consent Statement

Since this retrospective study only included analysis of anonymous medical records, the IRB gave an exemption from written informed consent.

Data Availability Statement

Data sharing not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

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Articles from Journal of Clinical Medicine are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

# data[].attributes.attachment_link.title
Hypertension and Its Associations with Dental Status: Data from the Dental, Oral, Medical Epidemiological (DOME) Nationwide Records-Based Study

# data[].attributes.attachment_link.description
Conflicting results have been published regarding the associations between dental status and hypertension. This study aims to explore whether or not hypertension is associated with dental status among young to middle-aged adults. To that end, data from the Dental, Oral, Medical Epidemiological (DOME) study were analyzed.

# data[].attributes.headline
Diet behaviours and hypertension in US adults: the National Health and Nutrition Examination Survey 2013–2014 - Cole Zetter

# data[].attributes.subject
Diet behaviours and hypertension in US adults: the National Health and Nutrition Examination Survey 2013–2014 - Cole Zetter

# data[].attributes.body
For this week's weekly wall, I read an article that detailed a study between the diet behaviors and hypertension in US adults. Within the article, the main objective was to explore the association between ideal diet behaviors that have been recommended the the american heart association and hypertension in the US. This was done by using data from the national health and nutrition examination survey. I found this study to be important because the study surveyed a large group of people using a variety of foods that are commonly eaten and widely known across different nutritional food groups. This study included whole grains, fruits and vegetables, fish, sodium and sugar-sweetened vegetables. A key finding to this study was that the number of diet behaviors at the ideal level recommended by the american heart association was inversely associated with hypertension in adults in the US. The  clinical implications of this study are very important because it relays the importance in eating a healthy diet in order to maintain a healthy blood pressure. The diet of patients with hypertension should be closely examined and then changes made based off of a provider's recommendation.

Zhou, Long et al. “Diet Behaviours and Hypertension in US Adults: The National Health and Nutrition Examination Survey 2013–2014.” Journal of hypertension 37.6 (2019): 1230–1238. Web.

# data[].attributes.headline
Kate Mashburn - Effects of different aerobic exercise programmes with nutritional intervention in sedentary adults with overweight/obesity and hypertension: EXERDIET-HTA study

# data[].attributes.subject
Kate Mashburn - Effects of different aerobic exercise programmes with nutritional intervention in sedentary adults with overweight/obesity and hypertension: EXERDIET-HTA study

# data[].attributes.body
This study addresses the effectiveness of diet changes and exercise on treating hypertension and obesity in patients. The study addresses the effectiveness on prevention as well as treatment. The subjects of the study were patients who live a sedentary lifestyle. The control group made no changes to their overall day to day while the other three groups were assigned various diet and exercise changes. The group to see the most positive change in their overall health was the group that had a hypocaloric diet and did aerobic exercises rather than high intensity training. The group doing high intensity training had a greater reduction in body mass but did not manage their blood pressure or cardiorespiratory fitness well. Overall, a reduction in calorie consumption, and a slightly more active lifestyle resulted in a better treatment of hypertension than any major changes to a patient’s diet and exercise level. However, this study was done on a very short term basis and it would be interesting to see if high intensity training was better in the long run.

Gorostegi-Anduaga I, Corres P, MartinezAguirre-Betolaza A, Pérez-Asenjo J, Aispuru GR, Fryer SM, Maldonado-Martín S. Effects of different aerobic exercise programmes with nutritional intervention in sedentary adults with overweight/obesity and hypertension: EXERDIET-HTA study. Eur J Prev Cardiol. 2018 Mar;25(4):343-353. doi: 10.1177/2047487317749956. Epub 2018 Jan 9. PMID: 29313359.

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Association Between Hypertension, Menopause, and Cognition in Women: Tamunoerenomie Inimgba

# data[].attributes.subject
Association Between Hypertension, Menopause, and Cognition in Women: Tamunoerenomie Inimgba

# data[].attributes.body
The purpose of the article is to examine the relationship of cognitive state in women and menopause and hypertension. This is important as over the past two decades, with advances in knowledge, cardiovascular disease has been observed to occur 10 years later in women in comparison to men and shows a significant increase in prevalence after menopause. This stage is very critical for women, as risk factors such has hypertension, dyslipidemia, obesity, diabetes, among others increase in prevalence after menopause. This is because menopause is associated with a reduction in estradiol and a decrease the estrogen to testosterone ratio. This results in endothelial dysfunction and increases in body weight or type II diabetes, which causes an increase in sympathetic activation, which all contributes to increase in renal vasoconstriction that will cause hypertension. However, an important result from the article was that cognitive impairment was higher in hypertensive menopausal women. This is important to nutritional sciences as nutritional awareness plays a major role in management of chronic diseases such as hypertension. The clinical implication of the article is to help in determining better implementation of programs to improve nutritional awareness, especially lifestyle strategies that would help after menopause, and thereby decrease the incidence of hypertension, which would help improve cognitive function.

Zilberman, J. M., Cerezo, G. H., Del Sueldo, M., Fernandez‐Pérez, C., Martell‐Claros, N., & Vicario, A. (2015). Association between hypertension, menopause, and cognition in women. The Journal of Clinical Hypertension, 17(12), 970-976.

# data[].attributes.body
Resistant hypertension is characterized as hypertension that is resistant to therapeutic treatment of 3 or more antihypertensive drugs and affects 9-18% of people that meet the criteria for diagnosis. This paper looked at what properly defines resistant hypertension, to more accurately rule out incorrect measuring techniques, white coat syndrome, and pseudohypertension. It also looks at possible strategies for long term management of true resistant hypertension.

The paper contends that resistant hypertension should be considered as three overlapping dimensions, resistant physician, resistant patient, and actual resistant hypertension. The authors state that their finding support that 1/3 of primary care practitioners do not provide treatment for high (>90-100) DBP and even more do not treat high (140-160) SBP. Even other studies showed that isolated systolic hypertension was left untreated by most physicians, and that true resistant hypertension could only be truly diagnosed when these other factors are unequivocally ruled out. Their findings outside of patient and physician resistance was hyperaldosteronism, problems with the sympathetic nervous system as it relates to diuretics and the kidneys, and kidney disease.

At the time of this writing it seems that patient and physician resistance treatment are the biggest precursors to resistant hypertension.

Doroszko A, Janus A, Szahidewicz-Krupska E, Mazur G, Derkacz A. Resistant Hypertension. Adv Clin Exp Med. 2016 Jan-Feb;25(1):173-83. doi: 10.17219/acem/58998. PMID: 26935512.

# data[].attributes.headline
Rhoda Inimgba: High-fructose diet in pregnancy leads to fetal programmingof hypertension, insulin resistance, and obesity inadult offspring.

# data[].attributes.subject
Rhoda Inimgba: High-fructose diet in pregnancy leads to fetal programmingof hypertension, insulin resistance, and obesity inadult offspring.

# data[].attributes.body
This study is important because most processed foods, canned foods contain some kind of high fructose corn syrup or fructose derived sweeteners. Other studies have been able to find a link between fructose consumption and metabolic dysregulation. Also the diet of the mother, obesity and metabolic disorders have been shown to have a relationship with offspring having metabolic syndrome and cardiovascular disease later in life. This study then focuses on the effects of antenatal exposure to high fructose diet on the offspring development of metabolic syndrome and cardiovascular disease.
One key finding from the study was that high fructose intake during pregnancy can program the fetal to have hypertension, obesity and metabolic dysfunction during their adulthood. This relates to nutritional
sciences as this shows the impact of a high fructose diet on an unborn child and how it can affect their cardiovascular system due to them developing hypertension.
The clinical implications of this study is that it allows for the ob-gyn doctors of pregnant lady to advise them to reduce their intake of high fructose diet so it can bring about a better and quality health for their child later on in the future.

Saad, Dickerson, J., Kechichian, T. B., Yin, H., Gamble, P., Salazar, A., Patrikeev, I., Motamedi, M., Saade, G. R., & Costantine, M. M. (2016). High-fructose diet in pregnancy leads to fetal programming of hypertension, insulin resistance, and obesity in adult offspring. American Journal of Obstetrics and Gynecology, 215(3), 378.e1–378.e6. https://doi.org/10.1016/j.ajog.2016.03.038.

# data[].attributes.headline
A cross-talk between gut microbiome, salt and hypertension- Esraa Zamzami

# data[].attributes.subject
A cross-talk between gut microbiome, salt and hypertension- Esraa Zamzami

# data[].attributes.body
This review talks about the relationship between the gut microbiome, salt consumption, and hypertension. I know many diseases are strongly linked to the microbiome; however, I was surprised when I learned about the link between hypertension and the microbiome. Interestingly, high salt intake was related to dysbiosis and increased Trimethylamine N-oxide (TMAO) blood levels. TMAO has been proven to have adverse outcomes on the heart and kidneys. In addition, a high salt diet for 8 weeks was found to decrease bacterial fermentation and production of short-chain fatty acids that have a role in modulating vasodilation, regulating renin secretion, and blood pressure through acting with G-protein coupled receptors (GPCR). Salt intake affects the disease progression, but it also interacts with the pharmacokinetic and pharmacodynamics of hypertension medications.

This review is important because it gives us a good insight into the link between the gut microbiome and hypertension. Having a healthy gut microbiota can be met by a healthy diet. However, as seen in this review, consuming an unhealthy high-salt diet can cause disturbance in the microbiome, consequently causing health problems like hypertension.

Naqvi, S., Asar, T. O., Kumar, V., Al-Abbasi, F. A., Alhayyani, S., Kamal, M. A., & Anwar, F. (2021). A cross-talk between gut microbiome, salt and hypertension. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 134, 111156. https://doi.org/10.1016/j.biopha.2020.111156

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doi: 10.1016/j.biopha.2020.111156.

Affiliations

¹ Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman, United Arab Emirates.

² Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Biology, College of Science and Arts at Alkamil, University of Jeddah, Jeddah, Saudi Arabia.

³ Natural Product Discovery Laboratory, Department of Pharmaceutical Sciences, Shalom Institute of Health and Allied Sciences. Sam Higginbottom University of Agriculture, Technology and Sciences, Naini, Prayagraj, 211007, India. Electronic address: phvikas@gmail.com.

⁴ Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

⁵ Department of Chemistry. College of Sciences & Arts, Rabigh King Abdulaziz University, Jeddah, Saudi Arabia.

⁶ Novel Global Community Educational Foundation, Australia; King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah, 21589, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW, 27707, Australia.

⁷ Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: fanwar1@kau.edu.sa.

Free article

Free article

doi: 10.1016/j.biopha.2020.111156.

Affiliations

¹ Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman, United Arab Emirates.

² Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Biology, College of Science and Arts at Alkamil, University of Jeddah, Jeddah, Saudi Arabia.

³ Natural Product Discovery Laboratory, Department of Pharmaceutical Sciences, Shalom Institute of Health and Allied Sciences. Sam Higginbottom University of Agriculture, Technology and Sciences, Naini, Prayagraj, 211007, India. Electronic address: phvikas@gmail.com.

⁴ Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

⁵ Department of Chemistry. College of Sciences & Arts, Rabigh King Abdulaziz University, Jeddah, Saudi Arabia.

⁶ Novel Global Community Educational Foundation, Australia; King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah, 21589, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW, 27707, Australia.

⁷ Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: fanwar1@kau.edu.sa.

Abstract

Cardiac disorders contribute to one of the major causes of fatality across the world. Hypertensive patients, even well maintained on drugs, possess a high risk to cardiovascular diseases. It is, therefore, highly important to identify different factors and pathways that lead to risk and progression of cardiovascular disorders. Several animals and human studies suggest that taxonomical alterations in the gut are involved in the cardiovascular physiology. In this article, with the help of various experimental evidences, we suggest that the host gut-microbiota plays an important in this pathway. Short chain fatty acids (SCFAs) and Trimethyl Amine -n-Oxide (TMAO) are the two major products of gut microbiome. SCFAs present a crucial role in regulating the blood pressure, while TMAO is involved in pathogenesis of atherosclerosis and other coronary artery diseases, including hypertension. We prove that there exists a triangular bridge connecting the gap between dietary salt, hypertension and gut microbiome. We also present some of the dietary interventions which can regulate and control microbiota that can prevent cardiovascular complications.We strongly believe that this article would improve the understanding the role of gut microbiota in hypertension, and will be helpful in the development of novel therapeutic strategies for prevention of hypertension through restoring gut microbiome homeostasis in the near future.

Keywords: Cardiovascular disease; Gut microbiota; Hypertension; Salt; TMAO.

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Verhaar BJH, Prodan A, Nieuwdorp M, Muller M. Verhaar BJH, et al. Nutrients. 2020 Sep 29;12(10):2982. doi: 10.3390/nu12102982. Nutrients. 2020. PMID: 33003455 Free PMC article. Review.

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national center for biotechnology information

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A cross-talk between gut microbiome, salt and hypertension - PubMed

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Cardiac disorders contribute to one of the major causes of fatality across the world. Hypertensive patients, even well maintained on drugs, possess a high risk to cardiovascular diseases. It is, therefore, highly important to identify different factors and pathways that lead to risk and progression ...

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Nutrition and hypertension: Jaida Garrett

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Nutrition and hypertension: Jaida Garrett

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This article is important because it provides essential information on nutritional supplementation and its benefits. Sometimes supplements are known to be the last resort or not entirely useful to reduce certain risks regarding the chronic disease. A key finding of this article is that dietary supplementation with vitamin C, E, B6, and lipoic acid help increase endogenous cysteine and glutathione levels. An increase in this helps with intracellular antioxidant support and encourages healthy liver function. Increasing dietary supplementation can also improve carbohydrate metabolism, lower blood pressure, and more. It targets underlying causes of hypertension which is essential in treatment. Hypertensive individuals will need more dietary intake than the recommended RDA amount in order to stimulate metabolic enzymes to achieve normal blood pressure. Other than using dietary supplements you can also have a diet that is rich in fruit, and vegetables. Grain, and low-fat intake for low to mild hypertension. This research is great to know for future patients because there are multiple ways to treat the population who suffers from low to severe hypertension.

VASDEV, LONGERICH, L., & SINGAL, P. (2002). Nutrition and hypertension: Special Issue Preventive Nutrition. Nutrition Research (New York, N.Y.), 22(1-2), 111–123.

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Dietary Approaches to Stop Hypertension (DASH) Diet and Blood Pressure Reduction in Adults with and without Hypertension

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Dietary Approaches to Stop Hypertension (DASH) Diet and Blood Pressure Reduction in Adults with and without Hypertension

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Posted by Mitchell Watts

The aim of this review of 30 randomized controlled trials (n = 5545 participants) was to assess the effect of the DASH diet compared to a control diet on blood pressure (BP) in adults with and without hypertension (HTN), independent of baseline BP. The participants were 45% male, mean age 51 years, mean BMI of 29.2 kg/m², mean baseline BP 134.3/84.9 mmHg, and mean follow-up period of 15.3 weeks. They tested different variables include age, BMI, controlled feeding, daily sodium intake, energy restriction diet, and duration of the follow-up period.

What they found is that the DASH diet was correlated with a significant reduction in BP in adults with and without HTN; however, BP reduction was most significant in participants less than 50 years old. What I found interesting is that greater BP reduction was seen in trials with sodium intake greater than 2400 mg compared to trials with sodium intake less than 2400 mg. This is counterintuitive in my opinion. The authors didn’t go into much detail as to why this would be, they speculated that higher amounts of sodium enhance the BP lowering effect of the DASH diet, as low amounts of sodium reduce the hypotensive effects of potassium. I haven’t heard about this concept before, I had always assumed that the greater the reduction in sodium intake, the more profound effect on BP. There is even a modified DASH diet with a much lower sodium intake goal of 1500 mg.

Overall though, this review supports the already established clinical recommendations that lifestyle changes, including the DASH diet, are an integral part of the treatment plan for those aiming to reduce their BP. This reduction is even seen independently of medication. This is important to delay the onset of HTN and to increase the effectiveness of antihypertensive medications.

Filippou, C. D., et al. (2020). Dietary Approaches to Stop Hypertension (DASH) Diet and Blood Pressure Reduction in Adults with and without Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Advances in nutrition (Bethesda, Md.), 11(5), 1150–1160.

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Affiliations

¹ First Cardiology Clinic, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece.

² Department of Cardiology, Helena Venizelou Hospital, Athens, Greece.

Free PMC article

Abstract

The Dietary Approaches to Stop Hypertension (DASH) diet is recognized as an effective dietary intervention to reduce blood pressure (BP). However, among randomized controlled trials (RCTs) investigating the DASH diet-mediated BP reduction, there are significant methodological and clinical differences. The purpose of this study was to comprehensively assess the DASH diet effect on BP in adults with and without hypertension, accounting for underlying methodological and clinical confounders. We systematically searched Medline and the Cochrane Collaboration Library databases and identified 30 RCTs (n = 5545 participants) that investigated the BP effects of the DASH diet compared with a control diet in hypertensive and nonhypertensive adults. Both random-effects and fixed-effect models were used to calculate the mean attained systolic BP (SBP) and diastolic BP (DBP) differences during follow-up. Subgroup and meta-regression analyses were also conducted. Compared with a control diet, the DASH diet reduced both SBP and DBP (difference in means: -3.2 mm Hg; 95% CI: -4.2, -2.3 mm Hg; P < 0.001, and -2.5 mm Hg; 95% CI: -3.5, -1.5 mm Hg; P < 0.001, respectively). Hypertension status did not modify the effect on BP reduction. The DASH diet compared with a control diet reduced SBP levels to a higher extent in trials with sodium intake >2400 mg/d than in trials with sodium intake ≤2400 mg/d, whereas both SBP and DBP were reduced more in trials with mean age <50 y than in trials of older participants. The quality of evidence was rated as moderate for both outcomes according to the Grading of Recommendations, Assessment, Development, and Evaluation approach. The adoption of the DASH diet was accompanied by significant BP reduction in adults with and without hypertension, although higher daily sodium intake and younger age enhanced the BP-lowering effect of the intervention. This meta-analysis was registered at www.crd.york.ac.uk/prospero as CRD42019128120.

Keywords: DASH; Dietary Approaches to Stop Hypertension; blood pressure; diet; hypertension; meta-analysis; randomized controlled trials; systematic review.

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The Potential Role of Gut Microbiota in Alzheimer's Disease: From Diagnosis to Treatment.

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dietary approaches to stop hypertension*

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national center for biotechnology information

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Dietary Approaches to Stop Hypertension (DASH) Diet and Blood Pressure Reduction in Adults with and without Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials - PubMed

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The Dietary Approaches to Stop Hypertension (DASH) diet is recognized as an effective dietary intervention to reduce blood pressure (BP). However, among randomized controlled trials (RCTs) investigating the DASH diet-mediated BP reduction, there are significant methodological and clinical difference ...

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Experience in using acupuncture reflexotherapy combined with weight-reducing diet therapy in hypertension

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Experience in using acupuncture reflexotherapy combined with weight-reducing diet therapy in hypertension

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One article I found considered acupuncture and a diet consisting of unloading days. This is important because it brought to my attention another approach to dieting that can help correct hypertension. I wasn’t aware of what unloading days were until this article it is basically breaking your food down into easily digestible starches or other sources of food that is not hard on the body to digest. For example, on an unloading day consists of boiled meat, sour milk products, beans, mushrooms or lean fish. On days where you do have unloading days you lose 500 grams of weight, which can add up over time. The key to this diet is patience. There are several cons that accompany almost any diet even an unloading diet such as a tolerance or deterioration of mood or sleep. In this study they looked at combining acupuncture and an unloading diet and its efficacy on reducing hypertension. They found a decrease in cholesterol levels and blood pressure. For 3 years 20 patients with hypertension had normal blood pressure. During this time, they were kept on a diet but had short term courses of fasted and were able to exercise on their one time. This relates to nutritional sciences in the way our body digests food and how certain foods are more easily digestible having a more positive effect on our weight loss. I think this is a great study. I know that a lot of American’s are on quite a bit of medications that they must take daily. If we were able to reduce their hypertension without pills and through a combination of acupuncture and diet this would be easier for patients to manage than having to remember to take all their medications daily. -Ashley Wahlman

Citation:Vukolova ZP, Oganova AG, Sukhanova MV. [Experience in using acupuncture reflexotherapy combined with weight-reducing diet therapy in hypertension]. Terapevticheskii Arkhiv. 1998 ;70(8):41-45. PMID: 9770743.

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EZProzy login, off-campus access University of Kentucky Libraries

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Hypertension in Athletes- Cole Cincinelli

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Hypertension in Athletes- Cole Cincinelli

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Hypertension affects approximately 25% of the world population(Niebauer et al). Hypertension is a prevalent disease and is associated with increased risk for cardiovascular morbidity. Many studies report an inverse relationship between blood pressure(BP) and exercise. Some organizations, such as the American Heart Association, recommend exercise as preventive therapy of hypertension. Interestingly enough, hypertension is also reflected in athletes. Berge et al. reported a prevalence of hypertension among athletes similar to that of the sedentary population(25%) but found that BP levels vary greatly between athletes participating in different kinds of sports. Sports like weightlifting and American football showed higher BP levels and an increased risk of prehypertension or hypertension compared to endurance athletes. Endurance sports consist of swimming and cycling. Hypertension also primarily occurs in male athletes(Berge et al) and BP levels exhibit a linear correlation with BMI, height, and the amount of training per week. I think the different types of exercise are valuable to distinguish between when making recommendations to patients that have a genetic predisposition to hypertension. Also, more research on the mechanisms regarding why exercised induced hypertension is more prevalent in males than females could give us better insight on how to prevent it.

Berge HM, Isern CB, Berge E. Blood pressure and hypertension in athletes: a systematic review. Br J Sports Med. 2015;49(11):716–23.

Niebauer J, Börjesson M, Carre F, et al. Recommendations for participation in competitive sports of athletes with arterial hypertension: a position statement from the sports cardiology section of the European Association of Preventive Cardiology (EAPC). Eur Heart J. 2018;39:3664–

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Effect of Low Salt Diet on Insulin Resistance in Salt-Sensitive Versus Salt-Resistant Hypertension-Andrea Ballinger

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Effect of Low Salt Diet on Insulin Resistance in Salt-Sensitive Versus Salt-Resistant Hypertension-Andrea Ballinger

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While looking for an article for this week's modules, I found multiple that discussed the continued debate of the direct relationship between salt intake and hypertension. The article I chose takes a further look as to why simply decreasing salt intake may not be enough for those with hypertension. I also thought this article was particularly interesting because it really looked at the intersectionality of many of the topics we have discussed in class so far including diabetes and metabolic syndrome and how they are directly related to hypertension.

Traditionally, low salt is recommended for those with Hypertension to help reduce the probability of a cardiac event or generalized cardiovascular disease. This article mentions that recent studies have shown a correlation between low sodium intake and increased CVD. This may be in part due to the increased stimulation of the RAAS during low sodium diets. Additionally, increased RAAS stimulation was shown have an association between increased insulin resistance in healthy subjects and hypertensive subjects. RAAS stimulation and it's impact on insulin resistance depended on whether the subject was considered to have salt-resistant hypertension or salt-sensitive hypertension. The study concluded that a low sodium diet for salt resistant subjects did not have a significant impact on blood pressure, but instead increased Insulin resistance. Although insulin resistance increased in salt-sensitive subjects, blood pressure was also shown to significantly decrease. The study gives a good foundation for dietitians and physicians to really examine the long term benefits for their patients of particular nutritional recommendations. There seems to be a trade off with hypertension and diabetes and the risk of developing cardiovascular disease, as both are risk factors.

Nutritionally, the study shows that altering a hypertensive client's diet to focus on reducing their sodium intake my not be universally beneficial. This adds another level of individualization when it comes to monitoring one's diet and the impact nutrients may have on the interconnected organ systems. Low sodium may be beneficial for one aspect of CVD (hypertension), but may induce another aspect of CVD (diabetes).

Garg, Rajesh et al. “Effect of low salt diet on insulin resistance in salt-sensitive versus salt-resistant hypertension.” Hypertension (Dallas, Tex. : 1979) vol. 64,6 (2014): 1384-7. doi:10.1161/HYPERTENSIONAHA.114.03880

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Dietary calcium and pregnancy-induced hypertension: is there a relation? -Cassie Craig

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Dietary calcium and pregnancy-induced hypertension: is there a relation? -Cassie Craig

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This study is important because it evaluates the importance of calcium intake in the development, prevention and treatment of pregnancy induced hypertension (PIH). It further assesses the impacts of dietary calcium amongst different groups of women, which helped these researchers to clarify previous research. This study found that there is evidence to support calcium supplementation in both the prevention of PIH in high-risk groups, as well as in the treatment of PIH. This is helpful in nutritional science because it shows that more research needs to be done in understanding the influence dietary calcium has on these patients’ health. This is important in a clinical setting because not all pregnant women need to be significantly increasing their calcium intake. Physicians should shift the focus to high-risk groups of pregnant women. High risk groups include teen pregnancies, patients with low calcium intake, and patients who are high risk for PIH. This implies that there should be specific reason in recommending calcium supplementation to pregnant women, therefore specialization treatment to the patient.

Lorrene D Ritchie, Janet C King, Dietary calcium and pregnancy-induced hypertension: is there a relation?, The American Journal of Clinical Nutrition, Volume 71, Issue 5, May 2000, Pages 1371S–1374S, https://doi-org.ezproxy.uky.edu/10.1093/ajcn/71.5.1371s

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Seonwook Kim: The Potential Benefits of Red Beetroot Supplementation in Health and Disease

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Seonwook Kim: The Potential Benefits of Red Beetroot Supplementation in Health and Disease

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My selected article for hypertension is the potential benefits of red beetroot supplementation in health and disease. There has been a growing interest in the effect of red beetroot. Also, this beetroot is known as a high source of potassium. As we learned in the lecture, potassium is another important factor to control blood pressure against sodium. In this study, they review the beetroot’s potential utility as a health promoting and disease preventing functional food. One of the key findings in this study is that hypertension has been the target of many therapeutic interventions. And, numerous studies show that beetroot significantly reduces systolic and diastolic blood pressure. Beetroot is easily accessible in grocery stores, so we can easily add beetroot to our daily nutrition. In clinical approaches, for treating hypertension patients, adding beetroot to their diet may help to manage blood pressure. This is not only beneficial to hypertension but also beneficial to cardio-protective effects.

Clifford T, Howatson G, West DJ, Stevenson EJ. The potential benefits of red beetroot supplementation in health and disease. Nutrients. 2015 Apr 14;7(4):2801-22. doi: 10.3390/nu7042801. PMID: 25875121; PMCID: PMC4425174.

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Abstract

In recent years there has been a growing interest in the biological activity of red beetroot ( Beta vulgaris rubra) and its potential utility as a health promoting and disease preventing functional food. As a source of nitrate, beetroot ingestion provides a natural means of increasing in vivo nitric oxide (NO) availability and has emerged as a potential strategy to prevent and manage pathologies associated with diminished NO bioavailability, notably hypertension and endothelial function. Beetroot is also being considered as a promising therapeutic treatment in a range of clinical pathologies associated with oxidative stress and inflammation. Its constituents, most notably the betalain pigments, display potent antioxidant, anti-inflammatory and chemo-preventive activity in vitro and in vivo. The purpose of this review is to discuss beetroot's biological activity and to evaluate evidence from studies that specifically investigated the effect of beetroot supplementation on inflammation, oxidative stress, cognition and endothelial function.

Keywords: beetroot, betalains, nitrate, antioxidants, inflammation, oxidative stress

1. Introduction

The well-documented health benefits of a diet high in fruit and vegetables has led to a growing interest in so-called "functional foods" and their application in health and disease. In recent years, the root vegetable Beta vulgaris rubra, otherwise known as red beetroot (herein referred to as beetroot) has attracted much attention as a health promoting functional food. While scientific interest in beetroot has only gained momentum in the past few decades, reports of its use as a natural medicine date back to Roman times [ 1]. Today, beetroot is grown in many countries worldwide, is regularly consumed as part of the normal diet, and commonly used in manufacturing as a food colouring agent known as E162 [ 2, 3].

The recent interest in beetroot has been primarily driven by the discovery that sources of dietary nitrate may have important implications for managing cardiovascular health [ 4]. However, beetroot is rich in several other bioactive compounds that may provide health benefits, particularly for disorders characterised by chronic inflammation. Consequently, the potential role for beetroot as an adjunct treatment in several clinical conditions will be presented; Specifically, the aims of this review are twofold: (1) to highlight evidence from recent studies showing the physiological and biological actions of beetroot; and (2) to evaluate its use as a nutritional intervention in health and disease, with a special emphasis on experimental studies relating to oxidative stress, inflammation, endothelial function and cognition.

Recent studies have provided compelling evidence that beetroot ingestion offers beneficial physiological effects that may translate to improved clinical outcomes for several pathologies, such as; hypertension, atherosclerosis, type 2 diabetes and dementia [ 1, 5, 6, 7, 8]. Hypertension in particular has been the target of many therapeutic interventions and there are numerous studies that show beetroot, delivered acutely as a juice supplement [ 9, 10, 11] or in bread [ 12, 13] significantly reduce systolic and diastolic blood pressure. Further discussion of beetroot's anti-hypertensive potential is summarised in several reviews: [ 14, 15, 16].

Beetroot's effect on the vasculature is largely attributed to its high inorganic nitrate content (250 mg∙kg −1 of fresh weight; [ 17]). Nitrate itself is not considered to mediate any specific physiological function; rather, nitrates beneficial effects are attributed to its in vivo reduction to nitric oxide (NO), a multifarious messenger molecule with important vascular and metabolic functions [ 14, 18]. The generation of NO via nitrate involves a series of sequential steps that have been well described in the literature [ 4, 19]. Briefly, ingested nitrate is first absorbed through the upper part of the small intestine into the systemic circulation [ 4, 15]. It is then estimated that 25% of the circulating nitrate enters the entero-salivary cycle where bacterial species located at the posterior aspect of the tongue bioactivate or reduce salivary nitrate to nitrite [ 16, 19]. Because salivary bacteria facilitate the reduction reaction that converts nitrate to nitrite, spitting out saliva or taking oral anti-bacterial treatments, like dental mouthwash for example, has been shown to diminish nitrate-nitrite conversion [ 10, 18]. Under normal circumstances, however, salivary nitrite is re-absorbed into the circulation via the stomach where it is metabolised to NO and other nitrogen oxides by a variety of reductase enzymes [ 4, 10, 13].

However, as previously mentioned, nitrate is not the only constituent of beetroot proposed to have beneficial effects in health and disease. Beetroot is a rich source of phytochemical compounds ( Figure 1 ), that includes ascorbic acid, carotenoids, phenolic acids and flavonoids [ 2, 20, 21]. Beetroot is also one of the few vegetables that contain a group of highly bioactive pigments known as betalains [ 22, 23]. Members of the betalain family are categorised as either betacyanin pigments that are red-violet in colour or betaxanthin pigments that are yellow-orange in colour [ 1]. A number of investigations have reported betalains to have high antioxidant and anti-inflammatory capabilities in vitro and a variety of in vivo animal models [ 3, 23, 24, 25, 26]. This has sparked interest in a possible role for beetroot in clinical pathologies characterised by oxidative stress and chronic inflammation such as liver disease [ 1, 23], arthritis [ 27] and even cancer [ 28, 29, 30, 31].

2. Bioavailability

For a food component to be considered beneficial for health it must be bioavailable in vivo, that is, following ingestion, the active compounds are absorbed through the gastro-intestinal tract and made available in the circulation, in sufficient quantities, to be utilized by cells [ 21, 32]. However, in order to reach the systemic circulation and exert any salubrious functions, a food component must maintain its molecular structure through several phases of digestion that each present a significant metabolic challenge for the molecule and affect its eventual rate and extent of absorption [ 33, 34]. It is therefore critically important that any alleged health benefit of a food source be firstly verified with well-designed bioavailability studies that characterise the extent of its in vivo absorption [ 34]. In this respect, the bioavailability of both inorganic nitrate and the betalains, the major bioactive components of beetroot, have been considered in the literature. The high bioavailability of inorganic dietary nitrate is well established and there are reports of close to 100% absorption following digestion [ 35]. The extent to which betalains are absorbed is, however, less clear.

Two studies have directly investigated betalain bioavailability by measuring their appearance in human urine after ingesting a single bolus of beetroot juice [ 36, 37]. Kanner et al. [ 37] identified 0.5%-0.9% of the ingested betacyanins (betanin and isobetanin) in volunteer's urine in the 12 h after consuming 300 mL of beetroot juice. This indicates that although in small amounts, betacyanins can be successfully absorbed in humans. They also showed that the peak urinary elimination rate of betacyanains (indicative of absorption), occurred 2-4 h after ingestion; however, there was a high level of inter-individual variability within this time period. Frank et al. [ 36] reported similar findings while investigating betacyanin bioavailability. After providing six healthy participants with 500 mL of beetroot juice, they identified betacyanins in urine at concentrations equivalent to ~0.3% of the ingested dose over a 24 h period. These studies might be interpreted to suggest only small level of bioavailability; however, it is important to realise that betacyanins are unlikely to be exclusively eliminated via the renal pathway [ 36] Indeed, the use of urinary excretion as a sole indicator of bioavailability has received criticism because it does not account for the biliary and circulatory clearance of compounds, thus underestimating true bioavailability [ 33]. In addition, the extent to which betalains are metabolised and structurally transformed to secondary metabolites is yet to be characterized, but should be taken into consideration when examining their bioavailability [ 36].

Given these limitations, Tesoriere et al. [ 38] employed a different approach to investigate the bioavailability of betalains. Tesoriere and colleagues developed a simulated in vitro model of the human intestinal epithelium using Caco-2 cell monolayers to mimic a functional barrier. This model allowed them to examine whether betalains can be absorbed through a functioning intestinal barrier and hence give an indication of their bioavailability. They demonstrated that two betalains; betanin and to a greater extent indicaxanthin were well absorbed through the simulated model of the intestinal lining (Caco-2 cell monolayer) and mostly in their unmetabolised form via paracellular transport. The latter finding is particularly important, because it reveals that betalains can be absorbed into the systemic circulation in their unchanged form, allowing them to retain their molecular structure and high biological activity [ 34]. There was some evidence that betanin may be absorbed through transcellular transport as well. Nevertheless, it is important to note that results from in vitro experiments, even when designed to mimic the biological milieu of the human GI tract, do not necessarily translate in vivo, given that several other factors ( i.e., first pass metabolism, interactions with gut microflora and protease enzyme degradation) have a significant influence on the concentration of the nutrient that eventually reaches the circulation [ 33, 34].

In addition to the betalain family, other aforementioned plant derived antioxidants have been identified in beetroot, including epicatechin, rutin, and caffeic acid [ 2], which to varying degrees appear to be well absorbed and bioavailable in humans [ 39]. Although, the bioavailability of these compounds and other phenolics from beetroot have not been individually determined, there are data describing the bioavailability of the total phenolic compounds present in beetroot. Netzel et al. [ 40] measured the urinary excretion of total phenolic substances following a single 500 mL bolus of beetroot juice. They identified ~685 mg of phenolic compounds in participant's urine ≤24 h following beetroot juice ingestion; 97% more than the ~347 mg identified after consuming water ( i.e., basal concentrations). While the relative bioavailability from the individual compounds could not be determined, these findings clearly show that beetroots phenolic constituents are extremely well absorbed and likely increase beetroot's in vivo antioxidant power.

Taken together, the results of the aforementioned studies provide a good base of evidence that beetroot is a bioavailable source of bioactive compounds in humans. With that said, further work is still required to firstly; elucidate the bioavailability of beetroot's individual bioactive components and secondly; to establish the extent that plasma, biliary and other metabolic pathways contribute to the excretion of these components. Together, these data would give a better understanding of beetroots phytochemical bioavailability and thus elucidate the potential as a health-promoting intervention for humans.

3. Oxidative Stress

Beetroot supplementation might serve as a useful strategy to strengthen endogenous antioxidant defences, helping to protect cellular components from oxidative damage. Under normal metabolic conditions, the biological environment of a cell is considered to be in a state of redox balance, or in other words, an equilibrium exists between reducing (antioxidants) and oxidising (pro-oxidants) agents [ 41, 42]. Molecules capable of oxidation are commonly known as reactive oxygen and nitrogen species (RONS) and are continuously generated in cellular metabolism [ 42]. At these low concentrations, RONS play an important role in a diverse multitude of cellular and biochemical processes, including gene expression, cell proliferation, apoptosis and muscular contraction [ 41, 42, 43, 44]. However, excess exposure of a cell to exogenously generated RONS (UV radiation, xenobiotics) or endogenously synthesised RONS (aberrant cell metabolism, inflammation), can overwhelm the cells antioxidant defences, causing an imbalance in redox homeostasis, which gives rise to the condition typically referred to as oxidative stress [ 42]. This imbalance may overwhelm the endogenous antioxidant defence network leaving DNA, carbohydrate, protein and lipid structures susceptible to oxidation and functional impairments [ 45, 46, 47].

In some instances, cells can suffer from acute spells of oxidative stress that temporarily weaken antioxidant defences [ 48]. This can occur through excessive heat exposure, infectious pathogens and strenuous physical exercise, which are capable of generating RONS that leave cells vulnerable to transient oxidation [ 44, 48]. However, in many human disease states, such as cancer, oxidative stress is a chronic disorder perpetuated by continual and excess production of RONS that induce long-term cellular disruption [ 48, 49]. A previous estimate [ 42] suggested that oxidative stress plays a role in the pathophysiology of over 200 clinical conditions. It is therefore unsurprising that many antioxidant food sources have been evaluated for their ability to scavenge RONS and avert oxidative stress.

Beetroot is as an exceptionally rich source of antioxidant compounds. The betalain pigments in particular, has been shown by several in vitro studies to protect cellular components from oxidative injury [ 37, 50, 51]. For example, in the study by Kanner et al. [ 37] two betalain metabolites (betanin and betanidin) were shown to reduce linoleate damage induced by cytochrome C oxidase and lipid membrane oxidation induced by H ₂O ₂-activated metmyoglobin and free iron (AA-Fe). The authors also reported that betanin, the most abundant betalain found in beetroot (300-600 mg∙kg −1), was the most effective inhibitor of lipid peroxidation. Betanin's high antioxidant activity appeared to stem from its exceptional electron donating capacity and ability to defuse highly reactive radicals targeting cell membranes [ 37]. However, as alluded to earlier, betalains are not the only antioxidant compounds present in beetroot. Beetroot contains several highly bioactive phenolics, such as rutin, epicatechin and caffeic acid which are also known to be excellent antioxidants [ 2, 36, 39]. Furthermore, nitrite and other NO donors akin to beetroot have been shown to suppress radical formation and directly scavenge potentially damaging RONS such as superoxide and hydrogen peroxide, suggesting nitrate may also exhibit antioxidant effects [ 19, 52, 53].

A number of studies report that beetroot, in the form of a juice supplement, protects against oxidative damage to DNA, lipid and protein structures in vitro [ 27, 54, 55]. A study by Wootton-Beard and Colleagues suggests that a key mechanism by which beetroot juice exerts its antioxidant effects is by scavenging radical species [ 56]. They found that two commercially available beetroot juices inhibited in vitro radical formation in the 2,2-diphenyl-1-picrylhydrazyl (DPPH*) and (3-ethylbenzothiazoline-6-sulfonicacid) ABTS* assays by 100% and 92%, respectively. Importantly, when these assays were repeated, but in conditions designed to simulate the human digestive process, the juices still retained ≥55% of their pre-digestion radical scavenging capacity. Furthermore, the antioxidant capacity of both drinks, as measured by ferric reducing antioxidant power (FRAP), was higher than the other 22 vegetable juice drinks under investigation. In another study [ 21], they showed that the FRAP of beetroot juice actually increases following simulated digestion. This is probably a consequence of several compounds being structurally altered to secondary metabolites that possess antioxidant functions [ 21, 56]. Further work from this group has shown that the antioxidant capacity of beetroot juice is comparable to or higher than a variety of fruit and vegetable juices (See Figure 2 and Figure 3 ) [ 56, 57]. Interestingly, the antioxidant capacity of beetroot juice in both the (DPPH*) and FRAP assays was far greater than more well-known vegetable juices, such as tomato and carrot, and fruit juices, such as orange and pineapple, with only pomegranate juice displaying a higher antioxidant capacity in the FRAP assay.

In addition to being a source of antioxidants in vitro, a growing body of evidence using animal models illustrates that beetroot exhibits radical scavenging ability in vivo (see Table 1 ). In a recent study [ 23], rats were provided with 1-3 mL∙kg∙bm −1 of a beetroot pomace extract for 7 days prior to being exposed to 2 mL∙kg∙bm −1 of carbon-tetrachloride (CCl4), a well-established carcinogen and RONS generator. After CCI4 administration, liver homogenate was removed from rats pre-treated with the beetroot extracts and those acting as controls ( i.e., CCl4 only). Rats treated with beetroot extracts expressed significantly lower levels of lipid peroxidation measured as thiobarbituric acid reactive substances (TBARS). Furthermore, the beetroot extracts appeared to maintain endogenous antioxidant activity (reduced glutathione, glutathione peroxidase and catalase enzymes) at normal cellular concentrations following the oxidative insult. This led the authors to speculate that in response to in vivo cellular attack, beetroot may exhibit indirect antioxidant effects that act to up regulate antioxidant defence mechanisms [ 23].

Table 1

Authors

Cohort under Investigation

Dosage

Antioxidant Capacity of Treatment

Duration

Toxic inducing Protocol

Inflammation

Oxidative Stress

Enzymatic Antioxidant Activity

[ 54]

48 male wistar rats

Beetroot juice delivered by gavage (8 mL∙kg∙bm∙day −1; ≈1.92 mL∙day −1)

23.5 μmol Trolox equivalents∙mL −1

28 days

Intraperitoneal injection of CCl ₄ (2 mL∙kg∙bm −1) or NDEA (150 mL∙kg∙bm −1)

N/A

TBARS ↓ PC ↓ DNA damage ↓

SOD ↑ GPX ↑ CAT ↑ GR ↑

[ 63]

80 male ICR mice

Betalains from beetroot delivered orally (0, 5, 20 and 80 mg∙kg∙bm∙day −1; ≈0-1.44 mg∙day −1)

N/A

30 days

Exposed to cobalt-60-γ-gamma radiation (6.0 Gy, 1.5 Gy min −1)

N/A

MDA ↓

SOD ↑ CAT ↑ GSH ↑

[ 64]

24 male wistar rats

Beetroot juice delivered by gavage (8 mL∙kg∙bm∙day −1)

N/A

28 days

Intraperitoneal injection of NDEA (150 mL∙kg∙bm −1)

LDH ↓ AST ↓ ALT ↓

DNA damage ↓

GST ↑

[ 27]

10 osteoarthritic patients

Capsules made from beetroot extract delivered orally (70-200 mg∙day −1)

N/A

10 days

N/A

TNF-α ↓ IL-6 ↓ RANTES ↓ GRO-α ↓

AOPP ↓

N/A

[ 23]

48 albino wistar rats

Beetroot pomace extract delivered intraperitoneally (1-3 mL∙kg∙bm∙day −1; ≈0.2-0.6 ml∙day −1)

N/A

7 days

Intraperitoneal injection of CCl ₄ (2 mL∙kg∙bm −1)

N/A

MDA ↓

GSH ↑ GSHPx ↑ GR ↑ CAT ↑

[ 65]

24 albino wistar rats

Extracts of fresh beetroot delivered orally (250 and 500 mg∙kg∙bm∙day −1; ≈45-90 mg∙day −1)

90.1% radical inhibition in the DPPH* assay (500 μg∙mL −1)

28 days

Intraperitoneal injection of gentamicin (8 mg∙kg∙bm −1 for 8 days)

IL-6 ↓ TNF-α ↓ MPO ↓ NF-κB ↓

MDA ↓

CAT ↑ NP-SH ↑

[ 58]

24 female Sprague-dawley rats

Beetroot juice delivered by gavage (8 mL∙kg∙bm∙day −1; ≈1.92 mL∙day −1)

N/A

28 days

Intraperitoneal injection of DMBA (10 mg∙kg∙bm −1 for 2 days)

LDH ↓ ALT↓

N/A

GST ↑ NQO1 ↑

Similar antioxidant effects have also been reported with studies using beetroot juice. Providing rats beetroot juice (8 mL∙kg∙bm∙day −1) for 28 days was shown to attenuate lipid peroxidation, protein oxidation and DNA damage following xenobiotic induced liver injury [ 54]. In a more recent, rats were fed beetroot juice (8 mL∙kg∙bm∙day −1 for 28 days) and treated with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) on day 27 and 28 of the beetroot juice-feeding period study [ 58]. Several markers of liver damage and inflammation were significantly increased following the DMBA treatment; however, these were markedly reduced in the rats pre-treated with beetroot juice compared to the control group that received water only (see Table 1 ). There were no differences in DNA damage between the groups. Intriguingly, rats given beetroot juice only ( i.e., not treated with DMBA) exhibited increased activity of phase II detoxifying enzymes (GST and NQO1), which play an important role in endogenous antioxidant defense.

The enhanced endogenous antioxidant activity in vivo, by beetroot is a consistent finding in the literature (see Table 1 ). According to recent in vitro data, such effects might be related, in part, to betanin and its effect on signalling pathways that mediate the transcription of antioxidant genes. Esatbeyoglu et al. [ 59] found that betanin (extracted from beetroot) dose dependently (5-15 μm) increased the activity of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor that activates a gene promoter sequence: the antioxidant response element (ARE) responsible for the transcription of several endogenous antioxidant enzymes [ 59, 60, 61]. Krajka-Kuźniak et al. [ 62] presented similar findings, showing that betanin (2, 10 and 20 μm concentration) activates the Nrf2-ARE binding sequence in non-tumor human hepatic cell lines. Furthermore, this led to increased activity and mRNA expression of several phase II detoxifying enzymes, including glutathione S-tranferases and NAD(P)H:quinone oxidoreductase, which play important roles in host defense against xenobiotics. This raises the possibility that beetroot's antioxidant potential is not limited to just scavenging and suppressing RONS, but includes the ability to reinforce the endogenous antioxidant network; however, whether such effects translate in vivo, particularly in humans is yet to be investigated.

Given these findings, it should also be considered that other compounds in beetroot (and their downstream metabolites upon ingestion) possess similar effects to betanin on transcriptional activity. Thus, in vivo, these compounds and metabolites could work synergistically to activate the NRF2-ARE pathway, which, in turn, mediates an increase in endogenous antioxidant activity. Such a possibility deserves further attention.

Collectively, the studies to date provide evidence that beetroot is an excellent source of antioxidants that protects cellular components from oxidation in vitro and importantly, in vivo. This would suggest that beetroot supplementation might be a promising adjunct strategy to help manage diseased states propagated by oxidative stress, such as liver injury and cancer. With that said, there is still a lack of well-conducted human trials, which precludes any definitive recommendations for its clinical use. Moreover, data is currently limited to paradigms inducing oxidative stress through exogenous pathways ( i.e., xenobiotics) while endogenously generated RONS play a significant role in human disease [ 66]. In this respect, strenuous physical exercise could serve as a useful model to study the antioxidant potential of beetroot and its constituents in humans. There are several reports documenting that the mechanical and metabolic muscle damage sustained during intense exercise induces short-term oxidative stress, which can persist for several days until redox balance is restored [ 67, 68]. Therefore, it should be considered that application of a beetroot preparation following an exercise task might serve as a useful model to give an insight into beetroot's efficacy as an antioxidant agent in humans, and most importantly, provide a more in-depth understanding of its potential application in clinical settings.

4. Inflammation

Under normal circumstances, inflammation is regarded as a beneficial process, governing our innate response to biological or physical stimuli such as trauma, infection and other pathogens that may cause the organism harm and disrupt homeostasis [ 69, 70, 71]. With that said, immune activation may still have undesirable consequences for the host. In the short term, redness, swelling, pain and diminished function may be experienced at the site of inflammation; however, more concerning is the potential long-term implications if inflammation persists, and is unresolved [ 71, 72]. Failure to remove the invading element and restore normal immune function can cause chronic inflammation resulting in long-term cell dysfunction [ 73]. Chronic inflammation is often implicated in the onset and progression of several clinical disorders such as obesity, liver disease, cancer and heart disease [ 69, 74, 75].

Since the 1970's, traditional treatment for inflammatory disorders has been non-steroidal anti-inflammatory drugs (NSAIDS) [ 71]. However, these drugs, particularly in chronic doses, may actually have deleterious consequences for health and evoke negative side effects [ 74, 76]. Above all, they have been deemed ineffective in the treatment of many inflammatory related conditions [ 74]. Consequently, focus has shifted towards the anti-inflammatory effects of natural food sources and their potential use as alternatives to synthetic NSAID treatments [ 72].

Betalains and beetroot extracts have emerged as potent anti-inflammatory agents. At least part of their anti-inflammatory effects seems to be mediated by interfering with pro-inflammatory signalling cascades and are summarised in Figure 4 . The most important of these is the Nuclear Factor-Kappa B (NF-κB) cascade, as it directly activates and transcribes most gene targets that regulate and amplify the inflammatory response ( i.e., cytokines, chemokines, apoptotic and phagocytic cells) [ 43]. Consequently, NF-κB activity plays a central role in the inflammatory processes that manifest in chronic disease [ 43]. In a recent study [ 65], NF-κB DNA-binding activity was dose-dependently attenuated in nephrotoxic rats administered a beetroot extract for 28 days (250 mg or 500 mg∙kg∙bm −1). Furthermore, kidney homogenates from the beetroot treated rats had lower concentrations of immune cells (TNF-α, IL-6 and MPO) and reduced signs of oxidative damage (MDA), which could be directly related to the blunting of the NF-κB pathway. These effects are likely to be mediated, at least in part, by the betalains present in beetroot; recent evidence shows that betanin treatment (25 and 100 mg∙kg∙bm −1 for 5 days) significantly inhibits NF-κB DNA-binding activity in rats induced with acute renal damage [ 77]. Betalains have also been shown to markedly supress cyclooxygenase-2 (COX-2) expression in vitro, which is an important precursor molecule for pro-inflammatory arachidonic acid metabolites known as prostaglandins [ 3, 26, 50]. Reddy et al. [ 50] who found that betanin (IC50 value 100 μg·mL −1) inhibited cyclooxygenase-2 (COX-2) enzyme activity by 97%, first illustrated this. It is interesting to note that although a slightly higher concentration of betanin was required, its COX-2 inhibitory effects were comparable or greater than several phenolic compounds (cyanidin-3-O-glucoside, lycopene, chlorophyll, b-carotene, and bixin) and anti-inflammatory drugs (Ibuprofen, Vioxx and Celebrex). This raises the possibility that betanin rich beetroot supplements, in sufficient doses, could exhibit anti-inflammatory effects to rival synthetic drugs.

A recent study from Vidal et al. [ 26] provided further support for the anti-inflammatory effects of betalains. As well as supressing COX-2 synthesis, betanidin, extracted from beetroot, dose dependently inhibited (to 9% of control activity), lipoxygenase (LOX), a catalytic enzyme vital for the synthesis of pro-inflammatory leukotriene molecules [ 70]. Interestingly, these inhibitory effects appeared to be mediated by a blocking action on membrane binding activity, indicating that betalains target cell signalling pathways at the molecular level, acting in a similar fashion to selective COX-2 inhibitor drugs [ 26, 70].

There are a limited number of studies demonstrating that beetroot supplements have anti-inflammatory effects in vivo. Pietrzkowski et al. [ 27] showed that therapeutic administration of betalain-rich oral capsules made from beetroot extracts alleviated inflammation and pain in osteoarthritic patients. After 10 days of supplementation (100, 70 or 35 mg per day), the pro-inflammatory cytokines; tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), had decreased from baseline by 8.3%-35% and 22%-28.3%, respectively. The activity of two chemokines; regulated oncogene-alpha (GRO-alpha) and regulated upon activation normal T cell growth (RANTES) were also markedly inhibited by the beetroot treatment. Furthermore, the moderated inflammatory response coincided with a significant reduction in self-reported pain on the McGill Pain Questionnaire. Krajka-Kuźniak et al. [ 64] examined the protective effect of beetroot juice (8 mL∙kg∙bm∙day −1 for 28 days) on markers of liver injury and inflammation induced by the toxic chemical N-nitrosodiethylamine (NDEA) in rats. Compared to an untreated control, the beetroot juice conferred significant hepatic protection against a range of inflammatory markers induced by NDEA administration; lactate dehydrogenase, aspartate aminotransferase, gamma glutamyl transferase and alanine aminotransferase were all shown to be markedly attenuated. In a more recent study, El Gamal et al. [ 65] fed rats either water (control) or oral doses of beetroot ethanol extract (250 or 500 mg∙kg∙bm∙day −1) for 28 days; from day 20-28 they were treated with the nephrotoxic drug gentamicin (85 mg∙kg∙bm∙day −1). After 28 days, kidney homogenates were removed from both groups and analysed for several markers of renal damage. They found that the beetroot-treated rats had significantly lower concentrations of several pro-inflammatory mediators, including Il-6, TNF-α, myeloperoxidase (representing neutrophil infiltration) and the transcription factor NF-κB. They also found reduced oxidative stress (MDA, uric acid) and increased endogenous antioxidant activity (CAT, non protein sulfhydryl; NP-SH) in the homogenates removed from the rats pre-treated with beetroot. Taken together, these studies support the notion that beetroot supplementation offers anti-inflammatory protection in vivo; however, well designed, long-term clinical trials are clearly required to elucidate whether such a strategy would assist in the management of inflammatory-related disorders.

The antioxidant and anti-inflammatory activity of beetroot has also led to interest in its potential use in diseases characterized by aberrant immune cell function. Indeed, chronic inflammation is increasingly being implicated in the development of malignant tumours and evidence is accumulating to suggest betalain extracts obtained from beetroot may suppress these effects. For instance, Lechener et al. [ 78] examined whether long term (35 weeks) treatment with a betacyanin containing extract (78 μg∙mL∙day −1 of E162, red food colour prepared from beetroot) would inhibit tumour incidence in rats exposed to a potent tumour promoter ( N-nitrosomethylbenzylamine). In comparison to control, the beetroot extracts markedly inhibited cell proliferation, angiogenesis and tumorgenesis in oesophageal lesions, effects largely attributed to its radical scavenging and anti-inflammatory activity. This was evidenced by the significantly reduced number of inflammatory lymphocytes present in the oesophageal tumours of the beetroot-treated rats only. The chemo-preventive effects of betacyanin extracts have also been observed in lung, skin and liver cancer cells in animal models, and recently, in human prostate, skin, breast and pancreatic tumour cells [ 28, 29, 30, 31]. Furthermore, co-administration of beetroot extracts with doxorubicin, an effective but highly toxic chemotherapy drug, significantly reduces its cytotoxicity, probably by modulating the drug's induction of tumour promoting RONS [ 28, 31]. Although far from conclusive, these initial findings in animal and human cell lines suggest beetroot supplementation holds promise as a future strategy to at least help manage some of the symptoms of inflammation in cancer.

5. Endothelial Function

As described earlier, nitrate delivered via a beetroot source is metabolised to nitrite, which can be further reduced to produce NO [ 4, 13]. The conversion of nitrite to NO can be catalysed by a number of molecules with reductase potential ( i.e., electron donors), and to date, several proteins ( i.e., deoxymyoglobin, xanthine oxioreducatse) and antioxidants ( i.e., vitamin C) have been reported to facilitate this reduction [ 4, 79, 80]. One of the most important functions of endogenous NO is to maintain endothelial function [ 13, 81]. The endothelium plays a critical role in the regulation of vascular homeostasis by maintaining thrombotic activity, platelet function, vascular tone and the delicate balance between the release of vasodilating ( i.e., NO, prostacyclin) and vasoconstricting agents ( i.e., endothelin-1, thromboxane) [ 81, 82]. Because NO mediates many of the endothelium's functions, a depletion in NO availability, as seen with aging, has been singled out as the principal cause of endothelial dysfunction [ 81]. Endothelial dysfunction is proposed as a primary risk factor for several cardiovascular disorders and has been implicated in the pathogenesis of hypertension and atherosclerosis [ 16, 83]. Therefore, beetroot, as a natural NO donor, has been explored as a nutritional approach to preserve or restore endothelial function.

Webb et al. [ 10] were the first to investigate the effects of a beetroot supplement on endothelial function in healthy participants. They measured brachial artery (BA) endothelial function using the flow mediated dilation technique (FMD), which involved calculating BA dilation before and after a 20 min ischemic insult. The ischemic procedure (BA occlusion) was effective at inducing endothelial dysfunction, as evidenced by the 60% decrease from pre to post BAFMD response. However, when participants were pre-treated 2 h prior with a single serving of beetroot juice (500 mL; 23 mmol of nitrate) the BAFMD response was maintained at pre-ischemic levels, suggesting that beetroot juice acted to preserve endothelial function.

Hobbs et al. [ 12] extended these findings, examining the acute intake of a novel beetroot enriched bread (100 g beetroot, nitrate; 1.1 mmol) on micro vascular function and peripheral arterial stiffness in young healthy males. Although arterial stiffness, assessed by pulse wave velocity and augmentation index, was unaffected by the intervention, the beetroot bread increased micro vascular vasodilation, as measured by changes in cutaneous perfusion using laser doppler imaging (LDI). Endothelium-independent vasodilation (perfusion units) was ~343% greater in the 6 h after ingesting the beetroot enriched bread compared to the control bread. Importantly, this study provided evidence that even a small nitrate load (1.1 mmol) can augment marked improvements in intravascular function. Similar vascular effects were also reported in a study with older populations. Using apparently healthy but slightly obese, older participants (~61 years), Joris and Mensink, [ 83] investigated whether beetroot juice supplementation would prevent postprandial impairments in BAFMD. In a randomized crossover design, BAFMD response fell by ~1.6% in the control condition, whereas after beetroot juice (140 mL, nitrate; 500 mg) the impairment was only ~0.4%, indicative of a beetroot-mediated protective effect on postprandial endothelial function.

Replicating the aforementioned findings in volunteers with an increased risk of endothelial dysfunction has proved more difficult. For instance, Kenjale et al. [ 84] reported that acute beetroot juice intake (500 mL) had no influence on endothelial function in peripheral arterial disease (PAD) patients, as assessed by BAFMD response (% arterial dilation) to a hyperaemic stimulus. In another study, type 2 diabetic volunteers were given either beetroot juice (250 mL·day −1; nitrate: 7.5 mmol) or a nitrate depleted placebo but otherwise nutritionally matched beetroot juice for 14 days [ 85]. After the treatment period, BAFMD response was similar between control and beetroot juice groups (4.94% vs. 4.97% change in vessel diameter, respectively) and no differences in micro vascular vasodilation, as measured by LDI, could be detected between the two conditions. However, perhaps the lack of an effect in these studies is not surprising, given that unlike the studies with healthy cohorts, most volunteers were already receiving vasoactive medications for their respective conditions. It is conceivable that these medications diminished or confounded any potential vascular response afforded by nitrate. Perhaps a more profound response to beetroot supplementation could be elicited in pre-clinical patients, i.e., those not yet requiring prescription medications that interfere with vascular function. An alternative explanation for the findings in the latter study is that bioactive constituents ( i.e., betalains, caffeic acid) other than nitrate (likely present in both the nitrate depleted placebo and nitrate rich beetroot juice) could have mediated a dilatory response. Indeed, there is evidence that other antioxidants such as flavonoids possess dilatrory effects in humans [ 86]. If betalains or indeed other antioxidants present in beetroot exerted similar effects in this study then BAFMD and micro vascular function would not be expected to differ between the two conditions. However, the dilatory effects of these compounds and consequences for endothelial function are yet to be investigated and therefore such an effect can only be speculated at present.

It is also important to note that several disease states, including type 2 diabetes, are characterised by persistent inflammation and an excess production of RONS [ 87, 88]. This could limit the efficacy of nitrate supplementation, because RONS such as superoxide (O ₂-) directly react with NO, diminishing its bioavailability [ 85]. Therefore, any benefits of the surplus NO generated by ingesting dietary nitrate could be reduced in the presence of oxidative stress. To counter this, perhaps these pathologies would benefit from higher doses of beetroot juice, not only to increase the amount of ingested nitrate (and NO generation) but also to provide a stronger antioxidant defence ( i.e., betalains) against RONS. Such an approach might help enhance nitrate mediated NO bioavailability. Further research is required to establish the role of beetroot supplementation in endothelial dysfunction.

6. Cognitive Function

Cognitive function deteriorates with age and one of the key pathological events that precedes its development is reduced cerebral blood flow [ 89, 90, 91]. Indeed, an age related decrease or impairment in cerebral perfusion has been implicated in several neurological disorders associated with poor cognitive ability, such as brain damage, clinical dementia and Alzheimer's disease [ 92, 93]. One of the major triggers and risk factors for the onset and development of cerebral hypo-perfusion is a disruption in neurovascular function; an effect that is, in part, mediated by impaired NO activity [ 92, 93]. A diminished capacity to generate NO can impair the normal function of cerebral energy metabolism ( i.e., glucose delivery) and neuronal activity ( i.e., cellular communication), which over a chronic period might induce neurodegeneration and cognitive deficits [ 90, 91, 92]. Therefore, it is conceivable that a NO generator like beetroot has the potential to improve cerebrovascular blood flow and challenge detriments in cognitive function.

Two recent human studies examined the influence of dietary nitrate on cerebral blood flow. Presley et al. [ 6] measured cerebral perfusion after providing a group of older adults (~75 years) a high nitrate diet (~12 mmol) including beetroot juice, or a nitrate depleted diet (~0.09 mmol) for 24 h. Magnetic resonance imaging (MRI) revealed that the high nitrate diet stimulated a substantial and preferential increase in frontal cortex perfusion, a region of the brain responsible for essential cognitive processes such as executive function, working memory and task-switching. Further work by Bond et al. [ 89] supports these conclusions, showing a decrease in cerebrovascular arterial resistance (indicative of increased cerebral blood flow) following a single serving of nitrate rich beetroot juice (500 mL). However, it is important to note that the subjects in this study were young (~21 years), asymptomatic and apparently disease-free, limiting the application of these findings in elderly and diseased populations.

Although long-term clinical trials are yet to be conducted, two recent preliminary studies explored the influence of acute beetroot supplementation on age-related cognitive function. In one of these studies, older (~67 years), type 2 diabetics, supplemented with 250 mL of beetroot juice (nitrate: 7.5 mmol) for 14 days, experienced a significant improvement in simple reaction time compared to a control group [ 5]. However, no effects were evident in other cognitive tests associated with decision-making, rapid processing, shape and spatial memory [ 5]. Another study from the same group [ 94] investigated the effects of a beetroot juice supplement (140 mL·day −1: nitrate: 9.6 mmol) on cognitive function in healthy, older adults (~63 years). After 3 days of supplementation, they failed to detect any changes in cognitive performance for concentration, memory, attention and information processing ability between the beetroot juice and control condition. Furthermore, a range of brain metabolites associated with neuronal functioning ( N-acetylaspartate, creatine, choline and myo-Inositol) were not, as hypothesized, upregulated after taking beetroot juice. The somewhat contrasting results between these two studies may be partly explained by differences in participant cohort (type 2 diabetics vs. healthy older adults), cognitive tests employed (Kelly et al. [ 94] did not use a simple reaction time test) and dose duration. With regards to the latter posit, perhaps the cerebrovascular response required to elicit measurable changes in cognitive function can only be achieved with longer term dosing strategies that have the potential to induce sustained modifications to cerebrovascular function [ 94]. Nonetheless, the beetroot-mediated increases in simple reaction time reported by Gilchrist et al. [ 5] is worthy of further investigation, given the potential benefits for clinical populations.

A recent addition to the literature investigated whether acute beetroot juice supplementation could augment cerebral oxygenation status and subsequently aid cognition during a fatiguing exercise task [ 95]. Beetroot juice (500 mL, nitrate: 5 mmol) ingested 90 min before exercise reduced cerebral deoxygenation status, as measured by near infrared spectroscopy, but failed to improve reaction time and information processing at rest, while cycling at 50%, 70% and 90% of VO ₂ peak and upon completion of the exercise task. As with the previously mentioned study [ 94], a single serving of beetroot juice may not have been sufficient to induce measurable changes in cognitive performance. This is the only study that has examined beetroot in this fashion; consequently, there is scope for further research to investigate the potential role of beetroot juice in cognitive function at rest and during exercise.

7. Conclusions

Based on the available data, beetroot appears to be a powerful dietary source of health promoting agents that holds potential as therapeutic treatment for several pathological disorders. The powerful antioxidant, anti-inflammatory and vascular-protective effects offered by beetroot and its constituents have been clearly demonstrated by several in vitro and in vivo human and animal studies; hence its increasing popularity as a nutritional approach to help manage cardiovascular disease and cancer. In the human studies to date, beetroot supplementation has been reported to reduce blood pressure, attenuate inflammation, avert oxidative stress, preserve endothelial function and restore cerebrovascular haemodynamics. Furthermore, although beyond the scope of this review, several studies have now established beetroot supplementation as an effective means of enhancing athletic performance [ 96, 97].

8. Future Directions

While the precise mechanisms by which beetroot exerts these beneficial effects are yet to be fully elucidated, the present status quo dictates that the cardio-protective, physiological and metabolic effects are mediated by nitrate and its subsequent conversion to NO, while the anti-oxidative and anti-inflammatory effects are mediated by betalains and other phenolics. However, it is important to recognise that the relative contribution of each compound is far more complex and that additive and synergistic effects cannot be ruled out.

The present data indicates that the bioactive constituents in beetroot, especially nitrate, appear to be well absorbed and bioavailable in humans. While an optimal dosing strategy does not currently exist, the available data suggests that the multitude of beneficial health effects offered by beetroot can be realised with amounts easily achievable in the diet or with a supplement such as beetroot juice; although at present, there is insufficient evidence regarding the efficacy, and above all, safety of beetroot supplementation to recommend a long-term strategy. Indeed, potentially detrimental health effects arising from excessive intake of beetroot and supplemental derivatives have not been adequately explored. The historical belief that nitrite is a carcinogenic substance in humans still reverberates and concerns have been raised over the uncontrolled use or excessive intake of nitrate rich substances [ 98, 99]. However, natural beetroot juice supplements, as opposed to sodium nitrite salts for instance, are unlikely to pose a significant health risk, at least in the short term [ 99, 100]. While there is presently no anticipated negative health outcomes associated with other constituents of beetroot, consumers should be aware that some supplements ( i.e., juices) could have a relatively high sugar content, which might need to be taken into consideration by some individuals ( i.e., diabetics). Future studies are still required to evaluate the long term safety of a dietary beetroot intervention particularly in clinical settings. In this respect, beetroot supplementation could be easily administered, and of course, there would be economic and practical benefits of such an approach.

A variety of beetroot based supplements including juices and capsules are now widely available and relatively inexpensive, particularly in comparison to synthetically manufactured drugs. It is therefore critical that future studies focus on the long-term effects (≥4 weeks) of beetroot supplementation.

Although the results so far are promising, most studies tend to use healthy cohorts as participants which limit the applicability of their findings to clinical populations. Furthermore, the overwhelming majority of human studies have focused on the ergogenic or cardio-protective effects of beetroot supplementation, while little attention has been given to the potential anti-oxidative and anti-inflammatory effects. Consequently, there is a great deal of scope to explore the influence of beetroot supplementation in human disorders characterised by chronic inflammation and oxidative stress ( i.e., cancers, arthritis, inflammatory bowel disease etc.).

Nevertheless, beetroot supplementation is a new and exciting area of research that to date has been shown to induce favourable effects in several facets of health and disease. This indicates that beetroot supplementation holds promise as an economic, practical and importantly natural dietary intervention in clinical settings. Because of beetroot's high biological activity, there are still several unexplored areas in which supplementation might confer health benefits. This includes but is not limited to; pain reduction, cognitive function, vascular function, insulin resistance, cancer and inflammation, especially in older and diseased populations.

Author Contributions

TC, along with GH and ES conceived title headings for the review; TC completed initial drafting of the manuscript; TC, GH, ES and DW edited and drafted the manuscript. TC and ES completed the editorial process. All authors approved the final version of the manuscript.

Conflicts of Interest

This review was written as part of a doctor degree that receives financial support from Gs Fresh Ltd. The funders had no role in the preparation and writing of the manuscript. The authors declare no conflict of interest.

References

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9. Bailey S.J., Winyard P., Vanhatalo A., Blackwell J.R., Dimenna F.J., Wilkerson D.P., Tarr J., Benjamin N., Jones A.M. Dietary nitrate supplementation reduces the O[ ₂ cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. J. Appl. Physiol. 2009;107:1144-1155. doi: 10.1152/japplphysiol.00722.2009. [ PubMed] [ CrossRef] Google Scholar]

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27. Pietrzkowski Z., Nemzer B., Spórna A., Stalica P., Tresher W., Keller R., Jiminez R., Michalowski T., Wybraniec S. Influence of betalin-rich extracts on reduction of discomfort associated with osteoarthritis. New. Med. 2010;1:12-17. [ Google Scholar]

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65. El Gamal A.A., AlSaid M.S., Raish M., al-Sohaibani M., al-Massarani S.M., Ahmad A., Hefnawy M., al-Yahya M., Basoudan O.A., Rafatullah S. Beetroot ([[ Beta vulgaris L.) extract ameliorates gentamicin-induced nephrotoxicity associated oxidative stress, inflammation, and apoptosis in rodent model. Mediat. Inflamm. 2014;2014:983-952. doi: 10.1155/2014/983952. PMC free article] [ PubMed] [ CrossRef] Google Scholar]

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Articles from Nutrients are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

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The Potential Benefits of Red Beetroot Supplementation in Health and Disease

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In recent years there has been a growing interest in the biological activity of red beetroot (Beta vulgaris rubra) and its potential utility as a health promoting and disease preventing functional food. As a source of nitrate, beetroot ingestion provides ...

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Hypertension is greater than cholesterol in association with coronary heart disease.

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Hypertension is greater than cholesterol in association with coronary heart disease.

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Posted by Richard Proudfoot

For this week, the research paper selected is titled: “Association of Lipid, Inflammatory, and Metabolic Biomarkers with Age at Onset for Incident Coronary Heart Disease in Women” This January 20, 2021 article was published online in the JAMA Cardiology. 2021;6(4):437-447. The authors are Sagar B. Dugani, MD, PhD; M. Vinayaga Moorthy, PhD; Chunying Li, MPH; Olga V. Demler, PhD; Alawi A. Alsheikh-Ali, MD, MSc; Paul M Ridker, MD, MPH; Robert J. Glynn, PhD; Samia Mora, MD, MHS. Their affiliations are Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Dugani, Moorthy, Li, Demler, Glynn, Mora); Division of Hospital Internal Medicine, Mayo Clinic, Rochester, Minnesota (Dugani); Division of Preventive Medicine, Brigham and Women’s -Hospital, Harvard Medical School, Boston, Massachusetts (Moorthy, Li, Demler, Ridker, Glynn, Mora); College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (Alsheikh-Ali); Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Ridker, Mora)

This study is a prospective cohort of US female health professionals participating in the Women’s Health Study. The study median follow-up was 21.4 years. Participants included 28,024 women aged 45 years or older without known cardiovascular disease. Baseline profiles were obtained from April 30, 1993, to January 24, 1996, and analyses were conducted from October 1, 2017, to October 1, 2020.The main outcomes and measures are as follows:  Four age groups were examined (<55, 55 to <65, 65 to <75, and75 years) for coronary heart disease (CHD) onset, and adjusted hazard ratios (aHRs) were calculated using stratified Cox proportional hazard regression models with age as the time scale and adjusting for clinical factors. Women contributed to different age groups over time.

This study is important because the diabetes and insulin resistance, in addition to hypertension, obesity, and smoking, appeared to be the strongest risk factors for premature onset of CHD. Most risk factors had attenuated relative rates at older ages. The lipoproteins and apoproteins except for lipoprotein insulin resistance (LP-IR) showed weaker associations with CHD onset. LP-IR is measured by nuclear magnetic resonance spectroscopy as a weighted score of VLDL, LDL and HDL particle sizes, and their subsets concentrations, and a biomarker for insulin resistance.

The key findings from this study are of the clinical factors in the women, diabetes had the highest aHR for CHD onset at any age, ranging from 10.71 (95%CI, 5.57-20.60) at CHD onset in those younger than 55 years to 3.47 (95%CI, 2.47-4.87) at CHD onset in those 75 years or older. Risks that were also noted for CHD onset in participants younger than 55 years included metabolic syndrome (aHR, 6.09; 95%CI, 3.60-10.29), hypertension (aHR, 4.58; 95%CI, 2.76-7.60), obesity (aHR, 4.33; 95%CI, 2.31-8.11), and smoking (aHR, 3.92; 95%CI, 2.32-6.63). Myocardial infarction in a parent before age 60 years was associated with 1.5- to 2-fold risk of CHD in participants up to age 75 years. From approximately 50 biomarkers, lipoprotein insulin resistance had the highest standardized aHR: 6.40 (95%CI, 3.14-13.06) for CHD onset in women younger than 55 years, attenuating with age. In comparison, weaker but significant associations with CHD in women younger than 55 years were noted (per SD increment) for low-density lipoprotein cholesterol (aHR, 1.38; 95%CI, 1.10-1.74), non–high-density lipoprotein cholesterol (aHR, 1.67; 95%CI, 1.36-2.04), apolipoprotein B (aHR, 1.89; 95%CI, 1.52-2.35), triglycerides (aHR, 2.14; 95%CI, 1.72-2.67), and inflammatory biomarkers (1.2- to 1.8-fold)—all attenuating with age. (Mora et al., 2021) These findings relate to nutritional sciences because dietary lifestyles strongly correlated with diabetes, metabolic syndrome, hypertension, obesity, and insulin resistance. And these same diseases (metabolic biomarkers) showed the highest hazard ratios for CHD onset.

Clinical implication of this study is our concern about fats as reflected by lipoproteins and apoproteins should be overshadow by the concern about carbohydrates as reflected by diabetes, insulin resistance, metabolic syndrome, hypertension, and obesity.

Mora, S., Dugani, S. B., Moorthy, M. V., Li, C., Demler, O. v., Alsheikh-Ali, A. A., Ridker, P. M., & Glynn, R. J. (2021). Association of Lipid, Inflammatory, and Metabolic Biomarkers with Age at Onset for Incident Coronary Heart Disease in Women. JAMA Cardiology, 6(4). https://doi.org/10.1001/jamacardio.2020.7073

Posted by Richard Proudfoot

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Food groups and Risk of Hypertension: Systemic Review & Meta-Analysis -Lydia Duncan

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Food groups and Risk of Hypertension: Systemic Review & Meta-Analysis -Lydia Duncan

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For this weeks topic, I picked an article reviewing different food groups, and their role as a risk factor for Hypertension. The full title of the article is Food Groups and Risk of Hypertension: A Systematic Review and Dose-Response Meta-Analysis of Prospective Studies. They complied a large number of articles to assess 12 different food groups. These groups were whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meats, and sugar-sweetened beverages (SSB's). This study is important to me for two reasons. The first reason being that it was one of the first meta-analysis's of all food groups in comparison to hypertension. By compiling known information, it helps us further understand the role of different types of food (and the nutrients that make them up) in dietary patterns leading to hypertension. The second reason I found this study to be important was because of the large cohort group examined. By having a large amount of different articles reviewed throughout the meta-analysis, it helps solidify the results of the review, since they have multiple sources to back up their claims.

There were numerous key points throughout the article, but I'll be highlighting a few that I felt related most to what we have seen in class. First, an increase in whole grains led to a decreased risk of hypertension (~ 15% decreased risk when consuming around 90 grams per day (g/d)). This makes sense, since we know that whole grains contain more nutrients than its refined counterpart. Second, SSB's seemed to increase the risk of hypertension ( ~13% higher risk when consuming ~450mL per day (mL/d)). This also makes sense, because we have learned that large amounts of sugar intake are associated with numerous health risks (Obesity, Diabetes, CVD's, etc.). The last finding I wanted to mention was that a combination of all the food groups that showed an increased risk (red meat, fish, processed meats, and SSB's) increased the likelihood of developing hypertension by ~78%. This percentage specifically included having 2 servings of red meat a day, 1 serving of fish per day, 1 serving of processed meats per day, and 2 servings of SSB's per day. On the other side of that, cutting down on these food groups showed a 44% decrease in the risk of developing hypertension. These findings relate to nutritional sciences because they show the effects of consuming a specific group/type of food in relation to hypertension. This helps to keep the dietary guidelines updated for people who may be at risk for hypertension.

A clinical implication of this study is that the diets typically suggested for patients with hypertension (DASH diet, Mediterranean diet, etc.) accurately follow the data that has been presented through the articles reviewed (as well as other research). Therefore, in a clinical setting, these previously mentioned diets should still be suggested with patients at risk for (or have already developed) hypertension.

Citations:
Schwingshackl, L., Schwedhelm, C., Hoffmann, G., Knüppel, S., Iqbal, K., Andriolo, V., Bechthold, A., Schlesinger, S., & Boeing, H. (2017). Food Groups and risk of hypertension: A systematic review and dose-response meta-analysis of prospective studies. Advances in Nutrition: An International Review Journal, 8(6), 793–803. https://doi.org/10.3945/an.117.017178

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Abstract

The aim of this systematic review and meta-analysis was to summarize the evidence on the relation of the intakes of 12 major food groups, including whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages (SSBs) with the risk of hypertension. PubMed, Scopus, and Web of Science were searched systematically until June 2017 for prospective studies having quantitatively investigated the above-mentioned foods. We conducted meta-analysis on the highest compared with the lowest intake categories and linear and nonlinear dose-response meta-analyses to analyze the association. Summary RRs and 95% CIs were estimated by using a random-effects model. Overall, 28 reports were included in the meta-analysis. An inverse association for the risk of hypertension was observed for 30 g whole grains/d (RR: 0.92; 95% CI: 0.87, 0.98), 100 g fruits/d (RR: 0.97; 95% CI: 0.96, 0.99), 28 g nuts/d (RR: 0.70; 95% CI: 0.45, 1.08), and 200 g dairy/d (RR: 0.95; 95% CI: 0.94, 0.97), whereas a positive association for 100 g red meat/d (RR: 1.14; 95% CI: 1.02, 1.28), 50 g processed meat/d (RR: 1.12; 95% CI: 1.00, 1.26), and 250 mL SSB/d (RR: 1.07; 95% CI: 1.04, 1.10) was seen in the linear dose-response meta-analysis. Indication for nonlinear relations of the intakes of whole grains, fruits, fish, and processed meats with the risk of hypertension was detected. In summary, this comprehensive dose-response meta-analysis of 28 reports identified optimal intakes of whole grains, fruits, nuts, legumes, dairy, red and processed meats, and SSBs related to the risk of hypertension. These findings need to be seen under the light of very-low to low quality of meta-evidence. However, the findings support the current dietary guidelines in the prevention of hypertension.

Introduction

Approximately 40% of people aged >25 y worldwide have hypertension, amounting to 1 billion in 2015, and the prevalence keeps rising sharply ( 1, 2). Additionally, hypertension is the most important risk factor for premature cardiovascular disease and accounts globally for 50% of all ischemic heart diseases and stroke events ( 3).

Recently, we showed that the optimal consumption of risk-decreasing foods (whole grains, vegetables, fruits, and dairy) resulted in a 42% reduction of type 2 diabetes, and a high intake of risk-increasing foods [red and processed meats, sugar-sweetened beverages (SSBs), and eggs] resulted in a 200% increase compared with nonconsumption of the respective foods ( 12). Similar results could be observed regarding all-cause mortality ( 13).

Because of the high prevalence of hypertension and the preventive effects of dietary factors, the following question has yet to be answered: What is the trustworthiness of meta-evidence regarding the association of food groups in relation to the risk of hypertension?

Therefore, this meta-analysis was conducted with the aim of investigating the associations of 12 previously used food groups, including whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and SSBs, with the risk of hypertension by evaluating the available evidence. Special focuses in our analyses were the strength and the shape (dose-specific) of the relation to identify an optimal intake of food groups for the lowest risk of hypertension. By applying the NutriGrade scoring system, we aimed to evaluate the food groups' trustworthiness of meta-evidence on their relation to hypertension risk.

Methods

The previously registered systematic review protocol was updated in PROSPERO ( https://www.crd.york.ac.uk/prospero/, identifier CRD42016037069). Our strategy for the systematic review and meta-analysis was predefined in a published protocol ( 14) and has already been implemented for 2 recently published meta-analyses on all-cause mortality and type 2 diabetes, respectively ( 12, 13). This meta-analysis followed the guidelines for reporting proposed by the Meta-analyses Of Observational Studies in Epidemiology ( 15).

Search strategy

PubMed, Scopus, Web of Science, and Google Scholar, were searched until June 2017. The search was not restricted to calendar date or language. The full search strategy for PubMed is given in Supplemental Material 1.

Searches of reference lists from included prospective studies supplemented the electronic database searches. One author (LS) performed the literature search, while another author (HB) reviewed uncertain cases. Consensus was reached through discussion between both authors.

Study selection

We included studies with cohort, case-cohort, and nested case-control designs, as well as follow-ups of randomized controlled trials (RCTs). Included studies investigated the association for ≥1 of the 12 food groups (whole grains or cereals, refined grains or cereals, vegetables, fruits, nuts, legumes, eggs, dairy products, fish, red meat, processed meat, and SSBs) on the risk of hypertension; the incidence of hypertension was defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg for the first time in any follow-up checkup or when taking antihypertensive medication also for the first time in the follow-up visits in adults (those ≥18 y old).

Data extraction

Information extracted from the included studies included the name of first author, year of the publication, country, cohort name, number of participants, number of incident hypertension cases, baseline age, sex, length of follow-up, specification of outcome assessment, method of dietary assessment, quantity of food intake, multivariable effect estimate (RRs, HRs, or ORs including the corresponding CIs), and adjusted covariates. When the risk estimates for participants were reported only separately for men and women in a study, the RRs were combined by using a fixed-effect model.

Statistical analysis

As previously described, if studies reported only the total number of cases or person-years and the exposure was defined in categories, the number of person-years or cases in each category was obtained from the total number of person-years or cases divided by the number of reported categories. We assigned the median or mean intake by quantile to the corresponding risk estimate. If studies reported intakes only as a range by quantile, the midpoint was calculated. In the case of an open-ended intake range, we assumed that the width was the same as the contiguous category. If the exposure was expressed per given unit of energy intake, we used the provided mean energy intake to rescale it.

The dose-response was expressed in the quantities as previously described ( 12- 14). If studies reported exposure in serving size but did not specify the amount, recommended conversions were used ( Supplemental Table 1).

Restricted cubic splines for each study with >3 quantiles of exposure were calculated to explore possible nonlinear associations. We used 3 fixed knots through the total range of the reported intake at 10%, 50%, and 90% and combined these using multivariate meta-analysis ( 19).

Moreover, the potential of foods to reduce the risk of hypertension was calculated by multiplying the RR by selecting an optimal consumption of risk-reducing foods (calculated by ) and risk-increasing foods noted as (calculated by ). The optimal consumption of single food groups was defined as the serving category with the strongest association for hypertension risk.

Heterogeneity between studies was evaluated by using the Q test and the I ² statistic. A value >50% for the I ² statistic was regarded as potentially important statistical heterogeneity ( 20). If >5 studies were available for a food group in the linear dose-response analysis, subgroup analyses were performed to identify potential sources of heterogeneity by the following characteristics: sex, length of follow-up (mean or median ≥5 compared with <5 y), geographic location (by continent), number of cases (≥1000 compared with <1000), and validated or nonvalidated dietary assessment. Moreover, sensitivity analysis was carried out for a low risk of bias studies (>5 studies available).

As recommended by the Cochrane Handbook, if ≥10 studies were available ( 21), we explored potential small-study effects, such as publication bias by using Egger´s test and funnel plots ( 22). Stata version/SE 14.2 software (StataCorp) and Review Manager 5.3 (Nordic Cochrane Centre) were used to conduct statistical analyses.

Risk of bias assessment

The risk of bias of the included prospective studies was assessed by considering 4 categories ( 23): 1) exposure assessment [low risk of bias: validated, calibrated FFQ or 24-h recall, diet history, or diet records (multiple days)], 2) assessment of outcome (low risk of bias: accepted clinical criteria, record linkage (International Classification of Diseases codes), self-reported, and validated], 3) adequacy of follow-up length (low risk of bias: ≥5 y), and 4) adjusted basic model (low risk of bias, ≥2 factors: e.g., sex, education, and ethnicity; if only one sex included, then ≥1 factor) and outcome-relevant adjustments [low risk of bias, ≥3 factors: e.g., BMI (in kg/m ²), smoking, energy intake, and physical activity].

As previously described, included reports were considered to be at low risk of bias if the rating did not correspond to high or unclear risk of bias in any of the 4 domains ( 13).

Quality of meta-evidence

Evidence-based dietary recommendations should be based on the completeness of the available evidence. However, many meta-analyses have not evaluated the quality of such evidence, which decreases our confidence in the observed effect.

To evaluate the trustworthiness (credibility) of meta-evidence for the association between 12 predefined food groups and the risk of hypertension we applied our recently developed NutriGrade scoring system (maximum of 10 points). NutriGrade should be applied to summarize the meta-evidence of diet-disease relations in meta-analyses, umbrella reviews, and meta-epidemiological studies ( 23).

Compared with the well-established Gradings of Recommendations Assessment, Development and Evaluation approach, NutriGrade differs in the following aspects: it gives more weight to the evaluation of prospective observational study designs, because such design is important for the investigation of diet-disease relations; it assesses nutrition-specific aspects, such as dietary assessment methods and their validation, calibration of FFQs, or the assessment of diet associated biomarkers; and finally it also considers the conflict of interest and funding bias as a separate item.

This tool is based on the following 8 items for cohort studies: 1) risk of bias, study quality, study limitations (maximum 2 points); 2) precision (maximum 1 point); 3) heterogeneity (maximum 1 point); 4) directness (maximum 1 point); 5) publication bias (maximum 1 point); 6) funding bias (maximum 1 point); 7) effect size (maximum 2 points); and 8) dose-response (maximum 1 point) ( 23). To evaluate and interpret the meta-evidence, we recommend 4 categories based on this scoring system: high (≥8 points), moderate (6 to <8 points), low (4 to <6 points), and very low (0 to <4 points).

Results

Of the 6502 records that were identified by the literature search, 98 full text articles were assessed in detail because they reported on ≥1 of the targeted 12 foods groups and risk of hypertension ( Figure 1, Supplemental Material 2).

Whole grains

Refined grains

Three studies with 18,842 incident hypertension cases were included in the highest compared with lowest intake category meta-analysis (range of intake: 0−122 g/d). Comparing categories of highest and lowest intake of refined grains, we observed no association with the risk of hypertension (RR: 0.95; 95% CI: 0.88, 1.03; I ² = 17%; P-heterogeneity = 0.30) ( Supplemental Figure 3). Similarly, an increase in refined-grain intake by 30 g/d was not associated with the risk of hypertension (RR: 0.99; 95% CI: 0.96, 1.02; I ² = 37%; P-heterogeneity = 0.20; n = 3) ( Supplemental Figure 4). No evidence of a nonlinear dose-response association was detected ( P-nonlinearity = 0.11; n = 3 studies) ( Figure 2).

Vegetables

The subgroup analyses showed an inverse association in studies conducted in Asia and Australia but not in Europe and America, in studies with a follow-up term <5 y, and in studies with <1000 cases ( Supplemental Table 14). The stratified analyses showed evidence of heterogeneity between subgroups. There was no evidence of a nonlinear dose-response association ( P-nonlinearity = 0.25; n = 7 studies) ( Figure 2).

Fruits

The heterogeneity persisted largely in stratified analyses ( Supplemental Table 15). The subgroup analyses showed no inverse association in shorter-term studies, in European studies, and in studies with <1000 cases. Some evidence of heterogeneity was detected between subgroups in stratified analyses for country.

Nuts

Legumes

Eggs

One study with 144 incident hypertension cases was detected (range of intake: 0−23 g/d). This study showed an inverse association between the highest and lowest egg-intake category (RR: 0.54; 95% CI: 0.32, 0.91) ( Supplemental Figure 13) and for each additional daily 50-g intake (RR: 0.25; 95% CI: 0.08, 0.74) ( Supplemental Figure 14).

Dairy

No significant differences were observed when comparing low- and high-fat dairy products. No inverse association was observed in studies with a shorter-term follow-up or in studies with nonvalidated dietary assessment ( Supplemental Table 16). No evidence of a nonlinear dose-response association between dairy products and the risk of hypertension was detected ( P-nonlinearity = 0.22; n = 8 studies). The risk of hypertension decreased by ~15% with increasing the intake of dairy ≤∼800 g/d ( Figure 2).

Fish

None of the subgroup analyses showed an association between fish intake and the risk of hypertension ( Supplemental Table 17). Evidence of a nonlinear dose-response association was observed ( P-nonlinearity < 0.01; n = 7 studies). The risk increased by 8% with increasing the intake of fish ≤100 g/d. No additional risk increasing association is apparent above this value ( Figure 2).

Red meat

Seven studies with 97,745 incident hypertension cases were included in the meta-analysis comparing extreme intake categories (range of intake: 0−121 g/d). A positive association between the risk of hypertension and red meat intake was observed (RR: 1.15; 95% CI: 1.02, 1.28; I ² = 84%; P-heterogeneity < 0.001) when comparing extreme categories ( Supplemental Figure 19). Each additional daily 100-g red-meat intake was associated with a 14% increased risk of hypertension (RR: 1.14; 95% CI: 1.02, 1.28; I ² = 88%; P-heterogeneity < 0.001; n = 7) ( Supplemental Figure 20). The observed heterogeneity persisted in the additional subgroup analyses. The positive associations were present in studies with a longer-term follow-up, studies including women and larger number of cases, and in studies conducted in the United States ( Supplemental Table 18).

Processed meat

SSBs

Five studies including 81,495 incident hypertension cases were included in the meta-analysis comparing extreme intake categories (range of intake: 0−457 mL/d). A positive association between the risk of hypertension and SSB intake was observed (RR: 1.12; 95% CI: 1.06, 1.18; I ² = 59%; P-heterogeneity = 0.04) when comparing extreme categories ( Supplemental Figure 23), as well as for each additional daily 250-mL SSB consumption (RR: 1.07; 95% CI: 1.04, 1.10; I ² = 64%; P-heterogeneity = 0.04; n = 4) ( Supplemental Figure 24). There was no evidence for a nonlinear relation ( P-nonlinearity = 0.73; n = 4 studies); the risk of hypertension increased by ~13% with increasing the intake of SSB ≤∼450 mL/d ( Figure 2).

Summary across food groups

Table 1 shows the RR for hypertension from the nonlinear dose-response analysis of the 12 predefined food groups according to servings per day. Optimal consumption (lowest serving with significant results and no further substantial change in risk or no further data for higher amounts) of risk-decreasing foods (3 servings/d = 90 g whole grains/d, RR: 0.85; 2 servings/d = 160 g fruits/d, RR: 0.93; 1 serving/d = 28 g nuts/d, RR: 0.88; three-fourths serving/d = 75 g legumes/d, RR: 0.94; 4 servings/d = 800 g dairy/d, RR: 0.85) results in a 44% reduction of hypertension (calculated by ) when compared with nonconsumption of these foods.

Risk-increasing foods were red meat, processed meat, fish, and SSBs. Compared with nonconsumption, an intake of 2 servings red meat/d (170 g, RR: 1.35), 1 serving processed meat/d (35 g, RR: 1.07), 1 serving fish/d (100 g, RR: 1.08), and 2 servings SSBs/d (500 mL, RR: 1.14) was associated with a 78% increased risk ( ). On the other hand, a risk reduction by ∼44% would be achieved by not consuming these foods (calculated by ).

Risk of bias and quality of meta-evidence

Because of the overall low number of included studies for each food group, it was not possible to conduct low-risk-of-bias sensitivity analysis for all food groups, except in the case of vegetable, fruit, dairy, fish, and red-meat intake (Supplemental Table 16). Findings including studies with a low risk of bias confirmed the results of the primary meta-analysis for these food groups. Overall, the quality of meta-evidence for the association between the 12 a priori defined food groups and the risk of hypertension was rated very low (refined grains, vegetables, legumes, and eggs) to low (whole grains, fruits, nuts, dairy, fish, red meat, processed meat, and SSBs) ( Supplemental Table 19).

Discussion

This meta-analysis systematically evaluated the associations between 12 food groups (defined a priori) and the risk of hypertension by comparing extreme intake quantiles (highest compared with lowest) and by analyzing linear and nonlinear dose-responses.

In the linear dose-response meta-analysis an inverse association was present for whole grains, fruits, nuts, eggs, and dairy. On the other side, red meat, processed meat, and SSBs were associated with a higher risk of hypertension. We observed some evidence of nonlinearity between the intakes of whole grains, fruits, fish, and processed meat with the risk of hypertension. The trustworthiness of meta-evidence was rated very-low to low by applying the NutriGrade scoring system, suggesting that further high-quality research would provide important evidence on the confidence for the association between the 12 food groups and the risk of hypertension.

The present meta-analysis shows a 13% lower risk of hypertension for 3 servings dairy/d. Several beneficial components of dairy products may contribute to the antihypertensive effect, including calcium and potassium ( 79), or lactotripeptides ( 80). Potential mechanistic evidence suggests that these peptides may inhibit the blood vessel-constrictive effect of angiotensin I-converting enzyme ( 81). Moreover, some evidence suggests that dairy products, especially fermented ones, are associated with a reduced risk of adiposity ( 82), one of the main causes of hypertension. Contradictory to our findings, a meta-analysis of the published clinical trials showed that a higher dairy intake has no significant effect on change in systolic blood pressure ( 83).

In our study, fish consumption was associated with a slight increase in hypertension risk in the nonlinear dose-response analysis. No other association was observed in the high-compared with low-intake categories and dose-response meta-analysis. Because of these inconsistencies further research will provide important evidence.

With our operational definition, the optimal consumption of foods inversely associated with incident hypertension was associated with 44% lower risk, whereas avoidance of foods associated with higher risk was also associated with 44% lower incidence of hypertension.

Some strengths of the present meta-analysis are the large number of investigated food groups, the multiple types of meta-analyses performed (highest compared with lowest intake category, as well as linear and nonlinear dose-response), calculation of the optimal intake of combined food groups, the risk of bias assessment, and the assessment of the trustworthiness of the quality of the meta-evidence.

In summary, this comprehensive meta-analysis of 28 studies identified the optimal intakes of whole grains, fruits, nuts, legumes, dairy, red meat, processed meat, and SSBs regarding the risk of hypertension. These findings need to be seen under the light of very-low to low credibility of meta-evidence. However, the findings support the current dietary recommendations in the primary prevention of hypertension.

Acknowledgments

All authors read and approved the final manuscript.

References

Diet quality as assessed by the healthy eating index, the alternate healthy eating index, the dietary approaches to stop hypertension score, and health outcomes: an updated systematic review and meta-analysis of cohort studies

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Abbreviations

Author notes

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Food Groups and Risk of Hypertension: A Systematic Review and Dose-Response Meta-Analysis of Prospective Studies

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The aim of this systematic review and meta-analysis was to summarize the evidence on the relation of the intakes of 12 major food groups, including whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages (SSBs) with the risk of hypertension.

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Sidney Harm: Effectiveness and Safety of Hwangchil–Unripe Bokbunja Extract Mixture on Blood Pressure: A Randomized Double-Blind Placebo-Controlled Clinical Trial

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Sidney Harm: Effectiveness and Safety of Hwangchil–Unripe Bokbunja Extract Mixture on Blood Pressure: A Randomized Double-Blind Placebo-Controlled Clinical Trial

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This study is looking into a Korean fruit and tree extract mixture and it’s impacts on blood pressure. The Korean tree leaf extract is coming from a tree type called Hwangchil. The fruit called Bokbunja is also known as the Korean blackberry, attached is a picture of the fruit. This randomized double blind placebo trial consists of 88 individuals split into two groups, the treatment group received 900 mg/day of the extract mixture while the placebo group is getting a placebo capsule that resembles the extract capsule the treatment group is given. Blood pressure was taken three different times within the study; before the trial, 4 weeks into the trial, as well as 8 weeks. The overall results did show a significant difference within the treatment groups blood pressure compared to placebo group. This is a significant finding, showing this extract mixture could be a potential treatment for individuals with hypertension.

References:
1. Shen, Gwak, S. R., Joo, J. C., Ha, K. C., Park, Y. K., Kim, S., & Park, S. J. (2021). Effectiveness and Safety of Hwangchil–Unripe Bokbunja Extract Mixture on Blood Pressure: A Randomized Double-Blind Placebo-Controlled Clinical Trial. Journal of Medicinal Food, 24(3), 258–266. https://doi.org/10.1089/jmf.2020.4820

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Ivana Djuricic: Flavonoids in hypertension

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Ivana Djuricic: Flavonoids in hypertension

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Maaliki, Shaito, A. A., Pintus, G., El-Yazbi, A., & Eid, A. H. (2019). Flavonoids in hypertension: a brief review of the underlying mechanisms. Current Opinion in Pharmacology, 45, 57–65. https://doi.org/10.1016/j.coph.2019.04.014

This is a review of studies done on the effects of flavonoids on hypertension. Since hypertension is a prevalent and strong predicator of the development of CVD, but one with an unclear etiology at times, it is important to understand how we can lower BP through dietary supplementation.

One key finding is that flavonoids apply their vasorelaxant effects by increasing NO levels through multiple mechanisms. For each of the 6 flavonoids reviewed in the study, they all had similar decreasing BP effects, with a large majority working to increase endothelium-derived nitric oxide (NO), which is critical in regulating BP.

Different types of flavonoids are found in celery, garlic, chamomile tea, onions, broccoli, other teas, fruits, apples, pears, cocoa, and grape product. Supporting a nutrition plan that includes flavonoid-heavy foods could be beneficial if you are working with a hypertensive patient. The clinical implications are that, due to their anti-hypertensive and vasodilation properties, flavonoids could either be concentrated and given as a supplement or patients could increase dietary intake of these foods (although the efficacy of dietary intake is unclear).

Worthy to note that although there seems to be potential for clinical use of flavonoids, they also have a very low bioavailability and most are not well absorbed in high does from diet, although repeated intake could have a cumulative effect. Even with this, some of them still have large biological effects which the article contributed to slower elimination or generation of metabolites that are more active. If it is to be concentrated and supplemented, it is also important to understand dosing and drug-drug interaction as high doses could have harmful effects, especially for elderly patients because some have the ability to affect metabolism of other drugs. So, even though they seem to have anti-hypertensive qualities in these studies, it might be more difficult to apply it to a broad based nutritional guideline for food intake or clinical use as a supplement.

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Effects of Sodium Reduction and the DASH Diet in Relation to Baseline Blood Pressure

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Effects of Sodium Reduction and the DASH Diet in Relation to Baseline Blood Pressure

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Emalee Haynes

This study followed 412 patients around the age of 48 years old through a controlled diet trial that included reducing sodium, followed a DASH diet that had increased fruits, vegetables, and low-fat dairy. Patient selected were either prehypertensive or in stage one and were not currently taking medications to assist with stabilization of blood pressure. Throughout there was a tracking of blood pressure readings to monitor for differences done solely through diet modifications. The result of this study showed that when following a DASH diet in combination with decreased sodium intake there was an improvement in blood pressure levels which allowed for patients to have lower blood pressure. This is important to note because it illustrates the impact of dietary modifications on disease progression. These patients were not making any other changes other than diet choice which allowed for decreased blood pressure, and improved classification within the hypertension groupings. The clinical implications of this would be counseling suggestions and evidence behind recommendations for anyone at risk for hypertension development, or throughout any stage of hypertension.

Juraschek, Stephen P et al. “Effects of Sodium Reduction and the DASH Diet in Relation to Baseline Blood Pressure.” Journal of the American College of Cardiology vol. 70,23 (2017): 2841-2848. doi:10.1016/j.jacc.2017.10.011

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Affiliations

¹ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; The Johns Hopkins University School of Medicine, The Johns Hopkins Bloomberg School of Public Health, and The Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, Maryland. Electronic address: sjurasch@bidmc.harvard.edu.

² The Johns Hopkins University School of Medicine, The Johns Hopkins Bloomberg School of Public Health, and The Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, Maryland.

³ Department of Nutrition Sciences, Purdue University, West Lafayette, Indiana.

Free PMC article

Randomized Controlled Trial

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Affiliations

¹ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; The Johns Hopkins University School of Medicine, The Johns Hopkins Bloomberg School of Public Health, and The Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, Maryland. Electronic address: sjurasch@bidmc.harvard.edu.

² The Johns Hopkins University School of Medicine, The Johns Hopkins Bloomberg School of Public Health, and The Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, Maryland.

³ Department of Nutrition Sciences, Purdue University, West Lafayette, Indiana.

Abstract

Background: Both sodium reduction and the DASH (Dietary Approaches to Stop Hypertension) diet, a diet rich in fruits, vegetables, and low-fat dairy products, and reduced in saturated fat and cholesterol, lower blood pressure. The separate and combined effects of these dietary interventions by baseline blood pressure (BP) has not been reported.

Objectives: The authors compared the effects of low versus high sodium, DASH versus control, and both (low sodium-DASH vs. high sodium-control diets) on systolic blood pressure (SBP) by baseline BP.

Methods: In the DASH-Sodium (Dietary Patterns, Sodium Intake and Blood Pressure) trial, adults with pre- or stage 1 hypertension and not using antihypertensive medications, were randomized to either DASH or a control diet. On either diet, participants were fed each of 3 sodium levels (50, 100, and 150 mmol/day at 2,100 kcal) in random order over 4 weeks separated by 5-day breaks. Strata of baseline SBP were <130, 130 to 139, 140 to 149, and ≥150 mm Hg.

Results: Of 412 participants, 57% were women, and 57% were black; mean age was 48 years, and mean SBP/diastolic BP was 135/86 mm Hg. In the context of the control diet, reducing sodium (from high to low) was associated with mean SBP differences of -3.20, -8.56, -8.99, and -7.04 mm Hg across the respective baseline SBP strata listed (p for trend = 0.004). In the context of high sodium, consuming the DASH compared with the control diet was associated with mean SBP differences of -4.5, -4.3, -4.7, and -10.6 mm Hg, respectively (p for trend = 0.66). The combined effects of the low sodium-DASH diet versus the high sodium-control diet on SBP were -5.3, -7.5, -9.7, and -20.8 mm Hg, respectively (p for trend <0.001).

Conclusions: The combination of reduced sodium intake and the DASH diet lowered SBP throughout the range of pre- and stage 1 hypertension, with progressively greater reductions at higher levels of baseline SBP. SBP reductions in adults with the highest levels of SBP (≥150 mm Hg) were striking and reinforce the importance of both sodium reduction and the DASH diet in this high-risk group. Further research is needed to determine the effects of these interventions among adults with SBP ≥160 mm Hg. (Dietary Patterns, Sodium Intake and Blood Pressure [DASH-Sodium]; NCT00000608).

Keywords: DASH; blood pressure; diet; sodium; trial.

Conflict of interest statement

Conflicts of interest: The authors have no conflicts of interest to report.

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dietary approaches to stop hypertension*

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national center for biotechnology information

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Effects of Sodium Reduction and the DASH Diet in Relation to Baseline Blood Pressure - PubMed

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The combination of reduced sodium intake and the DASH diet lowered SBP throughout the range of pre- and stage 1 hypertension, with progressively greater reductions at higher levels of baseline SBP. SBP reductions in adults with the highest levels of SBP (≥150 mm Hg) were striking and reinforce the i ...