The research paper selected for this week is titled: “Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study” This August 29, 2017, article was published online in the Lancet 2017; 39o: 2050-62. The authors are Mahshid Dehghan, Andrew Mente, Xiaohe Zhang, Sumathi Swaminathan, Wei Li, Viswanathan Mohan, Romaina Iqbal, Rajesh Kumar, Edelweiss Wentzel-Viljoen, Annika Rosengren, Leela Itty Amma, Alvaro Avezum, Jephat Chifamba, Rafael Diaz, Rasha Khatib, Scott Lear, Patricio Lopez-Jaramillo, Xiaoyun Liu, Rajeev Gupta, Noushin Mohammadifard, Nan Gao, Aytekin Oguz, Anis Safura Ramli, Pamela Seron, Yi Sun, Andrzej Szuba, Lungiswa Tsolekile, Andreas Wielgosz, Rita Yusuf, Afzal Hussein Yusufali, Koon K Teo, Sumathy Rangarajan, Gilles Dagenais, Shrikant I Bangdiwala, Shofiqul Islam, Sonia S Anand, Salim Yusuf, on behalf of the Prospective Urban Rural Epidemiology (PURE) study investigators.

The Prospective Urban Rural Epidemiology (PURE) study is a large, epidemiological cohort study of individuals aged 35–70 years (enrolled between Jan 1, 2003, and March 31, 2013) in 18 countries with a median follow-up of 7.4 years (IQR 5·3–9·3). The dietary intake of 135 335 individuals was recorded using validated food frequency questionnaires. The primary outcomes were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke, and heart failure). Secondary outcomes were all myocardial infarctions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality. The Participants were categorized into quintiles of nutrient intake (carbohydrate, fats, and protein) based on the percentage of energy provided by nutrients. The authors assessed the associations between consumption of carbohydrates, total fat, and each type of fat with cardiovascular disease and total mortality. The investigators calculated hazard ratios using a multivariable Cox frailty model.

This study is important because the findings from 18 less industrialized countries on 5 continents differed significantly from previous North American and Europe countries' studies.  

The key findings from this study are that high carbohydrate intake was associated with a higher risk of total mortality, whereas total fat and types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke (more saturated fat quintile was associated with less incidence of stroke and vice versa.)

The clinical implication of this study does not support the old recommendation to limit total fat intake to less than 30% of energy and current recommendations to limit saturated fat intake to less than 10% of energy. Individuals with high carbohydrate intake might benefit from a reduction in carbohydrate intake and an increase in the consumption of fats. This PURE study findings also suggest that predicting the net clinical effect based on considering only the effects of nutrient intake on LDL cholesterol is not reliable in projecting the effects of diet on cardiovascular disease events or on total mortality. 

Dehghan M, Mente A, Zhang X, et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet. 2017;390(10107):2050-2062. doi:10.1016/S0140-6736(17)32252-3

Posted by Richard Proudfoot

One of the key findings is that, although HDL did not appear to be affected, there was a significant increase in LDL particle size and decrease in LDL-C concentration in the treatment group (given omega-3) than the control at week 8 of the study.

With regard to nutrition and the clinical implications of this study, it is further evidence that perhaps patients would benefit from the implementation of a Mediterranean diet plan that focuses on omega-3 fatty acids, in addition to decreasing saturated fats and increasing soluble fiber, as a treatment plan for complex metabolic syndromes where one of the underlying risk factors is dyslipidemia.

Wang Y, Xu D. Effects of aerobic exercise on lipids and lipoproteins. Lipids Health Dis. 2017;16(1):132. Published 2017 Jul 5. doi:10.1186/s12944-017-0515-5

ated fat mass and hypertension all lead to increased cytokine production, including tumor necrosis factor-alpha, interferon -gamma, IL-1 and IL-6 that reduce the appetite, the intake of calories and proteins, thereby leading to muscle wasting, weight loss, decreased serum albumin, lymphopenia and

low cholesterol levels. These effects only advance atherosclerosis, which is deposition of plaques of fatty materials within the arteries. The clinical implications of this study would be that dyslipidemia poses a greater risk for cardiovascular disease in the late stages of chronic kidney disease. To combat this, malnutrition and inflammation need to be combated as well with healthy lifestyle and nutrition choices as well as strong healthcare plan. 





Peev, Vasil, Ali Nayer, and Gabriel Contreras. “Dyslipidemia, Malnutrition, Inflammation, Cardiovascular Disease and Mortality in Chronic Kidney Disease.” Current opinion in lipidology 25.1 (2014): 54–60. Web.

Gheflati, Alireza et al. “The effect of apple vinegar consumption on glycemic indices, blood pressure, oxidative stress, and homocysteine in patients with type 2 diabetes and dyslipidemia: A randomized controlled clinical trial.” Clinical nutrition ESPEN vol. 33 (2019): 132-138. doi:10.1016/j.clnesp.2019.06.006

 

This review summarizes recent guidelines and research relating to the use of nutraceuticals in the management of individuals at high risk of atherosclerotic cardiovascular disease.

 

In brief, they reviewed the following neutraceuticals: Icosapent ethyl (EPA), L-Carnitine, Coenzyme Q-10, plant sterols and stanols, red yeast rice, bergamot, berberine, polyunsaturated omega-3 fatty acids, Vitamin D, and Armolipid Plus (which contains berberine, red yeast rice, monacolin K, policosanol, coenzyme Q10, astaxanthin, and folic acid). Some of the benefits they listed are as follows: managing residual risk associated with lipids other than LDL-C, managing non-lipid-mediated residual risk, optimizing LDL-C treatment for patients with statin intolerance, optimizing LCL-C treatment when add-on therapies for statins are not available. Also, all these nutraceuticals may be adjuncts to lifestyle management for individuals at high risk of ASCVD.

 

What I found interesting is that this review cited two large placebo-controlled randomized control trials with fish oil supplementation with EPA and DHA, and no significant difference was found between the treatment and placebo groups with respect to vascular event risk reduction. This is despite using AHA recommended dosing of EPA and DHA. However, there was one RCT (REDUCE-IT) that used a substantially larger dose (4g) of highly purified EPA (icosapent ethyl). Supplementation with icosapent ethyl led to a 25% relative reduction in first events of a cardiovascular outcomes, and was also found to reduce subsequent and total ischemic events. Therefore, the dose and composition of PUFA preparations is important in determining vascular outcomes.

 

Clinically, while there are many lipid-lowering medications, nutraceuticals may play an important role in ASCVD management, particularly in statin intolerant patients.

 

Penson, P. E., & Banach, M. (2020). The Role of Nutraceuticals in the Optimization of Lipid-Lowering Therapy in High-Risk Patients with Dyslipidaemia. Current atherosclerosis reports, 22(11), 67.

Wang, Li, P. P., Liu, S. S., Zhang, B. B., Hu, Y. Y., Ma, H. H., & Wang, S. S. (2020). Green tea leaf powder prevents dyslipidemia in high-fat diet-fed mice by modulating gut microbiota. Food & Nutrition Research, 64, 1–14. https://doi.org/10.29219/fnr.v64.367 

One key finding from this study was that Chemotherapy does alter HDL'S, LDL's, and other associated apolipoprotein levels in breast cancer patients. For HDL's, over the full time of the treatment, the mean level started at 1.45mmol/L and ended at 1.13mmol/L. Therefore, there was an overall decrease in the amount of HDL's. Because of the decrease in HDL's, there was also a reduction in apolipoprotein A1 levels. The baseline level at the start of the experiment was 1.81g/L, and the mean levels at the end of the treatment were 1.61g/L. For LDL's, chemotherapy treatment showed an increase in said LDL particles. The average at the start of the study was 3.11mmol/L, and the average at the end of the study was 3.69mmol/L. The increase in LDL particles also led to an increase in apolipoprotein B levels. The baseline started at 0.97g/L, and by the end of the treatment the average levels were 1.12g/L. These result relate to nutritional science because we have seen how low levels of HDL and high levels of LDL are risk factors for diseases like cardiovascular disease. Continuing off of that, an interesting way this study could be continued is by examining the number of individuals who develop CVD after undergoing chemotherapy for breast cancer. One overall limitation of this study is that a larger cohort is needed to fully understand how lipid metabolism can affect large groups of different people.

A clinical application from this study is that the chemotherapy agents used in treatment are important. Most of the lipid side effects came from Doxorubicin and Paclitaxil. On the other hand, Cyclophosphamide seemed to have no effect on lipid metabolism. Another application is that lipid levels should be monitored in individuals undergoing chemotherapy for breast cancer. That way, dietary or supplemental arrangements could be made to keep up HDL levels and decrease LDL levels while undergoing chemotherapy treatment for breast cancer.

Sharma, M., Tuaine, J., McLaren, B., Waters, D. L., Black, K., Jones, L. M., & McCormick, S. P. (2016). Chemotherapy agents alter plasma lipids in breast cancer patients and show differential effects on lipid metabolism genes in liver cells. PLOS ONE, 11(1). https://doi.org/10.1371/journal.pone.0148049 

Chakrabarti, Anirikh et al. “Impact of Multi-Micronutrient Supplementation on Lipidemia of Children and Adolescents.” Clinical nutrition (Edinburgh, Scotland) 39.7 (2020): 2211–2219. Web.

 

This study is important clinically because they showed that in diabetes patients, tighter glycemic control is necessary for lipoprotein clearance and reduction in atherosclerosis. They showed this clearance of lipoprotein was exclusive of Ldlr, acting via bile acid pathways and mediated by heparin sulfate proteoglycans. Nutrition is critical in managing diabetes and the other diseases that come along with it. Finding new correlations in what we eat and how our bodies interact with it is important for helping find new approaches to treatment for disease.

Stephen Mayer

 

Al-Sharea, A., Murphy, A. J., Huggins, L. A., Hu, Y., Goldberg, I. J., & Nagareddy, P. R. (2018). SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr-/- type 1 diabetic mice. Atherosclerosis, 271, 166–176. https://doi.org/10.1016/j.atherosclerosis.2018.02.028

This study highlights the importance of adjusting lifestyle changes to find a treatment that best suits the patient.  We also need to be aware that we need to treat the entire patient and not hyperfocus on one condition without considering the effects of comorbidities.