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1. Therapeutic Target: Atrial Arrhythmias 

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1. Therapeutic Target: Atrial Arrhythmias 

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- Would systematic screening for AF in HFpEF (with subsequent treatment of AF if present) result in improved outcomes (e.g., reduced stroke risk)? - Is rate control alone or rhythm control the best strategy in these patients? - Does treatment efficacy of AF differ by HFpEF subphenotype? - Could AF ablation or maze procedure worsen HFpEF by inducing scarring or dysfunction?

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2. Therapeutic Target: Cardiomyocyte Hypertrophy

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2. Therapeutic Target: Cardiomyocyte Hypertrophy

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- How do hypertrophy and cardiac atrophy (from disuse) impact HFpEF? - Is tachypacing to induce LV dilation helpful or harmful? - Does reducing pathological LV hypertrophy improve outcomes?

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3. Therapeutic Target: Chronotropic Incompetence 

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3. Therapeutic Target: Chronotropic Incompetence 

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- What is the best definition of chronotropic incompetence in HFpEF? - Can rate-adaptive pacing improve exercise capacity? - Are β-blockers helpful or harmful in this context?

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- What are optimal disease management strategies for HFpEF? - Which patients benefit most from remote hemodynamic monitoring? - Are there less invasive tools to measure congestion? - How should we define adequate decongestion during hospitalization?

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5. Therapeutic Target: Exercise Capacity & Weight Loss 

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5. Therapeutic Target: Exercise Capacity & Weight Loss 

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- We need large multicenter outcome studies on weight loss and exercise in HFpEF. - What are the best strategies to improve cardiac and skeletal muscle energetics?

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6. Therapeutic Target: Functional Atrioventricular Valve Regurgitation 

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6. Therapeutic Target: Functional Atrioventricular Valve Regurgitation 

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- What is the impact of valve repair/replacement on HFpEF outcomes? - What are the determinants and pathophysiologic effects of tricuspid regurgitation in HFpEF?

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7. Therapeutic Target: Impaired NO- and NPcGMP Signaling 

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7. Therapeutic Target: Impaired NO- and NPcGMP Signaling 

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- Why have NO-cGMP–enhancing therapies failed in trials? - How can we identify patients with NO-cGMP pathway deficiencies? - What is the best way to augment NP signaling? Neprilysin inhibition or direct NP administration? - Who benefits most from NP signaling enhancement? - Can PDE9 inhibition improve outcomes via NP-cGMP pathway?

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8. Therapeutic Target: LA Myopathy - How can we identify the "LA myopathy" HFpEF phenotype?

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8. Therapeutic Target: LA Myopathy - How can we identify the "LA myopathy" HFpEF phenotype?

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- Will targeted treatment improve outcomes in this subset? - What role does AF play in this group? - Could mechanical unloading (e.g., interatrial shunt) help?

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9. Therapeutic Target: Microvascular Dysfunction

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9. Therapeutic Target: Microvascular Dysfunction

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- Can treating coronary microvascular dysfunction improve outcomes?

- How can we differentiate causes of microvascular dysfunction?

- Do current treatments work, or are novel ones needed?

- How do aortic hemodynamics impact coronary perfusion?

- How do we identify and treat microvascular inflammation?

- Can we target monocytes/macrophages therapeutically?

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- How can we diagnose mitochondrial dysfunction (cardiac or skeletal) in HFpEF?

- What are the best strategies to prevent or treat it?

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11. Therapeutic Target: Myocardial Fibrosis

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11. Therapeutic Target: Myocardial Fibrosis

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- Which patients show prominent fibrosis?

- What are the best antifibrotic strategies?

- Does fibrosis influence treatment efficacy?

- Can we differentiate reactive vs reparative fibrosis?

- Should antifibrotic trials only enroll patients with fibrosis?

- Are there reliable fibrosis biomarkers?

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12. Therapeutic Target: Pulmonary Hypertension & RV Dysfunction

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12. Therapeutic Target: Pulmonary Hypertension & RV Dysfunction

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- Can novel agents improve LA/LV diastolic function while opposing PA vasoconstriction?

- Do non-PDE5 pulmonary vasodilators improve outcomes?

- Which HFpEF subtypes benefit from pulmonary vasodilators?

- How can we prevent pulmonary venous remodeling?

- Can inotropes help patients with RV systolic dysfunction?

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13. Therapeutic Target: Renal Dysfunction

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13. Therapeutic Target: Renal Dysfunction

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- What are better methods to assess kidney health in HFpEF?

- How does renal venous congestion impact kidney function and HFpEF?

- What role do renal hormones (e.g., FGF23) play in HFpEF?

- How does the gut-kidney axis influence HFpEF, especially with right-sided HF?

- What is the role of tubular function (e.g., SGLT-2, NHE3) in disease progression?

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- Is loss of estrogen a factor in HFpEF development in women?

- How do adverse pregnancy outcomes (e.g., preeclampsia) relate to HFpEF?

- How does androgenicity affect NP signaling and HFpEF?

- Are sex differences in cGMP-PKG signaling critical?

- Do sex hormones lead to a profibrotic phenotype?

- Do men and women respond differently to HFpEF therapies?

- Is female sex protective against HFrEF or predisposed to HFpEF?

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15. Therapeutic Target: Vascular Dysfunction

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15. Therapeutic Target: Vascular Dysfunction

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- What therapies can reduce arterial stiffness and improve ventricular-arterial coupling?

- How do we identify and treat excessive splanchnic vasoconstriction?

- How do venous congestion syndromes impact organ function and symptoms in HFpEF?