1. There is strong but indirect evidence that hypertension therapy can be beneficial in prevention of HFpEF, but less clear data on reducing morbidity or mortality in known HFpEF; aggressive blood pressure control is associated with less HF hospitalizations. The current evidence is thin that renin-angiotensin-aldosterone system blockade is beneficial in HFpEF, but data suggest that it may be beneficial at the lower end of the EF spectrum (EF <55%).

2. Whether rhythm control would be of benefit in patients with HFpEF and atrial fibrillation remains unclear.

3. Appropriate management of coronary artery disease (CAD) remains an important consideration, since observational data have shown that CAD is common in patients with HFpEF and is associated with worse outcomes that may be improved with revascularization.

4. The authors postulate three hemodynamic mechanisms (left heart congestion/diastolic dysfunction/left atrial hypertension, pulmonary vascular disease/right ventricular [RV] dysfunction, and plasma volume expansion), and three potential molecular mechanisms (systemic microvascular inflammation, cardiometabolic functional abnormalities, and cellular [titin]/extracellular [fibrosis] structural abnormalities).

5. Reducing left heart congestion and left atrial hypertension is beneficial in HFpEF. Interatrial shunt device (IASD) treatment unloaded the left atrium and produced greater reduction in pulmonary capillary wedge pressure compared to sham-control at 1 month (p = 0.028 accounting for all stages of exercise) in phase 2 of the REDUCE LAP-HF I trial. A concern with this device is the potential rise in right-sided pressures—itself a potential detrimental mechanism in HFpEF. A larger trial (REDUCE LAP-HF II) is currently examining the effects of the IASD on clinical outcomes and quality of life. Among 119 patients with HFpEF (EF ≥40%) in the CHAMPION trial, a greater reduction in pulmonary pressures was associated with a 46% reduction in HF hospitalization over 6 months. As a result, wireless monitoring of pulmonary artery pressure has received a Class IIb, Level of Evidence B recommendation in HF in the most recent European Society of Cardiology HF guidelines.

6. The presence and severity of pulmonary hypertension are strongly associated with the development of RV dysfunction, but beyond increased pulmonary pressure, RV-arterial uncoupling plays an important role, further contributing to worse outcomes in HFpEF. However, therapy directly aimed at pulmonary hypertension, to reduce RV afterload thereby improving RV function in HFpEF, so far has been disappointing.

7. Plasma volume expansion has been suggested as the primary pathophysiologic mechanism in a subgroup of patients with HFpEF, particularly obese patients with HFpEF (body mass index ≥35 kg/m2), in whom increases in pulmonary capillary wedge pressure correlated with plasma volume expansion. Data from the CHAMPION trial suggests that addressing volume overload via diuresis may be a fundamental component of the optimal management of HFpEF. Beneficial effects of sodium-glucose luminal cotransporter-2 inhibitor (including natriuresis, and favorable cardiometabolic and renal effects) make them attractive for obese HFpEF patients with volume overload and adipose inflammation.

8. Several studies support a key role for chronic systemic inflammation specifically in patients with HFpEF. It has been shown/suggested that comorbidities in HFpEF lead to microvascular inflammation, which adversely affects the adjacent cardiomyocyte through decreased nitric oxide bioavailability, reduced cyclic guanosine monophosphate (cGMP) availability, and altered phosphorylation of titin. Microvascular ischemia, concentric left ventricular remodeling, and fibrosis from endothelial to mesenchymal transition contribute further to diastolic dysfunction. However, the assumption that systemic inflammation causally drives the development of HFpEF is still not fully proven, since interventional trials to prove causality have not been conclusive.

9. Impaired myocardial energetics in HFpEF patients suggest that targeting cardiometabolic functional abnormalities may be an important approach in these patients. Currently being evaluated are partial adenosine A1-agonists (capadenoson and neladenoson), carnitine palmitoyltransferase-1 inhibitors (etomoxir and perhexiline), fatty acid beta-oxidation inhibitor (trimetazidine), mitochondrial enhancer (elamipretide), and intravenous iron (ferric carboxymaltose).

10. The heart is comprised of two compartments, myocytic and a nonmyocytic, which contribute to diastolic stiffness and increased filling pressures. The (giant) elastic sarcomeric protein titin is the dominant regulator of myocardial passive tension, and thus, of the cardiomyocyte-derived stiffness. Post-translational modification of the titin N2B segment by protein kinase A (PKA)- and G (PKG)-mediated phosphorylation has been shown to change cardiomyocyte passive tension and is currently being evaluated. Extracellular matrix is a potential therapeutic target, and therefore, ongoing studies are evaluating inhibitors of transforming growth factor-beta (e.g., pirfenidone) and galectin-3, a lectin binding galactoside that is upregulated in HFpEF.

Reference

Heart failure with preserved ejection fraction: from mechanisms to therapies