Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction: A Multiorgan Roadmap

Abstract

Heart failure (HF) with preserved ejection fraction (EF; HFpEF) accounts for 50% of HF cases, and its prevalence relative to HF with reduced EF continues to rise. In contrast to HF with reduced EF, large trials testing neurohumoral inhibition in HFpEF failed to reach a positive outcome. This failure was recently attributed to distinct systemic and myocardial signaling in HFpEF and to diversity of HFpEF phenotypes. In this review, an HFpEF treatment strategy is proposed that addresses HFpEF-specific signaling and phenotypic diversity. In HFpEF, extracardiac comorbidities such as metabolic risk, arterial hypertension, and renal insufficiency drive left ventricular remodeling and dysfunction through systemic inflammation and coronary microvascular endothelial dysfunction. The latter affects left ventricular diastolic dysfunction through macrophage infiltration, resulting in interstitial fibrosis, and through altered paracrine signaling to cardiomyocytes, which become hypertrophied and stiff because of low nitric oxide and cyclic guanosine monophosphate. Systemic inflammation also affects other organs such as lungs, skeletal muscle, and kidneys, leading, respectively, to pulmonary hypertension, muscle weakness, and sodium retention. Individual steps of these signaling cascades can be targeted by specific interventions: metabolic risk by caloric restriction, systemic inflammation by statins, pulmonary hypertension by phosphodiesterase 5 inhibitors, muscle weakness by exercise training, sodium retention by diuretics and monitoring devices, myocardial nitric oxide bioavailability by inorganic nitrate-nitrite, myocardial cyclic guanosine monophosphate content by neprilysin or phosphodiesterase 9 inhibition, and myocardial fibrosis by spironolactone. Because of phenotypic diversity in HFpEF, personalized therapeutic strategies are proposed, which are configured in a matrix with HFpEF presentations in the abscissa and HFpEF predispositions in the ordinate.

Keywords: diastole; heart failure; heart failure, diastolic; phenotype; therapeutics; ventricular function, left.

Figure 1. Systemic and myocardial signalling in HFPEF

Comorbidities induce systemic inflammation, evident from elevated plasma levels of inflammatory biomarkers such as soluble interleukin 1 receptor-like 1 (IL1RL1), C-reactive protein (CRP) and growth differentiation factor 15 (GDF15). Chronic inflammation affects the lungs, myocardium, skeletal muscle and kidneys leading to diverse HFpEF phenotypes with variable involvement of pulmonary hypertension (PH), myocardial remodeling, deficient skeletal muscle oxygen extraction (ΔA-VO₂) during exercise (Ex) and renal Na⁺ retention. Myocardial remodeling and dysfunction begins with coronary endothelial microvascular inflammation manifest from endothelial expression of adhesion molecules such as vascular cell adhesion molecule (VCAM) and E-Selectin. Expression of adhesion molecules attracts infiltrating leukocytes secreting transforming growth factor β (TGF- β), which converts fibroblasts to myofibroblasts with enhanced interstitial collagen deposition. Endothelial inflammation also results in presence of reactive oxygen species (ROS), reduced nitric oxide (NO) bioavailability and production of peroxynitrite (ONOO⁻). This reduces soluble guanylate cyclase (sGC) activity, cyclic guanosine monophosphate (cGMP) content and the favorable effects of protein kinase G (PKG) on cardiomyocyte stiffness and hypertrophy.

Figure 2. Phenotype-specific HFpEF treatment strategy using a matrix of predisposition phenotypes and clinical presentation phenotypes

A stepwise approach is proposed that begins in the left hand upper corner of the matrix with general treatment recommendations, presumed to be beneficial to the vast majority of HFpEF patients as they address the presentation phenotype of lung congestion and the predisposition phenotype of overweight/obesity present in >80% of HFpEF patients. Subsequently, supplementary (+) recommendations are suggested for additional predisposition-related phenotypic features when moving downward in the matrix and for additional presentation-related phenotypic features when moving rightward in the matrix. Arterial hypertension, renal dysfunction and coronary artery disease are proposed as additional predisposition phenotypes. Additional clinical presentation phenotypes, in whom specific therapeutic interventions could be meaningful, include chronotropic incompetence, pulmonary hypertension (especially combined precapillary and postcapillary pulmonary hypertension; CpcPH), skeletal muscle weakness and atrial fibrillation. Only therapeutic measures indicated in bold are currently established. All other therapeutic measures require further testing in specific phenotypes.

Figure 3. Effects of a 20 week caloric restriction diet on exercise capacity and quality of life in HFpEF

The graph displays percent changes ± standard errors at the 20-week follow-up relative to baseline by randomized group for: peak VO2 (ml/kg/min, panel A), and KCCQ (Kansas City Cardiomyopathy Questionnaire) overall score (= Quality of Life Score) (panel B). AT=aerobic exercise training; CR=caloric restriction diet. P-values represent effects for AT and CR.

Figure 4. Effects of acute infusion of inorganic nitrite on exercise hemodynamics in HFpEF

ΔPCWP_EX : change in exercise induced pulmonary capillary wedge pressure; ΔExerciseCO : increase in exercise induced cardiac output; mean PAP: mean pulmonary artery pressure; ΔCO/ ΔVO₂: ratio of exercise induced increase in cardiac output over exercise induced increase in oxygen consumption.

Figure 5. Myocardial cGMP signaling and pharmacological interventions in HFpEF

Nitric Oxide (NO) produced by nitric oxide synthases (NOS) stimulates soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), which activates protein kinase G (PKG). Inorganic nitrate/nitrite, sGC stimulators and phosphodiesterase (PDE) 5 inhibitors target this pathway. The natriuretic peptides ANP and BNP attach to the natriuretic peptide receptors A/B (NPRA/NPRB). This stimulates receptor guanylate cyclase (rGC) to produce cGMP, which again activates PKG. Neprilysin inhibitors such as sacubitril and PDE9 inhibitors act through this pathway.

Figure 6. Sequential steps of collagen metabolism

Collagen metabolism involves sequential steps consisting of procollagen synthesis, procollagen processing to collagen fibrils, post-translational modification of collagen fibrils and collagen degradation.

Figure 7. Heightened afterload sensitivity of the right ventricle in HFpEF

The relation between echocardiographic right ventricular (RV) fractional area change (FAC) and mean pulmonary artery (PA) pressure is flat in controls but steep in HFpEF patients.

Figure 8. Peak VO₂ and skeletal muscle histology in HFpEF

Relationship of capillary to fiber ratio (Panel A) and percent type 1 muscle fibers (Panel B) with peak VO₂ in older HFpEF patients (squares) and age-matched healthy controls (triangles).