Drug Targets for Heart Failure with Preserved Ejection Fraction: A Mechanistic Approach and Review of Contemporary Clinical Trials

Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for over half of prevalent heart failure (HF) worldwide, and prognosis after hospitalization for HFpEF remains poor. Due, at least in part, to the heterogeneous nature of HFpEF, drug development has proved immensely challenging. Currently, there are no universally accepted therapies that alter the clinical course of HFpEF. Despite these challenges, important mechanistic understandings of the disease have revealed that the pathophysiology of HFpEF is distinct from that of HF with reduced ejection fraction and have also highlighted potential new therapeutic targets for HFpEF. Of note, HFpEF is a systemic syndrome affecting multiple organ systems. Depending on the organ systems involved, certain novel therapies offer promise in reducing the morbidity of the HFpEF syndrome. In this review, we aim to discuss novel pharmacotherapies for HFpEF based on its unique pathophysiology and identify key research strategies to further elucidate mechanistic pathways to develop novel therapeutics in the future.

Keywords: heart failure with preserved ejection fraction; pathophysiology; pharmacotherapy.

Figure 1

Schematic representation of current and future therapeutic targets for heart failure with preserved ejection fraction. Abbreviations: A1R, adenosine A1 receptor; AGE, advanced glycosylation end products; ARNI, angiotensin receptor–neprilysin inhibition; CDC, cardiosphere-derived cell therapy; ERA, endothelin receptor antagonist; FGF23, fibroblast growth factor 23; Gal3, galectin 3; HDAC, histone deacetylase; IL, interleukin; I_Na, inward sodium current; MAPK, mitogen activated protein kinase; MRA, mineralocorticoid antagonist; NHE3, sodium-hydrogen exchanger 3; PDE, phosphodiesterase; RBM20, RNA binding motif 20; Rx, therapy; SERCA2a, sarcoplasmic/endoplasmic reticulum calcium ATPase 2A; sGC, soluble guanylate cyclase; SGLT2, sodium-glucose cotransporter 2.

Figure 2

Classes of drugs that modulate the cGMP-PKG pathway in relation to SERCA2a within cardiac myocytes (cardiomyocytes). cGMP is produced by sGC, which is activated by NO, or by the transmembrane pGC, which is activated by natriuretic peptides (ANP, BNP). Class of NO and nitroxyl donors is shown (①). sGC stimulators (②) target only nonoxidized sGC (Fe²⁺); in contrast, sGC activators (③) target oxidized sGC (Fe³⁺) by ROS. NEPs responsible for ANP and BNP breakdown are indicated (④). PDE5 operates the breakdown of cGMP produced by sGC, while PDE9 is responsible for the breakdown of cGMP produced by pGC (⑤). Abbreviations: 5’GMP, guanosine 5’-monophosphate; Ang-II, angiotensin-Π; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; cGMP, cyclic guanosine monophosphate; ECM, extracellular matrix; ET-1, endothelin-1; GTP, guanosine triphosphate; HFpEF, heart failure with preserved ejection fraction; IC, intracellular; LTCC, L-type calcium channel; NEP, inhibitor of neprilysin; NO, nitric oxide; P, phosphate group; PDE5, phosphodiesterase 5; pGC, particulate guanylate cyclase; PKG, protein kinase G; PLB, phospholamban; ROS, reactive oxygen species; RyR2, ryanodine receptor 2; SERCA2a, sarco-/endoplasmic reticulum calcium ATPase 2a; sGC, soluble guanylate cyclase; SR, sarco-/endoplasmic reticulum; T-tubule, transverse tubule; TGF-β, transforming growth factor-β. Figure adapted with permission from Kovacs et al. (12; https://creativecommons.Org/licenses/by/4.0/).

Figure 3

Right-sided heart failure, splanchnic hemodynamics, and the gut microenvironment in relation to the cardiorenal syndrome, pulmonary hypertension, and adverse outcomes. Right-sided heart failure is associated with the cardiorenal syndrome, worsening renal failure, worsening heart failure, and death. The mechanisms by which these processes are interrelated are not clear. Here, we propose a conceptual overview of potential pathophysiologic mechanisms underlying those associations. Right-sided heart failure results in venous congestion and, in turn, splanchnic congestion. Venous congestion of the intestines results in reduced blood flow to the gut enterocytes, thereby resulting in hypoxia in these cells. Anaerobic metabolism ensues, with buildup of lactate and acidosis. In an effort to extrude H⁺ into the gut lumen, the sodium-hydrogen exchanger 3 (NHE3) channel is upregulated resulting in increased Na⁺ absorption, which exacerbates fluid overload. Right-sided heart failure may also increase aldosterone secretion, which also stimulates NHE3. The increased H⁺ (decreased pH) in the gut lumen may result in microbial dysbiosis, increases trimethylamine-N-oxide. and may trigger inflammation that is involved in cardiac cachexia and poor outcomes in heart failure. Renal failure results in increased retention of phosphates and increased production of the phosphoturic hormone fibroblast growth factor 23. Both these foctors may play a role in the promotion of pulmonary artery stiffening, which is associated with increased pulmonary artery pressure and increased load on the right ventricle, thereby worsening right-sided heart failure. Figure adapted with permission from Polsinelli et al. (73).

Figure 4

Adenosine A1 receptor signaling pathways in the felling heart. Abbreviations: AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; K_ATP, adenosine triphosphate–dependent potassium channel; MPTP, mitochondrial permeability transition pore; PKA, phosphokinase A; PKC, phosphokinase C; PLC, phospholipase C; PLD, phospholipase D; SR, sarcoplasmic reticulum. Figure adapted with permission from Greene et al. (97).