Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future

Abstract

In contrast to the wealth of proven therapies for heart failure with reduced ejection fraction (HFrEF), therapeutic efforts in the past have failed to improve outcomes in heart failure with preserved ejection fraction (HFpEF). Moreover, to this day, diagnosis of HFpEF remains controversial. However, there is growing appreciation that HFpEF represents a heterogeneous syndrome with various phenotypes and comorbidities which are hardly to differentiate solely by LVEF and might benefit from individually tailored approaches. These hypotheses are supported by the recently presented PARAGON-HF trial. Although treatment with LCZ696 did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among HFpEF patients, subanalyses suggest beneficial effects in female patients and those with an LVEF between 45 and 57%. In the future, prospective randomized trials should focus on dedicated, well-defined subgroups based on various information such as clinical characteristics, biomarker levels, and imaging modalities. These could clarify the role of LCZ696 in selected individuals. Furthermore, sodium-glucose cotransporter-2 inhibitors have just proven efficient in HFrEF patients and are currently also studied in large prospective clinical trials enrolling HFpEF patients. In addition, several novel disease-modifying drugs that pursue different strategies such as targeting cardiac inflammation and fibrosis have delivered preliminary optimistic results and are subject of further research. Moreover, innovative device therapies may enhance management of HFpEF, but need prospective adequately powered clinical trials to confirm safety and efficacy regarding clinical outcomes. This review highlights the past, present, and future therapeutic approaches in HFpEF.

Keywords: Device therapy; Heart failure; LCZ696; Pharmacotherapy in HFpEF; Preserved ejection fraction.

Fig. 1

Current model on pathophysiology and management of comorbidities and risk factors in HFpEF. Cumulative expression of the shown comorbidities and risk factors can cause systemic inflammation which can then lead to development of HFpEF [2]. ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, CCB calcium channel blocker, MRA mineralocorticoid receptor antagonist, PDE5 hosphodiesterase-5, sCG soluble guanylate cyclase, SGLT2 sodium-glucose cotransporter-2. Figure modified according to Tschöpe et al. [4] and Lam et al. [9]

Fig. 2

Main approaches regarding device and pharmacological therapy in HFpEF patients. Renal denervation can lower sympathetic activity resulting in decreased neprilysin activation, end-systolic volumes, and cardiac fibrosis as well as increased levels of natriuretic peptides. By implantation of an atrial shunt device, left-atrial pressure can be reduced. Continuous measurement of pulmonary artery pressure with the CardioMEMS device helps to prevent cardiac decompensation. CRT devices target mechanical LV dyssynchrony in HFpEF patients. CCM devices aim to enhance myocardial contractility. Main pharmacological approaches in HFpEF comprise regulation of the NO–cGMP–PKG-axis, restoring mitochondrial energy, modulation of intracellular Ca²⁺ sensitivity as well as targeting cardiac inflammation and fibrosis. Furthermore, inhibition of the sodium glucose cotransporter-2 represents another important approach in HFpEF therapy, although the exact pathomechanisms are currently unknown. ASD atrial shunt device, CCM cardiac contractility modulation, CRT cardiac resynchronization therapy, eNOS endothelial nitric oxide synthase, miRNA micro-RNA, MRA mineralocorticoid receptor antagonist, NO–cGMP–PKG nitrogen monoxide–cyclic guanosine monophosphate–protein kinase, RDN renal denervation. Figure modified according to Lam et al. [9] and Böhm et al. [135]

Fig. 3

Current pharmacological approaches regarding regulation of the NO–cGMP–PGK-axis. Drugs targeting the NO–cGMP–PGK-axis aim to promote formation of cGMP, which increases PKG activity. PKG plays a pivotal role in titin phosphorylation contributing to reduction in cardiomyocyte passive stiffness [136]. PKG phosphorylation targets can also lower levels of key transcription factors and sarcomeric proteins mediating LV hypertrophy, diastolic relaxation, LV stiffness, and vasorelaxation. Furthermore, PKG-dependent phosphorylation of phospholamban can improve sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) activity [137] and, therefore, helps to prevent Ca²⁺ mishandling. PDE5 inhibitors (I) protect cGMP from degradation by PDE5. While sGC activators (II) bind to nonoxidized sGC (Fe²⁺), sGC stimulators (III) target oxidized sGC (Fe³⁺). Neprilysin inhibitors (V) prevent degradation of natriuretic peptides, particularly ANP and BNP, which can then bind to pGC. NO-donating drugs (IV) enhance bioavailability of NO, leading to stimulation of sGC. By binding to β3-AR on endothelial cells, β3-AR-selective agonists (VI) promote activity of eNOS, resulting in production of NO. The eNOS enhancer AVE3085 (VII) directly affects eNOS. ANP atrial natriuretic peptide, β3-AR β3 adrenergic receptor, BH2 dihydrobiopterin, BH4 tetrahydrobiopterin, BNP B-type natriuretic peptide, DHFR dihydrofolate reductase, DPP4 dipeptidyl peptidase-4, eNOS endothelial nitric oxide synthase, GTP guanosine triphosphate, PDE phosphodiesterase, pGC particulate guanylate cyclase, PKG protein kinase G, ROS reactive oxygen species, sGC soluble guanylate cyclase. Figure modified according to Papp et al. [138] and Kovacs et al. [139]