Future Therapies in HFpEF

Introduction

The treatment of diastolic heart failure (HF), also known as heart failure with preserved systolic function (HFpEF), has been challenging, partly because there is a lack of consensus regarding the definition of the disease entity as well as a paucity of large-scale clinical trials to demonstrate effective therapeutic strategies. Diastolic and systolic HF may have certain similar pathophysiologic processes in common, but there are also distinct differences in myocardial structure and function. Most treatment strategies for diastolic HF strive to alleviate signs and symptoms or prevent exacerbating factors rather than alter the underlying pathophysiologic abnormalities (such as improving active relaxation or reducing passive stiffness). Several lines of new investigations have identified regression of left ventricular (LV) hypertrophy as a potential target of therapy, while others hope to improve outcomes in patients with features of diastolic HF via novel targets. Some of these drugs have already been approved for other indications, and improvement in diastolic dysfunction is considered an ancillary property that may have potential for further clinical development. This chapter summarizes the ongoing efforts to develop future therapies targeting extrinsic or intrinsic factors in diastolic HF.

Pathophysiology and Clinical Relevance

HFpEF patients have underlying diastolic stiffness, which can be attributed to excessive myocardial collagen deposition and cardiomyocyte stiffness. A new paradigm has been recently postulated that identifies a proinflammatory state in the endothelium induced by comorbidities as the origin of endothelial cell inflammation, which triggers the cardiac remodeling that is specific for HFpEF.

Targeting Intracellular Intrinsic Factors: Metabolic Modulation

NO-cGMP-PK Activators

The endothelium plays an important role in cardiovascular homeostasis by regulating cardiac function, vasomotor tone, and vascular permeability. The release of nitric oxide (NO) by the endothelium is crucial for normal function. The HFpEF-associated comorbidities lead to endothelial dysfunction through disruption of the intracellular nitrogen monoxide–cyclic guanosine monophosphate (cGMP)–protein kinase (NO-cGMP-PK) signal cascade. A disorder in this signal cascade contributes to the development of remodeling, including increased cardiomyocyte stiffness that is characteristic of HFpEF. The disruption of the NO-cGMP-PK signal cascade has been showed to lead to disturbances in the regulation of titin and an increase in fibrosis. Specifically the decline of cGMP through a NO mediated signal cascade has been shown to be specific during HFpEF remodeling and differs from HFrEF. Targeting the NO-cGMP-PK signal cascade offers new future therapeutic options to intervene in the remodeling that is characteristic of HFpEF. Possible future therapies that interfere with this signal cascade include endothelial NO-synthase (eNOS) activators, inorganic nitrates, neprilysin inhibition, phosphodiesterase-5 inhibition, or soluble guanylate cyclase stimulators, which will be discussed in the following sections.

Organic Nitrates and eNOS Activators

Direct NO donators such as isosorbide mononitrate are not seen as an effective treatment for HFpEF. A prior double-blinded crossover study with 110 patients with HFpEF showed that HFpEF patients on isosorbide mononitrate were less active and did not have a better quality of life compared to placebo. However, eNOS activators such as the eNOS transcription amplifier AVE3085 have had favorable outcomes in animal models. In this study HFpEF was induced in 60 salt-sensitive rats, with 30 treated with AVE3085 and 30 treated with placebo. Treatment with AVE3085 significantly increased eNOS messenger ribonucleic acid (mRNA) and protein levels in cardiac tissue in the test animals. Diastolic dysfunction as measured by invasive pressure-volume (P-V) loop measurements, were attenuated in the AVE3085 group. Additionally, cardiac hypertrophy as measured by LV mass measurements by echocardiography showed improvement compared to the untreated animals. Treatment with AVE3085 for improvement in cardiac hypertrophy appears promising, but since the majority of data have been in animal models up to this point, applicability to patients with HFpEF still remains to be proven.

Inorganic Nitrates, Nitrites, and Beetroot Juice

In addition to organic nitrates, inorganic nitrates also represent an important route to increase myocardial NO bioavailability in patients with HFpEF. The prior evidence of benefit of inorganic nitrates is based in prior studies involving acute infusion of sodium nitrate. In this study 28 patients with HFpEF underwent invasive cardiac catheterization at rest and during exercise and were randomized to either receiving sodium nitrite or placebo. The infusion of sodium nitrite resulted in significant reduction in exercise pulmonary capillary wedge pressure (PCWP), improvement of cardiac output with exercise, and normalization in the increase of cardiac output relative to oxygen consumption. Other studies showed similar effects by inhaled sodium nitrite. Further studies have looked at inorganic nitrates, which are precursors to nitrite and converted within the body. A study looking at beetroot juice drink as a source of inorganic nitrates showed improved submaximal exercise endurance in patients with HFpEF who were given daily beetroot juice for 1 week. Recently the trial INDIE-HFpEF looked at the effect of 4 weeks of administration of inhaled inorganic nitrates on exercise capacity in patients with HFpEF, showing no significant improvement in exercise capacity. Overall the data have shown that inhaled inorganic nitrates show no definitive benefits in patients with HFpEF; however, other modes of inorganic delivery may show benefit in future studies. The currently ongoing Inorganic Nitrate and Exercise Performance in Heart Failure (iNIX-HF) study is looking at the effects of an orally delivered inorganic nitrate pill compared to a beet juice drink, which is a source of inorganic nitrates. If the results of this study are promising, this allows reliable oral delivery of inorganic nitrates, which could be crucial for future HFpEF therapy.

Angiotensin Receptor and Neprilysin Inhibition

Sacubitril/valsartan is an active drug of investigation for future HFpEF therapies. Prior studies suggest that sacubitril/valsartan can stimulate the NO-cGMP-PK signal cascades. Specifically, neprilysin prevents degradation of numerous vasoactive peptides, including brain natriuretic peptide (BNP), which are thought to stimulate the formation of cGMP, which is involved in the remodeling process within HFpEF. The phase II PARAMOUNT trial investigated the change in N-terminal proBNP (NT-proBNP) in patients with HFpEF and showed a significant reduction in NT-proBNP levels in patients with HFpEF treated with sacubitril/valsartan. Clinical outcomes were not assessed in these patients in the PARAMOUNT trial. Recently completed, the PARAGON-HF trial examined the effect of sacubitril/valsartan on reduction of cardiovascular death and HF hospitalizations in patients with HFpEF. The results of PARAMOUNT showed no benefit of sacubitril/valsartan in total hospitalization for heart failure and death from cardiovascular causes with ejection fraction > 45%. However, subgroup analysis showed possible benefit in HFpEF patients with low normal ejection fractions and women. Further studies are necessary to further study these subgroups. In this study, sacubitril–valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes. Moreover, patients assigned to the sacubitril–valsartan group had a higher incidence of hypotension and angioedema.

Phosphodiesterease-5 (PDE5) Inhibitors

Many patients with primary pulmonary hypertension also have concomitant HFpEF. Prior studies with patients with HFpEF and pulmonary hypertension showed that treatment with the PDE5 inhibitor sildenafil led to decreased pulmonary arterial pressures and improved functional capacity and improved diastolic dysfunction. However, the RELAX study looked at HFpEF patients without pulmonary hypertension and showed no improvement in exercise capacity or clinical status. Similarly, the BADDHY study looked at patients with HFpEF and pulmonary hypertension and looked at bosentan versus placebo therapy and noted no beneficial effects in the bosentan group. Further studies are ongoing looking at the combination of phosphodiesterase inhibitors with endothelin antagonists in patients with HFpEF and pulmonary hypertension; however, given the negative results of the BADDHY study and the lack of improvement in exercise capacity in the RELAX study, the future of PDE5 inhibitors in HFpEF remains in question.

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