Heart Failure with Preserved Ejection Fraction (HFpEF): Finally, Effective Treatments?

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a major clinical challenge, characterized by complex pathophysiology and historically limited treatment options. Unlike the case of heart failure with reduced ejection fraction (HFrEF), effective pharmacological interventions for HFpEF have been elusive. However, renewed hope has emerged with emerging evidence supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRAs), and other targeted therapies. This article plunges into the pathophysiology of HFpEF, assesses the available clinical trial data for these exciting new treatments, and discusses what these treatments promise to bring into the management of this difficult disorder.  

Introduction

Heart failure is a serious disorder that afflicts millions and ranks as one of the most frequent causes of hospitalization and death worldwide. Despite such a huge burden, there is considerable progress made in the treatment of heart failure with reduced ejection fraction, with left ventricular systolic dysfunction. On the contrary, heart failure with preserved ejection fraction (HFpEF) remains a treatment challenge. HFpEF is a heterogeneous syndrome with complex pathophysiology, defined by normal or near-normal left ventricular ejection fraction (≥50%) in association with signs and symptoms of heart failure. Historically, the treatment strategy for HFpEF has been the management of comorbidities and relief of symptoms, with limited evidence to support specific pharmacologic interventions that would improve outcomes. However, recent clinical trials have brought much-needed evidence to the table regarding the efficacy of some drugs in HFpEF, which may represent a turning point in the management of this complex condition. This article will review the pathophysiology of HFpEF, review the latest clinical trial data for emerging therapies, including SGLT2 inhibitors and MRAs, and discuss their potential to transform the management of HFpEF.  

Literature Review

The literature on HFpEF has evolved significantly in recent years, shifting from a focus on symptomatic management to the investigation of targeted therapies. Early research emphasized the role of diastolic dysfunction in HFpEF, highlighting impaired left ventricular relaxation and increased stiffness. However, it is now recognized that HFpEF is a complex syndrome with multiple contributing factors, including:  

• Myocardial dysfunction: Impaired cardiomyocyte relaxation, hypertrophy, and fibrosis contribute to diastolic dysfunction.

• Systemic inflammation: Chronic low-grade inflammation plays a key role in the development and progression of HFpEF.  

• Endothelial dysfunction: Impaired nitric oxide bioavailability and increased oxidative stress contribute to vascular dysfunction and further exacerbate myocardial dysfunction.

• Comorbidities: Conditions such as hypertension, diabetes, obesity, and chronic kidney disease are frequently present in patients with HFpEF and contribute to its pathophysiology.  

Clinical trials evaluating traditional HFrEF therapies, such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and beta-blockers, have generally shown neutral or modest effects in HFpEF. However, recent trials focusing on specific pathways and mechanisms have yielded more promising results.

Emerging Therapies for HFpEF

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, initially developed for the treatment of type 2 diabetes, have emerged as a promising therapeutic class for HFpEF. These agents exert their effects through several mechanisms, including:  

• Diuresis and natriuresis: SGLT2 inhibitors promote glucose excretion in the urine, leading to mild diuresis and natriuresis, which can reduce preload and improve cardiac function.  

• Improved cardiac energetics: SGLT2 inhibitors may improve myocardial energy metabolism by shifting fuel utilization from glucose to ketones.  

• Reduced inflammation and oxidative stress: These agents have been shown to have anti-inflammatory and antioxidant effects, which may contribute to their beneficial effects in HFpEF.

Clinical trials such as EMPEROR-Preserved and DELIVER have shown that SGLT2 inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death in patients with HFpEF, with or without diabetes.

Mineralocorticoid receptor antagonists such as spironolactone and eplerenone, in particular, also show promising evidence for the treatment of HFpEF. Their use will cancel out aldosterone action with concomitant roles of sodium retention, inflammation, and fibrosis. A possible role for MRA was demonstrated with a subpopulation effect from results seen in trials such as TOPCAT; results otherwise are inconsistent in demonstrating clinical outcomes for these populations. Future trials continue to aim to delineate populations of likely responders and nonresponders.

Other emerging therapies for HFpEF are being investigated, including:

• Nitric oxide donors: These agents aim to improve endothelial function and enhance vasodilation.

• Soluble guanylate cyclase (sGC) stimulators: These agents enhance nitric oxide signaling and improve cardiac function.  

• Myocardial contractility modulators: These agents aim to improve myocardial contractility without increasing myocardial oxygen consumption.  

Clinical Implications and Management Strategies

The results of these recent clinical trials have important implications for the management of HFpEF. SGLT2 inhibitors are now recommended as foundational therapy for patients with HFpEF, regardless of diabetes status. MRAs may be considered in selected patients, especially those with evidence of aldosterone activation or persistent symptoms despite other therapies.

A comprehensive management strategy for HFpEF should include:

• Management of comorbidities: Addressing conditions such as hypertension, diabetes, obesity, and chronic kidney disease is crucial.  

• Lifestyle modifications: Encouraging healthy lifestyle habits, such as regular exercise, a balanced diet, and weight management, can improve symptoms and quality of life.  

• Symptom management: Diuretics may be used to relieve congestion, and other medications may be used to manage specific symptoms.  

Challenges and Future Directions

Despite recent progress, several challenges remain in the management of HFpEF:

• Heterogeneity of the syndrome: HFpEF is a complex syndrome with multiple phenotypes, making it challenging to develop targeted therapies.  

• Lack of clear diagnostic criteria: Establishing a definitive diagnosis of HFpEF can be challenging.

• Need for further research: More research is needed to identify specific therapeutic targets and develop more effective treatments for HFpEF.

Future research should focus on:

• Identifying specific HFpEF phenotypes and developing personalized treatment strategies.

• Investigating the role of novel therapeutic targets and agents.

• Developing better diagnostic tools for HFpEF.

Conclusion

HFpEF is a therapeutic challenge that has posed a problem throughout history, but more recent developments now offer hope for improvement. One of the significant cornerstones that have emerged includes SGLT2 inhibitors; these have shown significant improvements in reducing the occurrence of cardiovascular events. Further potential improvements could be achieved using MRAs and emerging therapies in HFpEF. A comprehensive management strategy that aims to address comorbidities, promote healthy lifestyle habits, and utilize evidence-based pharmacotherapy is crucial to improving the lives of individuals who live with this complex condition.