Emerging Therapies Targeting Cardiac Myosin Energetics in Heart Failure With Preserved Ejection Fraction

Abstract

Heart Failure with Preserved Ejection Fraction (HFpEF) is a complex clinical syndrome characterized by symptoms of heart failure, preserved left ventricular ejection fraction, and significant morbidity and mortality. The absence of effective, disease-modifying therapies has fueled interest in novel targets, particularly the energetics of cardiac myosin. Recent breakthroughs in the understanding of myosin's role in myocardial energetics have led to the development of pharmacologic agents aimed at optimizing cardiac muscle contraction and relaxation. This review synthesizes contemporary evidence, highlights clinical implications, and discusses the future scope of therapies targeting cardiac myosin energetics in HFpEF.

Introduction

HFpEF accounts for approximately half of all heart failure cases and presents a unique clinical and therapeutic challenge. While the pathophysiology is multifactorial, impaired cardiac relaxation and altered myocardial energetics are central to disease progression. Despite advances in the management of Heart Failure with Reduced Ejection Fraction (HFrEF), these strategies have not translated to improved outcomes in HFpEF. As a result, novel therapeutic approaches are crucial, with recent focus on the sarcomeric protein myosin and its energetic dynamics within the cardiomyocyte.

Epidemiology / Disease Burden

The prevalence of HFpEF is rising globally, paralleling the aging population and increasing rates of comorbid conditions such as hypertension, obesity, and diabetes. Epidemiological studies estimate that HFpEF constitutes nearly 50% of all heart failure diagnoses. Patients with HFpEF experience frequent hospitalizations, diminished quality of life, and high mortality comparable to those with HFrEF. The burden on healthcare systems is substantial, with recurrent admissions and prolonged hospital stays contributing to significant costs.

Pathophysiology

HFpEF is characterized by diastolic dysfunction, myocardial stiffness, and impaired ventricular relaxation, all occurring despite preserved systolic function as measured by ejection fraction. Central to these processes is the dysregulation of myocardial energetics, notably at the level of cardiac myosin. In HFpEF, altered myosin cross-bridge cycling, reduced ATP availability, and impaired energy utilization contribute to suboptimal cardiac performance. Additionally, comorbidities promote systemic inflammation, microvascular dysfunction, and interstitial fibrosis, further exacerbating energetic deficits.

Risk Factors

Multiple risk factors predispose individuals to HFpEF. Advanced age, female sex, obesity, hypertension, diabetes mellitus, chronic kidney disease, and atrial fibrillation are well-established contributors. These factors not only promote ventricular remodeling and increased myocardial stiffness but also influence metabolic pathways and mitochondrial function, thereby impacting myosin energetics and cardiac efficiency.

Clinical Features

Patients with HFpEF typically present with exertional dyspnea, fatigue, peripheral edema, and exercise intolerance. Physical examination may reveal elevated jugular venous pressure, pulmonary rales, and an S4 heart sound. The nonspecific nature of these symptoms often complicates diagnosis, especially in the elderly with multiple comorbidities. Clinical features reflect not only hemodynamic congestion but also the underlying impairment in myocardial relaxation and energetic reserve.

Diagnosis

Diagnosis of HFpEF requires a multifaceted approach, integrating clinical, laboratory, and imaging findings. Echocardiography is central, demonstrating preserved ejection fraction (≥50%), evidence of diastolic dysfunction (e.g., abnormal E/e' ratio), and left atrial enlargement. Biomarkers such as natriuretic peptides support the diagnosis, particularly in distinguishing HFpEF from non-cardiac causes of dyspnea. Advanced imaging modalities, including cardiac MRI and speckle-tracking echocardiography, provide additional insights into myocardial structure and function. The diagnostic process emphasizes exclusion of alternative etiologies and careful assessment of comorbid conditions.

Treatment & Management

Management of HFpEF is centered on symptom relief, optimization of comorbidities, and prevention of hospitalizations. Diuretics are the mainstay for congestion, while careful blood pressure and heart rate control are essential. Evidence for disease-modifying pharmacotherapies remains limited. Recent trials of renin-angiotensin-aldosterone system (RAAS) inhibitors, beta-blockers, and mineralocorticoid receptor antagonists have demonstrated modest or no benefit in HFpEF populations. Non-pharmacologic interventions, including exercise rehabilitation and weight management, offer additional benefits but do not address underlying myocardial dysfunction.

Recent Advances / Emerging Therapies

Given the central role of myosin in cardiac contractility and energy utilization, targeting myosin energetics has emerged as a promising therapeutic strategy. Myosin modulators, such as omecamtiv mecarbil and aficamten, have shown efficacy in HFrEF by enhancing contractile performance. In HFpEF, research is now focused on myosin inhibitors and agents that optimize myosin ATPase activity to improve relaxation and reduce myocardial stiffness. Early-phase clinical trials are evaluating the safety and efficacy of these agents in patients with diastolic dysfunction. Additionally, metabolic modulators targeting mitochondrial function and oxidative phosphorylation are under investigation, aiming to restore energetic balance at the cellular level. These therapies hold the potential to address the root cause of impaired relaxation in HFpEF, moving beyond symptomatic management toward disease modification.

Guideline Recommendations

Current guidelines from the American Heart Association (AHA) and European Society of Cardiology (ESC) emphasize individualized care in HFpEF, focusing on comorbidity management and symptomatic therapy. While emerging therapies targeting myosin energetics are not yet incorporated into standard recommendations, ongoing clinical trials may inform future guidelines. The evolving landscape underscores the need for robust evidence and integration of novel agents into therapeutic algorithms once safety and efficacy are established.

Conclusion

HFpEF remains a major unmet need in cardiovascular medicine, with limited effective therapies and substantial clinical burden. Advances in the understanding of cardiac myosin energetics have catalyzed the development of novel pharmacologic agents, offering hope for improved outcomes in this challenging syndrome. Ongoing research and future clinical trials will determine the role of these therapies in routine care, potentially revolutionizing the management of HFpEF through targeted, mechanism-based interventions.