How do different drug classes work in treating Heart failure with normal ejection fraction?

Overview of Heart Failure with Preserved Ejection Fraction (HFpEF)

Definition and Pathophysiology
Heart failure with preserved ejection fraction (HFpEF) is a distinct clinical syndrome in which patients exhibit signs and symptoms of heart failure while maintaining a normally preserved or near‐normal left ventricular ejection fraction (commonly defined as ≥50%). Unlike heart failure with reduced ejection fraction (HFrEF), the primary abnormality in HFpEF lies in diastolic dysfunction, impaired myocardial relaxation, and increased ventricular stiffness. The pathophysiology involves complex interactions between myocardial fibrosis, altered calcium handling, endothelial dysfunction, and components of systemic inflammation. This leads to abnormal ventricular-arterial coupling, increased filling pressures, and resultant symptoms of congestion even in the presence of normal systolic function. In addition, comorbidities such as hypertension, obesity, diabetes mellitus, atrial fibrillation, and renal insufficiency contribute not only to the onset but also to the progression of HFpEF. Biohumoral markers like elevated natriuretic peptides (e.g., NT-proBNP) are frequently used to aid in diagnosis, reflecting the hemodynamic congestion and diastolic stress.

Epidemiology and Risk Factors
HFpEF now accounts for roughly 50% of all heart failure cases, a prevalence that has markedly increased with the aging population and rising incidences of metabolic diseases. The syndrome is most common among older adults, particularly females, and frequently coexists with obesity, type 2 diabetes mellitus, and systemic hypertension. Epidemiological studies emphasize that the increasing burden of comorbidities has played a critical role in the growing prevalence of HFpEF. In addition, the racial and sex differences observed in HFpEF prevalence further underscore the heterogeneous nature of the syndrome; for example, women are more prone to diastolic dysfunction, partly due to differences in myocardial remodeling and vascular compliance. These multifactorial risk profiles inform the complexity of therapeutic management by necessitating an individualized and often multifaceted approach to treatment.

Drug Classes Used in HFpEF

Diuretics
Diuretics are a cornerstone of symptomatic management in HFpEF despite the lack of convincing evidence for improved survival outcomes. They function primarily by promoting natriuresis and diuresis, thereby alleviating symptoms associated with fluid overload such as pulmonary congestion and peripheral edema. Loop diuretics (such as furosemide) act in the thick ascending limb of the loop of Henle to inhibit the sodium-potassium-chloride cotransporter (NKCC2), leading to reduced sodium and water reabsorption. Thiazide diuretics and potassium-sparing diuretics work at downstream sites and are sometimes used in combination to overcome diuretic resistance. Although effective in relieving congestive symptoms, the chronic use of diuretics may activate neurohormonal pathways and can be associated with “diuretic resistance” and electrolyte imbalances, complicating long-term management.

Beta-blockers
Beta-blockers are well established in the treatment of HFrEF for their ability to decrease sympathetic nervous system activity, reduce heart rate, and improve myocardial oxygen consumption. However, in HFpEF the role of beta-blockers remains more controversial. Their mechanism of action in HFpEF largely pertains to reducing heart rate, which prolongs diastolic filling time and may reduce myocardial oxygen demand, potentially improving diastolic function. Several observational studies suggest that beta-blockers might lower all-cause mortality in patients with HFpEF, but large-scale randomized controlled trials have produced mixed results, with some trials demonstrating neutral outcomes in terms of hospitalization and mortality. Moreover, patient heterogeneity—in terms of age, comorbid conditions, and baseline heart rate—can modulate the beneficial effects observed in specific subgroups.

ACE Inhibitors and ARBs
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) target the renin–angiotensin–aldosterone system (RAAS), which is implicated in the pathogenesis of cardiac hypertrophy, myocardial fibrosis, and vascular remodeling in heart failure. In HFpEF, these agents are primarily used to control hypertension and mitigate maladaptive remodeling. Although multiple randomized trials, such as CHARM-Preserved and I-PRESERVE, have evaluated the efficacy of these agents in HFpEF, the results have not demonstrated significant improvements in mortality. However, evidence suggests that these drugs may reduce rates of heart failure hospitalization, possibly by moderating adverse remodeling processes and reducing afterload through vasodilation. The beneficial effects appear to be modest and may be more pronounced in certain phenotypic subgroups of HFpEF, underscoring the need for refined patient selection and tailored therapy.

Mechanisms of Action

How Diuretics Work in HFpEF
Diuretics exert their therapeutic effect in HFpEF through several interrelated mechanisms:
- Natriuresis and Diuresis:
Loop diuretics inhibit the NKCC2 cotransporter in the thick ascending limb of the loop of Henle, resulting in increased excretion of sodium and water. This effect reduces plasma and interstitial volume, thereby lowering preload and alleviating pulmonary and peripheral congestion.
- Symptomatic Relief from Fluid Overload:
In HFpEF, where elevated filling pressures are a central part of the clinical picture, diuretics help reduce symptoms such as dyspnea and edema by decreasing intravascular volume and subsequently reducing the ventricular filling pressure.
- Potential Limitations:
Chronic diuretic usage can lead to compensatory activation of the RAAS and sympathetic nervous system, thereby worsening neurohormonal activation in some patients. This phenomenon, along with adaptations such as tubular tolerance, can result in diuretic resistance—a significant clinical challenge where higher doses of diuretics fail to achieve the desired natriuretic effect.
- Combination Strategies:
To overcome diuretic resistance, clinicians sometimes employ sequential or combination diuretic therapy—such as adding a thiazide diuretic or a potassium-sparing agent—which can lead to a more robust and sustained natriuresis.

Mechanism of Beta-blockers in HFpEF
Beta-blockers function by antagonizing β-adrenergic receptors, which play a central role in mediating the effects of the sympathetic nervous system on the heart:
- Heart Rate Reduction:
By lowering the heart rate, beta-blockers prolong diastolic time. This extension of diastole allows for improved myocardial relaxation and optimal ventricular filling, which can translate into better diastolic function in HFpEF.
- Reduction of Myocardial Oxygen Demand:
A reduction in heart rate and myocardial contractility decreases oxygen consumption, potentially mitigating ischemia in myocardial segments that are already compromised by stiff ventricles.
- Modulation of Sympathetic Activity:
Elevated sympathetic tone is a pathophysiologic hallmark in many patients with heart failure. In HFpEF, where comorbid conditions such as hypertension and diabetes can exacerbate neurohormonal dysregulation, beta-blockers can help blunt excessive adrenergic stimulation, which in turn may prevent adverse cardiac remodeling and myocardial fibrosis.
- Clinical Controversies and Heterogeneity:
Despite these potential benefits, the clinical efficacy of beta-blockers in HFpEF has been variable. Observational studies have suggested a reduction in mortality, while randomized controlled trials have sometimes failed to demonstrate significant improvements in key outcomes like hospitalization and mortality. Factors such as patient age, presence of atrial fibrillation, and baseline heart rate can influence the effectiveness of beta-blockers, indicating that a one-size-fits-all approach may not be feasible in HFpEF.

Role of ACE Inhibitors and ARBs
ACE inhibitors and ARBs work primarily by attenuating the RAAS:
- Vasodilation and Afterload Reduction:
ACE inhibitors block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, thereby inducing vasodilation and reducing peripheral vascular resistance. ARBs, on the other hand, prevent the binding of angiotensin II to its receptors. Both mechanisms contribute to lowering afterload, which can help in reducing the workload on the heart.
- Modulation of Cardiac Remodeling:
Angiotensin II is known to promote myocardial fibrosis and adverse remodeling. By reducing levels of angiotensin II, ACE inhibitors and ARBs can help in preventing or attenuating myocardial fibrosis and hypertrophy, crucial factors in the diastolic dysfunction seen in HFpEF.
- Improvement in Endothelial Function:
Beyond their hemodynamic benefits, these agents may improve endothelial function by decreasing oxidative stress and inflammation, which are both implicated in the pathogenesis of HFpEF.
- Limited Impact on Mortality:
Although ACE inhibitors and ARBs have clear benefits in HFrEF, their effects in HFpEF are less pronounced. Several randomized controlled trials have demonstrated only modest, if any, improvements in mortality rates, although some studies indicate a reduction in hospitalization rates and improvements in symptoms.
- Implications for Combination Therapy:
Given the multifaceted nature of HFpEF pathophysiology, the use of ACE inhibitors or ARBs is often complemented by other therapies—including diuretics and beta-blockers—to achieve a more comprehensive management of the syndrome. Optimizing blood pressure control and mitigating neurohormonal activation remain central to their role in HFpEF treatment.

Clinical Efficacy and Outcomes

Clinical Trials and Studies
The clinical outcomes associated with different drug classes in HFpEF have been studied extensively, though with mixed results:
- Diuretics:
Despite the absence of robust evidence for altering long-term mortality, diuretics are universally accepted for symptom relief. Clinical practice and registry data highlight that timely and appropriately titrated diuretic therapy can significantly reduce hospitalizations driven by fluid overload. However, the limitations posed by diuretic resistance and neurohormonal activation dampen their utility in improving overall survival.
- Beta-blockers:
Observational studies have often shown a survival benefit with beta-blocker use in HFpEF, particularly in subsets of patients who are younger or have recovered from previous systolic dysfunction. In contrast, several randomized clinical trials have failed to demonstrate a clear mortality benefit, reflecting the complex interplay of comorbidities and the heterogeneity of the HFpEF population.
- ACE Inhibitors and ARBs:
Large trials such as CHARM-Preserved and I-PRESERVE have evaluated the use of RAAS inhibitors in HFpEF and have largely demonstrated neutral effects on all-cause mortality. Nonetheless, subgroup analyses and meta-analyses have indicated that ACE inhibitors and ARBs may reduce hospitalization rates and improve quality of life despite the absence of a significant mortality signal.
- Comparative Data:
Comparative effectiveness research in HFpEF suggests that while beta-blockers and RAAS inhibitors may each offer modest benefits, their impact is generally less robust than that observed in HFrEF. The lack of a “magic bullet” has led clinicians to rely on symptomatic management with diuretics while using beta-blockers and RAAS inhibitors to control comorbid conditions such as hypertension and atrial fibrillation.

Comparative Effectiveness of Drug Classes
When comparing the various drug classes, several important points arise:
- Symptom Relief Versus Mortality Benefit:
Diuretics are excellent for relieving symptoms related to congestion; however, they have not been shown to reduce mortality. In contrast, beta-blockers and ACE inhibitors/ARBs may provide a modest reduction in hospitalizations and potentially improve survival in select patient populations, though the evidence is more robust in HFrEF than in HFpEF.
- Patient Heterogeneity:
The efficacy of beta-blockers appears to be influenced by patient-specific factors such as age and the presence or absence of atrial fibrillation. For instance, observational studies have reported a survival benefit in patients under 75 years of age, but this benefit diminishes in older populations.
- Neurohormonal Modulation:
Both beta-blockers and RAAS inhibitors work to counteract pathological neurohormonal activation. While their benefits are clearly documented in systolic dysfunction (HFrEF), their role in attenuating diastolic dysfunction-related remodeling in HFpEF is less clearly defined.
- Combination Therapy Considerations:
Given the multifactorial pathophysiology of HFpEF, combination therapy is commonly employed. For example, concomitant use of diuretics (for symptomatic relief) with beta-blockers and ACE inhibitors/ARBs (for neurohormonal modulation and blood pressure control) is a typical strategy, although the optimal combination and dosing remain areas of active investigation.

Challenges and Future Directions

Current Challenges in Treating HFpEF
Treating HFpEF remains one of the most intricate challenges in cardiology, and several issues contribute to the current therapeutic limitations:
- Heterogeneity of HFpEF:
HFpEF is not a single disorder but rather a syndrome that encompasses numerous distinct pathophysiological processes. This heterogeneity makes it difficult to identify a universal therapeutic target. For instance, while some patients’ symptoms are driven predominantly by myocardial stiffness and fibrosis, others may have significant contributions from endothelial dysfunction, pulmonary vascular disease, or systemic inflammation.
- Limited Impact on Mortality:
Unlike in HFrEF, where beta-blockers, ACE inhibitors, and ARBs have demonstrable survival benefits, clinical trials in HFpEF have generally failed to show similar mortality benefits. This discrepancy is partly due to the fact that the underlying mechanisms of HFpEF are more complex and less responsive to conventional neurohormonal antagonism.
- Diuretic Resistance and Neurohormonal Activation:
The symptomatic relief provided by diuretics is sometimes offset by the adverse effects of neurohormonal activation and the development of diuretic resistance, which complicates the long-term management of fluid overload in HFpEF patients.
- Difficulties in Patient Phenotyping:
The absence of a clear diagnostic “gold standard” for HFpEF, compounded by the diverse spectrum of comorbidities, complicates patient selection for clinical trials. This has led to inconsistent study results and sometimes underpowered subgroup analyses, which in turn hamper the development of effective therapies.

Future Research and Potential Therapies
A multitude of future directions are being explored to address these challenges:
- Phenotype-Specific Therapies:
Given the observed heterogeneity in HFpEF, future clinical trials are likely to focus on patient stratification and personalized therapy. Better phenotyping based on diastolic function, systemic inflammation, comorbidity burden, and even genetics may allow for targeted treatment strategies that go beyond traditional neurohormonal antagonism.
- Novel Therapeutic Agents:
In addition to the established drug classes, newer agents such as sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as promising therapies. Although initially developed as anti-hyperglycemic agents, SGLT2 inhibitors have shown benefit in reducing heart failure hospitalizations and improving cardiovascular outcomes regardless of diabetic status. Other novel medications, including angiotensin receptor-neprilysin inhibitors (ARNIs) and immunomodulatory drugs, are also under investigation, with some early-phase trials showing promising hemodynamic and clinical benefits in HFpEF patients.
- Combination and Multimodal Strategies:
The complexity of HFpEF may necessitate combination therapies that simultaneously address multiple pathophysiological pathways. For instance, combining diuretics for volume control with beta-blockers and RAAS inhibitors for neurohormonal modulation and possibly SGLT2 inhibitors for their osmotic diuretic and renal protective effects could offer a more comprehensive approach.
- Nonpharmacological Interventions:
Adjunct strategies such as exercise training have demonstrated improvements in exercise capacity and quality of life, even if they do not directly impact mortality. Future research is likely to explore how tailored exercise programs, along with lifestyle modifications, can complement pharmacological therapy in HFpEF.
- Biomarker-Guided Therapy:
There is growing interest in using biomarkers—such as natriuretic peptides, troponin, C-reactive protein (CRP), and emerging markers of myocardial fibrosis and oxidative stress—to guide therapy and predict response. Such approaches may enable clinicians to better monitor treatment efficacy and adjust therapy on an individual basis.

Detailed and Explicit Conclusion

In summary, treating heart failure with preserved ejection fraction (HFpEF) involves a multifaceted approach that reflects the underlying pathophysiological heterogeneity of the condition. The management strategy broadly relies on three major drug classes:

1. Diuretics play a crucial role in providing symptomatic relief by promoting natriuresis and reducing volume overload. Their mechanism is well understood, involving the inhibition of sodium reabsorption in various nephron segments; however, issues such as diuretic resistance and the potential for neurohormonal activation limit their use as disease-modifying agents.
2. Beta-blockers reduce myocardial oxygen demand and extend diastolic filling time by decreasing heart rate. They also help attenuate sympathetic overdrive, a critical component in the neurohormonal axis implicated in HFpEF. Despite observational evidence suggesting benefits on survival, large randomized trials have not conclusively established their efficacy in HFpEF, partly due to the complex interplay of patient factors such as age and atrial fibrillation.
3. ACE inhibitors and ARBs target the renin–angiotensin–aldosterone system to reduce afterload, mitigate adverse myocardial remodeling, and improve endothelial function. Although these agents are central to HFrEF management, their effects in HFpEF are modest, with trials demonstrating limited impact on mortality but some benefit on reducing hospitalization rates and improving symptomatic control.

The clinical efficacy of these drug classes varies significantly, reflecting the inherent challenges in treating a syndrome as heterogeneous as HFpEF. Comparative data suggest that while diuretics are essential for managing congestion, beta-blockers and RAAS inhibitors may confer modest benefits in select patient subgroups, although their performance is far less robust than in HFrEF. The ongoing evolution of therapies, including the advent of SGLT2 inhibitors and ARNIs, promises to expand the therapeutic armamentarium, yet personalized approaches driven by detailed patient phenotyping and biomarker-guided strategies will likely be necessary to fully address this complex syndrome.

Future research must focus on dissecting the varied underlying mechanisms of HFpEF to develop targeted treatments. This involves fine-tuning combination therapies that can address both the hemodynamic and neurohormonal disturbances while being mindful of patient heterogeneity. Moreover, nonpharmacological interventions such as exercise training, along with progress in the understanding of immunomodulatory pathways, may provide synergistic benefits.

In conclusion, the treatment of HFpEF using different drug classes works through distinct yet sometimes overlapping mechanisms. Diuretics mainly relieve symptoms by reducing fluid overload, beta-blockers improve diastolic function and modulate sympathetic activity, and ACE inhibitors/ARBs target the maladaptive neurohormonal axis to protect against fibrosis and adverse remodeling. However, due to the complexity and diversity of HFpEF, a generalized therapeutic approach has proven elusive, and future strategies must be tailored to individual patient phenotypes to improve long-term clinical outcomes. This comprehensive understanding not only enhances current management but also lays the groundwork for innovation in therapeutic strategies for HFpEF in the years to come.