HfpefEdit

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome in which patients experience symptoms of heart failure despite a left ventricular ejection fraction (LVEF) that is normal or near-normal. Historically called “diastolic heart failure,” HFpEF reflects a spectrum of pathophysiology rather than a single defect, and it poses distinctive diagnostic and therapeutic challenges. The condition is common in older adults and is associated with a cluster of comorbidities that include hypertension, obesity, diabetes, and atrial fibrillation. Because the heart’s pumping function appears preserved on standard tests, recognizing HFpEF requires careful assessment of symptoms, imaging, and risk factors, along with exclusion of heart failure with reduced ejection fraction (HFrEF) and other conditions that can mimic the clinical picture. In recent years, advances in pharmacotherapy have begun to shift the management landscape, particularly with the emergence of sodium-glucose cotransporter-2 (SGLT2) inhibitors as a class that benefits some patients with HFpEF.

HFpEF exists in a broad clinical and pathophysiological spectrum. The ejection fraction threshold used in practice often places HFpEF at an LVEF of roughly 50% or higher, but many patients fall into a borderline range (for example, 40–49%, sometimes labeled HFmrEF) that requires nuanced interpretation. Patients with HFpEF frequently show pronounced comorbidity-driven myocardial and vascular changes, including stiffening of the left ventricle, impaired relaxation, atrial enlargement, microvascular dysfunction, and systemic inflammation. These processes contribute to elevated filling pressures and exertional limitation, manifesting as dyspnea, fatigue, and reduced exercise tolerance. Because HFpEF overlaps with metabolic and hypertensive phenotypes, clinicians routinely address concomitant conditions as part of a comprehensive treatment plan, not solely the heart’s pumping capacity.

Epidemiology and definitions HFpEF accounts for a substantial and growing share of heart failure cases, especially in aging populations. It is more commonly diagnosed in women and is strongly linked to obesity, long-standing hypertension, metabolic syndrome, and diabetes. The condition often coexists with atrial fibrillation and chronic kidney disease, and its presentation can be influenced by race, body habitus, and access to healthcare. Because HFpEF is defined more by clinical syndrome and preserved LVEF than by a single pathogen, its exact prevalence and subtype distribution depend on the criteria used by different clinical guidelines and studies. Efforts to refine classification continue, reflecting a broader shift toward phenotype-based approaches in cardiology.

Pathophysiology The pathophysiology of HFpEF is multifactorial and heterogeneous. Key elements include left ventricular and arterial stiffening, impaired ventricular-arterial coupling, and diastolic dysfunction that increases filling pressures during activity. In addition, microvascular dysfunction, endothelial dysfunction, systemic inflammation, and comorbidity-driven remodeling of the myocardium and extracellular matrix contribute to the clinical syndrome. Right-sided pressures can rise in advanced cases, and atrial dysfunction or arrhythmias such as atrial fibrillation frequently accompany HFpEF. This complexity has implications for treatment, because therapies that target a single mechanism often show limited efficacy across the broad HFpEF population. A growing body of work emphasizes phenotyping HFpEF patients into subgroups based on dominant mechanisms (for example, metabolic syndrome–driven, obese, or atrial-entrained phenotypes) to guide therapy in a more targeted fashion.

Diagnosis Diagnosing HFpEF requires synthesis of clinical symptoms and signs of heart failure with objective evidence that LVEF is preserved and that elevated filling pressures contribute to the patient’s physiology. Key elements include: - Clinical symptoms such as dyspnea on exertion, fatigue, and reduced exercise capacity. - Echocardiographic evidence of preserved LVEF, along with features consistent with diastolic dysfunction or elevated filling pressures (e.g., left atrial enlargement, certain diastolic parameters). - Elevated natriuretic peptide levels (BNP or NT-proBNP) in the appropriate clinical context. - Exclusion of HFrEF and other conditions that could account for the presentation. Because HFpEF is a heterogeneous syndrome, additional testing—such as advanced imaging, exercise hemodynamics, or cardiopulmonary exercise testing—may be used to clarify the diagnosis and guide management.

Management Therapies for HFpEF focus on symptom relief, control of fluid overload, and aggressive management of comorbidities. The management landscape has evolved as evidence accumulates for therapies that impact hospitalization risk and outcomes.

Symptom relief and decongestion: Diuretics are commonly used to manage fluid overload and relief of dyspnea, particularly during decompensation.
Blood pressure and vascular health: Given the strong link with hypertension and vascular stiffness, antihypertensive strategies (including ACE inhibitors, ARBs, or mineralocorticoid receptor antagonists in appropriate patients) are used to reduce cardiovascular risk and improve diastolic function in some subsets.
SGLT2 inhibitors: A major development in recent years is the demonstration that SGLT2 inhibitors can reduce hospitalizations for heart failure in HFpEF. Trials such as EMPEROR-Preserved with empagliflozin and DELIVER with dapagliflozin showed benefit in the composite outcomes related to HF hospitalization and cardiovascular events, even in patients without diabetes. This class has shifted guidelines and practice toward broader use in HFpEF, reflecting a shift away from the notion that pharmacotherapy would be of limited value in this group.
Mineralocorticoid receptor antagonists: Spironolactone and eplerenone have been studied in HFpEF, with TOPCAT showing mixed results that were complicated by regional differences and trial design, underscoring the heterogeneity of HFpEF and the need for careful patient selection.
Other therapies: While some drugs have proven benefits in HFrEF, their impact in HFpEF has been inconsistent. Beta-blockers, ACE inhibitors, and ARBs may be used for comorbidity management (hypertension, ischemic heart disease, atrial fibrillation) but do not have as consistent mortality benefits in HFpEF as in HFrEF. The concept of targeted therapy based on patient phenotype rather than a one-size-fits-all approach is gaining traction in both research and clinical practice.

Controversies and debates - Diagnostic and classification issues: Because HFpEF is a syndrome with multiple contributing mechanisms, there is ongoing debate about the best way to define and subclassify HFpEF. Phenotype-based approaches—identifying subgroups with dominant pathophysiology—are increasingly discussed as a way to tailor therapy, but consensus on criteria remains evolving. - Drug efficacy and mortality benefits: For many years, there was skepticism about whether pharmacologic therapy could meaningfully alter outcomes in HFpEF. The emergence of SGLT2 inhibitors has changed this perspective, but debates continue about which patients derive the most benefit, how to integrate these therapies with existing comorbidity management, and how to interpret results from heterogeneous trials such as TOPCAT. - Heterogeneity and trial design: The diverse etiologies and comorbidity profiles in HFpEF complicate clinical trial design and interpretation. Some observers advocate for more precise phenotyping in trials to identify responsive subgroups, while others caution against over-framing subtypes if it leads to fragmentation of evidence. - Emphasis on prevention and comorbidity management: Given the strong links with hypertension, obesity, diabetes, and sedentary lifestyle, there is broad agreement that managing these factors is essential. Debates arise around resource allocation, access to preventive care, and how best to balance pharmacologic and non-pharmacologic interventions in a healthcare system with finite resources.

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