Clinical Advances in Heart Failure with Preserved Ejection Fraction: A Systematic Review of Therapeutic and Mechanistic Evidence

Introduction

Heart failure with preserved ejection fraction (HFpEF) has become a predominant and increasingly prevalent subtype of heart failure (HF), currently accounting for more than half of all HF diagnoses worldwide. This trend is particularly evident among older adults and individuals with cardiometabolic comorbidities, including hypertension (HTN), diabetes mellitus (DM), and obesity.^1,2 In contrast to HF with reduced ejection fraction (HFrEF), for which robust evidence-based therapeutic strategies are well established, and heart failure with mildly reduced ejection fraction (HFmrEF), which is frequently grouped with HFpEF in clinical trials and practice guidelines because of overlapping management approaches despite distinct pathophysiological mechanisms, HFpEF remains diagnostically challenging and therapeutically constrained.^3,4 Over the past decade, increasing scientific attention has been directed toward the complex interplay of structural, functional, and systemic abnormalities underlying HFpEF. Central contributors include left ventricular diastolic (LVD) dysfunction, coronary microvascular inflammation, and progressive myocardial fibrosis, all of which collectively impair ventricular compliance and elevate intracardiac filling pressures.^5–7

This maladaptive remodeling most commonly manifests as concentric left ventricular hypertrophy (LVH) and diffuse interstitial myocardial fibrosis, features observed in the majority of patients with HFpEF and strongly associated with increased myocardial stiffness and adverse hemodynamic consequences.⁸ At the molecular level, these changes are driven by activation of transforming growth factor beta (TGF-β) signaling pathways, dysregulation of matrix metalloproteinases (MMPs), and inflammatory cytokine mediated fibroblast proliferation, culminating in excessive extracellular matrix deposition and fibrotic remodeling.^9,10 The epidemiological landscape of HFpEF has evolved substantially, with rising incidence reported across both high-income and low- to middle-income countries (LMICs). Data from the Global Burden of Disease (GBD) study and large-population based cohort analyses demonstrate a disproportionate burden among older women and individuals with coexisting conditions such as HTN, DM, obesity, and atrial fibrillation (AF).^11,12 Valvular heart disease (VHD) is also frequently observed in this population, with moderate or greater aortic stenosis (AS) or aortic regurgitation (AR) identified in approximately 6–8% of HFpEF cases, further accelerating disease progression and worsening clinical outcomes.¹³ Despite its growing prevalence, HFpEF is remains underdiagnosed, largely because hallmark symptoms including exertional dyspnea, fatigue, and reduced exercise tolerance overlap extensively with those of other cardiac and noncardiac disorders, complicating timely recognition and appropriate management.¹⁴ Current international guidelines define HFpEF by the presence of a left ventricular ejection fraction (LVEF) ≥50%, accompanied by objective evidence of structural cardiac abnormalities and elevated left ventricular (LV) filling pressures.¹⁵ Circulating natriuretic peptides, notably N terminal pro B type natriuretic peptide (NT proBNP), play a central role in diagnostic evaluation. However, NT proBNP levels do not reliably reflect the presence or severity of myocardial fibrosis or LVH and are influenced by sex, race, renal function, and adiposity, which may reduce diagnostic sensitivity in selected patient subgroups.^16,17 Emerging biomarkers, including soluble suppression of tumorigenicity 2 (sST2), galectin 3, and growth differentiation factor 15 (GDF 15), have demonstrated potential for improving diagnostic accuracy and risk stratification in HFpEF, although their routine clinical application remains under investigation.^18,19 Importantly, conventional diagnostic frameworks do not fully capture the marked heterogeneity of HFpEF. Contemporary clinical and translational studies have identified multiple phenotypic subsets, including inflammatory, metabolic, and fibrotic variants, each characterized by distinct pathobiological pathways, clinical trajectories, and therapeutic responses.^20,21 Clinically, HFpEF is associated with substantial morbidity, high rates of recurrent hospitalization, and mortality risks comparable to those observed in HFrEF. Although growing recognition of its clinical impact, effective disease modifying therapies remain limited, highlighting the urgent need for individualized, phenotype guided treatment strategies.^22–24 Moreover, HFpEF imposes a considerable economic burden on healthcare systems, driven by frequent hospital admissions, complex diagnostic assessments, and prolonged longitudinal follow up.

The present systematic review aims to critically appraise and synthesize contemporary evidence related to HFpEF, with a focus on epidemiological trends, underlying pathophysiological mechanisms, diagnostic challenges, therapeutic interventions, and long-term management strategies. By providing a comprehensive and clinically relevant synthesis, this review seeks to support the development of more effective, personalized, and multidisciplinary approaches to the care of patients with HFpEF.

Materials and Methods

Search Strategy and Data Sources

A systematic and comprehensive literature search was conducted across four major electronic databases: PubMed, Scopus, Web of Science, and the Cochrane Library. The search covered studies published between January 2015 and June 2025. Relevant keywords and Medical Subject Headings (MeSH) terms, including “heart failure with preserved ejection fraction”, “HFpEF”, “diastolic dysfunction”, “phenotypic heterogeneity”, “management”, and “long-term outcomes”, were combined using Boolean operators (AND, OR, NOT) to optimize search sensitivity and specificity.

To minimize selection bias and enhance methodological rigor, two independent investigators performed the literature searches and screened retrieved records. Any discrepancies regarding study selection or eligibility were resolved through consensus, with arbitration by a third investigator when necessary. Additional relevant studies were identified by manually reviewing the reference lists of included articles, relevant systematic reviews, and contemporary clinical guidelines issued by the European Society of Cardiology (ESC) and the American Heart Association (AHA). Trial registry records were not included, as this review was restricted to peer-reviewed published literature.

Inclusion and Exclusion Criteria

Studies were selected based on the following predefined criteria.

Inclusion Criteria

1. Studies involving adult patients with a confirmed diagnosis of HFpEF, defined as LVEF ≥50%.
2. Studies addressing any aspect of HFpEF, including etiology, pathophysiology, diagnostic approaches, therapeutic strategies, long-term outcomes, or clinical management.
3. Peer-reviewed original research articles, including randomized controlled trials (RCTs), observational cohort studies, meta-analyses, and comprehensive review articles. Studies available in full text and published in English language.

Exclusion Criteria

1. Studies primarily focused on HFrEF or HFmrEF.
2. Studies based exclusively on animal models or in vitro experiments without direct clinical relevance.
3. Editorials, letters to the editor, conference abstracts, and other publications lacking original data.
4. Studies published in languages other than English.

Study Selection Process Based on PRISMA Framework

All records retrieved from the database search were imported into EndNote reference management software (Version 21), where duplicate entries were identified and removed. Approximately 2700 duplicate records were excluded, resulting in 6000 unique titles and abstracts for initial screening by two independent reviewers. Based on the predefined inclusion and exclusion criteria, 900 articles were selected for full-text evaluation. After detailed assessment, 830 studies were deemed potentially eligible and subjected to methodological quality appraisal. Ultimately, 83 studies met all eligibility and quality criteria and were included in the final qualitative synthesis.

The study selection process was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure transparency and reproducibility.²⁵ Data extraction was performed using a standardized data collection form capturing study design, sample size, diagnostic criteria for HFpEF, interventions, clinical outcomes, and principal findings.

The methodological quality of observational studies was assessed using the Newcastle–Ottawa Scale (NOS),²⁶ while RCTs were evaluated with the Cochrane Risk of Bias (RoB) tool.²⁷ The quality of included systematic reviews was assessed using the updated “A MeaSurement Tool to Assess Systematic Reviews 2” (AMSTAR 2) instrument.²⁸ Studies failing to meet predefined quality thresholds were excluded from the final analysis. The PRISMA flow diagram illustrating the study selection process is presented in Figure 1.

Figure 1 Systematic flow diagram of the study selection process. *Records Identified: Electronic database searches retrieved 8900 records, including PubMed (n = 2800), Scopus (n = 3500), and Web of Science (n = 2600). Additionally, 200 records were identified through manual screening of reference lists in relevant reviews and clinical guidelines. No records were found in trial registers. **Records Excluded: Following deduplication, 2700 duplicate records were removed manually. Records were excluded by human reviewers no automation tools were used during screening for the following reasons: primarily focused on HFrEF or HFmrEF (n = 400), animal or laboratory studies without direct clinical relevance (n = 150), editorials, letters, or conference abstracts lacking original data (n = 120), and studies with low methodological quality or outdated data (n = 77). These exclusions ensured alignment with the review’s focus on epidemiology, pathophysiology, diagnostics, and therapeutic strategies for HFpEF. Notes: Page MJ, et al. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. This work is licensed under CC BY 4.0. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

Results

A total of 83 studies fulfilled the predetermined eligibility and quality assessment criteria and were included in this systematic review. Among these, 22 were RCTs, 38 were observational cohort studies, and 23 were systematic reviews or meta-analyses. Collectively, the included studies addressed a broad spectrum of topics relevant to HFpEF. Specifically, 25 studies investigated epidemiology and associated risk factors, 20 explored pathophysiological mechanisms and phenotypic heterogeneity, 15 evaluated diagnostic strategies, 15 examined therapeutic interventions, and 8 focused on long-term clinical outcomes.

Epidemiological Trends and Risk Factors in HFpEF: Demographic Shifts and Clinical Implications

HFpEF is currently recognized as accounting for estimated at half of all HF cases worldwide.²⁹ In European cohorts, HFpEF represents nearly 50–55% of diagnosed HF cases, with a disproportionately high prevalence among women aged 65 years and older.³⁰ Comparable epidemiological patterns have been reported in highly urbanized regions of East Asia, where HFpEF prevalence ranges from 30% to 45%, again predominantly affecting older female populations.³¹ In the United States (US data from large registries, including the Get With The Guidelines^®–Heart Failure (GWTG-HF) program, indicate that HFpEF constitutes approximately 47–50% of HF cases, with notable regional variation influenced by comorbidity burden and disparities in healthcare access.³²

Advancing age remains the most significant non-modifiable risk factor for HFpEF, with incidence increasing markedly after 65 years of age. Female sex is consistently associated with greater susceptibility, a phenomenon attributed to sex-specific patterns of myocardial remodeling and hormonal alterations, particularly the decline in estrogen levels following menopause.^33,34 Comorbid conditions, such as HTN, DM, obesity, chronic kidney disease (CKD), and AF, are highly prevalent among patients with HFpEF and play a central role in both disease onset and progression.^34,35 These conditions are not merely coincidental but contribute mechanistically to HFpEF pathogenesis through interconnected pathways involving systemic inflammation, endothelial dysfunction, and impaired nitric oxide signaling. Population-based studies have further highlighted the pronounced phenotypic variability characteristic of HFpEF, in contrast to the relatively more homogeneous presentation of HFrEF.³⁴ One prominent HFpEF phenotype comprises patients with metabolic syndrome (MetS), defined by the coexistence of obesity, insulin resistance, dyslipidemia, and HTN. The metabolic–inflammatory axis has emerged as a dominant driver of HFpEF pathophysiology, especially in Asian populations experiencing rapid increases in the prevalence of type 2 diabetes mellitus (T2DM) and obesity.¹⁰

In European populations, obesity is increasingly recognized as a key modifiable risk factor, strongly associated with adverse structural cardiac remodeling and impaired diastolic function.^30,36 In contrast, in resource-limited regions of Asia, restricted access to advanced diagnostic modalities contributes to under recognition and misclassification of HFpEF, resulting in an underestimation of disease burden and missed opportunities for timely intervention.³¹ These observations underscore the urgent need for region-specific public health strategies aimed at mitigating modifiable risk factors and improving early detection.

Overall, regional variations in HFpEF prevalence reflect the combined influence of demographic characteristics, comorbidity profiles, and healthcare system factors, emphasizing the importance of preventive and therapeutic frameworks tailored to population-specific needs. Figure 2 illustrates the global epidemiological landscape of HFpEF, highlighting variations in prevalence according to geographic region, age, sex, and comorbidity burden.

Figure 2 Worldwide distribution of HFpEF, depicting regional variations in prevalence by age group, sex, and associated comorbidities.

Risk Factors for HFpEF in Younger Populations

Although HFpEF has traditionally been viewed as a disorder primarily of older adults, emerging evidence reveals a notable increase in its incidence among younger populations. This trend largely reflects the escalating prevalence of MetS, a constellation of interrelated conditions encompassing obesity, insulin resistance, HTN, and dyslipidemia, that collectively promote early myocardial dysfunction and predispose individuals to HFpEF.³⁷ In a large analysis of 264,571 patients with HFpEF in the Veradigm registry (formerly PINNACLE) between 2016 and 2019, 52.5% met criteria for MetS and 55.7% were classified as obese. These results underscore the central role of cardiometabolic comorbidities in HFpEF pathogenesis, particularly among younger populations.³⁷

Environmental exposures, such as ambient air pollution and industrial chemical toxins have been implicated in endothelial damage and microvascular inflammation, processes that accelerate the fundamental pathophysiology of HFpEF.³⁸ Sedentary lifestyles, suboptimal dietary patterns, and substance abuse further amplify CV risk and are increasingly related to early onset HFpEF phenotypes in younger individuals.³⁹ Moreover, autoimmune diseases such as systemic lupus erythematosus(SLE), rheumatoid arthritis(RA), and autoimmune myocarditis contribute to persistent myocardial inflammation and fibrotic remodeling, both of which are central to the development of HFpEF, even in the absence of traditional risk factors.⁴⁰

The long-term cardiovascular sequelae of coronavirus disease 2019 (COVID-19) are increasingly recognized as significant contributors to HFpEF in younger adults. Cardiovascular magnetic resonance (CMR) imaging has identified persistent myocardial inflammation, interstitial fibrosis, and diastolic dysfunction in as many as 78% of recovered individuals, many of whom were previously healthy and under 50 years of age.⁴¹ A recent systematic review examining COVID-19 sequelae in patients with pre-existing heart failure further delineates the pathophysiological mechanisms and heightened cardiovascular risk, underscoring the necessity for vigilant post-COVID monitoring in this population.⁴² Notably, Parizad et al characterized these multifactorial determinants as a growing public health concern, emphasizing the importance of early risk identification and preventive strategies tailored to younger adults.⁴³ Mitigating these interrelated risk pathways through comprehensive clinical assessments, lifestyle modification, and regionally adapted public health policies is essential to curbing the rising burden of HFpEF among younger individuals.

Pathophysiological Insights into HFpEF: Mechanisms and Clinical Implications

HFpEF is a complex, multifactorial syndrome defined by preserved LVEF in the setting of impaired diastolic relaxation and increased myocardial stiffness. Unlike HFrEF, HFpEF predominantly manifests as diastolic dysfunction with elevated ventricular filling pressures even a normal LVEF.⁴⁴

The pathophysiology of HFpEF encompasses systemic inflammation, endothelial dysfunction, myocardial fibrosis, and cardiomyocyte (CMC) alterations. Chronic low-grade inflammation, frequently driven by comorbid conditions such as obesity, HTN, and T2DM, initiates endothelial activation and oxidative stress, which in turn fosters interstitial myocardial fibrosis and increased ventricular stiffness.^2,5 Coronary microvascular dysfunction further contributes to myocardial ischemia (MI), further exacerbating fibrotic remodeling and myocardial stiffness.⁴⁵

At the molecular level, reduced bioavailability of nitric oxide (NO) and dysregulation of the cyclic guanosine monophosphate protein kinase G (cGMP PKG) signaling cascade are critical in impairing diastolic function in HFpEF. Moreover, defective calcium (Ca²⁺) handling and heightened stiffness of the sarcomeric protein titin diminish myocardial compliance, impair diastolic relaxation, and contribute to exercise intolerance.^7,46,47 Extracardiac comorbidities, including pulmonary hypertension (PH), renal impairment, and chronotropic incompetence, are commonly prevalent in HFpEF, amplifying clinical heterogeneity and complicating management These factors exacerbate cardiac impairment and adversely affect prognosis.⁴⁸ The broad spectrum of phenotypic manifestations underscores the necessity for individualized treatment approaches and reinforces the concept of HFpEF as a syndrome with multiple pathophysiological pathways rather than a single disease entity. Figure 3 illustrates the principal mechanisms underlying HFpEF.

Figure 3 Overview of the major pathophysiological pathways contributing to HFpEF development and progression.

Economic Burden of HFpEF: Healthcare Costs and Resource Utilization

HFpEF imposes a substantial economic burden on healthcare systems worldwide. Frequent hospital admissions, extended inpatient stays, and ongoing outpatient management are the primary drivers of this burden. Although LVEF is preserved, individuals with HFpEF frequently experience recurrent episodes of decompensation, resulting in repeated utilization of healthcare resources and significant direct medical costs.^49–51 Hospitalization represents the largest component of total costs in this population. Emerging data indicate that more than one third of patients delay seeking care due to financial barriers, and many experience notable economic hardship following hospitalization.⁵¹ In addition to acute care expenditures, long term disease management further escalates financial strain.

Recent evidence suggests that integrating pharmacologic treatments such as sacubitril/valsartan with structured cardiac rehabilitation (CR) may improve patient outcomes and confer potential cost saving benefits by reducing rehospitalization and enhancing functional status.⁵² Beyond direct medical costs, HFpEF also incurs significant indirect costs, including loss of productivity, caregiving demands, and reduced health-related quality of life (QoL). These factors collectively intensify the societal and economic impact of the condition.^50,53 The chronic and progressive nature of HFpEF, which necessitates frequent clinical assessments, long-term pharmacologic therapy, and multidisciplinary interventions, results in sustained healthcare resource utilization.⁵⁴ Comparative analyses indicate that total healthcare spending for HFpEF is comparable to or may even exceed that of HFrEF, despite the absence of equally effective targeted therapies.^54,55 Figure 4 depicts the complex economic burden of HFpEF, encompassing direct costs such as hospitalization and outpatient care as well as indirect societal costs associated with productivity losses and caregiving responsibilities.

Figure 4 Overview of the economic burden of HFpEF.

Psychosocial Aspects of HFpEF

HFpEF exerts a substantial psychosocial burden alongside its physical manifestations. Patients commonly report persistent fatigue and dyspnea, which may contribute to social isolation, emotional distress, and marked reductions in QoL. A multicenter study of hospitalized patients with HFpEF reported substantial levels of anxiety and depression in both sexes, with women demonstrating particularly elevated anxiety symptoms. These results underscore the importance of routine psychological evaluation in clinical practice.⁵⁶

Cognitive impairment is increasingly recognized as a significant non cardiac complication in HFpEF. A scientific statement fromt he Heart Failure Society of America (HFSA) indicates that cognitive deficits, likely resulting from chronic cerebral hypoperfusion and systemic inflammation, can substantially impair patients’ ability to adhere to medication regimens, make informed health decisions, and maintain beneficial lifestyle practices.⁵⁷

Psychosocial stressors may further exacerbate HFpEF progression via activation neurohormonal and inflammatory pathways. The Aldosterone in Diastolic Heart Failure (Aldo-DHF) trial identified correlations between elevated anxiety, reduced social support, and increased biomarkers of cardiac stress.⁵⁸

Interventions such as peer support groups, patient education programs, and multidisciplinary care models have demonstrated effectiveness in enhancing coping strategies and emotional wellbeing.

Systematic screening for anxiety, depression, and cognitive dysfunction should be integrated into HFpEF management protocols. Timely referral for cognitive behavioral therapy, psychosocial support, and patient education is essential. Such a comprehensive approach not only alleviates emotional and cognitive burdens but also promotes improved treatment adherence, reduces hospitalization rates, and enhances patient centered outcomes.

Diagnosis and Contemporary Therapeutic Approaches to the Management of HFpEF

The differential diagnosis of HFpEF encompasses conditions that can mimic its hallmark symptoms, including dyspnea, fatigue, and exercise intolerance, as well as signs of congestion. These conditions include chronic obstructive pulmonary disease (COPD), PH, anemia, CKD, obesity-related deconditioning, VHD, constrictive pericarditis, cardiac amyloidosis, and atrial myxoma. Accurate diagnosis requires integration of clinical history, biomarkers, and advanced imaging modalities such as echocardiography and CMR, and, in select cases, invasive hemodynamic assessment to exclude mimics and confirm HFpEF.^59,60

Currently, no single pharmacologic therapy is universally recognized as disease-modifying across all HFpEF phenotypes, and management primarily targets comorbidities, symptom relief, and SGLT2 inhibitors, which constitute the principal evidence-based option. Recent advances include the nonsteroidal mineralocorticoid receptor antagonist finerenone. In the Finerenone in Subjects with Heart Failure (FINEARTS-HF) trial, finerenone significantly reduced the composite endpoint of CV death and total worsening HF events, including hospitalizations, by approximately 16% in patients with HFmrEF or HFpEF (LVEF ≥40%). Benefits were consistent across EF ranges, with a favorable safety profile regarding hyperkalemia when appropriately monitored.^61,62 Emerging device-based therapies for select HFpEF patients with resistant HTN include renal sympathetic denervation (RDN), which reduces sympathetic overactivation, improves diastolic function, and lowers blood pressure. While observational studies demonstrate promising outcomes, large-scale randomized data remain limited.^63,64 Baroreflex activation therapy (BAT), via implanted carotid sinus stimulation, has shown potential to improve hemodynamics and symptoms relief in early HFpEF studies with resistant HTN, though its application remains investigational.⁶⁵

Diagnostic Evaluation of HFpEF

Prompt and accurate diagnosis is critical, as effective management depends on distinguishing HFpEF from alternative causes of dyspnea. Initial assessment begins with a comprehensive clinical evaluation identifying HF symptoms in patients with preserved LVEF (≥50%), supported by echocardiographic evidence of LV enlargement and diastolic dysfunction, as well as elevated natriuretic peptide levels, including B-type natriuretic peptide (BNP) or NT-proBNP.⁶⁶

Contemporary diagnostic algorithms enhance precision by combining clinical features, imaging, and biomarkers. The H2FPEF score incorporates HTN, obesity, AF, age >60 years, PH, and elevated filling pressures to provide a non-invasive rule-in/rule-out tool.⁶⁷ The Heart Failure Association Pre-test Assessment, Echocardiography and natriuretic peptides, Functional testing, Final etiological work-up (HFA-PEFF) algorithm follows a stepwise approach using echocardiography and natriuretic peptides, with functional testing reserved for cases with intermediate probability.⁶⁰ Both scoring systems demonstrate robust diagnostic and prognostic utility, particularly when applied together.^60,67

Therapeutic Strategies

Upon confirmation of HFpEF, treatment aims to relieve symptoms and attenuate disease progression. Loop diuretics remain the cornerstone of congestion management; however, they do not improve long-term prognosis and require cautious use to prevent over-diuresis.⁵³ Neurohormonal modulation is advised for managing comorbidities. Mineralocorticoid receptor antagonists (MRAs) such as spironolactone reduced hospitalizations in specific subgroups of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT), although variable adherence and regional differences have limited their universal recommendation.^68,69 In the Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction (PARAGON-HF) trial, sacubitril–valsartan did not meet the primary efficacy endpoint in the overall study population. However, subgroup analyses indicated potential benefit among women and in patients with LVEF at the lower end of the preserved range.⁷⁰

SGLT2 inhibitors represent a major therapeutic advancement. In the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) trial, empagliflozin reduced the composite endpoint of CV death or HF hospitalization by about 21% in patients with LVEF > 40%. Similarly, in the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, dapagliflozin exhibited comparable benefits across the spectrum of preserved EF. These findings have supported robust guideline recommendations endorsing the use of SGLT2 inhibitors for the management of HFpEF.^71,72

Exercise-based rehabilitation improves functional capacity and QoL. The REHAB-HF trial demonstrated that tailored physical training enhanced mobility and psychosocial well-being in older HFpEF patients.⁷³ Device-based interventions, including percutaneous interatrial shunts, aim to reduce LV filling pressure and improve exercise tolerance in selected patients; however, long-term safety and efficacy data are still limited.⁷⁴

Comprehensive management necessitates the optimal management of prevalent comorbidities, including HTN, DM, CKD, and AF, while individualizing therapy according to metabolic, inflammatory, or fibrotic phenotypes. Such precision medicine approaches hold promise for the development of future personalized therapies for heart failure with preserved ejection fraction.

Follow-Up and Prognosis in HFpEF

HFpEF imposes a substantial long-term clinical burden. Despite diagnostic and therapeutic advances, prognosis remains poor, with mortality rates comparable to HFrEF.⁷⁵ Key determinants of outcomes include age, comorbidity burden, sex, and baseline functional status. Rehospitalization serves as a critical marker of disease severity and healthcare utilization. Contemporary registries report 30-day readmission rates of 18–23%, with nearly 50% of patients rehospitalized within one year.⁷⁶ Precipitants of recurrent hospitalizations include volume overload, exacerbations of comorbid conditions such as CKD and AF, and non-cardiac complications including infections and frailty-related syndromes.⁷⁷ These results underscore the multifactorial and systemic nature of HFpEF pathophysiology, which often limits the effectiveness of therapies targeting a single pathogenic mechanism.⁷⁸ Recurrent hospitalizations are independently associated with higher all-cause mortality and progressive functional decline, particularly in older adults.⁷⁹ Survival outcomes vary across populations and healthcare systems. Five-year all-cause mortality rates are estimated to range from 50% to 60%, largely driven by advanced age and a high burden of comorbidities.⁸⁰ About half of all deaths are attributable to cardiovascular causes, with the remainder related to renal disease, infections, and malignancies.⁸¹

Structured and proactive follow-up is essential for improving clinical outcomes and preserving QoL. Current guidelines recommend regular outpatient monitoring focused on fluid status, symptom assessment, and optimization of comorbidity management.¹⁵ Multidisciplinary care models that integrate cardiology, nephrology, geriatrics, nursing, and palliative care have been illustrated to reduce hospitalizations and improve patient-centered outcomes.⁸² Risk stratification tools, including the H2FPEF score and serial measurement of natriuretic peptides, assist in identifying high-risk patients and tailoring the intensity of follow-up.⁶⁷ In addition, telemonitoring and structured rehabilitation programs have been showento enhance treatment adherence and reduce adverse events among elderly populations.⁸³

HFpEF remains associated with an unfavorable prognosis, with increased risk of rehospitalization and mortality. Optimizing outcomes requires a multidisciplinary, personalized approach that integrates early risk stratification with evidence-based interventions. Recent studies underscore phenotypic heterogeneity and the influence of comorbidities such as obesity, DM, and AF on disease trajectory. Tailored management strategies addressing these diverse phenotypes are increasingly recognized as essential.^5,24,35 RCTs have demonstrated the efficacy SGLT2 inhibitors, including empagliflozin and dapagliflozin, in reducing the composite endpoint of CV death and HF hospitalization in patients with preserved EF, representing a major therapeutic advance in HFpEF care.^84,85 Angiotensin receptor–neprilysin inhibition with sacubitril/valsartan has shown variable benefits depending on sex and baseline LVEF, further underscoring the need for individualized treatment approaches.⁸⁶ Non-pharmacologic interventions, particularly structured rehabilitation and exercise training, consistently improve functional status and QoL and should be integrated into standard HFpEF management.^87,88 Emerging evidence also emphasizes the impact of psychosocial stressors, environmental exposures, and metabolic disturbances in younger populations, supporting the need for early detection and integrative management strategies tailored to this cohort.^43,58 Table 1 provides a chronological overview of selected landmark studies, focusing on those with significant impact on epidemiology, pathophysiology, diagnostics, and therapeutics.

Table 1 Chronological Overview of Selected Landmark Clinical Investigations in Heart Failure with Preserved Ejection Fraction (HFpEF)

Discussion

This systematic review synthesizes current evidence regarding the epidemiology, diagnosis, treatment approaches, follow-up, and prognosis of HFpEF, emphasizing recent therapeutic advances while also delineating persistent clinical management.

The accumulated data reinforce HFpEF as a complex, heterogeneous syndrome characterized by diverse clinical presentations and a high burden of comorbidities. Accurate diagnosis remains essential, increasingly supported by algorithms such as the H2FPEF score and the HFA-PEFF algorithm, which integrate clinical, imaging, and biomarker data to enhance diagnostic precision and prognostic stratification.^60,67

Therapeutically, SGLT2 inhibitors, including empagliflozin and dapagliflozin, have transformed HFpEF management by significantly reducing CV mortality and HF hospitalizations across a broad spectrum of preserved EF.^84,85 Other pharmacologic agents, including MRAs and sacubitril/valsartan, demonstrate more selective or subgroup-specific benefits.^68,87

While SGLT2 inhibitors now constitute the foundational pillar of HFpEF therapy with robust guideline recommendations (Class I, ESC/AHA), recent landmark trials have expanded therapeutic options targeting metabolic, inflammatory, and fibrotic pathways in specific phenotypes. The FINEARTS-HF trial (2024) established finerenone as the first nonsteroidal MRA to significantly reduce total worsening HF events—including hospitalizations—and CV death in patients with HFmrEF, with consistent benefits across EF ranges and favorable hyperkalemia risk under monitoring.^61,62 In obesity-related HFpEF, the STEP-HFpEF program demonstrated that semaglutide improved symptoms, physical function, exercise capacity, and reduced inflammation/weight, with pooled analyses showing lower risks of CV death or HF events.¹⁰² Similarly, the SUMMIT trial (2024–2025) reported that tirzepatide, a dual GLP-1/GIP receptor agonist, reduced the composite of CV death or HF worsening by about 38%, improved patient-reported health status, and mitigated circulatory overload and inflammation, achieving greater weight loss compared with semaglutide.^103,104 These findings underscore the heterogeneity of HFpEF and the potential for targeted metabolic and anti-fibrotic interventions, although no single agent is universally disease-modifying across all phenotypes. Integration with existing foundational therapies, such as SGLT2 inhibitors, requires careful consideration of comorbidities and vigilant monitoring.

Despite these therapeutic advances, rehospitalization rates remain high, and long-term outcomes are often poor, especially among patients with multimorbidity or frailty. These challenges highlight the critical role of multidisciplinary care models integrating cardiology, geriatrics, nephrology, and palliative care to optimize outcomes and reduce healthcare utilization.⁶ Additionally, nonpharmacologic interventions, notably structured exercise rehabilitation as demonstrated in the Rehabilitation Therapy in Older Acute Heart Failure Patients(Patients (REHAB HF) trial, improve physical function, QoL, and psychosocial well-being, emphasizing their integral role in routine care.⁸⁷

Knowledge Gaps and Future Directions

Notwithstanding significant progress, important gaps remain. The absence of a universally effective pharmacologic therapy across all HFpEF phenotypes underscores its conceptualization as a spectrum of overlapping pathophysiological processes rather than a single disease entity. Future research should focus on identifying reliable biomarkers and advanced imaging modalities to enable phenotype-driven stratification and targeted therapeutic interventions.

Emerging therapies include cellular approaches, epigenetic modifiers, and regulatory RNAs targeting maladaptive remodeling. The Phase 1b/2 trial of the microRNA132 inhibitor CDR-132L(CDR-132L (Phase 1b/2 trials of CDR-132L), a synthetic antisense oligonucleotide inhibiting miR-132, have demonstrated safety, sustained miR-132 suppression, and potential to prevent or reverse post-MI cardiac remodeling, with ongoing evaluation in the HF-REVERT trial (primarily HFrEF-focused, but potentially relevant to HFpEF fibrosis).^105,106 Fibroblast-targeted approaches, such as Fibroblast Activation Protein(FAP) imaging, antifibrotic strategies and, C-C Chemokine Receptor type 2(CCR2) inhibitors (targeting monocyte/macrophage recruitment in inflammation-driven HFpEF) are under investigation in preclinical and early-phase studies for anti-inflammatory and anti-fibrotic effects.^107,108 Pirfenidone, a Transforming Growth Factor-beta (TGF-β) inhibitor approved for idiopathic pulmonary fibrosis, has demonstrated preclinical card ioprotective effects by reducing cardiac fibroblast proliferation, myofibroblast differentiation, and myocardial fibrosis in animal models, supporting its potential rationale for HFpEF trials like PIROUETTE (though clinical data remain limited to modest changes in extracellular volume).^109–111

Sex-specific differences in treatment response, as observed in PARAGON-HF subgroup analyses, suggest hormonal and structural factors may confer differential benefit in women, warranting further investigation.⁸⁶ Moreover, frailty, sarcopenia, and cognitive impairment likely influence therapeutic outcomes but remain underexplored in clinical trial design and care pathways.

Device-based therapies, including interatrial shunt devices, represent a promising symptom-relief strategy in select patients. Early feasibility studies report favorable safety profiles and functional improvement at six months, while REDUCE LAP-HF II suggests potential benefit in carefully selected subgroups despite the trial not meeting its primary endpoint.¹¹² Furthermore, global disparities in HFpEF outcomes and access to care further emphasize the need for inclusive research encompassing low- and middle-income populations.

The future of HFpEF care will increasingly depend on precision medicine, integrating individualized treatment strategies guided by pathophysiology, comorbidity profiles, and patient preferences.

Limitations

This review has several limitations. Despite a comprehensive literature search, studies published in non-English languages or indexed outside the selected databases may have been inadvertently excluded. In addition, substantial heterogeneity in diagnostic criteria and outcome measures across the included studies limits direct comparisons and may reduce the generalizability of the findings. Given the rapidly evolving therapeutic landscape of heart failure with preserved ejection fraction, evidence published after completion of this review may not have been captured. Finally, although efforts were made to include data from diverse global populations, most available evidence originates from high-income countries, potentially limiting the applicability of the findings to low- and middle-income settings.

Conclusion

HFpEF represents a growing clinical and public health challenge due to its rising prevalence, diagnostic complexity, and limited availability of evidence-based therapies. Although recent advances have enhanced understanding of its heterogeneous pathophysiology, current management remains predominantly symptom-directed, with relatively few pharmacologic interventions demonstrating meaningful effects on hospitalization or mortality. The introduction of SGLT2 inhibitors represents a pivotal milestone, delivering clinically significant improvements in patient outcomes.

Optimal HFpEF management requires a comprehensive, individualized approach that addresses comorbidities, promotes lifestyle modification, and integrates emerging device-based therapies in carefully selected patients. Continued research into phenotype-specific pharmacologic and non-pharmacologic strategies is essential to improve long-term outcomes and reduce the societal and economic burden of HFpEF.