Introduction

Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex and increasingly prevalent clinical syndrome, accounting for approximately 50% of all HF cases. It is characterized by symptoms and signs of HF despite left ventricular ejection fraction of ≥50%, along with structural and / or functional cardiac abnormalities (such as left ventricular hypertrophy [LVH] or diastolic dysfunction) and / or elevated natriuretic peptide concentration, indicating cardiac stress or dysfunction.1,2 The epidemiology of HFpEF highlights its growing burden due to an aging population and the rising prevalence of comorbid conditions, such as hypertension, obesity, and diabetes mellitus.1 Pathophysiologically, HFpEF is characterized by diastolic dysfunction, increased left ventricular stiffness, microvascular dysfunction, and systemic inflammation, which contribute to elevated filling pressures and clinical symptoms such as dyspnea, fatigue, and exercise intolerance.2

HFpEF is closely linked to several metabolic and cardiovascular disorders, including type 2 diabetes mellitus (T2DM), hypertension, obesity, and atrial fibrillation (AF). T2DM promotes myocardial fibrosis, endothelial dysfunction, and systemic inflammation, all of which contribute to the pathogenesis of HFpEF.3 Hypertension is a major driver of LVH and arterial stiffness, exacerbating diastolic dysfunction and increasing the likelihood of HFpEF development.4 Obesity, particularly central adiposity, is associated with increased myocardial workload, inflammation, and altered cardiac metabolism, further predisposing individuals to HFpEF.5 AF, frequently observed in patients with HFpEF, worsens diastolic dysfunction by causing tachycardia-induced cardiomyopathy and a loss of atrial contraction, leading to further hemodynamic compromise.6

Recent advancements in HFpEF treatment suggest that addressing comorbidities can yield significant cardiovascular benefits. Sodium-glucose cotransporter-2 inhibitors (SGLT2is), originally developed for T2DM, have demonstrated substantial efficacy in reducing HF-related hospitalizations and mortality in patients with HFpEF.7 For example, empagliflozin and dapagliflozin have been shown to improve cardiac function, reduce fluid retention, and enhance exercise tolerance in patients with HFpEF, regardless of their diabetes status.8 Similarly, semaglutide a glucagon-like peptide-1 (GLP-1) receptor agonist (RA), has been associated with improved cardiac outcomes and weight reduction in individuals with obesity and HFpEF.9

Given the overlapping pathophysiological mechanisms between HFpEF and its comorbidities, the use of shared pharmacological interventions presents a promising therapeutic approach. SGLT2is, in particular, offer a dual benefit by not only improving glycemic control in T2DM but also reducing the burden of HFpEF through diuretic and cardioprotective effects.10 Integrating these therapies into a multidisciplinary treatment strategy could significantly enhance patient outcomes by simultaneously managing HFpEF and its associated metabolic disorders. The recognition of HFpEF as an interdisciplinary challenge underscores the need for collaborative management across cardiology, endocrinology, and internal medicine to optimize patient care.11

Heart failure with preserved ejection fraction: epidemiology and characteristics

HFpEF accounts for approximately half of all HF cases and is associated with significant morbidity and mortality.1 The pathophysiology of HFpEF is multifaceted, involving both cardiac and extracardiac factors. Central to HFpEF is diastolic dysfunction, where increased left ventricular stiffness impairs relaxation and filling during diastole. This stiffness is often a consequence of myocardial fibrosis and hypertrophy, leading to elevated filling pressures and subsequent symptoms, such as dyspnea and exercise intolerance.2 Beyond the myocardium, systemic inflammation plays a pivotal role in the pathogenesis of HFpEF. Comorbidities such as obesity, hypertension, and T2DM contribute to a proinflammatory state, which adversely affects endothelial function and promotes coronary microvascular dysfunction.4 This endothelial dysfunction further exacerbates myocardial stiffness and impairs cardiac output.12

Epidemiologically, HFpEF predominantly affects older adults, with a higher prevalence in women.13 The aging population and improved survival rates of other cardiovascular conditions have contributed to the increasing incidence of HFpEF. Comorbid conditions are highly prevalent in patients with HFpEF and significantly influence its development and progression,3 with hypertension,6 obesity,5 T2DM,14 and AF playing major roles.14,15 The intricate interplay between HFpEF and its comorbidities underscores the necessity for an interdisciplinary approach to management. Addressing these comorbid conditions is crucial, as they not only contribute to the development of HFpEF but also complicate its treatment and prognosis.16 HFpEF represents a significant and growing public health concern, intricately linked to various comorbidities through shared pathophysiological pathways. A comprehensive understanding of these interconnections is essential for developing effective, multidisciplinary management strategies aimed at improving patient outcomes.11

Hypertension in heart failure with preserved ejection fraction

Hypertension is the most frequent comorbidity in HFpEF and plays a crucial role in the pathogenesis and clinical manifestation of this syndrome.6 The sustained elevation in systemic blood pressure inherent to hypertension directly increases afterload on the left ventricle. This chronic pressure overload initiates a compensatory response, leading to LVH. While initially serving as an adaptive mechanism to maintain cardiac output, the LVH eventually becomes maladaptive, culminating in increased myocardial stiffness and impaired diastolic relaxation, leading to the development of HFpEF.6 Furthermore, hypertension induces systemic and coronary microvascular stiffness and endothelial dysfunction. Increased arterial stiffness elevates systolic blood pressure and increases wave reflection, further amplifying left ventricular afterload and stress.4 Concurrently, microvascular dysfunction, frequently exacerbated by hypertension, compromises myocardial perfusion and oxygen delivery, contributing to cardiomyocyte ischemia and fibrosis, and thereby exacerbating diastolic dysfunction.4,6 The persistent low-grade inflammation that accompanies hypertension also contributes to myocardial remodeling and fibrosis.3 Moreover, the renin-angiotensin-aldosterone system (RAAS), often intrinsically activated in hypertensive states, contributes to both the maintenance of elevated blood pressure and the promotion of myocardial fibrosis, establishing a detrimental positive feedback loop in HFpEF pathogenesis.4,6

Hypertension frequently coexists with other HFpEF risk factors, such as obesity and diabetes, creating a synergistic effect that exacerbates the severity of HFpEF.1 Individuals with hypertensive HFpEF often exhibit more pronounced symptoms of dyspnea, fatigue, and exercise intolerance. They are also at a heightened risk of hospitalizations due to HF and adverse cardiovascular events, as compared with patients with HFpEF and no history of hypertension.1-6 First-line antihypertensive treatment frequently employed in HFpEF includes diuretics, primarily to address volume overload, and RAAS inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), which aim to inhibit RAAS activation and its associated fibrotic effects.4,6 β-Adrenergic receptor blockers may be considered with caution, particularly in patients with coexisting conditions such as chronic obstructive pulmonary disease (COPD). However, in carefully selected patients with hypertensive HFpEF, these agents can be used for heart rate control and may offer potential antiremodeling benefits. Mineralocorticoid receptor antagonists (MRAs) also play a crucial therapeutic role, especially given the activation of aldosterone in both hypertension and HF.2 Calcium channel blockers (CCBs)—particularly dihydropyridine CCBs, which primarily act as vasodilators—can be incorporated as add-on agents to achieve optimal blood pressure control in HFpEF. Of note, SGLT2is not only provide HFpEF-specific benefits but also contribute to blood pressure reduction, offering a synergistic therapeutic effect in patients with hypertensive HFpEF.7-9 Nonpharmacological interventions, including dietary sodium restriction, weight management, regular physical exercise, and moderation of alcohol consumption, are indispensable lifestyle modifications that complement antihypertensive medications in the comprehensive management of hypertensive HFpEF.3 The intricate interplay between hypertension and HFpEF necessitates a comprehensive and individualized therapeutic approach, targeting both effective blood pressure control and the underlying pathophysiological mechanisms that drive HFpEF progression.

Type 2 diabetes mellitus and obesity in heart failure with preserved ejection fraction

Both obesity and T2DM significantly contribute to HFpEF pathogenesis, and their management can directly influence cardiovascular outcomes.1 Recent advancements in pharmacotherapy and lifestyle interventions offer promising strategies to mitigate the adverse effects of these metabolic disorders on cardiac function. SGLT2is have emerged as a cornerstone in the treatment of both T2DM and HFpEF. Initially developed for glycemic control, these agents have demonstrated significant cardiovascular benefits, including reduction in HF hospitalizations and improvement in diastolic function.2 Both dapagliflozin and empagliflozin have demonstrated a reduction in HF-related events regardless of diabetic status, supporting their role in the management of HFpEF.13,17,18 The cardioprotective effects of SGLT2is are attributed to multiple mechanisms, including reductions in preload and afterload, improvement in myocardial energetics, and attenuation of systemic inflammation.3

Another promising class of drugs for patients with HFpEF and obesity are GLP-1RAs. These drugs, such as semaglutide, have shown efficacy in weight reduction and improvement of metabolic parameters, which can indirectly benefit cardiac function.6 The SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial demonstrated that GLP-1RAs not only facilitate weight loss but also reduce cardiovascular events in patients with overweight and obesity, highlighting their potential role in HFpEF therapy.6 By modulating inflammatory pathways and reducing insulin resistance, GLP-1RAs may alleviate myocardial stiffness and improve left ventricular relaxation.14

Beyond pharmacotherapy, lifestyle interventions remain a cornerstone in managing HFpEF in patients with obesity and T2DM. Structured weight loss programs, including calorie restriction and physical activity, have been associated with improvements in exercise capacity and diastolic function.15 Bariatric surgery has also emerged as an effective intervention for severe obesity, demonstrating significant benefits in reducing HF incidence and improving cardiac structure and function.16 Additionally, dietary modifications, such as the Mediterranean diet, have been linked to improved metabolic health and cardiovascular outcomes in patients with HFpEF.7

Comprehensive management strategies targeting both metabolic and cardiovascular pathways are crucial for optimizing outcomes in patients with HFpEF and coexisting T2DM and obesity. The integration of pharmacological agents, such as SGLT2is and GLP-1RAs, with lifestyle modifications offers a synergistic approach to improving diastolic function and overall cardiovascular health.8,11

Atrial fibrillation in heart failure with preserved ejection fraction

AF exacerbates HFpEF pathophysiology by promoting left atrial enlargement, impairing ventricular filling, and increasing left ventricular end-diastolic pressures, leading to worsening symptoms and functional decline.1 The presence of AF in patients with HFpEF is associated with higher morbidity and mortality, highlighting the necessity for an optimized treatment approach.2 The management of AF in patients with HFpEF revolves around 3 key pillars: rhythm control, rate control, and anticoagulation. Rhythm control strategies, including catheter ablation and antiarrhythmic therapy, aim to restore sinus rhythm and improve hemodynamics.4 Catheter ablation has demonstrated potential benefits in improving exercise tolerance and reducing hospitalizations in selected patients with HFpEF and symptomatic AF.12 However, procedural success rates are lower in patients with HFpEF than in those with preserved diastolic function due to underlying myocardial fibrosis and atrial remodeling.13 Pharmacological rhythm control remains an alternative for patients in whom catheter ablation is not feasible. The use of antiarrhythmic drugs such as amiodarone and dronedarone is common; however, these agents must be used cautiously due to their potential proarrhythmic effects and systemic toxicity, particularly in older individuals with HFpEF.3 Rate control is often prioritized in patients with HFpEF and persistent AF, as adequate ventricular rate management can help reduce symptoms and prevent tachycardia-induced cardiomyopathy. β-Blockers and nondihydropyridine CCBs (eg, verapamil, diltiazem) are commonly used for rate control, but their effectiveness in HFpEF is variable, as excessive heart rate reduction may impair cardiac output in patients dependent on atrial contraction.6 Digoxin remains an option for rate control, particularly in patients with hypotension or those who cannot tolerate β-blockers, although its role in HFpEF remains controversial.5 Anticoagulant therapy is essential for stroke prevention in patients with AF and HFpEF, given the increased thromboembolic risk associated with both conditions.14 Direct oral anticoagulants, such as apixaban, rivaroxaban, and dabigatran, are preferred over vitamin K antagonists due to their superior safety profile and reduced risk of intracranial hemorrhage.15 The selection of an anticoagulant should be made after considering renal function, bleeding risk, and patient preferences.16 Recent studies have suggested that SGLT2is, initially developed for diabetes management, may have beneficial effects in patients with HFpEF and AF. These agents have demonstrated improvement in cardiac remodeling, diastolic function, and reduction in HF hospitalizations, suggesting a potential role in AF management within this population.7 Additionally, MRAs may provide benefit by reducing myocardial fibrosis and improving atrial structure and function.8

Chronic kidney disease

Chronic kidney disease (CKD) and HFpEF exhibit a particularly strong and bidirectional relationship. CKD is highly prevalent in HFpEF cohorts and is frequently observed in over half of patients. The compromised renal function in CKD directly contributes to the pathophysiology of HFpEF through several mechanisms. Fluid overload, a hallmark of both conditions, is exacerbated by impaired renal sodium and water excretion, leading to increased preload and ventricular wall stress.1,3 Furthermore, CKD activates the RAAS and the sympathetic nervous system, promoting vasoconstriction, sodium retention, and myocardial fibrosis, all of which worsen diastolic dysfunction.1,3 Systemic inflammation, a recognized driver of HFpEF pathophysiology, is also heightened in CKD, further contributing to myocardial injury and remodeling.3 The coexistence of CKD and HFpEF significantly worsens patient prognosis and is associated with an increased risk of hospitalization, cardiovascular events, and all-cause mortality.3 SGLT2is have emerged as a particularly promising therapeutic class in HFpEF. Clinical trials have demonstrated the efficacy of SGLT2is in reducing HF events in patients with HFpEF, irrespective of diabetes status.7,8 Importantly, publications emphasize the role of fibrogenesis and inflammation in the worsening of renal function in patients with HFpEF,19,20 while SGLT2is also confer renal protection and slow CKD progression.9 This dual benefit makes them particularly attractive for managing HFpEF in patients with concurrent CKD. Additionally, newer studies suggest that SGLT2is may have a beneficial impact on renal microcirculation, which is relevant in the pathophysiology of cardiorenal syndrome.21 Moreover, recent research suggests that abnormal calcium handling in cardiomyocytes may contribute to both cardiac and renal dysfunction in the context of HFpEF and CKD comorbidity.22 MRAs, while requiring careful monitoring of potassium concentration and renal function in patients with CKD, can also be beneficial. They have been shown to reduce cardiovascular events and HF hospitalizations in HFpEF.2 Newer selective MRAs, such as finerenone, have demonstrated significant clinical benefits. In patients with HF with mildly reduced or preserved ejection fraction, finerenone was associated with a reduction in worsening HF events and cardiovascular mortality.23 Additionally, in individuals with CKD and T2DM, it significantly decreased the risk of CKD progression and cardiovascular events.24

Chronic obstructive pulmonary disease

COPD is another prevalent comorbidity that frequently overlaps with HFpEF, leading to a significant burden of respiratory and cardiovascular morbidity. The shared risk factors of smoking and advanced age contribute to the frequent co-occurrence of these conditions.25 Dyspnea, a cardinal symptom of both COPD and HFpEF, often presents a diagnostic challenge in patients with both diseases, requiring careful clinical assessment and diagnostic testing to differentiate and manage each condition appropriately. COPD can contribute to the development and progression of HFpEF through several pathways. Chronic hypoxia and hypercapnia in COPD induce pulmonary vasoconstriction and remodeling, leading to pulmonary hypertension and increased right ventricular afterload. This, in turn, can impair left ventricular filling and contribute to diastolic dysfunction.25 Systemic inflammation, a prominent feature of COPD, may also directly contribute to myocardial inflammation and fibrosis, further promoting HFpEF pathophysiology.3 Furthermore, recent research highlights the role of oxidative stress in both COPD and HFpEF, suggesting a common mechanistic link.25

Patients with coexisting HFpEF and COPD often have a significantly diminished quality of life, characterized by increased dyspnea, exercise limitation, and frequent exacerbations of both respiratory and cardiac symptoms.26 The presence of COPD complicates the pharmacological management of HFpEF. β-Blockers, a cornerstone therapy in HF with reduced ejection fraction (HFrEF), are often used cautiously or avoided in COPD due to concerns about bronchospasm. While this approach is common in clinical practice, current guidelines suggest that cardioselective β-blockers can be safely used in many patients with COPD. SGLT2is, again, offer a potential therapeutic advantage, demonstrating benefits in HFpEF management7,8 and showing promise in reducing exacerbations and improving outcomes in COPD, although further research is needed to fully elucidate their role in COPD specifically.27 A holistic management strategy addressing both respiratory and cardiac components is crucial in these patients, often requiring a multidisciplinary approach involving cardiologists and pulmonologists. New publications emphasize the importance of pulmonary rehabilitation in patients with COPD and coexisting heart disease, as it can improve exercise tolerance and quality of life.26

Iron deficiency and anemia

Iron deficiency and anemia are increasingly recognized as important comorbidities in HFpEF, contributing to symptom burden, functional impairment, and adverse outcomes. Despite their clinical significance, they are often underdiagnosed and undertreated in this population. The interplay between iron deficiency / anemia and HFpEF is complex and multifaceted. Chronic inflammation, a central feature of HFpEF, disrupts iron homeostasis and impairs erythropoiesis, leading to anemia of chronic disease.3 Furthermore, HFpEF and its associated comorbidities, such as CKD and gastrointestinal disorders, can contribute to iron deficiency through impaired iron absorption, increased iron losses, and reduced erythropoietin production.26 Iron is essential for mitochondrial function and energy production in cardiomyocytes. Iron deficiency can directly impair myocardial contractility and relaxation, worsening diastolic dysfunction and contributing to HF symptoms.26 By reducing oxygen-carrying capacity, anemia further exacerbates myocardial ischemia and limits exercise tolerance in patients with HFpEF.26 Newer research emphasizes the role of iron deficiency in HFpEF pathophysiology, pointing to its impact on mitochondrial dysfunction and oxidative stress.27 Specifically, impaired iron use may contribute to exercise intolerance and fatigue in patients with HFpEF.22 Moreover, recent studies suggest a link between iron deficiency and adverse cardiac remodeling in HFpEF.25

Iron deficiency and anemia are strong independent predictors of adverse outcomes in HFpEF, including increased hospitalization rates and mortality. They significantly contribute to the hallmark symptoms of HFpEF, such as fatigue, dyspnea, and reduced exercise capacity, severely impacting patients’ quality of life. Current guidelines recommend routine screening for iron deficiency and anemia in all patients with HFpEF.26 New meta-analyses confirm the benefits of intravenous iron repletion in HFpEF, highlighting improvements in quality of life and reductions in hospitalizations.27 Oral iron supplementation may be less effective, particularly in the presence of inflammation-driven impaired iron absorption.15 Therefore, prompt diagnosis and targeted iron repletion strategies are crucial components of comprehensive HFpEF management. In the context of diagnosing iron deficiency, new research highlights the potential role of hepcidin as a diagnostic and prognostic marker in patients with HFpEF.28 Furthermore, ferric carboxymaltose has been shown to improve exercise capacity and reduce HF hospitalizations in patients with HFpEF and iron deficiency.29

Sleep apnea

Sleep apnea, particularly obstructive sleep apnea (OSA), is highly prevalent in patients with HFpEF, with estimates suggesting a higher incidence compared with patients with HFrEF.30 The relationship between OSA and HFpEF is bidirectional and mutually reinforcing. The intermittent hypoxia, sleep fragmentation, and surges in sympathetic nervous system activity characteristic of OSA contribute to the development and progression of several HFpEF risk factors, including systemic hypertension, pulmonary hypertension, and endothelial dysfunction.30 Increased negative intrathoracic pressure during obstructive apneic episodes places additional hemodynamic stress on the heart, further exacerbating cardiac dysfunction.30 Conversely, HFpEF can predispose individuals to OSA. Nocturnal fluid shifts from peripheral tissues to the neck, common in HFpEF due to recumbency and altered hemodynamics, can increase upper airway collapsibility, promoting obstructive events during sleep.31 Newer research points to a potential link between OSA and left ventricular remodeling in patients with HFpEF, suggesting an additional pathophysiological mechanism.30 In the context of OSA diagnosis in HFpEF, it is important to highlight the importance of polysomnography and alternative diagnostic methods.31 Furthermore, recent studies highlight the prevalence and clinical impact of sleep-disordered breathing, including central sleep apnea, in patients with HFpEF.32 Clinical guidelines emphasize the importance of screening for sleep apnea in patients with HFpEF, particularly in those presenting with suggestive symptoms, such as snoring, witnessed apneas, nocturnal awakenings, and excessive daytime somnolence.32 Continuous positive airway pressure (CPAP) therapy, the mainstay of OSA treatment, has been shown to improve symptoms, blood pressure control, and potentially cardiovascular outcomes in patients with HFpEF and coexisting OSA.31 Therefore, recognition and appropriate management of sleep apnea are integral to a comprehensive care strategy for patients with HFpEF. Moreover, recent studies explore the role of positional therapy and positional therapy devices in the management of OSA in patients with HFpEF, which may offer an alternative therapeutic option for those intolerant to CPAP.33 Importantly, new research highlights the potential benefits of adaptive servo-ventilation in carefully selected patients with HFpEF with central sleep apnea, suggesting a potential therapeutic avenue for this specific subgroup.32 Furthermore, managing risk factors for both OSA and HFpEF, such as obesity, is crucial in this population.34 The complex interplay between OSA and HFpEF necessitates a comprehensive and individualized management approach.31 Finally, future research should focus on developing personalized treatment strategies for sleep-disordered breathing in HFpEF, considering the diverse phenotypes and underlying mechanisms.31

Therapeutic strategies in heart failure with preserved ejection fraction addressing comorbidities

Several pivotal clinical trials have significantly advanced the treatment landscape of HFpEF by directly or indirectly addressing the impact of comorbidities. The EMPEROR-Preserved18 and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure)17 trials, which evaluated empagliflozin and dapagliflozin, respectively, stand out by demonstrating the efficacy of SGLT2is across a broad spectrum of patients with HFpEF, irrespective of diabetes status, thus targeting the intertwined burden of hyperglycemia and HFpEF. Similarly, trials investigating tirzepatide9 in individuals with obesity and HFpEF highlight the potential of addressing obesity—a key comorbidity—to improve cardiac outcomes and reduce weight burden in this population. Furthermore, while not explicitly targeting a single comorbidity, the VICTORIA-HF (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial,35 which assessed vericiguat, enrolled a broad HFpEF population often characterized by multiple coexisting conditions, suggesting that the benefits of soluble guanylate cyclase stimulation may extend across diverse comorbidity profiles. These landmark trials collectively underscore the importance of therapeutic strategies in HFpEF that not only address core cardiac dysfunction but also actively manage the prevalent and impactful comorbidities significantly contributing to the complexity of this syndrome.

Conclusions

HFpEF is a multifaceted syndrome significantly influenced by various comorbidities, including hypertension, T2DM, obesity, AF, CKD, COPD, iron deficiency, and sleep apnea. Each of these conditions contributes to the progression and symptom burden of HFpEF through distinct yet interrelated mechanisms, necessitating a comprehensive and individualized therapeutic approach. Pharmacological advances, particularly SGLT2is, GLP-1RAs, and MRAs, have emerged as promising therapies, offering benefits that extend beyond their primary indications to improve cardiovascular outcomes in HFpEF. Additionally, nonpharmacological strategies, including lifestyle modifications, pulmonary rehabilitation, weight management, and iron repletion, play a crucial role in optimizing patient care. Given the heterogeneous nature of HFpEF, future research should focus on personalized treatment approaches that address both the underlying cardiac dysfunction and the specific comorbidities contributing to disease progression. A multidisciplinary strategy integrating cardiology, nephrology, endocrinology, pulmonology, and sleep medicine is essential for improving outcomes and enhancing the quality of life in patients with HFpEF.