Heart failure with preserved ejection fraction and metabolic dysfunction-associated steatotic liver disease: Twin challenges, one metabolic solution

Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) has exceeded HF with reduced ejection fraction (HFrEF), becoming the most common type of HF. Unlike HFrEF, HFpEF is primarily a chronic low-grade inflammatory process closely associated with metabolic disorders. The coexistence of HFpEF and metabolic dysfunction-associated steatotic liver disease (MASLD) presents significant clinical challenges due to shared metabolic pathophysiology and complex interplay. Management strategies for HFpEF and MASLD remain challenging. Sodium-glucose cotransporter 2 inhibitors have shown benefits in managing both conditions. Additionally, glucagon-like peptide-1 receptor agonists are being actively investigated for their potential benefits, particularly in MASLD. A comprehensive, patient-centered approach that combines metabolic and cardiovascular care is essential for improving outcomes in patients with HFpEF and MASLD, addressing the global metabolic health challenges.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Heart failure; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Sodium-glucose cotransporter 2 inhibitors

Core Tip: The coexistence of heart failure with preserved ejection fraction (HFpEF) and metabolic dysfunction-associated steatotic liver disease (MASLD), poses significant clinical challenges due to their intricate relationship and similar metabolic pathophysiology. Clinical management strategies for HFpEF and MASLD still faces challenges. Sodium-glucose cotransporter 2 inhibitors showing benefits in HFpEF or MASLD, while other drugs, such as glucagon-like peptide-1 receptor agonists and statins remains under investigation. A holistic, patient-centered approach combining metabolic and cardiovascular care is vital for improving HFpEF and MASLD outcomes in global metabolic health challenges.

TO THE EDITOR

Heart failure (HF) and chronic liver disease frequently coexist due to the impact of systemic disorders on both organs and the intricate interplay between cardiovascular and hepatic systems[1]. Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, has become the most prevalent chronic liver disease globally[2]. This change in nomenclature is crucial as it highlights the association between MASLD and metabolic dysfunction, which is also implicated in cardiovascular complications, notably HF[3,4]. As highlighted in the recent letter by Hirao et al[5] in the World Journal of Cardiology, the interplay between MASLD and HF is complex and multifaceted.

METABOLIC DYSFUNCTION: LINKING HF WITH PRESERVED EJECTION FRACTION AND MASLD

Historically, HF with reduced ejection fraction (HFrEF) has garnered more attention. However, HF with preserved ejection fraction (HFpEF), a form of HF characterized by preserved systolic function but significant diastolic dysfunction, is increasingly recognized due to its rising prevalence. Epidemiological studies indicated that HFpEF now accounts for over 50% of HF population, with mortality risks comparable to those of HFrEF[6,7].

Metabolic dysfunction is a key factor linking HFpEF and MASLD. Unlike HFrEF, HFpEF is strongly associated with metabolic disorders such as obesity, diabetes, hypertension, and MASLD[8-11]. These comorbidities trigger chronic inflammation and oxidative stress, leading to myocardial hypertrophy and stiffness[6,12]. Additionally, high-sensitivity C-reactive protein has been found to be associated with HF hospitalization in patients with MASLD and normal left ventricular ejection fraction (LVEF). MASLD progression, characterized by hepatic steatosis, fibrosis, and inflammation, is influenced by systemic inflammation and inflammatory cell migration[13]. Serum bile acid profiles have been found to be associated with HFpEF in patients with MASLD, further highlighting the metabolic connection. Notably, up to 50% of HFpEF patients are diagnosed with MASLD, a prevalence much higher than in HFrEF patients[14]. This significant overlap suggests that the pathophysiological processes of HFpEF and MASLD are deeply intertwined, primarily through shared metabolic and inflammatory pathways. Building on this strong metabolic connection, ectopic fat accumulation further reinforces the interplay between HFpEF and MASLD[15]. Epicardial fat, in particular, is a critical mediator, with HFpEF patients exhibiting significantly greater epicardial fat burden than those with HFrEF[16]. This fat depot releases proinflammatory and profibrotic factors, promoting myocardial fibrosis and contributing to the diastolic dysfunction characteristic of HFpEF. Additionally, epicardial fat may physically restrict cardiac expansion, exacerbating HFpEF pathophysiology[17].

The "obesity paradox" further complicates the understanding of the relationship between HFpEF, MASLD, and metabolic dysfunction. Obese HF patients, including those with HFpEF and HFrEF, tend to have a lower mortality rate than patients with normal body mass index[18,19]. Studies have found that the obesity paradox is more strongly associated with HFpEF than HFrEF[20]. Proposed explanations include the anti-inflammatory properties of adiponectin, increased lipoprotein levels, and a diminished responsiveness of the renin-angiotensin–aldosterone system[21,22]. While obesity is a major risk factor for MASLD and can increase mortality rates[23], the presence of the obesity paradox in HFpEF makes it challenging to fully comprehend how obesity impacts outcomes in patients with both HFpEF and MASLD.

CHALLENGS IN DIAGNOSIS OF HFPEF IN THE MASLD POPULATION

Currently, the diagnosis of HFpEF mainly relies on patients' clinical manifestations, LVEF ≥ 50% and objective evidence of cardiac structural and/or functional abnormalities consistent with the presence of LV diastolic dysfunction/ raised LV filling pressures, including raised N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels[7]. As resistance in hepatic sinusoids increases in MASLD, a decreased preload would be anticipated, leading to lower intracardiac pressure and subsequently reduced levels of NT-proBNP[24]. Furthermore, as MASLD progresses and more venous return impedance occurs, NT-proBNP levels are expected to decrease even further. Therefore, the use of natriuretic peptides in screening for and diagnosing HFpEF in patients with MASLD may yield misleading results. Identifying high-risk HFpEF populations in MASLD is crucial because, in the early stages of MASLD and HFpEF, when symptoms are absent, most patients are unlikely to seek medical attention. Early identification could facilitate targeted interventions, such as lifestyle modifications and lipid control, to prevent disease progression. Further in-depth research is needed to develop more accurate screening tools and diagnostic criteria for this patient group. Diagnostic algorithms such as HFA-PEFF and have been developed to identify HFpEF noninvasively[25,26]. While diagnostic algorithms have been developed to identify HFpEF noninvasively, these algorithms may not be directly applicable to the MASLD population.

The characteristics of HFpEF patients whose LVEF later transforms into the HFrEF population, as well as their association with MASLD and clinical prognosis, require further investigation. Previous studies had inconsistent results regarding the change of LVEF in HFpEF group[27-29]. When HFpEF is combined with MASLD, the situation may become even more intricate. Moreover, the question of whether HFpEF patients whose LVEF transiently falls into the HFrEF range can still be diagnosed with HFpEF also needs further exploration.

POTENTIAL CLINICAL MANAGEMENT OF HFpEF AND MASLD

The coexistence of HFpEF and MASLD presents unique challenges due to their shared metabolic and inflammatory pathways. These overlapping mechanisms necessitate distinct management strategies that address both cardiac and hepatic dysfunction. Non-pharmacological treatments form the foundation of MASLD management, primarily encompassing dietary modifications, weight loss through exercise, caloric restriction, and bariatric surgery[23,30]. These approaches are not only effective in treating MASLD but have also demonstrated potential in slowing the progression of HFpEF[10].

For HFpEF, traditional HF therapies have shown limited success due to the distinct metabolic nature of the disease[7,31]. However, Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have emerged as the only treatment with strong evidence of benefit, as demonstrated in the EMPEROR-Preserved and DELIVER trials[32,33]. These studies showed that SGLT-2is significantly reduced HF hospitalizations and cardiovascular mortality in patients with LVEF > 40%. Consequently, SGLT-2is are now recommended as first-line therapy for HFpEF[7]. For patients with both HFpEF and MASLD, SGLT-2is offer additional advantages. While they are not yet specifically indicated for MASLD or MASH, the EASL-EASD-EASO guidelines recognize their safety and encourage their use for approved indications, such as HF[23]. This dual benefit makes SGLT-2is the preferred therapeutic option for managing these overlapping conditions.

Emerging therapies, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), may also hold promise in this context. GLP-1 RAs have shown benefits in improving metabolic dysfunction and liver outcomes in MASLD, and early evidence suggests potential cardiovascular effects in HFpEF[34]. However, GLP-1 RAs may cause a decrease in skeletal muscle mass, which may affect exercise ability and quality of daily life[35]. While muscle mass and strength are generally positively correlated, they don't always change in proportion due to factors like obesity, metabolic issues, or aging. It's possible that even with a reduction in total muscle mass, improvements in muscle composition could enhance muscle quality. This, in turn, could improve body composition and potentially maintain or even boost muscle functions, including strength. Recent animal study showed that semaglutide treatment resulted in smaller cardiomyocytes and reduced heart mass in both obese and lean mice, but it had no significant effect on cardiac function[36]. However, recent STEP-HFpEF Program revealed that semaglutide appeared to improve adverse cardiac remodeling compared with placebo, but the short follow-up time limits the strength of this evidence[37]. Given the potential of GLP-1RAs to alter cardiac structure, particularly in settings where cardiac mass may be reduced, it is crucial to carefully evaluate cardiac structure and function in both previous and ongoing clinical studies. This is especially important as GLP-1RAs are increasingly used and endorsed by guidelines for patients both in MASLD and cardiovascular disease patients.

Other potential drugs for MASLD patients with HFpEF, such as statins, metformin, and renin-angiotensin aldosterone system inhibition with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, may offer benefits[38-40]. However, further randomized controlled trials (RCTs) are necessary to confirm the efficacy and potential risks of these drugs in MASLD patients with HFpEF.

CONCLUSION

The effective management of MASLD with HFpEF requires a comprehensive approach that acknowledges the interplay between metabolic dysfunction and cardiac pathology. SGLT-2is currently represent the cornerstone therapy for HFpEF, with potential benefits in MASLD. Emerging therapies, such as GLP-1 RAs and statins, warrant further exploration. Bridging the current gaps in evidence through robust RCTs will be essential for improving outcomes in this complex patient population.