Metabolic dysfunction-associated steatotic liver disease and the heart

Abstract

The prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) are increasing. Physicians who treat patients with MASLD may acknowledge the strong coincidence with cardiometabolic disease, including atherosclerotic cardiovascular disease (asCVD). This raises questions on co-occurrence, causality, and the need for screening and multidisciplinary care for MASLD in patients with asCVD, and vice versa. Here, we review the interrelations of MASLD and heart disease and formulate answers to these matters. Epidemiological studies scoring proxies for atherosclerosis and actual cardiovascular events indicate increased atherosclerosis in patients with MASLD, yet no increased risk of asCVD mortality. MASLD and asCVD share common drivers: obesity, insulin resistance and type 2 diabetes mellitus (T2DM), smoking, hypertension, and sleep apnea syndrome. In addition, Mendelian randomization studies support that MASLD may cause atherosclerosis through mixed hyperlipidemia, while such evidence is lacking for liver-derived procoagulant factors. In the more advanced fibrotic stages, MASLD may contribute to heart failure with preserved ejection fraction by reduced filling of the right ventricle, which may induce fatigue upon exertion, often mentioned by patients with MASLD. Some evidence points to an association between MASLD and cardiac arrhythmias. Regarding treatment and given the strong co-occurrence of MASLD and asCVD, pharmacotherapy in development for advanced stages of MASLD would ideally also reduce cardiovascular events, as has been demonstrated for T2DM treatments. Given the common drivers, potential causal factors and especially given the increased rate of cardiovascular events, comprehensive cardiometabolic risk management is warranted in patients with MASLD, preferably in a multidisciplinary approach.

FIGURE 1

MASLD and asCVD are both multifactorial diseases. The epidemiological relations between MASLD and asCVD are in part explained by common pathophysiological drivers occurring predominantly in the setting of obesity. Abbreviations: AGE, advanced glycation end products; AMPKα, 5’ adenosine monophosphate-activated protein kinase α; asCVD, atherosclerotic cardiovascular disease; FFA, free fatty acid; NO, nitric oxide; LPS, lipopolysaccharide; MASLD, metabolic dysfunction–associated steatotic liver disease; OSAS, obstructive sleep apnea syndrome; RAAS, renin-angiotensin-aldosterone system.

FIGURE 2

MASLD susceptibility genes can have different effects on coronary artery disease, depending on the different types of pleiotropy that can occur. When gene variants affect two or more phenotypic traits, pleiotropy occurs. Vertical pleiotropy happens when traits are further downstream in a physiological pathway and do not invalidate Mendelian randomization assumptions. SNPs that predispose to MASLD through VLDL impairment, simultaneously might lower plasma lipids and create horizontal pleiotropy, therefore invalidating Mendelian randomization assumptions. Abbreviations: FFA, free fatty acid; MASLD, metabolic dysfunction–associated steatotic liver disease; SNP, single nucleotide polymorphism.

FIGURE 3

Cardiac remodelling and MASLD have several common pathophysiological drivers and can both lead to HFpEF. Cardiac remodelling occurs through structural changes, which lead to functional alterations and, subsequently, HFpEF. MASLD leads to hepatic flow obstruction due to increased vascular resistance, resulting in preload reserve failure. Abbreviations: HFpEF, heart failurewith preserved ejection fraction; LV, left ventricle; MASLD, metabolic dysfunction–associated steatotic liver disease; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.