CCM remains a multifaceted and incompletely understood complication of advanced liver disease, characterized by subtle yet clinically significant alterations in cardiac structure and function. This review is intended to synthesize the current body of evidence regarding the diverse molecular, cellular, and hemodynamic mechanisms responsible for the development of CCM, with particular emphasis on both well-established pathways and emerging insights from recent research. By critically examining these mechanisms, we aimed to clarify how cirrhosis exerts its detrimental cardiac effects, identify inconsistencies in the literature, and highlight areas that warrant further investigation to allow a more accurate diagnosis and targeted therapeutic strategies.

With regard to the role of beta-adrenergic receptors, the mechanisms contributing to the development of CCM are both complex and multifactorial. Consistent with our research, recent studies by Ryu et al. [78] and Liu et al. [79] have demonstrated similar findings, underscoring the intricate interplay between altered beta-adrenergic signaling and cardiac dysfunction in cirrhosis. Specifically, Ryu et al. reported that chronic sympathetic overactivity in cirrhotic patients leads to beta-adrenergic receptor desensitization and downregulation, thereby impairing myocardial contractility and contributing to the blunted cardiac response to stress [78].

Similarly, Liu et al. highlighted the role of altered beta-adrenergic receptor density and downstream signaling pathways, which exacerbate myocardial dysfunction and increase susceptibility to hemodynamic instability in advanced liver disease [79]. Together, these observations emphasize the pivotal role of beta-adrenergic dysregulation in the pathophysiology of CCM and point to the need for therapeutic strategies that address this maladaptive response. Furthermore, with respect to muscarinic receptors, this review also highlights recent research that has advanced our understanding of their role in the pathogenesis of CCM. Additionally, this our research draws attention to recent advances in the understanding of muscarinic receptors and their involvement in the pathophysiology of CCM. Recent studies have demonstrated that dysregulation of muscarinic receptor signaling may contribute to impaired autonomic balance and exacerbate myocardial dysfunction in cirrhosis, highlighting the need for continued research into their potential as diagnostic or therapeutic targets [79].

The involvement of voltage-gated ion channels in the pathogenesis of CCM is described in both of the aforementioned reviews, as well as in the study by Desai et al. [80]. These channels play a critical role in regulating myocardial excitability and contractility, and their dysfunction in cirrhosis has been associated with altered calcium handling, impaired action potential propagation, and an increased susceptibility to arrhythmias. By disrupting normal ion fluxes, cirrhosis-induced changes in channel expression and function may contribute to the development of both systolic and diastolic dysfunction, further aggravating cardiac performance in affected patients.

Notably, the last five years have witnessed a marked surge in preclinical and clinical studies that have expanded our understanding of the multifaceted pathways underlying myocardial dysfunction in cirrhosis.

Emerging evidence has refined classical concepts of autonomic dysregulation and β-adrenergic receptor desensitization by integrating novel insights into inflammatory mediators, fibrotic remodeling, ion channel dysregulation, and the role of key molecular pathways such as the P2X7 receptor, CD73(5’-nucleotidase, ecto-5’-nucleotidase)–A2AR axis, galectin-3 signaling, and the endocannabinoid system. Collectively, these discoveries highlight the intricate interplay between chronic systemic inflammation, maladaptive neurohumoral responses, and progressive myocardial structural alterations.

The activation of the purinergic–adenosinergic axis may interface with other key pathways involved in cirrhosis-induced myocardial injury, including TGF-β1 signaling, Notch1 suppression through epigenetic regulation, and the activation of P2X7R-mediated inflammatory pathways. Together, these interconnected pathways create a self-amplifying loop of sterile inflammation, fibroblast activation, and maladaptive cardiac remodeling. The ability of CD73(5’-nucleotidase, ecto-5’-nucleotidase) to shift this balance by enhancing local adenosine generation suggests a promising target for interrupting this cycle at multiple levels.

Parallel to these receptor-level changes, inflammation-driven molecular alterations have also emerged as critical contributors. TGF-β1, a well-established profibrotic cytokine, was shown by Sun et al. [64] to regulate cardiac fibrosis epigenetically in cirrhosis. Their work revealed that TGF-β1 suppresses Notch1 signaling through activation of the DNMT3A/MeCP2 epigenetic axis, resulting in Notch1 promoter methylation and pathological cardiac remodeling.

Adding further complexity to CCM pathogenesis, recent studies implicate purinergic signaling and immunometabolic pathways as critical modulators of myocardial injury and repair. CD73, an ecto-5’-nucleotidase that catalyzes the conversion of ATP to adenosine, plays a cardioprotective role by regulating inflammation. Activation of CD73(5’-nucleotidase, ecto-5’-nucleotidase) in a murine CCM model suppressed myocardial apoptosis and reduced pro-inflammatory cytokine production. These effects are mediated via A2A adenosine receptor signaling, which promotes an anti-inflammatory milieu and facilitates tissue repair. The CD73(5’-NUCLEOTIDASE, ECTO-5’-NUCLEOTIDASE)–adenosine axis likely intersects with other key pathways—including TGF-β1–Notch1 epigenetic suppression and P2X7 receptor (P2X7R)-mediated inflammasome activation—to create a self-amplifying loop of fibrosis, inflammation, and cardiac dysfunction.

Galectin-3 (Gal-3) has emerged as a central mediator of myocardial inflammation and fibrosis in cirrhotic cardiomyopathy (CCM), underscoring its dual role as both a pathogenic effector and a potential biomarker. Pharmacologic inhibition of Gal-3 resulted in reduced myocardial levels of TNF-α and brain natriuretic peptide (BNP), along with a marked improvement in systolic function and systemic blood pressure. These findings implicate Gal-3 as a key upstream regulator of the inflammatory-fibrotic axis in CCM, with direct effects on ventricular remodeling. Given its established role in cardiac fibrosis and heart failure in non-cirrhotic populations, Gal-3 may represent a novel therapeutic target in patients with cirrhosis who are at risk of cardiovascular complications. Its detectability in serum further supports its utility as a non-invasive biomarker for early CCM detection and progression monitoring, potentially guiding risk stratification in transplant candidates.

In parallel, myofibrillar remodeling has been identified as a structural correlate of myocardial dysfunction in CCM. Significant shifts in myosin heavy chain isoform expression, alongside abnormalities in calcium transients, contribute to a protracted systolic and diastolic phase, reduced contractile force, and a blunted force–frequency relationship. These alterations mirror the maladaptive remodeling seen in heart failure with preserved ejection fraction (HFpEF), reinforcing the notion that CCM shares pathophysiological features with classic cardiomyopathies. The presence of these cellular-level abnormalities underscores the chronicity and irreversible nature of myocardial involvement in advanced cirrhosis and highlights the urgent need for early detection and therapeutic intervention before irreversible remodeling occurs. Collectively, these findings emphasize that beyond hemodynamic dysregulation, inflammatory, metabolic, and structural changes converge to create a heart failure phenotype in CCM, with Gal-3 and myofibrillar remodeling representing key mechanistic and translational targets for future research.

Cannabinoid receptor signaling has also been shown to influence cardiac function in cirrhosis. Gaskari et al. [46] demonstrated that activation of CB1 receptors in cirrhotic rats leads to suppressed β-adrenergic responsiveness and reduced inotropy. In contrast, CB2 receptor activation, as shown by Matyas et al. [72], ameliorated hepatic inflammation, oxidative stress, and myocardial dysfunction, suggesting differential therapeutic potentials of cannabinoid receptor subtypes.

Taken together, these findings underscore the multifactorial nature of CCM, where structural, neurohumoral, inflammatory, and epigenetic mechanisms converge to promote myocardial dysfunction. Although animal models have been instrumental in elucidating these pathways, limitations persist. Standard models such as bile duct ligation (BDL) or carbon tetrachloride (CCl₄) exposure do not capture the complexity of human cirrhosis etiologies (e.g., NAFLD, viral hepatitis, alcohol) or associated comorbidities. This etiological mismatch hinders translation of preclinical insights into clinical practice.

Future studies should prioritize the development of comorbidity-inclusive and etiology-specific models, alongside clinical stratification of CCM patients by underlying liver disease type. Integrating mechanistic insights with biomarker discovery—such as anti-β1-AR, Gal-3, CD73(5’-NUCLEOTIDASE, ECTO-5’-NUCLEOTIDASE), and TGF-β1/Notch1 epigenetic profiles—may enable earlier diagnosis and targeted intervention. The expanding recognition of immune-metabolic pathways and receptor-based signaling cascades offers fertile ground for precision medicine approaches in CCM management.

Animal models have been instrumental in elucidating the pathophysiology of cirrhotic cardiomyopathy (CCM). Commonly used models include bile duct ligation (BDL) and carbon tetrachloride (CCl₄) administration in rodents, which reliably induce cirrhosis and its hemodynamic sequelae [81]. However, several limitations restrict the translatability of these findings to humans.

First, the progression of cirrhosis in animal models occurs over weeks, whereas human cirrhosis develops over years or decades, with multiple insults and fluctuating disease activity [82]. Second, animal models generally lack comorbidities prevalent in patients with cirrhosis, such as alcohol consumption, metabolic syndrome, or cardiac risk factors, which significantly influence myocardial function. Third, interspecies differences in cardiac electrophysiology, neurohumoral regulation, and myocardial architecture further complicate direct extrapolation. Moreover, most animal studies utilize young, genetically homogeneous subjects under controlled conditions—a stark contrast to the heterogeneous, often elderly, and medically complex human population.

A critical yet often overlooked obstacle in CCM research is the fundamental difference in cirrhosis etiology between humans and animal models.

Human cirrhosis is highly heterogeneous in cause and progression. Major etiologies include chronic viral hepatitis (HBV, HCV), alcohol-associated liver disease (ALD), non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), autoimmune and cholestatic liver diseases, and genetic disorders (e.g., hemochromatosis, Wilson’s disease). Many of these factors can directly or indirectly affect the heart—for example, chronic alcohol misuse may cause alcoholic cardiomyopathy regardless of cirrhosis, while iron overload in hemochromatosis can induce restrictive cardiomyopathy. In contrast, experimental cirrhosis is typically induced by a single, controlled mechanism. Hepatotoxins such as carbon tetrachloride (CCl₄) or thioacetamide (TAA) cause direct liver injury; bile duct ligation (BDL) models pure cholestatic fibrosis. Reliable ethanol-induced cirrhosis in rodents is difficult to achieve without co-toxins and rarely mimics the metabolic context of human ALD. Similarly, chronic viral hepatitis models are impractical in most species due to host barriers.

These etiological gaps matter. For example, CCM in NAFLD (non-alcoholic fatty liver disease)/NASH (non-alcoholic steatohepatitis) patients may overlap with metabolic cardiomyopathy driven by obesity, diabetes, and atherosclerosis—factors largely absent in standard rodent toxin models. BDL (bile duct ligature) models overrepresent cholestasis, which accounts for only a minority of cirrhosis cases in clinical practice. Such mismatches limit the direct applicability of experimental findings.