Inflammation and mitochondrial dysfunction in cirrhotic cardiomyopathy: Therapeutic implications

Cirrhotic cardiomyopathy (CCM) is a serious cardiac complication affecting patients with cirrhosis, characterized by impaired contractile response, diastolic dysfunction, and electrophysiological abnormalities such as QT interval prolongation. Despite its high reported prevalence (26–81%), the precise mechanisms driving CCM remain unclear, and no specific preventive treatments exist. This study aimed to investigate the dynamic progression of CCM in a bile duct ligation (BDL) mouse model and correlate findings with clinical data from cirrhosis patients, focusing on the roles of inflammation and mitochondrial dysfunction.

Methods
An eight-week longitudinal study was conducted using a BDL-induced cirrhosis model in male C57BL/6J mice. Cardiac function was assessed via echocardiography, electrocardiography, serum biomarkers (e.g., BNP, troponin I), and treadmill exercise tests. Histopathological evaluation (H&E, Masson’s trichrome, Sirius Red, TUNEL, immunohistochemistry) and Western blotting were used to analyze myocardial structure, apoptosis, fibrosis, inflammation (IL-1β, IL-6, TNF-α, p65), and mitochondrial markers (CPT1A, PPARα, HK2, PKM2, LDHA). Additionally, echocardiographic and biochemical data were collected from 65 cirrhosis patients and 39 healthy controls.

Results
Animal Model Findings:

1. Progressive Cardiac Dysfunction: BDL mice developed significant diastolic dysfunction (reduced E/A ratio, increased E/e' ratio), hypotension, prolonged QTc interval, and reduced exercise capacity over eight weeks. Notably, ejection fraction (EF) was paradoxically increased, attributed to reduced left ventricular volumes and myocardial atrophy rather than preserved systolic function.

2. Structural and Cellular Remodeling: The heart exhibited progressive atrophy (reduced heart weight/tibia length ratio, decreased cardiomyocyte diameter), apoptosis (increased Bax, caspase-3; decreased Bcl-2), and interstitial/perivascular fibrosis (elevated α-SMA, Col1a1, TGF-β1).

3. Inflammatory Activation: Myocardial levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and NF-κB p65 phosphorylation were significantly elevated, indicating sustained inflammatory signaling.

4. Mitochondrial Dysfunction and Metabolic Shift: Severe mitochondrial damage (swelling, cristae rupture) was observed alongside decreased expression of fatty acid oxidation markers (CPT1A, PPARα) and increased glycolytic enzymes (HK2, PKM2, LDHA), suggesting a shift from oxidative metabolism to glycolysis (Warburg effect).

Clinical Patient Findings:
Cirrhosis patients displayed impaired cardiac structure (increased left ventricular wall thickness, left atrial diameter) with preserved EF. In decompensated cirrhosis patients, total bilirubin and total bile acid levels were significantly elevated and positively correlated with BNP levels and echocardiographic indicators of chamber dilation, linking cardiac dysfunction directly to cirrhosis severity.

Discussion
The study confirms that CCM involves a complex interplay of structural, inflammatory, and metabolic pathologies. The observed myocardial atrophy in mice contrasts with the hypertrophy often seen in human CCM, potentially explaining the discrepant EF findings. This highlights model-specific differences but underscores shared pathways of injury.
Key mechanistic insights include:

• Fibrosis and Apoptosis: Progressive collagen deposition and cardiomyocyte loss contribute directly to ventricular stiffening and systolic/diastolic impairment.

• Inflammation as a Driver: Elevated cytokines and activated NF-κB signaling promote both structural damage and mitochondrial dysfunction.

• Metabolic Reprogramming: The shift from fatty acid oxidation to glycolysis reflects mitochondrial injury and may exacerbate energy deficiency in the high-demand cardiac tissue.

The positive correlation between liver dysfunction markers (bilirubin) and cardiac stress markers (BNP) in patients reinforces the concept of a liver-heart axis, where cirrhotic severity directly impacts cardiac health.

Conclusions
CCM progression is closely associated with the severity of cirrhosis and is driven by a cascade of myocardial atrophy, apoptosis, fibrosis, inflammation, and mitochondrial dysfunction. The BDL mouse model effectively recapitulates key features of CCM, particularly the inflammatory and metabolic disturbances. In patients, cardiac dysfunction correlates with the degree of liver impairment, emphasizing the need for routine cardiac monitoring in cirrhosis management. Future therapeutic strategies should target these interconnected pathways—particularly inflammation and mitochondrial metabolism—to mitigate cardiac damage in cirrhosis.

Full text

https://www.xiahepublishing.com/2310-8819/JCTH-2025-00237

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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