Myocardial Infarction Accelerates the Progression of Metabolic Dysfunction-Associated Steatohepatitis by Inducing Immune Inflammatory Response and Periostin

Background and Study Motivation

Metabolic-associated steatohepatitis (MASLD, formerly NAFLD) is one of the most common chronic liver diseases worldwide, affecting about 25% of the adult population. MASLD is not only bidirectionally related to various components of metabolic syndrome but is also considered a significant contributor to additional comorbidities like cardiovascular disease (CVD), diabetes, and chronic kidney disease. Related studies indicate that patients with more advanced forms of MASLD have a higher risk of all-cause mortality, with cardiovascular disease being the primary cause of death. Nevertheless, it remains unclear whether cardiovascular events conversely affect the pathological progression of MASLD.

In response to this issue, the authors aim to investigate whether myocardial infarction (MI) accelerates the liver pathological progression of MASLD, particularly metabolic dysfunction-associated steatohepatitis (MASH), by promoting immune inflammatory response and upregulating cardiac periostin (Postn) levels.

Source of Study

“Myocardial Infarction Accelerates the Progression of Metabolic Dysfunction-Associated Steatohepatitis by Inducing Immune Inflammatory Response and Periostin” is a co-authored paper by Wei Xie, Jing Gan, Xiaodong Zhou, et al., published on June 4, 2024, in the journal “Cell Metabolism”. This study was jointly completed by experts from Dongguan Songshan Lake Central Hospital Affiliated to Guangdong Medical University, First Affiliated Hospital of Wenzhou Medical University Cardiology, Anzhen Hospital Capital Medical University, The University of Hong Kong, and other institutions.

Research Process and Details

Research Process

1. Clinical Retrospective Cohort Study: The study investigates the progression of liver fibrosis in MASLD patients following cardiovascular events.
2. Mouse Model Experiments: The impact of MI on liver pathological progression in MASLD mice was studied using myocardial infarction models, including the use of CDAHFD diet (choline-deficient, L-amino acid-defined, and high-fat diet), high-fat diet (HFD), and high-fat/high-sugar diet (HFHS).

Subjects and Experimental Procedures

1. Clinical Cohort Study: 1,740 MASLD patients without previous cardiovascular disease were investigated, and during an average follow-up of 8.5 years, the relationship between newly diagnosed cardiovascular events (MI and heart failure) and liver fibrosis scores (FIB-4 and NFS) was analyzed.
2. Mouse Experiment:
   • Myocardial Infarction Model: After CDDAHFD diet, mice were induced with MI by ligating the left anterior descending coronary artery, with sham surgery performed for the control group.
   • Liver Pathology Assessment: Evaluated histological changes in the liver, such as hepatic lipid content, inflammatory foci, and collagen deposition.
   • Immune Cell Study: Analyzed the recruitment of intrahepatic immune cells using flow cytometry, specifically analyzing Ly6Chi monocytes and F4/80 positive macrophages.
   • Role of Periostin: Investigated the role of cardiac Postn in mice by analyzing differentially expressed proteins in heart and plasma samples through proteomics.

Research Findings

1. Clinical Findings: Cardiovascular events significantly associated with liver fibrosis progression in MASLD patients. MASLD patients had more rapid liver fibrosis progression after cardiovascular events.
2. Mouse Experimental Results:
   • MI promoted liver fibrosis development in CDDAHFD diet mice, with increased circulating Ly6Chi monocyte levels and their recruitment to hepatic injury sites.
   • MI substantially increased Postn levels in the heart and circulation of mice, leading to hepatocyte and stellate cell activation, promoting hepatic lipid accumulation and fibrosis.
3. Molecular Mechanism Study:
   • Periostin (Postn) accelerates lipid accumulation in hepatocytes by activating JNK1/2 signaling pathways and inhibiting PPARa expression.
   • Overexpression of Postn in hepatic stellate cells significantly promotes the expression of fibrogenic factors (like α-SMA and collagen 1) through the activation of Integrin b3 signaling pathway.
   • Blocking CCR2+Ly6Chi monocytes significantly reduced liver damage induced by MI in both in vivo and in vitro experiments.

Conclusion and Value

The study demonstrates that myocardial infarction, as an acute pathological stressor, significantly accelerates the liver pathological progression in MASLD patients by inducing a systemic immune inflammatory response. MI not only exacerbates localized liver inflammation through Ly6Chi monocyte recruitment but also promotes hepatic lipid accumulation and fibrosis via cardiac periostin upregulation, fostering inter-organ disease communication.

Scientific Significance

The study unveils the mechanism of interaction between cardiovascular disease and liver disease in pathological progression, providing a new perspective on the role of myocardial infarction in MASLD exacerbation. More importantly, this study identifies cardiac periostin as a key molecular target with potential therapeutic applicability in blocking MI-induced liver pathology progression.

Application Prospects

The findings suggest that interventions targeting immune inflammatory cells and anti-fibrosis may positively impact the long-term treatment outcomes for MASLD patients with cardiovascular disease. Moreover, periostin, as a new therapeutic target, may have significant research and application value in future clinical practice.

This study holds significant scientific and clinical implications in elucidating the heart-liver interaction mechanism and proposing new therapeutic strategies, providing new insights for the combined treatment of cardiovascular and liver diseases. Future research will continue to explore whether other cardiovascular diseases, such as heart failure and hypertension, similarly accelerate MASLD pathological progression, and further validate the findings in large animal models and clinical applications.