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Updated: Mar 20, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Molecular profiling of dilated cardiomyopathy that progresses to heart failure
Michael A Burke1, Stephen Chang2, Hiroko Wakimoto3
1Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Insights
Dilated cardiomyopathy (DCM) involves early nonmyocyte proliferation and pro-inflammatory signaling. Metabolic shifts in cardiomyocytes and fibrosis characterize DCM progression, distinguishing it from hypertrophic cardiomyopathy (HCM).
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetic Models of Disease
Background:
- Dilated cardiomyopathy (DCM) is characterized by progressive cardiac dysfunction and structural remodeling.
- Understanding the molecular underpinnings of DCM progression is crucial for developing targeted therapies.
- Genetic models offer insights into disease mechanisms and potential therapeutic targets.
Purpose of the Study:
- To define the molecular signaling pathways involved in the progression of dilated cardiomyopathy (DCM).
- To investigate the transition from pre-DCM to overt heart failure (HF) using a genetic DCM model.
- To compare molecular signatures of DCM with those of hypertrophic cardiomyopathy (HCM).
Main Methods:
- RNA sequencing (RNA-seq) was employed at distinct disease stages in a genetic phospholamban (PLNR9C/+) mouse model.
- Quantitative analysis of nonmyocyte proliferation and cardiac fibrosis was performed.
- Transcriptional profiles were analyzed to identify key signaling and metabolic pathways.
Main Results:
- Pre-DCM hearts showed increased nonmyocyte proliferation and pro-inflammatory signaling, with cardiomyocyte-specific induction of TGFβ2 and TGFβ3.
- Disease progression led to significant left ventricular fibrosis and a shift in cardiomyocyte metabolism from aerobic respiration to glucose utilization.
- Attenuated expression of PGC1α/β and increased Tbx15 expression were observed in cardiomyocytes, alongside disease-specific profibrotic and metabolic network alterations distinguishing DCM from HCM.
Conclusions:
- Cardiomyopathy progression is marked by cardiomyocyte-specific cytokine expression, early fibroblast activation, and metabolic gene reprogramming.
- Distinct molecular networks differentiate DCM from HCM, highlighting potential therapeutic targets specific to DCM.
- Genetic modeling provides a framework for dissecting the complex molecular events driving cardiomyopathy progression.
Abstract:
Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10-4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 × 10-33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM.
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