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Experimental models of inherited cardiomyopathy and its therapeutics
Miki Nonaka1, Sachio Morimoto1
1Miki Nonaka, Sachio Morimoto, Department of Clinical Pharmacology, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
Insights
Cardiomyopathy, a heart muscle disease, is often monogenic. This review covers animal and stem cell models, exploring molecular mechanisms and therapeutic strategies for hypertrophic, dilated, and restrictive cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Genetics
- Regenerative Medicine
Background:
- Cardiomyopathy encompasses hypertrophic (HCM), dilated (DCM), and restrictive (RCM) forms, increasingly recognized as monogenic diseases.
- Mutations in HCM/RCM affect Ca(2+) sensitivity, causing hyperfunction and diastolic dysfunction.
- DCM mutations impair Ca(2+) sensitivity or force transmission, leading to systolic dysfunction.
Purpose of the Study:
- To review experimental models for studying inherited cardiomyopathies.
- To highlight molecular and cellular pathogenic mechanisms.
- To discuss potential therapeutic strategies.
Main Methods:
- Utilizing genetically-manipulated animal models (transgenic and knock-in).
- Employing patient-derived induced pluripotent stem cells (iPSCs) for in vitro cardiomyocyte differentiation.
- Analyzing molecular and cellular pathways.
Main Results:
- Animal models reveal insights into in vivo pathogenesis.
- iPSC-derived cardiomyocytes offer a platform for in vitro disease modeling.
- Specific mutation effects on myofilament Ca(2+) sensitivity and force generation are elucidated.
Conclusions:
- Experimental models are crucial for understanding cardiomyopathy.
- Targeting molecular and cellular mechanisms holds therapeutic promise.
- Integrated approaches using animal and stem cell models advance cardiomyopathy research.
Abstract:
Cardiomyopathy is a disease of myocardium categorized into three major forms, hypertrophic (HCM), dilated (DCM) and restrictive cardiomyopathy (RCM), which has recently been demonstrated to be a monogenic disease due to mutations in various proteins expressed in cardiomyocytes. Mutations in HCM and RCM typically increase the myofilament sensitivity to cytoplasmic Ca(2+), leading to systolic hyperfunction and diastolic dysfunction. In contrast, mutations in DCM typically decrease the myofilament sensitivity to cytoplasmic Ca(2+) and/or force generation/transmission, leading to systolic dysfunction. Creation of genetically-manipulated transgenic and knock-in animals expressing mutant proteins exogenously and endogenously, respectively, in their hearts provides valuable animal models to discover the molecular and cellular mechanisms for pathogenesis and promising therapeutic strategy in vivo. Recently, cardiomyocytes have been differentiated from patient's induced pluripotent stem cells as a model of inherited cardiomyopathies in vitro. In this review, we provide overview of experimental models of cardiomyopathies with a focus on revealed molecular and cellular pathogenic mechanisms and potential therapeutics.
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