Genetic and non-genetic determinants of clinical phenotypes in cardiomyopathy

Genetic and non-genetic determinants of clinical phenotypes in cardiomyopathy





Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan



Journal of cardiology



  • Cardiomyopathy phenotypes are determined by genetic and non-genetic factors.
  • TTN truncating mutations and LMNA mutations are major genetic determinants of dilated cardiomyopathy (DCM).
  • DCM transcriptomic/epigenomic signatures include the DNA damage response and dedifferentiation.
  • DCM proteomic/metabolomic analyses can be used to dissect metabolic reprogramming in DCM.
  • Integration of multi-omics data will lead to the development of precision medicine.





Cardiomyopathy, a leading cause of death worldwide, is etiologically and phenotypically heterogeneous and is caused by a combination of genetic and non-genetic factors. Major genomic determinants of dilated cardiomyopathy (DCM) are titin truncating mutations and lamin A/C mutations. Patients with these two genotypes show critically different phenotypes, including penetrance, coexistence with a conduction system abnormality, cardiac prognosis, and treatment response. The transcriptomic and epigenomic characteristics of DCM include activation of the DNA damage response, metabolic reprogramming, and dedifferentiation. The proteomic and metabolomic signatures of the DCM heart include a rigorous dependency for free fatty acids, activation of the stress response, and metabolic reprogramming. Proteomic and metabolomic analyses of blood show a distinct immune response and an unexpected link with pathology-specific microbiota in DCM. The direct integration of multi-omics data will not only elucidate inter-omics associations but also enable omics-based patient stratification, which will lead to a deeper understanding of cardiomyopathy and the development of precision medicine in cardiology.



Cardiomyopathy; Multi-omics; Data integration; Precision medicine


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