Priyanka Narvekar

Introduction. Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and systolic dysfunction in the absence of other cardiovascular pathology.^1,2.3 Titin mutations are the most common familial cause of DCM and result in a truncated titin called titin truncating variant (TTNtv). ^1,2,3,4 Studies suggest that TTNtvs contribute to DCM by promoting maladaptive remodeling of cardiac tissue via alteration of cardiac metabolism, sarcomere abnormalities, and an impaired cardiac response to hemodynamic stress.^4,5 MicroRNA (miRNA) studies indicate that miRNA expression is associated with regulation of cardiac remodeling.^6,7  Together, these findings suggest a high potential for microRNA therapy for titin-based DCM. Methods. Quantitative metabolomic profiling of hearts from wild-type and TTNtv rats was conducted using liquid chromatography and mass spectrometry.⁴ DCM patient induced pluripotent stem cell derived cardiomyocytes with A band TTNtvs (iPS-CMs) were labeled for titin (9D10 antibody recognizing the N-terminus of TTNtvs), alpha-actinin, and F-actin to describe sarcomere architecture.⁵ The iPS-CMs were grown on flexible and rigid cantilevers to test their contractile performance at baseline and in response to isoproterenol stimulation.⁵ Cardiac morphology and function were analyzed by Masson trichrome stain and echocardiography in miRNA-22 knockout mice exposed to transverse aortic constriction.⁶ LNA-modified mimic miR-208b and miR-208b anti miRNA were injected into TTNtv mice in which DCM was induced via administration of angiotensin II.⁷ Echocardiography was used to analyze the ventricular wall thickness, end systolic and diastolic diameters, ventricular dimensions and volumes, and ejection fraction of the TTNtv mice’s hearts. ⁷ Results. Hearts with TTNtvs experienced a shift in cardiac metabolism from fatty acid oxidation to branched chain amino acids and glycolytic intermediates, resulting in decreased ATP production.⁴ Cardiomyocytes with TTNtvs had irregular sarcomeres with fewer myofibrils and impaired contractile performance at both baseline and in response to adrenergic stress.⁵  TTNtv hearts with a deletion of miRNA-22 experienced accelerated maladaptive cardiac remodeling with a loss in cardiac contractility.⁶ In contrast, upregulation of miR-208b in TTNtv mice with DCM was associated with progressive hypertrophy, left ventricle dilatation, and reduced cardiac contractility in response to stress. ⁷ Conclusion. TTNtv induced DCM results in maladaptive cardiac remodeling in response to stress. This remodeling was shown to be regulated by expression of miRNA-22 and miRNA-208b. Manipulation of miRNA expression through miRNA mimics and inhibitors can potentially prevent or slow the progression of maladaptive cardiac remodeling in DCM-induced heart failure, thereby significantly improving prognosis for titin-based DCM patients and prevention to deterioration into heart failure.

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