Cardiomyocyte Hypocontractility and Reduced Myofibril Density in End-Stage Pediatric Cardiomyopathy.

Ilse A E Bollen,Kyra De Goede,Michiel Dalinghaus,Jolanda Van Der Velden,Diederik W D Kuster,Marijke Van Der Meulen

doi:10.3389/fphys.2017.01103

Abstract

Dilated cardiomyopathy amongst children (pediatric cardiomyopathy, pediatric CM) is associated with a high morbidity and mortality. Because little is known about the pathophysiology of pediatric CM, treatment is largely based on adult heart failure therapy. The reason for high morbidity and mortality is largely unknown as well as data on cellular pathomechanisms is limited. Here, we assessed cardiomyocyte contractility and protein expression to define cellular pathomechanisms in pediatric CM. Explanted heart tissue of 11 pediatric CM patients and 18 controls was studied. Contractility was measured in single membrane-permeabilized cardiomyocytes and protein expression was assessed with gel electrophoresis and western blot analysis. We observed increased Ca2+-sensitivity of myofilaments which was due to hypophosphorylation of cardiac troponin I, a feature commonly observed in adult DCM. We also found a significantly reduced maximal force generating capacity of pediatric CM cardiomyocytes, as well as a reduced passive force development over a range of sarcomere lengths. Myofibril density was reduced in pediatric CM compared to controls. Correction of maximal force and passive force for myofibril density normalized forces in pediatric CM cardiomyocytes to control values. This implies that the hypocontractility was caused by the reduction in myofibril density. Unlike in adult DCM we did not find an increase in compliant titin isoform expression in end-stage pediatric CM. The limited ability of pediatric CM patients to maintain myofibril density might have contributed to their early disease onset and severity.

Highlights

Disease Progression in Pediatric CardiomyopathyDilated cardiomyopathy (DCM) is a cardiac disease characterized by dilatation of the ventricle and systolic dysfunction
Heart tissue was obtained from 9 pediatric patients diagnosed with Disease Progression in Pediatric CardiomyopathyDilated cardiomyopathy (DCM) and 2 pediatric patients diagnosed with noncompaction cardiomyopathy during cardiac transplantation
We show that end-stage pediatric CM patients harbor similar changes in protein modifications and sarcomeric function compared to adult DCM

Summary

Introduction

Dilated cardiomyopathy (DCM) is a cardiac disease characterized by dilatation of the (left) ventricle and systolic dysfunction. A genetic cause is found in 20–50% of DCM cases (Hershberger et al, 2010; Herman et al, 2012; van Spaendonck-Zwarts et al, 2013). The disease often develops in adulthood and treatment is currently only able to slow down disease progression (Hershberger et al, 2013). DCM is a rare disease with an annual incidence estimated around 0.6/100,000 (Towbin et al, 2006). In two large studies the 1- and 5-year transplantation-free survival rates have been reported to be only 69–74 and 54–65%, respectively (Towbin et al, 2006; Alexander et al, 2013).

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