Molecular and cellular correlates of cardiac function in end-stage DCM: a study using speckle tracking echocardiography

Abstract

Objectives: We sought to compare the effects of interstitial fibrosis and myocardial force generation/relaxation elements on left ventricular (LV) function in patients with end-stage dilated cardiomyopathy (DCM).

Background: Interstitial fibrosis is common in patients with advanced heart failure. However, the extent to which it affects cardiac function remains unclear.

Methods: Longitudinal, radial, and circumferential strain; strain rate during systole (SRS) and strain rate during early diastole (SRE); LV volume; LV ejection fraction; mean pulmonary capillary wedge pressure (PCWP); and e' were measured in 20 DCM patients. Myocyte diameter, interstitial fibrosis, messenger ribonucleic acid (mRNA) levels of molecules implicated in fibrosis and function (transforming growth factor beta, titin [TTN] N2B and N2BA isoforms, collagen type I, collagen type III, sarcoplasmic reticulum Ca(2+)-ATPase [SERCA2a], phospholamban [PLB], and protein levels of SERCA2a, phosphorylated PLB, and Smad2/3) were correlated with strain from 4 regions per patient (LV apex, midlateral, septum, and right ventricular free wall) as well as LV global function. In another group of 8 DCM patients, we evaluated LV structure and function before and after LV assist device.

Results: Significant correlations were present among ejection fraction, e' velocity, PCWP, LV end-diastolic volume/PCWP ratio, strain, SRS, SRE, and mRNA expression of TTN N2B, N2BA, SERCA2a, PLB, and protein levels of SERCA2a and phosphorylated PLB (r = 0.53 to 0.95, p < 0.05). Weak to no associations were present between strain and interstitial fibrosis and its molecular determinants. In patients with repeat studies, regional strain and SRE best tracked the changes in mRNA expression of TTN isoform N2BA and mRNA and protein expression of SERCA2a.

Conclusions: LV systolic and diastolic functions in DCM are primarily associated with myocardial force generation/relaxation elements.

Keywords: cardiomyopathy; diastole; echocardiography; molecular; strain.