Molecular and cellular correlates of cardiac function in end-stage DCM: a study using speckle tracking
Andrea M Cordero-Reyes1, Keith Youker1, Jerry D Estep1
1Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, Texas.
Insights
In dilated cardiomyopathy (DCM), myocardial force generation and relaxation significantly impact left ventricular (LV) function, more so than interstitial fibrosis. This finding is crucial for understanding heart failure progression.
Area of Science:
- Cardiovascular Medicine
- Cardiac Physiology
- Heart Failure Research
Background:
- Interstitial fibrosis is a prevalent characteristic in advanced heart failure, particularly in dilated cardiomyopathy (DCM).
- The precise impact of interstitial fibrosis on cardiac function in DCM remains incompletely understood.
Purpose of the Study:
- To investigate the relative contributions of interstitial fibrosis and myocardial force generation/relaxation mechanisms to left ventricular (LV) function in patients with end-stage DCM.
- To correlate molecular and structural markers with functional parameters of LV performance.
Main Methods:
- Evaluated LV function using strain, strain rate (SRS, SRE), ejection fraction, and diastolic parameters (e') in 20 DCM patients.
- Assessed myocyte diameter, interstitial fibrosis, and mRNA/protein levels of key fibrotic and contractile/relaxation molecules (e.g., TGF-β, TTN, collagen, SERCA2a, PLB).
- Correlated these parameters with regional and global LV strain and function; analyzed LV structure/function changes pre- and post-LV assist device in 8 additional patients.
Main Results:
- Significant correlations were observed between LV function parameters (ejection fraction, e', strain, SRS, SRE) and molecular markers related to myocardial force generation/relaxation (e.g., TTN isoforms, SERCA2a, PLB).
- Weak or no associations were found between LV strain and interstitial fibrosis or its molecular mediators.
- Regional strain and SRE effectively tracked changes in TTN isoform N2BA and SERCA2a expression in patients with serial assessments.
Conclusions:
- Left ventricular systolic and diastolic functions in dilated cardiomyopathy are predominantly influenced by myocardial force generation and relaxation processes.
- Interstitial fibrosis appears to play a lesser role in modulating LV function compared to intrinsic myocardial contractile and relaxation elements in end-stage DCM.
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.
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