Gene and Protein Expression Alterations in the Myocardium following Mechanical Circulatory Assist in Heart Failure Patients

Abstract

Purpose: The number of patients suffering from end-stage heart failure (HF) continues to mount alongside an aging demographic. Management of the failing heart involves medical therapy, mechanical circulatory assist (MCA) devices and ultimately heart transplantation. Unloading of the heart by MCA may induce reverse remodeling and normalize cardiac parameters (chamber geometry, heart size, ventricular volume, ejection fraction, fetal gene expression). We undertook the identification of markers within the heart correlating with patient response to MCA, and of changes in gene and protein expression in the myocardium following MCA. Methods: Myocardial tissue cores removed during left ventricular assist device (LVAD) implantation, and explanted hearts obtained at the time of cardiac transplantation are archived for flash frozen, paraffin-fixed formalin embedded (PPFE), RNAlater and OCT preserved samples. Serial sections from PPFE samples of left ventricular (LV) apical tissue cores were prepared with standard histology stains (H&E, Movat's pentachrome and picrosirius red) for quantification of fibrosis and degree of myocardial remodeling. Immunohistochemical staining of markers of myocardial dysfunction and remodeling (brain natriuretic peptide (BNP), galectin-3, versican, matrix metalloproteinases (MMP)-2 and -9, tissue inhibitor of metalloproteinases (TIMP)-1 were performed. RNA extracted from LV apical tissue cores was analyzed on Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays. Differential staining, gene expression and degree of remodeling were quantitated and correlated with patient response (non-reponders: death, cardiac transplantation; responders: recovery with explantation of device). Comparison of gene and protein signatures from LV core samples at time of MCA initiation with myocardial tissue samples from the LV in matched explanted hearts was also performed. Results and Conclusions: Increased galectin&-3 and versican staining was seen in patients who did not respond to MCA, suggesting that activation of fibrosing pathways may impair the ability of the myocardium to recover despite chronic unloading. Differential gene expression of MMP-2 and -9 was observed in patients who subsequently required cardiac transplantation following MCA. Differential gene and protein expression was also seen in explanted hearts following MCA when compared to initial LV cores removed during MCA device implantation.