Myocardial gene expression of regulators of myocyte apoptosis and myocyte calcium homeostasis during hemodynamic unloading by ventricular assist devices in patients with end-stage heart failure

Background-In patients with end-stage heart failure, characterized by an in creased susceptibility to cardiomyocyte apoptosis and a labile cardiomyocyt e calcium homeostasis, a ventricular assist device (VAD) is implanted for b ridging to cardiac transplantation and results in myocardial unloading. Alt hough phenotype changes in the failing heart are assumed to result from hem odynamic overload, the reversibility of these changes under unloading is un known. Methods and Results-By use of quantitative reverse-transcription polymerase chain reaction, mRNA expression analyses were performed on left ventricula r specimens obtained from 10 nonfailing donor hearts (from 8 patients with dilated cardiomyopathy and 2 patients with coronary heart disease) at the t ime of VAD implantation and 36 to 169 days later during VAD removal with su bsequent cardiac transplantation. In terminally failing hearts before VAD s upport, left ventricular mRNA analyses revealed increased Pro-ANP, reduced antiapoptotic Bcl-x(L) and antitipoptotic Fas isoform FasExo6Del, and a dec reased ratio of sarcoplasmic reticulum Ca2+-ATPase per sarcolemmal Na+-Ca2 exchanger in comparison with nonfailing ventricles. After VAD unloading, v entricular transcription of Pro-ANP was immediately normalized, and apoptot ic DNA fragmentation was attenuated, in patients with dilated cardiomyopath y, mRNAs of Bcl-x(L) and FasExo6Del/Fas were enhanced depending on time on VAD. The Bcl-x(L) mRNA level correlated positively with that of the Bcl-x(L ) protein. Transcription of sarcoplasmic reticulum Ca2+-ATPase/Na+-Ca2+ exc hanger demonstrated recovery in only 4 of 10 patients. Conclusions-Mechanical support of the failing heart induces a time-dependen t change in myocardial gene expression compatible with a decreased suscepti bility to apoptosis.