Key result
VAD unloading linked to molecular and calcium-handling recovery in ~40% of failing hearts.
Why the study?
Phenotype changes in the failing heart, including increased susceptibility to cardiomyocyte apoptosis and labile calcium homeostasis, are assumed to result from hemodynamic overload, but their reversibility under ventricular assist device unloading was unknown.
Does hemodynamic unloading by a ventricular assist device reverse alterations in myocardial gene expression of regulators of myocyte apoptosis and calcium homeostasis in patients with end-stage heart failure?
Observational (n=20)
Does hemodynamic unloading by a ventricular assist device reverse alterations in myocardial gene expression of regulators of myocyte apoptosis and calcium homeostasis in patients with end-stage heart failure?
Mechanical unloading with a ventricular assist device in end-stage heart failure induces time-dependent normalization of antiapoptotic gene expression, though calcium homeostasis gene expression recovers in only a minority of patients.
May indicate partial molecular recovery with VAD in end-stage HF; hypothesis-generating and should not yet change practice.
Background —In patients with end-stage heart failure, characterized by an increased susceptibility to cardiomyocyte apoptosis and a labile cardiomyocyte calcium homeostasis, a ventricular assist device (VAD) is implanted for bridging to cardiac transplantation and results in myocardial unloading. Although phenotype changes in the failing heart are assumed to result from hemodynamic overload, the reversibility of these changes under unloading is unknown. Methods and Results —By use of quantitative reverse-transcription polymerase chain reaction, mRNA expression analyses were performed on left ventricular specimens obtained from 10 nonfailing donor hearts (from 8 patients with dilated cardiomyopathy and 2 patients with coronary heart disease) at the time of VAD implantation and 36 to 169 days later during VAD removal with subsequent cardiac transplantation. In terminally failing hearts before VAD support, left ventricular mRNA analyses revealed increased Pro-ANP, reduced antiapoptotic Bcl-x L and antiapoptotic Fas isoform FasExo6Del, and a decreased ratio of sarcoplasmic reticulum Ca 2+ -ATPase per sarcolemmal Na + -Ca 2+ exchanger in comparison with nonfailing ventricles. After VAD unloading, ventricular transcription of Pro-ANP was immediately normalized, and apoptotic DNA fragmentation was attenuated. In patients with dilated cardiomyopathy, 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 Ca 2+ -ATPase/Na + -Ca 2+ exchanger demonstrated recovery in only 4 of 10 patients. Conclusions —Mechanical support of the failing heart induces a time-dependent change in myocardial gene expression compatible with a decreased susceptibility to apoptosis.
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Bartling et al. (1999) conducted an observational in End-stage heart failure (dilated cardiomyopathy and coronary heart disease) (n=20). Ventricular assist device (VAD) hemodynamic unloading vs. Pre-VAD implantation baseline and nonfailing donor hearts was evaluated on Left ventricular mRNA expression of Pro-ANP, antiapoptotic regulators (Bcl-xL, FasExo6Del), and sarcoplasmic reticulum Ca2+-ATPase/Na+-Ca2+ exchanger ratio. VAD unloading normalized Pro-ANP transcription, enhanced antiapoptotic mRNAs (Bcl-xL, FasExo6Del/Fas), and recovered SR Ca2+-ATPase/Na+-Ca2+ exchanger transcription in 4 of 10 patients (40%).
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