Pharmacogenetics of cardiac inotropy.

The ability to stimulate cardiac contractility is known as positive inotropy. Endogenous hormones, such as adrenaline and several natural or synthetic compounds possess this biological property, which is invaluable in the modern cardiovascular therapy setting, especially in acute heart failure or in cardiogenic shock. A number of proteins inside the cardiac myocyte participate in the molecular pathways that translate the initial stimulus, that is, the hormone or drug, into the effect of increased contractility (positive inotropy). Genetic variations (polymorphisms) in several genes encoding these proteins have been identified and characterized in humans with potentially significant consequences on cardiac inotropic function. The present review discusses these polymorphisms and their effects on cardiac inotropy, along with the individual pharmacogenomics of the most important positive inotropic agents in clinical use today. Important areas for future investigations in the field are also highlighted.

Negative impact of ß-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms.

ß-Arrestin (ßarr)-1 and ß-arrestin-2 (ßarrs) are universal G-protein-coupled receptor adapter proteins that negatively regulate cardiac ß-adrenergic receptor (ßAR) function via ßAR desensitization and downregulation. In addition, they mediate G-protein-independent ßAR signaling, which might be beneficial, for example, antiapoptotic, for the heart. However, the specific role(s) of each ßarr isoform in cardiac ßAR dysfunction, the molecular hallmark of chronic heart failure (HF), remains unknown. Furthermore, adrenal ßarr1 exacerbates HF by chronically enhancing adrenal production and hence circulating levels of aldosterone and catecholamines. Herein, we sought to delineate specific roles of ßarr1 in post-myocardial infarction (MI) HF by testing the effects of ßarr1 genetic deletion on normal and post-MI cardiac function and morphology. We studied ßarr1 knockout (ßarr1KO) mice alongside wild-type controls under normal conditions and after surgical MI. Normal (sham-operated) ßarr1KO mice display enhanced ßAR-dependent contractility and post-MI ßarr1KO mice enhanced overall cardiac function (and ßAR-dependent contractility) compared with wild type. Post-MI ßarr1KO mice also show increased survival and decreased cardiac infarct size, apoptosis, and adverse remodeling, as well as circulating catecholamines and aldosterone, compared with post-MI wild type. The underlying mechanisms, on one hand, improved cardiac ßAR signaling and function, as evidenced by increased ßAR density and procontractile signaling, via reduced cardiac ßAR desensitization because of cardiac ßarr1 absence, and, on the other hand, decreased production leading to lower circulating levels of catecholamines and aldosterone because of adrenal ßarr1 absence. Thus, ßarr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF.