By Gilles De Keulenaer, MD/PhD
University of Antwerp
Heart Failure 2006 Congress
Session 707001, Monday 19/06/2006, 14:00
Apart from their indirect effects through regulation of coronary perfusion, endothelial cells in the heart also directly modulate myocardial function by direct interactions with cardiomyocytes. The close proximity to cardiomyocytes in the microvasculature and in the endocardium allow cardiac endothelial cells to communicate with cardiomyocytes through paracrine and non-paracrine mechanisms.
This intercellular cross-talk has modulatory effects on the rhythmicity and mechanical performance of the adult myocardium, and on the differentiation, growth and survival of cells in the developing and remodelling heart.
An important advance in the understanding of the mechanisms of endothelial control of cardiac function has been the recent discovery that neuregulin-1 (NRG-1) is indispensable during cardiac development and post-natal cardiovascular physiology.
NRG-1 is synthesized in endothelial cells in the cardiac microvasculature and endocardium and acts through activation of the oncogene tyrosine-kinase receptors ErbB2 and ErbB4 on cardiomyocytes. Disruption of NRG-1/ErbB signalling by gene targeting in the mouse leads to dilated cardiomyopathy. In patients, inhibitory ErbB2 antibodies used in the treatment of mammary carcinomas increases the risk for heart failure when associated with standard chemotherapy. Based on these observations, it has been postulated that cardiac endothelial NRG-1 is essential to preserve ventricular function in conditions predisposing to heart failure, probably by initiating a cell survival pathway in cardiomyocytes.
Apart from its protective role on cell viability, cardiac endothelium-derived NRG-1 also plays a modulatory role on the neurohormonal control of myocardial performance. These actions may be essential in blood pressure homeostasis. Indeed, NRG-1 exerts anti-adrenergic effects through cooperation with the parasympatic nerve system and, hence, affects cardiac output and blood pressure. NRG-1 secretion from cardiac endothelium is diminished, however, by angiotensin II and phenylephrine, released in conditions of low blood pressure to increase cardiac output and peripheral resistence. Hence, by sensing circulating levels of neurohormones in the blood, the cardiac endothelium may adapt NRG-1 signalling in the heart to adjust ventricular adrenergic responsiveness for correction of blood pressure.
Apart from novel speculations on impaired NRG-1 signalling in cardiac endothelial dysfunction, above insights also raise questions on possible novel mechanisms of action of commonly used drugs. For example, it is tempting to speculate that the beneficial actions of ACE inhibitors and beta-1 receptor blockers in chronic heart failure would be explained by enhancing NRG-1 expression and release from the cardiac endothelium.
Similarly, it may be questioned whether disappointing results of endothelin receptor antagonists are related to an unforeseen downregulation of cardiac endothelial NRG-1 activity.