Abstract 14297: Hypothalamic Activation Due to Ccl2 Causes Stress (takotsubo) Cardiomyopathy via Upregulation of Neuropeptide Y in the Cardiac Sympathetic Nerves
[Background]Brain-heart interactionsare integrated to maintain cardiovascular function. Abrupt conditional changes, however, can interfere with the harmony between the brain and the heart, thereby following impaired cardiovascular function. Stress cardiomyopathy (SC) is a typical sample. SC is a disorder associated with transient left ventricular apical ballooning that is usually induced by emotional or physical stress. Although the first case was reported more than 20 years ago, the precise molecular mechanisms remain unclear.
[Methods and Results](1) We developed a new animal model of SC in rodents inducing by epilepsy, whichisa trigger of SC in clinical scene.(2) We identified the central neuronal cells in the paraventricular hypothalamic nucleus (PVN) that innervate the apex of left ventricle (LV) by injecting pseudoravies virus (PRV), the retrograde neuronal tracer. (3) Stress-induced reactive astrocyte produced chemokine ligand 2 (CCL2) in the PVN inan animal model of SC.(4) Chemokine receptor 2 (CCR2) is merged with the retrograde neuronal tracer injected into the apex of left ventricle (LV) in neuronal cells of the PVN. (5) The Central portion of cardiac sympathetic nerve is activatied by upregulated CCL2 via CCR2. (6)CCL2 injection into the PVN induces SC-like LV wall motion abnormalities. (7)Pretreatment with a CCR2 antagonist reduced the incidence of SC by inducing epilepsy. (8) The incidence of SC was less frequent in CCR-/- mice than in CCR+/+ mice. (9) Upstream sympathetic activation induces strong upregulation of neuropeptide Y (NPY) expression in the left stellate ganglion and left ventricular sympathetic nerves. (10) NPY reduced the frequency of Ca2+ sparks when co-injected with noradrenaline in the ventricular myocytes of adult rat. (11) NPY injection into the left stellate ganglion induces SC-like LV wall motion abnormalities. (12)The incidence of SC was less frequent in NPY-/- mice than in NPY+/+ mice.
[Conclusions]Our results demonstrate how emotional or physical stress translates into molecular signals in the brain and leads to LV apical ballooning.
- © 2012 by American Heart Association, Inc.