Wag the Dog

Abstract

Pathological cardiac hypertrophy emerges in the mammalian heart during chronically increased workload (eg, arterial hypertension or aortic stenosis). Although it might in the short term help to compensate cardiac function, it predisposes to the development of heart failure in the long term. It is characterized by an increase in cardiomyocyte size and profound changes in gene expression and is accompanied by fibrosis and contractile dysfunction.1 Myocardial hypertrophy was previously thought to be mainly a disease of cardiomyocytes, but research in recent years revealed important contributions by other cell types. Myocardial endothelial cells are found in the endocardium, in cardiac conductance vessels, and as main component of capillaries. As an organ mainly dependent on oxidative energy production, the capillary density in the heart is high, and each cardiomyocyte is supplied roughly by one capillary. Capillary endothelial cells are closely associated with cardiomyocytes in an ideal diffusion range for capillary-derived nutrients and oxygen, but also for reciprocal paracrine signals between these cells. It has been demonstrated that cardiomyocytes regulate the formation and adaptation of the myocardial capillary network. For example, about 70% of the VEGF-A within the heart is produced by cardiac myocytes.2 Cardiomyocyte specific deletion of VEGF-A, consequently, leads to myocardial capillary rarefaction and dilated cardiomyopathy.2 Upstream cardiomyocyte signaling molecules that induce VEGF-A production are, for example, the transcription factors HIF1α and GATA4 and the proteinkinase B/Akt.3–5 GATA4 and Akt are activated by myocardial overload and are themselves capable of inducing cardiomyocyte growth.1 Indeed, during pathological cardiac hypertrophy an increased abundance of myocardial capillaries has been demonstrated.3–5 However, as pathological hypertrophy progresses to heart failure, capillary rarefaction emerges.6 See accompanying article on page 654 What is the consequence of a reduction in capillary density in the stressed heart? Use of …