The heart is a dynamic organ capable of cellular and ventricular chamber remodeling in response to pathologic and physiologic stimulation. These different stimuli involve extrinsic signals in the form of neuroendocrine agonists and growth factors that are transduced through membrane bound receptors on cardiac myocytes, as well as intrinsic stress sensing associated with mechanical stretch. Intracellular signal transduction cascades then transmit these stimuli throughout the cytoplasm and nucleus to alter cardiac gene expression, metabolism, protein turnover, and contractile function during the remodeling process. Over the past 2 decades the use of genetically engineered mouse models has suggested nodal molecular regulator factors that mediate ventricular remodeling and the transition to heart failure with sustained pathophysiologic stimulation. Here we will highlight emerging concepts in cellular and ventricular remodeling and the more recent molecular signaling pathways that mediate these processes leading to disease, thereby suggesting novel therapeutic targets.
Cardiac remodeling involves molecular, cellular and interstitial changes that manifest clinically as changes in size, shape and function of the heart after injury or stress stimulation1. Although the term “cardiac remodeling” was initially coined to describe the prominent changes that occur following myocardial infarction2, 3, it is clear that similar processes transpire following other types of injury such as with pressure overload (aortic valve stenosis, hypertension), inflammatory disease (myocarditis), idiopathic dilated cardiomyopathy, and volume overload (valvular regurgitation). Although the etiologies of these diseases are different, they share molecular, biochemical and cellular events to collectively change the shape of the myocardium.
Cardiac hypertrophy is a common type of cardiac remodeling that occurs when the heart experiences elevated workload. The heart and individual myocytes enlarge as a means of reducing ventricular wall and septal stress when faced with increased workload or injury. Cardiac hypertrophy is classified as “physiological” when it occurs in healthy individuals following exercise or pregnancy and is not associated with cardiac damage. In contrast, hypertrophy that results from pressure or volume overload or after myocardial infarction is usually referred to as “pathological”. This name may be misleading though, because pathological hypertrophy may also involve a compensatory and adaptive phase that tends to reduce wall stress and maintain output, although ultimately these positive aspects are lost and ventricular function declines, often leading to heart failure.