Mechanisms of remodeling of gap junction distributions and the development of anatomic substrates of arrhythmias

Time for primary review 28 days. Alteration of structure (remodeling) is a fundamental response of the heart to injury or disease. It originates in changes in gene expression which, in turn, alter the types and amounts of regulatory and structural proteins in myocytes, the form and distribution of subcellular organelles (including the contractile apparatus and other specialized subcellular structures responsible for cardiac function), and changes in the structure of whole cells, the extracellular matrix and, ultimately, the tissue and whole organ. A change in cardiac structure inevitably leads to a change in cardiac function, but the complex relationships between altered structure and function are only beginning to be revealed. Although structural remodeling serves important adaptive purposes, maladaptive consequences of remodeling are likely to contribute to morbidity and mortality in patients with heart disease. An important clinical setting in which altered structure begets altered function and in which responses to injury may serve adaptive purposes, but also lead to maladaptive changes, is the development of anatomic substrates of ventricular arrhythmias. These ‘substrates’ arise as a consequence of structural alterations in response to common forms of heart disease such as myocardial infarction or systemic hypertension. Clearly, replacement of a transmural myocardial infarct by fibrous scar tissue limits the likelihood of fatal ventricular rupture and helps preserve optimal ventricular geometry. Similarly, development of myocyte hypertrophy allows the heart to function better in the face of chronic pressure overload. However, although these adaptations are beneficial, the structural alterations that result from these myocardial responses to injury can also change patterns of electrical activation of the heart that may enhance the risk of developing a serious ventricular arrhythmia. For example, sudden death in patients who have survived myocardial infarction often occurs by a reentrant mechanism in which derangements in conduction play a critical pathogenic role …