Ventricular remodelling: Chamber dyssynchrony and effects of cardiac resynchronization

Cardiac failure is frequently complicated by intraventricular conduction delay that results in dyssynchronized cardiac contraction. In the presence of depressed myocardial function and limited alternative reserve mechanisms, dyssynchrony substantially worsens cardiac function, impairs energetic efficiency and results in molecular maladaptations. Cardiac resynchronization therapy (CRT) uses electrical pre-excitation of both left and the right ventricles or solely of the left ventricular free wall to re-coordinate cardiac contraction, improving systolic function without augmenting (or even lowering) metabolic demand. Dyssynchrony increases net end-systolic volume and wall stress, and induces a regional redistribution of stress, being higher in the late-activated territory (typically the left ventricular free wall). Chronically, this leads to hypertrophy of this region, with increased metabolic demand coupled with higher glucose metabolism and blood flow requirements. There can be striking localized molecular changes in the late-activated lateral wall, with reduced endocardial expression of calcium handling and gap junction proteins, and enhanced stress kinase activity. Chronic elevation of chamber volumes exacerbates progressive remodelling, and this appears partially reversible by CRT. Chronic CRT lowers both systolic and diastolic volumes by approximately 10% increasing the ejection fraction. Reverse remodelling - as reflected by reduced end-sytsolic volume - best correlates with measures of baseline intraventricular dyssynchrony, rather than ORS duration. Reverse remodelling has been accompanied by improved homogeneity of myocardial blood flow metabolic demand, and is probably a potent contributor to the sustained clinical benefits from chronic CRT.