MECHANISMS OF HYPERTROPHY IN VALVULAR HEART DISEASE


Niels T. Olsen, M.D., Ph.D., Rigshospitalet, Copenhagen, Denmark

Myocardial hypertrophy has a prominent role in valvular heart disease. The evaluation of hypertrophy is invaluable when determining the hemodynamic significance of a valve lesion, as the myocardium responds to increased load from regurgitant or stenotic valve lesions with growth in predictable patterns. Cardiac hypertrophy is initially adaptive to the pathologically increased load, but with time the hypertrophic response may itself contribute to the development of heart failure in severe valve disease. Better understanding of this progression could allow pharmacological targeting of responsible molecular pathways. It is increasingly clear that a number of interconnected intra-cellular signaling pathways are involved in the development of physiological and pathological cardiac hypertrophy. Known triggers for hypertrophy include mechanical stretch sensed at the level of the extra-cellular matrix, the cell membrane, or the sarcomere, and receptor activation. The mechanical signal sensed by the myocardium differs in important ways between pressure and volume overload. Most work has been done in pressure overload models displaying concentric hypertrophy, where activation of a number of pathways is associated with a phenotype similar to that of human aortic stenosis. Characteristics for these models are myocardial fibrosis and an activation pattern dissimilar to that of physiologic hypertrophy. Volume overload models are less used, and have typically been fistula-type models. Recently, we and others have used a closed-chest rat model of aortic regurgitation to evaluate the development of left-sided eccentric hypertrophy. In contrast to the findings in pressure overload, volume overload hearts display much less fibrosis, and a different pattern of hypertrophic pathway activation is seen – in several ways similar to that seen in physiologic hypertrophy.