ALTERED CALCIUM HANDLING IN HYPERTENSIVE HEART DISEASE

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DESCRIPTION: (Adapted from the Investigator's Abstract)): The proposed research aims to answer the question: "What are the cellular mechanisms responsible for the alterations in contractility associated with hypertensive heart disease?" The prevailing view of cardiac hypertrophy and heart failure describes the observed abnormalities in [Ca]i handling in terms of decreased contractility and progressive uncoupling of Ca entry and sarcoplasmic reticulum (SR) Ca release. Preliminary and literature data support the alternative view that mild to moderate hypertrophy is associated with enhanced contractility which end stage hypertrophy and failure is associated with decreased contractility. The overall hypothesis is that abnormalities in [Ca]i handling are a consequence of alterations in the gain between Ca entry and Ca release. Aim 1 will test the hypothesis that mild to moderate hypertrophy is associated with enhanced contractility and increased gain between Ca entry and SR Ca release whereas severe hypertrophy and failure are associated with decreased contractility and decreased gain. The hypothesis that reversal of hypertrophy and prevention of failure is dependent on correction of systemic hypertension only during the stage of the disease characterized by increased gain also will be tested. Aim 2 tests at the whole cell and single channel level whether ICa, the trigger for SR Ca release, is unaltered in hypertrophy and failure. Gain will be determined from the [Ca]i transients (whole cell and local) and L-type Ca currents (whole cell and single channel) in voltage clamped ventricular cells and by measuring force, [Ca]i transients in intact trabeculae. This proposal will provide insights regarding the cellular mechanisms of altered contractility in hypertensive heart disease by combining (1) the new concept of local control, (2) new experimental methodologies (1 and 2 photon laser scanning confocal microscopy), and (3) the longitudinal study of the development of hypertrophy and its progression to failure in a relevant experimental model.