Abstract 17504: Compensatory Alterations in Cardiomyocyte Ca2+ Homeostasis During Aortic Stenosis
Concentric left ventricular hypertrophy is commonly associated with impaired myocardial relaxation, leading to reduced end diastolic volume and lower cardiac output. Indeed, diastolic dysfunction underlies approximately 50% of heart failure cases. Stiffening of the myocardium may be caused by active and/or passive mechanisms, which are respectively determined by Ca2+ homeostasis or properties of the cytoskeleton/extracellular matrix. In aortic stenosis patients with diastolic dysfunction we observed marked SERCA and NCX upregulation in ventricular biopsies, suggesting that cardiomyocyte Ca2+ homeostasis may be enhanced. To investigate this hypothesis, we examined the contribution of active and passive mechanisms to myocardial stiffness in a rat model of hypertrophy following aortic banding (AB). Experiments were performed six weeks after AB, and sham-operated animals served as controls. AB rats with detectable systolic heart failure were excluded. Hypertrophy and diastolic dysfunction in AB were confirmed in vivo by echocardiography, indicated by thickening of the posterior wall and reduced peak early diastolic tissue velocities. When stimulated to develop isometric force across a range of pacing frequencies (0.5 - 6 Hz), excised left ventricular muscle strips also exhibited slower relaxation kinetics in AB. Interestingly, isolated cardiomyocytes stimulated at the same frequencies exhibited opposite characteristics, as time to 50% relaxation was faster in AB (78±4% of SHAM at 1 Hz, P<0.05). Similarly, Ca2+ transients in single cardiomyocytes (whole-cell fluo-4 AM fluorescence) were faster to 50% decay in AB (63±2% of SHAM at 1 Hz, P<0.05). Consistent with enhanced Ca2+ removal, we measured significantly increased rates of both sarcoplasmic reticulum Ca2+ reuptake and sarcolemmal Ca2+ extrusion in AB, suggesting increased SERCA and NCX activity. In conclusion, there is a discrepancy between the phenotype of single cardiomyocytes and intact myocardial tissue in AB. We propose that enhanced Ca2+ homeostasis in aortic banding / aortic stenosis compensates for increased passive stiffness and that the primary determinants of diastolic dysfunction in this condition are alterations in the extracellular matrix or ventricular geometry.
- © 2013 by American Heart Association, Inc.