Pressure Overload Hypertrophy and Aging: Effects on Myocardial vs Cellular Viscoelastic Properties

Abstract

Introduction: Both pressure overload hypertrophy (POH) and aging cause increased diastolic chamber stiffness. Whether and to what extent these changes are dependent on increased LV mass, increased myocardial viscoelastic stiffness, changes in the extracellular matrix (ECM) and/or changes in the constitutive properties of the cardiac muscle cells is not completely defined. Methods: Three groups of mice (C57Bl) were studied: young adults (controls; n = 7, age=16±5 wks), POH (n = 6, age = 16±1 wks) and senescent (n = 7, age = 96±10 wks). POH was created by transverse aortic constriction (TAC) for 4 weeks. Left ventricular (LV) structure and function were determined by echocardiography. LV papillary muscles were isolated and viscoelastic properties studied. Cardiomyocytes were isolated (collagenase), embedded in a gel matrix and viscoelastic properties studied. In both papillary muscles and cardiomyocytes a stress vs strain hysteresis loop was derived, which was fit by a constitutive equation to derive the elastic stiffness constant β. Additionally, normalized area of the hysteresis loop was used to derive the viscosity constant η. Results: In the POH mice echocardiography showed a significant increase in LV/Body Weight ratio (3.04±0.16 before vs 5.69±1.09∗ mg/gm after TAC) with no change in end diastolic volume or ejection fraction. Stiffness and viscosity were increased in papillary muscle and cardiomyocytes in both POH and senescent mice (Table). POH caused a 118% increase in myocardial stiffness and a 21% increase in cardiomyocyte stiffness. Aging caused a 29% increase in myocardial stiffness and a 31% increase in cardiomyocyte stiffness. Therefore, both the ECM and cardiomyocyte properties play a role in increased myocardial stiffness. Conclusion: Data suggest that the observed increase in myocardial stiffness may be more dependent on changes in the ECM in POH, but more dependent on changes in the cardiomyocyte in aging. Therefore, treatment developed to decrease myocardial stiffness may target either ECM or cardiomyocyte but must affect both to completely normalize the increased stiffness that occurs in POH and aging. ≠ Comparison of viscoelastic properties Control POH Senescent Papillary muscle Stiffness ß 0.028±0.005 0.061±0.014 ≠ p<0.001 0.036±0.004 ∗ p<0.05 vs control Viscosity η 33.5±1.5 43.4±5.0 ∗ p<0.05 vs control 37.2±2.9 Cardiomyocytes Stiffness ß 6.7±2.5 8.1±5.5 ∗ p<0.05 vs control 8.8±2.9 ∗ p<0.05 vs control Viscosity η 33.8±5.1 46.1±14.2 ∗ p<0.05 vs control 34.8±5.0 Mean±SD ≠ p<0.001 ∗ p<0.05 vs control Open table in a new tab Mean±SD