Increased passive stiffness promotes diastolic dysfunction despite improved Ca2+ handling during left ventricular
Åsmund T Røe1, Jan Magnus Aronsen1,2, Kristine Skårdal1
1Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, NO-0407 Oslo, Norway.
Cardiovascular Research
|May 5, 2017
Summary
Pressure overload causes heart hypertrophy and diastolic dysfunction despite preserved systolic function. Cardiac fibrosis and altered titin phosphorylation increase stiffness, impairing relaxation, even with compensatory cardiomyocyte calcium handling.
Area of Science:
- Cardiovascular Physiology
- Cardiac Hypertrophy
- Diastolic Dysfunction
Background:
- Pressure-overload induced concentric hypertrophy preserves systolic function but impairs diastolic function, a precursor to heart failure with preserved ejection fraction.
- Increased passive myocardial stiffness is a suspected cause of diastolic dysfunction, but the role of active diastolic calcium cycling in cardiomyocytes is unclear.
Purpose of the Study:
- To investigate the roles of passive and active mechanisms in diastolic dysfunction within the concentrically hypertrophied heart following pressure overload.
Main Methods:
- Rats underwent aortic banding (AB) or sham surgery, with experiments conducted 6 weeks post-surgery.
- Evaluated in vivo cardiac function, isolated left ventricular muscle strip relaxation, and cardiomyocyte calcium handling.
- Assessed passive tension, viscosity, extracellular collagen, and titin phosphorylation profiles.
Main Results:
- AB rats showed preserved ejection fraction but developed concentric hypertrophy, diastolic dysfunction, slowed muscle strip relaxation, increased passive tension, viscosity, and collagen.
- Titin phosphorylation was altered, increasing passive stiffness.
- Isolated cardiomyocytes from AB rats exhibited faster relaxation and enhanced diastolic calcium handling via increased NCX and SERCA2 activity.
Conclusions:
- Diastolic dysfunction in hypertrophied hearts with preserved systolic function arises from cardiac fibrosis and altered titin phosphorylation, which reduce left ventricular compliance.
- Compensatory changes in cardiomyocyte calcium handling do not fully overcome the passive stiffness and fibrosis contributing to diastolic dysfunction.
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