Changes in diastolic stress, not systolic stress, attenuate the development of load‐induced hypertrophy in FHL1 null myocardium

Although most studies correlate an increase in systolic stress with pressure overload hypertrophy, there is some evidence suggesting diastolic stress/strain may play the greater role. A culture system was developed in which the application of uniaxial stresses to papillary muscles from knockout (KO) mice can induce a hypertrophic response, while simultaneously assessing tissue mechanical properties. After 5 hrs of 15% stretch, muscles express hypertrophic markers ANP & BNP. By comparing the linear regressions of ANP expression verses passive or active stress we found that a higher statistical correlation exists between ANP induction and passive stress than active systolic stress. We compared the development of hypertrophy in KO mice with abnormal diastolic tissue mechanical properties. ANP gene expression in muscles from muscle LIM protein KO mice, a well characterized mouse model having significant diastolic dysfunction, was ~4 times lower when compared to controls. Four & a half LIM protein (FHL1) KO mice exhibited a blunted hypertrophic response and lower ANP levels after 35 days aortic banding. ANP induction by stretch in muscles from FHL1KO mice was also reduced (P<0.05). FHL1KO muscles exhibited greater diastolic tissue compliance, with no change in systolic mechanics. We conclude that changes in passive mechanics correlate with attenuated development of pressure overload hypertrophy in FHL1KO mice.