Brief repetitive pressure overload in mice induces eccentric remodeling and impaired contractile reserve

Repetitive pressure overload (RPO) in swine leads to the rapid development of increased left ventricular (LV) chamber stiffness, a preserved ejection fraction, and the absence of anatomic hypertrophy, which appears to protect the heart from chronic strain-induced injury. Murine hearts are more amenable to mechanistic approaches modifying specific molecular pathways, but whether mice develop similar adaptive responses to RPO remains undefined. We hypothesized that repetitive pressure overload in mice would increase LV chamber stiffness and attenuate strain-induced myocardial injury, recapitulating key features of the swine model. We subjected mice to single (SPO, n = 8) or daily repetitive pressure overload (RPO, n = 6) using 30-min phenylephrine infusions via a chronically implanted catheter. At baseline, LV end-diastolic pressure was increased after RPO compared with SPO (13 ± 2 mmHg vs. 6 ± 1 mmHg, P < 0.05), whereas ejection fraction remained preserved. During phenylephrine infusion, LV end-diastolic volume increased to a greater extent in RPO than in SPO mice (4.0 ± 0.5 µL/g vs. 2.4 ± 0.1 µL/g, P < 0.05). In contrast to the increased stiffness that develops in swine subjected to RPO, end-diastolic LV chamber stiffness decreased (end-diastolic pressure-volume relationship slope 5 ± 3 vs. 24 ± 4 mmHg/µL/g after SPO, P < 0.05) along with a reduction in contractility (end-systolic pressure-volume relationship 10 ± 2 vs. 33 ± 5 mmHg/µL/g after SPO, P < 0.05). Markers of myocardial injury were increased following pressure overload, including cardiomyocyte apoptosis and circulating troponin I levels, with no attenuation following repetitive exposure. Thus, despite a preserved ejection fraction, repetitive pressure overload in mice results in ventricular dilation, reduced chamber stiffness, and persistent myocardial injury. These findings contrast with the adaptive response observed in swine and highlight important species-specific differences in myocardial remodeling in response to transient pressure overload.NEW & NOTEWORTHY This study introduces a novel murine model of RPO using serial phenylephrine infusions to mimic chronic episodic hemodynamic stress. Unlike porcine models of RPO that demonstrate increased LV chamber stiffness and protection against strain-induced myocyte injury, mice exhibit reduced LV chamber stiffness and persistent myocyte apoptosis that is accompanied by loss systolic dysfunction with a preserved ejection fraction at rest. These findings indicate important species differences in the response to transient pressure overload.