Abstract
Neonatal mice exhibit natural heart regeneration after myocardial infarction (MI) on postnatal day 1 (P1), but this ability is lost by postnatal day 7 (P7). Cardiac biomechanics intricately affect long-term heart function, but whether regenerated cardiac muscle is biomechanically similar to native myocardium remains unknown. We hypothesized that neonatal heart regeneration preserves native left ventricular (LV) biomechanical properties after MI. C57BL/6J mice underwent sham surgery or left anterior descending coronary artery ligation at age P1 or P7. Echocardiography performed 4 weeks post-MI showed that P1 MI and sham mice (n = 22, each) had similar LV wall thickness, diameter, and ejection fraction (59.6% vs 60.7%, p = 0.6514). Compared to P7 shams (n = 20), P7 MI mice (n = 20) had significant LV wall thinning, chamber enlargement, and depressed ejection fraction (32.6% vs 61.8%, p < 0.0001). Afterward, the LV was explanted and pressurized ex vivo, and the multiaxial lenticular stress-strain relationship was tracked. While LV tissue modulus for P1 MI and sham mice were similar (341.9 kPa vs 363.4 kPa, p = 0.6140), the modulus for P7 MI mice was significantly greater than that for P7 shams (691.6 kPa vs 429.2 kPa, p = 0.0194). We conclude that, in neonatal mice, regenerated LV muscle has similar biomechanical properties as native LV myocardium.
Highlights
Cardiac regeneration represents a promising potential solution for the treatment or prevention of heart failure after MI11
Our study is the first to investigate left ventricular (LV) biomechanics after myocardial infarction (MI) induced by coronary artery ligation in a neonatal mammalian model of natural heart regeneration
Using lenticular hydrostatic deformation analysis, we observed that the endogenous neocardiomyogenesis program that acts in response to MI in postnatal day 1 (P1) mice fully preserves native LV biomechanical properties at 4 weeks after injury
Summary
Cardiac regeneration represents a promising potential solution for the treatment or prevention of heart failure after MI11. Recent studies by our team and others have demonstrated that newborn mice are capable of robust natural heart regeneration after MI15–18. This intrinsic neocardiomyogenic process, which is active in mice on postnatal day 1 (P1) but lost by postnatal day 7 (P7), results in preservation of normal LV size and function, as well as minimal replacement of LV muscle by collagen scar after MI. A previous study employed a cryoinjury model in adult zebrafish, and demonstrated using micropipette aspiration that while the injured myocardium stiffened acutely after sustaining damage, myocardial biomechanics fully normalized by 5 weeks after injury in association with complete natural cardiac regeneration[24]. We apply lenticular hydrostatic deformation analysis to study the biomechanical properties of neonatal mouse hearts after MI-induced natural cardiac regeneration. After P7 MI, mouse hearts that fail to regenerate exhibit significant tissue stiffening due to collagen scar formation
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