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- W2321923883 abstract "Rationale: Inhibition of calpains, ubiquitous cysteine proteases that require Ca2+ for activity, preserves left ventricular (LV) structure and function at short term post myocardial infarction (MI). However long term effects of this inhibition are still unclear. Objective: The purpose of this study was to examine the effects of calpain inhibition by ubiquitous calpastatin overexpression at long term post MI. Methods and results: Myocardial infarction was generated in transgenic (TG) male mice constitutively overexpressing calpastatin and wild-type (WT) controls. Acute phase mortality (<48h) was comparable between groups. All-cause mortality from 48h to 6w post MI was 43% in TG-MI and 20% WT-MI (log-rank P<0.05). Mortality by LV rupture was 31% in TG-MI and 11% in WT-MI (P<0.05). At 6w post MI, infarct size and LV dilation were comparable, while LV contractility was reduced (+dP/dt 7635±782 vs. 9110±1292mmHg/s; P<0.05), LV end-diastolic pressure was increased (6.7±1.8 vs. 4.9±2.2mmHg, P<0.05), and wet pulmonary weight was more important (185.8±14.4 vs. 153.0±8.6mg, P<0.05) in TG-MI as compared to WT-MI survivors. At that time, remote myocardium (RM) of TG-MI showed more fibrosis (12.8±0.9 vs. 8.8±0.4% in WT-MI, P<0.01) and more cardiac myocyte hypertrophy (539.6±9.4 vs. 463.2±20.2μm2 in WT-MI, P<0.05). To identify underlying mechanisms that might contribute to the worse outcome in TG-MI, a subgroup of animals was sacrificed 5d post MI. Infarct size was comparable between TG-MI and WT-MI. In the peri-infarct myocardium (PIM) of TG-MI mice, fibrosis was less pronounced, microvascularization was reduced, and macrophage and CD4+ T lymphocyte infiltration was impaired as compared to WT-MI (57%, P<0.01; and 79%; P<0.001, respectively). Conclusions: Calpastatin overexpression is deleterious at long term post MI with more severe LV failure and increased mortality owing to cardiac rupture. This is primarily due to an insufficiency in wound healing of the myocardium associated with reduced capillary repair, inflammatory response and extracellular matrix synthesis in the PIM." @default.
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- W2321923883 date "2013-08-02" @default.
- W2321923883 modified "2023-10-15" @default.
- W2321923883 title "Calpastatin overexpression favors cardiac rupture and aggravates left ventricular dysfunction in mice after myocardial infarction" @default.
- W2321923883 doi "https://doi.org/10.1093/eurheartj/eht308.773" @default.
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