Search

Apoptosis is a common pathological feature in acute myocardial infarction (AMI), however, its role in the later phases (>10 days) of AMI and in post-infarction left ventricular remodeling has not been characterized. The aim of the study was to identify signs of ongoing cell apoptosis late post AMI. Sixteen hearts were collected at autopsy from subjects 12 to 62 days after the onset of AMI. In situ end-labeling of DNA fragmentation (TUNEL) and co-staining with caspase-3 were performed. Double-positive cells were defined as apoptotic and the apoptotic rate was calculated. Values are expressed as median and interquartile range. Co-stainings with muscle-actin, splicing factor (SC35), PCNA, bax and bcl-2 were also performed. Apoptotic rates at site of infarction [25.4% (17.0–28.4%)] were significantly higherv those at remote regions [0.7% (0.5–0.8%) P<0.001] and significantly correlated to left ventricular longitudinal and transverse diameters [ r=+0.70 (P=0.016) andr =+0.63 (P=0.004) respectively]. Moreover, in subjects with persistently occluded infarct-related artery (14 cases) there was a significantly higher apoptotic rate at the site of infarction compared to those (2 cases) with patent artery [26.0% (21.9–28.5%) v 4.5% (0.6% and 8,4%);P=0.033]. A significantly greater bax immuno-reactivity close to the infarction v remote areas was found (P<0.001). High grade apoptosis is present at sites of infarction in the later phases post AMI. This is more evident if the infarct-related artery is persistently occluded and signs of ventricular remodeling are present. These data may provide an explanation of progressive late left ventricular dysfunction. [ABSTRACT FROM AUTHOR]

• Aging promotes diastolic dysfunction and fibrosis. • Genetic deletion of the IL-1RI protected mice from age-associated diastolic dysfunction. • IL-1RI deficiency mitigates interstitial myocardial fibrosis. • Interleukin-1 signaling promotes the development of aging-associated cardiomyopathy. Aging is associated with metabolic and structural changes causing heart failure with preserved ejection fraction (HFpEF). Interleukin-1 (IL-1) is a pro-inflammatory cytokine involved in aging-related inflammation. We sought to determine whether IL-1 mediates aging-related changes in the heart, as seen in HFpEF. We studied age-matched young (4-month-old), middle-aged (14-month-old), and old (23-month-old) wild-type (WT) C57BL/6J and IL-1 receptor type I deficient (IL1RI-KO) male mice. Echocardiography was used to evaluate left ventricular (LV) dimensions and systolic/diastolic function, and a pressure transducer was used to measure the LV end-diastolic pressure. Picrosirius red stain was used to assess for myocardial interstitial fibrosis (MIF) at pathology. WT and IL-1RIKO mice showed a normal cardiac phenotype at young age, without any differences between the two groups. With aging, the WT mice developed LV concentric hypertrophy (as measured by a significant increase in LV mass [+42%, P < 0.01] and relative wall thickness [+34%, P < 0.01]), whereas the aging IL-1RI-KO mice did not. With aging, the WT mice also developed diastolic dysfunction (as measured by a significant increase in isovolumetric relaxation time [+148%, P < 0.01] and a significantly higher LV end-diastolic pressure [+174%, P < 0.01]), whereas the aging IL1RI-KO did not. Aged WT mice showed a significant increase in MIF (+124%, P < 0.01) at cardiac pathology, whereas the aging IL-1RI-KO did not. Genetically-modified mice lacking the IL-1RI receptor, not responsive to IL-1, are protected from aging-related LV hypertrophy, fibrosis, and diastolic dysfunction. These data support a central role of IL-1 in the pathophysiology of aging-related HFpEF. [ABSTRACT FROM AUTHOR]

Abstract: Alpha-1-antitrypsin (AAT) possesses anti-inflammatory and tissue-protective properties. Here, we studied the effects of exogenously administered AAT on caspase-1 activity and on the outcome of ischemia–reperfusion injury (I/R) in a mouse model of acute myocardial infarction (AMI). Adult male mice underwent 30min of coronary artery ligation followed by reperfusion and were randomly assigned to receive clinical-grade AAT or albumin at reperfusion. Infarct size was evaluated after 1 and 7days. Caspase-1 activity was measured in homogenates of heart tissue. Left ventricular (LV) end-diastolic diameter (EDD) and end-systolic diameter (ESD) were measured and LV fractional shortening (FS) and ejection fraction (EF) were calculated using transthoracic echocardiography. The effect of AAT on caspase-1 activity was determined in cultures of mouse HL-1 cardiomyocytes stimulated with LPS and triggered with nigericin or when HL-1 cells were exposed to simulated ischemia. AAT-treated mice had significantly smaller infarct sizes (−30% day 1 and −55% day 7) compared with mice treated with albumin. AAT treatment resulted in >90% reduction in caspase-1 activity in homogenates of hearts 24h after I/R. Seven days after AMI, AAT-treated mice exhibited a >90% smaller increase in LVEDD and LVESD and smaller reduction in LVEF. The increase in caspase-1 activity in HL-1 cells induced by LPS and nigericin or following exposure to simulated ischemia was reduced by >80% and AAT similarly reduced cell death by >50%. In conclusion, exogenous administration of clinical grade AAT reduces caspase-1 activity in the ischemic myocardium leading to preservation of viable myocardium and prevention of adverse cardiac remodeling. [Copyright &y& Elsevier]