Search

Background: Polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the benefits of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on cardiovascular events after acute coronary syndrome. We hypothesized that Adcy9 inactivation could improve cardiac function and remodelling following myocardial infarction (MI) in absence of CETP activity., Methods: Wild-type (WT) and Adcy9-inactivated (Adcy9 Gt/Gt ) male mice, transgenic or not for human CETP (tgCETP +/- ), were subjected to MI by permanent left anterior descending coronary artery ligation and studied for 4 weeks. Left ventricular (LV) function was assessed by echocardiography at baseline, 1, and 4 weeks after MI. At sacrifice, blood, spleen and bone marrow cells were collected for flow cytometry analysis, and hearts were harvested for histologic analyses., Results: All mice developed LV hypertrophy, dilation, and systolic dysfunction, but Adcy9 Gt/Gt mice exhibited reduced pathologic LV remodelling and better LV function compared with WT mice. There were no differences between tgCETP +/- and Adcy9 Gt/Gt tgCETP +/- mice, which both exhibited intermediate responses. Histologic analyses showed smaller cardiomyocyte size, reduced infarct size, and preserved myocardial capillary density in the infarct border zone in Adcy9 Gt/Gt vs WT mice. Count of bone marrow T cells and B cells were significantly increased in Adcy9 Gt/Gt mice compared with the other genotypes., Conclusions: Adcy9 inactivation reduced infarct size, pathologic remodelling, and cardiac dysfunction. These changes were accompanied by preserved myocardial capillary density and increased adaptive immune response. Most of the benefits of Adcy9 inactivation were only observed in the absence of CETP., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

MK5 is a protein serine/threonine kinase activated by p38, ERK3, and ERK4 MAPKs. MK5 mRNA and immunoreactivity are detected in mouse cardiac fibroblasts, and MK5 haplodeficiency attenuates the increase in collagen 1-α1 mRNA evoked by pressure overload. The present study examined the effect of MK5 haplodeficiency on reparative fibrosis following myocardial infarction (MI). Twelve-week-old MK5 +/- and wild-type littermate (MK5 +/+ ) mice underwent ligation of the left anterior descending coronary artery (LADL). Surviving mice were euthanized 8 or 21 days post-MI. Survival rates did not differ significantly between MK5 +/+ and MK5 +/- mice, with rupture of the LV wall being the primary cause of death. Echocardiographic imaging revealed similar increases in LV end-diastolic diameter, myocardial performance index, and wall motion score index in LADL-MK5 +/+ and LADL-MK5 +/- mice. Area at risk did not differ between LADL-MK5 +/+ and LADL-MK5 +/- hearts. In contrast, infarct size, scar area, and scar collagen content were reduced in LADL-MK5 +/- hearts. Immunohistochemical analysis of mice experiencing heart rupture revealed increased MMP-9 immunoreactivity in the infarct border zone of LADL-MK5 +/- hearts compared with LADL-MK5 +/+ . Although inflammatory cell infiltration was similar in LADL-MK5 +/+ and LADL-MK5 +/- hearts, angiogenesis was more pronounced in the infarct border zone of LADL-MK5 +/- mice. Characterization of ventricular fibroblasts revealed reduced motility and proliferation in fibroblasts isolated from MK5 -/- mice compared with those from both wild-type and haplodeficient mice. siRNA-mediated knockdown of MK5 in fibroblasts from wild-type mice also impaired motility. Hence, reduced MK5 expression alters fibroblast function and scar morphology but not mortality post-MI. NEW & NOTEWORTHY MK5/PRAK is a protein serine/threonine kinase activated by p38 MAPK and/or atypical MAPKs ERK3/4. MK5 haplodeficiency reduced infarct size, scar area, and scar collagen content post-myocardial infarction. Motility and proliferation were reduced in cultured MK5-null cardiac myofibroblasts.

Background: Atrial tissue fibrosis is often an important component of the atrial fibrillation (AF) substrate. Small noncoding microRNAs are important mediators in many cardiac remodeling paradigms. MicroRNA-21 (miR-21) has been suggested to be important in ventricular fibrotic remodeling by downregulating Sprouty-1, a protein that suppresses fibroblast proliferation. The present study examined the potential role of miR-21 in the atrial AF substrate resulting from experimental heart failure after myocardial infarction (MI)., Methods and Results: Large MIs (based on echocardiographic left ventricular wall motion score index) were created by left anterior descending coronary artery ligation in rats. Changes induced by MI versus sham controls were first characterized with echocardiography, histology, biochemistry, and in vivo electrophysiology. Additional MI rats were then randomized to receive anti-miR-21 (KD21) or scrambled control sequence (Scr21) injections into the left atrial myocardium. Progressive left ventricular enlargement, hypocontractility, left atrial dilation, fibrosis, refractoriness prolongation, and AF promotion occurred in MI rats versus sham controls. Atrial tissues of MI rats showed upregulation of miR-21, along with dysregulation of the target genes Sprouty-1, collagen-1, and collagen-3. KD21 treatment reduced atrial miR-21 expression levels in MI rats to values in sham rats, decreased AF duration from 417 (69-1595; median [Q1-Q3]) seconds to 3 (2-16) seconds (8 weeks after MI; P<0.05), and reduced atrial fibrous tissue content from 14.4 ± 1.8% (mean ± SEM) to 4.9 ± 1.2% (8 weeks after MI; P<0.05) versus Scr21 controls., Conclusions: MI-induced heart failure leads to AF-promoting atrial remodeling in rats. Atrial miR-21 knockdown suppresses atrial fibrosis and AF promotion, implicating miR-21 as an important signaling molecule for the AF substrate and pointing to miR-21 as a potential target for molecular interventions designed to prevent AF.

Background: Early prediction of infarct size and of the subsequent development of congestive heart failure (CHF) and pulmonary hypertension (PH) would be useful in therapeutic trials using the rat myocardial infarction (MI) model., Methods: A total of 194 rats were subjected to MI or sham surgery, and plasma cardiac troponin T (cTnT) was measured 24 h after surgery in rats. Echocardiography was performed after 2 and 5 weeks. Hemodynamic and morphometric parameters were evaluated 5 weeks after MI., Results: cTnT had strong positive correlations with left ventricular (LV) wall motion abnormalities at 2 and 5 weeks (R=.85 and .89; P<.0001), and with histological infarct size (R=.87, P<.0001). cTnT ≥5.1 μg/l predicted LV wall motion abnormalities ≥ 30% with a sensitivity of 90.9% and specificity of 84.0%. Rats with cTnT≥5.1 μg/l developed PH [right ventricular (RV) systolic pressure 37 ± 3 vs. 23 ± 0.6 mmHg], RV hypertrophy (RV/LV+septum weight 42 ± 4% vs. 24 ± 0.5%), and lung structural remodeling (all P<.01)., Conclusion: Early single cTnT measurement correlates with infarct size in rats, and a cutoff value of 5.1 μg/l provides good sensitivity and specificity to predict CHF with secondary PH. cTnT could be used for treatment allocations in therapeutic trials of secondary pulmonary hypertension using this model., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Studies have suggested some benefit of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors in congestive heart failure (CHF), although the mechanisms remain uncertain. We hypothesized that statins could improve pulmonary hypertension and right ventricular function in ischemic CHF by reducing lung remodeling., Methods and Results: Two weeks after myocardial infarct, rats received atorvastatin (n = 23) or no treatment (n = 23) for 3 weeks and were compared with a sham group (n = 16). Infarct size was similar by echocardiography and pathologic evaluations. Atorvastatin greatly reduced pulmonary hypertension and right ventricular hypertrophy: right ventricular systolic pressure 42 +/- 5 vs. 28 +/- 2 mm Hg (P < .01). Atorvastatin did not reduce left ventricular fibrosis and had minimal effects on left ventricular function. Right ventricular myocardial performance index was markedly improved by therapy (P < .01). CHF caused a restrictive lung syndrome with a downward shift of the respiratory pressure-volume loop, increased dry lung weight, and interstitial fibrosis that were greatly improved by atorvastatin. Reduced lung nitric oxide synthase expression was normalized by treatment. Atorvastatin also reduced isolated lung myofibroblasts proliferation after transforming growth factor-beta stimulation (-36 +/- 6%, P < 0.01)., Conclusions: 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibition reduces lung remodeling and dysfunction associated with heart failure with prevention of right ventricular hypertrophy and pulmonary hypertension., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)