Alteration in Left Ventricular Contractile Function Develops in Puppies With Duchenne Muscular Dystrophy

International audienceBackground: Dystrophin-deficient cardiomyopathy is becoming the dominant cause of death in patients with Duchenne muscular dystrophy (DMD), but its developmental process remains elusive. This study aimed to assess the development of left ventricular (LV) dysfunction that mimics DMD pathologies in golden retriever muscular dystrophy (GRMD) dogs.Methods: Transthoracic echocardiography was sequentially performed in GRMD dogs (n = 23) and age-matched healthy littermates (n = 7) from 2 to 24 months old. Conventional, tissue Doppler imaging, and speckle-tracking echocardiography parameters were analyzed.Results: At 2 months of age, GRMD dogs showed a pathologic decrease in the subendocardial-subepicardial gradient of radial systolic myocardial velocity along with altered LV twist and longitudinal strain, all being aggravated with age (analysis of variance, P < .001). Receiver operator characteristic curve analysis showed good ability to discriminate normal from GRMD dogs. LV ejection fraction was significantly decreased in GRMD dogs starting from 9 months and reached a pathologic level (<50%) at 24 months.Conclusions: The development of cardiomyopathy in GRMD dogs was characterized by subendocardial dysfunction, altered LV twist, and reduced longitudinal strain at a very young age to overall LV dysfunction in adults with transmural dysfunction, reduced LV ejection fraction and diastolic abnormalities, and even heart failure. This indicates the necessity to evaluate LV transmural myocardial velocity gradient, twist, and longitudinal strain in the early childhood of DMD patients

The cardiac renin-angiotensin system is responsible for high-salt diet-induced left ventricular hypertrophy in mice.

International audienceAIMS: This study aimed to determine the role of the renin-angiotensin system (RAS) in high-salt (HS) diet-induced left ventricular hypertrophy (LVH). METHODS AND RESULTS: Swiss mice were subjected to regular salt (RS) diet (0.6% NaCl), HS diet (4% NaCl), and HS plus irbesartan (50 mg/kg/day) or ramipril (1 mg/kg/day). After 8 weeks, arterial pressure was similar in all groups and similar to baseline, whereas left ventricle/body weight ratio was higher in HS mice than in RS mice (P < 0.005). There were also significant increases in collagen density, angiotensin-converting enzyme activity, angiotensin II type 1 receptor (AT1 receptor) density, and extracellular signal-regulated kinase (ERK1/2) phosphorylation in the left ventricle. Interestingly, increases in wall thickness and ERK1 phosphorylation were more marked in the septum than in the rest of the left ventricle. Irbesartan or ramipril treatment prevented LVH and the increase in ERK phosphorylation and reduced collagen content and AT1 up-regulation but up-regulated AT2 receptors. CONCLUSION: In normal mice, HS diet induces septum-predominant LVH and fibrosis through activation of the cardiac RAS-ERK pathway, which can be blocked by irbesartan or ramipril, indicating a key role of the cardiac RAS in HS diet-induced LVH

Ivabradine improves left ventricular twist and untwist during chronic hypertension

International audienceBackgroundLeft ventricular (LV) dysfunction develops during LV hypertrophy and particularly during tachycardia. Thus we investigated the effects of heart rate (HR) reduction with ivabradine, an If-channel blocker, on LV twist and untwist which represents myocardial deformation occurring during the overall systole and diastole and therefore provide valuable evaluation of global LV systolic and diastolic function.MethodsEight chronically instrumented pigs receiving continuous angiotensin II infusion during 28 days to induce chronic hypertension and LV hypertrophy. Measurements were performed at Days 0 and 28 after stopping angiotensin II infusion in the presence and absence of ivabradine.ResultsAt Day 0, reducing HR from 75 ± 3 to 55 ± 2 beats/min with ivabradine did not affect LV twist but slowed LV untwist along with an increase in LV end-diastolic pressure. At Day 28, LV posterior and septal wall thickness as well as the estimated LV mass increased, indicating LV hypertrophy. LV twist and untwist were significantly reduced by 33 ± 4% from 16 ± 1° and 32 ± 6% from − 154 ± 9°/s, respectively, showing global LV systolic and diastolic dysfunction. In this context, ivabradine decreased HR by 25% from 86 ± 5 beats/min and significantly improved LV twist from 11 ± 1 to 14 ± 1° and LV untwist from − 104 ± 8 to − 146 ± 5°/s.ConclusionsAdministration of ivabradine during chronic hypertension and LV hypertrophy improved LV twist and untwist. This further supports the beneficial effect of this drug on both LV systolic and diastolic function during the development of LV hypertrophy

Cardioprotective effect of sonic hedgehog ligand in pig models of ischemia reperfusion.

International audienceSonic hedgehog (SHH) signaling pathway is involved in embryonic tissue patterningand development. Our previous work identified, in small rodent model of ischemiareperfusion, SHH as a specific efficient tool to reduce infarct size and subsequentarrhythmias by preventing ventricular repolarization abnormalities. The goal of thepresent study was to provide a proof of concept of the cardioprotective effect of SHHligand in a porcine model of acute ischemia.Methods: The antiarrhythmic effect of SHH, either by a recombinant peptide (NSHH)or shed membrane microparticles harboring SHH ligand (MPsSHH+), wasevaluated in a first set of pigs following a short (25 min) coronary artery occlusion(CAO) followed by 24 hours-reperfusion (CAR) (Protocol A). The infarct-limitingeffect was evaluated on a second set of pigs with 40 min of coronary artery occlusionfollowed by 24 hours reperfusion (Protocol B). Electrocardiogram (ECG) wasrecorded and arrhythmia’s scores were evaluated. Area at risk and myocardial infarctsize were quantified.Results: In protocol A, administration of N-SHH 15 min. after the onset of coronaryocclusion significantly reduced the occurrence of ventricular fibrillation compared tocontrol group. Evaluation of arrhythmic score showed that N-SHH treatmentsignificantly reduced the overall occurrence of arrhythmias. In protocol B, massiveinfarction was observed in control animals. Either N-SHH or MPsSHH+ treatmentreduced significantly the infarct size with a concomitant increase of salvaged area. Thereduction in infarct size was both accompanied by a significant decrease in systemicbiomarkers of myocardial injury, i.e., cardiac troponin I and fatty acid-binding proteinand an increase of eNOS activation.Conclusions: We show for the first time in a large mammalian model that the activationof the SHH pathway by N-SHH or MPsSHH+ offers a potent protection of the heart toischemia-reperfusion by preventing the reperfusion arrhythmias, reducing the infarctarea and the circulating levels of biomarkers for myocardial injury. These data open uppotentially theranostic prospects for patients suffering from myocardial infarction toprevent the occurrence of arrhythmias and reduce myocardial tissue damage

Impaired left ventricular function in the presence of preserved ejection in chronic hypertensive conscious pigs.

International audienceSystolic function is often evaluated by measuring ejection fraction and its preservation is often assimilated with the lack of impairment of systolic left ventricular (LV) function. Considering the left ventricle as a muscular pump, we explored LV function during chronic hypertension independently of increased afterload conditions. Fourteen conscious and chronically instrumented pigs received continuous infusion of either angiotensin II (n = 8) or saline (n = 6) during 28 days. Hemodynamic recordings were regularly performed in the presence and 1 h after stopping angiotensin II infusion to evaluate intrinsic LV function. Throughout the protocol, the mean arterial pressure steadily increased by 55 ± 4 mmHg in angiotensin II-treated animals. There were no significant changes in stroke volume, LV fractional shortening or LV wall thickening, indicating the lack of alterations in LV ejection. In contrast, we observed maladaptive changes with (1) the lack of reduction in isovolumic contraction and relaxation durations with heart rate increases, (2) abnormally blunted isovolumic contraction and relaxation responses to dobutamine and (3) a linear correlation between isovolumic contraction and relaxation durations. None of these changes were observed in saline-infused animals. In conclusion, we provide evidence of impaired LV function with concomitant isovolumic contraction and relaxation abnormalities during chronic hypertension while ejection remains preserved and no sign of heart failure is present. The evaluation under unloaded conditions shows intrinsic LV abnormalities

Concomitant systolic and diastolic alterations during chronic hypertension in pig

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Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling.

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction