Serial magnetic resonance imaging based assessment of the early effects of an ACE inhibitor on postinfarction left ventricular remodeling in rats

In vivo assessment of treatment efficacy on postinfarct left ventricular (LV) remodeling is crucial for experimental studies. We examined the technical feasibility of serial magnetic resonance imaging (MRI) for monitoring early postinfarct remodeling in rats. MRI studies were performed with a 7-Tesla unit, 1, 3, 8, 15, and 30 days after myocardial infarction (MI) or sham operation, to measure LV mass, volume, and the ejection fraction (EF). Three groups of animals were analyzed: sham-operated rats (n = 6), MI rats receiving lisinopril (n = 11), and MI rats receiving placebo (n = 8). LV dilation occurred on day 3 in both MI groups. LV end-systolic and end-diastolic volumes were significantly lower in lisinopril-treated rats than in placebo-treated rats at days 15 and 30. EF was lower in both MI groups than in the sham group at all time points, and did not differ between the MI groups during follow-up. Less LV hypertrophy was observed in rats receiving lisinopril than in rats receiving placebo at days 15 and 30. We found acceptable within- and between-observer agreement and an excellent correlation between MRI and ex vivo LV mass (r = 0.96; p < 0.001). We demonstrated the ability of MRI to detect the early beneficial impact of angiotensin-converting enzyme (ACE) inhibitors on LV remodeling. Accurate and noninvasive, MRI is the tool of choice to document response to treatment targeting postinfarction LV remodeling in rats

RISK and SAFE signaling pathway interactions in remote limb ischemic perconditioning in combination with local ischemic postconditioning

Local ischemic postconditioning (IPost) and remote ischemic perconditioning (RIPer) are promising methods to decrease ischemia–reperfusion (I/R) injury. We tested whether the use of the two procedures in combination led to an improvement in cardioprotection through a higher activation of survival signaling pathways. Rats exposed to myocardial I/R were allocated to one of the following four groups: Control, no intervention at myocardial reperfusion; IPost, three cycles of 10-s coronary artery occlusion followed by 10-s reperfusion applied at the onset of myocardial reperfusion; RIPer, 10-min limb ischemia followed by 10-min reperfusion initiated 20 min after coronary artery occlusion; IPost+RIPer, IPost and RIPer in combination. Infarct size was significantly reduced in both IPost and RIPer (34.25 ± 3.36 and 24.69 ± 6.02%, respectively) groups compared to Control (54.93 ± 6.46%, both p < 0.05). IPost+RIPer (infarct size = 18.04 ± 4.86%) was significantly more cardioprotective than IPost alone (p < 0.05). RISK pathway (Akt, ERK1/2, and GSK-3β) activation was enhanced in IPost, RIPer, and IPost+RIPer groups compared to Control. IPost+RIPer did not enhance RISK pathway activation as compared to IPost alone, but instead increased phospho-STAT-3 levels, highlighting the crucial role of the SAFE pathway. In IPost+RIPer, a SAFE inhibitor (AG490) abolished cardioprotection and blocked both Akt and GSK-3β phosphorylations, whereas RISK inhibitors (wortmannin or U0126) abolished cardioprotection and blocked STAT-3 phosphorylation. In our experimental model, the combination of IPost and RIPer improved cardioprotection through the recruitment of the SAFE pathway. Our findings also indicate that cross talk exists between the RISK and SAFE pathways

Three-dimensional MRI assessment of regional wall stress after acute myocardial infarction predicts postdischarge cardiac events

PURPOSE: To determine the prognostic significance of systolic wall stress (SWS) after reperfused acute myocardial infarction (AMI) using MRI. MATERIALS AND METHODS: A total of 105 patients underwent MRI 7.8 +/- 4.2 days after AMI reperfusion. SWS was calculated by using a three-dimensional (3D) MRI approach to left ventricular (LV) wall thickness and to the radius of curvature. Between hospital discharge and the end of follow-up, an average of 4.1 +/- 1.7 years after AMI, 19 patients experienced a major cardiac event, including cardiac death, nonfatal reinfarction or heart failure (18.3%). RESULTS: The results were mainly driven by heart failure outcome. In univariate analysis the following factors were predictive of postdischarge major adverse cardiac events: 1) at the time of AMI: higher heart rate, previous calcium antagonist treatment, in-hospital congestive heart failure, proximal left anterior descending artery (LAD) occlusion, a lower ejection fraction, higher maximal ST segment elevation before reperfusion, and ST segment reduction lower than 50% after reperfusion; 2) MRI parameters: higher LV end-systolic volume, lower ejection fraction, higher global SWS, higher SWS in the infarcted area (SWS MI) and higher SWS in the remote myocardium (SWS remote). In the final multivariate model, only SWS MI (odds ratio [OR]: 1.62; 95% confidence interval [CI]: 1.01-2.60; P = 0.046) and SWS remote (OR: 2.17; 95% CI: 1.02-4.65; P = 0.046) were independent predictors. CONCLUSION: Regional SWS assessed by means of MRI a few days after AMI appears to be strong predictor of postdischarge cardiac events, identifying a subset of at risk patients who could qualify for more aggressive management

Myocardial reperfusion injury management: erythropoietin compared with postconditioning

Ischemic postconditioning (IPost) and erythropoietin (EPO) have been shown to attenuate myocardial reperfusion injury using similar signaling pathways. The aim of this study was to examine whether EPO is as effective as IPost in decreasing postischemic myocardial injury in both Langendorff-isolated-heart and in vivo ischemia-reperfusion rat models. Rat hearts were subjected to 25 min ischemia, followed by 30 min or 2 h of reperfusion in the isolated-heart study. Rats underwent 45 min ischemia, followed by 24 h of reperfusion in the in vivo study. In both studies, the control group (n = 12; ischemia-reperfusion only) was compared with IPost (n = 16; 3 cycles of 10 s reperfusion/10 s ischemia) and EPO (n = 12; 1,000 IU/kg) at the onset of reperfusion. The following resulted. First, in the isolated hearts, IPost or EPO significantly improved postischemic recovery of left ventricular developed pressure. EPO induced better left ventricular developed pressure than IPost at 30 min of reperfusion (73.18 ± 10.23 vs. 48.11 ± 7.92 mmHg, P < 0.05). After 2 h of reperfusion, the infarct size was significantly lower in EPO-treated hearts compared with IPost and control hearts (14.36 ± 0.60%, 19.11 ± 0.84%, and 36.21 ± 4.20% of the left ventricle, respectively; P < 0.05). GSK-3β phosphorylation, at 30 min of reperfusion, was significantly higher with EPO compared with IPost hearts. Phosphatidylinositol 3-kinase and ERK1/2 inhibitors abolished both EPO- and IPost-mediated cardioprotection. Second, in vivo, IPost and EPO induced an infarct size reduction compared with control (40.5 ± 3.6% and 28.9 ± 3.1%, respectively, vs. 53.7 ± 4.3% of the area at risk; P < 0.05). Again, EPO decreased significantly more infarct size and transmurality than IPost (P < 0.05). In conclusion, with the use of our protocols, EPO showed better protective effects than IPost against reperfusion injury through higher phosphorylation of GSK-3β

De novo atrial fibrillation as an independent prognostic marker after ST-segment elevation myocardial infarction: Results from the RIMA registry

BACKGROUND: Atrial fibrillation (AF) is common in ST-segment elevation myocardial infarction (STEMI), but its influence on prognosis remains controversial. AIM: We examined the 1-year prognostic value of AF in STEMI, distinguishing patients with prior AF from patients with de novo AF. METHODS: Between January 2004 and December 2015, 3173 STEMI patients were enrolled in the RIMA registry (Registre des Infarctus en Maine Anjou). They were divided into 3 groups: (1) AF-free patients; (2) patients with known prior AF; and (3) patients with de novo AF during hospitalization (including admission). We defined 3 primary outcomes at 1-year post-discharge: cardiovascular mortality, readmission for heart failure (HF), and stroke. Temporal onset of de novo AF was also studied. RESULTS: A total 158 patients (5%) had prior AF, and 278 (8.8%) presented de novo AF. Prior AF patients were significantly older [81 (73;86) years] with more comorbidities, but de novo AF patients presented with a greater creatine kinase peak and lower left ventricular ejection fraction [LVEF=44 (35;50)% for de novo AF vs 50 (40;55)% for prior AF, p<0.001]. At 1-year follow-up, cardiovascular mortality was higher in cases of AF (13.5% for prior AF vs 9.2% for de novo AF, compared with 2.4% for AF-free patients, p<0.001). After adjustments, only de novo AF was correlated with cardiovascular mortality (hazard ratio 2.49; 95% CI 1.32-4.67; p=0.004), but both types of AF were correlated with readmission for HF. There was no significant difference in respect of stroke between prior AF, de novo AF, and AF-free (2.2%, 0.5%, and 0.8%, respectively, p=0.327). Finally, outcomes did not differ between AF occurring <24h after admission (n=127) and de novo AF occurring within ≥24h (n=151). CONCLUSION: De novo AF was independently associated with 1-year cardiovascular mortality. It should not be considered as an intercurrent event of STEMI, but rather as a strong prognostic marker

Animal welfare implications of surgical castration and its alternatives in pigs

This paper constitutes a review on the welfare aspects of piglet castration that considers the scientific literature published after 2004. Castrating during the neonatal period (1 to 3 days of age) is clearly painful. In addition, inflammatory processes may take place at the sites of incision, thus adding further pain to the procedure. Surgical castration with general and local anaesthesia, in combination with long-term analgesia, has been shown to reduce pain but the additional handling and injection of the anaesthetic, the effectiveness and limited safety margins have to be thoroughly evaluated. Raising entire males during the whole fattening period or immunocastration of males towards the end of the fattening period are other alternatives with welfare benefits in young pigs compared to current surgical castration, but with some potential welfare drawbacks regarding handling stress and behaviour during fattening. Based on the current knowledge, it can be concluded that sperm sexing and raising entire males after genetic control of boar taint are potentially preferable alternatives to current practices, but need further research, as these methods are not yet availabl

Endoplasmic reticulum stress pathway involvement in local and remote myocardial ischemic conditioning.

Remote ischemic perconditioning (RIPer) and local ischemic postconditioning (IPost) are promising methods to decrease ischemia-reperfusion injury. We tested whether these two methods were effective in reducing infarct size through activation of endoplasmic reticulum (ER) stress response, a potential survival pathway. Rats exposed to myocardial ischemia-reperfusion were allocated to one of six groups: control, no intervention at myocardial reperfusion; IPost, three cycles of 10-s coronary artery occlusion followed by 10-s reperfusion applied at the onset of myocardial reperfusion; RIPer, 10-min limb ischemia followed by 10-min reperfusion initiated during coronary artery occlusion; control + 4-PBA, injection of ER stress inhibitor 4-phenylbutyrate (4-PBA) 1 h before coronary occlusion; IPost + 4-PBA; and RIPer + 4-PBA. Infarct size was significantly reduced in IPost and RIPer groups (33.32% ± 3.65% and 21.86% ± 3.98%, respectively) compared with the control group (54.86% ± 6.01%, P < 0.05). Western blot analysis of GRP78 (glucose-regulated protein) level and cleaved activating transcription factor 6, two ER stress markers, demonstrated an enhancement of ER stress response in IPost group but not in RIPer group at 15-min reperfusion. Furthermore, 4-PBA abolished cardioprotection induced by IPost (infarct size 53.75 ± 3.49 vs. 33.32 ± 3.65%, P < 0.05) but not by RIPer (28.80 ± 10.45% vs. 21.86 ± 3.98%, not statistically significant). GRP78 and cleaved activating transcription factor 6 levels were no longer increased in IPost group after 4-PBA. These findings point to a role for ER stress response in cardioprotection against reperfusion injury in IPost but not RIPer, suggesting differences in cardioprotective mechanisms between local and remote conditioning

Microparticle release in remote ischemic conditioning mechanism

Remote ischemic conditioning (RCond) induced by short periods of ischemia and reperfusion of an organ or tissue before myocardial reperfusion is an attractive strategy of cardioprotection in the context of acute myocardial infarction. Nonetheless, its mechanism remains unknown. A humoral factor appears to be involved, although its identity is currently unknown. We hypothesized that the circulating microparticles (MPs) are the link between the remote tissue and the heart. MPs from rats and healthy humans undergoing RCond were characterized. In rats, RCond was induced by 10 min of limb ischemia. In humans, RCond was induced by three cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff. In the second part of the study, rats underwent 40 min myocardial ischemia followed by 2 h reperfusion. Infarct size was measured and compared among three groups of rats: 1) myocardial infarction alone (MI) (n = 6); 2) MI + RCond started 20 min after coronary ligation (n = 6); and 3) MI + injection of RCond-derived rat MPs (MI + MPs) (n = 5). MPs from endothelial cells (CD54(+) and CD146(+) for rats and humans, respectively) and procoagulant MPs (Annexin V(+)) markedly increased after RCond, both in rats and humans. RCond reduced infarct size (24.4 ± 5.9% in MI + RCond vs. 54.6 ± 4.7% in MI alone; P < 0.01). Infarct size did not decrease in MI + MPs compared with MI alone (50.2 ± 6.4% vs. 54.6 ± 4.7%, not significantly different). RCond increased endothelium-derived and procoagulant MPs in both rats and humans. However, MP release did not appear to be a biological vector of RCond in our model