Continuous Infusion of Angiotensin IV Protects against Acute Myocardial Infarction via the Inhibition of Inflammation and Autophagy

Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Angiotensin (Ang) IV possesses many biological properties that are not yet completely understood. Therefore, we investigated the function and mechanism of Ang IV in AMI in in vivo and in vitro conditions. AMI was performed by ligation of the left anterior descending coronary artery (LAD) in male C57 mice. Ang IV was continuously infused by a minipump 3 d before AMI for 33 d. The neonatal rat ventricular myocytes (NRVCs) were stimulated with Ang IV and cultured under hypoxic conditions. In vivo, Ang IV infusion significantly reduced the mortality after AMI. By the 7th day after AMI, compared with the AMI group, Ang IV reduced the inflammatory cytokine expression. Moreover, terminal deoxyribonucleotidyl transferase- (TDT-) mediated dUTP nick-end labeling (TUNEL) assay showed that Ang IV infusion reduced AMI-induced cardiomyocyte apoptosis. Compared with AMI, Ang IV reduced autophagosomes in cardiomyocytes and improved mitochondrial swelling and disarrangement, as assessed by transmission electron microscopy. By 30th day after AMI, Ang IV significantly reduced the ratio of heart weight to body weight. Echocardiography showed that Ang IV improved impaired cardiac function. Hematoxylin and eosin (H&E) and Masson staining showed that Ang IV infusion reduced the infarction size and myocardial fibrosis. In vitro, dihydroethidium (DHE) staining and comet assay showed that, compared with the hypoxia group, Ang IV reduced oxidative stress and DNA damage. Enzyme-linked immunosorbent assay (ELISA) showed that Ang IV reduced hypoxia-induced secretion of the tumor necrosis factor- (TNF-) ɑ and interleukin- (IL-) 1β. In addition, compared with the hypoxia group, Ang IV reduced the transformation of light chain 3- (LC3-) I to LC3-II but increased p62 expression and decreased cardiomyocyte apoptosis. Overall, the present study showed that Ang IV reduced the inflammatory response, autophagy, and fibrosis after AMI, leading to reduced infarction size and improved cardiac function. Therefore, administration of Ang IV may be a feasible strategy for the treatment of AMI.

Myocardial Infarction as An Independent Predictor of Intramyocardial Hemorrhage in Acute Reperfused Myocardial Ischemic Rats

Background: In the previous studies, hemorrhage occurred only with the largest infarctions and studies confirmed a moderate correlation between the extent of necrosis and hemorrhage, but the extent of infarction size of these studies was limited. This study was to find the correlations between intramyocardial hemorrhage (IMH), myocardial infarction (MI), and myocardial edema (ME) from days 2 to 7 in a 7.0T MR scanner.Methods: The different degrees of myocardial ischemia were induced by occluding different sections of the proximal left anterior descending coronary artery (1–3 mm under the left auricle). T2*-mapping, T2-mapping and late gadolinium enhancement (LGE) sequences were performed on a 7.0T MR system at day 2 and 7. T2*- and T2-maps were calculated using a custom-made software. All areas were expressed as a percentage of the whole myocardial tissue of the left ventricle. The rats were divided into two groups based on the T2* results; MI with IMH was referred to as the +IMH group, while MI without IMH was referred to as the –IMH group.Results: The final experimental sample consisted of 25 rats in the +IMH group and 10 rats in the –IMH group. For the +IMH group. On day 2, There was a significant positive correlation between IMH size and MI size (r = 0.677, P<0.01), and a positive correlation between IMH size and ME size (r = 0.552, P<0.01). On day 7, There was a significant positive correlation between IMH size and MI size (r = 0.711, P<0.01), while no correlation was found between IMH size and ME size (r = 0.429, P = 0.097). Conclusions: Infarction size prior to reperfusion is a critical factor in determining whether a MI is hemorrhagic or non-hemorrhagic in rats.

Nerolidol, a Sesquiterpene Alcohol, Attenuates Acute Myocardial Infarction in Rats

Cardiovascular diseases have a high morbidity and mortality rate and their treatment is not effective in reducing the damage caused by tissue reperfusion during an acute myocardial infarction (MI). This study aimed to investigate whether nerolidol (NRD), a sesquiterpene alcohol, would attenuate the MI in isoproterenol-treated rat model. MI was induced by the administration of two doses of ISO (100 mg/kg, i.p.) in an interval of 24 h. The animals were divided into 4 groups: control (CTR) (vehicle – saline NaCl 0.9% + TWEEN 80 0.2%), ISO (ISO + vehicle), ISO + NRD (NRD 50 or 100 mg/kg). Electrocardiogram, contractile parameters, cardiac enzymes, infarction size and antioxidant parameters in the heart were measured. ISO group showed a significant rise in ST-segment, QTc and heart rate associated to a reduction of left ventricular developed pressure (LVDP), +dP/dt and –dP/dt. Increase in content of creatine kinase (CK), CK-MB, lactate dehydrogenase (LDH), TBARS and infarction size as well as fall in activities of superoxide dismutase (SOD) and catalase (CAT) were observed. NRD significantly prevented almost all the parameters of ISO-induced MI mentioned above. Our results suggests that nerolidol has a significant effect on the protection of heart through maintaining endogenous antioxidant enzyme activities.

miR155 Deficiency Reduces Myofibroblast Density but Fails to Improve Cardiac Function after Myocardial Infarction in Dyslipidemic Mouse Model

Myocardial infarction remains the most common cause of heart failure with adverse remodeling. MicroRNA (miR)155 is upregulated following myocardial infarction and represents a relevant regulatory factor for cardiac remodeling by engagement in cardiac inflammation, fibrosis and cardiomyocyte hypertrophy. Here, we investigated the role of miR155 in cardiac remodeling and dysfunction following myocardial infarction in a dyslipidemic mouse model. Myocardial infarction was induced in dyslipidemic apolipoprotein E-deficient (ApoE−/−) mice with and without additional miR155 knockout by ligation of the LAD. Four weeks later, echocardiography was performed to assess left ventricular (LV) dimensions and function, and mice were subsequently sacrificed for histological analysis. Echocardiography revealed no difference in LV ejection fractions, LV mass and LV volumes between ApoE−/− and ApoE−/−/miR155−/− mice. Histology confirmed comparable infarction size and unaltered neoangiogenesis in the myocardial scar. Notably, myofibroblast density was significantly decreased in ApoE−/−/miR155−/− mice compared to the control, but no difference was observed for total collagen deposition. Our findings reveal that genetic depletion of miR155 in a dyslipidemic mouse model of myocardial infarction does not reduce infarction size and consecutive heart failure but does decrease myofibroblast density in the post-ischemic scar.

Effect of early Trimetazidine on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention

Purpose: Trimetazidine, a metabolic agent with anti-ischemic effects, was reported to reduce reperfusion injury in animal models. In this randomized double-blind placebo-controlled trial, we investigated the effects of trimetazidine on reducing infarction size in patients undergoing revascularization for ST-segment elevation myocardial infarction (STEMI). Methods: Patients with STEMI randomly received trimetazidine (n=87) or placebo (n= 86) in a double-blind manner before primary percutaneous coronary intervention (PCI), and study treatment was maintained for 12 months after the procedure. The primary endpoint was infarction size measured by cardiac magnetic resonance (CMR) after primary PCI. Results: The clinical characteristics of patients (90% male, mean age 57±12 years) in both groups were well-matched on the baseline. Compared with patients in control group, the percentage and weight of infarction size of patients in trimetazidine group were both significantly lower (22.1±11.8% [n =74] vs. 26.9±11.9% [n=74], p=0.010; 28±18g [n =74] vs. 35±19g [n=74], p=0.022), the myocardial microvascular obstruction (MVO) rate measured by CMR was lower in trimetazidine group (29.7% [22/7] vs. 52.7% [39/74], p=0.007), while myocardial salvage index (MSI) was significantly higher in trimetazidine group (48±20% vs. 39±27%, p=0.008). The incidence of readmission due to aggravated heart failure in trimetazidine group was lower than that in the control group without significance (8.0% vs 14.0%, p=0.234). Conclusions: Our study provides suggests that trimetazidine initiated prior to primary PCI, improves myocardial infarct size, MVO and MSI, possibly by reducing reperfusion injury.

C-reactive protein increases myocardial damage after STEMI

Background The CAMI-1 study dealt with the depletion of CRP by apheresis in patients with acute myocardial infarction (AMI). CRP, the prototype human acute phase protein, has been known as a marker of poor prognosis in AMI and independently predicts 30-day mortality. Methods 66 STEMI patients were enrolled in the study following complete coronary revascularization (2–12 h after the onset of symptoms). 32 patients received CRP apheresis, whereas 34 patients treated by standard protocols served as controls. CRP apheresis started 24±12 h and 48±12 h after onset of symptoms. In case of a rapid increase in CRP plasma levels following the 2nd session, a 3rd session was carried out another 24 h later. A specific CRP adsorber removed up to 79% of the original CRP. In each apheresis session, 6000 ml of plasma was treated via peripheral venous access. Primary study endpoint was myocardial infarction size as determined by Cardiac Magnetic Resonance Imaging (CMR) 2–9 days after STEMI. Results Aphereses sessions were well tolerated with no relevant side effects. Peak CRP plasma levels after STEMI ranged from 9 to 279 mg/l. The expected peak CRP level after AMI can be calculated precisely with 2–3 CRP quantifications during the first 24 h after the onset of symptoms. The regression coefficient for this analysis is 0.91. This mathematical step allows for the comparison of the CRP-apheresis group and the controls on the basis of their individual CRP peak levels. The statistical evaluation shows that the CRP concentration is significantly associated with the damage (infarct size, LVEF, circumferential strain) in the controls. This association was lost in the aphereses patients: they performed significantly better at all endpoints (infarct size, LVEF, circumferential strain) than the controls. The CRP apheresis significantly reduced myocardial damage. To our surprise, two apheresis patients had an infarct size of 0%. Conclusions For the first time we find an unequivocal association between myocardial infarct size and the CRP concentration. This is in some respects a surprise, since the basic assumption in AMI is that the vascular occlusion leads to primary damage and the reperfusion to secondary damage, which would not have led one to expect such a clear dose-response relationship as that observed here. In addition, our results show a significant beneficial effect of CRP apheresis on myocardial infarction size and wall motion. Selective CRP apheresis is now being further evaluated as a therapeutic approach in the treatment of acute myocardial infarction in a registry (CAMI registry). Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Pentracor GmbH

Unique role of admission hyperglycemia on myocardial infarction size and area at risk following an acute ST-elevation myocardial infarction

Background Hyperglycemia can adversely affect patients with acute ST-elevation myocardial infarction (STEMI) in both diabetic and non-diabetic patients. The majority of the studies had investigated the impact of admission hyperglycemia (AH) on cardiovascular morbidity and mortality while, in ours, we entailed its impact on final infarction size (FIS) and more interestingly, on the area at risk (AAR), both were estimated by cardiac magnetic resonance (CMR) imaging. Results AH showed significant positive correlations to FIS and AAR. Moreover, AH group had higher summation of ST segment elevation (sum STE), more maximum ST segment elevation (max STE), higher echocardiographic wall motion score index (WMSI), higher CMR estimated WMSI, and lower segmental ejection fraction (EF). Multivariate analysis showed that AH was independently associated with increased FIS. Conclusion Current study showed an association between AH and large FIS in STEMI patients.

B-type natriuretic peptide and cardiac remodelling after myocardial infarction: a randomised trial

ObjectiveB-type natriuretic peptide (BNP) has favourable effects on left ventricular remodelling, including antifibrotic and antiapoptotic properties. We tested the hypothesis that infusion of BNP after an acute myocardial infarction would reduce left ventricular systolic and diastolic volumes and improve left ventricular ejection fraction compared with placebo.MethodsA total of 58 patients who underwent successful revascularisation for an acute ST elevation anterior myocardial infarction were randomised to receive 72-hour infusion of BNP at 0.006 µg/kg/min or placebo. Left ventricular end diastolic and systolic volumes and left ventricular ejection fraction were measured at baseline and at 30 days by multigated acquisition scan. Left ventricular infarction size was measured by cardiac MRI.ResultsBNP infusion led to significantly higher BNP levels and plasma cyclic guanosine monophosphate at 72 hours. No significant difference in change of left ventricular volumes or ejection fraction from baseline to 30 days was observed between groups. Although left ventricular infarction size measured by cardiac MRI was not significantly different between BNP infusion versus placebo (p=0.39), there was a trend towards reduced infarction size in patients with a baseline ejection fraction of <40% (p=0.14).ConclusionsInfusion of BNP in patients with an anterior myocardial infarction did not affect parameters of left ventricular remodelling. Patients treated with BNP who had a baseline left ventricular ejection fraction of <40% had a trend towards reduced left ventricular infarction size compared with placebo. These results do not support the use of intravenous BNP in patients after recent myocardial infarction.Trial registration numberNCT00573144.