Metformin Increases Cardiac Rupture After Myocardial Infarction via the AMPK-MTOR/PGC-1α Signaling Pathway in Rats with Acute Myocardial Infarction.

BACKGROUND Cardiac rupture often occurs after acute myocardial infarction due to complex and unclear pathogenesis. This study investigated whether metformin increases the incidence of cardiac rupture after myocardial infarction through the AMPK-MTOR/PGC-1α signaling pathway. MATERIAL AND METHODS An acute myocardial infarction (MI) mouse model was established. A series of experiments involving RT-qPCR, Western blot, TUNEL staining, and Masson staining were performed in this study. RESULTS Myocardial infarction occurred, resulting in the cardiac rupture, and the expression level of PGC-1α increased in the cardiac myocardium. Meanwhile, the proportion of myocardial NT-PGC-1α/PGC-1α decreased. The expression level of myocardial PGC-1α in MI mice with cardiac rupture after MI was significantly higher than that in the mice without cardiac rupture, and the ratio of myocardial NT-PGC-1α/PGC-1α was low. In addition, increasing the dose of metformin significantly increased the incidence of cardiac rupture after myocardial infarction in MI mice. High-dose metformin caused cardiac rupture in MI mice. Moreover, high-dose metformin (Met 2.0 nM) reduces the proportion of NT-PGC-1α/PGC-1α in primary cardiomyocytes of SD mice (SD-NRVCs [Neonatal rat ventricular cardiomyocytes]), and its effect was inhibited by Compound C (AMPK inhibitor). Further, after 3 days of treatment with high-dose metformin in MI mice, myocardial fibrin synthesis decreased and fibrosis was significantly inhibited. Meanwhile, cardiomyocyte apoptosis increased significantly. With the increase in metformin concentration, the expression level of myocardial LC3b gradually increased in MI mice, suggesting that metformin enhances the autophagy of cardiomyocytes. CONCLUSIONS These results suggest that metformin increases cardiac rupture after myocardial infarction through the AMPK-MTOR/PGC-1α signaling pathway.

Effect of thrombolytic therapy on the risk of cardiac rupture and mortality in older patients with first acute myocardial infarction.

AIMS: To evaluate the effect of thrombolysis on mortality and its causes in older patients with acute myocardial infarction (AMI). METHODS AND RESULTS: An analysis of 706 consecutive patients > or =75 years old with a first AMI enrolled in the PPRIMM75 registry showed that although there were important differences in baseline characteristics among patients treated with thrombolysis, primary angioplasty (PA) and those who did not receive reperfusion therapy, 30 day mortality did not differ (29, 25, and 32%, respectively). The main cause of death in patients treated with thrombolysis was cardiac rupture (54%), whereas most of the other patients died in cardiogenic shock. Patients who received thrombolysis had a higher (P<0.0001) incidence of free wall rupture (FWR) (17.1%) compared with those who did not receive reperfusion therapy (7.9%) or who underwent PA (4.9%). By multivariable analysis, patients treated with thrombolytic therapy (TT) showed an excess risk of FWR (OR, 3.62; 95% CI, 1.79-7.33), a hazard not observed in patients who underwent PA. When compared with patients who did not receive reperfusion therapy, the odds ratio of 30 day mortality was 1.07 (95% CI, 0.65-1.76) for patients treated with thrombolysis and 0.78 (95% CI, 0.45-1.34) for those who underwent PA. The figures for 24 month mortality were 0.78 (95% CI, 0.65-1.76) and 0.67 (95% CI, 0.28-0.81), respectively. CONCLUSION: Treatment of first AMI with TT increases the risk of FWR in very old patients, a risk not observed in patients treated with PA.

A subacute left ventricular free wall rupture after thrombolytic and glycoprotein IIb/IIIa inhibitor treatment: an overlooked finding of left ventriculography.

Subacute left ventricular free wall rupture is a rare complication in acute myocardial infarction. With the increasing use of thrombolytic agents and glycoprotein IIb/IIIa inhibitors, this complication has been increasing recently. We report a case of subacute cardiac rupture with frank pericardial effusion receiving thrombolytic and glycoprotein IIb/IIIa inhibitor therapies.

Free wall rupture following rescue angioplasty and intravenous abciximab for failed thrombolysis.

Early thrombolytic therapy reduces the risk of cardiac rupture but delayed thrombolysis may increase this risk, despite improving overall survival. The mechanism appears to be related to both unsuccessful early reperfusion and haemorrhagic transformation following delayed reperfusion. The effect of antiplatelet therapy with glycoprotein IIb-IIIa receptor blockers (abciximab) on cardiac rupture is unknown. It is possible that they may contribute to cardiac rupture by promoting haemorrhagic transformation of the infarcted area. In this report we describe a 57 year old man who underwent emergency coronary angioplasty and stenting following failed thrombolytic therapy for an acute anterior myocardial infarction. A suboptimal result was obtained which necessitated an intravenous bolus of abciximab followed by an infusion. He abruptly developed electromechanical dissociation. Echocardiogram confirmed pericardial tamponade and a pericardial drain was inserted but the patient could not be resuscitated. Postmortem examination confirmed a large transmural rupture of the infarcted anterior wall which had undergone haemorrhagic transformation.

Successful repair of myocardial free wall rupture after thrombolytic therapy for acute infarction.

BACKGROUND: Controversy exists regarding the timing of thrombolytic administration and rupture rate. METHODS: Hospital records at St. Luke's-Roosevelt Hospital of the 4 study patients were reviewed and compared with those of 41 patients from a group of 537 patients concurrently admitted with a diagnosis of myocardial infarction (MI). RESULTS: Four patients experienced ventricular free wall rupture after having a MI between November 17, 1993, and July 28, 1995. All received tissue plasminogen activator. In 1 patient, pericardial effusion associated with a pseudoaneurysm was discovered in the operating room. The 3 others developed clinical pericardial tamponade before surgery. All 4 patients survived and left the hospital on postoperative days 10, 11, 11, and 82, respectively. During this same time period, 537 patients were admitted with MI, 41 of whom died; the study's 4 patients were compared with these 41. CONCLUSIONS: These data demonstrate that rupture of the ventricular free wall can occur early after thrombolytic therapy and may have a subacute course. Prompt diagnosis and surgery offer excellent chances of surviving this fatal condition.

Early cardiac rupture following streptokinase in patients with acute myocardial infarction: retrospective cohort study.

AIM: To assess the incidence and timing of cardiac rupture following streptokinase (SK) administration in acute myocardial infarction (AMI). METHODS: We analyzed retrospectively the clinical sheets of AMI patients treated at the Coronary Care Unit in University Hospital Split, Croatia, between January 1, 1996, and December 31, 1998. We selected the patients who died after SK administration (1.5 million U in a 30 min iv. infusion), with a discharge diagnosis of "AMI" and "cardiac tamponade - ventricular rupture". AMI was defined by typical chest pain, ECG, and/or enzymatic changes. Echo or autopsy verified diagnosis of cardiac tamponade and/or rupture, as well as pericardial effusion and/or free-wall rupture. RESULTS: Out of 726 AMI patients, 136 (18.7%) were treated with SK, and 6 had cardiac rupture (4 men and 2 women; 4.4%). Autopsy revealed that 1 patient had ischemic and 2 had transmural hemorrhagic AMI. Three out of 6 patients died 2-4, and 3 died 5-7 hours after SK administration. Six patients who died from cardiac rupture (mean age 72.3+/-9.0) were significantly older than AMI survivors treated with SK (121 patients, mean age 60.5+/-12.0 years, p<0.001). CONCLUSION: In case of unexplained clinical deterioration in AMI patients over 70 during the first hours after SK administration, cardiac tamponade due to a free-wall rupture should be suspected. SK administration in patients with AMI over 70 years should be a selective and not a routine treatment.

Adverse effects of corticosteroids on the cardiovascular system.

OBJECTIVE: To review the potential adverse effects of glucocorticoid therapy on the cardiovascular system and to provide insight into the mechanisms of these effects. DATA SOURCES: Case reports and studies demonstrating adverse effects of glucocorticoid therapy on the cardiovascular system were examined from a MEDLINE search. Animal data and in vitro studies were identified to provide insight on the mechanisms of these effects. DATA SYNTHESIS: Undesirable effects identified were dyslipidemia, hypertension and left ventricular free wall rupture after myocardial infarction. Elevations of total plasma cholesterol, triglycerides, low density lipoprotein cholesterol and high density lipoprotein cholesterol are often reported. The elevation of various lipid subfractions is likely mediated by increased plasma insulin levels, impaired lipid catabolism and increased lipid production in the liver. Hypertension was shown to be more prevalent in patients treated with high doses of glucocorticoid. The mechanisms are complex, but final pathways include increased systemic vascular resistance, increased extracellular volume and increased cardiac contractility. Glucocorticoids were demonstrated to increase the incidence of left ventricular free wall rupture by delaying myocardial scar formation in the postmyocardial infarction period. CONCLUSIONS: The major adverse effects of glucocorticoids on the cardiovascular system include dyslipidemia and hypertension. These effects may predispose treated patients to coronary artery disease if high doses and prolonged courses are used. Accordingly, corticosteroids should be employed judiciously in patients with other risk factors for cardiovascular disease, and attention should be paid to risk modification. Low dose and alternate day therapy may reduce the incidence of complications in corticosteroid therapy. The mechanisms of these adverse effects are complex and have not yet been fully explained.

[Usefulness and safety of intravenous thrombolytic therapy for elderly patients with acute myocardial infarction: relationship with cardiac rupture].

The usefulness and safety of intravenous thrombolytic therapy were investigated in 298 patients older than 65 years (145 males, 153 females, mean age 78 years) with acute myocardial infarction from 1984 to 1993. These patients were divided into 2 groups of 88 patients younger than 74 years (Group A) and 210 patients older than 75 years (Group B). Seventy patients received thrombolytic therapy with urokinase (UK) or tissue-plasminogen activator [t-PA (UK96 X 10(4)U: 57 patients, t-PA 30-40 X 10(4)U/kg: 12, UK + t-PA: 1)] within 6 hours after the onset of acute myocardial infarction (Group TL). Two hundred twenty-eight patients received conventional therapy (Group C). There were no differences in the frequencies of the site of myocardial infarction, Killip class, admission within 6 hours after the onset of acute myocardial infarction or thrombolytic therapy between the 2 age groups. In-hospital mortality was significantly higher in Group B than in Group A (43% vs 24%, p < 0.01). In Groups A and B, in-hospital mortality was 20% lower in Group TL compared with Group C (20% vs 25% in Group A, 36% vs 45% in Group B). In Group B, the mortality from pump failure including shock and congestive heart failure was half in Group TL compared with Group C (13% vs 30%). Cardiac rupture was found in 11 patients of Group TL and 7 patients of Group C. Therefore, the mortality from cardiac rupture was fivefold higher in Group TL compared with Group C (8% vs. 1.6% in Group A, 20% vs 3.6% in Group B). Of 11 patients with cardiac rupture in Group TL, 8 patients suffered rupture in the early phase within 12 hours after the onset of acute myocardial infarction and the tear was present near the center of infarcted area in all 7 autopsy cases. The case of recanalization of the infarct-related coronary artery in Group TL revealed moderate to massive hemorrhagic infarction at autopsy. This indicates that the mechanisms involved in cardiac rupture are different in thrombolytic therapy and conventional therapy. Intravenous thrombolytic therapy is effective for the reduction of mortality from pump failure in elderly patients with acute myocardial infarction older than 75 years. However, it must be evaluated as one of the risk factors of cardiac rupture in elderly patients.

Cardiac rupture complicating cerebral intraarterial thrombolytic therapy.

We report a case of fatal cardiac rupture occurring during intraarterial thrombolytic therapy for acute embolic stroke in a patient with recent myocardial infarction.

Thrombolysis and postinfarction ventricular septal rupture.

We studied all patients with postinfarction ventricular septal rupture referred to the Oxford Heart Centre for operation over a 4 1/2-year period. Twenty one women and 8 men were admitted to the Centre, 13 of whom had received streptokinase and 16 of whom had not. The median interval between symptomatic onset of myocardial infarction and the development of septal rupture was 24 hours for those treated by early thrombolysis (all streptokinase) and six days for those who were not. Of the 26 patients who underwent surgical repair, three were operated on less than 36 hours after streptokinase infusion, in one case within 12 hours of thrombolytic treatment. Macroscopic observation of the disintegrating myocardium showed muscle bundles dissected by blood rendered incoagulable by thrombolytic treatment, together with the histologic features of reperfusion injury. The overall surgical mortality rate for the streptokinase group was 33% and for the others 21%. The patient operated on within 12 hours of thrombolytic treatment recovered uneventfully. Six of seven surgical deaths were caused by left ventricular or biventricular failure and one by gastrointestinal hemorrhage. All survivors were in New York Heart Association classes II or III between 2 weeks and 4 1/2 years after operation. We conclude that thrombolysis leads to early breakdown of the interventricular septum after acute myocardial infarction but does not preclude early repair.

[Thrombolysis in acute myocardial infarction in the aged. A greater risk of cardiac rupture?]. / Trombólise no enfarte agudo do miocárdio no idoso. Um risco acrescido de ruptura cardíaca?

OBJECTIVE: To evaluate age group and i.v. thrombolytic therapy (TT) influences on cardiac rupture complicating acute myocardial infarction (AMI). CONCEPTION: Retrospective analysis of patients (pts) admitted during 1988-89 to an Intensive Care Unit of a Terciary Hospital (UCIM) with AMI. POPULATION: 430 pts were admitted with AMI. During this period 89 pts were submitted to TT (25% age greater than or equal to 65 years). Eighty four pts died during hospital stay and 42 had autopsy study (50%). Only 7 of nonautopsied pts died of undetermined cause. Dead pts had age m +/- SD 72 +/- 11 years old (yo) (37% female, 63% male and 74% age greater than or equal to 65 yo). RESULTS: Nineteen pts died of cardiac rupture (CR) (23%). CR prevalence was 1.4% (3/218) in pts less than 65 yo and 7.5% (16/212) in pts greater than or equal to 65 yo (p less than 0.01). CR prevalence in pts submitted to TT (4.5%) 4/89, was similar to pts not submitted to TT (4.4%) 15/341 (n.s.). Pts less than 65 yo had nonsignificant differences in CR wether submitted or not to TT (0% vs 2%). Elderly pts (greater than or equal to 65 yo) CR prevalence was 18% (4/22) in those submitted to TT vs 6% (12/190) in those not submitted to TT (p less than 0.05). CONCLUSIONS: Thrombolytic therapy may carry an additional risk for cardiac rupture in elderly patients (greater than or equal to 65 yo).