Colchicine Prevents Cardiac Rupture in Mice with Myocardial Infarction by Inhibiting P53-Dependent Apoptosis.

Cardiac rupture is a fatal complication following myocardial infarction (MI) and there are currently no effective pharmacological strategies for preventing this condition. In this study, we investigated the effect of colchicine on post-infarct cardiac rupture in mice and its underlying mechanisms.We induced MI in mice by permanently ligating the left anterior descending artery. Oral colchicine or vehicle was administered at a dose of 0.1 mg/kg/day from day 1 to day 7 after MI. Cultured neonatal cardiomyocytes and fibroblasts were exposed to normoxia or anoxia and treated with colchicine.Colchicine significantly improved the survival rate (colchicine, n = 46: 82.6% versus vehicle, n = 42: 61.9%, P < 0.05) at 1 week after MI. Histological analysis revealed colchicine significantly reduced the infarct size and the number of macrophages around the infarct area. Colchicine decreased apoptosis in the myocardium of the border zone and cultured cardiomyocytes and fibroblasts as assessed by TUNEL assay. Colchicine also attenuated the activation of p53 and decreased the expression of cleaved-caspase 3 and bax, as assessed by Western blotting.Colchicine prevents cardiac rupture via inhibition of apoptosis, which is attributable to the downregulation of p53 activity. Our findings suggest that colchicine may be a prospective preventive medicine for cardiac rupture, however, large clinical trials are required.

Interleukin-35 Promotes Macrophage Survival and Improves Wound Healing After Myocardial Infarction in Mice.

RATIONALE: Targeting inflammation has been shown to provide clinical benefit in the field of cardiovascular diseases. Although manipulating regulatory T-cell function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. IL (interleukin)-35, an immunosuppressive cytokine mainly produced by regulatory T cells, is a novel member of the IL-12 family and is composed of an EBI3 (Epstein-Barr virus-induced gene 3) subunit and a p35 subunit. However, the role of IL-35 in infarct healing remains elusive. OBJECTIVE: This study aimed to determine whether IL-35 signaling is involved in healing and cardiac remodeling after myocardial infarction (MI) and, if so, to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: IL-35 subunits (EBI3 and p35), which are mainly expressed in regulatory T cells, were upregulated in mice after MI. After IL-35 inhibition, mice showed impaired infarct healing and aggravated cardiac remodeling, as demonstrated by a significant increase in mortality because of cardiac rupture, decreased wall thickness, and worse cardiac function compared with wild-type MI mice. IL-35 inhibition also led to decreased expression of α-SMA (α-smooth muscle actin) and collagen I/III in the hearts of mice after MI. Pharmacological inhibition of IL-35 suppressed the accumulation of Ly6Clow and major histocompatibility complex IIlow/C-C motif chemokine receptor type 2- (MHC IIlow CCR2-) macrophages in infarcted hearts. IL-35 activated transcription of CX3CR1 (C-X3-C motif chemokine receptor 1) and TGF (transforming growth factor) ß1 in macrophages by inducing GP130 signaling, via IL12Rß2 and phosphorylation of STAT1 (signal transducer and activator of transcription family) and STAT4 and subsequently promoted Ly6Clow macrophage survival and extracellular matrix deposition. Moreover, compared with control MI mice, IL-35-treated MI mice showed increased expression of α-SMA and collagen within scars, correlating with decreased left ventricular rupture rates. CONCLUSIONS: IL-35 reduces cardiac rupture, improves wound healing, and attenuates cardiac remodeling after MI by promoting reparative CX3CR1+Ly6Clow macrophage survival.

Cardiac rupture complicating acute myocardial infarction: the clinical features from an observational study and animal experiment.

BACKGROUND: Cardiac rupture (CR) is a fatal complication of ST-elevation myocardial infarction (STEMI) with its incidence markedly declined in the recent decades. However, clinical features of CR patients now and the effect of reperfusion therapy to CR remain unclear. We investigated the clinical features of CR in STEMI patients and the effect of reperfusion therapy to CR in mice. METHODS: Two studies were conducted. In clinical study, data of 1456 STEMI patients admitted to the First Hospital, Xi'an Jiaotong University during 2015.12. ~ 2018.12. were analyzed. In experimental study, 83 male C57BL/6 mice were operated to induce MI. Of them, 39 mice were permanent MI (group-1), and remaining mice received reperfusion after 1 h ischemia (21 mice, group-2) or 4 h ischemia (23 mice, group-3). All operated mice were monitored up to day-10. Animals were inspected three times daily for the incidence of death and autopsy was done for all mice found died to determine the cause of death. RESULTS: CR was diagnosed in 40 patients: free-wall rupture in 17, ventricular septal rupture in 20, and combined locations in 3 cases. CR presented in 19 patients at admission and diagnosed in another 21 patients during 1 ~ 14 days post-STEMI, giving an in-hospital incidence of 1.4%. The mortality of CR patients was high during hospitalization accounting for 39% of total in-hospital death. By multivariate logistic regression analysis, older age, peak CK-MB and peak hs-CRP were independent predictors of CR post-STEMI. In mice with non-reperfused MI, 17 animals (43.6%) died of CR that occurred during 3-6 days post-MI. In MI mice received early or delayed reperfusion, all mice survived to the end of experiment except one mouse died of acute heart failure. CONCLUSION: CR remains as a major cause of in-hospital death in STEMI patients. CR patients are characterized of being elderly, having larger infarct and more server inflammation. Experimentally, reperfusion post-MI prevented CR.

Inhibition of the Renin-Angiotensin System Post Myocardial Infarction Prevents Inflammation-Associated Acute Cardiac Rupture.

PURPOSE: Inhibition of the renin-angiotensin system (RAS) is beneficial in patient management after myocardial infarction (MI). However, whether RAS inhibition also provides cardiac protection in the acute phase of MI is unclear. METHODS: Male 129sv mice underwent coronary artery occlusion to induce MI, followed by treatment with losartan (L, 20 and 60 mg/kg), perindopril (P, 2 and 6 mg/kg), amlodipine (20 mg/kg as a BP-lowering agent) or vehicle as control. Drug effects on hemodynamics were examined. Effects of treatments on incidence of cardiac rupture, haematological profile, monocyte and neutrophil population in the spleen and the heart, cardiac leukocyte density, expression of inflammatory genes and activity of MMPs were studied after MI. RESULTS: Incidence of cardiac rupture within 2 weeks was significantly and similarly reduced by both losartan (L) and perindopril (P) in a dose-dependent manner [75% (27/36) in vehicle, 40-45% in low-dose (L 10/22, P 8/20) and 16-20% (L 5/32, P 4/20) in high-dose groups, all P < 0.05]. This action was independent of their BP-lowering action, as amlodipine reduced BP to a similar degree without effect on rupture (70%, 21/30). Compared to the control group, high dose losartan and perindopril decreased counts of white blood cells, neutrophils and lymphocytes (all P < 0.05), and inhibited splenic monocyte and neutrophil release into the circulation. Consequently, monocyte, neutrophil and leukocyte infiltration, inflammatory gene expressions (IL-1ß, IL-6, MMP9, MCP-1, TNF-α and TGFß1) and activity of MMP2 and MMP9 in the infarct tissue were attenuated by losartan and/or perindopril treatment (all P < 0.05). CONCLUSIONS: RAS inhibition by losartan or perindopril prevented cardiac rupture at the acute phase of MI through blockade of splenic release of monocytes and neutrophils and consequently attenuation of systemic and regional inflammatory responses.

Thymosin-ß4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction.

Thymosin-ß4 (Tß4) promotes cell survival, angiogenesis, and tissue regeneration and reduces inflammation. Cardiac rupture after myocardial infarction (MI) is mainly the consequence of excessive regional inflammation, whereas cardiac dysfunction after MI results from a massive cardiomyocyte loss and cardiac fibrosis. It is possible that Tß4 reduces the incidence of cardiac rupture post-MI via anti-inflammatory actions and that it decreases adverse cardiac remodeling and improves cardiac function by promoting cardiac cell survival and cardiac repair. C57BL/6 mice were subjected to MI and treated with either vehicle or Tß4 (1.6 mg·kg(-1)·day(-1) ip via osmotic minipump) for 7 days or 5 wk. Mice were assessed for 1) cardiac remodeling and function by echocardiography; 2) inflammatory cell infiltration, capillary density, myocyte apoptosis, and interstitial collagen fraction histopathologically; 3) gelatinolytic activity by in situ zymography; and 4) expression of ICAM-1 and p53 by immunoblot analysis. Tß4 reduced cardiac rupture that was associated with a decrease in the numbers of infiltrating inflammatory cells and apoptotic myocytes, a decrease in gelatinolytic activity and ICAM-1 and p53 expression, and an increase in the numbers of CD31-positive cells. Five-week treatment with Tß4 ameliorated left ventricular dilation, improved cardiac function, markedly reduced interstitial collagen fraction, and increased capillary density. In a murine model of acute MI, Tß4 not only decreased mortality rate as a result of cardiac rupture but also significantly improved cardiac function after MI. Thus, the use of Tß4 could be explored as an alternative therapy in preventing cardiac rupture and restoring cardiac function in patients with MI.

Novel role of platelets in mediating inflammatory responses and ventricular rupture or remodeling following myocardial infarction.

OBJECTIVE: The goal of this study was to investigate the role of platelets in systemic and cardiac inflammatory responses and the development of postinfarct ventricular complications, as well as the efficacy of antiplatelet interventions. METHODS AND RESULTS: Using a mouse myocardial infarction (MI) model, we determined platelet accumulation and severity of inflammation within the infarcted myocardium by immunohistochemistry and biochemical assays, analyzed peripheral blood platelet-leukocyte conjugation using flow cytometry, and tested antiplatelet interventions, including thienopyridines and platelet depletion. Platelets accumulated within the infarcted region early post-MI and colocalized with inflammatory cells. MI evoked early increase in circulating platelet-leukocyte conjugation mediated by P-selectin/P-selectin glycoprotein ligand-1. Antiplatelet interventions inhibited platelet-leukocyte conjugation in peripheral blood, inflammatory infiltration, content of matrix metalloproteinases or plasminogen activation, and expression of inflammatory mediators in the infarcted myocardium (all P<0.05) and lowered rupture incidence (P<0.01). Clopidogrel therapy alleviated the extent of chronic ventricular dilatation by serial echocardiography. CONCLUSIONS: Platelets play a pivotal role in promoting systemic and cardiac inflammatory responses post-MI. Platelets accumulate within the infarcted myocardium, contributing to regional inflammation, ventricular remodeling, and rupture. Antiplatelet therapy reduces the severity of inflammation and risk of post-MI complications, demonstrating a previously unrecognized protective action.

Trimetazidine suppresses oxidative stress, inhibits MMP-2 and MMP-9 expression, and prevents cardiac rupture in mice with myocardial infarction.

BACKGROUND/AIMS: Cardiac rupture (CR) is a catastrophic complication of acute myocardial infarction (MI). At present, there are no effective pharmacological strategies for preventing post-MI rupture. Here we investigated the effect of trimetazidine (TMZ) on post-MI CR. METHODS: MI models were induced by left coronary artery ligation in male C57BL/6 mice. Animals allocated to the rupture incidence were closely monitored for 7 days; autopsy was performed once animals were found dead to determine the reason of death. Heart function was detected by echocardiography. Oxidative stress markers and matrix metalloproteinases (MMPs) were analyzed by Western Blotting. RESULTS: TMZ markedly reduced the post-MI CR incidence of mice. We found that the expression of metalloproteinase (MMP) -2 and MMP-9 in the TMZ-treated group was significantly lower than the saline-treated group. Further, TMZ markedly attenuated MI-induced oxidative stress. To investigate the mechanism of the effect of TMZ on CR, we pretreated H9c2 cells with H2 O2 and found that TMZ treatment markedly decreased H2 O2 -induced MMP-2 and MMP-9 expression. TMZ prevents CR through inhibition of oxidative stress, which is attributable to the down-regulation of MMP-2, MMP-9 expression. CONCLUSIONS: Our findings indicate that TMZ suppresses oxidative stress, inhibits MMP-2 and MMP-9 expression, and prevents CR in mice with MI.

Surgical treatment of post-infarction left ventricular pseudoaneurysm: a two-decade experience.

Herein, we present a retrospective analysis of our experience with acquired pseudoaneurysms of the left ventricle over a 20-year period.From February 1985 through September 2004, 14 patients underwent operation for left ventricular pseudoaneurysm in our clinic. All pseudoaneurysms (12 chronic, 2 acute) were caused by myocardial infarction. The mean interval between myocardial infarction and diagnosis of pseudoaneurysm was 7 months (range, 1-11 mo). The pseudoaneurysm was located in the inferior or posterolateral wall in 11 of 14 patients (78.6%). In all patients, the pseudoaneurysm was resected and the ventricular wall defect was closed with direct suture (6 patients) or a patch (8 patients). Most patients had 3-vessel coronary artery disease. Coronary artery bypass grafting was performed in all patients. Five patients died (postoperative mortality rate, 35.7%) after repair of a pseudoaneurysm (post-infarction, 2 patients; chronic, 3 patients). Two patients died during follow-up (median, 42 mo), due to cancer in 1 patient and sudden death in the other. Although repair of left ventricular pseudoaneurysm is still a surgical challenge, it can be performed with acceptable results in most patients. Surgical repair is warranted particularly in cases of large or expanding pseudoaneurysms because of the propensity for fatal rupture.

Targeted deletion of p53 prevents cardiac rupture after myocardial infarction in mice.

OBJECTIVE: Apoptosis may play an important role in cardiac remodeling after myocardial infarction (MI). p53 is a well-known proapoptotic factor. However, its pathophysiological significance in these conditions remains unclear. We thus examined the effects of target deletion of the p53 gene on post-MI hearts. METHODS: Anterior MI was created in male heterozygous p53-deficient (p53(+/-); n = 28) mice and sibling wild-type (p53(+/+); n = 29) mice by ligating the left coronary artery. RESULTS: By day 7, p53(+/-) mice had significantly better survival rate than p53(+/+) mice (89% vs. 69%, P < 0.05). Notably, p53(+/-) mice had a significantly lower incidence of left ventricular (LV) rupture (7% vs. 28%, P < 0.05) despite comparable infarct size (60 +/- 2% vs. 59 +/- 2%, P = NS), heart rate (488 +/- 15 vs. 489 +/- 17 bpm, P = NS), or mean arterial blood pressure (80 +/- 2 vs. 78 +/- 3 mm Hg, P = NS). The extent of infiltrating interstitial cells including macrophages into the post-MI hearts was not altered by the deletion of p53. Further, collagen deposition as well as the zymographic MMP-2 and -9 activities were comparable between p53(+/-) and p53(+/+) mice with MI. However, the p53(+/-) mice had a significantly thicker infarct wall. The number of TUNEL-positive cells in the infarct area was significantly lower in p53(+/-) mice than in p53(+/+) mice (423+/-86 vs. 1330 +/- 275/10(5) cells, P < 0.01). CONCLUSIONS: p53 is involved in cardiac rupture after MI, probably via the induction of a proapoptotic pathway. The inhibition of p53 may be a potentially useful therapeutic strategy to manage post-MI patients.

Beta-blockers reduced the risk of cardiac rupture in patients with acute myocardial infarction: A meta-analysis of randomized control trials.

BACKGROUND: Cardiac rupture (CR) is a catastrophic complication that occurs after acute myocardial infarction (MI) and, at present, there are no effective pharmacological strategies for preventing this condition. The objective of this meta-analysis was to assess the effect of beta-blockers on CR in patients with acute MI. METHODS: An extensive search of the PUBMED, EMBASE, ISI Web of Science, MEDLINE and Cochrane was performed to retrieve the studies of beta-blockers treatment in patients with acute MI. Data were combined using a random effects model. A meta-analysis was performed using Review Manager 5.3. RESULTS: Four randomized controlled trials (RCTs) involving 68, 842 patients, 603 of whom occurred CR, were met criteria. Meta analysis showed that beta-blockers caused a statistically and clinically significant decrease in the incidence of CR of 32% (RR: 0.68, 95% CI: 0.47 to 0.99, P=0.04). CONCLUSIONS: The findings of this meta-analysis confirmed that the early use of beta-blockers is associated with decreased incidence of CR, suggesting some beneficial effects of beta-blockers on infarct healing after acute MI.

Topiramate modulates post-infarction inflammation primarily by targeting monocytes or macrophages.

AIMS: Monocytes/macrophages response plays a key role in post-infarction inflammation that contributes greatly to post-infarction ventricular remodelling and cardiac rupture. Therapeutic targeting of the GABAA receptor, which is enriched in monocytes/macrophages but not expressed in the myocardium, may be possible after myocardial infarction (MI). METHODS AND RESULTS: After MI was induced by ligation of the coronary artery, C57BL/6 mice were intraperitoneally administered with one specific agonist or antagonist of the GABAA receptor (topiramate or bicuculline), in the setting of presence or depletion of monocytes/macrophages. Our data showed that within the first 2 weeks after MI, when monocytes/macrophages dominated, in contrast with bicuculline, topiramate treatment significantly reduced Ly-6Chigh monocyte numbers by regulating splenic monocytopoiesis and promoted foetal derived macrophages preservation and conversion of M1 to M2 or Ly-6Chigh to Ly-6Clow macrophage phenotype in the infarcted heart, though GABAAergic drugs failed to affect M1/M2 or Ly-6Chigh/Ly-6Clow macrophage polarization directly. Accordingly, pro-inflammatory activities mediated by M1 or Ly-6Chigh macrophages were decreased and reparative processes mediated by M2 or Ly-6Clow macrophages were augmented. As a result, post-infarction ventricular remodelling was attenuated, as reflected by reduced infarct size and increased collagen density within infarcts. Echocardiographic indices, mortality and rupture rates were reduced. After depletion of monocytes/macrophages by clodronate liposomes, GABAAergic drugs exhibited no effect on cardiac dysfunction and surrogate clinical outcomes. CONCLUSION: Control of the GABAA receptor activity in monocytes/macrophages can potently modulate post-infarction inflammation. Topiramate emerges as a promising drug, which may be feasible to translate for MI therapy in the future.

Left ventricular volume reduction by radiofrequency heating of chronic myocardial infarction in patients with congestive heart failure.

BACKGROUND: Myocardial infarct expansion and left ventricular (LV) remodeling are integral components in the evolution of chronic heart failure and predict morbidity and mortality. Radiofrequency (RF) heating and patch placement of chronic LV aneurysms caused a sustained reduction in LV infarct area and volume in an ovine infarct model. This study evaluated the effect of RF heating and epicardial patch as an adjunct to coronary artery bypass graft on LV volumes in patients with prior myocardial infarction, evidence of akinetic/dyskinetic scar, and LV ejection fraction < or =40%. METHODS AND RESULTS: Ten patients (3 female; mean age, 64+/-11 years) scheduled for coronary artery bypass graft were enrolled (Canadian Cardiovascular Society angina class 2.1+/-1.1; New York Heart Association class 3.1+/-0.5). Intraoperative digital photography demonstrated an acute 39% reduction in infarct area (n=5; P=0.01), and transesophageal ECGs demonstrated a 16% acute reduction in LV end-diastolic volumes (n=9; P=0.002) after RF treatment. There were no intraoperative or procedure-related postoperative complications, and during an average follow-up of >180 days, there have been no safety issues. All patients had complete relief of their angina and improvement in exercise tolerance. Serial transthoracic ECGs over the 6 months of follow-up after RF treatment demonstrated persistent reductions in LV end-diastolic volume (29%; P<0.0001) and LV end-systolic volume (37%; P<0.0001) with improved ejection fraction (P<0.02). CONCLUSIONS: RF heating and patch placement in these 10 patients resulted in acute reduction in infarct area and ventricular volumes that were maintained 180 days after procedure. This technique may reduce the incidence of congestive heart failure and mortality in these patients and warrants investigation in larger clinical trials.

Reduction of infarct size and prevention of cardiac rupture in transgenic mice overexpressing FrzA.

BACKGROUND: FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled pathway, is expressed in the heart and vessels during mouse embryogenesis and adulthood. FrzA is involved in cell cycle control of vascular cells and angiogenesis. We assessed the hypothesis that FrzA could control the healing process after myocardial infarction (MI). METHODS AND RESULTS: We demonstrated an upregulation of sFRP-1 and distinct wnt and fz member expression after MI. We established transgenic (Tg) mice that overexpress FrzA under a cytomegalovirus promoter and developed a model of MI by coronary artery ligation. FrzA reduced cardiac rupture after MI in Tg (6.5% versus 26.4% in controls; n=165, P<0.01). MI was smaller in Tg at each time point (18+/-10.8% of left ventricular circumference versus 30+/-14.2% in controls at day 30; P<0.001). Similar results were found in cryolesion-induced MI. Cardiac function was improved in Tg mice (3800+/-370 mm Hg/s dP/dtmax versus 2800+/-840 in controls; -2800+/-440 dP/dtmin versus -1800+/-211 in controls at day 15; P<0.001). Early leukocyte infiltration had decreased in Tg mice during the first week. Apoptotic index was decreased by 50% in Tg mice at day 7. Matrix metalloproteinase-2 and -9 activity was reduced in Tg mice at day 4, and collagen deposition in the scar was increased in Tg mice. Capillary density in the scar was higher in Tg mice (290+/-103 vessels/mm2 versus 104+/-43 in controls at day 15; P<0.001). Vessels were more muscularized, and mean lumen area was 3-fold higher in Tg animals. CONCLUSIONS: Overexpression of FrzA, through direct or indirect interaction with different phases of infarct healing, reduced infarct size and improved cardiac function.

Cardiac rupture, mortality and the timing of thrombolytic therapy: a meta-analysis.

This study examined the relation between the risk of cardiac rupture and the timing of thrombolytic therapy for acute myocardial infarction. To test the hypothesis that cardiac rupture is prevented by early thrombolytic therapy but is promoted by late treatment, randomized controlled trials of thrombolytic agents for myocardial infarction were pooled. A logistic regression model including 58 cases of cardiac rupture among 1,638 patients from four trials showed that the odds ratio (treated/control) of cardiac rupture was directly correlated with time to treatment (p = 0.01); at 7 h, the odds ratio was 0.4 (95% confidence limits 0.17 to 0.93); at 11 h, it was 0.93 (0.53 to 1.60) and at 17 h, it was 3.21 (1.10 to 10.1). Analysis of data from the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) trial independently confirmed the relation between time to thrombolytic therapy and risk of cardiac rupture (p = 0.03). Analysis of 4,692 deaths in 44,346 patients demonstrated that the odds ratio of death was also directly correlated with time to treatment (p = 0.006); at 3 h, the odds ratio for death was 0.72 (0.67 to 0.77); at 14 h, it was 0.88 (0.77 to 1.00) and at 21 h, it was 1 (0.82 to 1.37). Thrombolytic therapy early after acute myocardial infarction improves survival and decreases the risk of cardiac rupture. Late administration of thrombolytic therapy also appears to improve survival but may increase the risk of cardiac rupture.

Novel hemostatic patch achieves sutureless epicardial wound closure during complex cardiac surgery, a case report.

Treatment of damaged cardiac tissue in patients with high bleeding tendency can be very challenging, damaged myocardial tissue has a high rupture risk when being sutured subsequently on-going bleeding is a major risk factor for poor clinical outcome. We present a case demonstrating the feasibility in using a novel haemostatic collagen sponge for the management of a myocardial wound. This report is the first description in cardiac surgery where Hemopatch sponges are used to successfully seal a left ventricle wound. Our patient was diagnosed with endocarditis, had a low pre-operative haemoglobin count and underwent cardiac surgery for multiple valve repairs. The procedure was performed on cardiopulmonary bypass, which meant our patient had to be heparinized. Despite these major risk factors for bleeding Hemopatch managed to contain bleeding and seal the wound, no sutures were needed.

Frizzled A, a novel angiogenic factor: promises for cardiac repair.

OBJECTIVE: Frizzled A is a very recent protein expressed in the cardiovascular hood by cardiomyocytes and by endothelial cells. This protein plays key roles in vitro in vascular cell proliferation and is able to induce an in vivo angiogenic response. Regarding these properties, we assess the hypothesis that Frizzled A could act in the healing process after myocardial infarction. METHODS: To investigate the role of Frizzled A, we established a transgenic mouse line overexpressing the protein and developed a model of myocardial infarction by coronary artery ligation. RESULTS: The incidence of cardiac rupture after myocardial infarction was reduced in transgenic mice (6.5 versus 26.4% in controls, n=165; P<0.01). Infarct sizes were smaller in transgenic mice (18% of left ventricle circumference versus 28.1% in control at day 30; P<0.001; n=6) and the cardiac function was improved (3800 +/- 370 versus 2800 +/- 840 mmHg/s dp/dtmax in controls, -2800 +/- 440 versus -1800 +/- 211 dp/dtmin in controls at day 15; P<0.001; n=6). Early leukocyte infiltration had decreased in transgenic mice during the first week (103 +/- 59 versus 730 +/- 463 cells/mm2 in controls at day 7; P<0.001; n=6) and the apoptotic index was decreased by 50% at day 7. Capillary density in the scar was higher in transgenic mice (290 +/- 103 versus 104 +/- 43 vessels/mm2 in control at day 15; P<0.001) and vessels were more muscularized and mean lumen area was 3-fold higher (952 +/- 902 versus 313 +/- 350 microm2 in control; P<0.001). CONCLUSION: Overexpression of Frizzled A reduced the infarct size, improved cardiac recovery, modified inflammatory response and amplified angiogenesis. For these reasons, this protein would be of interest for cardiac surgeons using angiogenic therapy (as gene or protein injection) in ischemic heart diseases in non-revascularizable patients.

Ventricular free wall rupture in acute myocardial infarction.

Despite a progressive reduction in acute myocardial infarction mortality over the years, death related to ventricular free wall rupture has not changed. This is mostly related to the catastrophic presentation and death within minutes in the majority of these patients. Once rupture is suspected, bedside echocardiography should be performed immediately, followed by pericardiocentesis and repair of the rupture site as quickly as possible. Measures to prevent cardiac rupture include the administration of beta-blockers and angiotensin-converting enzyme inhibitors unless contraindications exist, and the avoidance of steroidal and nonsteroidal anti-inflammatory agents such as ibuprofen and indomethacin.

Coronary angioplasty reduces free wall rupture and improves mortality and morbidity of acute myocardial infarction.

BACKGROUND: Free wall rupture (FWR) is one of the major causes of mortality in acute myocardial infarction (AMI). To what extent coronary angioplasty for AMI would modify the predictors of FWR is not clear. METHODS: In prospective database of consecutive 3,138 AMI patients seen between May 1985 to May 2002, 3,096 patients (98.7%) who underwent emergent coronary angiography were analyzed retrospectively. The incidence of FWR was determined by univariate and multivariate analyses. RESULTS: FWR after admission occurred in 40 (1.3%) patients. A higher rate of FWR was associated with: 1) not having coronary angioplasty (3.2% vs. 0.9%, p< 0.0001); 2) thrombolytic agents usage (2.4% vs. 1.0%, p = 0.004); 3) female gender (2.5% vs. 1.1%, p = 0.0004); 4) failed reperfusion (5.4% vs. 0.9%, p< 0.0001); and 5) LMT-related infarct (4.7% vs. 1.2%, p = 0.02) in univariate analysis. Five conditions were identified as significant protective or predictive factors of FWR in multivariate logistic regression analysis: having coronary angioplasty (odds ratio [OR]: 0.45, 95% confidence interval [95% CI] 0.22-0.94, p = 0.03), failed reperfusion (OR: 4.57, 95% CI: 2.31-9.05, p< 0.0001), LMT-related infarct (OR: 4.96, 95% CI: 1.42-17.34, p = 0.01), female gender (OR: 2.17, 95% CI: 1.11-4.25, p = 0.02) and age (OR: 1.04, 95% CI: 1.00-1.07, p = 0.03). Coronary angioplasty alone resulted in a lower incidence of FWR (0.5%) than thrombolysis alone (1.6%, p = 0.02), coronary angioplasty with thrombolysis (3.3%, p< 0.0001) and without either treatment (6.3%, p< 0.0001). CONCLUSIONS: Angiographic reperfusion success was the most significant protective factor from FWR. Coronary angioplasty reduced FWR complicating AMI and its concomitant fatality.

Cardiac free wall rupture in acute myocardial infarction: ameliorative effect of coronary reperfusion.

To investigate the pathophysiology of cardiac free wall rupture (cardiac rupture) following acute myocardial infarction (AMI), and to clarify whether reperfusion therapy prevents cardiac rupture, 1,329 cases of AMI (conventional therapy group: 807 cases and reperfusion therapy group: 533 cases) were studied retrospectively. The overall incidence of cardiac rupture was 2.3% (2.7% in the conventional therapy group vs. 1.7% in the reperfusion therapy group). Patients with cardiac rupture were divided into two subgroups according to the time interval from the onset of AMI to cardiac rupture (early rupture less than or equal to 72 h and late rupture greater than or equal to 4 days). The indices of initial evolution of AMI was a significant risk of early cardiac rupture. The reperfusion therapy group showed significantly lower incidence of late rupture (0.4 vs. 1.5% in conventional therapy group; p less than 0.05). The incidence of cardiac rupture in the unsuccessful reperfusion therapy group was higher than that of the successful group (5.9% of 118 cases vs. 0.5% of 404 cases; p less than 0.05). It is concluded that the etiology of cardiac rupture following AMI cannot be explained by any single factor. Early rupture depends on the initial evolution of AMI, and early reperfusion and collateral flow prevent the late onset cardiac rupture.

The potential impact of the thrombolytic era on cardiac rupture complicating acute myocardial infarction.

Cardiac rupture complicating acute myocardial infarction (AMI) remains a serious diagnostic and therapeutic challenge. The authors present 27 consecutive patients who died from cardiac rupture following AMI. These included 22 patients from 1975 through 1983 (prethrombolytic era) and 5 patients from 1984 through 1992 (postthrombolytic era) and all had postmortem examination. There were 16 men and 11 women with a mean age of seventy-two years. Myocardial infarction was anterior/anterolateral in 10 and inferior/inferoposterior in 17. Cardiac rupture followed AMI within one day in 14 (52%), two to five days in 8 (30%), and six to fourteen days in 5 (18%). Chest pain followed by sudden hypotension leading to electromechanical dissociation was the common terminal event. Cardiopulmonary resuscitation was unsuccessful in all patients. Postmortem findings showed three-vessel coronary disease in 21 (78%) and two-vessel disease in 6 (22%). Isolated free left ventricular wall rupture was found in 22 (81%), was anterior/anterolateral in 13 (48%), posterior in 9 (33%), and in conjunction with interventricular septum or papillary muscle in 5 (18%). Patients encountered in this series were mostly elderly hypertensives with multivessel coronary disease and postinfarction angina. Furthermore, cardiac rupture commonly occurred within the first five days of AMI and cardiopulmonary resuscitation was uniformly unsuccessful. During the thrombolytic era at their institution, this complication is now being seen much less often. These observations suggest that such interventions are expected to have a favorable impact on reducing the incidence of this catastrophic event.