Incidence Of Cardiac Rupture Research Articles

N-acetyl-seryl-aspartyl-lysyl-proline treatment protects heart against excessive myocardial injury and heart failure in mice.

Myocardial infarction (MI) in mice results in cardiac rupture at 4-7 days after MI, whereas cardiac fibrosis and dysfunction occur later. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory, anti-fibrotic, and pro-angiogenic properties. We hypothesized that Ac-SDKP reduces cardiac rupture and adverse cardiac remodeling, and improves function by promoting angiogenesis and inhibiting detrimental reactive fibrosis and inflammation after MI. C57BL/6J mice were subjected to MI and treated with Ac-SDKP (1.6 mg/kg per day) for 1 or 5 weeks. We analyzed (1) intercellular adhesion molecule-1 (ICAM-1) expression; (2) inflammatory cell infiltration and angiogenesis; (3) gelatinolytic activity; (4) incidence of cardiac rupture; (5) p53, the endoplasmic reticulum stress marker CCAAT/enhancer binding protein homology protein (CHOP), and cardiomyocyte apoptosis; (6) sarcoplasmic reticulum Ca2+ ATPase (SERCA2) expression; (7) interstitial collagen fraction and capillary density; and (8) cardiac remodeling and function. Acutely, Ac-SDKP reduced cardiac rupture, decreased ICAM-1 expression and the number of infiltrating macrophages, decreased gelatinolytic activity, p53 expression, and myocyte apoptosis, but increased capillary density in the infarction border. Chronically, Ac-SDKP improved cardiac structures and function, reduced CHOP expression and interstitial collagen fraction, and preserved myocardium SERCA2 expression. Thus, Ac-SDKP decreased cardiac rupture, ameliorated adverse cardiac remodeling, and improved cardiac function after MI, likely through preserved SERCA2 expression and inhibition of endoplasmic reticulum stress.

Apoptosis inhibitor of macrophage depletion decreased M1 macrophage accumulation and the incidence of cardiac rupture after myocardial infarction in mice.

BackgroundCardiac rupture is an important cause of death in the acute phase after myocardial infarction (MI). Macrophages play a pivotal role in cardiac remodeling after MI. Apoptosis inhibitor of macrophage (AIM) is secreted specifically by macrophages and contributes to macrophage accumulation in inflamed tissue by maintaining survival and recruiting macrophages. In this study, we evaluated the role of AIM in macrophage accumulation in the infarcted myocardium and cardiac rupture after MI.Methods and resultsWild-type (WT) and AIM‒/‒ mice underwent permanent left coronary artery ligation and were followed-up for 7 days. Macrophage accumulation and phenotypes (M1 pro-inflammatory macrophage or M2 anti-inflammatory macrophage) were evaluated by immunohistological analysis and RT-PCR. Matrix metalloproteinase (MMP) activity levels were measured by gelatin zymography. The survival rate was significantly higher (81.1% vs. 48.2%, P<0.05), and the cardiac rupture rate was significantly lower in AIM‒/‒ mice than in WT mice (10.8% vs. 31.5%, P<0.05). The number of M1 macrophages and the expression levels of M1 markers (iNOS and IL-6) in the infarcted myocardium were significantly lower in AIM‒/‒ mice than in WT mice. In contrast, there was no difference in the number of M2 macrophages and the expression of M2 markers (Arg-1, CD206 and TGF-β1) between the two groups. The ratio of apoptotic macrophages in the total macrophages was significantly higher in AIM‒/‒ mice than in WT mice, although MCP-1 expression did not differ between the two groups. MMP-2 and 9 activity levels in the infarcted myocardium were significantly lower in AIM‒/‒ mice than in WT mice.ConclusionsThese findings suggest that AIM depletion decreases the levels of M1 macrophages, which are a potent source of MMP-2 and 9, in the infarcted myocardium in the acute phase after MI by promoting macrophage apoptosis, and leads to a decrease in the incidence of cardiac rupture and improvements in survival rates.

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

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. Male 129sv mice underwent coronary artery occlusion to induce MI, followed by treatment with losartan (L, 20 and 60mg/kg), perindopril (P, 2 and 6mg/kg), amlodipine (20mg/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. Incidence of cardiac rupture within 2weeks 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-1β, IL-6, MMP9, MCP-1, TNF-α and TGFβ1) and activity of MMP2 and MMP9 in the infarct tissue were attenuated by losartan and/or perindopril treatment (all P < 0.05). 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.

Long-Term Administration of Eicosapentaenoic Acid Improves Post-Myocardial Infarction Cardiac Remodeling in Mice by Regulating Macrophage Polarization.

BackgroundConsumption of n‐3 fatty acids reduces the incidence of cardiovascular mortality in populations that consume diets rich in fish oil. Eicosapentaenoic acid (EPA) is an n‐3 fatty acid known to reduce the frequency of nonfatal coronary events; however, the frequency of mortality after myocardial infarction (MI) is not reduced. The aims of this study were to determine whether long‐term administration of EPA regulated cardiac remodeling after MI and to elucidate the underlying therapeutic mechanisms of EPA.Methods and ResultsC57BL/6J mice were divided into control (phosphate‐buffered saline–treated) and EPA‐treated groups. After 28 days of treatment, the mice were subjected to either sham surgery or MI by left anterior descending coronary artery ligation. Mortality due to MI or heart failure was significantly lower in the EPA‐treated mice than in the phosphate‐buffered saline–treated mice. However, the incidence of cardiac rupture was comparable between the EPA‐treated mice and the phosphate‐buffered saline–treated mice after MI. Echocardiographic tests indicated that EPA treatment attenuated post‐MI cardiac remodeling by preventing issues such as left ventricular systolic dysfunction and left ventricle dilatation 28 days after MI induction. Moreover, during the chronic remodeling phase, ie, 28 days after MI, flow cytometry demonstrated that EPA treatment significantly inhibited polarization toward proinflammatory M1 macrophages, but not anti‐inflammatory M2 macrophages, in the infarcted heart. Furthermore, EPA treatment attenuated fibrosis in the noninfarcted remote areas during the chronic phase.ConclusionsLong‐term administration of EPA improved the prognosis of and attenuated chronic cardiac remodeling after MI by modulating the activation of proinflammatory M1 macrophages.

Risk factors of cardiac rupture in patients with acute myocardial infarction

Objective: To analyze the risk factors of cardiac rupture in patients with acute myocardial infarction. Methods: Clinical data were analyzed from 10 284 acute myocardial infarction patients admitted to Beijing Anzhen Hospital from January 2012 to March 2015. Cardiac rupture occurred in 81 patients, including 67 patients of acute left ventricular free wall rupture and 14 patients of ventricular septal defect, were retrospectively analyzed. Binary logistics regression analysis was performed to analyze the risk factors of cardiac rupture. Results: Incidence of cardiac rupture was significantly higher in patients with ST-segment elevation myocardial infarction than in patients with non-ST-segment elevation myocardial infarction (1.5%(70/4 724) vs. 0.2%(11/5 560), P<0.01). Binary logistic regression analysis showed that age (OR=0.827, 95%CI 0.726-0.941, P<0.01), recurrent myocardial infarction during hospital(OR=0.001, 95%CI 0.000-0.418, P<0.05), systolic blood pressure(OR=1.114, 95%CI 1.029-1.206, P<0.01), left anterior descending artery lesion (OR=0.003, 95%CI 0.000-0.334, P<0.05), lower hemoglobin(OR=1.129, 95%CI 1.051-1.212, P<0.01), serum total protein (OR=1.453, 95%CI 1.070-1.971, P<0.05), and serum magnesium level (OR=0.000, 95%CI 0.000-0.001, P<0.01) were associated with cardiac rupture. Conclusion: Older age, recurrent myocardial infarction, lower systolic blood pressure, left anterior descending artery lesion, lower serum hemoglobin, lower serum total protein, and higher serum magnesium level are risk factors of cardiac rupture and these factors should be carefully managed to prevent the occurrence of cardiac rupture.

Abstract 028: Effects of N-acetyl-seryl-aspartyl-lysyl-proline on Inflammatory Cells During the Acute Stage of Myocardial Infarction

Background: The natural peptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) decreases inflammation in chronic diseases such as hypertension and heart failure. The effects of Ac-SDKP on acute inflammatory responses during myocardial infarction (MI) are unknown. During the first 72 hours post-MI, neutrophils, M1 macrophages (pro-inflammatory), and M2 macrophages (pro-resolution) and the release of myeloperoxidase (MPO) and matrix metalloproteinases (MMP) play a role in the development of cardiac rupture which is an uncommon, but fatal complication. We hypothesize that in the acute stage of MI, Ac-SDKP decreases the incidence of cardiac rupture and mortality by preventing the infiltration of immune cells and by decreasing the activation of MPO and MMP. Methods: MI was induced by the ligation of the left descending coronary artery in C57 mice. Vehicle or Ac-SDKP (1.6 mg/kg/d) was infused via osmotic minipump. Cardiac immune cell infiltration was assessed by flow cytometry, cardiac MPO and MMP activities were measured at 24-48 hrs post-MI. The incidence of cardiac rupture and mortality was determined at 7 days post-MI. Neutrophil migration was studied in vitro by chemotaxis transwell assay. Results: In infarcted mice, Ac-SDKP decreased the incidence of cardiac rupture from 51.0% (26 of 51 animals) to 27.3% (12/44; p=0.015) and mortality from 56.9% (29/51) to 31.8% (14/44; p=0.019). Ac-SDKP also reduced the cardiac infiltration by the M1 macrophages (veh: 1,495±236 vs Ac-SKDP: 765±69 cells/heart, p=0.027), without affecting M2 macrophages. Ac-SDKP did not affect neutrophil and MPO activity in vivo and neither affected neutrophil chemotaxis in vitro . However, Ac-SDKP prevented the activation of MMP-9 (veh: 3,686±508 vs Ac-SDKP: 1,696±512 optical density units, p=0.029) in infarcted hearts. Conclusion: Ac-SDKP prevents cardiac rupture and mortality in acute MI. These protective effects of Ac-SDKP are associated with a decrease in pro-inflammatory M1 macrophage infiltration and MMP-9 activation. Perspective: Cardiac rupture is an uncommon, but fatal complication of MI that could be prevented by the administration of Ac-SDKP or a peptidase resistant analog.

Trends in the clinical and pathological characteristics of cardiac rupture in patients with acute myocardial infarction over 35 years.

BackgroundThere is little known about whether the clinical and pathological characteristics and incidence of cardiac rupture (CR) in patients with acute myocardial infarction (AMI) have changed over the years.Methods and ResultsThe incidence and clinical characteristics of CR were investigated in patients with AMI, who were divided into 3 cohorts: 1977–1989, 1990–2000, and 2001–2011. Of a total of 5699 patients, 144 were diagnosed with CR and 45 survived. Over the years, the incidence of CR decreased (1977–1989, 3.3%; 1990–2000, 2.8%; 2001–2011, 1.7%; P=0.002) in association with the widespread adoption of reperfusion therapy. The mortality rate of CR decreased (1977–1989, 90%; 1990–2000, 56%; 2001–2011, 50%; P=0.002) in association with an increase in the rate of emergent surgery. In multivariable analysis, first myocardial infarction, anterior infarct, female sex, hypertension, and age >70 years were significant risk factors for CR, whereas impact of hypertension on CR was weaker from 2001 to 2011. Primary percutaneous coronary intervention (PPCI) was a significant protective factor against CR. In 64 autopsy cases with CR, myocardial hemorrhage occurred more frequently in those who underwent PPCI or fibrinolysis than those who did not receive reperfusion therapy (no reperfusion therapy, 18.0%; fibrinolysis, 71.4%; PPCI, 83.3%; P=0.001).ConclusionsWith the development of medical treatment, the incidence and mortality rate of CR have decreased. However, first myocardial infarction, anterior infarct, female sex, and old age remain important risk factors for CR. Adjunctive cardioprotection against reperfusion‐induced myocardial hemorrhage is emerging in the current PPCI era.

Olmesartan prevents cardiac rupture in mice with myocardial infarction by modulating growth differentiation factor 15 and p53.

Cardiac rupture is a catastrophic complication that occurs after acute myocardial infarction (MI) and, at present, there are no effective pharmacological strategies for preventing this condition. Here we investigated the effect of the angiotensin II receptor blocker olmesartan (Olm) on post-infarct cardiac rupture and its underlying mechanisms of action. C57Bl/6 mice with MI were treated with Olm, aldosterone (Aldo) or vehicle. Cultured neonatal cardiomyocytes and fibroblasts were exposed to normoxia or anoxia and treated with angiotensin II (Ang II), RNH6270 (active ingredient of Olm) or Aldo. The mortality rate and incidence of cardiac rupture in MI mice during the first week in the Olm-treated group were significantly lower than in the vehicle-treated group. Olm or RNH6270 reduced myeloperoxidase staining in the infarcted myocardium, decreased apoptosis in cultured cardiomyocytes and fibroblasts, as assessed by Hoechst staining and TUNEL assay, attenuated the accumulation of p53 and phosphorylated p53 and cleaved caspase 3 induced by MI or Ang II, as assessed by Western blotting, and up-regulated growth differentiation factor-15 (GDF-15). In cultured cardiomyocytes and fibroblasts, treatment with Ang II, Aldo or anoxia significantly down-regulated the expression of GDF-15. Olm prevents cardiac rupture through inhibition of apoptosis and inflammation, which is attributable to the down-regulation of p53 activity and up-regulation of GDF-15. Our findings suggest that early administration of an AT1 receptor anatagonist to patients with acute MI is a potential preventive approach for cardiac rupture.

221 Myocardial Ischemic Injury Is Unexpectedly Increased In Mice Lacking The H2s Metabolising Enzyme Thiosulfate Sulfurtransferase

BackgroundIncreased H2S availability, through use of H2S donors, or in mice overexpressing the H2S synthetic enzyme cystathionine gamma-lyase (CSE), reduces injury associated with myocardial ischemia (MI) and ischemia-reperfusion. The mitochondrial...

P4 Myocardial ischaemic injury is unexpectedly increased in mice lacking the H2S metabolising enzyme thiosulfate sulfurtransferase

Increased H 2 S availability reduces injury associated with myocardial ischemia (MI) and ischemia–reperfusion. The mitochondrial enzyme thiosulfate sulfurtransferase (TST) has a putative role in removal of H 2 S and is a potential target to increase H 2 S bioavailability. This study investigated the hypothesis that TST deletion ( Tst −/− ) would improve outcome following MI. TST expression was assessed by qRT-PCR and Western blotting. Tst −/− and WT mice were examined in vivo by ultrasound. MI was induced by coronary artery ligation in vivo , or ex vivo in perfused hearts, when 30 min ischemia was followed by 120 min reperfusion. qRT-PCR and Western blots confirmed the presence of TST in the murine heart and deletion in Tst −/− . Tst −/− mice survived to adulthood and had normal cardiac function. Expression of the H 2 S synthesising enzyme, cystathionine gamma-lyase (CSE), was reduced in Tst −/− relative to WT hearts ( n = 5, p < 0.01). Following MI the incidence of cardiac rupture was increased in Tst −/− mice (66%, vs 20% in WT). Studies in isolated hearts revealed increased infarct size in Tst −/− (88 ± 2% area at risk, vs 65 ± 6% in WT, n = 6, p = 0.01). TST is present in the heart and deletion does not influence function. Tst −/− mice have reduced cardiac CSE expression, suggesting reduced H 2 S synthetic capacity. This may underlie the increased susceptibility of Tst −/− mice to myocardial injury and increased mortality. TST may act with CSE to regulate H 2 S availability. Alteration in the balance of these enzymes has no overt physiological effect, but is associated with reduced capacity of the heart to resist ischemic stress.

Pro-Inflammatory Action of MIF in Acute Myocardial Infarction via Activation of Peripheral Blood Mononuclear Cells

ObjectivesMacrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, has been implicated in the pathogenesis of multiple inflammatory disorders. We determined changes in circulating MIF levels, explored the cellular source of MIF, and studied the role of MIF in mediating inflammatory responses following acute myocardial infarction (MI).Methods and ResultsWe recruited 15 patients with MI, 10 patients with stable angina and 10 healthy volunteers and measured temporal changes of MIF in plasma. Expression of MIF, matrix metalloproteinase-9 (MMP-9) and interleukin-6 (IL-6) in cultured peripheral blood mononuclear cells (PBMCs) and the media were measured by ELISA or real-time PCR. Compared to controls, plasma levels of MIF and IL-6 were significantly elevated at admission and 72 h post-MI. In contrast, expression of MIF, MMP-9 and IL-6 by PBMCs from MI patients was unchanged at admission, but significantly increased at 72 h. Addition of MIF activated cultured PBMCs by upregulating expression of inflammatory molecules and also synergistically enhanced stimulatory action of IL-1β which were inhibited by anti-MIF interventions. In a mouse MI model we observed similar changes in circulating MIF as seen in patients, with reciprocal significant increases in plasma MIF and reduction of MIF content in the infarct myocardium at 3 h after MI. MIF content in the infarct myocardium was restored at 72 h post-MI and was associated with robust macrophage infiltration. Further, anti-MIF intervention significantly reduced inflammatory cell infiltration and expression of monocyte chemoattractant protein-1 at 24 h and incidence of cardiac rupture in mice post-MI.ConclusionMI leads to a rapid release of MIF from the myocardium into circulation. Subsequently MIF facilitates PBMC production of pro-inflammatory mediators and myocardial inflammatory infiltration. Attenuation of these events, and post-MI cardiac rupture, by anti-MIF interventions suggests that MIF could be a potential therapeutic target following MI.

Abstract 99: Ac-SDKP Protects the Heart From Post-myocardial Infarction Remodeling and Dysfunction in Mice

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory, anti-fibrotic and pro-angiogenic effects. We previously observed that Ac-SDKP reduces incidence of cardiac rupture in mice with acute myocardial infarction (MI), which is associated with its anti-inflammatory and pro-angiogenic properties. We hypothesized that Ac-SDKP, via its anti-fibrotic and pro-angiogenic actions, ameliorates left ventricular (LV) dilatation and fibrosis, thus improving cardiac function post-MI. C57BL/6J mice were divided into three groups: 1) sham MI, 2) MI + vehicle (VEH), and 3) MI + Ac-SDKP. Ac-SDKP (1.6 mg/kg/day) was given immediately after MI induction ( i.p. via osmotic pump) for 5 weeks. Cardiac remodeling and function were assessed by echocardiography, and interstitial collagen fraction (ICF) and capillary density was determined histologically. We found that Ac-SDKP 1) reduced LV remodeling, evidenced by decreased LV chamber dimensions and areas, and reduced ICF and increased capillary density, with no changes in posterior wall thickness and LV weight (LVW), and 2) improved cardiac function, demonstrated by increased fractional shortening (FS) and ejection fraction (EF) (Table). We conclude that in murine models of MI, Ac-SDKP protects the heart from more severe remodeling and dysfunction, possibly via its anti-fibrotic and pro-angiogenic actions. Thus, the use of Ac-SDKP or its analogues could be a new and effective alternative in restoring cardiac function in patients after MI.

Critical role for white blood cell NAD(P)H oxidase-mediated plasminogen activator inhibitor-1 oxidation and ventricular rupture following acute myocardial infarction

Plasminogen activator inhibitor-1 (PAI-1) is an oxidant-sensitive protease inhibitor that is inactivated by oxidation and has a critical role in ventricular remodeling post myocardial infarction (MI). PAI-1 knockout (KO) mice die within 7days of myocardial infarction post MI due to increased plasmin activity leading to ventricular rupture. The goal of this study was to assess the relevant pathways of leukocyte-derived oxidants post MI that alter PAI-1 activity. Transplantation of wild-type (WT) bone marrow into PAI-1 null mice prolonged survival after MI (WT marrow: 41.66% vs. PAI-1 KO marrow: 0% in PAI-1 KO mice at day 7 (p<0.02). To determine relevant enzyme systems, we transplanted marrow from mice with specific deletions relevant to leukocyte-derived oxidants (NAD(P)H oxidase, iNOS, myeloperoxidase (MPO)) to determine which deletion controls PAI-1 oxidative inactivation and prolongs survival. MI was induced by ligation of the left anterior descending artery (LAD) and the incidence of cardiac rupture was monitored. PAI-1 KO transplanted with MPO KO, or iNOS KO bone marrow died within 9days after MI. PAI-1 KO mice transplanted with p47phox KO marrow exhibited prolonged survival 21days after MI (30% survival, p<0.03, n=10) compared to WT marrow (8.3%, n=12). Three days after MI, PAI-1 KO mice transplanted with p47phox KO marrow had increased PAI-1 activity and decreased nitration of PAI-1 in myocardial tissue compared to PAI-1 KO mice transplanted with WT marrow. These data suggest that modulating O2•− generation by NAD(P)H oxidase appears to be a therapeutically relevant target for increasing myocardial PAI-1 levels after MI, whereas downstream enzymes like MPO and iNOS may not be.

Changes in Hospital Mortality Rates in 425 Patients With Acute ST-Elevation Myocardial Infarction and Cardiac Rupture Over a 30-Year Period

Possible changes in the incidence and outcome of cardiac rupture in patients with ST-elevation myocardial infarction over a long period of time have not been investigated. The incidence of cardiac rupture in ST-elevation myocardial infarction patients and its mortality rate were investigated during a 30-year period divided into 5 intervals (1977 to 1982, 1983 to 1988, 1989 to 1994, 1995 to 2000, and 2001 to 2006). Of a total of 6678 consecutive patients, 425 experienced a free wall rupture (280 with cardiac tamponade: 227 with electromechanical dissociation and 53 with hypotension) or a septal rupture (145). After the exclusion of referrals from other centers (n=44), the incidence of definite cardiac rupture (septal rupture, anatomic evidence of free wall rupture, or electromechanical dissociation) declined progressively (6.2% in 1977 to 1982 to 3.2% in 2001 to 2006; P<0.001) in parallel with a progressive use of reperfusion therapy (0% to 75.1%; P<0.001). In addition, among patients with cardiac rupture, there was a progressive fall in the rate of death (94% to 75%; P<0.001) despite a trend toward increasing age (66+/-8 to 75+/-8 years; P<0.054) in conjunction with better control of systolic blood pressure at 24 hours (130+/-24 versus 110+/-18 mm Hg; P<0.001); an increased use of reperfusion therapy (0% to 59%; P<0.001), beta-blockers (0% to 45%; P<0.001), angiotensin-converting enzyme inhibitors (0% to 38%; P<0.001), and aspirin (0% to 96%; P<0.001); and a lower use of heparin (99% to 67%; P<0.001). The decline in the incidence in cardiac rupture and its rate of death over the last 30 years appears to be associated with the increasing use of reperfusion strategies and adjunct medical therapy.

Age-related differences in postinfarct left ventricular rupture and remodeling

Cardiac rupture is more prevalent in elderly patients with first onset of acute myocardial infarct (MI), but the mechanism remains unexplored. We investigated the differences in the incidence of cardiac rupture and early left ventricular (LV) remodeling following coronary artery ligation between old (12-mo) and young (3-mo) C57Bl/6 male mice and explored responsible mechanisms. The incidence of rupture within 1 wk after MI was significantly higher in old than in young mice (40.7 vs. 18.3%, P = 0.013) despite a similar infarct size in both age groups. Old mice dying of rupture had more severe infarct expansion than young counterparts. Echocardiography and catheterization at day 7 revealed more profound LV chamber dilatation and dysfunction as well as higher blood pressures in aged mice. At day 3 after MI immediately before the peak of rupture occurrence, we observed significantly higher content of type I and III collagen, a greater density of macrophage and neutrophil, and markedly enhanced mRNA expression of inflammatory cytokines in the infarcted myocardium in old than in young mice. Furthermore, a more dramatic increment of matrix metalloproteinase (MMP)-9 activity was found in old than in young infarcted hearts, in keeping with enhanced inflammatory response. Collectively, these results revealed that old mice had a higher risk of post-MI cardiac rupture despite a higher level of collagen content and cross-linking. Enhanced inflammatory response and subsequent increase in MMP-9 activity together with higher blood pressure are important factors responsible for the higher risk of cardiac rupture and more severe LV remodeling in the aged heart following acute MI.

CARDIAC RUPTURE IN MYOCARDIAL INFARCTION: INCIDENCE AND PREDISPOSING FACTORS (15 YEAR FOLLOW-UP)

Aim. To evaluate the incidence of cardiac rupture (CR) in patients with acute myocardial infarction (MI) as well as predisposing factors during 15-year follow-up. Material and methods. 1453 patients with acute MI who were admitted to Krasnoyarsk cardiological center during 1989, 1993 and 2003 years were studied. All patients were divided into three groups: group I - 447 patients, who were on treatment in 1989, group II - 475 patients of 1993, and group III – 531 patients of 2003. There were no differences in groups on patient sex, location and depth of MI, previous MI, arrhythmias, heart failure and diabetes mellitus. Results. CR was found in 18 of 447 patients (4%) of group I (1989), in 16 of 475 patients (3,4%) of group II (1993) and in 10 of 531 patients (1,9%) of group 3 (2003), (p1,3 <0,05). Incidence of CR significantly decreased from 1989 to 2003 in female patients (7,2%; 5,7% and 1,6% in 1989, 1993 and 2003, respectively; p1,3 < 0,01, p2,3 < 0,05). Incidence of CR in male patients didn’t changed (2,5%, 1,8% and 2,1%, respectively). The average blood pressure (BP) during the first day of MI in female patients was higher than this in male ones in 1989 and 1993. There were no significant differences in BP between women and men in 2003. Heart rate (HR) during the first day of MI in female patients was higher than this in male patients in 1989. However in 1993 and 2003 there were no differences in HR between women and men. MI therapy more often included betablockers, angiotensin converting enzyme inhibitors, intravenous nitrates, statins, thrombolythics and anticoagulants in 2003 than in 1989 and 1993. Conclusion. Effective BP and HR control is the most effective way to prevent CR in patients with MI.

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

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. 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. 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). 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.

New strategy for successful repairment of post infarction cardiac rupture

Reperfusion therapy for acute myocardial infarction (AMI) has reduced early mortality, however the incidence of cardiac rupture following AMI has not significantly decreased. Cardiac rupture is a catastrophic complications and there are few reports of patients who have successfully recovered. The percutaneous cardiopulmonary support system (PCPS) is useful in maintaining circulation during circulatory collapse. Surgical interventions using PCPS were performed in eleven patients with cardiac rupture. Attempts at surgical repair were possible in six patients when PCPS was used as the circulatory assist deveice. On the other hand, when PCPS was used as a circulatory assistance device, but none survived. PCPS was used in five patients as both a circulatory assistance device and for surgical support at low temperature (20°C). Two of these five patients survived and were uneventfully discharged. This new strategy of using hypothermic percutaneous cardiopulmonary support bypass should prove to be useful for successful repair of post-infarction rupture.

A composite view of cardiac rupture in the United States national registry of myocardial infarction

Objectives.This study was done to determine the incidence, timing and prevalence as a cause of death from cardiac rupture in patients with acute myocardial infarction.Background.Several clinical trials and overview analyses have suggested that the survival benefit conferred by thrombolytic therapy may be offset by a paradoxic increase in early deaths from cardiac rupture.Methods.Demographic, procedural and outcome data from patients with acute myocardial infarction were collected at 1,073 United States hospitals collaborating in the United States National Registry of Myocardial Infarction.Results.Among the 350,755 patients enrolled, 122,243 received thrombolytic therapy. In-hospital mortality for the overall patient population, those not treated with thrombolytics (m = 228,512) and those given thrombolytics were 10.4%, 12.9% and 5.9%, respectively (p < 0.001). Cardiogenic shock was the most common cause of death in each patient group. Although the incidence of cardiac rupture was low (<1.0%), it was responsible for 7.3%, 6.1% and 12.1%, respectively, of in-hospital deaths (p < 0.001). Death from rupture occurred earlier in patients given thrombolytic therapy, with a clustering of events within 24 h of drug administration. Despite the early risk, death rates were comparatively low in thrombolytic-treated patients on each of the first 30 days. By multivariable analysis, thrombolytics, prior myocardial infarction, advancing age, female gender and intravenous beta-blocker use were independently associated with cardiac rupture.Conclusions.This large registry experience, including over 350,000 patients with myocardial infarction, suggests that thrombolytic therapy accelerates cardiac rupture, typically to within 24 to 48 h of treatment. The possibility that rupture represents an early hemorrhagic complication of thrombolytic therapy should be investigated.

A clinicopathological analysis of cardiac rupture following acute myocardial infarction in elderly patients

In all autopsied cases from January 1980 to June 1988 (56-102 years old, 243 men and 307 women), cardiac rupture death was observed in 14 cases out of 68 deaths of acute myocardial infarction in our hospital. Cardiac rupture occurred in 2, 4, 3, and 5 cases in their 60's, 70's, 80's, and 90' respectively, and 4 in men and 10 in women. Complaints of chest pain were present in 4 cases. Cerebrovascular disease was present in 9 cases and hypertension in 7. In 9 cases, the thickness of the ruptured wall was over 14 mm. The location of the ruptured lesion was the anterior wall in 4 cases, anteroseptal in 3, anterolateral in 1, lateral in 1, posterior in 1, and apical in 1. In conclusion, the incidence of cardiac rupture was higher in female than in males, and in silent myocardial infarction than in painful one. The location of rupture was frequently in the anterior or lateral wall. Aging and hypertension would not be a worsening factor in the pathogenesis of cardiac rupture in myocardial infarction, but cerebrovascular disease might be a risk factor in respect to masking occurrence of myocardial infarction.