Association between acute myocardial infarction-to-cardiac rupture time and in-hospital mortality risk: a retrospective analysis of multicenter registry data from the Cardiovascular Research Consortium-8 Universities (CIRC-8U).

Despite the known association of cardiac rupture with acute myocardial infarction (AMI), it is still unclear whether the clinical characteristics are associated with the risk of in-hospital mortality in patients with AMI complicated by cardiac rupture. The purpose of this study was to investigate the association between the time of cardiac rupture occurrence and the risk of in-hospital mortality after AMI. We conducted a retrospective analysis of multicenter registry data from eight medical universities in Eastern Japan. From 10,278 consecutive patients with AMI, we included 183 patients who had cardiac rupture after AMI, and examined the incidence of in-hospital deaths during a median follow-up of 26 days. Patients were stratified into three groups according to the AMI-to-cardiac rupture time, namely the > 24-h group (n = 111), 24-48-h group (n = 20), and < 48-h group (n = 52). Cox proportional hazards regression analysis was used to estimate the hazard ratio (HR) and the confidence interval (CI) for in-hospital mortality. Around 87 (48%) patients experienced in-hospital death and 126 (67%) underwent a cardiac surgery. Multivariable Cox regression analysis revealed a non-linear association across the three groups for mortality (HR [CI]; < 24 h: 1.0, reference; 24-48 h: 0.73 [0.27-1.86]; > 48 h: 2.25 [1.22-4.15]) after adjustments for age, sex, Killip classification, percutaneous coronary intervention, blood pressure, creatinine, peak creatine kinase myocardial band fraction, left ventricular ejection fraction, and type of rupture. Cardiac surgery was independently associated with a reduction in the HR of mortality (HR [CI]: 0.27 [0.12-0.61]) and attenuated the association between the three AMI-to-cardiac rupture time categories and mortality (statistically non-significant) in the Cox model. These data suggest that the AMI-to-cardiac rupture time contributes significantly to the risk of in-hospital mortality; however, rapid diagnosis and prompt surgical interventions are crucial for improving outcomes in patients with cardiac rupture after AMI.

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.

Sutureless repair for postinfarction left ventricular free wall rupture.

OBJECTIVE: Left ventricular free wall rupture is a catastrophic complication of acute myocardial infarction. Sutureless repair has been reported to be an effective surgical procedure for left ventricular free wall rupture. However, the outcomes of sutureless repair remain unclear. METHODS: Between January 2001 and December 2016, 42 patients were treated for left ventricular free wall rupture at Jichi Medical University. Of them, 35 consecutive patients undergoing sutureless repair using the TachoComb (CSL Behring, Tokyo, Japan) or TachoSil (Nycomed, Zurich, Switzerland) patches were included in this study. No patient required cardiopulmonary bypass. The oozing type of left ventricular free wall rupture was observed in 33 patients (94%), and the blow-out type was observed in 2 patients (6%). The rupture sites were the anterior wall in 16 patients (46%), the posterior-lateral wall in 11 patients (31%), and the inferior wall in 8 patients (23%). RESULTS: The in-hospital mortality rate was 17% (6 patients). Re-rupture after sutureless repair occurred in 17% (6 patients). Of them, 4 cases (67%) of re-rupture occurred within 24 hours after surgery. The 2 patients with blow-out type left ventricular free wall rupture experienced re-rupture. Three patients required mitral valve surgery after sutureless repair during the admission. The overall survivals at 1, 5, and 10 years were 71.4%, 68.6%, and 62.9%, respectively. Multivariable analysis revealed that re-rupture was an independent predictor for decreased survival (hazard ratio, 58.6; 95% confidence interval, 4.9-701.6; P = .001). Postoperative pseudoaneurysm formation was not detected during the follow-up. CONCLUSIONS: Sutureless repair using TachoComb/TachoSil patches can be a viable treatment option for left ventricular free wall rupture. Care should be taken when applying this technique in cases of the blow-out type left ventricular free wall rupture.

Cardiomyocyte-specific deficiency of HSPB1 worsens cardiac dysfunction by activating NFκB-mediated leucocyte recruitment after myocardial infarction.

Aims: Inadequate healing after myocardial infarction (MI) leads to heart failure and fatal ventricular rupture, while optimal healing requires timely induction and resolution of inflammation. This study tested the hypothesis that heat shock protein B1 (HSPB1), which limits myocardial inflammation during endotoxemia, modulates wound healing after MI. Methods and results: To test this hypothesis, cardiomyocyte-specific HSPB1 knockout (Hspb1-/-) mice were generated using the Cre-LoxP recombination system. MI was induced by ligation of the left anterior descending coronary artery in Hspb1-/- and wild-type (WT) littermates. HSPB1 was up-regulated in cardiomyocytes of WT animals in response to MI, and deficiency of cardiomyocyte HSPB1 increased MI-induced cardiac rupture and mortality within 21 days after MI. Serial echocardiography showed more aggravated remodelling and cardiac dysfunction in Hspb1-/- mice than in WT mice at 1, 3, and 7 days after MI. Decreased collagen deposition and angiogenesis, as well as increased MMP2 and MMP9 activity, were also observed in Hspb1-/- mice compared with WT controls after MI, using immunofluorescence, polarized light microscopy, and zymographic analyses. Notably, Hspb1-/- hearts exhibited enhanced and prolonged leucocyte infiltration, enhanced expression of inflammatory cytokines, and enhanced TLR4/MyD88/NFκB activation compared with WT controls after MI. In-depth molecular analyses in both mice and primary cardiomyocytes demonstrated that cardiomyocyte-specific knockout of HSPB1 increased nuclear factor-κB (NFκB) activation, which promoted the expression of proinflammatory mediators. This led to increased leucocyte recruitment, thereby to excessive inflammation, ultimately resulting in adverse remodelling, cardiac dysfunction, and cardiac rupture following MI. Conclusion: These data suggest that HSPB1 acts as a negative regulator of NFκB-mediated leucocyte recruitment and the subsequent inflammation in cardiomyocytes. Cardiomyocyte HSPB1 is required for wound healing after MI and could be a target for myocardial repair in MI patients.

Association of the SYNTAX Score II with cardiac rupture in patients with ST-segment elevation myocardial infarction undergoing a primary percutaneous coronary intervention.

BACKGROUND: Despite advances in reperfusion strategies, medical therapy, and emergent surgery, cardiac rupture (CR) is still a major lethal complication. Numerous parameters have been found to be associated with CR development after a primary percutaneous coronary intervention (pPCI). SYNTAX Score (SS) and SYNTAX Score II (SSII) have been studied in ST-segment elevation myocardial infarction (STEMI) patients, and higher scores have been associated with higher mortality. However, the relationship between CR and SSII is unclear. This study investigates the possible relationship between CR and SS, SSII in STEMI patients treated with pPCI. PATIENTS AND METHODS: We enrolled 1663 consecutive STEMI patients treated with pPCI, who were divided into two groups according to CR development and compared with each other. Patients were further stratified into the three groups according to their SSII values. RESULTS: In this study, 33 (1.98%) patients developed CR. Both SS and SSII of those with CR were significantly higher than those without (19.27±4.0 vs. 16.40±4.55; P<0.001 and 49.40±16.54 vs. 30.92±11.80; P<0.001, respectively). It was also observed that CR increased gradually according to increasing SSII tertiles. SSII was found to be an independent predictor for CR (odds ratio=1.043, 95% confidence interval: 1.012-1.074; P=0.006). In the long-term follow-up, all-cause mortality was significantly higher in patients with CR than those without (60.6 vs. 8.8%; P<0.001). CONCLUSION: This study shows that SSII is an independent predictor for CR. Furthermore, patients with CR were associated with a poor prognosis. Closer follow-up of patients with high SSII may be useful in the early detection and treatment of this fatal complication.

Splenic Ly6Chi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice.

Heme oxygenase-1 (Hmox1) is a stress-inducible protein crucial in heme catabolism. The end products of its enzymatic activity possess anti-oxidative, anti-apoptotic and anti-inflammatory properties. Cardioprotective effects of Hmox1 were demonstrated in experimental models of myocardial infarction (MI). Nevertheless, its importance in timely resolution of post-ischemic inflammation remains incompletely understood. The aim of this study was to determine the role of Hmox1 in the monocyte/macrophage-mediated cardiac remodeling in a mouse model of MI. Hmox1 knockout (Hmox1-/-) and wild-type (WT, Hmox1+/+) mice were subjected to a permanent ligation of the left anterior descending coronary artery. Significantly lower incidence of left ventricle (LV) free wall rupture was noted between 3rd and 5th day after MI in Hmox1-/- mice resulting in their better overall survival. Then, starting from 7th until 21st day post-MI a more potent deterioration of LV function was observed in Hmox1-/- than in the surviving Hmox1+/+ mice. This was accompanied by higher numbers of Ly6Chi monocytes in peripheral blood, as well as higher expression of monocyte chemoattractant protein-1 and adhesion molecules in the hearts of MI-operated Hmox1-/- mice. Consequently, a greater post-MI monocyte-derived myocardial macrophage infiltration was noted in Hmox1-deficient individuals. Splenectomy decreased the numbers of circulating inflammatory Ly6Chi monocytes in blood, reduced the numbers of proinflammatory cardiac macrophages and significantly improved the post-MI LV function in Hmox1-/- mice. In conclusion, Hmox1 deficiency has divergent consequences in MI. On the one hand, it improves early post-MI survival by decreasing the occurrence of cardiac rupture. Afterwards, however, the hearts of Hmox1-deficient mice undergo adverse late LV remodeling due to overactive and prolonged post-ischemic inflammatory response. We identified spleen as an important source of these cardiovascular complications in Hmox1-/- mice.

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.

A Case of Post Myocardial Infarction Papillary Muscle Rupture.

Papillary muscle rupture is a rare, life-threatening post myocardial infarction mechanical complication. Without surgical intervention, prognosis is very poor. Clinicians need to recognize this complication early, as prompt therapy is crucial. We present a case of inferior ST elevation myocardial infarction complicated by posteromedial papillary muscle rupture resulting in severe acute mitral regurgitation (flail anterior mitral leaflet), acute pulmonary edema and cardiogenic shock. In our patient, a new mitral regurgitation murmur suggested this mechanical complication. Complete disruption of papillary muscle was visualized by transesophageal echocardiography. This case illustrates the importance of good physical examination for early diagnosis of papillary muscle rupture, so that life-saving treatment can be administered without delay.

Calpastatin overexpression impairs postinfarct scar healing in mice by compromising reparative immune cell recruitment and activation.

The activation of the calpain system is involved in the repair process following myocardial infarction (MI). However, the impact of the inhibition of calpain by calpastatin, its natural inhibitor, on scar healing and left ventricular (LV) remodeling is elusive. Male mice ubiquitously overexpressing calpastatin (TG) and wild-type (WT) controls were subjected to an anterior coronary artery ligation. Mortality at 6 wk was higher in TG mice (24% in WT vs. 44% in TG, P < 0.05) driven by a significantly higher incidence of cardiac rupture during the first week post-MI, despite comparable infarct size and LV dysfunction and dilatation. Calpain activation post-MI was blunted in TG myocardium. In TG mice, inflammatory cell infiltration and activation were reduced in the infarct zone (IZ), particularly affecting M2 macrophages and CD4(+) T cells, which are crucial for scar healing. To elucidate the role of calpastatin overexpression in macrophages, we stimulated peritoneal macrophages obtained from TG and WT mice in vitro with IL-4, yielding an abrogated M2 polarization in TG but not in WT cells. Lymphopenic Rag1(-/-) mice receiving TG splenocytes before MI demonstrated decreased T-cell recruitment and M2 macrophage activation in the IZ day 5 after MI compared with those receiving WT splenocytes. Calpastatin overexpression prevented the activation of the calpain system after MI. It also impaired scar healing, promoted LV rupture, and increased mortality. Defective scar formation was associated with blunted CD4(+) T-cell and M2-macrophage recruitment.

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.

Decreased myocardial dendritic cells is associated with impaired reparative fibrosis and development of cardiac rupture after myocardial infarction in humans.

BACKGROUND: Dendritic cells (DC) play pivotal roles in regulating the immune system and inflammatory response. We previously reported DC infiltration in the infarcted heart and its immunoprotective roles in the post-infarction healing process after experimental myocardial infarction (MI). However, its clinical significance has not been determined. METHODS AND RESULTS: The degree of DC infiltration and its correlation with the post-infarction healing process in the human infarcted heart were investigated in 24 autopsy subjects after ST-elevation MI. Patients were divided into two groups according to the presence (n=13) or absence (n=11) of cardiac rupture. The numbers of infiltrated DC and macrophages and the extent of fibrosis in the infarcted area were examined. In the rupture group, CD68(+) macrophage infiltration was increased and CD209(+) DC, and CD11c(+) DC infiltration and the extent of reparative fibrosis were decreased compared with the non-rupture group, under matched baseline characteristics including the time from onset to death and use of revascularization. Furthermore, there was a significant positive correlation between the number of infiltrating CD209(+) DC, and CD11c(+) DC and the extent of reparative fibrosis. CONCLUSIONS: Decreased number of DC in human-infarcted myocardial tissue was associated with increased macrophage infiltration, impaired reparative fibrosis, and the development of cardiac rupture after MI. These findings suggest a protective role of DC in post-MI inflammation and the subsequent healing process.

Triple cardiac rupture.

Left ventricular free wall rupture and acute ischaemic mitral regurgitation are nowadays rare, but still potentially lethal mechanical complications after acute myocardial infarction. We report a case of a sequential left ventricular free wall rupture, anterolateral papillary muscle disruption, secondary severe mitral regurgitation and subsequent posteromedial papillary muscle head rupture in a single patient during the same ischaemic episode after myocardial infarction, and their related successful surgical procedures and management until discharge. Prompt bedside diagnosis and emergent consecutive surgical procedures, as well as temporary left ventricular assistance, were crucial in the survival of this patient.

Surgical treatment of complete anterolateral papillary muscle rupture following acute myocardial infarction.

Papillary muscle rupture is a lethal complication of after acute myocardial infarction. We report the successful surgical management of complete anterolateral papillary muscle rupture associated with cardiogenic shock in an 80-year-old woman. The patient was admitted with the sudden onset of chest pain and dyspnea. After hemodynamics deteriorated rapidly, she was intubated and intra-aortic balloon pump was started immediately. Transthoracic echocardiography revealed severe mitral regurgitation due to complete anterolateral papillary muscle rupture associated with lateral myocardial infarction. Coronary angiography demonstrated complete occlusion of the first obtuse marginal artery. She underwent emergency mitral valve replacement and coronary artery bypass grafting. There were no complications of surgery and she was discharged on postoperative day 35. Rapid preoperative assessment and aggressive surgical management are important to improve the prognosis in this setting.

Post-infarction biventricular free wall rupture with extracardiac shunt presenting as ventricular septal rupture.

Ventricular free wall rupture is a rare, usually fatal complication of acute myocardial infarction. Subacute free wall rupture with pseudoaneurysm formation is even rarer, but may be associated with a chance of survival if surgery is performed expeditiously. Although rupture of the left ventricle is more common, right-sided rupture has also been reported. We report an unusual case of post-infarct biventricular rupture masquerading as a ventricular septal defect, due to an extracardiac shunt within the pseudoaneurysm. Our patient underwent urgent surgery, made an excellent recovery and was discharged home in a fully functional condition within a week post-surgery.

[Mortality of interventricular septum rupture after acute myocardial infarction with surgical management]. / Mortalidad de la ruptura de septum interventricular posterior a infarto agudo del miocardio con manejo quirúrgico.

BACKGROUND: ventricular septal rupture is a rare complication of myocardial infarction. It is considered the most serious mechanical disturbance in these cases. The mortality of patients during the hospital period receiving surgical treatment for this complication is described. METHODS: a case series study, including patients with ventricular septal rupture posterior to myocardial infarction, detected with a retrospective review of records of patients subjected to surgical repair from December 2005 to December 2010. RESULTS: a total of 20 patients were included, with an average age of 56 years (48-65 years), male gender in 16 cases (80%), and a male: female relation of 4:1. Ten (50%) of the patients died; five due to multiple organ failure, one from nosocomial pneumonia, two from ventricular fibrillation, and two from refractory shock secondary to biventricular failure during the surgery. The factors identified for poor prognosis were the average time of 145 minutes on cardiopulmonary bypass, and acute kidney injury in six cases, requiring replacement therapy. CONCLUSIONS: ventricular septal rupture is a rare complication with a high mortality. Without surgical treatment mortality can reach almost 100%. The mortality of this pathology treated with surgical closing in our hospital was 50%, similar to other published reports. Our findings confirm that although surgery for ventricular septal rupture has a high mortality it should be carried out because it is a surgical emergency.

Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction.

The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell-matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC-null infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor beta (TGF)-mediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-beta rescued cardiac rupture in SPARC-null mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI.

[Early interventricular septum rupture after systemic thrombolysis in a patient with STEMI]. / Rottura precoce di setto interventricolare dopo trombolisi sistemica nell'infarto miocardico acuto con ST elevation.

Intraventricular septal rupture (ISR) is one of the most dreadful complications during AMI, requiring early diagnosis and urgent surgery. However, medical (90%) and surgical (50%) mortality remain elevated. We report a case of a 59 years old patient with infero-posterior AMI complicated by ISR after thrombolysis. Despite early recognition of this complication by trans-thoracic echocardiography at bedside and prompt surgical intervention the patient died on the second post-surgical day.