Proteomic analysis of plasma proteins from patients with cardiac rupture after acute myocardial infarction using TMT-based quantitative proteomics approach.

BACKGROUND: Cardiac rupture (CR) is a rare but catastrophic mechanical complication of acute myocardial infarction (AMI) that seriously threatens human health. However, the reliable biomarkers for clinical diagnosis and the underlying signaling pathways insights of CR has yet to be elucidated. METHODS: In the present study, a quantitative approach with tandem mass tag (TMT) labeling and liquid chromatography-tandem mass spectrometry was used to characterize the differential protein expression profiles of patients with CR. Plasma samples were collected from patients with CR (n = 37), patients with AMI (n = 47), and healthy controls (n = 47). Candidate proteins were selected for validation by multiple reaction monitoring (MRM) and enzyme-linked immunosorbent assay (ELISA). RESULTS: In total, 1208 proteins were quantified and 958 differentially expressed proteins (DEPs) were identified. The difference in the expression levels of the DEPs was more noticeable between the CR and Con groups than between the AMI and Con groups. Bioinformatics analysis showed most of the DEPs to be involved in numerous crucial biological processes and signaling pathways, such as RNA transport, ribosome, proteasome, and protein processing in the endoplasmic reticulum, as well as necroptosis and leukocyte transendothelial migration, which might play essential roles in the complex pathological processes associated with CR. MRM analysis confirmed the accuracy of the proteomic analysis results. Four proteins i.e., C-reactive protein (CRP), heat shock protein beta-1 (HSPB1), vinculin (VINC) and growth/differentiation factor 15 (GDF15), were further validated via ELISA. By receiver operating characteristic (ROC) analysis, combinations of these four proteins distinguished CR patients from AMI patients with a high area under the curve (AUC) value (0.895, 95% CI, 0.802-0.988, p < 0.001). CONCLUSIONS: Our study highlights the value of comprehensive proteomic characterization for identifying plasma proteome changes in patients with CR. This pilot study could serve as a valid foundation and initiation point for elucidation of the mechanisms of CR, which might aid in identifying effective diagnostic biomarkers in the future.

Is vacuum-assisted closure therapy the main culprit in right ventricular rupture after deep sternal wound infection?

Right ventricular rupture after deep sternal wound infection (DSWI) is a rare but fatal complication, and can occur with or without vacuum assisted closure (VAC) therapy. There is currently no strong evidence to suggest whether or not VAC therapy is a contributing factor to this complication. In total, 30 articles were retrieved and assessed through a systematic review strategy from 1953 to 2022. The keywords: 'vacuum assisted closure'; 'VAC'; 'negative pressure wound therapy'; 'deep sternal wound infection'; 'DSWI'; 'right ventricular rupture'; and 'cardiac rupture' were used in the search. Overall, 15 of the included articles satisfied the predefined eligibility criteria. Fatal right ventricular ruptures were reported in 18 (36%) out of 50 cases. In this article, the risk factors, mechanisms and management of right ventricular rupture are discussed. A novel view of the mechanism of VAC-associated right ventricular rupture is highlighted, with a focus on both pre- and intraoperative management.

Heart Rate Reduction with Ivabradine Prevents Cardiac Rupture after Myocardial Infarction in Mice.

PURPOSE: Cardiac rupture is a fatal complication following myocardial infarction (MI). An increase in heart rate (HR) is reportedly an independent risk factor for cardiac rupture during acute MI. However, the role of HR reduction in cardiac rupture after MI remains to be fully elucidated. We aimed to evaluate the therapeutic efficacy of HR reduction with ivabradine (IVA) on post-MI cardiac rupture in mice. METHODS: We induced MI in mice by ligating the left anterior descending coronary artery. Subsequently, we subcutaneously implanted osmotic pumps filled with IVA solution or vehicle (Veh) in the surviving MI mice at 24 h postoperatively. We biochemically analyzed the myocardium on day 5, additionally observed the mice for 10 days, and analyzed the rates of cardiac rupture and non-cardiac rupture death, and survival after MI. RESULTS: HR was significantly lower in the IVA-treated mice, whereas blood pressure was comparable between the two groups. Compared to the Veh-treated mice, apoptosis was significantly reduced in the MI border zone in the IVA-treated mice. Although there were no differences in the infarct size of the surviving MI mice between the two groups, HR reduction with IVA significantly reduced cardiac rupture (rupture rate 26 and 8% in the Veh-treated and IVA-treated groups, respectively) and improved survival after MI. CONCLUSION: Our findings suggest that HR reduction with IVA prevents cardiac rupture after MI. This may be particularly effective in MI patients with a high HR who are either unable to adequately tolerate ß-blockers or whose HR remains high despite receiving ß-blockers.

Blunt Trauma to the Heart: A Review of Pathophysiology and Current Management.

Blunt cardiac injury (BCI), defined as an injury to the heart from blunt force trauma, ranges from minor to life-threatening. The majority of BCIs are due to motor vehicle accidents; however, injuries caused by falls, blasts, and sports-related injuries also can be sources of BCI. A significant proportion of patients with BCI do not survive long enough to receive medical care, succumbing to their injuries at the scene of the accident. Additionally, patients with blunt trauma often have coexisting injuries (brain, spine, orthopedic) that can obscure the clinical picture; therefore, a high degree of suspicion often is required to diagnose BCI. Traditionally, hemodynamically stable injuries suspicious for BCI have been evaluated with electrocardiograms and chest radiographs, whereas hemodynamically unstable BCIs have received operative intervention. More recently, computed tomography and echocardiography increasingly have been utilized to identify injuries more rapidly in hemodynamically unstable patients. Transesophageal echocardiography can play an important role in the diagnosis and management of several BCIs that require operative repair. Close communication with the surgical team and access to blood products for potentially massive transfusion also play key roles in maintaining hemodynamic stability. With proper surgical and anesthetic care, survival in cases involving urgent cardiac repair can reach 66%-to-75%. This narrative review focuses on the types of cardiac injuries that are caused by blunt chest trauma, the modalities and techniques currently used to diagnose BCI, and the perioperative management of injuries that require surgical correction.

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.

Incremental value of live/real-time three-dimensional transthoracic echocardiography over the two-dimensional technique in the assessment of left ventricular endocardial rupture with myocardial dissection and contained apical epicardial rupture following myocardial infarction.

We report the incremental value of live/real-time three-dimensional transthoracic echocardiography (3DTTE) over two-dimensional transthoracic echocardiography (2DTTE) in making a definitive diagnosis of left ventricular endocardial rupture with myocardial dissection and contained apical epicardial rupture in an elderly male patient presenting with acute myocardial infarction. To the best of our knowledge, this has not been described previously.

[Cardiac ruptures in acute myocardial infarction]. / Razryvy serdtsa pri ostrom infarkte miokarda.

Presented in the article are the generalized data of the Russian and foreign literature addressing the currently important problem of myocardial ruptures as one of the most dangerous complications of infarction, also analysing the results of clinical studies on interconnection of heart ruptures with systemic thrombolytic therapy and with a percutaneous coronary intervention. This is followed by describing the mechanisms that may lead to myocardial rupture during thrombolytic therapy and surgical endovascular treatment, underlying the necessity of pharmacological pre- and post-conditioning for prevention of reperfusion myocardial lesions. The article also touches upon the clinical and instrumental diagnosis of myocardial ruptures, as well as approaches to surgical treatment depending on the type of rupture and necessity of myocardial revascularization.

Validation of diagnostic criteria and histopathological characterization of cardiac rupture in the mouse model of nonreperfused myocardial infarction.

In patients with myocardial infarction (MI), cardiac rupture is an uncommon but catastrophic complication. In the mouse model of nonreperfused MI, reported rupture rates are highly variable and depend not only on the genetic background and sex of animals but also on the method used for documentation of rupture. In most studies, diagnosis of cardiac rupture is based on visual inspection during autopsy; however, criteria are poorly defined. We performed systematic histopathological analysis of whole hearts from C57BL/6J mice dying after nonreperfused MI and evaluated the reliability of autopsy-based criteria in identification of rupture. Moreover, we compared the cell biological environment of the infarct between rupture-related and rupture-independent deaths. Histopathological analysis documented rupture in 50% of mice dying during the first week post-MI. Identification of a gross rupture site was highly specific but had low sensitivity; in contrast, hemothorax had high sensitivity but low specificity. Mice with rupture had lower myofibroblast infiltration, accentuated macrophage influx, and a trend toward reduced collagen content in the infarct. Male mice had increased mortality and higher incidence of rupture. However, infarct myeloid cells harvested from male and female mice at the peak of the incidence of rupture had comparable inflammatory gene expression. In conclusion, the reliability of autopsy in documentation of rupture in infarcted mice is dependent on the specific criteria used. Macrophage-driven inflammation and reduced activation of collagen-secreting reparative myofibroblasts may be involved in the pathogenesis of post-MI cardiac rupture.NEW & NOTEWORTHY We show that cardiac rupture accounts for 50% of deaths in C57BL/6J mice undergoing nonreperfused myocardial infarction protocols. Overestimation of rupture events in published studies likely reflects the low specificity of hemothorax as a criterion for documentation of rupture. In contrast, identification of a gross rupture site has high specificity and low sensitivity. We also show that mice dying of rupture have increased macrophage influx and attenuated myofibroblast infiltration in the infarct. These findings are consistent with a role for perturbations in the balance between inflammatory and reparative responses in the pathogenesis of postinfarction cardiac rupture. We also report that the male predilection for rupture in infarcted mice is not associated with increased inflammatory activation of myeloid cells.

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.

Clinical Manifestation, Timing Course, Precipitating Factors, and Protective Factors of Ventricular Free Wall Rupture Following ST-Segment Elevation Myocardial Infarction.

Ventricular free wall rupture (FWR) is a catastrophic complication of that occurs after acute myocardial infarction (AMI), and at present, its clinical characteristics are unclear. We analyzed a total of 6,712 consecutive patients who presented with ST-segment elevation myocardial infarction (STEMI), and 78 patients with FWR after STEMI were enrolled in the study. Patients' demographic data, clinical manifestation, laboratory test results, and angiographic features were then collected and analyzed. FWR occurred in 78 cases (1.16%), and the inhospital mortality of FWR was up to 92.3%. Among the 78 FWR patients, 72 obtained accurate rupture time. FWR typically occurred within the first week after the infarct. Compared to late-phase FWR (more than 48 hours after STEMI) patients, early-phase FWR (during 48 hours after STEMI) patients showed significantly higher random glucose and higher percentage of anterior myocardial infarction. Besides, dual antiplatelet therapy (DAPT), ß-blockers, and angiotensin-converting enzyme inhibitors/angiotensin receptor blocker (ACEI/ARB) were used less frequently in early-phase FWR patients. Moreover, we first reported the precipitating factors of FWR. Defecating, transporting, acute emotional upset, diets, and invasive treatment turned out to be the main triggers for FWR. Furthermore, we found that patients who survived from FWR were younger, had higher ß-blocker coverage in the inhospital treatment, and had a higher frequency of primary PCI. FWR remains an infrequent but devastating complication of STEMI. We have found several factors related to the occurrence and prognosis of FWR. This study provides evidence for a better understanding of FWR.

Endogenous muscle atrophy F-box is involved in the development of cardiac rupture after myocardial infarction.

Muscle atrophy F-box (MAFbx/atrogin-1), an E3 ubiquitin ligase, is a crucial mediator of skeletal muscle atrophy and cardiac hypertrophy in response to pressure overload and exercise. The role of MAFbx in the regulation of cardiac remodeling after myocardial infarction (MI) remains unclear. Permanent coronary ligation of the left coronary artery was performed on MAFbx knockout (KO) and wild-type (WT) mice and MAFbx expression in the WT mice was shown to be significantly increased in the left ventricles after MI. The mortality rate due to post-MI cardiac rupture was significantly decreased in MAFbx KO mice compared to that in the WT mice. DNA microarray and mRNA expression analyses revealed that the upregulation of genes involved in inflammatory processes and cell motility of leukocytes and neutrophils, including Mmp9, Il1b, Cxcl2, and Nlrp3, was significantly attenuated in MAFbx KO mice 1 day after MI. MAFbx downregulation inhibited nuclear factor-κB (Nfkb) activation after MI. Flow cytometry results demonstrated that the myocardial infiltration of neutrophils was suppressed in MAFbx KO mice 1 day after MI. Nlrp3 and Il1b protein levels were decreased in MAFbx KO mice compared with those in the WT mice. MAFbx downregulation significantly attenuated Tnfa-induced Cxcl2, Il1b, and Nlrp3 expression in cardiomyocytes. We conclude that MAFbx plays an important role in the mediation of excessive inflammation, including neutrophil infiltration, inflammasome formation, and production of proinflammatory cytokines through the activation of Nfkb, promoting cardiac rupture after MI.

IRAK3 gene silencing prevents cardiac rupture and ventricular remodeling through negative regulation of the NF-κB signaling pathway in a mouse model of acute myocardial infarction.

Cardiac rupture and ventricular remodeling are recognized as the severe complications and major risk factors of acute myocardial infarction (AMI). This study aims to evaluate the regulatory roles of interleukin-1 receptor-associated kinase 3 (IRAK3) and nuclear factor-κB (NF-κB) signaling pathway in cardiac rupture and ventricular remodeling. Microarray analysis was performed to screen AMI-related differentially expressed genes and IRAK3 was identified. The models of AMI were established in male C57BL/6 mice to investigate the functional role of IRAK3. Afterwards, lentivirus recombinant plasmid si-IRAK3 was constructed for IRAK3 silencing. Next, cardiac function parameters were measured in response to IRAK3 silencing. The regulatory effects that IRAK3 had on myocardial infarct size and the content of myocardial interstitial collagen were analyzed. The regulation of IRAK3 silencing on the NF-κB signaling pathway was further assayed. The obtained results indicated that highly expressed IRAK3 and activated NF-κB signaling pathway were observed in myocardial tissues of mouse models of AMI, accompanied by increased expression of matrix metalloproteinase (MMP)-2/9 and tissue inhibitor of metalloproteinase 2 (TIMP-2). Notably, IRAK3 gene silencing inhibited the activation of NF-κB signaling pathway. Furthermore, IRAK3 gene silencing led to the decreased thickness of infarct area and collagen content of myocardial interstitium, alleviated diastolic, and systolic dysfunctions, as well as, facilitated cardiac functions in mice with AMI, corresponding to decreased expression of MMP-2/9 expression and increased expression of TIMP-2. Taken together, silencing of IRAK3 inactivates the NF-κB signaling pathway, and thereby impeding the cardiac rupture and ventricular remodeling, which eventually prevents AMI progression.

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.

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.

Development and validation of clinical risk score to predict the cardiac rupture in patients with STEMI.

BACKGROUND: Cardiac rupture (CR) is a fatal complication of ST-elevation myocardial infarction (STEMI) with poor prognosis. The aim of this study was to develop and validate practical risk score to predict the CR after STEMI. METHODS: A total of 11,234 STEMI patients from 7 centers in China were enrolled in our study, we firstly developed a simplified fast-track CR risk model from 7455 STEMI patients, and then prospectively validated the CR risk model using receiver-operating characteristic (ROC) curves by the other 3779 consecutive STEMI patients. This trial is registered with ClinicalTrials.gov, number NCT02484326. RESULTS: The incidence of CR was 2.12% (238/11,234), and the thirty-day mortality in CR patients was 86%. We developed a risk model which had 7 independent baseline clinical predictors (female sex, advanced age, anterior myocardial infarction, delayed admission, heart rate, elevated white blood cell count and anemia). The CR risk score system differentiated STEMI patients with incidence of CR ranging from 0.2% to 13%. The risk score system demonstrated good predictive value with area under the ROC of 0.78 (95% CI 0.73-0.84) in validation cohort. Primary percutaneous coronary intervention decreased the incidence of CR in high risk group (3.9% vs. 6.2%, p<0.05) and very high risk group (8.0% vs. 15.2%, p<0.05). CONCLUSIONS: A simple risk score system based on 7 baseline clinical variables could identify patients with high risk of CR, for whom appropriate treatment strategies can be implemented.

Coronary or ventricular rupture after blunt chest trauma? A clinical dilemma.

Cardiac rupture (CR) is one of the most serious and life-threatening complications of blunt chest trauma (BCT) usually associated with high mortality. Moreover, its diagnosis and treatment strategies may be extremely challenging for clinicians due to various anatomical localisations of the tear. Whereas most injuries fall under the category of right atrial ruptures, left ventricular lesions represent a rare type of this injury, with greater mortality, particularly in cases of multi-chamber injuries. However, not only cardiac chamber or great vessel ruptures may occur as a result of BCT; a growing number of reports also describe BCT-induced isolated coronary artery injuries, including ruptures. Whereas CR requires immediate surgical treatment, less invasive interventional techniques, such as stent placement and closure with fibrin glue or coils, can be the treatment of choice in selected cases of hemodynamically less relevant coronary artery ruptures. In this report, we present a rare case of a ventricular rupture following BCT, with the tear localized in the right ventricular wall and an occult connection to the left ventricle without ventricular septum injury. Also, another contemporaneous emergency in our department that had to be managed at the same time resulted in challenging the decision-making process. As such an emergency constellation is difficult to manage, this report may help clinicians in difficult situations in terms of diagnosis and choosing the right treatment strategy.

Twinkle overexpression prevents cardiac rupture after myocardial infarction by alleviating impaired mitochondrial biogenesis.

Cardiac rupture is a fatal complication after myocardial infarction (MI). However, the detailed mechanism underlying cardiac rupture after MI remains to be fully elucidated. In this study, we investigated the role of mitochondrial DNA (mtDNA) and mitochondria in the pathophysiology of cardiac rupture by analyzing Twinkle helicase overexpression mice (TW mice). Twinkle overexpression increased mtDNA copy number approximately twofold and ameliorated ischemic cardiomyopathy at day 28 after MI. Notably, Twinkle overexpression markedly prevented cardiac rupture and improved post-MI survival, accompanied by the suppression of MMP-2 and MMP-9 in the MI border area at day 5 after MI when cardiac rupture frequently occurs. Additionally, these cardioprotective effects of Twinkle overexpression were abolished in transgenic mice overexpressing mutant Twinkle with an in-frame duplication of amino acids 353-365, which resulted in no increases in mtDNA copy number. Furthermore, although apoptosis and oxidative stress were induced and mitochondria were damaged in the border area, these injuries were improved in TW mice. Further analysis revealed that mitochondrial biogenesis, including mtDNA copy number, transcription, and translation, was severely impaired in the border area at day 5 In contrast, Twinkle overexpression maintained mtDNA copy number and restored the impaired transcription and translation of mtDNA in the border area. These results demonstrated that Twinkle overexpression alleviated impaired mitochondrial biogenesis in the border area through maintained mtDNA copy number and thereby prevented cardiac rupture accompanied by the reduction of apoptosis and oxidative stress, and suppression of MMP activity.

Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation.

We have reported that the Toll-like receptor 9 (TLR9) signaling pathway plays an important role in the development of pressure overload-induced inflammatory responses and heart failure. However, its role in cardiac remodeling after myocardial infarction has not been elucidated. TLR9-deficient and control C57Bl/6 wild-type mice were subjected to left coronary artery ligation. The survival rate 14 days postoperation was significantly lower in TLR9-deficient mice than that in wild-type mice with evidence of cardiac rupture in all dead mice. Cardiac magnetic resonance imaging showed no difference in infarct size and left ventricular wall thickness and function between TLR9-deficient and wild-type mice. There were no differences in the number of infiltrating inflammatory cells and the levels of inflammatory cytokine mRNA in infarct hearts between TLR9-deficient and wild-type mice. The number of α-smooth muscle actin (αSMA)-positive myofibroblasts and αSMA/Ki67-double-positive proliferative myofibroblasts was increased in the infarct and border areas in infarct hearts compared with those in sham-operated hearts in wild-type mice, but not in TLR9-deficient mice. The class B CpG oligonucleotide increased the phosphorylation level of NF-κB and the number of αSMA-positive and αSMA/Ki67-double-positive cells and these increases were attenuated by BAY1-7082, an NF-κB inhibitor, in cardiac fibroblasts isolated from wild-type hearts. The CpG oligonucleotide showed no effect on NF-κB activation or the number of αSMA-positive and αSMA/Ki67-double-positive cells in cardiac fibroblasts from TLR9-deficient hearts. Although the TLR9 signaling pathway is not involved in the acute inflammatory response in infarct hearts, it ameliorates cardiac rupture possibly by promoting proliferation and differentiation of cardiac fibroblasts.

Haploinsufficiency of Hand1 improves mice survival after acute myocardial infarction through preventing cardiac rupture.

Previous studies have demonstrated a significantly lower level of Hand1 in ischemic cardiomyopathy than in normal heart tissue. The role of decreased Hand1 in myocardial infarction remains unclear. This study was designed to investigate the effects of haploinsufficiency of Hand1 on mouse heart after myocardial infarction. 8-10 weeks old male heterozygous Hand1-deficient (Hand1(+/-)) mice and wild-type littermates (control) were subjected to sham operation or ligation of the left anterior descending coronary artery to induce acute myocardial infarction (AMI). Hand1(+/-) mice have low incidence of left ventricular free wall rupture in the first week after operation than control mice. Then we found lower MMP9 activity and less cardiomyocytes apoptosis in Hand1(+/-) than in control mice. All of these contribute to the protection role of haploinsufficiency of Hand1 after AMI.

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.