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ST-segment elevation myocardial infarction (STEMI) is the most acute manifestation of coronary artery disease and is associated with great morbidity and mortality. A complete thrombotic occlusion developing from an atherosclerotic plaque in an epicardial coronary vessel is the cause of STEMI in the majority of cases. Early diagnosis and immediate reperfusion are the most effective ways to limit myocardial ischaemia and infarct size and thereby reduce the risk of post-STEMI complications and heart failure. Primary percutaneous coronary intervention (PCI) has become the preferred reperfusion strategy in patients with STEMI; if PCI cannot be performed within 120 minutes of STEMI diagnosis, fibrinolysis therapy should be administered to dissolve the occluding thrombus. The initiation of networks to provide around-the-clock cardiac catheterization availability and the generation of standard operating procedures within hospital systems have helped to reduce the time to reperfusion therapy. Together with new advances in antithrombotic therapy and preventive measures, these developments have resulted in a decrease in mortality from STEMI. However, a substantial amount of patients still experience recurrent cardiovascular events after STEMI. New insights have been gained regarding the pathophysiology of STEMI and feed into the development of new treatment strategies. ST-segment elevation myocardial infarction (STEMI) is an acute coronary syndrome in which transmural ischaemia (mostly caused by the formation of a thrombus on a ruptured atherosclerotic plaque) leads to cardiomyocyte death. STEMI is associated with considerable morbidity and mortality worldwide.

Key Points One-fifth of acutely symptomatic patients admitted to an emergency department have elevated levels of cardiac troponins (cTn), but the majority do not have an acute coronary syndrome (ACS) Reasons for elevated cTn levels in acute or chronic non-ACS conditions are likely to be multifactorial, including myocardial ischaemia, ventricular strain, myocyte trauma, impaired renal clearance, and unknown mechanisms High-sensitivity assays for cTn can rule out non-ST-segment elevation myocardial infarction at an early stage in the diagnostic process The result of a test for cTn levels should not be interpreted in isolation, but in the context of clinical findings Even low levels of cTn can be prognostically important and associated with adverse outcomes in the absence of an ACS, and require investigation of the underlying causes Cardiac troponins (cTn) are the preferred biomarkers for the noninvasive detection of myocardial injury. However, cTn are not exclusively released as a result of ischaemic myocardial cell necrosis, but also with acute and chronic nonischaemic conditions. In this Review, Giannitsis and Katus describe the causes and the prognostic importance of the release of cTn not related to acute coronary syndromes, and recommend strategies to discriminate between ischaemic and nonischaemic cTn elevation. Over the past 2 decades, cardiac troponins (cTn) have emerged as the preferred biomarkers for the noninvasive detection of myocardial injury. In conjunction with typical clinical findings of ischaemia, elevated cTn levels in blood confirm a diagnosis of myocardial infarction. However, neither cTnT or cTnI are exclusively released as a result of ischaemic myocardial cell necrosis, but also with numerous nonischaemic acute and chronic cardiac conditions, such as myopericarditis, toxic injury, or severe cardiac overload. With the advent of high-sensitivity assays, causes of cTn elevation not related to an acute coronary syndrome (ACS) have become common findings in patients with chest pain and in those with acute or chronic systemic disorders. Elevated cTn levels in blood are associated with increased rates of cardiac events and mortality, independently of the underlying disease. However, the clinical conditions leading to cTn release in patients who do not have ACS, and the appropriate diagnostic and therapeutic strategies for these individuals, are largely unknown. Here, we provide an overview of the many causes and the prognostic importance of the release of cTn not related to ACS. We also recommend strategies to discriminate between ischaemic and nonischaemic cTn elevation, and describe the clinical evaluation of these patients.

The clinical use of the chemotherapeutic doxorubicin (Dox) is limited by cardiotoxic side-effects. One of the early Dox effects is induction of a sarcoplasmic reticulum (SR) Ca2+ leak. The chaperone Glucose regulated protein 78 (GRP78) is important for Ca2+ homeostasis in the endoplasmic reticulum (ER)-the organelle corresponding to the SR in non-cardiomyocytes-and has been shown to convey resistance to Dox in certain tumors. Our aim was to investigate the effect of cardiac GRP78 gene transfer on Ca2+ dependent signaling, cell death, cardiac function and survival in clinically relevant in vitro and in vivo models for Dox cardiotoxicity.By using neonatal cardiomyocytes we could demonstrate that Dox induced Ca2+ dependent Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activation is one of the factors involved in Dox cardiotoxicity by promoting apoptosis. Furthermore, we found that adeno-associated virus (AAV) mediated GRP78 overexpression partly protects neonatal cardiomyocytes from Dox induced cell death by modulating Ca2+ dependent pathways like the activation of CaMKII, phospholamban (PLN) and p53 accumulation. Most importantly, cardiac GRP78 gene therapy in mice treated with Dox revealed improved diastolic function (dP/dtmin) and survival after Dox treatment. In conclusion, our results demonstrate for the first time that Ca2+ dependent CaMKII activation fosters Dox cardiomyopathy and provide additional insight into possible mechanisms by which GRP78 overexpression protects cardiomyocytes from Doxorubicin toxicity.

Data from 15 international cohorts of patients with suspected acute MI were used to create and validate a risk-assessment tool integrating high-sensitivity troponin I or T at presentation, the change during serial sampling, and the time between samples to estimate the probability of MI on ED presentation and 30-day outcomes.

Translucent zebrafish larvae represent an established model to analyze genetics of cardiac development and human cardiac disease. More recently adult zebrafish are utilized to evaluate mechanisms of cardiac regeneration and by benefiting from recent genome editing technologies, including TALEN and CRISPR, adult zebrafish are emerging as a valuable in vivo model to evaluate novel disease genes and specifically validate disease causing mutations and their underlying pathomechanisms. However, methods to sensitively and non-invasively assess cardiac morphology and performance in adult zebrafish are still limited. We here present a standardized examination protocol to broadly assess cardiac performance in adult zebrafish by advancing conventional echocardiography with modern speckle-tracking analyses. This allows accurate detection of changes in cardiac performance and further enables highly sensitive assessment of regional myocardial motion and deformation in high spatio-temporal resolution. Combining conventional echocardiography measurements with radial and longitudinal velocity, displacement, strain, strain rate and myocardial wall delay rates after myocardial cryoinjury permitted to non-invasively determine injury dimensions and to longitudinally follow functional recovery during cardiac regeneration. We show that functional recovery of cryoinjured hearts occurs in three distinct phases. Importantly, the regeneration process after cryoinjury extends far beyond the proposed 45 days described for ventricular resection with reconstitution of myocardial performance up to 180 days post-injury (dpi). The imaging modalities evaluated here allow sensitive cardiac phenotyping and contribute to further establish adult zebrafish as valuable cardiac disease model beyond the larval developmental stage.

The objective of the current study was to find a metabolic signature associated with the early manifestations of type-2 diabetes mellitus. Modern metabolic profiling technology (MxP™ Broad Profiling) was applied to find early alterations in the plasma metabolome of type-2 diabetic patients. The results were validated in an independent study. Eicosanoid and single inon monitoring analysis (MxP™ Eicosanoid and MxP™ SIM analysis) were performed in subsets of samples. A metabolic signature including significantly increased levels of glyoxylate as a potential novel marker for early detection of type-2 diabetes mellitus was identified in an initial study (Study1). The signature was significantly altered in fasted diabetic and pre-diabetic subjects and in non-fasted subjects up to three years prior to the diagnosis of type-2 diabetes; most alterations were also consistently found in an independent patient group (Study 2). In Study 2 diabetic and most control subjects suffered from heart failure. In Study 1 a subgroup of diabetic subjects, with a history of use of anti-hypertensive medication further showed a more pronounced increase of glyoxylate levels, compared to a non-diabetic control group when tested in a hyperglycemic state. In the context of a prior history of anti-hypertensive medication, alterations in hexosamine and eicosanoid levels were also found. A metabolic signature including glyoxylate was associated with type-2 diabetes mellitus, independent of the fasting status and of occurrence of another major disease. The same signature was also found to be associated with pre-diabetic subjects. Glyoxylate levels further showed a specifically strong increase in a subgroup of diabetic subjects. It could represent a new marker for the detection of medical subgroups of diabetic subjects.

Background: We report the development of a novel high-sensitivity cardiac troponin T (hs-cTnT) assay, a modification of the Roche fourth-generation cTnT assay, and validation of the analytical performance of this assay. Methods: Validation included testing of analytical sensitivity, specificity, interferences, and precision. We established the 99th percentile cutoff from healthy reference populations (n = 616). In addition, we studied differences in time to a positive result when using serial measurements of hs-cTnT vs cTnT in patients with a confirmed diagnosis of non-ST elevation myocardial infarction (non-STEMI). Results: The hs-cTnT assay had an analytical range from 3 to 10 000 ng/L. At the 99th percentile value of 13.5 ng/L, the CV was 9% using the Elecsys® 2010 analyzer. The assay was specific for cTnT without interferences from human cTnI or cTnC, skeletal muscle TnT, or hemoglobin concentrations up to 1000 mg/L, above which falsely lower values would be expected. When the assay was evaluated clinically, a hs-cTnT higher than the 99th percentile concentration identified a significantly higher number of patients with non-STEMI on presentation (45 vs 20 patients, P = 0.0004) compared with cTnT, and a final diagnosis of non-STEMI was made in 9 additional patients (55 vs 46 patients, P = 0.23) after serial sampling. Time to diagnosis was significantly shorter using hs-cTnT compared with cTnT [mean 71.5 (SD 108.7) min vs 246.9 (82.0) min, respectively; P < 0.01]. Conclusions: The analytical performance of hs-cTnT complies with the ESC-ACCF-AHA-WHF Global Task Force recommendations for use in the diagnosis of MI.

A randomized trial involving patients with acute coronary syndromes showed that prasugrel was superior to ticagrelor with regard to the incidence of death, myocardial infarction, or stroke within 1 year, with no increased risk of bleeding.

Hypertrophic cardiomyopathy is the most-common form of monogenically inherited heart disease, and is associated with a high incidence of sudden cardiac death in young patients. The authors review the genetic mutations known to cause the disease, discuss potential pathological mechanisms that might lead to the clinical phenotype, and consider the implications for targeted therapies. Hypertrophic cardiomyopathy (HCM) is the most-common monogenically inherited form of heart disease, characterized by thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. HCM is also the most-common cause of sudden cardiac death in individuals younger than 35 years of age. Much progress has been made in the elucidation of the genetic basis of HCM, resulting in the identification of more than 900 individual mutations in over 20 genes. Interestingly, most of these genes encode sarcomeric proteins, such as myosin-7 (also known as cardiac muscle β-myosin heavy chain; MYH7 ), cardiac myosin-binding protein C ( MYBPC3 ), and cardiac muscle troponin T ( TNNT2 ). However, the molecular events that ultimately lead to the clinical phenotype of HCM are still unclear. We discuss several potential pathways, which include altered calcium cycling and sarcomeric calcium sensitivity, increased fibrosis, disturbed biomechanical stress sensing, and impaired cardiac energy homeostasis. An improved understanding of the pathological mechanisms involved will result in greater specificity and success of therapies for patients with HCM. Key Points Hypertrophic cardiomyopathy (HCM) is the most-common form of monogenic heart disease, affecting up to 0.2% of the population The clinical course of HCM is remarkably variable, ranging from lifelong, asymptomatic, mutation-carrier status to early sudden cardiac death in adolescents During the past 2 decades, much progress has been made in unraveling the genetic basis of HCM; disease-causing mutations have been identified in over 20 genes, mostly encoding sarcomeric proteins The molecular mechanisms of HCM are unclear; potential pathways include altered calcium cycling and sarcomeric calcium sensitivity, increased fibrosis, disturbed biomechanical stress sensing, and impaired cardiac energy homeostasis An improved understanding of the pathological mechanisms involved in HCM should increase the specificity and efficacy of therapy for this condition

Background: We sought to determine the diagnostic performance of the new high-sensitivity cardiac troponin T (hs-cTnT) assay for early detection of non–ST-segment myocardial infarction (NSTEMI) in patients with acute coronary syndrome. Methods: We enrolled patients with retrospectively confirmed unstable angina or NSTEMI and an initially negative cTnT concentration and compared the performance of baseline concentrations and serial changes in concentration within 3 and 6 h. Percentage change criteria included ≥20% δ change and ROC-optimized value. Results: Based on the standard fourth-generation cTnT result of ≥0.03 μg/L, an evolving NSTEMI was diagnosed in 26 patients, and 31 patients were classified as having unstable angina. With the use of the hs-cTnT assay at the 99th-percentile cutoff, the percentage of NSTEMI cases detected increased gradually from 61.5% on presentation to 100% within 6 h, and the overall number of MI diagnoses increased by 34.6% (35 vs 26 cases). A δ change ≥20% or ≥ROC-optimized value of >117% within 3 h or ≥243% within 6 h yielded a specificity of 100% at sensitivities between 69% and 76%. The standard cTnT at the 99th percentile was less sensitive than hs-cTnT for early diagnosis of MI on presentation, and follow-up samples obtained within the initial 3 h demonstrated very low specificity of cTnT compared with hs-cTnT. Conclusions: The high-sensitivity cTnT assay increases the number of NSTEMI diagnoses and enables earlier detection of evolving NSTEMI. A doubling of the hs-cTnT concentration within 3 h in the presence of a second concentration ≥99th percentile is associated with a positive predictive value of 100% and a negative predictive value of 88%.