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Objectives: End-stage renal disease is associated with a high risk of cardiovascular disease. We compared the concentration and prognostic ability of high sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) and cardiac myosin-binding protein C (cMyC) among stable hemodialysis patients., Methods: Patients were sampled before and after hemodialysis. We measured hs-cTnI, hs-cTnT and cMyC and used Cox regressions to assess the association between quartiles of concentrations and all-cause mortality and a combination of cardiovascular events and all-cause mortality during follow-up., Results: A total of 307 patients were included, 204 males, mean age 66 years (SD 14). Before dialysis, 299 (99 %) had a hs-cTnT concentration above the 99th percentile, compared to 188 (66 %) for cMyC and 35 (11 %) for hs-cTnI. Hs-cTnT (23 %, p<0.001) and hs-cTnI (15 %, p=0.049) but not cMyC (4 %, p=0.256) decreased during dialysis. Follow-up was a median of 924 days (492-957 days); patients in the 3rd and 4th quartiles of hs-cTnT (3rd:HR 3.0, 95 % CI 1.5-5.8, 4th:5.2, 2.7-9.8) and the 4th quartile of hs-cTnI (HR 3.8, 2.2-6.8) had an increased risk of mortality. Both were associated with an increased risk of the combined endpoint for patients in the 3rd and 4th quartiles. cMyC concentrations were not associated with risk of mortality or cardiovascular event., Conclusions: Hs-cTnT was above the 99th percentile in almost all patients. This was less frequent for hs-cTnI and cMyC. High cTn levels were associated with a 3-5-fold higher mortality. This association was not present for cMyC. These findings are important for management of hemodialysis patients., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Aims: Cardiac myosin-binding protein C (cMyC) demonstrated high diagnostic accuracy for the early detection of non-ST-elevation myocardial infarction (NSTEMI). Its dynamic release kinetics may enable a 0/1h-decision algorithm that is even more effective than the ESC hs-cTnT/I 0/1 h rule-in/rule-out algorithm., Methods and Results: In a prospective international diagnostic study enrolling patients presenting with suspected NSTEMI to the emergency department, cMyC was measured at presentation and after 1 h in a blinded fashion. Modelled on the ESC hs-cTnT/I 0/1h-algorithms, we derived a 0/1h-cMyC-algorithm. Final diagnosis of NSTEMI was centrally adjudicated according to the 4th Universal Definition of Myocardial Infarction. Among 1495 patients, the prevalence of NSTEMI was 17%. The optimal derived 0/1h-algorithm ruled-out NSTEMI with cMyC 0 h concentration below 10 ng/L (irrespective of chest pain onset) or 0 h cMyC concentrations below 18 ng/L and 0/1 h increase <4 ng/L. Rule-in occurred with 0 h cMyC concentrations of at least 140 ng/L or 0/1 h increase ≥15 ng/L. In the validation cohort (n = 663), the 0/1h-cMyC-algorithm classified 347 patients (52.3%) as 'rule-out', 122 (18.4%) as 'rule-in', and 194 (29.3%) as 'observe'. Negative predictive value for NSTEMI was 99.6% [95% confidence interval (CI) 98.9-100%]; positive predictive value 71.1% (95% CI 63.1-79%). Direct comparison with the ESC hs-cTnT/I 0/1h-algorithms demonstrated comparable safety and even higher triage efficacy using the 0h-sample alone (48.1% vs. 21.2% for ESC hs-cTnT-0/1 h and 29.9% for ESC hs-cTnI-0/1 h; P < 0.001)., Conclusion: The cMyC 0/1h-algorithm provided excellent safety and identified a greater proportion of patients suitable for direct rule-out or rule-in based on a single measurement than the ESC 0/1h-algorithm using hs-cTnT/I., Trial Registration: ClinicalTrials.gov number, NCT00470587., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Cardiac troponin (cTn) is the biochemical gold standard for diagnosing myocardial infarction (MI). We compared the Siemens ADVIA Centaur High-Sensitivity (hs-cTnI) assay with the Siemens Ultra assay (cTnI-U)., Methods: Over 3 months cTnI-U and hs-cTnI were measured simultaneously at Herlev-Gentofte Hospital. Acute myocardial injury was diagnosed using the 4th universal definition. Disputed cases were adjudicated using clinical data. We compared diagnostic accuracy using area under the curve (AUC) of the receiver operating characteristic. Outliers in between-assay differences were defined as a factor-5 difference and ≥1 measurement >40 ng/L. Patients with outlier differences were invited for re-sampling and tested with serial dilution and heterophilic blocking tubes., Results: From the 18th January to the 20th April 2019, 4,369 samples on 2,658 patients were included. cTnI-U measured higher concentrations than hs-cTnI (mean 23%, -52-213%), resulting in a higher frequency of acute myocardial injury, 255 (9.6%) vs. 203 (7.6%), p<0.001. This remained significant after adjudication, 212 vs 197, p<0.001. AUC for the prediction of MI for was 0.963 for cTnI-U and 0.959 for hs-cTnI, p=0.001. Outlier differences were seen in 35 (1.2%) patients, primarily with elevated hs-cTnI (n=33, 94%). On two re-samplings (median 144 and 297 days since inclusion), 16 of 20 (80%) and 11 of 11 had sustained elevation of hs-cTnI. The samples showed no signs of heterophilic antibodies., Conclusions: Using hs-cTnI resulted in a subset of patients with large, discrepant elevations in concentration. These patients still had elevated hs-cTnI 6-10 months post admission but no heterophilic antibodies., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Provisional stenting using drug-eluting stent is effective for simple coronary bifurcation lesions. Kissing balloon inflation using conventional non-compliant balloon is the primary treatment of side branch (SB) after main vessel (MV) stenting. Drug-coating balloon (DCB) is reported to be associated with less frequent clinical events in in-stent restenosis and small vessel disease. The importance of DCB in bifurcation treatment is understudied. Accordingly, this trial is designed to investigate the superiority of DCB to non-compliant balloon angioplasty for SB after provisional stenting in patients with true coronary bifurcation lesions., Methods and Analysis: The DCB-BIF trial is a prospective, multicentre, randomised, superiority trial including 784 patients with true coronary bifurcation lesions. Patients will be randomised in a 1:1 fashion to receive either DCB or non-compliant balloon angioplasty if SB diameter stenosis >70% after MV stenting. The primary endpoint is the composite of major adverse cardiac event at the 1-year follow-up, including cardiac death, myocardial infarction (MI) or clinically driven target lesion revascularisation. The major secondary endpoints include all-cause death, periprocedural MI, spontaneous MI, clinically driven target vessel revascularisation, in-stent restenosis, stroke and individual component of the primary endpoint. The safety endpoint is the risk of stent thrombosis., Ethics and Dissemination: The study protocol and informed consent have been reviewed and approved by the Institutional Review Board of all participating centres. The written informed consent for participation in the trial will be obtained from all participants. The results of this study will be published in a peer-reviewed journal and disseminated at conferences., Trial Registration Number: NCT04242134., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Myocardial infarction (MI) is a multifactorial global disease, recognized as one of the leading causes of cardiovascular morbidity and mortality. Timely and correct diagnoses and effective treatments could significantly reduce incidence of complications and improve patient prognoses. In this study, seven unconventional differentially expressed genes (DEGs) (MAN2A2, TNFRSF12A, SPP1, CSNK1D, PLAUR, PFKFB3, and CXCL16, collectively termed the MTSCPPC signature) were identified through integrating DEGs from six MI microarray datasets. The pathological and theranostic roles of the MTSCPPC signature in MI were subsequently analyzed. We evaluated interactions of the MTSCPPC signature with ovatodiolide, a bioactive compound isolated from Anisomeles indica (L.) Kuntze, using in silico molecular docking tools and compared it to specific inhibitors of the members of the MTSCPPC signature. Single-cell transcriptomic analysis of the public databases revealed high expression levels of the MTSCPPC signature in immune cells of adult human hearts during an MI event. The MTSCPPC signature was significantly associated with the cytokine-cytokine receptor interactions, chemokine signaling, immune and inflammatory responses, and metabolic dysregulation in MI. Analysis of a micro (mi)RNA regulatory network of the MTSCPPC signature suggested post-transcriptional activation and the roles of miRNAs in the pathology of MI. Our molecular docking analysis suggested a higher potential for ovatodiolide to target MAN2A2, CSNK1D, and TNFRSF12A. Collectively, the results derived from the present study further advance our understanding of the complex regulatory mechanisms of MI and provide a potential MI theranostic signature with ovatodiolide as a therapeutic candidate.

The 4th Universal Definition of Myocardial Infarction has stimulated considerable debate since its publication in 2018. The intention was to define the types of myocardial injury through the lens of their underpinning pathophysiology. In this review, we discuss how the 4th Universal Definition of Myocardial Infarction defines infarction and injury and the necessary pragmatic adjustments that appear in clinical guidelines to maximize triage of real-world patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Cardiac Troponin (hs-TnT) elevation has been reported in unselected patients hospitalized with COVID-19 however the mechanism and relationship with mortality remain unclear. Consecutive patients admitted to a high-volume intensive care unit (ICU) in London with severe COVID-19 pneumonitis were included if hs-TnT concentration at admission was known. Kaplan-Meier survival analysis performed, with cohorts classified a priori by multiples of the upper limit of normal (ULN). 277 patients were admitted during a 7-week period in 2020; 176 were included (90% received invasive ventilation). hs-TnT at admission was 16.5 (9.0 to 49.3) ng/L, 56% had concentrations >ULN. 56 patients (31.8%) died during the index admission. Admission hs-TnT level was lower in survivors (12.0 (8.0-27.8) vs 28.5 (14.0 to 81.0) ng/L, p = 0.001). Univariate predictors of mortality were age, APACHE-II Score and admission hs-TnT (HR 1.73, p = 0.007). By multivariate regression, only age (HR 1.33, CI: 1.16.to 1.51, p < 0.01) and admission hs-TnT (HR 1.94, CI: 1.22 to 3.10, p = 0.006) remained predictive. Survival was significantly lower when admission hs-TnT was >ULN (log-rank p-value<0.001). Peak hs-TnT was higher in those who died but was not predictive of death after adjustment for other factors. In conclusion, in critically ill patients with COVID-19 pneumonitis, the hs-TnT level at admission is a powerful independent predictor of the likelihood of surviving to discharge from ICU. In most cases, hs-TnT elevation does not represent major myocardial injury but acts as a sensitive integrated biomarker of global stress. Whether stratification based on admission Troponin level could be used to guide prognostication and management warrants further evaluation., Competing Interests: Declaration of Interests The authors declare that they have no known competing financial interests or personal relations that could have appeared to influence the work reported in this study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background Early triage is essential to improve outcomes in patients with suspected acute myocardial infarction (AMI). This study investigated whether cMyC (cardiac myosin-binding protein), a novel biomarker of myocardial necrosis, can aid early diagnosis of AMI and risk stratification. Methods and Results cMyC and high-sensitivity cardiac troponin T were retrospectively quantified in blood samples obtained by ambulance-based paramedics in a prospective, diagnostic cohort study. Patients with ongoing or prolonged periods of chest discomfort, acute dyspnoea in the absence of known pulmonary disease, or clinical suspicion of AMI were recruited. Discrimination power was evaluated by calculating the area under the receiver operating characteristics curve; diagnostic performance was assessed at predefined thresholds. Diagnostic nomograms were derived and validated using bootstrap resampling in logistic regression models. Seven hundred seventy-six patients with median age 68 [58;78] were recruited. AMI was the final adjudicated diagnosis in 22%. Median symptom to sampling time was 70 minutes. cMyC concentration in patients with AMI was significantly higher than with other diagnoses: 98 [43;855] versus 17 [9;42] ng/L. Discrimination power for AMI was better with cMyC than with high-sensitivity cardiac troponin T (area under the curve, 0.839 versus 0.813; P=0.005). At a previously published rule-out threshold (10 ng/L), cMyC reaches 100% sensitivity and negative predictive value in patients after 2 hours of symptoms. In logistic regression analysis, cMyC is superior to high-sensitivity cardiac troponin T and was used to derive diagnostic and prognostic nomograms to evaluate risk of AMI and death. Conclusions In patients undergoing blood draws very early after symptom onset, cMyC demonstrates improved diagnostic discrimination of AMI and could significantly improve the early triage of patients with suspected AMI.

Chest pain is responsible for 6-10% of all presentations to acute healthcare providers. Triage is inherently difficult and heavily reliant on the quantification of cardiac Troponin (cTn), as a minority of patients with an ultimate diagnosis of acute myocardial infarction (AMI) present with clear diagnostic features such as ST-elevation on the electrocardiogram. Owing to slow release and disappearance of cTn, many patients require repeat blood testing or present with stable but elevated concentrations of the best available biomarker and are thus caught at the interplay of sensitivity and specificity.We identified cardiac myosin-binding protein C (cMyC) in coronary venous effluent and developed a high-sensitivity assay by producing an array of monoclonal antibodies and choosing an ideal pair based on affinity and epitope maps. Compared to high-sensitivity cardiac Troponin (hs-cTn), we demonstrated that cMyC appears earlier and rises faster following myocardial necrosis. In this review, we discuss discovery and structure of cMyC, as well as the migration from a comparably insensitive to a high-sensitivity assay facilitating first clinical studies. This assay was subsequently used to describe relative abundance of the protein, compare sensitivity to two high-sensitivity cTn assays and test diagnostic performance in over 1900 patients presenting with chest pain and suspected AMI. A standout feature was cMyC's ability to more effectively triage patients. This distinction is likely related to the documented greater abundance and more rapid release profile, which could significantly improve the early triage of patients with suspected AMI.

The definition of a high-sensitivity cardiac Troponin (cTn) assay describes the ability to quantify a cardiac biomarker level in at least 50% of healthy individuals. This advance in analytic sensitivity has come with a perceived loss of specificity in the most classic application - chest pain triage and the diagnosis of acute myocardial infarction (AMI). As cardiac Troponin can no longer be used as a dichotomous test, the medical field is increasingly moving towards a more granular interpretation. However, rapid rule-out/rule-in algorithms for AMI still rely on concrete thresholds for efficient triage, irrespective of the patient's comorbidities. Owing to a slightly elevated cTn value, evermore patients appear to fall into an indeterminate risk zone of diagnostic uncertainty. The reasons are manifold, spanning biological variation, analytical issues, increased plasma membrane permeability and the potential cytosolic release of cTn. This review provides a contemporary overview of the literature concerning the use of cardiac Troponin in chronic and acute cardiovascular care. Key messages High-sensitivity cardiac Troponin assays have transformed the assessment of cardiovascular disease. Rapid rule-out algorithms for chest pain triage have become increasingly complicated, but enable safe rule-out. Cardiac Troponin tracks mid- to long-term risk in patients with hyperlipidaemia, heart failure and renal dysfunction.

Background: Multiple genetic variants have been reliably associated with obesity-related traits in Europeans, but little is known about their associations and interactions with lifestyle factors in South Asians., Methods: In 16,157 Pakistani adults (8232 controls; 7925 diagnosed with myocardial infarction [MI]) enrolled in the PROMIS Study, we tested whether: a) BMI-associated loci, individually or in aggregate (as a genetic risk score--GRS), are associated with BMI; b) physical activity and smoking modify the association of these loci with BMI. Analyses were adjusted for age, age(2), sex, MI (yes/no), and population substructure., Results: Of 95 SNPs studied here, 73 showed directionally consistent effects on BMI as reported in Europeans. Each additional BMI-raising allele of the GRS was associated with 0.04 (SE = 0.01) kg/m(2) higher BMI (P = 4.5 × 10(-14)). We observed nominal evidence of interactions of CLIP1 rs11583200 (P(interaction) = 0.014), CADM2 rs13078960 (P(interaction) = 0.037) and GALNT10 rs7715256 (P(interaction) = 0.048) with physical activity, and PTBP2 rs11165643 (P(interaction) = 0.045), HIP1 rs1167827 (P(interaction) = 0.015), C6orf106 rs205262 (P(interaction) = 0.032) and GRID1 rs7899106 (P(interaction) = 0.043) with smoking on BMI., Conclusions: Most BMI-associated loci have directionally consistent effects on BMI in Pakistanis and Europeans. There were suggestive interactions of established BMI-related SNPs with smoking or physical activity.

Objective: To validate the global registry of acute coronary event (grace) risk score in a Pakistani population at Tabba Heart Institute Karachi in patients with non ST-Elevation Myocardial Infarction (NSTEMI) and Unstable Angina (UA)., Methods: In this prospective Observational registry study, 530 adults hospitalized patients with a diagnosis of Non-ST-Elevation Myocardial Infarction and unstable angina were enrolled between March 2012 and August 2012 at the Tabba Heart Institute, Karachi, Pakistan. For each patient, the grace risk score was calculated and its discrimination evaluated and correlated with in-hospital mortality using the Kendall's tau-b bivariate correlation test. Each patient was grouped either into high, intermediate or low risk groups according to their GRS., Results: A total of 530 patients with NSTEMI and UA were included; the overall mean grace risk score in our population was 131.87 +/- 41.56. The GRACE Risk Score showed good discrimination, with Area under the ROC curve of 0.803 (95% CI 0.705-0.902, P < 0.001). During the in-hospital stay, total of 19 (3.6%) patients died, and out of those 15 (8.4%) patients belonged to high risk group., Conclusion: GRACE RS strongly validates the in-hospital mortality among our patient population presenting with a wide spectrum of complications. However, more multicentre registries on a larger population with long-term follow up are required to study detailed trends in our population.

Objective: To determine the outcomes of primary percutaneous coronary intervention via transradial approach in a tertiary care cardiac centre., Methods: The study retrospectively reviewed the medical records of 160 consecutive patients who presented to Tabba Heart Institute, a private-sector facility in Karachi, between January 2009 and January 2011 with acute ST-elevation myocardial infarction and treated with primary percutaneous coronary intervention via transradial approach. The primary end-points were in-hospital mortality and procedural success. Secondary end-points were access site bleeding complication and 30-day outcomes (mortality, myocardial infarction and congestive cardiac failure)., Results: The mean age of the patients was 55.9+/-11.7 years and 126 (79%) were males. The procedural success was 98% (n=157). Three (1.8%) patients died during hospitalisation. Forearm haematoma (>5cm) was observed in three (1.8%) patients. No mortality was observed in 30-day follow-up after discharge, while myocardial infarction and congestive cardiac failure were 1.25% (n=2) and 4% (n=6) respectively., Conclusions: High procedural success and favourable clinical outcomes matching the international data can be achieved in our patients undergoing primary percutaneous coronary intervention via transradial approach.

The case of a 55 years old, hypertensive, obese female is presented, who came to the emergency department with inferoposterior ST segment elevation myocardial infarction (STEMI) with right ventricular infarction. After thrombolytic therapy, she reperfused but had anginal symptoms on minimal activity. The patient underwent coronary angiogram which showed aneurysmal right coronary artery (RCA) with 60% stenosis and thrombus in mid portion and distal bifurcation of RCA with TIMI III distal blood flow. Left main coronary artery was normal. Left anterior descending (LAD) and Left circumflex (LCX) arteries were also aneurysmal and non obstructive. The patient was started on intravenous heparin and warfarin in view of aneurysmal coronary arteries and large thrombus burden. The patient was discharged home in one week and is doing well at follow up.

Objective: To determine factors affecting cardiac rehabilitation attendance after myocardial infarction and coronary revascularization., Methods: A cross-sectional study was conducted on 416 patients admitted in Tabba Heart Institute, Karachi from December 2010 to May 2011. Patients admitted with diagnosis of acute myocardial infarction (AMI) or who underwent elective coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI) procedures were offered cardiac rehabilitation (CR). Out of these, patients who enrolled in 6 weeks outpatient CR programme were followed for number of CR sessions and their socio-demographic and clinical data were collected. Data was analyzed by Statistical Package for Social Sciences (SPSS) software, version 15.0. Chi-square test was applied to test association between categorical variables and Student's t-test for continuous variables., Results: Out of 416 patients identified, only 151 patients (36.2%) enrolled and attended the CR programme. Of the 151 attendees, 111 (73.4%) patients subsequently completed more than 6 weeks of outpatient CR programme. We found significant association between CR attendance and easy access to the programme, elective CABG procedure, employment status, presence of diabetes or hypertension and baseline level of exercise (all p < or = 0.01). No association was found between CR attendance and patient age, gender, body mass index or different economic groups., Conclusion: Attendance rates of patients attending outpatient CR programme after AMI or coronary revascularization procedures are suboptimal. Patients who underwent elective CABG surgery and had easy access to the CR programme had better attendance. Factors contributing to poor attendance rates at CR programmes in developing countries need to be explored and subsequently addressed.

Objective: To determine the correlation of cardiac troponin I (cTnI) 10 folds upper limit of normal (ULN) and extent of coronary artery disease (CAD) in Non-ST-elevation myocardial infarction (NSTEMI)., Methods: A cross-sectional study was conducted on 230 consecutive NSTEMI patients admitted in Tabba Heart Institute, Karachi between April to December 2008. cTnI was measured using MEIA method. All patients underwent coronary angiography in the index hospitalization. Stenosis > or = 70% in any of the three major epicardial vessels was considered significant CAD. Extent of CAD was defined as significant single, two or three vessel CAD. Chi-square test was applied to test the association between cTnI levels and CAD extent., Results: Out of 230 patients, in 111 patients with cTnI levels < or = 10 folds upper limit of normal (ULN), 25 (22.52%) had single vessel, 40 (36%) had two vessel and 34 (30.6%) had three vessel significant CAD, whereas in 119 patients with cTnI levels > 10 folds ULN, 23 (19.3%) had single vessel, 37 (31.1%) had two vessel and 55 (46.2%) had three vessel significant CAD. The results suggest that there was an insignificant association between the cTnI levels and single vessel, two vessel and the overall CAD extent (p = 0.35, p = 0.21 and p= 0.13 respectively), however there was a statistically significant association between the cTnI levels and three vessel CAD (p < 0.04)., Conclusion: Higher cTnI levels are associated with an increased proportion of severe three vessel CAD involvement. Prompt identification and referral of this patient subset to early revascularization strategies would improve clinical outcomes.

Objective: To determine the serum levels of troponin-I in identifying left ventricular ejection fraction (LVEF) of 63.5 ng/ml predicted LVEF of 87.5 ng/ml predicted LVEF < 40% with a sensitivity of 86% and specificity of 100%., Conclusion: Troponin-I concentration of > 63.5 ng/ml and > 87.5 ng/ml can predict LVEF