Imperial College London



The impact of co-morbidities on peak troponin levels and mortality in acute myocardial infarction: A population based, nationwide studyVarun Sundaram 1, 2, 3, Kieran J Rothnie 1,4 ,Chloe Bloom 1 , Rosita Zakeri 1, 5 , Jayakumar Sahadevan 3, 6, Ajay K. Singh 7 , Toshiyuki Nagai 1, 8, 9 , James Potts 1 ,Jadwiga Wedzicha 1 , Liam Smeeth 4 , Daniel. I Simon2, 3, Adam Timmis 10, Sanjay Rajagopalan 2, 3 *, Jennifer K Quint 1, 4, 5*Author Affiliations1. Department of Population Science, National Heart and Lung Institute, Imperial College London, London, UK2. Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Centre, Cleveland, Ohio, USA3. Case Western Reserve University School of Medicine, Cleveland, Ohio, USA 4. Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK5. Royal Brompton and Harefield NHS Foundation trust, London, UK6. Louis Stokes Veteran Affairs Medical Center, Cleveland, Ohio, USA7. Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA8. Hokkaido University Graduate School of Medicine, Sapporo, Japan9. National Cerebral and Cardiovascular Centre, Osaka, Japan10. Bart’s NIHR Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK* Corresponding authorsWord count: 3691Corresponding Authors: Prof Sanjay Rajagopalan, MD, FACC, FAHAHarrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, Ohio, 44106, USA.Email: sanjay.rajagopalan@; Phone: 216-368-4737 Fax: 216-368-8898Dr. Varun Sundaram MD, FRCP,Emmanuel Kaye Building, Manresa RoadNational Heart and Lung Institute, Imperial College London, SW3 6LRHarrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, Ohio, 44106, USA.Email: v.sundaram@imperial.ac.uk; Varun.sundaram@Dr. Jennifer Kathleen Quint, MBChB PhD FRCP,Emmanuel Kaye Building, Manresa RoadNational Heart and Lung Institute, Imperial College London, SW3 6LR. Email: j.quint@imperial.ac.uk Key questionsWhat is already known on this topic?Previous studies have suggested that peak cardiac troponin levels are higher in patients with acute myocardial infarction(AMI) and chronic kidney disease(CKD) compared to those without CKD. However, the magnitude of troponin increase has not been evaluated. Patients with prior coronary artery disease(CAD), congestive heart failure(CHF) or chronic obstructive pulmonary disease(COPD) presenting with AMI reportedly have lower peak troponin levels compared to patients without the respective co-morbidities; however, these studies had not adjusted for age, sex and other relevant co-morbidities. What this study adds?In this study, we show for the first time the magnitude and directionality of troponin change in common co-morbidities and the impact of the severity of co-morbidities (e.g., severity of CKD) on peak troponin levels in 330,000 patients with AMI. In contrast to widely held assumptions, in AMI, comorbid illness is a more important predictor of mortality than peak troponin levels. How might this impact on clinical practice?Clinicians should refrain from being reassured by lower peak troponin levels in patients with NSTEMI and concomitant HF, COPD, or prior CAD. Conversely, a higher peak troponin level may be less informative in the setting of CKD where up to 40% of the elevation may relate to the presence of CKD alone.ABSTRACTObjectives: To characterize peak cardiac troponin levels, in patients presenting with acute myocardial infarction (AMI), according to their comorbid condition and determine the influence of peak troponin (cTn) levels on mortality. Methods: We included patients with the first admission for AMI in the United Kingdom. We used linear regression to estimate the association between eight common co-morbidities {diabetes mellitus(DM), previous angina, peripheral arterial disease(PAD), previous myocardial infarction(MI), chronic kidney disease(CKD), cerebrovascular disease(CVD), chronic heart failure(CHF), and chronic obstructive pulmonary disease(COPD)} and peak cTn. Peak cTn levels were adjusted for age, sex, smoking status and co-morbidities. Logistic regression and restricted cubic spline models were employed to investigate the association between peak cTn and 180-day mortality for each co-morbidity. Results: 330,367 patients with AMI were identified. Adjusted peak cTn levels were significantly higher in patients with CKD[adjusted % difference in peak cTnT for CKD=42%, 95%CI 13.1 to 78.4] and significantly lower for patients with COPD, previous angina, previous MI and CHF when compared to patients without the respective co-morbidities (reference group) [cTnI;COPD=-21.7%,95%CI -29.1 to -13.4;previous angina=-24.2%, 95%CI -29.6 to -8.3;previous MI=-13.5%, 95%CI -20.6 to -5.9;CHF=-28% 95%CI -37.2 to -17.6]. Risk of 180-day mortality in most of the co-morbidities did not change substantially after adjusting for peak cTn. In general, cTnI had a stronger association with mortality than cTnT.Conclusions: In this nationwide analyses of patients presenting with acute myocardial infarction, co-morbidities substantially influenced systemic concentrations of peak cTn. Comorbid illness is a significant predictor of mortality regardless of peak cTn levels and should be taken into consideration while interpreting cTn both as a diagnostic and prognostic biomarker.Funding: This work was funded by an MRC Population Health Scientist Fellowship held by JKQ [G0902135]Keywords: troponin I, troponin T, hsTnT, Acute Myocardial Infarction, Non -ST elevation MI, STEMI, mortality, co-morbiditiesINTRODUCTIONCardiac troponin T (cTnT) and cardiac troponin I (cTnI) isoforms, are regulatory proteins within the myocardium that are released into the circulation following myocardial injury, regardless of the underlying etiology. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tyP4XHr8","properties":{"formattedCitation":"\\super 2,3\\nosupersub{}","plainCitation":"2,3","noteIndex":0},"citationItems":[{"id":6,"uris":[""],"uri":[""],"itemData":{"id":6,"type":"article-journal","title":"Biology of the troponin complex in cardiac myocytes","container-title":"Progress in Cardiovascular Diseases","page":"159-176","volume":"47","issue":"3","source":"PubMed","abstract":"Troponin is the regulatory complex of the myofibrillar thin filament that plays a critical role in regulating excitation-contraction coupling in the heart. Troponin is composed of three distinct gene products: troponin C (cTnC), the 18-kD Ca(2+)-binding subunit; troponin I (cTnI), the approximately 23-kD inhibitory subunit that prevents contraction in the absence of Ca2+ binding to cTnC; and troponin T (cTnT), the approximately 35-kD subunit that attaches troponin to tropomyosin (Tm) and to the myofibrillar thin filament. Over the past 45 years, extensive biochemical, biophysical, and structural studies have helped to elucidate the molecular basis of troponin function and thin filament activation in the heart. At the onset of systole, Ca2+ binds to the N-terminal Ca2+ binding site of cTnC initiating a conformational change in cTnC, which catalyzes protein-protein associations activating the myofibrillar thin filament. Thin filament activation in turn facilitates crossbridge cycling, myofibrillar activation, and contraction of the heart. The intrinsic length-tension properties of cardiac myocytes as well as the Frank-Starling properties of the intact heart are mediated primarily through Ca(2+)-responsive thin filament activation. cTnC, cTnI, and cTnT are encoded by distinct single-copy genes in the human genome, each of which is expressed in a unique cardiac-restricted developmentally regulated fashion. Elucidation of the transcriptional programs that regulate troponin transcription and gene expression has provided insights into the molecular mechanisms that regulate and coordinate cardiac myocyte differentiation and provided unanticipated insights into the pathogenesis of cardiac hypertrophy. Autosomal dominant mutations in cTnI and cTnT have been identified and are associated with familial hypertrophic and restrictive cardiomyopathies.","ISSN":"0033-0620","note":"PMID: 15736582","journalAbbreviation":"Prog Cardiovasc Dis","language":"eng","author":[{"family":"Parmacek","given":"Michael S."},{"family":"Solaro","given":"R. John"}],"issued":{"date-parts":[["2004",12]]}}},{"id":8,"uris":[""],"uri":[""],"itemData":{"id":8,"type":"article-journal","title":"Development and in vitro characterization of a new immunoassay of cardiac troponin T","container-title":"Clinical Chemistry","page":"386-393","volume":"38","issue":"3","source":"PubMed","abstract":"We describe a new one-step enzyme immunoassay of troponin T that uses two specific monoclonal antibodies and streptavidin-coated tubes as the solid phase. The monoclonal antibodies were obtained by conventional hybridoma technology, with human troponin T as antigen. The identity of the cardiac troponin T antigen was confirmed by analysis of the amino acid composition and by partial sequence analysis. The specificity of the monoclonal antibodies for cardiac troponin T was proved by immunoblot analysis and displacement curves. The capture antibody is labeled with biotin. The second antibody is conjugated to horseradish peroxidase (EC 1.11.1.7). The assay [Enzymun-TestR system (Boehringer Mannheim GmbH)] is performed in only 90 min at room temperature; the measuring range for troponin T is 0.1 to 15 micrograms/L. The assay shows excellent between-run precision (CV = 3.3-4.9%).","ISSN":"0009-9147","note":"PMID: 1547556","journalAbbreviation":"Clin. Chem.","language":"eng","author":[{"family":"Katus","given":"H. A."},{"family":"Looser","given":"S."},{"family":"Hallermayer","given":"K."},{"family":"Remppis","given":"A."},{"family":"Scheffold","given":"T."},{"family":"Borgya","given":"A."},{"family":"Essig","given":"U."},{"family":"Geuss","given":"U."}],"issued":{"date-parts":[["1992",3]]}}}],"schema":""} 2,3 The use of cTnT and cTnI as protein markers of acute myocardial infarction (AMI) was first recommended two decades ago and is now the cornerstone for establishing a diagnosis of AMI. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"k4T0iDcC","properties":{"formattedCitation":"\\super 4,5\\nosupersub{}","plainCitation":"4,5","noteIndex":0},"citationItems":[{"id":4,"uris":[""],"uri":[""],"itemData":{"id":4,"type":"article-journal","title":"Cardiac-specific troponin-I radioimmunoassay in the diagnosis of acute myocardial infarction","container-title":"American Heart Journal","page":"1333-1344","volume":"113","issue":"6","source":"PubMed","abstract":"The cardiac isotype of the myofibrillar contractile protein, troponin-I, is located specifically in the mammalian heart. A sensitive radioimmunoassay has been developed to detect human and nonhuman primate cardiac troponin-I in serum down to 10 ng/ml. Immunochemical cross reactivity with skeletal troponin-I was only 2% and was species nonspecific. Normal patient levels of cardiac troponin-I are about 10 ng/ml. In patients with acute myocardial infarction (n = 32), serum cardiac troponin-I was elevated within 4 to 6 hours, reached a mean peak level of 112 ng/ml (range 20 to 550 ng/ml) at 18 hours, and remained above normal for up to 6 to 8 days following infarction. Peak cardiac troponin-I correlated with peak creatine kinase (CK) MB isoenzyme (r = 0.75). In subjects (n = 34) with skeletal muscle damage (total CK = 338 to 5384 IU/L), cardiac troponin-I levels were not elevated above normal, although CK-MB isoenzyme was elevated in some patients. Cardiac troponin-I levels were normal or slightly elevated in patients with ischemic heart disease and were normal in patients with chest pain of noncardiac origin. Immunoassay of cardiac troponin-I could be a valuable diagnostic aid in the cardiac-specific detection of cell necrosis.","ISSN":"0002-8703","note":"PMID: 3591601","journalAbbreviation":"Am. Heart J.","language":"eng","author":[{"family":"Cummins","given":"B."},{"family":"Auckland","given":"M. L."},{"family":"Cummins","given":"P."}],"issued":{"date-parts":[["1987",6]]}}},{"id":2,"uris":[""],"uri":[""],"itemData":{"id":2,"type":"article-journal","title":"Unstable angina: is it time for a requiem?","container-title":"Circulation","page":"2452-2457","volume":"127","issue":"24","source":"PubMed","DOI":"10.1161/CIRCULATIONAHA.113.001258","ISSN":"1524-4539","note":"PMID: 23775194","shortTitle":"Unstable angina","journalAbbreviation":"Circulation","language":"eng","author":[{"family":"Braunwald","given":"Eugene"},{"family":"Morrow","given":"David A."}],"issued":{"date-parts":[["2013",6,18]]}}}],"schema":""} 4,5 Following AMI, systemic blood concentrations of cardiac troponin (cTn) rise and their peak levels strongly correlate with the infarct size of the myocardium and thus cTn has excellent prognostic value; with higher levels associated with a worse prognosis. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rOqmo4qA","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":12,"uris":[""],"uri":[""],"itemData":{"id":12,"type":"article-journal","title":"Usefulness of peak troponin-T to predict infarct size and long-term outcome in patients with first acute myocardial infarction after primary percutaneous coronary intervention","container-title":"The American Journal of Cardiology","page":"779-784","volume":"103","issue":"6","source":"PubMed","abstract":"In acute myocardial infarction cardiac troponin-T (cTnT) is the preferred biomarker to detect myocardial necrosis. Our aim was to investigate the prognostic value of peak plasma cTnT in patients with ST-elevation myocardial infarction treated by primary percutaneous coronary intervention (PCI). Patients were eligible if ST-elevation myocardial infarction symptoms started <9 hours before the primary PCI. During the first 48 hours after primary PCI, cTnT and creatine kinase were measured repeatedly. Main outcome measures were left ventricular ejection fraction assessed by myocardial scintigraphy at 90 days, and clinical outcomes through 1-year follow-up after primary PCI in a dedicated outpatient clinic; 168 consecutive patients (79% men) with first ST-elevation myocardial infarction were studied. Mean age +/- SD was 59 +/- 12 years. Peak cTnT values were reached within 24 hours after primary PCI in all patients. The enzymatic infarct size, measured by cumulative 48-hours creatine kinase release, correlated positively with peak cTnT (r = 0.73, p <0.001). Left ventricular ejection fraction at 3 months was negatively correlated with peak cTnT (r = -0.52, p <0.001). A peak plasma cTnT > or = 6.5 microg/L predicted a left ventricular ejection fraction < or = 40% at follow-up with 86% sensitivity and 74% specificity. Multivariable Cox regression analysis identified peak cTnT as an independent predictor of major adverse cardiac events (hazard ratio 1.07, 95% confidence limits 1.01 to 1.12) and heart failure (hazard ratio 1.12, 95% confidence limits 1.05 to 1.20) during follow-up. In conclusion, peak cTnT after primary PCI for ST-elevation myocardial infarction offers a good estimation of infarct size and is a prognostic indicator in patients with first acute myocardial infarction.","DOI":"10.1016/j.amjcard.2008.11.031","ISSN":"1879-1913","note":"PMID: 19268731","journalAbbreviation":"Am. J. Cardiol.","language":"eng","author":[{"family":"Hassan","given":"Ayman K. M."},{"family":"Bergheanu","given":"Sandrin C."},{"family":"Hasan-Ali","given":"Hosam"},{"family":"Liem","given":"Su San"},{"family":"Laarse","given":"Arnoud","non-dropping-particle":"van der"},{"family":"Wolterbeek","given":"Ron"},{"family":"Atsma","given":"Douwe E."},{"family":"Schalij","given":"Martin J."},{"family":"Jukema","given":"J. Wouter"}],"issued":{"date-parts":[["2009",3,15]]}}}],"schema":""} 6Patients presenting with an AMI, particularly non-ST elevation myocardial infarction (NSTEMI), frequently have multiple co-morbidities which may affect systemic concentrations of both cTnT and cTnI. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ODxChKkN","properties":{"formattedCitation":"\\super 7,8\\nosupersub{}","plainCitation":"7,8","dontUpdate":true,"noteIndex":0},"citationItems":[{"id":16,"uris":[""],"uri":[""],"itemData":{"id":16,"type":"article-journal","title":"Dynamic prognostication in non-ST-elevation acute coronary syndromes: insights from GUSTO-IIb and PURSUIT","container-title":"American Heart Journal","page":"62-71","volume":"148","issue":"1","source":"PubMed","abstract":"BACKGROUND: Risk assessment in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) traditionally focuses on and is limited to admission findings. The objective of the current study was to develop an approach to predicting outcome in NSTE-ACS that could account for the changing nature of risk.\nMETHODS: In 7294 of 8010 patients with NSTE-ACS and complete electrocardiographic data in the GUSTO-IIb trial, we predicted the mortality probability at days 0-2, 0-30, 3-30, 5-30, and 7-30 using multiple logistic regression. Resulting risk estimates were incorporated into a composite, dynamic model to estimate the effects of changing probabilities over time. These models were validated against an independent sample of 9461 patients from the PURSUIT trial.\nRESULTS: As time passed after admission, the risk of 30-day death declined in stable patients. This risk, which was 3.72% at baseline, declined to 1.92% in 6-day survivors, and the risk reduction was greatest for those with the highest baseline risk. Importantly, however, the development of inhospital complications modified these trends. The use of dynamic models not only allowed us to estimate early (<48 h) mortality with a high degree of accuracy (C-index of 0.87), but also to continuously update the longer-term prognosis with increasing accuracy: the C-index increased from 0.75 for the day 0-30 model to 0.81 and 0.82 for the composite and day 7-30 models, respectively.\nCONCLUSIONS: Dynamic risk assessment is feasible and reliable. This approach can improve risk assessment and provide valuable guidance for management of patients with NSTE-ACS.","DOI":"10.1016/j.ahj.2003.05.004","ISSN":"1097-6744","note":"PMID: 15215793","shortTitle":"Dynamic prognostication in non-ST-elevation acute coronary syndromes","journalAbbreviation":"Am. Heart J.","language":"eng","author":[{"family":"Chang","given":"Wei-Ching"},{"family":"Boersma","given":"Eric"},{"family":"Granger","given":"Christopher B."},{"family":"Harrington","given":"Robert A."},{"family":"Califf","given":"Robert M."},{"family":"Simoons","given":"Maarten L."},{"family":"Kleiman","given":"Neal S."},{"family":"Armstrong","given":"Paul W."},{"literal":"GUSTO-IIb and PURSUIT Investigators"}],"issued":{"date-parts":[["2004",7]]}}},{"id":117,"uris":[""],"uri":[""],"itemData":{"id":117,"type":"article-journal","title":"Association of Clinical Factors and Therapeutic Strategies With Improvements in Survival Following Non–ST-Elevation Myocardial Infarction, 2003-2013","container-title":"JAMA","page":"1073-1082","volume":"316","issue":"10","source":"","abstract":"<h3>Importance</h3><p>International studies report a decline in mortality following non–ST-elevation myocardial infarction (NSTEMI). Whether this is due to lower baseline risk or increased utilization of guideline-indicated treatments is unknown.</p><h3>Objective</h3><p>To determine whether changes in characteristics of patients with NSTEMI are associated with improvements in outcomes.</p><h3>Design, Setting, and Participants</h3><p>Data on patients with NSTEMI in 247 hospitals in England and Wales were obtained from the Myocardial Ischaemia National Audit Project between January 1, 2003, and June 30, 2013 (final follow-up, December 31, 2013).</p><h3>Exposures</h3><p>Baseline demographics, clinical risk (GRACE risk score), and pharmacological and invasive coronary treatments.</p><h3>Main Outcomes and Measures</h3><p>Adjusted all-cause 180-day postdischarge mortality time trends estimated using flexible parametric survival modeling.</p><h3>Results</h3><p>Among 389 057 patients with NSTEMI (median age, 72.7 years [IQR, 61.7-81.2 years]; 63.1% men), there were 113 586 deaths (29.2%). From 2003-2004 to 2012-2013, proportions with intermediate to high GRACE risk decreased (87.2% vs 82.0%); proportions with lowest risk increased (4.2% vs 7.6%;<i>P</i>= .01 for trend). The prevalence of diabetes, hypertension, cerebrovascular disease, chronic obstructive pulmonary disease, chronic renal failure, previous invasive coronary strategy, and current or ex-smoking status increased (all<i>P</i> &lt; .001). Unadjusted all-cause mortality rates at 180 days decreased from 10.8% to 7.6% (unadjusted hazard ratio [HR], 0.968 [95% CI, 0.966-0.971]; difference in absolute mortality rate per 100 patients [AMR/100], ?1.81 [95% CI, ?1.95 to ?1.67]). These findings were not substantially changed when adjusted additively by baseline GRACE risk score (HR, 0.975 [95% CI, 0.972-0.977]; AMR/100, ?0.18 [95% CI, ?0.21 to ?0.16]), sex and socioeconomic status (HR, 0.975 [95% CI, 0.973-0.978]; difference in AMR/100, ?0.24 [95% CI, ?0.27 to ?0.21]), comorbidities (HR, 0.973 [95% CI, 0.970-0.976]; difference in AMR/100, ?0.44 [95% CI, ?0.49 to ?0.39]), and pharmacological therapies (HR, 0.972 [95% CI, 0.964-0.980]; difference in AMR/100, ?0.53 [95% CI, ?0.70 to ?0.36]). However, the direction of association was reversed after further adjustment for use of an invasive coronary strategy (HR, 1.02 [95% CI, 1.01-1.03]; difference in AMR/100, 0.59 [95% CI, 0.33-0.86]), which was associated with a relative decrease in mortality of 46.1% (95% CI, 38.9%-52.0%).</p><h3>Conclusions and Relevance</h3><p>Among patients hospitalized with NSTEMI in England and Wales, improvements in all-cause mortality were observed between 2003 and 2013. This was significantly associated with use of an invasive coronary strategy and not entirely related to a decline in baseline clinical risk or increased use of pharmacological therapies.</p>","DOI":"10.1001/jama.2016.10766","ISSN":"0098-7484","journalAbbreviation":"JAMA","language":"en","author":[{"family":"Hall","given":"Marlous"},{"family":"Dondo","given":"Tatendashe B."},{"family":"Yan","given":"Andrew T."},{"family":"Goodman","given":"Shaun G."},{"family":"Bueno","given":"Héctor"},{"family":"Chew","given":"Derek P."},{"family":"Brieger","given":"David"},{"family":"Timmis","given":"Adam"},{"family":"Batin","given":"Phillip D."},{"family":"Deanfield","given":"John E."},{"family":"Hemingway","given":"Harry"},{"family":"Fox","given":"Keith A. A."},{"family":"Gale","given":"Christopher P."}],"issued":{"date-parts":[["2016",9,13]]}}}],"schema":""} 7, 8 Previous studies have suggested that cTn levels are higher in patients with AMI and chronic kidney disease (CKD) compared to those without, though the magnitude of cTn increase and the impact of severity of CKD on peak cTn levels have not been systematically evaluated. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Jo7rxwMd","properties":{"formattedCitation":"\\super 9\\uc0\\u8211{}12\\nosupersub{}","plainCitation":"9–12","noteIndex":0},"citationItems":[{"id":24,"uris":[""],"uri":[""],"itemData":{"id":24,"type":"article-journal","title":"Role of troponin in patients with chronic kidney disease and suspected acute coronary syndrome: a systematic review","container-title":"Annals of Internal Medicine","page":"502-512","volume":"161","issue":"7","source":"PubMed","abstract":"BACKGROUND: Patients with chronic kidney disease (CKD) have high prevalence of elevated serum troponin levels, which makes diagnosis of acute coronary syndrome (ACS) challenging.\nPURPOSE: To evaluate the utility of troponin in ACS diagnosis, treatment, and prognosis among patients with CKD.\nDATA SOURCES: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through May 2014.\nSTUDY SELECTION: Studies examining elevated versus normal troponin levels in terms of their diagnostic performance in detection of ACS, effect on ACS management strategies, and prognostic value for mortality or cardiovascular events after ACS among patients with CKD.\nDATA EXTRACTION: Paired reviewers selected articles for inclusion, extracted data, and graded strength of evidence (SOE).\nDATA SYNTHESIS: Twenty-three studies met inclusion criteria. The sensitivity of troponin T for ACS diagnosis ranged from 71% to 100%, and specificity ranged from 31% to 86% (6 studies; low SOE). The sensitivity and specificity of troponin I ranged from 43% to 94% and from 48% to 100%, respectively (8 studies; low SOE). No studies examined how troponin levels affect management strategies. Twelve studies analyzed prognostic value. Elevated levels of troponin I or troponin T were associated with higher risk for short-term death and cardiac events (low SOE). A similar trend was observed for long-term mortality with troponin I (low SOE), but less evidence was found for long-term cardiac events for troponin I and long-term outcomes for troponin T (insufficient SOE). Patients with advanced CKD tended to have worse prognoses with elevated troponin I levels than those without them (moderate SOE).\nLIMITATION: Studies were heterogeneous in design and in ACS definitions and adjudication methods.\nCONCLUSION: In patients with CKD and suspected ACS, troponin levels can aid in identifying those with a poor prognosis, but the diagnostic utility is limited by varying estimates of sensitivity and specificity.\nPRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.","DOI":"10.7326/M14-0746","ISSN":"1539-3704","note":"PMID: 25111593","shortTitle":"Role of troponin in patients with chronic kidney disease and suspected acute coronary syndrome","journalAbbreviation":"Ann. Intern. Med.","language":"eng","author":[{"family":"Stacy","given":"Sylvie R."},{"family":"Suarez-Cuervo","given":"Catalina"},{"family":"Berger","given":"Zackary"},{"family":"Wilson","given":"Lisa M."},{"family":"Yeh","given":"Hsin-Chieh"},{"family":"Bass","given":"Eric B."},{"family":"Michos","given":"Erin D."}],"issued":{"date-parts":[["2014",10,7]]}}},{"id":214,"uris":[""],"uri":[""],"itemData":{"id":214,"type":"article-journal","title":"Interpreting Cardiac Biomarkers in the Setting of Chronic Kidney Disease","container-title":"Clinical Chemistry","page":"59-65","volume":"63","issue":"1","source":"PubMed","abstract":"BACKGROUND: Chronic kidney disease (CKD) is common, particularly in those of advanced age. Because patients with CKD frequently have cardiac comorbidities and acute or chronic symptoms that may represent heart failure or an acute myocardial infarction (AMI), testing for concentrations of cardiac troponins and natriuretic peptides is frequent. Interpretation of these biomarkers can be challenging when differentiating acute from chronic processes, potentially resulting in missed opportunities to direct appropriate treatment.\nCONTENT: This review is designed to provide clinicians and laboratorians a platform to understand cardiac specific biomarker interpretation in patients with CKD by summarizing the extensive literature base that has developed specific to this population. First we review the epidemiology and unique contributions of CKD to cardiac pathophysiology. Next we consider the interpretation of cardiac troponin tests for the diagnosis AMI and the prognostic significance of chronic increases across the spectrum of CKD including those requiring renal replacement therapy. Last, we consider the caveats of interpreting natriuretic peptide results for the diagnosis of acute decompensated heart failure in addition to the short- and long-term prognostic implications of increased natriuretic peptide concentrations and CKD in a patient with heart failure.\nSUMMARY: CKD is common and associated with acceleration of cardiovascular disease. Cardiac biomarker concentrations are often increased even in an absence of symptoms; typically reflecting the extent of underlying cardiovascular disease rather than impairment of renal clearance. Thoughtful interpretation of cardiac biomarkers in those with CKD can continue to provide important diagnostic and prognostic information.","DOI":"10.1373/clinchem.2016.254748","ISSN":"1530-8561","note":"PMID: 27811207","journalAbbreviation":"Clin. Chem.","language":"eng","author":[{"family":"deFilippi","given":"Christopher R."},{"family":"Herzog","given":"Charles A."}],"issued":{"date-parts":[["2017",1]]}}},{"id":217,"uris":[""],"uri":[""],"itemData":{"id":217,"type":"article-journal","title":"0/1-Hour Triage Algorithm for Myocardial Infarction in Patients With Renal Dysfunction","container-title":"Circulation","page":"436-451","volume":"137","issue":"5","source":"PubMed","abstract":"BACKGROUND: The European Society of Cardiology recommends a 0/1-hour algorithm for rapid rule-out and rule-in of non-ST-segment elevation myocardial infarction using high-sensitivity cardiac troponin (hs-cTn) concentrations irrespective of renal function. Because patients with renal dysfunction (RD) frequently present with increased hs-cTn concentrations even in the absence of non-ST-segment elevation myocardial infarction, concern has been raised regarding the performance of the 0/1-hour algorithm in RD.\nMETHODS: In a prospective multicenter diagnostic study enrolling unselected patients presenting with suspected non-ST-segment elevation myocardial infarction to the emergency department, we assessed the diagnostic performance of the European Society of Cardiology 0/1-hour algorithm using hs-cTnT and hs-cTnI in patients with RD, defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2, and compared it to patients with normal renal function. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including cardiac imaging. Safety was quantified as sensitivity in the rule-out zone, accuracy as the specificity in the rule-in zone, and efficacy as the proportion of the overall cohort assigned to either rule-out or rule-in based on the 0- and 1-hour sample.\nRESULTS: Among 3254 patients, RD was present in 487 patients (15%). The prevalence of non-ST-segment elevation myocardial infarction was substantially higher in patients with RD compared with patients with normal renal function (31% versus 13%, P<0.001). Using hs-cTnT, patients with RD had comparable sensitivity of rule-out (100.0% [95% confidence interval {CI}, 97.6-100.0] versus 99.2% [95% CI, 97.6-99.8]; P=0.559), lower specificity of rule-in (88.7% [95% CI, 84.8-91.9] versus 96.5% [95% CI, 95.7-97.2]; P<0.001), and lower overall efficacy (51% versus 81%, P<0.001), mainly driven by a much lower percentage of patients eligible for rule-out (18% versus 68%, P<0.001) compared with patients with normal renal function. Using hs-cTnI, patients with RD had comparable sensitivity of rule-out (98.6% [95% CI, 95.0-99.8] versus 98.5% [95% CI, 96.5-99.5]; P=1.0), lower specificity of rule-in (84.4% [95% CI, 79.9-88.3] versus 91.7% [95% CI, 90.5-92.9]; P<0.001), and lower overall efficacy (54% versus 76%, P<0.001; proportion ruled out, 18% versus 58%, P<0.001) compared with patients with normal renal function.\nCONCLUSIONS: In patients with RD, the safety of the European Society of Cardiology 0/1-hour algorithm is high, but specificity of rule-in and overall efficacy are decreased. Modifications of the rule-in and rule-out thresholds did not improve the safety or overall efficacy of the 0/1-hour algorithm.\nCLINICAL TRIAL REGISTRATION: URL: . Unique identifier: NCT00470587.","DOI":"10.1161/CIRCULATIONAHA.117.028901","ISSN":"1524-4539","note":"PMID: 29101287\nPMCID: PMC5794234","journalAbbreviation":"Circulation","language":"eng","author":[{"family":"Twerenbold","given":"Raphael"},{"family":"Badertscher","given":"Patrick"},{"family":"Boeddinghaus","given":"Jasper"},{"family":"Nestelberger","given":"Thomas"},{"family":"Wildi","given":"Karin"},{"family":"Puelacher","given":"Christian"},{"family":"Sabti","given":"Zaid"},{"family":"Rubini Gimenez","given":"Maria"},{"family":"Tschirky","given":"Sandra"},{"family":"Fay de Lavallaz","given":"Jeanne","non-dropping-particle":"du"},{"family":"Kozhuharov","given":"Nikola"},{"family":"Sazgary","given":"Lorraine"},{"family":"Mueller","given":"Deborah"},{"family":"Breidthardt","given":"Tobias"},{"family":"Strebel","given":"Ivo"},{"family":"Flores Widmer","given":"Dayana"},{"family":"Shrestha","given":"Samyut"},{"family":"Miró","given":"?scar"},{"family":"Martín-Sánchez","given":"F. Javier"},{"family":"Morawiec","given":"Beata"},{"family":"Parenica","given":"Jiri"},{"family":"Geigy","given":"Nicolas"},{"family":"Keller","given":"Dagmar I."},{"family":"Rentsch","given":"Katharina"},{"family":"Eckardstein","given":"Arnold","non-dropping-particle":"von"},{"family":"Osswald","given":"Stefan"},{"family":"Reichlin","given":"Tobias"},{"family":"Mueller","given":"Christian"}],"issued":{"date-parts":[["2018",1,30]]}}},{"id":237,"uris":[""],"uri":[""],"itemData":{"id":237,"type":"article-journal","title":"Cardiac troponin T and C-reactive protein for predicting prognosis, coronary atherosclerosis, and cardiomyopathy in patients undergoing long-term hemodialysis","container-title":"JAMA","page":"353-359","volume":"290","issue":"3","source":"PubMed","abstract":"CONTEXT: Cardiac troponin T (cTnT) and C-reactive protein (CRP) are prognostic markers in acute coronary syndromes. However, for patients with end-stage renal disease (ESRD) the ability of combinations of these markers to predict outcomes, and their association with cardiac pathology, are unclear.\nOBJECTIVE: To investigate the association between levels of cTnT and CRP and long-term risk of cardiac pathology and death in patients with ESRD.\nDESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study initiated February through June 1998 and enrolling 224 patients with ESRD from 5 hemodialysis centers in the Houston-Galveston region of Texas. Levels of cTnT and CRP were analyzed at study entry in patients without ischemic symptoms.\nMAIN OUTCOME MEASURES: All-cause mortality during a mean follow-up of 827 (range, 29-1327) days. Secondary outcomes in predefined substudies were coronary artery disease (CAD), decreased (< or =40%) left ventricular ejection fraction (LVEF), and presence of left ventricular hypertrophy (LVH).\nRESULTS: One hundred seventeen (52%) patients died during follow-up. For levels of cTnT and CRP, progressively higher levels predicted increased risk of death compared with the lowest quartile (for cTnT quartile 2: unadjusted hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1; quartile 3: HR, 2.7; 95% CI, 1.5-4.9; quartile 4: HR, 3.0; 95% CI, 1.6-5.3. For CRP quartile 2: HR, 0.9; 95% CI, 0.5-1.6; quartile 3: HR, 1.8; 95% CI, 1.1-3.1; quartile 4: HR, 1.8; 95% CI, 1.1-3.2). Both cTnT and CRP remained independent predictors of death after adjusting for a number of potential confounders. The combination of cTnT and CRP results provided prognostic information when patients were divided into groups at or above and below the biomarker medians (high cTnT/high CRP levels vs low cTnT/low CRP levels for risk of death: HR, 2.5; 95% CI, 1.5-4.0). Elevated levels of cTnT, but not CRP, were strongly associated with diffuse CAD (n = 67; 0%, 25%, 50%, and 62% prevalence of multivessel CAD across progressive cTnT quartiles, P<.001). An LVEF of 40% or less was identified in 4 (9%), 3 (8%), 10 (27%), and 7 (19%) of patients across cTnT quartiles (P =.07). No trend for cTnT levels was found among patients with LVH (P =.45); similarly, no trend for CRP was found among patients with LVH (P =.65) or an LVEF of 40% or less (P =.75).\nCONCLUSIONS: Among stable patients with ESRD, increasing levels of cTnT and CRP are associated with increased risk of death. Furthermore, higher levels of cTnT may identify patients with severe angiographic coronary disease.","DOI":"10.1001/jama.290.3.353","ISSN":"1538-3598","note":"PMID: 12865376","journalAbbreviation":"JAMA","language":"eng","author":[{"family":"deFilippi","given":"Christopher"},{"family":"Wasserman","given":"Steven"},{"family":"Rosanio","given":"Salvatore"},{"family":"Tiblier","given":"Eric"},{"family":"Sperger","given":"Heidi"},{"family":"Tocchi","given":"Monica"},{"family":"Christenson","given":"Robert"},{"family":"Uretsky","given":"Barry"},{"family":"Smiley","given":"Mathew"},{"family":"Gold","given":"Judith"},{"family":"Muniz","given":"Henry"},{"family":"Badalamenti","given":"John"},{"family":"Herzog","given":"Charles"},{"family":"Henrich","given":"William"}],"issued":{"date-parts":[["2003",7,16]]}}}],"schema":""} 9–12 Conversely, patients with prior coronary artery disease (CAD), congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) presenting with AMI reportedly have lower peak cTn levels compared to patients without the respective co-morbidities, albeit these studies did not adjust for age, smoking status, medications, and other relevant co-morbidities; moreover, the relevance of lower peak troponin levels in these patients have not been studied. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"RGsP8fbT","properties":{"formattedCitation":"\\super 13\\uc0\\u8211{}16\\nosupersub{}","plainCitation":"13–16","noteIndex":0},"citationItems":[{"id":26,"uris":[""],"uri":[""],"itemData":{"id":26,"type":"article-journal","title":"Chronic obstructive pulmonary disease and acute myocardial infarction: effects on presentation, management, and outcomes","container-title":"European Heart Journal. Quality of Care & Clinical Outcomes","page":"81-90","volume":"2","issue":"2","source":"PubMed","abstract":"Cardiovascular disease is a common cause of death in patients with chronic obstructive pulmonary disease (COPD) and is a key target for improving outcomes. However, there are concerns that patients with COPD may not have enjoyed the same mortality reductions from acute myocardial infarction (AMI) in recent decades as the general population. This has raised questions about differences in presentation, management and outcomes in COPD patients compared to non-COPD patients. The evidence points to an increased risk of death after AMI in patients with COPD, but it is unclear to what extent this is attributable to COPD itself or to modifiable factors including under-treatment with guideline-recommended interventions and drugs. We review the evidence for differences between COPD and non-COPD patients in terms of the presentation of AMI, its treatment, and outcomes both in hospital and in the longer term.","DOI":"10.1093/ehjqcco/qcw005","ISSN":"2058-1742","note":"PMID: 29474627\nPMCID: PMC5862020","shortTitle":"Chronic obstructive pulmonary disease and acute myocardial infarction","journalAbbreviation":"Eur Heart J Qual Care Clin Outcomes","language":"eng","author":[{"family":"Rothnie","given":"Kieran J."},{"family":"Quint","given":"Jennifer K."}],"issued":{"date-parts":[["2016",4,1]]}}},{"id":28,"uris":[""],"uri":[""],"itemData":{"id":28,"type":"article-journal","title":"Chronic obstructive pulmonary disease after myocardial infarction in the community","container-title":"American Heart Journal","page":"95-101","volume":"160","issue":"1","source":"PubMed","abstract":"BACKGROUND: Myocardial infarction (MI) and chronic obstructive pulmonary disease (COPD) are frequent and share common risk factors. Yet, studies on MI patients reported limited and conflicting results on the prevalence of COPD, its impact on outcome, and how these may have changed over time. We examined, in a geographically defined community, the prevalence of COPD in patients with MI, its impact on mortality, and how these associations changed over time.\nMETHODS: Residents of Olmsted County, Minnesota, who experienced an MI meeting standardized criteria from 1979 to 2007 were included (3,438, 42% women, mean age 68 +/- 15 years). Chronic obstructive pulmonary disease was ascertained from the medical records.\nRESULTS: Of 3,438 patients, 415 (12%) had COPD. During the study, COPD prevalence increased from 7% in 1979-1985 to 15% in 2000-2007 (P < .001). Survival was worse in patients with COPD than in those without COPD (5-year survival rate: 46% [95% CI 41%-52%] vs 68% [95% CI 66%-70%], respectively; P < .01). The association between COPD and death was independent of age and risk factors (adjusted hazard ratio 1.30, 95% CI 1.10-1.54, P < .01) and did not change over time.\nCONCLUSIONS: In a large community of patients with MI, the prevalence of COPD increased over time and was associated with a markedly increased risk of death after MI independently of age, risk factors, and comorbidity. This underscores the importance of this condition and the need to optimize care for these high-risk patients.","DOI":"10.1016/j.ahj.2010.05.004","ISSN":"1097-6744","note":"PMID: 20598978\nPMCID: PMC2897833","journalAbbreviation":"Am. Heart J.","language":"eng","author":[{"family":"Bursi","given":"Francesca"},{"family":"Vassallo","given":"Robert"},{"family":"Weston","given":"Susan A."},{"family":"Killian","given":"Jill M."},{"family":"Roger","given":"Véronique L."}],"issued":{"date-parts":[["2010",7]]}}},{"id":30,"uris":[""],"uri":[""],"itemData":{"id":30,"type":"article-journal","title":"Association of chronic lung disease with treatments and outcomes patients with acute myocardial infarction","container-title":"American Heart Journal","page":"43-49","volume":"165","issue":"1","source":"PubMed","abstract":"BACKGROUND: Although chronic lung disease (CLD) is common among patients with myocardial infarction (MI), little is known about the influence of CLD on patient management and outcomes following MI.\nMETHODS: Using the National Cardiovascular Data Registry's ACTION Registry-GWTG, demographics, clinical characteristics, treatments, processes of care, and in-hospital adverse events after acute MI were compared between patients with (n = 22,624) and without (n = 136,266) CLD. Multivariable adjustment was performed to determine the independent association of CLD with treatments and adverse events.\nRESULTS: CLD (17.0% of non-ST-elevation MI [NSTEMI] and 10.1% of ST-elevation MI [STEMI] patients) was associated with older age, female sex, and a greater burden of comorbidities. Among NSTEMI patients, those with CLD were less likely to undergo cardiac catheterization, percutaneous coronary intervention, and coronary artery bypass graft compared to those without; in contrast, no differences were seen in invasive therapies for STEMI patients with or without CLD. Multivariable-adjusted risk of major bleeding was significantly increased in CLD patients with NSTEMI (13.0% vs 8.1%, OR(adj) = 1.27, 95% CI = 1.20-1.34, P < .001) and STEMI (16.0% vs 10.5%, OR(adj) = 1.19, 95% CI = 1.10-1.29, P < .001). In NSTEMI, CLD was associated with a higher risk of inhospital mortality (OR(adj) = 1.21, 95% CI = 1.11-1.33); in STEMI no association between CLD and mortality was seen (OR(adj) = 1.05, 95% CI = 0.95-1.17).\nCONCLUSIONS: CLD is common among patients with MI and is independently associated with an increased risk for major bleeding. In NSTEMI, CLD is also associated with receiving less revascularization and with increased in-hospital mortality. Special attention should be given to this high-risk subgroup for the prevention and management of complications after MI.","DOI":"10.1016/j.ahj.2012.09.010","ISSN":"1097-6744","note":"PMID: 23237132","journalAbbreviation":"Am. Heart J.","language":"eng","author":[{"family":"Enriquez","given":"Jonathan R."},{"family":"Lemos","given":"James A.","non-dropping-particle":"de"},{"family":"Parikh","given":"Shailja V."},{"family":"Peng","given":"S. Andrew"},{"family":"Spertus","given":"John A."},{"family":"Holper","given":"Elizabeth M."},{"family":"Roe","given":"Matthew T."},{"family":"Rohatgi","given":"Anand"},{"family":"Das","given":"Sandeep R."}],"issued":{"date-parts":[["2013",1]]}}},{"id":284,"uris":[""],"uri":[""],"itemData":{"id":284,"type":"article-journal","title":"Predictors of Peak Troponin Level in Acute Coronary Syndromes: Prior Aspirin Use and SYNTAX Score","container-title":"The International Journal of Angiology : Official Publication of the International College of Angiology, Inc","page":"54-63","volume":"25","issue":"1","source":"PubMed Central","abstract":"The peak troponin level has been associated with cardiovascular (CV) mortality and adverse CV events. The association of peak troponin with CV risk factors and severity and complexity of coronary artery disease remains unknown. We assessed the predictors of peak troponin in patients with acute coronary syndrome (ACS). This study aims to determine the predictors of peak troponin in ACS. Cardiac catheterization (CC) reports and electronic medical records from 2010 to 2013 were retrospectively reviewed. A total of 219 patients were eligible for the study. All major CV risk factors, comorbidities, laboratory data, CC indications, and coronary lesion characteristics were included. Univariate and multivariate regression analyses were done. On multivariate linear regression analysis, ST-elevation myocardial infarction (p?=?0.001, β?=?65.16) and increasing synergy between percutaneous coronary intervention with Taxus and cardiac surgery (SYNTAX) score (p?=?0.002, β?=?1.15) were associated with higher peak troponin. The Pearson correlation between SYNTAX score and peak troponin was r?=?0.257, p?=?0.001. History of daily aspirin use was associated with lower peak troponin (p?=?0.002, β?=??24.32). Prior statin use (p?=?0.321, β?=??8.98) and the presence of CV risk factors were not associated with peak troponin. Coronary artery disease severity and complexity, urgency of CC, and prior aspirin use are associated with peak troponin levels in ACS. Our findings may help predict patient population with ACS who would be at a greater risk for short- and long-term CV morbidity and mortality due to elevated peak troponin.","DOI":"10.1055/s-0035-1547396","ISSN":"1061-1711","note":"PMID: 26900312\nPMCID: PMC4758844","shortTitle":"Predictors of Peak Troponin Level in Acute Coronary Syndromes","journalAbbreviation":"Int J Angiol","author":[{"family":"Bhatt","given":"Hemal A."},{"family":"Sanghani","given":"Dharmesh R."},{"family":"Lee","given":"David"},{"family":"Julliard","given":"Kell N."},{"family":"Fernaine","given":"George A."}],"issued":{"date-parts":[["2016",3]]}}}],"schema":""} 13–16 Indeed, the influence of common co-morbidities on peak cTn levels in patients presenting with AMI has not been systematically evaluated and the quantum of change in cTn caused by such co-morbidities needs further investigation. This has important clinical implications, particularly in the context of NSTEMI, the most common type of AMI, where implementation of guideline-recommended therapies in real world rely heavily on the degree of cTn elevation, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qk2gXYq0","properties":{"formattedCitation":"\\super 17\\nosupersub{}","plainCitation":"17","noteIndex":0},"citationItems":[{"id":86,"uris":[""],"uri":[""],"itemData":{"id":86,"type":"article-journal","title":"Relationship between risk stratification by cardiac troponin level and adherence to guidelines for non-ST-segment elevation acute coronary syndromes","container-title":"Archives of Internal Medicine","page":"1870-1876","volume":"165","issue":"16","source":"PubMed","abstract":"BACKGROUND: The threshold of troponin elevation that stimulates changes in clinical decision making for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACSs) has not been previously evaluated.\nMETHODS: A total of 23 298 patients with NSTE ACSs from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) initiative were separated into categories of maximum troponin ratios (ratio of the highest recorded troponin value in the first 24 hours to the local laboratory troponin assay upper limit of normalization [ULN]).\nRESULTS: Unadjusted rates of in-hospital mortality increased from the group with troponin levels below the reference limit (maximum troponin ratio 0-1 x ULN; n = 5291) to those with minor (1-2 x ULN; n = 2499), intermediate (2-5 x ULN; n = 3825), and major (>5 x ULN; n = 11 683) elevations (-2.8% vs 4.6% vs 4.7% vs 6.0%). The use of early (<24 hours) aspirin, heparin, glycoprotein IIb/IIIa inhibitors, and beta-blockers was similar for the group with troponin levels below the reference limit compared with those with minor troponin elevations, and greater use of medications was demonstrated in patients with intermediate and major troponin elevations. Use of cardiac catheterization and percutaneous coronary intervention was higher in patients with troponin levels below the reference limit compared with those with minor troponin elevations, and procedures were used most frequently in patients with major troponin elevations. Similar patterns of care were demonstrated after excluding patients with chronic renal insufficiency.\nCONCLUSIONS: Any degree of troponin elevation is associated with a higher risk of mortality for patients with NSTE ACSs, but guideline-recommended medical therapies are used more commonly only in patients with intermediate and major troponin elevations, whereas patients with troponin levels below the reference limit underwent invasive procedures more frequently than those with mild troponin elevations.","DOI":"10.1001/archinte.165.16.1870","ISSN":"0003-9926","note":"PMID: 16157831","journalAbbreviation":"Arch. Intern. Med.","language":"eng","author":[{"family":"Roe","given":"Matthew T."},{"family":"Peterson","given":"Eric D."},{"family":"Li","given":"Yun"},{"family":"Pollack","given":"Charles V."},{"family":"Christenson","given":"Robert H."},{"family":"Peacock","given":"W. Frank"},{"family":"Fesmire","given":"Francis M."},{"family":"Newby","given":"L. Kristin"},{"family":"Jesse","given":"Robert L."},{"family":"Hoekstra","given":"James W."},{"family":"Gibler","given":"W. Brian"},{"family":"Ohman","given":"E. Magnus"}],"issued":{"date-parts":[["2005",9,12]]}}}],"schema":""} 17 and in older patients with multiple co-morbidities where the interpretation of cTn could be marred due to a complex interplay of age, sex, co-morbidities, type of cTn assay and AMI [i.e. STEMI versus NSTEMI]. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ze09XO13","properties":{"formattedCitation":"\\super 18\\uc0\\u8211{}25\\nosupersub{}","plainCitation":"18–25","noteIndex":0},"citationItems":[{"id":222,"uris":[""],"uri":[""],"itemData":{"id":222,"type":"article-journal","title":"Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay","container-title":"Journal of the American College of Cardiology","page":"1441-1448","volume":"63","issue":"14","source":"PubMed","abstract":"OBJECTIVES: The study sought to determine the 99th percentile upper reference limit for the high-sensitivity cardiac troponin T assay (hs-cTnT) in 3 large independent cohorts.\nBACKGROUND: The presently recommended 14 ng/l cut point for the diagnosis of myocardial infarction using the hs-cTnT assay was derived from small studies of presumably healthy individuals, with relatively little phenotypic characterization.\nMETHODS: Data were included from 3 well-characterized population-based studies: the Dallas Heart Study (DHS), the Atherosclerosis Risk in Communities (ARIC) Study, and the Cardiovascular Health Study (CHS). Within each cohort, reference subcohorts were defined excluding individuals with recent hospitalization, overt cardiovascular disease, and kidney disease (subcohort 1), and further excluding those with subclinical structural heart disease (subcohort 2). Data were analyzed stratified by age, sex, and race.\nRESULTS: The 99th percentile values for the hs-cTnT assay in DHS, ARIC, and CHS were 18, 22, and 36 ng/l (subcohort 1) and 14, 21, and 28 ng/l (subcohort 2), respectively. These differences in 99th percentile values paralleled age differences across cohorts. Analyses within sex/age strata yielded similar results between cohorts. Within each cohort, 99th percentile values increased with age and were higher in men. More than 10% of men 65 to 74 years of age with no cardiovascular disease in our study had cardiac troponin T values above the current myocardial infarction threshold.\nCONCLUSIONS: Use of a uniform 14 ng/l cutoff for the hs-cTnT assay may lead to over-diagnosis of myocardial infarction, particularly in men and the elderly. Clinical validation is needed of new age- and sex-specific cutoff values for this assay.","DOI":"10.1016/j.jacc.2013.12.032","ISSN":"1558-3597","note":"PMID: 24530665\nPMCID: PMC3984900","journalAbbreviation":"J. Am. Coll. Cardiol.","language":"eng","author":[{"family":"Gore","given":"M. Odette"},{"family":"Seliger","given":"Stephen L."},{"family":"Defilippi","given":"Christopher R."},{"family":"Nambi","given":"Vijay"},{"family":"Christenson","given":"Robert H."},{"family":"Hashim","given":"Ibrahim A."},{"family":"Hoogeveen","given":"Ron C."},{"family":"Ayers","given":"Colby R."},{"family":"Sun","given":"Wensheng"},{"family":"McGuire","given":"Darren K."},{"family":"Ballantyne","given":"Christie M."},{"family":"Lemos","given":"James A.","non-dropping-particle":"de"}],"issued":{"date-parts":[["2014",4,15]]}}},{"id":220,"uris":[""],"uri":[""],"itemData":{"id":220,"type":"article-journal","title":"Impact of age on the performance of the ESC 0/1h-algorithms for early diagnosis of myocardial infarction","container-title":"European Heart Journal","page":"3780-3794","volume":"39","issue":"42","source":"PubMed","abstract":"Aims: We aimed to evaluate the impact of age on the performance of the European Society of Cardiology (ESC) 0/1h-algorithms and to derive and externally validate alternative cut-offs specific to older patients.\nMethods and results: We prospectively enrolled patients presenting to the emergency department (ED) with symptoms suggestive of acute myocardial infarction in three large diagnostic studies. Final diagnoses were adjudicated by two independent cardiologists. High-sensitivity cardiac troponin (hs-cTn) T and I concentrations were measured at presentation and after 1?h. Patients were stratified according to age [<55?years (young), ≥55 to <70?years (middle-age), ≥70?years (old)]. Rule-out safety of the ESC hs-cTnT 0/1h-algorithm was very high in all age-strata: sensitivity 100% [95% confidence interval (95% CI) 94.9-100] in young, 99.3% (95% CI 96.0-99.9) in middle-age, and 99.3% (95% CI 97.5-99.8) in old patients. Accuracy of rule-in decreased with age: specificity 97.0% (95% CI 95.8-97.9) in young, 96.1% (95% CI 94.5-97.2) in middle-age, and 92.7% (95% CI 90.7-94.3) in older patients. Triage efficacy decreased with increasing age (young 93%, middle-age 80%, old 55%, P?<?0.001). Similar results were found for the ESC hs-cTnT 0/1h-algorithm. Alternative, slightly higher cut-off concentrations optimized for older patients maintained very high safety of rule-out, increased specificity of rule-in (P?<?0.01), reduced overall efficacy for hs-cTnT (P?<?0.01), while maintaining efficacy for hs-cTnI. Findings were confirmed in two validation cohorts (n?=?2767).\nConclusion: While safety of the ESC 0/1h-algorithms remained very high, increasing age significantly reduced overall efficacy and the accuracy of rule-in. Alternative slightly higher cut-off concentrations may be considered for older patients, particularly if using hs-cTnI.\nClinical Trial Registration: , number NCT00470587 and NCT02355457 (BACC).","DOI":"10.1093/eurheartj/ehy514","ISSN":"1522-9645","note":"PMID: 30169752","journalAbbreviation":"Eur. Heart J.","language":"eng","author":[{"family":"Boeddinghaus","given":"Jasper"},{"family":"Nestelberger","given":"Thomas"},{"family":"Twerenbold","given":"Raphael"},{"family":"Neumann","given":"Johannes Tobias"},{"family":"Lindahl","given":"Bertil"},{"family":"Giannitsis","given":"Evangelos"},{"family":"S?rensen","given":"Nils Arne"},{"family":"Badertscher","given":"Patrick"},{"family":"Jann","given":"Janina E."},{"family":"Wussler","given":"Desiree"},{"family":"Puelacher","given":"Christian"},{"family":"Rubini Giménez","given":"Maria"},{"family":"Wildi","given":"Karin"},{"family":"Strebel","given":"Ivo"},{"family":"Du Fay de Lavallaz","given":"Jeanne"},{"family":"Selman","given":"Farah"},{"family":"Sabti","given":"Zaid"},{"family":"Kozhuharov","given":"Nikola"},{"family":"Potlukova","given":"Eliska"},{"family":"Rentsch","given":"Katharina"},{"family":"Miró","given":"?scar"},{"family":"Martin-Sanchez","given":"F. Javier"},{"family":"Morawiec","given":"Beata"},{"family":"Parenica","given":"Jiri"},{"family":"Lohrmann","given":"Jens"},{"family":"Kloos","given":"Wanda"},{"family":"Buser","given":"Andreas"},{"family":"Geigy","given":"Nicolas"},{"family":"Keller","given":"Dagmar I."},{"family":"Osswald","given":"Stefan"},{"family":"Reichlin","given":"Tobias"},{"family":"Westermann","given":"Dirk"},{"family":"Blankenberg","given":"Stefan"},{"family":"Mueller","given":"Christian"},{"literal":"APACE, BACC, and TRAPID-AMI Investigators"}],"issued":{"date-parts":[["2018",11,7]]}}},{"id":250,"uris":[""],"uri":[""],"itemData":{"id":250,"type":"article-journal","title":"Sex-specific troponin measures for diagnosis of acute coronary syndrome","container-title":"Heart (British Cardiac Society)","page":"91-92","volume":"102","issue":"2","source":"PubMed","DOI":"10.1136/heartjnl-2015-308962","ISSN":"1468-201X","note":"PMID: 26729606","journalAbbreviation":"Heart","language":"eng","author":[{"family":"Giannitsis","given":"Evangelos"}],"issued":{"date-parts":[["2016",1]]}}},{"id":247,"uris":[""],"uri":[""],"itemData":{"id":247,"type":"article-journal","title":"Counterpoint: Potential Concerns Regarding the Use of Sex-Specific Cutpoints for High-Sensitivity Troponin Assays","container-title":"Clinical Chemistry","page":"264-266","volume":"63","issue":"1","source":"PubMed","DOI":"10.1373/clinchem.2016.254680","ISSN":"1530-8561","note":"PMID: 27895085","shortTitle":"Counterpoint","journalAbbreviation":"Clin. Chem.","language":"eng","author":[{"family":"Giannitsis","given":"Evangelos"}],"issued":{"date-parts":[["2017",1]]}}},{"id":252,"uris":[""],"uri":[""],"itemData":{"id":252,"type":"article-journal","title":"High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study","container-title":"BMJ (Clinical research ed.)","page":"g7873","volume":"350","source":"PubMed","abstract":"OBJECTIVE: To evaluate the diagnosis of myocardial infarction using a high sensitivity troponin I assay and sex specific diagnostic thresholds in men and women with suspected acute coronary syndrome.\nDESIGN: Prospective cohort study.\nSETTING: Regional cardiac centre, United Kingdom.\nPARTICIPANTS: Consecutive patients with suspected acute coronary syndrome (n=1126, 46% women). Two cardiologists independently adjudicated the diagnosis of myocardial infarction by using a high sensitivity troponin I assay with sex specific diagnostic thresholds (men 34 ng/L, women 16 ng/L) and compared with current practice where a contemporary assay (50 ng/L, single threshold) was used to guide care.\nMAIN OUTCOME MEASURE: Diagnosis of myocardial infarction.\nRESULTS: The high sensitivity troponin I assay noticeably increased the diagnosis of myocardial infarction in women (from 11% to 22%; P<0.001) but had a minimal effect in men (from 19% to 21%, P=0.002). Women were less likely than men to be referred to a cardiologist or undergo coronary revascularisation (P<0.05 for both). At 12 months, women with undisclosed increases in troponin concentration (17-49 ng/L) and those with myocardial infarction (≥50 ng/L) had the highest rate of death or reinfarction compared with women without (≤16 ng/L) myocardial infarction (25%, 24%, and 4%, respectively; P<0.001).\nCONCLUSIONS: Although having little effect in men, a high sensitivity troponin assay with sex specific diagnostic thresholds may double the diagnosis of myocardial infarction in women and identify those at high risk of reinfarction and death. Whether use of sex specific diagnostic thresholds will improve outcomes and tackle inequalities in the treatment of women with suspected acute coronary syndrome requires urgent attention.","DOI":"10.1136/bmj.g7873","ISSN":"1756-1833","note":"PMID: 25609052\nPMCID: PMC4301191","shortTitle":"High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women","journalAbbreviation":"BMJ","language":"eng","author":[{"family":"Shah","given":"Anoop S. V."},{"family":"Griffiths","given":"Megan"},{"family":"Lee","given":"Kuan Ken"},{"family":"McAllister","given":"David A."},{"family":"Hunter","given":"Amanda L."},{"family":"Ferry","given":"Amy V."},{"family":"Cruikshank","given":"Anne"},{"family":"Reid","given":"Alan"},{"family":"Stoddart","given":"Mary"},{"family":"Strachan","given":"Fiona"},{"family":"Walker","given":"Simon"},{"family":"Collinson","given":"Paul O."},{"family":"Apple","given":"Fred S."},{"family":"Gray","given":"Alasdair J."},{"family":"Fox","given":"Keith A. A."},{"family":"Newby","given":"David E."},{"family":"Mills","given":"Nicholas L."}],"issued":{"date-parts":[["2015",1,21]]}}},{"id":255,"uris":[""],"uri":[""],"itemData":{"id":255,"type":"article-journal","title":"Impact of High-Sensitivity Troponin I Testing with Sex-Specific Cutoffs on the Diagnosis of Acute Myocardial Infarction","container-title":"Clinical Chemistry","page":"831-838","volume":"62","issue":"6","source":"PubMed","abstract":"BACKGROUND: High-sensitivity cardiac troponin I (hs-cTnI) assays show sex-dependent differences in the 99th percentile of healthy populations, with concentrations in women approximately 50% lower. The adoption of sex-specific cutoffs seems appropriate, although it is not yet clear what effect these will have on acute myocardial infarction (AMI) diagnosis and management.\nMETHODS: We conducted a retrospective pre- and postchangeover analysis of troponin I testing in the 6 months before and after moving from the contemporary Abbott Architect TnI assay (cTnI) to hs-cTnI at 2 tertiary centers in Australia and New Zealand. The cTnI cutoff was 30 ng/L for both sexes, whereas a female-specific cutoff of 16 ng/L was adopted upon changeover to hsTnI.\nRESULTS: Changeover from the cTnI assay to the hs-cTnI assay increased the number of female patients with increased troponin I concentrations at both sites (from 29.7% to 34.9% and from 22.4% to 30.8%; P < 0.001). There was no statistically significant change in the number of men with increased concentrations in the same time period (P = 0.09). The increased percentage of women with increased troponin I was not associated with an increase in the number of women with AMI diagnoses at either center. Angiographic data available from 1 center showed no change in the percentage of angiograms performed in women.\nCONCLUSIONS: Although increasing the proportion of women with increased troponin I, adopting sex-specific cutoffs with the hs-cTnI assay did not lead to an increase in AMI diagnoses in females, or in the number of women undergoing angiography.","DOI":"10.1373/clinchem.2015.252569","ISSN":"1530-8561","note":"PMID: 27117468","journalAbbreviation":"Clin. Chem.","language":"eng","author":[{"family":"Trambas","given":"Christina"},{"family":"Pickering","given":"John W."},{"family":"Than","given":"Martin"},{"family":"Bain","given":"Chris"},{"family":"Nie","given":"Lucy"},{"family":"Paul","given":"Eldho"},{"family":"Dart","given":"Anthony"},{"family":"Broughton","given":"Arch"},{"family":"Schneider","given":"Hans Gerhard"}],"issued":{"date-parts":[["2016"]]}}},{"id":258,"uris":[""],"uri":[""],"itemData":{"id":258,"type":"article-journal","title":"Diagnostic and prognostic implications using age- and gender-specific cut-offs for high-sensitivity cardiac troponin T - Sub-analysis from the TRAPID-AMI study","container-title":"International Journal of Cardiology","page":"26-33","volume":"209","source":"PubMed","abstract":"OBJECTIVES: To evaluate the impact of age- and gender-specific cut-offs for high-sensitivity cardiac troponin T (hs-cTnT) compared to the general 99th percentile hs-cTnT cut-off on diagnosis and prognosis of acute myocardial infarction (AMI).\nMETHODS: 1282 unselected patients presenting to the emergency department with suspected AMI were enrolled as part of the TRAPID-AMI study. In the present sub-analysis, reclassification of AMI diagnosis was performed by comparing the general hs-cTnT cut-off of 14ng/L to previously proposed age- and gender-dependent hs-cTnT 99th percentile cut-offs (28ng/L for ≥65years, 9ng/L for female and 15.5ng/L for male patients). Patients were further clinically adjudicated into acute coronary syndrome (ACS) and non-ACS.\nRESULTS: For patients ≥65years, application of age-specified cut-offs resulted in a decrease of AMI from 29.8% to 18.3% in the entire cohort (n=557) and 54.7% to 40.9% in the ACS subcohort (n=225). Using gender-specific cut-offs, AMI-rate increased from 16.6% to 22.6% (entire cohort, n=477) and 62.6% to 71.7% (ACS subcohort, n=99) in women, whereas in men, rates decreased from 23.1% to 21.1% (entire cohort, n=805) and 48.8% to 45.9% (ACS, n=281), respectively. Age-specified cut-offs significantly reclassified patients for outcomes of 1-month and 3-month mortality in the entire and ACS cohort (14.2% net reclassification improvement, p<0.001, respectively). Contrary, no significant differences in outcomes could be found using gender-specific cut-offs.\nCONCLUSIONS: While influence of gender-specific hs-cTnT cut-offs on diagnostic and prognostic reclassification was only modest in patients with suspected AMI, age-specific cut-offs showed a significant impact and may be considered for further validation.","DOI":"10.1016/j.ijcard.2016.01.213","ISSN":"1874-1754","note":"PMID: 26878470","journalAbbreviation":"Int. J. Cardiol.","language":"eng","author":[{"family":"Mueller-Hennessen","given":"Matthias"},{"family":"Lindahl","given":"Bertil"},{"family":"Giannitsis","given":"Evangelos"},{"family":"Biener","given":"Moritz"},{"family":"Vafaie","given":"Mehrshad"},{"family":"deFilippi","given":"Christopher R."},{"family":"Christ","given":"Michael"},{"family":"Santalo-Bel","given":"Miguel"},{"family":"Panteghini","given":"Mauro"},{"family":"Plebani","given":"Mario"},{"family":"Verschuren","given":"Franck"},{"family":"Jernberg","given":"Tomas"},{"family":"French","given":"John K."},{"family":"Christenson","given":"Robert H."},{"family":"Body","given":"Richard"},{"family":"McCord","given":"James"},{"family":"Dilba","given":"Peter"},{"family":"Katus","given":"Hugo A."},{"family":"Mueller","given":"Christian"},{"literal":"TRAPID-AMI Investigators"}],"issued":{"date-parts":[["2016",4,15]]}}},{"id":269,"uris":[""],"uri":[""],"itemData":{"id":269,"type":"article-journal","title":"Sex-specific versus overall cut points for a high sensitivity troponin I assay in predicting 1-year outcomes in emergency patients presenting with chest pain","container-title":"Heart (British Cardiac Society)","page":"120-126","volume":"102","issue":"2","source":"PubMed","abstract":"OBJECTIVE: To evaluate the incidence of major adverse cardiac events (MACE) at 1?year in emergency department (ED) patients with possible acute coronary syndromes, stratified by high sensitivity troponin (hs-cTnI) concentrations using sex-specific cut points compared with overall cut points.\nMETHODS: In a multicentre observational study of 2841 patients, presentation hs-cTnI concentrations were categorised using sex-specific (women 16?ng/L; men 34?ng/L) and overall (26?ng/L) cut points. The primary outcome was MACE occurring within 1?year of presentation. Patients with hs-cTnI values concentrations within these categories were reported by sex and 1-year MACE. Net reclassification improvement (NRI) was computed to measure the change in prediction after altering the hs-cTnI cut points, and was calculated separately for events and non-events.\nRESULTS: Application of sex-specific 99th percentile cut points rather than the overall cut point of 26?ng/L, reclassified 25 females from having a non-elevated troponin to having an elevated troponin, and 29 males from having an elevated troponin value to having a non-elevated troponin value on presentation. Of these, 7 (28.0%) females and 12 (41.4%) males had a 1-year MACE. There was no reclassification improvement for those with or without 1-year MACE (NRIevents=-1.5%, 95% CI -4.0% to 1.1%; NRInon-events -0.04%, 95% CI -0.5% to 0.4%).\nCONCLUSIONS: Sex-specific cut points improve the identification of women but not men at risk for 1-year MACE. The net-effect across the whole ED population with possible cardiac chest pain is minimal. Lowering the clinical cut point for both sexes may be appropriate for prognostic purposes.\nTRIAL REGISTRATION NUMBER: ISRCTN No. 21109279, ACTRN12609000283279.","DOI":"10.1136/heartjnl-2015-308506","ISSN":"1468-201X","note":"PMID: 26729608","journalAbbreviation":"Heart","language":"eng","author":[{"family":"Cullen","given":"Louise"},{"family":"Greenslade","given":"Jaimi H."},{"family":"Carlton","given":"Edward W."},{"family":"Than","given":"Martin"},{"family":"Pickering","given":"John W."},{"family":"Ho","given":"Ariel"},{"family":"Greaves","given":"Kim"},{"family":"Berndt","given":"Sara L."},{"family":"Body","given":"Richard"},{"family":"Ryan","given":"Kimberley"},{"family":"Parsonage","given":"William A."}],"issued":{"date-parts":[["2016",1]]}}}],"schema":""} 18–25Previous studies have demonstrated a linear and graded relationship of peak cTn and mortality in patients presenting with AMI. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LYHJaozD","properties":{"formattedCitation":"\\super 26\\nosupersub{}","plainCitation":"26","noteIndex":0},"citationItems":[{"id":84,"uris":[""],"uri":[""],"itemData":{"id":84,"type":"article-journal","title":"Relationship Between Peak Troponin Values and Long-Term Ischemic Events Among Medically Managed Patients With Acute Coronary Syndromes","container-title":"Journal of the American Heart Association","volume":"6","issue":"4","source":"PubMed","abstract":"BACKGROUND: The relationship between troponin level and outcomes among patients with non-ST-segment elevation ACS is established, but the relationship of troponin level with long-term outcomes among medically managed non-ST-segment elevation ACS patients receiving contemporary antiplatelet therapy is inadequately defined.\nMETHODS AND RESULTS: In 6763 medically managed non-ST-segment elevation ACS patients randomized in TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) (prasugrel versus clopidogrel), we examined relationships between categories of peak troponin/upper limit of normal (ULN) ratio within 48?hours of the index ACS event (≈4.5?days before randomization) and 30-month outcomes (cardiovascular death, myocardial infarction, or stroke; cardiovascular death or myocardial infarction; and all-cause death). Patients with peak troponin levels <1×ULN were younger, were more often women, and had lower GRACE risk scores than those in other troponin groups. Those with ratios ≥5×ULN were more frequently smokers but less often had prior myocardial infarction or percutaneous coronary intervention. Diabetes mellitus prevalence, body mass index, serum creatinine, and hemoglobin were similar across groups. For all end points, statistically significant differences in 30-month event rates were observed between peak troponin categories. The relationship was linear for 30-month mortality (<1×ULN, n=1849 [6.2%]; 1 to <3×ULN, n=1203 [9.6%]; 3 to <5×ULN, n=581 [10.8%]; and ≥5×ULN, n=3405 [12.8%]) but plateaued for composite end points beyond peak troponin values ≥3×ULN. There was no statistically significant heterogeneity in treatment effect by peak troponin ratio for any end point.\nCONCLUSIONS: Among medically managed non-ST-segment elevation ACS patients selected for medical management, there was a graded relationship between increasing peak troponin and long-term ischemic events but no heterogeneity of treatment effect for prasugrel versus clopidogrel according to peak troponin.\nCLINICAL TRIAL REGISTRATION: URL: . Unique identifier: NCT00699998.","DOI":"10.1161/JAHA.116.005334","ISSN":"2047-9980","note":"PMID: 28400368\nPMCID: PMC5533023","journalAbbreviation":"J Am Heart Assoc","language":"eng","author":[{"family":"Goldstein","given":"Sarah A."},{"family":"Newby","given":"L. Kristin"},{"family":"Cyr","given":"Derek D."},{"family":"Neely","given":"Megan"},{"family":"Lüscher","given":"Thomas F."},{"family":"Brown","given":"Eileen B."},{"family":"White","given":"Harvey D."},{"family":"Ohman","given":"E. Magnus"},{"family":"Roe","given":"Matthew T."},{"family":"Hamm","given":"Christian W."}],"issued":{"date-parts":[["2017",4,11]]}}}],"schema":""} 26 However, this linear relationship between peak cTn and mortality could vary based on the baseline co-morbidities and the type of cTn assay (cTnT vs cTnI). To characterize peak cTn levels in common co-morbid conditions and determine the impact of these varying cTn levels on mortality in AMI, we carried out this large population based study across the United Kingdom. METHODSStudy PopulationWe included all patients with hospitalisation for acute coronary syndrome (ACS) between January 2003 and June 2013 from the Myocardial Infarction National Audit (MINAP), which is contributed to by all 230 National Health Service (NHS) trusts in England and Wales. MINAP was linked to the Office of National Statistics (ONS), providing mortality data at 180 days post discharge. Records were excluded if they did not have a measurement for either cTnI or cTnT, were missing a patient unique identifier, or ONS mortality data. Patients with prior coronary artery bypass graft surgery (CABG) were excluded from the analysis, as coronary bypass grafts can significantly influence peak levels of cTn and infarct size. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ENdU6WQW","properties":{"formattedCitation":"\\super 16,17\\nosupersub{}","plainCitation":"16,17","dontUpdate":true,"noteIndex":0},"citationItems":[{"id":100,"uris":[""],"uri":[""],"itemData":{"id":100,"type":"article-journal","title":"Does arterial revascularization decrease the risk of infarction after coronary artery bypass grafting?","container-title":"The Annals of Thoracic Surgery","page":"1-10; discussion 10-11","volume":"66","issue":"1","source":"PubMed","abstract":"BACKGROUND: This study sought to determine whether extensive arterial grafting reduces the prevalence and consequences of infarct after coronary artery bypass grafting.\nMETHODS: Post-primary coronary artery bypass grafting infarcts and time-related events thereafter were identified by 99.9% complete follow-up of 9,600 patients (1971 to 1992). The contribution of arterial grafting to freedom from infarct was assessed by multivariable hazard function analysis to adjust for other risk factors.\nRESULTS: Unadjusted 1-month and 10-year freedom from infarction was 97% and 86%. By multivariable analysis, arterial grafting lowered the prevalence of periprocedural (p = 0.005), intermediate term (p = 0.007 and 0.006), and late infarction (arterial grafting to the left anterior descending coronary artery, p = 0.0006). Unadjusted survival after first infarct after coronary artery bypass grafting was 74% and 52% at 1 and 10 years; arterial grafting improved 10-year survival from 48% to 59% (p = 0.002). An additional benefit or cost of extending arterial grafting (n = 1,727) beyond a single one could not be identified (p > 0.1).\nCONCLUSIONS: Arterial conduits, particularly to the left anterior descending coronary artery, should be used for coronary artery bypass grafting to reduce early and late myocardial infarction and its consequences. However, use of more than a single arterial graft appears to confer no additional benefit.","ISSN":"0003-4975","note":"PMID: 9692431","journalAbbreviation":"Ann. Thorac. Surg.","language":"eng","author":[{"family":"Sergeant","given":"P. T."},{"family":"Blackstone","given":"E. H."},{"family":"Meyns","given":"B. P."}],"issued":{"date-parts":[["1998",7]]}}},{"id":98,"uris":[""],"uri":[""],"itemData":{"id":98,"type":"article-journal","title":"Long-term prognosis after myocardial infarction in patients with previous coronary artery bypass surgery","container-title":"Journal of the American College of Cardiology","page":"873-880","volume":"12","issue":"4","source":"PubMed","abstract":"A group of 205 patients hospitalized with myocardial infarction 2 to 162 months (mean 66) after bypass surgery and 205 control patients with myocardial infarction were compared and followed up for 34 +/- 25 months after hospital discharge. At baseline the postbypass group contained more men (p less than 0.03) and more patients with previous myocardial infarction (p less than 0.06), but the groups were otherwise comparable. Indexes of infarct size were lower in postbypass patients: sum of ST elevation, QRS score, peak serum creatine kinase (CK) (1,115 +/- 994 versus 1,780 +/- 1,647 IU/liter) and peak MB CK (all p less than or equal to 0.001). Postmyocardial infarction ejection fraction was 45 +/- 15% in the postbypass group and 43 +/- 15% in the control group (p = NS); in-hospital mortality rate was 4 and 5%, respectively (p = NS). When patent grafts were taken into account, the two groups were comparable in extent of coronary artery disease. At 5 years after discharge, cumulative mortality was similar in the postbypass and control groups (30 versus 25%, respectively, p = NS). However, postbypass patients had more reinfarctions (40 versus 23%, p = 0.007), more admissions for unstable angina (23 versus 18%, p = 0.04) and more revascularization procedures (34 versus 20%, p = 0.04) than did control patients. The total for these events at 5 years was 70% in the postbypass group and 49% in the control group (p = 0.001). Thus, although patients with previous bypass surgery who develop acute myocardial infarction have a smaller infarct, their subsequent survival is no better than that of other patients with acute myocardial infarction. They experience more reinfarctions and unstable angina. Previous bypass surgery is an important clinical marker for recurrent cardiac events after myocardial infarction.","ISSN":"0735-1097","note":"PMID: 3262130","journalAbbreviation":"J. Am. Coll. Cardiol.","language":"eng","author":[{"family":"Wiseman","given":"A."},{"family":"Waters","given":"D. D."},{"family":"Walling","given":"A."},{"family":"Pelletier","given":"G. B."},{"family":"Roy","given":"D."},{"family":"Théroux","given":"P."}],"issued":{"date-parts":[["1988",10]]}}}],"schema":""} 16, 17 The details of data collection in MINAP and completeness of the data are outlined in the Supplementary Appendix.Identification of co-morbiditiesCo-morbid conditions were pre-defined by MINAP (Supplementary Appendix Table S1). According to common practice when analysing MINAP data, missing clinical variables were assumed to be absent. Troponin valuesThe peak cTn levels in MINAP where entered by the physician as part of the audit. We primarily used cTnT and cTnI for this analysis. The European Society of Cardiology Study Group on Biomarkers in Cardiology recommended the routine use of High sensitivity troponin as a diagnostic biomarker for AMI in 2012; hence in the UK, high sensitivity troponin was seldom measured prior to 2012. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"aWDeAWpL","properties":{"formattedCitation":"\\super 30\\nosupersub{}","plainCitation":"30","noteIndex":0},"citationItems":[{"id":"vy0Zot17/f7LqjLQy","uris":[""],"uri":[""],"itemData":{"id":36,"type":"article-journal","title":"How to use high-sensitivity cardiac troponins in acute cardiac care","container-title":"European Heart Journal","page":"2252-2257","volume":"33","issue":"18","source":"PubMed","DOI":"10.1093/eurheartj/ehs154","ISSN":"1522-9645","note":"PMID: 22723599","journalAbbreviation":"Eur. Heart J.","language":"eng","author":[{"family":"Thygesen","given":"Kristian"},{"family":"Mair","given":"Johannes"},{"family":"Giannitsis","given":"Evangelos"},{"family":"Mueller","given":"Christian"},{"family":"Lindahl","given":"Bertil"},{"family":"Blankenberg","given":"Stefan"},{"family":"Huber","given":"Kurt"},{"family":"Plebani","given":"Mario"},{"family":"Biasucci","given":"Luigi M."},{"family":"Tubaro","given":"Marco"},{"family":"Collinson","given":"Paul"},{"family":"Venge","given":"Per"},{"family":"Hasin","given":"Yonathan"},{"family":"Galvani","given":"Marcello"},{"family":"Koenig","given":"Wolfgang"},{"family":"Hamm","given":"Christian"},{"family":"Alpert","given":"Joseph S."},{"family":"Katus","given":"Hugo"},{"family":"Jaffe","given":"Allan S."},{"literal":"Study Group on Biomarkers in Cardiology of ESC Working Group on Acute Cardiac Care"}],"issued":{"date-parts":[["2012",9]]}}}],"schema":""} 30 Despite the paucity of data, we were able to perform a subgroup analysis of patients with high sensitivity troponin T (hsTnT) (grouping together STEMI and NSTEMI) to investigate the trends in peak hsTnT stratified by co-morbidities. Statistical analysisFor the primary analysis (difference in peak cTn), we log transformed peak cTn levels and used linear regression to compare peak cTn values between patients with and without specific co-morbidities of interest, stratified by the type of MI (included STEMI and NSTEMI). We exponentiated linear regression coefficients to obtain a ratio of geometric means, adjusting for age, sex, smoking status, and co-morbidities. We performed additional analysis stratified by severity of CKD, to ascertain the impact of the degree of CKD on cTn elevation. To evaluate the relationship between comorbidity, peak cTn and mortality, we restricted the analysis to patients with NSTEMI, as peak cTn levels have greater therapeutic implications in the management of this group as compared with a STEMI where primary percutaneous coronary intervention (PCI) is the standard of care regardless of cTn value. Three sets of analysis were performed for the outcome of 180-day all-cause mortality; 1) To investigate whether any differences in peak cTn associated with a specific comorbidity had an impact on the risk of death, we used logistic regression models to investigate the risk of death associated with the specific comorbidity – before and after adjustment for peak cTn level. We used likelihood ratio tests to test for statistical evidence (p<0.05) that peak cTn modified the association between each comorbidity and mortality at 180 days. 2) Peak cTn was further categorized into quartiles for each specific co-morbidity (i.e. 180-day mortality in CKD patients with <25th percentile of troponin elevation among all CKD patients etc.) and adjusted mortality was estimated for each category. 3) We used restricted cubic splines with three knots {0.8, 3.82 and 22.57 for cTnI and 0.09, 0.38 and 2.15 for cTnT for the overall analysis in NSTEMI (Supplementary Appendix Figure S1) to evaluate the non-linear association between peak cTn level and risk of death at 180 days for each of the co-morbidities in our study. The knots differed when spline analysis was performed for each co-morbidity (Supplementary Appendix Table S2-S3). Troponin was used as a continuous variable for the spline analyses. Data for 180-day all-cause mortality were presented as adjusted OR [adjusting for age, sex, smoking status, co-morbidities: peripheral arterial disease (PAD), cerebrovascular disease (CVD), COPD, CKD, CHF, hypertension (HTN), previous myocardial infarction (MI), diabetes mellitus (DM), previous angina; location of infarct (anterior vs non- anterior), medications (antiplatelet therapy, angiotensin converting enzyme inhibitor, angiotensin receptor blocker, beta-blockers and statins) and revascularization and maximally adjusted OR (adjusting for peak cTn for each co-morbidity). We did not perform multiple imputation as previous studies have shown that imputation analyses on the MINAP registry did not significantly alter effect sizes, suggesting that missingness in MINAP is at random. Additionally, the level of missingness of data in MINAP did not affect the mortality ratios.Results657,376 patients with ACS were identified in MINAP database between January 2003 and June 2013. The baseline characteristics of patients with missing data on peak troponin data were largely similar to those with the available data (Supplementary appendix Table S4). Among the patients admitted, 32% (128,960) of the patients presented with STEMI, 49.9% (201,407) with non-STEMI and 18.1% (72,664) had unstable angina (UA) (Figure 1). As expected, patients with NSTEMI were older and had a higher comorbidity burden than patients with STEMI (Table 1). Peak troponin levels stratified by co-morbidities following NSTEMI In patients with NSTEMI, those with COPD (-21.7%, 95%CI -29.1 to -13.4%), previous angina (-24.2%, 95%CI -29.6 to -18.3 %), previous MI (-13.5%, 95% CI -20.6 to -5.9%), CVD (-16%, 95% CI -24.2 to -7.0%) and CHF (-28.0%, 95%CI -37.2 to -17.6%) had significantly lower adjusted difference in peak cTnI, (Figure 2A & Table 2). There were no significant differences in adjusted peak cTnI levels in patients with DM, PAD and CKD compared to those without the respective co-morbidity. Similarly, in patients whose cTnT was measured, a similar association was seen for COPD (-14.3%, CI -18.7 to -9.7%), and CHF (-9.1%, 95%CI -30.4 to -18.7%), although patients with CKD had a substantially higher adjusted difference in peak cTnT (+42%, CI +13.1 to +78.4%) (Table 2) (Figure 2A)Peak troponin levels stratified by co-morbidities following STEMIIn patients presenting with STEMI, after adjustment for age, sex, smoking status, MI location (anterior or non-anterior), and other co-morbidities, a similar pattern was observed. Peak cTnI was lower for patients with previous angina (-20.4%, 95% CI -29.7 to - 17.1%), previous MI (-20.4 % 95%CI -27.2 to -13.0 %), and CHF (-26.7% 95%CI -40.0 to -10.6%) compared to patients with STEMI without the respective co-morbidity (Figure 2B & Table 3). In the case of cTnT, peak levels were found to be lower for previous angina (-13.2 % 95% CI -21.5 to -4.1 %), previous MI (-18.6% 95% CI -26.9 to -8.0 %), CHF (-24.8% 95% CI-40.9 to -4.2%) and with COPD (-14.7% 95CI -23.8 to -4.6 %). There were no significant differences in adjusted peak cTnI and cTnT levels in patients with DM, PAD and CVD (Table 3). There was a trend towards lower peak cTnI in patients with COPD and higher cTnT in patients with CKD but this was not statistically significant, most likely due to small sample sizes within these groups (Figure 2B & Table 3)Peak hsTnT following AMIThe trends in adjusted peak hsTnT values in patients with COPD, CKD, CHF, previous MI and previous angina were quite similar to the groups with cTnT (Figure 3). However, the trends in peak values did not reach statistical significance in certain groups (CKD and CHF), probably due to small sample size (Table 4).Risk of 180-day all-cause mortality with each comorbidity before and after adjustment of peak troponinIn patients with NSTEMI, almost all co-morbidities were associated with increased risk of death at 180-days after adjustment for age, sex, smoking status and other co-morbidities. After adjusting for peak cTn level, odds ratios (OR) for risk of death for each comorbidity at 180-days did not change substantially for all the co-morbidities (Table 2). In patients with STEMI, a similar pattern was observed (Table 3). Additional analysis performed by categorizing peak cTn into quartiles for each co-morbidity did not reveal a clear relationship between increasing quartiles of peak cTn and mortality in most of the co-morbidities (in NSTEMI and STEMI), with the exception of DM (Supplementary Appendix Tables S5-S8). The joint association between increased cTn and comorbidity on the risk of 180-day mortality following NSTEMI and STEMI are presented in (Supplementary Appendix Table S9-S10). Relationship between peak troponin and mortality stratified by co-morbidities in patients with NSTEMI; results of spline analysisIn patients with NSTEMI, the results of spline regression indicated that mortality increased with rising peak cTnI up to at least 50ng/mL (Supplementary Appendix Figure S1). However, there appeared to be a ceiling effect on the association between peak cTnT and mortality following NSTEMI after around 1.5ng/mL, after which rising peak cTn was not associated with increased mortality (Supplementary Appendix Figure S2). Splitting this analysis by co-morbidity produced associations with broadly similar shapes. There was a clear positive association between peak cTnI and 180 day-mortality for most of the co-morbidities (Figure 4). No such relationship was observed for cTnT (Figure 5).Subgroup analysis in CKDWe included 277,071 patients with serum creatinine values for this analysis (Supplementary Appendix Figure S3). GFR was calculated using CKD-epi cohort equation. In patients with AMI (both STEMI and NSTEMI), adjusted percentage difference in peak troponin was significantly higher in CKD stages 3b, 4 and 5{Stage 3b: 8.6% 95% CI: 0.8- 16.9%; Stage 4: 27.2% 95% CI: 15.4-40.2%; Stage 5: 30.8% 95% CI: 9-53.2%} when compared to patients with CKD stage 1. The adjusted odds ratio for mortality increased with increasing severity of CKD (Figure 6A and 6B). There was no evidence of interaction between CKD severity and peak troponin (p >0.05) for the outcome of 180-day mortalityDiscussion:This nationwide study of patients presenting with AMI, revealed that co-morbidities substantially influenced systemic concentrations of cTn; however the presence of comorbidity alone, irrespective of peak cTn, was the major determinant of mortality. Major findingsThe major findings of our study could be summarized as follows – 1) In patients presenting with AMI and COPD, previous angina, previous MI or CHF, peak cTn levels were significantly lower compared to patients without the respective co-morbidity, with similar trends regardless of cTn assays (i.e. peak cTnT and cTnI) or AMI presentation (STEMI and NSTEMI). Results for hsTnT, although limited by the small sample size, revealed similar trends. 2) Among the comorbidities analysed, the quantum of change in cTnT was highest for patients with CKD (42% higher) as compared to those without CKD. 3) There was a significant impact of CKD severity (GFR<45ml/min/1.73m2) on the degree of cTn elevation. 4) All co-morbidities were associated with an increased risk of mortality in AMI, which was not altered after adjusting for peak cTn with the exception of DM. 5) CTnI had a stronger association with mortality than cTnT for most of the co-morbidities analysed. i) Chronic kidney disease The interpretation of cTn in the setting of CKD can be challenging, as patients with CKD can have elevated cTn levels even in the absence of ischemia. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8SWNbKBq","properties":{"formattedCitation":"\\super 9,17\\nosupersub{}","plainCitation":"9,17","dontUpdate":true,"noteIndex":0},"citationItems":[{"id":22,"uris":[""],"uri":[""],"itemData":{"id":22,"type":"article-journal","title":"Cardiac troponins in renal insufficiency: review and clinical implications","container-title":"Journal of the American College of Cardiology","page":"2065-2071","volume":"40","issue":"12","source":"PubMed","abstract":"Patients with renal insufficiency may have increased serum troponins even in the absence of clinically suspected acute myocardial ischemia. While cardiovascular disease is the most common cause of death in patients with renal failure, we are just beginning to understand the clinical meaning of serum troponin elevations. Serum troponin T is increased more frequently than troponin I in patients with renal failure, leading clinicians to question its specificity for the diagnosis of myocardial infarction. Many large-scale trials demonstrating the utility of serum troponins in predicting adverse events and in guiding therapy and intervention in acute coronary syndromes have excluded patients with renal failure. Despite persistent uncertainty about the mechanism of elevated serum troponins in patients with reduced renal function, data from smaller groups of renal failure patients have suggested that troponin elevations are associated with added risk, including an increase in mortality. It is possible that increases in serum troponin from baseline in patients with renal insufficiency admitted to hospital with acute coronary syndrome may signify myocardial necrosis. Further studies are needed to clarify this hypothesis.","ISSN":"0735-1097","note":"PMID: 12505215","shortTitle":"Cardiac troponins in renal insufficiency","journalAbbreviation":"J. Am. Coll. Cardiol.","language":"eng","author":[{"family":"Freda","given":"Benjamin J."},{"family":"Tang","given":"W. H. Wilson"},{"family":"Van Lente","given":"Frederick"},{"family":"Peacock","given":"W. Franklin"},{"family":"Francis","given":"Gary S."}],"issued":{"date-parts":[["2002",12,18]]}}},{"id":98,"uris":[""],"uri":[""],"itemData":{"id":98,"type":"article-journal","title":"Long-term prognosis after myocardial infarction in patients with previous coronary artery bypass surgery","container-title":"Journal of the American College of Cardiology","page":"873-880","volume":"12","issue":"4","source":"PubMed","abstract":"A group of 205 patients hospitalized with myocardial infarction 2 to 162 months (mean 66) after bypass surgery and 205 control patients with myocardial infarction were compared and followed up for 34 +/- 25 months after hospital discharge. At baseline the postbypass group contained more men (p less than 0.03) and more patients with previous myocardial infarction (p less than 0.06), but the groups were otherwise comparable. Indexes of infarct size were lower in postbypass patients: sum of ST elevation, QRS score, peak serum creatine kinase (CK) (1,115 +/- 994 versus 1,780 +/- 1,647 IU/liter) and peak MB CK (all p less than or equal to 0.001). Postmyocardial infarction ejection fraction was 45 +/- 15% in the postbypass group and 43 +/- 15% in the control group (p = NS); in-hospital mortality rate was 4 and 5%, respectively (p = NS). When patent grafts were taken into account, the two groups were comparable in extent of coronary artery disease. At 5 years after discharge, cumulative mortality was similar in the postbypass and control groups (30 versus 25%, respectively, p = NS). However, postbypass patients had more reinfarctions (40 versus 23%, p = 0.007), more admissions for unstable angina (23 versus 18%, p = 0.04) and more revascularization procedures (34 versus 20%, p = 0.04) than did control patients. The total for these events at 5 years was 70% in the postbypass group and 49% in the control group (p = 0.001). Thus, although patients with previous bypass surgery who develop acute myocardial infarction have a smaller infarct, their subsequent survival is no better than that of other patients with acute myocardial infarction. They experience more reinfarctions and unstable angina. Previous bypass surgery is an important clinical marker for recurrent cardiac events after myocardial infarction.","ISSN":"0735-1097","note":"PMID: 3262130","journalAbbreviation":"J. Am. Coll. Cardiol.","language":"eng","author":[{"family":"Wiseman","given":"A."},{"family":"Waters","given":"D. D."},{"family":"Walling","given":"A."},{"family":"Pelletier","given":"G. B."},{"family":"Roy","given":"D."},{"family":"Théroux","given":"P."}],"issued":{"date-parts":[["1988",10]]}}}],"schema":""} 9, 17 The AMI cut-off based on a healthy general population has been shown to be significantly lower than the receiver operating curve optimal cut-off for patients with CKD. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zg76RU1F","properties":{"formattedCitation":"\\super 36\\nosupersub{}","plainCitation":"36","noteIndex":0},"citationItems":[{"id":231,"uris":[""],"uri":[""],"itemData":{"id":231,"type":"article-journal","title":"Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction","container-title":"Circulation","page":"2041-2050","volume":"131","issue":"23","source":"PubMed","abstract":"BACKGROUND: It is unknown whether more sensitive cardiac troponin (cTn) assays maintain their clinical utility in patients with renal dysfunction. Moreover, their optimal cutoff levels in this vulnerable patient population have not previously been defined.\nMETHODS AND RESULTS: In this multicenter study, we examined the clinical utility of 7 more sensitive cTn assays (3 sensitive and 4 high-sensitivity cTn assays) in patients presenting with symptoms suggestive of acute myocardial infarction. Among 2813 unselected patients, 447 (16%) had renal dysfunction (defined as Modification of Diet in Renal Disease-estimated glomerular filtration rate <60 mL·min(-1)·1.73 m(-2)). The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography and serial levels of high-sensitivity cTnT. Acute myocardial infarction was the final diagnosis in 36% of all patients with renal dysfunction. Among patients with renal dysfunction and elevated baseline cTn levels (≥99th percentile), acute myocardial infarction was the most common diagnosis for all assays (range, 45%-80%). In patients with renal dysfunction, diagnostic accuracy at presentation, quantified by the area under the receiver-operator characteristic curve, was 0.87 to 0.89 with no significant differences between the 7 more sensitive cTn assays and further increased to 0.91 to 0.95 at 3 hours. Overall, the area under the receiver-operator characteristic curve in patients with renal dysfunction was only slightly lower than in patients with normal renal function. The optimal receiver-operator characteristic curve-derived cTn cutoff levels in patients with renal dysfunction were significantly higher compared with those in patients with normal renal function (factor, 1.9-3.4).\nCONCLUSIONS: More sensitive cTn assays maintain high diagnostic accuracy in patients with renal dysfunction. To ensure the best possible clinical use, assay-specific optimal cutoff levels, which are higher in patients with renal dysfunction, should be considered.\nCLINICAL TRIAL REGISTRATION: URL: . Unique identifier: NCT00470587.","DOI":"10.1161/CIRCULATIONAHA.114.014245","ISSN":"1524-4539","note":"PMID: 25948542\nPMCID: PMC4456169","journalAbbreviation":"Circulation","language":"eng","author":[{"family":"Twerenbold","given":"Raphael"},{"family":"Wildi","given":"Karin"},{"family":"Jaeger","given":"Cedric"},{"family":"Gimenez","given":"Maria Rubini"},{"family":"Reiter","given":"Miriam"},{"family":"Reichlin","given":"Tobias"},{"family":"Walukiewicz","given":"Astrid"},{"family":"Gugala","given":"Mathias"},{"family":"Krivoshei","given":"Lian"},{"family":"Marti","given":"Nadine"},{"family":"Moreno Weidmann","given":"Zoraida"},{"family":"Hillinger","given":"Petra"},{"family":"Puelacher","given":"Christian"},{"family":"Rentsch","given":"Katharina"},{"family":"Honegger","given":"Ursina"},{"family":"Schumacher","given":"Carmela"},{"family":"Zurbriggen","given":"Felicitas"},{"family":"Freese","given":"Michael"},{"family":"Stelzig","given":"Claudia"},{"family":"Campodarve","given":"Isabel"},{"family":"Bassetti","given":"Stefano"},{"family":"Osswald","given":"Stefan"},{"family":"Mueller","given":"Christian"}],"issued":{"date-parts":[["2015",6,9]]}}}],"schema":""} 36 Twerenbold et al showed that while the European Society of Cardiology (ESC) 0/1-hour algorithm (using hsTnT and hsTnI) had high sensitivity in patients with CKD, the specificity of rule-in and the overall efficacy of the ESC algorithm was substantially reduced. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"X6DycB9s","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":217,"uris":[""],"uri":[""],"itemData":{"id":217,"type":"article-journal","title":"0/1-Hour Triage Algorithm for Myocardial Infarction in Patients With Renal Dysfunction","container-title":"Circulation","page":"436-451","volume":"137","issue":"5","source":"PubMed","abstract":"BACKGROUND: The European Society of Cardiology recommends a 0/1-hour algorithm for rapid rule-out and rule-in of non-ST-segment elevation myocardial infarction using high-sensitivity cardiac troponin (hs-cTn) concentrations irrespective of renal function. Because patients with renal dysfunction (RD) frequently present with increased hs-cTn concentrations even in the absence of non-ST-segment elevation myocardial infarction, concern has been raised regarding the performance of the 0/1-hour algorithm in RD.\nMETHODS: In a prospective multicenter diagnostic study enrolling unselected patients presenting with suspected non-ST-segment elevation myocardial infarction to the emergency department, we assessed the diagnostic performance of the European Society of Cardiology 0/1-hour algorithm using hs-cTnT and hs-cTnI in patients with RD, defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2, and compared it to patients with normal renal function. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including cardiac imaging. Safety was quantified as sensitivity in the rule-out zone, accuracy as the specificity in the rule-in zone, and efficacy as the proportion of the overall cohort assigned to either rule-out or rule-in based on the 0- and 1-hour sample.\nRESULTS: Among 3254 patients, RD was present in 487 patients (15%). The prevalence of non-ST-segment elevation myocardial infarction was substantially higher in patients with RD compared with patients with normal renal function (31% versus 13%, P<0.001). Using hs-cTnT, patients with RD had comparable sensitivity of rule-out (100.0% [95% confidence interval {CI}, 97.6-100.0] versus 99.2% [95% CI, 97.6-99.8]; P=0.559), lower specificity of rule-in (88.7% [95% CI, 84.8-91.9] versus 96.5% [95% CI, 95.7-97.2]; P<0.001), and lower overall efficacy (51% versus 81%, P<0.001), mainly driven by a much lower percentage of patients eligible for rule-out (18% versus 68%, P<0.001) compared with patients with normal renal function. Using hs-cTnI, patients with RD had comparable sensitivity of rule-out (98.6% [95% CI, 95.0-99.8] versus 98.5% [95% CI, 96.5-99.5]; P=1.0), lower specificity of rule-in (84.4% [95% CI, 79.9-88.3] versus 91.7% [95% CI, 90.5-92.9]; P<0.001), and lower overall efficacy (54% versus 76%, P<0.001; proportion ruled out, 18% versus 58%, P<0.001) compared with patients with normal renal function.\nCONCLUSIONS: In patients with RD, the safety of the European Society of Cardiology 0/1-hour algorithm is high, but specificity of rule-in and overall efficacy are decreased. Modifications of the rule-in and rule-out thresholds did not improve the safety or overall efficacy of the 0/1-hour algorithm.\nCLINICAL TRIAL REGISTRATION: URL: . Unique identifier: NCT00470587.","DOI":"10.1161/CIRCULATIONAHA.117.028901","ISSN":"1524-4539","note":"PMID: 29101287\nPMCID: PMC5794234","journalAbbreviation":"Circulation","language":"eng","author":[{"family":"Twerenbold","given":"Raphael"},{"family":"Badertscher","given":"Patrick"},{"family":"Boeddinghaus","given":"Jasper"},{"family":"Nestelberger","given":"Thomas"},{"family":"Wildi","given":"Karin"},{"family":"Puelacher","given":"Christian"},{"family":"Sabti","given":"Zaid"},{"family":"Rubini Gimenez","given":"Maria"},{"family":"Tschirky","given":"Sandra"},{"family":"Fay de Lavallaz","given":"Jeanne","non-dropping-particle":"du"},{"family":"Kozhuharov","given":"Nikola"},{"family":"Sazgary","given":"Lorraine"},{"family":"Mueller","given":"Deborah"},{"family":"Breidthardt","given":"Tobias"},{"family":"Strebel","given":"Ivo"},{"family":"Flores Widmer","given":"Dayana"},{"family":"Shrestha","given":"Samyut"},{"family":"Miró","given":"?scar"},{"family":"Martín-Sánchez","given":"F. Javier"},{"family":"Morawiec","given":"Beata"},{"family":"Parenica","given":"Jiri"},{"family":"Geigy","given":"Nicolas"},{"family":"Keller","given":"Dagmar I."},{"family":"Rentsch","given":"Katharina"},{"family":"Eckardstein","given":"Arnold","non-dropping-particle":"von"},{"family":"Osswald","given":"Stefan"},{"family":"Reichlin","given":"Tobias"},{"family":"Mueller","given":"Christian"}],"issued":{"date-parts":[["2018",1,30]]}}}],"schema":""} 11 Multiple mechanisms have been postulated for the elevation of cTn and contrary to common belief, decreased renal clearance seems to be an implausible explanation, as cardiac troponins are high molecular weight compounds (37kDa), unlikely to be cleared by the kidneys. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kfY5vdEe","properties":{"formattedCitation":"\\super 37,38\\nosupersub{}","plainCitation":"37,38","noteIndex":0},"citationItems":[{"id":46,"uris":[""],"uri":[""],"itemData":{"id":46,"type":"article-journal","title":"Origin of Cardiac Troponin T Elevations in Chronic Kidney Disease","container-title":"Circulation","page":"1073-1075","volume":"136","issue":"11","source":"PubMed","DOI":"10.1161/CIRCULATIONAHA.117.029986","ISSN":"1524-4539","note":"PMID: 28893963","journalAbbreviation":"Circulation","language":"eng","author":[{"family":"Linden","given":"Noreen","non-dropping-particle":"van der"},{"family":"Cornelis","given":"Tom"},{"family":"Kimenai","given":"Dorien M."},{"family":"Klinkenberg","given":"Lieke J. J."},{"family":"Hilderink","given":"Judith M."},{"family":"Lück","given":"Sarah"},{"family":"Litjens","given":"Elisabeth J. R."},{"family":"Peeters","given":"Frederique E. C. M."},{"family":"Streng","given":"Alexander S."},{"family":"Breidthardt","given":"Tobias"},{"family":"Loon","given":"Luc J. C.","non-dropping-particle":"van"},{"family":"Bekers","given":"Otto"},{"family":"Kooman","given":"Jeroen P."},{"family":"Westermark","given":"P?l O."},{"family":"Mueller","given":"Christian"},{"family":"Meex","given":"Steven J. R."}],"issued":{"date-parts":[["2017",9,12]]}}},{"id":262,"uris":[""],"uri":[""],"itemData":{"id":262,"type":"article-journal","title":"Clearance of cardiac troponin T with and without kidney function","container-title":"Clinical Biochemistry","page":"468-474","volume":"50","issue":"9","source":"PubMed","abstract":"OBJECTIVE: The extent of kidney-dependent clearance of the cardiac damage biomarker cardiac troponin T (cTnT) is not known.\nMETHODS AND RESULTS: We examined clearance of cTnT after injection of heart extracts in rats with or without clamped kidney vessels. The extent of degradation of cTnT to fragments able to pass the glomerular membrane and the kidney extraction index of cTnT was examined in human subjects. After a bolus injection of rat cardiac extract, simulating a large myocardial infarction, there was no significant difference in clearance of cTnT with or without kidney function. However, a slower clearance was observed late in the clearance process, when cTnT levels were low. When low levels of rat cardiac extract were infused at a constant rate to steady state, clamping of the renal vessels resulted in significant 2-fold reduction in clearance of cTnT. Over 60% of the measured cTnT in human subjects had a molecular weight below 17kDa, expected to have a relatively free passage over the glomerular membrane. The extraction index of cTnT in three heart failure patients undergoing renal vein catheterization was 8-19%. Kidney function adjusted cTnT levels increased the area under the ROC curve for diagnosis of myocardial infarction of the cTnT analysis in an emergency room cohort.\nCONCLUSIONS: At high concentrations, often found after a large myocardial infarction, extrarenal clearance of cTnT dominates. At low levels of cTnT, often found in patients with stable cTnT elevations, renal clearance also contribute to the clearance of cTnT. This potentially explains why stable cTnT levels tend to be higher in patients with low kidney function.","DOI":"10.1016/j.clinbiochem.2017.02.007","ISSN":"1873-2933","note":"PMID: 28193484","journalAbbreviation":"Clin. Biochem.","language":"eng","author":[{"family":"Fridén","given":"Vincent"},{"family":"Starnberg","given":"Karin"},{"family":"Muslimovic","given":"Aida"},{"family":"Ricksten","given":"Sven-Erik"},{"family":"Bjurman","given":"Christian"},{"family":"Forsgard","given":"Niklas"},{"family":"Wickman","given":"Anna"},{"family":"Hammarsten","given":"Ola"}],"issued":{"date-parts":[["2017",6]]}}}],"schema":""} 37,38 Some of the other possible explanations are the presence of, increased left ventricular (LV) mass, left ventricular systolic dysfunction or subclinical CAD, resulting in increased membrane permeability and cTn leaks. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"W6vhjkkl","properties":{"formattedCitation":"\\super 39,40\\nosupersub{}","plainCitation":"39,40","noteIndex":0},"citationItems":[{"id":228,"uris":[""],"uri":[""],"itemData":{"id":228,"type":"article-journal","title":"Association of cardiac troponin T with left ventricular structure and function in CKD","container-title":"American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation","page":"701-709","volume":"61","issue":"5","source":"PubMed","abstract":"BACKGROUND: Serum cardiac troponin T (cTnT) is associated with increased risk of heart failure and cardiovascular death in several population settings. We evaluated associations of cTnT levels with cardiac structural and functional abnormalities in a cohort of patients with chronic kidney disease (CKD) without heart failure.\nSTUDY DESIGN: Cross-sectional.\nSETTING & PARTICIPANTS: Chronic Renal Insufficiency Cohort (CRIC; N=3,243).\nPREDICTOR: The primary predictor was cTnT level. Secondary predictors included demographic and clinical characteristics, hemoglobin level, high-sensitivity C-reactive protein level, and estimated glomerular filtration rate using cystatin C.\nOUTCOMES: Echocardiography was used to determine left ventricular (LV) mass and LV systolic and diastolic function.\nMEASUREMENTS: Circulating cTnT was measured in stored sera using the highly sensitive assay. Logistic and linear regression models were used to examine associations of cTnT level with each echocardiographic outcome.\nRESULTS: cTnT was detectable in 2,735 (84%) persons; median level was 13.3 (IQR, 7.7-23.8) pg/mL. Compared with undetectable cTnT (<3.0 pg/mL), the highest quartile (23.9-738.7 pg/mL) was approximately 2 times as likely to have LV hypertrophy (OR, 2.43; 95% CI, 1.44-4.09) in the fully adjusted model. cTnT level had a more modest association with LV systolic dysfunction; as a log-linear variable, a significant association was present in the fully adjusted model (OR of 1.4 [95% CI, 1.2-1.7] per 1-log unit; P < 0.001). There was no significant independent association between cTnT level and LV diastolic dysfunction. When evaluated as a screening test, cTnT level functioned only modestly for LV hypertrophy and concentric hypertrophy detection (area under the curve, 0.64 for both), with weaker areas under the curve for the other outcomes.\nLIMITATIONS: The presence of coronary artery disease was not formally assessed using either noninvasive or angiographic techniques in this study.\nCONCLUSIONS: In this large CKD cohort without heart failure, detectable cTnT had a strong association with LV hypertrophy, a more modest association with LV systolic dysfunction, and no association with diastolic dysfunction. These findings indicate that circulating cTnT levels in patients with CKD are predominantly an indicator of pathologic LV hypertrophy.","DOI":"10.1053/j.ajkd.2012.11.034","ISSN":"1523-6838","note":"PMID: 23291148\nPMCID: PMC3627820","journalAbbreviation":"Am. J. Kidney Dis.","language":"eng","author":[{"family":"Mishra","given":"Rakesh K."},{"family":"Li","given":"Yongmei"},{"family":"DeFilippi","given":"Christopher"},{"family":"Fischer","given":"Michael J."},{"family":"Yang","given":"Wei"},{"family":"Keane","given":"Martin"},{"family":"Chen","given":"Jing"},{"family":"He","given":"Jiang"},{"family":"Kallem","given":"Radhakrishna"},{"family":"Horwitz","given":"Edward J."},{"family":"Rafey","given":"Mohammad"},{"family":"Raj","given":"Dominic S."},{"family":"Go","given":"Alan S."},{"family":"Shlipak","given":"Michael G."},{"literal":"CRIC Study Investigators"}],"issued":{"date-parts":[["2013",5]]}}},{"id":245,"uris":[""],"uri":[""],"itemData":{"id":245,"type":"article-journal","title":"Use and interpretation of high sensitivity cardiac troponins in patients with chronic kidney disease with and without acute myocardial infarction","container-title":"Clinical Biochemistry","page":"247-253","volume":"48","issue":"4-5","source":"PubMed","abstract":"It is well known that the population with chronic kidney disease (CKD) is at greater risk for cardiovascular disease and death than the general population. The use and interpretation of high sensitivity cardiac troponin (hs-cTn) assays have been particularly challenging in these patients with the majority having elevated levels at baseline. The diagnostic accuracy of acute myocardial infarction (AMI) may be decreased in patients with CKD when using these newer troponins. In order to improve the sensitivity and specificity for the diagnosis of AMI, one must look at the change in cTn and consider using higher cut-off values. In asymptomatic patients with CKD, research has shown increased prevalence of cardiovascular risk factors and underlying structural heart disease with increasing cTn levels. Prognostically, elevated cTn has been associated with adverse outcomes including incident heart failure and cardiovascular mortality. The purpose of the review is to evaluate hs-cTn in patients with CKD for the diagnosis of AMI and for the prognostic significance of elevated levels in CKD patients without AMI. Although the underlying etiology of persistently elevated cTn in the CKD population remains unclear, the review will also evaluate studies attempting to explain whether the source of cTn is from increased cardiac production versus decreased renal clearance. Further longitudinal studies are required in order to bridge the gap between the prognostic importance of elevated cTn and clinical management to prevent symptomatic cardiac disease.","DOI":"10.1016/j.clinbiochem.2015.01.004","ISSN":"1873-2933","note":"PMID: 25617663","journalAbbreviation":"Clin. Biochem.","language":"eng","author":[{"family":"Parikh","given":"Ravi H."},{"family":"Seliger","given":"Stephen L."},{"family":"deFilippi","given":"Christopher R."}],"issued":{"date-parts":[["2015",3]]}}}],"schema":""} 39,40 To our knowledge, our study is the first to report the quantum of cTn elevation in patients with CKD, impact of severity of CKD on cTn elevation and its prognostic relevance after accounting for important confounders including HF and type of MI. ii) Chronic Heart FailureOur analysis demonstrated that while patients with HF had substantially lower adjusted peak cTn levels than those without HF, the presence of HF was associated with a higher mortality. This was corroborated with the spline analysis, which revealed a ceiling effect in prognostic value for both cTnT and cTnI in patients with CHF (Figures 4C and 5C). The lower peak cTn and high mortality in this group could be due to a multitude of reasons including the possibility that patients ischemic cardiomyopathy may have reduced viable myocardium. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KetE4hhZ","properties":{"formattedCitation":"\\super 41,42\\nosupersub{}","plainCitation":"41,42","noteIndex":0},"citationItems":[{"id":52,"uris":[""],"uri":[""],"itemData":{"id":52,"type":"article-journal","title":"Coronary-Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy","container-title":"The New England Journal of Medicine","page":"1511-1520","volume":"374","issue":"16","source":"PubMed","abstract":"BACKGROUND: The survival benefit of a strategy of coronary-artery bypass grafting (CABG) added to guideline-directed medical therapy, as compared with medical therapy alone, in patients with coronary artery disease, heart failure, and severe left ventricular systolic dysfunction remains unclear.\nMETHODS: From July 2002 to May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to undergo CABG plus medical therapy (CABG group, 610 patients) or medical therapy alone (medical-therapy group, 602 patients). The primary outcome was death from any cause. Major secondary outcomes included death from cardiovascular causes and death from any cause or hospitalization for cardiovascular causes. The median duration of follow-up, including the current extended-follow-up study, was 9.8 years.\nRESULTS: A primary outcome event occurred in 359 patients (58.9%) in the CABG group and in 398 patients (66.1%) in the medical-therapy group (hazard ratio with CABG vs. medical therapy, 0.84; 95% confidence interval [CI], 0.73 to 0.97; P=0.02 by log-rank test). A total of 247 patients (40.5%) in the CABG group and 297 patients (49.3%) in the medical-therapy group died from cardiovascular causes (hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006 by log-rank test). Death from any cause or hospitalization for cardiovascular causes occurred in 467 patients (76.6%) in the CABG group and in 524 patients (87.0%) in the medical-therapy group (hazard ratio, 0.72; 95% CI, 0.64 to 0.82; P<0.001 by log-rank test).\nCONCLUSIONS: In a cohort of patients with ischemic cardiomyopathy, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower over 10 years among patients who underwent CABG in addition to receiving medical therapy than among those who received medical therapy alone. (Funded by the National Institutes of Health; STICH [and STICHES] number, NCT00023595.).","DOI":"10.1056/NEJMoa1602001","ISSN":"1533-4406","note":"PMID: 27040723\nPMCID: PMC4938005","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Velazquez","given":"Eric J."},{"family":"Lee","given":"Kerry L."},{"family":"Jones","given":"Robert H."},{"family":"Al-Khalidi","given":"Hussein R."},{"family":"Hill","given":"James A."},{"family":"Panza","given":"Julio A."},{"family":"Michler","given":"Robert E."},{"family":"Bonow","given":"Robert O."},{"family":"Doenst","given":"Torsten"},{"family":"Petrie","given":"Mark C."},{"family":"Oh","given":"Jae K."},{"family":"She","given":"Lilin"},{"family":"Moore","given":"Vanessa L."},{"family":"Desvigne-Nickens","given":"Patrice"},{"family":"Sopko","given":"George"},{"family":"Rouleau","given":"Jean L."},{"literal":"STICHES Investigators"}],"issued":{"date-parts":[["2016",4,21]]}}},{"id":48,"uris":[""],"uri":[""],"itemData":{"id":48,"type":"article-journal","title":"Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals","container-title":"Lancet (London, England)","page":"572-580","volume":"391","issue":"10120","source":"PubMed","abstract":"BACKGROUND: Large-scale and contemporary population-based studies of heart failure incidence are needed to inform resource planning and research prioritisation but current evidence is scarce. We aimed to assess temporal trends in incidence and prevalence of heart failure in a large general population cohort from the UK, between 2002 and 2014.\nMETHODS: For this population-based study, we used linked primary and secondary electronic health records of 4 million individuals from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex. Eligible patients were aged 16 years and older, had contributed data between Jan 1, 2002, and Dec 31, 2014, had an acceptable record according to CPRD quality control, were approved for CPRD and Hospital Episodes Statistics linkage, and were registered with their general practice for at least 12 months. For patients with incident heart failure, we extracted the most recent measurement of baseline characteristics (within 2 years of diagnosis) from electronic health records, as well as information about comorbidities, socioeconomic status, ethnicity, and region. We calculated standardised rates by applying direct age and sex standardisation to the 2013 European Standard Population, and we inferred crude rates by applying year-specific, age-specific, and sex-specific incidence to UK census mid-year population estimates. We assumed no heart failure for patients aged 15 years or younger and report total incidence and prevalence for all ages (>0 years).\nFINDINGS: From 2002 to 2014, heart failure incidence (standardised by age and sex) decreased, similarly for men and women, by 7% (from 358 to 332 per 100?000 person-years; adjusted incidence ratio 0·93, 95% CI 0·91-0·94). However, the estimated absolute number of individuals with newly diagnosed heart failure in the UK increased by 12% (from 170?727 in 2002 to 190?798 in 2014), largely due to an increase in population size and age. The estimated absolute number of prevalent heart failure cases in the UK increased even more, by 23% (from 750?127 to 920?616). Over the study period, patient age and multi-morbidity at first presentation of heart failure increased (mean age 76·5 years [SD 12·0] to 77·0 years [12·9], adjusted difference 0·79 years, 95% CI 0·37-1·20; mean number of comorbidities 3·4 [SD 1·9] vs 5·4 [2·5]; adjusted difference 2·0, 95% CI 1·9-2·1). Socioeconomically deprived individuals were more likely to develop heart failure than were affluent individuals (incidence rate ratio 1·61, 95% CI 1·58-1·64), and did so earlier in life than those from the most affluent group (adjusted difference -3·51 years, 95% CI -3·77 to -3·25). From 2002 to 2014, the socioeconomic gradient in age at first presentation with heart failure widened. Socioeconomically deprived individuals also had more comorbidities, despite their younger age.\nINTERPRETATION: Despite a moderate decline in standardised incidence of heart failure, the burden of heart failure in the UK is increasing, and is now similar to the four most common causes of cancer combined. The observed socioeconomic disparities in disease incidence and age at onset within the same nation point to a potentially preventable nature of heart failure that still needs to be tackled.\nFUNDING: British Heart Foundation and National Institute for Health Research.","DOI":"10.1016/S0140-6736(17)32520-5","ISSN":"1474-547X","note":"PMID: 29174292\nPMCID: PMC5814791","shortTitle":"Temporal trends and patterns in heart failure incidence","journalAbbreviation":"Lancet","language":"eng","author":[{"family":"Conrad","given":"Nathalie"},{"family":"Judge","given":"Andrew"},{"family":"Tran","given":"Jenny"},{"family":"Mohseni","given":"Hamid"},{"family":"Hedgecott","given":"Deborah"},{"family":"Crespillo","given":"Abel Perez"},{"family":"Allison","given":"Moira"},{"family":"Hemingway","given":"Harry"},{"family":"Cleland","given":"John G."},{"family":"McMurray","given":"John J. V."},{"family":"Rahimi","given":"Kazem"}],"issued":{"date-parts":[["2018"]],"season":"10"}}}],"schema":""} 41,42 Poor myocardial reserve in this group of patients might therefore help explain high mortality with smaller infarct size based on lower peak cTn. Endogenous protective mechanisms following ischemia/reperfusion injury could be attenuated in patients with ventricular remodelling or clinical HF. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mhQsmKob","properties":{"formattedCitation":"\\super 43\\nosupersub{}","plainCitation":"43","noteIndex":0},"citationItems":[{"id":54,"uris":[""],"uri":[""],"itemData":{"id":54,"type":"article-journal","title":"Heart failure is associated with exaggerated endothelial ischaemia-reperfusion injury and attenuated effect of ischaemic preconditioning","container-title":"European Journal of Preventive Cardiology","page":"33-40","volume":"23","issue":"1","source":"PubMed","abstract":"BACKGROUND: Reperfusion is mandatory after ischaemia, but it also triggers ischaemia-reperfusion (IR)-injury. It is currently unknown whether heart failure alters the magnitude of IR-injury. Ischaemic preconditioning can limit IR-injury. Since ischaemic preconditioning is typically applied in subjects at risk for cardiovascular complications, it is of clinical importance to understand its efficacy in heart failure patients.\nOBJECTIVE: To examine the magnitude of endothelial IR-injury, and the ability of ischaemic preconditioning to protect against endothelial IR-injury in heart failure.\nMETHODS: We included 15 subjects with heart failure (67?±?10 years, New York Heart Association class II/III) and 15 healthy, age- and sex-matched controls (65?±?9 years). We examined brachial artery endothelial function using flow-mediated dilation before and after arm IR (induced by 5-min ischaemic handgrip exercise +15?min reperfusion). IR was preceded by ischaemic preconditioning (consisting in three cycles of 5-min upper arm cuff inflation to 220?mmHg) or no inflation.\nRESULTS: A significant interaction-effect was found for the change in flow-mediated dilation after IR between groups (two-way ANOVA interaction-effect: p?=?0.01). Whilst post-hoc analysis revealed a significantly decline in flow-mediated dilation in both groups (p?<?0.05), the decline in flow-mediated dilation in heart failure patients (6.2?±?3.6% to 3.3?±?1.8%) was significantly larger than that observed in controls (4.9?±?2.1 to 4.1?±?2.0). Neither in heart failure patients nor controls was the decrease in flow-mediated dilation after IR altered by ischaemic preconditioning (three-way ANOVA interaction: p?=?0.87).\nCONCLUSION: We found that patients with heart failure are associated with exaggerated endothelial IR-injury compared with age- and sex-matched, healthy controls, which may contribute to the poor clinical prognosis in heart failure. Furthermore, we found no protective effect of ischaemic preconditioning (3?×?5-min forearm ischaemia) against endothelial IR-injury in heart failure patients.","DOI":"10.1177/2047487314558377","ISSN":"2047-4881","note":"PMID: 25389072","journalAbbreviation":"Eur J Prev Cardiol","language":"eng","author":[{"family":"Seeger","given":"Joost P. H."},{"family":"Benda","given":"Nathalie M. M."},{"family":"Riksen","given":"Niels P."},{"family":"Dijk","given":"Arie P. J.","non-dropping-particle":"van"},{"family":"Bellersen","given":"Louise"},{"family":"Hopman","given":"Maria T. E."},{"family":"Cable","given":"N. Timothy"},{"family":"Thijssen","given":"Dick H. J."}],"issued":{"date-parts":[["2016",1]]}}}],"schema":""} 43 Morphological and biological alterations in HF can impact the signal transduction cascade of pre and post–conditioning cardio protection, resulting in increased mortality despite smaller initial infarct size. 35 Finally in ischemic cardiomyopathy, even minor infarcts could result in ventricular premature contractions. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"HLbgqsrC","properties":{"formattedCitation":"\\super 44\\nosupersub{}","plainCitation":"44","noteIndex":0},"citationItems":[{"id":67,"uris":[""],"uri":[""],"itemData":{"id":67,"type":"article-journal","title":"Focal mechanisms underlying ventricular tachycardia during prolonged ischemic cardiomyopathy","container-title":"Circulation","page":"1441-1458","volume":"90","issue":"3","source":"PubMed","abstract":"BACKGROUND: The present study was performed to define the mechanisms underlying spontaneously occurring ventricular arrhythmias in the failing heart.\nMETHODS AND RESULTS: Three-dimensional cardiac mapping from as many as 232 intramural sites was performed in five dogs with ischemic cardiomyopathy induced by multiple intracoronary embolizations. After 5 to 10 weekly embolizations with 90-microns latex microspheres into the left anterior and circumflex coronary arteries, left ventricular ejection fraction decreased from 63 +/- 3% to 22 +/- 3%. Subsequent weekly Holter monitoring of dogs in the conscious state demonstrated frequent multiform premature ventricular complexes (PVCs) (< or = 2000/d), couplets, and runs of ventricular tachycardia (VT) (< or = 70 beats in duration and < or = 560 beats per minute) in all dogs. Three-dimensional mapping of spontaneous rhythm for 60 minutes was performed an average of 6.4 weeks after the last embolization, during which time each dog demonstrated multiform PVCs, couplets, and runs of nonsustained VT at rates comparable to those in the conscious state. Mapping was of sufficient density to define the mechanism for 31 PVCs, 45 beats of ventricular couplets, and 99 beats of VT. Sinus beats preceding PVCs (n = 36) initiated in the septum and spread rapidly with a total activation time (46 +/- 1 milliseconds) that did not differ from that of sinus beats not preceding PVCs or VT (46 +/- 2 milliseconds, n = 10, P = .69). PVCs and the first beat of couplets or VT were initiated primarily in the subendocardium by a focal mechanism, based on the lack of intervening electrical activity between the termination of the preceding (sinus) beat and initiation of the ectopic beat (225 +/- 23 milliseconds), despite the presence of multiple intervening intramural recording sites. All subsequent beats of VT also were initiated by a focal mechanism, and their total activation time (89 +/- 1 milliseconds) did not differ from that of the initiating ectopic beats (86 +/- 2 milliseconds, P = .14), despite acceleration of VT to a cycle length of 200 milliseconds. Monomorphic VT was due to repetitive focal activation of subendocardial sites. Polymorphic VT was due to sequential focal activation from multiple sites arising in the subendocardium and, at times, in the subepicardium. Comparison of mapping data with results of detailed anatomic analysis of tissue demonstrated that focal sites of initiation exhibited patchy nontransmural fibrosis. Functional conduction delay of a moderate degree was evident only when fibrosis extended transmurally.\nCONCLUSIONS: Spontaneously occurring PVCs, couplets, and VT in a model of ischemic cardiomyopathy are initiated and maintained by focal mechanisms with no evidence of macroreentry. Thus, therapeutic regimens to treat or prevent VT in the presence of ischemic cardiomyopathy will likely require interruption of these focal mechanisms.","ISSN":"0009-7322","note":"PMID: 7522134","journalAbbreviation":"Circulation","language":"eng","author":[{"family":"Pogwizd","given":"S. M."}],"issued":{"date-parts":[["1994",9]]}}}],"schema":""} 44iii) COPD, Previous MI and previous anginaIn patients with COPD and heightened cardiovascular risk, plasma cTnI concentrations have been shown to be a major predictor of future cardiovascular events and cardiovascular death; ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"llqOwIOQ","properties":{"formattedCitation":"\\super 45\\nosupersub{}","plainCitation":"45","noteIndex":0},"citationItems":[{"id":234,"uris":[""],"uri":[""],"itemData":{"id":234,"type":"article-journal","title":"Cardiac Troponin I and Cardiovascular Risk in Patients With Chronic Obstructive Pulmonary?Disease","container-title":"Journal of the American College of Cardiology","page":"1126-1137","volume":"72","issue":"10","source":"PubMed","abstract":"BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have increased risk of cardiovascular events.\nOBJECTIVES: This study evaluated the association between high-sensitivity cardiac troponin I concentration and cardiovascular events in patients with COPD and heightened cardiovascular risk.\nMETHODS: In a double-blind randomized controlled trial, 16,485 patients with COPD and cardiovascular disease or risk?factors were randomized to once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or their combination. Plasma high-sensitivity cardiac troponin I concentrations were measured in a subgroup of 1,599 patients. Outcomes were on-treatment cardiovascular events and COPD exacerbations over a median of 18?months, and cardiovascular death over a median of 27?months.\nRESULTS: Baseline plasma cardiac troponin I concentrations were above the limit of detection (1.2?ng/l) in 1,542 (96%)?patients. Concentrations were unaffected by inhaled therapies at 3?months (p > 0.05). Compared with the lowest?quintile (cardiac troponin?<2.3?ng/l), patients in the highest quintile (≥7.7?ng/l) were at greater risk of cardiovascular events (hazard ratio [HR] 3.7; 95% confidence interval [CI]: 1.3 to 10.1; p?=?0.012) and cardiovascular death (HR: 20.1; 95% CI: 2.4 to 165.2; p?=?0.005) after adjustment for risk factors. By contrast, there were no differences in exacerbations between quintiles (HR: 1.1; 95% CI: 0.8 to 1.5; p?=?0.548).\nCONCLUSIONS: In patients with COPD and heightened cardiovascular risk, plasma cardiac troponin I concentrations are?a?specific and major indicator of future cardiovascular events and cardiovascular death. Inhaled therapies did not?affect cardiac troponin I concentrations consistent with their neutral effect on mortality and cardiovascular outcomes. (Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary?Disease?[SUMMIT]; NCT01313676).","DOI":"10.1016/j.jacc.2018.06.051","ISSN":"1558-3597","note":"PMID: 30165984\nPMCID: PMC6119211","journalAbbreviation":"J. Am. Coll. Cardiol.","language":"eng","author":[{"family":"Adamson","given":"Philip D."},{"family":"Anderson","given":"Julie A."},{"family":"Brook","given":"Robert D."},{"family":"Calverley","given":"Peter M. A."},{"family":"Celli","given":"Bartolome R."},{"family":"Cowans","given":"Nicholas J."},{"family":"Crim","given":"Courtney"},{"family":"Dixon","given":"Ian J."},{"family":"Martinez","given":"Fernando J."},{"family":"Newby","given":"David E."},{"family":"Vestbo","given":"J?rgen"},{"family":"Yates","given":"Julie C."},{"family":"Mills","given":"Nicholas L."}],"issued":{"date-parts":[["2018",9,4]]}}}],"schema":""} 45 however, the diagnostic and prognostic accuracy of cTn in COPD patients with AMI have not been established. We observed lower peak cTn levels in patients with COPD, angina and previous MI after adjusting for important confounders including smoking, age, CHF, HTN, DM, area of infarct and renal impairment. The lower peak cTn level among these patients may have arisen due to myriad reasons. Patients with prior CAD are more likely have been prescribed drugs for secondary prevention such as antiplatelet therapy, statins and angiotensin converting enzyme inhibitors which could have influenced the infarct size. The phenomenon of ischemic pre-conditioning may be an innate protective physiological mechanism for lower cTn peak among COPD, previous MI and angina co-morbidities. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"P9Ac0M4p","properties":{"formattedCitation":"\\super 46\\nosupersub{}","plainCitation":"46","noteIndex":0},"citationItems":[{"id":93,"uris":[""],"uri":[""],"itemData":{"id":93,"type":"article-journal","title":"Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning","container-title":"Pharmacological Reviews","page":"1142-1174","volume":"66","issue":"4","source":"PubMed","abstract":"Pre-, post-, and remote conditioning of the myocardium are well described adaptive responses that markedly enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and provide therapeutic paradigms for cardioprotection. Nevertheless, more than 25 years after the discovery of ischemic preconditioning, we still do not have established cardioprotective drugs on the market. Most experimental studies on cardioprotection are still undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of cardiovascular risk factors. However, ischemic heart disease in humans is a complex disorder caused by, or associated with, cardiovascular risk factors and comorbidities, including hypertension, hyperlipidemia, diabetes, insulin resistance, heart failure, altered coronary circulation, and aging. These risk factors induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury per se and responses to cardioprotective interventions. Moreover, some of the medications used to treat these risk factors, including statins, nitrates, and antidiabetic drugs, may impact cardioprotection by modifying cellular signaling. The aim of this article is to review the recent evidence that cardiovascular risk factors and their medication may modify the response to cardioprotective interventions. We emphasize the critical need to take into account the presence of cardiovascular risk factors and concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple risk factors.","DOI":"10.1124/pr.113.008300","ISSN":"1521-0081","note":"PMID: 25261534","journalAbbreviation":"Pharmacol. Rev.","language":"eng","author":[{"family":"Ferdinandy","given":"Péter"},{"family":"Hausenloy","given":"Derek J."},{"family":"Heusch","given":"Gerd"},{"family":"Baxter","given":"Gary F."},{"family":"Schulz","given":"Rainer"}],"issued":{"date-parts":[["2014",10]]}}}],"schema":""} 46 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bdXBR63w","properties":{"formattedCitation":"\\super 47\\nosupersub{}","plainCitation":"47","noteIndex":0},"citationItems":[{"id":71,"uris":[""],"uri":[""],"itemData":{"id":71,"type":"article-journal","title":"Ischemic preconditioning in humans: models, mediators, and clinical relevance","container-title":"Circulation","page":"559-563","volume":"100","issue":"5","source":"PubMed","abstract":"Ischemic preconditioning, a powerful form of endogenous protection against myocardial infarction, has been demonstrated in several animal species and, recently, in isolated human cardiomyocytes. For both logistic and ethical reasons, no clinical study can meet the strict conditions of experimental studies on preconditioning with infarct size as the end-point. Nevertheless, the demonstration of adaptation to ischemia observed during in vitro studies on human atrial trabeculae, in patients in the setting of coronary bypass surgery, and in the setting of coronary angioplasty in the absence of collateral vessel recruitment strongly suggests that ischemic preconditioning occurs in humans. This notion is further supported by the observation that in these human models, the adaptation to ischemia is influenced by drugs acting on K(ATP) channels and on purinergic and alpha-adrenergic receptors, similar to what is observed in accepted experimental models of ischemic preconditioning. This important form of myocardial endogenous protection may also play a role in the warm-up phenomenon and in mediating the beneficial effects of preinfarction angina. The demonstration of ischemic preconditioning in humans and the identification of some of its mediators suggests that in patients at high risk for myocardial infarction, drugs known to block this endogenous form of protection should be used with caution, whereas drugs known to elicit preconditioning might have a relevant therapeutic role.","ISSN":"1524-4539","note":"PMID: 10430772","shortTitle":"Ischemic preconditioning in humans","journalAbbreviation":"Circulation","language":"eng","author":[{"family":"Tomai","given":"F."},{"family":"Crea","given":"F."},{"family":"Chiariello","given":"L."},{"family":"Gioffrè","given":"P. A."}],"issued":{"date-parts":[["1999",8,3]]}}}],"schema":""} 47 The chronic hypoxic state in patients with COPD may pre-condition the myocardium to become more resistant to future infarcts. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tGw9L4yB","properties":{"formattedCitation":"\\super 48,49\\nosupersub{}","plainCitation":"48,49","noteIndex":0},"citationItems":[{"id":73,"uris":[""],"uri":[""],"itemData":{"id":73,"type":"article-journal","title":"Chronic obstructive pulmonary disease","container-title":"The New England Journal of Medicine","page":"269-280","volume":"343","issue":"4","source":"PubMed","DOI":"10.1056/NEJM200007273430407","ISSN":"0028-4793","note":"PMID: 10911010","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Barnes","given":"P. J."}],"issued":{"date-parts":[["2000",7,27]]}}},{"id":75,"uris":[""],"uri":[""],"itemData":{"id":75,"type":"article-journal","title":"Raised troponin in COPD: clinical implications and possible mechanisms","container-title":"Heart (British Cardiac Society)","page":"71-72","volume":"99","issue":"2","source":"PubMed","DOI":"10.1136/heartjnl-2012-302969","ISSN":"1468-201X","note":"PMID: 23184012","shortTitle":"Raised troponin in COPD","journalAbbreviation":"Heart","language":"eng","author":[{"family":"Stone","given":"Ian S."},{"family":"Petersen","given":"Steffen E."},{"family":"Barnes","given":"Neil C."}],"issued":{"date-parts":[["2013",1]]}}}],"schema":""} 48,49 This may explain why COPD patients do not have an equivalent high peak cTn level as compared to patients without COPD. Ischemic pre-conditioning still remains a topic for considerable future research on its role in MI amongst COPD patients and its potential use in clinical practice. Clinical implicationsThe results of this study has important clinical implications. It is well established that in patients with NSTEMI, implementation of guideline-recommended treatment in real world depends on the extent of cTn elevation i.e., patients with intermediate to major elevations are more likely to receive guideline directed therapy as compared to those with minor cTn elevations. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"adJXB0Es","properties":{"formattedCitation":"\\super 17\\nosupersub{}","plainCitation":"17","noteIndex":0},"citationItems":[{"id":86,"uris":[""],"uri":[""],"itemData":{"id":86,"type":"article-journal","title":"Relationship between risk stratification by cardiac troponin level and adherence to guidelines for non-ST-segment elevation acute coronary syndromes","container-title":"Archives of Internal Medicine","page":"1870-1876","volume":"165","issue":"16","source":"PubMed","abstract":"BACKGROUND: The threshold of troponin elevation that stimulates changes in clinical decision making for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACSs) has not been previously evaluated.\nMETHODS: A total of 23 298 patients with NSTE ACSs from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) initiative were separated into categories of maximum troponin ratios (ratio of the highest recorded troponin value in the first 24 hours to the local laboratory troponin assay upper limit of normalization [ULN]).\nRESULTS: Unadjusted rates of in-hospital mortality increased from the group with troponin levels below the reference limit (maximum troponin ratio 0-1 x ULN; n = 5291) to those with minor (1-2 x ULN; n = 2499), intermediate (2-5 x ULN; n = 3825), and major (>5 x ULN; n = 11 683) elevations (-2.8% vs 4.6% vs 4.7% vs 6.0%). The use of early (<24 hours) aspirin, heparin, glycoprotein IIb/IIIa inhibitors, and beta-blockers was similar for the group with troponin levels below the reference limit compared with those with minor troponin elevations, and greater use of medications was demonstrated in patients with intermediate and major troponin elevations. Use of cardiac catheterization and percutaneous coronary intervention was higher in patients with troponin levels below the reference limit compared with those with minor troponin elevations, and procedures were used most frequently in patients with major troponin elevations. Similar patterns of care were demonstrated after excluding patients with chronic renal insufficiency.\nCONCLUSIONS: Any degree of troponin elevation is associated with a higher risk of mortality for patients with NSTE ACSs, but guideline-recommended medical therapies are used more commonly only in patients with intermediate and major troponin elevations, whereas patients with troponin levels below the reference limit underwent invasive procedures more frequently than those with mild troponin elevations.","DOI":"10.1001/archinte.165.16.1870","ISSN":"0003-9926","note":"PMID: 16157831","journalAbbreviation":"Arch. Intern. Med.","language":"eng","author":[{"family":"Roe","given":"Matthew T."},{"family":"Peterson","given":"Eric D."},{"family":"Li","given":"Yun"},{"family":"Pollack","given":"Charles V."},{"family":"Christenson","given":"Robert H."},{"family":"Peacock","given":"W. Frank"},{"family":"Fesmire","given":"Francis M."},{"family":"Newby","given":"L. Kristin"},{"family":"Jesse","given":"Robert L."},{"family":"Hoekstra","given":"James W."},{"family":"Gibler","given":"W. Brian"},{"family":"Ohman","given":"E. Magnus"}],"issued":{"date-parts":[["2005",9,12]]}}}],"schema":""} 17 In contrast to generally held assumptions, our findings suggest that, AMI patients with specific co-morbidities and lower peak cTn levels may still have a poor prognosis. Clinicians should refrain from being reassured by lower peak cTn levels in patients with AMI (particularly NSTEMI) and concomitant HF, COPD, angina, or a previous MI. Conversely, a higher peak cTnT level may be less informative in the setting of CKD (Stage 3b and higher) where up to 40% of the elevation in cTnT may relate to the presence of CKD alone (or due to increased LV mass, subclinical CAD or subclinical LV systolic dysfunction), irrespective of AMI type or other relevant confounders. Limitations The diagnosis of acute coronary syndrome in the MINAP registry was made by the physician treating the patient using standard investigations, including clinical history, electrocardiogram and troponin. In a study performed by Herrett et al, only 50% of myocardial infarction’s reported in hospital episode statistics (nationwide in-hospital records in the UK) and Clinical Practice Research Registry- CPRD (Primary care records in the UK) were found to be included in the MINAP registry. Moreover, patients with AMI recorded in CPRD had about half the hazard of mortality (at 30 days) of patients with AMI recorded in the MINAP, indicating differences in case ascertainment between the registry, hospital admissions and primary care databases. We were not able to determine the impact of different combinations of comorbidities (multi-morbidity) on peak cTn using the data available, and further studies on comorbidity-to-comorbidity interactions are needed. The MINAP database did not have all the information we would have ideally included in the analysis such as socioeconomic status, results of structural imaging such as echocardiogram and timing of revascularisation. We were not able to conduct a complete analysis with the hsTnT assay alone due to small sample size (n=10,064). However, our analysis of hsTnT revealed that the magnitude and directionality of change in important co-morbidities such as chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) were similar to those of less sensitive cTnT (e.g., 40 to 50 % increase in adjusted peak values of hsTnT and regular cTnT in CKD, ~ 25% decrease in both hsTnT and cTnT in COPD, ~10-15% decrease in CHF). This is because the ratio of peak troponin for each comorbidity to those without the comorbidity is likely to be the same for both highly sensitive and less sensitive troponins. ConclusionIn this large nationwide analyses of patients presenting with AMI in the UK suggests that co-morbidities significantly affect peak cTn. Co-morbidities should be taken in to consideration while interpreting cTn in the setting of AMI, as the prognostication varies based on patient’s pre-existing co-morbid illness. AcknowledgementsThe extract from the MINAP database was provided through the MINAP Academic Group following peer review of our research proposal. We acknowledge all the hospitals in England and Wales for their contribution of data to MINAP. There are no competing interests and the authors have nothing to declare.References: ADDIN ZOTERO_BIBL {"uncited":[],"omitted":[],"custom":[]} CSL_BIBLIOGRAPHY 1. Makam AN, Nguyen OK. Use of Cardiac Biomarker Testing in the Emergency Department. JAMA Intern Med. 2015;175:67–75. 2. Parmacek MS, Solaro RJ. Biology of the troponin complex in cardiac myocytes. Prog Cardiovasc Dis. 2004;47:159–76. 3. 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