Different Causes of Death in Patients with Myocardial Infarction Type 1, Type 2, and Myocardial Injury.

BACKGROUND: Data outlining the mortality and the causes of death in patients with type 1 myocardial infarction, type 2 myocardial infarction, and those with myocardial injury are limited. METHODS: During a 1-year period from January 2010 to January 2011, all hospitalized patients who had cardiac troponin I measured on clinical indication were prospectively studied. Patients with at least one cardiac troponin I value >30 ng/L underwent case ascertainment and individual evaluation by an experienced adjudication committee. Patients were classified as having type 1 myocardial infarction, type 2 myocardial infarction, or myocardial injury according to the criteria of the universal definition of myocardial infarction. Follow-up was ensured until December 31, 2014. Data on mortality and causes of death were obtained from the Danish Civil Registration System and the Danish Register of Causes of Death. RESULTS: Overall, 3762 consecutive patients were followed for a mean of 3.2 years (interquartile range 1.3-3.6 years). All-cause mortality differed significantly among categories: Type 1 myocardial infarction 31.7%, type 2 myocardial infarction 62.2%, myocardial injury 58.7%, and 22.2% in patients with nonelevated troponin values (log-rank test; P < .0001). In patients with type 1 myocardial infarction, 61.3% died from cardiovascular causes, vs 42.6% in patients with type 2 myocardial infarction (P = .015) and 41.2% in those with myocardial injury (P < .0001). The overall mortality and the causes of death did not differ substantially between patients with type 2 myocardial infarction and those with myocardial injury. CONCLUSIONS: Patients with type 2 myocardial infarction and myocardial injury exhibit a significantly higher long-term mortality compared with patients with type 1 myocardial infarction . However, most patients with type 1 myocardial infarction die from cardiovascular causes in contrast to patients with type 2 myocardial infarction and myocardial injury, in whom noncardiovascular causes of death predominate.

Prognostic Impact of Myocardial Injury Related to Various Cardiac and Noncardiac Conditions.

BACKGROUND: Elevated cardiac troponins in clinical conditions other than myocardial infarction are well known. For such occurrences, the term "myocardial injury" has been proposed. The long-term outcome in patients with myocardial injury related to various cardiac and noncardiac clinical disorders is unknown. METHODS: During January 2010 to January 2011, we prospectively studied hospitalized patients who had cardiac troponin I measured on clinical indication. Patients with cardiac troponin I values >30 ng/L and no evidence of myocardial ischemia were diagnosed as having myocardial injury. Patients were classified into 5 categories of plausible related conditions: cardiac ischemic, cardiac nonischemic, noncardiac, multifactorial, or indeterminate. Follow-up was a minimum of 3 years, with all-cause mortality as the single end-point. RESULTS: A total of 3762 patients were considered, of whom 1089 (29%) had myocardial injury. The most common associated conditions were noncardiac (n = 346) or multifactorial (n = 359). Cardiac ischemic (n = 183) and cardiac nonischemic (n = 134) conditions occurred less frequently. After a median of 3.2 years, 645 patients (59%) had died. A multivariate Cox regression analysis showed no difference in mortality between patients with cardiac ischemic and cardiac nonischemic conditions (hazard ratio [HR] 0.75; 95% confidence interval [CI], 0.50-1.13; P = .2). Patients with noncardiac or multifactorial disorders, however, had significantly higher mortality than those with associated cardiac ischemic conditions (HR 1.39; 95% CI, 1.06-1.80; P = .02, and HR 1.94; 95% CI, 1.50-2.51; P <.001), respectively. CONCLUSIONS: In patients with myocardial injury, the most common associated conditions were noncardiac or multifactorial. Of notice, these patients had significantly higher long-term mortality when compared with those with associated cardiac conditions.

Clinical Characteristics and Outcomes of Patients with Myocardial Infarction, Myocardial Injury, and Nonelevated Troponins.

BACKGROUND: Cardiac troponins have emerged as the preferred biomarkers for detecting myocardial necrosis and diagnosing myocardial infarction. However, current cardiac troponin assays do not discriminate between ischemic and nonischemic causes of myocardial cell death. Thus, when an increased troponin value is encountered in the absence of obvious myocardial ischemia, a careful search for other clinical conditions is crucial. METHODS: In 2010 to 2011, we prospectively studied hospitalized patients who had cardiac troponin I measured on clinical indication. An acute myocardial infarction was diagnosed in cases of a cardiac troponin I increase or decrease pattern with at least 1 value >30 ng/L (99th percentile) together with myocardial ischemia. Myocardial injury was defined as cardiac troponin I values >30 ng/L, but without signs or symptoms indicating overt cardiac ischemia. Patients with peak values ≤30 ng/L were classified as nonelevated cardiac troponin I. Follow-up was at least 3 years with all-cause mortality as the sole clinical end point. RESULTS: A total of 3762 patients were included. Of these, 488 (13%) had acute myocardial infarction, 1089 (29%) had myocardial injury, and 2185 (58%) had nonelevated cardiac troponin I values. Patients with myocardial injury frequently presented with dyspnea, were older, and had more comorbidity than patients in the 2 other groups. During a median follow-up of 3.2 years, 1342 patients died. Mortality differed significantly between groups: 39% in those with myocardial infarction, 59% in those with myocardial injury, and 23% in those with nonelevated cardiac troponin I (log-rank test; P < .0001). No significant difference in mortality between patients with type 2 myocardial infarction and patients with myocardial injury was observed (63% and 59%, respectively). CONCLUSIONS: Patients with myocardial injury are older and have more comorbidity than those with acute myocardial infarction. Both groups exhibit a poorer prognosis than patients with nonelevated cardiac troponin I values. Of note, a very high long-term mortality is observed in patients with type 2 myocardial infarction and patients with myocardial injury.

Diagnosis of unstable angina pectoris has declined markedly with the advent of more sensitive troponin assays.

BACKGROUND: Since the arrival of the universal definition of myocardial infarction more sensitive troponin assays have been developed. How these occurrences have influenced the proportions and clinical features of the components of acute coronary syndrome have not been studied prospectively in unselected hospital patients. METHODS: During 2010 we evaluated all patients in whom cardiac troponin I had been measured at a single university hospital. The diagnosis of acute myocardial infarction (ST-elevation myocardial infarction [STEMI] or non-ST-elevation myocardial infarction [NSTEMI]) was established in cases of a rise and/or fall of cardiac troponin I together with cardiac ischemic features. Patients with unstable chest discomfort and cardiac troponin I values below the decision limit of myocardial infarction were diagnosed as having unstable angina pectoris. The definition of acute coronary syndrome included unstable angina pectoris, NSTEMI, and STEMI. Mortality data were obtained from the Danish Civil Personal Registration System. RESULTS: Of 3762 consecutive patients, 516 had acute coronary syndrome. Unstable angina pectoris was present in 7%, NSTEMI in 67%, and STEMI in 26%. The NSTEMI patients were older, more frequently women, and had more comorbidities than patients with unstable angina pectoris and STEMI. At median follow-up of 3.2 years 195 patients had died: 14% of unstable angina pectoris, 45% of NSTEMI, and 25% of STEMI patients. Age-adjusted log-rank statistics revealed differences in mortality: NSTEMI vs unstable angina pectoris (P = .0091) and NSTEMI vs STEMI (P = .0045). CONCLUSIONS: The application of the universal definition together with the use of a contemporary troponin assay seems to have reduced the proportion of patients with unstable angina pectoris to the benefit of patients with NSTEMI. Despite this, NSTEMI patients have a sustained higher mortality than patients with STEMI.

Comparison of mortality in patients with acute myocardial infarction accidentally admitted to non-cardiology departments versus that in patients admitted to coronary care units.

The aim of this study was to prospectively investigate the clinical characteristics including symptoms and long-term mortality in patients with acute myocardial infarction (AMI) accidentally admitted to non-cardiology departments (NCDs). For comparison, similar observations in patients admitted to the coronary care unit (CCU) were collected. During a 1-year period, consecutive patients having cardiac troponin I measured at the Odense University Hospital were considered. The hospital has 27 clinical departments. Patients were classified as having an AMI if the diagnostic criteria of the universal definition were met. Follow-up was at least 1 year with mortality as the clinical end point. Of 3,762 consecutive patients, an AMI was diagnosed in 479, of whom 114 patients (24%) were hospitalized in NCDs and 365 (76%) in the CCU. Chest pain or chest discomfort more frequently occurred in patients from the CCU (83%) than in patients from the NCDs (45%, p <0.0001). At median follow-up of 2.1 years, 150 patients had died: 73 (64%) of patients from the NCDs and 77 (21%) of the patients from the CCU. In the multivariable Cox regression analysis, the adjusted hazard ratio of mortality for patients from the NCDs versus CCU was 2.0 (95% confidence interval 1.3 to 3.2). In conclusion, chest pain/discomfort was absent in more than half of the patients with AMI admitted to NCDs, and admission to NCDs was an independent predictor of a 2 times higher long-term mortality in comparison with admission to the CCU.

Lipocalin-type prostaglandin D synthase is not a biomarker of atherosclerotic manifestations.

OBJECTIVE: Over the last decades Lipocalin-type prostaglandin D synthase (L-PGDS), Osteoprotegerin (OPG), Osteopontin (OPN) and Pregnancy associated plasma protein A (PAPP-A) have been reported to be associated with coronary artery disease, and L-PGDS has been proposed as a potential new diagnostic tool in the setting of stable coronary artery disease. We set out to investigate if measurement of concentrations of these biomarkers could be used to differentiate between four groups of individuals with different atherosclerotic manifestations. METHODS: A total of 120 individuals from four equal gender- and age-matched groups were studied: (i) no previous cardiovascular disease (CVD) and no coronary calcifications [CAC-negative group], (ii) no previous CVD but evidence of severe coronary calcifications [CAC-positive group], (iii) acute coronary syndrome [ACS-group], and (iv) clinical stable patients with CVD, who were referred for cardiovascular surgery [CVD-group]. Concentrations of L-PGDS, OPG, OPN and PAPP-A were analyzed and compared between the four groups. RESULTS: We did not find any significant differences in L-PGDS concentrations between the four groups (p = 0.32). OPG concentrations differed significantly (p = 0.003), with the highest concentration observed in ACS patients. Considering OPN (p = 0.12) and PAPP-A (p = 0.53) their concentrations between groups did not differ significantly. CONCLUSION: The main message from this study is the observation that L-PGDS based on a single blood test appears to be less valuable than previously proposed in identification of patients with coronary artery disease. However, ACS patients have higher OPG concentrations than patients with different manifestations of stable atherosclerosis. Neither OPN nor PAPP-A concentrations differed between groups.

A MMP derived versican neo-epitope is elevated in plasma from patients with atherosclerotic heart disease.

Extracellular matrix remodelling is a prerequisite for plaque rupture in atherosclerotic lesion. Versican, an extracellular matrix proteoglycan present in normal and atherosclerotic arteries is a substrate for matrix metalloproteinases (MMPs) present in macrophage rich areas. The aim of the current study was to develop an immunoassay to detect a specific MMP-12 derived versican degradation fragment (VCANM) and assess its potential as a biomarker for extracellular matrix remodelling in atherosclerosis. A mouse monoclonal antibody raised against VCANM was used for the development of a competitive ELISA for detection of the fragment in plasma. VCANM was measured in plasma of patients with different levels of heart diseases. Patients experiencing I) acute coronary syndrome, II) stable ischemic heart disease and III) demonstrating high levels of coronary calcium deposits had significantly higher plasma levels of VCANM compared to a control group of individuals with no detectable coronary calcium deposits. VCANM was also detected by immunohistochemistry in coronary artery sections of patients with different degrees of atherosclerosis. VCANM ability to separate patients with atherosclerotic diseases from healthy individuals suggested VCANM as a potential biomarker for the pathological arterial matrix remodelling associated with atherosclerosis.

An ELISA for the quantitation of von Willebrand factor: osteoprotegerin complexes in plasma.

BACKGROUND: Von Willebrand factor (VWF) is pivotal in arterial thrombosis, and osteoprotegerin (OPG) is besides being a bone protein also related to cardiovascular diseases. OPG can bind VWF, but the significance of this interaction is not known. OBJECTIVES: The aim was to develop an assay for measurement of von Willebrand factor-osteoprotegerin complex (VWF:OPG) in human plasma. Furthermore, the significance of VWF:OPG complex as a marker of cardiovascular disease (CVD) was evaluated. PATIENTS/METHODS: A sandwich ELISA for quantification of VWF:OPG was developed using a polyclonal rabbit anti-human VWF capturing antibody and a monoclonal anti-human OPG detecting antibody. Samples were quantified relative to a standard curve obtained from dilutions of a plasma pool from healthy individuals. The assay was evaluated in two groups of patients with CVD and two groups of asymptomatic individuals with and without documented coronary calcification (total n=118). RESULTS AND CONCLUSIONS: The assay detected VWF:OPG complexes in human plasma, while no significant signal was observed when testing solutions containing VWF or recombinant OPG alone. Importantly, the ELISA assay was able to detect in vitro formed complexes between human VWF and recombinant OPG in a dose-dependent manner. There was a large inter-individual variation in plasma VWF:OPG levels, but we found no significant differences in the level of VWF:OPG complexes between the four groups. Thus, we conclude that increasing OPG plasma levels in atherosclerotic CVD are not derived from increased levels of complexed form of VWF and OPG, but are more likely due to increased amounts of OPG secreted into the circulation.

Plasma osteoprotegerin is related to carotid and peripheral arterial disease, but not to myocardial ischemia in type 2 diabetes mellitus.

BACKGROUND: Cardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes. METHODS: Type 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured. RESULTS: The prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia. CONCLUSIONS: Increased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown.

Temporal course of pregnancy-associated plasma protein-A in angioplasty-treated ST-elevation myocardial infarction patients and potential significance of concomitant heparin administration.

Pregnancy-associated plasma protein-A (PAPP-A) is a putative plaque instability marker. In acute coronary syndromes, the disrupted culprit plaque contains abundant PAPP-A, and circulating PAPP-A levels predict clinical outcomes. Determinants of circulating PAPP-A levels, however, are not fully understood, and the potential role of concomitant heparin administration has not previously been evaluated. The purposes of the present study were to evaluate in-hospital levels of PAPP-A compared with other circulating biomarkers in patients with acute myocardial infarctions and to explore the potential impact of concomitant heparin administration on PAPP-A levels in an animal experiment. Group A comprised 84 patients with ST elevation myocardial infarctions (STEMIs) who were treated with heparin and transferred for primary percutaneous coronary intervention. Plasma samples were obtained at the time of primary percutaneous coronary intervention, twice within the next 24 hours, and subsequently daily during hospitalization. Levels of PAPP-A, troponin T, soluble cluster of differentiation 163, N-terminal-pro-brain natriuretic peptide, and high-sensitivity C-reactive protein were determined. PAPP-A levels were also determined in 2 historical cohorts not given heparin: 14 patients with STEMIs (group B) and 56 patients with non-ST elevation myocardial infarctions (group C). The impact of concomitant heparin administration on the clearance of PAPP-A from the circulation was also explored in mice. In group A, PAPP-A levels were increased in the initial plasma sample in 95% of patients presenting within 3 hours of symptom onset, whereas increased levels of troponin T, soluble cluster of differentiation 163, N-terminal-pro-brain natriuretic peptide, and high-sensitivity C-reactive protein were detectable in 45%, 15%, 50%, and 35% of patients, respectively. Compared with group A, lower levels of PAPP-A were observed in the initial plasma samples drawn in groups B (p = 0.07) and C (p <0.001) not given heparin. In the animal experiment, concomitant heparin administration resulted in increased levels of PAPP-A and delayed clearance of PAPP-A from the circulation. In conclusion, PAPP-A is markedly elevated in the earliest hours after the onset of symptoms in patients with STEMIs treated with heparin and primary percutaneous coronary intervention, and in animal studies, heparin administration is associated with a significant increase in PAPP-A levels, presumably because of the detachment of PAPP-A from the vessel wall. If future studies confirm that concomitant heparin administration also increases PAPP-A levels in humans, the prognostic role of PAPP-A in patients with STEMIs needs to be reevaluated.