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.

The association between uric acid levels and different clinical manifestations of coronary artery disease.

AIMS: Uric acid (UA) has been associated with the presence and severity of coronary artery disease. To further assess the role of UA role in coronary artery disease, we investigated UA levels in both healthy asymptomatic middle-aged individuals and in different subgroups of hospitalized patients with suspected or definite myocardial infarction (MI). PATIENTS AND METHODS: The severity of coronary artery calcification (CAC) was examined in asymptomatic individuals (n=1039) using a noncontrast computed tomography scan. Hospitalized patients with suspected acute MI (n=772) were grouped according to troponin I (TnI) concentrations: (i) elevated TnI concentrations (>0.03 µg/l) with subdivision according to the type of MI and other clinical conditions associated with myocardial injury, or (ii) nonelevated TnI concentrations (≤0.03 µg/l). RESULTS: UA was not associated with the severity of CAC in asymptomatic individuals when adjusting for relevant risk factors. Patients with type 2 MI and patients with myocardial injury associated with conditions of myocardial ischemia showed significantly higher UA levels (0.390 mmol/l, P=0.002 and 0.400 mmol/l, P=0.001, respectively) than patients with type 1 MI (0.329 mmol/l), after adjusting for other risk factors. CONCLUSION: UA was not correlated with the severity of CAC in asymptomatic middle-aged individuals, and patients with type 2 MI or ischemic myocardial injury were shown to have higher UA levels than type 1 MI patients. This observation is concordant with the hypothesis that UA might be involved in the pathophysiological mechanisms leading to an imbalance in the oxygen supply/demand ratio in type 2 MI and ischemic myocardial injury.

Incidence, Frequency, and Clinical Characteristics of Type 3 Myocardial Infarction in Clinical Practice.

OBJECTIVES: Cardiac death in a patient with symptoms and electrocardiographic changes indicative of myocardial ischemia but without available measurements of cardiac biomarkers is designated a type 3 myocardial infarction. We wanted to investigate the incidence, the frequency, and the characteristics of patients diagnosed as type 3 myocardial infarction. METHODS: The occurrence of deaths in a well-defined geographic region was retrieved from the Danish Civil Registration System during a 1-year period from 2010 to 2011. Complementary data concerning causes of deaths were obtained from the Danish Register of Causes of Death, and ambulance and hospital patient files. Adjudication of the diagnosis was done by 2 local experts and one external senior cardiologist. RESULTS: A total of 2766 of the 246,723 adult residents in the region had died. A type 3 myocardial infarction was diagnosed in 18 individuals, corresponding to an annual incidence of 7.3/100,000 person-years. During the same 1-year period, 488 patients had other types of myocardial infarction implying a 3.6% frequency of type 3 myocardial infarction (18 of 506) among all myocardial infarctions. CONCLUSION: Type 3 myocardial infarction is a rare observation in clinical practice with an annual incidence below 10/100,000 person-years and a frequency of 3%-4% among all types of myocardial infarction. If autopsy data are included, the number of type 3 myocardial infarctions will increase.

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.

Can osteoprotegerin be used to identify the presence and severity of coronary artery disease in different clinical settings?

PURPOSE: The biomarker Osteoprotegerin (OPG) is associated with coronary artery disease (CAD). The main purpose of this study was to evaluate the diagnostic value of OPG in healthy subjects and in patients with suspected angina pectoris (AP). METHODS: A total of 1805 persons were enrolled: 1152 healthy subjects and 493 patients with suspected AP. For comparison 160 patients with acute myocardial infarction (MI) were included. To uncover subclinical coronary atherosclerosis, a non-contrast cardiac-CT scan was performed in healthy subjects; while in patients with suspected AP a contrast coronary angiography was used to detect significant stenosis. OPG concentrations were analyzed and compared between groups. ROC-analyses were performed to estimate OPG cut-off values. RESULTS: OPG concentrations increased according to disease severity with the highest levels found in patients with acute MI. No significant difference (p = 0.97) in OPG concentrations was observed between subgroups of healthy subjects according to severity of coronary calcifications. A significant difference (p < 0.0001) in OPG concentrations was found between subgroups of patients with suspected stable AP according to severity of CAD. ROC-analysis showed an AUC of 0.62 (95% CI: 0.57-0.67). The optimal cut-off value of OPG (<2.29 ng/mL) had a sensitivity of 56.2% (95% CI: 49.2-63.0%) and a specificity of 62.9% (95% CI: 57.3-68.2%). CONCLUSION: OPG cannot be used to differentiate between healthy subjects with low versus high levels of coronary calcifications. In patients with suspected AP a single OPG measurement is of limited use in the diagnosis of CAD.

Mortality rate in type 2 myocardial infarction: observations from an unselected hospital cohort.

BACKGROUND: The classification of myocardial infarction into 5 types was introduced in 2007. The prognostic impact of this universal definition, with particular focus on type 2 myocardial infarction, has not been studied prospectively in unselected hospital patients. METHODS: During a 1-year period, all hospitalized patients having cardiac troponin I measured were considered. The diagnosis of a myocardial infarction was according to the universal definition, and specified criteria were used in the classification of type 2 myocardial infarction. Follow-up was at least 1 year, with mortality as the end point. RESULTS: A total of 3762 consecutive patients were studied, of whom 488 (13%) had a myocardial infarction. In 119 patients a type 2 myocardial infarction was diagnosed. After a median of 2.1 years (interquartile range, 1.6-2.5 years), 150 patients had died, with a mortality rate of 49% (58/119) in those with type 2 myocardial infarction and 26% (92/360) in those with type 1 myocardial infarction (P < .0001). In a multivariable Cox regression analysis the following variables were independently associated with mortality: current or prior smoker, high age, prior myocardial infarction, type 2 myocardial infarction, hypercholesterolemia, high p-creatinine, and diabetes mellitus. The multivariable-adjusted hazard ratio for type 2 myocardial infarction was 2.0 (95% confidence interval, 1.3-3.0). With shock as the only exception, mortality was independent of the triggering conditions leading to type 2 myocardial infarction. CONCLUSIONS: Mortality in patients with type 2 myocardial infarction is high, reaching approximately 50% after 2 years. Further descriptive and survival studies are needed to improve the scientific evidence on which treatment of type 2 myocardial infarction is based.

Plasma proteome profiling of atherosclerotic disease manifestations reveals elevated levels of the cytoskeletal protein vinculin.

Atherosclerosis is a chronic disease of the arterial wall that is recognized as the leading cause of mortality and morbidity worldwide. There is an eminent need for better biomarkers that can aid in patient care before the onset of the first cardiovascular event. We used quantitative proteomics to identify proteins with altered concentrations in plasma samples from four groups: 1) Individuals without cardiovascular symptoms and without the presence of coronary calcium, 2) individuals without cardiovascular symptoms, but with high amounts of coronary calcium, 3) individuals operated because of atherosclerotic diseases, and 4) individuals with an acute coronary syndrome. Immunoassays and SRM-MS were used for single patient verification of candidate proteins. Proteins involved in cardiovascular diseases i.e. serum amyloid protein A (SAA), C-reactive protein (CRP), and apolipoprotein(a) [apo(a)] displayed an increased expression profile from groups 1 to 4. The top-most elevated protein, vinculin (Vcl) displayed a similar profile. Immunoassays confirmed the expression profile of apo(a) and CRP. A 5-plex SRM-MS assay for Vcl, SAA, CRP, apo(a) and thrombospondin-4 (TSP-4) was developed for multiplex verification in all 120 individual samples. The 5-plex SRM assay confirmed a statistically significant up-regulation of Vcl in the acute coronary syndrome group. BIOLOGICAL SIGNIFICANCE: The aim of this study was to identify new candidate plasma markers of atherosclerosis manifestations, which may develop into screening-, diagnostic- or monitoring biomarkers for risk stratification of cardiovascular disease (CVD). At present no studies have elucidated the proteomic changes that occur along with several stages and manifestations of atherosclerotic disease. By using 4-plex iTRAQ, we identified and quantified proteins with altered concentrations in pooled plasma samples from 120 individuals from four middle-aged groups. Proteins involved in cardiovascular diseases i.e. serum amyloid protein A (SAA), C-reactive protein (CRP), and apolipoprotein(a) [apo(a)] displayed an increased expression profile along with increased manifestations of CVD. A novel candidate marker was identified as vinculin (Vcl), a multi-protein linker that connects cell-matrix adhesions and cell-cell adhesions to the actin-based cytoskeleton. Immuno- and SRM-assays were used for single patient validation of candidate proteins. While further studies needs to address the role of Vcl in the development of atherosclerosis, the combined data provided in this report offers a catalog of the proteomic changes that occurs in plasma over several stages and manifestations of atherosclerotic disease.

Classification of myocardial infarction: frequency and features of type 2 myocardial infarction.

BACKGROUND: The classification of myocardial infarction into 5 types was introduced in 2007 as an important component of the universal definition. In contrast to the plaque rupture-related type 1 myocardial infarction, type 2 myocardial infarction is considered to be caused by an imbalance between demand and supply of oxygen in the myocardium. However, no specific criteria for type 2 myocardial infarction have been established. METHODS: We prospectively studied unselected hospital patients who had cardiac troponin I measured on clinical indication. The diagnosis and classification of myocardial infarction were established, and the frequency and features of type 2 myocardial infarction were investigated by use of novel developed criteria. RESULTS: From January 2010 to January 2011, a total of 7230 consecutive patients who had cardiac troponin I measured were evaluated, and 4499 patients qualified for inclusion. The diagnosis of myocardial infarction was established in 553 patients, of whom 386 (72%) had a type 1 myocardial infarction and 144 (26%) had a type 2 myocardial infarction. Patients in the group with type 2 myocardial infarction were older and more likely to be female, and had more comorbidities. The proportion of patients without significant coronary artery disease was higher in those with type 2 myocardial infarction (45%) than in those with type 1 myocardial infarction (12%) (P < .001). Tachyarrhythmias, anemia, and respiratory failure were the most prevalent mechanisms causing type 2 myocardial infarction. CONCLUSIONS: In a cohort of patients with myocardial infarction who were admitted consecutively through 1 year, the category of type 2 myocardial infarction comprised one fourth when diagnosed by the use of newly developed criteria. Approximately half of patients with type 2 myocardial infarction had no significant coronary artery disease.

Acute Myocardial Infarction and Pulmonary Diseases Result in Two Different Degradation Profiles of Elastin as Quantified by Two Novel ELISAs.

BACKGROUND: Elastin is a signature protein of the arteries and lungs, thus it was hypothesized that elastin is subject to enzymatic degradation during cardiovascular and pulmonary diseases. The aim was to investigate if different fragments of the same protein entail different information associated to two different diseases and if these fragments have the potential of being diagnostic biomarkers. METHODS: Monoclonal antibodies were raised against an identified fragment (the ELM-2 neoepitope) generated at the amino acid position '552 in elastin by matrix metalloproteinase (MMP) -9/-12. A newly identified ELM neoepitope was generated by the same proteases but at amino acid position '441. The distribution of ELM-2 and ELM, in human arterial plaques and fibrotic lung tissues were investigated by immunohistochemistry. A competitive ELISA for ELM-2 was developed. The clinical relevance of the ELM and ELM-2 ELISAs was evaluated in patients with acute myocardial infarction (AMI), no AMI, high coronary calcium, or low coronary calcium. The serological release of ELM-2 in patients with chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF) was compared to controls. RESULTS: ELM and ELM-2 neoepitopes were both localized in diseased carotid arteries and fibrotic lungs. In the cardiovascular cohort, ELM-2 levels were 66% higher in serum from AMI patients compared to patients with no AMI (p<0.01). Levels of ELM were not significantly increased in these patients and no correlation was observed between ELM-2 and ELM. ELM-2 was not elevated in the COPD and IPF patients and was not correlated to ELM. ELM was shown to be correlated with smoking habits (p<0.01). CONCLUSIONS: The ELM-2 neoepitope was related to AMI whereas the ELM neoepitope was related to pulmonary diseases. These results indicate that elastin neoepitopes generated by the same proteases but at different amino acid sites provide different tissue-related information depending on the disease in question.

Discordant diagnoses of acute myocardial infarction due to the different use of assays and cut-off points of cardiac troponins.

OBJECTIVES: Several assays for the measurement of cardiac troponin (cTn) are available, but differences in their analytical performances may affect the diagnosis of acute myocardial infarction (MI). METHODS: A survey was conducted at all Danish departments of clinical biochemistry at hospitals receiving patients with suspected acute MI to gather information about the assay and cut-off value used. cTn was measured in blood samples from 574 patients enrolled into the Odense Chest Pain Biobank with 3 different assays: the 4th generation cTnT (cTnT(4th)), high-sensitivity cTnT (cTnT(hs); Roche Diagnostics) and cTnI (Abbott Diagnostics). To evaluate concordance, patients were dichotomised according to the 99th percentile value for each assay. Additionally, a cut-off at 50 ng/l for cTnT(hs) was used, as this is the currently employed cut-off point in Denmark. RESULTS: Using a cTnT(4th) cut-off value of >0.03 µg/l, 130 patients (23%) had potential MI. With the cTnT(hs) assay and cut-off values at 50 versus 14 ng/l, respectively, 136 (24%) versus 301 (52%) patients had potential MI. With the cTnI cut-off point, 205 patients (36%) should be considered as having had an acute MI. CONCLUSIONS: The use of different cTn assays and cut-off values may result in a discordant frequency of MI diagnoses. This makes efforts to harmonize cTn assays and cut-off levels mandatory.