Anna M. Nordenskjöld

Short- and Long-term Individual Variation in Cardiac Troponin in Patients with Stable Coronary Artery Disease

BACKGROUND A rise or fall of cardiac troponin is a prerequisite for the diagnosis of acute myocardial infarction. Defining significant changes requires knowledge of both biological and analytical variation. The short-term biological variation of cardiac troponin in healthy individuals is 3%-48%. However, healthy individuals may not be representative for patients in whom cardiac troponin measurement is often of clinical importance. Therefore, we studied the individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease. METHODS Twenty-four patients scheduled for elective coronary angiography were included. Blood samples were drawn once at enrollment and serially at six 4-h intervals on the day before coronary angiography. Cardiac troponin was measured with hs-cTn assays from Abbott Laboratories (premarket cTnI assay) and Roche Diagnostics (Elecsys(®) cTnT assay with two different lots). RESULTS The short-term individual variation in cardiac troponin I (cTnI) was 14%, the reference change value (RCV) 49%, and RCV-log-normal (rise/fall) 54%/-35%. The corresponding values for cTnT were 7%, 23%, and 26%/-21%. The long-term variation for cTnI was 24%, RCV 69%, and RCV-log-normal (rise/fall) 97%/-49%. The corresponding values for cTnT were 11%, 32%, and 37%/-27%. CONCLUSIONS The short-term individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease is similar to the biological variation previously demonstrated in healthy individuals. Our results suggest that a change in cardiac troponin concentrations of >50% can be used in attempting to diagnose acute myocardial injury. To detect significant long-term changes in cardiac troponin concentrations, larger changes will be required.

Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease

Background: Myocardial infarction with nonobstructive coronary arteries (MINOCA) occurs in 5% to 10% of all patients with myocardial infarction. Clinical trials of secondary prevention treatment in MINOCA patients are lacking. Therefore, the aim of this study was to examine the associations between treatment with statins, renin-angiotensin system blockers, &bgr;-blockers, dual antiplatelet therapy, and long-term cardiovascular events. Methods: This is an observational study of MINOCA patients recorded in the SWEDEHEART registry (the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapy) between July 2003 and June 2013 and followed until December 2013 for outcome events in the Swedish Cause of Death Register and National Patient Register. Of 199 162 myocardial infarction admissions, 9466 consecutive unique patients with MINOCA were identified. Among those, the 9136 patients surviving the first 30 days after discharge constituted the study population. Mean age was 65.3 years, and 61% were women. No patient was lost to follow-up. A stratified propensity score analysis was performed to match treated and untreated groups. The association between treatment and outcome was estimated by comparing between treated and untreated groups by using Cox proportional hazards models. The exposures were treatment at discharge with statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, &bgr;-blockers, and dual antiplatelet therapy. The primary end point was major adverse cardiac events defined as all-cause mortality, hospitalization for myocardial infarction, ischemic stroke, and heart failure. Results: At discharge, 84.5%, 64.1%, 83.4%, and 66.4% of the patients were on statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, &bgr;-blockers, and dual antiplatelet therapy, respectively. During the follow-up of a mean of 4.1 years, 2183 (23.9%) patients experienced a major adverse cardiac event. The hazard ratios (95% confidence intervals) for major adverse cardiac events were 0.77 (0.68–0.87), 0.82 (0.73–0.93), and 0.86 (0.74–1.01) in patients on statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and &bgr;-blockers, respectively. For patients on dual antiplatelet therapy followed for 1 year, the hazard ratio was 0.90 (0.74–1.08). Conclusions: The results indicate long-term beneficial effects of treatment with statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on outcome in patients with MINOCA, a trend toward a positive effect of &bgr;-blocker treatment, and a neutral effect of dual antiplatelet therapy. Properly powered randomized clinical trials to confirm these results are warranted.

Risk prediction in patients with chest pain: early assessment by the combination of troponin I results and electrocardiographic findings.

ObjectiveTo evaluate the prognostic value of point of care troponin I (TnI) results in combination with findings from the admission electrocardiogram (ECG) in patients with chest pain. MethodsRapid measurements of TnI were performed in 191 consecutive patients with chest pain and a non-diagnostic ECG for myocardial infarction. ResultsWithin 6 h from admission, maximum TnI elevations of ≥0.07 μg/l and ≥0.1 μg/l were noted in 59 and 39% of all patients, respectively. TnI elevations in the range of 0.07–0.09 μg/l were found in many patients with diagnoses other than acute coronary syndrome. By 6-month follow-up, cardiac death had occurred in 7.1 and 11% of patients with maximum TnI ≥0.07 μg/l and ≥0.1 μg/l, respectively and myocardial reinfarction was documented in 12 and 15%, respectively. ST-segment depression on the admission ECG was present in 16% of all patients and was the electrocardiographic abnormality with the highest risk (cardiac death 7.7%, myocardial reinfarction 15%). The combination of TnI ≥0.1 μg/l and ST-segment depression or an abnormal admission ECG in general allowed the identification of patients at low, intermediate and high cardiac risk, 3 h after admission. ConclusionA threshold of TnI ≥0.1 μg/l corresponding to the 10% coefficient of variation is prognostically most suitable for prediction of cardiac events in patients with chest pain. The combination of TnI results and findings from the admission ECG improves prognostic assessment and allows early and reliable risk stratification in this patient population.

Combining different biochemical markers of myocardial ischemia does not improve risk stratification in chest pain patients compared to troponin I alone

ObjectiveEarly evaluation of patients with chest pain is important not only for the detection of acute myocardial infarction (AMI) but also for identification of patients at high risk for future cardiac events. A multimarker strategy applying results of early measurements of different biochemical markers of cardiac necrosis in combination may improve risk prediction in chest pain patients. MethodsRapid measurements of troponin I (TnI), creatine kinase MB and myoglobin were performed in 191 consecutive patients with chest pain and a non-diagnostic electrocardiogram for AMI. The prognostic value of these markers and different multimarker strategies was evaluated and compared. ResultsTen (5.2%) patients died during follow-up, which for eight (4.2%) patients was due to cardiac causes. Myocardial reinfarctions occurred in 17 (6.8%) patients. TnI was most predictive for cardiac mortality (TnI ≥0.1 μg/l, 10.7% event rate compared with TnI <0.1 μg/l, 0%, P<0.001) and myocardial reinfarction (14.9% compared with 1.7%, P<0.001). The other markers and multimarker strategies had a lower capacity for predicting adverse events apart from myoglobin and the combination of TnI or myoglobin regarding the endpoint of total mortality. ConclusionThe combinations of different markers were prognostically non-superior compared to TnI, which thus, should be preferred as a biochemical marker for risk stratification in patients with chest pain.

Unrecognized Myocardial Infarction Assessed by Cardiac Magnetic Resonance Imaging - Prognostic Implications

Background Clinically unrecognized myocardial infarctions (UMI) are not uncommon and may be associated with adverse outcome. The aims of this study were to determine the prognostic implication of UMI in patients with stable suspected coronary artery disease (CAD) and to investigate the associations of UMI with the presence of CAD. Methods and Findings In total 235 patients late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging and coronary angiography were performed. For each patient with UMI, the stenosis grade of the coronary branch supplying the infarcted area was determined. UMIs were present in 25% of the patients and 67% of the UMIs were located in an area supplied by a coronary artery with a stenosis grade ≥70%. In an age- and gender-adjusted model, UMI independently predicted the primary endpoint (composite of death, myocardial infarction, resuscitated cardiac arrest, hospitalization for unstable angina pectoris or heart failure within 2 years of follow-up) with an odds ratio of 2.9; 95% confidence interval 1.1–7.9. However, this association was abrogated after adjustment for age and presence of significant coronary disease. There was no difference in the primary endpoint rates between UMI patients with or without a significant stenosis in the corresponding coronary artery. Conclusions The presence of UMI was associated with a threefold increased risk of adverse events during follow up. However, the difference was no longer statistically significant after adjustments for age and severity of CAD. Thus, the results do not support that patients with suspicion of CAD should be routinely investigated by LGE-CMR for UMI. However, coronary angiography should be considered in patients with UMI detected by LGE-CMR. Trial Registration ClinicalTrials.gov NTC01257282

Short-and long-term individual variation in NT-proBNP levels in patients with stable coronary artery disease

BACKGROUND In addition to diagnosis of heart failure (HF) natriuretic peptides (BNP and NT-proBNP) may be used for risk prediction in stable and acute coronary artery disease. The aim of the study was to evaluate the short- and long-term individual variation of NT-proBNP in patients with stable coronary artery disease. METHODS Twenty-four patients with suspected stable coronary artery disease and scheduled for elective coronary angiography were included. Blood samples were drawn at enrolment and, on average 3 weeks later, serially the day prior to coronary angiography. NT-proBNP was determined using Elecsys proBNP sandwich immunoassay (Roche Diagnostics). RESULTS The individual variation in NT-proBNP over 4h was 11.8%, over 20 h 12.4% and over 3 weeks 20.4%. The corresponding positive and negative lognormal reference change values (RCV) were +41/-29%, +42/-30% and +76/-43%, respectively. No significant circadian variation was found. CONCLUSIONS Our results suggest that an increase in NT-proBNP levels of >42% or a decrease of >30% is needed to indicate a reliable short-term change; and for a long-term change an increase of >76% or a decrease of >43% is required. This should be considered when interpreting changes in NT-proBNP levels.

Unrecognized myocardial infarctions detected by cardiac magnetic resonance imaging are associated with cardiac troponin I levels

BACKGROUND Both unrecognized myocardial infarction (UMI) and elevated levels of biomarkers are common in patients with stable coronary artery disease (CAD). The objective of this study was to determine the association between levels of cardiac biomarkers, UMI and extent of CAD in patients with stable CAD. METHODS A total of 235 patients (median age: 65years; 34% women) with stable CAD without previously known myocardial infarction were examined with late gadolinium enhancement cardiovascular magnetic resonance imaging and coronary angiography. Blood samples were drawn at enrolment and high sensitivity cardiac troponin I (cTnI), NT-proBNP and Galectin-3 were analyzed. RESULTS UMI was detected in 58 patients (25%). The median levels of cTnI, NT-proBNP and Galectin-3 were significantly higher in patients with UMI compared to those without, (p<0.001, p=0.006 and p=0.033, respectively). After adjustment for cardiovascular risk factors, left ventricular ejection fraction and renal function, cTnI remained independently associated with the presence of UMI (p=0.031) and the extent of CAD (p=0.047). Neither NT-proBNP, nor Galectin-3, was independently associated with UMI or extent of CAD. CONCLUSIONS The independent association between levels of cTnI and UMI indicates a common pathophysiological pathway for the cTnI elevation and development of UMI. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (NCT01257282).

Predictors of adverse outcome in patients with myocardial infarction with non-obstructive coronary artery (MINOCA) disease

BACKGROUND Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCAs) is an increasingly recognized entity. No previous study has evaluated predictors for new major adverse cardiacvascular events (MACEs) and death in patients with MINOCA. METHODS We conducted an observational study of MINOCA patients recorded between July 2003 and June 2013 and followed until December 2013 for outcome events. Out of 199,163 MI admissions, 9092 consecutive unique patients with MINOCA were identified. The mean age was 65.5 years and 62% were women. MACE was defined as all-cause mortality, rehospitalization for acute MI, ischemic stroke and heart failure. Hazard ratio and 95% confidence interval (HR; 95% CI) was calculated using Cox-regression. RESULTS A total of 2147 patients (24%) experienced a new MACE and 1254 patients (14%) died during the mean follow-up of 4.5 years. Independent predictors for MACE after adjustment, were older age (1.05; 1.04-1.06), diabetes (1.44; 1.21-1.70), hypertension (1.25; 1.09-1.43), current smoking (1.38; 1.15-1.66), previous myocardial infarction (1.38; 1.04-2.82), previous stroke (1.69; 1.35-2.11), peripheral vascular disease (1.55; 1.97-2.23), chronic obstructive pulmonary disease (1.63; 1.32-2.00), reduced left ventricular ejection fraction (2.00; 1.54-2.60), lower level of total cholesterol (0.88; 0.83-0.94) and higher level of creatinine (1.01; 1.00-1.03). Independent predictors for all cause death were age, current smoking, diabetes, cancer, chronic obstructive pulmonary disease, previous stroke, reduced left ventricular fraction, lower level of total cholesterol and higher levels of creatinine and CRP. CONCLUSIONS The clinical factors predicting new MACE and death of MINOCA patients seem to be strikingly similar to factors previously shown to predict new cardiovascular events in patients with MI and obstructive coronary artery disease.

Reinfarction in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) – coronary findings and prognosis

BACKGROUND Myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is common. There are limited data on the mechanisms and prognosis for reinfarction in MINOCA patients. METHODS In this observational study of MINOCA patients hospitalized in Sweden and registered in the SWEDEHEART registry between July 2003 and June 2013 and followed until December 2013, we identified 9092 unique patients with MINOCA of 199,163 MI admissions in total. The 570 (6.3%) MINOCA patients who were hospitalized due to a recurrent MI constituted the study group. RESULTS The mean age was 69.1 years and 59.1% were women. The median time to readmission was 17 months. A total of 340 patients underwent a new coronary angiography and 180 (53%) had no obstructive coronary artery disease (CAD) and 160 (47%) had obstructive CAD; 123 had 1-vessel, 26 had 2-vessel, 9 had 3-vessel disease, and 2 had left main together with 1-vessel disease. Male sex, diabetes, peripheral vascular disease, higher levels of creatinine, and ST elevation at presentation were more common in patients with MI with obstructive CAD than in patients with a recurrent MINOCA. Mortality during a median follow-up of 38 months was similar whether the reinfarction event was MINOCA or MI with obstructive CAD 13.9% vs 11.9% (P = .54). CONCLUSIONS About half of patients with reinfarction after MINOCA who underwent coronary angiography had progression of coronary stenosis. Angiography should be strongly considered in patients with MI after MINOCA. Mortality associated with recurrent events was substantial, though there was no difference in mortality between those with or without significant CAD.

Unrecognized myocardial infarction assessed by cardiac magnetic resonance imaging is associated with adverse long-term prognosis

Background Unrecognized myocardial infarctions (UMIs) are common. The study is an extension of a previous study, aiming to investigate the long-term (>5 year) prognostic implication of late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) detected UMI in patients with suspected stable coronary artery disease (CAD) without previously diagnosed myocardial infarction (MI). Methods In 235 patients with suspected stable CAD without previous MI, LGE-CMR imaging and coronary angiography were performed. LGE with a subendocardial component detectable in more than one imaging plane was required to indicate UMI. The stenosis grade of the coronary arteries was determined, including in the artery supplying an infarcted area. Stenosis ≥70% stenosis was considered significant. Patients were followed for 5.4 years in mean regarding a composite endpoint of cardiovascular death, MI, hospitalization due to heart failure, stable or unstable angina. Results UMI were present in 58 of 235 patients (25%). Thirty-nine of the UMIs were located downstream of a significant coronary stenosis. During the follow-up 40 patients (17.0%) reached the composite endpoint. Of patients with UMI, 34.5% (20/58) reached the primary endpoint compared to 11.3% (20/177) of patients with no UMI (HR 3.7, 95% CI 2.0–6.9, p<0.001). The association between UMI and outcome remained (HR 2.3, 95% CI 1.2–4.4, p = 0.012) after adjustments for age, gender, extent of CAD and all other variables univariate associated with outcome. Sixteen (41%) of the patients with an UMI downstream of a significant stenosis reached the endpoint compared to four (21%) patients with UMI and no relation to a significant stenosis (HR 2.4, 95% CI 0.8–7.2, p = 0.12). Conclusion The presence of UMI was independently associated with an increased risk of cardiovascular events during long-term follow up.