Background: High-sensitivity cardiac troponin T (hs-cTnT) is used to diagnosis acute myocardial infarction, often based on values exceeding the 99th percentile threshold (14 ng/L) of normal populations. The short- and long-term variability of hs-cTnT in stable patients with or without coronary artery disease (CAD) is unknown. Methods: Prospective cohort study of 75 stable patients with CAD and 3 differing clinical profiles (stable angina [SA]; remote myocardial infarction [MI]; repetitive acute coronary syndrome [ACS]) and 25 controls without angiographic CAD, each with 15 hs-cTnT measurements over 1 year. Results: Individual results (1491 measurements) did not vary over within-day, daily, weekly, monthly, seasonal, or yearly time windows. The overall median was 2.8 ng/L (interquartile range [IQR] 5.2 ng/L) with the highest median (6.3 ng/L) and variability (IQR 6.9 ng/L) in the repetitive ACS group. Diabetes, impaired renal function, and raised C-reactive protein were independent predictors of higher hs-cTnT values (average increase by 8.5 ng/L [95% CI, 5.0-11.9], 5.0 ng/L [95% CI, 2.0-8.1] and 4.0 ng/L (95% CI, 1.0-7.0), respectively). The 99th percentile value of all hs-cTnT measurements in the combined stable patients with CAD was 39 ng/L compared with 14 ng/L in the non-CAD patients. Conclusions: Individual hs-cTnT readings in both patients with and without CAD were stable over hours, days, weeks, and months. Diabetes, poor renal function, and elevated C-reactive protein were independent predictors of higher median and IQR hs-cTnT values, often exceeding conventional thresholds. These findings highlight the need for caution and clinical contextualization in the interpretation of hs-cTnT results.

In addition to necrosis, important biological pathways such as inflammation and apoptosis contribute to acute coronary syndromes (ACS)[ 1 Akiyama K. Gluckman T.L. Terhakopian A. et al. Apoptosis in experimental myocardial infarction in situ and in the perfused heart in vitro. Tissue Cell. 1997; 29: 733-743 Crossref PubMed Scopus (26) Google Scholar , 2 Olivetti G. Quaini F. Sala R. et al. Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol. 1996; 28: 2005-2016 Abstract Full Text PDF PubMed Scopus (453) Google Scholar , 3 Wencker D. Chandra M. Nguyen K. et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest. 2003; 111: 1497-1504 Crossref PubMed Scopus (631) Google Scholar ]. We previously reported that at the time of hospital admission, measurement of sFas, a circulating biomarker of increased apoptosis, improved diagnostic accuracy for ACS [ [4] Cardinal H. Brophy J.M. Bogaty P. et al. Usefulness of soluble fas levels for improving diagnostic accuracy and prognosis for acute coronary syndromes. Am J Cardiol. 2010; 105: 797-803 Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar ]. However, the time variation in this biomarker after an ACS and its association with clinical outcomes were not investigated. Therefore we undertook a mechanistic investigation to determine: a) whether longitudinal trends in sFas levels are different in patients with an initial hospitalization discharge diagnosis of ACS versus non-cardiac chest pain; b) if the time trends differ amongst patients with ACS who experience recurrent myocardial infarction (MI), unstable angina (UA), heart failure (HF) or cardiac death during a 1-year follow-up compared to those who do not.

The prognostic value of high-sensitivity cardiac troponin T (hs-cTnT) in patients with stable coronary artery disease (CAD) is based on a single measurement although plasma fluctuations of the biomarker are not well defined. We assessed hs-cTnT variability over a year and hypothesized that hs-cTnT detections and its fluctuations may vary according to patients' specific CAD history. We prospectively studied 100 stable subjects (aged 64 ± 8 y, 83% men) belonging to 4 groups (N=25/group) according to their history of: 1) recurrent (≥3) acute coronary events; 2) an isolated myocardial infarction ≥7 years previously; 3) longstanding (≥7 years) always stable CAD; 4) no angiographically documented CAD (age-matched controls). We obtained 15 hs-cTnT samples per subject covering 21 time-points: 3 times during one day; 5 consecutive days; 4 consecutive weeks; 4 consecutive months; and every 3 months (x 4). The assay detection limit is 3 ng/L and the necrosis threshold value is 14 ng/L. Reference change values (RCV) were used to assess the variability in each group, during a week (RCVw) and months (RCVm). Table shows number of subjects in each group with detectable hs-cTnT in ≥1 sample, in all 15 samples, with ≥1 sample value ≥14 ng/L, the range and the RCV of detectable hs-cTnT. Hs-cTnT was detected in 71% of CAD subjects including 16% above the necrosis threshold value, and was independently associated with recurrent events group (p=0.0016) and hypertension (p=0.027). There was marked variability in detectable hs-cTnT within groups. In these stable CAD patients the detection of hs-cTnT but not its fluctuations was related to the clinical history. Study is needed to understand the marked hs-cTnT fluctuations, even over the necrosis threshold, and their prognostic implications.

BACKGROUND:C-reactive protein (CRP) is proposed as a screening test for predicting risk and guiding preventive approaches in coronary artery disease (CAD). However, the stability of repeated CRP measurements over time in subjects with and without CAD is not well defined. We sought to determine the stability of serial CRP measurements in stable subjects with distinct CAD manifestations and a group without CAD while carefully controlling for known confounders.METHODS:We prospectively studied 4 groups of 25 stable subjects each 1) a history of recurrent acute coronary events; 2) a single myocardial infarction ≥7 years ago; 3) longstanding CAD (≥7 years) that had never been unstable; 4) no CAD. Fifteen measurements of CRP were obtained to cover 21 time-points: 3 times during one day; 5 consecutive days; 4 consecutive weeks; 4 consecutive months; and every 3 months over the year. CRP risk threshold was set at 2.0 mg/L. We estimated variance across time-points using standard descriptive statistics and Bayesian hierarchical models.RESULTS:Median CRP values of the 4 groups and their pattern of variability did not differ substantially so all subjects were analyzed together. The median individual standard deviation (SD) CRP values within-day, within-week, between-weeks and between-months were 0.07, 0.19, 0.36 and 0.63 mg/L, respectively. Forty-six percent of subjects changed CRP risk category at least once and 21% had ≥4 weekly and monthly CRP values in both low and high-risk categories.CONCLUSIONS:Considering its large intra-individual variability, it may be problematic to rely on CRP values for CAD risk prediction and therapeutic decision-making in individual subjects.

Although both inflammation and apoptosis occur in acute coronary syndromes (ACSs), previous studies have not tested the diagnostic and prognostic utility of an approach that measures circulating markers of these pathways. The aim of the present study was to assess whether measuring soluble Fas (sFas) and high-sensitivity C-reactive protein (hs-CRP), as markers of apoptosis and inflammation, improve ACS diagnostic and prognostic accuracy. In a prospective cohort of consecutive subjects admitted to the hospital for suspicion of ACS, we measured sFas, hs-CRP, and troponin T in those who had a final noncardiac chest pain diagnosis (n = 100), those who had an ACS diagnosis and experienced (n = 218) or did not experience (n = 170) recurrent cardiac events during 1 year of follow-up. sFas was strongly and independently associated with a discharge diagnosis of an ACS versus noncardiac chest pain during the index hospitalization (odds ratio 16.16 for the second vs first tertile, 95% confidence interval [CI] 7.07 to 36.91; and odds ratio 25.40 for the third vs first tertile, 95% CI 9.38 to 68.75). However, hs-CRP was not. sFas significantly improved the diagnostic accuracy for ACSs (C statistic increased from 0.85 to 0.93, difference +0.08, 95% CI for the difference 0.05 to 0.11). The sFas levels were high and did not vary with time in the subjects having early versus late measurements (beta 0.00 In pg/ml/hour, 95% CI -0.01 to 0.01). In contrast, troponin increased with time since the beginning of the symptoms (beta 0.07 In mu g/L/hour, 95% CI 0.04 to 0.10). Baseline sFas and hs-CRP did not predict recurrent cardiac events. In conclusion, our results suggest that in suspected ACS cases, sFas, but not hs-CRP, helps to improve the diagnostic accuracy and timeliness over and above standard diagnostic criteria. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:797-803)

The cardiovascular safety of cyclooxygenase-2-selective (coxibs) and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is of concern, although most users remain free of adverse outcomes. A gene-drug interaction could modulate this cardiovascular risk through prostaglandin synthesis or inflammatory pathways. From an existing acute coronary syndrome cohort (Recurrence and Inflammation in the Acute Coronary Syndromes Study) (n = 1,210), a case-only study was performed by identifying 115 patients exposed to NSAIDs (rofecoxib [n = 43], celecoxib [n = 49], or nonselective NSAIDs [n = 23]) and 345 unexposed patients matched for age, gender, and hospital center. These patients were genotyped for 115 candidate single-nucleotide polymorphisms (SNPs). Statistically significant associations between NSAID exposure and 9 SNPs in 6 genes were observed. Analyzing patients exposed only to coxibs and their matched unexposed cases, significant associations remained for 5 SNPs at 4 loci (prostaglandin-endoperoxide synthase-1 [PTGS1], chromosome 9p21.3, C-reactive protein [CRP], and klotho [KL]). Two independent SNPs from the PTGS1 gene gave similar results under a recessive model, with odds ratios for the association with NSAID exposure of 6.94 (95% confidence interval 1.35 to 35.65, p = 0.016) and 7.11 (95% confidence interval 1.38 to 36.74, p = 0.033). A significant association was also observed for a SNP in the CRP gene (rs1205) (additive odds ratio 1.64, 95% confidence interval 1.18 to 2.27, p = 0.003). In conclusion, these findings suggest that genetic variability may contribute to the susceptibility for acute coronary syndromes observed in some NSAID users. In particular, genetic polymorphisms in the PTGS1 and CRP genes appear to be candidates for a possible gene-drug interaction influencing the acute coronary risk associated with NSAID use, but these findings will require confirmation in larger cohorts.

BACKGROUND AND OBJECTIVES:Prior reports have suggested that patients with impaired renal function receive less aggressive care after an acute coronary syndrome (ACS). The aim of this study was to determine whether this held true in a contemporary cohort, after thorough adjustment for cotreatments/comorbidities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Patients who were admitted for an ACS in eight participating hospitals were stratified into three groups according to estimated creatinine clearance (CrC): less than 45 ml/min, 45 to 60 ml/min, and reference >60 ml/min. RESULTS:During hospitalization, uses of reperfusion therapy in tertiary care centers [difference between CrC < or =45 ml/min and reference group (Delta): 4%, 95% confidence interval (CI): (-13%, 21%)] and systemic anticoagulation [Delta: 0%, CI (-5%, 5%)] were similar in the three groups. Coronary angiography was performed less often in patients with lower CrC [Delta: -16%, CI: (-31%, -1%)]. At discharge, nearly all patients received either an antiplatelet agent or warfarin regardless of CrC [Delta: -1%, CI: (-3%, 1%)]. Discharge use of angiotensin converting enzyme (ACE) inhibitors or angiotensin-receptor blockers was comparable [Delta: 7%, CI: (-1%, 15%)]. beta-blockers [Delta: -9%, CI: (-17%, -1%)] and lipid-lowering drugs (LLDs) [Delta: -7%, CI: (-13%, -1%)] were used less frequently in patients with lower CrC. In multivariate analyses, decreased CrC predicted lower coronary angiography and LLD use, but not lower beta-blocker use at discharge. CONCLUSIONS:These results suggest that in patients with ACS, the extent of undertreatment due to chronic kidney disease is less than reported previously, which is partially explained by more complete adjustment for cotreatments/comorbidities.

BACKGROUND:The aim of the study is to compare the impact of intravenous glucose versus lipid versus saline on exercise-induced myocardial ischemia in patients with stable angina.METHODS:Twelve men with coronary artery disease and positive exercise tests performed a symptom-limited, modified Bruce electrocardiogram (ECG) exercise test at 3 sessions, 3 weeks apart. They randomly received, in double-blind design, at each session equal intravenous volumes of 10% glucose/insulin or Intralipid plus heparin or saline. We assessed the effects on (1) ischemic threshold (heart rate x systolic pressure at 1-mm ST-segment depression [STD]) and (2) maximum ST-depression (Max STD) corresponding to the highest heart rate x systolic pressure common to the 3 tests.RESULTS:During glucose infusion, glycemia increased from 5.7 +/- 0.4 to 9.4 +/- 3.0 mmol/L but did not change during lipid or saline infusion. During lipid infusion, free fatty acids increased from 0.32 +/- 0.19 to 1.44 +/- 0.46 mmol/L but decreased during glucose infusion from 0.39 +/- 0.21 to 0.04 +/- 0.03 mmol/L and did not change during saline. Exercise times were 10.0 +/- 3.4, 9.8 +/- 3.4, and 10.3 +/- 3.5 minutes, during glucose, lipid, and saline infusions, respectively. Ischemic thresholds (x 10(-3)) were 16.5 +/- 2.8, 16.8 +/- 2.7, and 16.6 +/- 2.6, respectively. MaxSTD was 2.5 +/- 1.4, 2.5 +/- 1.0, and 2.5 +/- 1.0 mm, respectively.CONCLUSION:Neither glucose-insulin nor lipid infusion modified exercise ischemic parameters compared with saline control, suggesting that marked and acute changes in exogenous energy substrate are unlikely to affect exercise-induced myocardial ischemia.

Objectives This study was designed to prospectively determine, in patients with an acute coronary syndrome, whether the inflammatory marker, C-reactive protein (CRP), measured at hospital admission, discharge, and 1 month later has incremental value to predict outcomes at 1 year.Background The clinical utility of CRP measurements in patients with acute coronary syndromes remains uncertain. Limitations of previous studies have been retrospective design and incomplete adjustment for readily available clinical prognosticators.Methods The CRP marker was measured at admission, hospital discharge, and 1 month later in consecutive patients hospitalized for acute coronary syndromes in 8 tertiary and secondary hospitals. The primary outcome was a composite of death, nonfatal myocardial infarction (MI), and unstable angina (UA) with electrocardiogram (ECG) changes at 1 year.Results A total of 1,210 patients, age 62 +/- 12 years, 64% with acute myocardial infarction (MI) and 36% with unstable angina (UA), were recruited. At 1 year, the primary outcome occurred in 142 patients (11.7%) and included 58 deaths (4.8%), 79 nonfatal MIs (6.5%), and 26 UA episodes with ECG changes (2.1%). The unadjusted odds ratios (ORs) (95% confidence intervals) of CRP values at admission, hospital discharge, and 1 month later for the occurrence of the primary outcome were 1.20 (1.06 to 1.36), 0.98 (0.85 to 1.14), and 1.23 (1.00 to 1.50), respectively. After multivariate adjustment, ORs were 1.04 (0.91 to 1.20), 0.90 (0.77 to 1.06), and 1.12 (0.93 to 1.34), respectively. The individual components of the primary outcome were also not independently associated with any of the 3 CRP measurements.Conclusions The modest predictive ability of CRP following admission for an acute coronary syndrome disappeared after adjusting for common clinical variables. This large prospective study does not support the incremental value of measuring CRP in this clinical setting.

Background: In patients with ischemic heart disease (IHD), the current guidelines on exercise prescription recommend that exercise training intensity be 10 beats/min below the heart rate at which there is >1 mm ST-segment depression (ischemic threshold). However, it is not well established that exercise training above the ischemic threshold is harmful. Methods: Twenty-two patients with angiographically documented IHD (>70% stenosis) were randomized to exercise training either at a target intensity that induced myocardial ischemia (ischemic group) or that adhered to current guidelines (control group). Training was progressively increased to 60 min under continuous ECG monitoring. Cardiac troponin T (cTnT) was measured at regular intervals. Ambulatory ECG monitoring was performed before and after 6 wkof training and left ventricular function was evaluated by echocardiography in the ischemic group after at least 6 wk of training. Results: The ischemic training sessions were very well tolerated. The ischemic group had myocardial ischemia during the first 20, 40, and 60 min exercise sessions for 12.3 ± 6.8 min, 29.0 ± 12.9 min and 49.8 ± 2.2 min, respectively, with ST-segment depression ranging from 1.0 to 2.1 mm. The estimated myocardial work (as expressed by RPP) during the training session was also higher in the ischemic than in the control group for the first 20 min (17 354 ± 6 528 vs 13 355 ± 2 936 beats/min • mmHg, respectively; P=0.08), 40 min (16 329 ± 5 407 vs 12 452 ± 2 330 beats/min • mmHg, respectively; P=0.04), and 60 min training sessions (18 750 ± 5 698 vs 13 352 ± 2 947 beats/min • mmHg, respectively; P=0.02) No patient in either group demonstrated significant arrhythmias nor increased cTnT. The measured cTnT stayed below the detectable values of the essay (>0.01μg/l) for all patients at all times. Left ventricular function remained unchanged in the ischemic group. Conclusion: In patients with IHD, prolonged and repeated ischemic training sessions up to 60 min can be well tolerated without evidence of myocardial injury, significant arrhythmias or left ventricular dysfunction. Thus exercising at or above the ischemic threshold does not appear deleterious under this kind of supervision.

BACKGROUND:C-reactive protein (CRP), a marker of inflammation, is increasingly measured to stratify coronary artery disease risk and guide clinical management. However, little is known about how inflammatory markers fluctuate over time in patients with stable ischemic heart disease.METHODS:We examined serial serum CRP values in 159 patients with histories spanning the clinical spectrum of ischemic heart disease. Two to 8 CRP measurements were made at intervals varying from 15 days to 6 years. Successive interleukin (IL)-6 values were examined in 1 subgroup. Blood samples were always taken when patients were clinically stable, in the absence of any potentially confounding inflammatory condition.RESULTS:C-reactive protein values in individual patients fluctuated considerably when examined in the following ranges: less than 1 mg/L, 1 to 3 mg/L, and greater than 3 mg/L, proposed to indicate low, average, and high risk. Sixty-four patients (40.3%) changed risk category between the first and the second measurement. Within-patient variances of CRP and IL-6 levels were 1.79 mg/L (95% confidence interval, 1.60-2.00) and 2.69 pg/mL (95% confidence interval, 2.29-3.18), respectively. The variability of CRP was consistent over different times and across clinical groups, and independent of body mass index, smoking status, medication, and clinical events.CONCLUSIONS:Relatively important fluctuations in CRP levels in patients with stable ischemic heart disease may be problematic for risk stratification and treatment monitoring. A similar IL-6 variability suggests that these patients have a dynamic inflammatory status whose kinetics may modulate acute coronary risk.

Background—The impact of cyclooxygenase (COX)-2 antagonist treatment on acute coronary risk is controversial. We investigated the effect of prolonged COX-2 inhibition on inflammatory profile and endothelial function in patients with ischemic heart disease and high serum C-reactive protein (CRP) values. Methods and Results—In a double-blind study, 35 stable subjects on low-dose aspirin with ≥2 previous acute coronary events and 2 of 2 screening CRP values >2.0 mg/L were randomized to the COX-2 inhibitor rofecoxib (25 mg) or placebo daily for 6 months. Serum CRP, interleukin-6 (IL-6), P-selectin, matrix metalloproteinase-9 (MMP-9), and brachial artery endothelial function were evaluated. In the placebo group, CRP (median) was 3.16 mg/L (25% and 75% quartiles, 1.90 and 5.78 mg/L) at baseline and 4.22 mg/L (25% and 75% quartiles, 2.04 and 6.25 mg/L) at 6 months; in the rofecoxib group, CRP was 3.45 mg/L (25% and 75% quartiles, 2.08 and 5.78 mg/L) at baseline and 1.41 mg/L (25% and 75% quartiles, 1.17 and 4.81 mg/L) at 6 months (P=0.03). Rofecoxib compared with placebo also lowered IL-6 at 6 months (P=0.0002). There was a significant off-drug effect on CRP and IL-6 levels in the rofecoxib group 3 months after treatment (P=0.005 and P=0.009, respectively). Rofecoxib did not significantly affect P-selectin, MMP-9, and brachial artery vasoreactivity. Conclusions—Prolonged COX-2 inhibition attenuates CRP and IL-6, does not modify P-selectin and MMP-9, and has no deleterious effect on endothelial function in stable patients with a history of recurrent acute coronary events and raised CRP. These results strengthen the rationale for evaluating the clinical benefit of COX-2 inhibition in patients with ischemic heart disease.

BACKGROUND:The relation of the warm-up ischemia phenomenon to the presence and intensity of initial myocardial ischemia is unclear. We sought to determine whether the warm-up ischemia phenomenon requires initial myocardial ischemia or can be induced by exercise without ischemia and whether there is a relation between the intensity of initial ischemia and the attenuation of ischemia on reexercise. METHODS AND RESULTS:Twelve subjects with exertional myocardial ischemia performed 2 exercise ECG tests (1 and 2) at a +/-10-minute interval on 3 occasions (A, B, C) 1 month apart. A1 and A2 were symptom-limited. B1 was kept as long as A1, but its intensity was held under the ischemic threshold (heart ratexsystolic pressure at 1-mm ST depression [STD]) noted at A1. B2 was symptom-limited. C1 was also kept as long as A1 but with an intensity adjusted to maintain one-half maximum STD of A1. C2 was symptom-limited. Exercise duration of A2, B2, and C2 increased similarly compared with A1 (P=0.009). However, the ischemic threshold (x10-3) increased at A2 (23.5+/-6.0) compared with A1 (20.3+/-4.8; P<0.0001) but not at B2 (19.8+/-5.0) or C2 (21.5+/-5.8). Similarly, maximum STD adjusted to the highest heart rate-systolic pressure product common to A1, A2, B2, and C2 decreased at A2 (1.4+/-0.7 mm) compared with A1 (2.5+/-0.9 mm; P<0.0001) but not at B2 (2.7+/-0.9 mm) or C2 (2.3+/-0.9 mm). CONCLUSIONS:Exercises under the ischemic threshold and of intermediate ischemic intensity increase short-term exercise capacity, but myocardial ischemia of more than moderate intensity is needed to induce the warm-up ischemia phenomenon.

To investigate whether marked and sustained lipid-lowering in subjects with stable angina pectoris and dyslipidemia reduces exercise-induced myocardial ischemia, 17 subjects were treated with dose-adjusted atorvastatin over 1 year and underwent serial evaluation of exercise electrocardiographic ischemic parameters, serum biomarkers, and brachial artery endothelial function. Endothelial function improved progressively and C-reactive protein, P-selectin, and tissue plasminogen activator inhibitor levels decreased, but there was no decrease in exercise electrocardiographic ischemia.

Anteroseptal myocardial infarction is defined by the presence of electrocardiographic Q-waves limited to precordial leads V(1) to V(2), V(3), or V(4). We sought to determine whether this term is appropriate by correlating electrocardiographic, echocardiographic, and angiographic findings. We studied 50 consecutive patients admitted for a first acute myocardial infarction with Q-waves in precordial leads V(1) to V(2)-V(4), and who had undergone echocardiography and coronary angiography during hospitalization. Echocardiograms in the apical long-axis, two-chamber, and four-chamber views were studied using a wall motion scoring index.Q-waves were present in precordial leads V(1)-V(2) in 4 patients, V(1)-V(3) in 28 patients, and V(1)-V(4) in the remaining 18 patients. The presumptive culprit lesion was in the proximal segment of the left anterior descending artery in 15 patients, in the middle segment in 33 patients, and indeterminate in 2 patients. This lesion was before the first septal branch in 19 patients and after the first septal branch in 29. Mean (+/- SD) left ventricular ejection fraction was 51% +/- 10%. Echocardiographic analysis showed that the septal wall was never the only wall that was affected. However, the apex was affected in all patients and was the only wall that was affected in 26 (52%) patients (apical wall index, 2.1 +/- 0.5). In the remaining 24 patients, the septum was also affected (septal index, 1.5 +/- 0.3), but less severely than was the apex (apical index, 2.3 +/- 0.4; P <0.0001 vs. septum). In these 24 patients, the anterior and lateral walls were also affected (anterior index, 1.4 +/- 0.4; lateral index, 1.1 +/- 0.2), but again, less severely than was the apex (P <0.0001 for both vs. apex). Neither angiographic nor echocardiographic data support the notion of an isolated anteroseptal myocardial infarction. Left anterior descending artery involvement appears more often to be midsegment and postseptal. The apex is always and principally affected. These findings suggest that anteroseptal myocardial infarction is a misnomer and that the V(1) to V(2)-V(4) Q-wave pattern should be considered to indicate a predominantly apical, and generally limited, myocardial infarction.