Luce Boyer

Biological Profiles in Subjects With Recurrent Acute Coronary Events Compared With Subjects With Long-Standing Stable Angina

Background—At one end of the clinical spectrum of coronary artery disease (CAD) are subjects who have had repeated acute ischemic events, and at the other end are those with long-standing angina who have never been unstable. This study tests the hypothesis that a specific biological profile can distinguish these 2 extreme groups and predict acute coronary events. Methods and Results—Blood levels of lipoprotein(a), homocysteine, tissue plasminogen activator, plasminogen activator inhibitor-1, C-reactive protein (CRP), fibrinogen, and von Willebrand factor were compared in 3 groups of 50 subjects each: (1) those with previous multiple acute coronary events, (2) age-matched subjects with ≥3 years of stable angina and no prior acute coronary events, and (3) matched controls without evidence of atherosclerotic disease and a normal coronary angiogram. All subjects were followed for 4.0 years. Lipoprotein(a), homocysteine, tissue plasminogen activator, and plasminogen activator inhibitor-1 were similar in both CAD groups and significantly higher than in the control group. However, compared with subjects with long-standing stable angina, those with previous multiple coronary events had higher values of CRP (5.7±5.4 versus 3.0±5.2 mg/L, P =0.012), fibrinogen (3.38±0.75 versus 2.92±0.64 g/L, P =0.001), and von Willebrand factor (1.60±0.55 versus 1.25±0.36 U/mL, P =0.0003). On follow-up, myocardial infarction and unstable angina occurred in 42% of the group with multiple events, 4% of the stable angina group (P <0.0001), and none of the control subjects. In the 100 patients with CAD, CRP was 4.9 mg/L in those with and 1.8 mg/L in those without new instability (P <0.0001). In a multivariate analysis, only CRP distinguished those with follow-up acute coronary events (adjusted odds ratio 5.9, 95% CI 2.0 to 17.9;P =0.002). A baseline CRP >3.5 mg/L had a relative risk of 7.6 (2.6 to 21.7, P =0.0002) for subsequent acute events. Conclusions—An inflammatory biological profile distinguished patients with previous multiple acute coronary events from those with long-standing stable angina and predicted acute coronary instability.

Clinical Utility of C-Reactive Protein Measured at Admission, Hospital Discharge, and 1 Month Later to Predict Outcome in Patients With Acute Coronary Disease: The RISCA (Recurrence and Inflammation in the Acute Coronary Syndromes) Study

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.

Atherogenic, hemostatic, and other potential risk markers in subjects with previous isolated myocardial infarction compared with long-standing uncomplicated stable angina

BACKGROUND Several atherogenic, hemostatic, inflammatory, and genetic parameters and markers have been implicated as risk factors in coronary artery disease, although whether they are risk factors for acute as opposed to chronic coronary disease is unclear. METHODS AND RESULTS Fifty subjects with an isolated myocardial infarction >3 months previously were compared with 50 subjects with a minimum 3-year history of stable angina, documented coronary artery disease, normal electrocardiogram and normal ventricular wall motion, and no episode suggesting infarction or unstable angina. Biologic variables analyzed included apolipoprotein B (apo B), lipoprotein (a), C-reactive protein (CRP), fibrinogen, factor VII, tissue plasminogen activator (TPA) and inhibitor (PAI-1), thrombin-antithrombin (TAT), fragment 1+2 (F1+2), von Willebrand factor (vWF), activated protein C resistance, homocyst(e)ine, anticardiolipin antibodies, blood group, and the angiotensin-converting enzyme insertion/deletion (I/D) and angiotensin II receptor gene polymorphisms. There were no significant differences between the 2 groups for any of the variables studied, although fibrinogen and F 1+2 tended to be slightly higher in the angina group (P = .09 for each). These significant correlations were present: age with fibrinogen, homocyst(e)ine, and vWF; factor VII with apo B, homocyst(e)ine, and TPA; apo B with TPA and CRP; CRP with fibrinogen, TPA, PAI-1, and factor VII; fibrinogen with vWF. CONCLUSIONS Examination of atherogenic, hemostatic, inflammation, and genetic variables in the clinically quiescent state permitted no distinction between subjects with a previous isolated myocardial infarction in contrast to those with long-standing uncomplicated stable angina, favoring the notion that acute coronary events occur at random on a varying background of atherosclerosis. The multiple correlations found among these variables also underscore their complex interaction in the atherosclerotic process.

Is anteroseptal myocardial infarction an appropriate term

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.

What Induces the Warm-Up Ischemia/Angina Phenomenon: Exercise or Myocardial Ischemia?

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 rate×systolic 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 (×10−3) 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.

Myocardial perfusion imaging findings and the role of adenosine in the warm-up angina phenomenon

OBJECTIVES This study examined the roles of myocardial perfusion and adenosine in warm-up angina. BACKGROUND In warm-up angina, neither the role of an adenosine-mediated mechanism, as is found in experimental ischemic preconditioning, nor of increased myocardial perfusion is well defined. METHODS In substudy A, a single-photon emission computed tomography (SPECT)-thallium-201 exercise test was performed by 12 subjects with ischemic heart disease on three occasions one week apart. The third test was preceded by a warm-up test. The extent of the thallium deficit and its intensity on the third test were compared with the baseline tests controlling for the heart rate-systolic blood pressure product (RPP) at thallium injection. In substudy B, 12 similar subjects did two successive exercise tests at two separate sessions and received the adenosine antagonist, aminophylline (intravenous 5 mg/kg bolus and 0.9 mg/kg/h infusion) at one session, and equivalent saline at the other session. Change in ischemic threshold (RPP at 1 mm ST segment depression) and in maximum ST depression adjusted for RPP were analyzed. RESULTS In substudy A, despite a significant attenuation of electrocardiogram indexes of myocardial ischemia between the baseline and third (warmed-up) tests, the thallium extent deficits (20.8 +/- 15.1% and 16.8 +/- 12.4%) and intensity deficits (41.2 +/- 12.6% and 39.3 +/- 12.6%) did not differ significantly. In substudy B, the increase in ischemic threshold on re-exercise was unaffected by aminophylline. Adjusted maximum ST depression even decreased to a greater extent on re-exercise with aminophylline (by 51 +/- 21%) than with saline (by 32 +/- 19%) (p = 0.012). CONCLUSIONS While warm-up angina is associated with a significant attenuation of exercise electrocardiogram indexes of ischemia, it is unaccompanied by significant changes in SPECT perfusion and does not appear to be mediated by an adenosine-dependent mechanism since it is not blocked by aminophylline. Thus, its mechanism, which appears distinct from experimental ischemic preconditioning, remains unidentified.

Randomized trial of a noninvasive strategy to reduce hospital stay for patients with low-risk myocardial infarction

OBJECTIVES This study evaluated the feasibility, pertinence and psychosocial repercussions of a noninvasive reduced hospital stay strategy (three days) for low-risk patients with acute myocardial infarction using simple clinical criteria and predischarge 24-h ambulatory ST-segment ischemic monitoring. BACKGROUND Previous studies evaluating shorter stays for uncomplicated myocardial infarction have been limited by retrospective or nonrandomized design and overdependence on invasive cardiac procedures. METHODS One-hundred twenty consecutive patients admitted with an acute myocardial infarction fulfilling low-risk criteria were randomized 2:1 to a short hospital stay (80 patients) or standard stay (40 patients). Short-stay patients with no ischemia on ST-segment monitoring were discharged on day 3, returning for exercise testing a week later. All analyses were on an intention-to-treat basis. RESULTS Forty-one percent of all screened patients with acute myocardial infarction would have been medically eligible for the short-stay strategy. Seventeen patients (21%) were not discharged early because of ischemia on ST-monitoring or angina. Median initial hospital stay was halved from 6.9 days in the standard stay to 3.5 days in the short-stay group. At six months, median total days hospitalized were 7.5 in the standard stay and 3.6 in the short-stay group (p < 0.0001). Adverse events and readmissions were low and not significantly different, and there were 25% fewer invasive cardiac procedures in the short-stay group. Psychosocial outcomes, risk factor changes and exercise test results were similar in the two groups. CONCLUSIONS This reduced hospital stay strategy for low-risk patients with acute myocardial infarction is feasible and worthwhile, resulting in a substantial and sustained reduction in days hospitalized. It is without unfavorable psychosocial consequences, appears safe and does not increase the number of invasive cardiac procedures.

Time Variability of C-Reactive Protein: Implications for Clinical Risk Stratification

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.

Usefulness of Soluble Fas Levels for Improving Diagnostic Accuracy and Prognosis for Acute Coronary Syndromes

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 ln 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 ln microg/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.

Genetic Polymorphisms and the Cardiovascular Risk of Non-Steroidal Anti-Inflammatory Drugs

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.