Karen Stocke

Increased mortality after coronary artery bypass graft surgery is associated with increased levels of postoperative creatine kinase-myocardial band isoenzyme release: Results from the GUARDIAN trial

OBJECTIVES We sought to determine if elevated cardiac serum biomarkers after coronary artery bypass graft surgery (CABG) are associated with increased medium-term mortality and to identify patients that may benefit from better postoperative myocardial protection. BACKGROUND The relationship between the magnitude of cardiac serum protein elevation and subsequent mortality after CABG is not well defined, partly because of the lack of large, prospectively studied patient cohorts in whom postoperative elevations of cardiac serum markers have been correlated to medium- and long-term mortality. METHODS The GUARD during Ischemia Against Necrosis (GUARDIAN) study enrolled 2,918 patients assigned to the entry category of CABG and considered as high risk for myocardial necrosis. Creatine kinase-myocardial band (CK-MB) isoenzyme measurements were obtained at baseline and at 8, 12, 16 and 24 h after CABG. RESULTS The unadjusted six-month mortality rates were 3.4%, 5.8%, 7.8% and 20.2% for patients with a postoperative peak CK-MB ratio (peak CK-MB value/upper limits of normal [ULN] for laboratory test) of < 5, > or = 5 to <10, > or =10 to < 20 and > or =20 ULN, respectively (p < 0.0001). The relationship remained statistically significant after adjustment for ejection fraction, congestive heart failure, cerebrovascular disease, peripheral vascular disease, cardiac arrhythmias and the method of cardioplegia delivery. Receiver operating characteristic curve analysis revealed an area under the curve of 0.648 (p < 0.001); the optimal cut-point to predict six-month mortality ranged from 5 to 10 ULN. CONCLUSIONS Progressive elevation of the CK-MB ratio in clinically high-risk patients is associated with significant elevations of medium-term mortality after CABG. Strategies to afford myocardial protection both during CABG and in the postoperative phase may serve to improve the clinical outcome.

Prognostic value of dipyridamole thallium-201 imaging in elderly patients☆

The prognostic value of intravenous dipyridamole myocardial perfusion imaging has not been studied in a large series of elderly patients. Patients greater than or equal to 70 years of age with known or suspected coronary artery disease were evaluated to determine the predictive value of intravenous dipyridamole thallium-201 imaging for subsequent cardiac death or nonfatal myocardial infarction. Of the 348 patients, 207 were symptomatic and 141 were asymptomatic; 52% of the asymptomatic group had documented coronary artery disease. During 23 +/- 15 months of follow-up, there were 52 cardiac deaths, 24 nonfatal myocardial infarctions and 42 revascularization procedures (percutaneous transluminal coronary angioplasty in 20; coronary artery bypass surgery in 22). Clinical univariate predictors of a cardiac event included previous myocardial infarction, congestive heart failure symptoms, hypercholesterolemia and diabetes (all p less than 0.05). The presence of a fixed, reversible or combined thallium-201 defect was significantly associated with the occurrence of cardiac death or myocardial infarction during follow-up (p less than 0.05). Cardiac death or nonfatal myocardial infarction occurred in only 7 (5%) of 150 patients with a normal dipyridamole thallium-201 study (p less than 0.001). Stepwise logistic regression analysis of clinical and radionuclide variables revealed that an abnormal (reversible or fixed) dipyridamole thallium-201 study was the single best predictor of cardiac events (relative risk 7.2, p less than 0.001). As has been demonstrated in younger patients, previous myocardial infarction (relative risk 1.8, p less than 0.001) and symptoms of congestive heart failure at presentation (relative risk 1.6, p = 0.02) were also significant independent clinical predictors of cardiac death or myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

The Anti-Ischemic Mechanism of Action of Ranolazine in Stable Ischemic Heart Disease

OBJECTIVES The purpose of this explanatory analysis was to investigate the relationship between ST-segment depression and the rate-pressure product (RPP) during exercise to determine whether ranolazines mechanism of action was related to a reduction in myocardial oxygen demand or preservation of myocardial oxygen supply. BACKGROUND In patients with stable ischemic heart disease, ranolazine increases exercise duration and reduces maximal ST-segment depression while exerting minimal effects on heart rate and blood pressure, although its mechanism of action during exercise has not been investigated. METHODS Patients with stable ischemic heart disease (n = 191) were randomly allocated to a 4-period, double-blind, balanced Latin square crossover study to receive placebo, and ranolazine 500, 1,000, and 1,500 mg twice daily (bid) for 1 week each. Exercise treadmill tests were performed at baseline and at the end of each treatment period. The RPP and ST-segment depression were assessed before starting exercise, at each stage of exercise, and at maximal exercise. RESULTS Compared with placebo, ranolazine produced a dose-dependent reduction in ST-segment depression that became more marked as exercise-induced ischemia became more pronounced, associated with clinically minor decreases in heart rate and blood pressure. At 12-min exercise, the amount of ST-segment depression compared with placebo and controlled for RPP was reduced by 22.3% on ranolazine 500 mg bid (p = 0.137), by 35.4% on 1,000 mg bid (p = 0.005), and by 45.8% on 1,500 mg bid (p < 0.001). CONCLUSIONS The progressive magnitude of ischemia reduction on ranolazine was proportionally more substantial than the minor reductions in heart rate or RPP, suggesting that ranolazines beneficial mechanism of action is most likely primarily due to an improvement in regional coronary blood flow in areas of myocardial ischemia.

Methodology of Serial ECG Classification Using an Adaptation of the NOVACODE for Q Wave Myocardial Infarction in the Bypass Angioplasty Revascularization Investigation (BARI)

Serial electrocardiographic (ECG) changes are a critical component of the diagnostic algorithm for classification of myocardial ischemic events in large-scale clinical trials. This study describes a computerized serial ECG classification program developed at the St. Louis University Core ECG Laboratory for use in the Bypass Angioplasty Revascularization Investigation (BARI) trial, in which patients with multivessel coronary artery disease were randomized to receive either coronary artery bypass grafting or percutaneous transluminal coronary angioplasty. The St. Louis University program detects and codes serial changes in Q, ST, and T wave items according to Minnesota code (MC) criteria using a modified NOVACODE hierarchical classification system. Measurements using a seven-power calibrated coding loupe are used to generate the MC from a customized software program. Significant minor or major changes are detected by the serial comparison program and referred to a physician coder for verification. Serial comparison coding rules are used to adjust for weaknesses in the standard MC classification system resulting from instability at decision boundaries. Of 4,244 BARI randomized and registry study participants with follow-up ECGs received at the Core ECG Laboratory as of March 1995, a grade 2 MC Q wave progression was noted in 568 participants (13.4%) using MC criteria alone, as compared with 367 (8.6%) after the St. Louis University coding rules were applied. The incidence of grade 1 MC Q wave progressions was 16.4% (697/4,244) versus 6.1% (259/4,244) when the St. Louis University program was applied. Intraobserver variability for grade 2 Q wave progression codes determined from a sample of 812 serial.

Prognostic significance of exercise thallium-201 testing in patients aged ≥70 years with known or suspected coronary artery☆

Abstract The prognostic value of exercise thallium-201 myocardial perfusion imaging has not been studied in an elderly (aged ≥70 years) population. Retrospective analysis of 120 consecutive elderly patients undergoing Bruce protocol exercise stress with quantitative planar thallium-201 scintigraphy, followed clinically for a mean of 36 ± 12 months after testing, revealed a 10% cardiac event rate (6 cardiac deaths from arrhythmia or congestive heart failure, and 5 fatal and 1 nonfatal myocardial infarction). There were no exercise stress-related complications. Survival without cardiac events was associated with greater exercise duration (5.6 ± 2.4 vs 3.1 ± 2.4 minutes; p 15%, respectively.

The QT interval and risk of incident atrial fibrillation

BACKGROUND Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine. OBJECTIVE To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF. METHODS We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas. RESULTS Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts. CONCLUSIONS A prolonged QT interval is associated with an increased risk of incident AF.

Prognostic significance of elevated creatine kinase MB after coronary bypass surgery and after an acute coronary syndrome: Results from the GUARDIAN trial

OBJECTIVE To determine if the correlation between magnitude of creatine kinase-myocardial band release after coronary artery bypass surgery and 6-month mortality is comparable to that of patients admitted with an acute coronary syndrome. METHODS The GUARDIAN trial tested the efficacy of cariporide, an Na+/H+ exchange inhibitor, on reduction of myocardial ischemia or death in high-risk patients. We compared 6-month survival in a cohort of 2332 GUARDIAN patients scheduled for coronary artery bypass surgery at entry with 4233 acute coronary syndrome patients stratified by level of creatine kinase-myocardial band release. Cumulative 6-month survival by creatine kinase-myocardial band categories was performed using life table analysis, adjusting for variables known to impact prognosis using Cox regression. RESULTS The 6-month mortality rates for coronary artery bypass surgery patients with peak creatine kinase-myocardial band ratios of <1, > or =1 and <5, > or =5 and <10, and > or =10 upper limits of normal (ULN) were 5.8, 2.8, 5.9, and 12.0%, respectively (P <.0001). The 6-month mortality rates for acute coronary syndrome patients with peak creatine kinase-myocardial band ratios of <1, > or =1 and <5, > or =5 and <10, and > or =10 ULN were 6.3, 9.8, 10.0, and 12.3%, respectively (P <.0001). Patients with coronary artery bypass surgery or acute coronary syndrome had similar adjusted 6-month survival estimates at normal creatine kinase-myocardial band levels and when the creatine kinase-myocardial band level was > or =10 ULN. Patients with coronary artery bypass surgery had significantly better survival at intermediate enzyme levels (> or =1 and <10 ULN; P <.001). CONCLUSIONS Modest elevations of creatine kinase-myocardial band release (> or =1 and <10 ULN) after coronary artery bypass surgery are not associated with adverse 6-month survival, in contrast to that seen in acute coronary syndrome patients. Routine creatine kinase-myocardial band sampling should be considered in all higher-risk patients undergoing coronary artery bypass surgery procedures to identify the sizable cohort of patients with creatine kinase-myocardial band release > or =10 ULN; these patients may benefit from postoperative angiotensin-converting enzyme inhibitor and beta-blocker therapy. Newer cardioprotective agents that reduce the number of patients with marked creatine kinase-myocardial band release are currently being tested in large randomized controlled clinical trials.

Application of computerized exercise ECG digitization. Interpretation in large clinical trials.

The authors report on a semiautomated program that incorporates both visual identification of fiducial points and digital determination of the ST-segment at 60 ms and 80 ms from the J point, ST slope, changes in R wave, and baseline drift. The off-line program can enhance the accuracy of detecting electrocardiographic (ECG) changes, as well as reproducibility of the exercise and postexercise ECG, as a marker of myocardial ischemia. The analysis program is written in Microsoft QuickBASIC 2.0 for an IBM personal computer interfaced to a Summagraphics mm1201 microgrid II digitizer. The program consists of the following components: (1) alphanumeric data entry, (2) ECG wave form digitization, (2) calculation of test results, (4) physician overread, and (5) editor function for remeasurements. This computerized exercise ECG digitization-interpretation program is accurate and reproducible for the quantitative assessment of ST changes and requires minimal time allotment for physician overread. The program is suitable for analysis and interpretation of large volumes of exercise tests in multicenter clinical trials and is currently utilized in the TIMI II, TIMI III, and BARI studies sponsored by the National Institutes of Health.

Analysis of ST-segment shift in lead AVR improves short-term prognostic risk stratification in acute coronary syndrome

0.5 mm ST segment displacement was assessed in the 12-lead ECG at baseline for the remaining 3,657 pts. Results were correlated to &month mortality. Results: There were 442 (11.5%) pts who had STEz1.00 mm in lead aVR. The B-month mortality rates were 29.2% (129/442) in pts with STE 21 .OO mm in lead aVR vs 4.6% (165/3,415) in pts without STE 21 .OO mm in lead aVR (pcO.001). The 6-month mortality rates were 29.4% (1211412) in pts with STE 51.00.~2.00 mm I” lead aVR and 26.7% (6/ 30) in pts with STE ZOO mm in lead aVR (p=O.92). All pts with STE >I.00 mm in lead aVR had ST segment depression (STD) to.5 mm in other leads. There was a strong correlation between STE in lead aVR and the sum of STD in other leads (r=O.63, p l .OO mm in lead aVR were 7.2% (1 Oll1407) if STD was present vs 3.2% (64/2,006) if STD was absent (p

Effects of posture on metabolic and hemodynamic predischarge exercise response after acute myocardial infarction

Predischarge exercise testing after acute myocardial infarction (AMI) is an important noninvasive modality for risk stratification. To study the impact of position on cardiopulmonary exercise response, 30 patients performed symptom-limited upright treadmill and supine bicycle ergometry exercise an average of 8 days after an AMI. The exercise sequence was randomly assigned with a minimum 4-hour interval between tests. Exercise time and peak oxygen consumption were significantly greater in the upright position (7.0 +/- 2.0 vs 5.6 +/- 2.0 minutes; p less than 0.001 and 14.9 vs 12.0 ml/min/kg; p less than 0.001, respectively). Compared to the supine position, exercise in the upright position was associated with a significant increased incidence of ischemic exercise-induced ST-segment depression (33 vs 20%; p less than 0.03), and chest pain (20 vs 10%; p less than 0.04). Thus, position is an important determinant of myocardial ischemic response and exercise tolerance in patients who perform symptom-limited exercise tests early after AMI.