Thrombogenic factors and recurrent coronary events.

BACKGROUND: Thrombosis is a pivotal event in the pathogenesis of coronary disease. We hypothesized that the presence of blood factors that reflect enhanced thrombogenic activity would be associated with an increased risk of recurrent coronary events during long-term follow-up of patients who have recovered from myocardial infarction. METHODS AND RESULTS: We prospectively enrolled 1045 patients 2 months after an index myocardial infarction. Baseline thrombogenic blood tests included 6 hemostatic variables (D-dimer, fibrinogen, factor VII, factor VIIa, von Willebrand factor, and plasminogen activator inhibitor-1), 7 lipid factors [cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, lipoprotein(a), apolipoprotein (apo)A-I, and apoB], and insulin. Patients were followed up for an average of 26 months, with the primary end point being coronary death or nonfatal myocardial infarction, whichever occurred first. The hemostatic, lipid, and insulin parameters were dichotomized into their top and the lower 3 risk quartiles and evaluated for entry into a Cox survivorship model. High levels of D-dimer (hazard ratio, 2.43; 95% CI, 1.49, 3.97) and apoB (hazard ratio, 1.82; 95% CI, 1.10, 3.00) and low levels of apoA-I (hazard ratio, 1.84; 95% CI, 1.10, 3.08) were independently associated with recurrent coronary events in the Cox model after adjustment for 6 relevant clinical covariates. CONCLUSIONS: Our findings indicate that a procoagulant state, as reflected in elevated levels of D-dimer, and disordered lipid transport, as indicated by low apoA-1 and high apoB levels, contribute independently to recurrent coronary events in postinfarction patients.

Higher prevalence and greater severity of coronary disease in short versus tall men referred for coronary arteriography.

The incidence of myocardial infarction is higher in short individuals than in tall ones. To test whether the prevalence and severity of coronary disease is greater in short than in tall individuals, we compared a group of short men (height < [mean height - one SD]) to a group of tall men (height > [mean height + one SD]) drawn from a sample of 1046 consecutive men referred for coronary arteriography. Short men had a higher frequency of > or = 50% diameter stenosis; more diseased vessels (1.61 +/- 1.09 vs 1.15 +/- 1.11, p = 0.0004); a higher frequency of three-vessel disease (26.8% vs 16.1%, p = 0.04); and more total occlusions (40.1% vs 27.3%, p = 0.03). By multivariate analysis, height independently predicted > or = 50% lesions in the right coronary artery (p = 0.01) and left anterior descending artery (p = 0.06); three-vessel disease (p = 0.04); total occlusion (p = 0.04); and the number of diseased vessels (p = 0.005). This higher prevalence and greater severity of coronary disease may explain the higher incidence of and deaths caused by myocardial infarction previously reported in short men.

Spectral analysis of demodulated ultrasound returns: detection of scatterer periodicity and application to tissue classification.

Ultrasound returns from tissue display variations in amplitude on several spatial scales. Although large-scale variations result from factors such as attenuation, variations on smaller scales are caused by tissue characteristics such as variations in scatterer spacing and reflectance. These small scale variations cause a corresponding variation in the amplitude of the ultrasound return. A simple and direct method for detecting and quantifying periodicity in these variations in the presence of attenuation is described. The radiofrequency ultrasound return is first demodulated by full-wave rectification. The normalized power spectrum of the demodulated return then yields an index that we call the relative Fourier energy. Both computer simulations and in vitro experiments were performed in order to study how relative Fourier energy performed in discriminating between periodic and random scatterer distributions. Computer simulations demonstrated significant differences between the returns from periodic and random scatterer distributions. Ultrasound returns from aortic tissue yielded a relative Fourier energy index that was significantly different between normal vs. atherosclerotic tissue (normal: 0.868 +/- 0.076, mean +/- s.d., fibrofatty plaque: 0.705 +/- 0.109, p < 0.01 vs. normal, calcified plaque: 0.753 +/- 0.078, p < 0.01 vs. normal). In contrast, no difference was found in comparisons of overall reflectance.

Effect of coronary artery size on the prevalence of atherosclerosis.

To investigate the effect of coronary artery size on the prevalence of atherosclerosis, we measured the diameters of the major coronary arteries prospectively in 884 consecutive patients referred for coronary arteriography. For each artery, we assigned patients to 3 groups: group S (small) and group L (large) with diameters >1SD smaller and larger, respectively, than the mean; and group A (average), with diameters within 1SD of the mean. As specified during study design, we compared the frequency of lesions > or = 50% diameter stenosis in groups S and L for each artery. We adjusted for relevant covariates by performing logistic regression on data from all 884 patients with coronary diameter entered as a continuous variable. In group S versus L, respectively, the frequency of > or = 50% lesion was 6.5% versus 2.4% (p = 0.13) in the left main artery; 61.3% versus 35.8% (p = 0.0001) in the right coronary artery; 58.1% versus 40.7% (p = 0.008) in the left anterior descending artery, and 47.4% versus 22.2% (p = 0.0001) in the circumflex artery. Multivariate analysis showed that coronary diameter was a significant independent predictor of lesions in the right coronary artery (p = 0.000001), left anterior descending artery (p = 0.001), and circumflex artery (p = 0.0002) and nearly significant in the left main artery (p = 0.077). Thus, small coronary artery size may be a risk factor for atherosclerosis.

Detection and significance of myocardial ischemia in women versus men within six months of acute myocardial infarction or unstable angina. The Multicenter Myocardial Ischemia Research Group.

Ischemia detection after an acute coronary event predicts subsequent cardiac events. However, gender-related aspects in the prevalence and prognostic significance of ischemia detection after an acute coronary event have not been reported. Noninvasive tests, which included resting 12-lead electrocardiogram (ECG), 24-hour ambulatory ECG, exercise ECG, and thallium-201 stress scintigraphy were performed in 936 stable patients (224 women and 712 men) 1 to 6 months (average 2.7) after an acute coronary event (i.e., myocardial infarction or unstable angina). Primary end points during an average follow-up of 23 months included cardiac death, nonfatal myocardial infarction, and unstable angina, while restricted end points included the first 2. Ischemia detection was significantly less frequent among women than among men on 24-hour ambulatory ECG, exercise ECG, and thallium-201 stress scintigraphy. Primary end points occurred in 19.2% of women and in 19% of men, and restricted end points occurred in 5.8% of women versus 8%. of men (p = NS). Cox analyses revealed that gender and its interaction with each of the ischemia tests did not contribute to the prediction of the primary or restricted end points. We conclude that in stable patients 1 to 6 months after an acute coronary event, ischemia detection by noninvasive tests was significantly less prevalent in women than in men. However, subsequent cardiac event rates in women were similar to those observed in men, and there was no gender-ischemic detection interaction regarding subsequent events.

Noncardiac surgery in the cardiac patient: what is the question?

Before having major noncardiac surgery, patients with known or suspected coronary artery disease frequently have noninvasive cardiac testing to better define their cardiac risk. The rationale for this approach is that prophylactic coronary revascularization will significantly reduce the number of adverse cardiac events. No randomized studies support this conclusion. Furthermore, recent studies have suggested that adverse cardiac events result from postoperative stress and excess catecholamine levels, which cause an imbalance between myocardial oxygen supply and demand. Plaque rupture in this setting, if it occurs, is secondary and not primary, in contrast to its pivotal role in spontaneous myocardial infarction. Therefore, improved clinical outcomes are more likely to result from preventing excess oxygen demand after surgery rather than from deciding which tests optimally predict adverse events. The exception is the patient with a clinical syndrome consistent with existing plaque rupture who requires active therapy for the cardiac disease independent of the need for noncardiac surgery. Otherwise, the tests should be skipped and the patient cleared.

Use of P-wave-triggered, P-wave signal-averaged electrocardiogram to predict atrial fibrillation after coronary artery bypass surgery.

Atrial fibrillation occurs commonly after coronary artery bypass surgery. However, despite numerous attempts at prediction, no accurate and generally accepted method exists to predict its occurrence. P-wave-triggered P-wave signal averaging was performed on 54 patients before coronary artery bypass surgery to evaluate the utility of this method to predict atrial fibrillation after coronary artery bypass surgery. After excluding six patients with unevaluable P-wave signal averages and three patients with postoperative arrhythmias other than atrial fibrillation, the P-wave signal averages of 45 patients were analyzed. Sixteen patients had postoperative atrial fibrillation and 29 did not. The mean P-wave duration of the filtered, signal-averaged P wave was 163 +/- 19 msec in the 16 patients with atrial fibrillation and 144 +/- 16 msec in the 29 patients without (p < 0.005). Left atrial enlargement on the surface electrocardiogram (ECG) was the only other statistically significant variable that correlated weakly with the onset of postoperative atrial fibrillation (p = 0.04). Other clinical variables such as P-wave duration in ECG lead II, left ventricular hypertrophy on ECG, age, sex, hypertension, and left ventricular ejection fraction were not significantly different between the two groups. With a cut point of 155 msec, chi-squared analysis revealed a p value of < 0.005, yielding a sensitivity of 69%, a specificity of 79%, a positive predictive value of 65%, and a negative predictive value of 82%. Signal-averaging of the P wave in patients before coronary artery bypass surgery provides a good predictor of postoperative atrial fibrillation.

Prognostic significance of a fixed thallium defect one to six months after onset of acute myocardial infarction or unstable angina. Multicenter Myocardial Ischemia Research Group.

In a large prospective study of myocardial ischemia, exercise thallium studies were performed in 896 patients 1 to 6 months after an acute coronary event (acute myocardial infarction, 70%; unstable angina, 30%). Thallium images were analyzed quantitatively and classified as normal or demonstrating either a reversible defect after 2 to 4 hours or having only a fixed defect. The effect of the thallium findings on the time to end point (cardiac death, nonfatal infarction, or unstable angina) were examined by Kaplan-Meier curves and compared using the log-rank statistic. Follow-up averaged 23 months. The likelihood of cardiac death, nonfatal infarction, and unstable angina was similar in patients who had a normal exercise thallium test result or showed only a fixed defect. Moreover, cardiac events were not related to the size of a fixed defect. In contrast, both cardiac death and nonfatal infarction were increased in patients with the largest areas of reversible defects, although the sensitivity for nonfatal myocardial infarction was suboptimal. The presence of a fixed defect on exercise thallium in patients who are stable an average of 2.6 months after an acute cardiac event is associated with a prognosis similar to that of a normal exercise thallium test.

Limited usefulness of exercise testing and thallium scintigraphy in evaluation of ambulatory patients several months after recovery from an acute coronary event: implications for management of stable coronary heart disease. Multicenter Myocardial Ischemia Research Group.

OBJECTIVES: This study evaluated the value of noninvasive testing to predict cardiac events in patients with stable coronary disease after hospital admission (and risk stratification) for an acute coronary event. BACKGROUND: Exercise testing with thallium perfusion imaging identifies patients with obstructive coronary artery disease and has been used to stratify patients after myocardial infarction. Its usefulness for predicting cardiac events in patients with stable coronary disease after recovery from an acute coronary event was explored. METHODS: Nine hundred thirty-six patients were enrolled 1 to 6 months after hospital admission for a coronary event. Patients underwent exercise treadmill testing with planar thallium-201 scintigraphy and were followed up for an average of 23 months (range 6 to 43). End points were 1) unstable angina requiring hospital admission, nonfatal myocardial infarction or cardiac death; 2) nonfatal infarction or cardiac death; or 3) cardiac death alone. RESULTS: Twelve patients died of cardiac causes (1.2%); 32 had a nonfatal myocardial infarction (3.4%); and 79 patients (8.4%) developed unstable angina in the first year. Exercise testing improved proportional hazards models constructed from clinical variables for all three end points (p < 0.05). The perfusion scan further improved models for the end points (nonfatal infarction or cardiac death and cardiac death alone, p < 0.05). However, the exercise test with or without thallium added little to the overall prediction of primary events (area under the receiver operating curve increased from 0.649 to 0.663), and only 2% to 13% of patients with abnormal results either had a nonfatal infarction or died. CONCLUSIONS: Thallium-201 scintigraphy and exercise testing variables identify patients at risk for subsequent cardiac events. However, the poor predictive performance of these tests in this group of patients with stable coronary disease severely limits their usefulness. These results suggest a limited role for exercise and thallium testing in predicting cardiac events in patients with known coronary disease.

Relation between myocardial infarct location and stroke.

OBJECTIVES: We sought to compare the likelihood of stroke in patients with anterior versus nonanterior myocardial infarction. BACKGROUND: The association between anterior infarction and left ventricular thrombus has led to the assumption that embolization from thrombi is an important cause of stroke in patients with anterior infarction. We hypothesized that if anterior infarction is a cause of left ventricular thrombi, the number of strokes should be disproportionately higher in patients with anterior than nonanterior infarction. METHODS: We performed a retrospective analysis of 2,466 patients randomized from day 3 to day 15 after infarction as part of a multicenter placebo-controlled study of diltiazem to prevent cardiac death or myocardial infarction. Any acute focal cerebral disorder resulting in localizing findings characterized as a stroke or transient ischemic attack was considered an event. RESULTS: Of 91 events during a follow-up period of 12 to 52 months, 23 (3.2%) occurred in 724 patients with an anterior and 68 (3.9%) in 1,742 patients with a nonanterior myocardial infarction (relative risk 0.81; 95% confidence interval 0.51 to 1.30). Power analysis revealed that the negativity of the study was not the result of inadequate sample size. Life table analysis showed no difference in cumulative event rate (p = 0.42) according to site of infarction. Cox regression analysis showed that of 10 clinical covariates, only systolic blood pressure was predictive of stroke (p < 0.001). The use of warfarin did not contribute to the model. Finally, the addition of site of infarction (anterior vs. nonanterior) did not contribute significantly to the Cox model. CONCLUSIONS: Although there is a significant incidence of stroke after acute myocardial infarction, there is no relation between the occurrence of stroke and site of infarction. These data do not support the presumed causal relation between anterior myocardial infarction, thrombus and stroke.

Differentiation of beats of ventricular and sinus origin using a self-training neural network.

Despite advances in the computerized detection of arrhythmias, arrhythmia recognition by morphological waveform analysis still poses a difficult problem. Artificial neural networks, computer algorithms that are self-trained by an analog of biological synaptic modification to perform pattern recognition, hold great promise for the differentiation of various cardiac rhythms. The goal of this study was to differentiate beats of sinus and ventricular origin on a global basis and on a patient-specific basis by the use of artificial neural network analysis. Neural networks were trained to recognize digitized intracardiac electrograms (9 patients) and surface electrocardiograms (11 patients) obtained during sinus rhythm and ventricular tachycardia. After training, sinus rhythm or ventricular tachycardia beats were input into the neural network, and classified as to their origin. By the use of modified receiver operating characteristic curve plots, it was possible to differentiate with high sensitivity and specificity between beats of sinus origin and ventricular origin in all patients. The addition of high amounts of noise to the beats did not markedly degrade the performance of the surface ECG neural networks, and still allowed high sensitivity in differentiating beats of sinus origin from beats of ventricular origin, especially when noise was added to the training set. Neural networks provided sensitive and specific detection of cardiac electrical activity during sinus rhythm and ventricular tachycardia, and may play an important role in allowing development of improved arrhythmia recognition and management systems.

Echocardiographically guided electrophysiologic testing in pregnancy.

Electrophysiologic testing is usually performed with fluoroscopy to guide catheter positioning. This method of visualizing catheter placement may not be ideal for patients who are pregnant. We report four cases of echocardiographically guided placement of catheters for electrophysiologic testing because of the consideration of pregnancy. Adequate visualization of catheters was possible, allowing for proper catheter positioning and complete electrophysiologic testing, including the recording of atrial, His-bundle, and ventricular potentials, as well as cardiac stimulation and induction of tachycardia. This method holds promise for patients in whom fluoroscopy may be relatively contraindicated, such as pregnant patients, as well as patients in whom it is desirable to avoid x-ray exposure such as women of childbearing age and young children.

Effect of intravenous nitroglycerin on heparin dosage requirements in coronary artery disease.

Patients admitted to the coronary care unit who received both intravenous nitroglycerin and heparin were studied to evaluate heparin dosage requirements. Physicians ordered all nitroglycerin and heparin doses as well as coagulation studies without knowledge of this study. Activated partial thromboplastin time (APTT) values obtained during steady-state heparin administration were considered therapeutic if the ratio of APTT/APTT-baseline was > or = 1.5. Sixty patients with myocardial infarction or unstable angina were included in the study. The initial therapeutic heparin dose of 1,014 +/- 151 units/hour produced an APTT ratio of 2.0 +/- 0.5. At the time of the initial therapeutic dose, the nitroglycerin dose was 110 +/- 108 micrograms/min. There was a significant correlation between the initial therapeutic dose and both total (r = 0.56; p = 0.0001) and lean (r = 0.26; p < 0.05) body weight. Comparison of patients with nitroglycerin doses < and > or = 100 micrograms/min revealed a significant difference in the initial therapeutic dose (971 +/- 147 vs 1,077 +/- 136 U/hour, p < 0.01), but not the initial therapeutic dose standardized to total body weight (14.0 +/- 2.5 vs 13.5 +/- 2.7 U/kg/hour). Similarly, analysis of variance revealed a significant difference in the initial therapeutic dose (p < 0.05), but not the initial therapeutic dose standardized to weight among 5 different nitroglycerin dosage ranges (10 to 533 micrograms/min). Neither aspirin use, thrombolytic therapy nor decreasing or discontinuing the nitroglycerin dose significantly affected heparin requirements. Thus, contrary to prior reports, clinically significant heparin resistance induced by nitroglycerin was not found.

Prognostic significance from 10-year follow-up of a qualitatively normal planar exercise thallium test in suspected coronary artery disease.

A normal exercise thallium-201 scintigram has been shown to confer an excellent prognosis over a 1- to 4-year follow-up period. However, progression of coronary disease could result in cardiovascular mortality with increasing time. Therefore, the vital status of 309 patients with normal stress thallium myocardial imaging was determined after an average of 10.3 years. Deaths were classified as cardiac or noncardiac. Statistical analysis was performed using Kaplan-Meier survival curves. Standardized mortality ratios were calculated and compared with those of an age- and sex-matched general population. Follow-up was complete in 288 patients (93%). Of 18 deaths, only 3 were cardiac; the remaining 15 were mainly secondary to cancer. Thus, cardiac mortality was 1% and total mortality 6.3% at 10 years. In addition, both all-cause and cardiac mortality rates were significantly less than would be expected in an age- and sex-adjusted segment of the general population. Thus, normal exercise thallium scintigraphy retains its high negative predictive value for death < or = 10 years after initial testing. This supports the use of stress thallium imaging to predict which patients with suspected coronary artery disease are at low risk for cardiac death and thus do not need invasive testing.

Early and rapid prediction of patency of the infarct-related coronary artery by using left ventricular wall thickness as measured by two-dimensional echocardiography.

OBJECTIVES: The aim of this study was to determine whether echocardiography can distinguish between persistent coronary occlusion and reperfusion. BACKGROUND: There are no adequate clinical or noninvasive laboratory markers to accurately predict successful reperfusion in an acute myocardial infarction. METHODS: In a closed chest swine model, the effect of reperfusion on myocardial wall thickness was studied by comparing a 150-min total coronary artery occlusion (group 1) with 120 min of occlusion followed by 30 min of reperfusion (group 2) in the area of risk as measured by echocardiography. Wall thickness was measured at baseline and at 90 and 150 min. RESULTS: In group 1 (n = 4), there was no appreciable change in mean wall thickness from 90 min to 150 min of occlusion at either end-diastole or end-systole (0.54 +/- 0.02 to 0.52 +/- 0.03 cm, 0.55 +/- 0.03 to 0.54 +/- 0.03 cm, respectively; p = NS). In contrast, in group 2 (n = 6), an increase in mean wall thickness from 0.53 +/- 0.02 to 0.97 +/- 0.05 cm at end-diastole and from 0.56 +/- 0.04 to 1.04 +/- 0.07 cm at end-systole was found from 90 min of occlusion to 30 min of reperfusion (p < 0.001). Reperfusion resulted in an increase in wall thickness of 83 +/- 11% at end-diastole and 92 +/- 17% at end-systole. In contrast, persistent coronary occlusion showed minimal changes of -3.0 +/- 5% at end-diastole and -2.0 +/- 6% at end-systole. CONCLUSIONS: This study confirms the hypothesis that an increase in wall thickness can accurately distinguish between reperfusion and permanent coronary occlusion.

Risk stratification in coronary disease: a contrary viewpoint.

Noninvasive stress testing is generally recommended to detect patients who are at increased risk for cardiac death and myocardial infarction. Such tests depend on the presence of a physiologically significant coronary stenosis to detect disease. The low prevalence of events in patients who are able to exercise, however, results in a poor positive predictive value. Also, recent data suggest that a significant number of morbid events result from rapid progression of disease in segments of the coronary artery that initially had only minimal obstruction. Further, from a therapeutic standpoint, only catheterization has been shown in randomized trials to predict which patients are candidates for bypass surgery. Thus, noninvasive testing as an intermediate step to select those patients who require invasive study remains an attractive but unproven hypothesis.

Bypass surgery for chronic stable angina: predictors of survival benefit and strategy for patient selection.

The variable mortality risk associated with chronic stable angina calls for careful selection of patients for coronary artery bypass grafting (CABG) if the aim of management is to prolong life. The randomized and observational studies done in the last 20 years have identified the variables relevant to patient selection and thus have provided a rational basis for such clinical decisions. These studies showed that the sicker the patient, as gauged by relevant measures of coronary disease and cardiovascular morbidity, the more likely it is that CABG will prolong life. A CABG-related improvement in survival is therefore more likely to occur the worse the left ventricular function; the greater the number of diseased vessels; the more proximal the location of coronary lesions (more muscle is threatened by such lesions); the greater the severity of the lesions as determined by angiography; the more severe the angina; the more easily provocable the ischemia or the more extreme the measures of ischemia; and, within limits, the older the patient. Greater survival gain after CABG also occurs in patients with peripheral vascular disease, in patients with baseline electrocardiographic ST-segment and T-wave changes, and probably in women. Thus, patients are likely to live longer after CABG if they have left main disease; three-vessel disease with left ventricular dysfunction (ejection fraction less than 50%), class III or IV angina, provocable ischemia, or disease in the proximal left anterior descending coronary artery; two-vessel disease with proximal left anterior descending artery involvement; and two-vessel disease with class III or IV angina as well as either severe left ventricular dysfunction alone or moderate left ventricular dysfunction together with at least one proximal lesion. When the decision of whether to do CABG is less clear-cut, the presence of peripheral vascular disease, female sex, baseline electrocardiographic ST-segment and T-wave changes, or older age (over 60 but under 80 years) should weigh in favor of doing CABG. In general, patients with single-vessel disease do not seem to derive survival benefit from CABG.

Effect of coronary occlusion and myocardial viability on myocardial activity of technetium-99m-sestamibi.

The timing effect of sestamibi administration with respect to the onset of myocardial ischemia and reperfusion was studied in swine. In different groups of animals sestamibi was administered prior to coronary artery occlusion, during occlusion, or 1/2 hour following reperfusion. Sestamibi administered prior to coronary occlusion resulted in an insignificant decrease in 99mTc activity in the ischemic zone. However, infarct zone activity was reduced to 62 +/- 14% of the nonischemic zone. In contrast, administration during coronary occlusion resulted in similar significant reductions of both ischemic and infarct zone activity. Administration of sestamibi during reperfusion resulted in normal ischemic zone activity and markedly reduced activity in the infarct zone. Significantly reduced activity in the infarct zone was found to be independent of the timing of sestamibi administration with respect to the onset of myocardial ischemia and/or reperfusion. Thus, cell viability appears required for uptake and retention of isotope activity.