Khether E. Raby

Correlation between Preoperative Ischemia and Major Cardiac Events after Peripheral Vascular Surgery

Patients who undergo peripheral vascular surgery are at increased risk for postoperative cardiac events and are difficult to assess preoperatively because of limitations on their activity. We prospectively studied 176 consecutive eligible patients undergoing elective vascular surgery to determine the value in predicting a postoperative cardiac event of preoperative electrocardiographic monitoring to detect myocardial ischemia. Of the 176 patients, 32 (18 percent) had 75 episodes of monitored ischemic ST-segment depression preoperatively (of which 73 were asymptomatic), and 13 (7 percent) met strict criteria for major postoperative cardiac events, including 1 with a fatal myocardial infarction, 3 with nonfatal infarctions, 4 with unstable angina, and 5 with ischemic pulmonary edema. Of the 32 patients with ischemia before their operations, 12 had postoperative events (univariate relative risk, 54; 95 percent confidence interval, 7.2 to 400). Only 1 postoperative event occurred among 144 patients who did not have preoperative ischemia. The sensitivity of preoperative ischemia was 92 percent, the specificity 88 percent, the predictive value of a positive result 38 percent, and the predictive value of a negative result 99 percent. In multivariate analyses, preoperative ischemia was the most significant correlate of postoperative cardiac events and remained a statistically significant independent correlate even after we had controlled for all other preoperative factors (multivariate relative risk, 24.4; 95 percent confidence interval, 6.8 to 88). These preliminary data suggest that preoperative electrocardiographic monitoring to detect episodes of myocardial ischemia is a useful method for assessing cardiac risk in patients who undergo elective vascular surgery. In particular, the absence of ischemia during monitoring indicates a very low risk.

Effect of Cholesterol Reduction on Myocardial Ischemia in Patients With Coronary Disease

BACKGROUND Cholesterol lowering is associated with a reduction in cardiovascular morbidity and mortality. This study sought to determine whether cholesterol lowering also results in a reduction of myocardial ischemia during daily life. METHODS AND RESULTS We enrolled 40 patients with proven coronary artery disease, total serum cholesterol between 191 and 327 mg/dL, and at least one episode of ST-segment depression on ambulatory ECG monitoring. Twenty patients were randomized to an American Heart Association Step 1 diet plus placebo (placebo group) and 20 to the same diet plus lovastatin (treatment group). Serum cholesterol and LDL cholesterol levels and ambulatory monitoring were repeated after 4 to 6 months of therapy. The two groups were comparable with respect to baseline characteristics, number of episodes of ST-segment depression, and baseline serum cholesterol levels. The treatment group had lower mean total and LDL cholesterol levels at study end and experienced a significant reduction in the number of episodes of ST-segment depression compared with the placebo group. ST-segment depression was completely resolved in 13 of 20 patients (65%) in the treatment group versus 2 of 20 (10%) in the placebo group. The treatment group exhibited a highly significant reduction in ischemia (P < .001). By logistic regression, treatment with diet and lovastatin was an independent predictor of ischemia resolution. CONCLUSIONS Cholesterol lowering with lovastatin appears to be effective in eliminating myocardial ischemia during daily life in a significant proportion of patients.

Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. The ASIS Study Group.

Episodes of transient myocardial ischemia during ambulatory activities are common in patients with stable coronary artery disease and who are often asymptomatic. Selection of therapy for episodes of asymptomatic ischemia is limited by a lack of direct comparative studies. To determine the most effective monotherapy for patients with stable angina and a high frequency of asymptomatic ischemic episodes, propranolol-LA (mean daily dose, 293 mg), diltiazem-SR (mean daily dose, 350 mg), nifedipine (mean daily dose, 79 mg) were each compared with placebo, each for 2 weeks, in a randomized, double-blinded, crossover trial. Entry criteria were a positive exercise treadmill test during placebo therapy characterized by 1.0 mm or more ST segment depression and angina pectoris, and six or more episodes of transient ST segment depression of 1.0 mm or more on a 48-hour ambulatory electrocardiogram. One hundred ninety-four patients were screened, 63 were eligible and received randomized therapy, of which 56 patients completed at least two of the four treatment periods and were included in an intent-to-treat analysis. Fifty patients completed all four treatment phases and were included in the protocol-completed analysis. Anti-ischemia efficacy was assessed by 48-hour ambulatory electrocardiographic monitoring, exercise treadmill tests, and anginal diaries. Ninety-four percent of all episodes of ambulatory ischemia were asymptomatic. Compared with placebo, only propranolol was associated with a marked reduction in all manifestations of asymptomatic ischemia during ambulatory electrocardiographic monitoring (2.3 versus 1.0 episodes/24 hr; mean duration of ischemia per 24 hours, 43.6 versus 5.7 minutes; both p less than 0.0001). Diltiazems reduction of the frequency of episodes compared with placebo (2.3 versus 1.9 episodes/24 hr) was associated with a trend (p = 0.08) in the protocol-completed analysis and with a significant reduction in the intent-to-treat analysis (p = 0.03). Nifedipine had no significant effect on any measured variable of ambulatory ischemia. The dosages of medication used may have been excessive for some patients, and a more beneficial effect may have been evident at a lower dose. In contrast to the marked effects of the active agents on ambulatory asymptomatic ischemia, the effects on exercise performance and angina pectoris were slight. The active agents modestly improved treadmill exercise duration time until 1 mm ST segment depression (3%), and only propranolol and diltiazem had significant effects. Only diltiazem significantly prolonged the total exercise time. Anginal frequency was significantly decreased by both propranolol and diltiazem.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of asymptomatic ischemia on long-term prognosis in chronic stable coronary disease.

BackgroundIschemia on ambulatory electrocardiographic monitoring has been shown to adversely affect short-term prognoses in patients with unstable angina, after myocardial infarction, and with chronic stable angina. Methods and ResultsIn this long-term study, we followed 138 patients (mean age, 59±9 years) with chronic stable angina and positive exercise tests for cardiac events (e.g., death, myocardial infarction, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft surgery). In 105 patients, ambulatory electrocardiographic monitoring was performed after all antianginal medication was withheld for 48 hours. In 26 patients, the diagnostic tests were repeated while on their usual medication. In addition to the 105 patients, 33 patients had their monitoring performed only while on their usual medication. During 37±17 months of follow-up, there were nine deaths, nine myocardial infarctions, and 35 revascularization procedures. In patients monitored off medication, Cox survival analysis showed that the occurrence of ischemia on electrocardiographic monitoring was the most significant predictor of death and myocardial infarction in the subsequent 2 years (p = 0.02) and of all adverse events for 5 years p = 0.009). Patients who were monitored on medication and did not have ischemia (n =18) appeared to have more adverse events than patients who had no ischemia while being monitored off medication (n =43). ConclusionsAsymptomatic ischemia on ambulatory electrocardiographic monitoring in patients with stable angina predicts death and myocardial infarction for 2 years and all adverse events for 5 years. Monitoring performed while on medication may show no ischemia; however, this may not indicate low risk of future coronary events.

Low Plasma Ascorbic Acid Independently Predicts the Presence of an Unstable Coronary Syndrome

OBJECTIVES This study sought to investigate the relations between plasma antioxidant status, extent of atherosclerosis and activity of coronary artery disease. BACKGROUND Previous studies indicate that increased antioxidant intake is associated with decreased coronary disease risk, but the underlying mechanisms remain controversial. METHODS Plasma samples were obtained from 149 patients undergoing cardiac catheterization (65 with stable angina, 84 with unstable angina or a myocardial infarction within 2 weeks). Twelve plasma antioxidant/oxidant markers were measured and correlated with the extent of atherosclerosis and the presence of an unstable coronary syndrome. RESULTS By multiple linear regression analysis, age (p < 0.001), diabetes mellitus (p < 0.001), male gender (p < 0.001) and hypercholesterolemia (p = 0.02) were independent predictors of the extent of atherosclerosis. No antioxidant/oxidant marker correlated with the extent of atherosclerosis. However, lower plasma ascorbic acid concentration predicted the presence of an unstable coronary syndrome by multiple logistic regression (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.40 to 0.89, p = 0.01). The severity of atherosclerosis also predicted the presence of an unstable coronary syndrome (OR 1.7, 95% CI 1.14 to 2.47, p = 0.008) when all patients were considered. When only patients with significant coronary disease were considered (at least one stenosis >50%), ascorbic acid concentration (OR 0.56, 95% CI 0.37 to 0.85, p = 0.008) and total plasma thiols (OR 0.52, 95% CI 0.34 to 0.80, p = 0.004) predicted the presence of an unstable coronary syndrome, whereas the extent of atherosclerosis did not. CONCLUSIONS These data are consistent with the hypothesis that the beneficial effects of antioxidants in coronary artery disease may result, in part, by an influence on lesion activity rather than a reduction in the overall extent of fixed disease.

Waking and rising at night as a trigger of myocardial ischemia

A diurnal pattern of changes in transient myocardial ischemia has been well documented in patients with coronary artery disease (CAD) with an increase in the early morning hours. To further investigate potential triggers of ischemia, certain defined and distinct episodes of waking and rising during the nighttime were examined. Of 113 patients who underwent ambulatory monitoring of the electrocardiogram, 466 episodes of ischemia lasting 3,926 minutes were detected in 67 of the patients. In 30 patients who had ischemia at night, 21 reported 36 occasions of waking and rising, and 67% of these events were associated with ST-segment depression. Frequency and duration of ischemia were similar in the nocturnal episodes versus the early morning episodes of ischemia as were the increases in heart rate at 30, 10, 5 and 1 minute before the onset. Even before waking, there was an increase in heart rate beginning approximately 30 minutes before the onset of ischemia. This increase became significant 5 minutes before onset both in the early morning and on rising at night. Patients with nocturnal ischemia had significantly worse clinical signs of CAD. This study shows that rising at night is often associated with episodes of myocardial ischemia and, like the morning events on rising, is likely an important trigger of ischemia in patients with CAD.

Peripheral arterial-vascular disease in women: prevalence, prognosis, and treatment.

Lower extremity atherosclerosis results in significant morbidity in women, particularly in women following the menopause. Up to 25% of women aged 55 to 74 years are affected by this disease. When noninvasive testing is used to determine the prevalence of lower extremity atherosclerosis, and men in this age group are equally represented. Cigarette smoking, diabetes mellitus, and menopause are risk factors for atherosclerosis of particular interest in women. The prevalence of cigarette smoking is rising rapidly among women, and diabetes appears to be a greater risk factor for atherosclerosis in women than in men. Risk factor reduction, in addition to an exercise program, are important parts of the treatment program for stable claudication. In both men and women with more severe symptoms, an ankle/branchial index (ABI) of less than 0.3 is associated with more severe symptoms, an ankle/brachial index (ABI) of less than 0.3 is associated with a poor prognosis. Men and women fare equally well following revascularization for severe peripheral atherosclerosis. However, there are some data to suggest that women may be offered peripheral revascularization at a lower rate.

Pathophysiology of ischemia in patients with coronary artery disease

C ORONARY atherosclerosis is characterized by subintimal thickening that leads to plaque formation and stenosis.’ During the progression of this pathology in the large epicardial arteries, episodes of transient myocardial ischemia occur and each event is characterized by a reversible decrease in regional myocardial oxygen concentration that characteristically effects a segment of the left ventricle.2 This leads to the failure of systolic and diastolic muscle function, varying degrees of left ventricular failure, and profound metabolic disturbances. This functional expression of coronary artery disease can be induced by provoking disturbances in coronary blood supply and/or increases in myocardial demand for oxygen (ie, during exercise); ischemia also occurs during the activities of everyday life and it can precede damaging clinical events such as acute myocardial infarction, pulmonary edema, and sudden death.?,’ Transient myocardial ischemia in patients with obstructive coronary artery disease occurs in many different clinical syndromes (eg, chronic stable angina, unstable angina, and after myocardial infarction) and its presence always indicates the increased risk of adverse coronary events.2-7 In the majority of patients with ischemia and proven coronary artery disease, there are atherosclerotic stenoses that severely reduce crosssectional area in a segment of at least one epicardial artery. In these circumstances, standardized exercise protocols can provoke and reproduce ischemia and angina at a reproducible level of exercise. These clinical features have nurtured the belief that coronary blood supply is fixed and myocardial demand increases to cause ischemia. Although this concept is useful when considering the benefits of beta-adrenoreceptor blocking drugs, coronary angioplasty and by-pass graft surgery, these therapies probably do not address the disturbed biology of developing atherosclerotic lesions. Clinical studies of transient myocardial ischemia during daily life,8*9 studies of regional myocardial blood flow before and during ischemia”‘-I5 and studies of coronary vasomotion during cardiac catheterization all highlight the active role of the diseased epicardial arteries in causing transient ischemia.16-r9 An enhanced understanding of the biology of atherosclerotic stenoses has clarified pathophysiological mechanisms of myocardial ischemia and has suggested new directions in the development of therapies aimed at physical regression of coronary atherosclerosis and the control of constriction and thrombosis.20.2i This article will focus on transient myocardial ischemia by examining new clinical characteristics and pathogenic mechanisms rather than simply evaluating diagnostic techniques. It will discuss new clinical information about the biology of atherosclerosis and stenoses in relation to the occurrence of ischemia and adverse clinical outcomes. New insights from basic research will only be discussed as they provide fresh directions for clinical research. This paper will focus on transient ischemia rather than myocardial infarction or sudden death and will try to explore the relationship between coronary atherosclerosis, coronary vasoconstriction, and thrombosis as these problems occur in patients.

Changing vasomotor responses of coronary arteries to nifedipine

Coronary vasomotion is influenced by a variety of factors, including atherosclerosis and diurnal variations in alpha-adrenergic tone. The effect of such factors on the coronary response to vasodilator drugs is unknown. To determine whether there is a diurnal variation to the response of coronary arteries to nifedipine, and whether this response is altered by atherosclerosis, we studied 11 patients with smooth coronary arteries, six in the morning and five in the afternoon, and 12 patients with irregular coronary arteries, six in the morning and six in the afternoon. Changes in coronary blood flow and the vasomotor response of an epicardial coronary artery were measured before and after a 2 mg intracoronary infusion of nifedipine. There were no appreciable differences in epicardial vessel dilator response or coronary blood flow in the morning and afternoon among patients with smooth coronary arteries. By contrast, patients with irregular coronary arteries had a significantly diminished dilator response in the afternoon, without an appreciable change in coronary blood flow. We postulate that normal coronary arteries maintain basal tone throughout the day. By contrast, atherosclerotic coronary arteries cannot do the same, increasing tone in the morning in response to catecholamines. When catecholamine levels drop in the afternoon, basal tone decreases in atherosclerotic vessels, and the dilator response to nifedipine is blunted. This observation may have an important impact on the expected benefits and timing of vasodilator therapy in patients with coronary artery disease.

New insights into the management of myocardial ischemia

Episodes of ST depression are closely related to transient decreases in regional myocardial perfusion during physical or mental stress. At the onset of these events, there is transient constriction of atherosclerotic stenoses, with an increase in myocardial demand as reflected by increases in heart rate and blood pressure. Recent research has shown that normal epicardial coronary arteries respond to these provocations and to increasing blood flow with progressive vasodilation. In contrast, atherosclerotic vessels lose this ability to dilate and may show paradoxical constriction. This abnormal constriction parallels the response of the arteries to acetylcholine, which can be used to assess the ability of the coronary endothelium to regulate vasodilation. The loss of endothelium-dependent vasodilation appears to be an important functional manifestation of coronary atherosclerosis and a potential triggering mechanism for transient ischemia. Dysfunctional endothelium may also result in a procoagulant surface, with cell adherence and local thrombus formation. Restoration of normal endothelial function is likely to emerge as an important therapeutic objective in the management of myocardial ischemia and coronary atherosclerosis.