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Inflammation plays a crucial role in the cell biology of atherosclerosis. Coronary risk factors, and particularly low-density lipoprotein (LDL) cholesterol, injure the endothelium and decrease the bioavailability of nitric oxide to promote the expression of proinflammatory genes, cellular adhesion molecules, cytokines, chemokines, and growth factors. For example, the expression of CD40/CD40 ligand increases cell-mediated immune responses to activate a number of inflammatory cells and destabilize atherosclerosis. As part of this response, soluble markers of inflammation that are released into the blood offer insights into the cell biology of inflammation in atherosclerosis. In groups of patients, these markers have provided a means to study inflammatory mechanisms and have supported the value of many of our interventions that prevent cardiovascular disease. Statins have potent effects to reduce LDL cholesterol in the plasma and the artery wall and also appear to have a number of nonlipid effects that decrease inflammatory stimuli. Because statins also reduce some soluble markers of inflammation, it is likely that at least part of their benefit reflects a reduction in vascular inflammation in stable and unstable coronary syndromes. Although these inflammatory markers are valuable tools for studying the mechanisms of atherosclerosis, their use in clinical practice to stratify cardiovascular risk or assess treatment in individual patients requires further evaluation. [ABSTRACT FROM AUTHOR]

In children and adults, weight gain is accompanied by the early and more aggressive manifestations of well-recognized risk factors for atherosclerotic cardiovascular disease (CVD). Because insulin resistance and the later development of type 2 diabetes mellitus also accompany weight gain, the term cardiometabolic risk is now commonly used to describe this emerging global health problem. Weight loss will improve cardiometabolic risk. However, less is known about the effect of weight loss on the development of disease and, most importantly, type 2 diabetes and CVD outcomes in the form of death, myocardial infarction, and stroke. This review describes current clinical research that uses health-promoting lifestyle interventions, new drugs, and even surgery, which are all aimed at weight loss, reduction in disease manifestations, and improved outcomes. These anticipated data are essential for the future development of effective CVD prevention strategies. Results are awaited with great interest.

The acute coronary syndromes arise from procoagulant changes in complex plaques, which trigger both platelet activation and coagulation pathways. These 2 pathways intersect at a number of points that form positive-feedback loops to sustain and accelerate thrombus formation. In normal hemostasis and with a healthy endothelium, intravascular thrombosis is prevented, and vascular patency is protected by the fibrinolytic system and a number of antithrombotic factors, such as antithrombin, thrombomodulin, and tissue factor pathway inhibitor. However, atherosclerosis is characterized by a hypercoagulable state, and the fibrinolytic balance is skewed toward occlusive thrombus formation at critical sites on vulnerable plaques. This review focuses on cellular and humoral mechanisms and the antithrombotic strategies that are important during the acute phase of an ischemic coronary syndrome, both in patients managed conservatively and in patients scheduled for an interventional procedure. These strategies include fibrinolytic therapy, antiplatelet therapies (aspirin, clopidogrel, glycoprotein IIb/IIIa receptor inhibitors), and low-molecular-weight heparin.

Vascular closure devices offer advantages over traditional means of obtaining hemostasis after percutaneous coronary intervention (PCI) in terms of patient comfort and time to ambulation. We investigate whether such devices also reduce the risk of vascular complications in selected patient populations. We conducted a retrospective analysis of all patients who underwent PCI at our institution between January 1998 and December 1999. Of 3,151 consecutive patients, 3,027 were eligible to receive vascular closure devices. Of these, 1,485 received a closure device and 1,409 received glycoprotein IIb-IIIa antagonists. The overall vascular complication rate, as defined by the need for surgical repair or transfusion, or the development of arteriovenous fistula, pseudoaneurysm, or large hematoma, was 4.20%. By univariate analysis, the use of closure devices was associated with a lower vascular complication rate (3.03% vs 5.52%; p = 0.002) and a shorter length of hospital stay (2.77 vs 3.97 days, p <0.001). Multivariate analysis showed a significant reduction in vascular complications with closure devices (odds ratio 0.59, p = 0.007). For the subgroup of patients receiving glycoprotein IIb-IIIa antagonists, the use of closure devices was associated with an even more pronounced reduction in the risk of vascular complications (odds ratio 0.45, p <0.008). Thus, the use of closure devices in selected patients undergoing PCI is associated with a low rate of vascular complications and decreased length of stay. This benefit was most marked for patients receiving glycoprotein IIb-IIIa antagonists.

Percutaneous coronary interventions (PCIs) play an increasingly important role in the management of patients with coronary artery disease. However, these important procedures are complicated by restenosis in a sizeable number of patients. The pathobiology of atherosclerosis comprises a complex interaction among lipids, the endothelium, circulating and tissue inflammatory cells, platelets, and vascular smooth muscle cells. The superimposition of the mechanical and cellular consequences of PCIs on the abnormal substrate of atherosclerosis leads to a characteristic and distinct pathobiology that initiates and perpetuates restenosis. A clear understanding of the significant differences between atherosclerosis and restenosis will provide a rational basis for developing treatment plans that always address both problems. This article reviews and contrasts the pathobiology of atherosclerosis and restenosis and compares the mechanisms and time-course of these distinct entities.

Atherosclerosis is often asymptomatic, unrecognized, and undertreated. Lumen irregularities are important angiographic findings that should be addressed aggressively through risk factor modification, medical therapy, and coronary revascularization. Both angiographic and clinical benefits have been demonstrated with lipid reduction therapy in randomized clinical trials. Coronary revascularization is indicated for symptom relief and improvement in quality of life in patients with acute coronary syndromes at "intermediate" and "high" risk of subsequent death or myocardial infarction. In patients following percutaneous coronary intervention (PCI), future cardiac events may be related to lumen renarrowing or to progression of atherosclerotic disease at sites remote from the site of coronary revascularization. The time course of restenosis is relatively self-limiting, generally occurring within 6-12 months after the procedure. Clinical events occurring > 1 year after PCI generally relate to new lesions or progression of existing atherosclerotic disease. Patients with diabetes mellitus may be at higher risk for late coronary events than nondiabetic patients. In post-coronary artery bypass surgery (CABG) patients, the majority of late events relate to degeneration of saphenous vein grafts. Lipid lowering therapy after coronary revascularization has been shown to prevent clinical events related to plaque instability and inhibit progression of saphenous vein graft disease. Thus, there are 2 goals in management of patients with symptomatic coronary artery disease: (1) to relieve the flow-limiting stenosis, and (2) to prevent future clinical events with aggressive lipid lowering and modification of other risk factors. Patients, specialists, and primary care physicians each need to take accountability for this risk-factor modification.

Increased pulmonary resistance may reduce survival and treatment options in patients with congestive heart failure. Nitric oxide (NO) is a determinant of normal pulmonary resistance vessel tone. We tested the hypothesis that loss of NO function contributes to increased pulmonary vascular resistance index (PVRI) in congestive heart failure. Pulmonary arterial resistance vessel function was studied in 25 conscious adults. Three groups were studied: 8 controls, 9 patients with congestive heart failure and normal PVRI, and 8 patients with congestive heart failure and raised PVRI. Segmental arterial flow was determined with a Doppler wire and quantitative angiography. NG-monomethyl-L-arginine (L-NMMA) was used to inhibit NO, whereas phenylephrine was used as an endothelium-independent control. The response to inhibition of NO with L-NMMA was less in patients with congestive heart failure and elevated PVRI than in patients with congestive heart failure and normal PVRI (p <0.05). The difference in response between the congestive heart failure groups was specific to NO-dependent regulation because the response to the endothelium-independent constrictor phenylephrine was not different (p = 0.92). There was no difference in response to L-NMMA between controls and patients with congestive heart failure and normal PVRI. The response to L-NMMA correlated to PVRI. In adults with congestive heart failure, NO appears to play an important role in maintaining normal pulmonary resistance.

Many of the cellular mechanisms and dysfunctions that underlie atherosclerotic plaque formation have been identified, including adverse interactions between atherogenic lipids and the arterial endothelium, loss of endothelium-dependent dilation, accumulation of inflammatory cells and mediators of inflammation in the intima of the arteries, and a decline in anticoagulant defenses. Several studies have shown that these mechanisms, which appear to be active throughout the pathogenesis and progression of atherosclerosis, are reversible within days, weeks, or months with effective lipid-lowering therapy. In addition, the findings of large-scale trials of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors suggest that the rapid improvement observed in trial participants is attributable to a reversal of endothelial and vascular wall dysfunctions rather than to a reduction in plaque size. The accumulated evidence indicates that improved endothelial function can benefit patients who have angina pectoris and/or are at risk for myocardial infarction. Current understanding of the cellular mechanisms of atherogenesis also suggests avenues of future research to refine treatment approaches and further improve outcomes for patients with coronary artery disease.

The objective of this study was to determine whether abnormal flow-induced endothelium-dependent vasodilation in the brachial artery identifies young patients with coronary artery disease (CAD). High-resolution ultrasonography was used to measure vascular reactivity in a peripheral conduit vessel, the brachial artery, in 14 young men with CAD and in 11 age-matched, healthy, male volunteers. Endothelium-dependent vasodilation was determined by measuring the change in brachial artery diameter during increases in flow induced by reactive hyperemia. Endothelium-independent vasodilation was assessed by administration of sublingual nitroglycerin. To ascertain whether flow-mediated vasodilation in humans is mediated by endothelium-derived nitric oxide, brachial artery diameter was measured during reactive hyperemia, before and during administration of the nitric oxide synthase antagonist NG-monomethyl-L-arginine (L-NMMA). Brachial artery diameter was also measured during intraarterial infusion of acetylcholine and nitroprusside before and after administration of L-NMMA. Flow-induced vasodilation was less in patients with CAD than in healthy volunteers (1.3 +/- 1.1% vs 6.2 +/- 0.7%, p <0.05). Nitroglycerin increased brachial artery diameter similarly in each subject group (11.3 +/- 1.0% vs 15.8 +/- 1.2%, p =0.05). L-NMMA inhibited flow-mediated vasodilation and the vasodilative response to acetylcholine, but did not affect the response to nitroprusside. It is concluded that abnormal flow-induced endothelium-dependent vasodilation occurs in the brachial artery of young patients with CAD.

Vascular endothelium plays a pivotal role in the maintenance of vasodilation and the inhibition of platelet aggregation and smooth muscle cell proliferation through the release of nitric oxide and other factors. Extensive data have demonstrated abnormalities in coronary endothelial function in the epicardial coronary arteries in patients with atherosclerosis or risk factors for atherosclerosis. This dysfunction leads to abnormal vasoconstriction and platelet aggregation, which likely play a role in producing ischemia in patients with coronary artery disease. Invasive techniques have been available to assess endothelium-dependent vasodilator responses in the coronary arteries. However, until recently little has been known about endothelial responses in the peripheral vasculature, as methods to assess this have not been readily available. The hypothesis that endothelial dysfunction is a systemic process is explored, and new noninvasive methods of assessing endothelial function are discussed.

Several studies have shown that diabetes mellitus increases the risk of restenosis after coronary intervention, but the role of insulin in restenosis has not been defined. The relation between fasting insulin levels and restenosis was evaluated prospectively at 6-month angiographic follow-up in 70 patients undergoing excimer laser coronary angioplasty of 75 lesions. Restenosis (> 50% diameter narrowing on quantitative angiography) was observed at 37 of 75 treated sites (49%). Although patients with glucose intolerance and noninsulin-dependent diabetes mellitus showed a trend toward increased restenosis (restenosis rate 69%; odds ratio for restenosis 2.7 [95% confidence interval 0.76, 9.82]; p = 0.124), those with increased fasting insulin levels > 15 muU/ml had reduced restenosis (restenosis rate 24%; odds ratio 0.22 [0.07, 0.67]; p = 0.008). Other factors including fasting serum glucose, glycated hemoglobin and lipoprotein fraction were not predictive of restenosis. The relation between insulin levels and restenosis after excimer laser angioplasty may provide insights into the biology of vascular injury and repair after coronary intervention.

To determine if Holter monitoring can predict cardiac risk in patients when the exercise test is nondiagnostic, a total of 90 eligible patients were monitored for 24 hours after their exercise test without alterations in baseline medications. Prospective follow-up was obtained and events were confirmed by investigators unaware of subjects' clinical data. Nineteen patients (21%) had a total of 71 episodes of ST depression, all of which were asymptomatic. During a mean follow-up of 719 days, there were 10 patients with adverse events: 3 with cardiac deaths, 3 with nonfatal myocardial infarctions, and 4 with admissions for unstable angina. Of the 10 adverse events, 9 occurred in the group of 19 with ST depression detected by Holter (relative risk 34, 95% confidence interval 10 to 114). The sensitivity of ST depression was 90%, the specificity 88%, the predictive positive value 47%, and the predictive negative value 99%. In a multivariate Cox proportional-hazards model that controlled for prior history of coronary artery disease, hypercholesterolemia, and all exercise test variables, the presence of ST depression detected by Holter was the only independent predictor of outcome. In patients with nondiagnostic exercise tests, ST depression detected by Holter monitoring identified those with an increased risk of adverse cardiac events. The absence of ST depression detected by Holter was a useful predictor of low risk.

The recent discovery that the endothelium synthesizes several powerful vasodilators, including prostacyclin and endothelium-derived relaxing factor, has substantially changed our view of the importance of the vascular endothelium and the perspective from which we consider the mechanisms of vascular control. It is now known that the vascular endothelium plays a key role in circulatory homeostasis through its ability to sense the local vascular milieu and respond to it by the synthesis and release of a variety of biologically active substances. The endothelium influences not only vascular tone, but also vascular remodeling via the production of growth-promoting and growth-inhibiting substances; hemostasis and thrombosis through antiplatelet, anticoagulant, and fibrinolytic effects; and inflammation through the expression of chemotactic and adhesion molecules on the cell membrane. In diseases such as atherosclerosis, however, these functions of the endothelium are impaired and may even become counterproductive and disease-promoting. The "activated" or injured endothelial cells paradoxically become prothrombotic, growth-promoting, and leukocyte-adhesive. The endothelium also loses its vasodilating ability, rendering the underlying vascular smooth muscle susceptible to a preponderance of vasoconstrictive forces. It is now recognized that these disturbances in endothelial function are principal players in the ischemic manifestations of coronary artery disease. Endeavors to modify or reverse endothelial dysfunction may therefore be of significant therapeutic benefit in the treatment of myocardial ischemia. This review outlines several important insights into the biology of the arterial wall that are currently being applied to the study of coronary artery disease in humans.

Selective thrombin inhibitors are a new class of antithrombotic drugs that, unlike heparin, can effectively inhibit clot-bound thrombin and escape neutralization by activated platelets. Hirulog is a 20 amino acid hirudin-based synthetic peptide that has shown promise in experimental models of thrombosis. Little information is available about the effects of hirulog in patients with coronary artery disease. Forty-five patients undergoing cardiac catheterization, who were taking aspirin, were randomized to receive either (1) hirulog, 0.05 mg/kg intravenous bolus followed by 0.2 mg/kg/hour intravenous infusion until the end of the catheterization; (2) hirulog, 0.15 mg/kg intravenous bolus followed by 0.6 mg/kg/hour intravenous infusion; or (3) heparin; 5,000 U intravenous bolus. Serial activated partial thromboplastin time (APTT), prothrombin time, activated clotting time and fibrinopeptide A were measured. Hirulog produced a dose-dependent prolongation of all coagulation parameters; the 0.6 mg/kg/hour dose prolonged the APTT to 218 +/- 50% of baseline after 2 minutes and 248 +/- 50% of baseline after 15 minutes. The half-life of the effect on APTT was 40 minutes. The hirulog blood level correlated well with the APTT, prothrombin time and activated clotting time (r = 0.77, 0.73, and 0.82 respectively, all p < 0.001). Both doses of hirulog potently suppressed the generation of fibrinopeptide A (p < 0.05). There were no major hemorrhagic, thrombotic or allergic complications in patients treated with hirulog or heparin. Thus, hirulog, a direct thrombin inhibitor, provides a predictable level of anticoagulation and appears to have a potent yet well-tolerated anticoagulant profile in patients with coronary artery disease.

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.

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.

To assess the long-term prognostic significance of myocardial ischemia, as measured by ambulatory electrocardiographic monitoring, in patients with occlusive peripheral arterial disease, 176 eligible patients scheduled for elective peripheral arterial surgery at Brigham and Women's Hospital were prospectively studied. All patients were monitored preoperatively without alterations to baseline medications. Prospective follow-up was obtained during routine medical care as provided by blinded, independent physicians and by subsequent telephone contact with the patients. Thirty-two patients (18%) had a total of 75 episodes of myocardial ischemia, 73 (97%) of which were asymptomatic. During a mean follow-up period of 615 days, there were 9 cardiac deaths, 1 occurring in-hospital after peripheral vascular surgery, and 13 nonfatal myocardial infarctions, 4 occurring in-hospital after peripheral vascular surgery. Cardiac events occurred in 12 of 32 patients with ischemia (38%), including 6 cardiac deaths, and in 10 of 144 patients without ischemia (7%), including 3 cardiac deaths (risk ratio 5.4, 95% confidence interval 2.6 to 11.4). The sensitivity of ischemia was 55%, the specificity was 87%, the positive predictive value was 38%, and the negative predictive value was 93%. In a multivariate Cox proportional-hazards model controlling for age, gender, coronary risk factors, history of angina, myocardial infarction, coronary artery disease and antianginal medications, the presence of ischemia was the only independent predictor of outcome. In patients with peripheral arterial disease, who often are unable to perform adequate exercise testing, ambulatory monitoring for myocardial ischemia is a significant independent predictor of 1- to 2-year prognosis.

Physical exertion is a well-documented trigger of transient myocardial ischemia in patients with coronary disease. More recently, studies have shown that mental stress may also be a cause of myocardial ischemia. The purpose of this study was to examine the relationship of physical activities and perceived mental states to myocardial ischemia while patients were going about their normal daily activities. Twenty-eight patients with documented coronary artery disease underwent ambulatory monitoring of the electrocardiogram. Physical activity and perceived mental status were recorded by patients in a diary which was then graded according to intensity of the activity. Analyses of the continuous electrocardiographic recordings were done separately from the analysis of the diaries. The time of each episode of ischemia, the duration of each episode in minutes and the number of episodes in each 24-hour period were calculated. A total of 372 episodes of ST-segment depression occurred in 912 hours of monitoring. Ischemic events occurring during usual physical and usual mental activities were most frequent (36%). Twenty-six percent of ischemic episodes occurred during increased physical activity, but usual mental activities. Interestingly, 22% of the ischemic events occurred at high levels of mental stress, but low physical activity. Ten percent of episodes occurred during sleep. Although the majority of events occurred during usual daily activities, when duration of ischemia was normalized for time spent in each category, increasing physical or mental activity was associated with an increasing duration of ischemia per unit (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate the antiischemic efficacy and development of tolerance to transdermal nitroglycerin, 14 patients with chronic, stable angina pectoris were studied using continuous ambulatory electrocardiographic monitoring. Patients demonstrated initial hemodynamic responsiveness to sublingual nitroglycerin and were titrated to a maximally tolerated dose of 30 to 60 mg/24 hours (52 +/- 5 mg). Two crossover phases were use in a randomized, double-blind, placebo-controlled manner: continuous nitroglycerin therapy (patches containing active drug worn for 24 hours) and intermittent nitroglycerin therapy (12-hour active drug followed by a 12-hour nitrate-free period). There were no differences in frequency or duration of ischemic episodes between the placebo days of each phase. A significant effect in frequency of episodes was observed between placebo and treatment days of continuous therapy (p less than 0.05). Nonsignificant reductions in frequency and duration of ischemic episodes also occurred during intermittent therapy. The major antiischemic effect of transdermal nitroglycerin therapy occurred during the first day of treatment but was lost by 48 hours. Reductions in frequency and duration of ischemic episodes (p less than 0.05) were present on day 1 of continuous therapy but ischemic episodes returned to placebo levels by day 2, suggesting the development of tolerance. Intermittent therapy did not prevent the development of tolerance on day 2 of treatment. The results demonstrate that the use of high doses of transdermal nitroglycerin in patients with chronic, stable coronary artery disease produced a beneficial reduction in the frequency and duration of ischemia. However, the antiischemic benefit was lost between 24 nd 48 hours after the onset of continuous and intermittent therapy, presumably due to tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of selective intracoronary antiarrhythmic drug infusion on inducibility of cardiac arrhythmias was studied in 3 patients with recurrent sustained monomorphic ventricular tachycardia referred for comprehensive electrophysiologic studies. Each patient had evidence of prior myocardial infarction, 1 or more occluded coronary arteries and a readily identifiable collateral vessel that provided collateral flow to the infarct-related artery. In each patient, the clinical arrhythmia was reproducibly inducible by programmed stimulation in the control state. After positioning a small infusion catheter in the collateral vessel, selective intracoronary lidocaine 0.3 to 0.6 mg/min (patients 1 and 2) or procainamide 0.1 to 1.4 mg/min (patient 3) was infused for a 10-minute period. In each patient the clinical arrhythmia was rendered noninducible during selective intracoronary drug infusion. The arrhythmia was again inducible after a 10-minute drug-washout period and also after standard intravenous doses of antiarrhythmic drug. Selective intracoronary antiarrhythmic drug infusion may help to localize the site of origin of some cardiac arrhythmias, may provide a means of testing the effects of several drugs during a single study and may be a new method for studying mechanisms of action of antiarrhythmic drugs.

Patients with angina and coronary artery disease (CAD) have many episodes of transient ST-segment depression during ordinary daily life, and these are often asymptomatic. To investigate this signal as a marker of myocardial ischemia, 30 patients with chronic stable angina and CAD underwent positron tomography, recording the regional myocardial uptake of rubidium-82, pain and ST-segment changes before, during and after 59 technically satisfactory exercise tests, 35 cold pressor tests and 22 episodes of unprovoked ST depression. Exercise resulted in 53 episodes of ST depression with angina and in 5 episodes without pain. After cold pressor tests, there were 3 episodes of ST depression and pain and 12 of painless ST depression. Only 9 episodes of unprovoked ST depression were accompanied by pain. Tomography showed independent evidence of ischemia in 63 (97%) of the total 65 episodes of ST depression with angina and in all 30 episodes of painless ST depression. In each patient perfusion defects occurred in the same myocardial segment during painful and painless ST depression and responses were significantly different from those in 16 normal subjects studied in the same way. These findings support the use of transient ST depression in continuous monitoring to assess the activity of CAD, but only in patients with typical angina pectoris, ST depression during exercise and proved CAD. They strengthen the evidence derived from ambulatory monitoring for a wider picture of the disease than is generally appreciated, with more frequent episodes of silent myocardial ischemia than of angina pectoris.

To help characterize episodes of transient myocardial ischemia, 80 patients with chronic stable angina and evidence of obstructive coronary disease were studied by ambulatory electrocardiographic (ECG) monitoring outside the hospital to detect both symptomatic and asymptomatic episodes of ST-segment depression. In addition, patients were tested on an outpatient basis by means of positron emission tomography to assess regional coronary blood flow under different conditions. All patients showed ECG evidence of transient ischemia, with or without symptoms, while active outside the hospital. In-hospital testing showed that symptomatic and asymptomatic disturbances in regional coronary blood flow occurred with normal everyday activities and were not caused by physical exertion involving marked increases in heart rate and blood pressure. Most of these provocations were followed by a decrease in coronary blood flow in a poststenotic segment of myocardium and, like the ischemic events monitored out of hospital, the majority were silent. Many of these features characterizing the activity of ischemic heart disease may not be apparent from a patient's anginal history or results of hospital diagnostic testing.

Patients with coronary artery disease have frequent asymptomatic episodes of ischemic ST-segment depression. A new solid-state recorder that analyzes the digitized electrocardiogram (ECG) in real time has been tested for accuracy in detection and quantitation of these events by comparison with a direct ECG during exercise testing and a frequency-modulated recorder during ambulatory monitoring. The device can also be programmed to produce a tone at the onset of ischemic ST-segment depression, and this tone is used to initiate self-administration of nitroglycerin in an attempt to control myocardial ischemic events. The solid-state recorder demonstrated adequate sensitivity and specificity during exercise (100% and 92%, respectively) for detection and quantitation of episodes of ischemic ST-segment depression. In addition, Monitor One accurately measured the duration of ischemic events during exercise testing (r = 0.95, p = 0.001) and the number (r = 0.92, p = 0.001) and duration (r = 0.97, p = 0.001) of ischemic events during ambulatory monitoring. When the audible tone was used to initiate use of nitroglycerin, the duration of episodes of ischemic ST-segment depression was reduced from 105 +/- 74 min/24 hours to 58 +/- 49 min/24 hours (p = 0.02). Thus, a solid-state ECG recorder capable of long-term monitoring appears to accurately detect and quantify episodes of ischemic ST-segment depression in patients with coronary artery disease. Also, patients can interact with an audible tone to key self-administration of therapy in an attempt to control asymptomatic episodes of transient myocardial ischemia.

Fifteen patients with frequent anginal chest pain underwent diagnostic cardiac catheterization. After coronary arteriography a specially designed cardiac catheter was seated in the aortic root, permitting the continuous infusion of krypton-81m into the right and left aortic sinuses. A gamma camera, areas of interest and a visual display unit were used to record images and the regional myocardial equilibrium of activity before, during and after a standarized atrial pacing test. The unique physical properties of krypton-81m allowed the continuous imaging and recording of moment to moment changes in regional myocardial perfusion. This investigation revealed that when the coronary arteriogram was normal or revealed lumonal stenosis of less than 50 percent, regional myocardial perfusion was uniform at rest and during stress. Two patients with a previous history of myocardial infarction had defects of regional perfusion at rest and during stress. Krypton scintigraphy demonstrated reversible regional defects in myocardial perfusion during stress in seven patients with greater than 70 percent stenosis of one or more coronary arteries. Alterations in regional myocardial perfusion occurred within 30 seconds of the start of atrial pacing in all the patients and preceded the onset of electrocardiographic signs of ischemia or chest pain.

Experiments were undertaken using rubidium-82 and position tomography to examine the relation between myocardial perfusion and cation uptake during acute ischemia. Rubidium-82 was repeatedly eluted from a strontium-82-rubidium-82 generator. In six dogs emission tomograms were used to measure the delivered arterial and myocardial concentrations at rest and after coronary stenosis, stress and ischemia. There was a poor overall relation between regional myocardial uptake and flow measured by microspheres and a large individual variability. Extraction of rubidium-82 was inversely related to flow. Significant regional reduction of cation uptake was detected in the tomograms when regional flow decreased by more than 35 percent. This reduction was significantly greater when ischemia was present. A small but significantly greater when ischemia was present. A small but significant decrease (33.0 +/- 9.1 percent, mean +/- standard deviation) in the myocardial uptake of rubidium-82 was detected only when flow was increased by more than 120 percent in relation to a control area after administration of dypiridamole. The technique using rubidum-82 and tomography was applied in five volunteers and five patients with angina pectoris and coronary artery disease. Myocardial tomograms recorded at rest and after exercise in the volunteers showed homogeneous uptake of cation in reproducible and repeatable scans. In contrast, the patients with coronary artery disease showed an absolute mean decrease of 36 +/- 14 percent in regional myocardial uptake of rubidium-82 after exercise. These abnormalities persisted in serial tomograms for more than 20 minutes after the symptoms and electrocardiographic signs of ischemia.

Fifteen patients with intractable angina pectoris underwent coronary angiography and coronary arterial bypass graft surgery. After the operation, a continuous infusion of krypton-81m was delivered into each graft. A gamma camera and multichannel analyzer were used to record the regional myocardial distribution of perfusion provided by each graft. The disappearance of myocardial activity at the end of each infusion was used to calculate the flow per unit volume in the myocardial distribution provided by each vessel. Myocardial perfusion provided by the grafts to all the major coronary arteries were recorded individually as high spatial resolution images. Myocardial flow rates in the distribution of each graft were measured using the washout of krypton-81m. The rates were 0.5 to 2.0 ml/g per min in the 13 patients with no evidence of previous myocardial infarction. Krypton-81m was infused into grafts to the left anterior descending coronary artery in two patients with a history and electrocardiographic evidence of previous anterior myocardial infarction. The grafts provided poor perfusion to the anterior and apical portions of the ventricles. An experimental model of myocardial perfusion was used to demonstrate that the washout of krypton-81m can be used to measure flow per unit volume within or above the physiologic range.

The management of asymptomatic patients with coronary artery disease (CAD) is controversial, and the level of "activity" of their CAD during normal daily life remains largely unknown. To examine this question, ambulatory Holter monitoring of ST segments was performed out of the hospital in 7 asymptomatic subjects with CAD during normal daily activities. Their condition was detected because they all had a silent positive exercise test and angiographically proved CAD. During a total of 384 hours of monitoring, 37 asymptomatic episodes of ST depression (1 mm or greater and lasting at least 30 seconds) were recorded in 5 of the patients. Most episodes (68%) were 10 minutes or less in duration but ranged from 1 to 253 minutes, and most (70%) had a maximal ST depression of 1 to 2 mm. A small increase in heart rate, ranging from 1 to 34 beats/min, preceded 65% of the episodes, but 35% were associated with no change or even a decline before the onset of ischemia. Fifty-four percent of the episodes occurred during rest or usual light physical activity, 8% during sleep and only 38% during exercise, including 1 prolonged bout while jogging. During 78% of the episodes, the subjects rated their mental activity as usual and only 14% occurred during mental stress. In addition, a distinct diurnal variation was noted with 57% of the ischemia occurring between 0600 and 1200 hours (p = 0.008). Therefore, most asymptomatic subjects had active transient ischemia during daily life, with many of the characteristics already described in symptomatic subjects with CAD.

Cigarette smoking is strongly associated with ischemic heart disease and acute coronary events. The effect of smoking a single cigarette on regional myocardial perfusion was studied in 13 chronic smokers with typical stable angina pectoris using positron emission tomography and rubidium-82 (82Rb). Findings were compared with the effects of physical exercise. After exercise, 8 patients (61%) had angina, ST depression and abnormal regional myocardial perfusion. Uptake of 82Rb increased from 49 +/- 8 to 60 +/- 7 in remote myocardium, but decreased from 46 +/- 3 to 37 +/- 5 in an ischemic area. The remaining 5 patients (39%) had homogeneous increases in 82Rb uptake without angina or ST depression. After smoking, 6 of the 8 patients with positive exercise test responses had a decrease in 82Rb uptake, from 47 +/- 3 to 35 +/- 6 in the same segment of myocardium affected during exercise. However, in contrast to exercise, the events during smoking were largely silent. The absolute decreases in regional 82Rb uptake after smoking occurred at significantly lower levels of myocardial oxygen demand than after exercise. This suggests that an impairment of coronary blood supply is responsible. Thus, in smokers with coronary artery disease, each cigarette can cause profound silent disturbances of regional myocardial perfusion that are likely to occur frequently during daily life. Such repeated insults may represent an important mechanism linking smoking with coronary events.

Continuous monitoring of the electrocardiogram in patients with angina pectoris and coronary artery disease (CAD) has shown episodes of asymptomatic ST-segment depression, suggesting frequent silent myocardial ischemia during normal daily life. Interpretation of this new finding depends on whether similar changes occur in normal subjects. Frequency-modulated ambulatory electrocardiographic recordings were performed in 80 asymptomatic normal volunteers (20 from each decade between 20 and 50 years and, 20 more than 50 years old) and in 20 patients with noncardiac pain, negative exercise and provocative tests and angiographically normal coronary arteries. Treadmill exercise testing was performed in all subjects more than 40 years old. Episodes of T-wave change were identified in 53 subjects. Five subjects younger than 40 years had episodes of ST elevation that were prolonged; they usually occurred at night. In 3 patients they could be reproduced by postural change. Only 2 subjects, both older than 40 years had planar ST depression during tachycardia; one of these subjects had a positive exercise test response. No patient with normal coronary arteries had significant ST depression. Tachycardia was frequently associated with upsloping ST depression (36%), which was more common in younger subjects: Five subjects also showed isolated single complexes with ST depression during baseline instability. With use of frequency-modulated recordings, transient ST depression of 0.1 mV or greater that lasted 80 ms or longer and more than 30 seconds in duration, was rare in a normal population. This finding supports the use of this signal to follow the activity of CAD out of the hospital, specifically in patients with typical angina and proved CAD.

Continuous ambulatory electrocardiographic monitoring of ST-segment configuration has become a useful technique for evaluation of myocardial ischemia. Concern that direct or amplitude-modulated (AM) recording and playback systems have inherent limitations that cause inaccurate ST-segment recordings has led to preference for frequency-modulated (FM) devices. To determine the accuracy of AM and FM ambulatory electrocardiographic systems, the signal was compared from the same set of 2 bipolar leads simultaneously recorded by standard electrocardiography and AM and FM recorders in 14 patients during treadmill exercise. Also, simultaneous AM and FM recorders were compared in 9 ambulatory patients in 16 monitoring sessions. The AM recording system accurately reproduced ST segments recorded during treadmill exercise (range 4.0 mm of ST-segment depression to 2.0 mm of ST elevation) when measured at the J point (r = 0.91, p less than 0.0001), and 0.08 second after the J point (r = 0.95, p less than 0.0001). FM recording was equally accurate (r = 0.89 and 0.95, respectively, p less than 0.0001). Similarly, during ambulatory recording, the AM technique accurately recorded maximal ST depression in each episode as recorded by the FM device (28 episodes, range 0 to 3 mm of ST depression, r = 0.85, p less than 0.0001). Both AM and FM ambulatory electrocardiographic systems can accurately reproduce ST-segment deviation associated with ischemia and can be used to monitor transient ST-segment changes in patients with coronary artery disease.

The management of patients with angina pectoris is based largely on the severity of symptoms, coronary anatomy and left ventricular function. The outcome for these patients is highly variable and depends largely on the degree of ischemic damage to the left ventricular myocardium. Recent work suggests that exercise-induced myocardial ischemia with or without angina is associated with a poor prognosis. Ambulatory monitoring of the electrocardiogram has revealed that most patients have frequent and prolonged episodes of transient ischemia out of hospital. These episodes are often asymptomatic and associated with ordinary everyday activities. In addition, ambulatory monitoring has demonstrated that transient ischemia during daily life has a circadian variation with exacerbations and peak density of ischemia in the first 4 to 6 waking hours of the day. Further studies have demonstrated that regional decreases in coronary blood flow occur during these ischemic episodes and have the same features seen out of hospital on continuous monitoring. These newly noted characteristics of transient ischemia raise a number of practical questions for treatment. Is it necessary to relieve all ischemic activity quite apart from that which occurs with chest pain? Does present use of antianginal medication neglect the early morning increases in transient ischemia that occur, and are different dosage regimens required to treat ischemia adequately? Does suppression of all ischemic activity further protect myocardium and improve prognosis for the patient?

There is growing interest in the possible therapeutic and prognostic significance of silent myocardial ischemia in coronary artery disease (CAD) and its detection by ambulatory electrocardiographic (ECG) monitoring. In 100 apparently healthy normal subjects (20 with angiographically normal coronary arteries), Holter monitoring revealed significant ST-segment depression in only 2 (both over 40 years, one with positive treadmill test, the other with risk factor for CAD). No significant ECG changes were found in those with normal coronary vessels. In 30 patients with documented CAD, significant ST-segment depression during 1,934 episodes over 446 days of monitoring over 18 months was found. Only 24% of the episodes were associated with angina. Asymptomatic and symptomatic episodes were associated with comparable changes in perfusion detected by positron emission tomography. Heart rate increases greater than 10 beats/min preceding the onset of the ST-segment changes occurred in only 23% of the episodes. There was considerable variability in the ST-segment changes in the same patient monitored serially over long periods of time. The data indicate that it is extremely uncommon for patients without CAD to exhibit silent myocardial ischemia, whereas patients with stable angina exhibit frequent, variable and often asymptomatic ECG evidence of myocardial ischemia rarely triggered by increases in heart rate. These findings are likely to be of therapeutic and prognostic significance.

Circadian variations have long been observed in several metabolic functions, many of which are directly or indirectly related to the cardiovascular system and its pathophysiology. Recent reports linking circadian patterns to the development of symptomatic and asymptomatic myocardial ischemia, sudden cardiac death and myocardial infarction raise important questions concerning the mechanisms of myocardial ischemic activity in patients with coronary artery disease, and they have implications for prognosis, therapy and further research.