Clinical evaluation of oral mexiletine therapy in the treatment of ventricular arrhythmias.

The effect of oral mexiletine therapy on ventricular arrhythmias was evaluated in 58 patients in whom conventional drugs had been unsuccessful. Mean daily dose of mexiletine was 652 mg (range 250 to 1,500) and mean duration of therapy was 14.4 months (range 0.1 to 34.4). Mexiletine was associated with a decrease of 52% in total premature ventricular complexes in 24 hours compared with control (6,841 +/- 1,053 [SEM] versus 3,248 +/- 734, p less than 0.005) and 19 patients (36.5%) had a greater than 83% decrease in ventricular ectopic rhythm. The drug was discontinued in 6 of these 19 patients because 5 of them (26%) experienced side effects after a mean period of 29.6 weeks (range 0.83 to 63.2) and sudden death occurred in 1 patient (5%); this indicates effective suppression of ventricular ectopic rhythm without significant side effects in 13 (25%) of 52 patients during long-term therapy. Adjustment of drug dosage to achieve therapeutic blood levels resulted in an efficacy on ventricular ectopic rhythm similar to that obtained with the maximal tolerated dose. There was no correlation between drug dose and therapeutic effectiveness. Mexiletine was associated with a 48% decrease in episodes of ventricular tachycardia (345.5 versus 179.3/24 h) and 5 of 10 patients with a history of cardiac arrest remained free of symptomatic ventricular tachyarrhythmias for 14.8 months (range 3.7 to 24.3).(ABSTRACT TRUNCATED AT 250 WORDS)

Immediate exercise testing of low risk patients with known coronary artery disease presenting to the emergency department with chest pain.

OBJECTIVES: The purpose of this study was to demonstrate the safety and utility of immediate exercise treadmill testing (IETT) of low risk patients presenting to the emergency department with known coronary artery disease (CAD). BACKGROUND: More than 70% of the two million patients admitted to U.S. hospitals annually for suspected acute myocardial infarction (AMI) are found not to have had a cardiac event. We have previously demonstrated the safety and efficacy of IETT of selected low risk patients without known CAD presenting to the emergency department with chest pain. This study extends this approach to selected patients with a history of CAD. METHODS: One hundred patients evaluated by the chest pain emergency room to rule out AMI underwent IETT using a modified Bruce protocol upon admission to the hospital (median time <1 h). RESULTS: Twenty-three patients (23%) had positive exercise electrocardiograms (ExECGs); an uncomplicated non-Q wave AMI was diagnosed in two patients. Thirty-eight patients (38%) had negative ExECGs and 39 patients (39%) had nondiagnostic ExECGs. Of these 100 patients, 64 were discharged immediately after IETT, 19 were discharged in less than 24 h after negative serial cardiac enzymes and stable electrocardiograms and 17 were discharged after further evaluation and treatment. There were no complications from exercise testing and no late deaths or AMI during six-month follow-up. CONCLUSIONS: Immediate exercise treadmill testing of low risk patients with chest pain and known CAD is effective in further stratifying this group into patients who can be safely discharged and those who require hospital admission.

Limitation of myocardial infarct size in pigs with a dual lipoxygenase-cyclooxygenase blocking agent by inhibition of neutrophil activity without reduction of neutrophil migration.

OBJECTIVES: The purpose of this study was to assess the effect of the dual cyclooxygenase-lipoxygenase blocking agent BW755C on the extent of myocardial infarction in the pig and to identify the mechanisms of any cardioprotective action of this drug. BACKGROUND: Activated neutrophils contribute to reperfusion injury after myocardial infarction and inhibition of neutrophil function can limit infarct size. METHODS: In 9 control and 10 study pigs pretreated with intravenous BW755C (10 mg/kg body weight) 30 min before coronary occlusion, ischemia was induced by a 50-min occlusion of the mid-left anterior descending coronary artery, followed by 3 h of reperfusion. Heart rate, arterial pressure, left ventricular end-diastolic pressure, the first derivative of left ventricular pressure (dP/dt) and regional myocardial blood flow were measured during control, occlusion and reperfusion periods. Infarct size was determined by histochemical staining; and myeloperoxidase activity, a marker for tissue neutrophil content, was assessed in normal and infarcted myocardium. The effect of BW755C on the function of isolated neutrophils stimulated with zymosan-activated serum was evaluated by measuring neutrophil degranulation, leukotriene B4 production, superoxide generation and chemotaxis. RESULTS: Hemodynamic function and regional myocardial blood flow were similar in control and BW755C-treated animals. BW755C significantly reduced myocardial infarct size compared with that in control animals, as measured by infarct/risk areas by histochemical staining (39 +/- 5% vs. 63 +/- 7%, p < 0.05). Myocardial myeloperoxidase activity was similar in normal, salvaged and infarcted areas in the control and treated groups, indicating that neutrophil accumulation in injured myocardium was unaltered by BW755C. However, this agent attenuated function of isolated, stimulated (zymosan-activated serum) neutrophils. At a concentration of 0.03 mg/ml, BW755C inhibited degranulation (-46%), leukotriene B4 production (-48%) and superoxide generation (-74%), but there was minimal inhibition of chemotaxis in vitro. CONCLUSIONS: These findings demonstrate that myocardial infarct size can be reduced by selective inhibition of neutrophil cytotoxic activity without affecting neutrophil migration into injured myocardium.

Evaluation of the patient with 'rule out myocardial infarction'.

Evaluation in the emergency department of the patient with chest pain remains a common problem. Large numbers of patients are admitted to the hospital because of diagnostic uncertainty. Strategies dealing with this population include risk stratification by clinical presentation, serial cardiac enzyme assays to exclude myocardial infarction, and detection of myocardial ischemia with nuclear scintigraphy or echocardiography. Each of these strategies is rational with specific benefits and weaknesses. Bypassing these steps and performing immediate exercise testing is the newest approach that appears to be safe, timely, and cost-effective.

Evidence-based, cost-effective risk stratification and management after myocardial infarction. California Cardiology Working Group on Post-MI Management.

Current management of patients after an acute myocardial infarction (AMI) reflects a variety of approaches ranging from conservative to aggressive. Although each method is appropriate in certain subgroups, their application frequently lacks a scientific basis. Current, clinically relevant, evidence-based practice guidelines are needed for secondary prevention for survivors after an AMI. To meet this need, the California Cardiology Working Group was assembled to evaluate the available data from clinical trials and other published studies and develop evidence-based, cost-effective guidelines for clinicians to use as a basis for patient management after an AMI. The group consisted of 18 members, including cardiologists from academic institutions and physicians working in cardiac intensive care, private practices, and managed care settings, representing a broad spectrum of expertise pertaining to patients who have had an AMI. The members had expertise in cardiac intensive care, interventional cardiology, nuclear cardiology, lipid disorders, echocardiography, and cardiac rehabilitation. The intended audience for these practice guidelines includes all physicians who treat survivors of MI. A literature review of all relevant clinical trials and other published data about the natural history after AMI and the effects of current therapeutic modalities are discussed herein. Case histories served as models for application of the literature-based data. The recommendations for management were reached by consensus vote based on the scientific evidence. When more than 1 management option applied, this was recognized in the recommendations. The recommendations accompany the text.

Hydralazine-induced tachycardia and sodium retention in heart failure. Hemodynamic and symptomatic correction by prazosin therapy.

Severe tachycardia, ventricular ectopy, and sodium retention manifested by hemodynamic deterioration developed with hydralazine hydrochloride therapy in chronic coronary heart disease with congestive failure refractory to digitalis, diuretics, and nitrates. Coronary care unit admission with Swan-Ganz catheterization corrected hemodynamics by sodium nitroprusside treatment after hydralazine withdrawal. Satisfactory cardiac performance with oral long-acting nitrates were unsuccessful. However, the new oral vasocilator, prazosin hydrochloride, achieved considerable hemodynamic benefit by greatly reducing elevated left ventricular filling pressure and increasing severely depressed cardiac index to normal, accompanied by striking symptomatic improvement. Furthermore, long-term enhancement of cardiac dynamics and salutary functional status was maintained by ambulatory oral prazosin therapy for several months. This experience demonstrates the favorable alternative of prazosin nitroprusside-like actions over hydralazine-nitrate therapy in heart failure therapy and emphasizes prazosin's utility when untoward side effects to hydralazine develop.

Direct effects of hydralazine on cardiac contractile function, haemodynamics, and myocardial energetics in isolated myocardium.

The direct cardiac effects of hydralazine were studied in isolated working rat heart, isolated cat right ventricular papillary muscle, and isolated rabbit right atrium. The haemodynamics, myocardial energetics, and contractility of isolated hearts were measured at hydralazine concentrations of 0.01, 0.1, 0.5, 1.0, 10 and 100 mumol.litre-1. Coronary flow was significantly increased (greater than or equal to 21%, p less than 0.01) in paced (325 beats.min-1) rat hearts at greater than or equal to 0.5 mumol.litre-1 hydralazine and in spontaneously beating hearts (greater than or equal to 37%; p less than 0.05) at greater than or equal to 1.0 mumol.litre-1 hydralazine. The increases in coronary flow occurred without significant increases in heart rate, contractility (dP/dtmax), or coronary perfusion pressure. Myocardial oxygen consumption was not significantly changed at any hydralazine concentration in spontaneously beating hearts and was unaltered in paced hearts except for a small significant increase (9.8%) at 10 mumol.litre-1. A negative inotropic effect was apparent at 100 mumol.litre-1 hydralazine as indicated by a significant reduction of dP/dtmax (paced and non-paced hearts), peak aortic flow rate (non-paced), and maximum left ventricular pressure (paced). In isolated cat papillary muscles and rabbit right atria, cumulative hydralazine log dose-response curves (0.1-1000 mumol.litre-1) were obtained. A positive inotropic effect that could be abolished by beta adrenergic blockade was produced in papillary muscles only at concentrations greater than or equal to 100 mumol.litre-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic graded ethanol consumption on the metabolism, ultrastructure, and mechanical function of the rat heart.

Three sequential sets of ethanolic rats (E) and their matched controls (C) were fed regular chow containing standard vitamins with the ethanol group in each series also receiving a progressively greater alcohol intake for 3 to 6 months: E1 5%, E2 10%, and E3 25% ethanol. Electron microscopy showed swelling of mitochondria, transverse tubules and sarcoplasmic reticulum, dehiscence of intercalated discs and disintegration of myofibrils scattered throughout the ventricular myocardium in E1 and E2 as early as 7 wk after beginning 5% ethanol; in addition, there were clumping of mitochondria and supercontraction of myofibrils in E3. Concomitant with substructural abnormalities in E3, there were slight but significant depressions of cardiac myofibrillar ATPase activity and mitochondrial function. Cardiac catecholamines, hydroxyproline, and total bound glycerol were unchanged. Alteration of isometric contraction of isolated, supported left ventricular papillary muscles occurred initially in E2 and was clearly evident in E3 by significant reduction of duration of systolic active state (time from onset to peak tension), while total tension generated and peak rate of tension rise were not yet disturbed. Extra vitamin supplementation in additional rats drinking 25% ethanol minimally lessened decline in myofibrillar ATPase activity, but otherwise provided no protection. Thus, chronic daily ingestion of graded quantities of ethanol representing 10 to 30% of total calories in well-nourished animals exerted toxic effects on microstructure, metabolism and mechanics of the ventricle. These alterations are postulated to be pertinent to early pathogenesis of clinical alcoholic cardiomyopathy.

Cardiocirculatory actions of trimazosin and sodium nitroprusside in ischemic heart disease.

Although postload-reducing drugs are effective vasodilators in chronic congestive heart failure, the clinical application of the approach to ambulatory patient management remains difficult. We compared the hemodynamic effects of the new oral systemic vasodilator trimazosin (TZ) with those of nitroprusside (NP). Both TZ (172 mg) and NP (46 microgram/min) decreased mean blood pressure modestly (P less than 0.001), while causing considerable decline in elevated left ventricular filling pressure (TZ from 30 to 24 mm Hg; NP from 31 to 20 mm Hg; both P less than 0.001). TZ also raised the low cardiac index (CI) of 2.02 to 2.59 1/min/M2 (P less than 0.001), whereas NP elevated CI from 2.16 to 2.96 1/min/M2 (P less than 0.001). Both drugs lowered (P less than 0.05) total systemic vascular resistance and pressure time/minute while enhancing (P less than 0.01) stroke work index. The drugs diminished forearm venous tone (P less than 0.02) and forearm vascular resistance (P less than 0.01) concomitantly with elevation of forearm blood flow (P less than 0.05). Thus, TZ induced qualitatively similar marked augmentation of cardiac function to that by NP. These encouraging hemodynamic findings indicate that TZ may be beneficial to patients undergoing ambulatory vasodilator therapy of severe chronic congestive heart failure.

Short- and long-term therapy of mild essential hypertension with timolol.

The short and long-term antihypertensive action of timolol, a beta blocker, was assessed in 36 mild hypertensives in a 32-wk, double-blind, placebo-controlled study followed by an additional 96 wk of timolol in 17 responders. Diastolic blood pressure (DBP) and heart rate (HR) declined during the first phase from 103 to 93 mm Hg and from 73 to 61 bpm (P less than 0.01) but there was long-term timolol subjects (DBP 89 mm Hg at 32 wk and 88 mm Hg at 96 wk [NS] and HR 62 and 65 bpm [NS]). Although stimulated plasma renin activity in the entire group decreased from 1.08 to 0.28 ng/ml/hr (P less than 0.001), blood pressure reduction did not correlate with this decline (r = 0.29) or with serum timolol level (r = 0.29). In 20 patients who underwent treadmill was not altered. Thus, timolol is effective in reducing mild high blood pressure during short-term therapy and in maintaining this effect over the long term in responsive subjects. It is therefore potentially useful in chronic essential hypertension.

Hemodynamic effects of morphine and nalbuphine in acute myocardial infarction.

Hemodynamic effects of morphine and the new narcotic analgesic, nalbuphine, were compared in a randomized, double-blind study in 15 patients with acute myocardial infarction (11 men and four women, average age 56.2 yr) and normal group mean hemodynamic function. During a 1-hr evaluation the hemodynamic effects were small but there were changes in several parameters. Morphine reduced heart rate (78 to 72 bpm, p less than 0.01) and diastolic and mean arterial pressures (69 to 64 mm Hg, p less than 0.05; and 91 to 84 mm Hg, p less than 0.05); nalbuphine was associated with a decrease in heart rate (82 to 72 bpm, p less than 0.01), decrease in cardiac index, which remained within the normal range (3.16 to 2.75 l/min/m(2), p less than 0.01), and an increase in systemic vascular resistance (1,204 to 1,461 dynes . sec . cm(-5), p less than 0.05). Neither drug altered systolic arterial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, stroke index, stroke work index, or pulmonary vascular resistance. Echocardiographic assessment revealed diminution of left ventricular mean velocity of circumferential fiber shortening after nalbuphine (1.26 to 1.08 circ/sec, p less than 0.05). Both drugs induced small reductions in respiratory rate and arterial pH and increases in PAO2. There were no changes in PaO2. Because of the absence of clinically important deleterious effects on cardiac pump function, nalbuphine merits further investigation as an analgesic in acute myocardial infarction.

Effects of cardiac stress during a very-low-calorie diet and exercise program in obese women.

To assess the safety of very-low-calorie diets (VLCDs), stress tests known to induce arrhythmias in susceptible patients were performed in 24 obese women on a VLCD (660-720 kcal/d) for 6 wk. Half of the subjects had diet only (DO) and half underwent supervised exercise (DE) four times weekly. Five control subjects ate a balanced, moderately low-calorie diet (approximately 1400 kcal/d). Stress tests included maximal and submaximal (85%) exercise, psychological stress, and isometric handgrip tests, all with constant electrocardiogram (ECG) monitoring. Twenty-four-hour Holter monitors at weeks 0 and 6 and weekly resting ECGs were obtained. DO and DE lost similar amounts of weight. There were no changes in QT intervals or in voltage or width of the QRS complex on resting ECG and no arrhythmias on Holter monitoring. These data support the safety of VLCDs containing greater than or equal to 650 kcal/d and adequate amounts of high-quality protein, vitamins, and minerals for use for periods of at least 6 wk in normal, healthy obese women.

Effect of cardiac rehabilitation on postprandial response to a high fat meal in patients with coronary artery disease.

Past studies have shown decreased lipemic responses to a high fat meal in healthy trained vs. untrained subjects. The purpose of this study was to characterize fasting lipid profiles and lipemic responses in 13 male cardiac patients (6 in cardiac rehabilitation (CR) and 7 controls (NONCR]. Body composition and dietary composition were assessed. Plasma total cholesterol (TC), HDL-cholesterol (HDL-C) and triglyceride (TG) were determined after a 12-h fast. Subjects consumed a high fat meal (60% of calories) and the lipemic response to the meal was assessed by determining plasma TG hourly for 8 h following the meal. CR had a lower percent body fat than NONCR (26% vs. 34%, P less than 0.05). CR consumed fewer calories from fat than NONCR (28% vs. 41%, P less than 0.05). There were no significant differences between groups in TC, HDL-C or TG, although the differences approached significance (P less than 0.10). CR had a lower TC/HDL-C ratio than NONCR (5.0 vs. 7.7, P less than 0.05). Lipemic responses between groups were similar. There was no significant difference in peak TG, time to peak TG, or area under the TG curve between CR and NONCR groups. Thus, subjects undergoing cardiac rehabilitation appear to have both a more favorable diet and fasting lipid profile than NONCR; however, both groups had a similar response to a high fat meal.

A perspective on hyperlipidemia: concepts of management in the prevention of coronary artery disease.

The clinical benefits of lowering elevated serum cholesterol for both primary and secondary prevention of coronary artery disease are now well established. Reduction in clinical events occurs early and appears to be related to stabilization of atherosclerotic plaque. Despite these salutary findings, lipid-lowering therapy, both nondrug and pharmacologic, is still markedly underutilized in patients and high-risk individuals in the asymptomatic population. Recent practical and uncomplicated guidelines present a rational strategy for selection of patients for low-density lipoprotein (LDL) cholesterol reduction and have the potential to yield major clinical benefits if properly implemented. Preventive cardiology measures should be applied by matching the intensity of the intervention to the hazard for clinical events. We support the current guidelines of the expert panels described in this article and propose several extensions for cholesterol lowering in selected, high-risk populations.

Relation of ventricular arrhythmias in the late hospital phase of acute myocardial infarction to sudden death after hospital discharge.

To determine the prognostic significance of ventricular arrhythmias persisting during the hospital ambulatory phase of acute myocardial infarction, 64 patients with acute myocardial infarction underwent continuous 10-hour Holter monitoring an average of 11 days after discharge from the coronary care unit (CCU). Patients were categorized according to the results of ambulatory monitoring: 27 patients had ventricular extrasystoles, which were complicated (multifocal, R on T, paired, more than 5/min), or ventricular tachycardia; 22 had uncomplicated premature ventricular contractions; and 15 exhibited no ventricular arrhythmias. The 64 patients were followed prospectively for an average course of 25.8 months; 12 died suddenly; 8 died of other causes, and 44 survived. In all patients who died suddenly, ventricular ectopy was recorded on Holter monitoring before their discharge from the hospital (complicated premature ventricular contractions, eight patients; uncomplicated premature ventricular contractions, four patients); there were no sudden deaths in the patients without ventricular arrhythmias. Patients who died suddenly and those survived were similar in respect to age (60, 62 years), sex, location of infarction, presence of coronary risk factors, severity of acute myocardial infarction (Q waves, cardiac enzymes), serum cholesterol levels, evidence of cardiomegaly on roentgenograms, presence of ventricular gallop and drug therapy received. The occurrence of acute arrhythmias in the CCU did not separate patients who died suddenly from those who survived; there were no differences in ventricular tachycardia or ventricular fibrillation (3 or 12 patients who died suddenly, 6 of 44 patients who survived) or complicated premature ventricular contractions (4 or 12 patients who died suddenly, 18 of 44 patients who survived). Electrocardiograms obtained late in the hospital course revealed no differences in the extent of Q or T wave changes between these two groups. However, the extent of S-T segment abnormality was greater in patients who died suddenly than in patients who survived (5.6 compared to 1.8 leads/standard tracing, p smaller than 0.02) suggesting that the arrhythmias in the former were related to persistent ischemia or segmental ventricular dyssynergy. Thus, in this relatively small number of patients, ventricular arrhythmias persisting late in the hospital course of patients admitted for acute myocardial infarction are shown to predispose to subsequent sudden death.

Comparative effects of morphine, meperidine and pentazocine on cardiocirculatory dynamics in patients with acute myocardial infarction.

The cardiocirculatory effects of the commonly used parenteral analgesics, morphine sulfate 15 mg, meperidine hydrochloride 100 mg and pentazocine 60 mg, each administered intravenously, were compared in 12 patients with acute myocardial infarction during cardiac catheterization and by echocardiogram. No untoward hemodynamic effects occurred following the administration of morphine or meperidine. In contrast, pentazocine produced significant (p less than 0.01 to less than 0.05) increases in systemic and pulmonary arterial pressures, left ventricular filling pressure, systemic vascular resistance, and systolic and diastolic dimensions; and decreases in left ventricular ejection fraction and mean velocity of circumferential fiber shortening. These deleterious actions of pentazocine appeared due to peripheral vasoconstriction and negative inotropic properties. Further, pentazocine-induced increases in left ventricular preload and afterload increased myocardial oxygen demands. Since this study demonstrates that pentazocine is hazardous in myocardial infarction, morphine and meperidine are the preferred analgesics in this condition.

Multifactor evaluation of the determinants of ischemic electrocardiographic response to maximal treadmill testing in coronary disease.

Despite widespread use of treadmill stress in the detection of coronary disease, detailed information relating the important features of coronary pathoanatomy to the ischemic response noted on the electrocardiogram is lacking. Accordingly, 91 consecutive patients undergoing graded maximal exercise tests (MEXT) who were found to have clinical stenosis (larger than or equal to 75 per cent luminal narrowing) of at least one of the three major coronary arteries on coronary arteriography were evaluated. Positive MEXT was defined as larger than or equal to 0.1 mV horizontal or downsloping S-T segment depression larger than or equal to 0.08 second beyond J point. Over-all sensitivity of positive MEXT was 59 of 91 (65 per cent) patients; 11 of 26 (42 per cent) with single vessel stenosis, 20 of 30 (66 per cent) with two vessel disease and 28 of 35 (80 per cent) with three vessel disease. In patients with two vessel disease, the frequency (p less than 0.05) of positive MEXT was greater in those with (15 of 21;71 per cent) than in those without (five of nine; 55 per cent) stenosis of the left anterior descending artery. Concerning the site of intravessel stenosis, the frequency of positive MEXT was greater (p less than 0.05) with stenosis proximal to the left anterior descending artery in patients with one vessel disease. Quantification of total numbers of intra- and intervessel stenoses revealed 2.7 stenoses in the 59 patients with positive MEXT in contrast (p less than 0.01) to 1.9 in 32 patients with negative MEXT. Similarly, graded luminal narrowing index of severity of total stenoses per patient was 9.9 in those with positive MEXT compared (p less than 0.01) to 6.1 in those with negative MEXT. The poststenotic myocardial perfusion index, estimated by graded distal vessel opacification per major vessel disease, was only 1.5 in those with positive MEXT contrasted (p less than 0.01) to 2.4 in those with negative MEXT. These data indicate that sensitivity of positive MEXT in patients with coronary disease is most closely determined by the number of major coronary vessels involved, the total number of major vessels stenosed, the severity of total stenoses and poststenotic distal vessel perfusion. Less important factors are the precise site of intravessesl stenosis and the specific major coronary artery involved, although stenosis proximal to the left anterior descending artery favored positive MEXT. Unimportant variables were the quality of collateral vessels, ventricular function and prior inferior infarction. Angina occurred more frequently in those with positive MEXT, and marked degree of positive MEXT indicated stenosis proximal to the left anterior descending artery.

Relation of silent myocardial ischemia to ventricular arrhythmias and sudden death.

Silent myocardial ischemia is common in the clinical spectrum of coronary disease. Ambulatory electrocardiographic monitoring has provided the most objective evidence of silent ischemia, but the phenomenon has also been detected in patients with coronary artery disease through analysis of exercise-induced ischemic ST-segment alterations, scintigraphic myocardial perfusion defects and left ventricular wall motion abnormalities. Silent myocardial ischemia frequently occurs in patients with stable angina, unstable angina, myocardial infarction and completely asymptomatic coronary artery disease. In each of these groups, silent ischemia has been associated with an increased risk of subsequent cardiac events. However, it remains unclear whether silent ischemia is directly involved in the occurrence of these events, possibly by provoking ventricular arrhythmias. Only limited data are available on the relation between silent ischemia and arrhythmias in myocardial infarction, vasospastic angina, coronary angioplasty, exercise testing and ambulatory electrocardiography. However, fortuitous ambulatory monitoring coincident with sudden death has detected ischemia associated with lethal arrhythmias in some individual cases. This suggests that an ischemia-arrhythmia association may be important in certain patients at certain times, possibly in combination with other factors.

Rationale for intermittent nitrate therapy.

Tolerance to the pharmacologic and therapeutic effects of nitrate therapy is now well established. This phenomenon may be defined as either a decreased response to a given amount of nitrate or the need for an increased amount of nitrate to maintain a constant effect. Tolerance has been demonstrated with all forms of nitrate therapy that maintain continuous blood levels of the drug, including frequent oral dosing, constant intravenous infusion, and continuous transdermal delivery. It can develop rapidly after only a few doses of a nitrate preparation and tends to be partial rather than absolute. Strategies for the prevention of nitrate tolerance include the avoidance of maximum nitrate doses and the use of intermittent nitrate dosing regimens. Providing a relatively brief nitrate-free interval restores vascular responsiveness to nitrates, most likely due to a recovery of the metabolic mechanisms responsible for the therapeutic effect of these drugs. The duration of this period of nitrate abstinence varies, depending on the nitrate preparation used but is generally in the range of 8-12 hours. Such intermittent therapy not only reduces the risk of nitrate tolerance, but also provides a convenient approach to outpatient management.

Utility and safety of immediate exercise testing of low-risk patients admitted to the hospital for suspected acute myocardial infarction.

More than 2 million patients are admitted to U.S. hospitals annually for clinical suspicion of acute myocardial infarction (AMI), and > 70% are found not to have had a cardiac event. This study evaluates the safety and efficacy of immediate exercise testing for patients admitted to the hospital for suspected AMI. Ninety-three nonconsecutive low-risk patients admitted to the hospital from the emergency department to rule out AMI underwent exercise treadmill testing using a modified Bruce protocol immediately on admission to the hospital (median time < 1 hour). Twelve patients had positive exercise electrocardiograms, 6 of whom had significant coronary narrowing by angiography. An uncomplicated non-Q-wave AMI was diagnosed in 1 patient. Fifty-nine patients had negative and 22 patients had nondiagnostic exercise electrocardiograms. Of these 81 patients, 44 were discharged immediately after exercise testing, 17 were discharged within 24 hours, and 20 were discharged after 24 hours of observation. There were no complications from exercise testing. There were 2 late noncardiac deaths and 1 late AMI. Thus, immediate exercise testing of low-risk patients with chest pain who are at sufficient risk to be designated for hospital admission is effective in further stratifying this group into those who can be safely discharged immediately and those who require hospitalization.