Treatment of stable angina.

Severe atherosclerotic narrowing of one or more coronary arteries is responsible for myocardial ischemia and angina pectoris in most patients with stable angina pectoris. The coronary arteries of patients with stable angina also contain many nonobstructive plaques, which are prone to fissures or rupture resulting in presentation of acute coronary syndromes (unstable angina, myocardial infarction, sudden ischemic death). In addition to symptomatic relief of symptoms and an increase in angina-free walking time with antianginal drugs or revascularization procedures, the recent emphasis of treatment has been to reduce adverse clinical outcomes (coronary death and myocardial infarction). The role of smoking cessation, aspirin, treatment of elevated lipids, and treatment of high blood pressure in all patients and of beta-blockers and angiotensin-converting enzyme inhibitors in patients with diminished systolic left ventricular systolic function in reducing adverse outcomes has been well established. What is unknown, however, is whether any anti-anginal drugs (beta-blockers, long-acting nitrates, calcium channel blockers) effect adverse outcomes in patients with stable angina pectoris. Recent trials evaluated the usefulness of suppression of ambulatory ischemia in patients with stable angina pectoris, but it remains to be established whether suppression of ambulatory myocardial ischemia with antianginal agents or revascularization therapy is superior to pharmacologic therapy targeting symptom relief. Patients who have refractory angina despite optimal medical treatment and are not candidates for revascularization procedures may be candidates for newer techniques of transmyocardial revascularization, enhanced external counterpulsation, spinal cord stimulation, or sympathectomy. The usefulness of these techniques, however, needs to be confirmed in large randomized clinical trials.

Rapid-release and coat-core formulations of nisoldipine in treatment of hypertension, angina, and heart failure.

Nisoldipine, a dihydropyridine calcium antagonist, has greater vascular selectivity than other calcium channel antagonists and does not depress the intact myocardium in vivo. It should be taken on an empty stomach. Both rapid-release and coat-core formulations are available for clinical use, but only the coat-core formulation extends antihypertensive, antiischemic, and antianginal effects throughout the dosing interval when given once daily. The coat-core formulation in daily doses of 10 to 40 mg does not cause the proischemic effects reported with the rapid-release formulation. When given as monotherapy, the coat-core formulation is highly effective in lowering blood pressure to a similar extent as other long-acting calcium channel blockers, diuretics, beta-blockers, or angiotensin-converting enzyme (ACE) inhibitors. The antihypertensive effects are potentiated when the coat-core formulation of nisoldipine is given in combination with lisinopril. In patients with stable angina pectoris nisoldipine coat-core increases exercise duration, reduces anginal frequency and myocardial ischemia, and is effective as monotherapy or in combination with a beta-blockers. In monotherapy the drug is as effective as other long-acting calcium channel blockers or a beta-blocker. The effects of nisoldipine coat-core in patients with heart failure are unclear at present.

Supersensitivity to serotonin- and histamine-induced arterial contraction following ovariectomy.

The modulating role of estrogens and ovariectomy on coronary artery and thoracic aortic rings was examined in female rabbits. Three treatment groups were studied: (1) control, (2) ovariectomy, and (3) ovariectomy + 17beta-estradiol acetate (40 microg/kg per day, i.m. for 7 days). Coronary artery reactivity was studied in the isolated retrogradely perfused heart. Aortic reactivity was studied using endothelium intact and denuded aortic rings. Concentration-response curves were performed to serotonin (5-HT) and histamine. A 21-fold, a 4.7-fold, and a 5.2-fold increase in sensitivity to 5-HT-induced contraction were observed in the ovariectomy group compared to the control group for coronary artery, intact aortic, and denuded aortic preparations, respectively (P < 0.05 for each comparison). Similarly, 34-fold, 4.9-fold, and 5.0-fold increases in sensitivity to histamine-induced contraction were observed in the ovariectomy group compared to control group for coronary artery, intact aortic, and denuded aortic preparations, respectively (P < 0.05 for each comparison). 17beta-Estradiol administration reversed the supersensitivity to serotonin- and histamine-induced vascular contraction observed following ovariectomy. No differences in EC50 or maximal contraction were noted between control and ovariectomy + estrogen groups. Baseline nitric oxide release and maximal 5-HT- and histamine-induced nitric oxide release from the perfused heart were decreased (P < 0.05) in ovariectomy rabbits compared to control and ovariectomy + estrogen treatment groups. The data demonstrate that (1) reduced autacoid-induced nitrous oxide release following ovariectomy and (2) direct effects upon the vascular smooth muscle contractility, which are probably mediated by altered receptor sensitivity by ovariectomy and estrogen replacement therapy. The information obtained from this study provides additional information regarding possible beneficial actions of estrogen replacement therapy in post-menopausal women.

Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: a double-blind, randomized angiographic trial of lanoteplase versus alteplase.

BACKGROUND: Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase. METHODS AND RESULTS: InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the dose-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects, P<0. 001). Similar results were observed at 90 minutes (26.1% to 57.1%, P<0.001). At 90 minutes, coronary patency (TIMI 2 or 3) increased across the dose range up to 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. Thus, at this dose, lanoteplase was superior to alteplase in restoring coronary patency (difference, 12%; 95% CI, 1% to 23%). The early safety experience in this study suggests that lanoteplase was well tolerated at all doses with safety comparable to that of alteplase. CONCLUSIONS: Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent.

Choosing the most appropriate treatment for stable angina. Safety considerations.

The goals of stable angina pectoris treatment are: (i) symptom relief and increase in angina-free walking time; and (ii) reduction of mortality and adverse outcome. Strategies used for plaque stabilisation resulting in a reduction in cardiovascular mortality and morbidity are: smoking cessation; aspirin (acetylsalicylic acid); blood pressure control; lipid lowering agents when low density lipoprotein cholesterol is elevated despite dietary therapy; coronary bypass surgery in patients with left main stem disease or triple vessel coronary disease and diminished left ventricular function; and use of estrogen in postmenopausal women. For symptom relief and to increase angina-free walking time, long acting nitrates, beta-blockers, calcium antagonists and potassium channel openers can be used. Drugs from these 3 classes are all effective when used optimally and choice of initial therapy should consider the presence of concomitant disease and underlying left ventricular function. However, none of the long acting nitrates provide continuous prophylaxis because nitrate tolerance develops during long term therapy. In patients with uncomplicated stable angina, nitrates, beta-blockers and calcium antagonists are all effective. Intermittent nitrate therapy is not associated with tolerance, but headache is a common adverse effect and the patient is unprotected at night and in the early hours of the morning. Concomitant treatment with a beta-blocker may be beneficial if the patient experiences withdrawal or early morning angina. For patients with stable angina and hypertension, therapy with a beta-blocker or a calcium antagonist rather than nitrate is indicated. beta-Blockers are preferred in patients who have had a myocardial infarction, or in those with a history of supraventricular tachyarrhythmias. beta-Blockers may produce excessive slowing of the heart rate, fatigue and bronchospasm in susceptible patients. Calcium antagonists are indicated as initial therapy when beta-blockers are either not tolerated or contraindicated. beta-Blockers and nondihydropyridine calcium antagonists should not be used in patients with sinus bradycardia and those with greater than first degree atrioventricular (AV) block because of the possibility of further slowing of heart rate and/or the development of high grade AV block. When monotherapy with one class is ineffective or associated with adverse effects, the patient should be switched to another class rather than given an additional drug. Optimal monotherapy is often as effective as combination therapy. If maximum monotherapy is only partially effective, a combination therapy which is not additive in terms of adverse effects should be chosen. Triple therapy may be deleterious and no more effective than dual therapy.

Severe symptomatic sinus bradycardia associated with mesalamine use.

A 29-yr-old white woman was hospitalized with bloody diarrhea secondary to ulcerative colitis. Within 24 h of receiving intravenous steroids, loperamide, and mesalamine, she developed symptomatic hypotension, severe sinus bradycardia, sinus pauses, and junctional escape beats. The hypotension and sinus bradycardia resolved after discontinuing mesalamine. She had a family history of conduction tissue disease but her exercise ECG and Holter studies were normal. She was rehospitalized 6 wk later with an exacerbation of ulcerative colitis and, within 8 h of receiving mesalamine, developed hypotension and severe sinus bradycardia, which resolved after stopping mesalamine. Thus mesalamine should be used with caution, especially in patients predisposed to cardiac conduction tissue disease.

Ovariectomy and estrogen-induced alterations in myocardial contractility in female rabbits: role of the L-type calcium channel.

The effects of ovariectomy and estrogen replacement on myocardial contractility were examined in female rabbits. Ovariectomy failed to alter left ventricular mass, papillary muscle cross-sectional area or isometric force. Estrogen replacement after ovariectomy (0.15 microg/kg/day i.m. 17beta-estradiol acetate for 7 days) increased left ventricular mass and papillary muscle mass, and reduced isometric force compared to control and ovariectomy groups. Ovariectomy did not alter increased isometric force with isoproterenol, but decreased the ED50 for Bay K8644 (compared to control and estrogen groups). Estrogen replacement increased the ED50 for isoproterenol- and Bay K8644-induced isometric force compared to control and ovariectomy groups. Ovariectomy increased and estrogen replacement decreased isometric force associated with increased Ca++o. Acute exposure to 17beta-estradiol or diethylstilbesterol (10(-7) M, 10(-6) M) failed to alter isometric force in control papillary muscles. Estrogen replacement reduced the number, but not the dissociation constant for 3H-nitrendipine binding in plasma membrane preparations (compared to ovariectomy and control groups). Peak L-type calcium currents in isolated ventricular myocytes from the three treatment groups were not significantly different. The data are consistent with an ovariectomy-induced increase and estrogen-induced decrease in L-type calcium channel density in rabbit myocardium. Estrogen-induced alterations in L-type calcium channel expression and contractility are subsequently modified by estrogen-induced cardiac hypertrophy.

Effect of morning versus evening dosing of diltiazem on myocardial ischemia detected by ambulatory electrocardiographic monitoring in chronic stable angina pectoris. Dilacor XR Ambulatory Ischemia Study Group.

Myocardial ischemia occurs frequently during daily life and has a circadian pattern similar to that reported for myocardial infarction and sudden death. Because of the increased risk of myocardial ischemia in the morning hours, it has been suggested that the administration of anti-ischemic medication before bedtime may be more effective than the traditional morning dosing. This randomized, double-blind, placebo-controlled, crossover study evaluated the effects of 480-mg/day diltiazem (given either in the A.M. or the P.M.) on myocardial ischemia using ambulatory electrocardiographic monitoring in 68 patients with chronic stable angina and > or = 2 minutes of ischemia per 48 hours. During treatment with diltiazem, the duration and number of myocardial ischemic episodes were reduced by 45% (94 to 52 minutes, p <0.004) and by 40% (4.5 to 2.7 episodes, p <0.003), respectively. The duration and number of myocardial ischemic episodes during daytime (6 A.M. to 6 P.M.) hours were also reduced by 52% (74 to 36 minutes, p <0.002) and by 48% (3.1 to 1.6 episodes, p <0.001), respectively. There was no significant difference between A.M. and P.M. dosing. Morning ischemia (6 A.M. to noon), considered separately from daytime ischemia, was also significantly reduced by both A.M. and P.M. dosing regimens, with no difference between the regimens. The results of this study showed that both A.M. and P.M. dosing of long-acting diltiazem were equally effective in suppressing episodes of ambulatory myocardial ischemia at all times.

Lack of arrhythmogenicity with ST-segment elevation during high-dose of dobutamine atropine stress in patients with documented or suspected coronary artery disease.

The angiographic, echocardiographic, and electrocardiographic correlates of ST-segment elevation during high-dose dobutamine-atropine stress were prospectively looked at in a group of high-risk patients. Unlike exercise-induced ST elevation, ST-segment elevation with dobutamine-atropine stress, while indicating transmural ischemia, did not increase rate of arrhythmias and hence by itself may not be an indication to terminate the test.

Effect of 17-beta estradiol in the rabbit: endothelium-dependent and -independent mechanisms of vascular relaxation.

Short-term estrogen administration has been independently proposed to produce arterial vasodilation by both an indirect mechanism and a direct mechanism (inhibition of calcium entry though the L-type calcium channel). The proposed contributions of such diverse mechanisms to the vascular actions of 17beta-estradiol were examined in perfused hearts and in aortic ring sections isolated from female rabbits. In isolated rabbit hearts retrogradely perfused with Tyrode's solution, concentration-response curves to 17beta-estradiol (10(-9)-10(-5) M) were performed under control conditions and during perfusion with Bay K8644 (10(-7) M). 17beta-Estradiol produced a concentration-dependent decrease in coronary vascular resistance proportional to nitric oxide (NO) release in the presence and absence of Bay K8644. The addition of N(G)-nitro-L-arginine methyl ester (L-NAME; 10(-4) M) to the perfusate (a) completely inhibited NO formation, (b) produced a 2.3-fold and 1.55-fold rightward shift in the concentration-response curve to 17beta-estradiol for Bay K8644 treated and control hearts, respectively, and (c) failed to prevent coronary artery vasodilation. In isolated aortic rings contracted with Bay K8644, 17beta-estradiol (10(-5) M) relaxed both intact (58%) and denuded (54%) aortic rings. L-NAME (10(-4) M) completely blocked NO release in intact rings but did not prevent relaxation in denuded aortic rings. The data demonstrate (a) an endothelium-dependent relaxation by 17beta-estradiol, coincident with NO formation and suppressed by L-NAME, and (b) a direct relaxation of aortic and coronary smooth muscle independent of NO formation at higher 17beta-estradiol concentrations.

Management of patients with chronic stable angina at low risk for serious cardiac events.

Successful management of the patient with chronic stable angina requires correct stratification by assessing the risk of future coronary events. Patients at low risk for such events have a relatively good prognosis; revascularization procedures (balloon angioplasty or surgery) offer no benefit over medical management. Such patients should be offered medical therapy as their first option. The goals in management of chronic stable angina are (1) treatment of other conditions that may worsen angina; (2) treatment with aspirin and modification of risk factors for coronary artery disease (CAD) to improve outcome; and (3) effective relief of anginal symptoms. Most patients with stable angina will have CAD. It is well established that treatment with aspirin and modification of risk factors for CAD are beneficial in reducing cardiovascular mortality and morbidity. Blood pressure reduction, lowering of blood cholesterol level, and smoking cessation are interventions of proven value and appear to correct defects (at least partially) in the endothelial function of the coronary blood vessels. Other interventions that are helpful are estrogen replacement treatment in postmenopausal women, and low-dose aspirin therapy-which is recommended for all patients who can tolerate it. For controlling symptoms and improving angina-free walking time, nitrates, beta blockers, and calcium channel antagonists are efficacious as first-line monotherapy for chronic stable angina in this group of patients. Nitrates may be of special use in patients with impaired left ventricular function, overt congestive heart failure, intermittent coronary vasoconstriction, or coronary artery spasm. In patients with concomitant hypertension or supraventricular tachycardia, beta blockers are helpful. Calcium channel antagonists may be useful in patients with chronic obstructive pulmonary disease, peripheral vascular disease, or hypertension. When optimal monotherapy with a given class of drug fails to control symptoms, alternative monotherapy with a different class of agent should be tried before combination therapy. Combination therapy with 2 or 3 agents is not always superior to optimal monotherapy. Patients who fail to respond to adequate medical therapy should be considered for a revascularization procedure.

Effects of zatebradine (ULFS 49 CL), a sinus node inhibitor, on heart rate and exercise duration in chronic stable angina pectoris. Zatebradine Investigators.

Zatebridine selectively reduces resting and exercise heart rate without any other myocardial effects. In this study, despite significant reductions in resting and exercise heart rate, there were no clinically significant effects on myocardial ischemia, suggesting that the anti-ischemic effect of heart rate reduction should be reevaluated.

Oral nitrates: more than symptomatic therapy in coronary artery disease?

The predominant venodilator properties of the nitrates and their augmentation of collateral coronary blood flow to the ischemic myocardium endows them with some ideal characteristics for treating myocardial ischemic syndromes. Additional efficacy stems from the ability of the nitrates to replenish the deficient endothelium-derived relaxing factor (EDRF), nitric oxide (NO), in patients with coronary heart disease and also to inhibit platelet aggregation. In stable angina pectoris, the antianginal and antiischemic effects of oral nitrates are well established. Continuous administration of nitrates may lead to tolerance of their clinical efficacy. Recent studies, however, have demonstrated that when used in recommended doses, tolerance can be avoided during long-term treatment with oral nitrates without provocation of anginal attacks during periods of low nitrate levels at night and early hours of the morning. Thus, prolonged treatment with an asymmetric twice-daily regimen of immediate-release isosorbide-5-mononitrate in patients with stable angina pectoris does not give rise to clinical tolerance, prolongs exercise duration, and delays the onset of myocardial ischemia. In unstable angina pectoris, nitrates rapidly relieve chest pain and ameliorate the electrocardiographic signs of myocardial ischemia. In patients with acute myocardial infarction, early treatment with nitrates prevents left ventricular dilatation, improves pumping function, and reduces the risk of ventricular arrhythmias. In patients with chronic heart failure, oral nitrates improve exercise tolerance and, when given in combination with the systemic arterial dilator hydralazine, extend survival. Meta-analysis of published studies has demonstrated that both intravenous and oral nitrates reduced infarct size and morbidity and mortality in patients with acute myocardial infarction. In the ISIS 4 post-infarction study, isosorbide-5-mononitrate 60 mg once daily was not superior to placebo in reducing mortality risk. However, in the GISSI 3 study, the combination of nitrates with an angiotensin-converting enzyme (ACE) inhibitor reduced mortality risks by 17% in patients with acute myocardial infarction. In both the ISIS 4 and GISSI 3 studies, 62% and 57% of the patients in the placebo and control groups, respectively, were treated with nitrates for control of rest angina, myocardial ischemia, and or left ventricular failure symptoms, and this widespread use of open-label nitrates in the control groups may have diluted the true beneficial effects of nitrates in both studies. Taken together, these many studies with oral nitrate treatment in coronary heart disease and heart failure clearly emphasize that these drugs are safe and play more than a symptomatic role in the management of patients with acute and chronic ischemic syndromes due to coronary artery disease.

Additional antianginal and anti-ischemic efficacy of mibefradil in patients pretreated with a beta blocker for chronic stable angina pectoris.

This study assessed the safety, tolerability, and efficacy of mibefradil when added to beta-blocker monotherapy in patients with chronic stable angina pectoris. Two hundred five patients were randomized to receive double-blind treatment with either placebo (n = 70), mibefradil 25 mg (n = 67), or mibefradil 50 mg (n = 68) for 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of the run-in (baseline) and double-blind treatment periods, and patients maintained an anginal diary. Compared with placebo, treatment with mibefradil 50 mg resulted in significant increases in exercise duration (36 +/- 51 seconds; p = 0.036), time to onset of angina (48 +/- 65 seconds; p = 0.002), and time to persistent 1-mm ST-segment depression (47 +/- 77 seconds; p = 0.004). Greater reductions in heart rate, blood pressure, and the rate-pressure product were more apparent at each stage of the ETT in the 50-mg mibefradil group than in the placebo group. Daily treatment with mibefradil 50 mg was associated with a significant decrease in the number of weekly anginal attacks (-2.1 +/- 4.0, p = 0.020) compared with placebo. The addition of mibefradil to existing beta-blocker therapy was well tolerated. Dizziness was the most frequently reported adverse event in the mibefradil 50-mg dose, and occurred with an incidence of 4.4%. The addition of mibefradil 50 mg, administered once daily, to patients on stable beta-blocker therapy produced additive antianginal and anti-ischemic effects and was well tolerated.

Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure.

Vascular tolerance develops rapidly in isolated vascular strips exposed to millimolar concentrations of nitroglycerin. Several mechanisms, including depletion of sulfhydryl groups, reduced biotransformation of nitrates to NO or nitrosothiols, oxygen free radical injury, and downregulation of a membrane-bound enzyme or a nitrate receptor, have been proposed, but the exact mechanism responsible for in-vitro tolerance remains unknown. In-vivo tolerance of the beneficial effects of nitrates on hemodynamics, myocardial ischemia, and exercise performance develops rapidly. It has been suggested, but remains to be proven, that development of venous tolerance and not arterial tolerance is responsible for the attenuation of nitrate effects during long-term nitrate therapy. Several mechanisms, including neurohormonal activation, depletion of sulfhdryl groups, and the shift of fluid from the extravascular to intravascular compartment have been implicated. However, the use of agents to counteract these mechanisms (ACE inhibitors, sulfhydryl donors, diuretics) has produced conflicting results. Thus, at present the mechanism responsible for in vivo tolerance to nitrates remains unknown. Both in vitro and in vivo vascular tolerance to nitrates can be prevented or minimized by providing nitrate-free or low-nitrate intervals. However, during nitrate-free periods, rebound phenomena (rest angina in patients with ischemic heart disease or a deterioration in exercise performance prior to the renewal of the morning dose in patients with stable angina) remain a clinical concern. When treating patients with stable angina pectoris, it must be recognized that none of the nitrate preparations or formulations can provide round-the-clock antianginal or antiischemic prophylaxis. In these patients, beneficial antianginal and antiischemic effects of nitrates for 10-14 hours during the daytime can be maintained by using formulations and dosing regimens that avoid or minimize the development of tolerance (standard formulation of isosorbide-5-mononitrate, 20 mg in the morning and 7 hours later; slow-release formulation of isosorbide-5-mononitrate, 120-240 mg once a day; or nitroglycerin patch delivering 0.6 nitroglycerin per hour for 10-12 hours each day). Only the patch on and off treatment is associated with nitrate rebound. Although intermittent nitrate therapy is not associated with the development of tolerance, this strategy cannot be recommended for treating unstable angina because rebound angina during nitrate-free periods complicates clinical decision making. In the acute phase of unstable angina, continuous treatment with intravenous nitroglycerin is recommended because it permits rapid up- or down-titration. Tolerance towards antianginal and antiischemic effects does develop in a substantial number of patients with 24 hours, but this can be overridden by dose escalation and restoration of the therapeutic effectiveness of nitroglycerin. Tolerance towards the beneficial effects of nitrates on hemodynamics and on exercise performance also develops rapidly during continuous or long-term nitrate therapy, and for these reasons nitrates are not used as first-line therapy to treat chronic heart failure. In combination with hydralazine, high-dose isosorbide dinitrate (30-40 mg four times a day) improves survival, but this combination therapy is inferior to ACE inhibitors.

Secondary preventive potential of nitrates in ischaemic heart disease.

Nitrates exert their anti-anginal activity by a number of mechanisms. By reducing venous return and left ventricular end-diastolic pressure they lower myocardial oxygen demand and at the same time enhance blood flow to the sub-endocardium. They also directly increase myocardial oxygen supply by dilating the coronary artery stenoses and increasing collateral blood flow. These pharmacodynamic attributes are clinically efficacious in all the ischaemic myocardial syndromes. In stable angina pectoris, nitrates reduce myocardial ischaemia and ischaemic pain and increase exercise tolerance. In unstable angina, nitrates similarly reduce electrocardiographic evidence of myocardial ischaemia and relieve anginal pain. Following acute myocardial infarction, nitrates reduce ventricular dilatation and by so doing reduce pulmonary congestion and mitral regurgitation. The weak anti-aggregatory effect of nitrates on platelets may also play an adjuvant role in their anti-ischaemic activity. Early small-scale studies with both intravenous and oral nitrates demonstrated a trend to reduced mortality and reinfarction in survivors of acute myocardial infarction. However, the later and larger ISIS-4 and GISSI-3 trials have not confirmed this trend possibly due to the smaller doses of nitrates used and the diluting effect of the widespread use of open-label nitrates in the placebo group. In patients with congestive heart failure, including those of ischaemic aetiology, nitrates together with hydralazine have clearly demonstrated a significant reduction in the medium term mortality risk. Nitrates have the undoubted ability, probably greater than any other single anti-anginal drug, to rapidly and often completely relieve the pain and breathlessness associated with myocardial ischaemia. They are haemodynamically efficacious in reducing dilatation of the ischaemic left ventricle and enhancing coronary blood flow to ischaemic areas. Although their preventative impact in survivors of acute myocardial infarction awaits clarification, they have been shown in combination with hydralazine to extend survival in patients with congestive heart failure, including those of ischaemic origin.

Ricin depresses cardiac function in the rabbit heart.

Ricin, at toxic glycoprotein from the castor bean, causes myocardial hemorrhage and a decrease in blood pressure. We studied the effects of ricin on myocardial function in the isolated rabbit heart. Rabbits were given 0.22 micrograms/kg of ricin i.v. and 48 hr later, the heart was isolated and retrogradely perfused through the aorta with Tyrode's solution. A latex balloon was inserted into the left ventricle and isovolumic left ventricular function curves were generated. Left ventricular developed pressure (LVDP), heart rate, coronary artery flow, left ventricular end diastolic pressure, myocardial oxygen consumption, oxygen extraction (a - vO2), and contractility (+dp/dt) were measured over a range of left ventricular volumes. Dose-response curves to isoproterenol (10(-9)-10(-8) M) and phenylephrine (10(-9)-10(-6) M) were also obtained. Compared to the control group, ricin pretreatment markedly decreased ventricular compliance (p < 0.01), diminished maximum left ventricular developed pressure (p < 0.05), and reduced maximal +dp/dt (p < 0.05). Myocardial oxygen consumption, heart rate, electrocardiographic PR, QRS, and QT intervals were not different in control and ricin treatment groups. Ricin did not significantly alter the inotropic or chronotropic responses to isoproterenol and phenylephrine. The results from the binding studies showed that ricin neither reduced beta-adrenergic receptor numbers nor altered the dissociation constant. thus, ricin reduced both systolic (LVDP and +dp/dt) and diastolic (compliance) left ventricular functions, perhaps due to increased vascular permeability, without altering responses to the alpha- and beta-adrenoceptor agonists phenylephrine and isoproterenol.

Chronic stable angina pectoris. Strategies for effective drug therapy.

In most patients with stable angina pectoris, severe eccentric atherosclerotic narrowing of coronary arteries is responsible for chest pain and myocardial ischemia. If myocardial infarction or death occurs, it is usually the consequence of a ruptured plaque. About 10% to 20% of patients with stable angina have normal coronary arteries, and their long-term prognosis is excellent. In patients with angina secondary to atherosclerotic lesions, the annual mortality rate is 1.6% to 3.2%; prognosis is determined by systolic left ventricular function and the extent of coronary artery disease. Patients can be stratified into low- and high-risk groups by medical history, left ventricular function at rest, and results of physical examination and stress testing. Coronary angiography should be reserved for high-risk patients. Risk-factor modification and appropriate use of antianginal drugs are successful in most patients, but those who fail to respond should be considered for angioplasty or coronary bypass surgery; patients with left main coronary artery disease or three-vessel disease and poor left ventricular function should be considered for coronary artery bypass surgery.