Serial exercise testing in patients with effort angina: variable tolerance, fixed threshold

To investigate the frequency and mechanism of variable threshold angina, seven treadmill exercise tests were performed in each of 28 patients with stable effort angina and exercise-induced ST segment depression. Each patient had tests at 8 AM on 4 days within a 2 week period and on 1 of these days had three additional tests at 9 AM, 11 AM and 4 PM. Time to 1 mm ST depression increased from 277 +/- 172 seconds on day 1 to 319 +/- 186 seconds on day 2, 352 +/- 213 seconds on day 3 and 356 +/- 207 seconds on day 4 (p less than 0.05). Rate-pressure product at 1 mm ST depression remained constant. Similarly, time to 1 mm ST depression increased from 333 +/- 197 seconds at 8 AM to 371 +/- 201 seconds at 9 AM and to 401 +/- 207 seconds at 11 AM and decreased to 371 +/- 189 seconds at 4 PM (p less than 0.01). Again, rate-pressure product at 1 mm ST depression remained constant. The standard deviation for time to 1 mm ST depression, calculated as a percent of the mean for each patient's seven tests and then averaged for the entire group, was 22 +/- 11%. The standard deviation for rate-pressure product at 1 mm ST depression, calculated in the same way, was significantly less at 8.4 +/- 2.8% (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and safety of incremental doses of diltiazem for the treatment of stable angina pectoris

The safety and efficacy of incremental doses of diltiazem in treating angina pectoris were assessed in 20 patients with functional class II to III exertional angina. During an initial single-blind dose titration phase, dilitiazem produced a dose-related improvement in anginal frequency and exercise capacity. Weekly anginal attacks were reduced to 7.5 +/- 8.9, 5.6 +/- 7.8 and 4.9 +/- 7.3 on diltiazem, 120, 240 and 360 mg per day, respectively, as compared with 11.9 +/- 8.7 on placebo (all p less than 0.001). Treadmill time was significantly enhanced by high dose (360 mg per day) as compared with moderate dose (240 mg per day) diltiazem: 473 +/- 149 versus 424 +/- 146 seconds (p less than 0.05). Time to ischemic ST segment depression was similarly changed: 344 +/- 132 versus 298 +/- 142 seconds (p less than 0.05) by high dose as compared with moderate dose diltiazem. During a subsequent double-blind phase, high dose diltiazem significantly reduced weekly anginal frequency when compared with placebo: 3.1 +/- 3.0 versus 9.3 +/- 7.1 (p less than 0.001); and increased treadmill exercise time: 508 +/- 158 versus 418 +/- 172 seconds on placebo (p less than 0.05). Subjective and objective benefits of high dose diltiazem were sustained during a follow-up period of 6 months without major drug side effects.     

Oral nitroglycerin as a prophylactic antianginal drug: Clinical,physiologic, and statistical evidence of efficacy based on a three-phase experimental design

With the use of a three-phase experimental design, the efficacy of oral nitroglycerin has been evaluated in a total of 53 patients with documented angina pectoris due to coronary artery disease. The study was a double-blind, randomized, and cross-over comparison of controlled-release nitroglycerin (2.6 mg. tablets administered three times daily) and an indistinguishable placebo. Sixteen patients recorded anginal symptoms by the diary method over a 6 month trial of randomly sequenced 1 month periods of drug or placebo. In 15 patients, ST segments were monitored with a Holter dynamic electrocardiograph for periods of 10 to 12 hours under normal life style and evaluated by matching activities during periods of drug and placebo. In 22 patients, a multistage treadmill exercise test was conducted to an endpoint of anginal pain. The three phases of the investigation were run in succession; each phase was completed before the next one was begun.Oral nitroglycerin reduced the incidence and severity of anginal attacks by 47.2 and 49.4 per cent, respectively, and decreased the number of sublingual nitroglycerin tablets used by 51.1 per cent in comparison to placebo (p < 0.001). Eleven of 16 patients (69 per cent) decreased their need for sublingual nitroglycerin by over 50 per cent. Based on a polynomial trend analysis over a period of 8 weeks, no tolerance to the therapeutic effects of the drug was found. With DCG monitoring, drug decreased the ST segment depression from 1.76 mm. on placebo to 1.12 mm., with a significant difference of 0.64 mm. (p < 0.001). ST segment depression was decreased more than 0.5 mm. by drug in comparison to placebo in 10 of 15 patients (66 per cent). Larger depressions of the ST segment noted with placebo at heart rates greater than 80 beats per minute were prevented by administration of the drug. During treadmill exercise, drug delayed the onset of pain by 83 seconds (64 per cent) over placebo (p < 0.001) and decreased the duration of pain by 70 seconds (49 per cent) in comparison to placebo (p < 0.001). Drug did not affect heart rate or systolic blood pressure at rest or after exercise, as well as rate-pressure product for production of angina following exercise (p > 0.05). There were no side effects reported caused by the drug. The data demonstrate that oral nitroglycerin, given as controlled-release tablets, was absorbed from the gastrointestinal tract in quantities sufficient to provide statistically significant clinical improvement of angina pectoris.     

Antianginal efficacy and improved exercise performance with timolol. Twice-daily beta blockade in ischemic heart disease

Antianginal efficacy and improved exercise performance with timolol, a new beta-adrenergic blocking agent, was assessed in 23 patients with chronic stable angina pectoris in an 11-week double-blind, placebo-controlled study. Twenty-two of the 23 subjects completed the open-label phase of this investigation (weeks 0 to 6) while receiving 10 to 30 mg of timolol twice daily to optimize exercise capacity. Weekly anginal episodes and nitroglycerin consumption declined from 8.9 +/- 9.1 episodes/week and 8.1 +/- 10.6 tablets/week, respectively, with placebo to 2.7 +/- 5.2 episodes/week and 2.6 +/- 6.0 tablets/week with optimal timolol dose (p less than 0.05). Resting heart rate (HR) and systolic blood pressure (SBP) also decreased from 75.2 +/- 14.0 beats/min and 139.1 +/- 15.7 mm Hg with placebo to 55.1 +/- 8.9 beats/min and 130.5 +/- 15.9 mm Hg with timolol (p less than 0.05). Peak exercise HR, peak exercise SBP, and peak exercise double product (HR X SBP) were significantly (p less than 0.05) reduced when evaluated 12 to 13 hours after administration of timolol compared with placebo (101.5 +/- 21.1 beats/min verus 193.3 +/- 96.2 beats/min, 161.5 +/- 26.7 mm Hg versus 175.6 + 20.8 mm Hg, and 16.6 +/- 5.1 X 10(-3) versus 21.7 +/- 5.4 X 10(-3), respectively). Exercise duration was prolonged from 263.3 +/- 90.2 seconds to 330.3 +/- 73.9 seconds (p less than 0.05), while time to onset of 1 mm S-T segment depression was delayed in 15 patients from 231.8 +/- 86.4 seconds to 298.7 +/- 68.4 seconds (p less than 0.05). During the double-blind phase (weeks 7 to 10), 8 subjects received timolol and 11 patients received placebo. Nitroglycerin consumption at weeks 8 and 10 and anginal frequency at week 8 were unchanged compared with initial placebo treatment. Resting HR, peak exercise HR, and peak exercise double product were significantly attenuated at weeks 8 and 10 in timolol patients compared with their initial placebo exposure. However, these variables were unchanged in placebo subjects compared with their initial placebo therapy. Exercise duration was again prolonged at week 8 in timolol subjects compared with initial placebo results (315.1 +/- 61.2 seconds versus 261.3 +/- 68.8 seconds, p less than 0.05), but not at week 10. Placebo patients demonstrated no difference at week 8 or 10 in exercise performance compared with initial placebo treatment. Timolol twice daily, therefore, is potentially useful in some patients with angina pectoris. Other patients may, however, require a shorter dose interval for optimal angina control and maximal improvement in exercise capacity.     

Felodipine in chronic stable angina: a randomized, double-blind, placebo-controlled, crossover study

To investigate the antianginal efficacy and tolerability of felodipine, a new dihydropyridine calcium antagonist, 20 patients with stable exertional angina, not completely controlled by beta-blocker monotherapy, entered a randomized, double-blind, placebo-controlled, crossover study. Patients on standard beta-blocker therapy, who had at least 3 weekly anginal episodes and a reproducible exercise test (stopped for angina and ECG signs of ischaemia) at the end of 2 weeks placebo treatment, were eligible for the study. They were randomized to one sequence of treatment: felodipine 5 mg twice daily for 2 weeks followed by placebo for a further 2 weeks, or vice versa. Beta-blocker treatment was unchanged throughout the study. A treadmill test was carried out at the end of each crossover period, 2-4 h after drug administration. The number of anginal attacks and nitroglycerin consumption was recorded on a diary card. At rest, felodipine significantly (P less than 0.05) reduced standing systolic but not diastolic blood pressure. Heart rate was not modified by the active treatment. At ischaemic threshold and at peak exercise, heart rate, systolic blood pressure and rate-pressure product remained unchanged. Exercise duration was increased by felodipine (P less than 0.01) and maximal ST change was reduced (P less than 0.01). Time to 1 mm ST depression was prolonged non-significantly by felodipine (basal 5.7 +/- 1.5, felodipine 7.4 +/- 2.0, placebo 6.6 +/- 1.5 min). The number of patients who stopped exercise due to angina and ST change was 20/20 at baseline, 16/20 with placebo and 10/20 with felodipine. Felodipine significantly reduced weekly anginal episodes (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and safety of sustained-release diltiazem in stable angina pectoris

The safety and efficacy of a sustained-release preparation of diltiazem (diltiazem-SR), with dose levels of 240 and 360 mg/day, were assessed in 18 patients with stable angina of effort. A double-blind, placebo-controlled, randomized, crossover protocol was used. Diltiazem-SR, when given twice daily, reduced the frequency of weekly anginal attacks from 9.3 +/- 10.4 with placebo to 3.7 +/- 4.7 with 240 mg/day and to 3.1 +/- 4.7 with 360 mg/day (both p less than 0.01 compared with placebo). Treadmill time was increased from 410 +/- 180 seconds during the placebo phase to 519 +/- 177 seconds during the 240-mg/day dose and to 506 +/- 182 seconds during the 360-mg/day dose of diltiazem-SR (both p less than 0.01 compared with placebo). The time to the onset of angina and ischemic ST-segment depression were similarly prolonged by both doses of diltiazem-SR. The beneficial effects of diltiazem-SR appeared partly due to a reduction in the heart rate during submaximal exercise. Diltiazem-SR is effective and safe for the treatment of angina of effort when given twice daily.     

Double-blind, dose-response, placebo-controlled multicenter study of nisoldipine. A new second-generation calcium channel blocker in angina pectoris

BACKGROUND. Nisoldipine is a potent 1:4 dihydropyridine calcium channel antagonist, and doses of 5 or 10 mg administered either once or twice daily have been claimed to exert antianginal effects. There is, however, little information regarding the dose-response relation and whether the drug exerts any consistent effects throughout the dosing interval. In this placebo-controlled, parallel-design study, the dose-response relation of monotherapy with nisoldipine administered twice daily was studied in patients with stable angina pectoris. METHODS AND RESULTS. Two hundred thirty-one patients received single-blind placebo for 2 weeks; of these, 185 patients who reproducibly stopped treadmill exercise because of angina of moderate severity and had greater than or equal to 1 mm ST segment depression during exercise and experienced an average of three episodes of anginal attacks per week were randomized in a double-blind manner to one of the four treatment groups: placebo (n = 48), nisoldipine 2.5 mg (n = 47), nisoldipine 5 mg (n = 44), or nisoldipine 10 mg (n = 46). Nisoldipine or placebo was administered twice daily for 4 weeks and symptom-limited exercise tests were repeated at 2 and 10-14 hours after the double-blind medication. One hundred sixty-eight patients completed the study and 181 patients were valid for efficacy analysis. Compared with double-blind placebo, there were marginally significant trends toward increases for time to onset of angina for the 10-mg-b.i.d. group (83 versus 108 seconds, p = 0.08), time to 1 mm ST segment depression for the 5-mg-b.i.d. group (54 versus 83 seconds, p = 0.08), and total exercise time for the 5- (30 versus 50 seconds, p = 0.10) and 10-mg-b.i.d. (30 versus 58 seconds, p = 0.06) groups at 2 hours after the dose (peak effect) after 4 weeks of therapy. At 10-14 hours after the dose (trough effect), no differences between placebo and any of the nisoldipine doses on any of the exercise parameters were found after 4 weeks of therapy. A subset analysis of patients who stopped exercise within 10 minutes because of angina of moderate severity during single-blind placebo therapy (n = 123) revealed significant increase in total exercise duration and time to 1 mm ST segment depression at 2 hours after the dose in the 5- and 10-mg-b.i.d. dose groups compared with double-blind placebo (p less than 0.04). No significant trough effects, however, were observed even in this subgroup after any of the doses of nisoldipine. The frequency of anginal attacks decreased by 44%, 41%, 30%, and 41% after twice-daily therapy with 2.5 mg, 5 mg, 10 mg nisoldipine, and placebo groups, respectively (p = NS, nisoldipine versus placebo). The incidence of adverse events (minor and major) was 43.8% in the placebo group and 42.6%, 45.5%, and 56.5% in the nisoldipine 2.5-, 5-, and 10-mg-b.i.d. groups, respectively (p = NS compared with placebo). However, four patients developed unstable angina while on nisoldipine therapy (two in the 2.5-mg, one in the 5-mg, and one in the 10-mg-b.i.d. group) and two patients died suddenly in the nisoldipine 10-mg-b.i.d. group. CONCLUSIONS. Monotherapy with 2.5, 5, and 10 mg nisoldipine twice a day was not superior to placebo therapy in treating patients with angina pectoris, and the 10-mg-b.i.d. therapy resulted in a statistically insignificant but clinically important increase in the incidence of serious adverse events.     

A dose-ranging, placebo-controlled, double-blind trial of nisoldipine in effort angina: duration and extent of antianginal effects

Maximal treadmill exercise testing at 1, 3 and 8 hours was used to assess the onset, duration and antianginal efficacy of the dihydropyridine slow channel calcium-blocking agent, nisoldipine, in an oral dose range of 5, 10 and 20 mg. A double-blind, randomized, placebo-controlled design was used involving 12 patients with stable effort angina. Exercise tolerance was significantly increased 3 hours after each dose, when the maximal beneficial effect occurred. The improvement was observed as early as 1 hour after the 10 and 20 mg dose, and persisted for 8 hours after the 20 mg dose. At 3 hours, the onset of an exercise-induced ST segment depression of 0.1 mV or greater was increased by 62 (p less than 0.05), 75 (p less than 0.01) and 117 seconds (p less than 0.01) with the 5, 10 and 20 mg dose of nisoldipine, respectively, compared with placebo. Similarly, time to onset of angina was significantly increased. The sum of exercise-induced ST segment depression at peak exercise was significantly decreased (p less than 0.05) from 8.7 +/- 2.3 to 6.7 +/- 1.8 and 6.4 +/- 2.0 mm, respectively, after the 10 and 20 mg dose of nisoldipine. The rate-pressure product was significantly greater with nisoldipine than with placebo at the onset of ischemia and at peak exercise (22.8 +/- 1.1 versus 20 +/- 1.4 X 10(3) U for the 20 mg dose; p less than 0.01). Thus, nisoldipine is an effective antianginal agent with a rapid onset of action that improves exercise tolerance, increases angina threshold and persists for at least 8 hours after oral dosing.     

Preventive administration of intravenous N-acetylcysteine and development of tolerance to isosorbide dinitrate in patients with angina pectoris.

BACKGROUND. Development of tolerance to organic nitrates may be related to depletion of sulfhydryl groups in vascular smooth muscle. N-Acetylcysteine (NAC), a sulfhydryl donor, has been reported to potentiate the effect of nitroglycerin and reverse tolerance in humans. However, its ability to prevent or delay the development of nitrate tolerance in patients with angina pectoris has not been established. METHODS AND RESULTS. Ten patients with stable angina pectoris were treated with intravenous isosorbide dinitrate (ISDN; 5 mg/hr) combined with NAC (2 g i.v. over 15 minutes followed by 5 mg/kg/hr) or matching placebo for 30 hours in a double-blind, randomized, crossover study with a washout interval of 8 days. Bicycle exercise tests were performed before and at 1 1/2, 8, 20, 24, and 30 hours after start of treatment. After 24 hours of infusion, exercise parameters were not significantly different from pretreatment values (p greater than 0.05) during ISDN plus placebo, indicating development of tolerance to ISDN. In contrast, time to onset of angina, time to 1-mm ST segment depression, and total amount of ST segment depression were still significantly improved after 24-hour infusion of ISDN plus NAC (p less than 0.05). In addition, compared with placebo, a significant difference (p less than 0.05) in favor of NAC was observed regarding time to angina (507 +/- 63 versus 445 +/- 69 seconds, mean +/- SEM), time to 1-mm ST segment depression (435 +/- 43 versus 407 +/- 45 seconds), and total ST segment depression (1.8 +/- 0.9 versus 3.1 +/- 0.4 mm). CONCLUSIONS. These results suggest that infusion of high doses of NAC in combination with ISDN for 30 hours affects and partially prevents the development of tolerance to antianginal effects normally observed during infusion with ISDN.     

Beneficial effects of high-dose diltiazem in patients with persistent effort angina on beta-blockers and nitrates: a randomized, double-blind, placebo-controlled cross-over study

The effects of orally administered diltiazem combined with maximally tolerated doses of beta-blockers and nitrates were assessed in 12 patients, who during stress testing exhibited persistent effort angina and continued objective evidence for inducible myocardial ischemia. Patients performed multistage semisupine exercise on a bicycle ergometer during equilibrium-gated radionuclide angiography after consecutive 2 week treatment periods of placebo or diltiazem 90 mg qid (mean dose 340 mg/day) combined with maximally tolerated propranolol (mean dose 178 mg/day) and isosorbide dinitrate (mean dose 137 mg/day). All medications (including diltiazem or placebo) were administered four times daily for the duration of the study. Diltiazem or placebo was administered according to a double-blind design, with randomized cross-over at the end of each 2 week treatment period. The average number of angina attacks decreased during the double-blind cross-over phase of the trial (7 +/- 7 episodes/week at baseline vs 4 +/- 3 on placebo vs 2 +/- 2 on diltiazem; p = .08). Angina pectoris was abolished during peak exercise in eight of 12 patients on diltiazem (p less than .05 vs placebo). Diltiazem increased total exercise duration from 276 +/- 92 to 310 +/- 78 sec (p less than .005 vs baseline). Diltiazem likewise increased the time to onset of angina from 231 +/- 84 sec at baseline to 305 +/- 77 sec (p less than .005), as well as the time to the onset of 1 mm ischemic ST segment depression (p = .01). Diltiazem decreased heart rate at rest, during submaximal workload, and at peak exercise (p less than .05), and decreased systolic blood pressure at peak exercise only (p less than .05). A significant decline in rate-pressure product at submaximal and peak exercise was noted (p less than .05). At any given workload there was significantly less ST segment depression during submaximal (p = .05) and peak exercise (p less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic response to myocardial ischaemia during unrestricted activity, exercise testing, and atrial pacing assessed by ambulatory pulmonary artery pressure monitoring

Ambulatory pulmonary artery pressure monitoring by means of a transducer tipped catheter with a simultaneous frequency modulated electrocardiogram and a miniaturised tape recorder was used to study the haemodynamic implications of ST segment depression in patients with coronary artery disease. Nineteen male patients (mean (SD) age 58 (11) years) with clinical and angiographic evidence of coronary artery disease were studied together with six controls. Changes in the ST segment and pulmonary artery diastolic pressure during treadmill exercise, atrial pacing, and unrestricted ambulant activity were analysed. During exercise, pulmonary artery diastolic pressure rose significantly in patients with coronary artery disease but not in the controls. One patient with ST depression greater than 1 mm did not have a rise in pulmonary artery diastolic pressure on exercise; two had a rise in pulmonary artery diastolic pressure with no ST segment change despite severe angina. The pulmonary artery diastolic pressure tended to rise before or simultaneously with the onset of ST segment depression. The haemodynamic response to atrial pacing was similar in normal controls and patients with coronary artery disease. During ambulatory monitoring there were 29 episodes of ST segment depression all of which were associated with a rise in pulmonary artery diastolic pressure and chest pain. The onset of ST segment depression occurred before a rise in pulmonary artery diastolic pressure in 11 episodes, was simultaneous with it in 11, and followed it in seven episodes. During exercise and ambulatory monitoring there was a correlation between the magnitude of ST segment depression and the rise in pulmonary artery diastolic pressure. Pain was a late feature during exercise, atrial pacing, and anginal episodes. This technique for the first time allows the relation between ST segment changes and haemodynamic alterations in left ventricular function to be assessed in ambulant patients with coronary artery disease.     

Beneficial effects of betaxolol, a selective antagonist of beta-1 adrenoceptors, on exercise-induced myocardial ischemia in patients with coronary vasospasm

Although beta-blockers can not be used for the treatment of vasospastic angina, the effect of beta-blockers with vasorelaxant property on coronary vasospasm remains uncertain. In this study, we evaluated the effect of betaxolol, a new beta-blocker with calcium antagonistic property, as an additional therapy on vasospastic angina (VSA) with anginal attacks on effort. We enrolled 12 patients with VSA and anginal attacks with ST segment depression during exercise stress test. All patients received 1.25-5 mg of betaxolol for 3 months. Treadmill exercise stress test and adenosine triphosphate stress thallium-201 myocardial scintigraphy were performed before and 3 months after the onset of the betaxolol treatment. The other drugs including calcium antagonists, nitrates and nicorandil were continued. No patients experienced the exacerbation of angina during the betaxolol treatment. Exercise time to chest pain (317.5+/-72.1-454.2+/-75.5 s, P<0.01) and maximal ST segment depression (1.67+/-0.67-1.16+/-0.46 mm, P<0.01) obtained by exercise stress test, the defect score (8.6+/-2.7-5.3+/-2.1, P<0.01), the extent score (14.8+/-5.8-8.8+/-4.6%, P<0.01), the severity score (17.5+/-7.3-11.3+/-5.2, P<0.01) and washout rate (31.4+/-5.6-37.6+/-5.0%, P<0.01) obtained by the scintigraphy were improved by betaxolol. Our results suggest that betaxolol increases regional myocardial blood flow and improves exercise capacity in patients with VSA. Betaxolol may become a drug for a new potential therapy for VSA.     

Haemodynamic response to myocardial ischaemia during unrestricted activity, exercise testing, and atrial pacing assessed by ambulatory pulmonary artery pressure monitoring.

Ambulatory pulmonary artery pressure monitoring by means of a transducer tipped catheter with a simultaneous frequency modulated electrocardiogram and a miniaturised tape recorder was used to study the haemodynamic implications of ST segment depression in patients with coronary artery disease. Nineteen male patients (mean (SD) age 58 (11) years) with clinical and angiographic evidence of coronary artery disease were studied together with six controls. Changes in the ST segment and pulmonary artery diastolic pressure during treadmill exercise, atrial pacing, and unrestricted ambulant activity were analysed. During exercise, pulmonary artery diastolic pressure rose significantly in patients with coronary artery disease but not in the controls. One patient with ST depression greater than 1 mm did not have a rise in pulmonary artery diastolic pressure on exercise; two had a rise in pulmonary artery diastolic pressure with no ST segment change despite severe angina. The pulmonary artery diastolic pressure tended to rise before or simultaneously with the onset of ST segment depression. The haemodynamic response to atrial pacing was similar in normal controls and patients with coronary artery disease. During ambulatory monitoring there were 29 episodes of ST segment depression all of which were associated with a rise in pulmonary artery diastolic pressure and chest pain. The onset of ST segment depression occurred before a rise in pulmonary artery diastolic pressure in 11 episodes, was simultaneous with it in 11, and followed it in seven episodes. During exercise and ambulatory monitoring there was a correlation between the magnitude of ST segment depression and the rise in pulmonary artery diastolic pressure. Pain was a late feature during exercise, atrial pacing, and anginal episodes. This technique for the first time allows the relation between ST segment changes and haemodynamic alterations in left ventricular function to be assessed in ambulant patients with coronary artery disease.     

Oral sustained-release nitroglycerin in chronic stable angina: a multicenter, double-blind, randomized crossover trial

Forty-six patients with stable angina pectoris were randomized to receive either oral sustained-release nitroglycerin (SRNG, 6.5 mg) or placebo (P) 3 times a day for a 2-week double-blind trial. They were investigated for the frequency of anginal episodes, for sublingual nitroglycerin consumption and for exercise tolerance. There was a slight but significant decrease in the number of anginal episodes (6.4 +/- 1.5 episodes/week with P, 4.9 +/- 1.7 with SRNG, p less than 0.005) and sublingual nitroglycerin consumption (3.9 +/- 1 tablets/week with P, 2.7 +/- 1 with SRNG, p less than 0.005). The patients performed 3 upright multistage (increments of 30 W every 3 minutes) exercise tests on a bicycle ergometer before the start of the study and 1 hour after the intake of SRNG or P, at the end of each double-blind phase. Exercise capacity, expressed as exercise duration, increased from 8.9 +/- 3.8 minutes with P to 10.2 +/- 3.8 minutes with SRNG (14.6%; p less than 0.001). At symptom-limited exercise, ST depression was significantly reduced (p less than 0.05) during the SRNG phase. Thirty-four patients (74%) reached a higher peak heart rate (139 beats/min with P, 145 beats/min with SRNG; p less than 0.001) and 35 patients (76%) a higher rate-pressure product (+6%; p less than 0.001). These changes in exercise tolerance are relatively modest and at least 11 patients would have benefited from larger doses of nitrates.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relation between myocardial oxygen consumption and ischemia during exertion in patients with angina pectoris: effect of propranolol

Patients with coronary artery disease exhibit a reduced coronary vasodilator reserve in response to exercise testing. Drugs which block coronary beta adrenergic receptors could exacerbate this abnormality leaving the vasoconstrictor alpha tone unopposed and/or counteracting the beta 2-mediated vasodilation elicited by the increase in myocardial oxygen demand. To test this hypothesis we administered propranolol 40 mg qid and placebo, using a cross over randomized single blind protocol, to 14 patients each with effort angina and critical coronary stenosis (greater than or equal to 75%). We performed computer-assisted multistage bicycle ergometer testings (25 W increments at 2 min intervals) after 2 weeks open label placebo (control) and at 2 week intervals following daily administration of propranolol and placebo. Compared to placebo, propranolol reduced significantly (p less than 0.001) peak heart rate (x +/- SD: 114 +/- 6 vs 150 +/- 11 beats/min) and rate pressure product (20.1 +/- 2.1 vs 28.0 +/- 3.9 X 10(-3)) and increased exercise duration (462 +/- 91 vs 355 +/- 85 sec). Conversely 0.1 mV ST segment depression was observed at lower heart rate (106 +/- 9 vs 127 +/- 8 beats/min, p less than 0.001) and rate pressure product (16.9 +/- 3.6 vs 22.4 +/- 2.4 X 10(-3), p less than 0.001). No significant differences were found between placebo and control. Moreover, we assessed the regression lines of the relationship between ST segment depression (ST) and heart rate (HR) during exercise. These have been shown to be shifted to the right after surgical revascularization and are an indirect measure of coronary reserve.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of oral propranolol, digoxin and combination therapy on the resting and exercise electrocardiogram.

The effects of propranolol, digoxin and combination therapy (/D) on the resting and exercise ECG were studied in ten normal subjects and 20 patients with coronary artery disease (CAD) given a sequence of oral placebo, propranolol, P/D, digoxin and placebo, for two week periods. Digoxin produced a significant decrease in T-wave amplitude and often resulted in ST segment depression in the resting ECG. Propranolol, digoxin, and P/D tended to decrease the QTc interval and prolong the PR interval. However, CAD patients were more sensitive to PR prolongation than normals while receiving propranolol or digoxin alone. Propranolol therapy did not significantly affect the ST segment of the exercise ECG in the normal subjects or the CAD patients without an ischemic control exercise ECG. By contrast, 50 per cent of the normal subjects developed "false-positive" ischemic ST segment responses to exercise while receiving digoxin of P/D and three of eight CAD patients without ischemic control exercise ST segments had a similar response to digoxin or P/D. In 12 CAD patients with ischemic control exercise ST segments, propranolol did not affect the amount of ST segment depression at the onset of angina or the maximum amount of ST segment depression. Digoxin or P/D both uniformly increased the maximum amount of ST segment depression which was greater with digoxin than P/D. However, the maximum heart rate on P/D was significantly reduced as compared to that on digoxin. It is concluded that (1) CAD patients are more sensitive to propranolol or digoxin-induced AV block than normals, (2) propranolol does not change the magnitude of ischemic exercise ST segment depression, (3) digoxin increases ischemic exercise ST segment depression and results in a high incidence of false-positive exercise tests, and (4) the addition of propranolol to digoxin attenuates the effects of digoxin on the exercise ST segment.     

Limited efficacy of magnesium for the treatment of variant angina.

Some patients with variant angina show both ST segment elevation at rest and exercise-induced ST segment elevation. Magnesium deficiency has also been observed in patients with variant angina. This study investigated the correlation between the degree of magnesium deficiency and the efficacy of intravenous administration of magnesium in patients with variant angina. Fifteen patients with angiographically confirmed variant angina were assessed for magnesium deficiency and whether intravenous administration of magnesium (19.2 mEq/l) suppressed exercise-induced ST segment elevation. All 15 patients were studied with a magnesium retention test (0.2 mEq/kg over 4 hr) to analyze magnesium deficiency. In our study, magnesium retention rate in patients with variant angina was not higher than that of controls (57 +/- 24% vs 45 +/- 10%, NS). All 15 patients had anginal attacks during accelerated exercise combined with hyperventilation after placebo infusion, whereas only 8 patients had anginal attacks after magnesium administration. ST segment elevation occurred in 14 patients after placebo infusion, but in only 4 patients after magnesium administration. There were no correlations between disease activity, degree of magnesium deficiency or failure of suppression of ST elevation by the intravenous administration of magnesium. Intravenous administration of magnesium can suppress exercise-induced coronary spasms in some patients with variant angina, but the degree of magnesium deficiency did not correlate with the suppressions of exercise-induced ST elevation after magnesium administration. Intravenous administration of magnesium had limited efficacy in patients with variant angina and exercise-induced ST segment elevation.     

Effect of diltiazem on symptomatic and asymptomatic episodes of ST segment depression occurring during daily life and during exercise

BACKGROUND. Silent myocardial ischemia is an adverse prognostic marker in patients with coronary disease; however, controlled data on the effect of treatment are sparse and contradictory, and the relations among the occurrence of ST segment depression, drug efficacy, and heart rate are unclear. METHODS AND RESULTS. Sixty patients with stable coronary artery disease, a positive treadmill exercise test and asymptomatic ST segment depression on ambulatory electrocardiographic recording were assessed in a multicenter, double-blind, placebo-controlled, cross-over trial. Treadmill exercise tests and 72-hour electrocardiographic recordings were obtained at the end of two 2-week treatment periods with sustained-release diltiazem 180 mg b.i.d. or equivalent placebo. Episodes of asymptomatic ST depression decreased by 50% or more in 70% of the patients from a median number of 4.5 (range, 0-19) to 1.5 (range, 0-13) (p = 0.0001); their cumulative duration also decreased from 78.5 (range, 0-60) to 24.5 (range, 0-411) minutes (p = 0.001). No circadian variation was found in the efficacy of diltiazem. The occurrence of ischemic type ST segment depression was modulated by changes in heart rate rather than by absolute heart rate. Diltiazem also improved exercise test end points but to a lesser extent. Time to ST segment depression increased to 341 +/- 148 from 296 +/- 154 seconds (p = 0.005). Although less frequent with diltiazem administration (45 versus 54 patients, p less than 0.03), exercise-induced ST depression was more often asymptomatic (98% versus 72% of patients, p less than 0.0001). CONCLUSIONS. Diltiazem reduces the frequency and severity of ischemic type ST depression in patients with stable coronary artery disease.     

Exercise testing, clinical, and angiographic characteristics of anginal patients with and without diabetes mellitus

To elucidate the influence of coexisting diabetes mellitus (DM) on clinical and pathophysiologic characteristics in patients with coronary artery disease (CAD), the authors reviewed 1,211 consecutive patients who underwent coronary angiography (CAG) and selected 80 patients with significant CAD but without myocardial infarction, hypertension, or other heart diseases, who underwent both symptom-limited treadmill test (TM) and CAG within four weeks. DM was found in 22 of the 80 patients. No significant difference in the average number of diseased arteries of left ventricular ejection fraction at rest was found between DM patients and patients without DM (NDM patients). The incidences of exercise-induced ST depression and anginal pain revealed no difference between DM and NDM patients. Mean duration of exercise was shorter in DM patients (345 +/- 97 sec) than in NDM patients (423 +/- 162 sec, p less than 0.01). Furthermore, anginal pain during exercise occurred earlier in DM patients (187 +/- 68 sec) than in NDM patients (248 +/- 99 sec, p less than 0.05). No significant difference in double product or magnitude of ST segment depression at the onset of anginal pain was found between DM and NDM patients. However, heart rate responsiveness to exercise in DM patients was higher than that in NDM patients. These findings may indicate that pathophysiology of the heart in CAD patients with DM is affected not only by CAD itself but also by myocardial damage due to DM.     

The threshold for myocardial ischemia varies in patients with coronary artery disease depending on the exercise protocol

It is generally accepted that angina pectoris and, presumably, myocardial ischemia occur at a fixed heart rate-systolic blood pressure product in a given patient. This concept of a fixed threshold has recently been challenged. To evaluate the effects of varying exercise intensity on the ischemic threshold, 33 patients with coronary artery disease and provokable myocardial ischemia, documented by thallium-201 myocardial perfusion imaging, underwent two exercise tests 2 to 7 days apart. A symptom-limited incremental treadmill exercise test was followed by a 20 min submaximal treadmill test at an intensity approximating 70% of the peak heart rate attained during the incremental test. During the incremental exercise test, angina pectoris developed in 16 patients and 17 patients were asymptomatic. At least 0.1 mV of ST segment depression developed in all subjects during the incremental exercise test at a mean exercise duration of 5.3 +/- 2.6 min, a rate-pressure product of 19,130 +/- 5,735 and oxygen uptake of 19.6 +/- 7.0 ml/kg per min. During the submaximal exercise test, 28 (85%) of the 33 patients had significant ST segment depression. Of these patients, 24 (86%) were asymptomatic, including 10 patients who had previously reported anginal symptoms during the incremental test. The average time to onset of 0.1 mV ST segment depression during the submaximal test was 8.1 +/- 4.5 min. These changes occurred at a rate-pressure product of 15,250 +/- 3,705 and an oxygen uptake of 14.3 +/- 5.9 ml/kg per min, and were significantly (p less than 0.001) lower than values observed during the graded exercise.(ABSTRACT TRUNCATED AT 250 WORDS)