The use of angiotensin-converting enzyme inhibitors in patients with acute myocardial infarction in community hospitals. Michigan State University Inter-Institutional Collaborative Heart (MICH) Study Group.

BACKGROUND: Previous studies documenting underutilization of angiotensin-converting enzyme inhibitors (ACEIs) in acute myocardial infarction (AMI) have been limited to Medicare populations. HYPOTHESIS: This study examines ACEI prescription rates and predictors in a community sample of hospitalized patients with AMI. METHODS: The charts of 1163 community patients with AMI, prospectively identified at admission between January 1, 1994, and April 30, 1995, were reviewed. RESULTS: Only 64 of 158 (40%) patients considered ideal candidates for ACEI prescription were discharged with a prescription for an ACEI. In a multivariate logistic regression model, prior ACEI utilization [adjusted odds ration (OR) = 3.26; 95% confidence interval (CI) = 2.05-5.20], presence of congestive heart failure (OR = 2.33; CI = 1.50-3.61) and black race (OR = 2.20; CI = 1.34-3.64) were identified as positive predictors of ACEI prescription. Conversely, lack of left ventricular ejection fraction (LVEF) measurement (OR = 0.46; CI = 0.28-0.75), LVEF > 40 ( OR = 0.27; CI = 0.18-0.40), and acute renal failure (OR = 0.08; CI = 0.01-0.44) were negative predictors. Women were also less likely to be discharged with an ACEI prescription (OR = 0.71; CI = 0.48-1.05). Furthermore, women were significantly less likely to have LVEF measured prior to discharge than were males (77 vs. 85%, p = 0.001). CONCLUSION: This study underscores the need for improvement in the utilization of ACEI in eligible patients with AMI. It also identifies opportunities for improvement in prescription rates, especially in women.

Circadian variation in coronary tone in patients with stable angina. Protective role of the endothelium.

BACKGROUND: Coronary endothelium plays a key role in the regulation of coronary tone, platelet adhesion, and aggregation, which are important factors in triggering acute cardiovascular events. However, its role in modulating the effects of circadian variations on coronary tone is not known. METHODS AND RESULTS: Responses of 72 nonstenotic coronary segments to acetylcholine and nitroglycerin were measured in 12 patients with chronic stable angina at 6 AM and 1 PM. After baseline angiography, three infusions of acetylcholine (10(-6), 10(-5), and 10(-4) mol/L) were administered selectively into the left coronary artery, followed by nitroglycerin. Diameters (in millimeters) of proximal, middle, and distal segments were measured by quantitative techniques. Forty-seven segments showed a constrictor response to acetylcholine (group 1, dysfunctional endothelium), and 25 other segments showed a dilator response (group 2, normally functioning endothelium). In group 1, the constrictor response to acetylcholine was significantly greater in the morning than in the afternoon (23 +/- 3% and 10 +/- 1%, mean +/- SEM, respectively; P < .001), and the dilator response to nitroglycerin was also significantly greater in the morning than in the afternoon (19 +/- 2% and 11 +/- 2%; P < .01). In group 2, the dilator response to acetylcholine did not differ significantly between the morning and afternoon (22 +/- 3% and 17 +/- 2%, respectively; P = NS), and the dilator response to nitroglycerin was also similar at both times of the day (30 +/- 3% and 28 +/- 4%, respectively; P = NS). CONCLUSIONS: Coronary segments with dysfunctional endothelium exhibit an early morning exaggeration in vasomotor activity, whereas segments with normally functioning endothelium do not show circadian variations. This suggests a potential protective role for the endothelium in modulating variations in coronary tone that may contribute to increased incidence of cardiovascular events in the early morning hours.

Constrictor and dilator responses to intracoronary acetylcholine in adjacent segments of the same coronary artery in patients with coronary artery disease. Endothelial function revisited.

BACKGROUND: In patients with angiographically detectable atherosclerosis or in those with risk factors for coronary artery disease, intracoronary acetylcholine causes coronary constriction instead of endothelium-derived relaxing factor-mediated dilation. Therefore, it has been hypothesized that diffuse endothelial dysfunction precedes development of coronary atherosclerosis. We tested this hypothesis in a systematic investigation of the effects of ascending doses of acetylcholine on the diameters of nonstenotic segments of the left coronary artery in patients with advanced atherosclerosis and coronary risk factors. METHODS AND RESULTS: Effects of intracoronary infusion of acetylcholine (10(-6) to 10(-4) mol/L) on diameters of proximal, middle, and distal nonstenotic segments of the left coronary artery were studied in 28 consecutive patients with chronic stable angina, positive exercise tests, and angiographic evidence of obstructive atherosclerosis (> or = 50% reduction in lumen diameter in at least one vessel). Two patterns of response to the maximal acetylcholine dose (10(-4) mol/L) were observed. In 21 patients (group 1), only constriction was observed in all left anterior descending and circumflex artery segments studied (16 +/- 3%, 19 +/- 4%, and 23 +/- 4%, respectively; P < .01 compared with control). In 7 other patients (group 2), both constriction and dilation were observed in adjacent segments of the same vessel; maximal acetylcholine dose caused constriction in 14 left anterior descending artery segments from a control diameter of 1.94 +/- 0.19 to 1.33 +/- 0.26 mm (37% reduction, P < .01) and dilation in 16 other segments from 1.63 +/- 0.22 to 1.93 +/- 0.21 mm (25% increase, P < .01). In the circumflex artery, this dose caused constriction in 16 segments from a control diameter of 1.88 +/- 0.14 to 1.33 +/- 0.17 mm (31% reduction, P < .01) and dilation in 12 segments from 1.37 +/- 0.12 to 1.71 +/- 0.09 mm (34% increase, P < .01). CONCLUSIONS: In 25% of patients studied with advanced angiographic coronary atherosclerosis and coronary risk factors, coronary segments with acetylcholine-inducible dilatation are present. In these patients, the endothelium is not diffusely dysfunctional as currently believed but rather shows marked segmental heterogeneity in the response to acetylcholine reflecting degrees of endothelial dysfunction.

Comparison of coronary angiographic findings in acute and chronic first presentation of ischemic heart disease.

BACKGROUND: It is generally assumed that the clinical manifestations of ischemic heart disease occur randomly on the same underlying pathological process. Therefore, coronary angiographic findings should be similar whether the first presentation of ischemic heart disease is acute myocardial infarction or uncomplicated chronic stable angina. METHODS AND RESULTS: We studied 102 patients (men < or = 60 years old, women < or = 65 years old) presenting with either acute myocardial infarction as first manifestation of coronary artery disease with a concomitant coronary angiogram (55 patients; mean age, 50.2 years) or stable angina for at least 2 years with no history, ECG, or left ventriculographic evidence of any acute event and with an angiogram performed at least 2 years after initial symptoms (47 patients; mean age at symptom onset, 51.7 years). These angiograms were evaluated blindly for severity (number of vessels diseased, stenoses > or = 50%, occlusions), extent of disease (with an index derived by assigning a score of 0-3 per segment, depending on the proportion of lumen length irregularity and dividing the sum by the number of visualized segments), and pattern (discrete: three or fewer loci of disease never involving more than 50% of the length of any segment or diffuse: anything exceeding this). Patients with unheralded myocardial infarction had fewer vessels diseased, fewer stenoses and occlusion, and a lower extent index than those with uncomplicated stable angina (mean +/- SD of 1.3 +/- 0.8 versus 2.1 +/- 0.8, p < 0.001; 2.1 +/- 1.8 versus 3.9 +/- 1.8, p < 0.001; 0.6 +/- 0.6 versus 1.0 +/- 0.9, p < 0.02; and 0.6 +/- 0.5 versus 1.2 +/- 0.5, p < 0.001, respectively). A discrete pattern was present in 54.5% of patients with unheralded infarction and in only 8.5% of those with uncomplicated angina (p < 0.001). CONCLUSIONS: These very different angiographic findings suggest that unheralded acute myocardial infarction and uncomplicated chronic stable angina do not occur randomly on a common atherosclerotic background but rather that additional factors, such as a varying propensity to thrombosis, may predispose to one or the other of these two clinical syndromes.

Response of human coronary arteries to acetylcholine after injury by coronary angioplasty.

OBJECTIVES: The aim of this study was to investigate the effect of intracoronary administration of acetylcholine on large epicardial vessels 8 days after successful coronary angioplasty. BACKGROUND: Intracoronary infusion of acetylcholine causes vessel dilation in patients without angiographic evidence of coronary atherosclerosis, whereas it causes constriction of stenotic coronary branches. These findings were interpreted as evidence of endothelial dysfunction in patients with coronary atherosclerosis. METHODS: Eight patients who underwent successful single-vessel coronary angioplasty of the proximal left anterior descending artery were studied. Eight days after coronary angioplasty at the time of follow-up coronary angiography, intracoronary acetylcholine was infused (1 ml/min for 2 min) at concentrations ranging from 10(-7) to 10(-4) mol/liter. The diameter of the angioplasty and distal segments of the left anterior descending artery and that of the proximal and distal segments of the circumflex artery (control artery) were measured using computerized edge detection angiography. RESULTS: All patients showed a dose-dependent constriction in response to acetylcholine and experienced chest pain and ST segment changes. Intracoronary nitroglycerin (300 micrograms) relieved the effects of acetylcholine. The maximal tolerated dose of acetylcholine (10(-6) mol/liter in three patients, 10(-5) mol/liter in three patients and 10(-4) mol/liter in two patients) induced a mild constriction of the angioplasty segment from 1.84 +/- 0.11 mm to 1.52 +/- 0.13 mm (p < 0.02) similar to that of the proximal segment of the control artery (from 2.42 +/- 0.23 to 2.07 +/- 0.19 mm, p < 0.02). However, the degree of constriction of the vascular segments distal to the angioplasty site (from 1.24 +/- 0.09 to 0.62 +/- 0.13 mm, p < 0.01) was significantly greater (p < 0.05) than that observed in the distal segments of the control artery (from 1.23 +/- 0.03 to 0.71 +/- 0.01 mm, p < 0.01) and resulted in transient total occlusion in two patients. CONCLUSIONS: Eight days after coronary angioplasty, coronary segments distal to the dilated site but not at the dilated site are hyperreactive to acetylcholine. The response of epicardial coronary arteries to acetylcholine is influenced not only by the dose of acetylcholine and the endothelial function (as currently believed) but also by the location of the coronary segment considered, confirming the presence of a profound alteration of distal coronary vessels.

Optimal control of myocardial ischaemia: the benefit of a fixed combination of atenolol and nifedipine in patients with chronic stable angina.

OBJECTIVE: To study the effects on myocardial ischaemia of 50 mg of atenolol, 20 mg of slow release nifedipine, and their fixed combination given 12 hourly. DESIGN: A treadmill exercise test and 24 hour ambulatory electrocardiographic monitoring were carried out after a period of five days off treatment (control) and at the end of three weeks of each treatment period. PATIENTS: 23 patients with stable angina pectoris, documented coronary artery disease, and a positive exercise test were randomised in a double blind, three way, cross over study. RESULTS: Compared with the control, nifedipine significantly induced an increase in resting heart rate of (mean (SEM)) 14 (2) beats/min whereas atenolol and the combination significantly reduced it by 24 (2) and 20 (1) beats/min respectively. The number of exercise tests rendered negative after each intervention was five for nifedipine, nine for atenolol, and 11 for the combination. Compared with the control the time to the start of myocardial ischaemia (1 mm ST segment depression) during exercise significantly increased by 3.2 (0.6) min after nifedipine, by 4.6 (0.4) min after atenolol, and by 4.6 (0.5) min after the combination; rate-pressure product (beats/min. mm Hg) at 1 mm ST segment depression increased by 2824 (970) after nifedipine but fell by 4436 (900) and 4501 (719) after atenolol and the combination. The weekly frequency of angina was reduced from a mean of five while taking nifedipine, to three while taking atenolol, and to two while taking the combination. The total ischaemic time during ambulatory monitoring was significantly reduced from 69 (17) min during control to 37.5 (9.8) min during nifedipine, to 15.6 (5.5) min during atenolol, and to 6.5 (2.7) min during the combination. CONCLUSION: The undesirable effect of a high basal heart rate induced by nifedipine was neutralised by its combination with atenolol. Whereas atenolol and the combination were equally efficacious in controlling exercise induced ischaemia, the combination was more effective in reducing total ischaemic burden.

Preangioplasty complicated coronary stenosis morphology as a predictor of restenosis.

To assess whether complicated preangioplasty coronary stenosis morphology is associated with restenosis, 41 patients (47 stenoses) who underwent repeat angiography 6 to 8 months after percutaneous transluminal coronary angioplasty (PTCA) were studied. Stenosis diameter and morphology were assessed by computerized quantitative coronary angiography before and immediately after PTCA and at follow-up angiography. Before PTCA 18 stenoses were concentric (symmetric narrowings with smooth borders), 12 were eccentric (asymmetric narrowings with smooth borders), and 17 were complicated (asymmetric with rough borders and overhanging edges). Restenosis occurred in 18 lesions: two (11%) concentric, four (33%) eccentric, and 12 (70%) complicated (p less than 0.05), whereas 29 lesions remained unchanged. Stenosis diameter before and immediately after PTCA was not significantly different in the 18 patients with and the 23 patients without restenosis. Follow-up angiograms showed that 11 (61%) stenoses in the group with restenosis and 18 (63%) in the group without restenosis had morphology similar to that before PTCA. Restenosis occurred in seven (30%) patients who initially had chronic stable angina and in 11 (61%) who were first seen with unstable angina (p less than 0.05). In patients with stable angina 1 of 13 concentric stenoses, two of eight eccentric stenoses, and four of five complicated lesions restenosed. In patients with unstable angina one of five concentric, two of four eccentric, and 8 of 12 complicated lesions had restenosis. Stenoses that were complicated before PTCA tended to adopt an irregular morphology if they recurred, whereas concentric stenoses rarely occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Inappropriate constriction of small coronary vessels as a possible cause of a positive exercise test early after successful coronary angioplasty.

BACKGROUND: The mechanism responsible for exercise-induced myocardial ischemia early after successful coronary angioplasty (PTCA) is poorly understood. METHODS AND RESULTS: Twelve patients who underwent one-vessel PTCA were studied. Exercise testing was performed before and on day 7 after PTCA, which was repeated after 10 mg sublingual isosorbide dinitrate if the test was positive. Quantitative coronary arteriography was also performed on day 8 after PTCA in the basal state, after intracoronary infusion of 0.9% saline, 1, 5, 10, and 20 micrograms ergonovine, and after 300 micrograms nitroglycerin. All patients had a positive exercise test before PTCA but on day 7, six patients had a positive exercise test (group 1) and six patients (group 2) had a negative exercise test. In group 1, all positive exercise tests on day 7 became negative when repeated after isosorbide dinitrate. Intracoronary ergonovine was associated with a dose-dependent constriction of the PTCA segment, a segment distal to it, and a control segment, with no significant difference in the magnitude of the response between the two groups; maximum constriction for group 1 was 19 +/- 3%, 23 +/- 2%, and 16 +/- 3% (p less than 0.001 versus basal), and in group 2 was 20 +/- 4%, 18 +/- 4%, and 9 +/- 2% (p less than 0.01 versus basal). No angina, ischemic ST segment changes, occlusive, or subocclusive spasm occurred in any patient of either group. CONCLUSIONS: We could find no evidence that exercise-induced myocardial ischemia early after PTCA is related to the presence of fixed angiographic restenosis or to dynamic constriction of any epicardial coronary segment. Therefore, inappropriate small coronary vessel constriction responsive to nitrates should be considered as a possible alternative explanation.

Abnormal vasomotor changes early after coronary angioplasty. A quantitative arteriographic study of their time course.

BACKGROUND: To study the impact of percutaneous transluminal coronary angioplasty (PTCA) on coronary vasomotion, we prospectively analyzed spontaneous changes in coronary diameter and the response to the cold pressor test and intracoronary nitroglycerin in 11 patients subjected to successful single-vessel PTCA. METHODS AND RESULTS: All antianginal medications were stopped 48 hours before each study. The minimum diameter of the PTCA segment and the diameter of a distal segment in the angioplastied vessel and of a segment in a control vessel not manipulated by the balloon catheter or guide wire were measured by computerized edge detection immediately before PTCA and 5 minutes after, 4 hours after, and 8 days after PTCA. At 4 hours, PTCA and distal segments were constricted by 38 +/- 9% and 16 +/- 5%, respectively, compared with the values at 5 minutes (p less than 0.01). Before angioplasty, the cold pressor test caused vasoconstriction of PTCA and distal segments by 23 +/- 6% (p less than 0.0001) and 15 +/- 4% (p less than 0.008), respectively, but no constrictor response was elicited at 5 minutes or 4 hours after angioplasty. Eight days after PTCA, the basal coronary diameters were similar to those observed 5 minutes after PTCA and the response to the cold pressor test was similar to that observed before PTCA. All segments dilated significantly with nitroglycerin at all times, and no vasoconstriction changes were found in the control segments. CONCLUSIONS: Four hours after PTCA, transient spontaneous vasoconstriction of the PTCA and distal segments occurs, which is so intense that the cold pressor test does not cause any further constriction. These abnormalities resolve within 8 days of PTCA.

Effects of theophylline, atenolol and their combination on myocardial ischemia in stable angina pectoris.

The effects of theophylline (400 mg twice a day), atenolol (50 mg twice a day) and their combination on myocardial ischemia were studied in 9 patients with stable angina pectoris in a randomized, single-blind, triple crossover trial. Placebo was administered to the patients during the run-in and the run-off periods. A treadmill exercise test and 24-hour ambulatory electrocardiographic monitoring were obtained at the end of each treatment period. Compared with placebo, theophylline significantly improved the time to onset of myocardial ischemia (1 mm of ST-segment depression) from 7.8 +/- 3.7 to 9.5 +/- 3.7 minutes (p less than 0.03) and the exercise duration from 9 +/- 3.4 to 10.1 +/- 3.5 minutes (p less than 0.04). During atenolol and during combination treatment, the time to the onset of ischemia and the exercise duration were similar (10.8 +/- 4.2 and 11.2 +/- 3.2 minutes, 11.2 +/- 3.6 and 11.5 +/- 3.2 minutes, respectively) and longer than during theophylline administration (p less than 0.05). Ambulatory electrocardiographic monitoring showed that, during theophylline administration, the heart rate was higher than during placebo throughout the 24 hours (p less than 0.05). During atenolol and during combination treatment the heart rate was similar and in both cases lower than during placebo (p less than 0.05). Compared with placebo, theophylline decreased the total ischemic time from 97 +/- 110 to 70 +/- 103 minutes (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Response of angiographically normal and atherosclerotic left anterior descending coronary arteries to acetylcholine.

Acetylcholine-induced constriction of human coronary arteries in vivo is commonly attributed to endothelial dysfunction. To examine the effects of 2 other important determinants of vascular responses--namely, agonist concentration and the segment of circulation under study--the diameters of proximal, middle and distal segments of the left anterior descending artery (LAD) and coronary sinus oxygen saturation were measured in 10 patients with angiographically normal coronary arteries (group 1) and in 7 patients with coronary atherosclerosis (group 2) after intracoronary acetylcholine was infused at concentrations from 10(-7)M to between 10(-4)M and 10(-2)M. In group 1, acetylcholine caused minor (less than or equal to 6%) but progressive dilatation of the LAD up to 10(-4)M, but constriction, particularly of the distal segments and tertiary branches, occurred at higher concentrations. Over the same concentration range, coronary sinus oxygen saturation rose progressively from a basal level of 36 +/- 3% to a maximum of 72 +/- 3% in the absence of changes in heart rate and blood pressure, suggesting marked progressive dilatation of resistance vessels. Concentrations greater than or equal to 10(-3)M caused intense constriction of distal epicardial vessels and, in some cases, anginal pain and objective signs of ischemia. Conversely, in group 2, acetylcholine (infused only up to 10(-4)M for ethical reasons) failed to cause significant changes in LAD diameter. These data suggest that the local acetylcholine concentration and coronary vascular segment under study may determine the observed response to at least an equivalent extent as does the presence or absence of coronary atherosclerosis, raising the question of whether a constrictor response to intracoronary acetylcholine reliably indicates the presence of coronary atherosclerosis.

Very early prediction of restenosis after successful coronary angioplasty: anatomic and functional assessment.

To investigate the time course of restenosis, serial treadmill exercise testing was performed in the absence of medical therapy by 31 patients with single vessel coronary disease who underwent successful angioplasty. Exercise tests were performed before angioplasty and at 3 days and 1, 3 and 6 months after angioplasty; if the test was positive, it was repeated after administration of 10 mg of intravenous verapamil. At arteriography 6 months after coronary angioplasty, 17 patients (group 1) showed no restenosis but 14 patients (group 2) did. Before angioplasty all 31 patients had a positive exercise test with ST segment depression greater than or equal to 1 mm. At 3 days after angioplasty, three patients in group 1 had a positive exercise test compared with 11 patients in group 2 (p = 0.08). At 1, 3 and 6 months, 1 patient in group 1 had a positive exercise test compared with 14 patients in group 2 (p less than 0.01). The heart rate-blood pressure product (beats/min.mm Hg) calculated at 1 mm ST segment depression, or at peak exercise if the test was negative, was used as an index of the ischemic threshold. In group 1 (no restenosis) the ischemic threshold increased progressively from 14,840 +/- 1,075 (mean value +/- SEM) before angioplasty to 21,210 +/- 1,049 at 3 days and to 25,140 +/- 1,177 (p less than 0.001) at 6 months. In group 2 (restenosis) the ischemic threshold increased from 16,270 +/- 828 before angioplasty to 20,400 +/- 984 (p less than 0.0004) at 3 days but decreased to 16,090 +/- 1,298 (p less than 0.006) at 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of adenosine in pathogenesis of anginal pain.

The intravenous infusion of adenosine provokes anginalike chest pain. To establish its origin, an intracoronary infusion of increasing adenosine concentrations was given in 22 patients with stable angina pectoris. During adenosine infusion, 20 patients had chest pain without electrocardiographic signs of ischemia. They all reported that the chest pain was similar to their usual anginal pain. In 10 of the 22 patients adenosine was also infused into the right atrium, but it never produced symptoms at the doses that had provoked chest pain during intracoronary infusion. In seven other patients, the intracoronary adenosine infusion was repeated after intravenous administration of aminophylline, an antagonist of adenosine P1-receptors. Aminophylline decreased the severity of adenosine-induced chest pain (assessed with a visual analog scale) from 42 +/- 22 to 23 +/- 17 mm (p less than 0.002). In the remaining five of the 22 patients, monitoring of blood oxygen saturation in the coronary sinus during intracoronary adenosine administration showed that maximum coronary vasodilation was achieved at doses lower than those responsible for chest pain. A single-blind, placebo-controlled, randomized trial of the effect of aminophylline on exercise-induced chest pain was also performed in 20 other patients with stable angina. Aminophylline, compared with placebo, decreased the severity of chest pain at peak exercise from 67 +/- 21 to 51 +/- 23 mm (p less than 0.02), despite the achievement of a similar degree of ST-segment depression. Finally, the effect of intravenous adenosine was compared in 10 patients with predominantly painful myocardial ischemia and in 10 patients with predominantly silent ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Holter monitoring after PTCA.

There are several potential causes for the occurrence of myocardial ischaemia after successful coronary angioplasty, but the role of ambulatory electrocardiographic monitoring, particularly in the detection of coronary restenosis, remains undefined in these patients. Previous studies have shown that ambulatory monitoring demonstrates ST-segment changes in only a minority of patients before, and rarely after, successful angioplasty. The presence of transient myocardial ischaemia, whether symptomatic or silent, on ambulatory electrocardiographic monitoring has not been shown to relate to the outcome, frequency of complications, or rate of restenosis in patients after successful angioplasty. Ambulatory electrocardiographic monitoring and exercise testing are complementary investigative techniques for the detection of myocardial ischaemia after successfully coronary angioplasty. Their roles will depend on the type of ischaemic syndrome present, its presentation and the pathophysiological mechanisms involved.

Comparative effects of theophylline and isosorbide dinitrate on exercise capacity in stable angina pectoris, and their mechanisms of action.

While the role of nitrates in the prevention and treatment of myocardial ischemia is well established, the use of theophylline, proposed almost a century ago, is still controversial. Also controversial is its mechanism of action, initially thought to be coronary dilation. In this randomized, single-blind study, the acute effects on exercise capacity of sublingual isosorbide dinitrate (10 mg) and of intravenous theophylline ethylenediamine (7 mg/kg) were assessed in 10 patients with chronic stable angina and positive exercise test. After the administration of theophylline, the time to onset of angina, the heart rate-blood pressure product at 1-mm ST-segment depression and the exercise duration were similar to that after isosorbide dinitrate administration (9.8 +/- 2.3 vs 9.3 +/- 1.7 minutes, 207 +/- 41 vs 207 +/- 48 beats/min.mm Hg.10(-2) and 10.8 +/- 2 vs 10.4 +/- 2 minutes, respectively). Both drugs significantly (p less than 0.001) improved all these parameters compared to the baseline exercise test. The effect of the 2 drugs on the diameters of angiographically normal segments of large epicardial coronary arteries was then assessed using computerized quantitative angiography in 10 other patients with stable angina. Whereas theophylline failed to increase the coronary diameters compared to that in the baseline angiogram (2.9 +/- 0.6 vs 2.9 +/- 0.6 mm, respectively), the subsequent administration of isosorbide dinitrate resulted in an increase up to 3.2 +/- 0.7 mm (p less than 0.02). Thus, in patients with stable angina, theophylline delays the onset of angina, increases the ischemic threshold and prolongs the exercise duration to the same degree as isosorbide dinitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of diltiazem alone or with isosorbide dinitrate or with atenolol both acutely and chronically for stable angina pectoris.

To establish the contribution of combination therapy in stable angina, the short- and long-term effects of diltiazem (120 mg and 360 mg/day, respectively), and the additive effects of sublingual isosorbide dinitrate, 10 mg, and atenolol, 100 mg, were studied in 11 patients with chronic stable angina using an open-label sequential design. All patients underwent exercise testing without therapy, and with each drug and their combinations. Exercise time and heart rate-blood pressure product were measured at 1-mm ST-segment depression, or at peak exercise if the test result was negative. Exercise time increased from a control value of 8.0 +/- 2.3 minutes (mean +/- standard deviation) to 11.4 +/- 2.4 minutes (p less than 0.0001) after the administration of isosorbide dinitrate, to 11.3 +/- 1.8 minutes (p less than 0.001) after short-term diltiazem and to 12.4 +/- 1.5 minutes (p less than 0.001) after long-term diltiazem. The rate-pressure product increased from a control value of 19,070 +/- 3,564 to 24,431 +/- 4,795 beats/min X mm Hg (p less than 0.0001) after isosorbide dinitrate, to 22,287 +/- 4,753 beats/min X mm Hg (p less than 0.01) after short-term diltiazem and to 21,812 +/- 3,976 beats/min X mm Hg (p less than 0.007) after long-term diltiazem. The addition of atenolol to long-term diltiazem significantly reduced the rate-pressure product compared with long-term diltiazem alone (21,812 +/- 3,976 vs 13,926 +/- 2,880 beats/min X mm Hg, (p less than 0.002), although there was no further significant increase in exercise time (12.4 +/- 1.5 vs 13.3 +/- 1.6 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of theophylline on exercise-induced myocardial ischaemia.

In a single-blind, placebo-controlled, randomised trial in 20 patients with stable angina pectoris, intravenous theophylline ethylenediamine (aminophylline), 7 mg/kg, increased the time to onset of angina by 46%, the heart-rate/blood-pressure product (an index of myocardial oxygen consumption) at 1 mm ST segment depression by 22%, and exercise duration by 24%. In a subsequent double-blind placebo-controlled trial in 8 patients a single oral dose of theophylline (375 mg) increased the time to onset of angina by 56%, the heart-rate/blood-pressure product at 1 mm ST segment depression by 22%, and the exercise duration by 35%. Infusion of theophylline ethylenediamine during angiography (10 patients) did not affect the diameter of epicardial coronary arteries. The beneficial effects of theophylline may be due to redistribution of coronary blood flow from non-ischaemic to ischaemic myocardium.

Adenosine-induced chest pain in patients with silent and painful myocardial ischaemia: another clue to the importance of generalized defective perception of painful stimuli as a cause of silent ischaemia.

Adenosine is formed from adenosine triphosphate within the ischaemic cells from where it is released into the coronary circulation. Adenosine exhibits several cardiovascular effects which tend to protect the ischaemic myocardium. Based on the observation that in healthy volunteers the intravenous infusion of adenosine produces angina-like chest pain, it has been recently proposed that another cardioprotective action of this substance could be provocation of angina. If this is the case adenosine should not produce chest pain in patients with silent ischaemia. To test this hypothesis we infused this substance intravenously at increasing doses of 50, 100, 150, 200, 250 and 300 micrograms kg-1 min-1 in eight patients with silent ischaemia (group A). All of them developed ST depression (1.8 +/- 0.2 mm) during exercise testing and seven also during adenosine infusion (1.1 +/- 0.8 mm). However, none of the patients had chest pain during exercise while seven had chest pain during adenosine. We then infused adenosine in eight other patients (Group B) who had painful ischaemia and an exercise tolerance similar to that of Group A patients (time to 1 mm ST depression 8.6 +/- 2.7 min and 8.4 +/- 3 min, respectively, P = NS). Adenosine induced chest pain in all Group B patients. The time to pain onset during adenosine was similar in the two groups (9.3 +/- 2.3 min in Group B and 12.4 +/- 4.9 min in Group A).(ABSTRACT TRUNCATED AT 250 WORDS)