Production of arrhythmias by elevated carboxyhemoglobin in patients with coronary artery disease

OBJECTIVE: To assess the effects of exposure to 4% and 6% carboxyhemoglobin on ventricular arrhythmias in patients with coronary artery disease. DESIGN: Randomized, double-blind, crossover design. SETTING: Exercise laboratory with an environmentally controlled exposure. PATIENTS: Forty-one nonsmokers with documented coronary artery disease. INTERVENTION: On day 1, a training session with no exposure, the baseline carboxyhemoglobin level was measured, and a supine bicycle exercise test was done. On days 2 to 4, patients were exposed to room air, 100 ppm carbon monoxide (target, 4% carboxyhemoglobin) or 200 ppm carbon monoxide (target, 6% carboxyhemoglobin), and they then did supine bicycle exercise with radionuclide ventriculography. Ambulatory electrocardiogram recordings were made during the 4 consecutive days to determine the frequency of ventricular premature depolarization (VPD) at various intervals. MEASUREMENTS AND MAIN RESULTS: The frequency of single VPD/h was significantly greater on the 6% carboxyhemoglobin day than on the room air day during the exercise period (167.72 +/- 37.99 for 6% carboxyhemoglobin compared with 127.32 +/- 28.22 for room air, P = 0.03). During exercise, the frequency of multiple VPD/h was greater on the 6% carboxyhemoglobin day compared with room air (9.59 +/- 3.70 on the 6% carboxyhemoglobin compared with 3.18 +/- 1.67 on room air, P = 0.02). Patients who developed increased single VPD during exercise on the 6% carboxyhemoglobin day were significantly older than those who had no increased arrhythmia, whereas patients who developed complex arrhythmias were also older and, in addition, exercised longer and had a higher peak workload during exercise. CONCLUSION: The number and complexity of ventricular arrhythmias increases significantly during exercise after carbon monoxide exposure producing 6% carboxyhemoglobin compared with room air but not after exposure producing 4% carboxyhemoglobin.     

Carbon monoxide and lethal arrhythmias in conscious dogs with a healed myocardial infarction

Environmental studies suggested that exposure to carbon monoxide (CO) increases cardiovascular mortality among patients with coronary artery disease. We investigated whether, in dogs with a healed anterior myocardial infarction at low and high risk for ventricular fibrillation, acute exposure to CO has adverse effects during acute myocardial ischemia combined with exercise. One month after myocardial infarction, 17 dogs had ventricular fibrillation and 16 survived during the combined exercise and ischemia test. These tests were then repeated in all dogs with different concentrations of carboxyhemoglobin (COHb) (from 5% to 15%). With 15% COHb, heart rate (HR) at rest and during exercise was higher (p less than 0.05) than in the control tests. Surprisingly, the reflex HR response to acute ischemia was also altered; namely, the HR reduction characteristic of the low-risk animals was anticipated and accentuated (-31 +/- 25 versus 2 +/- 30 beats/min, p less than 0.05). Conversely, the HR increase characteristic of the high-risk group was reduced by CO (44 +/- 52 versus 72 +/- 43 beats/min, p less than 0.05). With 15% COHb, malignant arrhythmias occurred in two of the low-risk dogs and in none of the high-risk dogs. In the latter, CO was tested with a combination of exercise work load and myocardial ischemia duration not associated with ventricular fibrillation (VF) in the control condition. This study demonstrated that brief exposure to CO (1) profoundly alters the reflex HR response to exercise and to acute myocardial ischemia and (2) does not enhance the occurrence of malignant arrhythmias in conscious dogs with a healed myocardial infarction.     

Improved left ventricular performance during exercise with verapamil or nifedipine in patients with chronic stable angina

To examine the effects of chronic oral therapy with verapamil, 120 mg three times a day, and nifedipine, 20 mg four times daily, on left ventricular ejection fraction and regional wall motion at rest and exercise, 10 patients with chronic stable angina pectoris underwent serial rest and exercise radionuclide angiography. Pre drug control study revealed a resting left ventricular ejection fraction (LVEF) of 0.62 +/- 0.08, falling to 0.54 +/- 0.12 at peak exercise (p less than 0.05). Wall motion score deteriorated from a resting value of 13.8 +/- 2.3 to 10.6 +/- 1.8 (p less than 0.01) with exercise. Patients were subsequently randomized to verapamil or nifedipine for 4 weeks each in an open-labeled crossover design. Rest and exercise radionuclide angiography were repeated at the end of each 4-week period. Neither verapamil nor nifedipine had a significant effect on resting LVEF (verapamil LVEF = 0.61 +/- 0.10, nifedipine LVEF = 0.64 +/- 0.02). Likewise, they had no significant effect on resting wall motion score (verapamil = 14.2 +/- 2.2, nifedipine = 14.4 +/- 1.6). Both verapamil and nifedipine significantly increased LVEF at peak exercise (verapamil = 0.63 +/- 0.09, nifedipine = 0.65 +/- 0.08, p less than 0.05 vs pre drug control) and improved peak exercise wall motion score (verapamil = 13 +/- 1.9, nifedipine = 13.8 +/- 1.6, p less than 0.05 vs pre drug control). Both drugs significantly reduced maximal ST depression at peak exercise and prolonged exercise duration. Episodes of angina and nitroglycerin use were also significantly reduced. In summary, verapamil and nifedipine improved left ventricular performance at exercise in patients with angina pectoris.     

Short- and long-term efficacy of high-dose oral diltiazem for angina due to coronary artery disease: a placebo-controlled, randomized, double-blind crossover study

The effects of oral diltiazem (360 mg/day) on exercise tolerance, left ventricular performance, and plasma lactate and catecholamine levels were studied in 13 patients with atherosclerotic coronary artery disease in a placebo-controlled, randomized, double-blind protocol. Exercise duration to the onset of ischemic ST segment depression, time to angina pectoris, and time to peak exercise improved by 120, 174, and 144 sec, respectively (p less than .0001). Left ventricular ejection fraction, as determined by radionuclide angiography, increased in patients at rest from 52 +/- 11% (mean +/- SD) during placebo therapy to 58 +/- 11% during diltiazem therapy (p less than .001); at peak exercise ejection fraction increased from 44 +/- 11% during placebo treatment to 52 +/- 15% during diltiazem therapy (p less than .01). The mean plasma norepinephrine level in patients at rest increased from 498 +/- 221 pg/ml during placebo treatment to 667 +/- 272 pg/ml during diltiazem therapy (p less than .05). Resting standing blood pressure and supine and standing diastolic blood pressures decreased significantly with diltiazem. In all 10 patients followed over a long term, oral diltiazem caused persistent improvement in exercise performance at 12 to 20 weeks, without evidence of placebo effects. Thus, diltiazem is highly effective in divided doses of 360 mg/day for the therapy of chronic angina pectoris due to coronary artery disease.     

Evaluation of bepridil for the treatment of angina pectoris: evidence for preservation of left ventricular function

The efficacy of bepridil (400 mg once a day) was assessed in 15 patients with exertional angina pectoris. All 15 patients reported substantial clinical improvement during bepridil treatment compared with placebo treatment. Episodes of angina were 11.8 +/- 4.1 (mean +/- standard error of the mean)/week with placebo and 3.8 +/- 1.6 with bepridil (p less than 0.05); nitroglycerin use was 9.1 +/- 3.3 tablets/week with placebo and 3.5 +/- 1.7 with bepridil (p less than 0.05). Five of 15 patients receiving bepridil did not experience angina during treadmill exercise; in the remaining 10 patients, time to onset of angina during exercise was 5.7 +/- 0.9 minutes with bepridil as opposed to 4.5 +/- 0.8 minutes with placebo (p less than 0.05). Left ventricular (LV) performance at peak exercise as measured by first-pass radionuclide angiography revealed the ejection fraction to be 38 +/- 3% during placebo therapy and 47 +/- 4% during bepridil therapy (p less than 0.0025). End-diastolic LV volume was unchanged, but end-systolic volume was 136 +/- 11 and 117 +/- 13 ml (p less than 0.05) and stroke volume was 82 +/- 6 and 97 +/- 9 ml (p less than 0.05) during placebo and bepridil therapy, respectively. Heart rate at peak exercise was 136 +/- 3 beats/min with placebo and 128 +/- 3 beats/min with bepridil; however, blood pressure was unchanged. These studies demonstrate that bepridil results in significant clinical improvement and enhanced LV performance in patients with angina pectoris.     

Effect of carbon monoxide on exercise performance in chronic obstructive pulmonary disease

We evaluated the effect of breathing 100 ppm of carbon monoxide versus compressed, purified air for 1 hour on exercise performance in 10 patients with chronic obstructive pulmonary disease in a double-blind, randomized, crossover study. The mean arterial carboxyhemoglobin was 1.48 per cent in the carbon monoxide control period and increased from 1.43 to 4.08 per cent after breathing carbon monoxide (P less than 0.001). The mean arterial carboxyhemoglobin level was 1.52 percent in the air control period and decreased from 1.47 to 1.34 per cent after purified air (P less than 0.001). The mean exercise time until marked dyspnea decreased from 218.5 seconds in the carbon monoxide control period to 146.6 seconds after breathing carbon monoxide (P less than 0.001). The mean exercise time was 219.9 seconds in the air control period and 221.3 seconds after purified air (P not significant). Breathing 100 ppm of carbon monoxide for 1 hour caused a significant reduction in exercise performance in patients with chronic obstructive pulmonary disease.     

Indoor passive smoking: its effect on cardiac performance.

We studied 19 nonsmoker male volunteers, 9 healthy (mean age 30.5 +/- 8.5), and 10 with previous myocardial infarction (mean age 53.8 +/- 5.3), who underwent exercise stress testing twice: in a smoke-free environment and in a smoking environment (carbon monoxide concentration 30-35 ppm). We measured peak exercise power, time to recovery of pre-exercise heart rate, expired concentration of carbon monoxide and plasma carbon monoxide. Obtained data were compared by using t-test. P less than 0.05 was statistically significant. Mean data observed in healthy people were as follows. Peak exercise power 220 +/- 30 watts in a smoking environment versus 220 +/- 30 in a smoke-free environment (P greater than 0.05). Time to recovery of pre-exercise heart rate 19 +/- 4 minutes in a smoking environment versus 8.5 +/- 4 in a smoke-free environment (P less than 0.01). Expired concentration of carbon monoxide before exercise 2.3 +/- 2.01 ppm versus 8.5 +/- 1.6 (P less than 0.01) after exercise in a smoking environment, and 2.3 +/- 2 ppm before exercise versus 2.1 +/- 1.9 after exercise in a smoke-free environment (P less than 0.05). Plasma carbon monoxide before exercise 1.4 +/- 0.2% versus 1.7 +/- 0.4 after exercise in a smoking environment (P greater than 0.05), and 1.2 +/- 0.4% before exercise versus 1.2 +/- 0.4 in a smoke-free environment (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The predictive value of ventricular function during exercise after a myocardial infarct]

To assess the prognostic value of exercise left ventricular function, and if this test improves the prognostic value of clinical data and exercise test, 146 patients (mean age 56 +/- 9 years) underwent rest and exercise radionuclide angiography, 10 days after myocardial infarction. During follow-up (mean 16 +/- 5 months), 32 patients had new coronary events: 5 died, 9 had a new myocardial infarction and the remaining 18 developed unstable angina (Class III-IV of the CCS classification). Patients with new coronary events had more frequently severe left ventricular failure (Killip III-IV) (15% vs 3%; p less than 0.05) and postinfarction angina (32% vs 9%; p less than 0.01) than their counterparts. There were no differences regarding rest ejection fraction between both groups of patients. Exercise ejection fraction increased significantly (50 +/- 14% to 56 +/- 16%, p less than 0.001), while there was no change in patients with new coronary events (46 +/- 16% to 43 +/- 15%, NS). Logistic regression analysis including only clinical data identified postinfarction angina (p less than 0.01) and left ventricular failure (Killip III-IV) (p less than 0.01) as independent predictors of new coronary events. The sensitivity and specificity of the regression equation obtained with clinical data were 43% and 90%, respectively. Analyzing data from clinical variables, as well as exercise test and both, rest and exercise radionuclide angiography, logistic regression analysis identified, exercise ejection fraction (p less than 0.001), postinfarction angina (p less than 0.01) and rest ejection fraction (p less than 0.05) as independent predictors of new coronary events.(ABSTRACT TRUNCATED AT 250 WORDS)     

Left and right ventricular function at rest and during bicycle exercise in the supine and sitting positions in normal subjects and patients with coronary artery disease. Assessment by radionuclide ventriculography

To assess the hemodynamic influence of posture during radionuclide cardiac studies, rest and exercise electrocardiographically gated blood pool cardiac scintigraphy was performed in the supine and sitting positions in 22 normal subjects and in 20 patients with coronary artery disease (CAD). In normal subjects, left ventricular ejection fraction was higher in the sitting position both at rest (67 +/- 6% versus 64 +/- 5%, p less than 0.01) and during exercise (79 +/- 9% versus 76 +/- 6%, p less than 0.05). Left ventricular end-diastolic volume in the sitting position was smaller at rest (by 19 +/- 26%, p less than 0.001), but this variable was similar in both positions during exercise (p greater than 0.05). Left ventricular end-systolic volume was smaller in the sitting position both at rest, by 26 +/- 31 percent, and during exercise, by 14 +/- 20% (p less than 0.001). Left ventricular end-diastolic volume increased from rest to exercise, in the sitting position by 31 +/- 23% (p less than 0.001) and in the supine position by 6 +/- 22% (p greater than 0.05). In patients with CAD, similar left ventricular ejection fractions in both postures were found at rest and during exercise. Left ventricular end-diastolic volume in the sitting posture was smaller at rest by 16 +/- 22% (p less than 0.01) and during exercise by 8 +/- 18% (p less than 0.05). Sitting left ventricular end-systolic volume was smaller by 18 +/- 20% (p less than 0.001) at rest and by 14 +/- 21% (p less than 0.01) during exercise. Left ventricular end-diastolic volume increased from rest to exercise, in the sitting position by 45 +/- 36% (p less than 0.001) and in the supine position by 32 +/- 51% (p less than 0.01). Despite significant hemodynamic differences, the value of rest-exercise radionuclide cardiac studies to detect CAD was similar in the 2 positions.     

Myocardial mechanics in young adult patients with diabetes mellitus: effects of altered load, inotropic state and dynamic exercise

The disease entity "diabetic cardiomyopathy" has been extensively described in young patients with diabetes in the absence of ischemic, hypertensive or valvular heart disease. The most convincing data have been a 30% to 40% incidence of decreased radionuclide angiographic left ventricular ejection fraction response to dynamic exercise. In the current study, the hypothesis was tested that this abnormal ejection fraction response was due to alterations in ventricular loading conditions or cardiac autonomic innervation (extrinsic factors), or both, rather than to abnormalities in intrinsic ventricular systolic fiber function (contractility). Twenty normotensive patients with diabetes (mean age 30 +/- 5 years, mean duration 15 +/- 6 years) and 20 age-matched normal subjects were studied. All patients with diabetes had a normal treadmill exercise tolerance test without evidence of myocardial ischemia. By radionuclide angiography, all normal subjects increased ejection fraction with exercise (62 +/- 4% to 69 +/- 6%; p less than 0.001). In contrast, 11 (55%) of 20 patients with diabetes maintained or increased ejection fraction with exercise (group 1; 62 +/- 4% to 69 +/- 6%; p less than 0.001) and 9 (45%) of 20 showed an exercise-induced decrease (group 2; 73 +/- 4% to 66 +/- 6%; p less than 0.001). No difference in the incidence of microangiopathy, as noted by funduscopic examination, was present between the diabetic groups. Despite the abnormal ejection fraction response to exercise in the group 2 patients with diabetes, all patients with diabetes had a normal response to afterload manipulation, normal baseline ventricular contractility as assessed by load- and heart rate-independent end-systolic indexes and normal contractile reserve as assessed with dobutamine challenge. Autonomic dysfunction did not explain the disparate results between the group 2 patients' radionuclide angiographic data and their load-independent tests of ventricular contractility and reserve. In addition, the high ejection fraction at rest in group 2 patients (73 +/- 4% versus 62 +/- 4% for normal subjects; p less than 0.001) was not related to the abnormal tests of autonomic function. Thus, when left ventricular systolic performance was assessed by load- and rate-independent indexes, there was no evidence for cardiomyopathy in young adult patients with diabetes who have normal blood pressure and no ischemic heart disease.     

Differentiating cardiomyopathy of coronary artery disease from nonischemic dilated cardiomyopathy utilizing positron emission tomography

To determine if imaging of blood flow (using N-13 ammonia) and glucose metabolism (using F-18 2-deoxyglucose) with positron emission tomography can distinguish cardiomyopathy of coronary artery disease from nonischemic dilated cardiomyopathy, 21 patients with severe left ventricular dysfunction who were evaluated for cardiac transplantation were studied. The origin of left ventricular dysfunction had been previously determined by coronary angiography to be ischemic (11 patients) or nonischemic (10 patients). Images were visually analyzed by three observers on a graded scale in seven left ventricular segments and revealed fewer defects in dilated cardiomyopathy compared with ischemic cardiomyopathy for N-13 ammonia (2.7 +/- 1.6 versus 5 +/- 0.6; p less than 0.03) and F-18 deoxyglucose (2.8 +/- 2.1 versus 4.6 +/- 1.1; p less than 0.03). An index incorporating extent and severity of defects revealed more homogeneity with fewer and less severe defects in subjects with nonischemic than in those with ischemic cardiomyopathy as assessed by imaging of flow (2.8 +/- 1.8 versus 9.2 +/- 3; p less than 0.001) and metabolism (3.8 +/- 3.3 versus 8.5 +/- 3.6; p less than 0.005). Diagnostic accuracy for distinguishing the two subgroups by visual image analysis was 85%. Using previously published circumferential count profile criteria, patients with dilated cardiomyopathy had fewer ischemic segments (0.4 +/- 0.8 versus 2.5 +/- 2 per patient; p less than 0.01) and infarcted segments (0.1 +/- 0.3 versus 2.4 +/- 1.4 per patient; p less than 0.001) than did patients with cardiomyopathy of coronary artery disease. The sensitivity for differentiating the two clinical subgroups using circumferential profile analysis was 100% and the specificity 80%. An index incorporating both number and severity of defects derived from circumferential profile analysis was significantly lower in subjects with dilated cardiomyopathy than in ischemic cardiomyopathy (0.3 +/- 0.8 versus 2.7 +/- 2.4; p less than 0.005). Thus, noninvasive positron emission tomographic imaging with N-13 ammonia and F-18 deoxyglucose is helpful in distinguishing patients with severe left ventricular dysfunction secondary to coronary artery disease from those with nonischemic cardiomyopathy, and a semiquantitative index such as circumferential profile analysis is superior to that of visual analysis alone.     

Response of angina and ischemia to long-term treatment in patients with chronic stable angina: a double-blind randomized individualized dosing trial of nifedipine, propranolol and their combination.

Seventy-four patients with chronic stable mild angina, mild coronary artery disease (83% had one- or two-vessel disease) and normal left ventricular function were studied to measure the response of treadmill exercise performance and painful and silent ischemia in the ambulatory setting to randomly assigned treatment with nifedipine or propranolol and their combination; titration to maximal tolerated dosages was performed in double-blind manner. At 3 months both nifedipine and propranolol reduced the weekly angina rate (p less than 0.05); during treadmill exercise testing, increases (p less than 0.05) were noted in time to angina and total exercise time and decreases in maximal ST depression at the end of exercise. There were no differences between the responses to nifedipine and propranolol and no significant additional changes were seen after another 3 months of therapy. The combination of nifedipine and propranolol reduced the number of patients with angina on exercise treadmill testing from 64% to 38% (p less than 0.05). During ambulatory electrocardiographic monitoring before treatment, there were 1.4 +/- 2.4 (mean +/- SD) episodes/24 h of painful ischemia and a very low silent ischemia frequency: mean 1.1 +/- 2.7 episodes/24 h, mean duration 16 +/- 25 min/24 h. Treatment with propranolol and nifedipine resulted in reduction of episodes and duration of painful and painless ischemia; approximately 77% of patients were free of all ischemic episodes. It is concluded that patients with chronic stable mild angina have a low incidence of silent ischemia. Nifedipine or propranolol alone, titrated to individualized maximally tolerated dosages, are equally effective in long-term control of painful and painless ischemia, anginal episodes and exercise-induced ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in myocardial metabolism and function at rest in stable angina pectoris: relations with the amount of exercise-induced thallium-201 perfusion defect

The relation between the amount of exercise-induced ischemia and alterations in left ventricular (LV) function and metabolism at rest was studied in 18 coronary patients with stable angina pectoris. An ischemic defect area score was computed from quantitative exercise thallium-201 (Tl-201) scintigraphy; this estimation of the amount of ischemic myocardium was used to classify the patients in group I (n = 8; score less than 15%, mean 6.7 +/- 2.5%) and II (n = 10; score greater than 15%; mean 27.2 +/- 8.9%). Hemodynamics and metabolism were studied in basal state. No patient had anginal pain during the study, and the extent of angiographic coronary artery disease (CAD) was comparable in the two groups. Heart rate, aortic pressure, coronary blood flow, and myocardial oxygen uptake were also similar in both groups. However, ejection fraction was reduced in group II (51 +/- 13 vs 63 +/- 5%; p less than 0.01) and LV relaxation was impaired as shown by the increase in time-constant of isovolumic pressure fall (55 +/- 16 vs 44 +/- 6 ms in group I; p less than 0.05); the LV end-diastolic pressure was also increased in group II (19 +/- 8 vs 10 +/- 4 mmHg in group l; p less than 0.05). Furthermore, in group II, myocardial lactate uptake was reduced (4 +/- 19 vs 30 +/- 29 mumole/min in group I; p less than 0.01) and the productions of alanine and glutamine were augmented (-7.5 +/- 4.4 vs -4.6 +/- 1.6 mumole/min in group I; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of partial sympathetic denervation on the results of myocardial revascularization in variant angina

Poor results of the aortocoronary bypass graft operation in the treatment of variant angina have been ascribed to recurrent vasospastic activity due to autonomic imbalance. Cardiac sympathetic denervation (plexectomy) may represent a rational approach in the prevention of vasospasm. To test the value of plexectomy in the treatment of variant angina, 31 patients were studied, 17 of whom (Group 1) underwent conventional coronary artery grafting whereas the remaining 14 (Group 2) underwent cardiac sympathetic denervation also. The 2 groups were similar with respect to age (54 +/- 8 versus 50 +/- 7 years), sex distribution (male/female ratio 12/5 versus 9/5), prevalence of coexisting effort angina (10 versus 12 patients), previous myocardial infarction (7 versus 4 patients), and duration of variant angina (3.3 +/- 5.4 versus 2.4 +/- 2.7 months). The left ventricular ejection fraction was comparable in both groups (60 +/- 11 versus 60 +/- 4%) as were left ventricular end-diastolic pressure (15 +/- 4 versus 13 +/- 5 mm Hg) and extent of coronary artery disease (65 versus 71% prevalence of multivessel disease). The average duration of follow-up was 23 +/- 15 months in Group 1 and 22 +/- 18 months in Group 2 (p = not significant [NS]). There were no operative deaths. Four patients, 2 in each group, had a perioperative myocardial infarction. Seven patients in Group 1 and 1 patient in Group 2 had recurrent variant angina. There was sudden death and 2 infarcts in Group 1. Actuarial curves showed the cumulative probability of recurrent variant angina to be significantly lower (p less than 0.05 and p less than 0.001 at 6 and 10 months, respectively) in Group 2. This study suggests that cardiac sympathetic denervation may prevent recurrent vasospastic activity in variant angina.     

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.     

24-hour efficacy of a system of transcutaneous administration of nitroglycerin. Evaluation by the exercise test and gamma angiography

The effects of a nitroglycerin transdermal therapeutic system (TTS NG 10 mg/24 h) 24 hours after application were evaluated by exercise left ventricular radionuclide cineangiography. 20 patients with ischemic heart disease were included in a double-blind, within patient, acute study comparing TTS NG to placebo. Were measured: exercise-test parameters and global (EF) and regional (rEF) ejection fractions at rest and during exercise. At maximum load, the double product rose from 18,680 +/- 4,118 with placebo to 21,538 +/- 3,988 with TTs NG (p less than 0.01) and ST-segment depression at same load decreased from 2.6 +/- 0.7 mm with placebo to 1.0 +/- 0.7 mm with TTS NG (p less than 0.001). Exercise EF increased from 0.57 +/- 0.15 with placebo to 0.63 +/- 0.12 with TTS NG (p less than 0.001) and was higher at exercise than at rest. Two hypokinetic territories improved during exercise with TTS NG: basal rEF increased to 0.45 +/- 0.07 with TTS NG versus 0.31 +/- 0.13 with placebo (p less than 0.01); anteroseptal rEF increased to 0.49 +/- 0.14 versus 0.43 +/- 0.14 with placebo (p 0.05); no significant improvement was observed in anterolateral and inferior territories were previous myocardial infarction occurred predominantly. These data demonstrate the 24 hours efficacy of this new galenic form of TTS NG in ischemic heart disease on exercise test parameters. TTS NG improving predominantly regional kinetics of ischemic but non infarcted territories and thus improving EF at exercise.     

Aggravation of angina pectoris by two percent carboxyhemoglobin

A double-blind, randomized, crossover study was performed in 15 patients with stable angina to evaluate the effect of breathing carbon monoxide (CO), which raised the carboxyhemoglobin (COHb) from 1.09% to 2.02%, versus breathing compressed, purified air, which lowered the COHb from 1.07% to 1.00% on exercise duration until angina. The exercise duration until angina was 324.5 seconds in the air control period and 330.3 seconds after purified air compared to 321.7 seconds in the CO air control period and 289.7 seconds after CO. Breathing CO to raise the COHb from 1.09% to 2.02% caused a decrease in exercise duration until angina pectoris (p < 0.001) and a reduction in product of systolic blood pressure times heart rate at the onset of angina (p < 0.001). These data indicate that a 2% COHb level aggravates angina pectoris due to coronary artery disease.     

Improvement by oral metoprolol of exercise-induced ischemic dysfunction in patients with coronary heart disease

The effect of metoprolol on global left ventricular function during exercise was analyzed with nuclear ventriculography in 17 patients with ischemic heart disease. All had stable angina pectoris and ST-segment depression of more than 0.1 mV during treadmill exercise when not taking metoprolol. Each patient was stressed with supine bicycle exercise to the same load on a maintenance dose of metoprolol (100 mg X 2/day) and on a second occasion without the drug, the two being separated by 7 days. The mean heart rate and systolic blood pressure were significantly reduced both at rest and exercise with metoprolol. There was no significant difference of rest left ventricular ejection fraction with or without metoprolol. At exercise, however, every patient showed improvement of left ventricular function, the average left ventricular ejection fraction increasing by 14% (+/- 6) relative to the same exercise without metoprolol (p less than 0.001). We conclude that chronic metoprolol treatment in patients with ischemic heart disease can ameliorate left ventricular dysfunction induced by exercise and may thereby reduce myocardial ischemia.     

Comparative effects of nitroglycerin, nifedipine and metoprolol on regional left ventricular function in patients with one-vessel coronary disease

To compare acute effects of nitroglycerin (0.8 mg sublingually), nifedipine (5 ng/kg/min i.v.) and metoprolol (0.15 mg/kg i.v.) on normal, ischemic and scarred myocardial segments in man, we performed simultaneous hemodynamic and radionuclide measurements of left ventricular functions. Sixteen patients with isolated left anterior descending (LAD) disease were studied at rest and during exercise. Nine patients had angina and exercise-induced ischemia (LAD stenosis) and seven patients had previous transmural myocardial infarction and no ischemic changes during thallium imaging (LAD occlusion). The effects of the drugs on regional ejection fraction of the involved anteroseptal region and the normal posterolateral area were compared. Global ejection fraction at rest did not change after nitroglycerin, increased after nifedipine and decreased after metoprolol. In patients with ischemia, the exercise ejection fraction improved after all drugs due to increased regional ejection fraction in ischemic segments: i.e., a regional antiischemic effect evidenced by improved regional function could be demonstrated with all three agents. Regional ejection fraction increased from 35.8 +/- 19.5% to 66.2 +/- 15.2% (+/- SD) after nitroglycerin (p less than 0.001), to 61.7 +/- 8.7% after nifedipine (p less than 0.001), and to 48.4 +/- 7.0% after metoprolol (p less than 0.01). In regions of myocardial scar, regional ejection fraction was not changed after any drug. In normal areas, regional ejection fraction remained unchanged after nitroglycerin and nifedipine, but decreased after metoprolol. Despite similar antiischemic effects of all three drugs, underlying hemodynamic mechanisms were quite different and may provide a rationale for combined forms of treatment. These results may help to select optimal drug combinations to improve myocardial performance in patients with chronic ischemic heart disease.     

Differentiation between primary dilated cardiomyopathy and ischemic cardiomyopathy based on right ventricular performance.

The differentiation of primary dilated cardiomyopathy from ischemic cardiomyopathy, though important, is difficult clinically and may require coronary angiography or metabolic imaging. Both patient groups have severe left ventricular dysfunction and severe wall motion abnormality. This study examined the differences in right ventricular performance between the two groups. There were 90 patients with a left ventricular ejection fraction less than 30% who had coronary angiography and multigated radionuclide angiography (MUGA). Of these, 69 had ischemic cardiomyopathy and 21 had primary cardiomyopathy. The left ventricular ejection fraction was similar; 22 +/- 6% in ischemic cardiomyopathy and 21 +/- 6% in primary cardiomyopathy. However, the right ventricular ejection fraction was higher in ischemic cardiomyopathy (38 +/- 16% versus 29 +/- 12%, p less than 0.01). There were 59 patients with right ventricular ejection fraction greater than or equal to 30%, of whom 50 patients (85%) had ischemic cardiomyopathy. The left ventricular and right ventricular volumes were determined by a count-based method. The right ventricular end-diastolic volume/left ventricular end-diastolic volume ratio was 0.57 in ischemic cardiomyopathy and 1.07 in primary cardiomyopathy (p less than 0.05). Thus assessment of right ventricular function may help differentiate primary from ischemic cardiomyopathy; a preserved right ventricular performance is highly suggestive of ischemic cardiomyopathy.