Intracardiac electrophysiologic study of intravenous diltiazem and combined diltiazem-digoxin in patients

Fifteen patients without sinoatrial (SA) or atrioventricular (AV) node dysfunction underwent electrophysiologic study (EPS) before and after intravenous diltiazem: 0.20 mg/kg bolus followed by 0.0007 mg/kg/min infusion (seven patients) or 0.25 mg/kg bolus followed by 0.0012 mg/kg/min infusion (eight patients). In six patients intravenous digoxin (0.018 mg/kg) was given and 45 minutes later EPS was repeated while the diltiazem infusion continued. Diltiazem prolonged sinus cycle length (+7%, p < 0.01), lengthened AH conduction time (+22% in constant rate atrial paced rhythm, p < 0.001), prolonged AV node functional and effective refractory periods (+6%, p < 0.01 and +16%, p < 0.05, respectively), lengthened AV node Wenckebach cycle length (+13%, p < 0.001), shortened atrial functional refractory period (?3%, p < 0.05), and reduced mean arterial pressure (?8%, p < 0.005 in constant rate atrial paced rhythm). Subsequently, intravenous digoxin further prolonged sinus cycle length (+12%, p < 0.05), AH nonduction time (+17%, p < 0.05), AV node Wenckebach cycle length (+9%, p < 0.05), and AV node functional refractory period (+7%, p < 0.05), shortened atrial effective refractory period (?7%, p < 0.05) and ventricular effective refractory period (?6%, p < 0.05), and increased systolic arterial pressure (+6%, p < 0.05). Diltiazem and digoxin have additive depressant effects on SA and AV node function without significant adverse effects.     

Long-term study of high-dose diltiazem in chronic stable exertional angina

The efficacy of a calcium slow channel-blocking drug, diltiazem (360 mg/day), was compared to placebo in 15 men with exertional angina during a 21-week study. Symptom-limited exercise testing was used to evaluate the effects of the drug. Analysis of variance indicated the increase in the values of three time-related variables, time to onset of angina, time to onset of 1 mm ST depression, and total duration of exercise, were highly significant (all p < 0.001). The increase from the second week of placebo to the last week of diltiazem was 4 · 1 minutes for time to angina, 2 · 4 minutes for time to 1 mm ST depression, and 2 · 3 minutes for total duration. In addition, the differences between mean values of these variables for placebo and corresponding diltiazem period at weeks 3 and 4 were significant (p < 0.01, p < 0.01, p < 0.05) and for diltiazem week 20 and placebo week 21 were significant (p < 0.005, p < 0.01, p < 0.005). Weekly angina frequency was reduced from a mean of 17 episodes/week during placebo to one episode/week during diltiazem (p < 0.001). Submaximal pressure-rate product was reduced significantly during diltiazem (p < 0.001), and the ECG evidence of myocardial ischemia was reduced by diltiazem at submaximal (p < 0.02) and maximal exercise (p < 0.001). The drug was well tolerated and appears to be effective monotherapy for exertional angina.     

Improved exercise performance in persons with stable angina pectoris receiving diltiazem

The effects of diltiazem, a calcium antagonist drug, were compared with those of placebo on exercise performance during a series of symptom-limited upright exercise tests. Ten patients with chronic stable angina were studied over a period of 7 weeks. The drug was administered in a random double-blind fashion and was evaluated at increasing dose levels of 120, 180 and 240 mg/day. Diltiazem was effective in increasing the total duration of exercise (p <0.001) and the time to the first onset of angina (p <0.02) and to the first appearance of 1 mm of S-T depression (p <0.02). These effects were most marked at the highest dose level of diltiazem. The heart rate was reduced at rest (p <0.05) and during submaximal exercise (p <0.001). There was a reduction in diastolic blood pressure during submaximal exercise (p <0.04) but no change in systolic pressure. Pressure-rate product was significantly reduced at submaximal (p <0.001) but not maximal exercise. The reduction in pressure-rate product is postulated as the mechanism by which diltiazem enhances duration of exercise. There was no reduction in electrocardiographic evidence of myocardial ischemia at peak exercise by either clinical observation or computer analysis of spatial electrocardiographic variables. Five of the six patients who continued to take the drug maintained or improved their exercise performance on follow-up study 8 to 10 months later.     

Comparative effects of oral verapamil and propranolol on exercise-induced myocardial ischemia and energetics in patients with coronary artery disease: Single-blind placebo crossover evaluation using radionuclide ventriculography

Using multiple-gated equilibrium cardiac blood pool imaging and single-blind placebo crossover protocol, the effects of oral verapamil (VRP) (480 mg/day) were compared to those of oral propranolol (PRP) (320 mg/day) on the left ventricular ejection fraction (LVEF) and regional wall motion (RWM) abnormalities at rest and during supine bicycle exercise in 15 patients with coronary artery disease (CAD). During exercise on placebo before VRP the mean LVEF fell from the resting value of 0.54 ± 0.09 to 0.47 ± 0.12 (p < 0.05); on VRP (plasma level 283 ± 150 ng/dl and noverapamil 220 ± 97 ng/dl) the corresponding values were 0.54 ± 0.11 and 0.53 ± 0.13 (NS). On placebo before PRP, exercise reduced LVEF from 0.54 ± 0.13 to 0.48 ± 0.14 (p < 0.05); on PRP (plasma level 144 ± 59 ng/dl) the resting LVEF was 0.54 ± 0.11 and exercise LVEF 0.52 ± 0.13 (NS). Both drugs reduced the exercise-induced RWM (interoapical) abnormality and ST segment depression but the changes were only significant (p < 0.05) in the case of VRP. PRP attenuated the exercise-induced increase in heart rate by 24.5% (p < 0.005), in systolic blood pressure by 13.4% (p < 0.001), in diastolic pressure by 8.7% (p < 0.005), and in rate-pressure product by 34.5% (p < 0.001). VRP reduced the exercise heart rate response by 10.3% (p < 0.001), systolic pressure by 4.6% (NS), diastolic pressure by 7.9% (p < 0.005), and rate-pressure product by 14.6% (p < 0.001). These data suggest that VRP and PRP exhibit comparable potency in reducing the ischemic consequences of exercise stress in CAD patients. In the case of PRP, the beneficial effect was accountable in terms of reduction in oxygen demand; in the case of VRP, additional mechanisms such as those involving myocardial metabolism or primary changes in perfusion may be involved.     

Effects of diltiazem on cardiovascular responses during exercise in systemic hypertension and comparison with propranolol

Sixteen patients with uncomplicated systemic hypertension were treated with placebo, diltiazem (180 mg/day) and propranolol (60 mg/day) for 1 month each. Each patient performed multistage symptom-limited treadmill exercise tests during each period of administration. There was no significant difference in maximal exercise duration between placebo, diltiazem and propranolol. Diltiazem significantly decreased both systolic and diastolic blood pressure (BP) and heart rate at rest, during submaximal exercise at the same work load and maximal exercise. Propranolol produced similar changes in systemic BP and heart rate at rest and during exercise. However, the reductions in systolic BP, heart rate and pressure-rate product with diltiazem during exercise were smaller than those with propranolol at small doses, suggesting that diltiazem in its usual therapeutic dose was almost devoid of beta-blocking activity. Thus, diltiazem may be of benefit to hypertensive patients because it reduces systemic BP even during exercise. It is particularly useful when systemic hypertension occurs in association with coronary artery disease because of its effects of coronary artery dilatation and heart rate reduction.     

Comparison of Amlodipine and Long-Acting Diltiazem in the Treatment of Mild or Moderate Hypertension

The comparative effects of the once a day calcium channel antagonists amlodipine and long-acting diltiazem were assessed in a parallel design, investigator-blinded, multicenter trial in 123 patients with diastolic blood pressures ranging from 95 to 114 mm Hg before treatment. Patients were randomized to one of the two drugs and titrated at 2-week intervals to 5 or 10 mg of amlodipine or 180, 240, or 360 mg of long-acting diltiazem during a 10-week treatment period. Both drugs significantly reduced resting, sitting, standing, and 24-h ambulatory systolic and diastolic pressures. Amlodipine caused significantly greater reductions in sitting and standing systolic pressures, standing diastolic pressures, and 24-h ambulatory systolic and diastolic pressures versus diltiazem. Sitting systolic pressures were reduced from 151.9 ± 2.0 (SE) at baseline to 137.9 ± 1.8 mm Hg with amlodipine treatment and from 149.0 ± 2.1 to 145.1 ± 2.5 mm Hg with diltiazem. Sitting diastolic pressures were reduced from 100.2 ± 0.6 to 87.8 ± 1.0 mm Hg with amlodipine and from 101.1 ± 1.0 to 91.9 ± 1.1 mm Hg with diltiazem. Reductions in standing systolic pressures after treatment were −12.1 ± 1.5 mm Hg amlodipine v −4.6 ± 1.5 mm Hg diltiazem (P < .01), and reductions in standing diastolic pressures were −11.8 ± 0.9 mm Hg amlodipine v −8.6 ± 0.9 mm Hg diltiazem (P < .02). Heart rates did not change significantly with either drug during the study. Two subjects in each group dropped out because of adverse experiences. Although both agents were well tolerated and reduced blood pressures consistently over the 10-week test period, amlodipine was more effective than diltiazem in reducing systolic and diastolic blood pressures to the target pressures of <140 mm Hg systolic and <90 mm Hg diastolic over a range of doses widely used in clinical practice.     

Effects of nitroglycerin on supine and upright exercise in mitral stenosis

Resting, supine, and upright exercise hemodynamics were studied in 11 patients with pure or predominant mitral stenosis before and after 0.4 mg sublingual nitroglycerin. Resting mean pulmonary wedge pressure was reduced from 27 ± 1.6 to 21 ± 1.6 mm Hg (p < 0.001), while mean cardiac index (2.98 ± 0.40 vs 2.68 ± 0.30 cc/min/m²; NS) and mean heart rate (82 ± 4.4 vs 87 ± 6.7 bpm; NS) were unchanged after nitroglycerin. Resting mean left ventricular end-diastolic pressure dropped from 11 ± 1.7 to 8 ± 1.1 mm Hg (p < 0.02) after nitroglycerin, while stroke index (37 ± 5.1 vs 32 ± 3.8 mm Hg; NS) was unchanged. Left ventricular systolic pressure fell from 122 ± 6.0 to 111 ± 3.1 mm Hg (p < 0.001) after nitroglycerin. At peak supine exercise similar qualitative changes were observed. Mean pulmonary wedge pressure was lower after nitroglycerin (43 ± 2.3 vs 36 ± 2.1 mm Hg; p < 0.02), while cardiac index (3.62 ± 0.39 vs 3.4 ± 0.26 cc/min/m²; NS) and heart rate (116 ± 7.1 vs 113 ± 4.6 bpm; NS) were not different. Left ventricular end-diastolic pressure (13 ± 1.4 vs 10 ± 1.3; NS) was slightly but not significantly reduced by nitroglycerin. Left ventricular stroke index (34 ± 3.4 vs 31 ± 2.2 mm Hg; NS) was unchanged by nitroglycerin. Left ventricular systolic pressure (137 ± 7.3 vs 127 ± 6.1 mm Hg; p < 0.02) was reduced 10 mm Hg at peak supine exercise after nitroglycerin. During upright exercise, peak heart rate (160 ± 8.1 vs 160 ± 8.0 bpm; NS) and peak systolic blood pressure (117 ± 5.7 vs 112 ± 2.8 mm Hg; NS) were not changed with nitroglycerin. Exercise duration was improved after introglycerin (5.02 ± 0.62 vs 5.66 ± 0.65 minutes; p < 0.02). Thus sublingual nitroglycerin lowers mean pulmonary wedge pressure to reduce pulmonary congestive symptoms, improves supine exercise hemodynamics, and may enhance treadmill exercise duration in some patients with pure or predominant mitral stenosis.     

Improved efficacy of high-dose versus medium- and lowdose diltiazem therapy for chronic stable angina pectoris

The efficacy of therapy with diltiazem, 360 mg/day, was studied in 11 men with chronic, stable angina pectoris. An initial dose-titration schedule in which diltiazem was increased weekly from placebo to 120, 240 and 360 mg/day (Period I) was followed by a randomized, double-blind, 1-month crossover trial of placebo vs diltiazem at 360 mg/day (Period II). A computer-assisted treadmill exercise test was performed at the end of each dose and each 2-week crossover period. Diltiazem at 360 mg/day, compared with placebo (Period II), significantly improved exercise performance. Exercise duration to onset of chest pain increased 40% from 5.3 ± 2.1 to 7.4 ± 2.7 minutes (p < 0.01). Time to reach 1 mm of ST-segment depression increased 33%, from 5.1 ± 2.0 to 6.8 ± 1.8 minutes (p < 0.01). Total exercise duration increased 16%, from 7.5 ± 2.0 to 8.7 ± 2.0 minutes (p < 0.005). A computer-derived quantitative treadmill exercise score improved 27%, from ? 13.1 ± 9.4 to ? 9.5 ± 7.6 units (p < 0.005), and the ST-segment depression at peak exercise improved from ? 1.9 ± 1.1 to ? 1.6 ± 1.2 mm (p < 0.05). Progressive improvement in these variables was seen during the single-blind dose-titration period between 120 and 240 mg/day and between 240 and 360 mg/day (Period I). Baseline heart rate (HR) and diastolic blood pressure (BP) in the supine and upright position were significantly lower with diltiazem than with placebo. Diltiazem decreased the supine HR at rest from 67 ± 14 to 60 ± 10 beats/min (p < 0.05) and the upright HR at rest from 77 ± 14 to 69 ± 13 beats/min (p < 0.005). Diastolic BP at rest in the supine position decreased from 81 ± 6 to 75 ± 7 mm Hg (p < 0.05) and in the upright position from 82 ± 9 to 76 ± 8 mm Hg (p < 0.05). Thus, diltiazem improved exercise tolerance and exerciseinduced myocardial ischemia and showed good dose-response characteristics at doses as high as 360 mg/day in patients with stable angina pectoris.     

Reproducibility of equilibrium radionuclide ventriculography in patients with coronary artery disease: Response of left ventricular ejection fraction and regional wall motion to supine bicycle exercise

To evaluate the reproducibility of ejection fraction (EF) and regional wall motion (RWM) analyses by rest and exercise equilibrium radionuclide ventriculography (RNV) in the presence of coronary artery disease (CAD), 18 patients underwent two maximum, multistage supine bicycle exercise studies separated by an interval of 2 weeks. There were no significant differences in EF between the two studies, both at rest (56.0 ± 13.8% vs 58.2 ± 11.7%, p = NS) and with exercise (51.1 ± 17.6% vs 54.3 ± 17.6%, p = NS) and a highly significant correlation was shown between the two groups of values (rest r = 0.90, exercise r = 0.93, p < 0.001). There was no significant difference in the change from rest to exercise (?4.9 ± 12.0% vs ?3.8 ± 11.5%, p = NS) between the two studies and the correlation was highly significant (r = 0.69, p < 0.01). The interstudy variabilities were 2.2 ± 6.1% and 1.2 ± 7.3% for rest and exercise, respectively, and 2.0 ± 9.2% for the change from rest to exercise. Ninety-four percent of both rest and exercise regions had similar RWM. Eighty-one percent of the abnormally contracting regions were common to both exercise studies. Utilizing conventional criteria for the diagnosis of CAD, 11 patients had abnormal EF response and nine had abnormal RWM response to exercise on both studies. Combining EF and RWM criteria resulted in the diagnosis of CAD in 15 patients in both studies. We conclude that: (1) there were no significant differences in rest and exercise radionuclide EF and RWM between two supine bicycle exercise studies performed 2 weeks apart in patients with stable CAD and there were significant correlations between the two studies; (2) despite these correlations, the interstudy variabilities emphasize the need for the inclusion of reproducibility studies in all evaluations of interventions by exercise radionuclide ventriculography; and (3) the variations in EF and RWM response to exercise result in a lack of uniformity between the two studies regarding the diagnosis of CAD based on conventional RNV criteria.     

Hemodynamic and metabolic effects of diltiazem during coronary sinus pacing with particular reference to left ventricular ejection fraction

To determine the systemic and coronary hemodynamic effects of diltiazem at rest and during pacing, 14 patients with stable angina pectoris undergoing coronary angiography were studied before and after 0.165 mg/kg (n = 7) and 0.25 mg/kg (n = 7) of intravenously administered diltiazem. Hemodynamic variables, metabolic measurements and left ventricular (LV) ejection fraction (EF) were obtained at rest and during coronary sinus (CS) pacing before and during diltiazem administration. Lactate production during control pacing turned into extraction after diltiazem (p < 0.05). At rest, systemic resistance was reduced by 21% (p > 0.01) and mean arterial pressure by 12% (p < 0.01); cardiac index increased from 2.4 ± 0.4 to 2.6 ± 0.4 liters/min/m² (p < 0.01), with no significant change in heart rate. The mean pulmonary artery pressure increased from 17 ± 2 to 19 ± 3 mm Hg (p < 0.01), but other hemodynamic variables were not affected. Diltiazem given during pacing reduced the mean aortic pressure (from 112 ± 15 to 104 ± 15 mm Hg, p < 0.05), but other hemodynamic variables were not affected significantly. LVEF decreased 16%, from 0.63 ± 0.9 to 0.53 ± 0.8 with CS pacing (p < 0.01); when the pacing was performed after diltiazem administration the 8% decrease in LVEF from 0.64 ± 0.09 to 0.59 ± 13 was less marked (p < 0.01). Diltiazem had no significant effect on LVEF at rest. The overall data suggest that the ischemic manifestations of CS pacing are attenuated by diltiazem in doses of the drug that exert no significant depressant effect on LV function in patients with coronary artery disease.     

Acute Vascular Benefits of Finnish Sauna Bathing in Patients With Stable Coronary Artery Disease

BackgroundFinnish sauna bathing habits are associated with a decreased risk of cardiovascular mortality. The physiologic adaptations mediating this association remain to be fully elucidated. This study tested the hypothesis that Finnish sauna bathing acutely improves peripheral flow-mediated dilation (FMD) in middle-aged and older adults with stable coronary artery disease (CAD).MethodsTwenty-two adults (20 male, 2 female; 67 ± 10 years) with stable CAD underwent 2 periods of 10 minutes in a Finnish sauna (81.3 ± 2.7°C, 23 ± 3% humidity) separated by 10 minutes of thermoneutral rest. Before and 51 ± 8 minutes after sauna bathing, brachial artery FMD and postocclusive reactive hyperemia (PORH) were evaluated by means of Doppler ultrasound.ResultsSauna bathing increased core temperature (mean +0.66°C [95% CI 0.54-0.77], P < 0.01) and heart rate (+27 beats/min [24-29], P < 0.01), and decreased systolic (?19 mm Hg [?31 to ?6]; P < 0.01) and diastolic (?6 mm Hg [?11 to ?1], P < 0.01) blood pressures. Brachial artery FMD was greater after sauna bathing (+1.21% [0.16-2.26], P = 0.04), whereas PORH was unchanged (peak: +0.51 mL/min/mm Hg [?0.13 to 1.15], P = 0.11; area under the curve: +0.21 mL/mm Hg [?0.12 to 0.54]; P = 0.19).ConclusionsA typical Finnish sauna bathing session acutely improves peripheral FMD in middle-aged and older adults with stable CAD.     

Exercise training improves lipoprotein lipid profiles in patients with coronary artery disease

The effects of endurance exercise training on plasma lipoprotein lipids were determined in 10 men, ages 46 to 62 years, with coronary artery disease (CAD). Patients maintained body weight, health-related behaviors, and stable diets throughout the program. Training was at 50% to 85% of maximal oxygen consumption (V?O₂ max) for 40 to 60 minutes, 3 to 5 days/week for 29 ± 7 weeks. Training increased V?O₂ max (31 ± 19%, p < 0.001), reduced plasma cholesterol (C) (?8 ± 4%, p < 0.01), low-density lipoprotein-C (LDL-C) (?9 ± 9%, p < 0.01), and triglyceride (TG) (?13 ± 32%, p < 0.05) concentrations, and increased high-density lipoprotein-C (HDL-C) levels (11 ± 13%, p < 0.05) and $\text{HDL-C}\text{LDL-C}$ ratios (25 ± 20%, p < 0.01). Changes in LDL-C and V?O₂ max were correlated (r = ?0.73, p ± 0.01), while the changes in LDL-C and HDL-C each correlated inversely with pretraining lipoprotein levels (^rLDL-C = ?0.77, p < 0.01; ^rHDL-C = ?0.68, p < 0.05). Thus potentially “antiatherogenic” benefits of exercise seem to be due to a training effect, since they correlate best with changes in V?O₂ max and are maximal in patients with initially low V?O₂ max, high LDL-C, and low HDL-C levels.     

Effects of transluminal coronary angioplasty on left ventricular systolic and diastolic function at rest and during exercise

The left ventricular global and regional systolic function, ventricular volumes, and peak diastolic filling rate (PDFR) were studied in 30 patients with coronary artery disease, before and 2 to 5 days after transluminal coronary angioplasty (PTCA), utilizing equilibrium radionuclide angiography at rest and during exercise. At rest, the global ejection fraction (EF) was unchanged before (60 ± 9%) and after PTCA (62 ± 10%). During exercise, global EF increased from 59 ± 11% pre PTCA to 67 ± 10 post PTCA (p < 0.001). Twenty-two patients had abnormal EF response to exercise pre PTCA, versus seven post PTCA (p < 0.001). Improvements in exercise regional EF paralleled the changes in global EF. End-systolic volume was unchanged at rest but decreased significantly with exercise post PTCA (60 ± 36 ml pre vs 49 ± 32 ml post PTCA, p < 0.01). At rest, the PDFR was unchanged post PTCA (2.4 ± 0.9 end-diastolic volume (EDV)/sec pre vs 2.5 ± 0.8 EDV/sec post). During exercise, PDFR increased from 2.1 ± 0.7 EDV/sec pre PTCA to 2.5 ± 0.7 EDV/sec post PTCA (p < 0.02). In conclusion, in patients with coronary artery disease, successful PTCA improves global and regional systolic function during exercise. Diastolic function is improved during exercise, a fact not previously demonstrated.     

Influence of severity of ventricular dysfunction on hemodynamic responses to intravenously administered verapamil in ischemic heart disease

The effects of verapamil, 0.145 mg/kg body weight, administered intravenously in a bolus injection followed by 0.005 mg/kg per min, on cardiovascular hemodynamics and on ventricular ejection fraction, determined with gated cardiac blood pool scanning, were studted in 25 patients, 8 with acute myocardial infarction and 17 with symptomatic coronary artery disease who were undergoing diagnostic cardiac catheterization. The mean (± standard deviation) plasma verapamil level, determined with a gas liquid chromatographic technique utilizing a nitrogen detector, was 161 ± 47 ng/ml (n = 8) during steady state conditions of drug infusion. In 15 patients with stable coronary artery disease having a normal or moderately reduced ejection fraction, verapamil reduced mean arterial pressure (?16 percent, probability [p] < 0.001), systemic vascular resistance (?23 percent, p < 0.001), stroke work index (?13 percent, p < 0.02), with no significant change in pulmonary vascular resistance, ejection fraction or heart rate; cardiac index was increased (+11 percent, p < 0.001) as was the stroke volume index (+7 percent, p < 0.01) and mean capillary wedge pressure (+10 percent, p < 0.01). In the seven patients with uncomplicated infarction, there was no effect on ejection fraction, heart rate or pulmonary vascular resistance. There was a decrease in systemic vascular resistance (?22 percent, p < 0.01) and mean arterial pressure (?16 percent, p < 0.01) with an increase in cardiac index (+27 percent, p < 0.05), stroke volume index (+4 percent, p < 0.05) and mean capillary wedge pressure (+17 percent, p < 0.02). In three patients, one wlth acute infarction and two with coronary artery disease, having a severely reduced ejection fraction and elevated mean capillary wedge pressure (20 mm Hg or greater), mean arterial pressure decreased markedly with a fall in stroke volume index and an abrupt increase in the mean pulmonary capillary wedge pressure. These findings were associated with clinical evidence of heart failure and dyspnea.It is concluded that (1) in patients with cardiac disease having a mild to moderate decrease in left ventricular ejection fraction accompanied by a normal or mildly elevated mean pulmonary capillary wedge pressure, the intrinsic depressant effect of verapamil is offset almost entirely by its potent vasodilator proporties, but (2) in patients with a severely reduced ejection fraction and a high pulmonary capillary wedge pressure, the depressant effects of the compound become clinically apparent with sudden further increases in pulmonary capillary wedge pressure and a decrease in stroke volume and mean arterial pressure.     

Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 6. A comparison of pindolol and propranolol in treatment of patients with angina pectoris. The role of intrinsic sympathomimetic activity.

Pindolol, a new beta-adrenergic blocking drug with intrinsic sympathomimetic activity, and propranolol were given in increasing equipotent doses (pindolol: 2.5 to 10 mg. every 6 hours; propranolol: 10 to 40 mg. every 6 hours) over 12 weeks in a double-blind randomized trial to 41 patients with angina pectoris. The drugs were then gradually withdrawn over a two week period. With maximum doses, both pindolol and propranolol increased exercise capacity, compared to control, on multistage treadmill testing (pindolol: 8.0 ± 0.4 to 9.7 ± 0.3 mets, p < 0.01; propranolol: 8.0 ± 0.4 to 9.6 ± 0.3 mets, p < 0.05). At each exercise level both pindolol and propranolol decreased the heart rate, systolic blood pressure, and rate-pressure product (HR × BP). At the 9 met exercise level, the HR × BP decreased from 17,420 ± 850 to 13,205 ± 510 mm. Hg min.^?1 with pindolol (p < 0.002); with propranolol; 18,106 ± 440 to 13,205 ± 480 mm. Hg min.^?1 (p < 0.01). At the same level the magnitude of exercise-induced ECG ST depression decreased from 1.3 ± 0.3 to 0.4 ± 0.15 mm. with pindolol (p < 0.05), and from 1.3 ± 0.3 to 0.8 ± 0.2 mm. with propranolol (p < 0.05). Both drugs reduced the number of spontaneous attacks of angina pectoris per week. Pindolol did not appreciably decrease the resting heart rate (66.8 ± 1.9 vs 64.6 ± 1.2) or HR × BP (8,254 ± 418 vs 7,651 ± 210 mm. Hg min.^?1 in contrast to propranolol, which reduced both (heart rate: 70.5 ± 2.2 to 62.2 ± 2.4, p < 0.01; HR × BP: 8,677 ± 423 to 7,338 ± 455 mm. Hg min.^?1, p < 0.005). In addition, pindolol slightly increased the echocardiographically estimated ejection fraction at rest (0.59 ± 0.02 to 0.62 ± 0.02, p < 0.02), while propranolol depressed it (0.57 ± 0.02 to 0.51 ± 0.01, p < 0.04). Both pindolol and propranolol could be safely withdrawn over a gradual two week withdrawal interval.     

Reduction of exercise-induced ischemic regional myocardial dysfunction by verapamil in conscious dogs

The effects of verapamil on exercise-induced changes in left ventricular (LV) function were examined in nine conscious dogs in which an Ameroid constrictor and Doppler flow probe were placed around the left circumflex coronary artery. Ultrasonic crystals were implanted for measuring LV systolic wall thickness (SWTh) in control and ischemic regions, and a micromanometer measured high fidelity LV pressure. At 23 days (average) postoperatively, coronary collaterals had developed and complete cessation of coronary flow was confirmed by the flowmeter. Control treadmill exercise was then performed for 3.8 minutes at speed 12.1 km/hr and grade 5.3% (average). Two hours after oral administration of verapamil (120 to 160 mg), the same exercise bout was repeated. During the control runs, significant increases occurred in heart rate (101 to 243 bpm), LV end-diastolic pressure (13.3 to 27.5 mm Hg), peak LV pressure (129.8 to 165.7 mm Hg) and its first derivative (3140 to 6275 mm Hg/sec) with an increase of SWTh in control regions, while percent SWTh in ischemic regions decreased markedly (19.6% to 5.9%, p < 0.001); wall thickening velocity also decreased (0.90 to 0.44 SWTh/sec). During the runs after verapamil, the exercise heart rate was significantly lower than in the control run (221 ± 30 bpm), but other hemodynamic measures were similar. SWTh in control regions was unchanged, but exercise-induced dysfunction in the ischemic zone was substantially less (SWTh during exercise 11.5%, p < 0.01 compared to control runs) and wall thickening velocity did not fall. Thus verapamil can reduce regional LV dysfunction produced by exercise in collateral dependent zones, indicating a beneficial effect of this agent on stress-induced ischemia.     

Mechanisms of hemodynamic actions of furosemide: Differentiation of vascular and renal effects on blood pressure in functionally anephric hypertensive patients

To differentiate diuretic and direct cardiocirculatory properties of furosemide for elucidation of the vasodepressor mechanisms of action of the agent in the acute treatment of hypertension, the peripheral vascular effects of intravenous furosemide (3 mg/kg) on supine blood pressure (BP) and forearm hemodynamics in 11 functionally anephric hypertensive patients (creatinine clearance < 2 ml/min) were studied. BP was recorded by sphygmomanometer and forearm hemodynamics were measured by strain gauge plethysmography. While diastolic BP decreased only 2.7 mm Hg at 30 minutes, forearm blood flow increased 55% (p < 0.01) mediated by decreased peripheral vascular resistance of 30% (p < 0.01) at 15 minutes which dissipated by 30 minutes. Systolic BP, indices of venous capacity, weight, hematocrit, serum electrolytes, and plasma renin activity were unchanged. No diuresis occurred. It is concluded that the early hypotensive effect of furosemide depends upon diuresis.     

Efficacy of once daily penbutolol in chronic stable angina. An objective comparison with long-acting propranolol

The effects of penbutolol (40 mg daily) and long-acting propranolol (160 mg daily) were assessed in 26 patients with chronic stable angina in a placebo-controlled randomised double-blind crossover study with 2-weekly treatment periods. In addition to conventional subjective assessment, serial multistage treadmill exercise was used to obtain objective data on drug efficacy and 24-hr ambulatory electrocardiography performed for diurnal heart rate analysis. The mean exercise time of 6.3 ± 0.5 (SEM) min on placebo increased to 7.3 ± 0.6 min on penbutolol (P < 0.01) and to 7.9 ± 0.5 min on propranolol (P < 0.001). The pre-exercise resting heart rate was 73 ± 2 beats/min on placebo and decreased to 63 ± 2 beats/min on penbutolol (P < 0.001) and 58 ± 2 beats/min on propranolol (P < 0.001). The maximum exercise heart rate was similarly reduced by both drugs and there was a corresponding reduction in peak exercise double product. The time-corrected maximum ST segment depression was reduced by both drugs and neither produced a delay in ST segment recovery. Both drugs effected significant reductions in ambulatory maximum hourly heart rates throughout 24 hr. The lowest observed heart rate on penbutolol was 40 beats/min and 34 beats/min on propranolol. Penbutolol is an effective antianginal agent with a profile of action similar to that of propranolol.     

Aneurysmectomy and endocardial resection for ventricular tachycardia: Favorable hemodynamic and antiarrhythmic results in patients with global left ventricular dysfunction

Sixty-two patients underwent aneurysmectomy and endocardial resection for control of recurrent sustained ventricular tachycardia (VT). Forty patients also had coronary artery bypass grafting (CABG) (1.5 grafts per patient). The mean preoperative left ventricular end-diastolic pressure (LVEDP) was 18 ± 8 mm Hg, cardiac index (Cl) was 2.7 ± 0.7 L/min/m², and ejection fraction (EF) was 28 ± 10%. In a subset of 32 patients with clearly demarcated aneurysmal and contracting ventricular sections, the mean EF of the residual contracting section (CSEF) was 35 ± 13%, and 26 of these patients had a CSEF < 45%. There were five operative deaths (8%). No hemodynamic findings distinguished the patients who died during surgery. Patients with an LVEDP above the group mean or an overall EF below the group mean had an operative mortality of 10% and 7%, respectively. In the subgroup of 26 patients with a CSEF < 45%, the operative mortality was 12%. In the surgical survivors as a whole the LVEDP decreased from 17 ± 8 to 14 ± 5 mm Hg (p < 0.005) and the overall EF increased from 28 ± 9% to 39 ± 10% (p < 0.001) while the normal CI did not change. Linear regression analysis revealed that patients with the highest preoperative LVEDPs and the lowest overall EFs were most likely to have improvement in these parameters postoperatively. Patients with a preoperative CSEF < 45% had similar postoperative changes in their LVEDP (17 ± 6 to 15 ± 4 mm Hg) and overall EF (24 ± 7% to 38 ± 11%). In addition, the incidence of inducible VT postoperatively was similar in patients with a preoperative CSEF < 45% (4 of 23) and in the rest of the group (8 of 34, p = NS). We conclude that: (1) patients with ventricular aneurysms and medically refractory VT often have marked dysfunction of the residual contracting LV section; (2) aneurysmectomy and endocardial resection is an effective mode of therapy for VT and can be performed with a low operative mortality in this patient population; and (3) postoperatively the angiographic EF usually increases and the LVEDP often decreases, especially in patients with the most marked preoperative LV dysfunction.     

Diltiazem versus propranolol in essential hypertension: responses of rest and exercise blood pressure and effects on exercise capacity

Both beta-blocking and calcium channel-blocking drugs are being used with increasing frequency as initial therapy for essential hypertension. The present study was designed to compare the antihypertensive effects of a beta-blocking drug, propranolol, with a calcium channel-blocking drug, diltiazem, at rest and during upright bicycle exercise and to determine whether exercise capacity is altered by these therapies. Twenty-one patients with uncomplicated systemic hypertension and a diastolic blood pressure (BP) of 95 to 110 mm Hg without medication were randomly assigned to propranolol or diltiazem therapy in a double-blind manner. The total daily dosages were titrated as needed, from 160 to 480 mg of propranolol (mean 371 mg) and 120 to 360 mg of diltiazem (mean 307 mg) over 12 weeks, and the titrated dose was maintained for 4 additional weeks. Both drugs significantly reduced supine BP (from 149 +/- 14/101 +/- 4 to 136 +/- 17/89 +/- 10 mm Hg with propranolol and from 157 +/- 14/103 +/- 4 to 144 +/- 13/93 +/- 8 with diltiazem. Only diltiazem reduced BP during submaximal exercise, but both agents produced significant responses during maximal exercise. Diltiazem had no effect on maximal heart rate, exercise duration or O2 uptake, whereas propranolol reduced maximal VO2 from 27 +/- 6 to 22 +/- 6 ml/min/kg (p less than 0.01) and also shortened duration of exercise. Propranolol, despite its effects on heart rate, maintained the workload VO2 relation at submaximal loads, suggesting an increased oxygen delivery. However, these adaptive mechanisms appear to be insufficient during maximal effort.