Effect of chronic oral digoxin therapy on ventricular function at rest and peak exercise in patients with ischemic heart disease: Assessment with equilibrium gated blood pool imaging

The effect of chronic digoxin therapy on left ventricular ejection fraction, left ventricular volumes and cardiac output was assessed using multigated blood pool imaging both at rest and during supine exercise in 14 patients with known ischemic heart disease. Digoxin had no significant effect on ejection fraction at rest or at peak exercise. Neither exercise nor digoxin therapy had a significant influence on stroke volume index. Cardiac index was also not significantly influenced by digoxin either at rest (3.1 ± 1.15 without digoxin versus 2.9 ± 1.03 liters/min per m² during digoxin therapy) or at peak exercise (5.1 ± 2.08 versus 5.1 ± 2.04 liters/min per m², respectively), although the increase in heart rate resulted in a significant increase in cardiac index with exercise in each state (p <0.01).End-diastolic and end-systolic volume indexes both tended to be smaller at rest after digoxin therapy than before, but this difference was not significant. In the eight patients with an ejection fraction at rest of less than 0.50 (range 0.15 to 0.47), both end-diastolic and end-systolic volume indexes increased significantly with exercise (p <0.05) irrespective of therapy with digoxin. Conversely, in the six patients with a well preserved (greater than 0.50) ejection fraction at rest, digoxin prevented the exerciseinduced increase in end-diastolic and end-systolic volume indexes, and at peak exercise end-systolic volume index was significantly smaller during digoxin therapy than before it (p <0.05).It is concluded that chronic digoxin therapy in patients with stable ischemic heart disease (1) does not have a significant deleterious functional effect on the nonfailing heart, and (2) does not result in a significant change in left ventricular function at rest, but that it (3) does provide improved ventricular function at peak exercise in patients with well preserved left ventricular function at rest.     

Global and regional left ventricular response to bicycle exercise in coronary artery disease. Assessment by quantitative radionuclide angiocardiography.

The left ventricular response to bicycle exercise was evaluated in 60 patients with coronary artery disease and in 13 normal control subjects. Left ventricular ejection fraction, mean normalized ejection rate and regional wall motion were determined using first-pass radionuclide angiocardiograms obtained at rest and again during peak graded bicycle exercise. All normal subjects demonstrated improved left ventricular function with exercise. Left ventricular ejection fraction increased significantly from 67 ± 3 per cent (mean ± SE) at rest to 82 ± 4 per cent with exercise (p < 0.001). Similarly, the left ventricular ejection rate increased significantly from 3.47 ± 0.31 sec^?1 to 6.53 ± 0.42 sec^?1(p < 0.001). In contrast, in 44 of 60 patients with coronary artery disease, the ejection fraction or ejection rate either decreased or remained the same with exercise. New or exaggerated regional wall motion abnormalities were detected in 28 of 60 patients with coronary artery disease. Over-all, global or regional evidence of compromised left ventricular reserve was found in 48 of 60 patients with coronary artery disease.The major determinant of an abnormal left ventricular response to exercise was the presence or absence of electrocardiographic evidence of myocardial ischemia. Left ventricular ejection fraction decreased or remained the same with exercise in all patients with coronary artery disease and electrocardiographic ischemia. New regional wall motion abnormalities were detected in 20 of these patients. In this group, the left ventricular ejection fraction decreased from 66 ± 2 per cent at rest to 58 ± 2 per cent with exercise (p < 0.001), whereas the ejection rate was unchanged by exercise (rest 3.33 ± 0.21 sec^?1; exercise 3.34 ± 0.22 sec^?1, p > 0.05). Of the 30 patients with coronary artery disease who exercised to symptom-limiting fatigue without electrocardiographic ischemia, 18 demonstrated compromised left ventricular reserve with exercise. Twelve of the remaining patients with coronary artery disease had normal left ventricular reserve, in eight of whom ventricular function was completely normal both at rest and during exercise. In this group exercised to fatigue, the left ventricular ejection fraction increased from 53 ± 4 per cent at rest to 58 ± 2 per cent with exercise (p < 0.001). The ejection rate also increased from 2.48 ± 0.24 sec^?1 to 3.67 ± 0.39 sec^?1 (p < 0.001). The direction and magnitude of the left ventricular responses to exercise were not affected by long-term oral propranolol administration in 22 patients. Based upon either abnormal exercise left ventricular reserve or abnormal global and regional left ventricular function at rest, the over-all sensitivity of this radionuclide technic for the detection of coronary artery disease was 87 per cent (52 of 60 patients). These data demonstrate that exercise ventricular performance studies provide important physiologic insights into left ventricular functional reserve as well as a sensitive noninvasive approach for the detection of coronary artery disease.     

Verapamil in stable effort angina: Effects on left ventricular function evaluated with exercise radionuclide ventriculography

A double blind placebo-controlled study was performed in 12 patients with stable angina pectoris to evaluate the effects of oral verapamil (320 mg/day) on left ventricular function, as measured at rest and during exercise with gated equilibrium radionuclide ventriculography. On verapamil, patients had a lower heart rate-blood pressure product at each work load than with placebo. Anginal threshold increased by 28 ± 19 watts (p < 3.005), and maximal exercise capacity increased by 20 ± 14 watts (p < 0.001) with verapamil, but the rate-pressure product at the onset of angina and at maximal exercise was unchanged. Left ventricular ejection fraction at rest during verapamil therapy was the same as with placebo therapy. On exercise during placebo therapy, the ejection fraction decreased from 40 ± 9 to 35 ± 11 percent (p < 0.025) because end-systolic volume increased disproportionately compared with end-diastolic volume. On exercise during verapamil therapy, the ejection fraction did not decrease (44 ± 8 versus 45 ± 12 percent) and was significantly higher at identical work loads than on placebo because of a smaller increase in end-systolic volume. Oral verapamil is effective treatment for effort angina and may prevent the decrease in left ventricular ejection fraction due to exercise-induced ischemia.     

The cardiac response to exercise training: Echocardiographic analysis at rest and during exercise

The effect of exercise training on left ventricular dimensions at rest and during steady state exercise was studied. Fourteen healthy sedentary students were studied with echocardiograms performed at rest and during the 3rd minute of supine bicycle exercise (300 kilopond-meters/min) before and after 14 weeks of vigorous interval bicycle training. Ventricular dimensions at end-systole and end-diastole were measured and stroke dimension and dimensional shortening (stroke dimension/end diastolic dimension) were calculated. Maximal rate, measured before training during maximal exercise testing, oxygen consumption increased 31 percent ± 6 (mean ± standard error of the mean); heart rate decreased 9 ± 3 percent at rest and 11 ± 3 percent during exercise (p < 0.05). Blood pressure was not significantly changed at rest or during exercise. Training was associated with an increase in end-diastolic dimension at rest (from 4.7 ± 0.11 to 5.0 ± 0.11 cm) (p < 0.05) with no change noted in end-systolic dimension. Stroke dimension at rest was increased (from 1.4 ± 0.05 to 1.7 ± 0.05 cm) (p < 0.05) as was dimensional shortening (0.32 + 0.01 to 0.35 ± 0.01) (p < 0.05). Exercise before and after training was associated with an increase in stroke dimension mediated by a decrease in end-systolic dimension. End-diastolic dimension remained constant and dimensional shortening increased 15 ± 6 percent.Exercise was associated with an increase in stroke volume mediated by an increase in contractility. The Frank-Starling effect was not demonstrable. Training resulted in increased stroke volume at rest mediated by enhanced preload (Frank-Starling effect) and increased dimensional shortening, unexplained by a decrease in blood pressure. Exercise after training was associated with an increase in stroke dimension and dimensional shortening from the higher value at rest. These changes are suggestive of an enhanced contractile state at rest and during exercise consequent to training.     

Effect of nifedipine on exercise-induced left ventricular dysfunction and myocardial hypoperfusion in stable angina

To assess the effects of nifedipine on left ventricular function and regional myocardial perfusion, exercise radionuclide ventriculography was performed in 15 men (median age 59 years) and exercise thallium-201 scintigraphy was done in 11 of them, before and 90 minutes after the oral administration of 20 mg of nifedipine. All patients had stable angina and angiographically proved coronary artery disease without evidence of spasm. Exercise tolerance after administration of nifedipine increased from 343 ± 42 seconds to 471 ± 50 seconds (p < 0.01), whereas the peak exercise double product remained essentially unchanged (difference not significant). Ejection fraction improved significantly at rest (from 49 ± 3.6% to 52 ± 3.3%, p < 0.05) and at peak exercise (42 ± 3.3% to 47 ± 3.7%, p < 0.05). Nifedipine also resulted in an improved segmental wall motion score (4.3 ± 2.3 to 3.0 ± 2.3, p < 0.05; 0 = normal and 4 = worst degree of dysfunction). The ejection fraction increased by more than 5% in one third of the patients at rest, and in more than half of the patients at peak exercise. Improved exercise myocardial perfusion occurred in 5 of 11 patients (45%) and in 7 of 28 segments (25%) with reversible hypoperfusion. Thus, nifedipine produces significant improvement in global and regional left ventricular function in patients with coronary artery disease and stable angina. This may be accounted for, at least in part, by improvement in myocardial perfusion.     

Effect of nitrates on left ventricular size and function during exercise: Comparison of sublingual nitroglycerin and nitroglycerin paste

To compare the effects of sublingual nitroglycerin and nitroglycerin paste on left ventricular size and performance during supine bicycle exercise, equilibrium radionuclide angiography was performed in 36 persons classified into two groups of normal subjects and two groups of patients with angiographically proved coronary heart disease. Each group underwent a control exercise study, and then one group of normal subjects and one group of patients were restudied after the administration of 0.6 mg of nitroglycerin or 2 inches (5 cm) of nitroglycerin paste (but not both). Data were collected at rest and at peak exercise.In normal subjects exercise resulted in increased ejection fraction, decreased end-systolic volume and little change in end-diastolic volume. After either drug, volumes at rest markedly decreased, and during exercise, ejection fraction increased to levels comparable with pre-drug levels. After nitroglycerin paste the reduction in volume seen at rest persisted during exercise, but after sublingual nitroglycerin end-diastolic volume increased during exercise (88 ± 43 to 113 ± 30 ml [mean ± standard deviation]; p < 0.01). Peak exercise end-diastolic volume after nitroglycerin was still lower than that before nitroglycerin (113 ± 30 versus 120 ± 28 ml, p < 0.05).In patients with coronary disease, ejection fraction did not change during exercise, but both end-diastolic and end-systolic volumes increased. After either drug ejection fraction at rest was unchanged, although ventricular volumes were markedly lower (p < 0.05). Ejection fraction increased with exercise in both groups with coronary disease after either drug. After sublingual nitroglycerin, volumes increased during exercise although the peak exercise end-diastolic volume was still lower than the control value (113 ± 31 versus 145 ± 34 ml; p < 0.01). After paste administration, end-diastolic volume did not change during exercise, and end-systolic volume decreased (41 ± 20 to 36 ± 22 ml; p < 0.05).Thus, sublingual nitroglycerin and nitroglycerin paste improved left ventricular function during exercise. The effect of paste on end-diastolic volume appeared sustained, whereas that of sublingual nitroglycerin was transient, confirming the hypothesis that reduction in end-diastolic volume and, by implication, left ventricular wall tension, is a major mechanism of nitrate action.     

Amrinone and exercise performance in patients with chronic heart failure

Whether cardiotonic agents can improve the ability of patients with chronic heart failure to exercise remains unknown. Accordingly, the circulatory and respiratory response of 11 patients with severe heart failure refractory to digitalis, diuretic drugs and vasodilators was assessed during upright treadmill exercise before, within 24 hours and after 4 weeks of therapy with amrinone. The purpose of this study was to determine the ability of amrinone therapy to improve exercise hemodynamics, effort tolerance and aerobic capacity of these patients. Acute intravenous administration of amrinone (1.8 ± 0.1 mg/kg body weight) produced the following changes (mean values ± standard error of the mean) in hemodynamic variables during supine rest; increased cardiac index (from 2.04 ± 0.39 to 2.99 ± 0.38 liters/min per m²; p <0.01) and reduced pulmonary wedge pressure (from 24 ± 6 to 14 ± 6 mm Hg; p <0.01) without altering heart rate or mean arterial pressure. Within 24 hours after administration of amrinone, wedge pressure decreased at the onset of (from 25 ± 7 to 14 ± 7 mm Hg) and throughout exercise (p <0.01), whereas the exercise response of cardiac output, arteriovenous oxygen difference, heart rate, pulmonary and systemic vascular resistances, maximal oxygen uptake and the pattern of ventilation remained similar to control values. However, after 4 weeks of amrinone therapy, exercise and aerobic capacities were increased 44 and 48 percent (p <0.03), respectively, whereas the ventilatory response was unchanged. Thus, amrinone is a potent cardiotonic agent that acutely improves the function of the failing heart at rest and during exercise; the maximal aerobic capacity was increased after 4 weeks of therapy. Amrinone therefore appears to hold promise for the management of patients with chronic heart failure.     

Long-term amrinone therapy in patients with severe heart failure: Drug-dependent hemodynamic benefits despite progression of the disease

Six patients with severe congestive heart failure refractory to conventional therapy, including vasodilators, were treated with oral amrinone for a mean duration of 41 weeks (range 20 to 72 weeks). At initiation of therapy, the cardiac index increased from 1.74 ± 0.31 to 2.62 ± 0.52 (mean ± SD) liters/min/m² (p < 0.01) and pulmonary capillary wedge pressure decreased from 26.5 ± 3.5 to 19.5 ± 5.4 mm Hg (p < 0.05). Symptoms were alleviated and exercise capacity increased from 5.9 ± 3.9 to 11.5 ± 4.5 minutes (p < 0.05). During long-term therapy, exercise capacity remained constants in three patients whereas it decreased in three others. All patients demonstrated an increase in heart size. Withdrawal of amrinone therapy precipitated severe symptoms at rest and hemodynamic deterioration in all patients. The cardiac index decreased from 1.87 ± 0.49 to 1.32 ± 0.30 liter/min/m² (p < 0.05) and pulmonary capillary wedge pressure rose from 20.6 ± 2.9 to 28.8 ± 5.6 mm Hg (p < 0.05). These changes were reversed by reinstitution of therapy. Thus, amrinone-dependent hemodynamic benefits were demonstrated during long-term therapy without tachyphylaxis. In addition, progression of the underlying cardiac disease was observed in every patient.     

Influence of verapamil therapy on left ventricular performance at rest and during exercise in hypertrophic cardiomyopathy

To determine the hemodynamic effect of verapamil at rest and during exercise, 18 patients with hypertrophic cardiomyopathy were studied before and after 7 weeks of treatment with oral verapamil (maximal dose, 720 mg/day). At rest and at peak exercise, verapamil produced a significant increase in left ventricular (LV) systolic performance in terms of stroke volume index (rest, from 43 ± 11 to 53 ± 11 ml/m², p < 0.001; exercise, from 46 ± 11 to 51 ± 10 ml/m², p < 0.01), whereas heart rate decreased (rest, from 81 ± 14 to 70 ± 11 min^?1, p < 0.001; exercise, from 150 ± 21 to 141 ± 18 min^?1, p < 0.01). Cardiac index at rest and during exercise remained unchanged. Systolic vascular resistance did not change at rest, but decreased significantly during exercise (974 ± 243 to 874 ± 174 dynes s cm^?5; p < 0.05). After verapamil administration, pulmonary artery pressures did not change at rest, but decreased significantly during exercise. This was probably due to a shift in the LV pressure-volume relation. The improvement in LV hemodynamics was associated with a significant increase in exercise capacity. The findings of this study indicate that in patients with hypertrophic cardiomyopathy, hemodynamic improvement at rest and during exercise can be achieved by chronic administration of verapamil.     

Systolic and diastolic properties of the human left ventricle during valve replacement for chronic mitral regurgitation

M mode and two dimensional echocardiography were combined with pressure-flow data to analyze systolic mechanics and diastolic compliance in nine patients during valve replacement for chronic mitral regurgitation. Both M mode (six patients) and two dimensional (four patients) echographic analyses revealed large decreases in early postoperative shortening fraction (?24 ± 17 [standard deviation]percent M mode study, p < 0.01; ?30 ± 12 percent two dimensional study, p < 0.02), which were significantly different from small changes observed in control subjects (M mode study, + 7 ± 10 percent, 25 subjects and two dimensional study, ?7 ± 14 percent, 8 subjects). Additional data suggest that left ventricular compliance is increased in chronic mitral regurgitation and that elimination of the low impedance left atrial pathway by valve replacement is associated with a significant increase in wall stress (five patients, p < 0.02) that appears to be responsible for the decreased ejection fraction postoperatively. Analysis of hemodynamic variables other than ejection fraction and rate of circumferential shortening revealed no difference between five postoperative patients with chronic mitral regurgitation and five with coronary artery disease. These results in human subjects confirm predictions from studies in animal models and suggest that unique properties of chronic mitral regurgitation demand special attention when patients with this condition are being evaluated for surgery.     

Effects of digoxin on left ventricular function in coronary artery disease patients

To assess whether digitalis modifies or prevents the deterioration of the left ventricular ejection fraction and wall motion during acute ischemia, we performed gated blood pool radionuclide ventriculograms in 15 patients with angiographically documented coronary artery disease. All patients were studied in the resting state and during maximal supine bicycle exercise, both before and 1 hour after 1 mg intravenous digoxin.There was no significant difference, pre-digoxin vs post-digoxin, in exercise tolerance (415 ± 84 vs 418 ± 107 seconds), number of segments with abnormal resting wall motion (12 vs 11) or exercise wall motion (21 vs 19). Ten patients developed angina during the same exercise load, irrespective of digoxin administration. Twelve patients had subnormal left ventricular ejection fraction during exercise pre-digoxin, vs 13 patients post-digoxin (P = ns). In the resting state, the left ventricular ejection fraction was higher after digoxin (53 ± 14% pre vs 58 ± 14% post, P < 0.05). During exercise, however, the left ventricular ejection fraction was not significantly improved after digoxin (50 ± 16% pre vs 53 ± 17% post, P = ns).These data indicate that although acute administration of digoxin improves the resting left ventricular function, it does not improve exercise tolerance to angina. Furthermore, intravenous digoxin does not appear to prevent the deterioration of left ventricular wall motion and ejection fraction during exercise induced ischemia.     

Left ventricular response to isometric exercise and its value in predicting the change in ventricular function after mitral valve replacement for mitral regurgitation

Reduced left ventricular (LV) afterload and its effect on the resting ejection fraction may lead to over-estimation of LV function in mitral regurgitation (MR). To evaluate LV function during increased afterload of the heart, an isometric handgrip test was performed during cardiac catheterization in 15 patients with mitral regurgitation (MR group) and in 9 normal subjects (normal group). Twelve months after successful mitral valve replacement (MVR) the patients were recatheterized, and the value of preoperative stress testing in predicting the change in resting ventricular function after surgery was estimated.Isometric exercise caused an increase in end-systolic wall stress, a measure of ventricular afterload, in both the MR group and the control group (p < 0.001). The ejection fraction remained unchanged in the control group, but decreased from 0.58 ± 0.08 to 0.53 ± 0.08 in the MR group (p < 0.001). After MVR, end-systolic wall stress increased significantly (p < 0.001) and the ejection fraction decreased from 0.58 ± 0.05 to 0.51 ± 0.1 (p < 0.05). A positive correlation existed between the change in the ejection fraction during preoperative stress testing and the change in the resting ejection fraction after MVR (r = 0.65, p < 0.01). In 8 patients whose resting ejection fraction was within normal limits (> 0.55) preoperatively, the ejection fraction was depressed (< 0.55) 1 year after surgery. In all but 1 of these patients the isometric exercise revealed the reduced ventricular response to afterload stress preoperatively (decrease of the ejection fraction > 0.03 during exercise). Therefore, the isometric exercise-induced change in LV function appears to predict the influence of MVR on LV function.     

Exercise left ventriculography utilizing intravenous digital angiography

Exercise left ventriculography has been shown to be a sensitive and specific tool for the detection of coronary artery disease. At the present time, such studies require radionuclide-base methods. Computer-based techniques recently have been shown to provide high resolution images of the left ventricle when the levophase of an intravenous injection of radiopaque contrast medium is imaged with fluoroscopy. To evaluate the possible efficacy of using "intravenous digital subtraction left ventriculograms" in exercise ventriculography, such ventriculograms were performed at rest and during maximal supine bicycle exercise in 31 patients. Studies that could be analyzed were obtained in 29 patients. In 21 patients with coronary artery disease, ejection fraction was 58% at rest and 45% with exercise (p less than 0.001 vs. rest). In contrast, in seven patients with no coronary artery disease, ejection fraction was 65% at rest and 69% with exercise (difference not significant). In a subgroup of 8 patients with "severe" coronary obstruction, the change in ejection fraction from rest to exercise was -18%, while in the remaining 13 patients with less severe disease, it was -9% (p less than 0.001). All patients with coronary artery disease manifested new or worsening segmental wall abnormality with exercise, compared with two of seven patients without coronary disease (p less than 0.01). Sixteen patients underwent rest and exercise radionuclide cineangiography in addition to digital subtraction angiography. There was a strong correlation between the two techniques for ejection fraction at rest (r = 0.78, p less than 0.001), ejection fraction and with exercise (r = 0.83, p less than 0.001) and change in ejection fraction from rest to exercise (r = 0.88, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of propranolol and timolol on left ventricular volumes during exercise in patients with coronary artery disease

The hemodynamic effects of beta-receptor blocking agents on the ejection fraction of patients with coronary artery disease during exercise have been studied previously using radionuclide techniques. Left ventricular volume measurements and the peak systolic pressure/end-systolic volume (PSP/ESV) index have been shown to be variables of left ventricular function that are less influenced by preload and afterload than is ejection fraction. Left ventricular volumes and PSP/ESV were therefore measured in 18 patients with proven coronary artery disease in the control state and after 2 weeks of daily maintenance therapy with either 240 mg propranolol or 60 mg timolol. Values at rest and during symptom-limited upright exercise were compared using the first pass technique and a multicrystal scintillation camera. Left ventricular volumes were measured by the area-length method. Because there was no difference between the propranolol and timolol groups, the results for both groups were combined. The ejection fraction at rest after beta-receptor blocker treatment was not significantly different from pretreatment measurements because of an increase in both end-diastolic and end-systolic volumes (p less than 0.01). However, the value for peak systolic pressure/end-systolic volume (PSP/ESV) index at rest was lower after treatment. The exercise ejection fraction was greater after treatment (p less than 0.01), owing to an increase in end-diastolic volume and unchanged end-systolic volume. In addition, there was a significant improvement in the directional change in the PSP/ESV ratio between rest and exercise from pretreatment to treatment (-1.1 +/- 2.5 to +0.2 +/- 1.2, p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in left ventricular volumes and ejection fraction at rest and during exercise in patients with aortic regurgitation

This study was performed (1) to determine the changes in left ventricular volumes during exercise in patients with aortic regurgitation, and (2) to evaluate the importance of these alterations in characterizing left ventricular function in these patients. In 15 normal subjects (Group I) and in 17 patients with aortic regurgitation (Group II), left ventricular end-diastolic volume index, end-systolic volume index, ejection fraction and the ratio of peak systolic blood pressure to end-systolic volume index were measured at rest and during supine exercise. The patients with aortic regurgitation were classified into two groups on the basis of symptoms and chest radiographs: Group IIA, minimal or no symptoms, no cardiomegaly or pulmonary venous congestion; Group IIB, definite symptoms, with cardiomegaly and pulmonary venous congestion. Patients with aortic regurgitation had greater left ventricular end-diastolic and end-systolic volume indexes at rest and during exercise (p <0.05) than did normal subjects. During exercise, left ventricular end-diastolic volume index increased in normal subjects (53 ± 13 ml/m² [mean ± standard deviation] at rest, 67 ± 18 ml/m² during exercise, p <0.01), demonstrated a heterogeneous response in patients in Group IIA and increased in patients in Group IIB (180 ± 96 ml/m² at rest, 209 ± 102 ml/m² during exercise, p <0.05). During exercise, left ventricular end-systolic volume index decreased in normal subjects (18 ± 5 ml/m² at rest, $\text{15}\text{\$}\text{?}\text{6}$ ml/m² with exercise, p <0.01), increased in patients in Group IIB (82 ± 60 ml/m² at rest, 118 ± 93 ml/m² during exercise, p <0.05), and showed a variable response in those in Group IIA. At rest, left ventricular ejection fraction was similar in the three groups, but during exercise it increased in Group I (0.71 ± 0.07 at rest, 0.82 ± 0.07 with exercise, p <0.001), was unchanged in Group IIA and decreased in Group IIB (0.59 ± 0.15 at rest, 0.50 ± 0.16 during exercise, p <0.05). During exercise, there was an inverse relation between changes in left ventricular ejection fraction and endsystolic volume, but no relation between changes in end-diastolic volume and ejection fraction. Changes in the systolic pressure-volume ratio provided no more information than changes in end-systolic volume alone. Thus, abnormal alterations in left ventricular volumes occur during exercise in patients with aortic regurgitation and may be helpful in the further characterization of left ventricular performance in these patients.     

Sustained beneficial effects of oral amrinone on cardiac and renal function in patients with severe congestive heart failure

Although effectiveness of oral amrinone has been demonstrated in animals, amrinone has been shown in human subjects to improve cardiac performance in the failing heart only after acute intravenous administration. Therefore, we studied the hemodynamic and renal effects of orally administered amrinone (50 to 300 mg) in 10 patients with advanced congestive heart failure. Cardiac index increased from 1.56 ± 0.41 (mean ± standard deviation) to 2.20 ± 0.43 liters/min per m² (p < 0.001); pulmonary wedge pressure decreased from 26.1 ± 5.7 to 17.0 ± 5.7 mm Hg (p < 0.001). Mean arterial pressure decreased from 86.0 ± 8.4 to 81.3 ± 7.7 mm Hg (p < 0.001) and systemic vascular resistance from 2,406 ± 603 to 1,693 ± 261 dynes sec cm^?5 (p < 0.001). Heart rate was unchanged. The onset of action ranged from 30 to 120 minutes and the duration of action from 4 to 7 hours after a single oral administration. After 24 hours of continuous therapy, no tachyphylaxis to amrinone was observed. A correlation (r = 0.62, p < 0.001) was found between the oral dose of amrinone and the percent increase in cardiac index. Left ventricular ejection fraction, determined in five patients, increased from 14 ± 8 to 21 ± 8 percent (p < 0.01). Effective renal plasma flow, measured in six patients, increased from 186.0 ± 72.0 to 231.1 ± 88.8 ml/min (p < 0.05) and the glomerular filtration rate from 82.2 ± 14.9 to 110.0 ± 20.6 ml/min (p < 0.05). Thus, this study demonstrates the cardiotonic efficacy of orally administered amrinone in human subjects and recommends its further investigation as a therapeutic agent for the continued treatment of congestive heart failure.     

Noninvasive assessment of clinical response to oral propranolol therapy

Nineteen patients with severe but stable angina pectoris entered a double blind controlled study to evaluate the effect of orally administered propranolol on exercise tolerance measured with a bicycle ergometer, and left ventricular function measured by echocardiography and systolic time intervals. In the group treated with propranolol the dose was increased from 80 to 320 mg/day. Studies including determination of propranolol blood levels were obtained before treatment and for each dose of propranolol. With propranolol, 80 mg/day, total work performance increased by 128 percent from 765 ± 125 before treatment to 1,792 ± 285 kilopond-meters (mean ± standard error) (P < 0.01). With 160 mg of propranolol daily, total work performance decreased, but remained higher than at control levels. In the group given propranolol, left ventricular function decreased progressively with increasing doses of the drug. As measured from the echocardiogram, maximal endocardial posterior wall velocity decreased 42 percent, from 72 ± 7 to 41 ± 4 mm/sec (P < 0.02); ejection fraction decreased 13 percent, from 0.68 ± 0.01 to 0.59 ± 0.01; and end-diastolic volume increased 28 percent, from 79 ± 11 to 102 ± 9 ml/m² (P < 0.05). The preejection period and the ratio between preejection period and left ventricular ejection time significantly increased with progressive dose increments. There was no correlation between blood level of propranolol and improved work performance. Exercise tolerance was maximally improved with doses of 80 to 160 mg/day. At higher dose levels left ventricular function deteriorated and exercise work decreased. Noninvasive assessment of left ventricular function proved more valuable than determination of drug blood levels in managing patients with angina pectoris and provided a guide to optimal adjustment of dosage.     

Long-term therapy of heart failure with prazosin: a randomized double blind trial

There is evidence that repeated administration of prazosin to patients with severe congestive heart failure results in tolerance to its initial salutary effects as a vasodilator. Therefore, we used a randomized, double blind protocol to evaluate the clinical effectiveness of 2 months of continuous prazosin therapy in 22 patients with severe congestive heart failure. After 2 months, the patients treated with prazosin showed significant improvement in mean New York Heart Association functional class (3.7 ± 0.2 to 2.3 ± 0.2, p < 0.01), treadmill exercise duration (123 ± 30 to 209 ± 40 sec, p < 0.01), echocardiographic ejection fraction (31.8 ± 3.2 to 37.3 ± 4.2 percent, p < 0.01), stroke excursion (1.02 ± 0.10 to 1.24 ± 0.14 cm, p < 0.01), mean velocity of circumferential fiber shortening (0.69 ± 0.07 to 0.80 ± 0.09 circumferences/sec, p < 0.06) and ejection fraction measured with radionuclide ventriculography (24.8 ± 2.2 to 32.1 ± 2.9 percent, p < 0.001). A comparable placebo-treated group showed no significant change in any index of functional or hemodynamic performance. The radionuclide ventriculographic ejection fraction fell to pretreatment levels 48 hours after the withdrawal of chronic prazosin therapy and rose to the long-term treatment level on readministration of the drug, thus confirming that the improvement observed after 2 months was due to prazosin. After 2 months there was clinical evidence of attenuation of the initial response to prazosin, although patients continued to show improvement over their pretreatment state. Prazosin-treated patients had an increase in plasma renin activity and required an increase in diuretic dose, suggesting that the renin-angiotensin system may contribute to the observed attenuation of drug effect. Long-term therapy with prazosin results in significant functional and hemodynamic improvement in patients with severe congestive heart failure.     

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.     

Assessment of right ventricular function at rest and during exercise in patients with coronary heart disease: A new approach using equilibrium radionuclide angiography

To evaluate a new method of calculating right ventricular ejection fraction by equilibrium radionuclide angiography and to assess its response during supine bicycle exercise, 20 normal persons and 50 patients with angiographically documented coronary artery disease were studied. Each subject underwent a resting equilibrium and first pass right ventricular study as well as symptom-limited graded bicycle exercise while supine. The correlation between the two methods in all 70 cases was good (r = 0.81). Inter- and intraobserver variability was small (3.9 ejection fraction units or less) and serial reproducibility (two studies performed 2 weeks apart) was also good (4 ejection fraction units or less). There was no difference in the right ventricular ejection fraction at rest when normal subjects and patients with coronary disease were compared (0.49 ± 0.10 versus 0.46 ± 0.08). Ejection fraction increased with exercise in normal subjects (0.49 ± 0.10 to 0.64 ± 0.12, p < 0.005). As a group, patients with right coronary stenosis (alone or in combination with other lesions) showed no change in ejection fraction with exercise (0.46 ± 0.13 to 0.45 ± 0.12); and ejection fraction increased with exercise in patients with coronary disease without right coronary stenosis (0.46 ± 0.08 to 0.53 ± 0.11, p < 0.05). Among patients with both significant right and left coronary artery disease more severe right ventricular dysfunction during exercise was seen in the presence of more severe left ventricular dysfunction. It is concluded that during exercise the right ventricle shows dysfunction caused in part by local ischemia as well as by altered loading conditions due to left ventricular dysfunction. Equilibrium angiography is a useful and reliable method for evaluating right ventricular function in man.