Carol S. Maskin

Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure.

Lower limb blood flow, oxygen uptake, and femoral vein O2 content were measured at rest and during maximal bicycle exercise, performed with two legs and one leg, in four normal subjects and in five patients with severe congestive heart failure. While in normal subjects femoral vein blood flow and lower limb vascular conductance were significantly greater during one-leg exercise than during two-leg exercise (6084 +/- 745 vs 5370 +/- 803 ml/min, p less than .05, and 52.3 +/- 8.0 vs 45.1 +/- 8.2 U X 10(3), p less than .05, respectively), in patients with severe congestive heart failure these values were similar during the two forms of exercise (1082 +/- 459 vs 1053 +/- 479 ml/min and 9.6 +/- 3.7 vs 9.4 +/- 3.5 U X 10(3), respectively). In five additional patients, one-leg maximal bicycle exercise was performed before and after administration of phentolamine into the femoral artery of the active leg. Regional alpha-adrenergic blockade with phentolamine did not alter maximal oxygen uptake attained during one-leg bicycle exercise (9.8 +/- 1.5 vs 10.3 +/- 1.9 ml/kg). Lower limb blood flow and femoral vein O2 content attained during maximal one-leg exercise were also similar before and after phentolamine. Thus, in contrast with normal subjects, patients with severe congestive heart failure were unable to further increase limb blood flow during one-leg bicycle exercise. Moreover, local alpha-adrenergic blockade does not augment blood flow to the active limb during maximal one-leg bicycle exercise. This suggests that the ability of the muscular vasculature to vasodilate during exercise is impaired and may be a limiting factor to maximal exercise capacity in such patients.

Failure of dobutamine to increase exercise capacity despite hemodynamic improvement in severe chronic heart failure

The acute hemodynamic and metabolic effects of dobutamine administered during exercise were studied in 8 patients with severe chronic heart failure. Exercise was performed on an upright bicycle ergometer using a graded protocol. During exercise performed without administration of dobutamine, exhaustion occurred after 4.5 +/- 1.2 minutes of exercise. The cardiac index increased from 1.61 +/- 0.25 to 2.67 +/- 0.59 liters/min/m2 (p less than 0.001), the arteriovenous oxygen difference from 7.8 +/- 1.7 to 12.5 +/- 2.4 ml/100 ml (p less than 0.001), and oxygen uptake from 7.9 +/- 3.0 to 41.2 +/- 15.7 mg/100 ml (p less than 0.001). During exercise performed with the administration of dobutamine, the cardiac index was significantly greater than during the control state, 3.23 +/- 0.78 versus 2.67 +/- 0.59 liters/min/m2 (p less than 0.001), while the arteriovenous oxygen difference was significantly lower, 11.2 +/- 2.1 vs 12.5 +/- 2.4 ml/100 ml (p less than 0.01). The arterial lactate level was not significantly changed, 45.3 +/- 17.6 versus 41.2 +/- 15.7 mg/100 ml. Although the dobutamine level tended to increase maximal oxygen uptake compared with the control period of exercise, 9.1 +/- 1.2 versus 8.5 +/- 1.4 ml/kg/min (p less than 0.05), it did not significantly increase exercise capacity, 4.8 +/- 1.5 versus 4.5 +/- 1.2 min. Thus administration of dobutamine in patients with severe chronic heart failure increased the cardiac index during maximal exercise but failed to increase exercise capacity. Since arteriovenous oxygen difference is reduced, dobutamine probably increases blood flow to the nonexercising tissues and not to the actively metabolizing muscles.

Sustained hemodynamic and clinical effects of a new cardiotonic agent, WIN 47203, in patients with severe congestive heart failure.

The hemodynamic and clinical effects of WIN 47203, a newly synthesized noncatecholamine, nonglycosidic inotropic agent, were studied in 11 patients with severe chronic congestive heart failure. Intravenous WIN 47203 increased cardiac index from 1.93 ± 0.36 to 2.87 ± 0.45 I/min/m2 (p < 0.001) and reduced pulmonary capillary wedge pressure from 27.0 ± 8.4 to 16.3 ± 6.1 mm Hg (p < 0.001). Mean systemic arterial pressure decreased from 75.2 ± 6.7 to 72.4 ± 6.3 mm Hg (p < 0.01) and systemic vascular resistance from 1591 ± 397 to 1071 ± 293 dyn-sec-cm5 (p < 0.001); heart rate was unchanged. Oral WIN 47203 produced similar hemodynamic improvement. Hemodynamic monitoring of six consecutive doses did not demonstrate evidence for attenuation of effectiveness. Chronic therapy with WIN 47203 produced substantial symptomatic improvement and increased maximal oxygen uptake at 1 week. Patients were further improved after 4 weeks of WIN 47203, and maximal oxygen uptake increased from 9.0 ± 1.9 to 11.6 ± 2.5 ml/kg/min (p < 0.01 vs control). No overt clinical or laboratory manifestations of toxicity were observed. Withdrawal of WIN 47203 in two patients in whom clinical benefit was not sustained resulted in clinical and hemodynamic deterioration, which was reversed by reinstitution of the drug. Therefore, this study demonstrates the acute and sustained cardiotonic efficacy of WIN 47203 in man. If long-term administration remains well tolerated and without side effects, this drug appears to be very promising for treatment of chronic severe congestive heart failure.

Long-term therapy with a new cardiotonic agent, WIN 47203: Drug-dependent improvement in cardiac performance and progression of the underlying disease

Seven patients with severe chronic congestive heart failure were treated with a new cardiotonic agent, WIN 47203 (an analog of amrinone), for an average of 7.4 weeks (range 2 to 15). At the initiation of therapy, hemodynamic improvement occurred in all patients as the cardiac index increased from 1.79 +/- 0.39 to 2.30 +/- 0.44 liters/min per m2 (probability [p] less than 0.05) and pulmonary capillary wedge pressure decreased from 24.1 +/- 6.7 to 16.1 +/- 7.8 mm Hg (p less than 0.05). Long-term therapy produced a substantial symptomatic improvement in five of the seven patients. This improvement was fully sustained in two patients and the remaining three experienced a partial return of their symptoms even though the initial hemodynamic improvements at rest remained evident in all seven patients. Withdrawal of WIN 47203 precipitated hemodynamic deterioration in all patients. The cardiac index decreased from 2.25 +/- 0.40 to 1.64 +/- 0.46 liters/min per m2 (p less than 0.05) while the pulmonary capillary wedge pressure increased from 17.1 +/- 7.8 to 23.2 +/- 12.0 mm Hg (p less than 0.05). Stroke volume index after withdrawal was lower than the control level before therapy (17.0 +/- 6.6 versus 20.3 +/- 4.7 ml/m2; p less than 0.05) and pulmonary capillary wedge pressure was similar. During long-term therapy, no undesirable side effects or hematologic changes were observed. Thus, drug-dependent hemodynamic benefits and apparent progression of the underlying cardiac disease were demonstrated during long-term therapy with WIN 47203.

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 less than 0.01) and pulmonary capillary wedge pressure decreased from 26.5 +/- 3.5 to 19.5 +/- 5.4 mm Hg (p less than 0.05). Symptoms were alleviated and exercise capacity increased from 5.9 +/- 2.9 to 11.5 +/- 4.5 minutes (p less than 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 less than 0.05) and pulmonary capillary wedge pressure rose from 20.6 +/- 2.9 to 28.8 +/- 5.6 mm Hg (p less than 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.

Relationship between amrinone plasma concentration and cardiac index

Amrinone was given to 14 patients with congestive heart failure as an intravenous bolus (1 mg/sec) at doses ranging from 0.5 to 3.5 mg/kg. Simultaneous determinations of cardiac index were made by thermodilution and of amrinone plasma concentration by high‐performance liquid chromatography. A relationship between improvement in cardiac index and increasing plasma concentrations of amrinone was demonstrated for 13 of the 14 patients. The percentage increase in cardiac index correlated with amrinone plasma concentration (r = 0.81; p < 0.001). Amrinone was given to four patients as an intravenous bolus dose of 1.5 mg/kg followed by a constant infusion of 10 µg/kg/min for 10 hr; simultaneous determinations of cardiac index and circulating levels of amrinone indicated that both declined after the initial rise. The plasma concentration of amrinone remained relatively constant during the infusion at about 1.7 µg/ml. In all cases, despite the relatively constant plasma levels there was a decline in cardiac index after about 4 to 5 hr of infusion, although the cardiac index remained above the baseline; during the constant infusion the cardiac index rose again and was maintained at a reasonably constant level for the last 3 hr. Seven patients received oral doses of amrinone of about 3 mg/kg, and simultaneous determinations of cardiac index and plasma concentration showed a relationship between amrinone level and rise in cardiac index (p < 0.05). In 16 patients after amrinone orally sufficient blood samples were taken to estimate the apparent first‐order terminal elimination t½. The t½ as estimated by log‐linear regression ranged from about 3 to 15 hr; x ± SEM value was 8.3 (±1.1) hr.

Systemic and regional hemodynamic effects of captopril and milrinone administered alone and concomitantly in patients with heart failure.

The effects of milrinone and captopril on ventricular performance, renal blood flow, and femoral vein oxygen content were compared in 11 patients with severe chronic heart failure. The increase in stroke volume index was greater with milrinone than with captopril (28 +/- 7 vs 24 +/- 7 ml/m2; p less than .05), while pulmonary capillary wedge pressures fell similarly (19 +/- 10 vs 21 +/- 7 mm Hg). Mean systemic arterial pressure decreased significantly from 84 +/- 10 to 73 +/- 11 mm Hg (p less than .05) with captopril but did not with milrinone. Neither drug changed heart rate significantly. Although milrinone produced a greater improvement in ventricular performance than captopril, renal blood flow increased similarly with both drugs from 289 +/- 78 to 417 +/- 111 ml/min (p less than .05) and from 278 +/- 77 to 441 +/- 115 ml/min (p less than .05), respectively. Femoral vein oxygen content was increased by milrinone from 7.9 +/- 2.6 to 9.8 +/- 3.0 ml/100 ml (p less than .05) and was not changed by captopril. In seven additional patients, intravenous milrinone, administered at the peak effect of captopril, further augmented stroke volume index from 24 +/- 6 to 32 +/- 6 ml/m2 (p less than .05) and tended to reduce pulmonary capillary wedge pressure further from 20 +/- 8 to 18 +/- 9 mm Hg (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Regional and systemic metabolic effects of angiotensin-converting enzyme inhibition during exercise in patients with severe heart failure.

The acute hemodynamic and metabolic effects of captopril therapy were studied in 12 patients with severe heart failure during maximal exercise performed on an upright bicycle ergometer. During the control period, exhaustion occurred after 4.2 ± 2.7 minutes of exercise. Cardiac index increased from 1.54 ± 0.36 I/min/m2 at rest to 3.39 ± 1.54 I/min/m2 (p < 0.001) at exhaustion; systemic arteriovenous oxygen difference increased from 8.8 ± 2.1 to 12.8 ± 2.4 ml/100 ml (p < 0.001) and oxygen uptake from 3.4 ± 0.5 to 10.8 ± 3.0 ml/kg/min (p < 0.001). Pulmonary arterial oxygen content decreased from 7.3 ± 1.3 to 3.7 ± 1.5 ml/100 ml (p < 0.001) and femoral vein oxygen content from 5.0 ± 1.7 to 2.5 ± 1.2 ml/ 100 ml (p < 0.001). During captopril therapy, cardiac index significantly increased both at rest (1.83 ± 0.54 vs 1.54 ± 0.36 I/min/m2, p < 0.01) and during maximal exercise (3.67 ± 1.51 vs 3.39 ± 1.54 I/min/m2, p < 0.01). Systemic arteriovenous oxygen difference decreased significantly at rest, from 8.8 ± 2.1 to 7.7 ± 2.1 ml/100 ml (p < 0.01) and during maximal exercise from 12.8 ± 2.4 to 12.3 ± 2.2 ml/100 ml (p < 0.01). Pulmonary arterial oxygen content at exhaustion was significantly higher during captopril therapy than during the control period (4.1 ± 1.1 vs 3.7 ± 1.5 ml/100 ml, p < 0.05), while femoral venous blood content was unchanged. Captopril therapy did not significantly increase maximal oxygen uptake or exercise duration. Thus, the acute administration of captopril to patients with severe heart failure does not increase exercise capacity despite improved cardiac performance. Moreover, captopril therapy does not acutely result in metabolic benefits to the skeletal muscles during exercise.

Comparative systemic and renal effects of dopamine and angiotensin-converting enzyme inhibition with enalaprilat in patients with heart failure.

Renal and systemic hemodynamics were measured during titration of dopamine and serially after intravenous administration of enalaprilat in nine patients with chronic severe congestive heart failure. During titration of dopamine, renal blood flow increased by 99%, from 304 +/- 120 to 604 +/- 234 ml/min (p less than .01) at a dose of dopamine of 2.1 micrograms/kg/min, which produced only a 21% increase in cardiac index, from 1.96 +/- 0.36 to 2.38 +/- 0.35 liters/min/m2 (p less than .05). Cardiac index was increased maximally at a dose of 4.0 micrograms/kg/min dopamine; however, renal blood flow was not further augmented. In contrast, after intravenous administration of enalaprilat, peak improvement of renal blood flow and cardiac index occurred concomitantly. Renal blood flow increased by 35%, from 316 +/- 97 to 427 +/- 107 ml/min (p less than .05), and cardiac index increased by 18%, from 1.99 +/- 0.40 to 2.35 +/- 0.40 liters/min/m2 (p less than .05). At similar increases in cardiac index, dopamine produced a greater increase in renal blood flow than enalaprilat: 604 +/- 234 vs 427 +/- 107 ml/min (p less than .05). Mean systemic arterial pressure, however, was greater with dopamine than with enalaprilat (78.1 +/- 16.7 vs 70.2 +/- 17.2 mm Hg; p less than .05) at peak effect. Thus, although both drugs appear to be potent renal vasodilators in patients with severe congestive heart failure, dopamine may be more effective in augmenting renal blood flow.

Acute inotropic stimulation with dopamine in severe congestive heart failure: Beneficial hemodynamic effect at rest but not during maximal exercise

Hemodynamic and metabolic effects of dopamine were studied at rest and during maximal exercise in 13 patients with severe chronic congestive heart failure (CHF). During exercise before the administration of dopamine, the stroke volume index increased from 17.1 +/- 5.2 ml/m2 at rest to 28.1 +/- 10.9 ml/m2 (p less than 0.001) at exhaustion, while pulmonary capillary wedge (PCW) pressure increased from 22.7 +/- 12.7 to 43.9 +/- 11.9 mm Hg (p less than 0.001). The arteriovenous oxygen difference increased from 8.9 +/- 2.3 ml/100 ml to 12.4 +/- 2.0 ml/100 ml (p less than 0.001) and oxygen uptake increased from 3.5 +/- 0.6 0.6 to 11.9 +/- 2.5 ml/kg/min (p less than 0.001). At rest, dopamine increased the stroke volume index to 23.3 +/- 8.1 ml/m2 (p less than 0.001) and reduced the PCW pressure to 20.5 +/- 1.1 mm Hg (p less than 0.05). However, during maximal exercise, the stroke volume index and PCW pressure were not changed by dopamine: 28.1 +/- 10.9 versus 28.6 +/- 10.2 ml/m2 (difference not significant [NS]) and 43.9 +/- 11.9 versus 42.5 +/- 11.2 mm Hg (NS), respectively. In contrast, the maximal heart rate achieved during exercise was significantly higher with dopamine, 140.3 +/- 29.3 versus 136.0 +/- 29.7 beats/min (p less than 0.05), which contributed to a slight augmentation in the maximal cardiac index, 3.82 +/- 1.13 versus 3.64 +/- 1.17 liters/min/m2 (p less than 0.05). Nonetheless, neither peak arteriovenous oxygen difference nor maximal oxygen uptake were significantly changed by dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)