Lower limb blood flow, oxygen uptake, and femoral vein 02 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 < .05, and 52.3 8.0 vs 45.1 + 8.2 U x 1o3, p < .05, respectively), in patients with severe congestive heart failure these values were similar during the two forms of exercise (1082 ± 459 vs 1053 ± 479 m/min and 9.6 ± 3.7 vs 9.4 + 3.5 U x 103, 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 a-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 02 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 a-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. Circulation 74, No. 2, 245-251, 1986. PATIENTS with congestive heart failure, when compared with normal subjects, have a reduced metabolic arteriolar vasodilative response after restoration of flow to an ischemic limb.1 They also do not have an adequate increase in forearm blood flow in response to rhythmic handgrip exercise of increasing intensity.2 Thus, an inability of the peripheral muscle vasculature to dilate appropriately during dynamic exercise may be a limiting factor to maximal exercise capacity in patients with severe congestive heart failure.In normal subjects, during graded exercise involving 40% or more of the total muscle mass, such as bicycling with two legs, maximal functional capacity, i.e., oxygen uptake, is limited by the ability of the heart to increase its output. In contrast, when graded exercise involves a smaller percentage of the total mus- Received Jan. 9, 1986; revision accepted May 5, 1986. cle mass, such as bicycling with one leg, maximal exercise capacity is attained before maximal cardiac output or V02 max is reached, suggesting that a lack of output by the heart is no longer the limiting factor. Of interest, when the effects of one-leg vs two-leg bicycle exercise are compared in normal subjects, the maximal workload per leg is greater during one-leg exercise than during two-leg exercise, suggesting that peak blood flow to the active limb during two-leg exer...

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.PATIENTS with congestive heart failure become increasingly symptomatic as the severity of the disease progresses. In the advanced stage of the disease, patients are severely incapacitated despite optimal therapy with diuretics, digitalis and vasodilators.'-3 Amrinone, a nonglycosidic, nonadrenergic cardiotonic agent, improves ventricular performance and reduces symptoms at rest and during exertion.7 However, amrinone therapy is complicated by various side effects, e.g., thrombocytopenia, gastrointestinal intolerance, hepatotoxicity and fever. congestive heart failure. Methods SubjectsTherapy with WIN 47203 was offered to 11 patients with chronic congestive heart failure who were severely incapacitated despite treatment with diuretics, digitalis and nitrates. Eight of the patients had not benefited from therapy with arteriolar vasodilators, which were therefore discontinued. The severity of the functional impairment was confirmed by a maximal oxygen uptake below 12 ml/kg/min in every patient (average 9.0 ml/kg/min, range 6-11.2 ml/kg/min). The nature, benefits and risks of the study were fully explained and all patients gave informed consent. The protocol was approved by the Committee on Clinical

Maximal oxygen uptake (VO2), skeletal muscle blood flow by xenon-133 washout technique and femoral vein arteriovenous oxygen difference and lactate were measured at rest and during maximal bicycle exercise in eight patients with severe congestive heart failure before and after 8 weeks of therapy with captopril. During therapy, skeletal muscle blood flow at rest increased significantly from 1.5 +/- 0.6 to 2.6 +/- 1.0 ml/100 g per min (p less than 0.05), with a concomitant decrease in the femoral arteriovenous oxygen difference from 10.0 +/- 1.7 to 8.3 +/- 1.9 ml/100 ml (p less than 0.05). Maximal VO2 increased significantly from 13.4 +/- 3.0 to 15.5 +/- 4.1 ml/kg per min (p less than 0.05). In four patients, the increase in maximal VO2 averaged 3.7 ml/kg per min (range 2.7 to 4.9), whereas in the remaining four patients, it was less than 1 ml/kg per min. Overall, peak skeletal muscle blood flow attained during exercise did not change significantly during long-term therapy with captopril (19.6 +/- 6.2 versus 27.6 +/- 14.3 ml/100 g per min, p = NS). However, the four patients with a significant increase in maximal VO2 experienced substantial increases in peak skeletal muscle blood flow and the latter changes were linearly correlated with changes in maximal VO2 (r = 0.95, p less than 0.001). Femoral arteriovenous oxygen difference at peak exercise was unchanged (12.6 +/- 2.6 versus 12.6 +/- 2.4 ml/100 ml). Thus, improvement in maximal VO2 produced by long-term therapy with captopril is associated with an increased peripheral vasodilatory response to exercise, and this improvement only occurs when the peak blood flow is augmented.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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 < .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 < .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 + 1 1 ml/min (p < .05) and from 278 ± 77 to 441 + 115 ml/min (p < .05), respectively. Femoral vein oxygen content was increased by milrinone from 7.9 2.6 to 9.8 + 3.0 ml/100 ml (p < .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 mI/M2 (p < .05) and tended to reduce pulmonary capillary wedge pressure further from 20 ± 8 to 18 ± 9 mm Hg (p = NS). The addition of intravenous milrinone to captopril did not reduce mean systemic arterial pressure (71 + 8 vs 71 + 8 mm Hg) or significantly increase heart rate (89 ± 17 vs 92 ± 18 beats/min) when compared with captopril alone. Although renal blood flow was not further increased by the addition of intravenous milrinone to captopril. femoral vein oxygen content increased from 6.8 ± 1.9 to 9.9 + 1.8 ml/100 ml (p < .05). Thus simultaneous administration of captopril and milrinone has synergistic effect on cardiac performance and complementary effects on the peripheral circulation.