Oral Therapy with Phentolamine in Chronic Congestive Heart Failure

Oral Therapy with Phentolamine in Chronic Congestive Heart Failure* Lawrence A. Gould, M.D., F.G.G.P.; and G. V. R. Reddy, M.D., F.G.G.P.

Therapy with phentolamine can improve the condition of patients with congestive heart faDore due to the in0tropic effect of this drug, as weD as its vasodilating action. The use of oral therapy with phentolamine has not been adequately investigated in patients with chronic heart failure. Therefore, nine patients with chronic heart fanure due to underlying valvular disease received SO mg of phentolamine foor times a day for two weeks. Echocardiograms and measurements of systolic time intervals were obtained prior to administration of phentolamine and two weeks after the introduction of therapy

with the drug. As a result of therapy with phentolamine, the ejection fraction, the percentage of change in the minor axis, and the velocity of circumferential fiber shortening significandy increased, whUe the left atrial dimension decreased. Therapy with phentolamine produced a significant decrease in the preejection period index, as weD as the ratio of the preejection period over the left ventricular ejection time. Thus, oral therapy with phentolamine improves left ventricular function in patients with chronic heart failure.

In 1969, our group first reported that intravenous administration of phentolamine can improve cardiac performance in patients with heart failure. 1 Positive inotropism and a reduction in afterload were shown to be the mechanisms that led to the cardiac improvement Majid and co-workers2 in 1971 verified our initial observations and popularized the term, cCvasodilator therapy,n for the treatment of heart failure. Since that time the literature is replete with articles attesting to the benefits of vasodilator drugs in the treatment of acute and chronic heart failure. In the last few years, interest had focused on the oral use of vasodilator drugs for the treatment of chronic congestive heart failure. The nitrates,S hydralazine,4 and prazosin5 have all been shown to play a useful role in the treatment of patients with congestive heart failure. There is little information on the effects of oral therapy with phentolamine in patients with heart failure. In the present study, we administered phentolamine orally to nine patients with chronic heart failure. Left ventricular performance was assessed by using the combined techniques of echocardiographic studies and the determination of systolic time intervals.

severe mitral insufficiency as their major lesion, and two had a moderate degree of aortic insufficiency. All of these patients were receiving therapy with digitalis and diuretic drugs, and administration of these drugs was continued throughout the study. Echocardiographic studies Complete echocardiographic studies were pedormed in all of the patients with an echocardiograph (SKI), utilizing a 2.25-MHz transducer 1.3 em in diameter that was focused at 7.5 cm. The recordings were made on a recorder (Ekoline 2). The transducer was held at the fourth interspace just to the left of the sternum. Left ventricular end-diastolic and endsystolic volumes,6 the stroke volume, the ejection fraction,6,1 the percentage change of the minor axis, and the velocity of circumferential fiber shorteningS were calculated from the echocardiographic measurements. The left atrial dimension was also obtained. Systolic Time Intervals

°From the Deparbnent of Medicine, the Methodist Hospital, Brooklyn, NY. Manuscript received May_ 8; revision accepted October 17. Reprint requests: Dr. Reddy, 506 Sixth Street, Brooklyn 11215

All patients had systolic time intervals measured from simultaneous electrocardiographic, phonocardiographic, and carotid arterial pulse tracings recorded at a paper speed of 100 mm/sec using a recording system (Electronics for Medicine DR 12), according to the methods described by Weissler et al9 and Lewis et aI.I0 The total electromechanical systole ( Q-S 2), the left ventricular ejection time (LVET), and the preejection period ( PEP) in the adult patients were corrected for heart rate, employing linear regression equations, and were expressed as their respective indices ( Q-S2I, LVETI, and PEPI). The ratio of PEP/LVET was calculated using the uncorrected values for PEP and LVET. After the control measurements were obtained, the patients were placed on oral therapy with 50 mg of phentolamine four times per day for two weeks. Echocardiograms and measurements of systolic time intervals were obtained at the conclusion of the two-week period. Statistical analyses were performed using Student's t-test with paired comparisons.

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ORAL PHENTOLAMINE IN CONGESTIVE HEART FAILURE 487

MATERIALS AND METHODS

Nine outpatients with chronic heart failure due to underlying valvular disease were studied. Seven had moderate or

Table l--Clinical Data orad S,..tolic Time Inte",ala

Experimental State

Blood Pressure, mmHg

Cardiac Rate, beats per min

LVETI, msec

Q-StI, msec

PEPI, msec

PEP/LVET

Control Phentolamine

110/70 110/60

75 75

393 418

523 538

130 120

0.38 0.31

2, F, 66

Mitral insufficiency; Control Phentolamine minimal mitral stenosis

120/70 120/60

90

83

364 377

500 504

136 127

0.45 0.39

3, F, 54

Mitral insufficiency; Control Phentolamine minimal mitral stenosis; moderate aortic insufficiency

130/70 125/70

61 75

398 400

542 520

144 120

0.40 0.32

4, F, 69

Mitral insufficiency; Control Phentolamine minimal mitral stenosis

130/70 125/65

72 71

395 414

494 512

99 98

0.25 0.24

5, F, 31

Aortic insufficiency

Control Phentolamine

140/60 140/60

87 71

454 494

574 582

120 88

0.27 0.16

6, F, 45

Mitral insufficiency; Control Phentolamine minimal mitral stenosis

120/75 125/70

69

64

319 337

514 500

196 163

0.81 0.61

7, M, 61

Mitral insufficiency

Control Phentolamine

110/80 120/70

90

88

387 385

541 521

154 136

0.50 0.43

8, M, 46

~litral

insufficiency; Control minimal tricuspid Phentolamine insufficiency

135/80 130/75

78 69

388 357

534 495

156 138

0.49 0.46

9, M, 68

Aortic insufficiency

Control Phentolamine

130/60 115/60

80 86

413 423

535 532

122 109

0.32 0.26

Control Phentolamine

124±4/70±2 123±3/66±2

77±4 76±2

390±12 401 ±15

529±8 523±9

14O±9* 122±8*

0.43 ±0.06** 0.35 ±0.05**

Patient, Sex, Age (yr)

Condition

1, M, 54

Mitral insufficiency

Mean±BE *P
RESULTS

Complete data on all patients are presented in Tables 1 and 2. In addition, the average values before and after administration of phentolamine are listed, with the statistical analysis. Symptoms due to heart failure were greatly relieved with therapy with phentolamine in all nine patients. Prior to administration of phentolamine, despite therapy with digoxin and diuretic drugs, all patients had prominent dyspnea and fatigue (New York Heart Association's functional class 4 in three patients, class 3 in two patients, and class 2 in four patients). Of the three patients who were in class 4 prior to therapy with phentolamine, the oral administration of vasodilator drugs reduced the symptoms of heart failure to class 3 in two patients and to class 2 in one patient. Similarly, in the two patients in class 3, symptoms were diminished to class 2. The condition of all four patients in class 2 improved to class 1. The exercise tolerance test, which is an objective documentation of improvement, was not performed None of the patients had any side effects

•

GOULD, REDDY

associated with the use of the drug. Echocardiographic Findings

As a result of therapy with phentolamine, the average ejection fraction increased from 53 to 63 percent (P < 0.01). The percentage of change in the minor axis increased from a control value of 29 percent to a value after treatment of 36 percent (P < 0.01), while the velocity of circumferential fiber shortening also increased from a mean control value of 1.09 circumferences per second to a value after treatment of 1.26 circumferences per second (P < 0.05). The left atrial dimension decreased from 5.3 to 4.6 cm (P < 0.05). The left ventricular diastolic dimension decreased from 5.8 to 5.6 cm (P < 0.01), while the left ventricular systolic dimension decreased from 4.1 to 3.6 cm (P < 0.001). Systolic Time Intervals

The cardiac rate and blood pressure were essentially unchanged. Therapy with phentolamine proCHEST, 75: 4, APRIL, 1979

Table 2--Eehoeardiographic Finding.

Ejection Fraction, percent

Percentage of Change of Minor Axis

Velocity of Circumferential Fiber Shortening, circumferences per second

Case 1 Control Phentolamine

46 65

23 36

0.87 1.24

Case 2 Control Phentolamine

59 58

32 31

Case 3 Control Phentolamine

67 79

Case 4 Control Phentolamine

Experimental State

Left Atrial Dimension, cm

,

Left Ventricular Dimension, cm A

l

Diastolic

Systolic

4.0 3.8

5.2 5.0

4.0 3.2

1.43 1.26

7.6 5.4

6.0 5.5

4.1 3.8

38 48

1.25 1.70

5.6 5.4

4.8 4.6

3.0 2.4

80 80

50 50

1.75 1.75

5.6 5.6

6.8 6.4

3.4 3.2

Case 5 Control Phentolamine

66 72

36 41

1.30 1.37

3.0 2.5

5.5 5.1

3.5 3.0

Case 6 Control Phentolamine

51 64

26 35

0.83 0.92

4.0 3.2

4.6 4.6

3.4 3.0

Case 8 Control Phentolamine

22 40

10 20

0.49 0.85

7.0 6.8

6.8 6.5

6.1 5.2

Case 9 Control Phentolamine

40 47

20 24

0.78 1.01

5.2 3.7

7.0 7.0

5.6 5.3

Mean±SE Control Phentolamine

53±6* 63±5*

29±4* 36±4*

1.09 ±0.15** 1.26 ±0.11 **

5.3±0.6** 4.6 ±0.5**

5.8±0.3* 5.6±0.3*

4.1 ±0.4t 3.6±0.4t

Case 7 Control Phentolamine

*p <0.01. **p <0.05. tP <0.001.

In this study, we utilized echocardiographic measurements of left ventricular diameters, as well as an assessment of left ventricular pedormance from systolic time intervals. Both the echocardiographic measurements of overall pump pedormance (percentage of shortening of the left ventricular diameter and mean rate of circumferential shortening) and systolic time intervals have been shown to correlate

well with measurements derived from invasive methods. 11-14 Furthermore, the PEP/LVET closely correlates with the ejection fraction. 15 This relationship was obtained in patients with valvular and nonvalvular heart disease with a wide variation in functional impairment. Other workers have described a similar close relationship between the PEP and the ejection fraction. 16 In our present study, measurement of the systolic time intervals revealed a significant decline in the PEP and the PEP/LVET after therapy with phentolamine. The echocardiographic studies revealed a significant increase in the ejection fraction, the percentage of change of the minor axis, and the velocity of circumferential fiber shortening. Thus, both of these noninvasive studies demonstrated that oral therapy with phentolamine can improve left ventricular performance.

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ORAL PHENTOLAMINE IN CONGESTIVE HEART FAILURE 489

duced a nonsignificant increase in the LVETI and a nonsignificant decrease in Q-S2I; however, a significant decrease in the PEPI was observed. The control value of 140 msec fell to 122 msec after therapy with phentolamine (P < 0.(01). Similarly, the control value of 0.43 for PEP/LVET decreased to a value after treatment of 0.35 (P < 0.01). DISCUSSION

These results are similar to the experience with the intravenous administration of phentolamine. When the drug was infused at a rate of 0.3 mg/min in patients with congestive heart failure, a striking hemodynamic improvement was observed. 1 The cardiac output, cardiac rate, and stroke index increased, while the pulmonary arterial pressure, systemic peripheral resistance, and left ventricular end-diastolic pressure fell. In addition, the left ventricular end-diastolic and end-systolic volume diminished, while the ejection fraction increased. The effect of an infusion of phentolamine on the systolic time intervals has also been investigated in ten normal subjects.17 Administration of phentolamine at 0.3 mg/min for 12 minutes was associated with no significant change in the cardiac rate or arterial pressure. The Q-S2I did not show a significant change; however, therapy with phentolamine consistently shortened the PEP and the ratio of PEP/LVET, while it lengthened the LVETI. These results are comparable to the findings in the present study. The improvement in left ventricular performance can be explained by phentolamine's vasodilating action, as well as its positive inotropic activity.1 Miller and coworkers 18 have determined that therapy with phentolamine exerts a greater dilator effect on the arteriolar bed, as compared to nitropmsside, while therapy with nitroprusside has a greater dilating action on the capacitance bed than phentolamine. Therapy with nitroglycerin produces predominant relaxation of the venous bed. The inotropic action of phentolamine is not possessed either by nitroglycerin or by nitroprusside. This positive inotropic effect is indirect and is dependent on the release of norepinephrine. In support of this contention, phentolamine has no direct effect on the function of adenyl cyclase in denervated or reserpinetreated isolated preparations. 19 Thus, this combined vasodilating and inotropic activity makes phentolamine an excellent agent to use in patients with a reduced cardiac output in association with an elevated left ventricular end-diastolic pressure. In addition, a decrease in impedance to left ventricular ejection results in significant improvement in patients with mitral regurgitation. This has been reported by a number of workers using an intravenous infusion of nitroprusside.20,21 Similarly, therapy with nitroprusside can produce hemodynamic improvement in patients with aortic insufficiency.22 Thus, it is not unexpected that the oral administration of phentolamine results in an improvement in patients with mitral insufficiency and aortic insufficiency. Phentolamine for oral administration is available 490 GOULD, REDDY

in the United States as a 5O-mg tablet. The length of action of this preparation is not established, since there are only crude and relatively insensitive tests to measure levels of phentolamine in the blood. Recently, 100-mg and lSO-mg slow-release tablets have been developed in Switzerland and are currently being investigated. Imhof23 has reported that the newly developed slow-release formulation produces remarkably good effects in patients with chronic heart failure. He observed a decrease in the cardiac silhouette and a reduction in body weight, as well as a dramatic improvement of the patient's condition.

1 Gould L, Zahir M, Ettinger S: Phentolamine and cardiovascular performance. Br Heart J 31:154-162, 1969 2 Majid PA, Sharma B, Taylor SH: Phentolamine for vasodilator treabnent of severe heart failure. Lancet 2:719724,1971 3 Gray R, Chatterjee K, Vyden JK, et al: Hemodynamic and metabolic effects of isosorbide dinitrate in chronic congestive heart failure. Am Heart J 90:346-352, 1975 4 Chatterjee K, Parmley WW, Massie B, et al: Oral hydralazine therapy for chronic refractory heart failure. Circulation 54:879-883, 1976 5 Miller RR, Awan NA, Maxwell KS, et al: Sustained reduction of cardiac impedance and preload in congestive heart failure with the antihypertensive vasodilator prazosin. N Engl J Med 297 :303-307, 1977 6 Pombo JF, Troy BL, Russell RO Jr: Left ventricular volumes and ejection fraction by echocardiography. Circulation 43:480-490, 1971 7 Teicholz LE, Kreulen T, Herman MV, et al: Problem in echocardiographic volume determinations: Echocardiographic-angiographic correlation in the presence or absence of asynergy. Am J CardioI37:7-11, 1976 8 Quinones MA, Gaasch WH, Alexander JK: Echocardiographic assessment of left ventricular function with special reference to normalized velocities. Circulation 50:4251, 1974 9 Weissler AM, Harris WS, Schoenfeld CD: Bedside technique for the evaluation of ventricular function in man. Am J CardioI23:577-583, 1969 10 Lewis RP, Leighton RF, Forrester WF: Systolic time intervals. In Weissler AM (ed): Non-Invasive Cardiology. New York, Grone and Stratton, 1974, pp 301-358 11 Feigenbaum H, Popp RL, WoHe SB, et al: Ultrasound measurements of the left ventricle: A correlative study with angiocardiography. Arch Intern Med 129:461-467, 197~

12 Cooper RH, O'Rourke RA, Karliner JS, et al: Comparison of ultrasound and cineangiographic measurements of the mean rate of circumferential fiber shortening in man. Circulation 46:914-923, 1972 13 Garrard CL, Weissler AM, Dodge HT: The relationship of alterations in systolic time intervals to ejection fraction in patients with cardiac disease. Circulation 42:455-462, 1970 14 Ahmed S., Levinson GE, Schwartz CJ, et al: Systolic time intervals as measures of contractile state of the myocardium in man. Circulation 46:559-571, 1972 15 Thomas D, Basta L, Kioschos M: Factors inHuencing the

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19

validity of systolic time intervals in estimating left ventricular ejection fraction (abstract). Circulation 46 (suppl 2) :230, 1972 Sutton R, Hood WP Jr, Craige E: Correlation of preejection period with left ventricular ejection fraction (abstract). Clin Res 13:28, 1970 Gould L, Gomprecht RF, Jaynal F: The effects of phentolamine on the duration of the phases of ventricular systole in man. Am J Med Sci 260:29-33, 1970 Miller RR, Vismara LA, Williams DO, et al: Pharmacological mechanisms for left ventricular unloading in clinical congestive heart failure: Differential effects of nitroprusside, phentolamine and nitroglycerin on cardiac function and peripheral circulation. Circ Res 39: 127-133, 1976 Taylor SH: Physiology and clinical pharmacology of

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21 22

23

phentolamine. In Taylor SH, Gould LA: Phentolamine in Heart Failure and Other Cardiac Disorders: Proceedings of an International Workshop, London. Berne, Switzerland, Hans Huber, 1976, p 4 Chatterjee K, Parmley WW, Swan HJC, et al: Beneficial effects of vasodilator agents in severe mitral regurgitation due to dysfunction of subvalvular apparatus. Circulation 48:684-690, 1973 Goodman OJ, Rossen RM, Holloway EL, et al: Effects of nitroprusside on left ventricular dynamics in mitral regurgitation. Circulation 50: 1025-1032, 1974 Bolen JL, Alderman EL: Hemodynamic consequences of afterload reduction in patients with chronic aortic regurgitation. Circulation 53:879-883, 1976 Imhof P: Behandlung der Herzinsuffizienz mit Phentolamin. Schweiz Med Wochenschr 107:1041-1043, 1977

ORAL PHENTOLAMINE IN CONGESTIVE HEART FAILURE 491