Nifedipine in congestive heart failure: Effects on resting and exercise hemodynamics and regional blood flow

Nifedipine in congestive heart failure: Effects on resting and exercise hemodynamics and regional blood flow Ten patients with moderate to severe congestive heart failure (CHF) underwent central and regional hemodynamic measurements at rest and central hemodynamic measurements during exercise before and after the oral administration of nifedipine (0.2 mg/kg). Nifedipine significantly decreased systemic blood pressure, systemic vascular resistance, pulmonary artery pressure, pulmonary vascular resistance, and pulmonary capillary wedge pressure. Stroke volume and cardiac output increased after nifedipine. The measured parameters of left ventricular inotropy did not change significantly for this calcium channel blocker. While blood flow to renal, hepatic, and limb vascular beds increased (p < 0.05 for renal and limb) after nlfedipine, only limb blood flow increased in proportion to the increase in cardiac output, suggesting preferential dilatation of limb vasculature. Although initial-dose nifedipine did not increase exercise duration, it elicited an improvement in exercise hemodynamics by reducing systemic vascular resistance and pulmonary capillary wedge pressure and increasing stroke volume and cardiac output. The calcium channel blocker, nifedipine, can be administered safely in the setting of ventricular failure and appears to favorably alter resting and exercise hemodynamics. A select number of patients with CHF may benefit from its long-term administration. (AM HEART J 108:1481, 1984.)

Carl V. Leier, M.D., Teressa J. Patrick, M.D., James Hermiller, M.D., Karen Dalpiaz Pacht, R.N., Patricia HUSS, R.N., Raymond D. Magorien, and Donald V. Unverferth, M.D. Columbus, Ohio

Vasodilator therapy has become an important part of the medical management of many patients with congestive heart failure (CHF). The calcium channel blocker, nifedipine, has been shown to possess vasodilating properties.1-6 Several studies indicate that nifedipine favorably affects resting central hemodynamics in conditions of ventricular dysfunction and cardiac failure2e6; apparently the ability of nifedipine to reduce afterload mitigates any potential negative inotropy of this calcium antagonist. Variable and only modest hemodynamic effects have been reported by others.7-s This study was designed to look at various pharmacodynamic aspects of nifedipine in patients with CHF; these include central hemodynamic responses at rest and during exercise, effects

From the Division of Cardiology, Ohio State University College of Medicine. Supported in part by the S. J. Ro-essler Foundation and the James D. Caste Cardiovascular Research Fund. Received for publication Jan. 20, 1984; revision received Apr. 18, 1964; accepted May 16, 1984. Reprint requests: Carl V. Leier, M.D., 621 Means Hall, 1655 Upham Dr., Columbus, OH 43210.

M.D.,

on the inotropic indices of the left ventricle, and regional (hepatic, renal, and limb) hemodynamic properties. METHODS Patients. Ten patients, four women and six men, with moderate to severe CHF were studied. Mean age was 59 years with a range of 41 to 66 years. Each patient underwent diagnostic cardiac catheterization within 3 months of this study. Six patients had idiopathic dilated cardiomyopathy, two had ischemic cardiomyopathy secondary to occlusivecoronary artery disease,onedeveloped ventricular failure several months following aortic and mitral valve replacement, and one after mitral valve replacement. Two patients were classified as New York Heart Association functional classII, seven as functional class III, and one as functional class IV. None of the patients had evidence of intrinsic renal or hepatic dysfunction. Six patients were receiving digoxin (four on 0.25 mglday, two on 0.125 mglday) and seven patients were taking furosemide (40 to 160 mg/day) chronically. During the hemodynamic (rest, exercise, and regional flow) studies, digoxin and furosemide dosing was shifted to PM administration to avoid the hemodynamic variables of thesedrugs. All vasodilator and nitrate drugs were discontinued a minimum of 72 hours prior to study. 1481

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N = IO !t+ISD + p ~0.05

7

3000

Vs BASELINE

(B1

SYSTEMIC BLOOD PRESSURE

PULMONARY ARTERY PRESSURE

SYSTEMIC VASCULAR RESISTANCE

PULMONARY VASCULAR RESISTANCE

4 F 1500

1

B HOURS

4

2

6

HOURS

1. Changesin supineresting systemicblood pressure,systemicvascularresistance,pulmonary artery nressure.and nulmonarv vascular resistanceafter 0.2 mgikg nifedipine administered orally to 10patients with chronic dHF. ” Fig.

Cardiac catheterization. Written informed consentwas obtained from each patient before the initiation of the study. On the evening prior to study, a triple-lumen, balloon-tipped, flow-directed thermodilution catheter was introduced into a subclavian vein and positioned in the pulmonary artery. This catheter, interphased with Becton-Dickinson electrodyne PR 18-A pressure amplification and ST-149 and WR4D recording units, provided measurementsof right atrial, pulmonary arterial, and pulmonary capillary wedgepressures.Cardiac output was determined in triplicate (five determinations if variation exceeded 10%) by thermodilution with a Gould SP 1435 computer. Systemic blood pressure was measured by meansof a standard cuff and a mercury column sphygmomanometer. Central hemodynamic calculations included: mean systemic blood pressure= (systolic pressure- diastolic pressure)/3+ diastolic pressure; systemic vascular resistance(dynes-set-cmm5) = mean systemic blood pressure x 80/cardiac output; pulmonary vascular resistance (dynes-set-cm-5)= meanpulmonary artery pressurex 80/ cardiac output; cardiac index (L/min/m2) = cardiac output/body surface area; and stroke volume index (ml/ beat/m2) = cardiac index x lOOO/heartrate. Exercise testing. Exercise testing wasperformed in the upright position on a Quinton Uniwork bicycle ergometer. After baselineupright hemodynamicmeasurements,exercise was begun at a workload of 100 kg-m/min and was advanced by 100 kg-m/min every 180 seconds.Central hemodynamicmeasurementswere madeduring the last 30 secondsof eachworkload increment and at peak exercise. All patients completed the first 180 secondsof bicycle

exercise;the hemodynamicmeasurementsobtained at this level were used as the standard submaximal exercise values. Maximal exercise duration was the time at which excessivefatigue or dyspnea precluded continuation. Systolic time intervals. Systolic time intervals were obtained with an Electronics for Medicine Echo IV unit and measured according to specifications previously reported.7.‘0The systolic time intervals consist of total electromechanical systole (QS,), left ventricular ejection time (LVET), and the preejection period (PEP); these intervals were corrected for heart rate and designatedQS, interval, LVET interval, and PEP interval, respectively. The PEP interval and the PEP to LVET ratio (PEP/ LVET) were usedas indices of left ventricular inotropy.10 The ratio of left ventricular isovolumicdevelopedpressure to isovolumic contraction time (AP/At) wasalsousedasan index of left ventricular inotropy.“, ‘* Isovolumic developed pressureequalsdiastolic blood pressureminus pulmonary capillary wedgepressure,and isovolumic contraction time is obtained by subtracting electromechanical delay from the PEP. The electromechanical delay was measuredas the time interval from the onset of the QRS complex to the onset of left ventricular contraction (taken from the apexcardiogram). Echocardiography. M-mode echocardiography was performed on an Electronics for Medicine Echo IV unit. Echocardiographic parameters of left ventricular performance and inotropy included fractional shortening (%A D) and fractional shortening rate (VC~).‘~*~~ Regional blood flow. Regional hemodynamic measurements included hepatic, renal, and limb blood flow.

Volume

108

Number

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Nifedipine N = IO

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PULMONARY CAPILLARY WEDGE PRESSURE

MEAN RIGHT AlRlAL

CARDIAC

PRESSURE

0’ 2 4 HOURS

INDEX

T

STROKE VOLUME

04

Fig.

1463

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ST+-ISD + p< 0.05 Vs BASELINE (B 1

B

effects in CHF

6

5 B \” = t

INDEX

40 30

1

HEART

2. Effects of nifedipine (0.2 mg/kg orally) on supine

RATE

resting left and right ventricular filling pressures, as approximated by pulmonary capillary wedgepressureand right atria1 pressure,respectively. I

Hepatic and renal blood flows were determined by dye clearance techniques, indocyanine green, and paraaminohippurate, respectively.15-1g Limb blood flow (right upper arm) was determined by venous occlusive plethysmography and expressedin milliliters of blood/deciliter limb tissue/min. Plethysmography wasperformed by meansof a Meda Sonics SPG-16 amplifier interphased with a SG-24 indium-gallium strain gaugeand a R12A strip chart recorder. A minimum of five determinations were averaged for each limb blood flow value. Regional vascular resistance was calculated by dividing the mean arterial pressure (mm Hg) by the regional blood flow value (in L/min for renal and hepatic, ml/100 mUmin for limb). Protocol. All studieswere carried out in the postabsorptive state. Baseline regional blood flow measurements were made between 0930 and 1030hours of day 1; these were accompanied by central hemodynamic measurements of 0930 and 1030 hours. At 1030, baseline bicycle ergometry with hemodynamics was obtained. On the second day, baseline hemodynamic measurementswere made in duplicate (and averaged) between 0730 and 0800 hours. Nifedipine wasadministered orally in a doseof 0.2 mg/kg at 0800 hours. Central hemodynamic measurements were made hourly six times following dosing. Systolic time intervals, echocardiography, and AP/At determinations were made at baseline (0745) and at 1000 hours (2 hours after dosing). Regionalblood flow measurements weremade between0930and 1030hours (1‘/z to 2‘/z hours after dosing) and exerciseergometry with hemodynamics was performed at 1030 hours (2% hours after dosing).

I

B

I

2

I

4 HOURS

I

6

Fig. 3. Supine resting cardiac index, stroke volume

index, and heart rate responsesto nifedipine (0.2 mg/kg orally) in CHF.

Statistical analysis. Resting hemodynamic data were analyzed with analysisof variance for repeated measures. Baselineand postnifedipine exerciseergometry data were compared with two-way analysis of variance. Postnifedipine regional hemodynamics,systolic time intervals, echocardiography, and AP/At were compared to baselinevalueswith Student’s t test for paired data. RESULTS Supine

resting

hemodynamics.

Nifedipine caused a

significant reduction in systemic blood pressure, systemic vascular resistance, pulmonary arterial pressure, and pulmonary vascular resistance (Fig. 1). These changes persisted to 6 hours for the systemic circulation and returned to baseline between 4 and 5 hours for the pulmonary

Pulmonary from 1 to 4 hours after nifedipine, while the mean right atrial

capillary

circulation.

wedge pressure fell significantly

pressure was not altered (Fig. 2). Cardiac index rose significantly over 6 hours after nifedipine (Fig. 3); the increase was secondary to a significant increase in stroke volume from 1 to 4 hours and a modest but

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Amrrlcsn

MEAN PULMONARY PRESSURE

MEAN SYSTEMIC PRESSURE

ARTERY

December, 1984 Heart Journal

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Fig. 4. Upright resting and exercise(bicycle ergometry) hemodynamic data before and after initial-dose

nifedipine (0.2 mg/kg orally) in CHF.

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Pre Past Nifedipine

Fig. 5. Regional hemodynamic measurementsbefore and after nifedipine in CHF.

statistically insignificant increase in both stroke volume and heart rate from 4 to 6 hours after dosing. Nifedipine did not significantly alter mean supine resting heart rate.

Upright resting and exercise hemodynamics. During the upright resting state, 2% hours after 0.2 mg/kg oral nifedipine, systemic vascular resistance was lower and cardiac output and stroke volume were

Volume Number

106 6

higher than prenifedipine values (Fig. 4). These changes persisted into submaximal and maximal exercise. In addition, systemic blood pressure at submaximal exercise and pulmonary capillary wedge at maximal exercise were lower than prenifedipine values. First-dose nifedipine did not augment exercise duration. Regional hemodynamics. First-dose nifedipine caused a modest (8%) increase in renal blood flow, concomitant with a reduction in renal vascular resistance (Fig. 5). Limb vascular resistance decreased and limb blood flow increased (15 % ) after nifedipine. Neither hepatic blood flow nor hepatic vascular resistance changed after nifedipine. Ventricular inotropy and performance. Although the fractional shortening rate (velocity of circumferential fiber shortening) tended to increase (p = 0.10) after nifedipine, no other changes in the indices of left ventricular inotropy or performance were noted (Fig. 6). Chronic nifedipine. Three of the ten patients declined entry into a chronic phase of study, and one elected not to be rehospitalized for repeat hemodynamic evaluation. Of the six patients who were entered into the chronic phase of study, two died suddenly (at 6 and 10 weeks) and one patient had to discontinue nifedipine because of gastrointestinal symptoms (nausea and abdominal discomfort). Each of the three patients completing the study experienced enough improvement in heart failure symptoms to be advanced one functional class. However, these three patients gained 1.4, 2.3, and 3.6 kg over the 3-month period, requiring an increase in the diuretic dose in the latter patient. The resting and exercise hemodynamic recordings, obtained before nifedipine, after initial dosing, and with chronic dosing, from these three patients are presented in Table I. With chronic administration, exercise duration increased by 240 seconds in one patient and was essentially unchanged in the remaining two. The only consistent hemodynamic responses to chronic nifedipine dosing were a reduction in systemic vascular resistance and pulmonary capillary wedge pressure at rest and during exercise. With chronic dosing, two of the three patients also had a substantial reduction in mean systemic blood pressure, mean pulmonary artery pressure, and total pulmonary vascular resistance during upright rest and submaximal and maximal exercise. DISCUSSION Supine hemodynamics. In the setting of supine resting CHF, oral nifedipine at 0.2 mg/kg (dosing range of 10 to 20 mg) significantly reduced the pressure and resistance of both systemic and pul-

Nifedipine

effects in CHF

1465

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PRESSURE TIME

,

Fig. 6. Parameters of left ventricular inotropy and performance measuredduring the courseof this study.

manic vasculature with resultant augmentation of stroke volume and cardiac output. This biventricular reduction in afterload was accompanied by a mild drop in left ventricular filling pressure (approximated by the pulmonary capillary wedge pressure). These central hemodynamic findings are generally compatible with those reported by others2-s looking at first-dose oral or sublingual nifedipine in supine resting CHF. It is possible that some of the resting hemodynamic responses recorded 3 to 6 hours after nifedipine may have been altered somewhat by the exercise study performed between 2 and 3 hours after dosing. Upright hemodynamics. The upright position modified some of the supine resting hemodynamic responses to nifedipine. Mean pulmonary and systemic pressures and pulmonary capillary wedge pressure returned to predrug levels when the upright position was assumed. Presumably, the baroreceptor responses to upright positioning diminished the degree of nifedipine-induced vasodilation noted in the supine position. Since baroreceptor reflexes are generally blunted in patients with

1466

Table (Pre),

Leier et al.

American

December, 1994 Heart Journal

I. Hemodynamic data at upright resting, submaximal exercise, and maximal exercise obtained before dosing after first dose (Acute), and with chronic dosing (Chronic) in the three patients completing the study Upright Pre

Mean systemic blood pressure (mm Hg) Patient 1 111 2 110 3 73 Systemic vascular resistance (dynes-set-cm-s) Patient 1 3255 2 1964 3 2073 Mean pulmonary artery pressure (mm Hg) Patient 1 18 2 22 3 46 Total pulmonary vascular resistance (dynes-set-cm-‘) Patient 1 529 2 393 3 1300 Pulmonary capillary wedge pressure (mm Hg) Patient 1 15 2 15 3 30 Cardiac index (L/min/m*) Patient 1 1.80 2 2.24 3 1.70 Stroke volume index (ml/beat/m2) Patient 1 22 2 28 3 17 Heart rate (systoles/min) Patient 1 82 2 80 3 100 Exercise duration (set) Patient 1 2 3

Submaximal

resting

Acute

Chronic

Pre

exercise

Acute

Maximal

Chronic

Pre

exercise

Acute

Chronic

94 95 85

90 89 80

113 127 91

100 127 93

88 110 83

120 133 89

101 130 96

103 110 97

3032 1252 2547

2741 1537 1972

2123 1271 2218

1677 1120 1906

1622 1108 1437

1517 1287 1833

1303 1246 1726

1353 1108 1178

15 24 53

22 11 22

23 56 53

20 41 54

25 35 31

28 55 56

25 47 58

30 35 42

484 316 1582

670 189 542

431 562 1297

335 362 1111

461 353 534

354 531 1158

324 450 1043

393 353 508

11 18 35

8 6 18

13 34 39

11 23 41

9 20 21

17 34 40

10 23 40

5 20 31

2.84 3.99 1.90

3.12 4.45 2.35

2.88 3.85 2.80

4.14 4.10 2.32

1.67 3.04 1.63

1.75 2.27 1.93

4.07 4.10 2.62

4.06 3.85 3.97

19 39 16

19 28 23

29 35 17

30 42 21

30 36 28

37 36 20

36 38 22

39 36 31

88 78 102

92 81 84

98 114 112

104 106 112

96 107 100

112 114 116

113 108 120

104 107 128

510 540 315

480 257 462

525 240 555

CHF, the activation of baroreceptor reflexes during upright positioning after nifedipine is probably related to a drug effect. Several studies have shown that nifedipine augments the sensitivity and gain of the baroreceptor response.20-22Much of the postnifedipine reduction in systemic vascular resistance persisted in the upright position, suggesting that the primary effect of nifedipine, systemic arteriolar dilatation, generally survived the baroreceptor

responses of upright positioning; as a result, the postnifedipine augmentation of stroke volume and cardiac output remained intact when erect. Exercise hemodynamics. The reduction in systemic vascular resistance with improved cardiac output and stroke volume after nifedipine was also observed during exercise. While no other nifedipineexercise studies in heart failure are available for comparison or confirmation, the systemic vasodilat-

Volume

106

Number

6

ing effects of this drug during exercise appear to be an important mechanism for its antianginal properties.23 However, despite the favorable effects of nifedipine on afterload in CHF, exercise duration did not increase after initial dosing. This lack of acute improvement in exercise duration or oxygen consumption to initial dosing is characteristic for most of the vasodilating agents. Ventricular function. The calcium channel blocking effects of nifedipine did not adversely affect ventricular performance or inotropy in these patients with ventricular dysfunction. None of the inotropic indices measured changed significantly (Fig. 6). The augmented stroke volume occurring concomitantly with a reduced ventricular filling pressure indicates an improvement in overall ventricular performance after nifedipine. It appears that the calcium channel blocking effects of nifedipine at the myocardial level are mitigated by the vascular effects (afterload reduction) and therefore are not of major consequence in CHF. Ludbrook et al5 actually noted a positive inotropic response to nifedipine in patients with cardiac failure. However, in their study a higher dose (20 mg) was administered by the sublingual route; as a result, the drop in systemic blood pressure was greater, possibly improving ventricular function on the basis of augmented baroreceptor response mechanisms. While the Vcf in our study tended to increase (p = 0.10) after nifedipine, the lack of an otherwise demonstrable positive inotropic effect is probably related to dose and route of administration. The results of the two studies are compatible and quite complimentary. This study demonstrates a disparity in the responses of the pulmonary capillary wedge pressure and the right atrial pressure to nifedipine; the former decreased significantly and the latter remained unchanged. The same parameters were measured in the study by Bellocci et al6 with similar findings. At the doses used in this study nifedipine apparently had little effect on capacitance vessels or, alternatively, the mild venous relaxant effects were offset by increased flow leaving central venous pressure (mean right atrial pressure) unaltered. The postnifedipine drop in pulmonary capillary wedge pressure, noted in this and most previous studieP investigating this drug in CHF, is probably multifactoral; the major factors are probably related to ventricular unloading with improved performance, reduction in any degree of mitral regurgitation, and improvement of myocardial perfusion and oxygenation (even in patients with grossly normal coronary arteriesz4) in excess of any increase in myocardial oxygen consumption. Augmentation of diastolic

Nifedipine

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1467

function is also possible but is not supported by the studies of Ludbrook et al5 Regional hemodynamics. Nifedipine significantly reduced limb and renal vascular resistance, consistent with its systemic arteriolar dilating properties, with resultant augmentation of blood flow to these regions. The same trend was noted for the hepatic region, but the data did not achieve statistical significance. The increase in cardiac output averaged 13 % to 14 % during the regional flow determinations, which increased 7 % , 9%) and 15 % for renal, hepatic, and limb blood flow, respectively. This suggests that initial-dose nifedipine effects a mild redistribution of systemic blood flow in the setting of CHF; limb blood flow is increased to a similar degree as cardiac output and is preferentially augmented over visceral (specifically renal and hepatic) blood flow. Chronic nifedipine. Despite a mild increase in body weight, regular nifedipine administration elicited mild to moderate improvement of the symptoms of heart failure in the three patients who completed the chronic administration phase of study; this improvement was accompanied by persistent beneficial hemodynamic responses, noted at rest and during exercise in each. However, clinical improvement occurred in only three of six patients entering the chronic phase of study and prolongation of exercise duration occurred in only one of the three. Two of the six patients died suddenly and another developed side effects during chronic nifedipine administration. Actual deterioration of cardiac failure occurred after one dose of nifedipine in a patient reported by Gillmer and Kark.g These issues, plus the fact that nifedipine elicits only mild preload reduction, make it unlikely that nifedipine alone will become a first-line vasodilator in the setting of CHF. Nevertheless, this calcium channel blocker may be of benefit to some patients with chronic CHF, particularly patients refractory to or intolerant of other agents and, perhaps, patients with concomitant occlusive coronary artery disease. The authors would like to thank Max Bather, Deborah King, and Elena Popescu for their technical assistance and the nursing and house staff of the coronary unit for their professional care of these patients. REFERENCES

1. Mikkelsen E, Anderson K, Pederson OL: The effect of nifedipine on isolated human peripheral vessels. Acta Pharmacol Toxic01 43:291, 1978. 2. Polese A, Fiorentini C, Olivari MI, Guazzi MD: Clinical use of a calcium antagonist agent (nifedipine) in acute pulmonary edema. Am J Med 66:825, 1979. 3. Matsumoto S, Ito T, Sada T, Takabashi M, Su K, Ueda A, Okabe F, Sato M, Sekine I, Ito Y: Hemodynamic effects of

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4. 5.

6.

7.

8.

9. 10.

11. 12.

13.

14.

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nifedipine in congestive heart failure. Am J Cardiol 46:476, 1980. Klugman S, Salvi A, Camerini F: Hemodynamic effects of nifedipine in heart failure. Br Heart J 43:440, 1980. Ludbrook PA, Byrne JD, Reed FR, McKnight RC: Influence of nifedipine on left ventricular systolic and diastolic function. Am J Med 71:683, 1981. Bellocci F, Ansalone G, Santarelli P, Loperfido F, Scabbia E, Zecchi P, Manzoli U: Oral nifedipine in the long-term management of severe chronic heart failure. J Cardiovasc Pharmacol 4:847, 1982. Elkayam U, Weber L, Torkan B, Berman D, Rahimtoola SH: Acute hemodynamic effect of oral nifedipine in severe chronic congestive heart failure. Am J Cardiol 52:1041, 1983. Brooks N, Cattell M, Pidgeon J, Balcon R: Unpredictable response to nifedipine in severe cardiac failure. Br Med J 281:1324, 1980. Gillmer DJ, Kark P: Pulmonary oedema precipitated by nifedipine. Br Med J 280:1420, 1980. Lewis RP, Leighton RF, Forester WF, Weissler AM: Systolic time intervals. In Weissler AM, editor: Noninvasive cardiology. New York, 1974, Grune & Stratton, Inc, p 301. Diamond G, Forrester JS, Chatterjee K, Wegner S, Swan HJC: Mean electromechanical AP/At. Am J Cardiol 30:338, 1972. Agress CM, Wegner S, Forrester JS, Chatterjee K, Parmley WW, Swan HJC: An indirect method for evaluation of left ventricular function in acute myocardial infarction. Circulation 46:291, 1972. MacDonald IG, Feigenbaum H, Cheng S: Analysis of left ventricular wall motion by reflected ultrasound. Circulation 46:14, 1972. Fortuin NJ, Hood WP, Craig E: Evaluation of left ventricular function by echocardiography. Circulation 46:26, 1972.

American

15.

16.

17.

18.

19.

20.

21.

22.

23. 24.

December, 1984 Heart Journal

Magorien RD, Triffon DW, Desch CE, Bay WH, Unverferth DV, Leier CV: Prazosin and hydralazine in congestive heart failure: Regional hemodynamic effects in relation to dose. Ann Intern Med 965, 1981. Weigand BD, Ketterer SG, Rapaport E: The use of indocyanine green for the evaluation of hepatic function and blood flow in man. Am J Dig Dis 6427, 1960. Caesar J, Sheldon S, Chiandussi L, Guevera L, Sherlock S: The use of indocyanine green in the measurement of hepatic function. Clin Sci 21:431 1961. Wheeler HO. Cranston WE. Meltzer JD: Henatic untake and biliary excretion of indocyanine green in the dog.‘Proc Sot Exp Biol QQ:ll, 1958. Chasis H, Redisch J, Goldring W, Ranges HA, Smith HW: Use of sodium p-aminohippurate for functional evaluation of the human kidney. J Clin Invest 24:583, 1945. Prida XE, Kubo SH, Laragh JH, Cody RJ: Evaluation of calcium-mediated vasoconstriction in chronic congestive heart failure. Am J Med 75:795, 1983. McLeay RAB, Stallard TJ, Watson RDS, Littler WA: The effect of nifedipine on arterial pressure and reflex cardiac control. Circulation 67:1084, 1983. Heesch CM, Thames MD, Abboud FM: Effects of calcium antagonists on carotid sinus baroreceptors. Fed Proc 41:1116, 1982. Braunwald E: Mechanism of action of calcium channel blocking agents. N Engl J Med 307:1618, 1982. Unverferth DV. Maeorien RD. Lewis RP. Leier CV: The role of subendocardial &hernia in perpetuating myocardial failure in patients with nonischemic congestive cardiomyopathy. AM HEARTJ 105:176,1983.