Unloading effects of prazosin in patients with chronic aortic regurgitation

Unloading effects of pr chronic aortic regurgitation

n in #!S&#ents with

Seventeen patients with chronic aortic regurgitation (AR) were examined by echocardiography and left and right heart catheterization. Cardiac output and regurgitation volume were measured by the dye dilution method. Administration of single and four repeated doses of prazosin (PZ) led to reductions of left ventricular (LV) end-diastolic, end-systolic, and left atrial end-systolic diameters, and decrease of left ventricular filling pressure. Regurgitation fraction, regurgitation flow, and volume indexes decreased significantly (p < 0.01). Total left ventricular output decreased (p < 0.001) as did derived parameters of left ventricular work and performance. Fractional shortening, ejection fraction, and mean circumferential fiber shortening velocity increased as dld LV dP/dt and dP/dt/P. Changes in heart rate and cardiac and stroke indexes after PZ were not significant. Preload reduction (dilation of the venous bed and reduction of regurgitation) seems to be the most important effect of PZ in AR. We found PZ to be a suitable and effective drug for oral treatment of chronic AR. (AM HEART J 105567, 1963.)

Pave1 Jebavy, MUDr., CSc., Eva Koudelkova, MUDr., CSc., and Milena Henzlova, MUDr., CSc. Prague, Czechosloualzia

Vasodilating drugs have been shown to be beneficial in the treatment of congestive heart failure,*-3 as well as mitra14j 5 and aortic regurgitation.6-13 The failing left ventricle (LV) is burdened by a large diastolic volume and must overcome increased afterload as well. Dilation of the systemic venous bed, for example, by nitroglycerin, reduces pieload with decreased left ventricular filling which is followed by amelioration of pulmonary congestion. Arteriolar dilators such as phentolamine or hydralaxine lower left ventricular afterload; as a result LV emptying improves. Precise knowledge of the patient’s acute hemodynamic state makes the choice of an appropriate drug (or combination of drugs) easier. Effective vasodilating therapy should influence both systemic venous and arterial vascular beds. In patients with aortic regurgitation (AR) powerful arteriolar dilators such as sodium nitroprusside,8-1’ amyl nitrite,6v ’ and hydralaxine12* l3 have been found to be useful. With the possibility in mind of long-term outpatient therapy for severe chronic AR, we choose the oral vasodilator, praxosin (PZ). PZ (Minipress, Pfizer Laboratories, New York, NY), a postsynaptic alpha-blocking agent, seemed a promising alternative because of its balanced effect on From Received accepted Reprint kia.

the Institute

for Clinical

for publication Nov. 12, 1981. request:

P. Jebav+,

April

and

Experimental

14, 1981; NBm.

Miru

revision

Medicine. received

18, 120 00 Praha

Aug.

12, 1981;

2, Czechoslova-

venous and arterial beds, its prolonged action (at least 6 hours), and few side effect.s.14s15It has been used repeatedly for therapy of congestive heart failure.*6-20 Apart from demonstration of expected decrease of intracardiac pressures, we measured changes in regurgitation volume and left heart volume after single and repeated doses of PZ. METHODS Patients (Table I). We examined 17 patients (11 men and 6 women),whosemeanagewas44.5 years (range 13 to

55 years); all had severe chronic AR. Aortic stenosiswas present in 14 patients, the average peak systolic gradient never exceeding30 mm Hg. Mild mitral regurgitation was found in two patients and moderate mitral stenosisin one (orifice area 2.2 cm2).Coronary arteriograms were normal in all patients. Sixteen patients had sinusrhythm and one had atria1 fibrillation. None had clinical signs of heart failure; 14 patients weretaking cardiotonics, eight of them diuretics aswell. At the time of the study none wasbeing treated with hypotensives, nitrates, or beta-blocking agents. The patients received their usual dose of cardiotonics and diuretics 24 hours before investigation. Informed consent was obtained from all patients. Echocardiographic examination. Such evaluation was performed with Echocardio-Visor (Organon Teknika) using the M-mode technique with a 2.25 MHz transducer focused at 7.5 cm; recording speed was 50 mm . set-‘. Position of the transducer at the first examination was marked and used for all subsequent measurements;the patient’s position was also always the same. LV enddiastolic dimension(Dd) and end-systolic dimension(Ds) were measuredbelow the mitral leaflets, usingthe R spike 567

666

Jebavjr,

Koudelkovb,

and Henzlovb

April, 1983 Heart Journal

American

LA

w mm

mm

loo 1

contrd 1 L,.O.WNP:

Pi

PZ 24 (8) hours

p 0.0012 l

p

l

0.01

-I

1. Changesin left ventricular end-diastolic diameter (Dd) and left atrial end-systolic dimension (LA) after prazosin (PZ) (n = 15 patients).

Fig.

I. Clinical characteristics of the patient group

Table

Patient NO.

NYHA Sex

Age

BSA

1 2 3 4 5

M F

6 7 8 9 10 11 12 13 14 15 16 17

M M F M F M M M M M M F

32 42 18 37 38 50 55 55 53 52 30 46 32 34 39 49 39

1.93 1.73 1.90 2.08 1.80 1.63 1.90 1.61

M M F

Etiology RHD RHD RHD RHD RHD RHD RHD RHD

class

History of paroxysmal noctural dyspnea

Hypertrophy + + + + + + +

II III II III II I I II

+ -

2.06 Marfan syndrome

II

-

+

1.57 1.68 1.80 1.75 1.92 1.95 1.79 1.65

II III II

+ + -

+ + +

+ + -

RHD RHD RHD

-

Fourth heart

ECG signs of LV Strain

Therapy (total daily dose in mg)

sound

+ + + +

+ + + +

+ + +

+ +

+ + + +

+ +

Lan 0.5 Dig 0.25 Lan

0.5; Furo

Lan Dig Dig Dig Dig Dig

0.25 0.25; 0.25; 0.25; 0.5; 0.5

Furo 40 Furo 40 Furo 20 Furo 20

Marfan syndrome

II

-I-

+

+

Dig 0.25

RHD RHD RHD RHD

II II II III

+ + + +

+ + + +

+ +

Dig Dig Dig Dig

Abbreviations: BSA = body surface area; RHD = rheumatic Dig = oral digoxin; Furo = oral furosemide.

heart disease; NYHA

of simultaneousECG asreference. Left atrial end-systolic dimension (LA) was measuredbetween poet&or wall of the aortic root and the left atrial wall. All parameterswere calculated as the mean of 10 cardiac cycles. With the use of standard formulas the following parameters of LV function were caIculatedz’: fractional shortening (FS), ejection fraction (EF), and mean circumferential fiber

= New York Heart

Association

functional

40

0.5; Furo 40 0.25 0.25; Furo 40 0.25; Furo 40

class; Lan E lanabside;

shortening velocity (V,,). LV ejection time (ET) was measuredfrom a simultaneously recorded carotid pulse tracing. In all patients two examinations at rest were performed; the mean of recorded values served as the control value. Systemic pressurewasobtained by the cuff method. Satisfactory recordings of all parameters were obtained and analyzed in 15 patients.

Volume Number

105 4

Prazosin therapy in chronic aortic regurgitation

1.1 a9 -

CCNWd

1 Lpmol-1

.

A

4

PZ

PZ p.aoo?~

Pi? 24 (8) bum p ‘ 0.0s-I

Fig. 2. Changesin fractional shortening (FS) and mean circumferential fiber shortening velocity (V,,)

after prazosin (PZ) (n = 15 patients).

Cardiac catheterization. A Cournand catheter was introduced via the right femoral vein into the pulmonary artery by meansof the Seldinger technique; a Brockenbrough Teflon catheter wasadvanced via the femoral vein through septal puncture into the left atrium and further into the LV. A third catheter was inserted via the right femoral artery and placed above the aortic orifice. Heart rate (HR) wascalculated from simultaneousECG. Oxygen consumption (00,) was obtained by air collected in Douglas bags for 5 minutes at the time of pressure measurements.Intracardiac pressureswere recorded with Statham P 23Db pressuretransducers and registered on Mingograph 82 with paper speed of 106 mm . set-‘. The reference level was 5 cm below manubrium sterni. Mean pressuresin the pulmonary artery (Fri,,) and in the aorta (i?*,) were obtained by electric integration. Left ventricular filling pressure (LVEDP) was measured at the “z” point as the mean of one respiratory cycle. Mean systolic pressurein the left ventricle (ms) wasevaluated planimetrically as the area beneath the pressurecurve during ET from five (in atria1 fibrillation from 10) successivecardiac cycles. Aortic systolic gradient, if present, was evaluated alsoplanimetrically. Parameter of contractility (dP/dt/P) was obtained by dividing the maximal first derivative of LV pressure (dP/dt) by LV pressure at the time of maximum derivative. Fluid-filled LV catheter was always of standard length. Cardiac output (CO), cardiac index (CI), and stroke index (SI) were measured by the dye dilution method with Gilford 103 or Waters Cor 1OOA devices. The dilution curves were obtained by injecting Cardiogreen (2.5 to 5.0 mg in 1 ml of water) into the LV and drawing blood from the aorta via a flow cuvette. The mean of at least two measurementswas used. Regurgitation curve was obtained after slow injection (over several cardiac cycles) of the sameamount of dye into the aortic

bulbus; blood was drawn from the LV. The injection was repeated at least three times and the mean of two lower measurementscalculated to assessregurgitation volume index (RVI). Aortic regurgitation fraction (RF) wasevaluated as the ratio of the area of the curve from the LV and the area of the curve from the aorta expressed as a percentage.22 Calculations. Total systemic vascular resistance(SR), regurgitation flow index (RI), total left ventricular output index (CI-LV), left ventricular stroke index (SL-LV), left ventricular stroke work index (SWI-LV), left ventricular work index (LVWI), left ventricular stroke performance index (SPI-LV), and tension time index (TTI) were calculated according to the following formulas: SR = PA,,/ CO X 80 in dynes . set . cm+; RI = RF X CI/lOO-RF in ml . m+; CI-LV = CI + RI in L . min-’ . m+‘; SILV = CI-LV/HR in ml . m+; SWI-LV = SI-LV x (ms - LVEDP) X 13.6 X 10e3in gm . m . mm2;LVWI = SWI-LV x HR x 10F3in kg . mine1. me2;SPI-LV = SWILV/ET in gm . set-’ . rne2;andTTI=msxETxHRin mm Hg . set . min-I. Protocol design. Echocardiography was performed twice before PZ tablet administration (control), 1 hour and 6 hours after the first dose,and finally 8 hours after the last dose.The dose (2 to 7 mg) was adjusted to the patient’s body build, HR, blood pressure, and left heart volume recorded at rest. The samedosewasadministered at g-hour intervals over 24 hours (four dosesin all). PZ did not elicit untoward effects requiring discontinuation in any patient. Only two patients complained of vague orthostatic symptoms after the first dose,which did not reappear. Other complications did not occur. Catheterization began48 hours to 72 hours after the last echocardiographic examination. It was performed in the morning after an overnight fast with the patient supine.

April,

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Jebavi,

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and Henzlovci

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Heart

1983 Journal

50

40

30

20

10

p < 0.025

p < 0001

Fig. 3. Pulmonary arterial mean pressure and left ventricular filling pressure after prazosin (n = 17

patients).

After control measurementswere recorded, we administered the samedoseof PZ asbefore echocardiographyand repeated all measurementsone hour later. Angiography of the LV and aortic root, and selective coronary arteriography were performed after all hemodynamicmeasurements were completed. Statistlcal analysis. For statistical analysis we used paired t test and the method of linear regression. RESULTS Echocardiography. The echocardiographic examination (control) confirmed dilation of the LV and LA. The ejection parameters of the LV were depressed; FS was abnormal in five, EF in nine, and Vc, in 11 patients. HR did not change at any interval (72 + 10 control; 74 ? 12; 75 + 12; 74 + 10, 1, 6, and 24 hours after PZ). Decrease of P,,, was observed 1 and 6 hours after the first dose (94 f 11 control; 86 _+ 9; 86 f 13 mm Hg; p < 0.01); no change was present 8 hours after the last dose (94 + 11 mm I-k). One hour after PZ significant decrease of Dd and LA was seen, which was still present 6 hours after the first and 8 hours after the last dose (Fig. 1). Ds changed similarly (55 f 12 control; 50 + 12; 51 + 12; 52 -t 12 mm; p < 0.005). LV ejection parameters of FS and V,, improved 1 and 6 hours after PZ and remained so 8 hours after the Iast dose (Fig. 2); so did EF (54 + 12 control; 62 + 13; 62 f 13; 61 +

12%; p < 0.025). Hemodynamics. Hemodynamic examination (control) confirmed the diagnosis of severe AR with average RF of 64 + 18 % . RI from the aorta into the LV was 6.35 + 3.89 L . min -l. me2, RVI was 91 +65 ml . me2 and CI-LV and SI-LV were 8.99 f 3.94 L . min-’ . me2 and 129 rt 72 ml - mm2, respectively, confirming LV volume overload. The parameters of LV work and performance (SWI-LV, LVWI, and SPI-LV) were abnormally high. SR was slightly increased in only three patients. LVRDP exceeded the normal value of 12 mm Hg in 11 patients; increased ‘ppA (above 20 mm Hg) and depressed CI (below 2.5 L . min-’ . rnm2)were observed in seven and four patients, respectively. One hour after PZ we did not observe important changes in HR (75 + 23 control; 78 f 24 beats/ min), VO, (243.1 2 42.1; 271.6 _+ 68.3 ml - min-‘), CI (2.64 -+ 0.41; 2.69 + 0.59 L . min-’ . mp2), and SI (38 + 11; 36 f 9 ml . m-“). PZ induced significant decreases of PPA and LVEDP (Fig. 3) as weII as of FAO (88 f 12; 79 + 13 mm Hg; p < O.Ol), ms (127 & 17; 117 f +l mm Hg; p < O.Ol), SR (1512 + 392; 1368 + 336 dynes . set - cmb5; p < O.Ol), and TTI (3008 + 536; 2613 + 759 mm Hg . set . min-‘; p < 0.01). After PZ we found significant diminution of RF, RI, and RVI (Fig. 4). As a result CI-LV feII as did SI-LV, SWI-LV, LVWI, and SPI-LV (Figs. 5

Volume Number

105 4

Prazosin therapy in chronic aortic regurgitation

80-

571

200&‘E

70-

z x 8 c 9

6-

150-

“s 2 c 0

loo-

g p&

50

B

10-l

L

L

p < 0.001

p -z0.001

p
Fig. 4. Changesin regurgitation fraction, regurgitation flow index, and regurgitation volume index after

prazosin (n = 16 patients).

t-7 ‘E

300

z X

3

I

,

p< 0001

,

I

P<

0001

5. Changesin left ventricular output index and left ventricular stroke index after prazosin (n = 16 patients). Fig.

and 6). Both LV dP/dt and dP/dt/P increased significantly after PZ (1917 -+ 696 control; 2409 + 926 mm Hg . see-‘; p < 0.01 and 30.9 +- 13.6; 39.4 + 18.4 set-‘; p < 0.05). LVEDP reduction (ALVEDP) depended on

the initial level of LVEDP (ALVEDP = -0.599 X LVEDP control + 3.776, r = 0.754; p < 0.001. We found a correlation between ALVEDP and RI decrease (ARI) (AR1 = 0.225 X A LVEDP - 1.224, r = 0.705; p < O.Ol), as well 89

April,

572

Jebav$,

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and Henzlovci

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Heart

1983 Journal

I-

I-

e p< 0,005 Fig.

p < 0,005

p
6. Changesin left ventricular work and performance parameters after prazosin (n = 16 patients).

between ALVEDP and CI-LV decrease (ACI-LV) and LVWI decrease (ALVWI) (ACI-LV = 0.246 X ALVEDP - 1.016, r = 0.681; p < 0.01; A LVWI = 0.330 x ALVEDP - 1.820, r = 0.540; p < 0.05). Relation between SWI-LV, LVWI, and LVEDP is shown on Fig. 7. DISCUSSION Previous studies. Drug therapy of severe AR is seldom considered; surgical therapy is a better alternative. Yet for some patients operation is not feasible or there may be a waiting time for it. Apart from nitroprusside, amyl nitrite, and hydralazine,‘j-13 we observed in a preliminary studyz3 beneficial effects of nitroglycerin and PZ. To our knowledge only Hockings et alz4 reported desirable hemodynamic changes after PZ in eight patients with AR. They found slight decreases of FA,, and SR, and a 12% increase of CI. SR and Cl. In our study PZ lowered FAOand led to moderate reduction of SR. At rest both these parameters were within normal limits. Nevertheless, whenever increased SR was present it invariably decreased after PZ, as observed by others in patients with congestive heart failure.ls3 CI did not increase. However, again in all patients with low CI it increased after PZ with concomitant decrease of SR. LVEDP and LV work. The decreases of LVEDP and &A after PZ were significant, both being proof of its venodilating capacity. Decrease of RF was caused by

a fall of RI which represented a major portion of CI-LV and was accompanied by a fall of all derived indices of LV work and performance (SWI-LV, LVWI, and SPI-LV). Cardiac volumes. Reduction of cardiac volumes (Dd, Ds, and LAS) observed after PZ therefore seems to be attributable to a combination of improved LV ejection (decreased afterload), venodilation, and decreased regurgitation flow (decreased preload). HR did not change significantly enough after PZ to explain observed changes in heart volume. Preload and afterload changes. Improved ejection function of the LV (FS, EF, and Vc,) and increase of parameters of contractility (LV dP/dt and dP/dt/P) can also be explained by changes in loading rather than by the positive inotropic effect of PZ which this drug is not known to have.15 Observed changes are similar to those seen after nitroglycerin23; therefore we believe that preload reduction after PZ is more important than afterload decrease. AR quantifkation. Quantification of aortic regurgitation by means of the dye dilution method has its limitations.25*26 In order to avoid diastolic injection (and obtain falsely high regurgitation volumes), we injected the dye slowly over several cardiac cycles. Our method correlates well with the continuous 133-Xe infusion method27; nevertheless some overestimation of massive regurgitation cannot be ruled out.

Volume Number

105 4

Prazosin therapy in chronic aortic regurgitation

573

25 2015-

10-

s-

I Left ventricular

filling

pressure

Fig. 7. Relation between left ventricular performance (n = 16 patients).

filling pressure and parameters

Effects of PZ were similar after the first dose and after four doses 24 hours later. The last changes observed were less pronounced than the acute ones. According to some reports, patients with heart failure have developed resistance to PZ.28-30On the contrary, Rubin et aL31 and Goldman et a1.32 described sustained beneficial effects of PZ during exercise 7 to 12 weeks after initiation of therapy, Our data do not allow us to comment further on chronic therapy. Nevertheless, we believe that PZ decreases LV metabolic demand in chronic AR and can be recommended for prolonged oral therapy as is the case in congestive heart failure.33 Chronic

effects.

7.

8.

9.

10.

11.

We thank Mrs. B. Burianova for statistical analysis and Mrs. L. Sroiikova for help in preparation of the manuscript.

12.

REFERENCES

13.

1. Franciosa JA, Guiha NH, Limas CJ, Rodriguera E, Cohn JN: Improved left ventricular function during nitroprusside infusion in acute myocardial infarction. Lancet 1:650, 1972. 2. Miller RR, Vismara LA, Williams DO, Amsterdam EA, Mason DT: Pharmacological mechanism 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, 1976. 3. Chatterjee K, Parmley WW: Vasodilator treatment for acute and chronic heart failure. Br Heart J 39~706, 1977. 4. Chatterjee K, Parmley WW, Swan HJC, Berman G, Forrester J, Marcus HS: Beneficial effects of vasodilator agents in severe mitral regurgitation due to dysfunction of subvalvular apparatus. CirculaGon 48:684,1973. 5. Goodman DJ, Rossen RM, Holloway EL, Alderman EL, Harrison DC: Effect of nitroprusside on left ventricular dynamics in mitral regurgitation. Circulation 50~1025, 1974. 6. Delius W, Enghoff E: Studies of the central and peripheral

20

10 Left ventricular

i mmHg I

14.

15.

16.

17.

fdling

40

30 pressure

of left ventricular

(mmtfg

I

work and

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18. Awan NA, Miller RR, Mason DT: Comparison of effects of nitroprusside and prazosin on left ventricular function and the peripheral circulation in chronic refractory congestive heart failure. Circulation 57:152, 1978. 19. Mehta J, Iacona M, Feldman RL, Pepine CJ, Conti CR: Comparative hemodynamic effect of intravenous nitroprusside and oral prazosin in refractory heart failure. Am J Cardiol41:925, 1978. 20. Aronow WS, Lurie M, Turbow M, Whitaker K, Van Camp S, Hughes D: Effect of praxosin vs placebo in chronic left ventricular heart failure. Circulation 59:344, 1979. 21. Feigenbaum H: Echocardiography, ed 2. Philadelphia, 1976, Lea & Febiger, Publishers p 512. 22. Malooly DA, Donald DE, Marshall HW, Wood EH: Assessment of an indicator-dilution technic for quantitating aortic regurgitation by electromagnetic flowmeter. Circ Res 12:487, 1963. 23. Jebavy P, Koudelkova E: Effect of nitroglycerin and prazosin on aortic regurgitation. In: Abstracts VIII European Congress of Cardiology, Paris, June 22-26, 1980, Basel, 1980, S Karger AG, p 27. -24. Hockings BEF, Cope DG, Clarke GM, Taylor RR: Comparison of vasodilator drug prazosin with digoxin in aortic regurgitation. Br Heart J 43:550, 1980. 25. Armelin A, Michael L, Marshall HW, Donald DE, Cheesman RJ, Wood EH: Detection and measurement of experimentally produced aortic regurgitation by means of indicatordilution curves recorded from left ventricle. Circ Res 12:269, 1963. 26. Yousof AM, Endrys G, Steinhart L: Effect of rapid timed

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