Cardiovascular Drugs and Therapy 3: 313-317, 1989 © Kluwer Academic Publishers. Printed in the U.S.A.

REGRESSIONOF LEFTVENTRICULAR HYPERTROPHYBY ACEBUTOLOL AND NIFEDIPINE

SUMMARY. Fourteen patients with previously untreated essential hypertension and left ventricular hypertrophy were treated with a fixed-dose combination of acebutelol 200 m g and nifedipine 20 m g once daily for a followup of 25.6___1.8 months. Echocardiography showed a significant decrease after a mean period of 6.6 months in interventricular septal thickness (14.8%, p < 0.001), posterior wall thickness (14.8%, p < 0.001), and left ventricular mass index (21.3%). After 25.6 months, the reductions were 29% (p ,~ 0.001), 28.1% (p < 0.001), and 38.7% (p < 0.001), respectively. Left wall thickness was significantly reduced, but left ventricular end-systolic and end-diastolic dimensions and fractional shortening remained unchanged. Treatment reduced resting blood pressure from 161/102 mml-[g to 132/87 m m H g (p < 0.001) and reduced exercise blood pressure at 100 W from 208/113 mml-[g to 170/94 m m ~ g (p < 0.001). Thus, nifedipine in combination with acebutolol produces significant blood-pressure reduction accompanied by regression of left ventricular hypertrephy without noticeable changes in left ventricular function. KEY WORDS. hypertension, left ventricular hypertrophy, beta receptor blockers, calcium antagonists

L eft ventricular hypertrophy is a serious complication of sustained elevation of blood pressure. Until recently, reversal of left ventricular hypertrophy in hypertension was mainly studied in animals. Evidence from these studies has suggested that various antihypertensive drugs may have different effects on hypertrophy, despite exerting the same degree of blood-pressure control. When echocardiography became widely available, it provided a noninvasive method of assessment of left ventricular dimensions [1]. Studies have shown that the reversal of hypertrophy can be achieved either with methyldopa [2] or beta blockers [3-5], whereas diuretic drugs [6] and some vasodilators [7] were ineffective. In humans the effect of vasodilators has been investigated in only a small number of patients for short treatment periods. A reversal of left ventricular hypertrophy was demonstrated by Nakashima et al. [8] using enalapril in seven patients, by Strauer et al. [9] using nifedipine in 12 patients, and by Franz et al. [10] using gallopamil in 26 patients. The aim of this long-term study was to investigate the effects of a fixed-dose combination of the calcium antagonist nifedipine and the beta blocker acebutolol on left ventricular hypertrophy and function in patients with essential hypertension.

Ingomar-Werner Franz, Ulrich T6nnesmann, Ulrich Behr, Reinhard Ketelhut Klinik Wehrawald der BfA, Todtmoos, Federal Republic of Germany

Patients and Methods Fourteen male patients with essential hypertension (mean age 52.2 ± 8 years) participated in the study after giving informed consent. All patients had outpatient casual measurements of blood pressure greater than 140/90 m m H g on three separate occasions and a pathologically increased blood-pressure response during and after exercise.N o patient had received antihypertensive therapy before the study. The criteria for inclusion were as follows: left ventricular hypertrophy proved by echocardiographic measurements (septal thickness and posterior-wall thickness in enddiastole greater than 11 ram; left ventricular mass index, as described by Defereux and Reichek [I] greater than 95 g/m2); adequate blood-pressure reduction following a 4-week treatment period with a fixeddose combination of nifedipine 20 mg and acebutolol 200 mg once daily (resting blood pressure less than 140/ 90 mmHg, exercise blood pressure at 100 W less than 200/100 mmHg); no evidence of heart failure, myocardial infarction, angina pectoris, or complicating congenital or valvular heart disease; and no concomitant therapy with other antihypertensive agents. After the initial pretreatment study, the patients were treated with a fixed-dose combination of nifedipine 20 mg and acebutolol 200 mg once daily. This dose was kept constant over a period of 25.6 + 1.8 months. Echocardiographic studies were performed before treatment and after 6.6 _+ 1.5, 12.4 + 1.0, 19.9 ___1.2, and 25.6 _+ 1.8 months of treatment. M-mode echocardiography was performed with two-dimensional monitoring using a sonotron (model

Address for correspondence and reprint requests: Prof. Dr. I.- W. Franz, Klinik Wehrawald der BfA, 7865 Todtmoos, Federal Republic of Germany.

313

314

Franz et at.

3400 R) phased-array ultrasonic sector scanner and 2.4 mHz transducer. The patients were examined in the left lateral position, and the head of the bed was elevated by 30 ° . The transducer was placed in the third or fourth intercostal space, where the mitral valve could be seen clearly. Special care was taken to avoid misleading angulation of the left ventricular long axis. Measurements of the internal dimensions of the left ventrical, the thickness of the interventricular septum, and the posterior wall were made according to the recommendations of the American Society of Electrocardiography and were obtained by the same investigator, and all measurements were performed blind by two observers from at least two sets of a m i n i m u m of six consecutive cardiac cycles each. Left ventricular mass (LVM) was estimated by use of the formula of Devereux and Reichek [1] and was divided by the body surface area to derive the left ventricular mass index (LVMI). The relative wall thickness (RWT) was calculated at end diastole by the ratio: R W T = 2 P W T / LVID d. The standard procedure for ergometric exercise testing and the standard technique of blood-pressure measurement were used [12, 16]. All mean values are given with one standard deviation, and the Wilcoxin test was used for statistical analyses.

Septum, posterior wall, left ventricular mass index and relative wall thickness during antihyperlensive therapy interventricular septum thickness (IVST) posterior wall thickness

mm

(PWT)

16

T

14

r ...

""

"p<0.05 "'p<0.01 ""p<0.001

r

12 lO

I 1

g/m2 180

lelt ventricular mass inclex T (LVMI) .

relative wall thickness (RWT) T

140

..,

t [

0.7 0.6 0.5 OA

~o~ r-'i before theropy ~ 6.6 +_1.5 months 200rag acebutolol+ 20mg n fedip ne I l l 12.4 _+1.0 months 200 mg acebutolol + 20 mg nifedipine

Fig. 1. Regression of left ventricular hypertrophy during tong-term treatment with a fixed combination of acebutolol and nifedipine. 1 V S T = interventricular septal thickness; P W T = posterior wall thickness; L V M I = left ventricular mass index; R W T = relative wall thickness. * p < 0.05; ** p < 0.01; *** < 0.001.

Results Echocardiographic Indices After a mean treatment period of 6.6 months, there was a significant decrease (14.8%, p < 0.001) in interventricular septal thickness (IVST), a 14.8% (p < 0.001) decrease in posterior wall thickness (PWT), and a 21.3% decrease in LVMI (Table 1, Figure 1). In the

Table 1. Regression of left ventricular hypertrophy during long-term treatment with 200 mg acebutolol and 20 mg nifedipine in 14 hypertensive patients. Echocardiographic indexes of LVH during reversal (mean ± SD)

Before treatment 6.6 ± 1.5 m o n t h s 12.4 ± 1.0 months 19.9 ± 1.7 months 25.6 ± 1.8

IVST

PWT

LVMI

RWT

(mm)

(mm)

(g/m 2)

(%)

14.5 + 2

11.8 ± 1

12.4 _ 2 c

10.1 ± 1c

150.7 + 29

0.5

+ 0.06

LV1D d (mm)

LVIDs

FS

(mm)

(%)

47.6 _+ 4.3

27.4 + 4.4

42.9 _+ 5.8

118.6 ± 27 c

0.42 + 0.07 c

47.6 +_ 4.7

27.5 +_ 4.0

42.5 ± 5.5

108.2 ± 24

0.40 ± 0.05

47.8 ± 4.2

27.6 ± 3.9

42.2 ± 5.8

11.4 ± 1.7

9.6 ± 1.7

10.7 __ 1.2 b

8.9 ± 0.7 b

99.0 ± 22.5 b

0.37 ± 0.05 b

48.1 ± 5.0

26.6 ± 4.1

44.9 ± 4.4

10.3 ± 1.0b

8.5 ± 0.6 a

92.3 ± 21 b

0.36 ± 0.04

47.6 ± 4.7

26.4 ± 3.9

44.9 ± 5.0

months I V S T = interventricular septal thickness; P W T = posterior wall thickness; L V M I = leftventricular mass index; R W T = relative wall thickness; L V I D = left ventricular dimension in end-diastole (d) and end-systole (s); FS = fractional shortening, ap < 0.05; bp < 0.01; Cp < 0.001.

LV Hypertrophy

followup there was a further continuous and significant reduction after 12.4, 19.9, and 25.6 months of treatment, (LVMI: 28.2%, p < 0.001, 34.3%, p < 0.01, 38.7%, p < 0.01, respectively; IVST: 21.2%, p<0.001, 26.2%, p < 0.01, 29%, p < 0.01, respectively; PWT: 19%, p < 0.001, 24.7%, p < 0.01, 28.1%, p < 0.05, respectively). In addition to a reduction in previously elevated heart-wall thickness, there was a significant reduction in RWT (p < 0.001) and no change in left ventricular end-diastolic and end-systolic dimensions after 25.6 months of treatment. Fractional shortening (FS) also remained unchanged (Table 1).

Blood Pressure The mean blood pressure at rest of 161 + 17 mmHg over 102 + 8 mmHg before therapy was significantly reduced to 132 + 15.8 mmHg over 87 + 9 mmHg (p < 0.001) after 4 weeks of combined therapy and remained unchanged after 12.4 months (Table 2). Exercise blood pressure, at a 100-W workload, of 208 + 24 mmHg over 113 + 9 mmHg was also significantly reduced to 170 + 23 mmHg over 94 + 9 mmHg (p < 0.001) (Table 2).

Discussion The findings of this study show that, in hypertensive patients, long-term treatment with calcium antagonists and beta-blockers produces a significant lowering of blood pressure accompanied by regression of left ventricular hypertrophy (LVH). It is of clinical interest to compare the effects of different antihypertensive drugs on LVH. However, several prerequisites are essential to allow a reliable comparison of different studies. Only previously untreated hypertensives (not

315

included after a washout period) with echocardiographically confirmed L V H and undisturbed myocardial function should be included; the baseline levels of L V H and the age groups should be identical, and there should be similar and sufficient blood-pressure control under resting conditions. Our own studies fulfillthese criteria, and it therefore seems reasonable to compare the results (Figure 2). The percentage reduction of L V M I after 1 year of treatment with acebutolol and nifedipine (28.2%) is in good agreement with 30.8% after atenolol (50 rag) and nifedipine (20 rag) [10]. However, it is more pronounced than with beta-blocker monotherapy (200 m g metoprolol, 21.9%) [4], calcium antagonist monotherapy (100-150 m g gallopamil, 13.2%) [10], or combined therapy with a beta-blocker and an A C E inhibitor (50 m g atenolol and 10 m g enalapril). It is interesting to speculate why different antihypertensive drug treatments result in different reductions of L V H despite similar bloodpressure changes under resting conditions. Considering the fact that arterial hypertension is characterized both by a blood-pressure elevation at rest and, especially, by an excessive pressure response to physical and emotional stress [12], it is reasonable to ask whether the development of left ventricular hypertrophy could be mainly related to the severity of stresslinked blood-pressure elevations. Ren et al. [13] found that the correlation of exercise systolic blood pressure with leftventricular mass index was better than that of the resting systolic pressure (r = 0.58 vs. r = 0.16). Nathwani et al. [14] showed that although the correlation between casual blood pressures and left ventricular mass index was poor, the correlation between systolic blood pressure at submaximal exercise was good (r = 0.68, p < 0.01). Devereux et al. [15] found that only ambulatory recordings of blood pressure,

Table 2. Blood pressure before (Pre) and during 4-week and 12.4-month treatment with 200 mg acebutolol and 20 mg nifedipine at rest and during and after exercise in 14 hypertensive patients (mean + SD) Rest supine

100 W exercise

5 min after work

SBP

DBP

SBP

DBP

SBP

DBP

Pre

160.9 16.9

101.07 8

207.8 23.6

112.9 9.2

160.8 14.8

101.1 9.9

4-week t r e a t m e n t

132.2 15.8"**

86.6 8.7***

170. 23.2***

94.3 8.8***

131.7 14.1"**

83.4 9.7***

12.4-month t r e a t m e n t

134.9 11.5

88.8 6.6

174. 17.5

97.7 *7.4

130. 12.3

85.4 7.5

*p <0.05; ***p < 0.001. Asterisks on the right side denote statistical difference between pretreatment and 4 weeks of treatment. Asterisks on the left side denote statistical significance between 4 weeks and 12.4-month treatments.

316

Franz et al.

Reversalof leftventricularmass index during antihypertensivetherapy

(%) 0- ~ .

__ rnetoprolol . . . gallopamil ~ atenolol+ enalapril atenolol+ nifeclipine

% -I

-

01

2o -I

~k"" ............

+

",

e,=e acebutolol nifedipine

~~.___.~,~,,_,,

-30 -

~

~

.

.

~

,

-40 -

-50

~. 6

8 ib i~2 1'4 f6 1'8 20 2'2 24 26 2'8 30 3'2 months

Fig. 2. Regression of left ventricular mass index (percentage) during long-term treatment with metroprolol (n = 26), gallopamil (n ffi 26), atenolol + nifedipine (n = 36), acebutolol + nifedipine (n = 14), and atenolol + enalapril (n = 21).

while the patients were at work, were correlated with the left ventricular mass index, leading them to conclude that the blood-pressure response to recurrent stress was related to the development of left ventricular hypertrophy. It is quite possible that the different effects of betablockers, diuretics, vasodilators, and calcium antagonists on the reversal of hypertrophy relate to their different effects on the blood-pressure response to stress [12, 16-19]. Beta-blockers lower systolic blood pressure to the greatest extent during dynamic exercise [12, 16-19]. Calcium antagonists also lower systolic blood pressure significantly during exercise, but to a smaller extent than beta-blockers [17]. Diuretics [16] and the vasodilator prazosin [18] have only a small effect on systolic blood pressure elevation during exercise. These differential effects of antihypertensive drugs could explain w h y treatment with metoprolol produced a significantly greater reversal of hypertrophy compared with monotherapy using gallopamil, whereas vasodilators and diuretics were ineffective or less effective [6-8]. However, blood-pressure reduction does not seem to be an absolute condition for reversal of leftventricular hypertrophy, and specific drug effects m a y play a role, since methyldopa has been reported to induce hyper-

trophy reversal, even in the absence of concomitant afterload reduction [2]. Figure 2 demonstrates that combined therapy with a beta-blocker and an ACE inhibitor was less effective in reducing LVH than the combination of a betablocker and a calcium antagonist. This was true despite an identical reduction in blood pressure at rest and during exercise. This finding could support the hypothesis, that, in addition to blood-pressure reduction, specific drug effects play a role in reversal of LVH. Whether or not a reduction in previously elevated heart-wall thickness during antihypertensive therapy would be followed by an increase in ventricular enddiastolic dimension and impaired ventricular function has been discussed. Therefore, it is of particular interest to emphasize that, after a mean followup of 25.6 months, there were no significant changes in ventricular end-diastolic and end-systolic dimensions, nor in fractional shortening.

References 1. DevereuxRB, Reichek N. Echocardiographicdetermination of left ventricular mass in man: Anatomic validation of the method. Circulation 1977;55:613-618. 2. Fouad FM, Nakashima Y, Tarazi RC, Salcedo EE. Reversal of left ventricular hypertrophy in hypertensive patients treated with methyldopa. A m J Cardiol 1982;49:795-801. 3. Corea L, Bentivoglio M, Verdecchia P, Provvidenza M, Motolese M. Regression of left ventricular hypertrophy during metoprolol treatment. Int J Clin Pharmacol 1984; 22:365-370. 4. Franz I-W, Wiewel D, Behr U, Ketelhut R. Regression of myocardialhypertrophy in hypertensiveson long-termtreatment with beta-blockers. Dtsch IVied Wochenschr 1986; 111:530-534. 5. Kaul M, Mohan JC, Bhatia M. Effects of labetalol on left ventricular mass and function in hypertension: An assessment by serial echocardiography.Int J Cardiol 1984;5:461469. 6. Drayer JIM, Gardin JM, Weber MA, AranowWS. Increases and decreases in ventricular septal thickness during diuretic therapy. Clin Pharmacol Ther 1982;32:283. 7. Sen S, Tarazi RC, Khairallah PA, Bumpus FMM. Cardiac hypertrophy in spontaneously hypertensive rats. Circ Res 1974;35:775-781. 8. Nakashima J, Fouad F, Tarazi R. Regression of left vantricularhypertrophy from systemic hypertensionby enalapril.A m J Cardiol 1984;53:1044-1049. 9. StrauerBB, Mahmoud M, Bayer F, Bohn J, Motz M. Reversal of leftventricularhypertrophy and improvement of cardiac function in man by nifedipine.Eur Heart J 1984; 5(Suppl 7):53-60. 10. Franz I-W, T6nnesman U, Behr U, Ketelhut R. Long-term effectof antihypertensivetherapy on leftventricularhypertrophy.J Hyperten 1987;5(Suppl5): $415-$418. 11. Sahn DJ, de Maria A, KissloJ,Weymann A. The Committee on M-Mode Standardizationof the American Society of

LV Hypertrophy

12. 13.

14.

15.

Echocardiography. Recommendations regarding quantification in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 1977;58: 1072-1083. Franz I-W. Ergometry in hypertensive patients. Berlin: Springer, 1985. Ren J, Hakki A, Kotler MN. Exercise systolic blood pressure: A powerful determinant of increased left ventricular mass in patients with hypertension. J A m Coll Cardiol 1985;5:12241231. Nathwani D, Reevers RA, Marquez-Julio A. Left ventricular hypertrophy in mild hypertension: Correlation with exercise blood pressure. Am Heart J 1985;109:386-387. Devereux RB, Pickering TG, Harshfield GA. Left ventricular hypertrophy in patients with hypertension: Importance of blood pressure to regularly recurring stress. Circulation 1983;68:470-476.

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16. Franz I-W. Differential antihypertensive effect of acebutolol and the fixed combination hydrochlorothiazide/amiloride hydrochloride on elevated exercise blood pressure in hypertensive patients. Am J Cardiol 1980;46:301-305. 17. Franz I-W, Wiewel D. Antihypertensive effects of calcium antagonists, G-receptor blockers and their combination on blood pressures at rest and during exercise in hypertensive patients. J Cardiovasc Pharmacol 1985;6(Suppl 7):10371042. 18. Franz I-W. The effects of prazosin and acebutolol and their combination on blood pressure and pressure rate product during ergometric work in hypertensive patients. Z Kardiol 1983;72:746-754. 19. Franz I-W, Behr U, Ketelhut R. Resting and exercise blood pressure with atenolol, enalapril and a low-dose combination. J Hyperten 1987;5(Suppl 3):$37-$41.