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Time course of regression of left ventricular hypertrophy in treated hypertensive patients
Time Course of Regression of Left Ventricular Hypertrophy in Treated Hypertensive Patients
GARY L. WOLLAM, M.D. W. DALLAS HALL, M.D. VIVIAN D. PORTER, B.S., R.D.M.S. MARGARET B. DOUGLAS, M.C.H. DEANNE J. UNGER, R.N.P. BRENT A. BLUMENSTEIN, Ph.D. GEORGE A. COTSONIS, M.A. MERRELL L. KNUDTSON, M.D. JOEL M. FELNER, M.D. ROBERT C. SCHLANT, M.D. Atlanta, Georgia
From the Emory University Hypertension Research Clinic and the Divisions of Hypertension and Cardiology, Department of Medicine, Emory University School of Medicine and Grady Memorial Hospital, Atlanta, Georgia. This paper was presented in abstract form at the 31st Annual Scientific Session of The American College of Cardiology, Atlanta, Georgia, April 25-29, 1982. Requests for reprints should be addressed to Dr. Gary L. Wollam, Emory University School of Medicine, 69 Butler Street, S.E., Atlanta, Georgia 36393.
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in a prospective study, 32 hypertensive patients with echocardiographic evidence of left ventricular hypertrophy were treated with methyidopa, hydrochlorothiazide, or methyidopa and hydrochlorothiazide combined. Echocardiograms and electrocardiograms were obtained in each of the 32 patients before treatment, at the point of initial blood pressure control, and then one, three, and six months thereafter; in 27 patients these studies were also obtained after 12 and 18 months. Left ventricular end-diastolic posterior wail thickness decreased in seven patients whose blood pressure was controtled with methyldopa alone (p
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PATIENTS AND METHODS Study Protocol and Patient Population. Fifty-five patients with essential hypertension participated in this prospective investigation. The major criteria for admission to the study included an average supine diastolic blood pressure of 100 mm Hg or greater, and a left ventricular enddiastolic posterior wall thickness of 11 mm or greater, as measured by M-mode echocardiography. Patients who had congestive heart failure, who used cardiac drugs, or who had group III or IV hypertensive retinopathy, cardiomyopathy, valvular disease, angina, or previous myocardial infarction were excluded from the study. The patients, all of whom were black, included 24 men and 31 women, who ranged in age from 21 to 68 years. Following written and informed consent, all patients were enrolled in the Emory University Hypertension Research Clinic where the study was conducted. Prior to entry, the patients had received no antihypertensive medications for at least two weeks, except for one patient with severe hypertension who had not received therapy for only one week. The diagnosis of essential hypertension was based on the exclusion of secondary causes by history, physical examination, standard laboratory tests, and special procedures in selected cases. The patients were assigned at random to one of two treatment groups: in one, hydrochlorothiazide, 25 mg twice a day was given, in the other methyldopa 250 mg twice a day was given. (Three of the 55 patients were not randomized. Two had asymptomatic pretreatment supine diastolic pressures of 140 mm Hg or greater and were immediately started on combined treatment with methyldopa and hydrochlorothiazide. The third patient was started on hydrochlorothiazide because of severe hypertension and a remote history of congestive heart failure). During an average titration period of 43 days, the dosage of each drug was increased weekly until blood pressure was controlled, or until a maximum dose of either 100 mg of hydrochlorothiazide per day or 2 g of methyldopa per day was attained. If blood pressure remained uncontrolled at these dosage levels, methyldopa was added to the regimen of the patients receiving hydrochlorothiazide, and hydrochlorothiazide was added to the regimen of the patients receiving methyldopa. The dose of the second drug was then increased until blood pressure was controlled, or until maximum dosage levels were reached in the absence of adverse effects. Blood pressure control was defined as an average supine diastolic blood pressure (phase V) of less than 95 mm Hg on each of two consecutive clinic visits. Following the control of arterial pressure, the patients entered into a maintenance period for six to 18 months. The same drug regimen that initially controlled blood pressure was continued except for minor adjustments in dosage to maintain control of blood pressure and/or to minimize side effects. Blood pressure, heart rate, and weight were measured at protocol intervals of one to three months. Echocardiograms and electrocardiograms were obtained in each of the 32 patients before treatment, at the point of initial blood pressure control, and then one, three, and six months after arterial pressure was controlled; in 27 patients, these studies were also obtained after 12 and 18 months of therapy. Chest
HYPERTENSION-WOLLAM
ET AL
roentgenograms were obtained at baseline and after one year. The blood pressure data reported in this study represent the average of two supine measurements obtained at each clinic visit. Echocardiographic and Electrocardiographic Measurements. Standard M-mode echocardiograms were obtained using a Unirad ultrasonoscope, a 2.25 mHz 7.5 cm focused (1.3 cm diameter) transducer and a model 174 Tektronix strip chart recorder as previously described [2,3]. Fractional shortening of left ventricular transverse diameter (AD) was calculated as the result of LVlDd - LVlDs LVlDd where LVlDd is left ventricular internal diameter at enddiastole and LVlDs is left ventricular internal diameter at end-systole. The left ventricular mass index was calculated according to the formula: [(PWTd -t VSTd + LVIDd)3 LVIDd3] X 1.OS/BSA, where PWTd is left ventricular posterior wall thickness at end-diastole, VSTd is ventricular septal thickness at enddiastole, LVlDd is left ventricular internal diameter at end-diastole, and BSA is body surface area. Echocardiographic estimates of left ventricular end-systolic and enddiastolic volumes were calculated by the method of Teichholz et al [ 121. The h:r ratio was calculated as the result of (PWTd& LVIDd), where PWTd is left ventricular posterior wall thickness at enddiastole and LVlDd is left ventricular internal diameter at enddiastole. All echocardiograms were read by one experienced observer (Vivian D. Porter), who was unaware of the patients’ treatment group. To further assess the reproducibility of the measurements, 20 echocardiograms were selected at random and read by two observers (Dr. Joel M. Felner and Vivian D. Porter) in double-blind fashion; when the results were analyzed statistically, no significant observer differences were apparent. Left ventricular peak systolic circumferential wall stress was estimated by the method of Aziz et al [ 131. Left ventricular meridional end-systolic wall stress was estimated using the formula of Grossman et al [ 141. A standard 12 lead electrocardiogram was obtained at the time of each echocardiogram. All electrocardiograms were read by one of two observers (Dr. Hall and Dr. Wollam) and 13 specific electrocardiographic parameters were measured on each tracing. Statistical Analysis. The data are analyzed using repeated measures analysis of variance and the Tukey W multiple comparisons procedure [ 151. These methods were chosen because the experiment resulted in data structured according to the group-by-time repeated measures design; moreover, they provide for conservative control over the type I error rate. Other specific tests, such as a comparison between baseline values and a particular time point (using Tukey’s multiple comparison procedure), were performed when indicated. RESULTS Clinical and Echocardiographic Characteristics at Baseline (Table I). Thirty-two patients completed a six-month follow-up with complete data at each protocol point. Arterial pressure control was achieved with
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TABLE I
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ET A:
Clinical Characteristics of the 32 Patients at Baseline Methyldopa t Methyldopa (Number = 7)
Age (years) Weight (ibs) Body surface area (m’) Blood pressure (mm Hg) Systolic Diastolic Heart rate Electrocardiographic voltage (mm) Sv, or Sv2 + Rvg or Rvg Lead aVL Cardiothoracic ratio’
39.1 178.1 1.88 157.7 105.3 72.4
40.4 5.4 0.51
-
P -+
tlydrochlorothiazide (Number = 17)
+ P+
46.5 195.2 1.99
<0.05
NS NS NS
NS NS NS
185.3 116.2 81.9
38.9 8.1 0.51
Hydrochlorothiaride (Number = 8)
P (Methyldopa versus Hydrochlorothiazide)
NS NS
37.3 203.6 1.99
NS NS NS
NS NS NS
170.1 109.1 74.8
NS NS NS
NS NS NS
37.0 6.1 0.47
NS NS NS
NS = not significant. Ratio of maximum cardiac width to maximum thoracic width calculated from the chest roentgenogram. l
methyldopa alone in seven patients, with hydrochlorothiazide alone in eight patients and with methyldopa and hydrochlorothiazide combined in 17 patients. There were no statistically significant differences between the methyldopa and hydrochlorothiazide groups with regard to any of the pretreatment clinical or echocardiographic characteristics. Five of the eight patients in the hydrochlorothiazide group and four of the seven patients in the methyldopa group had received no pharmacologic therapy for hypertension for periods of 12 months or more prior to enrollment. As expected, blood pressure was higher in the group that required methyldopa and hydrochlorothiazide combined. Initial Time Course of Regression of Left Ventricular Hypertrophy. Arterial pressure, heart rate and weight: At the end of the titration period, blood pressure was reduced to 127/83 f 15/B in the group given methyldopa, 134180 f 12/9 in the group given hydrochlorothiazide and 139/89 f 12/6 mm Hg in the group given methyldopa and hydrochlorothiazide combined (p <0.005 for all three). There were no significant differences between the methyldopa and hydrochlorothiazide groups with regard to the duration of the titration period (which averaged 23.8 f 10.9 days in the hydrochlorothiazide group and 33.7 f 15.6 days in the methyldopa group), the reduction in blood pressure during the titration period, or the level of blood pressure control during the maintenance period. Supine heart rate increased by 9.1 f 10.1 beats per minute (end of titration) in the hydrochlorothiazide group; whereas, it decreased by 5.9 f 8.9 beats per minute (one month visit) in the methyldopa group and remained at essentially the pretreatment level in the methyldopa and hydrochlorothiazide group. At the end of the titration
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period, weight had decreased by 4.9 f 4.1 pounds in the hydrochlorothiazide group and by 3.1 f 4.3 pounds in the methyldopa and hydrochlorothiazide group; whereas, it increased by 3.9 f 3.4 pounds in the methyldopa group. Echocardiographic Indices (Table II): Assessment of the group-by-time changes that occurred in left ventricular posterior wall thickness at end-diastole within the three treatment groups during the six-month period revealed some differences (Table II).” Left ventricular posterior wall thickness at end-diastole decreased significantly in the groups given methyldopa and methyldopa and hydrochlorothiazide combined (p
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TABLE
II
Echocardiographic Changes in the Three Treatment Establishment of Arterial Pressure Control
Echocardiographic Parametersand Intervals
Methyldopa (Number = 7) SD. Mean
Groups
During
HYPERTENSION-WOLLAM
the Six-Month
interval
Hydrochlorothiazide (Number = 8) Mean S.D.
Methyldopaand Hydrochlorothiaride (Number = 17) Mean S.D.
Following
ET AL
the
Repealed Measures Analysis of Variance*
PWTd (mm) Pretreatment Initial blood pressure control 1 month 3 months 6 months
12.4 11.4 11.3 11.0 10.9
1.4 1.1 0.8 1.0 0.9
13.0 12.8 12.5 12.6 12.0
2.3 2.5 3.1 2.8 2.7
13.2 12.8 12.2 12.4 12.1
2.3 2.4
MH group 4 p = 0.002
2.3 2.6 2.9
M group 4 p = 0.006 H group p = 0.34
VSTd (mm) Pretreatment Initial blood pressure control 1 month 3 months 6 months
11.0 11.0 10.4 10.6 10.9
2.2 1.2 1.4 1.3 2.0
10.6 11.1 11.0 11.3 11.9
1.5 1.9 1.9 1.5 1.9
13.8 12.6 13.1 12.7 13.5
2.5 3.3 3.5 3.0 3.0
LVlDd (mm) Pretreatment Initial blood pressure control 1 month 3 months 6 months
47.0 47.9 46.0 48.0 48.7
3.3 2.3 5.4 3.4 3.9
49.1 44.3 45.8 45.6 44.1
8.2 7.6 6.5 6.6 5.4
47.4 47.1 47.6 47.5 47.1
4.5 5.7 4.9 4.9 5.7
LADS (mm) Pretreatment Initial blood pressure control 1 month 3 months 6 months
34.1 34.0 34.6 35.6 35.4
6.3 5.4 7.7 6.7 5.2
37.6 35.4 34.8 35.0 36.9
5.1 4.4 6.0 4.1 5.8
37.1 36.6 37.9
5.3 5.8 5.8
t 36.8
H group i p = 0.005
t
5.5
AD Pretreatment Initial blood pressure control 1 month 3 months 6 months
0.35 0.32 0.34 0.34 0.34
0.06 0.05 0.08 0.06 0.05
0.38 0.40 0.42 0.41 0.41
0.07 0.05 0.05 0.05 0.06
0.37 0.39 0.39 0.39 0.40
0.07 0.10 0.07 0.09 0.05
Ejection fraction Pretreatment Initial blood pressure control 1 month 3 months 6 months
0.72 0.69 0.70 0.71 0.71
0.08 0.07 0.11 0.08 0.07
0.76 0.78 0.80 0.79 0.79
0.08 0.05 0.05 0.05 0.06
0.75 0.76 0.77 0.76 0.78
0.08 0.10 0.08 0.11 0.06
M = group treated with methyldopa alone; H = group treated with hydrochlorothiaztde alone: MH = group treated with combined methyldopa-hydrochlorothiaide; PWTd = left ventricular posterior wall thickness at enddiastole; VSTd = ventricular septal thickness at enddiastole; LVIW = left ventricular internal diameter at enddiastole; LADs = left atrial diameter at end-systole; AD = fractional shortening of left ventricular end-diastolic diameter. The p values pertain only to the significance of the group-by-time changes (that is, non-flatness) within the treatment groups. 7 In two patients in the combined mefhyldopa-hydrochl~othiazide group, left atrial diameter at end-systole could not be assessed with precision from the echocardiograms obtained at the end of the three-month follow-up period. The data from this visit was therefore not included in the statistical analysis of changes in left atrial diameter at end-systole in this group. l
days) after arterial pressure control was established (p <0.05 for both). Whereas, in the hydrochlorothiazide group, the reduction in left ventricular posterior wall thickness at enddiastole was not statistically significant at any point during the six-month period (p >O.lO). Changes in ventricular septal thickness at end29.8
diastole also tended to differ among the three groups. In the methyldopa and methyldopa and hydrochlorothiazide groups, ventricular septal thickness at enddiastole tended to decrease, although the downward trends in these two groups were not statistically significant during the six-month period. In the hydrochlorothiatide group, ventricular septal thickness at end-
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ET AL
diastolic diameter (AD) and ejection fraction did not change significantly in any of the groups (Table II). For all 32 patients, the decrease in left ventricular mass index correlated with the reduction in systolic (r = 0.48, p
diastole increased from a pretreatment value of 10.6 f 1.5 mm to 11.9 f 1.9 mm after six months, and to 12.3 f 1.9 mm after 12 months of arterial pressure control; this increase in ventricular septal thickness at end-diastole was of borderline statistical significance (p = 0.08). Left ventricular internal diameter at end-diastole decreased in the hydrochlorothiazide group (p
TABLE III
Echocardiographic Changes in the Three Treatment Groups During an 18-Month Period Following the Establishment of Arterial Pressure Control
Echocardiographic Parametersand Intervals
Melhyldopa (Number= 4) Mean SD.
Hydrochlorothiazids (Number= 7) Mean SD.
Methyldopaand Hydrochlorothlaride (Number= 16) SD. Mean
Repeated Measures Analysisof Variance*
VSTs(mm) Pretreatment Initial blood pressure control 3 months 6 months 12 months 18 months
17.3 17.3 16.8 14.8 15.5 15.5
1.7 2.4 1.7 1.7 3.0 2.4
16.4 16.9 17.4 18.7 18.1 18.6
2.5 2.5 2.1 2.1 2.7 2.8
19.8 18.1 17.4 18.9 17.8 17.6
2.3 4.0 3.3 2.9 2.7 2.9
VSTd (mm) Pretreatment Initial blood pressure control 3 months 6 months 12 months 18 months
11.5 11.5 11.0 9.8 10.5 10.0
2.9 1.0 1.4 1.7 1.9 2.3
10.4 11.1 11.3 12.0 12.3 13.0
1.5 2.0 1.6 2.0 2.1 2.8
13.2 12.3 11.9 12.4 12.1 11.4
2.7 3.3 2.8 2.5 2.4 1.9
MH group 1 p = 0.03
PWTd (mm) Pretreatment Initial blood pressure control 3 months 6 months 12 months 18 months
12.5 10.8 10.5 10.3 10.0 10.0
1.9 1.0 1.0 0.5 0.8 1.4
13.1 12.7 12.9 12.3 12.6 12.3
2.5 2.8 3.0 2.8 2.8 3.7
12.8 12.2 11.8 11.4 11.7 11.6
2.2 2.2 2.3 2.3 2.3 2.2
MH group 4 p
LVlDd (mm) Pretreatment Initial blood pressure control 3 months 6 months 12 months 18 months
46.0 46.5 46.3 48.0 46.3 46.3
2.9 1.7 3.5 5.2 2.8 2.5
49.3 45.3 45.9 44.6 45.1 45.0
8.8 7.5 7.1 5.7 6.7 5.8
47.5 47.6 47.7 47.9 47.0 46.9
4.9 5.5 5.0 5.4 4.5 3.9
LVMI (g/m*) Pretreatment Initial blood pressure control 3 months 6 months 12 months 18 months
139 127 120 116 113 109
19 12 15 17 19 22
144 129 132 129 136 140
48 45 40 48 53 60
154 142 136 138 134 127
27 32 34 33 31 27
MH group 4 p
H group t p
M group 1 p
H group 4 p = 0.01
MH group 1 p
M Group = group treated with methyldopa alone; H Group = group treated with hydrochlorothiazide alone; MH Group = group treated with combined methyldopa-hydrochlorothiazide; VSTs = ventricular septal thickness at end-systole; LVMI = left ventricular mass index; other symbols as in Table II. The p values pertain only to the significance of the group-by-time changes (that is, non-flatness) within the treatment groups. The statistical analysis also includes the data from the one-month follow-up visit in the methyldopa and hydrochlorothiazide monotherapy groups. l
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LVH IN ESSENTIAL HYPERTENSION-WOLLAM
13.0 12.0
\ T,=xL__ \, --z*
11 .o 10.0
Hydrochlorothlar~de
n
Methyldopa
c
14.oF p/27
n
“%__ t
Methyldopa
ET AL
8 Hydrochlorothlarlde
l
a_-‘----
____z--____-___"o"
----d______--:----___--_____ A---__---_----_-4 t * *
14.oF
---+------_________ ___--*..*___--d
Figure 1. Serial long-term changes in left ventricular posterior wall thickness af end-diastole (PWTd), ventricular septal thickness at end-diastole (VSTd) and supine mean arterial pressure (MA@)(that is, DBP + 5/3 [SBP - DBP]) in the three treatment groups (27 patients) during an 1Smonth period.
80t
ness at enddiastole did not correlate well with changes in systolic (r = -0.07, p >O.lO) or diastolic pressure (r = -0.03, p >O.lO). In the methyldopa group, the reductions in left ventricular posterior wall thickness at end-diastole and left ventricular mass index also correlated with the baseline values (p CO.05 for both). In the hydrochlorothiazide group, the change in ventricular septal thickness at end-diastole paralleled the change in heart rate (r = 0.91, p cO.01) and ejection fraction (r = 0.73, p <0.05). At the three-month visit, the increase in ventricular septal thickness at enddiastole was also inversely related to the change in left ventricular internal diameter at enddiastole (r = -0.71, p <0.05). Electrocardiographic and roentgenographic indices: For the entire group of 32 patients, maximal summed precordial voltage on the electrocardiogram (lead Sv, or v2 i- Rvg or vg) decreased after three months (p
-.
LI_-____I BaselIne
‘;i;,$,,“,p
3 Months
6 Months
1
12 Months
16 Months
The change in electrocardiographic voltage in lead aVL correlated with the change in echocardiographic left ventricular mass index (r = 0.58, p
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26, 1963
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of Medlclne
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HYPERTENSION-WOLLAP
ET AL
Effect of therapy with METHYLbOPA over an 18 month period
(N = 4)
16.0 PWTo, mm
14.0 12.0 10.0
Effect of therapy with HYDROCHLOROTHIAZIDE (N = 7) over an 18 month period
8.OL
Figure 2. Serial long-term changes in left ventricular posterior wall thickness at end-diastole (PWTd) over an lb-month period in four patients treated with methyidopa alone and in seven patients treated with hydrochlorothiazide alone. Please note the break in the ordinate scale.
decreased significantly in the methyldopa group (p
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surements of ventricular septal thickness at end-systole (Table Ill). The change in ventricular septal thickness at end-diastole in the hydrochlorothiazide group correlated inversely with the change in left ventricular internal diameter at end-diastole during the initial three months of therapy (r = -0.78, p <0.05), but not at the six, 12, or 18-month points. The change in ventricular septal thickness at end-diastole in the hydrochlorothiazide group also paralleled the changes in heart rate (r = 0.92: p <0.05) and ejection fraction (r = 0.82, p <0.05). Left ventricular mass index decreased in the combined methyldopa and hydrochlorothiazide group (pO.lO). These left ventricular mass index values are, of course, calculated from left ventricular internal diameter at end-diastole, ventricular septal thickness at end-diastole, and left ventricular posterior wall thickness at end-diastole. Therefore, changes in left ventricular internal diameter at end-diastole induced by diuretic or sympatholytic drugs could modify the calculated left ventricular mass index independent of actual changes in left ventricular muscle mass. As was true after six months of blood pressure control, the 18-month change in electrocardiographic voltage in lead aVL (for all 27 patients) correlated with the change in left ventricular mass index (r = 0.40, p <0.05); whereas, changes in left ventricular mass index did not correlate well with changes in maximal summed precordial voltage on the electrocardiogram (r = 0.26, p O.lO). Electrocardiographic voltage in lead aVL decreased from 7.7 f 3.9 to 6.8 f 3.0 mm in the methyldopa and hydrochlorothiazide group (p
LVH IN ESSENTIAL
METHYLDOPA N=4
HYPERTENSION-WOLLAM
ET AL
METHYLDOPA + HYDf?OCHLOl?OTHlAZlDE N= 16
HYDROCHLOROTHlAZlDE N=7
20.0 F p>O.lO
19.0
p<.Ol
PC.02
k
18.0 17.0 16.0
V-D, mm
15.0 14.0 13.0 12.0 11 .o 10.0 9.0 8.0
i
I
I
Baseline
RX
I
(18 Months)
I
I
I
Baseline
RX
(18 Months)
Baseline
RX
(18 Months)
Figure 3. Long-term changes in ventricular septal thickness at end-diastole (VSTd) between baseline and the end of the 1Smonth follow-up period in the three treatment groups (27 patients). Of the 16 patients in the combined treatment group, 11 had an absolute decrease in ventricular septal thickness at end-diastole; whereas, five of the seven patients in the hydrochlorothiazide group had an increase.
decreased significantly at the end of these periods. Also, Reichek and co-workers [ 1 l] observed reductions in left ventricular posterior wall thickness at end-diastole and ventricular septal thickness at end-diastole in hypertensive patients treated with methyldopa and/or hydrochlorothiazide. In most studies, however, multiple therapeutic regimens have generally been employed, making the interpretation of the effects of individual drugs difficult. Moreover, in previous studies, echocardiograms have usually not been obtained repeatedly, to allow assessment of the relative time course of changes in left ventricular anatomy. Adequate long-term control of hypertension with sympatholytic drugs alone is often difficult because volume retention may result in loss of blood pressure control (that is, “pseudo-tolerance”). This latter phenomenon makes even more difficult the task of assembling large numbers of hypertensive patients with evidence of left ventricular hypertrophy in whom long-term control of blood pressure is maintained without concomitant diuretic therapy. In the present study, blood pressure control was maintained within each of the three treatment groups
to allow investigation of any changes in left ventricular anatomy that might be related to factors other than the reduction of blood pressure [ 16- 181. Assessment of changes in left ventricular posterior wall thickness at end-diastole and ventricular septal thickness at enddiastole revealed differences among the treatment groups. In the methyldopa and in the methyldopa and hydrochlorothiazide groups, left ventricular posterior wall thickness at end-diastole decreased significantly one month after arterial pressure was controlled. However, in the hydrochlorothiazide group, the reduction in left ventricular posterior wall thickness at enddiastole was not statistically significant during either the six- or 1El-month follow-up periods. These results are in accord with other studies in which sympatholytic drugs have been used in the treatment of hypertension. lbrahim et al [5] reported that left ventricular mass index decreased after eight weeks of therapy in hypertensive patients treated with atenolol. Others have reported similar findings after 12 weeks of therapy in relatively small groups of patients treated with propranolol or nadolol [4], or with methyldopa, alone or in conjunction with hydrochlorothiazide [6].
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LVH IN ESSENTIAL HYPERTENSION-WOLLAM
Changes diastole
in ventricular
septal
ET Ai
thickness
at end-
required
a longer period to occur and also differed among the treatment groups. In the methyldopa and hydrochlorothiazide group and the methyldopa group, ventricular septal thickness at end-diastole decreased during the 18-month period. Whereas, in the hydrochlorothiazide group, ventricular septal thickness at end-diastole increased over the l&month period. Changes in ventricular septal thickness at enddiastole in the hydrochlorothiazide group were non-parallel to those of the methyldopa group (p
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surement of ventricular septal thickness at enddiastole should be distributed equally among the groups. Drayer et al [24] have proposed that increases in ventricular septal thickness at enddiastole measurements during short-term (six-week) therapy with hydrochlorothiazide might be explained on the basis of anatomic adjustments to a decrease in left ventricular internal diameter at enddiastole. Our data also reveal an increase in ventricular septal thickness at enddiastole at the time of initial blood pressure control, when the reduction in left ventricular internal diameter at end-diastole in the hydrochlorothiazide group was near its nadir (Tables II and Ill). Moreover, the early changes in ventricular septal thickness at enddiastole in the hydrochlorothiazide group were inversely related to the change in left ventricular internal diameter at end-diastole. However, the correlations between changes in ventricular septal thickness at end-diastole and left ventricular internal diameter at end-diastole were not significant beyond the three-month follow-up period. Serial echocardiograms over the 18-month period revealed a continued increase in ventricular septal thickness at end-diastole in the absence of any further significant changes in left ventricular internal diameter at end-diastole. Hence, it would not seem likely that the long-term changes in ventricular septal thickness at end-diastole in the hydrochlorothiazide group could be completely due to anatomic adjustments resulting from the decrease in left ventricular internal diameter at end-diastole. In the present study, the decrease in electrocardiographic voltage tended to lag behind the echocardiographic indices and did not attain statistical significance until three to six months after blood pressure was controlled. The decrease in left ventricular mass index and left ventricular posterior wall thickness at enddiastole correlated better with the reduction in electrocardiographic voltage in lead aVL than with changes in either the maximal summed precordial voltage or the Romhilt-Estes total left ventricular hypertrophy point score. These findings are consistent with previous studies, which suggest that the electrocardiographic voltage in lead aVL may be a relatively specific electrocardiographic criteria for the assessment of left ventricular muscle mass [25,26]. Like left ventricular mass index, the h:r ratio decreased in the methyldopa and hydrochlorothiazide group (p <0.02), and the reduction in the methyldopa group attained borderline statistical significance (p = 0.06). Whereas, in the hydrochlorothiazide group, no decrease in the h:r ratio was apparent (p = 0.95). These findings are in agreement with the preliminary observations of Devereux et al [ 271, which also suggest that in hypertensive patients who receive long-term monotherapy with diuretics, regression of left ventric-
LVH IN ESSENTIAL
ular hypertrophy may be less than that in those treated with sympatholytic drugs, despite similar reductions in blood pressure. Monotherapy with diuretics [28], like that of vasodilators [29], may be associated with increased activity of the sympathetic nervous system and elevated plasma norepinephrine levels; whereas adrenergic blocking drugs generally suppress sympathetic neural activity [30]. In summary, the results of the present study indicate that, in patients treated with methyldopa or the combination of methyldopa and hydrochlorothiazide, a reduction in left ventricular posterior wall thickness at end-diastole may be apparent as early as one month after arterial pressure is controlled. Whereas, in patients treated with hydrochlorothiazide alone, left ventricular posterior wall thickness at end-diastole did not decrease significantly. During an 18-month follow-up period,
HYPERTENSION-WOLLAM
ET AL
ventricular septal thickness at enddiastole decreased in the group treated with methyldopa-hydrochlorothiazide combined and increased in the group treated with hydrochlorothiazide alone. Although the patient numbers are relatively small, the results suggest that there may be differences in the long-term effects of therapy with diuretics and sympatholytic drugs on left ventricular anatomy, which may, in part, relate to divergent effects on the sympathetic nervous system. ACKNOWLEDGMENT We wish to acknowledge the expert assistance of Ms. Marlis McDowell in the preparation of this manuscript. We are grateful to Elmer H. Funk, Jr., M.D. and his associates at Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania, for their generous supply of methyldopa and hydrochlorothiazide.
REFERENCES 1.
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Helmcke JG, Schneckloth R, Corcoran AC: Electrocardiographic changes of left ventricular hypertrophy: effects of antihypertensive treatment. Am Heart J 1957; 53: 549557. Schlant RC, Felner JM. Heymsfield SB, et al: Echocardiographic studies of left ventricular anatomy and function in essential hypertension. Cardiovasc Med 1977; 2: 477491. Schlant RC, Felner JM, Blumenstein BA, et al: Echocardiographic documentation of regression of left ventricular hypertrophy in patients treated for essential hypertension. Eur Heart J 1982: 3 (SUPDIA): 171-175. Hill LS, Monaghan M, Richardson PJ: Regression of left ventricular hypertrophy during treatment with antihypertensive agents. Br J Clin Pharmacol 1979; 7 (suppl 2): 255-260. lbrahim MM, Madkour MA, Mossallam R: Factors influencing cardiac hypertrophy in hypertensive patients. Clin Sci 1981; 61: lo!%-108s. Fouad FM, Nakashima Y, Tarazi RC, Salcedo EE: Reversal of left ventricular hypertrophy in hypertensive patients treated with methyldopa..Lack of association with blood pressure control. Am J Cardiol 1982: 49: 795-801. Dunn FG, Bastian 8, Lawrie TDV, Lorimer AR: Effect of blood pressure control on left ventricular hypertrophy in patients with essential hypertension. Clin Sci 1980; 59: 441s443s. Sonotani N, Kubo S, Nishioka A, Takatsu T: Electrocardiographic and echocardiographic changes after one to twoyears’ treatment of hypertension. Analyses of voltage (SV1 + RVs), wall thickness, cavity, mass, and hemodynamics of the left ventricle. Jpn Heart J 1981; 22: 325-333. Rowlands DB, Glover DR, Ireland MA, et al: Assessment of left-ventricular mass and its response to antihypertensive treatment. Lancet 1982; I: 467-470. Corea L, Bentivoglio M, Verdecchia P: Reversal of left ventricular hypertrophy in essential hypertension by early and long-term treatment with methyldopa. Clin Trials J 1981; 18: 380-394. Reichek N, Franklin BB, Chandler T, Muhammad A. Plappert T, St John-Sutton M: Reversal of left ventricular hypertrophy bv antihvDertensive therapy. Eur Heart J 1982: 3 (suppl A): 165-169.
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Teichholz LE, Kreulen T, Herman MV, Gorlin R: Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in presence or absence of asynergy. Am J Cardiol 1976; 37: 7-l 1. Aziz KU, van Grondelle A, Paul MH, Muster AJ: Echocardiographic assessment of the relation between left ventricular wall and cavity dimensions and peak systolic pressure in children with aortic stenosis. Am J Cardiol 1977; 40: 775-780. Grossman W, Jones D, McLaurin LP: Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 1975; 56: 56-64. Winer BJ: Statistical principles in experimental design. 2nd ed. New York: McGraw-Hill, 1971; 518-538. Tarazi RC, Sen S, Sargoca M, Khairallah P: The multifactorial role of catecholamines in hypertensive cardiac hypertrophy. Eur Heart J 1982; 3 (suppl A): 103-110. Frohlich ED, Tarazi RC: Is arterial pressure the sole factor responsible for hypertensive cardiac hypertrophy? Am J Cardiol 1979; 44: 959-963. Gans JH, Cater MR: Norepinephrine induced cardiac hypertrophy in dogs. Life Sci 1970; 9: 731-740. Safar ME, Lehner JP, Vincent MI, Plainfosse MT, Simon ACh: Echocardiographic dimensions in borderline and sustained hypertension. Am J Cardiol 1979; 44: 930-935. Esler M, Julius S, Zweifler A, et al: Mild high-renin essential hypertension. Neurogenic human hypertension? N Engl J Med 1977; 296: 405-411. Corea L, Bentivoglio M, Motolese M: Ruolo pathogenetico del sistema nervoso adrenergico nell ipertrofia ventricolare sinistra della ipertensione arteriosa sistemica essenziale borderline e stabilizzata (abstr). Congress0 Italian0 di Cardiologia. 1981; Roma 23-26 maggio. Felner JM, Blumenstein BA, Schlant RC, et al: Sources of variability in echocardiographic measurements. Am J Cardiol 1980; 45: 9951004. Fowles RE, Martin RP, Popp RL: Apparent asymmetric septal hypettrophy due to angled interventricular septum. Am J Cardiol 1980; 46: 386-392. Drayer JIM, Gardin JM, Weber MA, Aronow WS: Change in ventricular septal thickness during diuretic therapy. Clin Pharmacol Ther 1982; 32: 283-288.
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Reichek N, Devereux RB: Left ventricular hypertrophy: relationship of anatomic, echocardiographic and electrocardiographic findings. Circulation 1981; 63: 1391-1398. Romhilt DW, Bove KE, Norris RJ, et al: A critical appraisal of the electrocardiographic criteria for the diagnosis of left ventricular hypertrophy. Circulation 1969; 40: 185-195. Devereux RB, Savage DD, Sachs I, Laragh JH: Effect of blood pressure control on left ventricular hypertrophy and function in hypertension (abstr). Circulation 1980; 62 (suppl Ill):
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28.
29. 30.
36. Lake RC, Ziegler MG, Coleman MD, Kopin IJ: Hydrochlorothiazide-induced sympathetic hyperactivity in hypertensive patients. Clin Pharmacol Ther 1979; 26: 428-432. Linas SL, Nies AS: Minoxidil. Ann Intern Med 1981; 94: 6165. Anden NE, Henning M: Urinary excretion of noradrenaline after treatment with alpha-methyldopa: inhibition by a central nervous mechanism. Acta Physiol Stand 1974; 90: 6972.
GARY L. WOLLAM, M.D. W. DALLAS HALL, M.D. VIVIAN D. PORTER, B.S., R.D.M.S. MARGARET B. DOUGLAS, M.C.H. DEANNE J. UNGER, R.N.P. BRENT A. BLUMENSTEIN, Ph.D. GEORGE A. COTSONIS, M.A. MERRELL L. KNUDTSON, M.D. JOEL M. FELNER, M.D. ROBERT C. SCHLANT, M.D. Atlanta, Georgia
From the Emory University Hypertension Research Clinic and the Divisions of Hypertension and Cardiology, Department of Medicine, Emory University School of Medicine and Grady Memorial Hospital, Atlanta, Georgia. This paper was presented in abstract form at the 31st Annual Scientific Session of The American College of Cardiology, Atlanta, Georgia, April 25-29, 1982. Requests for reprints should be addressed to Dr. Gary L. Wollam, Emory University School of Medicine, 69 Butler Street, S.E., Atlanta, Georgia 36393.
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in a prospective study, 32 hypertensive patients with echocardiographic evidence of left ventricular hypertrophy were treated with methyidopa, hydrochlorothiazide, or methyidopa and hydrochlorothiazide combined. Echocardiograms and electrocardiograms were obtained in each of the 32 patients before treatment, at the point of initial blood pressure control, and then one, three, and six months thereafter; in 27 patients these studies were also obtained after 12 and 18 months. Left ventricular end-diastolic posterior wail thickness decreased in seven patients whose blood pressure was controtled with methyldopa alone (p
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PATIENTS AND METHODS Study Protocol and Patient Population. Fifty-five patients with essential hypertension participated in this prospective investigation. The major criteria for admission to the study included an average supine diastolic blood pressure of 100 mm Hg or greater, and a left ventricular enddiastolic posterior wall thickness of 11 mm or greater, as measured by M-mode echocardiography. Patients who had congestive heart failure, who used cardiac drugs, or who had group III or IV hypertensive retinopathy, cardiomyopathy, valvular disease, angina, or previous myocardial infarction were excluded from the study. The patients, all of whom were black, included 24 men and 31 women, who ranged in age from 21 to 68 years. Following written and informed consent, all patients were enrolled in the Emory University Hypertension Research Clinic where the study was conducted. Prior to entry, the patients had received no antihypertensive medications for at least two weeks, except for one patient with severe hypertension who had not received therapy for only one week. The diagnosis of essential hypertension was based on the exclusion of secondary causes by history, physical examination, standard laboratory tests, and special procedures in selected cases. The patients were assigned at random to one of two treatment groups: in one, hydrochlorothiazide, 25 mg twice a day was given, in the other methyldopa 250 mg twice a day was given. (Three of the 55 patients were not randomized. Two had asymptomatic pretreatment supine diastolic pressures of 140 mm Hg or greater and were immediately started on combined treatment with methyldopa and hydrochlorothiazide. The third patient was started on hydrochlorothiazide because of severe hypertension and a remote history of congestive heart failure). During an average titration period of 43 days, the dosage of each drug was increased weekly until blood pressure was controlled, or until a maximum dose of either 100 mg of hydrochlorothiazide per day or 2 g of methyldopa per day was attained. If blood pressure remained uncontrolled at these dosage levels, methyldopa was added to the regimen of the patients receiving hydrochlorothiazide, and hydrochlorothiazide was added to the regimen of the patients receiving methyldopa. The dose of the second drug was then increased until blood pressure was controlled, or until maximum dosage levels were reached in the absence of adverse effects. Blood pressure control was defined as an average supine diastolic blood pressure (phase V) of less than 95 mm Hg on each of two consecutive clinic visits. Following the control of arterial pressure, the patients entered into a maintenance period for six to 18 months. The same drug regimen that initially controlled blood pressure was continued except for minor adjustments in dosage to maintain control of blood pressure and/or to minimize side effects. Blood pressure, heart rate, and weight were measured at protocol intervals of one to three months. Echocardiograms and electrocardiograms were obtained in each of the 32 patients before treatment, at the point of initial blood pressure control, and then one, three, and six months after arterial pressure was controlled; in 27 patients, these studies were also obtained after 12 and 18 months of therapy. Chest
HYPERTENSION-WOLLAM
ET AL
roentgenograms were obtained at baseline and after one year. The blood pressure data reported in this study represent the average of two supine measurements obtained at each clinic visit. Echocardiographic and Electrocardiographic Measurements. Standard M-mode echocardiograms were obtained using a Unirad ultrasonoscope, a 2.25 mHz 7.5 cm focused (1.3 cm diameter) transducer and a model 174 Tektronix strip chart recorder as previously described [2,3]. Fractional shortening of left ventricular transverse diameter (AD) was calculated as the result of LVlDd - LVlDs LVlDd where LVlDd is left ventricular internal diameter at enddiastole and LVlDs is left ventricular internal diameter at end-systole. The left ventricular mass index was calculated according to the formula: [(PWTd -t VSTd + LVIDd)3 LVIDd3] X 1.OS/BSA, where PWTd is left ventricular posterior wall thickness at end-diastole, VSTd is ventricular septal thickness at enddiastole, LVlDd is left ventricular internal diameter at end-diastole, and BSA is body surface area. Echocardiographic estimates of left ventricular end-systolic and enddiastolic volumes were calculated by the method of Teichholz et al [ 121. The h:r ratio was calculated as the result of (PWTd& LVIDd), where PWTd is left ventricular posterior wall thickness at enddiastole and LVlDd is left ventricular internal diameter at enddiastole. All echocardiograms were read by one experienced observer (Vivian D. Porter), who was unaware of the patients’ treatment group. To further assess the reproducibility of the measurements, 20 echocardiograms were selected at random and read by two observers (Dr. Joel M. Felner and Vivian D. Porter) in double-blind fashion; when the results were analyzed statistically, no significant observer differences were apparent. Left ventricular peak systolic circumferential wall stress was estimated by the method of Aziz et al [ 131. Left ventricular meridional end-systolic wall stress was estimated using the formula of Grossman et al [ 141. A standard 12 lead electrocardiogram was obtained at the time of each echocardiogram. All electrocardiograms were read by one of two observers (Dr. Hall and Dr. Wollam) and 13 specific electrocardiographic parameters were measured on each tracing. Statistical Analysis. The data are analyzed using repeated measures analysis of variance and the Tukey W multiple comparisons procedure [ 151. These methods were chosen because the experiment resulted in data structured according to the group-by-time repeated measures design; moreover, they provide for conservative control over the type I error rate. Other specific tests, such as a comparison between baseline values and a particular time point (using Tukey’s multiple comparison procedure), were performed when indicated. RESULTS Clinical and Echocardiographic Characteristics at Baseline (Table I). Thirty-two patients completed a six-month follow-up with complete data at each protocol point. Arterial pressure control was achieved with
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TABLE I
HYPERTENSION-WOLLAN
ET A:
Clinical Characteristics of the 32 Patients at Baseline Methyldopa t Methyldopa (Number = 7)
Age (years) Weight (ibs) Body surface area (m’) Blood pressure (mm Hg) Systolic Diastolic Heart rate Electrocardiographic voltage (mm) Sv, or Sv2 + Rvg or Rvg Lead aVL Cardiothoracic ratio’
39.1 178.1 1.88 157.7 105.3 72.4
40.4 5.4 0.51
-
P -+
tlydrochlorothiazide (Number = 17)
+ P+
46.5 195.2 1.99
<0.05
NS NS NS
NS NS NS
185.3 116.2 81.9
38.9 8.1 0.51
Hydrochlorothiaride (Number = 8)
P (Methyldopa versus Hydrochlorothiazide)
NS NS
37.3 203.6 1.99
NS NS NS
NS NS NS
170.1 109.1 74.8
NS NS NS
NS NS NS
37.0 6.1 0.47
NS NS NS
NS = not significant. Ratio of maximum cardiac width to maximum thoracic width calculated from the chest roentgenogram. l
methyldopa alone in seven patients, with hydrochlorothiazide alone in eight patients and with methyldopa and hydrochlorothiazide combined in 17 patients. There were no statistically significant differences between the methyldopa and hydrochlorothiazide groups with regard to any of the pretreatment clinical or echocardiographic characteristics. Five of the eight patients in the hydrochlorothiazide group and four of the seven patients in the methyldopa group had received no pharmacologic therapy for hypertension for periods of 12 months or more prior to enrollment. As expected, blood pressure was higher in the group that required methyldopa and hydrochlorothiazide combined. Initial Time Course of Regression of Left Ventricular Hypertrophy. Arterial pressure, heart rate and weight: At the end of the titration period, blood pressure was reduced to 127/83 f 15/B in the group given methyldopa, 134180 f 12/9 in the group given hydrochlorothiazide and 139/89 f 12/6 mm Hg in the group given methyldopa and hydrochlorothiazide combined (p <0.005 for all three). There were no significant differences between the methyldopa and hydrochlorothiazide groups with regard to the duration of the titration period (which averaged 23.8 f 10.9 days in the hydrochlorothiazide group and 33.7 f 15.6 days in the methyldopa group), the reduction in blood pressure during the titration period, or the level of blood pressure control during the maintenance period. Supine heart rate increased by 9.1 f 10.1 beats per minute (end of titration) in the hydrochlorothiazide group; whereas, it decreased by 5.9 f 8.9 beats per minute (one month visit) in the methyldopa group and remained at essentially the pretreatment level in the methyldopa and hydrochlorothiazide group. At the end of the titration
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period, weight had decreased by 4.9 f 4.1 pounds in the hydrochlorothiazide group and by 3.1 f 4.3 pounds in the methyldopa and hydrochlorothiazide group; whereas, it increased by 3.9 f 3.4 pounds in the methyldopa group. Echocardiographic Indices (Table II): Assessment of the group-by-time changes that occurred in left ventricular posterior wall thickness at end-diastole within the three treatment groups during the six-month period revealed some differences (Table II).” Left ventricular posterior wall thickness at end-diastole decreased significantly in the groups given methyldopa and methyldopa and hydrochlorothiazide combined (p
LVH 1N ESSENTIAL
TABLE
II
Echocardiographic Changes in the Three Treatment Establishment of Arterial Pressure Control
Echocardiographic Parametersand Intervals
Methyldopa (Number = 7) SD. Mean
Groups
During
HYPERTENSION-WOLLAM
the Six-Month
interval
Hydrochlorothiazide (Number = 8) Mean S.D.
Methyldopaand Hydrochlorothiaride (Number = 17) Mean S.D.
Following
ET AL
the
Repealed Measures Analysis of Variance*
PWTd (mm) Pretreatment Initial blood pressure control 1 month 3 months 6 months
12.4 11.4 11.3 11.0 10.9
1.4 1.1 0.8 1.0 0.9
13.0 12.8 12.5 12.6 12.0
2.3 2.5 3.1 2.8 2.7
13.2 12.8 12.2 12.4 12.1
2.3 2.4
MH group 4 p = 0.002
2.3 2.6 2.9
M group 4 p = 0.006 H group p = 0.34
VSTd (mm) Pretreatment Initial blood pressure control 1 month 3 months 6 months
11.0 11.0 10.4 10.6 10.9
2.2 1.2 1.4 1.3 2.0
10.6 11.1 11.0 11.3 11.9
1.5 1.9 1.9 1.5 1.9
13.8 12.6 13.1 12.7 13.5
2.5 3.3 3.5 3.0 3.0
LVlDd (mm) Pretreatment Initial blood pressure control 1 month 3 months 6 months
47.0 47.9 46.0 48.0 48.7
3.3 2.3 5.4 3.4 3.9
49.1 44.3 45.8 45.6 44.1
8.2 7.6 6.5 6.6 5.4
47.4 47.1 47.6 47.5 47.1
4.5 5.7 4.9 4.9 5.7
LADS (mm) Pretreatment Initial blood pressure control 1 month 3 months 6 months
34.1 34.0 34.6 35.6 35.4
6.3 5.4 7.7 6.7 5.2
37.6 35.4 34.8 35.0 36.9
5.1 4.4 6.0 4.1 5.8
37.1 36.6 37.9
5.3 5.8 5.8
t 36.8
H group i p = 0.005
t
5.5
AD Pretreatment Initial blood pressure control 1 month 3 months 6 months
0.35 0.32 0.34 0.34 0.34
0.06 0.05 0.08 0.06 0.05
0.38 0.40 0.42 0.41 0.41
0.07 0.05 0.05 0.05 0.06
0.37 0.39 0.39 0.39 0.40
0.07 0.10 0.07 0.09 0.05
Ejection fraction Pretreatment Initial blood pressure control 1 month 3 months 6 months
0.72 0.69 0.70 0.71 0.71
0.08 0.07 0.11 0.08 0.07
0.76 0.78 0.80 0.79 0.79
0.08 0.05 0.05 0.05 0.06
0.75 0.76 0.77 0.76 0.78
0.08 0.10 0.08 0.11 0.06
M = group treated with methyldopa alone; H = group treated with hydrochlorothiaztde alone: MH = group treated with combined methyldopa-hydrochlorothiaide; PWTd = left ventricular posterior wall thickness at enddiastole; VSTd = ventricular septal thickness at enddiastole; LVIW = left ventricular internal diameter at enddiastole; LADs = left atrial diameter at end-systole; AD = fractional shortening of left ventricular end-diastolic diameter. The p values pertain only to the significance of the group-by-time changes (that is, non-flatness) within the treatment groups. 7 In two patients in the combined mefhyldopa-hydrochl~othiazide group, left atrial diameter at end-systole could not be assessed with precision from the echocardiograms obtained at the end of the three-month follow-up period. The data from this visit was therefore not included in the statistical analysis of changes in left atrial diameter at end-systole in this group. l
days) after arterial pressure control was established (p <0.05 for both). Whereas, in the hydrochlorothiazide group, the reduction in left ventricular posterior wall thickness at enddiastole was not statistically significant at any point during the six-month period (p >O.lO). Changes in ventricular septal thickness at end29.8
diastole also tended to differ among the three groups. In the methyldopa and methyldopa and hydrochlorothiazide groups, ventricular septal thickness at enddiastole tended to decrease, although the downward trends in these two groups were not statistically significant during the six-month period. In the hydrochlorothiatide group, ventricular septal thickness at end-
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diastolic diameter (AD) and ejection fraction did not change significantly in any of the groups (Table II). For all 32 patients, the decrease in left ventricular mass index correlated with the reduction in systolic (r = 0.48, p
diastole increased from a pretreatment value of 10.6 f 1.5 mm to 11.9 f 1.9 mm after six months, and to 12.3 f 1.9 mm after 12 months of arterial pressure control; this increase in ventricular septal thickness at end-diastole was of borderline statistical significance (p = 0.08). Left ventricular internal diameter at end-diastole decreased in the hydrochlorothiazide group (p
TABLE III
Echocardiographic Changes in the Three Treatment Groups During an 18-Month Period Following the Establishment of Arterial Pressure Control
Echocardiographic Parametersand Intervals
Melhyldopa (Number= 4) Mean SD.
Hydrochlorothiazids (Number= 7) Mean SD.
Methyldopaand Hydrochlorothlaride (Number= 16) SD. Mean
Repeated Measures Analysisof Variance*
VSTs(mm) Pretreatment Initial blood pressure control 3 months 6 months 12 months 18 months
17.3 17.3 16.8 14.8 15.5 15.5
1.7 2.4 1.7 1.7 3.0 2.4
16.4 16.9 17.4 18.7 18.1 18.6
2.5 2.5 2.1 2.1 2.7 2.8
19.8 18.1 17.4 18.9 17.8 17.6
2.3 4.0 3.3 2.9 2.7 2.9
VSTd (mm) Pretreatment Initial blood pressure control 3 months 6 months 12 months 18 months
11.5 11.5 11.0 9.8 10.5 10.0
2.9 1.0 1.4 1.7 1.9 2.3
10.4 11.1 11.3 12.0 12.3 13.0
1.5 2.0 1.6 2.0 2.1 2.8
13.2 12.3 11.9 12.4 12.1 11.4
2.7 3.3 2.8 2.5 2.4 1.9
MH group 1 p = 0.03
PWTd (mm) Pretreatment Initial blood pressure control 3 months 6 months 12 months 18 months
12.5 10.8 10.5 10.3 10.0 10.0
1.9 1.0 1.0 0.5 0.8 1.4
13.1 12.7 12.9 12.3 12.6 12.3
2.5 2.8 3.0 2.8 2.8 3.7
12.8 12.2 11.8 11.4 11.7 11.6
2.2 2.2 2.3 2.3 2.3 2.2
MH group 4 p
LVlDd (mm) Pretreatment Initial blood pressure control 3 months 6 months 12 months 18 months
46.0 46.5 46.3 48.0 46.3 46.3
2.9 1.7 3.5 5.2 2.8 2.5
49.3 45.3 45.9 44.6 45.1 45.0
8.8 7.5 7.1 5.7 6.7 5.8
47.5 47.6 47.7 47.9 47.0 46.9
4.9 5.5 5.0 5.4 4.5 3.9
LVMI (g/m*) Pretreatment Initial blood pressure control 3 months 6 months 12 months 18 months
139 127 120 116 113 109
19 12 15 17 19 22
144 129 132 129 136 140
48 45 40 48 53 60
154 142 136 138 134 127
27 32 34 33 31 27
MH group 4 p
H group t p
M group 1 p
H group 4 p = 0.01
MH group 1 p
M Group = group treated with methyldopa alone; H Group = group treated with hydrochlorothiazide alone; MH Group = group treated with combined methyldopa-hydrochlorothiazide; VSTs = ventricular septal thickness at end-systole; LVMI = left ventricular mass index; other symbols as in Table II. The p values pertain only to the significance of the group-by-time changes (that is, non-flatness) within the treatment groups. The statistical analysis also includes the data from the one-month follow-up visit in the methyldopa and hydrochlorothiazide monotherapy groups. l
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LVH IN ESSENTIAL HYPERTENSION-WOLLAM
13.0 12.0
\ T,=xL__ \, --z*
11 .o 10.0
Hydrochlorothlar~de
n
Methyldopa
c
14.oF p/27
n
“%__ t
Methyldopa
ET AL
8 Hydrochlorothlarlde
l
a_-‘----
____z--____-___"o"
----d______--:----___--_____ A---__---_----_-4 t * *
14.oF
---+------_________ ___--*..*___--d
Figure 1. Serial long-term changes in left ventricular posterior wall thickness af end-diastole (PWTd), ventricular septal thickness at end-diastole (VSTd) and supine mean arterial pressure (MA@)(that is, DBP + 5/3 [SBP - DBP]) in the three treatment groups (27 patients) during an 1Smonth period.
80t
ness at enddiastole did not correlate well with changes in systolic (r = -0.07, p >O.lO) or diastolic pressure (r = -0.03, p >O.lO). In the methyldopa group, the reductions in left ventricular posterior wall thickness at end-diastole and left ventricular mass index also correlated with the baseline values (p CO.05 for both). In the hydrochlorothiazide group, the change in ventricular septal thickness at end-diastole paralleled the change in heart rate (r = 0.91, p cO.01) and ejection fraction (r = 0.73, p <0.05). At the three-month visit, the increase in ventricular septal thickness at enddiastole was also inversely related to the change in left ventricular internal diameter at enddiastole (r = -0.71, p <0.05). Electrocardiographic and roentgenographic indices: For the entire group of 32 patients, maximal summed precordial voltage on the electrocardiogram (lead Sv, or v2 i- Rvg or vg) decreased after three months (p
-.
LI_-____I BaselIne
‘;i;,$,,“,p
3 Months
6 Months
1
12 Months
16 Months
The change in electrocardiographic voltage in lead aVL correlated with the change in echocardiographic left ventricular mass index (r = 0.58, p
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26, 1963
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of Medlclne
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LVH IN ESSENTIAL
HYPERTENSION-WOLLAP
ET AL
Effect of therapy with METHYLbOPA over an 18 month period
(N = 4)
16.0 PWTo, mm
14.0 12.0 10.0
Effect of therapy with HYDROCHLOROTHIAZIDE (N = 7) over an 18 month period
8.OL
Figure 2. Serial long-term changes in left ventricular posterior wall thickness at end-diastole (PWTd) over an lb-month period in four patients treated with methyidopa alone and in seven patients treated with hydrochlorothiazide alone. Please note the break in the ordinate scale.
decreased significantly in the methyldopa group (p
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surements of ventricular septal thickness at end-systole (Table Ill). The change in ventricular septal thickness at end-diastole in the hydrochlorothiazide group correlated inversely with the change in left ventricular internal diameter at end-diastole during the initial three months of therapy (r = -0.78, p <0.05), but not at the six, 12, or 18-month points. The change in ventricular septal thickness at end-diastole in the hydrochlorothiazide group also paralleled the changes in heart rate (r = 0.92: p <0.05) and ejection fraction (r = 0.82, p <0.05). Left ventricular mass index decreased in the combined methyldopa and hydrochlorothiazide group (p
LVH IN ESSENTIAL
METHYLDOPA N=4
HYPERTENSION-WOLLAM
ET AL
METHYLDOPA + HYDf?OCHLOl?OTHlAZlDE N= 16
HYDROCHLOROTHlAZlDE N=7
20.0 F p>O.lO
19.0
p<.Ol
PC.02
k
18.0 17.0 16.0
V-D, mm
15.0 14.0 13.0 12.0 11 .o 10.0 9.0 8.0
i
I
I
Baseline
RX
I
(18 Months)
I
I
I
Baseline
RX
(18 Months)
Baseline
RX
(18 Months)
Figure 3. Long-term changes in ventricular septal thickness at end-diastole (VSTd) between baseline and the end of the 1Smonth follow-up period in the three treatment groups (27 patients). Of the 16 patients in the combined treatment group, 11 had an absolute decrease in ventricular septal thickness at end-diastole; whereas, five of the seven patients in the hydrochlorothiazide group had an increase.
decreased significantly at the end of these periods. Also, Reichek and co-workers [ 1 l] observed reductions in left ventricular posterior wall thickness at end-diastole and ventricular septal thickness at end-diastole in hypertensive patients treated with methyldopa and/or hydrochlorothiazide. In most studies, however, multiple therapeutic regimens have generally been employed, making the interpretation of the effects of individual drugs difficult. Moreover, in previous studies, echocardiograms have usually not been obtained repeatedly, to allow assessment of the relative time course of changes in left ventricular anatomy. Adequate long-term control of hypertension with sympatholytic drugs alone is often difficult because volume retention may result in loss of blood pressure control (that is, “pseudo-tolerance”). This latter phenomenon makes even more difficult the task of assembling large numbers of hypertensive patients with evidence of left ventricular hypertrophy in whom long-term control of blood pressure is maintained without concomitant diuretic therapy. In the present study, blood pressure control was maintained within each of the three treatment groups
to allow investigation of any changes in left ventricular anatomy that might be related to factors other than the reduction of blood pressure [ 16- 181. Assessment of changes in left ventricular posterior wall thickness at end-diastole and ventricular septal thickness at enddiastole revealed differences among the treatment groups. In the methyldopa and in the methyldopa and hydrochlorothiazide groups, left ventricular posterior wall thickness at end-diastole decreased significantly one month after arterial pressure was controlled. However, in the hydrochlorothiazide group, the reduction in left ventricular posterior wall thickness at enddiastole was not statistically significant during either the six- or 1El-month follow-up periods. These results are in accord with other studies in which sympatholytic drugs have been used in the treatment of hypertension. lbrahim et al [5] reported that left ventricular mass index decreased after eight weeks of therapy in hypertensive patients treated with atenolol. Others have reported similar findings after 12 weeks of therapy in relatively small groups of patients treated with propranolol or nadolol [4], or with methyldopa, alone or in conjunction with hydrochlorothiazide [6].
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Changes diastole
in ventricular
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ET Ai
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at end-
required
a longer period to occur and also differed among the treatment groups. In the methyldopa and hydrochlorothiazide group and the methyldopa group, ventricular septal thickness at end-diastole decreased during the 18-month period. Whereas, in the hydrochlorothiazide group, ventricular septal thickness at end-diastole increased over the l&month period. Changes in ventricular septal thickness at enddiastole in the hydrochlorothiazide group were non-parallel to those of the methyldopa group (p
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surement of ventricular septal thickness at enddiastole should be distributed equally among the groups. Drayer et al [24] have proposed that increases in ventricular septal thickness at enddiastole measurements during short-term (six-week) therapy with hydrochlorothiazide might be explained on the basis of anatomic adjustments to a decrease in left ventricular internal diameter at enddiastole. Our data also reveal an increase in ventricular septal thickness at enddiastole at the time of initial blood pressure control, when the reduction in left ventricular internal diameter at end-diastole in the hydrochlorothiazide group was near its nadir (Tables II and Ill). Moreover, the early changes in ventricular septal thickness at enddiastole in the hydrochlorothiazide group were inversely related to the change in left ventricular internal diameter at end-diastole. However, the correlations between changes in ventricular septal thickness at end-diastole and left ventricular internal diameter at end-diastole were not significant beyond the three-month follow-up period. Serial echocardiograms over the 18-month period revealed a continued increase in ventricular septal thickness at end-diastole in the absence of any further significant changes in left ventricular internal diameter at end-diastole. Hence, it would not seem likely that the long-term changes in ventricular septal thickness at end-diastole in the hydrochlorothiazide group could be completely due to anatomic adjustments resulting from the decrease in left ventricular internal diameter at end-diastole. In the present study, the decrease in electrocardiographic voltage tended to lag behind the echocardiographic indices and did not attain statistical significance until three to six months after blood pressure was controlled. The decrease in left ventricular mass index and left ventricular posterior wall thickness at enddiastole correlated better with the reduction in electrocardiographic voltage in lead aVL than with changes in either the maximal summed precordial voltage or the Romhilt-Estes total left ventricular hypertrophy point score. These findings are consistent with previous studies, which suggest that the electrocardiographic voltage in lead aVL may be a relatively specific electrocardiographic criteria for the assessment of left ventricular muscle mass [25,26]. Like left ventricular mass index, the h:r ratio decreased in the methyldopa and hydrochlorothiazide group (p <0.02), and the reduction in the methyldopa group attained borderline statistical significance (p = 0.06). Whereas, in the hydrochlorothiazide group, no decrease in the h:r ratio was apparent (p = 0.95). These findings are in agreement with the preliminary observations of Devereux et al [ 271, which also suggest that in hypertensive patients who receive long-term monotherapy with diuretics, regression of left ventric-
LVH IN ESSENTIAL
ular hypertrophy may be less than that in those treated with sympatholytic drugs, despite similar reductions in blood pressure. Monotherapy with diuretics [28], like that of vasodilators [29], may be associated with increased activity of the sympathetic nervous system and elevated plasma norepinephrine levels; whereas adrenergic blocking drugs generally suppress sympathetic neural activity [30]. In summary, the results of the present study indicate that, in patients treated with methyldopa or the combination of methyldopa and hydrochlorothiazide, a reduction in left ventricular posterior wall thickness at end-diastole may be apparent as early as one month after arterial pressure is controlled. Whereas, in patients treated with hydrochlorothiazide alone, left ventricular posterior wall thickness at end-diastole did not decrease significantly. During an 18-month follow-up period,
HYPERTENSION-WOLLAM
ET AL
ventricular septal thickness at enddiastole decreased in the group treated with methyldopa-hydrochlorothiazide combined and increased in the group treated with hydrochlorothiazide alone. Although the patient numbers are relatively small, the results suggest that there may be differences in the long-term effects of therapy with diuretics and sympatholytic drugs on left ventricular anatomy, which may, in part, relate to divergent effects on the sympathetic nervous system. ACKNOWLEDGMENT We wish to acknowledge the expert assistance of Ms. Marlis McDowell in the preparation of this manuscript. We are grateful to Elmer H. Funk, Jr., M.D. and his associates at Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania, for their generous supply of methyldopa and hydrochlorothiazide.
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