Effect of Long-Term Antihypertensive Therapy on

Cardiac Anatomy in Patients with Essential Hypertension

JAN I. M. DRAYER, M.D.

MICHAEL A. WEBER, M.D.

JULIUS M. GARDIN, M.D.

JODI L. LIPSON, B.S.

long Beach, California

From the Section of Clinical Pharmacology and Hypertension, Section of Cardiology, Veterans Administration Medical Center, Long Beach, California and the University of California at Irvine, Irvine, California. Requests for reprints should be addressed to Dr. Jan I. M. Drayer, Hypertension Center W 130, Veterans Administration Medical Center, 5901 East Seventh Street, Long Beach, California 90822.

M-mode echocardiography was used in 12 patients with essential hypertension to study changes in cardiac anatomy during long-term therapy with hydrochlorothiazide (50 to 100 mg) and alpha-meth- yldopa (500 to 1,750 mg). Echocardiographic examination was performed after six weeks of treatment with hydrochlorothiazide alone and after four to six weeks, six months, and nine months of treatment with both hydrochlorothiazide and alpha-methyldopa. Hydrochlorothiazide alone induced a small, and not significant, change in blood pressure (from 157 f 16 (SD)/105 f 9 to 150 f 141101 f 5 mm Hg). Changes in echocardiographic parameters of cardiac anatomy were not observed during short-term diuretic therapy. Addition of alpha-methyldopa further reduced blood pressure (to 133 f II/90 f 6 mm Hg, p <O.OOl), which was maintained throughout the study. Gradual decreases in diastolic septal thickness (from 10.9 f 1.1 to 9.5 f 1.0 mm, p <O.Ol), relative wall thickness (from 0.40 f 0.06 to 0.36 f 0.06, p <0.05) and left ventricular cross-sectional area (from 16.9 f 2.9 to 17.3 f 2.6 cm*, p <0.05) were observed. Posterior wall thickness d&i not change significantly during the study. The results provide evidence for re- gression of echocardiographic parameters of cardiac muscle mass during long-term antihypertensive treatment with a diuretic and a centrally-acting sympatholytic drug. Regression of left ventricular mass was not clearly related to changes in casual blood pressure. However, patients who showed a decrease in septal thickness tended to have a greater decrease in systolic blood pressure than those in whom septal thickness did not change r&ring therapy. Moreover, patients in whom a decrease in left ventricular transverse dimension was observed, had a greater decrease in both systolic and diastolic blood pressure than those in whom left ventricular diastolic dimension did not change.

M-mode echocardiography has been used as a powerful and sensitive tool in the detection of changes in cardiac left ventricular anatomy in patients with hypertension [l-7]. M-mode echocardiography is more sensitive than electrocardiography in the detection of cardiac hy- pertrophy and in the evaluation of changes in cardiac muscle mass during antihypertensive therapy [8-121.

It is of interest to note that the occurrence of different forms of cardiac hypertrophy have been described in hypertensive patients. Concentric hypertrophy [ 1,4,6], eccentric hypertrophy [ 1,4,5], and predominant septal hypertrophy [ 1,2,5,7,8] have been documented in untreated hypertensive patients. Regression of concentric hyper- trophy [9-131 as well as regression of predominant septal hypertrophy [ 8,131 during antihypertensive therapy have been reported.

116 September 26, 1963 The American Journal 01 Medicine

LVH IN ESSENTIAL HYPERTENSION-DRAYER ET AL

In this study we analyzed the effects of antihyper- tensive therapy, using diuretics and the centrally-acting sympatholytic agent alpha-methyldopa, on different echocardiographic parameters of cardiac muscle mass in hypertensive patients. Moreover, we analyzed the relationships between regression of cardiac hypertro- phy and drug-induced changes in blood pressure.

METHODS

The study was performed in patients with moderate essential hypertension. Previous antihypertensive medication was discontinued for at least one week prior to the study. Patients with diabetes mellitus, alcohol abuse, renal insufficiency, congestive heart failure, or ischemic heart disease were excluded from the study. All patients gave informed consent prior to the start of the study.

The initial examination included a physical examination, measurements of body weight, blood pressure, heart rate, and an M-mode echocardiogram. Following this examination, each patient was treated with hydrochlorothiazide for six weeks, after which measurements of body weight, blood pressure, and heart rate were repeated. A second M-mode echocardiogram was then obtained. Following this exami- nation, each patient was treated with alpha-methyldopa and hydrochlorothiazide for nine months. The dose of alpha- methyldopa was increased at two-week intervals when blood pressure was not controlled (supine diastolic blood pressure greater than 90 mm Hg). Measurements of blood pressure, heart rate, and body weight were obtained at four to six weeks, six months, and nine months after the start of treat- ment with alpha-methyldopa. M-mode echocardiogram was obtained after each examination.

Blood pressure and heart rate were measured during each visit after at least five minutes of supine rest. The average of the two readings obtained was used to represent the pa- tient’s blood pressure at that time. Echocardiographic Measurements. All patients were studied in the left lateral decubitus position using standard echocardiographic techniques as described previously [ 131. The studies were performed using a 2.25 mega Hz transducer with a Smith Kline 20A Echograph (Smith Kline & French, Philadelphia, Pennsylvania). A Honeywell 1856 fiberoptic recorder (Honeywell, Denver, Colorado) was used. All echocardiograms were recorded by the same technician using the same equipment. The echocardiograms were pooled and coded after completion of the study and inter- preted by two observers (Dr. Drayer and Dr. Gardin). Mea- surements were obtained following the recommendations of the American Society of Echocardiography. The echo- cardiographic parameters analyzed for the purpose of this study include diastolic thickness of the interventricular septum (VSo) and left ventricular posterior wall (PWo) as well as the left ventricular transverse dimension during diastole (LVTDo). At least three beats were analyzed to obtain the variables from each echocardiogram. The average of the results ob- tained by the two interpreters was used to represent each echocardiographic parameter. The data from the two inter- preters were within acceptable limits for that particular measurement in approximately 90 percent of the echocar-

diograms. The results were expressed in millimeters. Serial changes in left ventricular mass probably are best reflected by echocardiographic indices based on both the diastolic transverse dimension of the left ventricle and the diastolic thickness of the muscle wall surrounding the ventricle. Therefore, different parameters of left ventricular muscle mass were derived: relative wall thickness, RWT = (VSo •F PWo)/LVTDo; left ventricular cross-sectional area [ 131 and CSA = [((LvTD~,~) + (VSo + PWo)/2)2 - (LVTDo/2)*] X 7r/ 100 cm*.

Standard statistical tests were used to calculate signifi- cances between parameters (paired Student’s t test), and to assess the significance of correlations between parameters (Pearson correlation coefficient). The data are expressed as mean f standard deviation of the mean, unless mentioned otherwise. Two tailed p values are given to express the sig- nificance of the results of the statistical procedures.

RESULTS

All 12 patients selected for the study were male; three were black and nine white. Their ages ranged from 38 to 70 years, with an average of 59.2 f 13.0 years. Four patients had never been treated prior to this study, an- other group of four patients had used antihypertensive medication until at most six weeks prior to the study. A last group of four patients had used antihypertensive medication until one week prior to the study. Previous therapy included hydrochlorothiazide, beta-blockers and/or vasodilator therapy. However, blood pressure had not been adequately controlled in these patients. The response to therapy was not signficantly different between patients who had been treated in the past and those who had not received previous therapy.

Hydrochlorothiazide was given to all patients, 11 received 100 mg in the morning, and the twelfth patient 50 mg in the morning. Potassium supplements were given to one patient (32 mEq per day). Alpha-methyl- dopa was given to the patients in doses ranging from 500 to 1,500 mg per day (mean 692 f 396 mg). M- mode echocardiography was performed prior to the start of diuretic therapy, after 42 f 4 days of diuretic therapy, and after 33 f 9, 141 f 12 and 234 f 33 days of treatment with both hydrochlorothiazide and alpha- methyldopa. The total duration of antihypertensive therapy at the time that echocardiograms and mea- surements of blood pressure, heart rate, and body weight were obtained was 42 f 4, 75 f 9, 184 f 15 and 267 f 33 days, respectively.

The effect of therapy on blood pressure, heart rate, and body weight is depicted in Table 1. Hydrochloro- thiazide alone did not induce a significant change in

blood pressure. However, heart rate increased (p

<0.05) and body weight decreased (p <0.05). Treat- ment with both hydrochlorothiazide and alpha-methyl- dopa significantly decreased systolic and diastolic blood pressure (p <O.Ol). Heart rate increased slightly. Body

September 26, 1983 The American Journal of Medicine 117

LVH IN ESSENTIA: FYPERTENS!ON-DPAYEP FT A’.

TABLE I Effect of Therapy on Blood Pressure, Heart Rate, and Body Weight (mean f SEM, number = 12) _------w-v---

8aseline _-_---_-______

Duration of therapy (days) 0 Supine blood pressure (mm Hg)

Systolic 157f5

Diastolic 105 i 3

Heart rate (beat per minute) 66 f 2 Body weight (kg) 83.2 f 3.9

l p <O.Ol and + p <0.05 versus baseline.

Hydrochlorolhlazide Hydrochlorothiaride plus Alpha-Methyldopa

42 f 1 75 f 3 184f4 287 f 10

150f4 133 f 3’ 131 f 2’ 137 f 3‘ 101 f 1 90 f 2’ 89 f 2’ 92f 2’

71*3+ 66 f 3 73 f 3’ 71 f3 82.1 f 4.1+ 81.5 f 4.2+ 82.0 f 4.1+ 82.8 zk 3.9

weight increased during therapy with alpha-methyldopa, but it never exceeded pretreatment values.

Changes observed in echocardiographic parameters of left ventricular muscle mass are given in Figure 1. Changes in blood pressure and echocardiographic parameters of left ventricular muscle mass in patients who had received antihypertensive therapy prior to this study did not differ from those in patients who had never received antihypertensive treatment before the start of this study.

Septal thickness decreased and posterior wall thickness increased slightly during diuretic therapy. Combined diuretic and sympatholytic therapy resulted in a significant decrease in septal thickness, septal- posterior wall ratio, and calculated left ventricular cross-sectional area. Relative wall thickness decreased significantly from 0.40 to 0.06 to 0.36 f 0.06 (p <0.05). Indeed, a significant correlation was found between treatment-induced changes in septal thickness and changes in relative wall thickness (r = 0.62, 12 patients, p <0.05) or in left ventricular cross-sectional area (r = 0.68, 12 patients, p <0.05). Left ventricular diastolic transverse dimension did not change significantly during the study; from a baseline value of 50.6 f 1.5 mm to 5 1.1 f 1.6 mm at the end of the study. Septal thickness was 1.8 f 0.8 mm (p <O.Ol) greater than posterior wail thickness during the baseline evaluation, and this dif- ference was significantly (p <0.05) less at the end of the study (1 .O f 1.2 mm). In fact, six of the 12 patients had a diastolic septal thickness greater than 11 mm during the baseline evaluation and only one patient had a posterior wall thickness exceeding 11 mm. At the end of the study, all patients had a septal and posterior wall thickness of less than 11 mm.

The correlations between changes in blood pressure and changes in echocardiographic parameters of left ventricular muscle mass were not significant. However, systolic blood pressure decreased more in patients in whom septal thickness decreased during combination therapy (-25 f 9 mm Hg, eight patients) than in those in whom septal thickness did not change (-14 f 7 mm Hg, four patients). Moreover, systolic blood pressure

decreased more in patients in whom left ventricular transverse dimension decreased (-36 f 10 mm Hg, five patients) than in those in whom diastolic transverse dimension did not change or increased (- 11 f 6 mm Hg, seven patients). Diastolic blood pressure also de- creased to a greater extent in the former group (- 17 f 5 mm Hg) than in the latter (-9 f 3 mm Hg).

COMMENTS

Echocardiographic signs of left ventricular hypertrophy are commonly seen in hypertensive patients. Blood pressure-induced changes in cardiac anatomy in hy- pertensive patients may be expressed as concentric hypertrophy [ 1,4-61, eccentric hypertrophy [ 1,4,5], as predominant septal hypertrophy [ 1,2,5,7,8], or as any combination of these forms of hypertrophy. The etiology of the different forms of hypertrophy remains to be elucidated. However, the height of the systolic blood pressure has been shown to be related to pre- dominant septal hypertrophy [ 141 and increases in renin activity and/or increases in sympathetic nervous system activity to concentric hypertrophy of the left ventricle [15,16].

The patient group studied here is small, and some have had previous antihypertensive therapy. Moreover, the patient population was characterized by a marked age range. It would have been preferred to enter larger groups of patients who had never been treated into this study. However, such patients are not often seen at our Center. In fact, the patients studied here closely re- flected the outpatient population visiting this institu- tion.

In the patients described in this study, septal thick- ness was clearly greater than posterior wall thickness, and the difference between septal and posterior wall thickness decreased during combined diuretic-sym- patholytic therapy. Therefore, our study supports the predominant involvement of the septum in hypertensive patients.

Fouad et al [lo] and Reichek et al [ 1 l] also reported significant reductions in echocardiographic parameters

118 September 28, 1983 The American Journal of Medlclne

LVH IN ESSENTIAL HYPERTENSION-DRAYER ET AL

Figure 1. Effect of therapy with hydro- chlorothiazide and hydrochlorothiazide and alpha-methyldopa on echocardio- graphic parameters of left ventricular muscle mass.

10 ’

Diastolic Posterior Wall 9. Thickness mm

8 J Septum 1 Posterior I2 Wall Ratio

20

LV Cross-

Sectional Area 18 cm2

16 !k&&$$igY I . . 0 75 150 225 300 DAYS

DURATION OF THERAPY

.P<O.D5 “P<O.Ol

of left ventricular muscle mass during treatment with hydrochlorothiazide and alpha-methyldopa. However, in all patients studied by these investigators left ven- tricular hypertrophy had been documented prior to the start of the study. Six of the 12 patients in our study had a septal thickness exceeding 11 mm. A reduction in septal thickness was apparent in five of these six pa- tients as well as in three of the six patients who had a septal thickness of less than 11 mm during the baseline evaluation. Therefore, although a treatment-induced reduction in cardiac muscle mass might be more pro- nounced in patients with cardiac hypertrophy, it also can be obtained in some patients with “normal” cardiac muscle mass prior to treatment.

Previous studies [lo-131 describe a lack of asso- ciation between changes in blood pressure and change in echocardiographic parameters of muscle mass. The

correlations between changes in wall thickness or left ventricular cross-sectional area and changes in casual blood pressure observed in this study also lacked sta- tistical significance. However, systolic blood pressure decreased more in patients who showed a treatment- induced decrease in septal thickness than in those who showed no change. This observation supports the role of systolic blood pressure in the development of septal hypertrophy. Moreover, the decrease in both casual systolic and diastolic blood pressure was greater in patients who showed a decrease in left ventricular di- astolic transverse dimension than in those who did not. It should be emphasized that the differences observed were fairly small. Therefore, it is unlikely that changes in casual blood pressure per se determined changes in cardiac muscle mass.

It has been reported that casual blood pressure is not

September 26, 1983 The American Journal of Medicine 119

a reIliable determinant of cairdiac hypertrophy. Indeed, correlations bleltween averages of blood pressures obtained during long-term ambulatory blood pressure monitoring and echocardiographic parameters of left ventricular muscle mass have been reported to be much more significant than those between casual blood pressure and parameters of left ventricular hypertrophy [ 17,181. Therefore, long-term blood pressure moni- toring might be needed to further evaluate this rela- tionship. Moreover, the relationship between drug- induced changes in blood pressure levels observed during ambulatory monitoring and regression of cardiac hypertrophy has not been studied yet.

6.

7.

8.

9.

In summary, a regression of cardiac hypertrophy was observed in hypertensive patients during long-term therapy with hydrochlorothiazide and alpha-methyldopa. Regression of hypertrophy was most pronounced at the level of the interventricular septum. Regression of septal thickness possibly is, at least in part, related to changes in casual systolic blood pressure. Decreases in left ventricular cavity size were observed especially in patients who had greater decreases in systolic and diastolic blood pressure. Long-term monitoring of blood pressure might be needed to further define the role of pressure in the induction or regression of cardiac hy- pertrophy.

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120 September 26, 1963 The American Journal of Medicine