Left Ventricular Systolic and Diastolic Function and Mass before and after Antihypertensive Treatment in Patients with Essential Hypertension

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1 23 Left Ventricular Systolic and Diastolic Function and Mass before and after Antihypertensive Treatment in Patients with Essential Hypertension Yuji Yoshitomi, Toshio Nishikimi, Hitoshi Abe, Seiki Nagata, Mono Kuramochi, Hiroaki Matsuoka, and Teruo Omae The effects of antihypertensive treatment on regression of left ventricular hypertrophy and on left ventricular systolic and diastolic function were investigated echocardiographically in 13 untreated patients with mild hypertension (group I) and 16 untreated patients with moderate to severe hypertension (group II). The left ventricular mass index, left ventricular wall thickness, end-systolic left ventricular wall stress, and diastolic filling indexes before treatment were significantly higher in group II than in group I (p < 0.01). The blood pressure of both groups decreased significantly after antihypertensive treatment (mean duration of follow-up, 1.8 ± 0.3 yr in group I and 2.0 ± 0.4 yr in group II) (p<0.01). The left ventricular mass index did not change in group I, whereas it decreased significantly in group II (p < 0.01). The relation between fractional shortening and end-systolic wall stress was similar in both groups before treatment and was unaltered by treatment in either group. After treatment, peak velocity in early diastole (E) significantly increased in both groups; however, peak velocity in late diastole (A) did not decrease in either group. The AlE ratio was significantly decreased in both groups and was significantly higher in group II than in group I (p< 0.01). In conclusion, the results suggest that intrinsic contractility may not be affected by left ventricular hypertrophy or regression of left ventricular hypertrophy. AlE ratio decreased after antihypertensive treatment in patients with mild hypertension mainly because of a decrease in blood pressure. (Hypertens Res 1997; 20: 23-28) Key Words: hypertension, echocardiography, systolic function, diastolic function Abnormalities in left ventricular compliance and diastolic filling have been described in hypertensive patients, even when the left ventricular mass and the systolic function are normal. Such changes have been detected in patients with mild hypertension without discernible myocardial hypertrophy (1, 2). Since these abnormalities may represent early markers of hypertensive heart disease, their early recognition could facilitate the understanding, treatment, and prevention of left ventricular hypertrophy and the progression to systolic dysfunction (3, 4). Although numerous studies have shown that left ventricular hypertrophy can be reduced by antihypertensive treatment (S-7), it is unclear whether such pharmacologic reversal benefits cardiac function, so as to constitute an independent goal of antihypertensive treatment, or whether it is deleterious. Doppler echocardiographic studies suggest that measurements of transmitral flow velocity may provide useful information about left ventricular diastolic filling (8). The effect of antihypertensive treatment on diastolic dysfunction remains to be determined. In this study, we performed echocardiographic studies to determine whether antihypertensive treatment, which is known to reduce left ventricular mass, has a beneficial effect on left ventricular systolic function and diastolic filling in previously untreated patients with mild hypertension and in those with moderate to severe hypertension. Methods Study Patients Twenty-nine Japanese patients with previously untreated essential hypertension were studied. There were 18 men and 11 women aged 35 to 67 (mean 52 ± 10) yr. None had evidence of underlying heart disease, as assessed by their cardiovascular history, physical examination, electrocardiography, or echocardiography. All had sinus rhythm without signs of heart failure. The duration of hypertension ranged from 1 to 7 yr in all patients, an average of 3.3 ± 3.7 yr. From the Division of Hypertension, National Cardiovascular Center, Osaka, Japan. This work was supported in part by a Research Grant for Cardiovascular Disease 6A-2 (Shunichi Kojima) from the Ministry of Health and Welfare. Address for Reprints: Toshio Nishikimi, M.D., Division of Hypertension, National Cardiovascular Center, Fujishirodai, Suita, Osaka 565, Japan. Received June 18, 1996; accepted in revised form October 3, 1996.

2 24 Hypertens Res Vol. 20, No. 1(1997) Blood pressure was measured with a standard mercury column sphygmomanometer, using the average of three readings performed on different days. Echocardiography was performed before treatment and again at the end of the follow-up period. Patients were classified into two groups according to the 1993 Guidelines for the Management of Mild Hypertension (9): Thirteen patients with mild hypertension (systolic blood pressure 140 to 180 mmhg, diastolic blood pressure 90 to 105 mmhg, or both; group I) and 16 patients with moderate to severe hypertension (systolic blood pressure over 180 mmhg, diastolic blood pressure over 105 mmhg, or both; group II). All protocols were reviewed and approved by our Ethical Review Committee, and informed consent was obtained from all patients. Echocardiographic Examination An M-mode echocardiography was obtained with two-dimensional monitoring using a Hewlett-Packard 77020A phased-array ultrasonic sector scanner (Hewlett Packard, Para-Alto, CA) and a 2.5-MHz transducer as previously reported (10-12). Strip chart recordings used a paper speed of 50 mm/s. Septal and posterior thickness and left ventricular chamber dimensions were measured according to the American Society of Echocardiography and Penn conventions (13, 14). Standard methods were used to calculate left ventricular mass and endocardial fractional shortening (fractional shortening) (15, 16). Stroke volume was estimated using the Teichholz correction of the cube formula (17). To minimize variance in echocardiographic measurement, echocardiograms were interpreted by two investigators blinded to the category of each patient and to whether the echocardiograms were taken before or after treatment (18). End-systolic left ventricular wall stress was calculated from echocardiographic findings and blood pressure, measured with a sphygmomanometer, at the time of echocardiography: end-systolic wall stress = [0.98 X (0.334 X endsystolic left ventricular internal dimension X systolic blood pressure)/ end-systolic posterior wall thickness X (1 fiend-systolic posterior wall thickness/end-systolic left ventricular internal dimension)]-2x 103 dynes/cm2 (19). Doppler Instrumentation and Recording Techniques Pulsed Doppler recordings of transmitral flow were taken from the apical four-chamber view as reported previously (20). The sample volume was placed in the left ventricular inflow tract between the mitral annulus and the tips of the mitral leaflets. This position was adjusted to maintain the sample volume at an angle that was as parallel as possible to the transmitral flow by using the audible signal and the spectral display. When the maximum peak velocity in early diastole (E) was detected, the velocity profile was recorded at a paper speed of 50 mm/s. The peak velocity in early diastole and that in late diastole (A) were then measured from three Table 1. Patient Characteristics to five consecutive cardiac cycles displaying the highest measurable velocity profiles. The average of each respective peak velocity was calculated, and the ratio of peak velocities (A/E) was determined (21). Study results were analyzed by two investigators who were unaware of the category of each patient and whether the measurements were made before or after treatment. The reproducibility of echocardiographic measurements were tested in our laboratory in 10 normal subjects, each of whom was examined twice by the same ultrasonic technique. The same operator digitized four consecutive cardiac cycles of each echocardiogram. The coefficients of variation were as follows: left ventricular end-diastolic diameter 1.0%; septal thickness 3.1%; posterior wall thickness 2.7%; peak velocity in early diastole 5.5%, and peak velocity in late diastole 6.3%. Antihypertensive Treatment No patient had received any antihypertensive agent before the study. The following treatments were administered. In group I, all patients received a calcium channel antagonist (nifedipine 8, nicardipine 5). In group II, all received two (9 patients) or three agents (7 patients) in combination; i. e., a calcium channel antagonist (nifedipine 9, nicardipine 5), a j3-adrenergic blocking agent (nadolol 3, pindolol 4, atenolol 5), or an angiotensin converting enzyme inhibitor (captopril 5, enalapril 8). Antihypertensive treatment was initiated after a baseline echocardiographic study. The goal of antihypertensive treatment was a reduction in diastolic blood pressure to less than 90 mmhg if the baseline blood pressure was greater than 100 mmhg, or a reduction of at least 10 mmhg if the baseline diastolic blood pressure was between 90 and 100 mmhg. In group I, all patients achieved this goal after 3 months, and all achieved this goal after 5 months in

3 Yoshitomi et al: Left Ventricular Function in Hypertension 25 Table 2. Echocardiographic after Treatment Characteristics before and Table 3. Systolic and Diastolic Function diography before and after Treatment of Echocar- group II. The echocardiographic study was repeated at the end of the follow-up period. Statistical Analysis Results are expressed as mean ± SD. Statistical analysis utilized Student's t-test for paired and unpaired data as appropriate. Linear regression analysis was used to evaluate whether a correlation existed between variables. Analysis of covariance was used to evaluate differences between the slope and intercept of the relation between fractional shortening and end-systolic wall stress. Al E ratio was adjusted for age by analysis of covariance. A level of p < 0.05 was accepted as statistically significant. Results Clinical Characteristics Table 1 lists the clinical data for each group. The age of the patients in the two groups did not differ significantly. The period of illness did not differ in the two groups. The mean duration of follow-up was similar in the two groups: 1.8 ± 0.3 yr in group I and 2.0 ± 0.4 yr in group II. Heart rate was similar in the two groups and did not change significantly at the end of follow-up in either group. The systolic and diastolic pressures decreased significantly in both groups (p < 0.01). The decreases in systolic and diastolic pressures were significantly greater in group II than in group I (p<0.01). Echocardiographic Characteristics Before treatment, left ventricular mass index, interventricular septal thickness, and left ventricular posterior wall thickness were significantly larger in group II than in group I (p< 0.01) (Table 2). There were no significant differences between the two groups in left ventricular end-diastolic or end-systolic dimensions. In group I, there was no significant difference before vs. after treatment for left ventricular mass index, left ventricular wall thickness, or left ventricular internal dimensions. In group II, left ventricular mass index, left ventricular wall thickness, and left ventricular end-systolic dimension decreased significantly after treatment (Table 2). Stroke index in group I was significantly higher than that in group II, whereas stroke index increased after treatment in both groups. End-systolic wall stress was significantly higher in group II than in group I and decreased after treatment in both groups. Fractional shortening improved significantly after treatment in both groups (p < 0.05) (Table 3). The relationship between fractional shortening and end-systolic wall stress was similar before treatment and did not change after treatment in either group (Fig. 1). Doppler Measurements Peak velocity in early diastole (E) in group I was higher than that in group II and peak velocity in late diastole (A) did not differ between the two groups before treatment. Peak velocity in early diastole increased significantly after treatment in both groups. However, peak velocity in late diastole did

4 26 Hypertens Res Vol. 20, No. 1(1997) Fig. 1. Relation between fractional shortening and endsystolic wall stress. There was a similar relation before and after treatment. a) group I (before r = 0.57, after r = 0.66), b) group II. (before r=0.75, after r=0.64), before: solid line; after: dotted line. not decrease in either group. There was significant difference between the two groups in peak velocity in early and late diastole after treatment. The ratio of late to early peak velocity (AlE) in both groups was significantly decreased after treatment (Table 3). A/E ratio in group II was higher than that in group I before and after treatment. A/E ratio positively correlated with systolic blood pressure in group I (r = 0.54, p < 0.05). In contrast, A/E ratio did not correlate with systolic blood pressure in group II. Discussion This study echocardiographically compared the effects of antihypertensive treatment on left ventricular systolic and diastolic function between patients with previously untreated mild hypertension and those with previously untreated moderate to severe hypertension. Antihypertensive treatment significantly improved diastolic filling, although intrinsic systolic function was apparently unchanged in mild hypertension. In patients with moderate to severe hypertension, intrinsic systolic function was unchanged and diastolic filling improved; however, diastolic filling was still impaired. These results suggest that intrinsic contractility may not be affected by regression of left ventricular hypertrophy in essential hypertension. In the absence of valvular obstruction, the major determinant of diastolic filling appears to be the instantaneous left atrial to left ventricular pressure difference. The peak velocity of early diastole, which reflects the peak left atrial/left ventricular pressure gradient during early diastole, is affected by many factors, including left atrial pressure, left ventricular compliance, rate of left ventricular relaxation, and afterload on the ventricle (8, 22). The ratio of late to early peak velocity of left ventricular filling is also sensitive to changes in heart rate (8, 22). In the present study, heart rate did not change before vs. after treatment and therefore did not influence the change in ratio of late to early peak velocity. Nishimura et al. (8) has shown that an increased afterload decreases the peak velocity in early diastole. Several studies reported that the degree of hypertrophy may be related to left ventricular diastolic dysfunction in hypertensive patients (3, 11), and a reduction in blood pressure may be one of the factors that improves diastolic function in patients with borderline hypertension (23). In this study, the ratio of late to early peak velocity positively correlated with systolic blood pressure in patients with mild hypertension. Therefore, in patients with mild hypertension without obvious hypertrophy, improved diastolic filling may correlate with decreased blood pressure. Patients with moderate to severe hypertension showed a significant improvement in the ratio of late to early peak velocity, but showed no correlation between diastolic filling and blood pressure. Blood pressure in patients with moderate to severe hypertension decreased more than that in patients with mild hypertension, while diastolic filling was still impaired after treatment. An improvement in diastolic filling may be the result of factors other than a reduction in blood pressure and a decrease in left ventricular mass in patients with moderate to severe hypertension with left ventricular hypertrophy. It is possible that left ventricular diastolic dysfunction may be mainly caused initially by the increased workload imposed on the left ventricle. Subsequently, when left ventricular hypertrophy develops, it may play an independent role in the genesis of the impairment in left ventricular diastolic filling. Trimarco et al. (24) reported that diastolic filling may improve with a decrease of blood pressure, independently from the effects of a decrease in left ventricular hypertrophy. Motz et al. (25) suggested that the regression of left ventricular mass in spontaneously hypertensive rats given antihypertensive treatment was accompanied by a reduction in collagen content. The muscle/collagen ratio was unchanged, and myocardial stiffness was unchanged after left ventricular mass regression. Changes at the cellular level in the muscle/collagen ratio or

5 Yoshitomi et al: Left Ventricular Function in Hypertension 27 other factors may impair left ventricular relaxation and lead to diastolic abnormalities. The time required to observe a reduction in ventricular muscle may differ from that required to observe an alteration in the collagen matrix because the former may occur early and the latter may occur late in the course of treatment. A longer period of treatment seems to be required to modify the left ventricular filling than to reduce the blood pressure and the cardiac mass in patients with obvious left ventricular hypertrophy. Thus, a comparison of left ventricular systolic and diastolic dysfunction in mild hypertension with those in moderate to severe hypertension disclosed a difference in diastolic performance after treatment. Several clinical studies show that ventricular systolic function (e.g., ejection fraction, fractional shortening, and velocity of circumferential fiber shortening) is apparently unchanged by antihypertensive treatment (5-7). These variables depend on afterload. The contractile quality of the left ventricular wall can be judged in part by studying the relationship between end-systolic wall stress and left ventricular fractional shortening (19). This linear relationship, which is independent of afterload, enables one to determine whether changes in cardiac function reflect loading conditions or myocardial changes. Some investigators have suggested that the left ventricular fractional shortening is reduced in hypertensive patients exclusively because of an increase in left ventricular afterload, while the left ventricular intrinsic contractility remains normal (26, 27). Furthermore, the reduction in left ventricular mass by antihypertensive treatment was not associated with a change in systolic function (28). In the present study, we found that the linear relationship did not change in either group after treatment. It appears that intrinsic contractility remained stable throughout the study. The intrinsic contractility may not be affected by left ventricular hypertrophy or regression of left ventricular hypertrophy. Many factors can modulate the development of left ventricular hypertrophy (10, 11, 29). Left ventricular hypertrophy can be prevented or reversed by a variety of antihypertensive agents (5-7). However, the effects of antihypertensive treatment on left ventricular function largely remain to be determined. Differences in methods, patient selection, severity of hypertension, and duration of treatment contribute to this variability. A particularly important feature of our study was that the patients were all previously untreated. Gosse et al. (30) suggested that previous treatment may have an influence on the regression of left ventricular hypertrophy. Several clinical studies have shown that ventricular systolic function appears to remain unchanged, whereas diastolic function may even improve in patients treated with calcium channel antagonists (31, 32). Antihypertensive treatment with calcium channel antagonists, known to be arteriolar dilators, corrects loading conditions of the left ventricle with a consequent reduction in wall stress and an improvement in diastolic filling. Among our patients with moderate to severe hypertension, 12 received a &- adrenergic blocking agent combined with a calcium channel antagonist, an angiotensin converting enzyme inhibitor, or both. Since all patients were treated with combinations of these agents, systolic function did not change after treatment. White et al. reported that left ventricular ejection fraction did not change in patients receiving metoprolol (33). In this study, antihypertensive treatment of patients with mild hypertension was accompanied by an improvement in left ventricular diastolic filling, without regression of left ventricular mass after treatment or a change in left ventricular intrinsic systolic function. Antihypertensive treatment reduced left ventricular mass and improved diastolic filling in moderate to severe hypertension, although intrinsic systolic function did not change and diastolic filling was still impaired. The results suggest that about two years of antihypertensive treatment is enough to reduce the blood pressure and the cardiac mass in patients with obvious left ventricular hypertrophy; however, further long-term treatment may be necessary to normalize the left ventricular filling. Left ventricular intrinsic contractility seems to remain unchanged irrespective of left ventricular hypertrophy or its regression. References 1. 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