Original Article
The Effects of Antihypertensive Therapy on Left Ventricular Mass in Elderly Patients
N Engl J Med 1990; 322:1350-1356May 10, 1990
- Abstract
- Abstract
Left ventricular mass sometimes decreases during treatment of hypertension, but this response is inconsistent and its effects on left ventricular function are unknown. In a six-month randomized trial, we studied the ability of verapamil and atenolol to reduce left ventricular mass in 42 elderly patients with hypertension and the effects of this reduction in mass on cardiac function.
The mean blood pressure (±SE) decreased in both the group that received verapamil (from 171.4±3.2/93.0±2.5 mm Hg to 142.9±2.8/79.0±2.0 mm Hg) and the group that received atenolol (from 179.6±4.6/98.5±2.4 mm Hg to 148.1±3.3/83.4±1.2 mm Hg), but the atenolol-treated patients more frequently required the addition of chlorthalidone to achieve blood-pressure reduction (P<0.01). Verapamil resulted in a reduction in the left-ventricular-mass index from 104±5 g per square meter of body-surface area to 85±5 g per square meter (P<0.01). Atenolol did not produce a reduction in the left-ventricular-mass index (109±9 g per square meter before treatment vs. 112±10 g per square meter after treatment).
Two weeks after the withdrawal of antihypertensive therapy, blood pressure returned to pretreatment values. Nevertheless, in patients whose left ventricular mass had decreased, two measures of diastolic filling, the peak diastolic filling rate of the left ventricle and the ratio of the peak filling rate to the peak ejection rate, were significantly higher than before treatment (2.42±0.2 vs. 3.31±0.4 [P<0.05] and 0.61±0.03 to 0.85±0.05 [P<0.05], respectively). Diastolic filling was unchanged in the group that had no reduction in left ventricular mass. Cardiac output and the ejection fraction at rest and during mild exercise were unchanged in both groups as compared with base-line values.
We conclude that left ventricular mass can be reduced in elderly patients with hypertension and mild ventricular hypertrophy who receive antihypertensive therapy. Reduction occurs more frequently with verapamil than with atenolol therapy, increases diastolic filling, and does not impair systolic function. (N Engl J Med 1990; 322: 1350–6.)
Media in This Article
Figure 1
Systolic and Diastolic Blood Pressures, Measured in a Sitting Position, in the Two Treatment Groups at Base Line, after One Month of Therapy, and One to Two Weeks after the Withdrawal of Therapy.Figure 2
Individual and Mean Changes in the Left-Ventricular-Mass Index from Base Line to the Six-Month Follow-up, as Determined by Two-Dimensional Echocardiography.Article Activity
- Article
HYPERTENSION is the most prevalent and most strongly predictive remediable risk factor for cardiovascular disease in older persons.1 Although the control of blood pressure is readily achieved and reduces the risk of cardiac death and stroke,2 , 3 it is not clear whether reduction in the mass of the left ventricle should also be a therapeutic goal of antihypertensive therapy in this age group.4 , 5 Although regression is theoretically desirable,6 , 7 it is not known whether it is possible in the elderly or whether it would, in fact, improve or impair ventricular function.5 This concern is emphasized by studies of an animal model of hypertension, which indicated that reduction in mass impairs the response of the left ventricle to an afterload stress.8
We conducted a six-month randomized, double-blind trial to compare the effects of a beta-adrenergic blocker, atenolol, and a calcium-channel blocker, verapamil, on blood pressure and left ventricular mass in 42 elderly patients with hypertension. Left ventricular mass was measured with two-dimensional echocardiography. Cardiac function at rest and during mild exercise was measured with use of gated blood-pool scanning; the effect of reduction in the left ventricular mass on cardiac function was assessed by repeat scans two weeks after the discontinuation of therapy, when the blood pressure had returned to base-line values.
Methods
Selection of Patients
Forty-two patients over 60 years of age who had hypertension and a left-ventricular posterior-wall thickness of ≥1.2 cm as measured by M-mode echocardiography were studied. All gave written informed consent, and the protocol was approved by the hospital's Joint Committee on Clinical Investigation. None of the patients had a history of coronary artery disease, Class III or IV congestive heart failure, conduction-system disease (unless a pacemaker was present), atrial fibrillation, or marked retinopathy or renal or cerebral vascular disease. Patients with a history of other major illnesses or contraindication to the use of beta-blockers or calcium-channel blockers were also excluded. Patients were selected from the general medical clinics of the Johns Hopkins Hospital. Approximately 60 percent of the elderly hypertensive patients screened for the study met the eligibility criteria.
Study Design
Placebo Phase
After the patients gave informed consent, all antihypertensive medications were discontinued and the patients were given placebo (in a single-blind portion of the study) for at least one week. While receiving placebo, all the patients had a systolic blood pressure between 160 and 220 mm Hg in a seated position, a diastolic blood pressure between 90 and 115 mm Hg, or both. Patients underwent two-dimensional echocardiography for the calculation of left ventricular mass and wall thickness. Because ischemia may alter filling rates and cardiac volumes independently of an effect of left ventricular mass, a standard thallium exercise test was also performed.9 In patients whose electrocardiograms during exercise tests were normal, gated blood-pool scanning was performed with the patients at rest and during exercise to determine the base-line cardiac volumes and output, ejection fraction, and left-ventricular-filling indexes.
Treatment Phase
Patients were randomly assigned to treatment groups in a double-blind fashion according to a computer-generated random-number code in blocks of 10. The code was matched to consecutively numbered boxes containing the study drug and matching placebo. At first the patients received either 25 mg of atenolol or 120 mg of sustained-release verapamil per day. The doses were increased weekly to achieve blood-pressure control, defined as a systolic pressure of ≤160 mm Hg and a diastolic pressure of ≤90 mm Hg in a seated position. Blood pressure was usually measured several hours after the morning dose of the study medication. Nine patients in each group underwent ambulatory blood-pressure monitoring over a 24-hour period; no time-dependent differences in blood pressure were noted in either group. If blood pressure was not controlled after four weeks of treatment at increasing doses, up to a maximum of 100 mg of atenolol or 480 mg of verapamil per day, chlorthalidone (25 mg and then 50 mg) was added to the regimen. Only the patients whose blood pressure was successfully controlled continued in the study. These patients were followed monthly for six months, at the end of which gated blood-pool scanning at rest and during exercise was performed.
Post-treatment Phase
Therapy was discontinued after the six-month follow-up evaluation. One to two weeks later (mean, 13 days), a two-dimensional echocardiogram was obtained for the determination of the left ventricular mass and gated blood-pool scanning was repeated to determine the effect of changes in mass on left ventricular function in the absence of antihypertensive medication.
Echocardiography and Gated Blood-Pool Scanning
Echocardiography was performed with a Hewlett—Packard model 77020 phased-array ultrasound unit with a 2.5-MHz transducer and an aperture size of 16 mm. The left ventricular mass was estimated by the area—length method of Wyatt et al.10 and normalized for body-surface area (values are reported here as left-ventricular-mass indexes). Posterior-wall and septal-wall thicknesses and the ratio of the mean wall thickness to the internal end-diastolic radius were also calculated. The results of the studies were digitized by two echocardiographers. Measures of distance correlated with phantoms of four to five different lengths and at several angles (r = 0.98). The variability of results for the same patient with our equipment was 6.1 percent. Both interobserver and intraobserver variability in eight repeated studies averaged 6 percent.
Gated blood-pool scanning at rest was performed with the patients in a 40-degree left anterior oblique position in order to define the ventricular septum most clearly after in vivo labeling of red cells with 9.3 to 11.1×108 Bq (25 to 30 mCi) of technetium-99m. Images were acquired in a 64-by-64-byte matrix with a 1.9 zoom, with use of a high-sensitivity parallel-hole collimator attached to a standard Anger camera interfaced with a commercial nuclear-medicine computer system. Twenty frames were acquired per R—R interval, and acquisition was discontinued after three minutes.
Left ventricular filling rates and volumes were calculated by a validated method described elsewhere.11 , 12 In brief, time—activity curves were constructed with a semiautomated commercial program in which edges were placed around the left ventricle in each frame according to a combined second-derivative and threshold algorithm. Background was automatically determined by a region of interest drawn below and to the side of the left ventricle in the end-systolic frame, and a background-subtracted time—activity curve constructed. A third-order smoothing spline was simultaneously fitted between each two points in such a way as to minimize the second derivative of each interval while remaining within a preestablished limit of fidelity to the raw data. The following measurements were calculated: the peak filling and ejection rates as the maximal positive and negative slopes of the curve, respectively (these values were normalized for left ventricular counts at the end of diastole and expressed as end-diastolic volumes per second); the ratio of the peak filling rate to the peak ejection rate, in order to differentiate changes in left ventricular diastolic filling more clearly from changes in systolic function13; the first-third filling fraction as the ratio of counts in the first third of diastole to the total stroke counts (normalized by the R—R interval); and the time to peak filling, calculated from the end-systolic point to the point of peak filling. Time—activity curves were read blindly and excluded from analysis if the heart rate deviated by more than 15 percent from the mean or if the patient's motion distorted the time—activity curve.
Time—activity curves were also obtained for 21 normotensive men and women, matched to the patients for age, who were participants in the Baltimore Longitudinal Study of Aging; these subjects had no history of cardiac disease and negative results of thallium exercise scans.
Absolute left ventricular volumes were calculated by a nongeometric count-based method; the end-diastolic volume was obtained from the ratio of the end-diastolic count rate, corrected for the attenuation and depth of the left ventricle in the body, to the count rate per milliliter in a sample of venous blood.
Statistical Analysis
Blood pressure, left ventricular mass, cardiac volumes, and measures of diastolic filling were compared by means of paired and unpaired Student's t-tests. The relation between the change in mass and the peak filling rate was determined by linear regression analysis. Categorical data were analyzed by chi-square tests. A two-tailed P value of ≤0.05 was considered to indicate statistical significance.14 The results are presented as means ±SE.
Results
Twenty-one patients (6 men and 15 women) were randomly assigned to receive verapamil, and 21 (8 men and 13 women) to receive atenolol. The mean ages of the patients in the verapamil and atenolol groups were 68.5±1.1 and 68.6±1.4 years, respectively. Four patients in each group had positive results on thallium exercise scans. Five of the verapamil-treated patients and four of the atenolol-treated patients had previously been treated with a calcium-channel blocker, beta-blocker, or angiotensin-converting—enzyme inhibitor. Three patients assigned to receive atenolol were excluded from the study: two because of inadequate blood-pressure control and one because of dizziness at a dose of 25 mg of atenolol. No major side effects or complications occurred in the remaining 39 patients; mild constipation was noted in two patients who received verapamil.
Figure 1Figure 1
Systolic and Diastolic Blood Pressures, Measured in a Sitting Position, in the Two Treatment Groups at Base Line, after One Month of Therapy, and One to Two Weeks after the Withdrawal of Therapy. illustrates the blood-pressure response to the two agents. As required by the protocol design, blood pressure was adequately controlled in both treatment groups during the initial four-week titration phase, and this control persisted throughout the six-month study period. In the verapamil group (shaded bars), the mean blood pressure decreased from 171.4±3.2/93.0±2.5 mm Hg at base line to 142.9±2.8/79.0±2.0 mm Hg during treatment; in the atenolol group (open bars), it decreased from 179.6±4.6/98.5±2.4 mm Hg to 148.1±3.3/83.4±1.2 mm Hg (P<0.01 for the comparisons with base-line values), and control was maintained throughout the six months of therapy. Blood pressure returned toward base-line values after the withdrawal of the study drugs. The change in blood pressure from base line (placebo) to the final dose of atenolol or verapamil before the institution of maintenance therapy or the addition of a diuretic was greater with verapamil alone than with atenolol alone. The change in systolic pressure was 28.4±2.4 mm Hg in the verapamil group and 13.8±5.3 mm Hg in the atenolol group (P<0.02). The change in diastolic pressure was 14.2±1.9 mm Hg in the verapamil group and 8.0±2.4 mm Hg in the atenolol group (P = 0.05). The change in the mean blood pressure was 18.6±1.7 mm Hg in the verapamil group and 10.2±3.2 mm Hg in the atenolol group (P<0.03).Adequate control was achieved with verapamil alone in 18 of 21 patients and with atenolol alone in 8 of 21 patients (P<0.01). The addition of chlorthalidone controlled blood pressure in all 3 remaining patients in the verapamil group and in 10 of the 13 remaining patients in the atenolol group. The average daily doses were 257±26 mg of sustained-release verapamil and 71±7 mg of atenolol.
Despite the similar reductions in blood pressure, there was a substantial difference in the degree of change in left ventricular mass in response to the two antihypertensive agents (Fig. 2Figure 2
Individual and Mean Changes in the Left-Ventricular-Mass Index from Base Line to the Six-Month Follow-up, as Determined by Two-Dimensional Echocardiography.). In the verapamil group, the left-ventricular-mass index was reduced by 18 percent, from a mean (±SE) of 104±5 g per square meter of body-surface area to 85±5 g per square meter (P<0.0001). In the atenolol group, the mean left-ventricular-mass index did not change over the six-month study period (109±9 g per square meter at base line vs. 112±10 g per square meter at six months). In the eight atenolol-treated patients who did not require the use of chlorthalidone, the mass index was 118±11 g per square meter at base line and 123±16 g per square meter at six months. The 14 atenolol-treated patients who were not previously treated with calcium-channel blockers, beta-blockers, or angiotensin-converting—enzyme inhibitors also had no significant reduction in the left-ventricular-mass index (116.6±10 g per square meter at base line vs. 114.2±12 g per square meter at six months).The left ventricular posterior-wall and septal-wall thicknesses were reduced by verapamil, from 13.0±0.4 mm and 12.8±0.4 mm, respectively, at base line to 10.8±0.4 mm and 10.5±0.6 mm six months later (P<0.01 for each comparison). There was also a significant reduction in the ratio of the mean wall thickness to the internal end-diastolic radius, from 0.57±0.02 to 0.45±0.02 (P<0.001). The atenolol group had no significant change in posterior-wall thickness (13.3±0.3 mm vs. 13.2±0.3 mm) or septal-wall thickness (12.5±0.6 mm vs. 13.2±0.7 mm). The ratio of the mean wall thickness to the internal end-diastolic radius also did not change substantially in the atenolol group (0.58±0.03 vs. 0.55±0.04). The end-diastolic area did not change in the verapamil group (16.4±0.9 vs. 16.9±1.4 cm2); it tended to increase in the atenolol group (16.0±1.0 vs. 17.8±1.4 cm2; P = 0.15).
Measurements of diastolic filling and other hemodynamic data were available for 15 patients in the verapamil group and 12 in the atenolol group. Excluded from these analyses were eight patients with positive results on thallium exercise scans and four with either substantial variations in heart rate or distortions due to motion during one of the gated blood-pool scans. The effects of the study drugs on diastolic filling are presented in Table 1Table 1
Effects of the Study Drugs on Diastolic Filling of the Left Ventricle.*. Atenolol therapy was not associated with any important change in the measures of left ventricular filling. The verapamil-treated patients had no major change in the peak filling rate or the first-third filling fraction. There was a significant increase in the ratio of the peak filling rate to the peak ejection rate and a significant decrease in the length of time to peak filling in the verapamil group.The effects of the study drugs on hemodynamics at rest and during exercise are summarized in Table 2Table 2
Effects of the Study Drugs on Hemodynamic Measurements.. All but one of the atenolol-treated patients were able to perform 25 W of bicycle exercise during the base-line (placebo) and treatment periods. The duration of exercise did not differ between the two groups. The two groups did not differ in terms of base-line measurements, except for the resting heart rate, which was higher in the patients who were later randomly assigned to receive atenolol therapy. The mean arterial pressure, measured at rest and during exercise, declined significantly and similarly during treatment in both groups. Verapamil had no effect on any other hemodynamic measurements. Atenolol decreased the heart rate, as measured both at rest and during exercise. The end-diastolic volume at rest and the stroke volume increased, and the increase in the stroke volume compensated for the diminished heart rate in the atenolol group; the result was an unchanged cardiac output. The heart rate during exercise also decreased in the atenolol group, but the cardiac output was maintained because of a trend toward an increase in stroke volume. Ventricular ectopy during exercise was minimal, and the degree did not differ between the two treatment groups or between the two study periods.To evaluate the effects of reduction in the left ventricular mass, diastolic filling and hemodynamics were measured both while the patients were receiving placebo and two weeks after the discontinuation of antihypertensive therapy in 15 patients (12 in the verapamil group and 3 in the atenolol group) in whom left ventricular mass had decreased over the six-month period and in 12 patients (3 in the verapamil group and 9 in the atenolol group) in whom left ventricular mass did not regress. The left-ventricular-mass index at base line was greater in those who subsequently had reductions in mass (mean [±SE], 116±7 g per square meter) than in those who did not (91±9 g per square meter; P<0.05). The mean decrease in the former group was 23±4 percent.
Indexes of left ventricular filling in the study patients and in 21 normotensive control subjects are presented in Table 3Table 3
Effects of a Reduction in Left Ventricular Mass on Diastolic Filling.*. As compared with the normotensive subjects, the 15 patients who had reductions in left ventricular mass had a lower ratio of the peak filling rate to the peak ejection rate; they also showed trends toward reduced peak filling rates and first-third filling fractions and greater lengths of time to peak filling. After the reductions in left ventricular mass, the peak filling rate and the ratio of the peak filling rate to the peak ejection rate increased significantly (P<0.05 for both comparisons), and there were nonsignificant trends toward a decrease in the length of time to peak filling (P = 0.12) and an increase in the first-third filling fraction (P = 0.2).In contrast, the 12 patients who did not have reductions in left ventricular mass had smaller initial masses and base-line filling values that were similar to those of the control subjects. No significant change in filling values was observed after six months of therapy in this group. For all patients, there was a significant inverse correlation between the percentage change in the left-ventricular-mass index and the percentage change in the peak filling rate from the base-line value to the final evaluation two weeks after therapy was discontinued (r = −0.52) (Fig. 3Figure 3
Relation between the Percent Changes in the Left-Ventricular-Mass Index and the Peak Filling Rate, Measured at Base Line and after the Withdrawal of the Study Drugs, in the 27 Patients with Time—Activity Curves and Negative Thallium Scans.).Hemodynamic measurements at rest and during exercise (to 25 W) for the patients who did and did not have reductions in left ventricular mass are summarized in Table 4Table 4
Effects of a Reduction in Left Ventricular Mass on Hemodynamic Measurements.*. At base line, the mean end-diastolic and stroke volumes at rest and during exercise were greater in the 15 patients who subsequently had reductions in mass than in those who did not. The remaining base-line hemodynamic values at rest and during exercise were similar in the two groups. Despite a 23 percent reduction in left-ventricular-mass index and a return of blood pressure to hypertensive levels two weeks after the study drugs were discontinued, the cardiac output and ejection fraction at rest and during exercise were not depressed from base-line values. Ventricular ectopy during exercise was minimal, and there was no difference between the base-line and post-treatment measurements in the patients who had reductions in mass.Discussion
Our results indicate that blood-pressure control was achieved in more elderly hypertensive patients with verapamil alone than with atenolol alone and that the treatment of mild-to-moderate hypertension in this age group with verapamil reduced left ventricular mass over a six-month period. Reduction of left ventricular mass in this population resulted in increases in the peak diastolic filling rate of the left ventricle and in the ratio of the peak filling rate to the peak ejection rate. These findings point to an improvement in the diastolic function of the left ventricle in association with a reduction in left ventricular mass. Even after the withdrawal of antihypertensive therapy and the return of blood pressure to hypertensive levels, systolic function at rest and during exercise was not impaired by the reduction in left ventricular mass.
The blood-pressure responses we observed were consistent with the findings of some, but not all, studies comparing the efficacy of calcium-channel blockers with that of beta-blockers for the treatment of hypertension in elderly patients.15 , 16 Peripheral vascular resistance increases and cardiac output declines with increasing age in persons with hypertension.17 In addition, decreased compliance of the arterial system and a low or normal plasma renin level18 suggest that older hypertensive patients would respond better to an arteriolar vasodilator than to a beta-adrenergic blocker.
Verapamil was also more effective than atenolol in producing a reduction in left ventricular mass. Although chlorthalidone was used more frequently for the control of blood pressure in the atenolol group, some but not all studies demonstrate that thiazide diuretics do not alter left ventricular mass,19 and there was no reduction in left ventricular mass in the eight patients who were treated with atenolol alone. Previous studies using M-mode echocardiography have demonstrated a decrease in left ventricular mass in younger patients receiving atenolol therapy.20 21 22 23 The mean ages of the patients in these studies were 44 to 48 years, and it is possible that older subjects require longer atenolol therapy to achieve reductions in mass. It is also possible that the persistent increase in end-diastolic and stroke volumes during atenolol therapy in our elderly patients prevented the reduction of left ventricular mass.24
It has been noted in previous studies that many patients with hypertension have a decreased rate of isovolumic relaxation, a decrease in the early left ventricular filling rate, and an increase in dependence on atrial contraction to maintain end-diastolic volume.25 26 27 28 Although some indexes of left ventricular filling changed with verapamil therapy, the most consistent changes were noted in the subjects who had reductions in left ventricular mass, irrespective of the treatment received. The indexes of left ventricular filling are influenced by age29 , 30 and by several hemodynamic factors, including the rate and duration of relaxation, end-systolic volume, left atrial and ventricular compliance, left atrial pressure, coronary blood flow, heart rate, and sympathetic tone.31 32 33 34 35 36 Although we evaluated filling in patients in one age group who had no evidence of coronary artery disease, intracardiac pressures were not measured, and therefore, our findings must be interpreted cautiously. Nevertheless, the inverse correlation of reductions in left ventricular mass with peak filling rates (Fig. 3) suggests that improvement in measures of diastolic filling with antihypertensive therapy depends on the reduction of left ventricular mass.
Although previous echocardiographic studies have found that reductions in mass do not adversely affect resting contractile function in patients who are receiving antihypertensive therapy,37 , 38 these studies were carried out in a younger group of patients than our study group, and function was not assessed during exercise or after the discontinuation of therapy and the return of blood pressure to hypertensive levels. The reduction of left ventricular mass in our patients did not impair systolic function at rest or during exercise. Therefore, at least in an elderly population with mild-to-moderate hypertension and normal resting systolic function, the reduction of left ventricular mass is well tolerated. It should be noted, however, that follow-up was limited to two weeks after the withdrawal of the study drugs, and it is possible that a more prolonged period of hypertension would not have been tolerated as well in the patients who had reductions in left ventricular mass.
The limitations of this study, in addition to the relatively short follow-up noted above and the lack of a placebo control group, include the one-week base-line (placebo) period and the caution that must be used in attempting to apply these findings to other groups of patients. The use of a short placebo period raises the possibility that the effects of previous antihypertensive therapy on cardiac function may have persisted during the base-line studies. However, only 9 of the 42 patients had been treated with calcium-channel blockers, beta-blockers, or angiotensin-converting—enzyme inhibitors, and blood pressure in all patients had returned to hypertensive levels by the time of the initial assessment. Furthermore, reductions in left ventricular mass were noted only in the verapamil group even when these nine patients were excluded. The patients who had reductions in left ventricular mass had the largest hearts at base line, suggesting that it is these patients who derive the most benefit from antihypertensive therapy. We cannot, however, exclude the possibility that some of the changes we noted were due to the phenomenon of regression to the mean. Finally, the time—activity curves were analyzed at 20 frames per cycle-length, which underestimates the peak filling rates and the length of time to peak filling. However, the heart rates in the patients who did and did not have reductions in left ventricular mass were similar at base line and after the discontinuation of the study drugs; therefore, the framing rates and filling rates should be comparable in the two studies.
In summary, verapamil reduces both blood pressure and left ventricular mass more effectively than atenolol in elderly patients with hypertension who have normal left ventricular function and mild left ventricular hypertrophy. Reduction in the left ventricular mass is associated with improved early diastolic filling of the left ventricle and does not compromise cardiac output or the ejection fraction at rest or during mild exercise. Whether these conclusions apply to patients with more severe left ventricular hypertrophy requires further study.
Supported in part by the Knoll Pharmaceutical Company, Whippany, N.J., and a grant from the National Institute on Aging (AG-89–0809).
We are indebted to Dr. Jerome L. Fleg for assistance in arranging for the subjects in the Baltimore Longitudinal Study on Aging to participate in the gated blood-pool scanning; to Ann Adams, Jean Cadden, Jon Clulow, and Terry Frank for technical assistance; and to the Johns Hopkins Osler house staff for patient referrals.
Source Information
From the Cardiology Division, Department of Medicine, the Johns Hopkins Medical Institutions, Baltimore. Address reprint requests to Dr. Schulman at 591 Carnegie Bldg., Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21205.
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Martin CS Wong, Harry HX Wang, Johnny Y Jiang, Stephen Leeder, Sian M Griffiths. (2011) Predictors of switching from beta-blockers to other anti-hypertensive drugs: a review of records of 19,177 Chinese patients seen in public primary care clinics in the New Territory East, Hong Kong. Asia Pacific Family Medicine 10:1, 10
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DOUGLAS S. LEE, RAMACHANDRAN S. VASAN. 2008. Hypertension and Valvular Heart Disease. , 233-246.
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Adrian M. Moran, Steven D. Colan, Mary Beth Mauer, Tal Geva. (2002) Adaptive mechanisms of left ventricular diastolic function to the physiologic load of pregnancy. Clinical Cardiology 25:3, 124-131
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Clovis De Carvalho Frimm, Álvaro Villela De Moraes, Caio César Jorge Medeiros, Antǒnio Esteves Filho, Júlio César Marino. (2000) Normalization of left ventricular dysfunction in systemic hypertension. Clinical Cardiology 23:6, 443-448
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Vasilios Papademetriou, John S. Gottdiener, Puneet Narayan, William G. Cushman, Prince K. Zachariah, Patricia S. Gottdiener, Gary A. Chase. (1997) Hydrochlorothiazide Is Superior to Isradipine for Reduction of Left Ventricular Mass: Results of a Multicenter Trial. Journal of the American College of Cardiology 30:7, 1802-1808
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Yves Lacourcière, Luc Poirier, Jean Cléroux. (1997) Physical Performance is Preserved After Regression of Left Ventricular Hypertrophy. Journal of Cardiovascular Pharmacology 30:3, 383-391
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