Effects of combination antihypertensive therapy on baroreflex sensitivity and heart rate variability in systemic hypertension

Effects of Combination Antihypertensive Therapy on Baroreflex Sensitivity and Heart Rate Variability in Systemic Hypertension Antti Ylitalo,

MD,

K. E. Juhani Airaksinen, MD, Lawrence Sellin, Heikki V. Huikuri, MD

PhD,

and

Earlier studies have shown that cardiovascular autonomic regulation is impaired in untreated or poorly controlled systemic hypertension. The purpose of this double-blind, randomized parallel trial was to evaluate whether improved blood pressure (BP) control can reverse this impairment. The study group consisted of 33 patients (age 45 to 63 years) with poor BP control who received randomized metoprolol or enalapril monotherapy. Baroreflex sensitivity (BRS) was assessed by phenylephrine test and time- and frequency-domain measurements of heart rate variability (HRV) were analyzed from 24-hour ambulatory electrocardiographic recordings during monotherapy and after 10 weeks of combination therapy with metoprolol 1 felodipine or enalaril 1 hydrochlorothiazide to lower casual BP to <140/90 mm Hg. Intensified treatment decreased 24-

hour systolic and diastolic BP from 139 6 12/86 6 8 mm Hg to 126 6 8/80 6 7 mm Hg (p <0.0001). BRS improved from 6.2 6 3.2 ms/mm Hg to 8.9 6 4.1 ms/mm Hg (p <0.0001) and measurements of HRV (e.g., SD of all RR intervals from 128 6 45 ms to 145 6 46 ms, p <0.001) improved significantly during the combination therapy. Changes in BRS and HRV were similar in magnitude in both treatment arms. Mean RR intervals were comparable before and after intensive antihypertensive therapy (850 6 124 ms vs 937 6 279 ms, p 5 NS). These data indicate that adequate BP control with modern antihypertensive combination therapy can improve cardiovascular autonomic function, which may partially explain the reduced cardiac mortality observed in patients with intensified antihypertensive therapy. Q1999 by Excerpta Medica, Inc. (Am J Cardiol 1999;83:885–889)

arly clinical studies have shown that untreated systemic hypertension is associated with reduced E baroreflex sensitivity (BRS) and heart rate variability

BRS and measurements of HRV by intensifying antihypertensive therapy in patients with long-term hypertension and poor BP control.

1– 6

(HRV). Previous population-based studies in middleaged subjects also showed that BRS7 and HRV8 are reduced in patients with long-term hypertension despite antihypertensive treatment. It is not known, however, whether the observed abnormal cardiovascular autonomic regulation is a primary feature related to systemic hypertension and precedes the onset of hypertension,4,9 or whether these abnormalities can be reversed by more intensive drug therapy. There is some information about whether commonly used antihypertensive drugs, metoprolol and enalapril, can augment the cardiac autonomic function in hypertensive patients,10,11 but the effect of combination of felodipine or thiazide with these drugs has not been studied. Furthermore, it is not known whether the improvement of autonomic regulation is related to blood pressure (BP) reduction or to the specific action of drugs themselves. The objectives of the present study were to evaluate whether it is possible to affect From the Division of Cardiology, Department of Internal Medicine; and the Department of Physical Sciences, University of Oulu, Oulu, Finland. This work was supported by grants from the Finnish Foundation for Cardiovascular Research, Helsinki, Finland, and Astra-Finland, Masala, Finland. Manuscript received September 8, 1998; revised manuscript received and accepted November 9, 1998. Address for reprints: Antti Ylitalo, MD, Division of Cardiology, Department of Medicine, University of Oulu, Kajaanintie 50, FIN90220 Oulu, Finland. E-mail: [email protected]. ©1999 by Excerpta Medica, Inc. All rights reserved.

METHODS

Patients and protocol: The study was a double blind, randomized, parallel trial designed to evaluate autonomic cardiovascular regulation on monotherapy and after intensified combination therapy in patients with long-term hypertension (2 to 15 years on medication). We screened 54 patients (aged 45 to 67 years) participating in a larger study,7 who had poor BP control on monotherapy and whose 24-hour BP was .140/90 mm Hg. The design of the study was approved by the Ethical Committee of the institution. Patients with renal, hepatic, neurologic, endocrine, or cardiac disease including atrial fibrillation or frequent ectopic beats, and patients with systolic BP .220 mm Hg were excluded from the study. Fifty-one patients gave written informed consent. Patients were randomized to 2 weeks monotherapy with either metoprolol 95 mg (group 1) slow release preparation (Seloken Zoc, Suomen Astra, Helsinki, Finland) or enalapril 20 mg (Renitec, Suomen MSD, Helsinki, Finland) (group 2). If at the end of this period on randomized monotherapy, the mean of 3 sitting values of office BP measured by a mercury sphygmomanometer were .140/90 mm Hg, patients were allocated to combination treatment for a period of 10 weeks. The dose was titrated according to study design schema to reach the target BP (Figure 1). Those patients who were 0002-9149/99/$–see front matter PII S0002-9149(98)01067-4

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FIGURE 1. Study design schema.

TABLE I Demographic Variables of the Study Groups

Age (yrs) Men Casual systolic BP (mm Hg) Casual diastolic BP (mm Hg) BMI (kg/m2) Duration of hypertension (yrs) Nonsmoker Previous smoker Smoker Total cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L)

Group 1 (n 5 16)

Group 2 (n 5 17)

54 6 6 10 (63%) 178 6 19 105 6 9 28 6 2 5 (2–15) 9 (56%) 3 (19%) 4 (25%) 6.0 6 0.9 1.4 6 0.3 1.7 6 0.9

52 6 5 11 (65%) 167 6 17 97 6 7 29 6 5 5 (2–11) 10 (59%) 7 (41%) 0 6.1 6 1 1.3 6 0.4 2.3 6 1.1

Values are expressed as mean 6 SD of normally distributed variables, medians (range) of asymmetrically distributed variables, or number (%) of categorical variables. BMI 5 body mass index; HDL 5 high-density lipoprotein.

randomized to metoprolol treatment, continued with the combination therapy of metoprolol with the longacting calcium antagonist felodipine; those who started with enalapril continued with enalapril with hydrochlorothiazide. All drugs were administered once daily in the morning at about 9 A.M. after breakfast. Other medications affecting BP were not allowed. Standard laboratory measurements and brief medical histories were documented and physical examinations were performed (Figure 1). All analyses were performed without knowledge of the characteristics or other data of the patient. Baroreflex sensitivity: Baroreflex sensitivity was analyzed by conventional phenylephrine technique using the Finapres finger-cuff method12 and a menu-driven software package (CAFTS, Medikro Oy, Kupio, Finland).13 886 THE AMERICAN JOURNAL OF CARDIOLOGYT

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Heart rate variability: HRV was analyzed by a method described in detail previously.14 Power spectra were calculated within 2 frequency bands: high-frequency (HF) power, from 0.15 to 0.40 Hz, and low-frequency (LF) power, from 0.04 to 0.15 Hz. The SD of all successive RR intervals (SDNN) was also calculated from the 24-hour recordings. Ectopic beats and artifacts were excluded.15 Blood pressure: Ambulatory BP were recorded using the SpaceLabs 90207 fully automatic oscillometric unit (SpaceLabs Inc., Redmond, Washington).16 The cut-off point for normal 24-hour BP was chosen to be .135/85 mm Hg.17 Conventional systolic and diastolic (Korotkoff, phase V) BPs were measured by a mercury sphygmomanometer at every visit. The mean of 3 sitting values at 5-minute intervals was calculated. Echocardiography: All the participants were examined by the Hewlett-Packard 77020A color Doppler echocardiographic system.18 The left ventricular mass was calculated using the formula of Devereux and Reichek.19 Patients were considered to have left ventricular hypertrophy when there was a left ventricular mass index of .135 g/m2 in men and .110 g/m2 in women.19 Electrocardiography: Standard 12-lead electrocardiography was recorded at 50 mm/s and 1 mV/cm standardization. The Cornell index (Ravl1SIII) was calculated. Statistical analyses: The sample size for this study was estimated to detect an average treatment difference in 24-hour systolic BP of 10 mm Hg on the basis of a 2-sided (a 5 0.05) t test. Within-patient SD of 10 mm Hg was determined by a minimum of 15 protocolcompliant patients in each group would be required to achieve $80% statistical power. Means (6SD) or median (range) are given. Comparisons between the monotherapy and combination therapy within each patient were made by paired t test, or in case of skewed variables, the Wilcoxon test was used separately in the 2 treatments. When comparing the data for the 2 treatment lines the unpaired t test was used, or in case of skewed distribution of variables, the Mann-Whitney test was used. Correlations were evaluated by Spearman’s correlation coefficient. A p value ,0.05 was considered statistically significant.

RESULTS After monotherapy, 11 of 51 patients were excluded: 10 patients (5 in each group) had normal BP and 1 in group 1 had paroxysmal atrial fibrillation. During combination therapy, 7 patients (3 in group 1 and 4 in group 2) discontinued treatment due to side effects or poor compliance. The main characteristics MARCH 15, 1999

patients (35%) in group 1 (metoprolol 1 felodipine) and 10 patients Group 1 (n 5 16) Group 2 (n 5 17) (63%) in group 2 (enalapril 1 hydrochlorothiazide) required the higher Metoprolol Metoprolol Enalapril Enalapril dose of the combination treatment. 95 mg 1 Felodipine 20 mg 1 HCTZ Casual BP on monotherapy was † ‡ 24-h systolic BP 137 6 12 126 6 7 142 6 13 126 6 9 172 6 19/100 6 9 mm Hg and the 24-h diastolic BP 84 6 8 80 6 8 88 6 7 79 6 6‡ values were comparable between the 24-h heart rate 66 6 10 67 6 8 71 6 9 73 6 9 Awake systolic BP 145 6 14 131 6 7† 148 6 14 131 6 11‡ study groups (Table I). Eleven paAwake diastolic BP 90 6 8 83 6 6† 94 6 9 83 6 8‡ tients had significant white coat efSleeping systolic BP 124 6 13 116 6 7* 128 6 12 118 6 10* fect (e.g., 24-hour BP was considSleeping diastolic BP 75 6 9 71 6 7* 76 6 7 71 6 7* ered to be normal [,135/85 mm Values are expressed as mean 6 SD, mm Hg. Hg]) after randomized monotherapy. *p ,0.05; †p ,0.01; ‡p ,0.001 between monotherapy and combination therapy. Ambulatory systolic and diastolic BP HCTZ 5 hydrochlorothiazide. were significantly reduced after intensification of the treatment (from 139 612/86 6 8 mm Hg to 126 6 TABLE III Echocardiographic and Electrocardiographic Data of the Study Groups 8/80 6 7 mm Hg, p ,0.001 for Group 1 (n 5 16) Group 2 (n 5 17) both); only 3 patients had 24-hour BP .135/85 mm Hg during the comMetoprolol Metoprolol Enalapril Enalapril bination therapy. Twenty-four-hour 95 mg 1 Felodipine 20 mg 1 HCTZ BP values of the study groups are Echocardiographic data displayed in Table II. † † Left atrial diameter (mm) 41 6 4 38 6 4 40 6 8 37 6 6 Echocardiographic and electroLeft ventricular internal diameter (mm) 48 6 6 48 6 5 50 6 7 49 6 5 Interventricular septum (mm) 12.5 6 1.9 10.8 6 1.3‡ 12.6 6 1.9 11.4 6 1.6‡ cardiographic data of the 2 groups Posterior wall thickness (mm) 11.4 6 1.6 10.2 6 1.3† 12.3 6 1.5 11.2 6 1.2‡ are shown in Table III. Left ventricLeft ventricular mass (g) 268 6 77 217 6 50‡ 304 6 75 250 6 53‡ ular hypertrophy according to echo2 ‡ ‡ Left ventricular mass index (g/m ) 144 6 37 116 6 24 152 6 33 124 6 17 cardiography was observed in 22 paFractional shortening (%) 42 6 19 45 6 7 48 6 7 47 6 7 tients (67%) on monotherapy and Early/late diastolic mitral flow 1.1 6 0.3 1.2 6 0.3* 1.0 6 0.3 1.0 6 0.3 Electrocardiography (mm) was still present in 13 patients (39%) RaVL 7.2 6 3.5 6.3 6 3.4* 7.8 6 4.4 6.1 6 3.7* after combination therapy. The CorRV5 17.5 6 6.3 15.5 6 4.5 15.3 6 5.3 15.5 6 5 nell index decreased from 14.7 6 6 RV6 15.6 6 3.8 14.2 6 3.5 14.2 6 4.8 13.6 6 4.3 mV to 12.8 6 5 mV (p 5 0.013) SIII 4.6 6 3.8 4.2 6 3.5 5.5 6 3.6 4.0 6 3.3* SV1 8.8 6 3.2 7.6 6 2.8† 9.3 6 2.9 8.3 6 2.9* during combination therapy (Table SV3 6.6 6 5.2 5.3 6 4.7 7.7 6 3.4 7.9 6 4.8 III). Heart rate variability: The effects Values are expressed as mean 6 SD. *p ,0.05; †p ,0.01, ‡p ,0.001. of the 2 combination therapies on Abbreviations as in Table II. HRV are displayed in Table IV. There was no significant change in the average heart rate after intensified treatment (mean RR interval 850 TABLE IV Baroreflex Sensitivity and Heart Rate Variability 6 124 ms on monotherapy and Group 1 (n 5 16) Group 2 (n 5 17) 937 6 279 ms on combination therMetoprolol Metoprolol Enalapril Enalapril apy, p 5 NS). After combination Characteristics 95 mg 1 Felodipine 20 mg 1 HCTZ therapy in the total study group, RR interval (ms) 901 6 117 947 6 63 813 6 120 931 6 365 SDNN (from 128 6 45 ms to 145 6 Baroreflex sensitivity 6.4 6 3.7 8.7 6 4.9* 6.1 6 3.3 9.0 6 3.3† 46 ms, p ,0.0001) and all frequen(ms/mm Hg) cy-domain measurements increased † ‡ SDNN (ms) 121 6 24 138 6 28 133 6 56 150 6 57 2 significantly: LF from 476 ms2 LF power (ms ) 564 547 443 680 (range 146 to 2,595) to 648 ms2 (211–1,899) (149–2,055) (146–2,595) (172–2,365)* HF power (ms2) 270 442 196 312 (range 149 to 2,365) (p 5 0.004) and (146–812) (137–981)* (72–629) (107–687)† HF from 216 ms2 (range 72 to 812) LF/HF ratio 1.8 (1.1–6.6) 1.8 (0.9–4.3) 2.1 (1.1–6.6) 1.7 (0.8–4.8) to 416 ms2 (range 107 to 981) (p Values are expressed as mean 6 SD of normally distributed variables or medians (range) of asym,0.0001). Consequently, the LF/HF metrically distributed variables. ratio reduced significantly from 2.0 † ‡ *p ,0.05; p ,0.01, p ,0.001 between monotherapy and combination therapy. Abbreviation as (1.1 to 6.6) to 1.7 (0.8 to 4.8) (p 5 in Table II. 0.036). Changes in measurements of HRV were similar in magnitude in both treatment groups (see Table of the remaining 33 patients are summarized in Table IV). No significant correlation was found between I. No clinically significant changes were observed in changes in any measurements of HRV and reduction safety laboratory assessments (data not shown). Six of 24-hour BP in either treatment group. TABLE II Ambulatory Blood Pressure

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DISCUSSION

FIGURE 2. Individual baroreflex sensitivity and mean BP values on monotherapy and after combination therapy for both study groups.

Baroreflex function: BRS increased significantly after combination therapy (from 6.2 6 3.4 ms/mm Hg to 8.9 6 4.1 ms/mm Hg, p ,0.0001) and the increase was evident in both treatment groups (Table IV). Individual BRS and 24-hour systolic BP values are shown in Figure 2. The change in BRS was not significantly correlated with initial ambulatory BP values, reduction in BP, or regression of left ventricular mass, but there was a nonsignificant tendency of relation of the increase in BRS and BRS during monotherapy (r 5 20.39, p 5 0.09). Thus, patients with more reduced BRS on monotherapy had a greater BRS increase during combination treatment (Figure 2). 888 THE AMERICAN JOURNAL OF CARDIOLOGYT

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The present study demonstrates that intensifying antihypertensive treatment for a period of 10 weeks by 2 commonly used drug combinations can significantly improve both BRS and HRV. BP was also normalized in most of the patients during follow-up and the medication used was well tolerated. The BRS increased by approximately 40% and substantial increases were also observed in the measurements of HRV during combination therapy. These data indicate that abnormal cardiovascular autonomic regulation is not an irreversible phenomenon in patients with long-term systemic hypertension, but can be improved by intensified antihypertensive therapy. Several factors may explain the effects of antihypertensive therapy on BRS and HRV. First, there is evidence that b blockers could directly improve cardiovascular autonomic regulation in hypertensive and normotensive patients.20,21 Also, the reduction of circulating levels of angiotensin II and aldosterone by angiotensin-converting enzyme inhibitors could augment BRS and increase HRV.22,23 To our knowledge this is the first clinical study to show that a combination of felodipine or hydrochlorothiazide with metoprolol or enalapril improves both BRS as well as short- and (to some extent) long-term measurements of HRV. However, it is unlikely that felodipine or hydrochlorothiazide could have intrinsic direct effects on autonomic nervous function. It is possible, however, that antihypertensive therapy could reverse structural changes in the large arteries and in the heart, which are known to be associated with hypertension and attenuate BRS.24 Combination therapy induced significant regression of left ventricular hypertrophy and although no significant relation was observed between changes of BRS or HRV and reduction of left ventricular hypertrophy, these factors may (together with reduction of BP) influence the cardiovascular autonomic regulation.3 Finally, there remains the obvious possibility that high BP itself deteriorates cardiovascular autonomic control and that BP reduction itself could improve BRS and HRV.4,24,25 However, similar to previous studies, BRS was not directly related to the magnitude of BP reduction26 and obviously remained below values among normotensive counterparts.7 Both reduced BRS and HRV are associated with increased risk of mortality after acute myocardial infarction.27 There is also increasing evidence to suggest that impaired cardiovascular autonomic regulation may predict mortality and adverse events in patients without documented ischemic heart disease.28,29 The recent Hypertension Optimal Therapy (HOT) study showed that the substantial BP reduction achieved with antihypertensive agents used in the present study was associated with reduced incidence of cardiovascular events.30 It is plausible that improved BRS and HRV achieved by combination therapy may partly contribute to the beneficial prognostic effects in patients with systemic hypertension, but this concept must be confirmed in future trials. Overall, the present data indicate that appropriate MARCH 15, 1999

antihypertensive combination therapy may not only improve poor BP control and induce regression of left ventricular hypertrophy, but also improves cardiovascular autonomic regulation, which may together result in a reduced risk of cardiac mortality and morbidity in patients with long-term systemic hypertension. Acknowledgment: The skillful technical assistance of Pirkko Huikuri is gratefully acknowledged.

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