Chronobiology Internalional Vol. 8, No. 5 , pp. 420-431 0 199 I International Society of Chronobiology
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Circadian Rhythm of Blood Pressure in Congestive Heart Failure and Effects of ACE Inhibitors Karl Josef Osterziel, Rainer Dietz, and *Bjorn Lemmer Innere Medizin III (Schwerpunkt Kardiologie, Angiologie und Pulmologie). Medizinische Universitatsklinik Heidelberg; and *Zentrum der Pharmakologie, J. W. Goethe-Universitat, Frankfurt/Main, Germany
Summary: In 33 patients with heart failure (NYHA 11-III), the 24-h blood pressure rhythm was examined before and after the titration period of two ACE inhibitors. Blood pressure was measured by the oscillometric method using the blood pressure monitor 90202 from SpaceLabs, Inc. The measurements were taken from 06:OO to 22:OO h every 20 min and from 22:OO to 06:OO h every hour. Patients were randomized to therapy with either captopril (group I , n = 17) or enalapril (group 2, n = 16). The average daily dosage of captopril was 41 f 3 mg given in three divided doses (08:00, 12:00, and 17:OO h). The mean dose of enalapril was 8 f 1 mg once daily (08:OO h). Serum electrolytes, serum creatinine, and plasma renin activity were measured before and during therapy with both ACE inhibitors. Twenty-four-hour blood pressure measurements were taken before and on the fifth day of treatment with ACE inhibitors. Both groups were not different with respect to the degree of heart failure, the concomitant medication, and the 24-h profiles of blood pressure and heart rate before initiation of ACE inhibition. The 24-h blood pressure values on day 5 were consistently below the pretreatment values (p < 0.005) in both groups. Both groups did not differ significantly during ACE inhibition in their 24-h blood pressure and heart rate profiles. In both groups, the mesor of the systolic and diastolic blood pressure decreased significantly by the same degree (by 4.7/5.1 mmg Hg in group 1 and 6.4/4.1 mm Hg in group 2). The systolic/diastolic blood pressure amplitude decreased slightly in both groups. Before treatment, serum sodium, potassium, and creatinine were within the normal range. The increase in potassium (0.5 f 0.1 mmol/L) reached statistical significance (p < 0.01) only in the captopril group, whereas it was not significant in the enalapril group (0.1 f 0.1 mmol/L). Serum creatinine was not significantlyaltered by both ACE inhibitors. No relationship could be found between the changes in serum potassium or creatinine and the mean of the 24-h blood pressure values during ACE inhibition. Captopril and enalapril showed comparable blood pressure profiles and similar effects on renal function at the end of the titration on day 5. It can therefore be concluded that the effects on blood pressure rhythm and renal function are similar with a single daily dose of enalapril compared to captoReceived June 6, 1991; accepted with revisions June 26, 1991. Address correspondence and reprint requests to Dr. K. J. Osterziel, Medizinische Universitatsklinik, Bergheimer Strasse 58, 6900 Heidelberg, Germany.
420
CIRCADIAN BP RHYTHM IN HEART FAILURE
421
Chronobiol Int Downloaded from informahealthcare.com by Flinders University of South Australia on 01/24/15 For personal use only.
pril given three times daily. Key Words: Heart failure-Captopril-EnalaprilTwenty-four-hour blood pressure.
Symptomatic arterial hypotension and functional renal impairment are important side effects during therapy of patients with heart failure receiving angiotensin converting enzyme (ACE) inhibitors (1-5). Even after identification of high-risk patients and reduction in the initial dose of enalapril, symptomatic hypotension occurred in 3.2% of patients with severe heart failure (NYHA IV) (3). Discontinuation of ACE inhibition was necessary in 4.7% of all patients because of increases in serum creatinine (3). Minor functional renal impairment during therapy with ACE inhibitors can be found in 13- 18% of patients with severe heart failure (2,3). Differences in plasma half-life may be responsible for observed differences in hemodynamic alterations by ACE inhibitors (2,4). With short-acting ACE inhibitors, periodic increases and decreases in blood pressure were reported whereas blood pressure remained at a nearly constant low level upon therapy with long-acting ACE inhibition (2). The degree of renal impairment is thought to be caused by the duration during which the blood pressure is below the renal autoregulatory threshold. To assess the influence of different ACE inhibitors on the blood pressure profile, a 24-h determination of blood pressure is necessary. However, most studies have measured arterial pressure for a few hours only (2-4,6). To investigate the influences of low doses of long- and short-acting ACE inhibitors on the 24-h blood pressure, 33 patients with heart failure were examined. Blood pressure was recorded before and after the titration period with either captopril or enalapril.
PATIENTS AND METHODS Thirty-three patients (26 men and 7 women) with heart failure (mean age of 56 k 3 years) were examined. Each patient was symptomatic with ordinary or less than ordinary physical activity (NYHA 11-111). The patients were randomized to therapy with either captopril (group I ) (von Heyden GmbH, Munich, Germany) or enalapril (group 2) (Merck Sharp & Dohme GmbH, Munich, Germany). The usual rest period was from 22:OO to 07:OO h. Both groups did not differ in age, height, weight, severity of heart failure, and concomitant medical therapy (Table 1). The only difference observed was in the relationship of men to women, including significantly more women in group 1 than in group 2 (p < 0.01). The diagnosis was confirmed in every patient by right and left heart catheterization and selective coronary angiography. Nine patients in each group suffered from coronary artery disease. Eight patients in group 1 and five patients in group 2 had idiopathic dilated cardiomyopathy. Two patients who had undergone prosthetic aortic valve replacement presented with severely impaired left ventricular function due to aortic valve insufficiency. Only changes in diuretic therapy according to clinical needs were allowed. The remaining medical therapy was held constant during the study. In two patients of each group, the diuretic therapy was increased by addition of another diuretic. Potas-
Chronobiol Int, Vol. 8. No. 5, 1991
K. J. OSTERZIEL ET AL.
422
Chronobiol Int Downloaded from informahealthcare.com by Flinders University of South Australia on 01/24/15 For personal use only.
TABLE 1. Characteristics of the two groups of patients with congestive heart failure
NYHA classification Etiology Ischemic CMP Dilative CMP AVR Age (years) Height (m) Weight (kg) Gender (M/F) Medication Digitalis Diuretics Nitrates Molsidomine &Blockers Nifedipine Diltiazem Amiodarone Mexiletine
Captopril ( n = 17)
Enalapril (n = 16)
P
2.7 f 0.1
2.7 f 0.1
ns.
9 8 0
9 5 2
56 f 3 1.68 0.02 69 f 3 1116
*
57 f 3 I .7 1 2 0.03 75 3 1511
ns. n.s. ns. ns.
*
ns. n.s. 0.0 1
2
6 16 6 2 2 0
n.s. n.s. ns. ns. ns.
16 4 3 6 I
0 I 1
1
0 0
n.s. n.s.
ns. n.s.
NYHA-functional classification according to the New York Heart Association; CMP-cardiomyopathy; AVR-impaired left ventricular function after aortic valve replacement with prosthetic valve insufficiency. n.s.-not significant.
sium supplements were given to two patients of group 1 on the first day of ACE inhibition and to one patient in group 2 on day 4 and 5 of ACE inhibition. Blood pressure and heart rate were determined with a Spacelab blood pressure monitor (Spacelab 90202) by the oscillometric method before and on day 5 of therapy with either captopril or enalapril. There is a close correlation of the blood pressure values obtained by this method with intra-arterial measured values (7). Blood pressure and heart rate were recorded from 06:OO to 22:OO h every 20 min and from 22:OO to 06:OO h every 60 min. Serum electrolytes and serum creatinine were measured by an autoanalyzer method (8) and plasma renin activity was determined by radioimmunoassay (9). Statistics The average hourly means of blood pressure and heart rate were used to analyze for daily variations. First, the areas under the original data curves were measured for each patient and the mean areas were compared between groups by the Mann-Whitney test. Within groups, the alterations of blood pressure and heart rate over time were compared by analysis of variance (ANOVA). Mean blood pressure values below 80 mm Hg were considered critically hypotensive and their frequency of occurence was compared within and between groups by ANOVA. In addition, rhythm analysis was performed by nonlinear fitting of the hourly data to a cosine function with the
Chronobiol Int. Vol. 8, No. 5 , 1991
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CIRCADIAN BP RHYTHM IN HEART FAILURE
423
PHARMFIT program (10). Data were fitted to a 24-h period and to a 24-h period overlapping with its first harmonics (12 h), and improvement of fit was tested (10). The MESOR (rhythm-adjusted mean), acrophase (peak time of rhythm), and amplitude before and after ACE inhibitor treatment were compared by t test. Differences in serum electrolytes and creatinine values were evaluated by t test, which was corrected according to Bonferroni for multiple comparisons. The correlation coefficient of linear regressions was calculated by the method of Pearson and the regression line was obtained by the method of least squares. A p value smaller than 0.05 was considered significant. Protocol
Before therapy with ACE inhibitors, the 24-h profile of blood pressure and heart rate was determined and serum electrolytes and serum creatinine were measured at 08:OO h and plasma renin activity was determined at 13:OO h after 30 min of supine rest. Then captopril therapy was started at an initial dose of 6.25 or 12.5 mg. The dose was increased to 3 X 12.5 mg daily. Only one patient did not improve clinically so that the captopril dose was increased further to 3 X 25 mg. Captopril was given at 08:00, 12:00, and 17:OO h. Enalapril was given only once daily at 08:OO h. The first dose of enalapril was 2.5 mg for each patient. The dose was increased to 5 mg on day 2 and 10 mg of enalapril was given from day 3 on. Only two patients did not improve so that enalpril was increased further to 15 mg once daily. On the fifth day of therapy with ACE inhibitors, the same measurements as before therapy were repeated.
RESULTS In addition to the previous medical therapy, 17 patients received captopril (group 1) and 16 patients were treated with enalapril (group 2). Both groups were comparable before initiation of ACE inhibition (Table 1). The mean doses of captopril were 40.7 f 3.3 mg and of enalapril was 8.4 +. 0.9 mg.
Blood Pressure Rhythm The arithmetic means of the 24-h blood pressure values before therapy were not different between the captopril group (88 f 2 mg Hg) and the enalapril group (86 f 2 mm Hg). Similarly, the arithmetic means of heart rate were not different (78 f 4 beats/min in group 1 and 8 1 k 3 beats/min in group 2). Both groups showed a similar blood pressure rhythm with highest values at about 08:OO h, a slight decrease in blood pressure in the early afternoon, a second increase in the evening, and a sustained decrease in blood pressure during the night (Fig. 1, Table 2). The MESOR of systolic and diastolic blood pressure and the blood pressure amplitudes were similar in both groups (Table 2). The profiles of the 24-h heart rate showed a less consistent but similar pattern as the blood pressure curves (Fig. 2, Table 2). Therapy with captopril or enalpril led to a significant decrease in the means as well as the mesor of systolic and diastolic blood pressure (Table 2). The MESOR of heart rate, however, was slightly lower only in the enalapril group and unchanged in the patients receiving captopril (Table 2). There was no significant shift in the acrophases
Chronobiol Inl, Vol. 8. No. 5. 1991
140a
-
K. J. OSTERZIEL ET AL.
424 CaptoprllA
140
EnalaprllA
-g
-E
1-
110.
L
i
Chronobiol Int Downloaded from informahealthcare.com by Flinders University of South Australia on 01/24/15 For personal use only.
i
110
L
i
i
80.
80
*
50
I
8
I 20
Captoprll C
1 4 ~ 1
Tlme (h)
50
8
140
1
D-'k
Enalaprll C
FIG. 1. Circadian rhythm of systolic and diastolic blood pressure in congestive heart failure before ( A ) and during (fifth day, C) therapy with captopril or enalapril. Captopril was administered at 08:00, 12:00, and 17:OO h and enalapril in a single dose at 08:OO h daily. Shown are mean hourly values k SEM of 17 (captopril) or 16 (enalapril) patients. For details, see the text.
of the two curves making up the curve for the blood pressure rhythm, so that the blood pressure rhythm was preserved in each group. There was a tendency in both groups to smaller amplitudes of the dominant 24-h fit (Table 2). Both ACE inhibitors, therefore, showed a trend to decrease differences in blood pressure between day and night. The 24-h rhythm of heart rate did not change during captopril or enalapril therapy. Through values in the fitted hemodynamic parameters without and under ACE inhibition were found around 0150 to 03:30 h as calculated by PHARMFIT (10) and as can be seen in Figs. 1 and 2. Hypotensive blood pressure values (mean blood pressure < 80 mm Hg) were recorded in group 1 in 34 -+ 7% and in group 2 in 35 f 6%of all measurements. The incidence of hypotensive measurements significantly increased during therapy with captopril to 45 f 7% and with enalapril to 52 k 7% (p < 0.005 for each group). However, there was no significant difference between the two groups before or during ACE inhibition (p = 0.4).
Chronohiol In(, Vol. 8. N o . 5. 1991
2
v)
b-
(n
3
00
$
3
c
%
x:
73.5 f 0.79 69.4 f 1.03 D < 0.01
113.6 f 0.77 107.2 k 0.67 p < 0.001
*
81.5 0.82 78.5 f 0.63 p < 0.01
5.02 2 1.07 4.10 f 1.39
6.15 f 1.04 4.23 -+ 0.92
4.72 f 1.15 3.67 k 0.86
6.21 -+ 0.72 4.50 -+ 1.44
2.42 f 1.08 2.40 f 1.41
3.76 ? 1.04 4.12 f 0.92
2.05 f 1.14 2.72 f 0.89
3.23 f 0.70 3.76 f 1.40
3.35 f 0.94 3.75 f 1.37
7.35 -+ 0.98 5.91 -+ 1.41
114.7 f 0.68 110.0 f 0.97 p < 0.001
74.7 f 0.50 69.1 f 0.99 p < 0.01
2.68 f 1.24 5.27 k 1.49
-
5.24 f 1.26 5.40 f 1.57
12h
76.3 f 0.87 76.4 f 1.08
24 h
Amplitude (mean f SD)
11.8 f 0.88 11.7 f 1.40
12.3 f 0.69 11.6 f 0.90
13.6 t 0.93 10.5 f 0.96 p < 0.05
14.1 f 0.42 14.1 f 1.14
14.3 k 0.48 13.8 k 0.86
13.7 f 0.88 13.8 f 1.05
24 h
8.8 f 0.89 9.0 f 1.15
8.7 f 0.56 8.0 f 0.45
10.2 f 1.06 10.0 f 0.62
8.4 f 0.4 1 7.2 f 0.70
8.4 f 0.54 7.3 f 0.69
7.5 f 0.87 9.7 f 0.56
12h
Acrophase (h f SD) % '
52.4 32.6
65.4" 6 I .7"
46.6 56.4"
80.5" 42.3
74.6" 53.9
49.2 54.1"
Rhythm
0.008 0.076
0.0010 0.00 19
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Circadian Rhythm of Blood Pressure in Congestive Heart Failure and Effects of ACE Inhibitors Karl Josef Osterziel, Rainer Dietz, and *Bjorn Lemmer Innere Medizin III (Schwerpunkt Kardiologie, Angiologie und Pulmologie). Medizinische Universitatsklinik Heidelberg; and *Zentrum der Pharmakologie, J. W. Goethe-Universitat, Frankfurt/Main, Germany
Summary: In 33 patients with heart failure (NYHA 11-III), the 24-h blood pressure rhythm was examined before and after the titration period of two ACE inhibitors. Blood pressure was measured by the oscillometric method using the blood pressure monitor 90202 from SpaceLabs, Inc. The measurements were taken from 06:OO to 22:OO h every 20 min and from 22:OO to 06:OO h every hour. Patients were randomized to therapy with either captopril (group I , n = 17) or enalapril (group 2, n = 16). The average daily dosage of captopril was 41 f 3 mg given in three divided doses (08:00, 12:00, and 17:OO h). The mean dose of enalapril was 8 f 1 mg once daily (08:OO h). Serum electrolytes, serum creatinine, and plasma renin activity were measured before and during therapy with both ACE inhibitors. Twenty-four-hour blood pressure measurements were taken before and on the fifth day of treatment with ACE inhibitors. Both groups were not different with respect to the degree of heart failure, the concomitant medication, and the 24-h profiles of blood pressure and heart rate before initiation of ACE inhibition. The 24-h blood pressure values on day 5 were consistently below the pretreatment values (p < 0.005) in both groups. Both groups did not differ significantly during ACE inhibition in their 24-h blood pressure and heart rate profiles. In both groups, the mesor of the systolic and diastolic blood pressure decreased significantly by the same degree (by 4.7/5.1 mmg Hg in group 1 and 6.4/4.1 mm Hg in group 2). The systolic/diastolic blood pressure amplitude decreased slightly in both groups. Before treatment, serum sodium, potassium, and creatinine were within the normal range. The increase in potassium (0.5 f 0.1 mmol/L) reached statistical significance (p < 0.01) only in the captopril group, whereas it was not significant in the enalapril group (0.1 f 0.1 mmol/L). Serum creatinine was not significantlyaltered by both ACE inhibitors. No relationship could be found between the changes in serum potassium or creatinine and the mean of the 24-h blood pressure values during ACE inhibition. Captopril and enalapril showed comparable blood pressure profiles and similar effects on renal function at the end of the titration on day 5. It can therefore be concluded that the effects on blood pressure rhythm and renal function are similar with a single daily dose of enalapril compared to captoReceived June 6, 1991; accepted with revisions June 26, 1991. Address correspondence and reprint requests to Dr. K. J. Osterziel, Medizinische Universitatsklinik, Bergheimer Strasse 58, 6900 Heidelberg, Germany.
420
CIRCADIAN BP RHYTHM IN HEART FAILURE
421
Chronobiol Int Downloaded from informahealthcare.com by Flinders University of South Australia on 01/24/15 For personal use only.
pril given three times daily. Key Words: Heart failure-Captopril-EnalaprilTwenty-four-hour blood pressure.
Symptomatic arterial hypotension and functional renal impairment are important side effects during therapy of patients with heart failure receiving angiotensin converting enzyme (ACE) inhibitors (1-5). Even after identification of high-risk patients and reduction in the initial dose of enalapril, symptomatic hypotension occurred in 3.2% of patients with severe heart failure (NYHA IV) (3). Discontinuation of ACE inhibition was necessary in 4.7% of all patients because of increases in serum creatinine (3). Minor functional renal impairment during therapy with ACE inhibitors can be found in 13- 18% of patients with severe heart failure (2,3). Differences in plasma half-life may be responsible for observed differences in hemodynamic alterations by ACE inhibitors (2,4). With short-acting ACE inhibitors, periodic increases and decreases in blood pressure were reported whereas blood pressure remained at a nearly constant low level upon therapy with long-acting ACE inhibition (2). The degree of renal impairment is thought to be caused by the duration during which the blood pressure is below the renal autoregulatory threshold. To assess the influence of different ACE inhibitors on the blood pressure profile, a 24-h determination of blood pressure is necessary. However, most studies have measured arterial pressure for a few hours only (2-4,6). To investigate the influences of low doses of long- and short-acting ACE inhibitors on the 24-h blood pressure, 33 patients with heart failure were examined. Blood pressure was recorded before and after the titration period with either captopril or enalapril.
PATIENTS AND METHODS Thirty-three patients (26 men and 7 women) with heart failure (mean age of 56 k 3 years) were examined. Each patient was symptomatic with ordinary or less than ordinary physical activity (NYHA 11-111). The patients were randomized to therapy with either captopril (group I ) (von Heyden GmbH, Munich, Germany) or enalapril (group 2) (Merck Sharp & Dohme GmbH, Munich, Germany). The usual rest period was from 22:OO to 07:OO h. Both groups did not differ in age, height, weight, severity of heart failure, and concomitant medical therapy (Table 1). The only difference observed was in the relationship of men to women, including significantly more women in group 1 than in group 2 (p < 0.01). The diagnosis was confirmed in every patient by right and left heart catheterization and selective coronary angiography. Nine patients in each group suffered from coronary artery disease. Eight patients in group 1 and five patients in group 2 had idiopathic dilated cardiomyopathy. Two patients who had undergone prosthetic aortic valve replacement presented with severely impaired left ventricular function due to aortic valve insufficiency. Only changes in diuretic therapy according to clinical needs were allowed. The remaining medical therapy was held constant during the study. In two patients of each group, the diuretic therapy was increased by addition of another diuretic. Potas-
Chronobiol Int, Vol. 8. No. 5, 1991
K. J. OSTERZIEL ET AL.
422
Chronobiol Int Downloaded from informahealthcare.com by Flinders University of South Australia on 01/24/15 For personal use only.
TABLE 1. Characteristics of the two groups of patients with congestive heart failure
NYHA classification Etiology Ischemic CMP Dilative CMP AVR Age (years) Height (m) Weight (kg) Gender (M/F) Medication Digitalis Diuretics Nitrates Molsidomine &Blockers Nifedipine Diltiazem Amiodarone Mexiletine
Captopril ( n = 17)
Enalapril (n = 16)
P
2.7 f 0.1
2.7 f 0.1
ns.
9 8 0
9 5 2
56 f 3 1.68 0.02 69 f 3 1116
*
57 f 3 I .7 1 2 0.03 75 3 1511
ns. n.s. ns. ns.
*
ns. n.s. 0.0 1
2
6 16 6 2 2 0
n.s. n.s. ns. ns. ns.
16 4 3 6 I
0 I 1
1
0 0
n.s. n.s.
ns. n.s.
NYHA-functional classification according to the New York Heart Association; CMP-cardiomyopathy; AVR-impaired left ventricular function after aortic valve replacement with prosthetic valve insufficiency. n.s.-not significant.
sium supplements were given to two patients of group 1 on the first day of ACE inhibition and to one patient in group 2 on day 4 and 5 of ACE inhibition. Blood pressure and heart rate were determined with a Spacelab blood pressure monitor (Spacelab 90202) by the oscillometric method before and on day 5 of therapy with either captopril or enalapril. There is a close correlation of the blood pressure values obtained by this method with intra-arterial measured values (7). Blood pressure and heart rate were recorded from 06:OO to 22:OO h every 20 min and from 22:OO to 06:OO h every 60 min. Serum electrolytes and serum creatinine were measured by an autoanalyzer method (8) and plasma renin activity was determined by radioimmunoassay (9). Statistics The average hourly means of blood pressure and heart rate were used to analyze for daily variations. First, the areas under the original data curves were measured for each patient and the mean areas were compared between groups by the Mann-Whitney test. Within groups, the alterations of blood pressure and heart rate over time were compared by analysis of variance (ANOVA). Mean blood pressure values below 80 mm Hg were considered critically hypotensive and their frequency of occurence was compared within and between groups by ANOVA. In addition, rhythm analysis was performed by nonlinear fitting of the hourly data to a cosine function with the
Chronobiol Int. Vol. 8, No. 5 , 1991
Chronobiol Int Downloaded from informahealthcare.com by Flinders University of South Australia on 01/24/15 For personal use only.
CIRCADIAN BP RHYTHM IN HEART FAILURE
423
PHARMFIT program (10). Data were fitted to a 24-h period and to a 24-h period overlapping with its first harmonics (12 h), and improvement of fit was tested (10). The MESOR (rhythm-adjusted mean), acrophase (peak time of rhythm), and amplitude before and after ACE inhibitor treatment were compared by t test. Differences in serum electrolytes and creatinine values were evaluated by t test, which was corrected according to Bonferroni for multiple comparisons. The correlation coefficient of linear regressions was calculated by the method of Pearson and the regression line was obtained by the method of least squares. A p value smaller than 0.05 was considered significant. Protocol
Before therapy with ACE inhibitors, the 24-h profile of blood pressure and heart rate was determined and serum electrolytes and serum creatinine were measured at 08:OO h and plasma renin activity was determined at 13:OO h after 30 min of supine rest. Then captopril therapy was started at an initial dose of 6.25 or 12.5 mg. The dose was increased to 3 X 12.5 mg daily. Only one patient did not improve clinically so that the captopril dose was increased further to 3 X 25 mg. Captopril was given at 08:00, 12:00, and 17:OO h. Enalapril was given only once daily at 08:OO h. The first dose of enalapril was 2.5 mg for each patient. The dose was increased to 5 mg on day 2 and 10 mg of enalapril was given from day 3 on. Only two patients did not improve so that enalpril was increased further to 15 mg once daily. On the fifth day of therapy with ACE inhibitors, the same measurements as before therapy were repeated.
RESULTS In addition to the previous medical therapy, 17 patients received captopril (group 1) and 16 patients were treated with enalapril (group 2). Both groups were comparable before initiation of ACE inhibition (Table 1). The mean doses of captopril were 40.7 f 3.3 mg and of enalapril was 8.4 +. 0.9 mg.
Blood Pressure Rhythm The arithmetic means of the 24-h blood pressure values before therapy were not different between the captopril group (88 f 2 mg Hg) and the enalapril group (86 f 2 mm Hg). Similarly, the arithmetic means of heart rate were not different (78 f 4 beats/min in group 1 and 8 1 k 3 beats/min in group 2). Both groups showed a similar blood pressure rhythm with highest values at about 08:OO h, a slight decrease in blood pressure in the early afternoon, a second increase in the evening, and a sustained decrease in blood pressure during the night (Fig. 1, Table 2). The MESOR of systolic and diastolic blood pressure and the blood pressure amplitudes were similar in both groups (Table 2). The profiles of the 24-h heart rate showed a less consistent but similar pattern as the blood pressure curves (Fig. 2, Table 2). Therapy with captopril or enalpril led to a significant decrease in the means as well as the mesor of systolic and diastolic blood pressure (Table 2). The MESOR of heart rate, however, was slightly lower only in the enalapril group and unchanged in the patients receiving captopril (Table 2). There was no significant shift in the acrophases
Chronobiol Inl, Vol. 8. No. 5. 1991
140a
-
K. J. OSTERZIEL ET AL.
424 CaptoprllA
140
EnalaprllA
-g
-E
1-
110.
L
i
Chronobiol Int Downloaded from informahealthcare.com by Flinders University of South Australia on 01/24/15 For personal use only.
i
110
L
i
i
80.
80
*
50
I
8
I 20
Captoprll C
1 4 ~ 1
Tlme (h)
50
8
140
1
D-'k
Enalaprll C
FIG. 1. Circadian rhythm of systolic and diastolic blood pressure in congestive heart failure before ( A ) and during (fifth day, C) therapy with captopril or enalapril. Captopril was administered at 08:00, 12:00, and 17:OO h and enalapril in a single dose at 08:OO h daily. Shown are mean hourly values k SEM of 17 (captopril) or 16 (enalapril) patients. For details, see the text.
of the two curves making up the curve for the blood pressure rhythm, so that the blood pressure rhythm was preserved in each group. There was a tendency in both groups to smaller amplitudes of the dominant 24-h fit (Table 2). Both ACE inhibitors, therefore, showed a trend to decrease differences in blood pressure between day and night. The 24-h rhythm of heart rate did not change during captopril or enalapril therapy. Through values in the fitted hemodynamic parameters without and under ACE inhibition were found around 0150 to 03:30 h as calculated by PHARMFIT (10) and as can be seen in Figs. 1 and 2. Hypotensive blood pressure values (mean blood pressure < 80 mm Hg) were recorded in group 1 in 34 -+ 7% and in group 2 in 35 f 6%of all measurements. The incidence of hypotensive measurements significantly increased during therapy with captopril to 45 f 7% and with enalapril to 52 k 7% (p < 0.005 for each group). However, there was no significant difference between the two groups before or during ACE inhibition (p = 0.4).
Chronohiol In(, Vol. 8. N o . 5. 1991
2
v)
b-
(n
3
00
$
3
c
%
x:
73.5 f 0.79 69.4 f 1.03 D < 0.01
113.6 f 0.77 107.2 k 0.67 p < 0.001
*
81.5 0.82 78.5 f 0.63 p < 0.01
5.02 2 1.07 4.10 f 1.39
6.15 f 1.04 4.23 -+ 0.92
4.72 f 1.15 3.67 k 0.86
6.21 -+ 0.72 4.50 -+ 1.44
2.42 f 1.08 2.40 f 1.41
3.76 ? 1.04 4.12 f 0.92
2.05 f 1.14 2.72 f 0.89
3.23 f 0.70 3.76 f 1.40
3.35 f 0.94 3.75 f 1.37
7.35 -+ 0.98 5.91 -+ 1.41
114.7 f 0.68 110.0 f 0.97 p < 0.001
74.7 f 0.50 69.1 f 0.99 p < 0.01
2.68 f 1.24 5.27 k 1.49
-
5.24 f 1.26 5.40 f 1.57
12h
76.3 f 0.87 76.4 f 1.08
24 h
Amplitude (mean f SD)
11.8 f 0.88 11.7 f 1.40
12.3 f 0.69 11.6 f 0.90
13.6 t 0.93 10.5 f 0.96 p < 0.05
14.1 f 0.42 14.1 f 1.14
14.3 k 0.48 13.8 k 0.86
13.7 f 0.88 13.8 f 1.05
24 h
8.8 f 0.89 9.0 f 1.15
8.7 f 0.56 8.0 f 0.45
10.2 f 1.06 10.0 f 0.62
8.4 f 0.4 1 7.2 f 0.70
8.4 f 0.54 7.3 f 0.69
7.5 f 0.87 9.7 f 0.56
12h
Acrophase (h f SD) % '
52.4 32.6
65.4" 6 I .7"
46.6 56.4"
80.5" 42.3
74.6" 53.9
49.2 54.1"
Rhythm
0.008 0.076
0.0010 0.00 19
