Preventing increases in early-morning blood pressure,heart rate,and the rate-pressure product with controlled onset extended release verapamil at bedtime versus enalapril,losartan, and placebo on arising

Background Therapeutic agents for the treatment of hypertension may differ in their efficacy during the early-morning period, a time when both morbid and mortal cardiovascular events are increased compared with other times of the day. Methods We studied the effects of a chronotherapeutic delivery system of verapamil (controlled-onset extended release [COER]-24 system) dosed at bedtime versus conventional morning administration of both enalapril and losartan on the blood pressure (BP), heart rate, and the heart rate systolic BP product during the first 4 hours after awakening in a placebo-controlled, forced-titration trial. There were 357 men and women enrolled in the trial with an untreated sitting diastolic BP of 95 to 114 mm Hg and ambulatory daytime diastolic BP ≥85 mm Hg. Patients were randomized to either COER-verapamil hydrochloride each evening (240 mg titrated to 360 mg), enalapril each morning (10 mg titrated to 20 mg), losartan each morning (50 mg titrated to 100 mg), or placebo. Early morning assessments of BP, heart rate, and the heart rate systolic BP product were performed by use of 24-hour ambulatory recordings after 4 weeks (low dose) and 8 weeks (high dose) of therapy. Results Results were similar at weeks 4 and 8 for all treatment groups except that the magnitude of change was greater at week 8. After 8 weeks of treatment, reductions in early morning BP by COER-verapamil were significantly greater (−15/−10 mm Hg) than enalapril (−9/−7 mm Hg, P < .01) and losartan (−8/−5 mm Hg, P < .001). COER-verapamil also led to greater reductions in morning heart rate, the rate-pressure product, and the rate-of-rise of BP compared with the other 2 active treatment groups. Reductions in mean 24-hour BP were greater in patients treated with COER-verapamil compared with placebo and losartan, and similar to reductions in patients treated with enalapril. Conclusions Bedtime administration of an agent designed to parallel the circadian rhythm of BP and heart rate led to significantly greater early morning hemodynamic effects compared with other conventional once-daily antihypertensive agents dosed in the morning. (Am Heart J 2002;144:657-65.)     

Effects of metoprolol succinate extended release vs. amlodipine besylate on the blood pressure,heart rate,and the rate-pressure product in patients with hypertension

Ambulatory monitoring of the blood pressure (BP) and heart rate allows for the assessment of the 24-hour rate-pressure product (RPP), a close correlate of myocardial oxygen demand, both in the untreated state and while on antihypertensive therapy. To evaluate the clinical effects of metoprolol succinate extended release (ER) tablets (100 mg titrated to 200 mg for clinic BP >140/90 mm Hg) vs. amlodipine (5 mg titrated to 10 mg for clinic BP >140/90 mm Hg) on the 24-hour and early morning hemodynamic parameters, we performed a double-blind crossover trial that included 8 weeks of active treatment, 4 weeks of placebo washout, and 8 weeks of active crossover treatment using 24-hour ambulatory blood pressure (ABP) measurements. Patients were included if they were untreated, had hypertension based on both clinic (140 to 179/90 to 109 mm Hg) and ABP recordings (>135/85 mm Hg while awake), and were 18 to 65 years of age. Patients enrolled in the trial (n = 35) had a mean age of 55 ± 7 years, 24-hour mean BP of 148/91 ± 11/7 mm Hg, heart rate (HR) of 76 ± 10 beats/minute, and a RPP of 11,230 ± 1717 mm Hg·beats·minute). In the early morning period (6 am to 10 am), baseline BP was 155/98 ± 11/7 mm Hg and the RPP was 12,084 ± 1752 mm Hg·beats·minute. The 24-hour diastolic blood pressure (DBP), HR, and RPP were lowered to a greater extent by metoprolol succinate compared with amlodipine. Additionally, changes from baseline in early morning DBP, HF, and RPP were lowered to a significantly greater extent by metoprolol (mean dose, 124 ± 44 mg daily) compared with amlodipine (mean dose, 7.2 ± 2.5 mg daily) (P = .02 for DBP and P < .0001 for HR and the RPP). The incident rates of adverse events were low and similar for the two treatment groups. These data demonstrate that metoprolol succinate ER induced greater reductions in early morning BP, HR, and FPP than amlodipine in middle-aged patients with Stages 1 and 2 hypertension. These findings have clinical implications for patients with hypertension and coronary heart disease.     

Cardiovascular risk and therapeutic intervention for the early morning surge in blood pressure and heart rate.

The incidence of most adverse cardiovascular events appears to follow a circadian pattern, reaching a peak in the morning shortly after wakening and arising. The activities of many physiologic parameters, including hemodynamic, hematologic and humoral factors, also fluctuate in a cyclical manner over the 24h. It has been suggested that, during the post-awakening hours, the phases of these cycles synchronize to create an environment that predisposes to atherosclerotic plaque rupture and thrombosis in susceptible individuals, thereby accounting for the heightened cardiovascular risk at this time of day. Blood pressure and heart rate are part of this physiologic process, following a clear circadian rhythm characterized by a fall during sleep and a sharp rise upon awakening. This so-called 'morning surge' in blood pressure may act as a trigger for cardiovascular events, including myocardial infarction and stroke. The clinical implication of these observations is that antihypertensive therapy should provide blood pressure control over the entire interval between doses. For agents taken once daily in the morning, the time of trough plasma drug level (and lowest pharmacodynamic effect) will often coincide with the early morning surge in blood pressure and heart rate. For these reasons, chronotherapeutic formulations of drugs and intrinsically long-acting antihypertensive agents provide the most logical approach to the treatment of hypertensive patients since they provide 24 h blood pressure control from a single daily dose as well as attenuating the early morning rise in blood pressure (and in some instances heart rate).     

Effects of diltiazem retard on ambulatory blood pressure and heart rate variability in patients with essential hypertension

BACKGROUND: Dihydropyridine calcium antagonists increase heart rate due to reflex activation of the sympathetic nervous system, although these effects are less obvious for long-acting agents. OBJECTIVE: To study the effects of diltiazem retard, a long-acting nondihydropyridine calcium antagonist, on 24h blood pressure, heart rate and autonomic nerve activity in patients with essential hypertension. DESIGN: Randomized crossover design. METHODS: Thirteen patients [five men and eight women, aged 64+/-2 years (mean+/-SEM)] were administered placebo or diltiazem retard (100-200mg once daily) for 4 weeks each. Ambulatory monitoring of blood pressure and heart rate, and electrocardiography were carried out at the end of each period using a multibiomedical recorder (TM-2425). Autonomic nerve activity was evaluated by power spectral analysis of variability of heart rate using the high-frequency component as an index of parasympathetic nerve activity and the ratio of the low-frequency component and the high-frequency component as an index of sympathovagal balance. RESULTS: Treatment with diltiazem retard significantly decreased 24h average blood pressure and heart rate by 11.6+/-3.6/5.7+/-1.8mmHg and 5.0+/-1.1 beats/min, respectively. The changes in daytime and night-time values were comparable. Diltiazem retard also significantly decreased daytime and 24h low:high-frequency-component ratio (2.0+/-0.2 versus 1.7+/-0.2 and 1. 8+/-0.2 versus 1.6+/-0.2, respectively). CONCLUSIONS: These results indicate that diltiazem retard is effective as a once-daily antihypertensive agent and has favorable effects on heart rate and the autonomic nervous system.     

Effects of work stress on ambulatory blood pressure, heart rate, and heart rate variability

Work stress has repeatedly been associated with an increased risk for cardiovascular disease. This study tested whether this relationship could be explained by exaggerated cardiovascular reactivity to work or impaired recovery in leisure time. Vagal tone was assessed as a possible determinant of these work stress effects. Participants included 109 male white-collar workers (age, 47.2+/-5. 3) who were monitored on 2 workdays and 1 nonworkday for ambulatory blood pressure, heart rate, and heart rate variability. Chronic work stress was defined according to Siegrist's model as (1) high imbalance, a combination of high effort and low reward at work, or (2) high overcommitment, an exhaustive work-related coping style indexing the inability to unwind. All findings were adjusted for possible differences in posture and physical activity between the work stress groups. High imbalance was associated with a higher heart rate during work and directly after work, a higher systolic blood pressure during work and leisure time, and a lower 24-hour vagal tone on all 3 measurement days. Overcommitment was not associated with an unfavorable ambulatory profile. Logistic regression analysis revealed that heart rate [odds ratio 1-SD increase 1.95 (95% CI, 1.02 to 3.77)] and vagal tone [odds ratio 1-SD decrease 2.67 (95% CI, 1.24 to 5.75)] were independently associated with incident mild hypertension. Surprisingly, the values during sleep were more predictive for mild hypertension than the values during work. The results from the present study suggest that the detrimental effects of work stress are partly mediated by increased heart rate reactivity to a stressful workday, an increase in systolic blood pressure level, and lower vagal tone.     

Effects of bedtime vs. morning administration of the long-acting lipophilic angiotensin-converting enzyme inhibitor trandolapril on morning blood pressure in hypertensive patients.

Cardiovascular events occur most frequently in the morning. To study the effects of the long-acting lipophilic angiotensin-converting enzyme (ACE) inhibitor trandolapril on morning blood pressure (BP), we performed ambulatory BP monitoring (ABPM) before and after administration of trandolapril just before going to bed (bedtime-administered group: n=17) or in the morning (morning-administered group: n=20) in 37 hypertensive patients. Both sets of ABPM data were available in 30 patients. The 24-h systolic BP (SBP) levels were significantly decreased by 7.2 mmHg in the morning-administered group (p=0.02) and by 5.2 mmHg in the bedtime-administered group (p=0.04). In the bedtime-administered group, prewaking SBP (the average of the 2-h SBP values just before waking) and morning SBP (the average of the 2-h SBP values just after waking) were significantly decreased by 11 mmHg (p=0.005) and by 8.4 mmHg (p=0.03), respectively. On the other hand, in the morning-administered group, the reduction of prewaking SBP (3.9 mmHg, n.s.) and morning SBP (6.6 mmHg, n.s.) did not reach the level of statistical significance. However, the differences in the reductions of prewaking and morning SBPs between the two groups were not statistically significant. There was no additional reduction of the nighttime lowest BP in either administration group. In conclusion, bedtime administration of the long-acting ACE inhibitor trandolapril seems to be a safe and effective means of controlling morning BP in hypertensive patients without an excessive fall in nocturnal BP.     

Effect of ramipril on 24-hour variability of blood pressure and heart rate in essential hypertension

Nonrestricted blood pressure recording was performed invasively or noninvasively, using new portable devices, for a period of 24 hours in 4 patients with essential hypertension before and after 6- to 17-day treatment with ramipril at an initial dosage of 1.25 mg daily. Ramipril produced a steady decrease in blood pressure without changing heart rate. Before initiation of ramipril treatment, the blood pressure was lower during the night than during the day. This day to night difference was not affected by ramipril. In addition, analysis of the standard deviation of the mean for each time point examined during 24 hours revealed no effect of ramipril on circadian variation of blood pressure.     

Effects of three methods of analysis on ambulatory blood pressure indices and the early morning rise in blood pressure

OBJECTIVE: To study the effects of actigraphic, diary and fixed-time methods of analysis on ambulatory blood pressure, the day (awake)-night (asleep) difference and early morning blood pressure. METHODS: We analyzed 50 ambulatory blood pressure studies of patients who also underwent actigraphic activity studies. We divided each study into awake and sleeping intervals by three methods: a patient diary of sleep hours, actigraphically determined sleep hours and a fixed schedule of estimated sleep (2200-0700 h). We then calculated the overall ambulatory blood pressure averages, the awake-asleep differences and the average blood pressure for 4 h after awakening. RESULTS: We found that actigraphic division of the data and patient-kept diaries provided similar ambulatory blood pressure averages whereas fixed-time analysis (2200-0700 h as the sleeping period) was less similar to that using the diary method. The nocturnal decline in diastolic blood pressure calculated by the diary method tended to be higher than that obtained by the fixed time method (16+/-6 versus 14+/-7%, P = 0.037). The limits of agreement for the early morning blood pressure rise for diary and fixed-time analyses were wider than those for diary and actigraphic analyses (-9.5 to +10.0/-6.6 to +7.0) versus (-4.4 to +4.7/-4.1 to +4.0 mmHg). CONCLUSION: Actigraphic division of the ambulatory blood pressure data is more similar to the diary than it is to the fixed-time method studied here. Researchers studying the early morning rise in blood pressure should consider using either actigraphy or diary rather than fixed-time methods of analysis to identify times of awakening.     

Single versus triplicate measurements of blood pressure and heart rate

The mean of rapidly repeated duplicate or triplicate measurements is often used in studies of antihypertensive drugs. Forty patients with hypertension had triplicate measurements of blood pressure and heart rate on two occasions, 1 week apart, during placebo treatment. The average difference between the first measurement and the mean of the triplicate measurements was -0.3 mm Hg. The average coefficient of variation for supine and standing, systolic and diastolic blood pressures was 8.4% for the single measurements and 8.0% for the mean of triplicate measurements. The correlations between the first measurements and the mean of triplicate measurements ranged from 0.90 to 0.98 (all p less than 0.01). The average difference between the two visits for all four blood pressure parameters was -0.6 mm Hg for the single measurements and -0.5 mm Hg for the mean of triplicate measurements (all p = NS). These results indicate that 1) blood pressure does not change further after 1 week of placebo treatment, and 2) use of the mean of triplicate measurements of blood pressure and heart rate gives the same result as use of single measurements, and the results are no less variable.     

清晨血压及血压晨峰的临床诊断价值

目的：探讨清晨血压在疾病诊断中的临床价值。方法对我院动态血压室近三个月的24 h 动态血压数据进行统计,分析心脑血管病患者的24 h 动态血压,对其清晨时段的血压状况进行研究。结果308例普通高血压患者中有202例清晨时段血压控制不佳,心脑血管病患者中有70％～80％清晨血压控制不佳。结论清晨血压升高在高血压患者中的发生率较高、危险性大,与心脑血管事件密切相关。清晨血压对隐匿性高血压的诊断具有临床意义。     

Effects of music on systolic blood pressure, diastolic blood pressure, and heart rate: a meta-analysis

There are a handful of studies that have been done investigating the effect of music on various vital signs, namely systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). Many studies have also assessed effects of music on self-reported anxiety level, attributing some degree of music-induced anxiety relief to the beneficial impacts of music on vital signs. Several randomised studies have shown varying effects of music on these vital parameters and so a metaanalysis was done to compare the effect of music on them. The fixed effects model was used as studies were homogenous. A two-sided alpha error < 0.05 was considered to be statistically significant. Compared to those who did not receive music therapy, those who did receive music therapy had a significantly greater decrease in SBP before and after (difference in means, -2.629, confidence interval (CI), -3.914 to -1.344, P < 0.001), a significantly greater decrease in DBP (difference in means, -1.112, CI, -1.692 to -0.532, P < 0.001), and a significantly greater decrease in HR (difference in means, -3.422, CI, -5.032 to -1.812, P < 0.001).     

高血压患者静息心率、率压乘积及其临床意义

目的　探讨高血压患者静息心率及率压乘积的变化及其意义。方法　 40 5例高血压患者 ,平均年龄 5 6.8岁 ,男 2 2 8例 ,女 177例 ,测定其静息心率、血压、血脂及血糖 ,并与正常对照组 2 38例进行比较。结果　高血压组静息心率及率压乘积显著高于正常对照组 (P<0 .0 5 ) ,合并左心室肥厚者高于无左心室肥厚者 (P<0 .0 5 )。合并高血糖及高胆固醇者 ,其静息心率显著高于血糖及胆固醇正常者。结论　静息心率及率压乘积与高血压的发展、高血压靶器官损害左心室肥厚及高血压合并代谢异常有关。     

Effects of alcohol restriction on ambulatory blood pressure,heart rate,and heart rate variability in Japanese men

We investigated the effects of alcohol restriction on ambulatory blood pressure (BP), heart rate, and heart rate variability in 33 Japanese male volunteers (37 ± 1 years, mean ± SE), who were all habitual drinkers. Subjects were told either to keep their usual drinking habits for 3 weeks (usual alcohol period), or to reduce alcohol intake by at least half of their usual drinking amount (reduced alcohol period). The ambulatory BP, heart rate, and electrocardiographic R-R intervals were measured during a 24-h period with a portable recorder on the last day of each period. A power spectral analysis of R-R intervals was performed to obtain the low-frequency (LF) and high-frequency (HF) components. The percentage of differences between adjacent normal R-R intervals >50 msec (pNN50) was also calculated. The amount of ethanol intake was significantly reduced from 70 ± 5 mL/day in the usual alcohol period to 19 ± 3 mL/day in the reduced alcohol period (P < .0001). The daytime systolic BP was significantly lower in the reduced alcohol period than in the usual alcohol period by 4 ± 1 mm Hg (P < .05). The daytime and nighttime heart rate was significantly lower in the reduced alcohol period than in the usual alcohol (P < .001 for each). The pNN50 and the HF component were significantly higher in the reduced alcohol period than in the usual alcohol period (P < .0001 for each). The LF/HF ratio was significantly lower in the reduced period than in the usual period (P < .01). These results demonstrate that 3-week alcohol restriction produced reductions in ambulatory systolic BP, heart rate, and the index of sympathovagal balance, and augmentations of parasympathetic indices of heart rate variability in Japanese male drinkers.     

Differential effects of morning and evening dosing of nisoldipine ER on circadian blood pressure and heart rate

The time of administration of once-daily antihypertensive agents may have a significant impact on blood pressure control during awake and sleep periods. Using 24-h ambulatory monitoring, we compared the effects of morning and evening dosing of the long-acting dihydropyridine calcium channel blocker, nisoldipine extended-release (ER), on circadian blood pressure (BP) and heart rate in patients with mild-to-moderate hypertension. After completing a 3-week placebo run-in period, 85 patients were randomized to morning versus evening nisoldipine ER treatment at a fixed 20-mg dose. Patients were treated for 4 weeks, followed by crossover to the alternate dosing regimen for 4 additional weeks. Twenty-four–hour ambulatory monitoring was performed at baseline and at 4 and 8 weeks after randomization. Awake and sleep times were determined by electronic activity recorders (Actigraphy). Similar least-squares (±SE) mean changes from baseline in 24-h BP (systolic BP/diastolic BP: −11.9/−7.4 ± 0.6/0.5 v −11.6/−6.5 ± 0.6/0.5 mm Hg) and heart rate (1.0/1.7 ± 0.4/0.4 beats/min) occurred with morning and evening administration, respectively. A significantly greater effect on awake diastolic BP (systolic BP/diastolic BP: −12.6/−8.1 ± 0.7/0.4 v −11.3/−6.4 ± 0.7/0.4 mm Hg; P = .16/.01) was observed with morning dosing compared with evening dosing. In addition, small increases in sleep and early morning heart rate were seen with evening compared with morning administration of nisoldipine (sleep, 3.1 ± 0.4 v 0.4 ± 0.4 beats/min; P < .001; early morning, 3.5 ± 0.7 v 0.5 ± 0.7 beats/min; P = .002). These differential effects on awake BP and sleep heart rate were also observed in patients who had normal (dippers) and elevated (nondippers) BP values during sleep. Appropriate evaluation of the efficacy and safety of long-acting antihypertensive agents is essential when evening administration is being considered. In the present study, the timing of nisoldipine ER administration had no effect on mean changes in BP and heart rate over a 24-h period. However, nisoldipine ER had some differential effects during sleep and awake periods with morning relative to evening dosing.     

Effects of cigarette smoking on ambulatory blood pressure,heart rate,and heart rate variability in treated hypertensive patients

We investigated the influence of cigarette smoking on the levels and circadian patterns of blood pressure (BP), heart rate (HR), and HR variability (HRV) in hypertensive patients. Sixteen hypertensive smokers (57 ± 2 years old) receiving antihypertensive treatments participated in this study. Ambulatory monitoring of BP, HR, and electrocardiograms was performed every 30 min for 24 hours on a smoking day and nonsmoking day in a randomized crossover manner. Average 24-hour BP and daytime BP were significantly higher in the smoking period than in the nonsmoking period. No significant differences were observed in nighttime BP between the two periods. Average 24-hour and daytime HR, but not nighttime HR, were also higher in the smoking period than in the nonsmoking period. The daytime high frequency (HF) component of HRV was attenuated more in the smoking period than in the nonsmoking period. No significant differences were observed in the low frequency (LF) components of HRV or LF/HF ratio between the two periods. These results demonstrated that cigarette smoking increased the daytime and average 24-hour BP and HR, and the increases observed in daytime BP and HR were associated with the attenuation of parasympathetic nerve activity.