The Effect of Pulse Rate and Blood Pressure Dipping Status on the Risk of Stroke and Cardiovascular Disease in Japanese Hypertensive Patients

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1 nature publishing group The Effect of Pulse Rate and Blood Pressure Dipping Status on the Risk of Stroke and Cardiovascular Disease in Japanese Hypertensive Patients Tomoyuki Kabutoya 1, Satoshi Hoshide 1, Joji Ishikawa 1, Kazuo Eguchi 1, Kazuyuki Shimada 1 and Kazuomi Kario 1 Background There have been few reports on the relationship between variation in the diurnal pulse rate (PR) in relation to a nondipper blood pressure (BP) pattern and cardiovascular events in elderly hypertensives. Methods Ambulatory BP monitoring (ABPM) was conducted at baseline in 811 older Japanese hypertensives (clinical BP >140/90 mm Hg; age >50 years old) enrolled in the Jichi Medical School ABPM study, wave 1. They were followed up for an average of 41 months, and the incidence of subsequent cardiovascular event and death was evaluated. PR nondipping status was defined as (awake PR sleep PR)/awake PR <0.1. Results The mean age of patients was 72.3 ± 9.8 years (311 men and 500 women). The nondipper patients had a higher risk of cardiovascular events (11.5% vs. 6.1%, P = 0.006) and stroke (9.9% vs. 5.7%, P = 0.039) than the dippers. Patients were classified into four subgroups: BP In recent years, many reports have shown that a decrease of nocturnal blood pressure (BP) decline (nondipping status) as measured by ambulatory BP monitoring (ABPM) is related to cardiovascular events and hypertensive target organ damage. 1 3 Like BP, pulse rate (PR) also shows a diurnal variation. PR is high in the morning and lower at night, reflecting the change in autonomic nervous activity, which is dominated by sympathetic nervous activity in the morning, and parasympathetic nervous activity at night. 4 However, there have been only a few reports examining the relation between an ABPM-measured PR dipper pattern and cardiovascular events. 5 7 Although two of these investigations showed that the sleep/awake ratio of PR measured by ABPM predicted cardiovascular death and cardiovascular events, 8,9 the clinical significance of a decrease in nocturnal PR decline 1 Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan. Correspondence: Kazuomi Kario (kkario@jichi.ac.jp) Received 29 September 2009; first decision 12 November 2009; accepted 15 February 2010; advance online publication 18 March doi: /ajh American Journal of Hypertension, Ltd. dipping plus PR dipping status (n = 471), BP dipping plus PR nondipping (n = 37), BP nondipping plus PR dipping (n = 250), and BP nondipping plus PR nondipping (n = 53). The combination of BP and PR nondipping constituted a higher risk of cardiovascular events and stroke than the other three combinations combined (cardiovascular events: 17.0% vs. 7.5%, P = 0.015; stroke: 17.0% vs. 6.6%, P = 0.005). On Cox proportional hazards modeling, BP nondipping with PR nondipping led to a significant synergistic increase in the risk of stroke (hazard ratio: 8.92; 95% confidence interval: , P = 0.048). Conclusions A blunted PR dip might predict a stroke in elderly hypertensives with a nondipping BP status. Keywords: blood pressure; elderly; hypertension; nondipper; pulse rate; risk factor; stroke Am J Hypertens 2010; 23: American Journal of Hypertension, Ltd. remains unclear in elderly hypertensives who have high cardiovascular risk. On the other hand, the diurnal variation of BP change and the ratio of nondippers to dippers are known to increase with age. 10 It has also been shown that the high-frequency heart rate variability activity decreases in elderly hypertensives, 11 and that a nondipping pattern is associated with a decrease of heart rate variability. 12 Although abnormal decline in nocturnal BP has been associated with cardiovascular risk, 13 it remains unclear whether there is a relationship between a diurnal variation of PR as measured by ABPM and cardiovascular events, and whether an abnormal diurnal variation of PR increases the cardiovascular risk of elderly hypertensives with a nondipping BP pattern. In the present study, we investigated the association between cardiovascular events and abnormal diurnal variation of PR in addition to a nondipper BP pattern in untreated elderly hypertensives. Methods Patients. We initially enrolled 821 older hypertensive outpatients (clinic BP >140/90 mm Hg and age >50 years) in AMERICAN JOURNAL OF HYPERTENSION VOLUME 23 NUMBER july

2 Nondipping of Sleep Pulse Rate and Stroke the Jichi Medical School ABPM study, wave 1, from six participating institutions (three clinics, two hospitals, and one outpatient clinic of a medical school) between 1 January 1992 and 1 January The patients who had a history of stroke, ischemic heart disease, chronic heart failure, peripheral vascular disease, chronic renal damage, or arrhythmia at baseline were excluded from this study. Measurement at baseline and follow-up was successfully conducted in 811 (99%) of the patients. Clinic BP was measured after an at least 5-min rest in the sitting position. Diabetes mellitus was defined as a fasting glucose level >140 mg/dl, a random nonfasting glucose level >200 mg/dl, hemoglobin A1c >6.2%, or the use of an oral hypoglycemic agent or insulin. Hyperlipidemia was defined as a total cholesterol level >240 mg/dl or the use of an oral lipid-lowering agent. Smokers were defined as current smokers. Body mass index (BMI) was calculated as weight (in kilograms)/height (in meters squared). This study was approved by the independent research ethics committee of Jichi Medical University School of Medicine, Japan, in Table 1 Baseline patient characteristics BP dipper Some of the data from the Jichi Medical School ABPM study were published previously ABPM and definition of dipping status. ABPM was measured using a validated machine: ABPM-630 (Nippon Colin, Komaki, Japan), 18 TM-2421, or TM-2425 (A&D, Tokyo, Japan). 19 Patients stopped antihypertensive medication for at least 14 days before the ABPM study, and 55% of the patients had a history of antihypertensive medication use. Measurements were performed at 30-min intervals for 24 h on a weekday. 16,20 We determined the periods of waking and sleeping based on the patient diaries. Sleep BP was defined as the average of the BP values from the time when the patient went to bed until the time he or she got out of bed, and awake BP was defined as the average of the BPs recorded during the rest of the day. BP dipper status was defined as (awake systolic BP (SBP) sleep SBP)/awake SBP 0.1, and BP nondipper status was defined as (awake SBP sleep SBP)/awake SBP <0.1. PR dipper status was defined as (awake PR sleep PR)/awake PR 0.1, and PR BP nondipper PR dipper (n = 471) PR nondipper (n = 37) PR dipper (n = 250) PR nondipper (n = 53) P Age, years 71.1 ± ± ± ± Male, % Body mass index, kg/m ± ± ± ± Current smoker, % Diabetes mellitus, % Hyperlipidemia, % Prior antihypertensive drug treatment, % Fasting glucose, mg/dl 94.0 ± ± ± ± Total cholesterol, mg/dl ± ± ± ± Triglyceride, mg/dl ± ± ± ± HDL-cholesterol, mg/dl 47.5 ± ± ± ± Creatinine, mg/dl 0.89 ± ± ± ± Clinic SBP, mm Hg 164 ± ± ± ± Clinic DBP, mm Hg 91 ± ± ± ± Clinic PR, bpm 77 ± ± ± ± h SBP, mm Hg 137 ± ± ± ± h DBP, mm Hg 78 ± 9 80 ± ± ± h PR, bpm 71 ± 7 74 ± ± 8 71 ± Awake SBP, mm Hg 147 ± ± ± ± 18 <0.001 Awake DBP, mm Hg 83 ± ± ± ± 10 <0.001 Awake PR, bpm 77 ± 8 75 ± ± 8 71 ± 8 <0.001 Sleep SBP, mm Hg 120 ± ± ± ± 17 <0.001 Sleep DBP, mm Hg 69 ± 9 71 ± ± ± 10 <0.001 Sleep PR, bpm 60 ± 7 71 ± ± 8 68 ± 8 <0.001 Awake/sleep SBP ratio 1.22 ± ± ± ± 0.05 <0.001 Awake/sleep PR ratio 1.30 ± ± ± ± 0.05 <0.001 BP, blood pressure; bpm, beats/min; DBP, diastolic blood pressure; HDL, high-density lipoprotein; PR, pulse rate; SBP, systolic blood pressure. 750 july 2010 VOLUME 23 NUMBER 7 AMERICAN JOURNAL OF HYPERTENSION

3 Nondipping of Sleep Pulse Rate and Stroke Table 2 Cardiovascular events of the study population subdivided according to dipping status Event PR dipper (n = 471) BP dipper PR nondipper (n = 37) nondipper status was defined as (awake PR sleep PR)/awake PR <0.1 (ref. 6). We classified all patients into four subgroups according to their BP- and PR-dipping status: those exhibiting BP dipping plus PR dipping (n = 471); BP dipping plus PR nondipping (n = 37); BP nondipping plus PR dipping (n = 250); and BP nondipping plus PR nondipping (n = 53). Follow-up and events. The collection of the follow-up data was performed on a single occasion for each patient, during a visit to the clinic between 1996 and 1998 (20-month period). Prior to the visit, the patient s medical records were reviewed for the use of antihypertensive drugs and the occurrence of cardiovascular events. When patients failed to come to the clinic, we interviewed them by telephone. We assessed three outcomes: fatal or nonfatal stroke, fatal or nonfatal myocardial infarction, and death. Strokes and cardiac events were diagnosed by the physician who was caring for the patient at the time of the event, and independent neurologists or cardiologists reviewed the cases and confirmed the diagnosis. 14 Cardiovascular events included stroke and myocardial infarction. All of the subjects gave informed consent to participate in the study. Statistical analysis. Data are shown as the mean ± s.d. The comparison between groups was based on the χ 2 test of independence for categorical variables and on the analysis of variance for continuous variables. Association between a dip of SBP and a dip of PR was tested using Pearson s correlation coefficient. Cumulative incidences of clinical total cardiovascular events, stroke events, and total mortality in four groups (patients exhibiting both BP and PR dipping; both BP dipping and PR nondipping; both BP nondipping and PR dipping; or both BP and PR nondipping) were plotted as Kaplan Meier curves, and the differences were assessed by the log-rank test. The multiplicity adjustment of P values was conducted by the Bonferroni method. In the multiple logistic regression model for BP nondippers, PR nondippers, and patients exhibiting both BP and PR nondipping, we adjusted PR dipper (n = 250) BP nondipper PR nondipper (n = 53) Total (n = 811) Cardiovascular events, no. (%) 30 (6.4) 1 (2.7) 26 (10.4) 9 (17.0) 66 (8.1) Stroke event, no. (%) 28 (5.9) 1 (2.7) 21 (8.4) 9 (17.0) 59 (7.3) Fatal stroke, no. (%) 5 (1.1) 1 (2.7) 5 (2.0) 2 (3.8) 13 (1.6) 0.39 Nonfatal stroke, no. (%) 23 (4.9) 0 (0) 16 (6.4) 7 (13.2) 46 (5.7) Myocardial infarction, no. (%) 3 (0.6) 0 (0) 8 (3.2) 0 (0) 11 (1.4) Fatal myocardial infarction, no. (%) 2 (0.4) 0 (0) 5 (2.0) 0 (0) 7 (0.9) 0.13 Nonfatal myocardial infarction, no. (%) 1 (0.2) 0 (0) 3 (1.2) 0 (0) 4 (0.5) 0.29 Total death, no. (%) 20 (4.3) 2 (5.4) 22 (8.8) 5 (9.4) 49 (6.0) Cardiovascular death, no. (%) 7 (1.5) 1 (2.7) 10 (4.0) 2 (3.7) 20 (2.5) 0.20 Noncardiovascular death, no. (%) 13 (2.8) 1 (2.7) 12 (4.8) 3 (5.7) 29 (3.6) 0.43 BP, blood pressure; PR, pulse rate. P value for age, gender, 24-h SBP, 24-h PR, and covariates that were associated by univariate analyses in Table 1. The hazard ratio and 95% CI of incidences of clinical total cardiovascular events, stroke events, and total mortality in the four groups described above were calculated using Cox regression analyses after adjustments for age, gender, BMI, 24-h SBP, 24-h PR, and BP nondipper in model 1; for age, gender, BMI, 24-h SBP, 24-h PR, and PR nondipper in model 2; and for age, gender, BMI, 24-h SBP, 24-h PR, BP nondipper, PR nondipper, and BP nondipper PR nondipper in model 3. Computer software (SPSS version 11.0J; SPSS, Chicago, IL) was used for the analyses, and a probability value <0.05 was considered statistically significant. Results At baseline, the average age was 72.3 ± 9.8 years, and the percentage of males was 38.3%. The patient characteristics of the four subgroups according to their BP- and PR-dipping status are shown in Table 1. The BP dipping plus PR dipping and BP dipping plus PR nondipping groups had similar awake/sleep SBP ratios (1.22 ± 0.09 vs ± 0.10, P = 0.62), and the BP nondipping plus PR dipping and BP nondipping plus PR nondipping groups had similar awake/sleep SBP ratios (1.03 ± 0.06 vs ± 0.05, P = 0.58). The mean duration of follow-up was 41 months (range: 1 68 months, 2,795 person-years). During the follow-up period, 66 cardiovascular events, including 59 strokes (Table 2), were recorded. The later events among BP nondippers with PR nondipping occurred after about ~45 50 months of follow-up (Figure 1). The incidence of stroke was 21 per 1,000 patientyears. BP nondipper patients had a higher incidence of cardiovascular events (11.5% vs. 6.1%, P = 0.006) and stroke events (9.9% vs. 5.7%, P = 0.039) than BP dipper patients; however, prior antihypertensive agents were not associated with cardiovascular events (8.3% vs. 8.0%, P = 0.90) or stroke events (7.8% vs. 6.8%, P = 0.58). A dip of SBP was significantly associated with a dip of PR (r = 0.14, P < 0.001). AMERICAN JOURNAL OF HYPERTENSION VOLUME 23 NUMBER 7 july

4 Nondipping of Sleep Pulse Rate and Stroke Multiple logistic regression analysis was conducted to investigate the determinants of BP nondipping, PR nondipping, and the combination of BP and PR nondipping adjusted for age, gender, BMI, 24-h SBP, 24-h PR, and covariates that were associated by univariate analyses. The determinants of the BP nondipping pattern were age and 24-h SBP, and those of the PR nondipping pattern were age, male gender, 24-h PR, and lower serum cholesterol level. Age was the only significant a Cardiovascular event free survival (%) b 100 Stroke-free survival (%) Log rank = P = Log rank = P = P = 0.52 BP nondipper with PR nondipper Follow-up (months) BP dipper with PR nondipper BP dipper with PR dipper BP nondipper with PR dipper BP nondipper with PR dipper P = 0.23 BP nondipper with PR nondipper Follow-up (months) BP dipper with PR nondipper BP dipper with PR dipper Table 3 Determinants of BP, PR, and BP and PR nondipper independent determinant of the combination of BP and PR nondipping (Table 3). The Kaplan Meier curve of the incidence of cardiovascular events in the four subgroups is shown in Figure 1a. Patients exhibiting BP nondipping plus PR nondipping had a significantly higher incidence of cardiovascular events than patients in the other three subgroups combined (17.0% vs. 7.5%, P = 0.015). Because stroke was the most common cardiovascular event in the present study, we next investigated stroke incidence. Figure 1b shows the Kaplan Meier curve of the incidence of stroke events in the four subgroups. Patients with BP nondipping plus PR nondipping had a significantly higher incidence of stroke events than the other three subgroups combined (17.0% vs. 6.6%, P = 0.005). After adjusting for age, gender, BMI, 24-h SBP, and 24-h PR, the difference of four subgroups was not significant of cardiovascular disease (P = 0.17), and of stroke (P = 0.13); however, the combination of BP and PR nondipping constituted a higher risk of cardiovascular events (P = 0.047) and stroke (P = 0.048) than the combination of BP and PR dipping. When considered individually, however, BP and PR nondipper status were not significant independent predictors of cardiovascular events after adjusting for age, gender, BMI, 24-h SBP, and PR (Table 4). BP and PR nondipping were not significant independent predictors of stroke events after adjusting for age, gender, BMI, 24-h SBP, and 24-h PR; however, the combination of BP and PR nondipping was a significant independent predictor of stroke (hazard ratio: 8.92; 95% confidence interval: , P = 0.048, Table 5). Thus, the PR and the BP nondipping patterns had a synergistic effect on stroke risk. The synergistic effect remained after adjusting for diabetes (hazard ratio: 8.89; 95% confidence interval: , P = 0.048). We also used Cox proportional hazard modeling to clarify the relationship of the awake/sleep BP or PR ratio with cardiovascular events as a continuous value. A decrease in the awake/ sleep ratio of PR was not associated with cardiovascular events BP nondipper PR nondipper BP nondipper with PR nondipper Correlates Odds ratio Odds ratio Odds ratio Age (10 years) 1.23 ( ) ( ) ( ) Gender, male 0.93 ( ) ( ) ( ) 0.18 Body mass index 0.93 ( ) ( ) ( ) 0.86 Current smoker 1.25 ( ) ( ) ( ) 0.32 Diabetes mellitus 1.15 ( ) ( ) ( ) 0.82 Fasting glucose (10 mg/dl) 1.02 ( ) ( ) ( ) Total cholesterol (10 mg/dl) 0.99 ( ) ( ) ( ) h SBP (10 mm Hg) 1.13 ( ) ( ) ( ) h PR (10 bpm) 1.01 ( ) ( ) ( ) 0.88 Odds ratio and 95% CI were adjusted for age, gender, body mass index, current smoker, diabetes mellitus, fasting glucose, 24-h SBP, and 24-h PR. BP, blood pressure; bpm, beats/min; CI, confidence interval; PR, pulse rate; SBP, systolic blood pressure. P = P = Figure 1 Kaplan Meier curves for (a) cardiovascular event survival and (b) stroke event survival in the groups subdivided according to dipping status. BP, blood pressure; PR, pulse rate. P = 0.27 P = july 2010 VOLUME 23 NUMBER 7 AMERICAN JOURNAL OF HYPERTENSION

5 Nondipping of Sleep Pulse Rate and Stroke Table 4 Cox regression analysis for cardiovascular events (hazard ratio = 1.09; 95% CI: ) or stroke ( hazard ratio = 1.41; 95% CI: ) after adjustment for age, gender, 24-h SBP, and 24-h PR. A decrease in the awake/sleep ratio of PR was also not associated with cardiovascular events (hazard ratio = 1.20; 95% CI: ) or stroke ( hazard ratio = 1.09; 95% CI: ) after adjustment for age, gender, BMI, 24-h SBP, and 24-h PR. An interaction between the awake/sleep ratio of SBP and awake/sleep ratio of PR was not significant (P = 0.55). In our Kaplan Meier curve analysis of total mortality, the combination of BP and PR nondipping was not associated with a significantly higher mortality than the other three combinations (log-rank 6.15, P = 0.11). Discussion We demonstrated that nondipping patterns of diurnal PR and diurnal BP synergistically enhanced the risk of stroke in elderly hypertensives. The synergistic effect was not due to a decrease in the awake/sleep SBP ratio. Aging was related to Model 1 Model 2 Model 3 Age (10 years) 1.85 ( ) < ( ) < ( ) <0.001 Gender, male 1.87 ( ) ( ) ( ) Body mass index 0.97 ( ) ( ) ( ) h SBP (10 mm Hg) 1.36 ( ) < ( ) < ( ) < h PR (10 bpm) 1.16 ( ) ( ) ( ) 0.21 BP nondipper 1.33 ( ) 0.27 NA NA 1.04 ( ) 0.89 PR nondipper NA NA 1.05 ( ) ( ) 0.14 BP nondipper PR nondipper NA NA NA NA 7.88 ( ) In model 1, hazard ratio and 95% CI were adjusted for age, gender, body mass index, 24-h SBP, 24-h PR, and BP nondipper. In model 2, hazard ratio and 95% CI were adjusted for age, gender, body mass index, 24-h SBP, 24-h PR, and PR nondipper. In model 3, hazard ratio and 95% CI were adjusted for age, gender, body mass index, 24-h SBP, 24-h PR, BP nondipper, PR nondipper, and BP nondipper PR nondipper. BP, blood pressure; bpm, beats/min; CI, confidence interval; NA, not applicable; PR, pulse rate; SBP, systolic blood pressure. Table 5 Cox regression analysis for stroke events Model 1 Model 2 Model 3 Age (10 years) 1.87 ( ) < ( ) < ( ) <0.001 Gender, male 1.88 ( ) ( ) ( ) Body mass index 0.98 ( ) ( ) ( ) h SBP (10 mm Hg) 1.37 ( ) < ( ) < ( ) < h PR (10 bpm) 1.26 ( ) ( ) ( ) BP nondipper 1.23 ( ) 0.44 NA NA 0.91 ( ) 0.76 PR nondipper NA NA 1.16 ( ) ( ) 0.15 BP nondipper PR nondipper NA NA NA NA 8.92 ( ) In model 1, hazard ratio and 95% CI were adjusted for age, gender, body mass index, 24-h SBP, 24-h PR, and BP nondipper. In model 2, hazard ratio and 95% CI were adjusted for age, gender, body mass index, 24-h SBP, 24-h PR, and PR nondipper. In model 3, hazard ratio and 95% CI were adjusted for age, gender, body mass index, 24-h SBP, 24-h PR, BP nondipper, PR nondipper, and BP nondipper PR nondipper. BP, blood pressure; bpm, beats/min; CI, confidence interval; NA, not applicable; PR, pulse rate; SBP, systolic blood pressure. BP nondipping, PR nondipping, and the combination of BP dipping plus PR nondipping. Previous studies have reported that a nondipping pattern of diurnal PR was related to all-cause mortality in outpatients referred to hospitals and a general Japanese population, 6,21 and that a nondipping pattern of diurnal PR was associated with all-cause mortality and cardiovascular mortality in elderly diabetics. 8 Hansen et al. performed ABPM in 6,928 subjects enrolled in prospective population studies, the results of which were collected in the International Database on ABPM in Relation to Cardiovascular Outcomes, and analyzed total mortality according to the presence or absence of hypertension. 7 The current study is the first to show that a nondipping pattern of diurnal PR and a nondipping pattern of diurnal BP synergistically enhanced the risk of stroke in elderly hypertensives. The participants in the present study were elderly hypertensives, and aging was found to be an independent predictor of a PR nondipping pattern. The PIUMA study similarly found that age was independently associated with a decrease of change in AMERICAN JOURNAL OF HYPERTENSION VOLUME 23 NUMBER 7 july

6 Nondipping of Sleep Pulse Rate and Stroke the PR from day to night. 5 Other studies have reported that the incidence of BP nondipping 10 and BP variability 22 increase with age. On the other hand, high-frequency heart rate variability decreases in elderly hypertensives, 12 and thus, the elderly have increased BP variability and decreased PR variability. An increase in sympathetic nerve activity induces an increase in PR through the production of epinephrine and norepinephrine, 23 and an abnormality of autonomic nervous activity results in a decrease of BP and PR diurnal change. 24 Grassi et al. showed that high muscle sympathetic nerve traffic was associated with a decrease in nocturnal BP reduction in middle-aged hypertensives. 25 It has also been reported that aging was associated with an increase in muscle sympathetic nerve activity in essential hypertension, 26 and that low- frequency activity of heart rate variability was increased in elderly hypertensives. 27 On the other hand, another study reported that both low- and high-frequency heart rate variability activity decreased in elderly hypertensives. 28 We previously reported that an increase of sympathetic nervous activity in elderly hypertensive patients was associated with a decrease in nocturnal BP reduction. 29 An increase of sympathetic nerve activity might play a role in the decrease in nocturnal PR reduction in elderly nondipper hypertensives observed in the present study. It has been reported that an imbalance between sympathetic and parasympathetic nervous activity affects the night:day PR ratio in progressive autonomic failure. 30 However, it has also been reported that sympathetic nervous activity is not associated with a BP nondipping pattern, 31 and thus, an imbalance of autonomic function, rather than an imbalance of sympathetic nervous function, might affect the variability of BP and PR. The circadian rhythm of BP and PR is dependent on the activity of the main body pacemaker localized in the suprachiasmatic nuclei of the hypothalamus, 32 and the nocturnal decrease of BP is related to an increase in melatonin secretion by the pineal gland. 33 It has also been shown that the secretion of melatonin is reduced in the elderly, resulting in an impairment of circadian rhythm. 34,35 Cagnacci et al. showed that prolonged administration of melatonin increased the night BP reduction, but had no effect on the diurnal change of PR. 36 The hypothalamic pituitary adrenal axis may thus have different effects on diurnal BP and PR. It is possible that ethnic differences in salt sensitivity play a role in the relationship between the nondipping pattern of PR and stroke observed in the present study. It has been reported that Japanese have a higher genetic risk of saltsensitive hypertension, 37 and that high salt sensitivity results in an increase of nocturnal BP. 38 It has also been shown that sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension, 39 and thus, in the present study, an increase of salt sensitivity could have affected stroke events by increasing sympathetic nervous hyperactivity, and thereby decreasing in nocturnal PR reduction. Although the mechanism is unknown, sympathetic nervous hyperactivity and an imbalance of autonomic function might have affected the result that a nondipping pattern of diurnal PR in hypertensives and a nondipping BP pattern synergistically enhanced the cardiovascular risk in the present study. High salt sensitivity might cause an increase of night BP and PR, and an increase in cardiovascular risk as a result of the combination of BP and PR nondipping. Obstructive sleep apnea also predominantly increases ambulatory BP during sleep compared with the awake period, with the result that obstructive sleep apnea is likely to be associated with the nondipping patterns of BP and PR. 40 Further studies will be needed to examine these underlying mechanisms in the association between cardiovascular disease and the combination of BP and PR nondipping. This study included some limitations. First, because we did not use actigraphy, the values of awake/sleep BP and PR may not have been entirely precise. The effects of some agents may not have been entirely washed out over the 2-week washout period, and the diurnal pattern of PR and BP might have been affected by prior antihypertensive medication. There were only small numbers of patients in the BP dipping plus PR nondipping and BP nondipping plus PR nondipping groups that limited the power of the statistical analysis. Stroke events were predominant in this study. However, because our patients were elderly and had high SBP levels, and because there is a very high incidence of stroke in Japan, 41 the results of this study cannot be extrapolated to any other ethnic group or population. In this study, the significant association between cardiovascular events and BP nondipper status disappeared after adjusting for age, gender, and other covariates. However, this result may have been due to the characteristics of the study population. That is, extreme-dipper ((awake SBP sleep SBP)/awake SBP 0.2) status has been shown to be a predictor for stroke in the elderly. 13 In the present study, the dippers included a subgroup of extreme dippers, and thus, the stroke risk of nondippers may have been underestimated in this study. We showed that PR and BP nondipper status had a significant synergistic effect on cardiovascular events, but we could not confirm this association in the linear association analysis using awake/sleep ratios of BP and PR. Further studies employing larger populations will be needed to investigate the relation between BP and PR dip and cardiovascular disease. In conclusion, we showed that a nondipping pattern of diurnal PR synergistically affected stroke events in elderly nondipper hypertensives. The PR nondipping status was thus useful for risk stratification of elderly nondipper hypertensives. Disclosure: The authors declared no conflict of interest. 1. O Brien E, Sheridan J, O Malley K. Dippers and non-dippers. Lancet 1988; 2: Shimada K, Kawamoto A, Matsubayashi K, Nishinaga M, Kimura S, Ozawa T. Diurnal blood pressure variations and silent cerebrovascular damage in elderly patients with hypertension. J Hypertens 1992; 10: Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, Guerrieri M, Gatteschi C, Zampi I, Santucci A. Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. 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