Circadian Blood Pressure Rhythm in Primary and Secondary Hypertension

Circadian blood pressure variability was recorded in patients with primary hypertension and with different forms of secondary hypertension using ambulatory 24-h blood pressure measurement. A group of 20 patients with different forms of secondary hypertension was compared with a matched group of patients with primary hypertension. Although the mean 24-h blood pressure was not different between the two groups, the patients with secondary hypertension had significantly higher systolic blood pressure during sleep and higher systolic and diastolic blood pressure in the early morning, compared with the primary hypertension group. This nocturnal blood pressure fall was then investigated in various groups of patients with different forms of secondary hypertension and compared with normotensives and patients with primary hypertension. Patients with mild primary hypertension (n = 152) and with severe primary hypertension (n = 30) had the same blood pressure fall (14–16 mm Hg systolic and diastolic) during the night (23:OO–05:OO h) as normotensives (n = 20). However, in patients with renoparenchymal hypertension (n = 29), renovascular hypertension (n = 20), hyperaldosteronism (n = 6), and hyperthyroidism (n = 14), the nocturnal blood pressure fall was significantly (p < 0.01) reduced. One patient with coarctation ofthe aorta and nine patients with primary hyperparathyroidism and elevated blood pressure had a normal circadian blood pressure profile with a normal nocturnal blood pressure fall. The heart rate decrease during the night was equal in all patient groups. Ambulatory blood pressure measurement allows blood pressure recording under everyday conditions, including nighttime. In primary hypertension the blood pressure variability exhibits the same circadian variation as in normotension, showing a marked nocturnal fall. However, in different forms of secondary hypertension, blood pressure shows a blunted circadian curve. This could have important diagnostic and therapeutic implications.     

Circadian blood pressure rhythm in primary and secondary hypertension.

Circadian blood pressure variability was recorded in patients with primary hypertension and with different forms of secondary hypertension using ambulatory 24-h blood pressure measurement. A group of 20 patients with different forms of secondary hypertension was compared with a matched group of patients with primary hypertension. Although the mean 24-h blood pressure was not different between the two groups, the patients with secondary hypertension had significantly higher systolic blood pressure during sleep and higher systolic and diastolic blood pressure in the early morning, compared with the primary hypertension group. This nocturnal blood pressure fall was then investigated in various groups of patients with different forms of secondary hypertension and compared with normotensives and patients with primary hypertension. Patients with mild primary hypertension (n = 152) and with severe primary hypertension (n = 30) had the same blood pressure fall (14-16 mm Hg systolic and diastolic) during the night (23:00-05:00 h) as normotensives (n = 20). However, in patients with renoparenchymal hypertension (n = 29), renovascular hypertensions (n = 20), hyperaldosteronism (n = 6), and hyperthyroidism (n = 14), the nocturnal blood pressure fall was significantly (p less than 0.01) reduced. One patient with coarctation of the aorta and nine patients with primary hyperparathyroidism and elevated blood pressure had a normal circadian blood pressure profile with a normal nocturnal blood pressure fall. The heart rate decrease during the night was equal in all patient groups. Ambulatory blood pressure measurement allows blood pressure recording under everyday conditions, including nighttime. In primary hypertension the blood pressure variability exhibits the same circadian variation as in normotension, showing a marked nocturnal fall.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impact of Strategically Located White Matter Hyperintensities on Cognition in Memory Clinic Patients with Small Vessel Disease

MethodsA total of 167 patients with SVD were recruited from memory clinics. Assumption-free region of interest-based analyses based on major white matter tracts and voxel-wise analyses were used to determine the association between WMH location and executive functioning, visuomotor speed and memory.ResultsRegion of interest-based analyses showed that WMHs located particularly within the anterior thalamic radiation and forceps minor were inversely associated with both executive functioning and visuomotor speed, independent of total WMH volume. Memory was significantly associated with WMH volume in the forceps minor, independent of total WMH volume. An independent assumption-free voxel-wise analysis identified strategic voxels in these same tracts. Region of interest-based analyses showed that WMH volume within the anterior thalamic radiation explained 6.8% of variance in executive functioning, compared to 3.9% for total WMH volume; WMH volume within the forceps minor explained 4.6% of variance in visuomotor speed and 4.2% of variance in memory, compared to 1.8% and 1.3% respectively for total WMH volume.ConclusionsOur findings identify the anterior thalamic radiation and forceps minor as strategic white matter tracts in which WMHs are most strongly associated with cognitive impairment in memory clinic patients with SVD. WMH volumes in individual tracts explained more variance in cognition than total WMH burden, emphasizing the importance of lesion location when addressing the functional consequences of WMHs.     

原发性高血压患者心率变异性及血压变异性与血管损害的相关性研究

目的:探讨原发性高血压患者心率变异性(HRV)及血压变异性(BPV)与血管损害的相关性。方法:选取2014年12月到2017年12月期间在我院接受治疗的原发性高血压患者94例,根据脉搏波传导速度(PWV)的不同分为对照组(60例)和血管受损组(34例)。比较两组患者的HRV、BPV指标,并分析PWV与HRV、BPV指标的相关性。结果:血管受损组的5 min心搏R-R间期平均值的标准差(SDANN)低于对照组,低频(LF)、高频(HF)、低高频之比(LF/HF)高于对照组,差异均有统计学意义(P0.05);血管受损组的24h平均收缩压(24h SBP)、24h平均脉压(24h PP)、白天平均收缩压(dSBP)、白天平均脉压(dPP)、夜间平均收缩压(nSBP)、夜间平均脉压(nPP)高于对照组,差异均有统计学意义(P0.05);PWV与LF、HF、LF/HF、24h SBP、24h PP、dSBP、dPP、nSBP、nPP均呈正相关(P0.05)。结论:原发性高血压患者部分HRV、BPV指标与PWV呈明显的相关性,说明HRV和BPV与患者的血管损害密切相关。     

Circadian and Short-Term Regulation of Blood Pressure and Heart Rate in Transgenic Mice with Cardiac Overexpression of The β1-Adrenoceptor

Congestive heart failure is associated with a loss of circadian and short-term variability in blood pressure and heart rate. In order to assess the contribution of elevated cardiac sympathetic activity to the disturbed cardiovascular regulation, we monitored blood pressure and heart rate in mice with cardiac overexpression of the β₁-adrenoceptor prior to the development of overt heart failure. Telemetry transmitters for continuous monitoring of blood pressure and heart rate were implanted in 8 to 9-week-old wildtype and transgenic mice, derived from crosses of heterozygous transgenic (line β₁TG4) and wildtype mice. Cardiovascular circadian patterns were analyzed under baseline conditions and during treatment with propranolol (500 mg/L in drinking water). Short-term variability was assessed by spectral analysis of beat-to-beat data sampled for 30 min at four circadian times. Transgenic β₁TG4 mice showed an increase in 24 h heart rate, while blood pressure was not different from wildtype controls. Circadian patterns in blood pressure and heart were preserved in β₁TG4 mice. Addition of propranolol to the animals’ drinking water led to a reduction in heart rate and its 24 h variation in both strains of mice. Short-term variability in blood pressure was not different between wildtype and β₁TG4 mice, but heart rate variability in the transgenic animals showed a rightward shift of the high-frequency component in the nocturnal activity period, suggesting an increase in respiratory frequency. In conclusion, the present study shows that both the circadian and the short-term regulation of blood pressure and heart rate are largely preserved in young, nonfailing β₁-transgenic mice. This finding suggests that the loss of blood pressure and heart rate variability observed in human congestive heart failure cannot be attributed solely to sympathetic overactivity but reflects the loss of adrenergic responsiveness to changes in the activity of the autonomic nervous system.     

Circadian and short-term regulation of blood pressure and heart rate in transgenic mice with cardiac overexpression of the beta1-adrenoceptor

Congestive heart failure is associated with a loss of circadian and short-term variability in blood pressure and heart rate. In order to assess the contribution of elevated cardiac sympathetic activity to the disturbed cardiovascular regulation, we monitored blood pressure and heart rate in mice with cardiac overexpression of the β₁-adrenoceptor prior to the development of overt heart failure. Telemetry transmitters for continuous monitoring of blood pressure and heart rate were implanted in 8 to 9-week-old wildtype and transgenic mice, derived from crosses of heterozygous transgenic (line β₁TG4) and wildtype mice. Cardiovascular circadian patterns were analyzed under baseline conditions and during treatment with propranolol (500 mg/L in drinking water). Short-term variability was assessed by spectral analysis of beat-to-beat data sampled for 30 min at four circadian times. Transgenic β₁TG4 mice showed an increase in 24 h heart rate, while blood pressure was not different from wildtype controls. Circadian patterns in blood pressure and heart were preserved in β₁TG4 mice. Addition of propranolol to the animals' drinking water led to a reduction in heart rate and its 24 h variation in both strains of mice. Short-term variability in blood pressure was not different between wildtype and β₁TG4 mice, but heart rate variability in the transgenic animals showed a rightward shift of the high-frequency component in the nocturnal activity period, suggesting an increase in respiratory frequency. In conclusion, the present study shows that both the circadian and the short-term regulation of blood pressure and heart rate are largely preserved in young, nonfailing β₁-transgenic mice. This finding suggests that the loss of blood pressure and heart rate variability observed in human congestive heart failure cannot be attributed solely to sympathetic overactivity but reflects the loss of adrenergic responsiveness to changes in the activity of the autonomic nervous system.     

Ambulatory blood pressure monitoring in the prediction of cardiovascular events and effects of chronotherapy: rationale and design of the MAPEC study

Ambulatory blood pressure (BP) measurements (ABPM) correlate more closely with target organ damage and cardiovascular events than clinical cuff measurements. ABPM reveals the significant circadian variation in BP, which in most individuals presents a morning increase, small post-prandial decline, and more extensive lowering during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced (non-dipper pattern) or even reversed (riser pattern). This is clinically relevant because the non-dipper and riser circadian BP patterns constitute a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia, and myocardial infarction. Hence, there is growing interest in how to best tailor and individualize the treatment of hypertension according to the specific circadian BP pattern of each patient. All previous trials that have demonstrated an increased cardiovascular risk in non-dipper as compared to dipper patients have relied on the prognostic significance of a single ABPM baseline profile from each participant without accounting for possible changes in the BP pattern during follow-up. Moreover, the potential benefit (i.e., reduction in cardiovascular risk) associated with the normalization of the circadian BP variability (conversion from non-dipper to dipper pattern) from an appropriately envisioned treatment strategy is still a matter of debate. Accordingly, the MAPEC (Monitorización Ambulatoria de la Presión Arterial y Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study was designed to investigate whether the normalization of the circadian BP profile toward more of a dipper pattern by chronotherapeutic strategies (i.e., specific timing during the 24 h of BP-lowering medications according to the 24 h BP pattern) reduces cardiovascular risk. The prospective MAPEC study investigates 3,000 diurnally active men and women >/=18 yrs of age. At inclusion, BP and wrist activity are measured for 48 h. The initial evaluation also includes a detailed medical history, an electrocardiogram, and screening laboratory blood and urine tests. The same evaluation procedure is scheduled yearly or more frequently (quarterly) if treatment adjustment is required for BP control. Cardiovascular morbidity and mortality are thus evaluated on the basis of changes in BP during follow-up. The MAPEC study, now on its fourth year of follow-up, investigates the potential decrease in cardiovascular, cerebrovascular, and renal risk from the proper modeling of the circadian BP profile by the timed administration (chronotherapy) of antihypertensive medication, beyond the reduction of clinic-determined daytime or ABPM-determined 24 h mean BP levels.     

Ambulatory Blood Pressure Monitoring in the Prediction of Cardiovascular Events and Effects of Chronotherapy: Rationale and Design of the MAPEC Study

Ambulatory blood pressure (BP) measurements (ABPM) correlate more closely with target organ damage and cardiovascular events than clinical cuff measurements. ABPM reveals the significant circadian variation in BP, which in most individuals presents a morning increase, small post‐prandial decline, and more extensive lowering during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced (non‐dipper pattern) or even reversed (riser pattern). This is clinically relevant because the non‐dipper and riser circadian BP patterns constitute a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia, and myocardial infarction. Hence, there is growing interest in how to best tailor and individualize the treatment of hypertension according to the specific circadian BP pattern of each patient. All previous trials that have demonstrated an increased cardiovascular risk in non‐dipper as compared to dipper patients have relied on the prognostic significance of a single ABPM baseline profile from each participant without accounting for possible changes in the BP pattern during follow‐up. Moreover, the potential benefit (i.e., reduction in cardiovascular risk) associated with the normalization of the circadian BP variability (conversion from non‐dipper to dipper pattern) from an appropriately envisioned treatment strategy is still a matter of debate. Accordingly, the MAPEC (Monitorización Ambulatoria de la Presión Arterial y Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study was designed to investigate whether the normalization of the circadian BP profile toward more of a dipper pattern by chronotherapeutic strategies (i.e., specific timing during the 24 h of BP‐lowering medications according to the 24 h BP pattern) reduces cardiovascular risk. The prospective MAPEC study investigates 3,000 diurnally active men and women ≥18 yrs of age. At inclusion, BP and wrist activity are measured for 48 h. The initial evaluation also includes a detailed medical history, an electrocardiogram, and screening laboratory blood and urine tests. The same evaluation procedure is scheduled yearly or more frequently (quarterly) if treatment adjustment is required for BP control. Cardiovascular morbidity and mortality are thus evaluated on the basis of changes in BP during follow‐up. The MAPEC study, now on its fourth year of follow‐up, investigates the potential decrease in cardiovascular, cerebrovascular, and renal risk from the proper modeling of the circadian BP profile by the timed administration (chronotherapy) of antihypertensive medication, beyond the reduction of clinic‐determined daytime or ABPM‐determined 24 h mean BP levels.     

Altered Orcadian Rhythms of Blood Pressure and Heart Rate in Non-Hemodialysis Chronic Renal Failure

The extended use of ambulatory monitoring has permitted the identification of many conditions in which the circadian rhythm of blood pressure is altered. The common denominator seems to be an impairment of the autonomic nervous system function. We examined whether the circadian blood pressure rhythm is altered in chronic renal failure (where autonomic dysfunction is usually present) by using a standardized chronobiological inferential statistical method in hospitalized subjects. For this purpose, a group of 30 non-hemodialysis hypertensive patients with chronic renal failure was compared with a second group of 30 patients affected by uncomplicated mild-to-moderate essential hypertension. The two groups were matched by age, sex and circadian mesors of blood pressure. Diet, meal times, sleep and activity logs were standardized. Blood pressure and heart rate recordings were obtained by using an automatic oscillometric recorder and subsequently analyzed according to the cosinor method. A mean circadian rhythm of blood pressure was documented in both groups, but while the mean acrophases occurred between 2 and 3 p.m. in essential hypertension, in renal failure they were between 11 p.m. and midnight for blood pressure and around 7 p.m. for heart rate. In addition, the mean circadian amplitudes were significantly lower in renal failure, while the mean circadian mesor of heart rate was significantly higher. Our data demonstrate that the circadian rhythms of blood pressure and heart rate are altered also in hypertension due to chronic renal failure.     

Altered Orcadian Rhythms of Blood Pressure and Heart Rate in Non-Hemodialysis Chronic Renal Failure

The extended use of ambulatory monitoring has permitted the identification of many conditions in which the circadian rhythm of blood pressure is altered. The common denominator seems to be an impairment of the autonomic nervous system function. We examined whether the circadian blood pressure rhythm is altered in chronic renal failure (where autonomic dysfunction is usually present) by using a standardized chronobiological inferential statistical method in hospitalized subjects. For this purpose, a group of 30 non-hemodialysis hypertensive patients with chronic renal failure was compared with a second group of 30 patients affected by uncomplicated mild-to-moderate essential hypertension. The two groups were matched by age, sex and circadian mesors of blood pressure. Diet, meal times, sleep and activity logs were standardized. Blood pressure and heart rate recordings were obtained by using an automatic oscillometric recorder and subsequently analyzed according to the cosinor method. A mean circadian rhythm of blood pressure was documented in both groups, but while the mean acrophases occurred between 2 and 3 p.m. in essential hypertension, in renal failure they were between 11 p.m. and midnight for blood pressure and around 7 p.m. for heart rate. In addition, the mean circadian amplitudes were significantly lower in renal failure, while the mean circadian mesor of heart rate was significantly higher. Our data demonstrate that the circadian rhythms of blood pressure and heart rate are altered also in hypertension due to chronic renal failure.     

Circadian blood pressure profile in patients with active Cushing's disease and after long-term cure.

Hypertension is a major feature of Cushing's disease, with the attendant increase in the rate of cardiovascular events. The circadian blood pressure profile also impacts cardiovascular risk and a few studies have shown that patients with Cushing's syndrome do not present the expected nocturnal blood pressure decrease and, further, that this alteration persists in short-range disease remission. These studies were performed by conventional discontinuous ambulatory pressure monitoring, a technique not devoid of limitations. Aim of our study was the assessment of blood pressure and heart rate profile by beat-to-beat noninvasive monitoring in twelve patients with active Cushing's disease (9 women and 3 men, age 33.3+/-2.36 years) and the assessment of its possible changes at short- (<1 year) and long-term (2-3 years) follow-up after curative surgery. No nocturnal blood pressure dipping (i.e., decrease by 10% of daytime values) was observed in 50% of patients both during active hypercortisolism and within 1 year from surgery. Recovery of blood pressure dipping profile was detected at long-term follow-up in a minority of patients. Daytime heart rate was higher in patients with active Cushing's disease and decreased over time after cure. In conclusion, patients with Cushing's disease present absent nocturnal blood pressure dipping and abnormal heart rate values which do not resolve after short-term remission of hypercortisolism and show only partial improvement in the long run. These findings identify additional cardiovascular risk factors for patients cured of Cushing's disease.     

原发性高血压患者血压昼夜节律与靶器官损害的关系研究

目的:研究原发性高血压患者血压昼夜节律异常是否与靶器官损害存在关联。方法:将2015年2~11月份在我院治疗的94例原发性高血压病人按照血压昼夜节律是否正常分为节律正常组52例和异常组42例。比较两组患者的24h、白天、夜间的收缩压(SBP)与舒张压(DBP)及血压负荷,并且比较两组患者心脏、脑、肾损伤相关指标。结果:异常组全天24h、白天、夜间SBP及DBP,血压负荷均高于正常组,差异具有统计学意义(P0.05)。异常组患者左室重量(LVM)和左室重量指数(LVMI)、发生心肌缺血次数及持续时间、发生脑梗死几率均明显高于正常组,差异有统计学意义(P0.05)。异常组尿微量白蛋白(MAU)、尿酸(UA)水平均高于正常组,差异有统计学意义(P0.05)。结论:原发性高血压患者出现昼夜节律异常,可能对相关靶器官造成损伤。     

Engineering and governmental challenge: 7-day/24-hour chronobiologic blood pressure and heart rate screening: Part I

This review provides evidence that the bioengineering community needs to develop cost-effective, fully unobtrusive, truly ambulatory instrumentation for the surveillance of blood pressure and heart rate. With available instrumentation, we document a disease risk syndrome, circadian blood pressure overswinging (CHAT, short for circadian hyper-amplitude-tension). Circadian hyper-amplitude-tension is defined as a week-long overall increase in the circadian amplitude or otherwise-measured circadian variability of blood pressure above a mapped threshold, corresponding to the upper 95% prediction limit of clinically healthy peers of the corresponding gender and age. A consistently reduced heart rate variability, gauged by a circadian standard deviation below the lower 5% prediction limit of peers of the corresponding gender and age, is an index of a separate yet additive major risk, a deficient heart rate variability (DHRV). The circadian amplitude, a measure of the extent of reproducible variability within a day, is obtained by linear curve-fitting, which yields added parameters: a midline-estimating statistic of rhythm, the MESOR (a time structure or chronome-adjusted mean), the circadian acrophase, a measure of timing of overall high values recurring in each cycle, and the amplitudes and acrophases of the 12-hour (and higher order) harmonic(s) of the circadian variation that, with the characteristics of the fundamental 24-hour component, describe the circadian waveform. The MESOR is a more precise and more accurate estimate of location than the arithmetic mean. The major risks associated with CHAT and/or DHRV have been documented by measurements of blood pressure and heart rate at 1-hour or shorter intervals for 48 hours on populations of several hundred people, but these risks are to be assessed in a 7-day/24-hour record in individuals before a physical examination, for the following reasons. (1) The average derived from an around-the-clock series of blood pressure measurements, computed as its MESOR, the proven etiopathogenetic factor of catastrophic vascular disease, can be above chronobiologic as well as World Health Organization limits for 5 days or longer and can be satisfactory for months thereafter, as validated by continued automatic monitoring. The MESOR can be interpreted in light of clock-hour-, gender-, and age-specified reference limits and thus can be more reliably estimated with a systematic account of major sources of variability than by casual time-unspecified spot checks (that conventionally are interpreted by a fixed and, thus, rhythm, gender-, and age-ignoring limit). With spot checks, in a diagnostically critical range of "borderline" blood pressures, an inference can depend on the clock-hour of the measurement, usually providing a diagnosis of normotension in the morning and of hypertension in the afternoon (for the same diurnally active, nocturnally resting patient!). Long-term treatment must not be based upon the possibility of an afternoon vs a morning appointment. Moreover, the conventional approach will necessarily miss cases of CHAT that are not accompanied by MESOR hypertension. (2) Circadian hyper-amplitude-tension indicates a greater risk for stroke than does an increase in the around-the-clock average blood pressure (above 130/80 mm Hg) or old age, whereas (3) CHAT can be asymptomatic, as can MESOR hyptertension. (4) Deficient heart rate variability, the fall below a threshold of the circadian standard deviation of heart rate, an entity in its own right, is also a chronome alteration of heart rate variability (CAHRV). Deficient heart rate variability can be present together with CHAT, doubling the relative risk of morbid events. In each case--either combined with CHAT or as an isolated CAHRV--a DHRV constitutes an independent diagnostic assessment provided as a dividend by current blood pressure monitors that should be kept in future instrumentation designs. CHAT and DHRV can be screened by systematic focus on variability, preferably by the use of automatic instrumentation and analyses, which are both available (affordably) for research in actual practice, in conjunction with the Halberg Chronobiology Center at the University of Minnesota.     

White Matter Hyperintensities in Parkinson’s Disease: Do They Explain the Disparity between the Postural Instability Gait Difficulty and Tremor Dominant Subtypes?

Background

Brain white matter hyperintensities (WMHs) commonly observed on brain imaging of older adults are associated with balance and gait impairment and have also been linked to cognitive deficits. Parkinson’s disease (PD) is traditionally sub-classified into the postural instability gait difficulty (PIGD) sub-type, and the tremor dominant (TD) sub-type. Considering the known association between WMHs and axial symptoms like gait disturbances and postural instability, one can hypothesize that WMHs might contribute to the disparate clinical sub-types of patients with PD.

Methods

110 patients with PD underwent a clinical evaluation and a 3T MRI exam. Based on the Unified Parkinson Disease Rating Scale, the patients were classified into motor sub-types, i.e., TD or PIGD, and scores reflecting PIGD and TD symptoms were computed. We compared white matter burden using three previously validated methods: one using a semi-quantitative visual rating scale in specific brain regions and two automated methods.

Results

Overall, MRI data were obtained in 104 patients. The mean WMHs scores and the percent of subjects with lesions in specific brain regions were similar in the two subtypes, p = 0.678. The PIGD and the TD scores did not differ even when comparing patients with a relatively high burden of WMHs to patients with a relatively low burden. Across most of the brain regions, mild to moderate correlations between WMHs and age were found (r = 0.23 to 0.41; p<0.021). Conversely, no significant correlations were found between WMHs and the PIGD score or disease duration. In addition, depressive symptoms and cerebro-vascular risk factors were similar among the two subtypes.

Conclusions

In contrast to what has been reported previously among older adults, the present study could not demonstrate any association between WMHs and the PIGD or TD motor sub-types in patients with PD.     

Development of Inverse Circadian Blood Pressure Pattern in Transgenic Hypertensive Tgr(mREN2)27 Rats

TGR(mREN2)27 (TGR) rats are transgenic animals with an additional mouse renin gene, which leads to overactivity of the renin-angiotensin system. Adult TGR rats are characterized by fulminant hypertension, hypertensive end-organ damage, and an inverse circadian blood pressure pattern. To study the ontogenetic development of cardiovascular circadian rhythms, telemetric blood pressure transmitters were implanted in male Sprague-Dawley (SPRD, n = 5) and heterozygous, transgenic TGR rats before 5 weeks of age. The TGR received either drinking water or enalapril 10 mg/L in drinking water (n = 5 per group). Drug intake was measured throughout the study by computerized monitoring of drinking volume. Circadian patterns in blood pressure and heart rate were analyzed from 5 to 11 weeks of age. In the first week after transmitter implantation, blood pressure did not differ among SPRD, untreated, and enalapril-treated TGR rats. In parallel with the rise in blood pressure of untreated TGR rats, a continuous delay of the circadian acrophase (time of fitted blood pressure maximum) was observed, leading to a complete reversal of the rhythm in blood pressure at an age of 8 weeks. Enalapril reduced blood pressure at night, but was less effective during the day, presumably due to the drinking pattern of the animals, which ingested about 90% of their daily water intake during the nocturnal activity period. After discontinuation of treatment, blood pressure returned almost immediately to values found in untreated TGR rats. In conclusion, the inverse circadian blood pressure profile in TGR rats develops in parallel with the increase in blood pressure. Direct effects of the brain renin-angiotensin system may be involved in the disturbed circadian rhythmicity in TGR(mREN2)27 rats.     

Blunting of circadian rhythms and increased acrophase variability in sleep-time hypertensive subjects

24 h and ultradian rhythms of blood pressure (BP) have been previously shown to be disorganized in nocturnal hypertensive subjects. The present study was undertaken to further analyze the ultradian and circadian BP rhythm structure in sleep-time hypertensive subjects with normal or elevated awake-time BP levels. Fourier analysis was used to fit 24, 12, 8, and 6 h curves to mean BP as well as heart rate (HR) time series data derived from 24 h ambulatory blood pressure monitoring. Awake and sleep periods were defined according to individual sleep diaries. Awake-time hypertension was defined as diurnal systolic (SBP) and/or diastolic BP (DBP) means ≥135/85 mmHg. Sleep-time hypertension was defined as nocturnal SBP and/or DBP means ≥120/70 mmHg. The sample included 240 awake-time normotensive subjects (180 sleep-time normotensives and 60 sleep-time hypertensives) and 138 untreated awake-time hypertensive subjects (31 sleep-time normotensives and 107 sleep-time hypertensives). The amplitude and integrity (i.e., percent rhythm) of the 24 and 12 h BP rhythms were lower in the sleep-time hypertensive subjects and higher in the awake-time hypertensive subjects. However, no differences were detected when the integrity and amplitude of the 6 and 8 h mean BP rhythms were analyzed. The sleep-time hypertensive group showed significantly higher 24 h BP rhythm acrophase variability. No differences could be found in any of the HR rhythm parameters. Altogether, the findings suggest a disorganization of the BP circadian rhythm in sleep-time hypertensives that results in reduced 24 h rhythm amplitude and integrity that could be related to cardiovascular risk.     

24-hour profiles of blood pressure and heart rate in Cushing's syndrome: relationship between cortisol and cardiovascular rhythmicities

We monitored the circadian profiles of cortisol, systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) in 33 matched normotensive subjects, 32 patients with essential hypertension and 16 patients with Cushing's Syndrome (8 pituitary adenomas, 6 adrenal adenomas and 2 adrenal carcinomas). Each subject underwent serial blood drawings at 4-hr intervals along the 24-hr cycle. BP and HR were automatically recorded every 30 min. Data were analyzed by conventional statistics and by chronobiological procedures (cosinor rhythmometry). Both the control subjects and essential hypertensives showed a circadian profile of BP and HR characterized by a peak in the early afternoon and a clear nocturnal fall (rhythm detection: P less than 0.001). The rhythmicity of BP was disrupted in patients affected by Cushing's Syndrome, whereas the 24-hr oscillation of HR was preserved (P less than 0.001). Our data are compatible with the view that glucocorticoids are involved in the control of BP circadian rhythm, whereas HR is not under their control.     

Chronophysiology of the cardiovascular system

The development of ambulatory blood pressure monitoring devices and the beat-by-beat measurement of heart rate have enabled it to be established that there are circadian rhythms in heart rate and blood pressure in subjects living normally. Investigations of these variables have led to quantification of their fall at night, and rapid rise on awakening and becoming active in the morning. These changes are of particular interest insofar as abnormalities in them are associated with cardiovascular problems and morbidity in patients and also act as risk factors in otherwise healthy individuals. It has also been shown that there are many other variables of the cardiovascular system. The causes of the circadian rhythms in heart rate and blood pressure are outlined, with particular stress upon the role of the autonomic nervous system, as assessed from low- and high-frequency components of the variation in heart rate measured beat-by-beat. Activity increases blood pressure, but there is evidence that this “reactivity” varies with time of day, and this also might be related to cardiovascular morbidity. Based upon data from several sources, including night work, resting subjects and bed-ridden patients, it is concluded that the contribution of the “body clock” to producing the circadian rhythm in heart rate and blood pressure is relatively small. A bias towards an exogenous cause applies also to most other circadian rhythms in the cardiovascular system. Knowledge of circadian rhythmicity in cardiovascular system, together with an understanding of its causes, provides a rationale for advice to reduce cardiovascular risk and to assess the efficacy of therapies.     

Coronary Heart Disease and Cortical Thickness,Gray Matter and White Matter Lesion Volumes on MRI

Coronary heart disease (CHD) has been linked with cognitive decline and dementia in several studies. CHD is strongly associated with blood pressure, but it is not clear how blood pressure levels or changes in blood pressure over time affect the relation between CHD and dementia-related pathology. The aim of this study was to investigate relations between CHD and cortical thickness, gray matter volume and white matter lesion (WML) volume on MRI, considering CHD duration and blood pressure levels from midlife to three decades later. The study population included 69 elderly at risk of dementia who participated in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study. CAIDE participants were examined in midlife, re-examined 21 years later, and then after additionally 7 years (in total up to 30 years follow-up). MRIs from the second re-examination were used to calculate cortical thickness, gray matter and WML volume. CHD diagnoses were obtained from the Finnish Hospital Discharge Register. Linear regression analyses were adjusted for age, sex, follow-up time and scanner type, and additionally total intracranial volume in GM volume analyses. Adding diabetes, cholesterol or smoking to the models did not influence the results. CHD was associated with lower thickness in multiple regions, and lower total gray matter volume, particularly in people with longer disease duration (>10 years). Associations between CHD, cortical thickness and gray matter volume were strongest in people with CHD and hypertension in midlife, and those with CHD and declining blood pressure after midlife. No association was found between CHD and WML volumes. Based on these results, long-term CHD seems to have detrimental effects on brain gray matter tissue, and these effects are influenced by blood pressure levels and their changes over time.     

Nocturnal blood pressure in normotensive subjects and those with white coat,primary, and secondary hypertension.

OBJECTIVE--To compare the mean nocturnal blood pressure of patients with various forms of renal and endocrine hypertension with that in patients with primary and white coat hypertension, and normal blood pressure. DESIGN--Ambulatory monitoring of blood pressure over 24 hours in a prospective study. SETTING--Two German centres for outpatients with hypertension and kidney diseases. SUBJECTS--176 normotensive subjects, 490 patients with primary hypertension including mild and severe forms, 42 with white coat hypertension, 208 patients with renal and renovascular hypertension, 43 with hypertension and endocrine disorders, and three with coarctation of the aorta. MAIN OUTCOME MEASURES--Fall in nocturnal blood pressure. RESULTS--Blood pressure in normotensive subjects fell by a mean of 14 mm Hg (11%) systolic and 13 mm Hg (17%) diastolic overnight (2200 to 0600). The falls in patients with primary and white coat hypertension were not significantly different. In all patients with renal and renovascular hypertension, however, the fall was significantly reduced (range of fall from 3/3 mm Hg to 7/9 mm Hg). In patients with hypertension and endocrine disorders the pattern of night time blood pressure was not uniform: patients with hyperthyroidism, primary hyperaldosteronism, and Cushing''s syndrome had significantly smaller reductions in blood pressure (6/8, 4/7, 3/6 mm Hg, respectively). In patients with phaeochromocytoma the mean night time blood pressure increased by 4/2 mm Hg. In patients with hypertension, primary hyperparathyroidism, and unoperated coarctation of the aorta the falls in blood pressure were normal. CONCLUSIONS--In normotensive subjects and those with primary hypertension there is usually a reduction in blood pressure at night. In all renal forms of secondary hypertension and in most endocrine forms the reduction in blood pressure is only a third to a half of normal. Patients with primary hyperparathyroidism and unoperated coarctation of the aorta show a normal reduction.