Nocturnal Headache-Hypertension Syndrome: A Chronobiologic Disorder

The study of blood pressure (BP) monitoring in essential hypertensive patients recurrently suffering from nocturnal headache revealed a rhythmic elevation of sphygmomanometric values during the night. Such a finding was not detected in essential hypertensive patients suffering from occasional headache. The nocturnal elevation of BP was seen to be paralleled by the circadian peak of heart rate, suggesting that the disorder is a systemic phenomenon. Importantly, the headache episodes were seen to disappear after antihypertensive therapy that was adjusted to lower the nocturnal increase of BP. The therapeutic results suggested that the nocturnal headache was dependent on the phasic elevation of BP. The beneficial effects further suggested that the nocturnal headache and the nocturnal elevation of BP may represent a particular syndrome with a cause-effect relationship. The term “nocturnal headache-hypertension syndrome” is proposed.     

Lack of nocturnal blood pressure fall in elderly bedridden hypertensive patients with cerebrovascular disease

To prevent recurrence of cerebrovascular disease (CVD), adequate control of blood pressure (BP) is extremely important for the treatment of hypertensive CVD patients. As absence of the nocturnal fall of BP by the expected 10-20% from daytime levels is reported to exaggerate target organ injury, 24-h ambulatory blood pressure monitoring (ABPM) was conducted, especially to obtain data during nighttime sleep. Forty-eight elderly bedridden chronic phase CVD hypertensive patients (assessed 1-3 mo after CVD accident) participated. As a group, nocturnal BP was higher than diurnal BP, whereas nocturnal pulse rate was lower than diurnal pulse rate. The nocturnal BP fall was blunted in most (～90%) of the patients. These results suggest that to perform a rational drug treatment, it is essential to do 24-h ABPM before initiation of antihypertensive therapy in elderly bedridden hypertensive CVD patients.     

Lack of Nocturnal Blood Pressure Fall in Elderly Bedridden Hypertensive Patients With Cerebrovascular Disease

To prevent recurrence of cerebrovascular disease (CVD), adequate control of blood pressure (BP) is extremely important for the treatment of hypertensive CVD patients. As absence of the nocturnal fall of BP by the expected 10–20% from daytime levels is reported to exaggerate target organ injury, 24-h ambulatory blood pressure monitoring (ABPM) was conducted, especially to obtain data during nighttime sleep. Forty-eight elderly bedridden chronic phase CVD hypertensive patients (assessed 1–3 mo after CVD accident) participated. As a group, nocturnal BP was higher than diurnal BP, whereas nocturnal pulse rate was lower than diurnal pulse rate. The nocturnal BP fall was blunted in most (～90%) of the patients. These results suggest that to perform a rational drug treatment, it is essential to do 24-h ABPM before initiation of antihypertensive therapy in elderly bedridden hypertensive CVD patients. (Author correspondence: akiofuji@jichi.ac.jp)     

Nocturnal Blood Pressure Pattern Affects Left Ventricular Remodeling and Late Gadolinium Enhancement in Patients with Hypertension and Left Ventricular Hypertrophy

Background

Left ventricular hypertrophy (LVH) is an independent predictor of cardiac mortality, regardless of its etiology. Previous studies have shown that high nocturnal blood pressure (BP) affects LV geometry in hypertensive patients. It has been suggested that continuous pressure overload affects the development of LVH, but it is unknown whether persistent pressure influences myocardial fibrosis or whether the etiology of LVH is associated with myocardial fibrosis. Comprehensive cardiac magnetic resonance (CMR) including the late gadolinium enhancement (LGE) technique can evaluate both the severity of changes in LV geometry and myocardial fibrosis. We tested the hypothesis that the nocturnal non-dipper BP pattern causes LV remodeling and fibrosis in patients with hypertension and LVH.

Methods

Forty-seven hypertensive patients with LVH evaluated by echocardiography (29 men, age 73.0±10.4 years) were examined by comprehensive CMR and 24-h ambulatory blood pressure monitoring (ABPM).

Results and Conclusions

Among the 47 patients, twenty-four had nocturnal non-dipper BP patterns. Patients with nocturnal non-dipper BP patterns had larger LV masses and scar volumes independent of etiologies than those in patients with dipper BP patterns (p = 0.035 and p = 0.015, respectively). There was no significant difference in mean 24-h systolic BP between patients with and without nocturnal dipper BP patterns (p = 0.367). Among hypertensive patients with LVH, the nocturnal non-dipper blood pressure pattern is associated with both LV remodeling and myocardial fibrosis independent of LVH etiology.     

Administration time-dependent effects of valsartan on ambulatory blood pressure in elderly hypertensive subjects

Previous results have indicated that valsartan administration at bed-time, as opposed to upon wakening, improves the diurnal/nocturnal ratio of blood pressure (BP) toward a normal dipping pattern, without loss of 24 h efficacy. This ratio is characterized by a progressive decrease with aging. Accordingly, we investigated the administration time-dependent antihypertensive efficacy of valsartan, an angiotensin blocking agent, in elderly hypertensive patients. We studied 100 elderly patients with grade 1-2 essential hypertension (34 men and 66 women), 68.2+/-4.9 years of age, randomly assigned to receive valsartan (160 mg/d) as a monotherapy either upon awakening or at bed-time. BP was measured for 48 h by ambulatory monitoring, at 20 min intervals between 07:00 to 23:00 h and at 30 min intervals at night, before and after 3 months of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately determine the duration of sleep and wake spans to enable the accurate calculation of the diurnal and nocturnal means of BP for each subject. There was a highly significant BP reduction after 3 months of valsartan treatment (p < 0.001). The reduction was slightly larger with bed-time dosing (15.3 and 9.2 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively) than with morning dosing (12.3 and 6.3 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively). The diurnal/nocturnal ratio, measured as the nocturnal decline of BP relative to the diurnal mean, was unchanged in the group ingesting valsartan upon awakening (-1.0 and -0.3 for systolic and diastolic BP; p > 0.195). This ratio was significantly increased (6.6 and 5.4 for systolic and diastolic BP; p < 0.001) when valsartan was ingested at bed-time. The reduction of the nocturnal mean was doubled in the group ingesting valsartan at bed-time, as compared to the group ingesting it in the morning (p < 0.001). In elderly hypertensive patients, mainly characterized by a diminished nocturnal decline in BP, bed-time valsartan dosing is better than morning dosing since it improves efficacy during the nighttime sleep span, with the potential reduction in cardiovascular risk that has been associated with a normalized diurnal/nocturnal BP ratio.     

Non-dipper treated hypertensive patients do not have increased cardiac structural alterations

Background

Non-dipping pattern in hypertensive patients has been shown to be associated with an excess of target organ damage and with an adverse outcome. The aim of our study was to assess whether a reduced nocturnal fall in blood pressure (BP), established on the basis of a single 24-h BP monitoring, in treated essential hypertensives is related to more prominent cardiac alterations.

Methods

We enrrolled 229 treated hypertensive patients attending the out-patient clinic of our hypertension centre; each patient was subjected to the following procedures : 1) clinic BP measurement; 2) blood and urine sampling for routine blood chemistry and urine examination; 3) standard 12-lead electrocardiogram; 4) echocardiography; 5) ambulatory BP monitoring (ABPM). For the purpose of this study ABPM was carried-out in three subgroups with different clinic BP profile : 1) patients with satisfactory BP control (BP < 140/90 mmHg; group I, n = 58); 2) patients with uncontrolled clinic BP (clinic BP values ≥ 140 and/or 90 mmHg) but lower self-measured BP (< 20 mmHg for systolic BP and/or 10 mmHg for diastolic BP; group II, n = 72); 3) patients with refractory hypertension, selected according to WHO/ISH guidelines definition (group III, n = 99). Left ventricular hypertrophy (LVH) was defined by two gender-specific criteria (LV mass index ≥125/m² in men and 110 g/m² in women, ≥51/gm^2.7 in men and 47/g/m^2.7 in women).

Results

Of the 229 study participants 119 (51.9%) showed a fall in SBP/DBP < 10% during the night (non-dippers). The prevalence of non-dippers was significantly lower in group I (44.8%) and II (41.6%) than in group III (63.9%, p < 0.01 III vs II and I). The prevalence of LVH varied from 10.3 to 24.1% in group I, 31.9 to 43.1% in group II and from 60.6 to 67.7% in group III (p < 0.01, III vs II and I). No differences in cardiac structure, analysed as continuous variable as well as prevalence of LVH, were found in relationship to dipping or non-dipping status in the three groups.

Conclusions

In treated essential hypertensives with or without BP control the extent of nocturnal BP decrease is not associated with an increase in LV mass or LVH prevalence; therefore, the non-dipping profile, diagnosed on the basis of a single ABPM, does not identify hypertensive patients with greater cardiac damage.     

Genes influencing circadian differences in blood pressure in hypertensive mice

Essential hypertension is a common multifactorial heritable condition in which increased sympathetic outflow from the central nervous system is involved in the elevation in blood pressure (BP), as well as the exaggerated morning surge in BP that is a risk factor for myocardial infarction and stroke in hypertensive patients. The Schlager BPH/2J mouse is a genetic model of hypertension in which increased sympathetic outflow from the hypothalamus has an important etiological role in the elevation of BP. Schlager hypertensive mice exhibit a large variation in BP between the active and inactive periods of the day, and also show a morning surge in BP. To investigate the genes responsible for the circadian variation in BP in hypertension, hypothalamic tissue was collected from BPH/2J and normotensive BPN/3J mice at the ‘peak’ (n = 12) and ‘trough’ (n = 6) of diurnal BP. Using Affymetrix GeneChip® Mouse Gene 1.0 ST Arrays, validation by quantitative real-time PCR and a statistical method that adjusted for clock genes, we identified 212 hypothalamic genes whose expression differed between ‘peak’ and ‘trough’ BP in the hypertensive strain. These included genes with known roles in BP regulation, such as vasopressin, oxytocin and thyrotropin releasing hormone, as well as genes not recognized previously as regulators of BP, including chemokine (C-C motif) ligand 19, hypocretin and zinc finger and BTB domain containing 16. Gene ontology analysis showed an enrichment of terms for inflammatory response, mitochondrial proton-transporting ATP synthase complex, structural constituent of ribosome, amongst others. In conclusion, we have identified genes whose expression differs between the peak and trough of 24-hour circadian BP in BPH/2J mice, pointing to mechanisms responsible for diurnal variation in BP. The findings may assist in the elucidation of the mechanism for the morning surge in BP in essential hypertension.     

Administration Time‐Dependent Effects of Valsartan on Ambulatory Blood Pressure in Elderly Hypertensive Subjects

Previous results have indicated that valsartan administration at bed‐time, as opposed to upon wakening, improves the diurnal/nocturnal ratio of blood pressure (BP) toward a normal dipping pattern, without loss of 24 h efficacy. This ratio is characterized by a progressive decrease with aging. Accordingly, we investigated the administration time‐dependent antihypertensive efficacy of valsartan, an angiotensin blocking agent, in elderly hypertensive patients. We studied 100 elderly patients with grade 1–2 essential hypertension (34 men and 66 women), 68.2±4.9 years of age, randomly assigned to receive valsartan (160 mg/d) as a monotherapy either upon awakening or at bed‐time. BP was measured for 48 h by ambulatory monitoring, at 20 min intervals between 07∶00 to 23∶00 h and at 30 min intervals at night, before and after 3 months of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately determine the duration of sleep and wake spans to enable the accurate calculation of the diurnal and nocturnal means of BP for each subject. There was a highly significant BP reduction after 3 months of valsartan treatment (p<0.001). The reduction was slightly larger with bed‐time dosing (15.3 and 9.2 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively) than with morning dosing (12.3 and 6.3 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively). The diurnal/nocturnal ratio, measured as the nocturnal decline of BP relative to the diurnal mean, was unchanged in the group ingesting valsartan upon awakening (?1.0 and ?0.3 for systolic and diastolic BP; p>0.195). This ratio was significantly increased (6.6 and 5.4 for systolic and diastolic BP; p<0.001) when valsartan was ingested at bed‐time. The reduction of the nocturnal mean was doubled in the group ingesting valsartan at bed‐time, as compared to the group ingesting it in the morning (p<0.001). In elderly hypertensive patients, mainly characterized by a diminished nocturnal decline in BP, bed‐time valsartan dosing is better than morning dosing since it improves efficacy during the nighttime sleep span, with the potential reduction in cardiovascular risk that has been associated with a normalized diurnal/nocturnal BP ratio.     

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.     

Cardiovascular-Sleep Interaction in Drug-Naïve Patients With Essential Grade I Hypertension

Lack of nighttime blood pressure (BP) reduction by 10–20% from the mean daytime values (dipping) has been described as a distinguishing feature of essential hypertension and associated, also in normotensive subjects, with increased cardiovascular (CV) risk. Mechanisms involved in the loss of the nocturnal dip are still unclear, but involvement of autonomic nervous system (ANS) activity probably plays a crucial role. Sleep is fundamental in modulating ANS activity to maintain the physiological BP circadian rhythm, and for this reason its integrity has been widely investigated in hypertension. We investigated, under controlled conditions, the autonomic control of the CV system through an autonomic reflex screen in the awake condition and by assessment of circadian rhythm–, day-night-, time-, and state-dependent changes of BP and heart rate (HR) and associated sleep parameters in patients with a recent (≤1 yr) diagnosis of essential grade I hypertension naïve of therapy. Fourteen hypertensive patients (6 males, age: 43?±?11 yrs; body mass index [BMI]: 24?±?3?kg/m²) were compared with 28 healthy controls matched for sex, age, BMI (2 controls/patient) for cardiovascular reflex and to 8 different subjects from previous controls (6 males), comparable for age and BMI, for the day-night and nighttime CV profiles during two consecutive nights. The cardiovascular reflex screen data showed increased sympathetic effect in hypertensive patients, represented by higher overshoot of BP after Valsalva maneuver. Nighttime sleep architecture during the dark period in terms of duration, representation of sleep stages, sleep fragmentation, and incidence of arousals—periodic limb movements in sleep (PLMS) and PLMS arousals—was similar in patients and controls. Hypertensive patients displayed higher 24-h BP and HR values, but their sleep-related BP decrease was significantly reduced compared with controls. The circadian rhythms of BP and HR were intact and similar in patients and controls, coupling with the expected physiological peak time. BP and HR showed normal state-dependent modulation in hypertensive patients that, however, was higher in all sleep stages compared with controls. The lowering of systolic blood pressure (SBP) during non–rapid eye movement (NREM) sleep stages 1 and 2 and REM sleep, relative to daytime wake values, was significantly attenuated in the hypertensive group, whereas it was comparable to controls during slow-wave sleep. In hypertensive patients, analysis of sleep and CV parameters in the 90?min following sleep onset and preceding morning awakening showed normal depressor effect during the first part of the night after sleep onset and significantly higher BP rise in the hours preceding morning awakening. These findings were associated with comparable sleep architecture, sleep fragmentation, incidence of arousals, and PLMS and PLMS arousals in patients and controls. Our data suggest that drug-naïve essential grade I hypertension is associated with signs of increased vascular sympathetic response to standardized stress of the Valsalva maneuver during the awake condition, and during sleep with a non-dipping BP profile plus higher BP surge preceding morning awakening, assessable only by around-the-clock ambulatory BP monitoring, both representing additional CV risk already in early-stage hypertension and, therefore, requiring proper selection of pharmacological treatment. (Author correspondence: pietro.cortelli@unibo.it)     

Systemic hypertension, headache, and ocular hemodynamics: a new hypothesis

The association between systemic hypertension and headache remains controversial and its pathophysiologic basis is uncertain. A rather characteristic early-morning pulsating headache is commonly seen in hypertensive patients, and a recent meta-analysis supports the link between these 2 entities. Epidemiologic evidence has paradoxically suggested a negative association between hypertension and headache. Unpredictable clinical association between severe hypertension and headache indicates that another cranial perfusion-related variable exerts a critical role. Neuroanatomically, head and neck pain primarily involves the ophthalmic division of the trigeminal nerve (V1). A link between systemic hypertension, pulsatile choroidal blood flow (CBF), and intraocular pressure (IOP) has been established. I propose that a trait ocular sympathetic hypofunction permits rapid episodic ocular choroidal overperfusion that stretches the ocular globe in the cohort of hypertensive patients with headache. Rapid distension of the pain-sensitive corneoscleral envelope can stimulate corneoscleral and iridial pain-sensitive V1 nerve endings and generate headache. Ocular tamponade function physiologically limits choroidal overperfusion. A higher basal IOP in some patients with moderate-to-severe hypertension may dampen pulsatile CBF and account for the negative epidemiologic link between sustained systemic hypertension and headache. Besides activation of the baroreceptor reflex, the association of hypalgesia with hypertension probably involves activation of the vasopressin-endorphin adaptive system consequent to mechanical stimulation of V1. The analogy between hypertensive headache and angle-closure glaucoma is rather limited because typical ocular and visual signs and symptoms of angle-closure glaucoma are not seen in hypertension-related headache. Hypertensive crises, including those associated with pheochromocytoma, are not accompanied by attacks of angle-closure glaucoma. Glaucoma is not associated with ocular choroidal congestion, but with reduced pulsatile CBF. The predisposition to develop angle-closure glaucoma is theoretically not associated with ocular autonomic hypofunction and should be conceptually dissociated from this hypothesis. The hypothesis can be evaluated by establishing significant circadian elevations of blood pressure, including nondipping nighttime pattern as well as circadian and periheadache measurements of IOP in patients with attacks of hypertension-related headache.     

Clonidine reduces elevated cerebrospinal fluid catecholamine levels in patients with essential hypertension

Cerebrospinal fluid (CSF) catecholamines were measured in normotensive patients and in patients with mild to moderate essential hypertension. CSF-norepinephrine (NE) concentrations were 50% lower in the normotensive individuals (127 ± 28 vs. 240 ± 23 pg/m1) (P<0.01). In hypertensive patients, CSF-NE was inversely related to age (r =-0.68; P<0.01) and directly related to plasma NE (r = 0.61; P<0.05). Clonidine (450 mcg/day for 2 weeks) significantly reduced CSF-NE (?40%) in hypertensive patients. In addition, it decreased blood pressure, plasma and urinary NE. Urinary VMA was not affected by clonidine. No correlation was observed between clonidine effects on BP and on plasma or CSF catecholamines. This study indicates that patients with essential hypertension have elevated levels of CSF-NE which are reduced after treatment with clonidine. The elevation of CSF-NE suggests that central (spinal?) noradrenergic activity may be increased in patients with mild to moderate essential hypertension, and that can be reduced by treatment with clonidine.     

Daytime blood pressure elevation after nocturnal hypoxia.

The purpose of this study was to investigate whether nocturnal hypoxia causes daytime blood pressure (BP) elevation. We hypothesized that overnight exposure to hypoxia leads the next morning to elevation in BP that outlasts the hypoxia stimulus. We studied the effect on BP of two consecutive night exposures to hypobaric hypoxia in 10 healthy normotensive subjects. During the hypoxia nights, subjects slept for 8 h in a hypobaric chamber at a simulated altitude of 4,000 m (barometric pressure = 462 mmHg). Arterial O(2) saturation and electrocardiogram were monitored throughout the night. For 30 min before the nocturnal simulated ascent and for 4 h after return to baseline altitude the next morning, BP was measured every 5 min while the subject was awake. The same measurements were made before and after 2 normoxic nights of sleep in the hypobaric chamber at ambient barometric pressure (745 mmHg). Principal components analysis was applied to evaluate patterns of BP response after the second night of hypoxia and normoxia. A distinct pattern of diastolic BP (DBP) elevation was observed after the hypoxia night in 9 of the 10 subjects but in none after the normoxia night. This pattern showed a mean increase of 4 mmHg in DBP compared with the presleep-awake baseline in the first 60 min and a return to baseline by 90 min. We conclude that nocturnal hypoxia leads to a carryover elevation of daytime DBP.     

Metabolic cycles are linked to the cardiovascular diurnal rhythm in rats with essential hypertension

Background

The loss of diurnal rhythm in blood pressure (BP) is an important predictor of end-organ damage in hypertensive and diabetic patients. Recent evidence has suggested that two major physiological circadian rhythms, the metabolic and cardiovascular rhythms, are subject to regulation by overlapping molecular pathways, indicating that dysregulation of metabolic cycles could desynchronize the normal diurnal rhythm of BP with the daily light/dark cycle. However, little is known about the impact of changes in metabolic cycles on BP diurnal rhythm.

Methodology/Principal Findings

To test the hypothesis that feeding-fasting cycles could affect the diurnal pattern of BP, we used spontaneously hypertensive rats (SHR) which develop essential hypertension with disrupted diurnal BP rhythms and examined whether abnormal BP rhythms in SHR were caused by alteration in the daily feeding rhythm. We found that SHR exhibit attenuated feeding rhythm which accompanies disrupted rhythms in metabolic gene expression not only in metabolic tissues but also in cardiovascular tissues. More importantly, the correction of abnormal feeding rhythms in SHR restored the daily BP rhythm and was accompanied by changes in the timing of expression of key circadian and metabolic genes in cardiovascular tissues.

Conclusions/Significance

These results indicate that the metabolic cycle is an important determinant of the cardiovascular diurnal rhythm and that disrupted BP rhythms in hypertensive patients can be normalized by manipulating feeding cycles.     

Comparison of the Effects on Ambulatory Blood Pressure of Awakening versus Bedtime Administration of Torasemide in Essential Hypertension

Torasemide is a high‐ceiling loop diuretic frequently used in the treatment of congestive heart failure, renal failure, and hypertension. Low doses of torasemide (2.5 to 5 mg/day) do not elevate 24 h natriuresis, and they constitute effective monotherapy for mild‐to‐moderate uncomplicated essential hypertension according to results based on clinic blood pressure (BP). However, there has yet to be a proper evaluation of its 24 h efficacy or potential dependency of effects according to the circadian time of treatment. Accordingly, this trial investigated the administration time‐dependent efficacy of torasemide in uncomplicated essential hypertensive patients. We studied a total of 113 grade 1 and 2 hypertensive patients, 51.7±10.6 yrs of age, randomly assigned to receive torasemide (5 mg/day) as a monotherapy either upon awakening or at bedtime. BP was measured by ambulatory monitoring for 48 consecutive hours before and after six weeks of treatment. The efficacy of torasemide was significantly greater with bedtime dosing (i.e., 14.8 and 9.5 mmHg reduction in the 24 h mean systolic and diastolic BP, respectively) as compared with morning dosing upon awakening (i.e., 6.4 and 3.4 mmHg reduction in mean systolic and diastolic BP; p<0.001 between the two treatment‐time groups). The percentage of patients with controlled ambulatory BP after treatment was also higher after bedtime treatment (64 vs. 23%; p<0.001). Safety and tolerability were comparable between the two treatment‐time groups. A dose of 5 mg/day torasemide is more effective for BP reduction for uncomplicated essential hypertensive patients when ingested at bedtime than in the morning upon arising. The difference in antihypertensive efficacy as a function of the circadian dosing‐time of torasemide here documented should be taken into account when prescribing this loop diuretic to treat essential hypertensive patients.     

Factors associated with severity of daytime sleepiness and indications for initiating treatment in patients with periodic limb movements during sleep

Obstructive sleep apnea syndrome (OSAS) is closely associated with hypertension. Activity of angiotensin II (Ang II) and non-dipping nocturnal blood pressure (BP) variability are implicated in hypertension-related target organ damage. We examined the correlation between OSAS with serum Ang II levels and evaluated the risk of non-dipping BP variability in 180 patients with essential hypertension (EHT). Eligible patients were divided into three subgroups based on their apnea-hypopnea index (AHI) evaluated by polysomnography. EHT alone, EHT with mild OSAS, and EHT with moderate/severe OSAS. Ambulatory BP monitoring was used to calculate mean BP over 24 h, as well as diurnal and nocturnal BP variability. Serum Ang II was determined with enzyme-linked immun-osorbent assay. EHT patients with OSAS had significantly higher systolic BP calculated either over 24 h, or by diurnal or nocturnal monitoring (P < 0.05). More EHT patients with OSAS showed non-dipping BP profiles than did EHT patients alone (P < 0.05). The number of patients with non-dipping BP increased with increasing OSAS severity. Surgical treatment alleviated OSAS and reduced AHI (P < 0.05). Preoperative serum Ang II in EHT patients with OSAS was significantly higher than that in those without OSAS (P < 0.05), and showed a rising trend with OSAS severity (P < 0.05). Postoperative serum Ang II, BP and the incidence of non-dipping BP were reduced by surgery to levels lower than preoperative values in patients with OSAS. We therefore conclude that OSAS leads to increased serum Ang II and increased risk of non-dipping BP in patients with EHT.

     

Administration‐Time‐Dependent Effects of Olmesartan on the Ambulatory Blood Pressure of Essential Hypertension Patients

Previous studies established that a single daily dose of olmesartan remains effective for the entire 24 h without alteration of the day‐night blood pressure (BP) pattern. On the other hand, the administration of valsartan or telmisartan at bedtime, as opposed to upon wakening, improves the sleep‐time relative BP decline toward a greater dipper pattern without loss of 24 h efficacy. Yet to be determined is whether this administration‐time‐dependent efficacy is a class‐related feature, characteristic of all angiotensin‐receptor‐blocker (ARB) medications. We studied 123 grade 1 and 2 hypertensive patients, 46.6±12.3 yrs of age, randomly assigned to receive olmesartan (20 mg/day) as a monotherapy either upon awakening or at bedtime for three months. BP was measured by ambulatory monitoring for 48 consecutive hours before and after treatment. The 24 h BP reduction was similar for both treatment times. Administration of olmesartan at bedtime, however, was significantly more efficient than morning administration in reducing the nocturnal BP mean. The sleep‐time relative BP decline was slightly reduced with olmesartan ingestion upon awakening but significantly increased with ingestion at bedtime, thus reducing the prevalence of non‐dipping from baseline by 48%. Olmesartan administration at bedtime, as opposed to in the morning, improved the awake/asleep BP ratio toward a greater dipper pattern without loss of 24 h efficacy. Nocturnal BP regulation was significantly better achieved with bedtime as compared to morning dosing of olmesartan. These effects are comparable to those previously reported for valsartan and telmisartan, thus suggesting that they may be class‐related features of ARB medications in spite of differences in their half‐life kinetics. These administration‐time‐dependent effects should be taken into account when prescribing ARB medications for treatment of essential hypertension     

Time-Qualified Reference Limits (Chronodesms) for 24-Hour Blood Pressure Values: Classical and Bayesian

Background - This paper is a concrete example of the problems raised by the need of constructing the time-qualified reference limits (chronodesms) for blood pressure (BP), in order to clinically estimate the hemodynamic parameter in its intrinsic nychtohemeral variability. Methods - Assuming that the noninvasive ambulatory BP monitoring (ABPM) is the eligible technique for this need, it must be realized that the BP chronodems may be of two types, depending on the sample being used for their calculation. The first type may be regarded as “ a priori ” because of the fact that they are derived by a sample of normotensive subjects who are unavoidably recruited via “ causal ” sphygmomanometric measurements and reclassified as normotensive by comparing their ABPM to the fixed reference limits (monodesms) given by WHO (monodiagnosis). Therefore, the “ a priori ” BP chonodesms are by principle derived by subjects who could not be correctly classified as normotensive, their ABPM being not tested versus the time-varying physiological limits. The second type may regarded as “ a posteriori ” in virtue of the fact that they may be constructed on a sample which contemplates the previous subjects who result to be true normotensive via the reassessment of their ABPM versus the “ a priori ” BP chronodesms (chronodiagnosis). The “ a posteriori ” chronodesms may be regarded as biometrically reliable, whether the sample for their construction is additionally constituted by those subjects of the local population who have been erroneously monodiagnosed as hypertensive, while they result to be true normotensive via the chronodiagnostic comparison of their ABPM versus the “ a priori ” BP chronodesms. Results - The biometric reliability of the “ a posteriori ” BP chronodems is demonstrated by the fact that their upper limits are statistically significantly less pronounced due to the fact that they are provided by a sample which has been depured by the falsely monodiagnosed normotensives. Conclusions - The “ a posteriori ” BP upper chronodesms are the time-qualified reference limits which should be used in clinical practice for the chronodiagnosis of hypertension.     

Comparison of Ambulatory Blood Pressure Parameters of Hypertensive Patients With and Without Chronic Kidney Disease

There is strong association between chronic kidney disease (CKD) and increased prevalence of hypertension, risk of end-organ damage, and cardiovascular disease (CVD). Non-dipping, as determined by ambulatory blood pressure (BP) monitoring (ABPM), is frequent in CKD and has also been consistently associated with increased CVD risk. The reported prevalence of non-dipping in CKD is highly variable, probably due to relatively small sample sizes, reliance only on a single, low-reproducibility, 24-h ABPM evaluation per participant, and definition of daytime and nighttime periods by arbitrary fixed clock-hour spans. Accordingly, we assessed the circadian BP pattern of patients with and without CKD by 48-h ABPM to increase reproducibility of the results. This cross-sectional study involved 10 271 hypertensive patients (5506 men/4765 women), 58.0?±?14.2 (mean?±?SD) yrs of age, enrolled in the Hygia Project. Among the participants, 3227 (1925 men/1302 women) had CKD. At the time of recruitment, 568/2234 patients with/without CKD were untreated for hypertension. Patients with than without CKD were more likely to be men and of older age, have diagnoses of obstructive sleep apnea, metabolic syndrome, diabetes, and/or obesity, plus have higher glucose, creatinine, uric acid, and triglyceride, but lower cholesterol, concentrations. In patients with CKD, ambulatory systolic BP (SBP) was significantly elevated (p?<?.001), mainly during the hours of nighttime sleep, independent of presence/absence of BP-lowering treatment. In patients without CKD, ambulatory diastolic BP (DBP), however, was significantly higher (p?<?.001), mainly during the daytime. Differing trends for SBP and DBP between groups resulted in large differences in ambulatory pulse pressure (PP), it being significantly greater (p?<?.001) for the entire 24?h in patients with CKD. Prevalence of non-dipping was significantly higher in patients with than without CKD (60.6% vs. 43.2%; p?<?.001). The largest difference between groups was in the prevalence of the riser BP pattern, i.e., asleep SBP mean?>?awake SBP mean (17.6% vs. 7.1% in patients with and without CKD, respectively; p?<?.001). The riser BP pattern significantly and progressively increased from 8.1% among those with stage 1 CKD to a very high 34.9% of those with stage 5 CKD. Elevated asleep SBP mean was the major basis for the diagnosis of hypertension and/or inadequate BP control among patients with CKD; thus, among the uncontrolled hypertensive patients with CKD, 90.7% had nocturnal hypertension. Our findings document significantly elevated prevalence of a blunted nocturnal BP decline in hypertensive patients with CKD. Most important, prevalence of the riser BP pattern, associated with highest CVD risk among all possible BP patterns, was 2.5-fold more prevalent in CKD, and up to 5-fold more prevalent in end-stage renal disease. Patients with CKD also presented significantly elevated ambulatory PP, reflecting increased arterial stiffness and enhanced CVD risk. Collectively, these findings indicate that CKD should be included among the clinical conditions for which ABPM is mandatory for proper diagnosis and CVD risk assessment, as well as a means to establish the best therapeutic scheme to increase CVD event-free survival. (Author correspondence: rhermida@uvigo.es)     

Morphological characteristics of the secretion of natriuretic factor by atrial cardiomyocytes in spontaneous hypertension in rats

The results of electron microscopic studies of the synthesis and secretion of atrial natriuretic factor (ANF) in right atrial cardiomyocytes of spontaneously hypertensive rats (SHR) and the corresponding normotensive controls are presented. Enhanced secretory activity in cardiomyocytes of SHR has been revealed. The role of enhanced ANF secretion in the origin of arterial hypertension is discussed. It is suggested that enhanced ANF secretion can be attributed to increased ANF demand in BP elevation, changes in the renal function in hypertensive subjects or genetic defect in the excretory renal function in SHR.