重力对锥形血管中血流压力的影响——基于考虑体位改变的三维流固耦合数学模型

重力是体位改变过程中最基本的生物力学刺激因素．血流压力是表征心血管功能状态的一个基本指标．目前,体位改变影响心血管系统的确切内部机制尚不清楚．为此,采用在流体和固体方程中分别引入体力项的方法,建立一个基于血流动力学概念的三维流固耦合数学模型,用以研究体位改变,确切量化重力对血流压力的影响．通过数值计算,得到以下结果．水平卧位条件下：a．单一血管中血流压力由无重力影响的轴对称二维分布变为重力影响下的三维不对称分布;b．随着进出口压差由小变大,重力对压力分布和极值的影响由大变小,当压差值分别达到10 665.6 Pa(80 mmHg)和2 666.4 Pa(20 mmHg)时,重力的影响就不再随进出口压差增大而变化;对三维单一流体,重力影响的总体趋势类似．对正、倒直立位,压力均为二维轴对称分布,其重力影响强度约为水平卧位的2倍以上．结果表明：基于血流动力学概念,引入体力项,建立三维流固耦合模型为研究体位改变提供了一种新思路,重力对单一血管中血流压力分布和大小的影响因体位不同而不同,并与进出口压差密切相关,提示,若血管进出口压差较小,忽略重力影响,不考虑体位改变,以二维轴对称模型来研究血管中血流状态,须谨慎解释所得结果．     

Increases in arterial blood pressure in the rat in response to a new vertebrate neuropeptide, LPLRFamide, and a related molluscan peptide, FMRFamide

Vasopressor responses in urethane-anaesthetized rats were evoked by a new peptide from chicken brain, LPLRFamide, and the immunochemically related molluscan neuropeptide, FMRFamide. In doses of 50 to 200 nmol X kg-1, i.v., both peptides produced a rapid increase in arterial pressure that returned to basal in 1-2 min. When given intracisternally in similar doses the two peptides again increased arterial pressure, but the time to peak response (1-2 min) and the duration of the responses (5-8 min) were prolonged. There was a marked, reversible, specific, tachyphylaxis following intracisternal but not intravenous injection of LPLRFamide, indicating separate sites of action after administration by these routes. Guanethidine and phentolamine blocked the responses to both intravenous and intracisternal administration, and hexamethonium significantly reduced the response to intracisternal administration. Both by intravenous and intracisternal routes it is therefore likely that responses are mediated by noradrenaline release from sympathetic endings. In addition, following adrenalectomy and propranolol the response to intravenous (but not intracisternal) LPLRFamide was increased, suggesting that adrenaline released from the adrenal medulla might act at beta-adrenoreceptors causing vasodilatation. The physiological significance of these observations remains to be established, but it is significant that peptides immunochemically related to FMRFamide and LPLRFamide occur in areas of rat brain concerned with autonomic control.     

Association between timing of hot water bathing before bedtime and night-/sleep-time blood pressure and dipping in the elderly: a longitudinal analysis for repeated measurements in home settings

ABSTRACT

Hot water bathing – a Japanese traditional practice – has not been evaluated for its association with night- and sleep-time blood pressure (BP) in large population. In this longitudinal analysis, bathing parameters and ambulatory BP were repeatedly measured for 2 nights in 758 Japanese elderly individuals. Participants were divided into three groups according to tertile values of time soaked in the bathtub (Duration: tertile value, 11 and 15 min), time from bathing-end to bedtime (Time before bedtime: tertile value, 42 and 106 min), and temperature of hot water in the bathtub (Water temp: tertile value, 40.3 and 41.2 °C). Participants’ mean age was 70.9 years, and mean night- and sleep-time systolic BP (SBP) and dipping were 115.1 ± 16.1, 114.2 ± 16.2 mmHg, and 14.2 ± 8.8%, respectively. Multivariable mixed-effect linear regression models adjusted for potential confounding factors suggested that nighttime SBP was significantly lower in the intermediate Time before bedtime group by 1.7 mmHg (95% CI, 0.2–3.1) and in the short group by 1.9 mmHg (95% CI, 0.1–3.7) than that in the long group. Dipping was significantly greater in the intermediate Time before bedtime group by 1.8% (95% CI, 0.7–2.9) and in the short group by 1.8% (95% CI, 0.6–3.1) than that in the long group. These associations were consistent regarding sleep-time SBP. Conversely, Water temp and Duration did not significantly associate with any ambulatory BP parameter. Remarkably, Time before bedtime significantly prolonged with increases in tertiles of Water temp (P for trend = 0.006). In conclusion, the findings of this study revealed that Japanese hot water bathing, especially the short time from bathing-end to bedtime, was associated with lower night- and sleep-time BP and greater dipping in an elderly population.     

Circadian Rhythm of Blood Pressure Challenges Office Values as the “Gold Standard” in the Diagnosis of Gestational Hypertension

Despite poor sensitivity and specificity, office blood pressure (BP) determinations are still the “gold standard” for diagnosing gestational hypertension. This prospective blind study evaluates the prognostic value of office values as compared with ambulatory monitoring in pregnancy. We analyzed 2175 BP series systematically sampled from 355 non-preeclamptic pregnant women for 48 h every 4 wks from the first hospital visit until delivery. Women were divided for comparative purposes into three groups: “detected” gestational hypertension, defined on the basis of casual clinical BP>140/90 mm Hg after 20 wks of gestation and hyperbaric index (area of BP excess above the upper limit of a time-specified tolerance interval adjusted for the circadian pattern of the reference population) consistently above the threshold for diagnosing hypertension in pregnancy; “undetected” gestational hypertension, women with office BP<140/90 mm Hg but hyperbaric index consistently above the threshold for diagnosis; and normotension, women with both office values and hyperbaric index below the respective thresholds for diagnosis. Small and insignificant differences in the 24 h mean BP between “detected” and “undetected” gestational hypertension is observed in all trimesters, in contrast with highly significant differences between these two groups and normotensive pregnancies. Normotensive women are characterized by highly significant lesser incidence by 60% in preterm delivery, 70% in intrauterine growth retardation, and 50% in delivery by cesarean section (P<0.001) compared with women with “detected” and “undetected” gestational hypertension (P>0.715). In pregnancy, the hyperbaric index is markedly superior to office BP measurements for diagnosis of what should be truly considered gestational hypertension, and for prediction of the outcome of pregnancy.     

Sleep-Time Blood Pressure: Prognostic Value and Relevance as a Therapeutic Target for Cardiovascular Risk Reduction

Correlation between blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than clinical BP measurements. Nevertheless, the latter continue to be the “gold standard” to diagnose hypertension, assess CVD risk, and evaluate hypertension treatment. Independent ABPM studies have found that elevated sleep-time BP is a better predictor of CVD risk than either the awake or 24-h BP mean. A major limitation of all previous ABPM-based prognostic studies is the reliance only upon a single baseline profile from each participant at the time of inclusion, without accounting for potential changes in the level and pattern of ambulatory BP thereafter during follow-up. Accordingly, impact of the alteration over time, i.e., during long-term follow-up, of specific features of the 24-h BP variation on CVD risk has never been properly investigated. We evaluated the comparative prognostic value of (i) clinic and ambulatory BP; (ii) different ABPM-derived characteristics, e.g., asleep or awake BP mean; and (iii) specific changes in ABPM characteristic during follow-up, mainly whether reduced CVD risk is more related to the progressive decrease of asleep or awake BP. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6?±?14.5 (mean?±?SD) yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00?h and at 30-min intervals at night for 48-h, and physical activity was simultaneously monitored every min by wrist actigraphy to accurately derive awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Data collected either at baseline or the last ABPM evaluation per participant showed that the asleep systolic BP mean was the most significant predictor of both total CVD events and major CVD events (a composite of CVD death, myocardial infarction, and stroke). Moreover, when the asleep BP mean was adjusted by the awake mean, only the former was a significant independent predictor of outcome in a Cox proportional-hazard model adjusted for sex, age, diabetes, anemia, and chronic kidney disease. Analyses of changes in ambulatory BP during follow-up revealed 17% reduction in CVD risk for each 5?mm Hg decrease in the asleep systolic BP mean (p?<?.001), independent of changes in any other clinic or ambulatory BP parameter. The increased event-free survival associated with the progressive reduction in the asleep systolic BP mean during follow-up was significant for subjects with either normal or elevated BP at baseline. The ABPM-derived asleep BP mean was the most significant prognostic marker of CVD morbidity and mortality. Most important, the progressive decrease in asleep BP mean, a novel therapeutic target that requires proper patient evaluation by ABPM and best achieved by ingestion of at least one hypertension medication at bedtime, was the most significant predictor of event-free survival. (Author correspondence: rhermida@uvigo.es)     

Method for detecting hemodynamic alterations following a single gavage in rats

It is known that administering a gavage to rodents evokes a cardiac reflex, due to gastrointestinal stimulation. Consequently, it is difficult to evaluate changes in hemodynamics after a single oral dose of a pungent or astringent, which alters the circulation by increasing sympathetic activity. In the present study, we developed a method for administering a gavage without significantly affecting hemodynamics measurements. We marked a gastric tube at 10 cm from the tip, to mark the distance from the oral cavity to the stomach body of Wistar male rats. Rats were intubated under urethane anesthesia.After 10–15 min of stabilization, we measured the mean blood pressure (MBP), heart rate (HR), and blood flow (BF) in the cremaster arteriole under two different conditions; condition 1: a pointed gastric tube, room temperature distilled water, and injected at normal speed (approximately 3 ml/min); condition 2: a rounded gastric tube, 37°C distilled water, and injection at 1.0 ml/min. Under condition 1, we observed striking hemodynamic alterations, due to the somatic afferent reflex. In contrast, under condition 2, these hemodynamic changes were nearly eliminated. In addition, we could clearly detect hemodynamic changes in rats after a single gavage treatment of pungent (capsaicin) or astringent (cinnamtannin A2). We observed transient increases in the HR and MBP soon after treatment with capsaicin. Moreover, cremasteric BF was elevated with cinnamtannin A2. These results confirmed the utility of the gavage method developed in this study.     

利用宏基因组学方法分析健康人群肠道微生物与其生理指标的关系

目的探究亚洲健康人群的肠道菌群组成特征及其与血压和年龄相关生理指标的关系。方法应用WGCNA分析,对22个健康个体肠道微生物细菌基因组进行解析。结果亚洲健康人肠道微生物相对丰度最高的细菌门水平分别是Firmicutes(厚壁菌门)、 Bacteroidetes(拟杆菌门)以及Proteobacteria(变形菌门),并且在Proteobacteria中显示高差异性。WGCNA分析结果表明两个模块(yellow,green)中微生物物种丰富度分别与收缩压和舒张压以及年龄呈正相关(t=3.098 1,P=0.005 6;t=3.015 9,P=0.006 8;t=2.390 8,P=0.026 7)。其中Ruminococcus sp.(瘤胃球菌)、Oscillospiraceae sp.(颤螺菌)、Clostridium hathewayi(哈氏梭菌)与血压呈现显著正相关;Intestinibacter(肠杆菌)、Clostridium(梭菌)、Blautia(劳特菌)以及Veillonella(韦荣球菌)属下的Aypic、Tobetsuensis rogosae与年龄呈现正相关。抗性基因注释结果表明,年龄和血压相关核心菌群均富集有较多的大环内酯-林可酰胺-链霉素类、杆菌肽类以及四环素类抗生素抗性基因。其中多黏菌素类抗性基因仅存在于年龄相关核心菌群而氯霉素抗性基因仅存在于血压相关核心菌群。结论健康人肠道微生物物种丰度与血压以及年龄相关,肠道菌群可能在心血管疾病以及衰老过程中发挥重要影响。     

Change in Vascular Adhesion Protein‐1 and Metabolic Phenotypes after Vertical Banded Gastroplasty for Morbid Obesity

Objective: The association between circulating vascular adhesion protein‐1 (VAP‐1) and metabolic phenotypes has been shown to be inconsistent. The current study explored whether the changes in serum VAP‐1 levels correlate with the changes in metabolic phenotypes after weight reduction surgery. Research Methods and Procedures: Clinical characteristics and serum VAP‐1 levels in 20 morbidly obese subjects (mean BMI 38.84 kg/m²) were measured before and after vertical banded gastroplasty. Results: Before surgery, serum VAP‐1 levels correlated positively with fasting plasma glucose (γ = 0.56, p = 0.01) and negatively with insulin levels (γ = ?0.51, p = 0.021). After surgery, the changes in serum VAP‐1 levels were negatively correlated with the changes in waist circumference (γ = ?0.57, p = 0.011), diastolic blood pressure (DBP) (γ = ?0.56, p = 0.015), and mean arterial pressure (γ = ?0.46, p = 0.055). In multivariate regression, serum VAP‐1 levels were negatively correlated with waist circumference (β = ?2.36, p = 0.014) and DBP (β = ?3.02, p = 0.017) after adjusting for age and gender. The change in DBP was negatively correlated with the change in VAP‐1 levels after adjusting for age, gender, and steady‐state plasma glucose. Discussion: The results suggest that VAP‐1 levels are correlated with fasting glucose and insulin levels in morbidly obese subjects. After surgery, the changes in VAP‐1 levels were associated with changes in visceral adiposity and DBP. Serum VAP‐1 might modulate DBP independently from the changes in insulin resistance in morbidly obese people.     

缬沙坦联合苯磺酸左旋氨氯地平治疗201例高危高血压患者的疗效评价

目的探讨缬沙坦联合苯磺酸左旋氨氯地平治疗高危高血压患者的临床疗效。方法选择常州市新北区春江人民医院2014年6月至2016年6月收治的201例高危高血压患者,随机分为治疗组(n=101)和对照组(n=100)。对照组采用苯磺酸左旋氨氯地平治疗,治疗组在对照组的基础上联合缬沙坦治疗。观察比较两组收缩压和舒张压水平、血钾和血肌酐浓度、SF-36评分及不良反应发生情况。结果治疗后,两组收缩压和舒张压水平均显著降低(P0.05),且观察组低于对照组(P0.05);治疗后4周,观察组收缩压和舒张压水平亦均显著低于对照组(P0.05)。治疗后,两组血K+浓度、血肌酐浓度均显著降低(P0.05),且观察组低于对照组(P0.05);治疗后4周,观察组血K+浓度和对照组无差异(P0.05),血肌酐浓度亦低于对照组(P0.05)。两组SF-36评分均显著升高(P0.05),且观察组显著高于对照组(P0.05)。观察组不良反应率为5.94%,对照组为8.00%,两组比较无统计学意义(χ~2=1.612,P=0.880)。结论缬沙坦联合苯磺酸左旋氨氯地平治疗高危高血压临床疗效显著,安全性高,可以有效改善患者生活质量,值得推广应用。     

Role of zinc in regulation of arterial blood pressure and in the etiopathogenesis of arterial hypertension

Increased gastrointestinal absorption and urinary excretion of zinc has been confirmed in experimental and clinical studies on primary arterial hypertension as a result from changes of intracellular and extracellular zinc content. In arterial hypertension, the levels of zinc in serum, lymphocyte, and bone decrease while increasing in heart, erythrocytes, kidney, liver, suprarenal glands and spleen. These changes result in the loss of zinc homeostasis that leads to various degrees of deficiency, not entirely compensated by nutritional factors or increased absorption in the gastrointestinal tract. Loss of zinc homeostasis can be both cause and effect of high blood pressure. In the present review, the role of zinc metabolism changes and its mechanisms in arterial hypertension are discussed.     

Action of sauvagine on the mesenteric vascular bed of the dog

Sauvagine, a linear peptide of 40 amino acids, produced hypotension when administered intravenously to anesthetized dogs. Diastolic pressure was always more affected than systolic pressure. Aortic blood flow and venous return both increased to the same extent. The mechanism of the hypotensive response was mainly, if not exclusively, due to dilatation of the superior and inferior mesenteric arteries. Intravenous infusion of sauvagine in doses ranging from 3 to 10 ng · kg^?1 · min^?1 produced a dose-related increased of mesenteric blood flow up to 400% control values. Mucosal-submucosal blood flow of ileum and colon was increased, while blood flow in muscle was unaffected or slight decreased. The mesenteric vasodilator response was not prevented by adrenergic or muscarinic receptor blockade. The hypotensive response was more marked and sustained in dibenamine-propranolol treated dogs.     

A literature review: the effects of magnetic field exposure on blood flow and blood vessels in the microvasculature

The effect of magnetic field (MF) exposure on microcirculation and microvasculature is not clear or widely explored. In the limited body of data that exists, there are contradictions as to the effects of MFs on blood perfusion and pressure. Approximately half of the cited studies indicate a vasodilatory effect of MFs; the remaining half indicate that MFs could trigger either vasodilation or vasoconstriction depending on initial vessel tone. Few studies indicate that MFs cause a decrease in perfusion or no effect. There is a further lack of investigation into the cellular effects of MFs on microcirculation and microvasculature. The role of nitric oxide (NO) in mediating microcirculatory MF effects has been minimally explored and results are mixed, with four studies supporting an increase in NO activity, one supporting a biphasic effect, and five indicating no effect. MF effects on angiogenesis are also reported: seven studies supporting an increase and two a decrease. Possible reasons for these contradictions are explored. This review also considers the effects of magnetic resonance imaging (MRI) and anesthetics on microcirculation. Recommendations for future work include studies aimed at the cellular/mechanistic level, studies involving perfusion measurements both during and post-exposure, studies testing the effect of MFs on anesthetics, and investigation into the microcirculatory effects of MRI.     

Non-dipping blood pressure in the metabolic syndrome among Arabs of the Oman family study

Objective: The objective was to examine the circadian changes in blood pressure and their relation to the metabolic syndrome and its components in Omani Arabs. Research Methods and Procedures: Ambulatory blood pressure (ABPM) was recorded in 1124 subjects from 5 large, extended, consanguineous, and young Arab pedigrees. According to the International Diabetes Federation's definition, 264 subjects had the metabolic syndrome, a prevalence of 23%. Subjects were defined as non‐dippers when their nocturnal systolic blood pressure (SBP) fell by <10% from daytime SBP. Results: Non‐dippers with the metabolic syndrome were 131 of 264 (50%), compared with 265 of 860 (31%) without the metabolic syndrome. Of the non‐dippers, 99 of 131 (76%) were females and 32 of 131 (24%) were males. Daytime and nighttime SBP and DBP and nighttime pulse pressure were significantly higher in non‐dipper subjects with the metabolic syndrome. The important determinants of a non‐dipping BP in this cohort were high BMI and high serum triglycerides. Discussion: We hypothesize that obesity and nocturnal volume‐dependent hypertension may be involved in the pathophysiology of non‐dipping in the metabolic syndrome. This study showed that non‐dipping BP was common in subjects with the metabolic syndrome. Higher 24‐hour blood pressure load may add to the indices of the overall cardiovascular burden already associated with the metabolic syndrome.     

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)     

急性减压病大鼠肺组织粘附分子的变化

目的:探讨急性减压病大鼠肺组织中内粘附分子的改变。方法:雄性SD大鼠置于加压舱内,压缩空气在3 min内匀速加压至0.7 MPa,停留60 min后,3 min内快速减压出舱。观察减压后生存率、减压病症状。在减压后30 min、6 h、24 h取大鼠脑、肺及肝脏组织,甲醛溶液固定、切片、HE染色观测病理改变。免疫组化测定肺组织中细胞间粘附分子-1(ICAM-1)、E-选择素(E-selectin)、主要组织相容性复合体-Ⅱ(MHC-Ⅱ)的表达变化。在减压后6h、24 h前30 min,大鼠尾静脉注射2%evans blue溶液。30 min后行生理盐水灌注,收集肺组织,观测肺组织蓝染程度,酶标仪测定血浆中evans blue含量。结果:肺、肝及脑组织在减压后30 min出现水肿、淤血等病理表现。和正常组比较,肺组织中ICAM-1、E-selectin、MHC-Ⅱ在减压后明显上升,并呈现动态变化。相对于正常组,减压后6 h、24h肺组织血浆中evans blue含量明显增加。结论:气泡导致的,粘附分子介导的血管内皮受损是减压病的发病机制之一。     

24-Hour Variation in the Reactivity of Rate-Pressure-Product to Everyday Physical Activity in Patients Attending a Hypertension Clinic

The exercise-related response of the rate-pressure-product (RPP) is a prognostic marker of autonomic imbalance, cardiovascular mortality, and silent myocardial ischemia in hypertension. In view of the well-known 24 h variation in out-of-hospital sudden cardiac events, our aim was to investigate whether the reactivity of RPP to everyday physical activities varies over the 24 h. Ambulatory measurements of systolic blood pressure (BP) and heart rate were recorded every 20 min for 24 h in 440 diurnally active patients attending a hypertension clinic. Wrist activity counts were summed over the 15 min that preceded a BP measurement. An RPP reactivity index was derived for each of twelve 2 h data bins by regressing the change in RPP against the change in logged activity counts. The RPP showed 24 h variation (p?<?0.0005), with a peak of 11,004 (95% CI?=?10,757 to 11,250) beat?·?min^?1?·?mmHg occurring at 10:00 h (2 h after mean wake-time). The overall 24 h mean of RPP reactivity was 477 beat?·?min^?1?·?mmHg?·?logged activity counts^?1 (95% CI?=?426 to 529). The largest increase in RPP reactivity occurred within the first 2 h after waking (p?<?0.0005). There were no subsequent significant differences in RPP reactivity up to 14 h after waking. The lowest RPP reactivity was found 18–20 h after waking, with a peak-to-trough variation of 593 beat?·?min^?1?·?mmHg?·?logged activity counts^?1 (95% CI?=?394 to 791, p?<?0.0005). Although this variation was not moderated by BP status, age, or sex, less variability in RPP reactivity was found for the medicated individuals during the waking hours. These data suggest that under conditions of normal living, the reactivity of RPP to a given change in physical activity increases markedly during the first 2 h after waking from nocturnal sleep, the time when out-of-hospital sudden cardiac events are also most common. Therefore, these data add weight to the notion that reactivity of RPP to physical activity could be a prognostic marker of autonomic imbalance and cardiovascular mortality, although more research is needed to assess the specific prognostic value of 24 h ambulatory measurements of RPP and physical activity.     

The tolerance-hyperbaric test: a chronobiologic approach for improved diagnosis of hypertension

Blood pressure (BP) displays predictable large-amplitude circadian variability. Thus, the identification and the proper definition of hypertension are highly ambiguous when based on single time-unspecified measurements. One way to deal with such variability in the diagnosis of hypertension is to replace the commonly used constant limits of BP by a time-specified reference interval based on the normal circadian BP rhythm assessed by ambulatory BP monitoring (ABPM). A proper reference limit can be constructed, for instance, as a tolerance interval computed for every specific time interval throughout the 24 h. Once such a threshold (given by the upper limit of the tolerance interval) is constructed, a hyperbaric index (HBI) can be computed by numerical integration of the total area of any given patient's BP profile above threshold. The HBI plus the duration of excess within the 24h day serves as nonparametric endpoints for assessing hypertension. Both retrospective and prospective evaluation of this tolerance-hyperbaric test validate its high sensitivity and specificity in the diagnosis of hypertension. We describe the theory of the HBI as well as a newly created dedicated software program that automatically derives the tolerance intervals from a reference database of normotensive subjects and calculates the HBI and other potentially valuable parameters based on data obtained by ABPM. The establishment of time-qualified tolerance limits and the assessment of the extent and timing of BP elevation represents a valuable tool for the more accurate diagnosis of hypertension as well as means of gauging response to treatment.     

Guidelines for the design and conduct of human clinical trials on ingestion-time differences – chronopharmacology and chronotherapy – of hypertension medications

ABSTRACT

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been “time-of-day,” i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be the primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the asleep (not “nighttime”) BP mean and sleep-time relative BP decline, calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called adjusted calculation procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens.