Nocturnal nondipping of heart rate predicts cardiovascular events in hypertensive patients

Objective: It has not been established whether nocturnal nondipping of heart rate (HR) predicts future cardiovascular disease (CVD). We performed this study to test the hypothesis that nocturnal nondipping of HR predicts the risk of incident CVD independent of nocturnal blood pressure dipping pattern. Methods: Ambulatory blood pressure monitoring was performed in 457 uncomplicated patients, who were being treated or evaluated for hypertension. They were followed for an average of 72 ± 26 months. Nondipping HR was defined as a night/day HR ratio greater than 0.90. We chose two outcomes for this analysis: CVD events (defined as stroke, myocardial infarction, or sudden cardiac death) and all-cause mortality. Cox regression analyses (stepwise method) were used to estimate hazard ratios and their 95% confidence interval after adjusting for covariates. Results: In univariate analysis, increased sleep HR and nondipping of HR were associated with increased risk of CVD and all-cause mortality, but awake HR was not. In multivariable analyses, HR nondipping status significantly predicted an increased risk of CVD events (hazard ratio, 2.37; 95% confidence interval, 1.22–4.62; P = 0.01), but not for all-cause mortality. Increased 24-h HR was significantly associated with increased risk of all-cause mortality (hazard ratio, 1.67; 95% confidence interval, 1.11–2.51; P = 0.01). Conclusion: The risk of future CVD was shown to be 2.4 times higher in those whose HR does not exhibit the typical nocturnal decline. The relationship was independent of nondipping of SBP and was not dependent on diabetes status or blood pressure level

Night Time Blood Pressure Variability Is a Strong Predictor for Cardiovascular Events in Patients With Type 2 Diabetes

Background: We aimed this study to test the hypothesis that short-term blood pressure (BP) variability and abnormal patterns of diurnal BP variation, evaluated by ambulatory BP (ABP), predicts risk of incident cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM). Methods: ABP monitoring (ABPM) was performed in 300 patients with uncomplicated T2DM without known CVD and without BP medications, who were followed for 54 ± 20 months. The relationships of different measures of BP variability, the presence of abnormal patterns of diurnal BP variation (nondipper, riser, or morning BP surge) and the standard deviations of awake and asleep ABP were determined. Cox proportional hazards models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) before and after controlling for various covariates. Results: The mean age was 67.8 ± 9.6 years, 48% were male, 253 (84%) had a diagnosis of hypertension, and the mean of the standard deviations of awake systolic BP/diastolic BP (SBP/DBP) were 18 ± 6/11 ± 4 mm Hg, and those of sleep SBP/DBP were 13 ± 5/9 ± 3 mm Hg. During follow-up, there were 29 cardiovascular events. In multivariable analyses, the standard deviations of sleep SBP (HR = 1.08; 95% CI, 1.01–1.16, P < 0.05) and sleep DBP (HR = 1.13; 1.04–1.23, P < 0.01) were independently associated with incident CVD. Neither the nondipper and riser patterns nor the morning BP surge were associated with incident CVD events independently of clinic and 24-h BP levels. Conclusions: Abnormal diurnal BP variation was not a predictor of CVD in patients with T2DM. Night time BP variability was an independent predictor of future incidence of CVD, suggesting that this measure could reflect pathophysiology of T2DM

Ambulatory Blood Pressure Is a Better Marker Than Clinic Blood Pressure in Predicting Cardiovascular Events in Patients With/Without Type 2 Diabetes

Background - The prognostic significance of ambulatory blood pressure (ABP) has not been established in patients with type 2 diabetes (T2DM). Methods - In order to clarify the impact of ABP on cardiovascular prognosis in patients with or without T2DM, we performed ABP monitoring (ABPM) in 1,268 subjects recruited from nine sites in Japan, who were being evaluated for hypertension. The mean age of the patients was 70.4 ± 9.9 years, and 301 of them had diabetes. The patients were followed up for 50 ± 23 months. We investigated the relation between incidence of cardiovascular diseases (CVDs) and different measures of ABP, including three categories of awake systolic blood pressure (SBP 150 mm Hg), sleep SBP (135 mm Hg), and dipping trends in nocturnal blood pressure (BP) (dippers, nondippers, and risers). Cox regression models were used in order to control for classic risk factors. Results - Higher awake and sleep SBPs predicted higher incidence of CVD in patients with and without diabetes. In multivariable analyses, elevated SBPs while awake and asleep predicted increased risk of CVD more accurately than clinic BP did, in both groups of patients. The relationships between ABP level and CVD were similar in both groups. In Kaplan–Meier analyses, the incidence of CVD in nondippers was similar to that in dippers, but risers experienced the highest risk of CVD in both groups (P < 0.01). The riser pattern was associated with a ∼150% increase in risk of CVD, in both groups. Conclusions - These findings suggest that ABPM is a better predictor of cardiovascular risk than clinic BP, and that this holds true for patients with or without T2DM

Effect Modification by Age on the Benefit or Harm of Antihypertensive Treatment for Elderly Hypertensives: A Systematic Review and Meta-analysis

BACKGROUND: The influence of age on balance of benefit versus potential harm of blood pressure (BP)-lowering therapy for elderly hypertensives is unclear. We evaluated the modifying effects of age on BP lowering for various adverse outcomes in hypertensive patients older than 60 years without specified comorbidities. METHODS: All relevant randomized controlled trials (RCTs) were systematically identified. Coronary heart disease, stroke, heart failure (HF), cardiovascular death, major adverse cardiovascular events (MACE), renal failure (RF), and all-cause death were assessed. Meta-regression analysis was used to explore the relationship between achieved systolic BP (SBP) and the risk of adverse events. Random-effects meta-analysis was used to pool the estimates. RESULTS: Our study included eighteen RCTs (n=53993). Meta-regression analysis showed a lower achieved SBP related with a lower risk of stroke and cardiovascular death, but an increased risk of RF. The regression slopes were comparable between populations stratifying by age 75 years. In subgroup analysis, the relative risks of a more aggressive BP lowering strategy were similar between patients aged older or less than 75 years for all outcomes except for RF (P for interaction=0.02). Compared to treatment with final achieved SBP 140-150 mmHg, a lower achieved SBP (<140 mmHg) was significantly associated with decreased risk of stroke (relative risk, 0.68; 95% confidence interval, 0.55-0.85), HF (0.77; 0.60-0.99), cardiovascular death (0.68; 0.52-0.89), and MACE (0.83; 0.69-0.99). CONCLUSIONS: To treat hypertension in the elderly, age had trivial effect modification on most outcomes, except for renal failure. Close monitoring of renal function may be warranted in the management of elderly hypertension

Drawing induced texture and the evolution of superconductive properties with heat treatment time in powder-in-tube in-situ processed MgB2 strands

Monocore powder-in-tube MgB2 strands were cold-drawn and heat-treated at 600C and 700C for times of up to 71 hours and structure-property relationships examined. Drawing-induced elongation of the Mg particles led, after HT, to a textured macrostructure consisting of elongated polycrystalline MgB2 fibers separated by elongated pores. The superconducting Tc, Jc and Fp were correlated with the macrostructure and grain size. Grain size increased with HT time at both 600C and 700C. Jc and hence Fp decreased monotonically but not linearly with grain size. Overall, it was observed that at 700C, the MgB2 reaction was more or less complete after as little as 30 min; at 600C, full reaction completion did not occur until 71 h. into the HT. Transport, Jct(B) was measured in a perpendicular applied field, and the magnetic critical current densities, Jcm\bot(B) and Jcm{\phi}(B), were measured in perpendicular and parallel (axial) applied fields, respectively. Particularly noticeable was the premature dropoff of Jcm\bot(B) at fields well below the irreversibility field of Jct(B). This effect is attributed to the fibrous macrostructure and its accompanying anisotropic connectivity. Magnetic measurements with the field directed along the strand axis yielded a critical density, Jcm\bot(B), for current flowing transversely to the strand axis that was less than and dropped off more rapidly than Jct(B). In the conventional magnetic measurement, the loop currents that support the magnetization are restricted by the lower of Jct(B) and Jcm{\phi} (B). In the present case the latter, leading to the premature dropoff of the measured Jcm(B) compared to Jct(B) with increasing field. This result is supported by Kramer plots of the Jcm{\phi} (B) and Jct(B) data which lead to an irreversibility field for transverse current that is very much less than the usual transport-measured longitudinal one, Birr,t.Comment: 41 pages, 14 figure

Predictive value of night-time heart rate for cardiovascular events in hypertension. The ABP-International study

Background - Data from prospective cohort studies regarding the association between ambulatory heart rate (HR) and cardiovascular events (CVE) are conflicting. Methods - To investigate whether ambulatory HR predicts CVE in hypertension, we performed 24-hour ambulatory blood pressure and HR monitoring in 7600 hypertensive patients aged 52 ± 16 years from Italy, U.S.A., Japan, and Australia, included in the ‘ABP-International’ registry. All were untreated at baseline examination. Standardized hazard ratios for ambulatory HRs were computed, stratifying for cohort, and adjusting for age, gender, blood pressure, smoking, diabetes, serum total cholesterol and serum creatinine. Results - During a median follow-up of 5.0 years there were 639 fatal and nonfatal CVE. In a multivariable Cox model, night-time HR predicted fatal combined with nonfatal CVE more closely than 24 h HR (p = 0.007 and = 0.03, respectively). Daytime HR and the night:day HR ratio were not associated with CVE (p = 0.07 and = 0.18, respectively). The hazard ratio of the fatal combined with nonfatal CVE for a 10-beats/min increment of the night-time HR was 1.13 (95% CI, 1.04–1.22). This relationship remained significant when subjects taking beta-blockers during the follow-up (hazard ratio, 1.15; 95% CI, 1.05–1.25) or subjects who had an event within 5 years after enrollment (hazard ratio, 1.23; 95% CI, 1.05–1.45) were excluded from analysis. Conclusions - At variance with previous data obtained from general populations, ambulatory HR added to the risk stratification for fatal combined with nonfatal CVE in the hypertensive patients from the ABP-International study. Night-time HR was a better predictor of CVE than daytime HR

Occupational and leisure time physical activity in contrasting relation to ambulatory blood pressure

Background: While moderate and vigorous leisure time physical activities are well documented to decrease the risk for cardiovascular disease, several studies have demonstrated an increased risk for cardiovascular disease in workers with high occupational activity. Research on the underlying causes to the contrasting effects of occupational and leisure time physical activity on cardiovascular health is lacking. The aim of this study was to examine the relation of objective and self-report measures of occupational and leisure time physical activity with 24-h ambulatory systolic blood pressure (BP). Methods: Results for self-reported physical activity are based on observations in 182 workers (60% male, mean age 51 years), while valid objective physical activity data were available in 151 participants. The usual level of physical activity was assessed by 5 items from the Job Content Questionnaire (high physical effort, lifting heavy loads, rapid physical activity, awkward body positions and awkward positions of head or arms at work) and one item asking about the general level of physical activity during non-working time. On a regular working day, participants wore an ambulatory BP monitor and an accelerometer physical activity monitor during 24 h. Associations were examined by means of Analysis of Covariance. Results: Workers with an overall high level of self-reported occupational physical activity as well as those who reported to often lift heavy loads at work had a higher mean systolic BP at work, at home and during sleep. However, no associations were observed between objectively measured occupational physical activity and BP. In contrast, those with objectively measured high proportion of moderate and vigorous leisure time physical activity had a significantly lower mean systolic BP during daytime, while no differences were observed according to self-reported level of leisure time physical activity. Conclusions: These findings suggest that workers reporting static occupational physical activities, unlike general physically demanding tasks characterized by dynamic movements of large muscle groups, are related to a higher daily systolic BP, while high objective levels of moderate and vigorous leisure time physical activity are related to lower daytime systolic BP. Ambulatory systolic BP may be a physiological explanatory factor for the contrasting effects of occupational and leisure time physical activity

Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design.

BACKGROUND: The SPYRAL HTN clinical trial program was initiated with two 80-patient pilot studies, SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED, which provided biological proof of principle that renal denervation has a blood pressure-lowering effect versus sham controls for subjects with uncontrolled hypertension in the absence or presence of antihypertensive medications, respectively. TRIAL DESIGN: Two multicenter, prospective, randomized, sham-controlled trials have been designed to evaluate the safety and efficacy of catheter-based renal denervation for the reduction of blood pressure in subjects with hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) or presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications. The primary efficacy endpoint is baseline-adjusted change from baseline in 24-h ambulatory systolic blood pressure. The primary safety endpoint is incidence of major adverse events at 1 month after randomization (or 6 months in cases of new renal artery stenosis). Both trials utilize a Bayesian design to allow for prespecified interim analyses to take place, and thus, the final sample sizes are dependent on whether enrollment is stopped at the first or second interim analysis. SPYRAL HTN-OFF MED Pivotal will enroll up to 300 subjects and SPYRAL HTN-ON MED Expansion will enroll up to 221 subjects. A novel Bayesian power prior approach will leverage historical information from the pilot studies, with a degree of discounting determined by the level of agreement with data from the prospectively powered studies. CONCLUSIONS: The Bayesian paradigm represents a novel and promising approach in device-based hypertension trials. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02439749 (SPYRAL HTN-OFF MED Pivotal) and NCT02439775 (SPYRAL HTN-ON MED Expansion)

Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design.

BACKGROUND: The SPYRAL HTN clinical trial program was initiated with two 80-patient pilot studies, SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED, which provided biological proof of principle that renal denervation has a blood pressure-lowering effect versus sham controls for subjects with uncontrolled hypertension in the absence or presence of antihypertensive medications, respectively. TRIAL DESIGN: Two multicenter, prospective, randomized, sham-controlled trials have been designed to evaluate the safety and efficacy of catheter-based renal denervation for the reduction of blood pressure in subjects with hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) or presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications. The primary efficacy endpoint is baseline-adjusted change from baseline in 24-h ambulatory systolic blood pressure. The primary safety endpoint is incidence of major adverse events at 1 month after randomization (or 6 months in cases of new renal artery stenosis). Both trials utilize a Bayesian design to allow for prespecified interim analyses to take place, and thus, the final sample sizes are dependent on whether enrollment is stopped at the first or second interim analysis. SPYRAL HTN-OFF MED Pivotal will enroll up to 300 subjects and SPYRAL HTN-ON MED Expansion will enroll up to 221 subjects. A novel Bayesian power prior approach will leverage historical information from the pilot studies, with a degree of discounting determined by the level of agreement with data from the prospectively powered studies. CONCLUSIONS: The Bayesian paradigm represents a novel and promising approach in device-based hypertension trials. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02439749 (SPYRAL HTN-OFF MED Pivotal) and NCT02439775 (SPYRAL HTN-ON MED Expansion)