Somers, Virend K.

Abstract While the contribution of several physiological systems to arterial blood pressure regulation has been studied extensively, the role of normal and disrupted sleep as a modifiable determinant of blood pressure control, and in the pathophysiology of hypertension, has only recently emerged. Several sleep disorders, including sleep apnea and insomnia, are thought to contribute to the development of hypertension, although less attention is paid to the relationship between sleep duration and blood pressure independent of sleep disorders per se. Accordingly, this review focuses principally on the physiology of sleep and the consequences of abnormal sleep duration both experimentally and at the population level. Clinical implications for patients with insomnia who may or may not have abbreviated sleep duration are explored. As a corollary, we further review studies of the effects of sleep extension on blood pressure regulation. We also discuss epidemiological evidence suggesting that long sleep may also be associated with hypertension and describe the parabolic relationship between total sleep time and blood pressure. We conclude by highlighting gaps in the literature regarding the potential role of gut microbial health in the cross-communication of lifestyle patterns (exercise, diet, and sleep) with blood pressure regulation. Additionally, we discuss populations at increased risk of short sleep, and specifically the need to understand mechanisms and therapeutic opportunities in women, pregnancy, the elderly, and in African Americans.

There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF‐related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced‐based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF‐related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team‐based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.

Although insufficient sleep is associated with increased cardiovascular risk, evidence of a causal relationship is lacking. We investigated the effects of prolonged sleep restriction on 24-hour ambulatory blood pressure (BP) and other cardiovascular measures in 20 healthy young participants (aged 23.4±4.8 years, 9 females), who underwent a randomized, controlled, crossover, 16-day inpatient study consisting of 4 days of acclimation, 9 days of sleep restriction (4 hours of sleep/night) or control sleep (9 hours), and 3 days of recovery. Subjects consumed a weight maintenance diet with controlled nutrient composition throughout. A 24-hour BP (primary outcome) and cardiovascular biomarkers were measured repeatedly. Polysomnographic monitoring was continuous. Comparing sleep restriction versus control sleep, 24-hour mean BP was higher (adjusted mean difference, day 12: 2.1 mm Hg [95% CI, 0.6–3.6], corrected P =0.016), endothelial function was attenuated ( P <0.001), and plasma norepinephrine increased ( P =0.011). Despite increased deep sleep, BP was elevated while asleep during sleep restriction and recovery. Post hoc analysis revealed that 24-hour BP, wakefulness, and sleep BP increased during experimental and recovery phases of sleep restriction only in women, in whom 24-hour and sleep systolic BP increased by 8.0 (5.1–10.8) and 11.3 (5.9–16.7) mm Hg, respectively (both P <0.001). Shortened sleep causes persistent elevation in 24-hour and sleep-time BP. Pressor effects are evident despite closely controlled food intake and weight, suggesting that they are primarily driven by the shortened sleep duration. BP increases are especially striking and sustained in women, possibly suggesting lack of adaptation to sleep loss and thus greater vulnerability to its adverse cardiovascular effects.

Introduction: Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke; however the causal mechanisms are unknown. Understanding etiology of stroke in OSA patients may: (1) aid in ascertaining how OSA exerts its influence in increasing stroke risk, and (2) facilitate tailoring recurrent stroke prevention management strategies in OSA patients. Our study compares stroke subtypes in OSA cases versus controls without significant sleep disordered breathing. Hypothesis: We hypothesized cardioembolic (CE) strokes would occur more frequently in OSA cases than in controls. Methods: Consecutive patients were identified who underwent polysomnography (PSG) at Mayo Clinic and suffered an ischemic stroke within one year after PSG. Patients with an apnea-hypopnea index (AHI) ≤ 10 were classified as controls; AHI > 10 classified as OSA cases. Mechanism of stroke was determined using (1) the Causative Classification System for Ischemic Stroke (CCS) and (2) the phenotype definitions used in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Information on cardiovascular risk factors, neuroimaging, and echocardiography data were collected on each patient. Results: In 53 total subjects, CE strokes were more common among OSA cases (72% vs 33%, p=0.01). Large artery atherosclerosis and small vessel occlusion strokes were more common in controls. Atrial fibrillation (AF) was more frequent in OSA patients (59% vs 24%, p=0.01). Frequency of CE stroke increased with OSA severity. The association between OSA and CE stroke remained significant after controlling for AF (p=0.03, OR 4.5). Echocardiogram data revealed CE stroke risk factors were more frequent in OSA cases (84% vs 52% p=0.02). There were no significant differences between groups for left ventricular ejection fraction, left atrial volume index, or right ventricular systolic pressure. Conclusions: The results demonstrate a strong association between OSA and CE stroke. In OSA patients presenting with cryptogenic stroke, high clinical suspicion for cardioembolism is warranted. This may lead to consideration of further studies (eg, transesophageal echocardiography, Holter monitoring, or extended cardiac monitoring) to identify cardioembolic risk factors such as paroxysmal AF.

Introduction: Obesity is linked with heightened vulnerability to cardiovascular diseases including hypertension. Nonetheless, mechanistic studies addressing the effects of experimental weight gain on blood pressure are lacking. We sought to examine whether experimental weight gain raises ambulatory blood pressure in healthy individuals and identify any relationship between changes in blood pressure and changes in regional fat distribution. Methods: Twenty-six normal weight subjects were randomized to a 8-week period of weight gain through overfeeding (N=16; age 30.4±6.6 years, BMI 23.5±3.5 kg/m 2 ) or weight maintenance (N=10; age 27.1±7.7 years, BMI 23.6±2.7 kg/m 2 ). Measurements of body composition by dual-energy X-ray absorptiometry and abdominal computed tomographic scans and 24-h ambulatory blood pressure monitoring were obtained at baseline and at follow-up. Results: Overfeeding resulted in an increase in body weight of 3.7±1.5 kg ( p <0.001) in weight gainers, with increments seen in total (21994±8247.4 to 25180.7±8563.1 gr, p <0.001), visceral (61.6±32.7 to 75.5±30.9 cm 2 , p =0.002) and subcutaneous fat (135.5±77.4 to 167.9±82.9 cm 2 , p <0.001). No changes occurred in the maintenance group. Weight gainers exhibited an increase in 24-h systolic blood pressure at follow-up (113.7±8 to 117.7±7.9 mmHg, p =0.009) and mean blood pressure (MAP) (85.1±4.9 to 86.8±5.1 mmHg, p =0.02), while blood pressure was unchanged in controls. Changes in MAP were positively correlated only with changes in visceral fat (rho=0.452, p =0.02) but not with changes in weight or any other body composition measure. Conclusion: Modest weight gain leads to marked elevation in 24-h blood pressure in lean healthy subjects. The association between increased MAP and abdominal visceral fat accumulation suggests that visceral deposition of adipose tissue may contribute specifically and mechanistically to the enhanced risk of hypertension associated with weight gain.

Background: Regular exercise is considered a key element to maintain weight loss, but its role to induce weight loss has been controversial. Methods: In this retrospective study of 7237 individuals attending a worksite wellness center from September 2008 to October 2011 to assess predictors of weight loss at 12 months after joining. Upon joining the wellness center, participants completed a survey that assessed for the presence of cardiovascular risk factors, height, weight, self-perceived health behaviors and psychosocial factors using validated 11-point scale items. We limited the sample to 1927 overweight (25 < BMI ≤ 30) and obese (BMI > 30) participants who completed the survey in full at baseline and at 12 months (+/- 90 days). The outcome variable was weight change at 12 months after enrollment. Weight loss was defined as a loss of > 1kg. Results: Of 1927 participants, 998 (52%) were either overweight (n=573; 57%) or obese (n=425; 43%), and 60% were women. Mean (SD) age was 41 (11.5) yr, BMI 30.7 (5.5) kg/m 2 and they visited the wellness center 49 (90) times/year. At 12 months, 416 (42%) of the participants had lost >1 kg and 19% had lost > 5kg. The predictors of weight loss were: baseline BMI, [Odds Ratio (OR)= 1.56 (1.15-2.13); p < .0044] and [OR= 1.75 (1.26-2.44); p < .0010] for BMI between 30-35 and BMI ≥35, vs BMI between 25-29, respectively. In addition, visits/year [OR= 1.60 (1.19-2.16); p < .0010] and [OR= 1.85 (1.37-2.61); p < .0001] for those attending 13-52 sessions and > 52 visits/year, vs ≤ 12 visits/year, respectively. The association persisted after controlling for all covariates (ie, cardiovascular risk factors, self-perceived health behavior and psychosocial factors). The Table shows the results of the multivariate analysis assessing predictors for >1kg weight loss. Neither age, gender, perceived stress, self-perception of being overweight, following a healthy diet, nor history of hypertension, high blood cholesterol or diabetes predicted weight loss. Conclusions: A significant percentage of overweight or obese individuals lose weight after enrolling in a worksite wellness center. Frequency of attendance, baseline BMI, and support for maintaining a healthy living are associated with weight loss. These results suggest interventions to promote usage of wellness centers maybe be beneficial for the obese adult.

Background: This is the first systematic review and meta-analysis to investigate the effect of resistance training (RT) on survival and other cardiovascular outcomes including ischemic heart disease events and stroke. Methods: An experienced librarian searched databases up to September 25 th , 2017, for randomized trials and cohort studies that evaluated the effect of RT on survival and cardiovascular events in the general population. The databases included Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. Two investigators conducted the screening process independently and in duplicate. Cochrane tools were used to assess the risk of bias in clinical trials and observational studies. We calculated hazard ratios and 95% confidence intervals using RevMan and fixed and random effect models and had a subgroup analysis based on doses of RT and for the combination of RT and aerobic exercise (AE) vs no exercise. Results: The search identified 1429 studies from which 10 (one randomized trial) met the inclusion criteria, including 338,254 participants with a mean follow up of 8.14 years. The meta-analysis showed that RT, in comparison with no exercises, is associated with 24% lower all-cause mortality and 48% lower mortality when combined with AE. Based on subgroup analysis, performing 1-2 sessions of RT/week is associated with lower all-cause mortality by 28% (HR 0.72, 95% CI 0.66-0.78) whereas > 5 sessions of RT/week has no association with all-cause mortality (HR 0.99, 95% CI 0.76-1.31). Further, RT alone or combined with AE is associated with lower CV mortality compared to no exercise (Figures). Finally, RT alone also showed a borderline association with lower all-cancer mortality. Heterogeneity was present for several comparisons, and subsequent analysis will explore sources of this variability. Using study design-specific Cochrane risk of bias tools, no major sources of bias were identified in the included studies. One cohort study looked at the effect of RT on coronary heart disease events and found 23% risk reduction in men, while no study specifically assessed the effect of RT on cerebrovascular outcomes. Conclusion: RT is associated with lower all-cause, CV and all-cancer mortality. RT appears to have an additive effect when combined with AE.

Introduction: Identifying and mitigating factors that promote obesity will have a large public health impact. Sleep may be an important regulator of metabolism and energy expenditure. Voluntary sleep restriction is common, with 27% of US adults regularly getting ≤6 h of sleep per day. Epidemiologic evidence suggests a link between short sleep duration and obesity. Human experiments suggest that acute sleep deprivation reduces the anorexigenic hormone leptin, increases the orexigenic factor ghrelin, and promotes caloric intake. Meanwhile, increased energy expenditure during prolonged wakefulness may counterbalance any increased caloric intake associated with a lack of sleep. Hypothesis: We hypothesized that 8 days of modest sleep restriction would reduce leptin, increase ghrelin, promote caloric intake, and increase activity energy expenditure. Methods: We studied 17 healthy individuals age 18–40 y. Subjects completed a protocol consisting of one week of home actigraphy, a 3 night acclimation phase, followed by an 8 night experimental phase in which they were randomized to sleep ad lib or two-thirds of their normal sleep time. Blood was collected at the end of the two periods, food was freely available and caloric intake was calculated daily, and activity energy expenditure was assessed by a comprehensively validated system comprised of inclinometers and accelerometers. Sleep was confirmed using continuous electroencephalography. Mean change from the acclimation period ± standard deviation are presented, with statistical testing by two sample t tests on the changes between acclimation and experimental periods. Results: Subjects included 11 men and 6 women, of whom 8 were randomized to sleep deprivation and 9 served as controls. Sleep duration during the acclimation period averaged 6.5±0.9 h/day but fell to 5.2±0.1 h/d among those randomized to sleep deprivation. The sleep deprivation group consumed +549±583 kcal/d, whereas those randomized to ad lib sleep consumed −143±420 kcal/d (P<0.01). Activity energy expenditure by did not change in either group (+1.2±33.0% vs +8.4±34.0%, P=0.68). Sleep deprivation was associated with a trend towards increased leptin (+8.4±4.7% versus −9.8±13.5%, P=0.12) and decreased ghrelin (−4.9±5.3% vs +4.6±7.0%, P=0.38). Conclusions: Eight days of modest sleep restriction, similar to that encountered in everyday life, was associated with a striking increase in caloric intake with no change in activity energy expenditure. Contrary to expectations, we observed a trend towards increased circulating concentrations of leptin and reduced concentrations of ghrelin, more consistent with a consequence of a positive energy balance than a cause. Our data suggest that chronic sleep restriction may be an important and modifiable behavior promoting obesity.

Introduction: Elevated plasma levels of lipoprotein(a) [Lp(a)] are associated with increased risk for coronary artery disease (CAD), but the strength of the association and whether it is independent of other risk factors remains controversial. Differences in prospective studies may be partially explained by variability in methods used to measure Lp(a). Methods: We utilized two different analytical methods (electrophoretic and immunologic) to measure Lp(a) and determine the predictive value of Llp(a) in assessing angiographic coronary artery disease (CAD) and association with major adverse events in 500 patients. Results: In univariate analyses, median Lp(a) cholesterol and Lp(a) mass were significantly associated with angiographic CAD. In a multivariable model, Lp(a) cholesterol remained a significant correlate of CAD (OR 1.61, 95% CI 1.13-2.31, P = 0.009) while Lp(a) mass was not (OR 1.18, 95% CI 0.95-1.47, P = 0.14). Additionally, on multivariable analysis, the presence of a detectable amount of Lp(a) cholesterol (> or =2.5 mg/dL) was more strongly correlated with CAD than HDL cholesterol < 40 mg/dL, and, along withLp(a) cholesterol, was strongly correlated with major adverse events (OR 2.08 95% CI 1.22-3.56, P = 0.007 and OR 1.22, 95% CI 1.05-1.42, P = 0.012, respectively). Conclusions: Lp(a) cholesterol measured electrophoretically is independently correlated with angiographic CAD and presence of major adverse events, and may be used as an alternative or supplement to Lp(a) mass analysis.

Background: Endothelial dysfunction assessed by flow mediated dilation (FMD) of the brachial artery has been identified as an independent predictor of cardiovascular events. However, whether weight gain impairs endothelial function is unknown. Methods: A randomized blinded controlled-trial to assess the effects of weight gain on endothelial function. After a weight maintenance period supervised by an experience dietitian, volunteers were randomized to gain weight (4 kg) or maintain weight. We recruited lean (BMI 18.5–24.9 kg/m 2 ) healthy volunteers (no diseases, medications and non-smokers) from the community. Using ultrasound, endothelial function was measured by FMD and non-flow mediated dilation (NFMD) of the brachial artery in the early morning (6:30 a.m.). Endothelial function was measured at baseline, after fat gain at 8 weeks and after weight loss at 16 weeks for fat-gainers and at baseline and follow-up (8 weeks) for weight maintainers. Body composition techniques to measure body fat %, such as dual x-ray absorptiometry and abdominal CT scans were performed. Results: We recruited 35 fat-gainers and 8 weight maintainers. Mean age was 29 ± 6 years and 18 (42 %) were women. There were no differences in age, anthropometric and body composition measurements, blood pressure, heart rate or apnea hypopnea index at baseline between both groups. After an average gain of 4 kg, the fat-gainer group significantly increased their total, visceral and subcutaneous fat. Brachial artery FMD and NFMD remained unchanged in weight maintainers. However, it decreaed in fat-gainers (FMD=9.1 ± 3 vs. 7.6 ± 3.2, p=0.003 and NFMD=12.0 ± 4.9 vs. 10.1 ± 6.0, p=0.01), but recovered to baseline after subjects shed the gained weight (basleline vs. recovery: FMD=9.1 ± 3 vs. 9.0 ± 3, p=NS and NFMD =12.0 ± 4.9 vs.12.6 ± 5.0, p=NS). Visceral fat gain, but not subcutaneous fat gain was significantly correlated with the decrease in brachial artery FMD (rho =−0.42, p=0.004 and rho =−0.22, p=0.15, respectively). Conclusions: In lean healthy young subjects, modest weight gain results in impaired endothelial function, even in the absence of changes in blood pressure. Endothelial funcion recovers after weight loss. Viscerar rather than subcutaneous fat predicts endothelial dysfunction.