Effects of Lifestyle Modification on Patients With Resistant Hypertension: Results of the TRIUMPH Randomized Clinical Trial.

BACKGROUND: Although lifestyle modifications generally are effective in lowering blood pressure (BP) among patients with unmedicated hypertension and in those treated with 1 or 2 antihypertensive agents, the value of exercise and diet for lowering BP in patients with resistant hypertension is unknown. METHODS: One hundred forty patients with resistant hypertension (mean age, 63 years; 48% female; 59% Black; 31% with diabetes; 21% with chronic kidney disease) were randomly assigned to a 4-month program of lifestyle modification (C-LIFE [Center-Based Lifestyle Intervention]) including dietary counseling, behavioral weight management, and exercise, or a single counseling session providing SEPA (Standardized Education and Physician Advice). The primary end point was clinic systolic BP; secondary end points included 24-hour ambulatory BP and select cardiovascular disease biomarkers including baroreflex sensitivity to quantify the influence of the baroreflex on heart rate, high-frequency heart rate variability to assess vagally mediated modulation of heart rate, flow-mediated dilation to evaluate endothelial function, pulse wave velocity to assess arterial stiffness, and left ventricular mass to characterize left ventricular structure. RESULTS: Between-group comparisons revealed that the reduction in clinic systolic BP was greater in C-LIFE (-12.5 [95% CI, -14.9 to -10.2] mm Hg) compared with SEPA(-7.1 [-95% CI, 10.4 to -3.7] mm Hg) (P=0.005); 24-hour ambulatory systolic BP also was reduced in C-LIFE (-7.0 [95% CI, -8.5 to -4.0] mm Hg), with no change in SEPA (-0.3 [95% CI, -4.0 to 3.4] mm Hg) (P=0.001). Compared with SEPA, C-LIFE resulted in greater improvements in resting baroreflex sensitivity (2.3 ms/mm Hg [95% CI, 1.3 to 3.3] versus -1.1 ms/mm Hg [95% CI, -2.5 to 0.3]; P<0.001), high-frequency heart rate variability (0.4 ln ms2 [95% CI, 0.2 to 0.6] versus -0.2 ln ms2 [95% CI, -0.5 to 0.1]; P<0.001), and flow-mediated dilation (0.3% [95% CI, -0.3 to 1.0] versus -1.4% [95% CI, -2.5 to -0.3]; P=0.022). There were no between-group differences in pulse wave velocity (P=0.958) or left ventricular mass (P=0.596). CONCLUSIONS: Diet and exercise can lower BP in patients with resistant hypertension. A 4-month structured program of diet and exercise as adjunctive therapy delivered in a cardiac rehabilitation setting results in significant reductions in clinic and ambulatory BP and improvement in selected cardiovascular disease biomarkers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02342808.

Longer term benefits of exercise and escitalopram in the treatment of anxiety in patients with coronary heart disease: Six month follow-up of the UNWIND randomized clinical trial.

BACKGROUND: Anxiety is a common comorbidity in patients with coronary heart disease (CHD) and is associated with worse prognosis. However, effective treatment for anxiety in CHD patients is uncertain. The UNWIND randomized clinical trial showed that 12-week treatment of escitalopram was better than exercise training or placebo in reducing anxiety in anxious CHD patients. The longer-term benefits of treatment for anxiety are not known. METHODS: Patients were randomized to 12 weeks of Escitalopram (up to 20 mg), Exercise (3 times/wk), or placebo pill. At the conclusion of treatment, participants were followed for 6-months to determine the persistence of benefit on the primary anxiety endpoint assessed by the Hospital Anxiety and Depression Scale-Anxiety scale (HADS-A) and to assess the effects of treatment on major adverse cardiac events over a follow-up period of up to 6 years. RESULTS: Of the 128 participants initially randomized, 120 (94%) were available for follow-up. Participants randomized to the Escitalopram condition exhibited lower HADS-A scores (3.9 [3.1, 4.7]) compared to those randomized to Exercise (5.5 [4.6, 6.3]) (P = .007) and Placebo (5.3 [4.1, 6.5]) (P = .053). Over a median follow-up of 3.2 years (IQR: 2.3, 4.5), there were 29 adverse events but no significant between-group differences. CONCLUSION: In the UNWIND trial, 12 weeks of escitalopram treatment was effective in reducing anxiety. These beneficial effects were sustained for 6 months posttreatment. Although moderate or vigorous physical activity has a number of health benefits, exercise was not an effective treatment for anxiety in patients with CHD.

Ambulatory Heart Rate Variability Monitoring: Comparisons Between the Empatica E4 Wristband and Holter Electrocardiogram.

OBJECTIVE: Heart rate variability (HRV) is a useful index of psychological and physiological stress. Although several wristband devices have purported to measure HRV, none have demonstrated reliability when compared with the criterion-standard Holter monitor. We evaluated the reliability of HRV readings from the Empatica E4 wristband compared with a Holter monitor over a 24-hour period of simultaneous monitoring. METHODS: Agreement between the monitors was assessed by examining correlations and intraclass correlations (ICCs) for fixed sets in 13 individuals in a treatment trial for posttraumatic stress disorder (4 women; mean [standard deviation] age = 51.92 [6.17] years). Agreement was calculated at 1-second and 5-minute intervals for interbeat intervals (IBIs) and for 5-minute intervals of the root mean square of successive differences between normal heartbeats (RMSSD) and standard deviation of all normal R-R intervals (SDNN). Agreement across the entire 24-hour observation period was also measured. Frequency-domain measures of HRV could not be calculated because of too much missing data from the E4. RESULTS: Although high interdevice correlations and ICCs were observed between the E4 and Holter monitors for IBIs at 1-second (median r = 0.88; median ICC = 0.87) and 5-minute (median r = 0.94; median ICC = 0.94) intervals, reliabilities for 5-minute RMSSD (median r = -0.09; median ICC = -0.05) and 5-minute SDNN (median r = 0.48; median ICC = 0.47) were poor. Agreement between the devices on 24-hour measures of HRV was satisfactory (IBI: r = 0.97, ICC = 0.97; RMSSD: r = 0.77, IBI = 0.76; SDNN: r = 0.92, IBI = 0.89). CONCLUSIONS: Findings suggest that the low reliability of Empatica E4 as compared with the Holter monitor does not justify its use in ambulatory research for the measurement of HRV over time periods of 5 minutes or less.

Negative Affect-Related Autonomic Arousal Mediates the Association between Baroreflex Dysfunction and Insulin Resistance in Non-Diabetic Young Adults.

Autonomic dysfunction, in particular under-regulation of heart rate (HR) by the baroreflex, is implicated in development of insulin resistance (IR). According to reactivity hypothesis, sympathetic response to stressors may be more sensitive at predicting IR than baroreceptor sensitivity (BRS), a baseline measure of baroreflex functioning. Using ecological momentary assessment (EMA) of negative affect coupled with minute-to-minute HR and heart-rate variability (HRV) monitoring, we examined whether negative affect (NA)-related autonomic arousal mediates the association of BRS with IR. At baseline, BRS was measured, and fasting serum glucose and insulin levels were collected from 178 young adults (18-39 years old), from which homeostasis model assessment of IR (HOMA-IR) and beta-cell functioning (HOMA %B) were derived. Participants subsequently underwent one day of Holter HR and HRV monitoring while reporting negative affect levels via EMA. Multilevel modeling was used to assess the associations of momentary negative affect with HR and low- (LF) and high-frequency (HF) HRV during the 5-minute intervals following each EMA reading. Structural equation modeling was then used to determine whether individual differences in these associations mediated the association of BRS with IR, measured by HOMA-IR, HOMA %B, and insulin levels. As predicted, BRS was negatively associated with the IR (ß = -.17, p = .024). However, NA-related autonomic arousal mediated their association, accounting for 56% of the covariance between BRS and IR. Not only do these results provide support for reactivity hypothesis, they reveal a potential point of intervention in the treatment of affective dysregulation.

Microvascular Endothelial Function and Neurocognition Among Adults With Major Depressive Disorder.

BACKGROUND: Cardiovascular risk factors (CVRFs) and endothelial dysfunction have been associated independently with poorer neurocognition in middle-aged adults, particularly on tests of frontal lobe function. However, to our knowledge, no studies have examined markers of microvascular dysfunction on neurocognition or the potential interaction between macro- and microvascular biomarkers on neurocognition in middle-aged and older adults with major depressive disorder (MDD). METHODS: Participants included 202 adults with MDD who were not receiving mental health treatment. Microvascular endothelial function was assessed using a noninvasive marker of forearm reactive hyperemia velocity while macrovascular endothelial function was assessed using flow-mediated dilation (FMD) of the brachial artery. CVRFs were assessed using the Framingham Stroke Risk Profile and fasting lipid levels. A standardized neurocognitive assessment battery was used to assess three cognitive domains: executive function, working memory, and verbal memory. RESULTS: Greater microvascular dysfunction was associated with poorer neurocognition across all three domains. Microvascular function continued to predict verbal memory performance after accounting for background factors and CVRFs. Macro- and microvascular function interacted to predict working memory performance (F = 4.511, 178, p = 0.035), with a similar nonsignificant association for executive function (F = 2.731, 178, p = 0.095), with moderate associations observed between microvascular function and neurocognition in the presence of preserved FMD (r61 = 0.40, p = 0.001), but not when FMD was impaired (r63 = -0.05, p = 0.675). CONCLUSION: Greater microvascular dysfunction is associated with poorer neurocognition among middle-aged and older adults. This association was strongest in participants with preserved macrovascular function.

Trauma and Autonomic Dysregulation: Episodic-Versus Systemic-Negative Affect Underlying Cardiovascular Risk in Posttraumatic Stress Disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) has been linked to elevated heart rate (HR) and reduced heart rate variability (HRV) in cross-sectional research. Recent evidence suggests that this link may be driven by individual differences in autonomic arousal associated with momentary negative affect (NA). Using ecological momentary assessment (EMA) of NA and minute-to-minute HR/HRV monitoring, we examined whether NA-related HR/HRV mediated the association of PTSD symptom severity with 24-hour HRV and endothelial functioning. METHODS: One hundred ninety-seven young adults (18-39 years), 93 with PTSD, underwent 1 day of Holter monitoring while concurrently reporting NA levels via EMA. Two noninvasive measures of endothelial functioning-flow-mediated dilation and hyperemic flow-were also collected. Multilevel modeling was used to assess the associations of momentary NA with HR and low- and high-frequency HRV during the 5-minute intervals after each EMA reading. Latent variable modeling was then used to determine whether individual differences in these associations mediated the association of PTSD symptom severity with 24-hour HRV, flow-mediated dilation, and hyperemic flow. RESULTS: PTSD symptom severity was positively associated with NA-related autonomic arousal (ß = .21, p < .001), which significantly mediated the association of PTSD symptom severity with 24-hour HRV and hyperemic flow, accounting for 62% and 34% of their associations, respectively, while overshadowing the influence of smoking, lifetime alcohol dependence, sleep duration, mean NA, and episodes of acute NA. CONCLUSIONS: Results suggest that NA-related autonomic arousal is both a primary factor driving cardiovascular risk in PTSD and a potential point of intervention.

Racial differences in the association between heart rate variability and left ventricular mass.

NEW FINDINGS: What is the central question of this study? Decreased heart rate variability (HRV) is associated with increased cardiovascular disease (CVD) risk, including greater left ventricular mass (LVM). Despite their enhanced CVD risk profile, African Americans have been shown to exhibit higher HRV, relative to Whites; however, it is unclear whether this pattern extends to the association between HRV and LVM. What is the main finding and its importance? Using ECG and echocardiographic data, HRV was positively associated with LVM in a non-clinical sample of African Americans. These findings suggest that current assumptions regarding the meaning of higher HRV might not be universal, which might have implications for HRV as a risk marker among African Americans. Increased left ventricular mass (LVM) is an early precursor of target organ damage attributable to hypertension. Diminished parasympathetic cardiac control has been linked to both hypertension onset and left ventricular impairment; however, emerging evidence suggests that this pattern might be different in African Americans. The present study sought to determine whether race impacts the relationship between parasympathetic cardiac control and LVM. The LVM was assessed via echocardiography in a sample (n = 148) of African American and White adults (mean age 33.20 ± 5.71 years) with normal or mildly elevated blood pressure. Parasympathetic cardiac control was assessed by a measure of high-frequency heart rate variability (HF-HRV) determined from ECG recordings during 5 min of rest. In regression analysis, greater HF-HRV was associated with greater LVM among African Americans (P = 0.002) but was not related to LVM in Whites (P = 0.919). These are the first data to demonstrate that race moderates the relationship between HRV and LVM and further suggest that race might be an important factor in the association between parasympathetic cardiac control and other cardiovascular disease risk factors.

Computing a Synthetic Chronic Psychosocial Stress Measurement in Multiple Datasets and its Application in the Replication of G × E Interactions of the EBF1 Gene.

Chronic psychosocial stress adversely affects health and is associated with the development of disease [Williams, 2008]. Systematic epidemiological and genetic studies are needed to uncover genetic variants that interact with stress to modify metabolic responses across the life cycle that are the proximal contributors to the development of cardiovascular disease and precipitation of acute clinical events. Among the central challenges in the field are to perform and replicate gene-by-environment (G × E) studies. The challenge of measurement of individual experience of psychosocial stress is magnified in this context. Although many research datasets exist that contain genotyping and disease-related data, measures of psychosocial stress are often either absent or vary substantially across studies. In this paper, we provide an algorithm to create a synthetic measure of chronic psychosocial stress across multiple datasets, applying a consistent criterion that uses proxy indicators of stress components. We validated the computed scores of chronic psychosocial stress by observing moderately strong and significant correlations with the self-rated chronic psychosocial stress in the Multi-Ethnic Study of Atherosclerosis Cohort (Rho = 0.23, P < 0.0001) and with the measures of depressive symptoms in five datasets (Rho = 0.15-0.42, Ps = 0.005 to <0.0001) and by comparing the distributions of the self-rated and computed measures. Finally, we demonstrate the utility of this computed chronic psychosocial stress variable by providing three additional replications of our previous finding of gene-by-stress interaction with central obesity traits [Singh et al., 2015].

Treatment of anxiety in patients with coronary heart disease: Rationale and design of the UNderstanding the benefits of exercise and escitalopram in anxious patients WIth coroNary heart Disease (UNWIND) randomized clinical trial.

BACKGROUND: Anxiety is highly prevalent among patients with coronary heart disease (CHD), and there is growing evidence that high levels of anxiety are associated with worse prognosis. However, few studies have evaluated the efficacy of treating anxiety in CHD patients for reducing symptoms and improving clinical outcomes. Exercise and selective serotonin reuptake inhibitors have been shown to be effective in treating patients with depression, but have not been studied in cardiac patients with high anxiety. METHODS: The UNWIND trial is a randomized clinical trial of patients with CHD who are at increased risk for adverse events because of comorbid anxiety. One hundred fifty participants with CHD and elevated anxiety symptoms and/or with a diagnosed anxiety disorder will be randomly assigned to 12 weeks of aerobic exercise (3×/wk, 35 min, 70%-85% VO2peak), escitalopram (5-20 mg qd), or placebo. Before and after 12 weeks of treatment, participants will undergo assessments of anxiety symptoms and CHD biomarkers of risk, including measures of inflammation, lipids, hemoglobin A1c, heart rate variability, and vascular endothelial function. Primary outcomes include post-intervention effects on symptoms of anxiety and CHD biomarkers. Secondary outcomes include clinical outcomes (cardiovascular hospitalizations and all-cause death) and measures of quality of life. CONCLUSIONS: The UNWIND trial (ClinicalTrials.gov NCT02516332) will evaluate the efficacy of aerobic exercise and escitalopram for improving anxiety symptoms and reducing risk for adverse clinical events in anxious CHD patients.

Effects of Exercise and Sertraline on Measures of Coronary Heart Disease Risk in Patients With Major Depression: Results From the SMILE-II Randomized Clinical Trial.

OBJECTIVE: To assess the effects of supervised and home-based aerobic exercise training, and antidepressant pharmacotherapy (sertraline) on coronary heart disease (CHD) risk factors in a sample of participants with major depressive disorder (MDD). METHODS: The Standard Medical Intervention versus Long-term Exercise (SMILE)-II study randomized 202 adults (153 women, 49 men) diagnosed as having MDD to one of four interventions, each of 4-month duration: supervised exercise, home-based exercise, antidepressant medication (sertraline, 50-200 mg daily), or placebo pill. Patients underwent a structured clinical interview for depression and completed the Hamilton Depression Rating Scale. CHD risk factors included brachial artery flow-mediated dilation, carotid intima-media thickness, serum lipids, and 10-year atherosclerotic cardiovascular disease (ASCVD) risk. RESULTS: Compared with placebo, active treatment of depression (supervised exercise, home-based exercise, sertraline therapy) was associated with an improvement in CHD risk factors (improved flow-mediated dilation [p = .032], reduced progression of intima-media thickness [p = .037], and a reduction in 10-year ASCVD [p = .049]). The active treatments did not differ from each other in their effects on the CHD risk outcomes. CONCLUSIONS: Both exercise and antidepressant medication improved CHD risk factors and lowered ASCVD risk in patients with MDD. Because MDD is associated with increased risk for CHD events, treatment of depression with exercise or sertraline may reduce the risk of developing CHD in patients with MDD. TRIAL REGISTRATION: Clinical Trials Government Identifier: NCT-00331305.

Examining the Crux of Autonomic Dysfunction in Posttraumatic Stress Disorder: Whether Chronic or Situational Distress Underlies Elevated Heart Rate and Attenuated Heart Rate Variability.

OBJECTIVE: Posttraumatic stress disorder (PTSD) has been linked to elevated heart rate (HR) and reduced heart rate variability (HRV) in cross-sectional research. Using ecological momentary assessment and minute-to-minute HRV/HR monitoring, we examined whether cross-sectional associations between PTSD symptom severity and HRV/HR were due to overall elevations in distress levels or to attenuated autonomic regulation during episodes of acute distress. METHODS: Two hundred nineteen young adults (18-39 years old), 99 with PTSD, underwent 1 day of Holter monitoring and concurrently reported distress levels via ecological momentary assessment. Using multilevel modeling, we examined the associations between momentary distress and the 5-minute means for low-frequency (LF) and high-frequency (HF) HRV and HR immediately following distress ratings, and whether PTSD symptom severity moderated these associations. RESULTS: Compared with the controls, participants with PTSD recorded higher ambulatory distress (mean [standard deviation] = 1.7 [0.5] versus 1.2 [0.3], p < .001) and HR (87.2 [11.8] versus 82.9 [12.6] beats/min, p = .011), and lower ambulatory LF HRV (36.9 [14.7] versus 43.7 [16.9 ms, p = .002) and HF HRV (22.6 [12.3] versus 26.4 [14.6] milliseconds, p = .043). Overall distress level was not predictive of HR or HRV (p values > .27). However, baseline PTSD symptom severity was associated with elevated HR (t(1257) = 2.76, p = .006) and attenuated LF (t(1257) = -3.86, p < .001) and HF (t(1257) = -2.62, p = .009) in response to acute momentary distress. CONCLUSIONS: Results suggest that PTSD is associated with heightened arousal after situational distress and could explain prior findings associating PTSD with HR/HRV. Implications for treatment and cardiovascular risk are discussed.

Circadian Contrasts in Heart Rate Variability Associated With Posttraumatic Stress Disorder Symptoms in a Young Adult Cohort.

Prior research has demonstrated that individuals exposed to trauma have shown impaired autonomic function. We sought to determine if heart rate variability (HRV), a marker of impaired autonomic function, differed across periods of wake, rest, and sleep as a function of the level of symptoms of posttraumatic stress disorder (PTSD). A sample of young adults (N = 209), 95 of whom met full criteria for current PTSD based on the Clinician Administered PTSD Scale (CAPS; Blake et al., 1995), were evaluated for ≈ 24 hr using actigraphy and electrocardiogram. Actigraphy data were categorized as active, rest, or sleep. Multilevel modeling analyses showed that individuals with high PTSD symptom severity had lower high-frequency HRV than individuals with low PTSD symptom severity during periods of sleep, t(1083) = 2.20, p = .028, Cohen's d = 0.12. No differences were found during periods of activity, t(1083) = 1.34, p = .499, d = 0.05, or rest, t(1083) = 1.34, p = .180, d = 0.09. Our findings extended the import of prior studies to suggest that those with elevated PTSD symptoms may have decreased parasympathetic control during sleep. Moreover, relative to periods of wake and rest, sleep may represent a state of increased vulnerability for decreased parasympathetic cardiac control. Individuals with elevated PTSD symptoms may benefit from early screening for detection of cardiovascular disease.

Association of depressive and anxiety symptoms with 24-hour urinary catecholamines in individuals with untreated high blood pressure.

OBJECTIVE: Depression and anxiety are considered risk factors for cardiovascular disease (CVD). The explanatory mechanisms, however, are still to be characterized. One proposed pathophysiological pathway is dysregulation of the autonomic nervous system, including heightened sympathetic nervous system activity. This study examined the relationship between symptoms of depression, anxiety, and sympathetic nervous system activity in individuals with untreated high blood pressure. METHODS: A total of 140 participants with untreated high blood pressure (55% white, 38.5% female, mean [standard deviation] age = 45.5 [8.55] years) collected urine over a 24-hour period on 3 separate occasions. Urine samples were assayed for mean 24-hour epinephrine (EPI24) and norepinephrine excretion. Depressive symptoms were assessed using the Beck Depression Inventory, with anxiety symptoms assessed using the Spielberger State-Trait Anxiety Inventory. RESULTS: Depression and anxiety scores were intercorrelated (r = 0.76, p < .001). EPI24 was positively correlated with anxiety (r = 0.20, p = .02) but not depression (r = 0.02, p = .77), whereas 24-hour urinary norepinephrine excretion was not correlated with anxiety (r = 0.10, p = .21) or with depression (r = 0.07, p = .39). Regression models, accounting for sex, age, body mass index, race, mean systolic ambulatory blood pressure, tobacco use, alcohol use, physical activity, and sleep efficiency confirmed that anxiety was associated with EPI24 excretion (p = .023) and that depressive symptoms were not (p = .54). CONCLUSIONS: Anxiety was associated with heightened sympathoadrenal activity, suggesting a biological pathway through which anxiety could increase CVD risk. Anxiety and depression may confer increased CVD risk via different mechanisms.

Posttraumatic stress, heart rate variability, and the mediating role of behavioral health risks.

OBJECTIVE: Posttraumatic stress disorder (PTSD) has been linked to reduced heart rate variability (HRV), which is in turn a risk factor for cardiovascular disease and death. Although hyperarousal and anxiety are thought to underlie this association, behavioral health risks, including smoking, alcohol dependence, obesity, and sleep disturbance, represent potential mechanisms linking PTSD and HRV. METHODS: To test this hypothesis, short-term laboratory-based and 24-hour ambulatory measures of HRV were collected from 227 young adults (18-39 years), 107 of whom were diagnosed as having PTSD. Latent variable modeling was used to assess the relationship of PTSD symptoms with HRV along with potential behavioral health mediators. RESULTS: PTSD symptoms were associated with reduced HRV (ß = -0.21, p = .002). However, this association was reduced in models that adjusted for cigarette consumption and history of alcohol dependence and was rendered nonsignificant in a model adjusting for sleep disturbance. Independent mediation effects were deemed significant via bootstrapping analysis. Together, the three behavioral health factors (cigarette consumption, history of alcohol dependence, and sleep disturbance) accounted for 94% of the shared variance between PTSD symptoms and HRV. Abdominal obesity was not a significant mediator. CONCLUSIONS: These results indicate that behavioral factors-specifically smoking, alcohol overuse, and sleep disturbance-mediate the association between PTSD and HRV-based indices of autonomic nervous system dysregulation. Benefits from psychiatric and psychological interventions in PTSD may therefore be enhanced by including modification of health behaviors.

Higher Cardiovagal Baroreflex Sensitivity Predicts Increased Pain Outcomes After Cardiothoracic Surgery.

Excessive postoperative pain can lead to extended hospitalization and increased expenses, but factors that predict its severity are still unclear. Baroreceptor function could influence postoperative pain by modulating nociceptive processing and vagal-mediated anti-inflammatory reflexes. To investigate this relationship, we conducted a study with 55 patients undergoing minimally invasive cardiothoracic surgery to evaluate whether cardiovagal baroreflex sensitivity (BRS) can predict postoperative pain. We assessed the spontaneous cardiovagal BRS under resting pain-free conditions before surgery. We estimated postoperative pain outcomes with the Pain, Enjoyment, and General Activity scale and pressure pain thresholds on the first (POD1) and second (POD2) postoperative days and persistent pain 3 and 6 months after hospital discharge. We also measured circulating levels of relevant inflammatory biomarkers (C-reactive protein, albumin, cytokines) at baseline, POD1, and POD2 to assess the contribution of inflammation to the relationship between BRS and postoperative pain. Our mixed-effects model analysis showed a significant main effect of preoperative BRS on postoperative pain (P = .013). Linear regression analysis revealed a significant positive association between preoperative BRS and postoperative pain on POD2, even after adjusting for demographic, surgical, analgesic treatment, and psychological factors. Moreover, preoperative BRS was linked to pain interfering with general activity and enjoyment but not with other pain parameters (pain intensity and pressure pain thresholds). Preoperative BRS had modest associations with postoperative C-reactive protein and IL-10 levels, but they did not mediate its relationship with postoperative pain. These findings indicate that preoperative BRS can independently predict postoperative pain, which could serve as a modifiable criterion for optimizing postoperative pain management. PERSPECTIVE: This article shows that preoperative BRS predicts postoperative pain outcomes independently of the inflammatory response and pain sensitivity to noxious pressure stimulation. These results provide valuable insights into the role of baroreceptors in pain and suggest a helpful tool for improving postoperative pain management.

Effects of Lifestyle Modification on Psychosocial Function in Patients With Resistant Hypertension: SECONDARY OUTCOMES FROM THE TRIUMPH RANDOMIZED CLINICAL TRIAL.

PURPOSE: In a secondary analysis of the TRIUMPH clinical trial, psychological outcomes in patients with resistant hypertension (RH) receiving a diet and exercise intervention delivered in a cardiac rehabilitation setting were compared with those receiving a similar prescription of diet and exercise provided in a single counseling session by a health educator. METHODS: One hundred forty patients with RH were randomly assigned to a 4-mo program of dietary counseling, behavioral weight management, and exercise (C-LIFE) or a single counseling session providing standardized education and physician advice (SEPA). Participants completed a battery of questionnaires to assess psychological functioning before and after the intervention. A global measure of psychological functioning was derived from the General Health Questionnaire (GHQ), Perceived Stress Scale (PSS), Medical Outcomes Study 36-item Short Form Health Survey, Spielberger State-Trait Anxiety Inventory, Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory-II, and Patient-Reported Outcomes Measurement Information System (PROMIS) Anger scale. RESULTS: Participants in the C-LIFE intervention achieved greater improvements in psychological functioning compared with SEPA (C-LIFE: 58.9 [56.1, 61.8] vs SEPA: 66.5 [62.1, 70.9]; P = .024). Greater improvements were especially evident for the GHQ, PSS, and HADS. Examination of mediation revealed that greater weight loss ( B =-0.17, P = .004) and improved oxygen uptake ( B =-0.12, P = .044) were associated with improved psychological functioning. CONCLUSION: Compared with standard education and physician advice, a structured program of diet and exercise not only reduced blood pressure but also improved psychological functioning in patients with RH.

Multi-scale heart rate dynamics detected by phase-rectified signal averaging predicts mortality after acute myocardial infarction.

AIMS: Acceleration and deceleration capacity (AC and DC) for beat-to-beat short-term heart rate dynamics are powerful predictors of mortality after acute myocardial infarction (AMI). We examined if AC and DC for minute-order long-term heart rate dynamics also have independent predictive value. METHODS AND RESULTS: We studied 24-hr Holter electrcardiograms in 708 post-AMI patients who were followed up for up to 30 months thereafter. Acceleration capacity and DC was calculated with the time scales of T (window size defining heart rate) and s (wavelet scale) from 1 to 500 s and compared their prognostic values with conventional measures (AC(conv) and DC(conv)) that were calculated with (T,s) = [1,2 (beat)]. During the follow-up, 47 patients died. Both increased AC(conv) and decreased DC(conv) predicted mortality (C statistic, 0.792 and 0.797). Concordantly, sharp peaks of C statistics were observed at (T,s) = [2,7 (sec)] for both increased AC and decreased DC (0.762 and 0.768), but there were larger peaks of C statistics at around [30,60 (sec)] for both (0.783 and 0.796). The C statistic was greater for DC than AC at (30,60) (P = 0.0012). Deceleration capacity at (30,60) was a significant predictor even after adjusted for AC(conv) (P = 0.020) and DC(conv) (P = 0.028), but the predictive power of AC at (30,60) was no longer significant. CONCLUSION: A decrease in DC for minute-order long-term heart rate dynamics is a strong predictor for post-AMI mortality and the predictive power is independent of AC(conv) and DC(conv) for beat-to-beat short-term heart rate dynamics.

Effect of cognitive processing therapy on markers of cardiovascular risk in posttraumatic stress disorder patients: A randomized clinical trial.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with elevated risk of coronary heart disease (CHD); however, the effects of PTSD treatment on CHD biomarkers is unknown. This study examined whether cognitive processing therapy (CPT) improves 24-hourheart rate variability (HRV), a predictor of CHD mortality. METHODS: Individuals between the ages of 40 and 65 years with PTSD (n = 112) were randomized to receive 12 sessions of CPT or a Waiting List (WL) intervention comprised of 6 weekly telephone checks of emotional status. The primary outcome variable was 24-hour HRV estimated from the standard deviation of all normal R-R intervals (SDNN); secondary outcomes were the root mean square of successive differences between heart beats (RMSSD), low-frequency HRV (LF-HRV) and high-frequency HRV (HF-HRV). Secondary outcomes also included 24-hour urinary catecholamine excretion, plasma C-reactive protein (CRP), and flow-mediated dilation (FMD) of the brachial artery. For outcomes, linear mixed longitudinal models were used to estimate mean differences (Mdiff). RESULTS: Participants randomized to the CPT group did not show improved SDNN (Mdiff = 9.8; 95%CI, -2.7 to 22.3; p = 0.12), the primary outcome variable, but showed improved RMSSD (Mdiff = 3.8; 95% CI, 0.5 to 7.1; p = 0.02), LF- HRV (Mdiff =0.3; 95% CI, 0.1 to 0.5; p = 0.01), and HF-HRV (Mdiff = 0.3; 95% CI, 0.0 to 0.6; p = 0.03) compared to WL. There were no differences between groups in catecholamine excretion, FMD, or inflammatory markers. CONCLUSION: Treating PTSD may not only improve quality of life but may also help ameliorate heightened CHD risk characteristics of PTSD.

Interactive associations of depression and sleep apnea with adverse clinical outcomes after acute myocardial infarction.

OBJECTIVE: Depression and sleep apnea (SA) are common among patients with a recent acute myocardial infarction (AMI), and both are associated with increased risk for adverse outcomes. We tested the hypothesis that there is an interaction between them in relation to post-AMI prognosis. METHODS: Participants were patients with a recent AMI, 337 of them were depressed and 379 were nondepressed, who participated in a substudy of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial. SA was identified from Holter electrocardiogram by an algorithm that detects cyclic variation of heart rate. RESULTS: During a median follow-up of 25 months, 83 (11.6%) patients either died or experienced a recurrent AMI and 43 (6.0%) patients died. Among 94 patients with both depression and SA, these end points occurred in 25 (26.6%) and 20 (21.3%) at 3.9- and 6.9-times higher prevalence than predicted probabilities by ENRICHD clinical risk scores (p <.001 for both). In the patients with depression alone, SA alone, or neither, the prevalence was similar to the predicted probability. Depression and SA showed significant interactions in prediction of these end points (p = .02 and p = .03). SA independently predicted these end points in patients with depression (p = .001 and p <.001) but not in those without depression (p = .84 and p = .73). Similarly, depression independently predicted these end points in patients with SA (p <.001 for both) but not in those without SA (p = .12 and p = .61). CONCLUSIONS: Depression and SA are interactively associated with adverse clinical outcomes after AMI. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00313573.

Cerebrovascular Function, Vascular Risk, and Lifestyle Patterns in Resistant Hypertension.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) and blunted cerebral hemodynamic recruitment are thought to be important mechanisms linking hypertension to cerebrovascular and cognitive outcomes. Few studies have examined cardiovascular or dietary correlates of CVR among hypertensives. OBJECTIVE: To delineate associations between cardiometabolic risk, diet, and cerebrovascular functioning among individuals with resistant hypertension from the TRIUMPH trial (n = 140). METHODS: CVR was assessed by examining changes in tissue oxygenation (tissue oxygenation index [TOI] and oxygenated hemoglobin [HBO2]) using functional near-infrared spectroscopy (fNIRS) during a breath holding test, a standardized CVR assessment to elicit a hypercapnic response. Participants also underwent fNIRS during three cognitive challenge tasks. Vascular function was assessed by measurement of brachial artery flow-mediated dilation and hyperemic flow response. Cardiometabolic fitness was assessed from peak VO2 on an exercise treadmill test and body mass index. Dietary patterns were quantified using the DASH eating score. Cognitive function was assessed using a 45-minute test battery assessing Executive Function, Processing Speed, and Memory. RESULTS: Greater levels fitness (B = 0.30, p = 0.011), DASH compliance (B = 0.19, p = 0.045), and lower obesity (B = -0.30, p = 0.004), associated with greater changes in TOI, whereas greater flow-mediated dilation (B = 0.19, p = 0.031) and lower stroke risk (B = -0.19, p = 0.049) associated with greater HBO2. Similar associations were found for cerebral hemodynamic recruitment, and associations between CVR and cognition were moderated by duration of hypertension. CONCLUSION: Impaired CVR elevated cardiometabolic risk, obesity, vascular function, and fitness among hypertensives.