Inhaled endotoxin induces a systemic neutrophil response without affecting cardiovascular measures in a randomized cross-over exposure study.

OBJECTIVE: The gram-negative bacterial cell wall component endotoxin (lipopolysaccharide, LPS) is a key component of particulate matter (PM). PM exposure is associated with cardiovascular morbidity and mortality. However, the contribution of individual components of PM to acute and chronic cardiovascular measures is not clear. This study examines whether systemic inflammation induced by LPS inhalation causes acute changes in cardiovascular physiology measures. MATERIALS AND METHODS: In this double blinded, placebo-controlled crossover study, fifteen adult volunteers underwent inhalation exposure to 20,000 EU Clinical Center Reference Endotoxin (CCRE). Peripheral blood and induced sputum neutrophils were obtained at baseline and six hours post-exposure. Blood pressure, measures of left ventricular function (ejection fraction (LVEF) and global longitudinal strain (LVGLS)), and indices of endothelial function (flow mediated dilation (FMD) and velocity time integral during hyperemia (VTIhyp)) were measured before and after treatment. Wilcoxon sign-rank tests and linear mixed models were used for statistical analysis. RESULTS: In comparison with normal saline, LPS inhalation resulted in significant increases in peripheral blood and sputum neutrophils but was not associated with significant alterations in blood pressure, LVGLS, LVEF, FMD, or VTIhyp. DISCUSSION AND CONCLUSIONS: In healthy adults, systemic inflammation after LPS inhalation was not associated with acute changes in cardiovascular physiology. Larger studies are needed to investigate the effects of other PM components on inflammation induced cardiovascular dysfunction.

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.

Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients.

BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 µm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 µm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

The role of comorbid anxiety in exercise and depression trials: Secondary analysis of the SMILE-II randomized clinical trial.

OBJECTIVES: To explore the anxiolytic effects of a 4-month randomized, placebo-controlled trial of exercise and antidepressant medication in patients with major depressive disorder (MDD), and to examine the potential modifying effects of anxiety in treating depressive symptoms. MATERIALS AND METHODS: In this secondary analysis of the SMILE-II trial, 148 sedentary adults with MDD were randomized to: (a) supervised exercise, (b) home-based exercise, (c) sertraline, or (d) placebo control. Symptoms of state anxiety measured by the Spielberger Anxiety Inventory were examined before and after 4 months of treatment. Depressive symptoms were assessed by the Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory-II (BDI-II). Analyses were carried out using general linear models. RESULTS: Compared to placebo controls, the exercise and sertraline groups had lower state anxiety scores (standardized difference = 0.3 [95% CI = -0.6, -0.04]; p = 0.02) after treatment. Higher pretreatment state anxiety was associated with poorer depression outcomes in the active treatments compared to placebo controls for both the HAMD (p = .004) and BDI-II (p = .02). CONCLUSION: Aerobic exercise as well as sertraline reduced symptoms of state anxiety in patients with MDD. Higher levels of pretreatment anxiety attenuated the effects of the interventions on depressive symptoms, however, especially among exercisers. Patients with MDD with higher comorbid state anxiety appear to be less likely to benefit from exercise interventions in reducing depression and thus may require supplemental treatment with special attention to anxiety.

Does This Adult Patient Have Hypertension?: The Rational Clinical Examination Systematic Review.

Importance: Office blood pressure (BP) measurements are not the most accurate method to diagnose hypertension. Home BP monitoring (HBPM) and 24-hour ambulatory BP monitoring (ABPM) are out-of-office alternatives, and ABPM is considered the reference standard for BP assessment. Objective: To systematically review the accuracy of oscillometric office and home BP measurement methods for correctly classifying adults as having hypertension, defined using ABPM. Data Sources: PubMed, Cochrane Library, Embase, ClinicalTrials.gov, and DARE databases and the American Heart Association website (from inception to April 2021) were searched, along with reference lists from retrieved articles. Data Extraction and Synthesis: Two authors independently abstracted raw data and assessed methodological quality. A third author resolved disputes as needed. Main Outcomes and Measures: Random effects summary sensitivity, specificity, and likelihood ratios (LRs) were calculated for BP measurement methods for the diagnosis of hypertension. ABPM (24-hour mean BP ≥130/80 mm Hg or mean BP while awake ≥135/85 mm Hg) was considered the reference standard. Results: A total of 12 cross-sectional studies (n = 6877) that compared conventional oscillometric office BP measurements to mean BP during 24-hour ABPM and 6 studies (n = 2049) that compared mean BP on HBPM to mean BP during 24-hour ABPM were included (range, 117-2209 participants per analysis); 2 of these studies (n = 3040) used consecutive samples. The overall prevalence of hypertension identified by 24-hour ABPM was 49% (95% CI, 39%-60%) in the pooled studies that evaluated office measures and 54% (95% CI, 39%-69%) in studies that evaluated HBPM. All included studies assessed sensitivity and specificity at the office BP threshold of 140/90 mm Hg and the home BP threshold of 135/85 mm Hg. Conventional office oscillometric measurement (1-5 measurements in a single visit with BP ≥140/90 mm Hg) had a sensitivity of 51% (95% CI, 36%-67%), specificity of 88% (95% CI, 80%-96%), positive LR of 4.2 (95% CI, 2.5-6.0), and negative LR of 0.56 (95% CI, 0.42-0.69). Mean BP with HBPM (with BP ≥135/85 mm Hg) had a sensitivity of 75% (95% CI, 65%-86%), specificity of 76% (95% CI, 65%-86%), positive LR of 3.1 (95% CI, 2.2-4.0), and negative LR of 0.33 (95% CI, 0.20-0.47). Two studies (1 with a consecutive sample) that compared unattended automated mean office BP (with BP ≥135/85 mm Hg) with 24-hour ABPM had sensitivity ranging from 48% to 51% and specificity ranging from 80% to 91%. One study that compared attended automated mean office BP (with BP ≥140/90 mm Hg) with 24-hour ABPM had a sensitivity of 87.6% (95% CI, 83%-92%) and specificity of 24.1% (95% CI, 16%-32%). Conclusions and Relevance: Office measurements of BP may not be accurate enough to rule in or rule out hypertension; HBPM may be helpful to confirm a diagnosis. When there is uncertainty around threshold values or when office and HBPM are not in agreement, 24-hour ABPM should be considered to establish the diagnosis.

Race-Specific Patterns of Treatment Intensification Among Hypertensive Patients Using Home Blood Pressure Monitoring: Analysis Using Defined Daily Doses in the Heart Healthy Lenoir Study.

BACKGROUND: Racial disparities in blood pressure (BP) control persist, but whether differences by race in antihypertensive medication intensification (AMI) contribute is unknown. OBJECTIVE: To compare AMI by race for patients with elevated home BP readings. METHODS: This prospective cohort study followed adult patients from 6 rural primary care practices who used home BP monitoring (HBPM) and recorded/reported values. For providers, AMI was encouraged when mean HBPM systolic blood pressure (SBP) values were ⩾135 mm Hg; patients received phone-based coaching on HBPM technique and sharing HBPM findings. AMI was assessed between baseline and 12 months using defined daily dose (DDD) and summed to create a total antihypertensive DDD value. RESULTS: A total of 217 patients (mean age = 61.4 ± 10.2 years; 66% female; 57% black) provided usable HBPM data. Among 90 (41%) intensification-eligible hypertensive patients (ie, mean HBPM SBP values for 6-months ⩾135 mm Hg), mean total antihypertensive DDD was increased in 61% at 12 months. Blacks had significantly higher mean DDD at baseline and 12 months, but intensification (+0.72 vs +0.65; P = 0.83) was similar by race. However, intensification was greater in males than females (+1.1 vs +0.39; P = 0.031). Reduction in mean SBP following intensification was greater in white versus black patients (-8.2 vs -3.9 mm Hg; P = 0.14). Conclusion/Relevance: Treatment intensification in HBPM users was similar by race, differed significantly by gender, and may produce a greater response in white patients. Differential AMI in HBPM users does not appear to contribute to persistent racial disparities in BP control.

Impact of Racial Discrimination and Hostility on Adrenergic Receptor Responsiveness in African American Adults.

OBJECTIVE: Racial discrimination is increasingly recognized as a contributor to increased cardiovascular disease (CVD) risk among African Americans. Previous research has shown significant overlap between racial discrimination and hostility, an established predictor of CVD risk including alterations in adrenergic receptor functioning. The present study examined the associations of racial discrimination and hostility with adrenergic receptor responsiveness. METHODS: In a sample (N = 57) of young to middle-aged African American adults (51% female) with normal and mildly elevated blood pressure, a standardized isoproterenol sensitivity test (CD25) was used to evaluate ß-AR responsiveness, whereas the dose of phenylephrine required to increase mean arterial pressure by 25 mm Hg (PD25) was used to assess α1-AR responsiveness. Racial discrimination was measured using the Perceived Racism Scale and hostility was assessed using the Cook-Medley Hostility Scale. RESULTS: In hierarchical regression models, greater racial discrimination, but not hostility, emerged as a significant predictor of decreased ß-adrenergic receptor responsiveness (ß = .38, p = .004). However, moderation analysis revealed that the association between racial discrimination and blunted ß-adrenergic receptor responsiveness was strongest among those with higher hostility (ß = .49, 95% confidence interval = .17-.82, p = .004). In addition, hostility, but not racial discrimination, significantly predicted α1-AR responsiveness. CONCLUSIONS: These findings suggest racial discrimination was associated with blunted ß-adrenergic receptor responsiveness, providing further evidence of the potential contribution of racial discrimination to increased CVD risk among African Americans. The adverse effects of discrimination on cardiovascular health may be enhanced in individuals with higher levels of hostility.

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.

Modulation of Sympathetic Overactivity to Treat Resistant Hypertension.

PURPOSE OF REVIEW: To review the role and evidence for sympathetic overactivity in resistant hypertension and review the therapies that have been studied to modulate the sympathetic nervous system to treat resistant hypertension, with a focus on non-pharmacologic therapies such as renal denervation, baroreflex activation therapy, and carotid body ablation. RECENT FINDINGS: Based on the two best current techniques available for assessing sympathetic nerve activity, resistant hypertension is characterized by increased sympathetic nerve activity. Several device therapies, including renal denervation baroreflex activation therapy and carotid body ablation, have been developed as non-pharmacologic means of reducing blood pressure in resistant hypertension. With respect to renal denervation, the technologies for renal denervation have evolved since the unfavorable results from the HTN-3 study, and the revised technologies are being actively studied. Data from the first phase of the SPYRAL HTN Clinical Trial Program have been published. Results from the SPYRAL HTN-OFF MED trial suggest that ablating renal nerves can reduce blood pressure in patients with untreated mild-to-moderate hypertension. The SPYRAL HTN-ON MED trial demonstrated the safety and efficacy of catheter-based renal denervation in patients with uncontrolled hypertension on antihypertensive treatment. Interestingly, there was a high rate of medication non-adherence among patients with hypertension in this study. One attractive alternative to radiofrequency ablation is the use of ultrasound for renal denervation. Proof of concept data for the Paradise endovascular ultrasound renal denervation system was recently published in the RADIANCE-HTN SOLO trial. The results of this trial indicate that, among patients with mild to moderate hypertension on no medications, renal denervation with the Paradise system results in a greater reduction in both SBP and DBP at 2months compared with a sham procedure. Overall reductions were similar in magnitude to those noted in the SPYRAL HTN-OFF MED study. With respect to carotid body ablation, there is an ongoing proof of concept study that is investigating the safety and feasibility of ultrasound-based endovascular carotid body ablation in 30 subjects with treatment-resistant hypertension outside of the USA. The sympathetic nervous system is an important contributor to resistant hypertension. Modulation of sympathetic overactivity should be an important goal of treatment. Innovative therapies using non-pharmacologic means to suppress the sympathetic nervous system are actively being studied to treat resistant hypertension.

Implementing ABPM into Clinical Practice.

PURPOSE OF REVIEW: To review the data supporting the use of ambulatory blood pressure monitoring (ABPM), and to provide practical guidance for practitioners who are establishing an ambulatory monitoring service. RECENT FINDINGS: ABPM results more accurately reflect the risk of cardiovascular events than do office measurements of blood pressure. Moreover, many patients with high blood pressure in the office have normal blood pressure on ABPM-a pattern known as white coat hypertension-and have a prognosis similar to individuals who are normotensive in both settings. For these reasons, ABPM is recommended by the US Preventive Services Task Force to confirm the diagnosis of hypertension in patients with high office blood pressure before medical therapy is initiated. Similarly, the 2017 ACC/AHA High Blood Pressure Clinical Practice Guideline advocates the use of out-of-office blood pressure measurements to confirm hypertension and evaluate the efficacy of blood pressure-lowering medications. In addition to white coat hypertension, blood pressure phenotypes that are associated with increased cardiovascular risk and that can be recognized by ABPM include masked hypertension-characterized by normal office blood pressure but high values on ABPM-and high nocturnal blood pressure. In this review, best practices for starting a clinical ABPM service, performing an ABPM monitoring session, and interpreting and reporting ABPM data are described. ABPM is a valuable adjunct to careful office blood pressure measurement in diagnosing hypertension and in guiding antihypertensive therapy. Following recommended best practices can facilitate implementation of ABPM into clinical practice.

Enhancing Cardiac Rehabilitation With Stress Management Training: A Randomized, Clinical Efficacy Trial.

BACKGROUND: Cardiac rehabilitation (CR) is the standard of care for patients with coronary heart disease. Despite considerable epidemiological evidence that high stress is associated with worse health outcomes, stress management training (SMT) is not included routinely as a component of CR. METHODS AND RESULTS: One hundred fifty-one outpatients with coronary heart disease who were 36 to 84 years of age were randomized to 12 weeks of comprehensive CR or comprehensive CR combined with SMT (CR+SMT), with assessments of stress and coronary heart disease biomarkers obtained before and after treatment. A matched sample of CR-eligible patients who did not receive CR made up the no-CR comparison group. All participants were followed up for up to 5.3 years (median, 3.2 years) for clinical events. Patients randomized to CR+SMT exhibited greater reductions in composite stress levels compared with those randomized to CR alone (P=0.022), an effect that was driven primarily by improvements in anxiety, distress, and perceived stress. Both CR groups achieved significant, and comparable, improvements in coronary heart disease biomarkers. Participants in the CR+SMT group exhibited lower rates of clinical events compared with those in the CR-alone group (18% versus 33%; hazard ratio=0.49; 95% confidence interval, 0.25-0.95; P=0.035), and both CR groups had lower event rates compared with the no-CR group (47%; hazard ratio=0.44; 95% confidence interval, 0.27-0.71; P<0.001). CONCLUSIONS: CR enhanced by SMT produced significant reductions in stress and greater improvements in medical outcomes compared with standard CR. Our findings indicate that SMT may provide incremental benefit when combined with comprehensive CR and suggest that SMT should be incorporated routinely into CR. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00981253.

Effects of exercise and stress management training on nighttime blood pressure dipping in patients with coronary heart disease: A randomized, controlled trial.

INTRODUCTION: Blunted nighttime blood pressure (BP) dipping is prognostic of cardiovascular morbidity and mortality. Patients with coronary heart disease (CHD) are often characterized by a blunted nighttime BP dipping pattern. The present study compared the effects of 2 behavioral intervention programs, aerobic exercise (EX) and stress management (SM) training, with a usual care (UC) control group on BP dipping in a sample of CHD patients. METHODS: This was a secondary analysis of a randomized, controlled trial with allocation concealment and blinded outcome assessment in 134 patients with stable CHD and exercise-induced myocardial ischemia. Nighttime BP dipping was assessed by 24-hour ambulatory BP monitoring, at prerandomization baseline and after 16 weeks of one of the following treatments: usual medical care; UC plus supervised aerobic EX for 35 minutes, 3 times per week; UC plus weekly 1.5-hour sessions of SM training. RESULTS: The EX and SM groups exhibited greater improvements in systolic BP dipping (P=.052) and diastolic BP dipping (P=.031) compared with UC. Postintervention systolic BP percent-dipping means were 12.9% (SE=1.5) for SM, 11.1% (SE=1.4) for EX, and 8.6% (SE=1.4) for UC. Postintervention diastolic BP percent-dipping means were 13.3% (SE=1.9) for SM, 14.1% (SE=1.8) for EX, and 8.8% (1.8) for UC. CONCLUSIONS: For patients with stable CHD, EX or SM training resulted in improved nighttime BP dipping compared with usual medical care. These favorable effects of healthy lifestyle modifications may help reduce the risk of adverse clinical events.

Blood pressure reactivity to psychological stress is associated with clinical outcomes in patients with heart failure.

INTRODUCTION: Cardiovascular (CV) reactivity to psychological stress has been implicated in the development and exacerbation of cardiovascular disease (CVD). Although high CV reactivity traditionally is thought to convey greater risk of CVD, the relationship between reactivity and clinical outcomes is inconsistent and may depend on the patient population under investigation. The present study examined CV reactivity in patients with heart failure (HF) and its potential association with long-term clinical outcomes. METHODS: One hundred ninety-nine outpatients diagnosed with HF, with ejection fraction ≤40%, underwent an evaluation of blood pressure (BP) and heart rate reactivity to a laboratory-based simulated public-speaking stressor. Cox proportional hazards regression models were used to examine the prospective association between BP and heart rate reactivity on a combined end point of death or CV hospitalization over a 5-year median follow-up period. RESULTS: Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) reactivity, quantified as continuous variables, were inversely related to risk of death or CV hospitalization (Ps < .01) after controlling for established risk factors, including HF disease severity and etiology. In similar models, heart rate reactivity was unrelated to outcome (P = .12). In models with tertiles of reactivity, high SBP reactivity, compared with intermediate SBP reactivity, was associated with lower risk (hazard ratio [HR] = .498, 95% CI .335-.742, P =.001), whereas low SBP reactivity did not differ from intermediate reactivity. For DBP, high reactivity was marginally associated with lower risk compared with intermediate DBP reactivity (HR = .767, 95% CI .515-1.14, P =.193), whereas low DBP reactivity was associated with greater risk (HR = 1.49, 95% CI 1.027-2.155, P =.0359). No relationship of heart rate reactivity to outcome was identified. CONCLUSIONS: For HF patients with reduced ejection fraction, a robust increase in BP evoked by a laboratory-based psychological challenge was associated with lower risk for adverse CVD events and may be a novel and unique marker of left ventricular systolic reserve that is accompanied by a more favorable long-term prognosis.

Lifestyle and Neurocognition in Older Adults With Cardiovascular Risk Factors and Cognitive Impairment.

OBJECTIVE: The aim of the study was to determine the relationship of lifestyle factors and neurocognitive functioning in older adults with vascular risk factors and cognitive impairment, no dementia (CIND). METHODS: One hundred sixty adults (M [SD] = 65.4 [6.8] years) with CIND completed neurocognitive assessments of executive function, processing speed, and memory. Objective measures of physical activity using accelerometry, aerobic capacity determined by exercise testing, and dietary habits quantified by the Food Frequency Questionnaire and 4-Day Food Diary to assess adherence to the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets were obtained to assess direct effects with neurocognition. Potential indirect associations of high-sensitivity C-reactive protein and the Framingham Stroke Risk Profile also were examined. RESULTS: Greater aerobic capacity (ß = 0.24) and daily physical activity (ß = 0.15) were associated with better executive functioning/processing speed and verbal memory (ßs = 0.24; 0.16). Adherence to the DASH diet was associated with better verbal memory (ß = 0.17). Greater high-sensitivity C-reactive protein (ßs = -0.14; -0.21) and Framingham Stroke Risk Profile (ß = -0.18; -0.18) were associated with poorer executive functioning/processing speed and verbal memory. Greater stroke risk partially mediated the association of aerobic capacity with executive functioning/processing speed, and verbal memory and greater inflammation partially mediated the association of physical activity and aerobic fitness, with verbal memory. CONCLUSIONS: Higher levels of physical activity, aerobic fitness, and adherence to the DASH diet are associated with better neurocognitive performance in adults with CIND. These findings suggest that the adoption of healthy lifestyle habits could reduce the risk of neurocognitive decline in vulnerable older adults. CLINICAL TRIAL REGISTRATION: NCT01573546.

Risk factors for mortality in adult patients with sickle cell disease: a meta-analysis of studies in North America and Europe.

Although recent studies show an improved survival of children with sickle cell disease in the US and Europe, for adult patients mortality remains high. This study was conducted to evaluate the factors associated with mortality in adult patients following the approval of hydroxyurea. We first evaluated the association between selected variables and mortality at an academic center (University of North Carolina). Data sources were then searched for publications from 1998 to June 2016, with meta-analysis of eligible studies conducted in North America and Europe to evaluate the associations of selected variables with mortality in adult patients. Nine studies, combined with the UNC cohort (total n=3257 patients) met the eligibility criteria. Mortality was significantly associated with age (per 10-year increase in age) [7 studies, 2306 participants; hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.10-1.50], tricuspid regurgitant jet velocity 2.5 m/s or more (5 studies, 1577 participants; HR: 3.03; 95%CI: 2.0-4.60), reticulocyte count (3 studies, 1050 participants; HR: 1.05; 95%CI: 1.01-1.10), log(N-terminal-pro-brain natriuretic peptide) (3 studies, 800 participants; HR: 1.68; 95%CI: 1.48-1.90), and fetal hemoglobin (7 studies, 2477 participants; HR: 0.97; 95%CI: 0.94-1.0). This study identifies variables associated with mortality in adult patients with sickle cell disease in the hydroxyurea era.

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.

Periodontal Disease Associated with Aortic Arch Atheroma in Patients with Stroke or Transient Ischemic Attack.

BACKGROUND: Periodontal disease (PD) is associated with recurrent vascular event in stroke or transient ischemic attack (TIA). In this study, we investigated whether PD is independently associated with aortic arch atheroma (AA). We also explored the relationship PD has with AA plaque thickness and other characteristics associated with atheroembolic risk among patients with stroke or TIA. Finally, we confirmed the association between AA and recurrent vascular event in patients with stroke or TIA. METHODS: In this prospective longitudinal hospital-based cohort study, PD was assessed in patients with stroke and TIA. Patients with confirmed stroke and TIA (n = 106) were assessed by calibrated dental examiners to determine periodontal status and were followed over a median of 24 months for recurrent vascular events (stroke, myocardial infarction, and death). The extent of AA and other plaque characteristics was assessed by transesophageal echocardiography. RESULTS: Within our patient cohort, 27 of the 106 participants had recurrent vascular events (including 16 with stroke or TIA) over the median of 24-month follow-up. Severe PD was associated with increased AA plaque thickness and calcification. The results suggest that PD may be a risk factor for AA. In this cohort, we confirm the association of severe AA with recurrent vascular events. CONCLUSIONS: In patients with stroke or TIA, severe PD is associated with increased AA plaque thickness, a risk factor for recurrent events. Further studies are needed to confirm this finding and to determine whether treatment of PD can reduce the rate of AA plaque progression and recurrent vascular events.

Reactive hyperemia is associated with adverse clinical outcomes in heart failure.

INTRODUCTION: Impaired endothelial function, as assessed by brachial artery flow-mediated dilation (FMD), is an established risk factor for cardiovascular events. FMD is impaired in heart failure (HF) patients, but less is known about hyperemic brachial artery flow. We investigated the relationship between FMD and hyperemic flow with adverse clinical outcomes in HF patients. METHODS: Brachial artery FMD and hyperemic flow were assessed in 156 patients (70.5 % Male; 45.5% Caucasian; mean age (± SD) = 56.2 (±12.4) years) with HF and reduced left ventricular ejection fraction (LVEF). Cox proportional hazard models were used to assess the potential explanatory association of FMD and hyperemic flow with the composite outcome of death or cardiovascular hospitalization over a median 5-year follow-up period. RESULTS: Both FMD and hyperemic flow were negatively correlated with age, but unrelated to sex, race, body mass index, LVEF or N-terminal pro-B-Type natriuretic peptide (NT-ProBNP). Reduced hyperemic flow, but not FMD, was associated with an increased risk of death or cardiac hospitalization after controlling for traditional risk factors. CONCLUSION: The association of reduced hyperemic flow with increased risk of adverse clinical outcomes suggests that micro-vascular function may be an important prognostic marker in patients with HF.