Milos Milic

Depressed mood and flow-mediated dilation: a systematic review and meta-analysis.

Objective: This systematic and quantitative review evaluates the literature on associations between depressed mood and flow-mediated dilation (FMD), a measure of endothelial function, in adults. Methods: Published English-language articles (through December 2010) were identified from literature searches, assessed for data extraction, and evaluated for quality. Results: The literature includes cross-sectional (n = 9) and retrospective examinations (n = 3) of how FMD correlates with clinical or subclinical depression in healthy adults and cardiovascular patients (total N across 12 studies = 1491). FMD was assessed using a variety of methodologies. Samples were predominately older white and Asian subjects with higher socioeconomic status. In eight of the 12 articles selected for this review, at least one significant inverse association was noted between depressed mood and FMD, with primarily moderate effect sizes. The overall meta-analysis (random-effects model) revealed a combined effect size of correlation coefficient r = 0.19 (95% confidence interval = 0.08-0.29, p = .001). Significant combined effects were found for subgroups of studies that a) received better quality ratings (r = 0.29), b) examined patients with cardiovascular disease or with cardiovascular disease risk factors/comorbidity (r = 0.29), c) used maximum vasodilation to quantify FMD (r = 0.27), and d) assessed samples that had a mean age of 55 years and older (r = 0.15). Conclusions: Diverse studies support the inverse correlation between depressed mood and endothelial function, as measured by FMD. This literature would be strengthened by prospective studies, increased methodological consistency in FMD testing, and broader sampling (e.g., African Americans, younger age, lower socioeconomic status).BDI = Beck Depression Inventory; CVD = cardiovascular disease; FMD = flow-mediated dilation; MDD = major depressive disorder; SES = socioeconomic status

Association Between Chronic Caregiving Stress and Impaired Endothelial Function in the Elderly

OBJECTIVES We examined the relationship between chronic caregiving stress and endothelial function. BACKGROUND Evidence suggests that caregiving stress is associated with pathophysiologic processes related to atherosclerosis. Endothelial dysfunction is a possible underlying mechanism explaining the relationship between caregiving stress and cardiovascular morbidity. We investigated the relationship between chronic caregiving stress and endothelial dysfunction assessed by reactive hyperemia-induced flow-mediated dilation (FMD). METHODS Seventy-eight elderly individuals participated in the study. Fifty-five were providing in-home care to a spouse with Alzheimers disease, and 23 were married and living with a healthy, nondemented spouse. Analysis of covariance was used to examine the relationships between advancing dementia severity (Clinical Dementia Rating scores) and FMD and nitroglycerin-induced vasodilation of the brachial artery. Multiple linear regression was used to examine the relationship between years of caregiving and FMD. RESULTS Clinical Dementia Rating scale scores were significantly related to FMD (p = 0.033), with participants caring for a spouse with moderate to severe dementia showing significantly worse FMD than those caring for a spouse with mild dementia (p = 0.028) and noncaregivers (p = 0.032). Within the caregiver sample, the number of years of caregiving was significantly related to FMD (r = -0.465, p < 0.001). CONCLUSIONS These results suggest that the chronic stress of caregiving is associated with impaired endothelial function, which may be a potential mechanistic link to the observed increased risk of cardiovascular disease in elderly caregivers.

Adverse impact of mood on flow-mediated dilation.

Objective: To examine the impact of mood states on endothelial function, as measured noninvasively by brachial artery flow-mediated dilation (FMD). Substantial literature indicates that negative mood is linked to cardiovascular disease (CVD). However, the mechanisms underlying this relationship are not well defined. CVD is often preceded by dysfunction of the endothelium. Methods: Healthy adults (n = 70; mean age, 36 years) completed the Profile of Mood States (POMS), which contains six subscales (depression/dejection; tension/anxiety; anger/hostility; confusion/bewilderment; fatigue/inertia; vigor/activity) that are used to compute a total mood disturbance score for overall psychological distress. FMD was calculated (maximum percentage change in brachial artery diameter) from ultrasound assessment of arterial diameter at baseline and for 10 minutes after occlusion. Results: Regressions showed that increases in POMS total mood disturbance scores were associated with decreases in endothelial function. Mood disturbance explained 10% of the variance in FMD (p < .01), after controlling for age, sex, mean arterial pressure, body mass index, and socially desirable response bias. An exploratory set of separate regressions conducted to decompose the link between FMD and total mood disturbance revealed that the following POMS subscales were inversely correlated with FMD: depression/dejection, tension/anxiety, anger/hostility, fatigue/inertia (p’s < .05), and confusion/bewilderment (p < .01). Conclusions: Mood disturbance could contribute to CVD via impaired vasodilation. These preliminary results show that even mild levels of adverse psychological states, particularly depressed, anxious, angry, confused, and fatigued states, might be linked to increased cardiovascular risk. FMD = flow-mediated dilation; POMS = Profile of Mood States; TMD = total mood disturbance; MAP = mean arterial pressure; BMI = body mass index; CVD = cardiovascular disease.

Interactive Effects of Common β2-Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function

Few studies have examined to what extent genetic variants of the &bgr;2-adrenoceptor (ADRB2) are involved in the development of hypertension with age, although &bgr;2-adrenergic receptor responsiveness declines in older subjects. To investigate this, 10 common single-nucleotide polymorphisms (SNPs) in the promoter and coding regions of the ADRB2 gene were genotyped in an unrelated population consisting of 2 ethnic groups: European American (EA; n=610) and African American (AA; n=420). ADRB2 haplotypes were estimated by expectation maximization (EM) algorithm–based methods. In the general population for EAs and AAs, the variants of the ADRB2 gene, including the individual SNPs and their haplotypes, were not associated with hypertension. However, there was a significant interaction between age and one of the common haplotypes (haplotype 1) in EAs (P=0.01). Haplotype 1 was associated with protection against hypertension in young (≤50 years of age) but not in old (>50 years of age) EAs (odds ratio, 0.5; 95% confidence interval, 0.27 to 0.91; P=0.02). This age-specific effect was further supported by the observations that young subjects carrying ≥1 copy of haplotype 1 had significantly lower diastolic blood pressure and nearly 2-fold higher ADRB2 binding density than the noncarriers (P<0.05). With aging, their ADRB2 numbers decreased to the level of the noncarriers, along with increased body mass index (7%; P<0.05) and decreased heart rate (7%; P<0.001). Our study suggests that age is an important modifier for the effects of ADRB2 polymorphisms on ADRB2 function and the development of hypertension.

A Longitudinal Analysis of the Relations Among Stress, Depressive Symptoms, Leisure Satisfaction, and Endothelial Function in Caregivers

OBJECTIVE Stress and depressive symptoms have been associated with impaired endothelial function as measured by brachial artery flow-mediated dilation (FMD), possibly through repeated and heightened activation of the sympathetic nervous system. Behavioral correlates of depression, such as satisfaction with leisure activities (i.e., leisure satisfaction), may also be associated with endothelial function via their association with depressive symptoms. This study examined the longitudinal associations between stress, depressive symptoms, leisure satisfaction, and endothelial function as measured by FMD. METHOD Participants were 116 older Alzheimers caregivers (M age = 74.3 ± 8.1; 68% women; 87% white) who underwent 3 yearly assessments of FMD, stress, depressive symptoms, and leisure satisfaction. Mixed-regression analyses were used to examine longitudinal relationships between constructs of interest. RESULTS A significant and positive association was found between leisure satisfaction and FMD (p = .050), whereas a negative relationship was found for stress (p = .017). Depressive symptoms were not associated with FMD (p = .432). Time (p < .001) and the number of years caregiving (p = .027) were also significant predictors of FMD, suggesting that FMD decreased over time and was worse the longer a participant had been a caregiver prior to study enrollment. CONCLUSIONS These results suggest that behavioral correlates of depression (i.e., engagement in pleasurable activities) may be related to endothelial function in caregivers, and behavioral treatments for depression may be particularly useful in improving cardiovascular outcomes in caregivers.

Epinephrine and the Metabolic Syndrome

Epinephrine is the prototypical stress hormone. Its stimulation of all α and β adrenergic receptors elicits short-term systolic hypertension, hyperglycemia, and other aspects of the metabolic syndrome. Acute epinephrine infusion increases cardiac output and induces insulin resistance, but removal of the adrenal medulla has no consistent effect on blood pressure. Epinephrine is the most effective endogenous agonist at the β2 receptor. Transgenic mice that cannot make epinephrine and mice that lack the β2 receptor become hypertensive during exercise, presumably owing to the absence of β2-mediated vasodilatation. Epinephrine-deficient mice also have cardiac remodeling and poor cardiac responses to stress, but do not develop resting hypertension. Mice that cannot make epinephrine have a normal metabolism on a regular 14% fat diet but become hyperglycemic and insulin resistant when they eat a high fat diet. Vigorous exercise prevents diabetes in young mice and humans that overeat. However, exercise is a less effective treatment in older type 2 human diabetics and had no effect on glucose or insulin responses in older, diabetic mice. Sensitivity of the β2 receptor falls sharply with advancing age, and adrenal epinephrine release also decreases. However, treatment of older diabetic mice with a β2 adrenergic agonist improved insulin sensitivity, indicating that β2 subsensitivity can be overcome pharmacologically. Recent studies show that over the long term, epinephrine prevents hypertension during stress and improves glucose tolerance. The hyperglycemic influence of epinephrine is short-lived. Chronic administration of epinephrine and other β2 agonists improves cellular glucose uptake and metabolism. Overall, epinephrine counteracts the metabolic syndrome.

Antihypertensive therapy for patients with obstructive sleep apnea.

Purpose of reviewPatients with obstructive sleep apnea (OSA) often have hypertension that is difficult to control. We review the causes of OSA hypertension and evidence supporting specific therapies. Recent findingsSleep apnea commonly accompanies the metabolic syndrome and renal insuffiency. Apneas stimulate atrial natriuretic peptide release and sympathetic nerve activity, which persists throughout the daytime. The combination of increased sympathetic nerve activity and a nocturnal diuresis help explain reports that β-1 antagonists lower blood pressure more than thiazide diuretics in OSA. The angiotensin-converting enzyme (ACE) inhibitors and angiotensin II blocking drugs have been equally effective in some studies. Patients with treatment-resistant hypertension usually have OSA and have had a good antihypertensive response to spironolactone. SummaryAlthough most elderly hypertensives respond to diuretics and calcium channel blockers, patients with OSA responded to β-1 adrenergic blockers, ACE inhibitors, and angiotensin II blocking drugs. The response to a second drug is not known. However, many patients with OSA remain hypertensive on three antihypertensive agents, in which case the addition of spironolactone has been effective. It is reasonable to prescribe shorter acting antihypertensive drugs at night to treat nocturnal hypertension.

A comparison of pharmacologic and spontaneous baroreflex methods in aging and hypertension.

Background Phenylephrine bolus injection is an established technique to measure baroreflex sensitivity (BRS). This study quantified the relationship between the phenylephrine method and noninvasive measures of BRS and examined the effects of aging and hypertension on BRS. We also examined whether heart rate variability (HRV) provides as much information as does BRS. Methods BRS was determined by phenylephrine bolus (BRSphe), amyl nitrite inhalation (BRSamyl), Valsalva maneuver (BRSVals) and by time (BRS(+)) and spectral domain analysis (BRSLFα, 004–015 Hz) of spontaneous blood pressure and R–R interval changes over the 5-min time period. Results The phenylephrine method significantly correlated with other methods (BRSLFα R = 0.54, BRS(+) R = 0.55, BRSVals R = 0.43 and BRSamyl R = 0.39; P ≤ 0.001). Each method underestimated the BRSphe by the factors 0.62, 0.64, 0.59 and 0.33, respectively; P value less than 0.001. Only BRSLFα was significantly different between normotensive and hypertensive patients in young [24.3 ± 1.4 (n = 40) vs. 12.2 ± 2.3 (n = 7)] and middle-aged [16.5 ± 1.1 (n = 71) vs. 10.8 ± 1.1 (n = 31) groups, respectively]. HRV in the high frequency band (0.15–0.40 Hz) was significantly lower in young hypertensive patients than in normal controls (26 ± 6.0 vs. 50 ± 2.4, P < 0.05). Conclusion Although all methods correlated with the phenylephrine technique, none of them could be used interchangeably with that technique. BRSLFα detected the baroreflex loss of hypertension most clearly, and BRSamyl did not differ among groups.

Central hemodynamics in prehypertension: effect of the β-adrenergic antagonist nebivolol.

The aim of the current study was to characterize the effects of the novel β‐adrenergic antagonist nebivolol on central aortic blood pressures, arterial properties, and nitroxidergic activity in individuals with prehypertension. Prehypertension is emerging as a major risk factor for several adverse cardiovascular consequences. Increased pulse wave velocity, aortic augmentation index, and aortic blood pressures have been linked with augmented risk of cardiovascular disease and mortality. While the effects of antihypertensive drugs on these parameters in hypertensive patients have been studied, there are limited data so far in prehypertension. Fifty individuals with prehypertension were randomized to either nebivolol (5 mg per day) or placebo in a double‐blind clinical trial. Patients underwent measurement of pulse wave velocity as well as aortic blood pressure and aortic augmentation index via pulse wave analysis at baseline and 8 weeks. Patients also had blood and urine biochemistries done at each visit. Nebivolol achieved significant reductions in central aortic systolic (P=.011), diastolic (P=.009), and mean arterial blood pressure (P=.002). Pulse wave velocity trended toward improvement but did not achieve significance (P=.088). Nitric oxide production, measured as urinary nitrite/nitrite excretion, also rose substantially in the nebivolol group (by approximately 60%, P=.030). Central blood pressures can be effectively lowered by β‐blockade while patients are still in the prehypertension phase, and the effects may be coupled to improve nitric oxide release by the drug.

Endothelial function and sleep: Associations of flow-mediated dilation with perceived sleep quality and rapid eye movement (REM) sleep

Endothelial function typically precedes clinical manifestations of cardiovascular disease and provides a potential mechanism for the associations observed between cardiovascular disease and sleep quality. This study examined how subjective and objective indicators of sleep quality relate to endothelial function, as measured by brachial artery flow‐mediated dilation (FMD). In a clinical research centre, 100 non‐shift working adults (mean age: 36 years) completed FMD testing and the Pittsburgh Sleep Quality Index, along with a polysomnography assessment to obtain the following measures: slow wave sleep, percentage rapid eye movement (REM) sleep, REM sleep latency, total arousal index, total sleep time, wake after sleep onset, sleep efficiency and apnea–hypopnea index. Bivariate correlations and follow‐up multiple regressions examined how FMD related to subjective (i.e. Pittsburgh Sleep Quality Index scores) and objective (i.e. polysomnography‐derived) indicators of sleep quality. After FMD showed bivariate correlations with Pittsburgh Sleep Quality Index scores, percentage REM sleep and REM latency, further examination with separate regression models indicated that these associations remained significant after adjustments for sex, age, race, hypertension, body mass index, apnea–hypopnea index, smoking and income (Ps < 0.05). Specifically, as FMD decreased, scores on the Pittsburgh Sleep Quality Index increased (indicating decreased subjective sleep quality) and percentage REM sleep decreased, while REM sleep latency increased (Ps < 0.05). Poorer subjective sleep quality and adverse changes in REM sleep were associated with diminished vasodilation, which could link sleep disturbances to cardiovascular disease.