The Relationship Between Circulating Interleukin-6 Levels and Future Health Service Use in Dementia Caregivers.

OBJECTIVE: Older adults are among the most frequent users of emergency departments (EDs). Nonspecific symptoms, such as fatigue and widespread pain, are among the most common symptoms in patients admitted at the ED. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) are inflammation biomarkers associated with chronic stress (i.e., dementia caregiving) and nonspecific symptoms. This study aimed to determine whether IL-6 and TNF-α were prospectively associated with ED risk in dementia caregivers (CGs). METHODS: Participants were 85 dementia CGs, who reported during three assessments (3, 9, and 15 months after enrollment) if they had visited an ED for any reason. Cox proportional hazards models were used to examine the relations between resting circulating levels of IL-6 and TNF-α obtained at enrollment and subsequent risk for an ED visit, adjusting for age, sex, use of ED 1 month before enrollment, physical and mental health well-being, body mass index, and CG demands. RESULTS: (log) IL-6 significantly predicted ED visits during the 15-month follow-up (B = 1.96, SE = 0.82, p = .017). For every (log) picogram per milliliter increase in IL-6, the risk of visiting an ED was 7.10 times greater. TNF-α was not associated with subsequent ED visits. Exploratory analyses suggested that CGs with levels of IL-6 above the 80th percentile and experiencing high CG demands were at highest risk of an ED visit. CONCLUSIONS: IL-6 levels and CG demands may be useful for predicting vulnerability for future ED visits. Although further studies should be conducted to replicate and extend these findings, interventions that successfully modify inflammation markers, including the underlying pathophysiology related to stress and/or comorbid illnesses, may be useful in preventing costly and detrimental outcomes in this population.

Refining caregiver vulnerability for clinical practice: determinants of self-rated health in spousal dementia caregivers.

BACKGROUND: Caregivers of a family member with a chronic disability or illness such as dementia are at increased risk for chronic disease. There are many factors that contribute to dementia caregiver vulnerability and these factors can be challenging to assess in clinical settings. Self-rated health (SRH) is an independent measure of survival and physical health in the elderly. As an inclusive measure of health, SRH has been proposed as a reliable way to assess a patient's general health in primary care. Therefore, we sought to identify determinants of poor/fair SRH versus categories of at least good SRH in informal caregivers. METHODS: In a cross-sectional study, we examined 134 elderly (≥55 years) providing in-home care for a spouse with dementia who rated their own health with a single-item question: "In general, would you say your health is excellent, very good, good, fair or poor?". In a multivariable model, we compared caregivers with poor/fair SRH to those with good, very good, or excellent SRH on demographics, health characteristics (health behaviors, physical health indicators, psychosocial factors) and caregiving-specific stress (a composite index/total of four caregiving-specific stressors: years of caregiving, dementia severity, care recipient functional impairment and perceived caregiver burden). RESULTS: Compared with caregivers who rated their own health as either good (31.3%), very good (38.8%) or excellent (14.2%), caregivers with poor/fair SRH (15.7%) were more likely to have lower physical function and total greater caregiving-specific stress. More years of caregiving, severe dementia and care recipient functional impairment, but not perceived caregiver burden, were also more likely among caregivers with poor/fair SRH. Additionally, high negative affect and low positive affect were more likely in caregivers with poor/fair vs. good or excellent and very good or excellent SRH, respectively. CONCLUSIONS: Caregivers with poor/fair SRH were characterized by higher levels of medical comorbidity, low physical function, high negative, but low positive affect and longer duration of caregiving, as well as more severe dementia and greater functional impairment of the care recipient. These findings suggest that caregivers need to be more closely evaluated and targeted for preventive interventions in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT02317523 .

Sympathetic nerves and hypertension in stress, sleep apnea, and caregiving.

PURPOSE OF REVIEW: The sympathetic nervous system (SNS) mediates short-term increases in blood pressure. Evidence that psychosocial stress leads to chronic hypertension is mixed. The SNS activation found in obstructive sleep apnea (OSA), caregiving for a severely demented spouse, and obesity more specifically address whether SNS activation might lead to the metabolic syndrome and hypertension. RECENT FINDINGS: Obesity is associated with both increased SNS electrical activity and plasma norepinephrine. This is partly because of frequent OSA among the obese, but OSA does not fully explain SNS activation in obesity. Large stresses activate adrenal epinephrine release, but both animal and human studies indicate that epinephrine decreases aspects of the metabolic syndrome. On the other hand, norepinephrine is chronically elevated in OSA and among markedly stressed caregivers, and they have an increased incidence of hypertension. This is most striking in OSA, which causes a nocturnal diuresis. Hypertensive patients with OSA are resistant to the antihypertensive effects of diuretics, but respond to drugs that block SNS activity and the effects of renin. SUMMARY: The SNS may mediate chronic blood pressure increases in response to specific stresses and alter responses to therapy. Evidence linking psychosocial stress to hypertension is mixed.

Engagement in Pleasant Leisure Activities and Blood Pressure: A 5-Year Longitudinal Study in Alzheimer Caregivers.

OBJECTIVE: Elevated blood pressure is a significant public health concern, particularly given its association with cardiovascular disease risk, including stroke. Caring for a loved one with Alzheimer disease has been associated with physical health morbidity, including higher blood pressure. Engagement in adaptive coping strategies may help prevent blood pressure elevation in this population. This 5-year longitudinal study examined whether greater participation in pleasant leisure activities was associated with reduced blood pressure in caregivers. METHODS: Participants were 126 in-home spousal Alzheimer's caregivers (M [SD] age = 74.2 [7.9] years) that completed five yearly assessments. Linear mixed-effects models analysis was used to examine the longitudinal relationship between pleasant leisure activities and caregivers' blood pressure, after adjusting for demographic and health characteristics. RESULTS: Greater engagement in pleasant leisure activities was associated with reduced mean arterial blood pressure (B = -0.08, SE = 0.04, p = .040). Follow-up analyses indicated that engagement in activities was significantly associated with reduced diastolic (B = -0.07, SE = 0.03, p = .030) but not systolic blood pressure (B = -0.10, SE = 0.06, p = .114). In addition, mean arterial blood pressure was significantly reduced when caregiving duties ended because of placement of care recipients in nursing homes (B = -3.10, SE = 1.11, p = .005) or death of the care recipient (B = -2.64, SE = 1.14, p = .021). CONCLUSIONS: Greater engagement in pleasant leisure activities was associated with lowered caregivers' blood pressure over time. Participation in pleasant leisure activities may have cardiovascular health benefits for Alzheimer's caregivers.

Effect of obstructive sleep apnea on the response to hypertension therapy.

Obstructive sleep apnea (OSA) often precedes cardiovascular disease, partly due to treatment resistant hypertension. The nocturnal apneas of OSA trigger increased sympathetic nervous discharge during both sleep and wakefulness. Apneas also trigger cardiac release of the endogenous diuretic atrial natriuretic peptide. We hypothesized that treatment of the excess sympathetic nervous activity of OSA with a ß1 blocker would lower 24 h blood pressure (BP) more than diuretic therapy. Subjects with OSA associated hypertension received 2 weeks of placebo followed by the ß1 blocker nebivolol or hydrochlorothiazide (HCTZ) for 6 weeks in a blinded crossover study. BP, baroreflex sensitivity (BRS), heart rate variability (HRV), arterial reactivity, and stiffness were measured after placebo and each treatment. The ß1 blocker lowered clinic BP by -11/-8 mmHg, more than the -3/-1 effect of HCTZ (P < 0.01). The ß1 blocker lowered 24 h diastolic blood pressure (DBP) more than HCTZ. Although given at bedtime, neither drug increased BP dipping. Nebivolol increased HRV in the high-frequency band. Nebivolol did not alter BRS while HCTZ significantly diminished BRS compared to nebivolol (P < 0.01). Nebivolol increased flow-mediated brachial artery dilation when compared to HCTZ and slowed pulse wave velocity, indicating a decrease in arterial stiffness. Diuretic therapy failed to lower BP in OSA subjects and this might account for the frequent association of OSA with treatment resistant hypertension. However, blockade of the excess sympathetic nervous activity of OSA with a ß1 blocker lowered both clinic and 24 h DBP.

Genome of the pathogen Porphyromonas gingivalis recovered from a biofilm in a hospital sink using a high-throughput single-cell genomics platform.

Although biofilms have been shown to be reservoirs of pathogens, our knowledge of the microbial diversity in biofilms within critical areas, such as health care facilities, is limited. Available methods for pathogen identification and strain typing have some inherent restrictions. In particular, culturing will yield only a fraction of the species present, PCR of virulence or marker genes is mainly focused on a handful of known species, and shotgun metagenomics is limited in the ability to detect strain variations. In this study, we present a single-cell genome sequencing approach to address these limitations and demonstrate it by specifically targeting bacterial cells within a complex biofilm from a hospital bathroom sink drain. A newly developed, automated platform was used to generate genomic DNA by the multiple displacement amplification (MDA) technique from hundreds of single cells in parallel. MDA reactions were screened and classified by 16S rRNA gene PCR sequence, which revealed a broad range of bacteria covering 25 different genera representing environmental species, human commensals, and opportunistic human pathogens. Here we focus on the recovery of a nearly complete genome representing a novel strain of the periodontal pathogen Porphyromonas gingivalis (P. gingivalis JCVI SC001) using the single-cell assembly tool SPAdes. Single-cell genomics is becoming an accepted method to capture novel genomes, primarily in the marine and soil environments. Here we show for the first time that it also enables comparative genomic analysis of strain variation in a pathogen captured from complex biofilm samples in a healthcare facility.

Candidate phylum TM6 genome recovered from a hospital sink biofilm provides genomic insights into this uncultivated phylum.

The "dark matter of life" describes microbes and even entire divisions of bacterial phyla that have evaded cultivation and have yet to be sequenced. We present a genome from the globally distributed but elusive candidate phylum TM6 and uncover its metabolic potential. TM6 was detected in a biofilm from a sink drain within a hospital restroom by analyzing cells using a highly automated single-cell genomics platform. We developed an approach for increasing throughput and effectively improving the likelihood of sampling rare events based on forming small random pools of single-flow-sorted cells, amplifying their DNA by multiple displacement amplification and sequencing all cells in the pool, creating a "mini-metagenome." A recently developed single-cell assembler, SPAdes, in combination with contig binning methods, allowed the reconstruction of genomes from these mini-metagenomes. A total of 1.07 Mb was recovered in seven contigs for this member of TM6 (JCVI TM6SC1), estimated to represent 90% of its genome. High nucleotide identity between a total of three TM6 genome drafts generated from pools that were independently captured, amplified, and assembled provided strong confirmation of a correct genomic sequence. TM6 is likely a Gram-negative organism and possibly a symbiont of an unknown host (nonfree living) in part based on its small genome, low-GC content, and lack of biosynthesis pathways for most amino acids and vitamins. Phylogenomic analysis of conserved single-copy genes confirms that TM6SC1 is a deeply branching phylum.

MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension.

Hypertension is a common hereditary syndrome with unclear pathogenesis. Chromogranin A (Chga), which catalyzes formation and cargo storage of regulated secretory granules in neuroendocrine cells, contributes to blood pressure homeostasis centrally and peripherally. Elevated Chga occurs in spontaneously hypertensive rat (SHR) adrenal glands and plasma, but central expression is unexplored. In this report, we measured SHR and Wistar-Kyoto rat (control) Chga expression in central and peripheral nervous systems, and found Chga protein to be decreased in the SHR brainstem, yet increased in the adrenal and the plasma. By re-sequencing, we systematically identified five promoter, two coding and one 3'-untranslated region (3'-UTR) polymorphism at the SHR (versus WKY or BN) Chga locus. Using HXB/BXH recombinant inbred (RI) strain linkage and correlations, we demonstrated genetic determination of Chga expression in SHR, including a cis-quantitative trait loci (QTLs) (i.e. at the Chga locus), and such expression influenced biochemical determinants of blood pressure, including a cascade of catecholamine biosynthetic enzymes, catecholamines themselves and steroids. Luciferase reporter assays demonstrated that the 3'-UTR polymorphism (which disrupts a microRNA miR-22 motif) and promoter polymorphisms altered gene expression consistent with the decline in SHR central Chga expression. Coding region polymorphisms did not account for changes in Chga expression or function. Thus, we hypothesized that the 3'-UTR and promoter mutations lead to dysregulation (diminution) of Chga in brainstem cardiovascular control nuclei, ultimately contributing to the pathogenesis of hypertension in SHR. Accordingly, we demonstrated that in vivo administration of miR-22 antagomir to SHR causes substantial (∼18 mmHg) reductions in blood pressure, opening a novel therapeutic avenue for hypertension.

Beta-adrenergic receptor mediated inflammation control by monocytes is associated with blood pressure and risk factors for cardiovascular disease.

Overwhelming data indicate that individuals with even mildly elevated blood pressure (BP) are at great risk for developing clinical hypertension and future cardiovascular disease (CVD). There remains a lack of consensus regarding treatment strategies for mildly elevated BP, termed prehypertension, and the knowledge of pathophysiology and mechanisms of its clinical outcomes remains limited. Our primary aim was to investigate ßAR-mediated inflammation control (BARIC) responses of blood monocytes to isoproterenol (Iso) in relation to BP and CVD risk factors, including obesity, depressive mood, fasting glucose, triglycerides, and cholesterol levels in the 64 prehypertensive compared to 84 individuals with normal BP. BARIC was determined by measuring the degree of inhibition in lipopolysaccharides-stimulated monocytic intracellular TNF production by ex vivo Iso treatment (10(-8)M). Depressive mood was assessed by Beck Depression Inventory (BDI). Fasting metabolic and lipid panels were assessed, and plasma levels of inflammatory cytokines TNF, IL-1ß, IL-6 were measured in a subset to confirm proinflammatory state of prehypertensive participants. Prehypertensive participants were older, heavier, included more men, and presented higher levels of fasting glucose, triglycerides, cholesterol, and plasma TNF compared to normotensive participants (p's<.05). BARIC was significantly attenuated in the prehypertensive compared to normotensive group (p<.05). BARIC was negatively associated with systolic BP, diastolic BP, age, BMI, fasting glucose, triglycerides, total and low density cholesterol levels, and somatic depressive symptoms in all participants (p's<.0001 to .05). However, among the prehypertensive individuals BARIC was positively associated with SBP even after controlling for the covariates (age, gender, race, BMI, glucose and lipid panel, somatic BDI scores) (p<.05). This differing nature of the BARIC-SBP relationship between the two BP groups may be attributed to moderating factors such as cardiorespiratory fitness or depressive symptoms that could not be clearly deciphered in this current study. Nonetheless, our findings indicate the associations between inflammation dysregulation mediated by sympathoadrenal activation and BP that is observable even among individuals with normal to mildly elevated BP. BARIC may be a useful and sensitive indicator of elevated risk for vascular inflammatory disease that can be detected even at lower BP levels, especially given its associations with traditional CVD risk factors and the critical role of monocytes in atherogenic processes.

Leukocyte ß-adrenergic receptor sensitivity and depression severity in patients with heart failure.

OBJECTIVES: Clinical outcomes are worse for patients with heart failure (HF) and elevated depression symptoms. Depression-related sympathoimmune dysregulation may be one mechanism leading to poorer HF prognosis. Sympathetically mediated adrenergic activity is known to regulate immune activity via ß-adrenergic receptors (ß-ARs). However, studies show conflicting relationships between leukocyte ß-AR sensitivity and depression symptoms. The aim of this study was to determine in patients with HF the relationship of leukocyte ß-AR sensitivity with two diverse measures of depression, self-report questionnaire versus clinical diagnostic interview. METHODS: Patients with HF (N = 73, mean [standard deviation] age = 56.3 [13.0]) completed the Beck Depression Inventory-1A and a modified Structured Clinical Interview for the DSM-IV. Leukocyte ß-AR sensitivity was determined from isoproterenol-stimulated cyclic adenosine monophosphate levels; plasma norepinephrine and epinephrine were also assessed. RESULTS: Patients with major depression determined by Structured Clinical Interview for the DSM-IV had significantly higher ß-AR sensitivity than did nondepressed patients (F(6,72) = 9.27, p = .003, η = 0.12). The Beck Depression Inventory-1A revealed a more complex relationship. Minimal, mild, and moderate-to-severe depression symptom groups had significant differences in ß-AR sensitivity (F(7,72) = 7.03, p = .002, η = 0.18); mild symptoms were associated with reduced ß-AR sensitivity and moderate-to-severe symptoms with higher ß-AR sensitivity compared with patients with minimal depressive symptoms. CONCLUSIONS: Clinical depression was associated with elevated ß-AR sensitivity in patients with HF. By deconstructing depression measurements, a greater depth of information may be garnered to potentially reveal subtypes of depression symptoms and their relation to ß-AR sensitivity.

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.

In vivo ß-adrenergic receptor responsiveness: ethnic differences in the relationship with symptoms of depression and fatigue.

BACKGROUND: Depressive symptoms and fatigue frequently overlap in clinical samples and the general population. The link of depressive symptoms and fatigue with increased risk of cardiovascular disease has been partly explained by shared biological mechanisms including sympathetic overactivity. Prolonged sympathetic overactivity downregulates the responsiveness of the ß-adrenergic receptor (ß-AR), a receptor that mediates several end-organ sympathetic responses. PURPOSE: The authors studied whether depression and fatigue are related to reduced ß-AR responsiveness within the human body (in vivo) in an ethnically diverse sample of African and Caucasian Americans. METHODS: The chronotropic25 dose (CD25) was used to determine in vivo ß-AR responsiveness in 93 healthy participants. Psychometric measures included the Center of Epidemiological Studies-Depression Scale and the Multidimensional Fatigue Symptom Inventory. RESULTS: Hierarchical regression analyses (adjusted for age, gender, body mass index, blood pressure, smoking, and ethnicity) revealed that mental fatigue was significantly related to reduced ß-AR responsiveness (i.e., higher CD25 values) in the whole sample. Moderation analyses indicated significant ethnicity × depression/fatigue interactions. Depressive symptoms, total fatigue, emotional fatigue, mental fatigue, and physical fatigue were related to reduced ß-AR responsiveness in Caucasian American but not in African Americans. CONCLUSIONS: Our findings suggest that symptoms of depression and fatigue are related to decreased in vivo ß-AR responsiveness in Caucasian Americans. The lack of this association in African Americans highlights the importance for considering ethnicity as a potential moderator in research focusing on associations between psychological variables and cardiovascular function.

Plasma volume and flight duration effects on post-spaceflight soluble adhesion molecules.

BACKGROUND: We examined the effects of plasma volume (PV) changes and flight duration on circulating soluble adhesion markers (sP-selection, sE-selection, and sICAM-1). METHODS: Study participants were 22 astronauts (2 women). Missions ranged from 5 to 16 d. Astronauts were split into two groups: those who spent less than 8 d in space and those who spent more than 8 d in space. Soluble adhesion markers and PV were assessed 10 d prelaunch, immediately after landing, and 2-4 d postflight. RESULTS: Compared to prelaunch, PV significantly decreased by 4.9% after landing and increased by 9.9% 2-4 d postflight. After landing, sICAM-1 decreased (233.15 vs. 226.78 ng · ml⁻¹) and remained lowered 2-4 d after landing (223.25 ng · ml⁻¹). Adjusting for PV changes, sICAM-1 upon landing was less than prelaunch (218.23 ng · ml⁻¹), but became greater 2-4 d postflight (250.30 ng · ml⁻¹). From prelaunch to landing, sE-selection decreased significantly (30.25 vs. 28.51 ng · ml⁻¹) and returned to prelaunch levels 2-4 d postflight (30.10 ng · ml⁻¹). Adjusting for PV changes, sE-selection was significantly greater 2-4 d postflight (33.48 ng · ml⁻¹) compared to prelaunch. In those who spent less than 8 d in space only, sP-selection increased from prelaunch levels to landing day (31.66 vs. 48.06 ng · ml⁻¹), with and without adjustment for PV changes. Flight duration did not influence PV, sICAM-1, or sE-selection. DISCUSSION: Spaceflight leads to an internal environment that decreases PV during flight but rebounds after flight, leading to a dilution of sICAM-1 and sE-selection, but does not appear to affect sP-selection. Flight duration only affected sP-selection.

Sympathetic overactivity and nocturnal diuresis in obstructive sleep apnea alter the response to hypertension therapy.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with high blood pressure that responds poorly to usual antihypertensive therapy. METHODS AND RESULTS: Forty-one subjects with OSA had 25% higher plasma norepinephrine and 42% higher epinephrine measured every 2 h over 24 h than 20 control subjects. They also excreted more sodium during sleep. This suggested that that a sympatholytic would be a more successful antihypertensive than a diuretic. To test this hypothesis we treated a second group of 23 hypertensive apneics with placebo, 6 weeks of the sympatholytic guanfacine and 6 weeks of hydrochlorothiazide in a crossover study. Guanfacine lowered 24-hour blood pressure by 9.6/6.7 mmHg, more than the 5.4/2.9 mmHg effect of hydrochlorothiazide (P < 0.05). Nighttime systolic blood pressure dipping was poor at 6.6 ± 1.8%. Hydrochlorothiazide did not alter blood pressure dipping but guanfacine improved dipping to 9.1 ± 1.2%, a better result (P = 0.03) than from the diuretic. Central aortic pressure by pulse wave analysis was 120/84 mmHg on hydrochlorothiazide and 109/72 on guanfacine, (P < 0.05). Guanfacine, but not hydrochlorothiazide, improved baroreflex sensitivity, heart rate variability and flow mediated vascular dilation, suggesting that decreasing the elevated sympathetic nerve activity of obstructive sleep apnea returned vascular function toward normal. CONCLUSIONS: OSA is the most common condition associated with antihypertensive treatment failure. It increased sympathetic nerve activity day and night. Drugs that block sympathetic nerve function are not among the 4 most commonly recommended classes of antihypertensives but diuretics are. Sympatholytic therapy was superior to diuretic treatment for hypertension associated with sleep apnea. TRIAL REGISTRATION: NCT, NCT02699125, Registered 26 February 2016 - Retrospectively registered, https://clinicaltrials.gov/study/NCT02699125 .

Genetic variation at the delta-sarcoglycan (SGCD) locus elevates heritable sympathetic nerve activity in human twin pairs.

The Syrian Cardiomyopathic Hamster (BIO-14.6/53.58 strains) model of cardiac failure, resulting from naturally occurring deletion at the SGCD (delta-sarcoglycan) locus, displays widespread disturbances in catecholamine metabolism. Rare Mendelian myopathy disorders of human SGCD occur, although common naturally occurring SGCD genetic variation has not been evaluated for effects on human norepinephrine (NE) secretion. This study investigated the effect of SGCD genetic variation on control of NE secretion in healthy twin pairs. Genetic associations profiled SNPs across the SGCD locus. Trait heritability (h(2)) and genetic covariance (pleiotropy; shared h(2)) were evaluated. Sympathochromaffin exocytosis in vivo was probed in plasma by both catecholamines and Chromogranin B (CHGB). Plasma NE is substantially heritable (p = 3.19E-16, at 65.2 ± 5.0% of trait variance), sharing significant (p < 0.05) genetic determination with circulating and urinary catecholamines, CHGB, eGFR, and several cardio-metabolic traits. Participants with higher pNE showed significant (p < 0.05) differences in several traits, including increased BP and hypertension risk factors. Peak SGCD variant rs1835919 predicted elevated systemic vascular compliance, without changes in specifically myocardial traits. We used a chimeric-regulated secretory pathway photoprotein (CHGA-EAP) to evaluate the effect of SGCD on the exocytotic pathway in transfected PC12 cells; in transfected cells, expression of SGCD augmented CHGA trafficking into the exocytotic regulated secretory pathway. Thus, our investigation determined human NE secretion to be a highly heritable trait, influenced by common genetic variation within the SGCD locus. Circulating NE aggregates with BP and hypertension risk factors. In addition, coordinate NE and CHGB elevation by rs1835919 implicates exocytosis as the mechanism of release.

Association of in vivo ß-adrenergic receptor sensitivity with inflammatory markers in healthy subjects.

OBJECTIVE: Several stress-related states and conditions that are considered to involve sympathetic overactivation are accompanied by increased circulating levels of inflammatory immune markers. Prolonged sympathetic overactivity involves increased stimulation of the ß-adrenergic receptor (ß-AR). Although prior research suggests that one mechanism by which sympathetic stimulation may facilitate inflammation is via ß-AR activation, little work has focused on the relationship between circulating inflammatory immune markers and ß-AR function within the human body (in vivo). We examined whether decreased ß-AR sensitivity, an indicator of prolonged ß-adrenergic overactivation and a physiological component of chronic stress, is related to elevated levels of inflammatory immune markers. METHODS: Ninety-three healthy participants aged 19 to 51 years underwent the chronotropic 25 dose isoproterenol test to determine in vivo ß-AR function. Circulating levels of C-reactive protein, interleukin 6, and soluble tumor necrosis factor receptor 1 were determined. RESULTS: ß-AR sensitivity was lower in people with higher C-reactive protein concentrations (r = 0.326, p = .003). That relationship remained significant after controlling for sociodemographic and health variables such as age, sex, ethnicity, body mass index, mean arterial blood pressure, heart rate, leisure-time exercise, and smoking status. No significant relationship was found between chronotropic 25 dose and interleukin 6 or soluble tumor necrosis factor receptor 1. CONCLUSIONS: This study demonstrates a link between in vivo ß-adrenergic receptor function and selected circulating inflammatory markers (CRP) in humans. Future studies in specific disease states may be promising.

Effect of chronic dementia caregiving and major transitions in the caregiving situation on kidney function: a longitudinal study.

OBJECTIVE: To estimate the glomerular filtration rate (GFR) in relation to the chronic stress of dementia caregiving and major transitions in the caregiving situation. METHODS: We longitudinally assessed 119 people serving as caregivers for their spouses with Alzheimer's disease and 58 noncaregiving controls for a period of up to 3 years (mean of 2.8 assessments per participant). At baseline, the mean (standard deviation [SD]) age of all participants was 74.5 (7.5) years. Random regression models with fixed and time-variant effects for psychosocial factors, risk factors of chronic kidney disease, and caregiving transitions were used to evaluate changes over time in estimated GFR. RESULTS: The change in GFR did not differ between caregivers and controls during follow-up (p = .77). Further analyses revealed that GFR declined disproportionately after placement of the spouse in a nursing home at 3 months after placement (-4.9 [2.2] mL/min per 1.73 m(2); p = .03). Post hoc analyses showed that this effect was stronger in caregivers with hypertension compared with those without hypertension (-5.7 [3.1] versus -2.4 [3.4] mL/min per 1.73 m(2)), as well as in caregivers with diastolic blood pressure (BP) levels at 1 SD above the mean than in those with diastolic BP levels at 1 SD below the mean (-8.3 [2.9] versus -1.4 [2.7] mL/min per 1.73 m(2)). CONCLUSIONS: Kidney function did not differ between caregivers and controls over time. However, GFR had impaired at 3 months after a major caregiving transition. Because the effect of placement of the spouse with Alzheimer's disease on the decline in GFR was moderated by BP, it might be confined to caregivers who experience increased sympathetic activation after placement.

Chronic ß2 adrenergic agonist, but not exercise, improves glucose handling in older type 2 diabetic mice.

Insulin resistant type 2 diabetes mellitus in the obese elderly has become a worldwide epidemic. While exercise can prevent the onset of diabetes in young subjects its role in older diabetic people is less clear. Exercise stimulates the release of the ß(2)-agonist epinephrine more in the young. Although epinephrine and ß(2)-agonist drugs cause acute insulin resistance, their chronic effect on insulin sensitivity is unclear. We fed C57BL/6 mice a high fat diet to induce diabetes. These overweight animals became very insulin resistant. Exhaustive treadmill exercise 5 days a week for 8 weeks had no effect on their diabetes, nor did the ß(2)-blocking drug ICI 118551. In contrast, exercise combined with the ß(2)-agonist salbutamol (albuterol) had a beneficial effect on both glucose tolerance and insulin sensitivity after 4 and 8 weeks of exercise. The effect was durable and persisted 5 weeks after exercise and ß(2)-agonist had stopped. To test whether ß(2)-agonist alone was effective, the animals that had received ß(2)-blockade were then given ß(2)-agonist. Their response to a glucose challenge improved but their response to insulin was not significantly altered. The ß(2)-agonists are commonly used to treat asthma and asthmatics have an increased incidence of obesity and type 2 diabetes. Although ß(2)-agonists cause acute hyperglycemia, chronic treatment improves insulin sensitivity, probably by improving muscle glucose uptake.

Relationship between chronic stress and carotid intima-media thickness (IMT) in elderly Alzheimer's disease caregivers.

The stress associated with providing care for a spouse diagnosed with Alzheimer's disease can have adverse effects on cardiovascular health. One potential explanation is that chronic caregiving stress may contribute to the development of atherosclerosis. The purpose of this study was to determine whether the duration that one has provided care is associated with the degree of atherosclerotic burden, as measured by carotid artery intima-media thickness (IMT). One hundred and ten Alzheimer caregivers [mean age 74 ± 8 (SD) years, 69% female] underwent in-home assessment of carotid artery IMT via B-mode ultrasonography. Data regarding medical history, blood pressure, and multiple indicators of caregiving stress were also collected. Multiple regression indicated that duration of care was positively associated with IMT measured in the internal/bifurcation segments of the carotid artery (ß = 0.202, p = 0.044) independent of risk factors such as age, gender, body mass index, smoking history, sleep quality, hypertension status, and caregiving stressors. Duration of care was positively associated with IMT in the common carotid artery, but the relationship was not significant. These findings provide more evidence of the link between chronic caregiving stress and cardiovascular disease and indicate that enduring the experience of caregiving over a period of years might be associated with atherosclerotic burden.