Efficacy of Blended Collaborative Care for Patients With Heart Failure and Comorbid Depression: A Randomized Clinical Trial.

Importance: Depression is often comorbid in patients with heart failure (HF) and is associated with worse clinical outcomes. However, depression generally goes unrecognized and untreated in this population. Objective: To determine whether a blended collaborative care program for treating both HF and depression can improve clinical outcomes more than collaborative care for HF only and physicians' usual care (UC). Design, Setting, and Participants: This 3-arm, single-blind, randomized effectiveness trial recruited 756 participants with HF with reduced left ventricular ejection fraction (<45%) from 8 university-based and community hospitals in southwestern Pennsylvania between March 2014 and October 2017 and observed them until November 2018. Participants included 629 who screened positive for depression during hospitalization and 2 weeks postdischarge and 127 randomly sampled participants without depression to facilitate further comparisons. Key analyses were performed November 2018 to March 2019. Interventions: Separate physician-supervised nurse teams provided either 12 months of collaborative care for HF and depression ("blended" care) or collaborative care for HF only (enhanced UC [eUC]). Main Outcomes and Measures: The primary outcome was mental health-related quality of life (mHRQOL) as measured by the Mental Component Summary of the 12-item Short Form Health Survey (MCS-12). Secondary outcomes included mood, physical function, HF pharmacotherapy use, rehospitalizations, and mortality. Results: Of the 756 participants (mean [SD] age, 64.0 [13.0] years; 425 [56%] male), those with depression reported worse mHRQOL, mood, and physical function but were otherwise similar to those without depression (eg, mean left ventricular ejection fraction, 28%). At 12 months, blended care participants reported a 4.47-point improvement on the MCS-12 vs UC (95% CI, 1.65 to 7.28; P = .002), but similar scores as the eUC arm (1.12; 95% CI, -1.15 to 3.40; P = .33). Blended care participants also reported better mood than UC participants (Patient-Reported Outcomes Measurement Information System-Depression effect size, 0.47; 95% CI, 0.28 to 0.67) and eUC participants (0.24; 95% CI, 0.07 to 0.41), but physical function, HF pharmacotherapy use, rehospitalizations, and mortality were similar by both baseline depression and randomization status. Conclusions and Relevance: In this randomized clinical trial of patients with HF and depression, telephone-delivered blended collaborative care produced modest improvements in mHRQOL, the primary outcome, on the MCS-12 vs UC but not eUC. Although blended care did not differentially affect rehospitalization and mortality, it improved mood better than eUC and UC and thus may enable organized health care systems to provide effective first-line depression care to medically complex patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02044211.

Relationship between Dispositional Mindfulness, Psychological Health, and Diet Quality among Healthy Midlife Adults.

Mindfulness, a practice of non-judgmental awareness of present experience, has been associated with reduced eating psychopathology and emotion-driven eating. However, it remains unclear whether mindfulness relates to diet quality. Thus, the purpose of this study was to examine whether dispositional mindfulness is associated with diet quality and to explore psychological factors relating dispositional mindfulness to diet quality. Community-dwelling adults (N = 406; Mage = 43.19, SD = 7.26; Mbody mass index [BMI] = 27.08, SD = 5.28; 52% female) completed ratings of dispositional mindfulness, depressive symptoms, perceived stress, positive affect (PA), and negative affect (NA). Dietary intake was assessed using the Block Food Frequency Questionnaire, from which the 2015 Healthy Eating Index was derived. Analyses were conducted using the "lavaan" package in R with bias-corrected bootstrapped confidence intervals (BootCI). Age, sex, race, education, and BMI were entered as covariates in all models. Higher dispositional mindfulness was associated with higher diet quality (ß = 0.11, p = 0.03), and this effect was mediated through lower depressive symptoms (indirect effect ß = 0.06, p = 0.02, BootCI = 0.104-1.42, p = 0.03). Dispositional mindfulness was negatively correlated with perceived stress (ß = -0.31, p < 0.01) and NA (ß = -0.43, p < 0.01), as well as positively correlated with PA (ß = -0.26, p < 0.01). However, these factors were unrelated to diet quality. These cross-sectional data provide initial evidence that dispositional mindfulness relates to diet quality among midlife adults, an effect that may be explained in part by less depressive symptomatology. Given that lifestyle behaviors in midlife are leading determinants of risk for cardiovascular disease and neurocognitive impairment in late life, interventions to enhance mindfulness in midlife may mitigate disease risk. Additional research assessing the impact of mindfulness interventions on diet quality are warranted.

The effects of omega-3 fatty acids on neuropsychological functioning and brain morphology in mid-life adults: a randomized clinical trial.

BACKGROUND: The diet of most adults is low in fish and, therefore, provides limited quantities of the long-chain, omega-3 fatty acids (LCn-3FAs), eicosapentaenoic and docosahexaenoic acids (EPA, DHA). Since these compounds serve important roles in the brain, we sought to determine if healthy adults with low-LCn-3FA consumption would exhibit improvements in neuropsychological performance and parallel changes in brain morphology following repletion through fish oil supplementation. METHODS: In a randomized, controlled trial, 271 mid-life adults (30-54 years of age, 118 men, 153 women) consuming ⩽300 mg/day of LCn-3FAs received 18 weeks of supplementation with fish oil capsules (1400 mg/day of EPA and DHA) or matching placebo. All participants completed a neuropsychological test battery examining four cognitive domains: psychomotor speed, executive function, learning/episodic memory, and fluid intelligence. A subset of 122 underwent neuroimaging before and after supplementation to measure whole-brain and subcortical tissue volumes. RESULTS: Capsule adherence was over 95%, participant blinding was verified, and red blood cell EPA and DHA levels increased as expected. Supplementation did not affect performance in any of the four cognitive domains. Exploratory analyses revealed that, compared to placebo, fish oil supplementation improved executive function in participants with low-baseline DHA levels. No changes were observed in any indicator of brain morphology. CONCLUSIONS: In healthy mid-life adults reporting low-dietary intake, supplementation with LCn-3FAs in moderate dose for moderate duration did not affect neuropsychological performance or brain morphology. Whether salutary effects occur in individuals with particularly low-DHA exposure requires further study.

Omega-3 Supplementation and the Neural Correlates of Negative Affect and Impulsivity: A Double-Blind, Randomized, Placebo-Controlled Trial in Midlife Adults.

OBJECTIVE: In clinical trials, omega-3 fatty acid supplementation improves symptoms in psychiatric disorders involving dysregulated mood and impulse control, yet it is unclear whether in healthy adults, omega-3 fatty acid supplementation affects mood, impulse control, and the brain systems supporting these processes. Accordingly, this study tested the hypotheses that eciosapentaenoic (EPA) and docosahexaenoic (DHA) acid supplementation reduces negative affect and impulsive behaviors in healthy adults and that these changes correspond to alterations in corticolimbic and corticostriatal brain systems, which support affective and impulsive processes. METHODS: Healthy volunteers (N = 272) consuming 300 mg/d or less of EPA and DHA were enrolled in a double-blind, randomized, placebo controlled clinical trial. The participants received either capsules providing 1000 mg of EPA and 400 mg of DHA versus identical appearing soybean oil capsules per day for 18 weeks. Negative affect and impulsivity were measured by questionnaire and ecological momentary assessment, as well as functional alterations in corticolimbic and corticostriatal brain systems evoked by standardized functional magnetic resonance imaging tasks. RESULTS: There were no group by time interactions for any questionnaire or ecological momentary assessment measures of mood and impulsivity. Likewise, no group by time interactions were observed for functional magnetic resonance imaging responses evoked within corticolimbic and corticostriatal systems. CONCLUSIONS: In healthy adults with low intake of omega-3 fatty acids, moderate-dose supplementation for 18 weeks did not alter affect or impulsive behaviors nor alter corticolimbic and corticostriatal brain functionality. TRIAL REGISTRATION: Trial number NCT00663871.

Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives.

UNLABELLED: Dietary ω-3 polyunsaturated fatty acids (PUFAs) decrease cardiovascular risk via suppression of inflammation. The generation of electrophilic α,ß-unsaturated ketone derivatives of the ω-3 PUFAs docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) in activated human macrophages is catalyzed by cyclooxygenase-2 (Cox-2). These derivatives are potent pleiotropic anti-inflammatory signaling mediators that act via mechanisms including the activation of Nrf2-dependent phase 2 gene expression and suppression of pro-inflammatory NF-κB-driven gene expression. Herein, the endogenous generation of ω-3 PUFAs electrophilic ketone derivatives and their hydroxy precursors was evaluated in human neutrophils. In addition, their dietary modulation was assessed through a randomized clinical trial. METHODS: Endogenous generation of electrophilic omega-3 PUFAs and their hydroxy precursors was evaluated by mass spectrometry in neutrophils isolated from healthy subjects, both at baseline and upon stimulation with calcium ionophore. For the clinical trial, participants were healthy adults 30-55 years of age with a reported EPA+DHA consumption of ≤300 mg/day randomly assigned to parallel groups receiving daily oil capsule supplements for a period of 4 months containing either 1.4 g of EPA+DHA (active condition, n = 24) or identical appearing soybean oil (control condition, n = 21). Participants and laboratory technicians remained blinded to treatment assignments. RESULTS: 5-lypoxygenase-dependent endogenous generation of 7-oxo-DHA, 7-oxo-DPA and 5-oxo-EPA and their hydroxy precursors is reported in human neutrophils stimulated with calcium ionophore and phorbol 12-myristate 13-acetate (PMA). Dietary EPA+DHA supplementation significantly increased the formation of 7-oxo-DHA and 5-oxo-EPA, with no significant modulation of arachidonic acid (AA) metabolite levels. CONCLUSIONS: The endogenous detection of these electrophilic ω-3 fatty acid ketone derivatives supports the precept that the benefit of ω-3 PUFA-rich diets can be attributed to the generation of electrophilic oxygenated metabolites that transduce anti-inflammatory actions rather than the suppression of pro-inflammatory AA metabolites. TRIAL REGISTRATION: ClinicalTrials.gov NCT00663871.

Prospective investigation of nimodipine for acute vocal fold paralysis.

INTRODUCTION: Nimodipine has been shown to be beneficial for recovery from acute vocal fold paralysis (AVFP) in an animal model. METHODS: prospective, open-label trial of patients with AVFP was performed using nimodipine. Consecutive patients were evaluated and offered nimodipine therapy. RESULTS: Fifty-three patients were considered for treatment with nimodipine. Thirteen did not qualify for inclusion, 5 were lost to follow-up, and 7 had side effects requiring cessation of treatment. Thus 28 patients (30 paralyzed vocal folds) were analyzed. Eighteen of the paralyzed vocal folds experienced recovery of purposeful motion (60%). Historical controls and laryngeal electromyography meta-analysis suggest no more than a 20% recovery rate from AVFP. CONCLUSIONS: This open label study using nimodipine for treatment of AVFP demonstrates tripling of the recovery rate of vocal fold motion compared with historical controls. Further study in a randomized, controlled manner is warranted.

Concurrent physical activity modifies the association between n3 long-chain fatty acids and cardiometabolic risk in midlife adults.

Greater consumption of n3 (ω3) polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can reduce risk for cardiovascular disease events, yet their effects on metabolic risk factors and diabetes remain unclear. This cross-sectional study used a community volunteer sample to test whether the associations between n3 fatty acids and cardiometabolic risk vary as a function of physical activity. Participants were 344 generally healthy adults, 30-54 y of age, not taking fish oil supplements or confounding medications. Serum phospholipid EPA and DHA were used together (EPA+DHA) as a biomarker of n3 fatty acid exposure. Cardiometabolic risk was calculated as a continuous measure based on standardized distributions of blood pressure, waist circumference, HDL cholesterol, triglycerides, glucose, and a simple count of risk factors. Insulin resistance was estimated from the homeostatic model assessment. Physical activity was found to predict cardiometabolic risk (P ≤ 0.02) and insulin resistance (P ≤ 0.02) and to moderate the association between EPA+DHA and both cardiometabolic risk (P-interaction ≤ 0.02) and insulin resistance (P-interaction ≤ 0.02). Specifically, higher EPA+DHA was associated with lower cardiometabolic risk and insulin resistance in persons engaged in regular physical activity but not in relatively inactive individuals. These findings were noted in several components of cardiometabolic risk, in men and women separately, and in models adjusted for overall diet quality. In midlife adults, habitual physical activity may be necessary to unmask the salutary effects of n3 fatty acids on cardiometabolic risk and insulin resistance.

Long-chain, n-3 fatty acids and physical activity--independent and interactive associations with cardiac autonomic control.

BACKGROUND/OBJECTIVES: Intake of the marine-based, n-3 fatty acids and engagement in physical activity are inversely related to cardiac morbidity and mortality. Among putative mechanisms, both n-3 fatty acids and physical activity may act through modulation of autonomic control of the cardiovascular system. This investigation examined the independent and interactive associations of n-3 fatty acids (eicosapentaenoic and docosahexanenoic acid; EPA, DHA) and physical activity with heart rate variability (HRV). METHODS: Subjects were 259 healthy 30-54 year-old adults. Serum phospholipid fatty acid composition was employed as a biomarker of dietary n-3 fatty acid exposure. Physical activity based on the Paffenbarger questionnaire was coded as < or ≥ 2000 kcal/week. Standard time-domain (standard deviation of normal-to-normal intervals and root-mean squared of successive differences; SDNN, RMSSD) and frequency domain (high frequency and low frequency power) measures of HRV were derived from resting electrocardiographic recordings. RESULTS: In linear regression models with covariate adjustment for age, gender and race, greater n-3 fatty acid exposure was associated with greater SDNN and RMSSD, and high physical activity was associated with greater RMSSD. n-3 fatty acid exposure also predicted variation in SDNN, RMSSD, and high-frequency power in interaction with physical activity. Specifically, n-3 fatty acid exposure covaried positively with these three HRV indices only among participants expending 2000 kcal per week or more in physical activity. These latter findings were noted for DHA but not EPA. CONCLUSIONS: These results suggest that the cardiovascular benefits of n-3 fatty acid consumption may be mediated, in part, by effects on cardiac autonomic control and may be dependent upon concomitant habitual exercise.

Improved working memory but no effect on striatal vesicular monoamine transporter type 2 after omega-3 polyunsaturated fatty acid supplementation.

Studies in rodents indicate that diets deficient in omega-3 polyunsaturated fatty acids (n-3 PUFA) lower dopamine neurotransmission as measured by striatal vesicular monoamine transporter type 2 (VMAT2) density and amphetamine-induced dopamine release. This suggests that dietary supplementation with fish oil might increase VMAT2 availability, enhance dopamine storage and release, and improve dopamine-dependent cognitive functions such as working memory. To investigate this mechanism in humans, positron emission tomography (PET) was used to measure VMAT2 availability pre- and post-supplementation of n-3 PUFA in healthy individuals. Healthy young adult subjects were scanned with PET using [(11)C]-(+)-α-dihydrotetrabenzine (DTBZ) before and after six months of n-3 PUFA supplementation (Lovaza, 2 g/day containing docosahexaenonic acid, DHA 750 mg/d and eicosapentaenoic acid, EPA 930 mg/d). In addition, subjects underwent a working memory task (n-back) and red blood cell membrane (RBC) fatty acid composition analysis pre- and post-supplementation. RBC analysis showed a significant increase in both DHA and EPA post-supplementation. In contrast, no significant change in [(11)C]DTBZ binding potential (BP(ND)) in striatum and its subdivisions were observed after supplementation with n-3 PUFA. No correlation was evident between n-3 PUFA induced change in RBC DHA or EPA levels and change in [(11)C]DTBZ BP(ND) in striatal subdivisions. However, pre-supplementation RBC DHA levels was predictive of baseline performance (i.e., adjusted hit rate, AHR on 3-back) on the n-back task (y = 0.19+0.07, r(2) = 0.55, p = 0.009). In addition, subjects AHR performance improved on 3-back post-supplementation (pre 0.65±0.27, post 0.80±0.15, p = 0.04). The correlation between n-back performance, and DHA levels are consistent with reports in which higher DHA levels is related to improved cognitive performance. However, the lack of change in [(11)C]DBTZ BP(ND) indicates that striatal VMAT2 regulation is not the mechanism of action by which n-3 PUFA improves cognitive performance.

Long-chain omega-3 fatty acids and blood pressure.

BACKGROUND: High dose fish oil supplementation reduces blood pressure (BP) in hypertensive patients. The current study examines how modest variations in omega-3 fatty acid intake may affect BP in a healthy community sample. METHODS: Study participants included 265 Pittsburgh-area adults 30-54 years of age (11% black, 51% female) not taking omega-3 fatty acid supplements or antihypertensive medications. Standardized assessments of clinic and 24-h ambulatory BP, and pulse rate were obtained. Docosahexanenoic acid (DHA) and eicosapentaenoic acid (EPA) in fasting serum phospholipids were measured by capillary gas chromatography. Regression analyses controlled for age, gender, race, body mass index (BMI), self-reported sodium intake, and physical activity. RESULTS: Participants included 181(68%) normotensives, 66 (25%) prehypertensives, and 18 (7%) persons with untreated hypertension. DHA was inversely associated with clinic diastolic (ß = -0.121, P = 0.03), awake ambulatory diastolic BP (ß = -0.164, P = 0.004), and 24-h diastolic BP (ß = -0.135, P = 0.02). A two standard deviation greater DHA was associated with 2.1 mm Hg lower clinic and 2.3 mm Hg lower awake ambulatory diastolic BP. In addition, DHA was inversely associated with pulse rate measured at rest in the clinic. EPA was related to clinic pulse rate but not clinic or ambulatory BP. CONCLUSION: In this sample of American adults not on antihypertensive medications, a modest, inverse association was found between DHA exposure and both clinic and ambulatory diastolic BP. Therefore, increasing DHA consumption through diet modification rather than large dose supplementation represents a candidate strategy for future studies of hypertension prevention.

Serum phospholipid docosahexaenonic acid is associated with cognitive functioning during middle adulthood.

Existing evidence links greater dietary intake of fish and (n-3) PUFA to better early brain development and lowered risk of cognitive disorders in late life. The mechanisms for these associations remain unclear and may be related to specific (n-3) fatty acids and may concern cognitive function generally rather than only early brain development and age-related cognitive dysfunction. In this investigation, we tested potential associations between (n-3) fatty acids in serum phospholipids and major dimensions of cognitive functioning in mid-life adults. Participants were 280 community volunteers between 35 and 54 y of age, free of major neuropsychiatric disorders, and not taking fish oil supplements. Dietary biomarkers were alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenonic acid (DHA) in serum phospholipids measured using GC. Five major dimensions of cognitive functioning were assessed with a 75-min battery of neuropsychological tests. In covariate adjusted regression models, higher DHA (mol %) was related to better performance on tests of nonverbal reasoning and mental flexibility, working memory, and vocabulary (P

High omega-6 and low omega-3 fatty acids are associated with depressive symptoms and neuroticism.

OBJECTIVE: To examine the concentrations of omega-3 and omega-6 polyunsaturated fatty acids in serum obtained from nonpatient community volunteers not selected for hypercholesterolemia. Previously we reported that the relative concentrations of omega-3 and omega-6 polyunsaturated fatty acids in serum covary with depressive symptomatology and neuroticism in hypercholesterolemic adults. METHODS: A total of 116 adults without current Axis I psychopathology completed the Beck Depression Inventory (BDI) and the NEO Personality Inventory--Revised (NEO-PI-R). Fasting serum phospholipid eicosapentaenoic (EPA), docosahexaenoic (DHA), and arachidonic acid (AA) were determined (% of total pool). RESULTS: Higher AA and AA:EPA ratio, adjusted for age, gender, and race, were associated with greater depressive symptomatology (BDI score of >or=10). Lower EPA, and higher AA, AA:EPA ratio and AA:DHA ratio were associated with greater NEO-PI-R Neuroticism. The six Neuroticism subscales were each associated with two or more fatty acid measurements. CONCLUSIONS: In conjunction with other reports, these findings suggest that the omega-3 and omega-6 fatty acids are related to negative affect at both the symptom and trait levels.

Serum omega-3 fatty acids are associated with variation in mood, personality and behavior in hypercholesterolemic community volunteers.

Low dietary intake of omega-3 polyunsaturated fatty acids has been linked to several features of psychiatric symptomatology, including depression, disorders of impulse control, and hostility. Preliminary intervention trials of omega-3 fatty acid supplementation for clinical depression and other disorders have reported benefit. However, few studies have investigated the relationships between these fatty acids and normative variability in mood, behavior and personality. Participants were 105 hypercholesterolemic, but otherwise healthy, non-smoking adults. Fasting serum alpha-linolenic (alpha-LNA), eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) were assayed with gas chromatography. Participants completed the Beck Depression Inventory (BDI), the NEO Five Factor Personality Inventory (NEO-FFI) and the Barratt Impulsiveness Scale (BIS). In multivariate analyses, higher levels of the long chain omega-3 PUFAs, EPA and DHA, were associated with significantly reduced odds of scoring >or=10 on the BDI. Similarly, DHA and EPA covaried inversely with NEO-Neuroticism scores, whereas DHA was positively associated with NEO-Agreeableness. On the BIS, DHA was inversely related to cognitive impulsivity and alpha-LNA was inversely related to motor and total impulsivity. These findings suggest that omega-3 fatty acid status is associated with variability in affect regulation, personality and impulse control.