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Introduction: Breakdown of gut barrier integrity has been associated with inflammatory activation and is implicated in the etiology of several chronic medical conditions. Acute exercise is known to increase gut barrier permeability but the impact of chronic exercise is not clear. Most studies to date have examined how acute exercise impacts gut barrier integrity in healthy adults, while few studies have examined the impact of chronic exercise in older adults with comorbidities. We aim to investigate the impact of a 12-week program of aerobic and resistance training on biomarkers of gut barrier integrity in a sample of older adults with coronary artery disease., Methods: Participants were adults with coronary artery disease undergoing a moderate-intensity 12-week cardiac rehabilitation exercise program. Fasting blood samples were taken at baseline and study termination. Serum levels of biomarkers of gut barrier integrity (zonulin and fatty acid-binding protein 2 (FABP2)) were measured by ELISA. Cardiorespiratory fitness was assessed by peak oxygen uptake (VO2peak) at study start & completion. Data analyses were performed using SPSS software version 24.0., Results: Among study participants (n = 41, 70% male, age = 62.7± 9.35) we found a significant negative association between baseline FABP2 levels and baseline VO2peak in a multiple linear regression model adjusting for covariates (B = -0.3, p = 0.009). Over the course of the exercise program an increase in VO2peak (≥ 5 mL/kg/min) was independently associated with a relative decrease in FABP2 (B = -0.45, p = 0.018) after controlling for medical covariates., Conclusion: Our findings indicate that an increase in cardiorespiratory fitness during a 12-week exercise program resulted in a relative improvement in a biomarker of gut barrier integrity. This indicates a potential mechanism by which longer term exercise may improve gut barrier integrity., Competing Interests: The authors have declared that no competing interests exist.

The long-term benefits conferred by cardiac rehabilitation (CR) in those with coronary artery disease (CAD) are strongly linked with an improvement in cardiopulmonary fitness. This study aimed to determine the association between peripheral sphingolipids and cardiopulmonary fitness in CAD subjects undertaking CR. Patients with CAD (n = 100, mean age = 64 ± 6 years, 85% male, mean years of education = 17 ± 3 years) underwent 6 months of CR with blood collected at baseline, 3 and 6 months. Cardiopulmonary fitness was assessed by measuring peak oxygen uptake (VO2peak) at all time points. High performance liquid chromatography coupled electrospray ionization tandem mass spectrometry was used to quantify plasma sphingolipid concentrations. Cross-sectional and longitudinal associations between sphingolipids and VO2peak were assessed using linear regressions and mixed models, respectively. Higher concentrations of sphingomyelin C18:1 (β = -0.26, p = .01), ceramides C16:0 (β = -0.24, p = .02), C18:0 (β = -0.29, p = .002), C20:0 (β = -0.24, p = .02) and C24:1 (β = -0.24, p = .01) and monohexylceramide C18:0 (β = -0.23, p = .02) were associated with poorer VO2peak at baseline. An improvement in VO2peak was associated with a decrease in sphingomyelin C18:1 (b = -10.09, p = .006), ceramides C16:0 (b = -9.25, p = .0003), C18:0 (b = -5.44, p = .0003) and C24:1 (b = -2.46, p = .006) and monohexylceramide C18:0 (b = -5.37, p = .005). Specific long chain sphingolipids may be useful markers of fitness and response to exercise in CAD., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Patients with coronary artery disease have an increased risk for developing vascular cognitive impairment. Endothelial function is often diminished and has been associated with lower cognitive performance in these patients. The link between endothelial function and cognition in coronary artery disease is not fully understood. Angiogenesis may play a role in mediating the association between endothelial function and cognition since angiogenic processes rely heavily on the endothelium., Objective: The aim of this study was to determine if markers of angiogenesis mediate the relationship between endothelial function and cognition in coronary artery disease patients., Methods: In 50 participants with coronary artery disease, endothelial function was assessed using peripheral arterial tonometry. Vascular endothelial growth factor (pro-angiogenic) and endostatin (anti-angiogenic) were measured in peripheral serum samples. Cognition was assessed using the Montreal Cognitive Assessment. A mediation analysis, using a bias corrected inferential bootstrapping method with 10,000 permutations, was used to determine if vascular endothelial growth factor or endostatin mediated an association between peripheral arterial tonometry measures and cognitive performance on the Montreal Cognitive Assessment., Results: Endostatin, but not vascular endothelial growth factor, mediated a relationship between endothelial function and cognitive performance when controlling for total years of education, body mass index, coronary artery bypass graft, stent, diabetes, and diuretic use. This analysis was also significant when delayed recall was substituted for the overall score on the Montreal Cognitive Assessment., Conclusion: These results suggest that endostatin mediates an association between endothelial function and cognitive performance in coronary artery disease.

Objective: Subtle cognitive deficits indicating early neural risk are common in the clinical presentation of coronary artery disease (CAD). Although deterioration may be mitigated by exercise, cognitive response to exercise is heterogeneous. Vasculopathy including endothelial dysfunction is a hallmark of CAD and may play an important role in impairing neural adaptation to exercise. This study aimed to assess peripheral measurements of endothelial function as predictors of cognitive performance in CAD participants undertaking cardiac rehabilitation (CR)., Methods: CAD patients (N = 64) undergoing CR were recruited for this prospective observational study. Neuropsychological and endothelial function assessments were performed at baseline and after 3 months of CR. Z-scores for overall cognitive performance and specific cognitive domains (verbal and visuospatial memory, processing speed, and executive function) were calculated. Endothelial function was measured by the reactive hyperemia index (RHI) using peripheral arterial tonometry. Cross-sectional and longitudinal associations between RHI and overall cognition were assessed using linear regressions and mixed models, respectively. Domain-specific associations were also explored., Results: Although lower RHI was not associated with overall cognition at baseline (b = 0.26, p = .10), an increased RHI was significantly associated with an improvement in overall cognition (b = 0.55, p = .030) over 3 months. Lower RHI was associated with poorer verbal memory (β = 0.28, p = .027) at baseline and an increased RHI over 3 months was associated with an improvement in processing speed (b = 0.42, p = .033)., Conclusions: RHI may be a clinically useful predictor of cognitive change and might provide insight into the etiology of cognitive dysfunction in patients with CAD.

Background: Exercise prevents recurrent cardiovascular events and it may combat cognitive decline in coronary artery disease (CAD); however, evidence in type 2 diabetes (T2DM) has been mixed. T2DM and memory decline have been associated with differences in the plasma sphingolipidome., Objective: Here, we will investigate whether T2DM-related sphingolipids predict less memory improvement over an exercise intervention for CAD., Methods: Among participants with CAD entering a 6-month exercise intervention, we matched 20 with T2DM to 40 without T2DM for age, sex, and body mass index. We assessed 45 sphingolipid species using high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometry with multiple reaction monitoring. We assessed memory using the California Verbal Learning Test, 2nd Ed, and the revised Brief Visuospatial Learning Test., Results: Partial least squares discriminant analysis identified 8 species that distinguished T2DM from non-T2DM groups with 83% (95% confidence interval [70%, 95%]) accuracy in a receiver operator characteristic curve (validated by internal resampling, 1000 permutations, p = 0.01). At baseline, T2DM-associated sphingolipids (ceramide C22 : 0, monohexylceramide C16 : 1, and lactosylceramide C24 : 0) were associated with poorer memory, attention, and psychomotor processing speed performance. Among 50 completers, an indirect effect of T2DM on less improvement in verbal memory was mediated by monohexylceramide C16 : 1 (0.86 fewer words recalled, 95% bootstrap confidence interval [-2.32, -0.24]), and an indirect effect of T2DM on less visuospatial memory improvement was mediated by ceramide C22 : 0 concentrations (0.42 fewer points, 95% bootstrap confidence interval [-1.17, -0.05])., Conclusions: Ceramide species associated with T2DM predicted poorer cognitive responses to exercise in patients with CAD.

Depressive symptoms in patients with coronary artery disease (CAD) attenuate the cardiovascular benefits of cardiac rehabilitation (CR). Given that oxidative stress may be an important mechanism underlying depression, this study aimed to understand the longitudinal relationship between lipid peroxidation markers and depression in CAD. Serum levels of early (lipid hydroperoxides, LPH) and late (4‑hydroxy‑2-nonenal, 4-HNE; 8-isoprotane, 8-ISO) lipid peroxidation markers were measured in 120 CAD patients undergoing CR. The Structured Clinical Interview for DSM Axis I Disorders - Depression Module (SCID) was used to diagnose depression at baseline and the Center for Epidemiological Studies Depression Scale (CES-D) was used to measure depressive symptom severity. Multivariate mixed models compared the trajectories of serum LPH, 4-HNE, and 8-ISO between depressed and non-depressed CAD patients undergoing 6 months of CR. Similar models evaluated the associations between serum LPH, 4-HNE, and 8-ISO and CES-D score over the course of CR. Serum 4-HNE decreased less in CAD patients with depression compared to those without. In addition, a decrease in 4-HNE concentrations was significantly associated with a decrease in CES-D scores over 6 months. These findings suggest that 4-HNE may be an important marker of depressive symptoms in CAD and may be involved in its progression., (Copyright © 2018. Published by Elsevier B.V.)

Background: Depression in patients with coronary artery disease (CAD) is associated with increased cardiovascular morbidity. Given the proinflammatory actions of phospholipids, aberrant phospholipid metabolism may be an etiological mechanism linking CAD and depression. Our primary objective was to identify a phospholipid biomarker panel that characterizes CAD patients with significant depressive symptoms from those without., Methods and Results: We performed a targeted lipidomic analysis on CAD patients with significant depressive symptoms (n=37, Center for Epidemiologic Studies Depression score ≥16) and those without (n=49). Phospholipid species were selected using partial least-square discriminant analysis, and the ability of the resulting model to discriminate between groups was evaluated using receiver operator characteristic curves. Biosignature scores were calculated from this model, and analyses of covariance were performed to compare intergroup differences in biosignature scores, with adjustment for clinical differences between patients. Those with significant depressive symptoms had lower cardiopulmonary fitness, more prevalent history of depression, and a greater number of vascular risk factors. A model of 10 phospholipid species had an area under the curve value of 0.84 (95% confidence interval 0.72-0.95), sensitivity of 0.73, and specificity of 0.71. This model passed permutation testing (n=1000, P <0.001). Biosignature scores were higher in those with significant depressive symptoms after adjustment for potential confounders (F[1.86]=14.39, P <0.0005)., Conclusions: The present findings support the role of proinflammatory phospholipid species in the presence of depression in CAD patients from the CAROTID trial (Coronary Artery Disease Randomized Omega-3 Trial in Depression). Future investigations should aim to replicate findings in larger data sets and clarify possible pathophysiological mechanisms., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00981383., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objective: Coronary artery disease (CAD) is frequently accompanied by white matter hyperintensities and executive dysfunction. Because acetylcholine is important in executive function, these symptoms may be exacerbated by subcortical hyperintensities (SH) located in cholinergic (CH) tracts. This study investigated the effects of SH on cognitive changes in CAD patients undergoing a 48-week cardiac rehabilitation program., Methods: Fifty patients (age 66.5 ± 7.1 years, 84% male) underwent the National Institute of Neurological Disorders and Stroke - Canadian Stroke Network neurocognitive battery at baseline and 48 weeks. Patients underwent a 48-week cardiac program and completed neuroimaging at baseline. Subcortical hyperintensities in CH tracts were measured using Lesion Explorer. Repeated measures general linear models were used to examine interactions between SH and longitudinal cognitive outcomes, controlling for age, education, and max VO 2 change as a measure of fitness., Results: In patients with SH in CH tracts, there was a significant interaction with the Trail Making Test (TMT) part A and part B over time. Patients without SH improved on average 16.6 and 15.0% on the TMT-A and TMT-B, respectively. Patients with SH on average showed no improvements in either TMT-A or TMT-B over time. There were no significant differences in other cognitive measures., Conclusion: These results suggest that CAD patients with SH in CH tracts improve less than those without SH in CH tracts, over 48 weeks of cardiac rehabilitation. Thus, SH in CH tracts may contribute to longitudinal cognitive decline following a cardiac event and may represent a vascular risk factor of cognitive decline. © 2017 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd., (© 2017 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.)

Background: Biomarkers in cognitively vulnerable populations, like those with coronary artery disease (CAD), may inform earlier intervention in vascular neurodegeneration. Circulating ceramide C18:0 (CerC18:0) is associated with changes in verbal memory in early neurodegeneration and CAD progression., Objective: To investigate whether plasma CerC18:0 accumulation is associated with longitudinal declines in verbal memory performance in CAD., Methods: In addition to total CerC18:0, we assessed its relative abundance to its precursors as ratios: CerC18:0 to monohexosylceramide C18:0 (MHxCer18:0), CerC18:0 to sphingomyelin C18:0 (SM18:0), and CerC18:0 to sphingosine-1-phosphate (S1P). Verbal memory was assessed using the California Verbal Learning Test 2nd Ed. Using mixed models in 60 CAD participants, we evaluated associations between baseline CerC18:0 ratios and changes in verbal memory performance, adjusting for age, body mass index, and education. Given that cognitive decline is more rapid following onset of deficits, these associations were compared between those with possible mild vascular neurocognitive disorder (MVND)., Results: Increased baseline CerC18:0 concentrations correlated with worse verbal memory performance over time (b[SE] = - 0.91[0.30], p = 0.003). Increased baseline CerC18:0/SM18:0 (b[SE] = - 1.11[`], p = 0.03) were associated with worse verbal memory performance over time. These associations were not mediated by whether or not patients had possible MVND at baseline., Conclusion: These findings support aberrant CerC18:0 metabolism as an early neurobiological change in vascular neurodegeneration. Future studies should measure enzymes responsible for conversion of sphingolipid precursors into CerC18:0 to assess enzymatic activity.

Background: Depression is highly prevalent in individuals with coronary artery disease (CAD) and increases the risk of future cardiac events and mortality. Sphingolipids have been implicated in the pathophysiology of both CAD and depression. This study assessed the association between plasma sphingolipid concentrations and depressive symptoms in CAD subjects., Methods: Depressive symptoms were measured using the depression subscale of the self-reported Hospital Anxiety and Depression Scale (HADS). Sphingolipid concentrations were measured from fasting plasma samples using high-performance liquid chromatography-coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Linear regression models were used to assess associations between log-transformed concentrations of plasma sphingolipids and depressive symptoms., Results: A total of 111 CAD patients (mean ( SD ) age = 63.6 ± 6.4, 84.7% male) were included. In linear regression analyses, higher plasma concentrations of ceramides C16:0 (β = 0.204, p  = .026) and C18:0 (β = 0.209, p  = .023) and sphingomyelin SM18:1 (β = 0.210, p  = .024) were significantly associated with higher HADS depression subscale score after adjusting for covariates., Conclusion: Sphingolipids, in particular the ceramide species C16:0 and C18:0 and the sphingomyelin species SM18:1, may be implicated in the pathophysiology of depression in CAD. The association between plasma sphingolipid concentrations and depression should be further examined in CAD patients and in other populations.

Background: Antidepressant efficacy of omega-3 polyunsaturated fatty acid (n-3 PUFA) treatment in coronary artery disease (CAD) patients remains unpredictable. N-3 PUFA can mitigate oxidative stress, which is common in CAD and may contribute to depressive symptoms. This study investigated whether greater pre-treatment oxidative stress, measured by the ratios of late-stage lipid peroxidation markers (malondialdehyde [MDA], 4-hydroxy-2-nonenal [4-HNE], and 8-isoprostane [8-ISO]) to an early-stage marker (lipid hydroperoxides [LPH]), predicted n-3 PUFA antidepressant benefits in CAD., Methods: This was a secondary analysis of CAROTID (CAD Randomized Omega-3 Trial in Depression, NCT00981383). Patient demographics and medical characteristics were collected. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAM-D). Patients were then randomized to receive either 1.9g/day n-3 PUFA or placebo for 12weeks, after which HAM-D scores were reassessed. Baseline LPH, 4-HNE, 8-ISO, MDA and n-3 PUFA concentrations were analysed from fasting blood., Results: Seventy-nine patients (age=61.1±8.5, 76% male, HAM-D=7.5±6.1) were included (n=45 placebo, n=34 n-3 PUFA). In the n-3 PUFA group, higher baseline ratios of MDA/LPH (primary analysis: F 1,33 =6.20, beta=-0.35, p=0.018), 4-HNE/LPH (exploratory analysis: F 1,33 =5.35, beta=-0.32, p=0.027), and 8-ISO/LPH (exploratory analysis: F 1,33 =6.10, beta=-0.33, p=0.019), indicating higher oxidative stress, were associated with greater depressive symptom improvement. In each model, higher baseline EPA+DHA concentrations independently predicted depressive symptom improvement with n-3 PUFA (MDA/LPH: F 1,33 =11.05, p=0.002; 4-HNE/LPH: F 1,33 =11.36, p=0.002; 8-ISO/LPH: F 1,33 =13.15, p=0.001). No associations were observed in the placebo group., Conclusions: n-3 PUFA may be more likely to improve depressive symptoms in CAD patients with pre-treatment evidence of oxidative stress., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Early subtle deficits in verbal memory, which may indicate early neural risk, are common in patients with coronary artery disease (CAD). While exercise can improve cognition, cognitive response to exercise is heterogeneous. Sphingolipids have been associated with the development and progression of CAD, and impairments in sphingolipid metabolism may play roles in neurodegeneration and in the neural adaptation response to exercise., Objective: In this study, change in plasma concentrations of sphingolipids was assessed in relation to change in verbal memory performance and in other cognitive domains among CAD subjects undertaking a 6-month cardiac rehabilitation (CR) program., Methods: Patients with CAD (n = 120, mean age = 64±6 y, 84% male, years of education = 16±3) underwent CR with neuropsychological assessments and blood collected at baseline, 3-, and 6-months. Z-scores based on age, gender, and education were combined for verbal memory, visuospatial memory, processing speed, executive function, and global cognition tasks to calculate cognitive domain Z-scores. Plasma sphingolipid concentrations were measured from fasting blood samples using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Mixed models were used to identify sphingolipids significantly associated with performance in verbal memory and other cognitive domains, adjusting for potential confounders., Results: A decrease in ceramide C18:0 concentration was significantly associated with improvement in verbal memory performance (b[SE] = -0.51 [0.25], p = 0.04), visuospatial memory (b[SE] = -0.44 [0.22], p = 0.05), processing speed (b[SE] = -0.89 [0.32], p = 0.007), and global cognition (b[SE] = -1.47 [0.59], p = 0.01) over 6 months of CR., Conclusions: Plasma ceramide C18:0 concentrations may be a sensitive marker of cognitive response to exercise in patients with CAD.

This study examined associations between lipid peroxidation markers and cognition, and associations between these markers and cognitive response to an exercise intervention program, in adults with coronary artery disease at risk of dementia. Lipid peroxidation products were measured in serum in 118 patients (29 possible vascular mild cognitive impairment and 89 controls). Ratios of early- (lipid hydroperoxides, LPH) to late-stage (8-isoprostane, 8-ISO; 4-hydroxy-2-nonenal, 4-HNE) lipid peroxidation products were calculated. Cognitive performance was assessed before and at completion of a 24-week exercise intervention program. A global effect of group on lipid peroxidation markers was observed, adjusting for sex, years of education, and cardiopulmonary fitness (main effect of group F (3,102) = 2.957, p = 0.036). Lower lipid peroxidation at baseline, as determined by lower 8-ISO concentration, was associated with greater improvement in verbal memory (F (1, 64) = 4.738, p = 0.03) and executive function (F (1, 64) = 5.219, p = 0.026) performance. Similarly, higher ratios of 8-ISO/LPH (F (1, 65) = 6.592, p = 0.013) and (8-ISO+4-HNE) to LPH (F (1, 65) = 3.857, p = 0.054), were associated with less improvement in executive function performance over a 24-week exercise intervention. Lipid peroxidation may be a biomarker of early vascular cognitive impairment, and elevated lipid peroxidation might limit the cognitive benefits of exercise in this high-risk population.

This trial investigated the efficacy of omega-3 polyunsaturated fatty acid (n-3 PUFA) treatment for improving depressive symptoms and cognitive performance in patients with coronary artery disease (CAD) participating in cardiac rehabilitation. Patients with CAD aged 45 to 80 years were randomized to receive either 1.9-g/d n-3 PUFA treatment or placebo for 12 weeks. Depressive symptoms were measured using the Hamilton Depression Rating Scale (HAM-D, primary outcome) and the Beck Depression Inventory II (BDI-II). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria were used to identify a depressive episode at baseline. Cognitive performance was measured using a standardized battery for vascular cognitive impairment. In 92 patients (age, 61.7 ± 8.7 y; 76% male, 40% depressed; HAM-D, 6.9 ± 5.9; BDI-II, 12.3 ± 10.9; n = 45 n-3 PUFA, n = 47 placebo), depression decreased (HAM-D, F3,91 = 2.71 and P = 0.049; BDI-II, F3,91 = 6.24 and P < 0.01), and cognitive performance improved (attention/processing speed, F1,91 = 5.57, P = 0.02; executive function, F1,91 = 14.64, P < 0.01; visuospatial memory, F1,91 = 4.01, P = 0.04) over cardiac rehabilitation. Omega-3 PUFA treatment increased plasma eicosapentaenoic acid (F1,29 = 33.29, P < 0.01) and docosahexaenoic acid (F1,29 = 15.29, P < 0.01) concentrations but did not reduce HAM-D (F3,91 = 1.59, P = 0.20) or BDI-II (F3,91 = 0.46, P = 0.50) scores compared with placebo. Treatment did not improve cognitive performance; however, n-3 PUFAs significantly increased verbal memory compared with placebo in a subgroup of nondepressed patients (F1,54 = 4.16, P = 0.04). This trial suggests that n-3 PUFAs do not improve depressive and associated cognitive symptoms in those with CAD. The possible benefits of n-3 PUFAs for verbal memory may warrant investigation in well-powered studies.

Depressive symptoms are highly incident among coronary artery disease (CAD) patients and increase mortality. Reduced ratios of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (omega-3 fatty acids) to arachidonic acid (AA, omega-6 fatty acid) concentrations have been linked with depressive symptoms in CAD. It remains unclear whether depressive symptoms are differentially associated with that ratio in different phospholipid classes, and this may have mechanistic implications. This study investigated associations between depressive symptoms in CAD patients and the EPA+DHA to AA ratio in the major phospholipid classes. This was a cross-sectional study of stable CAD patients. Sociodemographic, medical, medication, and cardiopulmonary fitness data were collected from each patient. Each patient was assessed for depressive symptoms using the 17-item Hamilton Depression Rating Scale (HAM-D). The percentage of EPA, DHA, and AA in each erythrocyte phospholipid class was determined using gas chromatography from fasting blood. Relationships between EPA+DHA to AA ratios and depressive symptoms were assessed using linear regression and were corrected for multiple comparisons. Seventy-six CAD patients were included (age=61.9 ± 8.5, 74% male, HAM-D=7.2 ± 5.9). In a backward elimination linear regression model, lower EPA+DHA to AA in erythrocyte phosphatidylinositol (B=-12.71, β=-0.33, p<.01) and sphingomyelin (B=-2.52, β=-0.37, p<.01) was associated with greater depressive symptom severity, independently of other known predictors. Other phospholipid classes were not associated with depressive symptoms. In conclusion, the relationship between EPA+DHA to AA ratios and depressive symptoms in CAD may not be consistent across phospholipid classes. Continued investigation of these potentially differential relationships may clarify underlying disease mechanisms., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Coronary artery disease (CAD) is associated with an increased risk of cognitive decline. Although cerebral white matter (WM) damage predicts cognitive function in CAD, conventional neuroimaging measures only partially explain the effect of CAD on cognition. The purpose of this study was to determine if WM microstructural integrity and CAD using diffusion tensor imaging (DTI) correlates with cognitive function in older adults with CAD., Methods: Forty-nine CAD patients (66 ± 7 years old, 86% male) underwent neurocognitive assessments using the cognitive battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network for the study of vascular cognitive impairment. Composite scores for each cognitive domain were calculated. Microstructural integrity in normal-appearing WM was quantified as fractional anisotropy (FA) using DTI in nine bilateral and two interhemispheric WM tracts from the Johns Hopkins University WM Tractography Atlas. Linear regression models examined associations between FA and cognitive performance, controlling for age, sex, and education, with correction for multiple comparisons using a false discovery rate of 5%., Results: Executive function was most significantly associated with FA in the left parahippocampal cingulum (β = 0.471, t = 3.381, df = 44, p = 0.002) and left inferior fronto-occipital fasciculus (β = 0.430, t = 2.984, df = 44, p = 0.005). FA was not associated with memory in any of the WM tracts examined., Conclusion: These results suggest that WM microstructural integrity may be an important neural correlate of executive function even in cognitively intact CAD patients. This study suggests WM damage may be relevant to subtle cognitive decline in a population that may have early neural risk for dementia., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Patients with coronary artery disease (CAD) are at risk of accelerated cognitive decline, particularly those with major depression. Mechanisms for cognitive deficits associated with CAD, and the effects of depression, remain poorly understood. However, CAD is associated with inflammatory processes that have been linked to neurodegeneration, may contribute to cognitive decline, and are elevated in depression. Platelet-activating factors (PAFs) are emerging as key lipid mediators that may be central to those processes and highly relevant to cognitive decline in CAD., Methods: This cross-sectional study investigated relationships between various PAFs and cognitive performance in 24 patients with CAD (age, 60.3 ± 9.4; 70.8% male). Analyses were repeated in a subgroup of 15 patients with CAD with major depression (DSM-IV). Cognitive performance was assessed using a standardized battery and summary z scores were calculated based on age, sex, and education norms. Global cognitive performance was the average of domain-specific z scores. Plasma PAF analyses were performed using electrospray ionization mass spectrometry (precursor ion scan)., Results: A greater abundance of PAF PC(O-18:0/2:0) was associated with poorer global cognitive performance in patients with CAD (r=-0.45, P=0.03). In the major depressed subgroup, PAF PC(O-18:0/2:0) (r=-0.59, P=0.02) as well as PC(O-16:0/2:0) (r=-0.52, P=0.04), and lyso-PAF PC(O-16:0/0:0) (r=-0.53, P=0.04) were associated with poorer global cognitive performance. A greater abundance of PAF PC(O-19:5/2:0) was associated with better global cognitive performance (r=0.55, P=0.03), suggesting a possible compensatory species., Conclusions: This study suggests that certain PAFs might be associated with global cognitive performance in patients with CAD, with stronger relationships observed in those with major depression. Confirmation of these preliminary findings is warranted.

Purpose: Physical activity is associated with positive effects on the brain but there is a paucity of clinical neuroimaging data in patients with coronary artery disease (CAD), a cardiovascular condition associated with grey matter loss. The purpose of this study was to determine which brain regions are impacted by cardiopulmonary fitness and with the change in fitness after 6 months of exercise-based cardiac rehabilitation., Methods: CAD patients underwent magnetic resonance imaging at baseline, and peak volume of oxygen uptake during exercise testing (VO2Peak) was measured at baseline and after 6 months of training. T1-weighted structural images were used to perform grey matter (GM) voxel-based morphometry (VBM). Pseudo-continuous arterial spin labeling (pcASL) was used to produce cerebral blood flow (CBF) images. VBM and CBF data were tested voxel-wise using VO2Peak and age as explanatory variables., Results: In 30 men with CAD (mean age 65±7 years), VBM and CBF identified 7 and 5 respective regions positively associated with baseline VO2Peak. These included the pre- and post-central, paracingulate, caudate, hippocampal regions and converging findings in the putamen. VO2Peak increased by 20% at follow-up in 29 patients (t = 9.6, df = 28, p<0.0001). Baseline CBF in the left post-central gyrus and baseline GM density in the right putamen predicted greater change in VO2Peak., Conclusion: Perfusion and GM density were associated with fitness at baseline and with greater fitness gains with exercise. This study identifies new neurobiological correlates of fitness and demonstrates the utility of multi-modal MRI to evaluate the effects of exercise in CAD patients.

Background: Cognitive function is a significant determinant of overall quality of life in patients with coronary artery disease. Medications prescribed to control vascular risk factors often have anticholinergic effects, which can cause central side effects and affect cognitive function., Objective: This cross-sectional study aimed to identify cognitive deficits associated with the use of anticholinergic medications in patients with coronary artery disease., Methods: Demographics, medications, and vascular risk factors were assessed for each patient by interview and chart review. Anticholinergic burden was estimated using the anticholinergic cognitive burden scale. Cognition was assessed objectively using a battery of neuropsychologic tests, including the California Verbal Learning Test second edition, Revised Brief Visuospatial Memory Test, Stroop test, Trail-Making Test Parts A and B, Digit-Symbol Coding, FAS test, and animal naming., Results: Patients with coronary artery disease (mean ± standard deviation age 64.2 ± 9.1, 15.3% female) presented with 2.6 ± 1.4 vascular risk factors and were using 5.1 ± 1.8 medications. Scores on the anticholinergic cognitive burden scale were associated with poorer performance on the Trail-Making Test Part A (β = 0.280, p = 0.002), Trail-Making Test Part B (β = 0.256, p = 0.004), and animal naming (β = -0.212; p = 0.015) tasks in models controlling for age, gender, years of education, number of vascular risk factors and total medications. Beta-blockers frequently prescribed in this population (i.e., metoprolol and atenolol) accounted for a large proportion of the total anticholinergic cognitive burden score, and their use was independently associated with poorer cognitive performance in a post hoc model including the anticholinergic estimate., Conclusions: Anticholinergic exposure was associated with poorer performance on tests of attention, speed, and executive function in patients with coronary artery disease., (Copyright © 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Coronary artery disease (CAD) is associated with verbal memory decline, although deterioration may be mitigated in individuals undertaking exercise interventions. Ceramide sphingolipids, suggested to play a role in pathological neurodegeneration, have been associated with the development and progression of CAD but their relationship with cognitive response to exercise has not been assessed. In this study, concentrations of very long chain ceramides (C22:0 and C24:0) were assessed as predictors of changes in verbal memory performance over 1 year in subjects with CAD undertaking cardiac rehabilitation (CR)., Methods: Verbal memory was measured using the California Verbal Learning Test 2nd Ed. (CVLT-II), from which Z-scores were calculated based on age, gender and education matched norms. Baseline plasma C22:0 and C24:0 ceramide concentrations were measured from fasting blood samples using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Repeated measures general linear models were used to determine the association between baseline plasma ceramides and the change in verbal memory performance over 1 year of CR controlling for age and body mass index (BMI)., Results: In patients with CAD (n = 33, mean age = 62 ± 9 years, 84.8% male, years of education = 17 ± 3 years), higher baseline plasma C22:0 (F1, 29 = 5.30, p = 0.03) and C24:0 (F1, 29 = 4.04, p = 0.05) concentrations significantly predicted less improvement in verbal memory performance over 1 year of CR controlling for age and BMI., Conclusions: Plasma ceramide concentrations should be further examined as potential predictors of cognitive response to exercise and worse cognitive outcomes in patients with CAD.

The persistence of a depressive episode in coronary artery disease (CAD) patients not only heightens the risk of acute ischemic events, but it is also associated with accelerated cognitive decline. Antidepressant interventions for depression in CAD have only modest effects and novel approaches are limited by a poor understanding of etiological mechanisms. This review proposes that the platelet activating factor (PAF) family of lipids might be associated with the persistence of a depressive episode and related neurodegenerative pathology in CAD due to their association with leading etiological mechanisms for depression in CAD such as inflammation, oxidative and nitrosative stress, vascular endothelial dysfunction, and platelet reactivity. The evidence implicating PAFs in CAD, vascular pathology, and neurodegenerative processes is also presented. We also propose future directions for the investigation of PAFs as mediators of persistent depression. In summary, PAFs are implicated in leading mechanisms associated with depression in CAD. PAFs may therefore be associated with the persistence of depression in CAD and related to neurodegenerative and cognitive sequelae., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Background: Inflammatory activity plays a role in the development and progression of coronary artery disease (CAD), and exercise confers survival benefit. We performed a meta-analysis of changes in inflammatory biomarkers over the course of exercise interventions in patients with CAD., Methods: We searched MEDLINE, Embase, the Cochrane Collaboration, AMED, and CINAHL for studies reporting peripheral inflammatory biomarker concentrations before and after exercise interventions of ≥ 2 weeks in patients with CAD. Data were summarized using standard mean differences (SMD) and 95% CIs., Results: Twenty-three studies were included. Concentrations of C-reactive protein (CRP; SMD -0.345, 95% CI -0.444 to -0.246, n = 1,466, P < .001), interleukin 6 (SMD -0.546, 95% CI -0.739 to -0.353, n = 280, P < .001), fibrinogen (SMD -0.638, 95% CI -0.953 to -0.323, n = 247, P < .001), and vascular cell adhesion molecule 1 (SMD -0.413, 95% CI -0.778 to -0.048, n = 187, P = .027) were lower postintervention. Higher total cholesterol (B = -0.328, 95% CI -0.612 to -0.043, P = .026) and higher total/high-density lipoprotein cholesterol ratios (B = -0.250, 95% CI -0.425 to -0.076, P = .008) at baseline were associated with greater reductions in CRP. In controlled studies, follow-up concentrations of CRP (SMD -0.500, 95% CI -0.844 to -0.157, n(exercise/control) = 485/284, P = .004), and fibrinogen (SMD -0.544, 95% CI -1.058 to -0.030, n(exercise/control) = 148/100, P = .038) were lower in subjects who exercised compared with controls., Conclusion: Exercise training is associated with reduced inflammatory activity in patients with CAD. C-reactive protein and fibrinogen have provided the strongest evidence. Higher baseline CRP and adverse baseline lipid profiles predicted greater reductions in CRP., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: To assess cognitive performance as a predictor of noncompletion of cardiac rehabilitation (CR) using a standardized verbal memory test., Methods: This was a prospective cohort study of consecutive patients with coronary artery disease (n = 131) entering 1-year outpatient CR between April 2007 and May 2009. Verbal memory performance was assessed using the California Verbal Learning Test, Second Edition. Attendance at weekly CR sessions was recorded, and completion or noncompletion was determined according to comprehensive CR criteria. Depression was diagnosed according to DSM-IV criteria as a possible confounder., Results: Verbal memory performance at entry into CR differed significantly (F(1,130) = 7.80, p = .006) between noncompleters and completers (mean [SD] cumulative California Verbal Learning Test, Second Edition, score, -1.15 [2.59] versus 0.47 [3.12]) in analysis of covariance controlling for pertinent clinical confounders. Better verbal memory performance predicted a reduced risk of noncompletion (hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.77-0.96, p = .009) in time-to-event analysis adjusted for depression (HR = 2.62, 95% CI = 1.33-5.17, p = .006) and smoking history (HR = 2.03, 95% CI = 0.98-4.22, p = .06). A post hoc analysis suggested that better verbal memory performance predicted a reduced risk of noncompletion for medical reasons (HR = 0.83, 95% CI = 0.70-0.99, p = .03)., Conclusions: Poorer verbal memory performance was associated with an increased risk of noncompletion of CR among participants with coronary artery disease. Further studies exploring practical methods for screening and targeted support might improve rehabilitation outcomes.

Objectives: To investigate the association between cardiopulmonary fitness and cognitive performance in subjects with coronary artery disease (CAD)., Design: Cross-sectional observational study., Setting: Outpatient cardiac rehabilitation., Participants: Eighty-one subjects with CAD., Measurements: Cardiopulmonary fitness was assessed by measuring peak oxygen uptake (VO(2Peak) ) in a standardized exercise stress test. The fraction of the predicted age and sex norm for VO(2Peak) was computed for each patient. A battery of neuropsychological tests including the Stroop, Trail-Making Test Part B, Digit Symbol Coding, Revised Brief Visuospatial Memory Test, California Verbal Learning Test 2nd Edition, and Mini Mental State Examination (MMSE) was administered, from which composite Z-scores were computed for tasks involving executive function and memory., Results: Executive function, memory, and MMSE scores were correlated with VO(2Peak) , but only performance in the executive domain was independently associated with VO(2Peak) in multiple linear regression. In a multiple linear regression model controlling for potential clinical confounders, VO(2Peak) (β=.666, P<.001) and covariates accounted for 36% of the variance in executive function scores., Conclusion: Poorer VO(2Peak) is associated with poorer cognition, particularly executive function, in subjects with CAD independent of other cardiac risk factors. Cardiopulmonary fitness may be a protective factor for cognition in patients with CAD., (© 2010, Copyright the Authors. Journal compilation © 2010, The American Geriatrics Society.)

Objective: Depression occurs in 18% to 45% of patients with coronary artery disease (CAD) where it is associated with an increased risk of acute coronary events and mortality. Our objective was to quantitatively summarize the data on the efficacy and tolerability of antidepressant (AD) treatment for depression in CAD., Methods: We performed a meta-analysis of randomized, placebo-controlled, double-blind trials with a database search of the English literature (to March 2008) and manual search of references., Results: Four clinical trials with ADs (mirtazapine, citalopram, fluoxetine, and sertraline) of a 9- to 24-week duration involving 798 subjects (402 ADs, 396 placebo) with documented CAD and meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for depression were included. ADs were superior to placebo for decreasing Hamilton Depression Rating Scale (HDRS) scores (402 ADs, 396 placebo; weighted mean difference 1.41, 95% CI 0.53 to 2.29, P = 0.002) and Beck Depression Inventory (BDI) scores (373 ADs, 369 placebo; weighted mean difference 2.27, 95% CI 0.60 to 3.94, P = 0.008). The proportion of patients (216 ADs, 213 placebo) who responded (a 50% or more reduction in HDRS scores, OR 1.72, 95% CI 1.17 to 2.54) and remitted (HDRS of 8 or less at final assessment, OR 1.80, 95% CI 1.18 to 2.74), were also significantly higher with AD, compared with placebo, with no significant differences between the 2 groups for overall dropouts (OR 0.84, 95% CI 0.42 to 1.68) or dropout owing to adverse events (OR 1.30, 95% CI 0.75 to 2.25). The combined studies were homogeneous except for overall dropout rate (P = 0.01)., Conclusion: Treatment with ADs for depression in CAD results in significant therapeutic effects without substantially increased rates of discontinuation.

An increase in immune-stimulated synthesis of kynurenine from tryptophan by indoleamine 2,3-dioxygenase (IDO) has been observed in patients with coronary artery disease (CAD). However, neuropsychiatric correlates of IDO activation remain unexplored. We hypothesize that IDO activation, as measured by the kynurenine to tryptophan (K/T) ratio, is associated with depressive symptoms in those with CAD. This cross-sectional study recruited subjects with CAD (n=95) from a cardiac rehabilitation facility. Demographic, anthropometric and cardiac data were obtained by chart review. Patients using an antidepressant were excluded. The presence of a major depressive episode or minor depression was assessed using a structured clinical interview for depression based on Diagnostic and Statistical Manual 4th edition criteria. The Center for Epidemiological Studies-Depression Scale (CES-D) was used to quantify depressive symptoms. A standardized exercise stress test was used to assess cardiopulmonary fitness as summarized using the peak volume of oxygen consumption (Peak VO(2)). Kynurenine and tryptophan were assayed from fasting plasma samples to obtain the K/T ratio. Higher K/T ratios were significantly associated with higher CES-D scores (beta=.322, p=.002) in a linear regression controlling for time since most recent acute coronary syndrome (tACS), age and sex. Twenty-four patients met criteria for depression (16 major depression; 8 minor depression). There was a trend towards higher K/T ratios in depressed vs. non-depressed patients (45.6+/-20.0 micromol/mmol vs. 38.5+/-15.7 micromol/mmol, F=3.778, p=.055) when controlling for age, sex and tACS. Activation of IDO is associated with the severity of depressive symptoms among patients with CAD.

Objective: To identify independent predictors of depressive symptoms in a cohort of patients with coronary artery disease entering cardiac rehabilitation., Design: Cross-sectional cohort study., Patients and Methods: Consecutive patients entering a cardiac rehabilitation and secondary prevention programme underwent screening for depressive symptoms using the Center for Epidemiological Studies Depression (CES-D) scale and cardiopulmonary fitness testing to quantify peak oxygen consumption., Results: Of the 366 patients with coronary artery disease, 22.3% reported at least mild (CES-D > or = 16) and 10.4% reported significant (CES-D > or = 23) depressive symptoms. Antidepressant medications were being used by 6.3% of patients. Sociodemographic, cardiopulmonary and cardiac characteristics, and medical co-morbidities previously associated with depression accounted for 14.7% of the variance in a multiple linear regression model (F = 8.713, p < 0.001) predicting CES-D scores. Significant independent predictors of CES-D scores were lower peak oxygen consumption, younger age, female sex, lower maximum diastolic blood pressure, angina pectoris and antidepressant use., Conclusion: Reduced physical fitness, younger age, female sex and ischaemic symptoms of coronary artery disease predict higher depressive symptoms in patients entering cardiac rehabilitation.

Background: The co-occurrence of apathy and executive dysfunction, a correlate of vascular cognitive impairment (VCI), is highly prevalent, yet facilitating factors are largely unknown.Objective: This study investigates the relationship between lipid peroxidation, apathy, and executive dysfunction in patients at risk for VCI.Methods: In participants with coronary artery disease, who are at a high risk of VCI, apathy (Apathy Evaluation Scale), and executive function (composite z-score based on age and education population norms from trails making test B, animal naming, and phonemic fluency tests) were assessed. Serum concentrations of an early (lipid hydroperoxide (LPH)) and late (8-isoprostane (8-ISO)) lipid peroxidation marker, were measured and the 8-ISO/LPH ratio was calculated.Results: Participants (n = 206, age±SD = 63.0±7.5, 80% men, total years of education = 15.9±3.4, AES score = 28.3±8.8, executive function = 0±1) demonstrated significantly different 8-ISO/LPH ratios between groups (F(3, 202) = 10.915, p < 0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction (executive function composite score≤-1), only apathy (AES≥28), and both apathy and executive dysfunction. A model adjusting for demographics showed that lipid peroxidation was associated with both apathy (B(SE) = 4.63 (0.954), t = 4.852, p < 0.001) and executive function (B(SE) = -0.19 (0.079), t = -2.377, p = 0.018). However, when controlling for both demographics and vascular risk factors, lipid peroxidation was associated with only apathy (B(SE) = 3.11 (0.987), t = 3.149, p = 0.002).Conclusion: The results highlight a potentially important involvement of lipid peroxidation in the co-occurrence of apathy and executive dysfunction in those at risk for VCI. [ABSTRACT FROM AUTHOR]

Background: (1) Sleep disorders are prevalent in coronary artery disease (CAD) patients and predict cardiac events and prognosis. While increased oxidative stress (OS) has been associated with sleep disorders, less is known about its relationship with sleep quality. Similarly, little is known of how this relationship might change with exercise, which can improve sleep quality. Factors of sleep quality, such as sleep duration and disturbances, are also important as they predict cardiovascular diseases better than a global score alone. This study investigated whether OS was associated with self-rated sleep quality and its factors before and after completing a 24-week exercise intervention. (2) Methods: CAD patients undergoing an exercise program were recruited. OS was measured at baseline by the concentrations of early- (lipid hydroperoxides, LPH) and late-stage (8-isoprostane, 8-ISO) lipid peroxidation products and their ratio. Sleep quality was measured by the self-reported Pittsburgh Sleep Quality Index (PSQI) instrument at baseline and termination. Three sleep factors—perceived sleep quality, sleep efficiency, and daily disturbances—were derived from the PSQI. (3) Results: Among CAD patients (n = 113, 85.0% male, age = 63.7 ± 6.4 years, global PSQI = 5.8 ± 4.0), those with poor sleep (PSQI ≥ 5) had higher baseline 8-ISO levels (F(1, 111) = 6.212, p = 0.014, ηp2 = 0.053) compared to those with normal sleep. Concentrations of LPH (F(1, 105) = 0.569, p = 0.453, ηp2 = 0.005) and 8-ISO/LPH ratios (F(1, 105) = 2.173, p = 0.143, ηp2 = 0.020) did not differ between those with poor sleep and normal sleep. Among factors, perceived sleep quality was associated with 8-ISO and 8-ISO/LPH, and daily disturbances were associated with 8-ISO. (4) Conclusions: A marker of late-stage lipid peroxidation is elevated in CAD patients with poor sleep and associated with daily disturbances, but not with other factors or with sleep quality and its factors after exercise intervention. [ABSTRACT FROM AUTHOR]

Background: Coronary artery disease (CAD) increases risk for vascular cognitive impairment-no dementia (VCIND), a precursor to dementia, potentially through persistent oxidative stress.Objective: This study assessed peripheral glutathione peroxidase activity (GPX), which is protective against oxidative stress, in VCIND versus cognitively normal CAD controls (CN). GPX activity was also evaluated as a biomarker of cognition, particularly verbal memory.Methods: 120 CAD patients with VCIND (1SD below norms on executive function or verbal memory (VM)) or without (CN) participated in exercise rehabilitation for 24 weeks. Neurocognitive and cardiopulmonary fitness (VO2peak) assessments and plasma were collected at baseline and 24-weeks.Results: GPX was higher in VCIND compared to CN (F1,119 = 3.996, p = 0.048). Higher GPX was associated with poorer baseline VM (β= -0.182, p = 0.048), and longitudinally with VM decline controlling for sex, body mass index, VO2peak, and education (b[SE] = -0.02[0.01], p = 0.004). Only CN participants showed improved VM performance with increased fitness (b[SE] = 1.30[0.15], p < 0.005).Conclusion: GPX was elevated in VCIND consistent with a compensatory response to persistent oxidative stress. Increased GPX predicted poorer cognitive outcomes (verbal memory) in VCIND patients despite improved fitness. [ABSTRACT FROM AUTHOR]