Hepatocyte mARC1 promotes fatty liver disease.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ∼25% worldwide, with significant public health consequences yet few effective treatments. Human genetics can help elucidate novel biology and identify targets for new therapeutics. Genetic variants in mitochondrial amidoxime-reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality; however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Methods: Analyses including multi-trait colocalisation and Mendelian randomisation were used to assess the genetic associations of MTARC1. In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra Amylin NASH (GAN)-diet non-alcoholic steatohepatitis mouse model treated with hepatocyte-specific N-acetylgalactosamine (GalNAc)-siRNA to understand the in vivo impacts of MTARC1. Results: We showed that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids, and body composition, and these associations are attributable to the same causal variant (p.A165T, rs2642438 G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian randomisation, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion, and in vivo GalNAc-siRNA-mediated knockdown of mARC1 lowered hepatic but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo. Conclusions: Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD. Impact and implications: We report that genetically predicted increases in MTARC1 mRNA associate with poor liver health. Furthermore, knockdown of mARC1 reduces hepatic steatosis in primary human hepatocytes and a murine NASH model. Together, these findings further underscore the therapeutic potential of targeting hepatocyte MTARC1 for NAFLD.

Using genetic association data to guide drug discovery and development: Review of methods and applications.

Evidence on the validity of drug targets from randomized trials is reliable but typically expensive and slow to obtain. In contrast, evidence from conventional observational epidemiological studies is less reliable because of the potential for bias from confounding and reverse causation. Mendelian randomization is a quasi-experimental approach analogous to a randomized trial that exploits naturally occurring randomization in the transmission of genetic variants. In Mendelian randomization, genetic variants that can be regarded as proxies for an intervention on the proposed drug target are leveraged as instrumental variables to investigate potential effects on biomarkers and disease outcomes in large-scale observational datasets. This approach can be implemented rapidly for a range of drug targets to provide evidence on their effects and thus inform on their priority for further investigation. In this review, we present statistical methods and their applications to showcase the diverse opportunities for applying Mendelian randomization in guiding clinical development efforts, thus enabling interventions to target the right mechanism in the right population group at the right time. These methods can inform investigators on the mechanisms underlying drug effects, their related biomarkers, implications for the timing of interventions, and the population subgroups that stand to gain the most benefit. Most methods can be implemented with publicly available data on summarized genetic associations with traits and diseases, meaning that the only major limitations to their usage are the availability of appropriately powered studies for the exposure and outcome and the existence of a suitable genetic proxy for the proposed intervention.

Leveraging human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide signalling.

AIMS/HYPOTHESIS: The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. METHODS: Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. RESULTS: Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units -0.16, 95% CI -0.30, -0.02), C-reactive protein (-0.13, 95% CI -0.19, -0.08) and triacylglycerol levels (-0.17, 95% CI -0.22, -0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. CONCLUSIONS/INTERPRETATION: This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted. DATA AVAILABILITY: All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP .

SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle.

BACKGROUND AND PURPOSE: In addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ. In this study, we examine whether SENP2 is involved in prolonged stimulation of FAO by leptin. METHODS: The Effect of leptin on expression of SENP2 and on SENP2-mediated FAO was investigated by using western blotting and real time qPCR of C2C12 myotubes, and of C2C12 myotubes in which expression of specific genes was knocked down using siRNAs. Additionally, muscle-specific SENP2 knockout mice were generated to test the involvement of SENP2 in leptin-induced FAO in vivo. RESULTS: We show that leptin treatment of C2C12 myotubes causes signal transducer and activator of transcription 3 (STAT3) to bind to the Senp2 promoter, inducing SENP2 expression. We also show that leptin increases the binding of PPARδ and PPARγ to PPRE sites in the promoters of two FAO-associated genes: long-chain acyl-CoA synthetase 1 (Acsl1) or carnitine palmitoyl transferase 1b (Cpt1b). When SENP2 is knocked down in myotubes, leptin-induced expression of FAO-associated enzymes and prolonged increase of FAO are suppressed, but rapid increase of FAO is unaffected. In addition, leptin-induced expression of FAO-associated enzymes was not observed in muscle tissue of SENP2 knockout mice. CONCLUSIONS: We demonstrate that the peripheral actions of leptin on FAO are mediated by two different pathways: AMPK causes a rapid increase in FAO, and SENP2 of the STAT3 pathway causes a slow, prolonged increase in FAO.

Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of advanced chronic liver disease. The progression of NAFLD, including nonalcoholic steatohepatitis (NASH), has a strong genetic component, and the most robust contributor is the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 encoding the 148M protein sequence variant. We hypothesized that suppressing the expression of the PNPLA3 148M mutant protein would exert a beneficial effect on the entire spectrum of NAFLD. METHODS: We examined the effects of liver-targeted GalNAc3-conjugated antisense oligonucleotide (ASO)-mediated silencing of Pnpla3 in a knock-in mouse model in which we introduced the human PNPLA3 I148M mutation. RESULTS: ASO-mediated silencing of Pnpla3 reduced liver steatosis (p = 0.038) in homozygous Pnpla3 148M/M knock-in mutant mice but not in wild-type littermates fed a steatogenic high-sucrose diet. In mice fed a NASH-inducing diet, ASO-mediated silencing of Pnpla3 reduced liver steatosis score and NAFLD activity score independent of the Pnpla3 genotype, while reductions in liver inflammation score (p = 0.018) and fibrosis stage (p = 0.031) were observed only in the Pnpla3 knock-in 148M/M mutant mice. These responses were accompanied by reduced liver levels of Mcp1 (p = 0.026) and Timp2 (p = 0.007) specifically in the mutant knock-in mice. This may reduce levels of chemokine attracting inflammatory cells and increase the collagenolytic activity during tissue regeneration. CONCLUSION: This study provides the first evidence that a Pnpla3 ASO therapy can improve all features of NAFLD, including liver fibrosis, and suppress the expression of a strong innate genetic risk factor, Pnpla3 148M, which may open up a precision medicine approach in NASH.

Modeling human pancreatic beta cell dedifferentiation.

OBJECTIVE: Dedifferentiation could explain reduced functional pancreatic ß-cell mass in type 2 diabetes (T2D). METHODS: Here we model human ß-cell dedifferentiation using growth factor stimulation in the human ß-cell line, EndoC-ßH1, and human pancreatic islets. RESULTS: Fibroblast growth factor 2 (FGF2) treatment reduced expression of ß-cell markers, (INS, MAFB, SLC2A2, SLC30A8, and GCK) and activated ectopic expression of MYC, HES1, SOX9, and NEUROG3. FGF2-induced dedifferentiation was time- and dose-dependent and reversible upon wash-out. Furthermore, FGF2 treatment induced expression of TNFRSF11B, a decoy receptor for RANKL and protected ß-cells against RANKL signaling. Finally, analyses of transcriptomic data revealed increased FGF2 expression in ductal, endothelial, and stellate cells in pancreas from T2D patients, whereas FGFR1, SOX,9 and HES1 expression increased in islets from T2D patients. CONCLUSIONS: We thus developed an FGF2-induced model of human ß-cell dedifferentiation, identified new markers of dedifferentiation, and found evidence for increased pancreatic FGF2, FGFR1, and ß-cell dedifferentiation in T2D.

Publisher Correction: Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Hemoglobin A1c and C-reactive protein are independently associated with blunted nocturnal blood pressure dipping in obesity-related prediabetes.

Blunted nocturnal dipping in blood pressure (BP) is associated with increased cardiovascular disease (CVD) risk in middle-aged/older adults. The prevalence of blunted nocturnal BP dipping is higher in persons with obesity and diabetes, conditions that are also associated with elevated aortic stiffness and inflammation. Therefore, we hypothesized that elevated glycemia, inflammation and aortic stiffness would be inversely associated with the magnitude of nocturnal systolic BP dipping among middle-aged/older adults with obesity at high CVD risk. Twenty-four hour ambulatory BP monitoring, aortic stiffness (carotid-femoral pulse wave velocity, CF-PWV), hemoglobin A1c (HbA1c) and inflammation (C-reactive protein, CRP) were measured in 86 middle-aged/older adults with obesity and at least one other CVD risk factor (age 40-74 years; 34 male/52 female; body mass index=36.7±0.5 kg m-2; HbA1c=5.7±0.04%). In the entire cohort, CRP (ß=0.40±0.20, P=0.04), but not HbA1c or CF-PWV was independently associated with systolic BP dipping percent (Model R2=0.07, P=0.12). In stratified (that is, presence or absence of prediabetes) multiple linear regression analysis, HbA1c (ß=6.24±2.6, P=0.02) and CRP (ß=0.57±0.2, P=0.01), but not CF-PWV (ß=0.14± 2.6, P=0.74), were independently associated with systolic BP dipping percent (Model R2=0.32, P<0.01) in obese adults with prediabetes but were absent in obese adults without prediabetes (Model R2=0.01 P=0.95). However, nocturnal systolic BP dipping percent (P=0.65), CF-PWV (P=0.68) and CRP (P=0.59) were similar between participants with and without prediabetes. These data suggest that impaired long-term glycemic control and higher inflammation may contribute partly to blunted BP dipping in middle-aged/older adults with obesity-related prediabetes.

Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model.

Human in vitro physiological models studying disease and drug treatment effects are urgently needed as more relevant tools to identify new drug targets and therapies. We have developed a human microfluidic two-organ-chip model to study pancreatic islet-liver cross-talk based on insulin and glucose regulation. We have established a robust co-culture of human pancreatic islet microtissues and liver spheroids maintaining functional responses up to 15 days in an insulin-free medium. Functional coupling, demonstrated by insulin released from the islet microtissues in response to a glucose load applied in glucose tolerance tests on different days, promoted glucose uptake by the liver spheroids. Co-cultures maintained postprandial glucose concentrations in the circulation whereas glucose levels remained elevated in both single cultures. Thus, insulin secreted into the circulation stimulated glucose uptake by the liver spheroids, while the latter, in the absence of insulin, did not consume glucose as efficiently. As the glucose concentration fell, insulin secretion subsided, demonstrating a functional feedback loop between the liver and the insulin-secreting islet microtissues. Finally, inter-laboratory validation verified robustness and reproducibility. Further development of this model using tools inducing impaired glucose regulation should provide a unique in vitro system emulating human type 2 diabetes mellitus.

Higher augmentation index is associated with tension-type headache and migraine in middle-aged/older humans with obesity.

OBJECTIVE: Obesity is a major risk factor for chronic daily headaches, including migraine and tension-type headache (TTH). Although migraine is associated with increased risk of cardiovascular diseases (CVD), a relation between TTH and CVD risk has not been established. It was hypothesized that higher carotid-femoral pulse wave velocity (CFPWV) and augmentation index (AI), measures of aortic stiffness and pressure wave reflection, respectively, and biomarkers of CVD risk, would be higher among adults with obesity and migraine or TTH compared with those with no headache. METHODS: Adults with obesity (n = 93; body mass index ≥30 kg/m(2) ) who were between 40 and 75 years old with at least one additional CVD risk factor were enrolled. Subjects had CFPWV and AI assessed and a complete neurological exam for diagnosis of headache in the past 12 months. RESULTS: Adults with obesity and TTH (P = 0.018), but not migraine (P = 0.29), had significantly higher AI compared with those with no headache. When both CFPWV and AI were considered in a logistic regression model with migraine or TTH, only AI was associated with TTH (P = 0.008) and migraine (P = 0.032) but could not distinguish between the two headache phenotypes. CONCLUSIONS: Increased aortic AI but not stiffness is associated with TTH and migraine among middle-aged/older adults with obesity and high CVD risk.

Finger volume pulse waveforms facilitate reliable assessment of heart rate variability, but not blood pressure variability or baroreflex function.

BACKGROUND: We sought to determine whether heart rate variability (HRV), blood pressure (BP) variability, and baroreceptor-heart rate reflex sensitivity can be reliably assessed using finger volume pulse waveforms obtained from the commercially available EndoPAT device. METHODS: Non-invasive BP (Finometer Pro as a non-invasive standard) and finger volume (EndoPAT) waveforms were recorded in 65 adults (37 ± 14 years; 60% female) and systolic BP and heart rate (HR) time series were derived after calibrating the EndoPAT signal based on systolic and diastolic BP values obtained by a sphygomomanometer. Transfer function analyses were performed to test for coherence between systolic BP and HR time series derived from the Finometer and EndoPAT devices. Time-domain HRV parameters, frequency domain HR and systolic BP variability parameters, and baroreflex sensitivity (sequence technique) were computed from Finometer- and EndoPAT-derived time series and intraclass correlation coefficients (ICC) were calculated. RESULTS: Squared coherence between systolic BP time series derived from the Finometer and EndoPAT devices was low, suggesting poor correlation. In contrast, squared coherence between HR time series derived from the two devices was excellent [High Frequency (HF) = 0.80, Low Frequency (LF) = 0.81], with gain values close to 1.0. ICC values for time- and frequency-domain HRV parameters were excellent (>0.9 except for relative HF HRV, which was 0.77), while ICC values for frequency-domain BP variability parameters and baroreceptor-HR reflex sensitivity were low. CONCLUSIONS: Finger volume pulse waveforms can be used to reliably assess both time-domain and frequency-domain HR variability. However, frequency domain BP variability parameters cannot be reliably assessed from finger volume pulse waveforms using the simple calibration technique used in this study.

Body fat indices and biomarkers of inflammation: a cross-sectional study with implications for obesity and peri-implant oral health.

PURPOSE: To examine the relationships between three measures of body fat-body mass index (BMI), waist circumference (WC), and total body fat percent-and markers of inflammation around dental implants in stable periodontal maintenance patients. MATERIALS AND METHODS: Seventy-three subjects were enrolled in this cross-sectional assessment. The study visit consisted of a physical examination that included anthropologic measurements of body composition (BMI, WC, body fat %); intraoral assessments were performed (full-mouth plaque index, periodontal and peri-implant comprehensive examinations) and peri-implant sulcular fluid (PISF) was collected on the study implants. Levels of interleukin (IL)-1α, IL-1ß, IL-6, IL-8, IL-10, IL-12, IL-17, tumor necrosis factor-α, C-reactive protein, osteoprotegerin, leptin, and adiponectin in the PISF were measured using multiplex proteomic immunoassays. Correlation analysis with body fat measures was then performed using appropriate statistical methods. RESULTS: After adjustments for covariates, regression analyses revealed statistically significant correlation between IL-1ß in PISF and WC (R = 0.33; P = .0047). CONCLUSION: In this study in stable periodontal maintenance patients, a modest but statistically significant positive correlation was observed between the levels of IL-1ß, a major proinflammatory cytokine in PISF, and WC, a reliable measure of central obesity.

Effects of antipsychotic drugs on cardiovascular variability in participants with bipolar disorder.

OBJECTIVE: The risk for cardiovascular diseases is elevated in persons with bipolar disorder. However, it remains unknown how much of this excess risk is secondary to pharmacologic treatment. We tested the hypothesis that current and cumulative antipsychotic drug exposure is associated with increased cardiovascular risk as indicated by lower heart rate variability (HRV) and increased blood pressure variability (BPV). METHODS: Fifty-five individuals with bipolar disorder (33 ± 7 years; 67% female) underwent noninvasive electrocardiogram assessment of time-domain and frequency-domain HRV, as well as BPV analysis. Medication histories were obtained through systematic review of pharmacy records for the past 5 years. RESULTS: Current antipsychotic exposure was associated with lower standard deviation of NN intervals. Second-generation antipsychotics were associated with lower standard deviation of NN intervals and root mean square of successive differences. There was no significant relationship between 5-year antipsychotic exposure and HRV in subjects with bipolar disorder. Exploratory analysis revealed a possible link between selective serotonin reuptake inhibitor exposure and increased low-frequency spectral HRV. CONCLUSIONS: Current antipsychotic use (particularly second-generation antipsychotics with high affinities for the D2S receptor) is associated with reduced autonomic-mediated variability of the HR. The absence of an association with cumulative exposure suggests that the effects are acute in onset and may therefore relate more to altered autonomic function than structural cardiovascular abnormalities. Future studies should prospectively examine effects of these antipsychotics on autonomic function.

Sodium nitrite in patients with peripheral artery disease and diabetes mellitus: safety, walking distance and endothelial function.

Nitrite stores decrease after exercise in patients with peripheral artery disease (PAD) and diabetes represents decreased nitric oxide (NO) bioavailability that may contribute to endothelial dysfunction and limit exercise duration. The primary objective of this placebo-controlled study was the safety and tolerability of multiple doses of oral sodium nitrite in patients with PAD, predominantly with diabetes, over a period of 10 weeks. The primary efficacy endpoint was endothelial flow-mediated dilatation (FMD) and secondary efficacy endpoints included a 6-minute walk test and quality of life assessment. Of the 55 subjects, the most common side effects attributed to sodium nitrite were a composite of headache and dizziness occurring in 21% with the 40 mg dose and 44% with the 80 mg dose. There was no clinically significant elevation of methemoglobin. FMD non-significantly worsened in the placebo and 40 mg groups, but was stable in the 80 mg group. Diabetic patients receiving 80 mg had significantly higher FMD compared with the placebo and 40 mg groups. There was no significant change in 6-minute walk test or quality of life parameters over time compared to placebo. In conclusion, sodium nitrite therapy is well tolerated in patients with PAD. The possible clinical benefit of sodium nitrite should be studied in a larger and fully powered trial.

Association of anxiety with resistance vessel dysfunction in human atherosclerosis.

OBJECTIVE: Anxiety predicts cardiovascular events, although the mechanism remains unclear. We hypothesized that anxiety symptoms will correlate with impaired resistance and conduit vessel function in participants aged 55 to 90 years. METHODS: Anxiety symptoms were measured with the Symptom Checklist-90--Revised in 89 participants with clinically diagnosed atherosclerotic cardiovascular disease and 54 healthy control participants. Vascular function in conduit arteries was measured using flow-mediated dilatation, and vascular function in forearm resistance vessels (FRVs) was measured using intra-arterial drug administration and plethysmography. RESULTS: Anxiety symptoms were not associated with flow-mediated dilatation in either group. Participants with atherosclerosis exhibited significant inverse associations of anxiety symptoms with FRV dilatation (acetylcholine: ß = -.302, p = .004). Adjustment for medication, risk factors, and depression symptoms did not alter the association between anxiety and FRV dysfunction, except for body mass index (BMI; anxiety: ß = -.175, p = .060; BMI: ß = -.494, p < .001). Although BMI was more strongly associated with FRV function than anxiety, combined BMI and anxiety accounted for greater variance in FRV function than either separately. Control participants showed no association of anxiety with FRV function. CONCLUSIONS: Anxiety is uniquely and substantially related to poorer resistance vessel function (both endothelial and vascular smooth muscle functions) in individuals with atherosclerosis. These relationships are independent of medication, depression, and cardiovascular risk factors, with the exception of BMI. These findings support the concept that anxiety potentially increases vascular events through worsening of vascular function in atherosclerotic disease.

Sildenafil increases sympathetically mediated vascular tone in humans.

BACKGROUND: Sildenafil, a selective phosphodiesterase-type-5 (PDE-5) inhibitor, produces vasodilation that improves erectile dysfunction and pulmonary hypertension. Sildenafil could also cause baroreflex sympathetic activation that would enhance vascular tone and oppose direct vasodilation. We tested the hypothesis that sildenafil administration increases sympathetically mediated vascular tone in healthy middle-aged men. METHODS: We randomized 9 healthy, middle-aged, male volunteers (mean age 45±2 years) in a double-blind, crossover fashion to receive a single oral dose of sildenafil 100mg or placebo on 2 separate study days. Hemodynamics and forearm blood flow responses were measured at baseline, at 30 and 45 minutes after study drug administration, and then during intra-arterial infusions of vasoactive drugs. After sildenafil and placebo administration, intrabrachial medications were infused to test forearm alpha receptor sensitivity (norepinephrine), cyclic-AMP-mediated vasodilation (isoproterenol), and sympathetically mediated vascular tone (phentolamine) (adenosine was a control vasodilator). Blood samples were taken before and 60 minutes after study drug administration and at the end of the intrabrachial infusions for measurement of plasma norepinephrine concentrations. RESULTS: Forearm vascular responses to norepinephrine, isoproterenol, and adenosine were not different after placebo and sildenafil administration. Percentage reduction in forearm vascular resistance during phentolamine was significantly lower after sildenafil than placebo (-73% ± 3% vs -63% ± 3%; P = 0.0002). Sildenafil significantly increased plasma norepinephrine compared with placebo 60 minutes after study drug administration and at the end of the study session (P = 0.02). CONCLUSIONS: Sildenafil increased sympathetically mediated vascular tone in middle-aged healthy men. Alpha-adrenergic-mediated vasoconstriction may offset vasodilation during PDE-5 inhibition and may explain the significant hypotension observed in patients taking alpha-blockers with sildenafil.

White matter fractional anisotropy is inversely related to anxious symptoms in older adults with atherosclerosis.

OBJECTIVE: Clinical anxiety disorders are associated with white matter hyperintensities and diffusion abnormalities measured using diffusion tensor imaging. However, it is not known if this association extends into individuals with mild anxious symptoms without formal diagnosis, in those who are older, or in those who have atherosclerosis. The current study explores whether white matter integrity and/or organization significantly associates with anxious symptoms in older adults with and without atherosclerosis. METHODS: We recruited older adults (ages 55-90 years); 35 with clinically diagnosed atherosclerotic vascular disease (AVD) and 22 without AVD. Anxious symptoms were measured using the validated Symptom Checklist-90-Revised. Fractional anisotropy (FA), a proxy for white matter organization and health, was measured in the white matter globally, by lobe, and in several smaller regions of interest suggested by the literature. Partial correlations between anxious symptoms and FA were calculated, controlling for significant covariates. RESULTS: Participants with and without AVD did not differ in severity of anxious symptom endorsement. There was a unique inverse relationship between white matter health and anxious symptoms in the AVD participants, but not in healthy comparisons. Significant relationships were observed in the superior longitudinal fasciculus (r = -0.476, df = 32, p = 0.004), as well as the cingulum bundle, the frontal lobes, and the parietal lobes. CONCLUSIONS: Anxiety symptoms uniquely correlated with low FA in older adults with atherosclerosis. These findings may have implications for future research on the topic of anxiety in aging and vascular disease and warrant replication.

Evidence for accelerated vascular aging in bipolar disorder.

OBJECTIVE: Persons with bipolar disorder face excess risk of cardiovascular disease, although the biobehavioral mechanisms and time course are unclear. We measured vascular stiffness in a cross-sectional sample of participants with bipolar disorder and compared results to published normative data to assess time-course and relationship to behavioral risk factors. METHODS: 62 individuals with bipolar disorder (33±6.7years; 64% female) underwent non-invasive assessment of arterial stiffness through arterial applanation tonometry. Lifetime tobacco exposure was estimated on clinical interview. Physical activity was assessed using the long-version of the International Physical Activity Questionnaire (IPAQ). A food frequency questionnaire was used to compute Alternate Healthy Eating Index (AHEI), a measure of overall dietary quality. Medication histories were systematically abstracted from pharmacy records. RESULTS: Participants over the age of 32 (median split) had greater arterial stiffness than expected from age-based population norms for pulse wave velocity (PWV) (7.6 vs. 7.0m/s, p=.02) and estimated aortic augmentation pressure (AIx) (14.2 vs. 8.2%, p=.0002). The younger portion of the sample did not differ from population norms on these measures (PWV 6.3 vs. 6.4m/s, p=.45 and AIx 7.6 vs. 7.4%, p=.60). In the older half of the sample, physical activity was inversely associated with AIx and poorer diet marginally associated with PWV. These findings were independent of body mass index (BMI), which was strongly related to arterial stiffness. CONCLUSION: Risk for vascular disease may be acquired over the long-term course of affective illness. This risk appears to reflect maladaptive health behaviors, which may be amenable to intervention.

Rate of weight gain and cardiometabolic abnormalities in children and adolescents.

OBJECTIVE: To investigate whether the rate of weight gain is associated with cardiometabolic risk, independent of weight measured concurrently. STUDY DESIGN: Healthy 7- to 17-year-old risperidone-treated patients (N = 105, 88% were boys) had blood pressure, anthropometry, and laboratory tests performed. Growth history was extracted from medical records. The rate of change in age- and sex-adjusted weight and body mass index (BMI) z score after the initiation of risperidone was individually modeled. Multivariable linear regression analyses explored the association of the rate of weight or BMI z score change with cardiometabolic outcomes, independent of last measured weight or BMI z score, respectively. RESULTS: Following a mean of 1.9 years (SD = 1.0) of risperidone treatment, the absolute increase in weight and BMI z scores was 0.61 (SD = 0.61) and 0.62 (SD = 0.73), respectively. After controlling for the final weight z score, the rate of change in weight z score was significantly associated with final glucose (P < .04), C-peptide (P < .004), the homeostasis model assessment insulin resistance index (P < .02), high-density lipoprotein (HDL) cholesterol (P < .0001), a metabolic syndrome score (P < .005), adiponectin (P < .04), and high-sensitivity C-reactive protein (P < .04). After controlling for the final BMI z score, the rate of change in BMI z score was associated with final HDL cholesterol (P < .04), leptin (P < .03), and adiponectin (P < .04), with a suggestion of an association with the final homeostasis model assessment insulin resistance index (P < .08). CONCLUSIONS: Compared with weight measured concurrently, the rate of weight gain in risperidone-treated children accounts for an equal or larger share of the variance in certain cardiometabolic outcomes (eg, HDL cholesterol [ΔR(2) = 8% vs ΔR(2) = 11%] and high-sensitivity C-reactive protein [ΔR(2) = 5% vs ΔR(2) = 9%]) and may serve as a treatment target.

Systematic Review and Meta-analysis of Pharmacological Interventions for Weight Gain from Antipsychotics and Mood Stabilizers.

Pharmacological treatments for serious mental illness (SMI) can cause weight gain and adverse metabolic effects. Many second generation antipsychotics and mood stabilizers appear to be particularly problematic in this regard. Several studies have investigated interventions for antipsychotic-induced, or less commonly mood stabilizer -induced, weight gain. Both lifestyle and pharmacological interventions have demonstrated effectiveness. We systematically review randomized controlled trials of pharmacological interventions for weight gain related to these medications. We conducted a meta-analysis of clinical trials for the most studied agents to estimate mean weight loss: metformin (2.93 kg, 95% C.I. 0.97-4.89, p=0.003), H(2) antagonists (1.78 kg (95% C.I. -0.50-4.06, p=0.13), topiramate (3.95 kg 95% C.I. 1.77-6.12, p=0.0004), and norepinephrine reuptake inhibitors (1.30 kg (95% C.I. -0.06-2.66, p=0.06). Among the studied options for antipsychotic-related weight gain, metformin has the strongest evidence base and may improve vascular risk factors beyond obesity. The use of topiramate is also supported by the literature and may improve psychotic symptoms in those refractory to treatment. A marginal benefit is seen with norepinephrine reuptake inhibitors, and any vascular benefits from such weight loss may be counteracted by increases in blood pressure or heart rate. Pharmacological therapies may offer benefits as a means of supplementing the effects of lifestyle changes for weight loss. However, the existing evidence provides little evidence of specificity for pharmacological therapies to antipsychotic-induced weight gain and has not studied any connection between benefits and reduced incidence of diabetes mellitus or any vascular outcomes.