High-resolution free-breathing automated quantitative myocardial perfusion by cardiovascular magnetic resonance for the detection of functionally significant coronary artery disease.

AIMS: Current assessment of myocardial ischaemia from stress perfusion cardiovascular magnetic resonance (SP-CMR) largely relies on visual interpretation. This study investigated the use of high-resolution free-breathing SP-CMR with automated quantitative mapping in the diagnosis of coronary artery disease (CAD). Diagnostic performance was evaluated against invasive coronary angiography (ICA) with fractional flow reserve (FFR) measurement. METHODS AND RESULTS: Seven hundred and three patients were recruited for SP-CMR using the research sequence at 3 Tesla. Of those receiving ICA within 6 months, 80 patients had either FFR measurement or identification of a chronic total occlusion (CTO) with inducible perfusion defects seen on SP-CMR. Myocardial blood flow (MBF) maps were automatically generated in-line on the scanner following image acquisition at hyperaemic stress and rest, allowing myocardial perfusion reserve (MPR) calculation. Seventy-five coronary vessels assessed by FFR and 28 vessels with CTO were evaluated at both segmental and coronary territory level. Coronary territory stress MBF and MPR were reduced in FFR-positive (≤0.80) regions [median stress MBF: 1.74 (0.90-2.17) mL/min/g; MPR: 1.67 (1.10-1.89)] compared with FFR-negative regions [stress MBF: 2.50 (2.15-2.95) mL/min/g; MPR 2.35 (2.06-2.54) P < 0.001 for both]. Stress MBF ≤ 1.94 mL/min/g and MPR ≤ 1.97 accurately detected FFR-positive CAD on a per-vessel basis (area under the curve: 0.85 and 0.96, respectively; P < 0.001 for both). CONCLUSION: A novel scanner-integrated high-resolution free-breathing SP-CMR sequence with automated in-line perfusion mapping is presented which accurately detects functionally significant CAD.

Back-translating GWAS findings to animal models reveals a role for Hgfac and Slc39a8 in alcohol and nicotine consumption.

Alcohol and tobacco are the most commonly used addictive substances, with high comorbidity rates between alcohol use disorder and tobacco use disorder. Risk for alcohol and nicotine addiction is highly heritable, and they share common genetic factors. A GWAS in over 1 million individuals has revealed 566 genetic variants in 406 loci associated with multiple stages of alcohol and tobacco use. Three novel genes-SLC39A8, GRK4 and HGFAC-within loci associated with altered alcoholic drinks per week (ADW) or cigarettes per day (CPD) were selected to further study their role in alcohol and tobacco use disorder. The role of these genes was assessed using the two-bottle choice addiction paradigm in transgenic mice for each of the genes. We found significant decreases in chronic alcohol consumption and preference in female Hgfac knockout (KO) mice, and decreased nicotine preference in male Hgfac KO compared with wild-type (WT) mice. Additionally, male Slc39a8 hypomorph mice showed greater overall nicotine preference compared with WT mice, while no differences were detected for Grk4 KO mice in alcohol or nicotine consumption and preference in either sex. Thus, this study implicates Hgfac and Slc39a8 in alcohol and tobacco use in a sex-specific manner.

Flavor-specific enhancement of electronic cigarette liquid consumption and preference in mice.

BACKGROUND: The use of electronic cigarettes has increased over the past decade. To determine how the abuse liability of electronic cigarette liquids (e-liquids) differs from nicotine alone, and to determine the impact of flavor, we compared nicotine-containing fruit- and tobacco-flavored e-liquids, and their nicotine-free versions, to nicotine alone in mouse models of oral consumption, reward and aversion. METHODS: Adult male C57BL/6 J mice voluntarily consumed oral nicotine, equivalent nicotine concentrations of fruit- and tobacco-flavored e-liquid, and equivalent dilutions of the nicotine-free versions in 2-bottle choice tests. Conditioned place preference and place aversion were assessed with peripherally administered e-liquids or nicotine. Serum nicotine and cotinine levels were measured after subcutaneous injections of e-liquid or nicotine. RESULTS: Mice showed higher consumption and preference for the fruit-flavored e-liquid compared with nicotine alone. This increase was not due to the flavor itself as consumption of the nicotine-free fruit-flavored e-liquid was not elevated until the highest concentration tested. The increased consumption and preference were not observed with the tobacco-flavored e-liquid. The conditioned place preference, place aversion and nicotine pharmacokinetics of the fruit-flavored e-liquid were not significantly different from nicotine alone. CONCLUSIONS: Our data suggest that fruit, but not tobacco flavor, increased the oral consumption of e-liquid compared with nicotine alone. Moreover, this enhancement was not due to increased consumption of the flavor itself, altered rewarding or aversive properties after peripheral administration, or altered pharmacokinetics. This flavor-specific enhancement suggests that some flavors may lead to higher nicotine intake and increased use of e-liquids compared with nicotine alone.

Evening chronotype, disordered eating behavior, and poor dietary habits in bipolar disorder.

OBJECTIVE: Our aim was to evaluate the relationship between evening chronotype, a proxy marker of circadian system dysfunction, and disordered eating behavior and poor dietary habits in individuals with bipolar disorder (BD). METHODS: In this cross-sectional study, we evaluated 783 adults with BD. Chronotype was determined using item 5 from the reduced Morningness-Eveningness Questionnaire. The Eating Disorder Diagnostic Scale (EDDS) and the Rapid Eating Assessment for Participants-Shortened Version (REAP-S) were used to assess disordered eating behavior and dietary habits respectively. General linear models and logistic regression models were utilized to evaluate differences between chronotype groups. RESULTS: Two hundred and eight (27%) BD participants self-identified as having evening chronotypes. Compared to non-evening types, evening types were younger (P < 0.01) and, after controlling for age, had higher mean EDDS composite z-scores (P < 0.01); higher rates of binge-eating (BE) behavior (P = 0.04), bulimia nervosa (P < 0.01), and nocturnal eating binges (P < 0.01); and a higher body mass index (P = 0.04). Compared to non-evening types, evening chronotypes had a lower REAP-S overall score (P < 0.01) and scored lower on the 'healthy foods' and 'avoidance of unhealthy food' factors. Evening types also skipped breakfast more often (P < 0.01), ate less fruit (P = 0.02) and vegetables (P = 0.04), and consumed more fried foods (P < 0.01), unhealthy snacks (P = 0.02), and soft drinks (P = 0.01). CONCLUSIONS: Our findings suggest that the circadian system plays a role in the disordered eating and unhealthy dietary behaviors observed in BD patients. The circadian system may therefore represent a therapeutic target in BD-associated morbidity that warrants further investigation.

Leveraging electronic health records to study pleiotropic effects on bipolar disorder and medical comorbidities.

Patients with bipolar disorder (BD) have a high prevalence of comorbid medical illness. However, the mechanisms underlying these comorbidities with BD are not well known. Certain genetic variants may have pleiotropic effects, increasing the risk of BD and other medical illnesses simultaneously. In this study, we evaluated the association of BD-susceptibility genetic variants with various medical conditions that tend to co-exist with BD, using electronic health records (EHR) data linked to genome-wide single-nucleotide polymorphism (SNP) data. Data from 7316 Caucasian subjects were used to test the association of 19 EHR-derived phenotypes with 34 SNPs that were previously reported to be associated with BD. After Bonferroni multiple testing correction, P<7.7 × 10(-5) was considered statistically significant. The top association findings suggested that the BD risk alleles at SNP rs4765913 in CACNA1C gene and rs7042161 in SVEP1 may be associated with increased risk of 'cardiac dysrhythmias' (odds ratio (OR)=1.1, P=3.4 × 10(-3)) and 'essential hypertension' (OR=1.1, P=3.5 × 10(-3)), respectively. Although these associations are not statistically significant after multiple testing correction, both genes have been previously implicated with cardiovascular phenotypes. Moreover, we present additional evidence supporting these associations, particularly the association of the SVEP1 SNP with hypertension. This study shows the potential for EHR-based analyses of large cohorts to discover pleiotropic effects contributing to complex psychiatric traits and commonly co-occurring medical conditions.

Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder.

OBJECTIVE: Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder. METHOD: The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6-month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models. RESULTS: At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome. CONCLUSION: Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment.

More pernicious course of bipolar disorder in the United States than in many European countries: implications for policy and treatment.

BACKGROUND: There is some controversy but growing evidence that childhood onset bipolar disorder may be more prevalent and run a more difficult course in the United States than some European countries. METHODS: We update and synthesize course of illness data from more than 960 outpatients with bipolar disorder (average age 40) from 4 sites in the U.S. and 3 sites in Netherlands and Germany. After giving informed consent, patients reported on parental history, childhood and lifetime stressors, comorbidities, and illness characteristics. RESULTS: Almost all aspects of bipolar disorder were more adverse in patients from the US compared with Europe, including a significantly higher prevalence of: bipolar disorder in one parent and a mood disorder in both parents; childhood verbal, physical, or sexual abuse; stressors in the year prior to illness onset and the last episode; childhood onsets of bipolar illness; delay to first treatment; anxiety disorder, substance abuse, and medical comorbidity; mood episodes and rapid cycling; and nonresponse to prospective naturalistic treatment. LIMITATIONS: Selection bias in the recruit of patients cannot be ruled out, but convergent data in the literature suggest that this does not account for the findings. Potential mechanisms for the early onset and more adverse course in the U.S. have not been adequately delineated and require further investigation. CONCLUSIONS: The data suggest the need for earlier and more effective long-term treatment intervention in an attempt to ameliorate this adverse course and its associated heavy burden of psychiatric and medical morbidity.

Increased parental history of bipolar disorder in the United States: association with early age of onset.

OBJECTIVE: Early-onset bipolar (BP) disorder and other poor prognosis characteristics are more prevalent in patients from the United States than from the Netherlands and Germany (abbreviated as Europe). We explored the impact of parental loading for affective illness on onset and other characteristics of BP disorder. METHOD: Parental history for unipolar (UP) and bipolar (BP) depression and course of illness characteristics were obtained from self-report in adults (average age 42) with BP disorder. Illness characteristics were examined by χ2 and multinomial logistic regression in relationship to the degree of parental loading: i) both parents negative; ii) one UP disorder; iii) one with BP disorder; and iv) both affected. RESULTS: After controlling for many poor prognosis factors, compared with those from Europe, patients from the United States had more iii) one parent with BP disorder and iv) both parents affected. An early age of onset of BP disorder was independently associated with this increased parental loading for affective disorder. CONCLUSION: Parental history of BP disorder and both parents with a mood disorder were more common in the United States than Europe and were associated with an early onset of bipolar disorder and other poor prognosis characteristics. These findings deserve replication and exploration of the potential mechanisms involved and their therapeutic implications.

Genome-wide association study of bipolar disorder accounting for effect of body mass index identifies a new risk allele in TCF7L2.

Bipolar disorder (BD) is associated with higher body mass index (BMI) and increased metabolic comorbidity. Considering the associated phenotypic traits in genetic studies of complex diseases, either by adjusting for covariates or by investigating interactions between genetic variants and covariates, may help to uncover the missing heritability. However, obesity-related traits have not been incorporated in prior genome-wide analyses of BD as covariates or potential interacting factors. To investigate the genetic factors underlying BD while considering BMI, we conducted genome-wide analyses using data from the Genetic Association Information Network BD study. We analyzed 729,454 genotyped single-nucleotide polymorphism (SNP) markers on 388 European-American BD cases and 1020 healthy controls with available data for maximum BMI. We performed genome-wide association analyses of the genetic effects while accounting for the effect of maximum BMI, and also evaluated SNP-BMI interactions. A joint test of main and interaction effects demonstrated significant evidence of association at the genome-wide level with rs12772424 in an intron of TCF7L2 (P=2.85E-8). This SNP exhibited interaction effects, indicating that the bipolar susceptibility risk of this SNP is dependent on BMI. TCF7L2 codes for the transcription factor TCF/LF, part of the Wnt canonical pathway, and is one of the strongest genetic risk variants for type 2 diabetes (T2D). This is consistent with BD pathophysiology, as the Wnt pathway has crucial implications in neurodevelopment, neurogenesis and neuroplasticity, and is involved in the mechanisms of action of BD and depression treatments. We hypothesize that genetic risk for BD is BMI dependent, possibly related to common genetic risk with T2D.