Adipose tissue attenuation as a marker of adipose tissue quality: Associations with six-year changes in body weight.

OBJECTIVE: Weight gain is associated with fat volume increases, but associations with fat quality are less well characterized The associations of weight change with visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume and attenuation were investigated. METHODS: Computed tomography abdominal scans were acquired on a Framingham Heart Study subset (N = 836; 40.2% women; mean age 45.7 years), a mean of 6.1 years apart. Fat attenuation estimated fat quality. RESULTS: Mean weight change was +2.0 (SD 6.8; IQR -0.7, 5.0) kg in women and +2.7 (SD 6.0; IQR -0.5, 5.4) kg in men. Per 2.5 kg weight increase in women, VAT volume increased 126 cm(3) (95% CI, 112-140, p < 0.0001), SAT volume increased 258 cm(3) (95% CI, 239-278, p < 0.0001), and fat attenuation decreased (i.e., fat quality worsened) in VAT and SAT (p < 0.0001). Increasing VAT volume was associated with decreasing fat attenuation even after accounting for weight change. Relative to weight-stable women (n = 129), women who lost >2.5 kg (n = 58) had smaller SAT attenuation decreases (p < 0.0001). Similar patterns were seen in men. CONCLUSIONS: Weight gain was associated with decreases in fat attenuation independent of VAT and SAT volume changes. These findings highlighted the associations of weight gain and worsening fat attenuation, suggesting fat attenuation may be dynamic.

The Association Between Subcutaneous Fat Density and the Propensity to Store Fat Viscerally.

BACKGROUND: Alterations in the cellular characteristics of subcutaneous adipose tissue (SAT) may reduce its ability to expand in times of caloric excess, increasing the propensity to store excess calories viscerally (visceral adipose tissue [VAT]). We hypothesized (1) that increased SAT density, an indirect marker of fat quality, would be associated with an increased VAT/SAT ratio and increased cardiovascular disease (CVD) risk and (2) that these associations would be independent of the absolute volume of SAT. METHODS: We investigated the association of SAT density with the VAT/SAT ratio and CVD risk in 3212 participants (48% women, mean age, 50.7 years) from the Framingham Heart Study. Adipose tissue depot density and volume were quantified by computed tomography; traditional CVD risk factors were quantified. RESULTS: Higher SAT density was correlated with a higher VAT/SAT ratio in men (r = 0.17; P < .0001) but not in women (r = 0.04; P ≥ .05). More adverse levels of CVD risk factors were observed in the high SAT density/high VAT/SAT ratio group than in the referent group (low density/low ratio). For example, women had an increased risk of diabetes (odds ratio [OR], 6.7; 95% confidence interval [CI], 2.6-17.6; P = .0001) and hypertension (OR, 1.6; 95% CI, 1.1-2.4; P = .009). Additional adjustment for SAT volume generally strengthened these associations (diabetes OR, 10.8; 95% CI, 4.1-29.0; hypertension OR, 2.5; 95% CI, 1.7-3.7; all P < .0001). These trends were similar but generally weaker in men. CONCLUSION: High fat density, an indirect marker of fat quality, is associated with the propensity to store fat viscerally vs subcutaneously and is jointly characterized by an increased burden of CVD risk factors.

Fat quality and incident cardiovascular disease, all-cause mortality, and cancer mortality.

CONTEXT: Cellular characteristics of fat quality have been associated with cardiometabolic risk and can be estimated by computed tomography (CT) attenuation. OBJECTIVE: The aim was to determine the association between CT attenuation (measured in Hounsfield units [HU]) and clinical outcomes. METHODS: This was a prospective community-based cohort study using data from the Framingham Heart Study (n = 3324, 48% women, mean age 51 years) and Cox proportional hazard models. MAIN OUTCOMES: The primary outcomes of interest were incident cardiovascular disease (CVD) and all-cause mortality. The secondary outcomes of interest were incident cancer, non-CVD death, and cancer death. RESULTS: There were 111 incident CVD events, 137 incident cancers, 85 deaths including 69 non-CVD deaths, and 45 cancer deaths in up to 23 047 person-years of follow-up. A 1-SD increment in visceral adipose tissue (VAT) HU was inversely associated with incident CVD in the age- and sex-adjusted model (hazard ratio [HR] 0.78, P = .02) but not after multivariable adjustment (HR 0.83, P = .11). VAT HU was directly associated with all-cause mortality (multivariable HR 1.40, P = .003), which maintained significance after additional adjustment for body mass index (HR 1.53, P < .001) and VAT volume (HR 1.99, P < .001). Non-CVD death remained significant in all 3 models, including after adjustment for VAT volume (HR 1.97, P < .001). VAT HU was also associated with cancer mortality (HR 1.93, P = .002). Similar results were obtained for sc adipose tissue HU. CONCLUSIONS: Fat quality, as estimated by CT attenuation, is associated with all-cause mortality, non-CVD death, and cancer death. These associations highlight how indirect indices of fat quality can potentially add to a better understanding of obesity-related complications.

Development and reproducibility of a computed tomography-based measurement for upper body subcutaneous neck fat.

BACKGROUND: Upper body subcutaneous neck fat (UBSF) is a unique fat depot anatomically separate from visceral abdominal fat that appears to be associated with cardiometabolic risk above and beyond generalized adiposity. We sought to develop a protocol to quantify UBSF using multidetector computed tomography measurements. METHODS AND RESULTS: Protocol development was performed in participants from the Framingham Heart Study who had participated in the multidetector computed tomography scanning substudy, consisting of chest scans. Volumetric assessment of UBSF was defined by 40 contiguous 0.625­mm slices superior to the body of the sternum. The reader manually traced the chest to identify total neck fat. Breast tissue exterior to the chest wall was excluded. Subcutaneous and visceral fat volumes were obtained using standard protocols. Age­ and sex­adjusted Pearson correlation coefficients were used to assess the association among UBSF, traditional adiposity measures, and cardiometabolic risk factors. Inter­ and intrareader reproducibility was assessed using intraclass correlation coefficients. Volumetric assessments were obtained in 92 participants because 8 scans were not readable (51% women; mean age: 59 years [women], 58 years [men]). The mean volume of UBSF was 310 cm3 for women and 345 cm3 for men. Intra­ and interreader class correlation coefficients were 0.99 and 0.99, respectively. UBSF was correlated with waist circumference (r=0.90), neck circumference (r=0.75), body mass index (r=0.89), subcutaneous adipose tissue (r=0.87), and visceral adipose tissue (r=0.86). CONCLUSIONS: UBSF can be quantified reproducibly using computed tomography in a community­dwelling sample from the Framingham Heart Study.

Association of fat density with subclinical atherosclerosis.

BACKGROUND: Ectopic fat density is associated with cardiovascular disease (CVD) risk factors above and beyond fat volume. Volumetric measures of ectopic fat have been associated with CVD risk factors and subclinical atherosclerosis. The aim of this study was to investigate the association between fat density and subclinical atherosclerosis. METHODS AND RESULTS: Participants were drawn from the Multi-Detector Computed Tomography (MDCT) substudy of the Framingham Heart Study (n=3079; mean age, 50.1 years; 49.2% women). Fat density was indirectly estimated by computed tomography attenuation (Hounsfield Units [HU]) on abdominal scan slices. Visceral fat (VAT), subcutaneous fat (SAT), and pericardial fat HU and volumes were quantified using standard protocols; coronary and abdominal aortic calcium (CAC and AAC, respectively) were measured radiographically. Multivariable-adjusted logistic regression models were used to evaluate the association between adipose tissue HU and the presence of CAC and AAC. Overall, 17.1% of the participants had elevated CAC (Agatston score [AS]>100), and 23.3% had elevated AAC (AS>age-/sex-specific cutoffs). Per 5-unit decrement in VAT HU, the odds ratio (OR) for elevated CAC was 0.76 (95% confidence interval [CI], 0.65 to 0.89; P=0.0005), even after adjustment for body mass index or VAT volume. Results were similar for SAT HU. With decreasing VAT HU, we also observed an OR of 0.79 (95% CI, 0.67 to 0.92; P=0.004) for elevated AAC after multivariable adjustment. We found no significant associations between SAT HU and AAC. There was no significant association between pericardial fat HU and either CAC or AAC. CONCLUSIONS: Lower VAT and SAT HU, indirect estimates of fat quality, are associated with a lower risk of subclinical atherosclerosis.

Visceral and subcutaneous fat quality and cardiometabolic risk.

OBJECTIVES: The aim of this study was to evaluate whether computed tomography (CT) attenuation, as a measure of fat quality, is associated with cardiometabolic risk factors above and beyond fat quantity. BACKGROUND: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are pathogenic fat depots associated with cardiometabolic risk. Adipose tissue attenuation in CT images is variable, similar to adipose tissue volume. However, whether the quality of abdominal fat attenuation is associated with cardiometabolic risk independent of the quantity is uncertain. METHODS: Participants were drawn from the Framingham Heart Study CT substudy. The VAT and SAT volumes were acquired by semiquantitative assessment. Fat quality was measured by CT attenuation and recorded as mean Hounsfield unit (HU) within each fat depot. Sex-specific linear and logistic multivariable regression models were used to assess the association between standard deviation (SD) decrease in HU and each risk factor. RESULTS: Lower CT attenuation of VAT and SAT was correlated with higher body mass index levels in both sexes. Risk factors were generally more adverse with decreasing HU values. For example, in women, per 1 SD decrease in VAT HU, the odds ratio (OR) was increased for hypertension (OR: 1.80), impaired fasting glucose (OR: 2.10), metabolic syndrome (OR: 3.65), and insulin resistance (OR: 3.36; all p < 0.0001). In models that further adjusted for VAT volume, impaired fasting glucose, metabolic syndrome, and insulin resistance remained significant. Trends were similar but less pronounced for SAT and for men. There was evidence of an interaction between HU and fat volume among both women and men. CONCLUSIONS: Lower CT attenuation of VAT and SAT is associated with adverse cardiometabolic risk above and beyond total adipose tissue volume. Qualitative indices of abdominal fat depots may provide insight regarding cardiometabolic risk independent of fat quantity.

Effectiveness of quetiapine in rapid cycling bipolar disorder: a preliminary study.

OBJECTIVE: The authors examined long-term effectiveness and study retention during open-label quetiapine treatment for rapid cycling bipolar disorder. METHODS: An open-label, nonrandomized trial was conducted in 41 patients with rapid-cycling bipolar disorder (type I=33, type II=7, NOS=1) who received flexibly dosed quetiapine monotherapy (n=19) or add-on therapy (n=22) for up to one year. Linear growth curves were calculated to assess longitudinal changes in depression and mania. RESULTS: Linear growth curves demonstrated highly significant reductions in manic (p<.0001) and depressive (p<.0001) symptoms. Effect sizes were large against manic symptoms (add-on therapy: Cohen's d=0.66; monotherapy: Cohen's d=0.75) but small-to-moderate against depression (monotherapy: d=0.29; add-on therapy: d=0.40). Most patients (68%) prematurely terminated the protocol (mean duration: 18.0+/-16.9 weeks, mean dose: 195.6+/-196.1 mg/day), most often because of the need for additional psychotropic treatments. LIMITATIONS: The study protocol involved an open label design with no placebo or active comparator group. The sample size provided adequate statistical power to detect large but not medium or small within-group effects. Premature dropout during the first six months precluded inferences about longer-term treatment outcome. CONCLUSIONS: These observational findings provisionally suggest some benefit with quetiapine for both manic and depressive symptoms in rapid cycling bipolar disorder, at dosages somewhat lower than previously described either for mania or bipolar depression. The relatively high dropout rate underscores the complexity of rapid cycling bipolar disorder and likely necessity for pharmacotherapy adjustments over time.

Extrapyramidal side effects with atypical neuroleptics in bipolar disorder.

OBJECTIVE: To examine, in a real-world clinical setting, the risk of extrapyramidal symptoms (EPS) with atypical neuroleptics in bipolar patients. METHODS: The authors assessed 51 individual patient trials of atypical neuroleptic agents (17 risperidone, 13 olanzapine, 11 quetiapine, 8 ziprasidone, and 2 aripiprazole) in 37 bipolar patients (type I or type II). Risk of EPS was assessed using the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, and the Simpson-Angus Scale. Mean duration of treatment was 25.5 weeks (range 3-107 weeks) and 60.8% of patients were female. RESULTS: 62.7% of trials resulted in moderate to severe EPS. EPS and discontinuation frequencies were similar between specific neuroleptic agents or between high potency (risperidone/ziprasidone/aripiprazole; 52.9%, 27/51 trials) and low potency (quetiapine/olanzapine; 47.1%, 24/51 trials) agents. In a multiple regression model adjusted for confounders, akathisia was less common with low potency agents. Younger age was associated with more akathisia. 31.4% (11/35) of trials discontinued due to side effects. 7.8% (4/51) of trials led to mild de novo tardive dyskinesia. CONCLUSIONS: Over one-half of bipolar patients experienced EPS in this real world clinical setting. This rate is much higher than the 5-15% range reported in clinical trials, suggesting potential problems with clinical trial generalizability.