Michelle T. Long

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.

Female authorship in major academic gastroenterology journals: a look over 20 years

BACKGROUND Authorship in peer-reviewed medical journals is a marker for success in academic medicine. OBJECTIVE To determine the representation of female physicians among authors of original research in U.S. gastroenterology journals. DESIGN Retrospective. SUBJECTS All first and senior U.S. authors of original research published in the years 1992, 1997, 2002, 2007, and 2012 in the following journals: Gastroenterology, Hepatology, American Journal of Gastroenterology, Clinical Gastroenterology and Hepatology (CGH), and Gastrointestinal Endoscopy (GIE). MAIN OUTCOME MEASUREMENTS The percentage of female first and senior authors compared with the percentage of women practicing in academic gastroenterology. RESULTS We evaluated 6490 articles, of which 2275 original research articles and 455 editorials were eligible for inclusion. Author gender was determined for 98.5% of the 3792 authors. Overall, female first authors increased from 9.1±2.9% in 1992 to 29.3±4.9% in 2012 (P<.0001), and female senior authors increased from 4.8±2.3% in 1992 to 14.5±3.6% in 2012 (P<.0001). Female first and senior authors increased significantly in all journals (P for trend<.05), except for CGH, and CGH and GIE, respectively. For each of the years examined with the exception of 1997, the proportion of women in the senior author position was less than expected based on the proportion of women among academic gastroenterologists (P<.004; P=.18 for 1997). LIMITATIONS Descriptive study. CONCLUSIONS The percentage of U.S. female physician authors of original research in major gastroenterology journals has increased over time, yet the percentage of women in the senior author position remains lower than expected. Further research should explore potential reasons for this gender gap.

The Framingham Heart Study — 67 years of discovery in metabolic disease

The Framingham Heart Study (FHS), initiated in 1948, is the longest running prospective cohort study in the USA. Through >65 years of discovery, the FHS has contributed to our understanding of obesity, type 2 diabetes mellitus and prediabetes mellitus, the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD), and to how these conditions relate to our overall and cardiovascular-related mortality. This Timeline gives an overview of the substantial role the FHS has played in advancing the understanding of obesity, diabetes mellitus and NAFLD, and considers the direction the FHS will take in the years to come.

Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study

Nonalcoholic fatty liver disease is associated with metabolic risk factors including hypertension and dyslipidemia and may progress to liver fibrosis. Studies have shown that hepatic steatosis and fibrosis are heritable, but whether they have a significant shared gene effect is unknown. This study examined the shared gene effects between hepatic steatosis and fibrosis and their associations with metabolic risk factors. This was a cross‐sectional analysis of a prospective cohort of well‐characterized, community‐dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from southern California. Hepatic steatosis was assessed with magnetic resonance imaging‐proton density fat fraction and hepatic fibrosis with magnetic resonance elastography. A standard bivariate twin additive genetics and unique environment effects model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects and individual‐specific environmental effects. Genetic correlations estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Mean (± standard deviation) age and body mass index were 47.1 (±21.9) years and 26.2 (±5.8) kg/m2, respectively. Among the cohort, 20% (26/130) had hepatic steatosis (magnetic resonance imaging‐proton density fat fraction ≥5%), and 8.2% (10/122) had hepatic fibrosis (magnetic resonance elastography ≥3 kPa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high‐density lipoprotein had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high‐density lipoprotein had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% confidence interval 0.716‐1, P < 0.0001). Conclusions: Genes involved with steatosis pathogenesis may also be involved with fibrosis pathogenesis. (Hepatology 2016;64:1547‐1558)

Nonalcoholic Fatty Liver Disease and Vascular Function Cross-Sectional Analysis in the Framingham Heart Study

Objective— Patients with nonalcoholic fatty liver disease (NAFLD) have an increased risk of cardiovascular disease; however, it is not known whether NAFLD contributes to cardiovascular disease independent of established risk factors. We examined the association between NAFLD and vascular function. Approach and Results— We conducted a cross-sectional study of 2284 Framingham Heart Study participants without overt cardiovascular disease who had liver fat attenuation measured on computed tomography and who had measurements of vascular function and covariates. We evaluated the association between NAFLD and vascular function using multivariable partial correlations adjusting for age, sex, cohort, smoking, diabetes mellitus, hyperlipidemia, hypertension, body mass index, and visceral adipose tissue. The prevalence of NAFLD in our sample (mean age, 52±12 years; 51.4% women) was 15.3%. In age-, sex-, and cohort-adjusted analyses, greater liver fat was modestly associated with lower flow-mediated dilation ( r =−0.05; P =0.02), lower peripheral arterial tonometry ratio ( r =−0.20; P <0.0001), higher carotid-femoral pulse wave velocity ( r =0.13; P <0.0001), and higher mean arterial pressure ( r =0.11; P <0.0001). In multivariable-adjusted models, NAFLD remained associated with higher mean arterial pressure ( r =0.06; P =0.005) and lower peripheral arterial tonometry ratio ( r =−0.12; P <0.0001). The association between NAFLD and peripheral arterial tonometry ratio persisted after further adjustment for body mass index and visceral adipose tissue. Conclusions— For multiple measures of vascular function, the relationship with NAFLD appeared largely determined by shared cardiometabolic risk factors. The persistent relationship with reduced peripheral arterial tonometry response beyond established risk factors suggests that NAFLD may contribute to microvascular dysfunction. # Significance {#article-title-43}Objective— Patients with nonalcoholic fatty liver disease (NAFLD) have an increased risk of cardiovascular disease; however, it is not known whether NAFLD contributes to cardiovascular disease independent of established risk factors. We examined the association between NAFLD and vascular function. Approach and Results— We conducted a cross-sectional study of 2284 Framingham Heart Study participants without overt cardiovascular disease who had liver fat attenuation measured on computed tomography and who had measurements of vascular function and covariates. We evaluated the association between NAFLD and vascular function using multivariable partial correlations adjusting for age, sex, cohort, smoking, diabetes mellitus, hyperlipidemia, hypertension, body mass index, and visceral adipose tissue. The prevalence of NAFLD in our sample (mean age, 52±12 years; 51.4% women) was 15.3%. In age-, sex-, and cohort-adjusted analyses, greater liver fat was modestly associated with lower flow-mediated dilation (r=−0.05; P=0.02), lower peripheral arterial tonometry ratio (r=−0.20; P<0.0001), higher carotid-femoral pulse wave velocity (r=0.13; P<0.0001), and higher mean arterial pressure (r=0.11; P<0.0001). In multivariable-adjusted models, NAFLD remained associated with higher mean arterial pressure (r=0.06; P=0.005) and lower peripheral arterial tonometry ratio (r=−0.12; P<0.0001). The association between NAFLD and peripheral arterial tonometry ratio persisted after further adjustment for body mass index and visceral adipose tissue. Conclusions— For multiple measures of vascular function, the relationship with NAFLD appeared largely determined by shared cardiometabolic risk factors. The persistent relationship with reduced peripheral arterial tonometry response beyond established risk factors suggests that NAFLD may contribute to microvascular dysfunction.

Bi-directional analysis between fatty liver and cardiovascular disease risk factors

BACKGROUND & AIMS The relations of non-alcoholic fatty liver disease to cardiovascular disease (CVD) risk factors are not fully understood. The objective of our study is to explore the bi-directional relationships of fatty liver to CVD risk factors. METHODS We prospectively evaluated whether liver fat predicted the development of CVD risk factors and whether CVD risk factors predicted new onset fatty liver during 6years of follow-up in middle- to older-aged Framingham Heart Study participants. We estimated liver fat using multi-detector computed tomography. RESULTS We included 1051 participants (mean age 45±6years, 46% women). The prevalence of fatty liver was 18% at baseline. In participants without fatty liver at baseline, 101 participants developed incident fatty liver over approximately 6years. Baseline liver fat (per standard deviation increase) was associated with increased odds of incident hypertension (OR 1.42; 95% CI 1.15-1.76; p=0.001) and incident type 2 diabetes (OR 1.43; 95% CI 1.09-1.88, p<0.001). In a parallel analysis, individuals with hypertension (OR 3.34; 95% CI 2.04-5.49), hypertriglyceridemia (OR 3.04; 95% CI: 1.84-5.02), impaired fasting glucose (OR 2.92; 95% CI 1.76-4.82), or type 2 diabetes (OR 4.15; 95% CI 1.19-14.46) at baseline had higher odds of incident fatty liver compared to individuals without those conditions (all p<0.03). In both analyses, the observed associations remained similar after additional adjustments for measures of adiposity. CONCLUSIONS The present study demonstrated bi-directional relationships between fatty liver and CVD risk factors among middle- to older-aged Framingham Heart Study participants. LAY SUMMARY It is not fully understood whether non-alcoholic fatty liver (NAFLD) disease precedes or develops after increased cardiovascular disease (CVD) risk factors. The findings of our study suggest a bi-directional relationship between NAFLD and CVD risk factors.

Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes

Unbiased, “nontargeted” metabolite profiling techniques hold considerable promise for biomarker and pathway discovery, in spite of the lack of successful applications to human disease. By integrating nontargeted metabolomics, genetics, and detailed human phenotyping, we identified dimethylguanidino valeric acid (DMGV) as an independent biomarker of CT-defined nonalcoholic fatty liver disease (NAFLD) in the offspring cohort of the Framingham Heart Study (FHS) participants. We verified the relationship between DMGV and early hepatic pathology. Specifically, plasma DMGV levels were correlated with biopsy-proven nonalcoholic steatohepatitis (NASH) in a hospital cohort of individuals undergoing gastric bypass surgery, and DMGV levels fell in parallel with improvements in post-procedure cardiometabolic parameters. Further, baseline DMGV levels independently predicted future diabetes up to 12 years before disease onset in 3 distinct human cohorts. Finally, we provide all metabolite peak data consisting of known and unidentified peaks, genetics, and key metabolic parameters as a publicly available resource for investigations in cardiometabolic diseases.

Development and Validation of the Framingham Steatosis Index to Identify Persons With Hepatic Steatosis

BACKGROUND & AIMS Serum levels of aminotransferases are used as markers of nonalcoholic fatty liver disease in epidemiology research. However, it is not clear whether they can be used to identify patients with fatty liver. We investigated the accuracy of serum levels of aminotransferases in detection of hepatic steatosis. In addition, we derived a Framingham steatosis index (FSI) and tested its ability to identify patients with hepatic steatosis in an independent cohort. METHODS We performed a cross-sectional study of 1181 members of the Framingham Third Generation Cohort (46.1% women; mean age, 50.3 ± 6.7 years). People with hepatic steatosis were identified by computed tomography that was performed from 2008 through 2011. We compared the abilities of levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the ratio of ALT:AST to identify people with hepatic steatosis by using c-statistic analyses. We performed a stepwise regression procedure to identify demographic and clinical factors that correlated with hepatic steatosis; we used these, along with biochemical factors associated with steatosis, to develop the FSI. We validated the FSI by using data from the third National Health and Nutrition Examination Survey. RESULTS The prevalence of hepatic steatosis in the Framingham Third Generation Cohort was 26.8%. The ratio of ALT:AST identified people with hepatic steatosis with the highest c-statistic value (0.728); the value for only ALT was 0.706, and the value for only AST was 0.589. We derived the FSI on the basis of patient age, sex, body mass index, levels of triglycerides, hypertension, diabetes, and ratio of ALT:AST. The FSI identified patients with hepatic steatosis with a c-statistic value of 0.845. When it was applied to the third National Health and Nutrition Examination Survey cohort, the FSI identified patients with steatosis with a c-statistic value of 0.760 and was well-calibrated. CONCLUSIONS In an analysis of the Framingham Third Generation Cohort, we found the ratio of ALT:AST to identify people with hepatic steatosis more accurately than either ALT or AST alone. We used data from this cohort to develop and validate the FSI, which identifies patients with steatosis with a c-statistic value of about 0.8.

Hepatic steatosis is associated with lower levels of physical activity measured via accelerometry

Prior studies on the association of physical activity (PA) and nonalcoholic fatty liver disease are limited by reliance on subjective measures of PA. We examined the association between objectively measured PA and hepatic steatosis defined by computed tomography (CT).

Visceral and Intrahepatic Fat are Associated with Cardiometabolic Risk Factors Above Other Ectopic Fat Depots: the Framingham Heart Study

BACKGROUND We examined the associations among 8 different fat depots accumulated in various anatomic regions and the relationship between these fat depots and multiple cardiometabolic risk factors. METHODS Participants were from the Framingham Heart Study Offspring and Third Generation who also participated in the multidetector computed tomography substudy in 2002-2005. Exposures were multidetector computed tomography-derived fat depots, including abdominal subcutaneous adipose tissue, abdominal visceral adipose tissue, intramuscular fat, intrathoracic fat, pericardial fat, thoracic periaortic fat, intrahepatic fat, and renal sinus fat. Multivariable-adjusted regression analyses with a forward selection procedure were performed to identify the most predictive fat depots. RESULTS Of 2529 participants, 51.9% were women (mean age, 51.1 years). Visceral adipose tissue had the strongest correlations with each of the other fat measures (range, 0.26-0.77) and with various cardiometabolic risk factors (range, -0.34 to 0.39). As determined by the selection models, visceral adipose tissue was the only fat depot that was associated with all cardiometabolic risk factors evaluated in this study (all P<.05). Selection models also showed that subcutaneous adipose tissue and intrahepatic fat were associated with cardiometabolic risk factors related to the traits of dysglycemia, dyslipidemia, and hypertension (all P<.05). However, only associations with visceral adipose tissue and intrahepatic fat persisted after further adjustment for body mass index and waist circumference. CONCLUSIONS Visceral adipose tissue and intrahepatic fat were consistent correlates of cardiometabolic risk factors, above and beyond standard anthropometric indices. Our data provide important insights for understanding the associations between variations in fat distribution and cardiometabolic abnormalities.