Emma Barinas-Mitchell

The Chronic Inflammatory Hypothesis for the Morbidity Associated with Morbid Obesity: Implications and Effects of Weight Loss

Background: Obesity is a worldwide pandemic that causes a multitude of co-morbid conditions.However, there has been slow progress in understanding the basic pathophysiology that underlies co-morbid conditions associated with obesity. Recently, there has been intense interest in the role of inflammation in obesity. Using the inflammatory hypothesis, many of the mechanisms by which co-morbid conditions are associated with obesity are being elucidated. Methods: We searched the literature and reviewed all relevant articles. We focused on hormones and cytokines that have been associated with other inflammatory conditions such as sepsis and systemic inflammatory response syndrome. Findings: Angiotensinogen (AGT), transforming growth factor beta (TGFβ), tumor necrosis factor alpha (TNFα), and interleukin six (IL-6) are all elevated in obesity and correlate with several markers of adipocyte mass. These mediators have detrimental effects on hypertension, diabetes, dyslipidemia, thromboembolic phenomena, infections, and cancer. Weight loss results in a reduction of inflammatory mediators and a diminution of the associated co-morbid conditions. Conclusions: The success of weight loss surgery in treating the complications associated with obesity is most probably related to the reduction of inflammatory mediators. While some aspects of bariatric physiology remain unclear, there appears to be a strong association between obesity and inflammation, thereby rendering obesity a chronic inflammatory state. A clearer understanding of the physiology of obesity will allow physicians who treat the obese to develop better strategies to promote weight loss and improve the well-being of millions of individuals.

Surgically-induced Weight Loss Significantly Improves Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome

Objective:To evaluate the effects of surgical weight loss on fatty liver disease in severely obese patients. Summary Background Data:Nonalcoholic fatty liver disease (NAFLD), a spectrum that extends to liver fibrosis and cirrhosis, is rising at an alarming rate. This increase is occurring in conjunction with the rise of severe obesity and is probably mediated in part by metabolic syndrome (MS). Surgical weight loss operations, probably by reversing MS, have been shown to result in improvement in liver histology. Methods:Patients who underwent laparoscopic surgical weight loss operations from March 1999 through August 2004, and who agreed to have an intraoperative liver biopsy followed by at least one postoperative liver biopsy, were included. Results:There were 70 patients who were eligible. All patients underwent laparoscopic operations, the majority being laparoscopic Roux-en-Y gastric bypass. The mean excess body weight loss at time of second biopsy was 59% ± 22% and the time interval between biopsies was 15 ± 9 months. There was a reduction in prevalence of metabolic syndrome, from 70% to 14% (P < 0.001), and a marked improvement in liver steatosis (from 88% to 8%), inflammation (from 23% to 2%), and fibrosis (from 31% to 13%; all P < 0.001). Inflammation and fibrosis resolved in 37% and 20% of patients, respectively, corresponding to improvement of 82% (P < 0.001) in grade and 39% (P < 0.001) in stage of liver disease. Conclusion:Surgical weight loss results in significant improvement of liver morphology in severely obese patients. These beneficial changes may be associated with a significant reduction in the prevalence of the metabolic syndrome.

Reproducibility of the oral glucose tolerance test in overweight children.

OBJECTIVE We examined the reproducibility of the oral glucose tolerance test (OGTT) in overweight children and evaluated distinguishing characteristics between those with concordant vs. discordant results. DESIGN Sixty overweight youth (8-17 yr old) completed two OGTTs (interval between tests 1-25 d). Insulin sensitivity was assessed by the surrogate measures of fasting glucose to insulin ratio, whole-body insulin sensitivity index, and homeostasis model assessment of insulin resistance, and insulin secretion by the insulinogenic index with calculation of the glucose disposition index (GDI). RESULTS Of the 10 subjects with impaired glucose tolerance (IGT) during the first OGTT only three (30%) had IGT during the second OGTT. The percent positive agreement between the first and second OGTT was low for both impaired fasting glucose and IGT (22.2 and 27.3%, respectively). Fasting blood glucose had higher reproducibility, compared with the 2-h glucose. Youth with discordant OGTTs, compared with those with concordant results, were more insulin resistant (glucose/insulin 2.7+/-1.4 vs. 4.1+/-1.8, P=0.006, whole-body insulin sensitivity index of 1.3+/-0.6 vs. 2.2+/-1.1, P=0.003, and homeostasis model assessment of insulin resistance 10.6+/-8.1 vs. 5.7+/-2.8, P=0.001), had a lower GDI (0.45+/-0.58 vs. 1.02+/-1.0, P=0.03), and had higher low-density lipoprotein cholesterol (117.7+/-36.6 vs. 89.9+/-20.1, P=0.0005) without differences in physical characteristics. CONCLUSIONS Our results show poor reproducibility of the OGTT in obese youth, in particular for the 2-h plasma glucose. Obese youth who have discordant OGTT results are more insulin resistant with higher risk of developing type 2 diabetes mellitus, as evidenced by a lower GDI. The implications of this remain to be determined in clinical and research settings.

Lipids, menopause, and early atherosclerosis in Study of Women's Health Across the Nation Heart women.

Objective: The risk of cardiovascular disease increases after menopause. Recent evidence suggests that it is possible for high-density lipoprotein (HDL) to become proatherogenic or dysfunctional in certain situations. Our objective was to evaluate whether the relationship of HDL cholesterol (HDL-C) to subclinical cardiovascular disease differed across the menopausal transition, which would provide insight for this increased risk. Methods: Aortic calcification (AC), coronary artery calcification (CAC), carotid plaque, and intima media thickness (IMT) were measured in an ancillary study of the Study of Womens Health Across the Nation. Women not using hormone therapy were stratified into premenopausal or early perimenopausal (Pre/EP, n = 316) and late perimenopausal or postmenopausal (LP/Post, n = 224). Results: The inverse relationship of HDL-C to subclinical atherosclerosis measures among Pre/EP women was weaker or reversed among LP/Post women, adjusted for age, site, race, systolic blood pressure, glucose, body mass index, smoking, menopause status, and low-density lipoprotein cholesterol. Specifically, multivariable modeling demonstrated an inverse association between HDL-C level and AC and IMT among Pre/EP women; however, the protective effect of HDL-C for AC, left main CAC, carotid plaque, and IMT was not seen in LP/Post women. In a small subset (n = 53), LP/Post women had more total and small HDL particles, higher triglyceride levels, and more total low-density lipoprotein particles compared with Pre/EP women (P < 0.05). Conclusions: These results suggest that the protective effect of HDL may be diminished as women transition in menopause. Future studies should examine whether this may be due to changes in HDL size, functionality, or related changes in other lipids or lipoproteins.

Burden of Subclinical Cardiovascular Disease in “Metabolically Benign” and “At-Risk” Overweight and Obese Women: The Study of Women's Health Across the Nation (SWAN)

BACKGROUND Metabolically benign obese individuals have a 10-year cardiovascular disease (CVD) risk comparable to healthy normal weight individuals. However, the burden of subclinical CVD among metabolically benign obese is not well known. METHODS In cross-sectional analyses of 475 mid-life women, we compared common carotid artery intima media thickness (CCA-IMT), aortic pulse wave velocity (aPWV) and coronary (CAC) and aortic calcification (AC) among three groups: healthy normal weight, metabolically benign overweight/obese (<3 metabolic syndrome components/elevated CRP), and at-risk overweight/obese (≥3 metabolic syndrome components/elevated CRP). RESULTS The mean (SD) CCA-IMT and aPWV were lowest in the normal weight group (n=145), followed by the benign overweight/obese (n=260) and at-risk overweight/obese (n=70) groups [CCA-IMT: 0.64 (0.08) vs. 0.68 (0.09) vs. 0.73 (0.13) mm, p<0.001; aPWV: 731.0 (176.4) vs. 809.9 (182.3) vs. 875.7 (228.8) cm/s, p<0.001]. Similar results were found for the frequency (%) of women with increased CAC and AC [CAC: 13 (9%) vs. 53(20%) vs. 28(40%), p<0.001; AC: 47(32%) vs. 130 (50%) vs. 55(79%), p<0.001]. These differences remained significant after multivariable adjustment. Further adjustment for BMI attenuated the statistical significance of differences in aPWV and calcification between benign and at-risk overweight/obese women, but had little effect on the magnitude of these differences. CONCLUSIONS Metabolically benign overweight/obese women have a significantly greater subclinical CVD burden than normal weight women, despite published data finding similar CVD event rates between the two groups. Prospective studies tracking the progression of subclinical atherosclerosis to clinical CVD in these women are needed.

Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults

Objective: To determine arterial stiffness and β-amyloid (Aβ) deposition in the brain of dementia-free older adults. Methods: We studied a cohort of 91 dementia-free participants aged 83–96 years. In 2009, participants completed brain MRI and PET imaging using Pittsburgh compound B (PiB; a marker of amyloid plaques in human brain). In 2011, we measured resting blood pressure (BP), mean arterial pressure (MAP), and arterial stiffness by pulse wave velocity (PWV) in the central, peripheral, and mixed (e.g., brachial ankle PWV [baPWV]) vascular beds, using a noninvasive and automated waveform analyzer. Results: A total of 44/91 subjects were Aβ-positive on PET scan. Aβ deposition was associated with mixed PWV, systolic BP, and MAP. One SD increase in baPWV resulted in a 2-fold increase in the odds of being Aβ-positive (p = 0.007). High white matter hyperintensity (WMH) burden was associated with increased central PWV, systolic BP, and MAP. Compared to Aβ-negative individuals with low WMH burden, each SD increase in PWV was associated with a 2-fold to 4-fold increase in the odds of being Aβ-positive and having high WMH. Conclusions: Arterial stiffness was associated with Aβ plaque deposition in the brain, independent of BP and APOE ε4 allele. The associations differed by type of brain abnormality and vascular bed measured (e.g., WMH with central stiffness and Aβ deposition and mixed stiffness). Arterial stiffness was highest in individuals with both high Aβ deposition and WMH, which has been suggested to be a “double hit” contributing to the development of symptomatic dementia.

Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults

IMPORTANCE Recent studies show that cerebral β-amyloid (Aβ) deposition is associated with blood pressure and measures of arterial stiffness in nondemented individuals. OBJECTIVE To examine the association between measures of arterial stiffness and change in Aβ deposition over time. DESIGN, SETTING, AND PARTICIPANTS Deposition of Aβ was determined in a longitudinal observational study of aging by positron emission tomography using the Pittsburgh compound B twice 2 years apart in 81 nondemented individuals 83 years and older. Arterial stiffness was measured with a noninvasive and automated waveform analyzer at the time closest to the second positron emission tomography scan. All measures were performed under standardized conditions. Pulse wave velocity (PWV) was measured in the central (carotid-femoral and heart-femoral PWV), peripheral (femoral-ankle PWV), and mixed (brachial-ankle PWV) vascular beds. MAIN OUTCOMES AND MEASURES The change in Aβ deposition over 2 years was calculated from the 81 individuals with repeat Aβ-positron emission tomography. RESULTS The proportion of Aβ-positive individuals increased from 48% at baseline to 75% at follow-up. Brachial-ankle PWV was significantly higher among Aβ-positive participants at baseline and follow-up. Femoral-ankle PWV was only higher among Aβ-positive participants at follow-up. Measures of central stiffness and blood pressure were not associated with Aβ status at baseline or follow-up, but central stiffness was associated with a change in Aβ deposition over time. Each standard deviation increase in central stiffness (carotid-femoral PWV, P = .001; heart-femoral PWV, P = .004) was linked with increases in Aβ deposition over 2 years. CONCLUSIONS AND RELEVANCE This study showed that Aβ deposition increases with age in nondemented individuals and that arterial stiffness is strongly associated with the progressive deposition of Aβ in the brain, especially in this age group. The association between Aβ deposition changes over time and generalized arterial stiffness indicated a relationship between the severity of subclinical vascular disease and progressive cerebral Aβ deposition.

The Heterogeneity of Diabetes: Unraveling a Dispute: Is Systemic Inflammation Related to Islet Autoimmunity?

Diabetes is an emblematic example of a heterogeneous disease. Systemic inflammation has emerged as a prominent factor in the type 2 diabetes pathoetiology, but it remains ill-defined in type 1 diabetes. There is a wide spectrum of associations between inflammatory responses and diabetic syndromes. At one end of this spectrum, there is type 1 diabetes for which there is convincing evidence that chronic inflammation of pancreatic islets is a central aspect of disease pathogenesis. At the opposite end, is type 2 diabetes that is clearly associated with systemic inflammation, which could be either the cause or simply mark the underlying pathology. Accumulating evidence has substantiated that a subgroup of adult patients clinically diagnosed with type 2 diabetes exhibit autoantibody responses to islet autoantigens. The presence of these immunologic abnormalities is associated with a severe insulin secretory defect and the absence of signs of systemic inflammation as documented by plasma C-reactive protein and fibrinogen levels that are comparable with those of control populations. Islet autoantibody evaluation should be part of the diagnostic assessment for clinically diagnosed type 2 diabetes not only because it might predict the rate of progression to insulin requirement in adult populations but also to identify a pathogenically distinct disease phenotype characterized by the absence of systemic inflammation and its related disorders. A more appropriate characterization of this subgroup of clinically diagnosed type 2 diabetes, diabetes of autoimmune pathogenesis, will promote future research into the etiology, natural history, and treatment.

Aortic stiffness and calcification in men in a population-based international study.

OBJECTIVES Aortic stiffness, a hallmark of vascular aging, is an independent risk factor of cardiovascular disease and all-cause mortality. The association of aortic stiffness with aortic calcification in middle-aged general population remains unknown although studies in patients with end-stage renal disease or elderly subjects suggest that aortic calcification is an important determinant of aortic stiffness. The goal of this study was to examine the association of aortic calcification and stiffness in multi-ethnic population-based samples of relatively young men. METHODS We examined the association in 906 men aged 40-49 (81 Black Americans, 276 Japanese Americans, 258 White Americans and 291 Koreans). Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using an automated waveform analyzer. Aortic calcification from aortic arch to iliac bifurcation was evaluated using electron-beam computed tomography. RESULTS Aortic calcium score was calculated and was categorized into four groups: zero (n=303), 1-100 (n=411), 101-300 (n=110), and 401+ (n=82). Aortic calcification category had a significant positive association with cfPWV after adjusting for age, race, and mean arterial pressure (mean (standard error) of cfPWV (cm/s) from the lowest to highest categories: 836 (10), 850 (9), 877 (17) and 941 (19), P for trend <0.001). The significant positive association remained after further adjusting for other cardiovascular risk factors. The significant positive association was also observed in each race group. CONCLUSIONS The results suggest that aortic calcification can be one mechanism for aortic stiffness and that the association of aortic calcification with stiffness starts as early as the 40s.

Hopelessness, Depressive Symptoms, and Carotid Atherosclerosis in Women: The Study of Women’s Health Across the Nation (SWAN) Heart Study

Background and Purpose— Depression and hopelessness are associated with increased cardiovascular disease (CVD) morbidity and mortality; however, few studies have compared these constructs early in the atherogenic process, particularly in women or minorities. Methods— This cross-sectional study examined associations of hopelessness and depressive symptoms with carotid artery intimal-medial thickening (IMT) in 559 women (62% white, 38% black; mean±SD age, 50.2±2.8 years) without evidence of clinical CVD from the Study of Women’s Health Across the Nation (SWAN) Heart Study. Hopelessness was measured by 2 questionnaire items; depressive symptoms were measured with the 20-item Center for Epidemiological Studies Depression Scale. Mean and maximum IMT were assessed by B-mode ultrasonography of the carotid arteries. Results— Increasing hopelessness was significantly related to higher mean (P=0.0139) and maximum (P=0.0297) IMT in regression models adjusted for age, race, site, income, and CVD risk factors. A weaker pattern of associations was noted for depressive symptoms and mean (P=0.1056) and maximum (P=0.0691) IMT. Modeled simultaneously in a risk factor–adjusted model, hopelessness was related to greater mean IMT (P=0.0217) and maximum IMT (P=0.0409), but depressive symptoms were unrelated to either outcome (P>0.4). No interactions with race or synergistic effects of depressive symptoms and hopelessness were observed. Conclusions— Among middle-aged women, higher levels of hopelessness are associated with greater subclinical atherosclerosis independent of age, race, income, CVD risk factors, and depressive symptoms.