Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity.

AIMS: Aim of this study was to evaluate a possible association between endocannabinoid (EC) plasma levels, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and coronary circulatory function in obesity. METHODS AND RESULTS: Myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with (13)N-ammonia PET/CT. Study participants (n = 77) were divided into three groups based on their body mass index (BMI, kg/m(2)): control group 20 ≤ BMI <25 (n = 21); overweight group, 25 ≤ BMI <30 (n = 26); and obese group, BMI ≥ 30 (n = 30). Anandamide plasma levels, but not 2-AG plasma levels, were significantly elevated in obesity as compared with controls, respectively [0.68 (0.53, 0.78) vs. 0.56 (0.47, 0.66) ng/mL, P = 0.020, and 2.2 (1.21, 4.59) vs. 2.0 (0.80, 5.90) ng/mL, P = 0.806)]. The endothelium-related change in MBF during CPT from rest (ΔMBF) progressively declined in overweight and obese when compared with control group [0.21 (0.10, 0.27) and 0.09 (-0.01, 0.15) vs. 0.26 (0.23, 0.39) mL/g/min; P = 0.010 and P = 0.0001, respectively). Compared with controls, hyperaemic MBFs were significantly lower in overweight and obese individuals [2.39 (1.97, 2.62) vs. 1.98 (1.69, 2.26) and 2.10 (1.76, 2.36); P = 0.007 and P = 0.042, respectively)]. In obese individuals, AEA and 2-AG plasma levels were inversely correlated with ΔMBF to CPT (r = -0.37, P = 0.046 and r = -0.48, P = 0.008) and hyperaemic MBFs (r = -0.38, P = 0.052 and r = -0.45, P = 0.017), respectively. CONCLUSIONS: Increased EC plasma levels of AEA and 2-AG are associated with coronary circulatory dysfunction in obese individuals. This observation might suggest increases in EC plasma levels as a novel endogenous cardiovascular risk factor in obesity, but needing further investigations.

Nutrition in cardiovascular disease: salt in hypertension and heart failure.

There is much evidence for a causal relationship between salt intake and blood pressure (BP). The current salt intake in many countries is between 9 and 12 g/day. A reduction in salt intake to the recommended level of 5-6 g/day lowers BP in both hypertensive and normotensive individuals. A further reduction to 3-4 g/day has a much greater effect. Prospective studies and outcome trials have demonstrated that a lower salt intake is associated with a decreased risk of cardiovascular disease. Increasing evidence also suggests that a high salt intake is directly related to left ventricular hypertrophy (LVH) independent of BP. Both raised BP and LVH are important risk factors for heart failure. It is therefore possible that a lower salt intake could prevent the development of heart failure. In patients who already have heart failure, a high salt intake aggravates the retention of salt and water, thereby exacerbating heart failure symptoms and progression of the disease. A lower salt intake plays an important role in the management of heart failure. Despite this, currently there is no clear evidence on how far salt intake should be reduced in heart failure. Our personal view is that these patients should reduce their salt intake to <5 g/day, i.e. the maximum intake recommended by the World Health Organisation for all adults. If salt intake is successfully reduced, there may well be a need for a reduction in diuretic dosage.

Obesity and the incidence of chronic diseases: a seemingly unrelated probit approach

Western societies can reduce avoidable mortality and morbidity by better understanding the relationship between obesity and chronic disease. This paper examines the joint determinants of obesity and of heart disease, diabetes, hypertension, and elevated cholesterol. It analyzes a broadly representative Spanish dataset, the 1999 Survey on Disabilities, Impairments and Health Status, using a health production theoretical framework together with a seemingly unrelated probit model approach that controls for unobserved heterogeneity and endogeneity. Its findings provide suggestive evidence of a positive and significant, although specification-dependent, association between obesity and the prevalence of chronic illness

Obesity and the incidence of chronic diseases: a seemingly unrelated probit approach

Western societies can reduce avoidable mortality and morbidity by better understanding the relationship between obesity and chronic disease. This paper examines the joint determinants of obesity and of heart disease, diabetes, hypertension, and elevated cholesterol. It analyzes a broadly representative Spanish dataset, the 1999 Survey on Disabilities, Impairments and Health Status, using a health production theoretical framework together with a seemingly unrelated probit model approach that controls for unobserved heterogeneity and endogeneity. Its findings provide suggestive evidence of a positive and significant, although specification-dependent, association between obesity and the prevalence of chronic illness

Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study.

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities. BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited. METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism. RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF. CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

Cardiac structure and function in the obese: a cardiovascular magnetic resonance imaging study.

BACKGROUND: Obesity is a major health problem in the Western world. Among obese subjects cardiac pathology is common, but conventional noninvasive imaging modalities are often suboptimal for detailed evaluation of cardiac structure and function. We investigated whether cardiovascular magnetic resonance imaging (CMR) can better characterize possible cardiac abnormalities associated with obesity, in the absence of other confounding comorbidities. METHODS: In this prospective cross-sectional study, CMR was used to quantify left and right ventricular volumes, ejection fraction, mass, cardiac output, and apical left ventricular rotation in 25 clinically healthy obese men and 25 age-matched lean controls. RESULTS: Obese subjects had higher left ventricular mass (203 +/- 38 g vs. 163 +/- 22 g, p < 0.001), end-diastolic volume (176 +/- 29 mL vs. 156 +/- 25 mL, p < 0.05), and cardiac output (8.2 +/- 1.2 L/min vs. 6.4 +/- 1.3 L/min, p < 0.001). The obese also had increased right ventricular mass (105 +/- 25 g vs. 87 +/- 18 g, p < 0.005) and end-diastolic volume (179 +/- 36 mL vs. 155 +/- 28 mL, p < 0.05). When indexed for height, differences in left and right ventricular mass, and left ventricular end-diastolic volume remained significant. Apical left ventricular rotation and rotational velocity patterns were also different between obese and lean subjects. CONCLUSIONS: Obesity is independently associated with remodeling of the heart. Cardiovascular magnetic resonance imaging identifies subtle cardiac abnormalities and may be the preferred imaging technique to evaluate cardiac structure and function in the obese.

Metabolic predictors of obesity. Contribution of resting energy expenditure, thermic effect of food, and fuel utilization to four-year weight gain of post-obese and never-obese women.

This prospective study was designed to identify abnormalities of energy expenditure and fuel utilization which distinguish post-obese women from never-obese controls. 24 moderately obese, postmenopausal, nondiabetic women with a familial predisposition to obesity underwent assessments of body composition, fasting and postprandial energy expenditure, and fuel utilization in the obese state and after weight loss (mean 12.9 kg) to a post-obese, normal-weight state. The post-obese women were compared with 24 never-obese women of comparable age and body composition. Four years later, without intervention, body weight was reassessed in both groups. Results indicated that all parameters measured in the post-obese women were similar to the never-obese controls: mean resting energy expenditure, thermic effect of food, and fasting and postprandial substrate oxidation and insulin-glucose patterns. Four years later, post-obese women regained a mean of 10.9 kg while control subjects remained lean (mean gain 1.7 kg) (P < 0.001 between groups). Neither energy expenditure nor fuel oxidation correlated with 4-yr weight changes, whereas self-reported physical inactivity was associated with greater weight regain. The data suggest that weight gain in obesity-prone women may be due to maladaptive responses to the environment, such as physical inactivity or excess energy intake, rather than to reduced energy requirements.

Two-step postmortem angiography with a modified heart-lung machine: preliminary results.

OBJECTIVE: The purpose of this study was to adapt and improve a minimally invasive two-step postmortem angiographic technique for use on human cadavers. Detailed mapping of the entire vascular system is almost impossible with conventional autopsy tools. The technique described should be valuable in the diagnosis of vascular abnormalities. MATERIALS AND METHODS: Postmortem perfusion with an oily liquid is established with a circulation machine. An oily contrast agent is introduced as a bolus injection, and radiographic imaging is performed. In this pilot study, the upper or lower extremities of four human cadavers were perfused. In two cases, the vascular system of a lower extremity was visualized with anterograde perfusion of the arteries. In the other two cases, in which the suspected cause of death was drug intoxication, the veins of an upper extremity were visualized with retrograde perfusion of the venous system. RESULTS: In each case, the vascular system was visualized up to the level of the small supplying and draining vessels. In three of the four cases, vascular abnormalities were found. In one instance, a venous injection mark engendered by the self-administration of drugs was rendered visible by exudation of the contrast agent. In the other two cases, occlusion of the arteries and veins was apparent. CONCLUSION: The method described is readily applicable to human cadavers. After establishment of postmortem perfusion with paraffin oil and injection of the oily contrast agent, the vascular system can be investigated in detail and vascular abnormalities rendered visible.

Genetic factors of obesity and eating disorders: Copy number variations (CNV) involving SH2B1

Context : It is now clearly shown that genetic factors in association with environment play a key role in obesity and eating disorders. This project studies the clinical symptoms and molecular abnormalities in patients carrying a strong hereditary predisposition to obesity and eating behavior disorders. We have previously published the association between the 16:29.5-30.1 deletion and a very penetrant form of morbid obesity and macrocephaly. We have also demonstrated the association between the reciprocal 16:29.5-30.1 duplication and underweight and small head circumference. These 2 studies demonstrate that gene dosage of one or several genes in this region regulates BMI as well as brain growth. At present, there are no data pointing towards particular candidate genes. We are currently investigating a second non-overlapping recurrent CNV encompassing SH2B1, upstream of the aforementioned rearrangement. SNPs in this gene have been associated with BMI in GWAS studies and mice models confirmed this association. Bokuchova et al have reported an association between deletions encompassing this gene and severe early onset obesity, as well as insulin resistance. We are currently collecting and analyzing data to fully characterize the phenotype and the transcriptional patterns associated with this rearrangement. Aims : 1. Identify carriers of any CNVs in the greater 16p11.2 region (between 16:28MB and 32MB) in the EGG consortium. 2. Perform association studies between SNPs in the greater 16p11.2 region (16:28-32MB) and anthropometric measures with adjusted "locus-wide significance", to identify or prioritize candidate genes potentially driving the association observed in patients with the CNVs (and thus worthy of further validation and sequencing). 3. Explore associations between GSV genome-wide and brain volume. 4. Explore relationship between brain volumes (whole brain and regional for those who underwent brain MRI), head circumference and BMI. 5. Extrapolate this procedure to other regions covered by the Metabochip. Methods : - Examine and collect clinical informations, as well as molecular informations in these patients. - Analysis of MRI data in children and adults with BMI > 2SD. Compare changes to MRI data obtained in patients with monogenic forms of obesity (data from Lausanne study) and to underweight (BMI<-2SD) individuals from EGG. - Test whether opposite extremes of the phenotypic distribution may be highly informative Expected results : This is a highly focused study, pertaining to approximately 1 0/00 of the human genome. Yet it is clear that if successful, the lessons learned from this study could be extrapolated to other segments of the genome and would need validation and replication by additional studies. Altogether they will contribute to further explore the missing heritability and point to etiologic genes and pathways underlying these important health burdens.

Metabolic and physiologic effects of an endotoxin challenge in healthy obese subjects.

Aim: The obesity epidemic has increased the number of obese patients admitted to the ICU. In vitro studies suggest that adipose tissue response to inflammation is enhanced: in vivo data are not conclusive yet. The aim of this study was to test the physiologic response of healthy obese subjects to a standardized intravenous LPS challenge.Methods: Prospective single-blind, randomized, cross-over study in eight subjects (four men, four women), aged 34 +/- 7 years, BMI 34.7 +/- 4.2, without glucose intolerance and lipid abnormalities, testing the impact of intravenous LPS (2 ng kg(-1) of actual body weight) versus placebo.Results: Temperature, hemodynamic variables, indirect calorimetry and blood samples (TNF-alpha, IL-6, stress hormones, hs-CRP) were collected. After LPS temperature, heart rate. TNF-alpha and IL-6 concentrations and stress hormones (cortisol and glucagon) increased significantly, with maximal responses between 120 and 240 min after the injection. The pattern, the timing and the magnitude of change were similar to those observed in lean subjects.Conclusion: This study shows that healthy obese subjects have a similar response pattern to intravenous LPS as described in lean subjects.

Commentary : beyond vague causal effect estimation of obesity on health outcomes

In the current issue of epidemiology, Danaei and colleagues elegantly estimated both the direct effect and the indirect effect-that is, the effect mediated by blood pressure, cholesterol, glucose, fibrinogen, and high-sensitivity C-reactive protein-of body mass index (BMI) on the risk of coronary heart disease (CHD). they analyzed data from 9 cohort studies including 58,322 patients and 9459 CHD events, with baseline measurements between 1954 and 2001. Using sophisticated and cutting-edge methods for direct and indirect effect estimations, the authors estimated that half of the risk of overweight and obesity would be mediated by blood pressure, cholesterol, and glucose. Few additional percentage points of the risk would be mediated by fibrinogen and hs-CRP. How should we understand these estimates? Can we say that if obese persons reduce their body weight and reach a normal body weight, their excess risk of CHD would be reduced by half through an improvement in these mediators and by half through the reduction in BmI itself? Is that also true if these individuals are prevented from becoming obese in the first place? Can we also conclude that if these mediators are well controlled in obese individuals through other means than a body weight reduction, their excess risk of CHD would be reduced by half? Let us confront these estimates with observations from studies evaluating 2 interventions to reduce body weight, that is, bariatric surgery in patients with severe obesity and intensive lifestyle intervention in overweight patients with diabetes

Daily energy expenditure in free-living conditions in obese and non-obese children: comparison of doubly labelled water (2H2(18)O) method and heart-rate monitoring.

OBJECTIVE: To compare the heart-rate monitoring with the doubly labelled water (2H2(18)O) method to estimate total daily energy expenditure in obese and non-obese children. DESIGN: Cross sectional study of obese and normal weight children. SUBJECTS: 13 prepubertal children: six obese (4M, 2F, 9.1 +/- 1.5 years, 47.3 +/- 9.7 kg) and seven non-obese (3M, 4F, 9.3 +/- 0.6 years, 31.8 +/- 3.2 kg). MEASUREMENTS: Total daily energy expenditure was assessed by means of the doubly labelled water method (TEEDLW) and of heart-rate monitoring (TEEHR). RESULTS: TEEHR was significantly (P < 0.05) higher than TEEDLW in obese children (9.47 +/- 0.84 MJ/d vs 8.99 +/- 0.63 MJ/d) whereas it was not different in non-obese children (8.43 +/- 2.02 MJ/d vs 8.42 +/- 2.30 MJ/d, P = NS). The difference of TEE assessed by HR monitoring in the obese group averaged 6.2 +/- 4.7%. At the individual level, the degree of agreement (difference between TEEHR and TEEDLW +/- 2s.d.) was low both in obese (-0.36, 1.32 MJ/d) and in non-obese children (-1.30, 1.34 MJ/d). At the group level, the agreement between the two methods was good in nonobese children (95% c.i. for the bias:-0.59, 0.63 MJ/d) but not in obese children (0.04, 0.92 MJ/d). Duration of sleep and energy expenditure during resting and physical activity were not significantly different in the two groups. Patterns of heart-rate (or derived energy expenditure) during the day-time were similar in obese and non-obese children. CONCLUSION: The HR monitoring technique provides an estimation of TEE close to that assessed by the DLW method in non-obese prepubertal children. In comparison with DLW, the HR monitoring method yields a greater TEE value in obese children.

Evaluation of prenatal diagnosis of associated congenital heart diseases by fetal ultrasonographic examination in Europe.

Ultrasound scans in the mid trimester of pregnancy are now a routine part of antenatal care in most European countries. With the assistance of Registries of Congenital Anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of congenital heart defects (CHD) by routine ultrasonographic examination of the fetus. All congenital malformations suspected prenatally and all congenital malformations, including chromosome anomalies, confirmed at birth were identified from the Congenital Malformation Registers, including 20 registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK and Ukrainia. These registries follow the same methodology. The study period was 1996-1998, 709 030 births were covered, and 8126 cases with congenital malformations were registered. If more than one cardiac malformation was present the case was coded as complex cardiac malformation. CHD were subdivided into 'isolated' when only a cardiac malformation was present and 'associated' when at least one other major extra cardiac malformation was present. The associated CHD were subdivided into chromosomal, syndromic non-chromosomal and multiple. The study comprised 761 associated CHD including 282 cases with multiple malformations, 375 cases with chromosomal anomalies and 104 cases with non-chromosomal syndromes. The proportion of prenatal diagnosis of associated CHD varied in relation to the ultrasound screening policies from 17.9% in countries without routine screening (The Netherlands and Denmark) to 46.0% in countries with only one routine fetal scan and 55.6% in countries with two or three routine fetal scans. The prenatal detection rate of chromosomal anomalies was 40.3% (151/375 cases). This rate for recognized syndromes and multiply malformed with CHD was 51.9% (54/104 cases) and 48.6% (137/282 cases), respectively; 150/229 Down syndrome (65.8%) were livebirths. Concerning the syndromic cases, the detection rate of deletion 22q11, situs anomalies and VATER association was 44.4%, 64.7% and 46.6%, respectively. In conclusion, the present study shows large regional variations in the prenatal detection rate of CHD with the highest rates in European regions with three screening scans. Prenatal diagnosis of CHD is significantly higher if associated malformations are present. Cardiac defects affecting the size of the ventricles have the highest detection rate. Mean gestational age at discovery was 20-24 weeks for the majority of associated cardiac defects.

Ischemic heart disease and primary care: identifying gender-related differences. An observational study

Background: Gender-related differences are seen in multiple aspects of both health and illness. Ischemic heart disease (IHD) is a pathology in which diagnostic, treatment and prognostic differences are seen between sexes, especially in the acute phase and in the hospital setting. The objective of the present study is to analyze whether there are differences between men and women when examining associated cardiovascular risk factors and secondary pharmacological prevention in the primary care setting. Methods: Retrospective descriptive observational study from January to December of 2006, including 1907 patients diagnosed with ischemic heart disease in the city of Lleida, Spain. The clinical data were obtained from computerized medical records and pharmaceutical records of medications dispensed in pharmacies with official prescriptions. Data was analyzed using bivariate descriptive statistical analysis as well as logistic regression. Results: There were no gender-related differences in screening percentages for arterial hypertension, diabetes, obesity, dyslipemia, and smoking. A greater percentage of women were hypertensive, obese and diabetic compared to men. However, men showed a tendency to achieve control targets more easily than women, with no statistically significant differences. In both sexes cardiovascular risk factors control was inadequate, between 10 and 50%. For secondary pharmaceutical prevention, the percentages of prescriptions were greater in men for anticoagulants, beta-blockers, lipid-lowering agents and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, with age group variations up to 10%. When adjusting by age and specific diagnoses, differences were maintained for anticoagulants and lipid-lowering agents. Conclusion: Screening of cardiovascular risk factors was similar in men and women with IHD. Although a greater percentage of women were hypertensive, diabetic or obese, their management of risk factors tended to be worse than men. Overall, a poor control of cardiovascular risk factors was noted. Taken as a whole, more men were prescribed secondary prevention drugs, with differences varying by age group and IHD diagnosis.