Article

Cardiac Steatosis Associates With Visceral Obesity in Nondiabetic Obese Men

March 2013
The Journal of Clinical Endocrinology and Metabolism 98(3):1189-97

DOI:10.1210/jc.2012-3190

Source
PubMed

Authors:

Marit Granér

University of Helsinki

Reijo Siren

University of Helsinki

Kristofer Nyman

Helsinki University Central Hospital

Jesper Lundbom

University of Helsinki

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Background: Liver fat and visceral adiposity are involved in the development of the metabolic syndrome (MetS). Ectopic fat accumulation within and around the heart has been related to increased risk of heart disease. The aim of this study was to explore components of cardiac steatosis and their relationship to intra-abdominal ectopic fat deposits and cardiometabolic risk factors in nondiabetic obese men. Methods: Myocardial and hepatic triglyceride (TG) contents were measured with 1.5 T magnetic resonance spectroscopy, and visceral adipose (VAT), abdominal subcutaneous tissue (SAT), epicardial and pericardial fat by magnetic resonance imaging in 37 men with the MetS and in 40 men without the MetS. Results: Myocardial and hepatic TG contents, VAT, SAT, epicardial fat volumes, and pericardial fat volumes were higher in men with the MetS compared with subjects without the MetS (P < .001). All components of cardiac steatosis correlated with SAT, VAT, and hepatic TG content and the correlations seemed to be strongest with VAT. Myocardial TG content, epicardial fat, pericardial fat, VAT, and hepatic TG content correlated with waist circumference, body mass index, high-density lipoprotein cholesterol TGs, very low-density lipoprotein-1 TGs, and the insulin-resistance homeostasis model assessment index. VAT was a predictor of TGs, high-density lipoprotein cholesterol, and measures of glucose metabolism, whereas age and SAT were determinants of blood pressure parameters. Conclusions: We suggest that visceral obesity is the best predictor of epicardial and pericardial fat in abdominally obese subjects. Myocardial TG content may present a separate entity that is influenced by factors beyond visceral adiposity.

Myocardial steatosis across the spectrum of human health and disease

Article

Full-text available

Dec 2023
EXP PHYSIOL

Preclinical data strongly suggest that myocardial steatosis leads to adverse cardiac remodelling and left ventricular dysfunction. Using ¹H cardiac magnetic resonance spectroscopy, similar observations have been made across the spectrum of health and disease. The purpose of this brief review is to summarize these recent observations. We provide a brief overview of the determinants of myocardial triglyceride accumulation, summarize the current evidence that myocardial steatosis contributes to cardiac dysfunction, and identify opportunities for further research.

A prospective randomized study comparing effects of empagliflozin to sitagliptin on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes: the ASSET study

Article

Full-text available

Feb 2021
CARDIOVASC DIABETOL

Background While the cardioprotective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established in patients with cardiovascular disease (CVD), their advantages over other anti-diabetic drugs at earlier stages remain unclear. We compared the cardioprotective effects of empagliflozin, an SGLT2 inhibitor, with those of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, focusing on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes mellitus (T2DM) without CVD complications. Methods This was a prospective, randomized, open-label, blinded-endpoint, parallel-group trial that enrolled 44 Japanese patients with T2DM. The patients were randomized for 12-week administration of empagliflozin or sitagliptin. Pericardial fat accumulation and myocardial triglyceride content were evaluated by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Echocardiography, ¹²³ I-β-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, and laboratory tests were performed at baseline and after the 12-week treatment period. Results The patients were middle-aged (50.3 ± 10.7 years, mean ± standard deviation) and overweight (body mass index 29.3 ± 4.9 kg/m ² ). They had a short diabetes duration (3.5 ± 3.2 years), HbA1c levels of 7.1 ± 0.8%, and preserved cardiac function (ejection fraction 73.8 ± 5.0%) with no vascular complications, except for one baseline case each of diabetic nephropathy and peripheral arterial disease. After the 12-week treatment, no differences from baseline were observed between the two groups regarding changes in pericardial, epicardial, and paracardial fat content; myocardial triglyceride content; cardiac function and mass; and cardiac fatty acid metabolism. However, considering cardiometabolic biomarkers, high-density lipoprotein cholesterol and ketone bodies, including β-hydroxybutyric acid, were significantly increased, whereas uric acid, plasma glucose, plasma insulin, and homeostasis model assessment of insulin resistance were significantly lower in the empagliflozin group than in the sitagliptin group (p < 0.05). Conclusions Although the effects on cardiac fat and function were not statistically different between the two groups, empagliflozin exhibited superior effects on cardiometabolic biomarkers, such as uric acid, high-density lipoprotein cholesterol, ketone bodies, and insulin sensitivity. Therefore, when considering the primary preventive strategies for CVD, early supplementation with SGLT2 inhibitors may be more beneficial than DPP-4 inhibitors, even in patients with early-stage T2DM without current CVD complications. Clinical Trial Registration: UMIN000026340; registered on February 28, 2017. https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000030257

The association between triglycerides and ectopic fat obesity: An inverted U-shaped curve

Article

Full-text available

Nov 2020
PLOS ONE

Background Ectopic fat obesity and triglycerides are risk factors for diabetes and multiple cardiovascular diseases. However, there have been limited studies on the association between triglycerides and ectopic fat obesity. The purpose of this study was to explore the association between triglycerides and ectopic fat obesity. Methods and results In this cross-sectional study, we retrospectively analyzed 15464 adult participants recruited by Murakami Memorial Hospital (8430 men and 7034 women, average age of 43.71 ± 8.90). All patients were divided into two groups according to the threshold used to diagnose hypertriglyceridemia. The logistic regression model was used to analyze the association between triglycerides and the risk of ectopic fat obesity, and the generalized additive model was used to identify the nonlinear association. In this study population, the prevalence of ectopic fat obesity was 17.73%. After adjusting other covariables, triglycerides were positively correlated with the risk of ectopic fat obesity (OR: 1.54, 95% CI:1.41–1.69, P<0.0001). Through smooth curve fitting, we found that there was an inverted U-shaped curve association between triglycerides and ectopic fat obesity. This association remained unchanged even if the adjusted covariables were removed from the model, and the inflection point of the curve was 3.98. When triglyceride levels were ≤3.98, triglycerides were positively correlated with the risk of ectopic fat obesity (OR:1.784, 95% CI:1.611–1.975, P<0.0001). When triglyceride levels were >3.98 (right side of the inflection point), there was a negative correlation (OR:0.519, 95% CI:0.333–0.810, P = 0.0039). Conclusions Our research showed that there is a significant association between triglycerides and ectopic fat obesity. This relation is not a simple linear relationship but instead an inverted U-shaped curve association.

Rationale, Design for the ASSET Study: A Prospective Randomized Study Comparing Empagliflozin’s Effect to Sitagliptin on Cardiac Fat Accumulation/Function in Patients with Type 2 Diabetes

Article

Full-text available

Jun 2019

Introduction: Ectopic fat accumulation has been found to play a pathophysiological role in insulin resistance, type 2 diabetes (T2DM), and coronary artery diseases. Findings from a number of previous studies suggest that sodium glucose cotransporter 2 (SGLT2) inhibitors reduce lipid accumulation, including myocardial and pericardial fat, while dipeptidyl peptidase 4 (DPP4) inhibitors suppress ectopic lipid accumulation and improve cardiac function. However, a clinical study that precisely explains and compares the efficacy of SGLT2 inhibitors and DPP4 inhibitors on cardiac fat accumulation has not been performed. Moreover, the association between cardiac fat accumulation and cardiac function or metabolic changes, such as tissue-specific insulin resistance, remains unclear. It is our intention to conduct the first study to assess the effects of empagliflozin compared to sitagliptin in reducing ectopic fat accumulation, specifically pericardial fat, and its association with improvement in cardiac function and tissue-specific insulin sensitivity. Methods: We have designed a prospective, randomized open-label, and blinded-endpoint study with the intention to enroll 44 Japanese patients with T2DM. The patients are to be divided them into two groups, an empagliflozin group and an sitagliptin group, with the former to be supplemented with empagliflozin 10 mg and the latter to be supplemented with sitagliptin 100 mg, both groups for 12 weeks. The primary endpoint of the study is the change in the amount of pericardial fat. The secondary endpoints are the changes in the amount of intracellular fat in the myocardium, cardiac function, tissue-specific insulin sensitivity, fatty acid metabolism in myocardial tissue, assessed by parameters of iodine-123-β-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, blood and urine biomarkers, and lifestyle evaluation. Planned outcomes: The results of this study will be available in 2020. The aim of this study is to provide an effective treatment strategy for patients with T2DM by considering cardiac fat accumulation, cardiac function, and insulin resistance. Funding: Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Trial registration: University Hospital Medical Information Network Clinical Trial Registry: UMIN000026340.

Deep-Learning Segmentation of Epicardial Adipose Tissue Using Four-Chamber Cardiac Magnetic Resonance Imaging

Article

Full-text available

Jan 2022

In magnetic resonance imaging (MRI), epicardial adipose tissue (EAT) overload remains often overlooked due to tedious manual contouring in images. Automated four-chamber EAT area quantification was proposed, leveraging deep-learning segmentation using multi-frame fully convolutional networks (FCN). The investigation involved 100 subjects—comprising healthy, obese, and diabetic patients—who underwent 3T cardiac cine MRI, optimized U-Net and FCN (noted FCNB) were trained on three consecutive cine frames for segmentation of central frame using dice loss. Networks were trained using 4-fold cross-validation (n = 80) and evaluated on an independent dataset (n = 20). Segmentation performances were compared to inter-intra observer bias with dice (DSC) and relative surface error (RSE). Both systole and diastole four-chamber area were correlated with total EAT volume (r = 0.77 and 0.74 respectively). Networks’ performances were equivalent to inter-observers’ bias (EAT: DSCInter = 0.76, DSCU-Net = 0.77, DSCFCNB = 0.76). U-net outperformed (p < 0.0001) FCNB on all metrics. Eventually, proposed multi-frame U-Net provided automated EAT area quantification with a 14.2% precision for the clinically relevant upper three quarters of EAT area range, scaling patients’ risk of EAT overload with 70% accuracy. Exploiting multi-frame U-Net in standard cine provided automated EAT quantification over a wide range of EAT quantities. The method is made available to the community through a FSLeyes plugin.

Characterization of different fat depots in NAFLD using inflammation-associated proteome, lipidome and metabolome

Article

Full-text available

Sep 2018

Abstract Non-alcoholic fatty liver disease (NAFLD) is recognized as a liver manifestation of metabolic syndrome, accompanied with excessive fat accumulation in the liver and other vital organs. Ectopic fat accumulation was previously associated with negative effects at the systemic and local level in the human body. Thus, we aimed to identify and assess the predictive capability of novel potential metabolic biomarkers for ectopic fat depots in non-diabetic men with NAFLD, using the inflammation-associated proteome, lipidome and metabolome. Myocardial and hepatic triglycerides were measured with magnetic spectroscopy while function of left ventricle, pericardial and epicardial fat, subcutaneous and visceral adipose tissue were measured with magnetic resonance imaging. Measured ectopic fat depots were profiled and predicted using a Random Forest algorithm, and by estimating the Area Under the Receiver Operating Characteristic curves. We have identified distinct metabolic signatures of fat depots in the liver (TAG50:1, glutamate, diSM18:0 and CE20:3), pericardium (N-palmitoyl-sphinganine, HGF, diSM18:0, glutamate, and TNFSF14), epicardium (sphingomyelin, CE20:3, PC38:3 and TNFSF14), and myocardium (CE20:3, LAPTGF-β1, glutamate and glucose). Our analyses highlighted non-invasive biomarkers that accurately predict ectopic fat depots, and reflect their distinct metabolic signatures in subjects with NAFLD.

Epicardial adipose tissue is related to arterial stiffness and inflammation in patients with cardiovascular disease and type 2 diabetes

Article

Full-text available

Feb 2018
BMC Cardiovasc Disord

Background: Epicardial adipose tissue (EAT) is an emerging cardio-metabolic risk factor and has been shown to correlate with adverse cardiovascular (CV) outcome; however the underlying pathophysiology of this link is not well understood. The aim of this study was to evaluate the relationship between EAT and a comprehensive panel of cardiovascular risk biomarkers and pulse wave velocity (PWV) and indexed left ventricular mass (LVMI) in a cohort of patients with cardiovascular disease (CVD) and diabetes compared to controls. Methods: One hundred forty-five participants (mean age 63.9 ± 8.1 years; 61% male) were evaluated. All patients underwent cardiovascular magnetic resonance (CMR) examination and PWV. EAT measurements from CMR were performed on the 4-chamber view. Blood samples were taken and a range of CV biomarkers was evaluated. Results: EAT measurements were significantly higher in the groups with CVD, with or without T2DM compared to patients without CVD or T2DM (group 1 EAT 15.9 ± 5.5 cm2 vs. group 4 EAT 11.8 ± 4.1 cm2, p = 0.001; group 3 EAT 15.1 ± 4.3 cm2 vs. group 4 EAT 11.8 ± 4.1 cm2, p = 0.024). EAT was independently associated with IL-6 (beta 0.2, p = 0.019). When added to clinical variables, both EAT (beta 0.16, p = 0.035) and IL-6 (beta 0.26, p = 0.003) were independently associated with PWV. EAT was significantly associated with LVMI in a univariable analysis but not when added to significant clinical variables. Conclusions: In patients with cardio-metabolic disease, EAT was independently associated with PWV. EAT may be associated with CVD risk due to an increase in systemic vascular inflammation. Whether targeting EAT may reduce inflammation and/or cardiovascular risk should be evaluated in prospective studies.

Central Obesity is Associated with Increased Left Ventricular Maximal Wall Thickness and Intrathoracic Adipose Tissue Measured with Cardiac Magnetic Resonance

Article

Full-text available

Jun 2024
High Blood Pres Cardiovasc Prev

Central obesity (CO), characterized by an increased waist circumference increases the risk of cardiovascular disease (CVD) and morbidity, yet the underlying mechanisms are not fully understood. CO is often associated with general obesity, hypertension, and abnormal glucose tolerance, confounding the independent contribution of CO to CVD. We investigated the relationship of CO (without associated disorders) with left ventricular (LV) characteristics and intrathoracic adipose tissue (IAT) by cardiac magnetic resonance. LV characteristics, epicardial (EAT), and mediastinal adipose tissue (MAT) were measured from 29 normoglycemic, normotensive males with CO but without general obesity (waist circumference >100 cm, body mass index (BMI) <30 kg/m2) and 18 non-obese male controls. LV maximal wall thickness (LVMWT) and IAT but not LV mass or volumes were increased in CO subjects compared to controls (LVMWT, 12.3±1.2 vs. 10.7±1.5 mm, p < 0.001; EAT, 5.5±3.0 vs. 2.2±2.0 cm2, p = 0.001; MAT, 31.0±12.8 vs. 15.4±10.7 cm2, p < 0.001). The LVMWT was ≥12 mm in 69% of subjects with CO and 22% of controls (p = 0.002). In CO suspects, EAT correlated inversely with LV end-diastolic volume index (r = − 0.403, p = 0.037) and LV stroke volume (SV) (r = − 0.425, p = 0.027). MAT correlated inversely with SV (r = − 0.427, p=0.026) and positively with LVMWT (r = 0.399, p = 0.035). Among CO subjects, the waist-to-hip ratio (WHR) was an independent predictor of LVMWT (B = 22.4, β = 0.617, p < 0.001). The optimal cut-off with Youden’s index for LV hypertrophy was identified at WHR 0.98 (sensitivity 85%, specificity 89%). CO independent of BMI is associated with LV hypertrophy and intrathoracic adipose tissue contributing to cardiovascular burden.

Gastric Submucosal Fat Accumulation Is Associated with Insulin Resistance in Patients with Obesity

Article

Full-text available

Jan 2024
OBES SURG

Purpose Ectopic fat accumulation plays a significant role in obesity-related metabolic dysfunction, and few studies have reported an association between ectopic gastric fat and metabolic risk factors. We aim to fulfill this need by assessing the degree of gastric submucosal fat accumulation in pathologic sections of 190 sleeve gastrectomy specimens. Methods Study patients were divided into two groups (D1 and D2) based on whether fat accumulation exceeded 1/3 of the submucosa of the stomach. Demographic and metabolic risk factors were compared between the two groups. Metabolic risk variables that might be associated with the degree of fat accumulation were screened in the original cohort. After balancing for possible confounders, the robustness of the correlations was assessed using binary and conditional logistic regression analyses. Results All study patients had fat accumulation in the submucosa of the stomach. C-reactive protein (CRP), body mass index (BMI), visceral fat area (VFA), and insulin resistance (IR) were higher in the D2 group than in the D1 group in the original cohort (P < 0.05). Logistic regression analysis showed that BMI and IR may be associated with increased fat accumulation. After balancing variables other than obesity indicators and IR using propensity score matching, BMI and IR remained significantly different between the two groups (P < 0.05). Further analysis of the matched cohort using two logistic regression analyses showed that IR was an independent risk factor for increased fat accumulation. Conclusion This study indicated that gastric submucosal fat accumulation was prevalent in patients with obesity and was associated with IR. Graphical Abstract

Myocardial steatosis: An autopsy-discovered case

Article

Dec 2023

Introduction: Myocardial steatosis, a poorly documented pathology, is characterized by the accumulation of abnormal amounts of triglycerides in the cardiomyocytes. Myocardial steatosis is generally asymptomatic, but it can be the cause of heart failure. It is primarily of hypoxic or metabolic origin. Case Report: We report a case of postmortem diagnosis in a 53-year-old male patient, without known his pathological history, who was a victim of sudden death from abdominal pain. The autopsy revealed diffuse atheromatous cardiac, aortic, and hepatic lesions. Conclusion: It is very common for myocardial steatosis to be diagnosed postmortem due to its nonspecific symptomatology. The risk of mortality and morbidity could be reduced through a healthy lifestyle and regular biological examination to identify risk factors.

Assessing the usefulness of a newly proposed metabolic score for visceral fat in predicting future diabetes: results from the NAGALA cohort study

Article

Full-text available

Jul 2023

Objective Visceral adipose tissue assessment holds significant importance in diabetes prevention. This study aimed to explore the association between the newly proposed Metabolic Score for Visceral Fat (METS-VF) and diabetes risk and to further assess the predictive power of the baseline METS-VF for the occurrence of diabetes in different future periods. Methods This longitudinal cohort study included 15,464 subjects who underwent health screenings. The METS-VF, calculated using the formula developed by Bello-Chavolla et al., served as a surrogate marker for visceral fat obesity. The primary outcome of interest was the occurrence of diabetes during the follow-up period. Established multivariate Cox regression models and restricted cubic spline (RCS) regression models to assess the association between METS-VF and diabetes risk and its shape. Receiver operating characteristic (ROC) curves were used to compare the predictive power of METS-VF with body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and visceral adiposity index (VAI) for diabetes, and time-dependent ROC analysis was conducted to assess the predictive capability of METS-VF for the occurrence of diabetes in various future periods. Results During a maximum follow-up period of 13 years, with a mean of 6.13 years, we observed that the cumulative risk of developing diabetes increased with increasing METS-VF quintiles. Multivariable-adjusted Cox regression analysis showed that each unit increase in METS-VF would increase the risk of diabetes by 68% (HR 1.68, 95% CI 1.13, 2.50), and further RCS regression analysis revealed a possible non-linear association between METS-VF and diabetes risk (P for non-linearity=0.002). In addition, after comparison by ROC analysis, we found that METS-VF had significantly higher predictive power for diabetes than other general/visceral adiposity indicators, and in time-dependent ROC analysis, we further considered the time-dependence of diabetes status and METS-VF and found that METS-VF had the highest predictive value for predicting medium- and long-term (6-10 years) diabetes risk. Conclusion METS-VF, a novel indicator for assessing visceral adiposity, showed a significantly positive correlation with diabetes risk. It proved to be a superior risk marker in predicting the future onset of diabetes compared to other general/visceral adiposity indicators, particularly in forecasting medium- and long-term diabetes risk.

Recent assessment methods of epicardial adipose tissue

Article

Apr 2023

Epicardial adipose tissue (EAT) is a visceral depot of the heart fat, which has high plasticity and directly contact with the myocardium and coronary arteries. Epicardial fat is a unique paracrine organ closely anatomically and physiologically related to the myocardium. Recent studies have repeatedly confirmed the role of epicardial fat in the progression of the cardiovascular diseases. The accumulation of EAT, measured by using new non-invasive imaging techniques, is prospectively associated with the onset and progression of coronary heart disease (CHD) and atrial fibrillation. This review focuses on modern in vivo methods for assessing epicardial fat.

ULTRASOUND POSSIBILITIES IN THE DIAGNOSIS OF OBESITY IN PREGNANT WOMEN

Article

Jan 2017

Impact of body mass index and diabetes on myocardial fat content, interstitial fibrosis and function

Article

Full-text available

Oct 2022

Purpose We hypothesize that both increased myocardial steatosis and interstitial fibrosis contributes to subclinical myocardial dysfunction in patients with increased body mass index and diabetes mellitus. Background Increased body weight and diabetes mellitus are both individually associated with a higher incidence of heart failure with preserved ejection fraction. However, it is unclear how increased myocardial steatosis and interstitial fibrosis interact to influence myocardial composition and function. Methods A total of 100 subjects (27 healthy lean volunteers, 21 healthy but overweight volunteers, and 52 asymptomatic overweight patients with diabetes) were prospectively recruited to measure left ventricular (LV) myocardial steatosis (LV-myoFat) and interstitial fibrosis (by extracellular volume [ECV]) using magnetic resonance imaging, and then used to determine their combined impact on LV global longitudinal strain (GLS) analysis by 2-dimensional (2D) speckle tracking echocardiography on the same day. Results On multivariable analysis, both increased body mass index and diabetes were independently associated with increased LV-myoFat. In turn, increased LV-myoFat was independently associated with increased LV ECV. Both increased LV-myoFat and LV ECV were independently associated with impaired 2D LV GLS. Conclusion Patients with increased body weight and patients with diabetes display excessive myocardial steatosis, which is related to a greater burden of myocardial interstitial fibrosis. LV myocardial contractile function was determined by both the extent of myocardial steatosis and interstitial fibrosis, and was independent of increasing age. Further study is warranted to determine how weight loss and improved diabetes management can improve myocardial composition and function.

Stereological Estimation of Myocardial Fat and Its Associations with Obesity, Epicardial, and Visceral Adipose Tissue

Article

Full-text available

Oct 2022

The normal human heart contains epicardial adipose tissue (EAT) and myocardial fat. The associations between obesity, myocardial fat, visceral adipose tissue (VAT), and cardiovascular disease are not fully understood. The objective of this study was to estimate myocardial fat using stereological methods and investigate its relations with obesity, EAT, and VAT. To establish the EAT volume, 115 deceased individuals were included, and postmortem computed tomography was conducted on their eviscerated hearts. Six samples from the left and right ventricles (LV and RV) of the heart were stereologically examined to calculate the percentage of myocardial fat. Kidney and omental fat were weighed at autopsy, and the waist–hip ratio was calculated. Females had a slightly non-significantly (p = 0.054) larger proportion of RV fat (13.2% ± 4.4) compared to that in men (11.5% ± 2.7). We found a significant positive correlation between body mass index (BMI) and LV myocardial fat (p = 0.033). In the RV, this correlation was only at the borderline of significance (p = 0.052). The EAT volume was positively correlated with both RV and LV myocardial fat. We found no association with the waist–hip ratio (WHR) or the omental or kidney fat as measures of VAT. The myocardial fat was normal, most prominent in the RV, and correlated with the EAT and, partly, BMI. We found no association with VAT.

Postprandial triglyceride levels rather than fat distribution may reflect early signs of disturbed fat metabolism in Iraqi immigrants

Article

Full-text available

Aug 2022
LIPIDS HEALTH DIS

Purpose Previous studies have shown that at a similar body mass index, Middle Eastern immigrants are more insulin resistant and at higher risk for type 2 diabetes (T2D) than native Europeans. Insulin resistance is strongly associated with disturbed fat metabolism and cardiovascular disease (CVD). However, fat metabolism is poorly investigated comparing Middle Eastern and European ethnicities. Methods This observational study included 26 Iraqi and 16 Swedish-born men without T2D or clinical risk factors for CVD. An oral fat tolerance test (OFTT) was performed, where plasma triglycerides (p-TG) were measured for 6 h. mRNA expression and adipocyte size were measured in subcutaneous adipose tissue biopsies collected prior to OFTT, and magnetic resonance imaging was conducted to assess body fat distribution. Results The median p-TG accumulation was higher and the clearance slower among Iraqis than Swedes. None of the groups reached their fasting p-TG (Iraqis 1.55 mmol/l; Swedes 0.95 mmol/l) after 6 h (Iraqis p-TG 3.10 mmol/l; Swedes p-TG 1.50 mmol/l). Adipocyte size, mRNA expression, and fat accumulation in the liver, muscle and abdomen were similar in both groups. Conclusion Postprandial p-TG levels rather than fat distribution may reflect early signs of disturbed fat metabolism in Iraqi immigrants without CVD risk factors.

A novel approach for the automated segmentation and volume quantification of cardiac fats on computed tomography

Preprint

Dec 2021

The deposits of fat on the surroundings of the heart are correlated to several health risk factors such as atherosclerosis, carotid stiffness, coronary artery calcification, atrial fibrillation and many others. These deposits vary unrelated to obesity, which reinforces its direct segmentation for further quantification. However, manual segmentation of these fats has not been widely deployed in clinical practice due to the required human workload and consequential high cost of physicians and technicians. In this work, we propose a unified method for an autonomous segmentation and quantification of two types of cardiac fats. The segmented fats are termed epicardial and mediastinal, and stand apart from each other by the pericardium. Much effort was devoted to achieve minimal user intervention. The proposed methodology mainly comprises registration and classification algorithms to perform the desired segmentation. We compare the performance of several classification algorithms on this task, including neural networks, probabilistic models and decision tree algorithms. Experimental results of the proposed methodology have shown that the mean accuracy regarding both epicardial and mediastinal fats is 98.5% (99.5% if the features are normalized), with a mean true positive rate of 98.0%. In average, the Dice similarity index was equal to 97.6%.

Longitudinal effect of myocardial fat deposition on left ventricular diastolic function: a retrospective cohort study

Article

Full-text available

Nov 2021

There is a known correlation between myocardial steatosis and heart function, but it is unclear how left ventricular diastolic function worsens over time in the myocardial steatosis setting. We sought to investigate whether intramyocardial fat deposition affects diastolic function over time. This was a retrospective analysis of patients who had undergone 1–3 echocardiography assessments between April 2011 and April 2017. Patients were divided into two groups: those with the presence of myocardial fat deposition in the left ventricular myocardium (assessed by having tissue within any 10-mm² region with computed tomography values between − 190 and − 30 Hounsfield units; + MF), and those with absence of deposition not meeting the threshold (− MF). The rates of change of the standard early diastolic mitral annulus velocity (e′) and the transmitral early peak velocity (E)/e′ ratio at the second and third echocardiograph assessments were calculated relative to baseline. In total, 125 patients were eligible (+ MF, n = 39; − MF, n = 86) for inclusion. Compared with the − MF group, e′ was significantly lower and E/e′ was significantly higher in the + MF group at each scan timepoint, even when adjusted for body mass index and sex. A significant average decrease in e′ and increase in E/e′ was also observed in the + MF group across all scans compared with the − MF group. Myocardial steatosis was associated with an acceleration of decreased left ventricular diastolic function over time.

Pediatric Multidisciplinary Weight Management - How Can We Improve Further?

Preprint

Full-text available

Jun 2021

Purpose: Multidisciplinary weight management (MDM) significantly improves outcomes in youth, when compared to their routine care. However, this progress may be undermined by high follow-up attrition. We hypothesized that a pre-defined time-limited MDM clinic follow-up plan given to families from the “get-go” will improve individual clinic participation, weight, and metabolic parameters. Methods: Participant follow-up rates in 7 consecutive visits in a retrospective cohort of youth followed at an urban MDM clinic between April 2017 to September 2019 after the clinic follow-up protocol was changed (Post-PC) were compared to our previously published data (Pre-PC, December 2014 to January 2017). Secondary outcomes include changes (Δ) in body mass index z-score (z-BMI), body composition analysis (BCA), and laboratory parameters. Results: 615 records (12.3 + 3.7 years, 46% male) were reviewed. Participants’ follow up rates improved significantly starting visit 3 (Post-PC (49.2%) vs. Pre-PC (40.2%); p=0.03). With continued MDM participation, mean z-BMI Δ progressively improved. BCA Δ included a mean total body fat mass (FM) decrease (-2.07+7.3 kg) along with total body muscle mass (MM) increase (3.3+5.6 kg). Significant improvements were noted with hemoglobin A1c %, total cholesterol (TC), triglyceride, AST, and ALT concentrations. FM Δ correlated significantly with glucose and HOMA-IR Δ, while MM Δ was inversely associated with TC and LDL-cholesterol Δ. Conclusion: A protocolized MDM follow plan resulted in a small but significant improvement in the participants’ follow-up along with significant improvements in weight and metabolic outcomes. Further improvements will likely require additional behavioral economic strategies.

Identification of Subclinical Myocardial Dysfunction in Breast Cancer Patients with Metabolic Syndrome after Cancer-Related Comprehensive Therapy

Article

Full-text available

Mar 2021

Background: Breast cancer patients with metabolic syndrome have an increased risk of cardiovascular disease. These patients are more prone to suffer from cardiotoxicity after anticancer therapy. Patients after completion of cancer-related comprehensive therapy, who show normal myocardial function, may already have subclinical myocardial dysfunction. We sought to evaluate the subclinical myocardial dysfunction in breast cancer patients with metabolic syndrome after cancer-related comprehensive therapy. Methods. In this study, 45 breast cancer patients with metabolic syndrome after completion of cancer-related comprehensive therapy, 45 non-breast cancer patients with metabolic syndrome, and 30 breast cancer patients without metabolic syndrome after therapy were enrolled. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were measured using echocardiogram. Results: All the patients had normal LVEF. However, nine breast cancer patients with metabolic syndrome (20%) had GLS that was lower than -17%, while all the noncancer patients had normal GLS. Breast cancer patients with metabolic syndrome had a decrease of GLS and LVEF, compared with noncancer patients with metabolic syndrome. Furthermore, we found that decrease of age was associated with reduction of LVEF and that use of trastuzumab for 1 year was a significant factor associated with reduction of GLS. In addition, breast cancer patients with metabolic syndrome had a decrease of GLS, compared with breast cancer patients without metabolic syndrome after cancer-related therapy. Conclusions: Breast cancer patients with metabolic syndrome after completion of cancer-related comprehensive therapy suffered from subclinical myocardial dysfunction. GLS should be routinely performed to early identify subclinical myocardial damage of patients, in order to prevent the cardiotoxicity of cancer-related comprehensive therapy.

Diagnosis of obesity based on body composition‐associated health risks—Time for a change in paradigm

Article

Full-text available

Jan 2021

Traditional diagnosis and understanding of the pathophysiology of obesity are based on excessive fat storage due to a chronically positive energy balance characterized by body mass index (BMI). Quantitative and qualitative analysis of lean and adipose tissue compartments by body composition analysis reveals that characterization of obesity as “overfat” does not facilitate a comprehensive understanding of obesity‐associated health risk. Instead of being related to fat mass, body composition characteristics underlying BMI‐associated prognosis may depend (i) on accelerated growth by a gain in lean mass or fat‐free mass (FFM) in children with early BMI rebound or adolescents with early puberty; (ii) on a low muscle mass in aging, associated chronic disease, or severe illness; and (iii) on impaired adipose tissue expandability with respect to cardiometabolic risk. It is therefore time to call the adipocentric paradigm of obesity into question and to avoid the use of BMI and body fat percentage. By contrast, obesity should be seen in face of a limited FFM/muscle mass together with a limited capacity of fat storage.

Metabolic syndrome and myocardium steatosis in subclinical type 2 diabetes mellitus: a 1H-magnetic resonance spectroscopy study

Article

Full-text available

May 2020
CARDIOVASC DIABETOL

Abstract Background Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that collectively cause an increased risk of type 2 diabetes mellitus (T2DM) and nonatherosclerotic cardiovascular disease. This study aimed to evaluate the role of myocardial steatosis in T2DM patients with or without MetS, as well as the relationship between subclinical left ventricular (LV) myocardial dysfunction and myocardial steatosis. Methods and materials We recruited 53 T2DM patients and 20 healthy controls underwent cardiac magnetic resonance examination. All T2DM patients were subdivide into two group: MetS group and non-MetS. LV deformation, perfusion parameters and myocardial triglyceride (TG) content were measured and compared among these three groups. Pearson’s and Spearman analysis were performed to investigate the correlation between LV cardiac parameters and myocardial steatosis. The receiver operating characteristic curve (ROC) was performed to illustrate the relationship between myocardial steatosis and LV subclinical myocardial dysfunction. Results An increase in myocardial TG content was found in the MetS group compared with that in the other groups (MetS vs. non-MetS: 1.54 ± 0.63% vs. 1.16 ± 0.45%; MetS vs. normal: 1.54 ± 0.63% vs. 0.61 ± 0.22%; all p

Left ventricular myocardial deformation: A study on diastolic function in the Chinese male population and its relationship with fat distribution

Article

Full-text available

Mar 2020

Background: Obesity has become an epidemic in China with its increased prevalence, especially in the male population. Disparities in fat distribution rather than increasing body mass index (BMI) confer the risk of different diseases, including cardiac abnormalities. Therefore, early detection of cardiac abnormalities is important for treatment to reverse the progression to heart failure. Nowadays, strain analysis based on cardiac magnetic resonance (CMR) imaging has been established to assess myocardial function in diverse cardiac diseases. We aimed to assess the relationship between fat distribution and subclinical diastolic dysfunction in obese Chinese men assessed by deformation registration algorithm (DRA)-based myocardial strain rate (SR) analysis. Methods: A total of 115 male participants with different BMI underwent CMR scanning using a 1.5T MAGNETOM Aera (Siemens Healthcare, Erlangen, Germany) and computed tomography (CT) scan. All the participants were enrolled from September 2017 to April 2018. They were classified into 3 groups according to their BMIs with 23 and 27.5 kg/m2 being the cutoff values. A Trufi-Strain prototype software (version 2.0, Siemens Healthcare, Erlangen, Germany) was used to quantify SR in both early and late diastole from CMR cine images. Ratios of early and late SRs were calculated. Areas of epicardial and pericardial adipose tissue (EAT and PAT) were measured on a single 4-chamber-view slice of cine images. Volumes of visceral and subcutaneous adipose tissue (VAT and SAT) were acquired semi-automatically from CT images using the dedicated software Cardiac Risk2.0 (Siemens Healthcare). Waist and hip circumferences were manually measured (WC and HC). Analysis of variance or nonparametric tests, along with correlation and stepwise multivariate regression analysis models, was applied for statistical analysis. Results: Peak late diastolic SRs were higher in obese men compared with their lean counterparts [-36.25±10.46 vs. -29.46±8.17, 66.97±18.58 vs. 45.62 (42.44, 55.96), and 56.81±15.07 vs. 41.40±6.41 for radial, circumferential, and longitudinal SRs, respectively; P<0.05]. All SR ratios in the obese subgroups were lower than those of lean men (3.12±1.14 vs. 4.63±1.24, 2.12±0.58 vs. 2.96±0.62 and 1.63±0.50 vs. 2.20±0.63 for radial, circumferential, and longitudinal directions, respectively; P<0.05). EAT was a significant predictor of diastolic function assessed by radial and circumferential SR ratios (β=-0.439 and -0.337 respectively; all P<0.001), while VAT was a significant predictor of circumferential and longitudinal SR ratios (β=-0.216 and -0.355, respectively, P<0.05). Conclusions: Decreased LV diastolic function assessed by DRA-based SR analysis in obesity is associated with fat distribution. Furthermore, EAT and VAT might be better predictors of a decrease of diastolic function in obese Chinese men than BMI.

Severe Myocardial Steatosis: Incidental Finding or a Significant Anatomic Substrate for Sudden Cardiac Arrest?

Article

Jan 2020

Myocardial steatosis, also known as lipomatosis cordis, is characterized by adipose tissue within the myocardium without significant fibrosis. Evidence suggests that accumulation of fat can disturb the normal electromechanical physiology of the myocardium. Herein, we discuss the case of a 60-year-old woman with a history of chronic obstructive pulmonary disease who died because of anoxic encephalopathy after a sudden cardiac arrest (SCA). An electrocardiogram showed QRS fragmentation noted as notched R in inferior leads. The autopsy revealed a very small thromboembolus in a distal subsegmental branch of the pulmonary artery, which could not explain the SCA. There was an extensive intramyocardial accumulation of adipose tissue involving the right ventricle and interventricular septum, which split the myocardium into discrete bundles. Arrhythmogenic right ventricular cardiomyopathy was ruled out based on the absence of typical fibrofatty changes. The mechanism of fat replacement was likely secondary to redistribution of visceral fat in the setting of Cushing syndrome. We propose that severe myocardial steatosis can create an anatomic substrate to facilitate the development of SCA. Myocardial steatosis should be reported to identify patients who are at risk for developing cardiovascular events secondary to extreme cardiac adiposity.

Cardiac Obesity and Cardiac Cachexia: Is There a Pathophysiological Link?

Article

Full-text available

Sep 2019
J Obes

Obesity is a risk factor for cardiometabolic and vascular diseases like arterial hypertension, diabetes mellitus type 2, dyslipidaemia, and atherosclerosis. A special role in obesity-related syndromes is played by cardiac visceral obesity, which includes epicardial adipose tissue and intramyocardial fat, leading to cardiac steatosis; hypertensive heart disease; atherosclerosis of epicardial coronary artery disease; and ischemic cardiomyopathy, cardiac microcirculatory dysfunction, diabetic cardiomyopathy, and atrial fibrillation. Cardiac expression of these changes in any given patient is unique and multimodal, varying in clinical settings and level of expressed changes, with heart failure development depending on pathophysiological mechanisms with preserved, midrange, or reduced ejection fraction. Progressive heart failure with misbalanced metabolic and catabolic processes will change muscle, bone, and fat mass and function, with possible changes in the cardiac fat state from excessive accumulation to reduction and cardiac cachexia with a worse prognosis. The question we address is whether cardiac obesity or cardiac cachexia is to be more feared.

Adiposity measures and pre-diabetes or diabetes in adults with hypertension in Singapore polyclinics

Article

Full-text available

Jun 2019

Identification of hypertensive patients with pre‐diabetes or diabetes is important for timely prevention of complications including vascular disease. We aimed to compare the association and discrimination of central obesity measures (waist circumference [WC] and waist‐to‐height ratio [WHtR]) with generalized obesity measure (body mass index [BMI]) in relation to pre‐diabetes and diabetes among a group of Asian hypertensive patients for the first time. We used the baseline data of 925 subjects aged 40 years or older with uncontrolled hypertension recruited at eight primary care clinics in Singapore. Information on height, weight, WC, fasting blood glucose, and hemoglobin A1c (HbA1c) was collected. Pre‐diabetes or diabetes was defined as having reported physician‐diagnosed diabetes or taking anti‐diabetes medication, fasting blood glucose ≥ 5.6 mmol/dL or HbA1c ≥ 5.7%. Among 925 subjects, 495 (53.5%) had pre‐diabetes or diabetes. In logistic regression models, BMI was not associated with pre‐diabetes or diabetes after adjusting for WC or WHtR, while a positive association remained with both WC and WHtR after adjustment of BMI. Both WC and WHtR had significantly better discrimination than BMI (respective area under ROC curve: 0.63 for WC, 0.63 for WHtR, and 0.60 for BMI; P = 0.019), and adding WC or WHtR on top of BMI further correctly reclassified 42.7% and 38.7% hypertensive patients to the right risk group of pre‐diabetes or diabetes indicated by net reclassification improvement. However, WHtR was not superior to WC. In conclusion, our results suggested that central obesity has stronger association with and better discrimination for pre‐diabetes or diabetes than generalized obesity.

Early life stress and metabolism

Article

Jan 2019

Exposure to stress is a normal and constant facet of life. However, excessive or chronic stress at particular phases of brain development can have lasting detrimental effects on many aspects of physiology, including appetite regulation and metabolism. A specific window of vulnerability to the lasting effects of stress is the early life period, in utero and immediately postnatally. At these times, excessive psychological stress, such as parental withdrawal or a bereavement in the family, can influence hypothalamic–pituitary–adrenal (HPA) axis development, resulting in excessive glucocorticoid production throughout life. Although additional mechanisms contribute to aberrant programming of feeding and metabolism with early life stress, HPA axis dysregulation can play a major role, with excess glucocorticoids contributing to a chronically stimulated appetite for palatable foods, as well as increased fat deposition. Here we will review recent work examining the impact of early life stress on metabolic function in animal models and in humans, we will examine some of the glucocorticoid-mediated mechanisms by which this might occur, and we will highlight those cases of metabolic resilience in the face of early life stress.

Anthropometric indicators for the characterization of body adiposity in healthy pregnant women at the beginning of pregnancy

Article

Full-text available

Dec 2018

Introduction: Different locations of adipose tissue determine risks for the cardiovascular and metabolic health, without having enough knowledge on how this problem manifests in healthy pregnant at the start of pregnancy. Objectives: To identify possible groups of healthy pregnant women with body adiposity and to evaluate the diagnostic capability of the indicators used. Method: Cross-sectional observational study in 1305 pregnant women in a health area of Santa Clara, from 2012 to 2016. Frequency distributions and central tendency and dispersion measures were developed, as well as clustering techniques and ROC curves (Receiver Operating Characteristic). The general and central adiposity, and the components of corporal and abdominal adiposity were studied. Results: Three clusters of general adiposity and two of central adiposity were identified. The highest average values of body mass index and body fat percentage were in the high cluster of general adiposity (33.5 kg/m2 y 41.6%), whereas for the central adiposity indicators, these values manifested in the group of high central adiposity. The sum of the tricipital and subscapular skinfolds had the largest area under the curve, both for general (0.752) and central body adiposity (0.934); while for the abdominal adiposity corresponded to visceral (0.697) and preperitoneal (0.822) fat. Conclusions: The indicators used identified groups of pregnant women with different levels of general and central adiposity, with more diagnostic capability for the sum of subscapular and tricipital skinfolds.

FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3-associated inflammation and oxidative stress

Article

Full-text available

Apr 2019
J TRANSL MED

Background Chronic low-grade inflammation and oxidative stress play important roles in the development of obesity-induced cardiac hypertrophy. Here, we investigated the role of Fibronectin type III domain containing 5 (FNDC5) in cardiac inflammation and oxidative stress in obesity-induced cardiac hypertrophy. Methods Male wild-type and FNDC5−/− mice were fed normal chow or high fat diet (HFD) for 20 weeks to induce obesity, and primary cardiomyocytes and H9c2 cells treated with palmitate (PA) were used as in vitro model. The therapeutic effects of lentiviral vector-mediated FNDC5 overexpression were also examined in HFD-induced cardiac hypertrophy. Results High fat diet manifested significant increases in body weight and cardiac hypertrophy marker genes expression, while FNDC5 deficiency aggravated cardiac hypertrophy evidenced by increased Nppa, Nppb and Myh7 mRNA level and cardiomyocytes area, in association with enhanced cardiac inflammatory cytokines expression, oxidative stress level and JAK2/STAT3 activation in HFD-fed mice. FNDC5 deficiency in primary cardiomyocytes or FNDC5 knockdown in H9c2 cells enhanced PA-induced inflammatory responses and NOX4 expression. Exogenous FNDC5 pretreatment attenuated PA-induced cardiomyocytes hypertrophy, inflammatory cytokines up-regulation and oxidative stress in primary cardiomyocytes and H9c2 cells. FNDC5 overexpression attenuated cardiac hypertrophy as well as cardiac inflammation and oxidative stress in HFD-fed mice. Conclusions FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3 associated-cardiac inflammation and oxidative stress. The cardio-protective role of FNDC5 shed light on future therapeutic interventions in obesity and related cardiovascular complications. Electronic supplementary material The online version of this article (10.1186/s12967-019-1857-8) contains supplementary material, which is available to authorized users.

Indicadores antropométricos para la caracterización de la adiposidad corporal en gestantes sanas al inicio del embarazo

Article

Full-text available

Jul 2018

Introducción: Localizaciones distintas de tejido adiposo determinan riesgos para la salud cardiovascular y metabólica, sin que se conozca lo suficiente cómo se manifiesta esta problemática en gestantes sanas al inicio de la gestación. Objetivo: Identificar posibles agrupaciones de gestantes sanas con adiposidad corporal y evaluar la capacidad diagnóstica de los indicadores utilizados. Método: Estudio observacional transversal en 1305 gestantes de un área de salud de Santa Clara, desde 2012 al 2016. Se realizaron distribuciones de frecuencias y medidas de tendencia central y de dispersión, se aplicaron técnicas de conglomerados y curvas ROC (receiver operating characteristic). Se estudió la adiposidad general, central, y los componentes de adiposidad corporal y abdominal. Resultados: Se identificaron tres conglomerados de adiposidad general y dos de la central. Los valores medios más elevados del índice de masa corporal y el porcentaje de grasa corporal estuvieron en el conglomerado de adiposidad general alto (33,5 kg/m2) y 41,6%) y en el de adiposidad central alta. La suma de los pliegues cutáneos tricipital y subescapular tuvo la mayor área bajo la curva, tanto para la adiposidad corporal general (0,752) como central (0,934); mientras que para la adiposidad abdominal correspondió a la grasa visceral (0,697) y la preperitoneal (0,822). Conclusiones: Los indicadores utilizados identificaron agrupaciones de gestantes con diferentes niveles de adiposidad general y central, con mayor capacidad diagnóstica para la suma de los pliegues cutáneos subescapular y tricipital.

Pancreatic fat content is associated with β-cell function and insulin resistance in Chinese type 2 diabetes subjects

Article

Jan 2019

The pathogenesis of type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and β-cell dysfunction. Earlier studies reported that increased levels of pancreatic fat may lead to the development of β-cell dysfunction and insulin resistance. The present study aimed to demonstrate the relationship between pancreatic fat content (PFC) and insulin secretion and insulin resistance in Chinese subjects with T2DM. Seventy-eight T2DM subjects and 35 non-diabetic volunteers were recruited in this study. All subjects were subjected to an oral glucose tolerance test (OGTT). We also measured PFC and liver fat content (LFC) by three-point Dixon method (3p-Dixon), and we examined the relations between PFC and OGTT-derived parameters. T2DM subjects had higher PFC than non-diabetic subjects (p < 0.01). PFC was correlated with body mass index (BMI), liver fat content (LFC) and age in two groups, however, it was only positively associated with insulin secretion, insulin resistance, early- and late-phase insulin secretion in male T2DM subjects, but not in non-diabetic and female T2DM subjects. After adjusting for BMI, LFC and age, the association still existed (all p < 0.05). Furthermore, the relationship was more obvious in male T2DM subjects with a shorter course of disease. PFC was associated with β-cell dysfunction and insulin resistance in subjects with T2DM and was more obvious in male T2DM subjects with shorter duration of diabetes. Therefore, PFC might represent a potential risk factor for the development of T2DM.

Cardiac Steatosis in HIV-A Marker or Mediator of Disease?

Article

Full-text available

Oct 2018

Although people living with HIV (PLHIV) are approaching normal life expectancy, a limitation to achieving this goal is managing the higher prevalence of co-morbidities, including cardiovascular disease. Whilst ischaemic heart disease likely contributes to a large proportion of cardiac disease in the modern era of treatment, cardio-metabolic disease, including cardiac steatosis, akin to obesity-related heart disease, is also a possible mechanism of increased cardiac morbidity and mortality. HIV and other metabolic and inflammatory diseases affecting the heart, including obesity, share many cardio-metabolic abnormalities, with increased pericardial and myocardial fat content, in association with chronic systemic inflammatory changes and alterations in cardiac metabolism. Understanding the mechanisms of HIV-associated cardiac steatosis remains an important challenge, as managing the untreated metabolic and inflammatory precipitants may substantially improve cardiac outcomes for PLHIV.

Pericardial Fat Relates to Disturbances of Glucose Metabolism in Women with the Polycystic Ovary Syndrome, but Not in Healthy Control Subjects

Article

Full-text available

Aug 2018

Objective The objective of the present study is to investigate the relationship of cardiac fat depots with disturbances of the carbohydrate metabolism in women with PCOS. Methods An oral glucose tolerance test (OGTT) was realized, and metabolic parameters were collected in 48 women with PCOS and in 20 controls. Intramyocardial fat (MYCL) and pericardial fat (PERI) were measured using ¹H-magnetic resonance spectroscopy and imaging. Results Only in PCOS women, PERI was positively and independently related to parameters of glucose metabolism (HbA1c: p = 0.001, fasting plasma glucose: p < 0.001, stimulated glucose at 30 and 60 minutes in the OGTT). Thus, the disposition index, insulin sensitivity, and adiponectin also declined with the increase of PERI in women with PCOS; however, these results were not independent of BMI and age. In addition, PERI was positively related to atherogenic lipid profiles, BMI, waist circumference, CRP, and liver fat in women with PCOS. A negative relation of PERI with triglycerides and a positive relation with BMI and waist circumference could be observed in the controls. No relationship of MYCL with diabetes-specific parameters could be found in the study population. Conclusion PERI is related to metabolic disturbances in women with PCOS, but not in metabolically healthy lean subjects. This clinical trial was registered at ClinicalTrials.gov and has the registration number NCT03204461.

Subclinical myocardial disease by cardiac magnetic resonance imaging and spectroscopy in healthy HIV/Hepatitis C virus-coinfected persons

Article

Full-text available

Dec 2017
J INT MED RES

Objective The contribution of hepatitis C virus (HCV) infection to the risk of heart failure in human immunodeficiency virus (HIV)-coinfected persons is unknown. The objective was to characterize cardiac function and morphology in HIV-treated coinfected persons. Methods In a cross-sectional study, HIV-infected patients virologically suppressed on antiretroviral therapy without known cardiovascular disease or diabetes mellitus underwent cardiac magnetic resonance imaging and spectroscopy for measures of cardiac function, myocardial fibrosis, and steatosis. Results The study included 18 male patients with a median age of 44 years. Of these, 10 had untreated HCV coinfection and eight had HIV monoinfection. Global systolic and diastolic function in the cohort were normal, and median myocardial fat content was 0.48% (interquartile range 0.35–1.54). Left ventricular (LV) mass index and LV mass/volume ratio were significantly greater in the HIV/HCV-coinfected group compared with the HIV-monoinfected group. In the HIV-monoinfected group, there was more myocardial fibrosis as measured by extracellular volume fraction. Conclusions There were differences between HIV/HCV-coinfected and HIV-monoinfected patients in cardiac structure and morphology. Larger studies are needed to examine whether HIV and HCV independently contribute to mechanisms of heart failure.

Human cardiac metabolism

Article

Jul 2024
CELL METAB

Obesity Cardiomyopathy as a Cause of Sudden Cardiac Death

Article

Full-text available

Jul 2023

Timothy P Fitzgibbons

Corresponding Author

Obesity Cardiomyopathy in Sudden Cardiac Death: A Distinct Entity? A Comparative Study

Article

Full-text available

Jul 2023
J AM COLL CARDIOL

Background Obesity cardiomyopathy (OCM) can be associated with sudden cardiac death (SCD) but its pathologic features are not well described. Objectives The objective of this study was to characterize the clinical and pathological features of OCM associated with SCD. Methods This was a retrospective case control autopsy study. OCM was identified by an increased heart weight (>550 g in males; >450 g in females) in individuals with obesity (body mass index [BMI] ≥30 kg/m²) in the absence of other causes. Cases of OCM with SCD were compared to sex and age matched SCD controls with obesity or with normal weight (BMI 18.5-24.9 kg/m²) and morphologically normal hearts. Autopsy measures included: heart weight, atrial dimensions, ventricular wall thickness, and epicardial adipose tissue. Fibrosis was assessed microscopically. Results Of 6,457 SCD cases, 53 cases of OCM were identified and matched to 106 controls with obesity and 106 normal weight controls. The OCM mean age at death of individuals with OCM was 42 ± 12 with a male predominance (n = 34, 64%). Males died younger than females (40 ± 13 vs 45 ± 10, P = 0.036). BMI was increased in OCM cases compared to controls with obesity (42 ± 8 vs 35 ± 5). The average heart weight was 598 ± 93 g in OCM. There were increases in right and left ventricular wall thickness (all P < 0.05) in OCM cases compared to controls. Right ventricular epicardial fat was increased in OCM compared to normal weight controls only. Left ventricular fibrosis was identified in 7 (13%) cases. Conclusions OCM may be a specific pathological entity associated with SCD. It is most commonly seen in young males with increased BMI.

THE POSSIBILITIES OF ULTRASOUND DIAGNOSTICS IN THE PROGNOSTIC ASSESSMENT OF THE EPICARDIAL ADIPOSE TISSUE THICKNESS IN CARDIOVASCULAR PATHOLOGY

Article

Jan 2023

Recent studies have shown that different visceral fat depots can make a special contribution in development of endocrine and cardiovascular diseases. Epicardial adipose tissue (EAT) is a unique visceral fat depot, closely anatomically and physiologically related to the myocardium. This visceral fat depot has a transcriptome and secret that are very different from fat depots of other localizations. In healthy individuals, the EAT performs a buffer and cardioprotective function, but with the development of pathology, the EAT begins to secrete pro-inflammatory factors, and the synthesis of anti-inflammatory cytokines decreases. This fact is confirmed by numerous studies. A promising area of modern cardiology is the study of the prognostic value of epicardial fat in assessing the risk of cardiovascular disasters and survival of patients with various comorbid conditions. It has been proven, that people even with a normal body mass index have a risk of cardiovascular diseases and complications. People with normal body weight and the presence of visceral obesity have the cardiovascular risk in 2.75 higher, and the risk of death from all causes in 2.08 higher than in people with normal body weight without visceral obesity. Thus, only the use of anthropometric examination methods in practice may be insufficient for the diagnosis of visceral obesity. The most affordable, reproducible, cost-effective method of visualization of epicardial fat in clinic is echocardiography doppler methods. This review is devoted to the possibilities of using ultrasound diagnostics in the assessment of epicardial fat, as well as the possibility of improving the stratification of cardiovascular and metabolic risks based on an additional analysis of the epicardial fat thickness.

Reduction of cardiac adipose tissue volume with short‐term empagliflozin treatment in patients with type 2 diabetes: A substudy from the SIMPLE randomized clinical trial

Article

Full-text available

Jan 2023
DIABETES OBES METAB

Objective Ectopic accumulation of cardiac adipose tissue volume (CAT) has been associated with cardiac remodelling and cardiac dysfunction in type 2 diabetes and may be a future therapeutic target. In this substudy from the SIMPLE‐trial, we investigated short‐term empagliflozin therapy's effects on CAT in patients with type 2 diabetes. Research design and Methods Between 4 April 2017 and 11 May 2020, we randomized 90 patients with type 2 diabetes and established or high risk of cardiovascular disease to 25 mg empagliflozin or placebo for 13 weeks. The substudy focused on change in CAT evaluated by images acquired during ⁸²Rubidium‐positron emissions tomography/computed tomography. The analysis included 78 patients who had at least one scan. Furthermore, we report on the relation to the concurrent effects on left ventricular mass, end‐diastolic volume and end‐systolic volume, body composition and glucometabolic status. Results Mean ± SD baseline CAT was 258.5 ± 117.9 ml. Empagliflozin reduced CAT after 13 weeks by 12.41 ml [95% CI (−23.83 to −0.99), p = .034] as compared with placebo. Similarly, left ventricular mass [−5.16 g, 95% CI (−8.80 to −1.52), p = .006], end‐diastolic volume and end‐systolic volume decreased with empagliflozin. In addition, significant improvements were observed in body composition, with reduced total fat mass, and in measures of glucose and lipid metabolism. However, no correlation was observed between changes in CAT and changes in cardiac parameters and change in CAT appeared mediated primarily by concurrent change in weight. Conclusions Empagliflozin provides an early reduction of CAT; however, no association was observed with concurrent changes in cardiac volumetrics.

Pediatric multidisciplinary weight management—how can we improve further?

Article

Oct 2021

Fat biology and metabolic balance: On the significance of sex

Article

Jun 2021
MOL CELL ENDOCRINOL

Obesity and its related metabolic disorders have become prevalent and fatal, which are faced by the entire human beings since decades. An energy equilibrium is urgently important for human metabolic health, which requires the participation of multiple organs, such as adipose tissues, liver and skeletal muscles. It seems that both sex and age play a role in the above processes. In this review, we focus on the sexual dimorphism in energy metabolism mediated by adipose tissues, including white and thermogenic (brown/beige) adipose tissues. Remarkably, past investigations have focused on targeting brown/beige adipose tissues to combat obesity because of their contributions to non-shivering thermogenesis. However, sex differences in the regulation of adipose tissue metabolism are likely overlooked. Particularly, increasing data show that males display more visceral fat than females, and females show increased visceral fat after menopause. Visceral adiposity is more deleterious and closely related to metabolic disorders, such as cardiovascular diseases. In this review, we discuss current findings on sexual dimorphism in WAT and BAT biology for a better metabolic balance in humans.

Atherogenesis and Vascular Biology

Chapter

Jan 2021

Peter Paul Toth

Atherosclerotic disease is widely prevalent throughout the world and is a manifestation of a maladaptive response of the arterial vasculature to progressive injury. Arteries are histologically, biochemically, and physiologically complex conduits of blood that can undergo continuous structural alteration in response to cardiovascular risk factors (hyperlipidemia, hypertension, diabetes) as well as an extraordinary range of chemical influences that promote inflammation, oxidation, and thrombosis. Atherosclerosis is characterized by endothelial dysfunction, extensive histologic and connective tissue alterations of the intima, media, and adventitia, and an influx of inflammatory white cells from the blood into the subendothelial space. As the inflammatory and oxidative milieu in the arterial wall intensify, foam cells and fatty streaks develop, ultimately resulting in the formation of atheromatous plaques if the inciting factors are not brought under control. Plaque enlarges and can become vulnerable to rupture from superficial erosions or thinned fibrous cap regions, intra-plaque hemorrhage, or cholesterol crystal formation. With the exposure of tissue factor and collagen, platelets are activated and can form an overlying thrombus on the plaque leading to the development of acute tissue ischemia and necrosis. Atherogenesis is a tightly coordinated process that integrates many biochemical signaling pathways both within and between cells. The progression of atherosclerotic plaque can be arrested with appropriate intervention, and if not yet calcified, plaque can be regressed. There are many gaps in our knowledge of atherogenesis, but great strides have been made in our understanding of this disease during the past three decades.

Does Weight Loss Improve Clinical Outcomes in Overweight and Obese Patients with Heart Failure?

Article

Full-text available

Dec 2020
Curr Diabetes Rep

Purpose of Review Obesity increases the risk of new onset heart failure (HF), and particularly HF with preserved ejection fraction (HFpEF). Despite the observations of favorable clinical outcomes in HF patients with obesity in general, sometimes referred to as the “obesity paradox,” it is important to recognize that severe obesity is associated with worse clinical outcomes. This review summarizes the effects of obesity treatment on cardiovascular health and HF clinical outcomes. Recent Findings Treatment for obesity utilizes a variety of modalities to achieve purposeful weight loss including lifestyle intervention, medications, and bariatric surgery. There are a cluster of benefits of obesity treatment in terms of clinical outcomes in HF. The mechanisms of these benefits include both weight loss-dependent and weight loss-independent mechanisms. Summary Obesity treatment is safe and associated with favorable clinical outcomes across the spectrum of the HF population. The potential benefits are facilitated through multiple mechanisms.

The role of protein kinase D (PKD) in intracellular nutrient sensing and regulation of adaptive responses to the obese environment

Article

Sep 2020
OBES REV

Obesity is associated with ectopic accumulation of lipids, which is implicated in the development of insulin resistance, type 2 diabetes mellitus and cardiovascular disease. As the global prevalence of obesity continues to rise, it is becoming increasingly important to understand the underlying cellular mechanisms of this disease. Protein kinase D (PKD) is an intracellular signalling kinase with well characterized roles in intracellular vesicle transport and secretion, cancer cell proliferation and cardiac hypertrophy. However, emerging evidence also highlights PKD as a novel nutrient sensor. PKD activation is mediated by the accumulation of the lipid intermediate diacylglycerol, and PKD activity in the liver, heart and adipose tissue increases upon feeding. In obesity, PKD signalling is linked to reduced insulin signalling and dysfunction in adipose tissue, liver and heart, whilst in the pancreas, PKD is essential for the compensatory increase in glucose-stimulated insulin secretion from β-cells during obesity. Collectively, these studies reveal aspects of PKD signalling that are involved in the tissue-specific responses to obesity. This review summarizes the emerging evidence suggesting that PKD plays an important role in regulating the adaptive response to the obese environment.

Mécanismes moléculaires et cellulaires des processus de différenciation et de plasticité cellulaire pour la formation des adipocytes

Thesis

Dec 2019

Helene Lemenager

Les adipocytes sont les unités fonctionnelles du tissu adipeux (TA). Les adipocytes blancs du TA blanc assurent le stockage et la libération de l'énergie au sein de l'organisme, principalement sous forme d'acides gras1. A l'opposé, les adipocytes bruns du TA brun ont une grande capacité à consommer les acides gras par l'activité de la protéine UnCoupling Protein 1 (UCP1)2. Enfin, il a été observé des adipocytes UCP1+ dans le TA blanc, notamment en réponse à une exposition au froid3. Ces adipocytes sont appelés adipocytes beiges et sont issus de deux processus : d'une part via l'adipogenèse à partir des cellules souches/stromales mésenchymateuses du TA (ASC), et d'autre part par la conversion des adipocytes blancs en beiges4. Ce processus de conversion est réversible, ce qui montre le caractère très plastique de ces cellules. Le but de la thèse a été de caractériser les mécanismes moléculaires impliqués dans les processus d'adipogenèse et de plasticité cellulaire. Pour ce faire, nous avons utilisé des modèles innovants de culture d'ASC humaines et réalisé des expériences in vivo chez la souris. Compte tenu de la localisation péri-vasculaire et péricytaire des ASC in vivo5,6, nous nous sommes intéressés à l'utilisation du milieu Endothelial Growth Medium 2 (EGM2) pour leur expansion in vitro, comme une alternative aux méthodes de culture Standard (milieu de type Eagle's medium supplémenté en sérum de veau fœtal). Nos travaux ont montré que le TGFß1 contenu dans le sérum de culture altérait le caractère immature des ASC par leur engagement dans des voies de différenciation de type ostéoblastique, chondroblastique et vasculaire musculaire lisse. Aussi, grâce à sa faible quantité en sérum, et donc en TGFß1, le milieu EGM2 permet de conserver l'immaturité des ASC en culture ainsi que leurs fortes capacités à se différencier en adipocytes, notamment vers le phénotype beige. D'autre part, nous montrons que les ASC qui présentaient un fort potentiel à générer des adipocytes beiges sur-exprimaient la protéine SOX2. Nos résultats montrent que l'expression de SOX2 est positivement corrélée d'une part à la formation des adipocytes beiges et d'autre part à l'activation des adipocytes bruns in vivo chez la souris exposée au froid. [...]

Pathology and Cardiotoxicity of the Epicardial Adipose Tissue

Chapter

Mar 2020

Gianluca Iacobellis

Intra-organ fatty infiltration is associated with end-organ damages and increased cardiovascular risk. Ectopic fat deposition occurs also within the heart and may cause a metabolic cardiomyopathy. Epicardial fat (EAT) can be considered ectopic fat accumulation of the heart. Epicardial fat and intra-myocardial triglycerides content are related. Excessive EAT can produce lipotoxic effects throughout an abnormal lipid deposition and fatty infiltration in the myocardium. As cardiomyocytes fat storage capacity is very limited, high levels of plasma lipids cause cardiac steatosis, hypertrophy, dysfunction, and ultimately failure, as observed in morbid obesity and uncontrolled diabetes. Due to its anatomical and functional vicinity to the myocardium, EAT can affect the morphology and function of all of the heart chambers. Increased epicardial fat has been largely associated with increased left ventricular mass, abnormal geometry, enlarged atria, and diastolic dysfunction. Multifactorial physical and biomolecular mechanisms can explain the effects of excessive EAT on the heart.

Konya ilinde sağlıklı bireylerin demografik özelliklerine ve antropometrik ölçümlerine göre lipid düzeylerinin değerlendirilmesi

Article

Full-text available

Sep 2019

Amaç: Bu çalışmada Konya ilinde iç hastalıkları polikliniklerimize başvuran sağlıklı bireylerin serum lipid değerlerinin belirlenmesi, bu değerlerin yaş gruplarına göre karşılaştırılması, demografik faktörler, antropometrik ölçümlerle ilişkilerinin gösterilmesi amaçlanmıştır. Gereç ve Yöntem: İç hastalıkları polikliniklerine başvuran 18 yaş üzeri 200 sağlıklı birey çalışmaya dahil edildi. Bu kişilerin antropometrik ölçümleri yapılarak demografik özellikleri sorgulandı. Ayrıca bu kişilerden periferik kan örneği alınarak total kolesterol(TK), düşük dansiteli lipoprotein kolesterol(LDL), trigliserid(TG), yüksek dansiteli lipoprotein kolesterol(HDL), Apolipoprotein A-1(Apo A-1), Apolipoprotein B(Apo B) ve lipoprotein (a) düzeyleri çalışıldı. Bulgular: Çalışmamıza 123 kadın ve 77 erkek olmak üzere 200 gönüllü sağlıklı birey katıldı. TK düzeyi 183 ± 40 mg/dl, LDL düzeyi 112 ± 34 mg/dl, TG düzeyi 112 ± 61 mg/dl, HDL düzeyi 47 ± 11 mg/dl, Apo A-1 düzeyi 133 ± 22 mg/dl, Apo B düzeyi 79 ± 22 mg/dl, Lp(a) düzeyi 19 ± 12 mg/dl olarak ölçüldü. TK/HDL oranı 4.1 ± 1.3 olarak bulundu. HDL ve Apo B düzeyleri kadınlarda, TG ve TK/HDL oranı ise erkeklerde anlamlı oranda yüksek bulundu. Katılımcıların % 31’inde hiperkolesterolemi (≥200 mg/dl), % 27’sinde LDL yüksekliği (≥130 mg/dl) vardı. Total kolesterol, LDL, TG, Apo B değerleri yaşla beraber artış göstermekteydi.Sonuç: Türkiye’de yapılan geniş kapsamlı çalışmalarla karşılaştırdığımızda daha düşük TK, LDL, TG ve daha yüksek HDL düzeyleri saptadık.

Plin2-deficiency reduces lipophagy and results in increased lipid accumulation in the heart

Article

Full-text available

May 2019

Myocardial dysfunction is commonly associated with accumulation of cardiac lipid droplets (LDs). Perilipin 2 (Plin2) is a LD protein that is involved in LD formation, stability and trafficking events within the cell. Even though Plin2 is highly expressed in the heart, little is known about its role in myocardial lipid storage. A recent report shows that cardiac overexpression of Plin2 result in massive myocardial steatosis suggesting that Plin2 stabilizes LDs. In this study, we hypothesized that deficiency in Plin2 would result in reduced myocardial lipid storage. In contrast to our hypothesis, we found increased accumulation of triglycerides in hearts, and specifically in cardiomyocytes, from Plin2−/− mice. Although Plin2−/− mice had markedly enhanced lipid levels in the heart, they had normal heart function under baseline conditions and under mild stress. However, after an induced myocardial infarction, stroke volume and cardiac output were reduced in Plin2−/− mice compared with Plin2+/+ mice. We further demonstrated that the increased triglyceride accumulation in Plin2-deficient hearts was caused by altered lipophagy. Together, our data show that Plin2 is important for proper hydrolysis of LDs.

Epicardial fat, left ventricular strain, and T1-relaxation times in obese individuals with a normal ejection fraction

Article

Feb 2019

Background Cardiac magnetic resonance (CMR) may detect early signs of cardiomyopathy. Purpose The purpose of this CMR study was to evaluate epicardial fat volume (EFV), T1-relaxation times (T1), and left ventricular (LV) strain in non-obese (<30 kg/m ² ) and obese (>30 kg/m ² ) individuals with no other cardiovascular risk factor and with a normal LV ejection fraction (LVEF) to detect early changes of obesity cardiomyopathy. Material and Methods Seventy-five individuals (38 men) without additional cardiovascular risk factors were examined at 1.5 T. EFV was assessed by a 3D-Dixon sequence. A 3(3)3(3)5 MOLLI scheme was used to assess T1 (ms). Myocardial strain (%) was evaluated by longitudinal (LS) and circumferential strain (CS) analysis. Results Obese individuals (n = 34; age = 55.6 ± 13.8 years; BMI = 33.4 ± 2.9 kg/m ² ) had higher EFVs (70.2 ± 27.9 vs. 56.1 ± 25.2 mL/m ² ; P < 0.05) and T1 values (991.0 ± 38.6 vs. 974.6 ± 32.0; P = 0.061) as well as worse LS and CS values (LS = −21.0 ± 4.8 vs. −23.2 ± 3.7; CS = −23.8 ± 5.7 vs. −27.7 ± 4.2; P < 0.05, for all) compared to non-obese individuals (n = 41; age = 57.2 ± 15.5 years; BMI = 25.1 ± 2.3 kg/m ² ). Individuals with severe obesity (BMI > 35 kg/m ² ) had a significantly higher T1 compared to non-obese (1010.5 ± 39.9 vs. 974.6 ± 32.0 ms; P < 0.05). There were no significant differences regarding age or gender. Conclusion Obesity is associated with an increased EFV and a disturbed LV contractility despite a normal LVEF. Myocardial fibrosis as well as metabolic and inflammatory mechanisms of increased epicardial fat may play role. Multi-parametric CMR may be a valuable tool for the detection of such early signs of an obesity cardiomyopathy.

Abnormal Myocardial Dietary Fatty Acid Metabolism and Diabetic Cardiomyopathy

Article

Jan 2018
CAN J CARDIOL

André C Carpentier

Patients with diabetes are at very high risk of hospitalization and death from heart failure. Increased prevalence of coronary heart disease, hypertension, autonomic neuropathy and kidney failure all play a role in this increased risk. However, cardiac metabolic abnormalities are now recognized to play a role in this increased risk. Increased reliance on fatty acids to produce energy may predispose the diabetic heart to oxidative stress and ischemic damage. Intramyocellular accumulation of toxic lipid metabolites leads to a number of cellular abnormalities that may also contribute to cardiac remodeling and cardiac dysfunction. However, fatty acid availability from circulation and from intracellular lipid droplets to fuel the heart is critical to maintain its function. Fatty acids delivery to the heart is very complex and includes plasma nonesterified fatty acid (NEFA) flux as well as triglyceride (TG)-rich lipoprotein-mediated transport. While many studies have shown cross-sectional association between enhanced fatty acid delivery to the heart and reduction in left ventricular function in subjects with prediabetes and diabetes, these mechanisms change very rapidly during T2D treatment. The present review focus on the role of fatty acids in cardiac function, with particular emphasis on the possible role of early abnormalities of dietary fatty acid metabolism in the development of diabetic cardiomyopathy.

Harmonizing the Metabolic Syndrome A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity

Article

Full-text available

Jan 2009

The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction

Article

Full-text available

Jun 2011
J CLIN INVEST

Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1α through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr-/- mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr-/- mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.

Myocardial, Perivascular, and Epicardial Fat

Article

Full-text available

May 2011

Patricia Iozzo

Myocardial fat content refers to the storage of triglyceride droplets within cardiomyocytes. In addition, the heart and arteries are surrounded by layers of adipose tissue, exerting vasocrine and paracrine control of the subtending tissues. The rapid development of the field of noninvasive imaging has made it possible to quantify ectopic fat masses and contents with an increasing degree of accuracy. Myocardial triglyceride stores are increased in obesity, impaired glucose tolerance, and type 2 diabetes. The role of intramyocardial triglyceride accumulation in the pathogenesis of left ventricular (LV) dysfunction remains unclear. Increased triglyceride content is associated with states of fatty acid overload to the heart, saturating the oxidative capacity. It may initially serve as a fatty acid sink to circumscribe the formation of toxic lipid species and subsequently foster cardiac damage. Epicardial and perivascular fat depots may exert a protective modulation of vascular function and energy partition in a healthy situation, but their expansion turns them into an adverse lipotoxic, prothrombotic, and proinflammatory organ. They are augmented in patients with metabolic disorders and coronary artery disease (CAD). However, the progressive association between the quantity of fat and disease severity in terms of extent of plaque calcification or noncalcified areas, markers of plaque vulnerability, and number of vessels involved is less confirmed. Functional or hybrid imaging may contribute to a better definition of disease severity and unveil the direct myocardial and vascular targets of adipose tissue action.

Chylomicron- and VLDL-derived lipids enter the heart through different pathways: In vivo evidence for receptor- and non-receptor-mediated fatty acid uptake

Article

Full-text available

Dec 2010
J BIOL CHEM

Lipids circulate in the blood in association with plasma lipoproteins and enter the tissues either after hydrolysis or as non-hydrolyzable lipid esters. We studied cardiac lipids, lipoprotein lipid uptake, and gene expression in heart-specific lipoprotein lipase (LpL) knock-out (hLpL0), CD36 knock-out (Cd36−/−), and double knock-out (hLpL0/Cd36−/−-DKO) mice. Loss of either LpL or CD36 led to a significant reduction in heart total fatty acyl-CoA (control, 99.5 ± 3.8; hLpL0, 36.2 ± 3.5; Cd36−/−, 57.7 ± 5.5 nmol/g, p < 0.05) and an additive effect was observed in the DKO (20.2 ± 1.4 nmol/g, p < 0.05). Myocardial VLDL-triglyceride (TG) uptake was reduced in the hLpL0 (31 ± 6%) and Cd36−/− (47 ± 4%) mice with an additive reduction in the DKO (64 ± 5%) compared with control. However, LpL but not CD36 deficiency decreased VLDL-cholesteryl ester uptake. Endogenously labeled mouse chylomicrons were produced by tamoxifen treatment of β-actin-MerCreMer/LpLflox/flox mice. Induced loss of LpL increased TG levels >10-fold and reduced HDL by >50%. After injection of these labeled chylomicrons in the different mice, chylomicron TG uptake was reduced by ∼70% and retinyl ester by ∼50% in hLpL0 hearts. Loss of CD36 did not alter either chylomicron TG or retinyl ester uptake. LpL loss did not affect uptake of remnant lipoproteins from ApoE knock-out mice. Our data are consistent with two pathways for fatty acid uptake; a CD36 process for VLDL-derived fatty acid and a non-CD36 process for chylomicron-derived fatty acid uptake. In addition, our data show that lipolysis is involved in uptake of core lipids from TG-rich lipoproteins.

Myocardial Fat Imaging

Article

Full-text available

Apr 2010

The presence of intramyocardial fat may form a substrate for arrhythmias, and fibrofatty infiltration of the myocardium has been shown to be associated with sudden death. Therefore, noninvasive detection could have high prognostic value. Fat-water-separated imaging in the heart by MRI is a sensitive means of detecting intramyocardial fat and characterizing fibrofatty infiltration. It is also useful in characterizing fatty tumors and delineating epicardial and/or pericardial fat. Multi-echo methods for fat and water separation provide a sensitive means of detecting small concentrations of fat with positive contrast and have a number of advantages over conventional chemical-shift fat suppression. Furthermore, fat and water-separated imaging is useful in resolving artifacts that may arise due to the presence of fat. Examples of fat-water-separated imaging of the heart are presented for patients with ischemic and nonischemic cardiomyopathies, as well as general tissue classification.

Shedding light on the enigma of myocardial lipotoxicity: The involvement of known and putative regulators of fatty acid storage and mobilization

Article

Full-text available

May 2010
AM J PHYSIOL-ENDOC M

Excessive fatty acid (FA) uptake by cardiac myocytes is often associated with adverse changes in cardiac function. This is especially evident in diabetic individuals, where increased intramyocardial triacylglycerol (TG) resulting from the exposure to high levels of circulating FA has been proposed to be a major contributor to diabetic cardiomyopathy. At present, our knowledge of how the heart regulates FA storage in TG and the hydrolysis of this TG is limited. This review concentrates on what is known about TG turnover within the heart and how this is likely to be regulated by extrapolating results from other tissues. We also assess the evidence as to whether increased TG accumulation protects against FA-induced lipotoxicity through limiting the accumulations of ceramides and diacylglycerols versus whether it is a maladaptive response that contributes to cardiac dysfunction.

Contribution of Glucose Tolerance and Gender to Cardiac Adiposity

Article

Full-text available

Oct 2009
J CLIN ENDOCR METAB

To examine whether pericardial and myocardial fat depots may contribute to the association between diabetes and cardiovascular risk, including sex-related differences, and the role of adiponectin, we evaluated data in patients with obesity and without diabetes [nondiabetic (ND)] or with impaired glucose tolerance or type 2 diabetes and in lean ND controls. Magnetic resonance imaging and spectroscopy were used to measure left ventricular (LV) function and abdominal sc and visceral fat areas to estimate respective masses, pericardial fat depots, and myocardial triglyceride content in 53 subjects (10 lean ND, 25 obese ND, six impaired-glucose-tolerance, and 12 type 2 diabetic patients with macrovascular disease); gender effects and adiponectin levels were evaluated in the available subset of subjects. Myocardial and pericardial fat increased progressively across study groups. They were lower in obese women than men (P = 0.002), but cardiac steatosis caught up in hyperglycemic women (+81% vs. ND, P = 0.01). Adiponectin was inversely related with both fat depots (P < 0.01) and LV mass (P = 0.003) and positively with LV function (P = 0.03). In multiple regression analysis, myocardial and pericardial fat were independently related with plasma glucose levels, only pericardial fat mass was associated with visceral adiposity and myocardial fat with cardiac output and work. We conclude that glycemia, gender, adiponectin, and cardiac workload are associated with, and hyperglycemia and male gender are independent positive predictors of, heart adiposity. Once glucose tolerance becomes impaired, the evolution of cardiac steatosis is more pronounced in women.

Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: Implications for sex differences in markers of cardiovascular risk

Article

Full-text available

Sep 2004

Fat accumulation in the liver has been shown to be closely correlated with hepatic insulin resistance and features of insulin resistance, also independently of body weight. It remains to be established how fat in the liver correlates with that in other depots, and whether any association differs between men and women. Liver fat (assessed using proton spectroscopy), intra-abdominal and subcutaneous fat (measured using magnetic resonance imaging) and markers of insulin resistance, including serum adiponectin, were determined in 132 non-diabetic subjects: 66 men (age 41+/-1 years) and 66 women (age 42+/-1 years). Although the women had almost twice as much subcutaneous fat as the men (5045+/-207 vs 2610+/-144 cm3, p<0.0001), amounts of intra-abdominal fat (1305+/-80 vs 1552+/-111 cm3, NS) and liver fat (6.7+/-0.8 vs 8.9+/-1.2%, NS) were similar. In this study, no sex differences were observed with respect to serum insulin, adiponectin, triglyceride and HDL cholesterol concentrations. Of all measures of body composition, liver fat was best correlated with serum insulin (r=0.58, p<0.001), with no difference observed between men and women. Serum adiponectin was inversely correlated with liver fat content (r=-0.21, p<0.05). Multiple linear regression analysis revealed that intra-abdominal fat was significantly associated with liver fat, independently of serum adiponectin and subcutaneous fat. Liver fat, but not intra-abdominal fat, significantly explained the variation in serum insulin concentrations. Intra-abdominal fat is independently associated with liver fat, whereas subcutaneous fat is not. Liver fat, but not intra-abdominal fat, is independently associated with serum insulin. Men and women with similar amounts of intra-abdominal and liver fat do not exhibit sex differences in markers of insulin resistance (serum insulin, triglycerides, HDL cholesterol and adiponectin).

Magnetic resonance spectroscopy to measure hepatic triglyceride content: Prevalence of hepatic steatosis in the general population

Article

Full-text available

Mar 2005

Despite the increasing prevalence of nonalcoholic fatty liver disease (NAFLD), the criteria used to diagnose the disorder remain poorly defined. Localized proton magnetic resonance spectroscopy (MRS) accurately measures hepatic triglyceride content (HTGC) but has been used only in small research studies. Here, MRS was used to analyze the distribution of HTGC in 2,349 participants from the Dallas Heart Study (DHS). The reproducibility of the procedure was validated by showing that duplicate HTGC measurements were high correlated (r = 0.99, P < 0.001) and that the coefficient of variation between measurements was low (8.5%). Intake of a high-fat meal did not significantly affect the measurements, and values were similar when measurements were made from the right and left hepatic lobes. To determine the "upper limit of normal" for HTGC, the distribution of HTGC was examined in the 345 subjects from the DHS who had no identifiable risk factors for hepatic steatosis (nonobese, nondiabetic subjects with minimal alcohol consumption, normal liver function tests, and no known liver disease). The 95th percentile of HTGC in these subjects was 5.56%, which corresponds to a hepatic triglyceride level of 55.6 mg/g. With this value as a cutoff, the prevalence of hepatic steatosis in Dallas County was estimated to be 33.6%. Thus MRS provides a sensitive, quantitative, noninvasive method to measure HTGC and, when applied to a large urban US population, revealed a strikingly high prevalence of hepatic steatosis.

Myocardial Triglycerides and Systolic Function in Humans: In Vivo Evaluation by Localized Proton Spectroscopy and Cardiac Imaging

Article

Full-text available

Mar 2003

Recent experimental data suggest that adiposity directly damages the heart by promoting ectopic deposition of triglyceride, a process known as myocardial steatosis. The goal of this study was to develop and validate proton magnetic resonance spectroscopy ((1)H MRS) as an in vivo tool to measure myocardial lipid content. Complementary studies in rat tissue ex vivo and in 15 healthy humans in vivo provided evidence that (1)H MRS constitutes a reproducible technique for the measurement of myocardial triglyceride. In myocardial tissue from Zucker rats, the (1)H MRS measurement of triglyceride matched that obtained by biochemical measurement (P < 0.001). In human subjects triglyceride was evident in the hearts of even the very lean individuals and was elevated in overweight and obese subjects. Increased myocardial triglyceride content was accompanied by elevated LV mass and suppressed septal wall thickening as measured by cardiac imaging.

Overproduction of large VLDL is driven by increased liver fat content

Article

Full-text available

May 2006

We determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL(1) production. A multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI. Univariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL(1) TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL(1) in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL(1) TG and ApoB pool sizes, adiponectin was not linked to VLDL(1) TG or ApoB production and thus was not a predictor of VLDL(1) production. However, adiponectin correlated negatively with the removal rates of VLDL(1) TG and ApoB. We propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL(1) particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.

Myocardial Triglyceride Content and Epicardial Fat Mass in Human Obesity: Relationship to Left Ventricular Function and Serum Free Fatty Acid Levels

Article

Full-text available

Dec 2006

Ectopic fat accumulation within and around the myocardial wall has been implicated in the pathogenesis of heart disease in obesity. We evaluated myocardial and epicardial fat, left ventricular (LV) function, and metabolic risk factors in nine (five lean, four moderately obese) men. Myocardial fat percent was quantified in the septum by proton magnetic resonance spectroscopy. Reproducibility was assessed by triplicate systolic and diastolic measurements. LV parameters and epicardial fat were determined by magnetic resonance imaging. Waist-to-hip ratio and liver enzymes (alanine transaminase) were used as surrogate markers of visceral and liver fat contents. Myocardial fat (2.1 +/- 0.5 vs. 0.8 +/- 0.1, P = 0.03) and epicardial fat (120 +/- 33 vs. 55 +/- 12 g, P = 0.08) were higher in obese than lean subjects. Individuals with above-median alanine transaminase values had a 4-fold elevation in myocardial fat. The coefficient of variation of repeated myocardial fat percent determinations was 17 +/- 3 and 23 +/- 3% in systole and diastole, respectively. Myocardial fat was correlated with free fatty acid (FFA) levels (r = 0.76; P = 0.017), epicardial fat (r = 0.69; P = 0.042), and waist-to-hip ratio (r = 0.70; P = 0.035), and it showed a tendency to associate positively with LV work. Epicardial fat was associated with peripheral vascular resistance (positively) and the cardiac index (negatively). FFA levels were significantly correlated with LV mass (r = 0.72; P = 0.030) and forward work (r = 0.74; P = 0.023). The accumulation of triglyceride in and around the myocardium of moderately obese individuals is significant, and it is related to FFA exposure, generalized ectopic fat excess, and peripheral vascular resistance. These changes precede LV overload and hypertrophy.

Estimation of the concentration of low density lipoprotein cholesterol in plasma, without the use of preparative ultracentrifuge

Article

Jan 1976

Physical Activity Participation Among Overweight Adolescents With and Without the Metabolic Syndrome

Article

May 2007

Cardiac Adiposity and Global Cardiometabolic Risk

Article

Jan 2009

Michio Shimabukuro

The obesity epidemic is a global public health concern that increases the likelihood of morbidity and mortality of metabolic and cardiovascular disease (CVD), and threatens to reduce life expectancy around the world. The con-cept of the metabolic syndrome (MetS) takes into account the essential role that visceral fat plays in the development of metabolic and CVDs, and indicates how waist circumference measurement aids patient identication in the clinical setting. However, MetS cannot be used to assess global CVD risk and is, at best, another modifiable risk factor. Thus, the global cardiometabolic risk (ie, global risk of CVD resulting from traditional risk factors combined with the additional contribution of MetS) should be considered individually. The contribution of abdominal obesity to global cardiometabolic risk is reviewed and also discussed are potential underlying mechanisms including adipocytokine, insulin resistance, lipotoxicity and ectopic fat deposition in the heart components: (1) circulatory and locally recruited fat, (2) intra-and extra-myocellular fat, (3) perivascular fat, and (4) pericardial fat. (Circ J 2009; 73: 27 - 34)

Increased values of C-reactive protein in uhildren and adolescents with metabolic syndrome

Article

Jun 2007
Atherosclerosis Suppl

The Metabolic Syndrome

Article

Dec 2005

The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and cardiovascular disease risk reduction.

Body Fat Distribution and Risk of Cardiovascular Disease An Update

Article

Sep 2012
CIRCULATION

Jean-Pierre Després

Epidemiological, clinical, and mechanistic preclinical studies conducted in the field of cardiovascular medicine have led to remarkable progress in our understanding of nonmodifiable and modifiable risk factors for cardiovascular disease (CVD). For instance, although the prevalence of CVD had reached devastating levels in the 1950s, proper focus on the major CVD risk factors first identified at the time, such as smoking, hypertension, and high cholesterol levels, has allowed these risk factors to be targeted both at the clinical level and through public health policies.1 As a consequence, coronary heart disease mortality has decreased by ≈50% over the past 50 years.2 Ford et al2 have suggested that better screening and medical management of these CVD risk factors and the medical procedures developed to treat the various acute manifestations of CVD have had a favorable impact on its related mortality rates. However, the current overconsumption of processed and energy-dense food products of poor nutritional value combined with our sedentary lifestyle have contributed to the emergence of new drivers of CVD risk: obesity and type 2 diabetes mellitus (Figure 1).3,4 It has been proposed that our medical progress at tackling CVD could be offset, at least to a certain extent, by the dramatic consequences of our toxic lifestyle, which includes poor nutrition or excess caloric consumption and a sedentary lifestyle, both leading to obesity and type 2 diabetes mellitus.2 Figure 1. Some of the alterations in the metabolic risk profile that have been found to be related to abdominal obesity assessed by anthropometry and later to excess visceral adiposity/ectopic fat assessed by imaging techniques. This constellation of metabolic abnormalities increases the risk of type 2 diabetes mellitus and of various cardiovascular outcomes. CVD indicates cardiovascular disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein. Thus, the mosaic of modifiable …

The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk

Article

Aug 2012
DIABETOLOGIA

The anatomic location of excess body fat has an impact on associated cardiometabolic morbidity, and visceral adipose tissue (VAT) is more pathogenic than subcutaneous adipose tissue (SAT). However, VAT or SAT alone provides little information regarding the relative distribution of body fat. We hypothesised that the propensity to store energy in VAT relative to SAT depots may be a correlate of cardiometabolic risk, and tested this hypothesis using the VAT/SAT ratio as a metric of fat distribution. We investigated associations of the VAT/SAT ratio with cardiometabolic traits in 3,223 participants (48% women) from the Framingham Heart Study. Fat depots were quantified by multidetector computed tomography (CT) scanning. In women and men, higher VAT/SAT ratio was associated (p < 0.05) with most assessed cardiovascular risk factors reflecting blood pressure, dyslipidaemia and insulin resistance. Additional adjustment for BMI did not materially change the findings in women, and generally strengthened associations in men. Further adjustment for VAT attenuated some associations in women, but those with lower HDL-cholesterol, higher triacylglycerol (both p < 0.0001) and higher prevalence of hypertension (p = 0.02), diabetes (p = 0.01) and the metabolic syndrome (p = 0.005) remained significant. Similarly, in men, associations with higher systolic (p = 0.006) and diastolic blood pressure (p = 0.03), higher fasting glucose (p = 0.0005), lower HDL-cholesterol and higher triacylglycerol (both p < 0.0001) and higher prevalence of diabetes (p = 0.006) remained significant. VAT/SAT ratio is a correlate of cardiometabolic risk, above and beyond BMI and VAT. The propensity to store fat viscerally versus subcutaneously may be a unique risk factor independent of absolute fat volumes.

Epicardial adipose tissue: Emerging physiological, pathophysiological and clinical features

Article

Aug 2011

Epicardial adipose tissue is an unusual visceral fat depot with anatomical and functional contiguity to the myocardium and coronary arteries. Under physiological conditions, epicardial adipose tissue displays biochemical, mechanical and thermogenic cardioprotective properties. Under pathological circumstances, epicardial fat can locally affect the heart and coronary arteries through vasocrine or paracrine secretion of proinflammatory cytokines. What influences this equilibrium remains unclear. Improved local vascularization, weight loss, and targeted pharmaceutical interventions could help to return epicardial fat to its physiological role. This review focuses on the emerging physiological and pathophysiological aspects of the epicardial fat and its numerous and innovative clinical applications. Particular emphasis is placed on the paracrine/endocrine properties of epicardial fat and its role in the development and progression of atherosclerosis.

Prevention of Overweight/Obesity as a Strategy to Optimize Cardiovascular Health

Article

Aug 2011
CIRCULATION

Lipotoxicity in type 2 diabetic cardiomyopathy

Article

Jul 2011
CARDIOVASC RES

As obesity and type 2 diabetes are becoming an epidemic in westernized countries, the incidence and prevalence of obesity- and diabetes-related co-morbidities are increasing. In type 2 diabetes ectopic lipid accumulation in the heart has been associated with cardiac dysfunction and apoptosis, a process termed lipotoxicity. Since cardiovascular diseases are the main cause of death in diabetic patients, diagnosis and treatment become increasingly important. Although ischaemic heart disease is a major problem in diabetes, non-ischaemic heart disease (better known as diabetic cardiomyopathy) becomes increasingly important with respect to the impairment of cardiac function and mortality in type 2 diabetes. The underlying aetiology of diabetic cardiomyopathy is incompletely understood but is beginning to be elucidated. Various mechanisms have been proposed that may lead to lipotoxicity. Therefore, this review will focus on the mechanisms of cardiac lipid accumulation and its relation to the development of cardiomyopathy.

Pericardial Rather Than Epicardial Fat is a Cardiometabolic Risk Marker: An MRI vs Echo Study

Article

Jul 2011

Several studies using echocardiography identified epicardial adipose tissue (EPI) as an important cardiometabolic risk marker. However, validation compared with magnetic resonance imaging (MRI) or computed tomography has not been performed. Moreover, pericardial adipose tissue (PERI) has recently been shown to have some correlation with cardiovascular disease risk factors. The aims of this study were to validate echocardiographic analyses compared with MRI and to evaluate which cardiac fat depot (EPI or PERI) is the most appropriate cardiovascular risk marker. Forty-nine healthy subjects were studied (age range, 25-68 years; body mass index, 21-40 kg/m(2)), and PERI and EPI fat depots were measured using echocardiography and MRI. Findings were correlated with MRI visceral fat and subcutaneous fat, blood pressure, insulin sensitivity, triglycerides, cholesterol, insulin, glucose, and 10-year coronary heart disease risk. Most cardiac fat was constituted by PERI (about 77%). PERI thickness by echocardiography was well correlated with MRI area (r = 0.36, P = .009), and independently of the technique used for quantification, PERI was correlated with body mass index, waist circumference, visceral fat, subcutaneous fat, blood pressure, insulin sensitivity, triglycerides, cholesterol, glucose, and coronary heart disease risk. On the contrary, EPI thicknesses correlated only with age did not correlate significantly with MRI EPI areas, which were found to correlate with age, body mass index, subcutaneous fat, and hip and waist circumferences. Increased cardiac fat in the pericardial area is strongly associated with features of the metabolic syndrome, whereas no correlation was found with EPI, indicating that in clinical practice, PERI is a better cardiometabolic risk marker than EPI.

Myocardial steatosis, cardiac remodelling and fitness in insulin-sensitive and insulin-resistant obese women

Article

Jul 2011
HEART

Obesity predisposes to heart failure and premature cardiovascular death, particularly in sedentary women. In animal models and in men with type 2 diabetes mellitus, impaired cardiac function is associated with myocardial triglyceride (MTG) accumulation. Lipotoxic injury from altered myocardial metabolism may be causative. Whether such association also exists in obese, non-diabetic women is unknown. To explore the relation between MTG content, cardiac remodelling and cardiorespiratory fitness in obese, insulin-sensitive and insulin-resistant non-diabetic women. Cross-sectional investigation. Academic clinical research centre. 65 Overweight/obese and sedentary, but otherwise healthy women (body mass index 33±4 kg/m(2); age 45±10 years). None. Cardiac structure and function measured by cardiovascular magnetic resonance imaging and MTG content of the interventricular septum by (1)H MR spectroscopy. Additional outcomes were cardiopulmonary fitness and insulin sensitivity during oral glucose tolerance testing. Insulin resistance (composite insulin sensitivity index (C-ISI) <4.6) was present in 29 women. MTG content was higher (0.83±0.30 vs 0.61±0.23, p=0.002) and left ventricular diastolic (p<0.01), but not systolic function was reduced in women with insulin resistance compared with insulin-sensitive women. The remodelling index defined as left ventricular mass divided by end-diastolic volume was increased in women with impaired glucose tolerance (p=0.006). Furthermore, cardiopulmonary fitness was equal in both groups, but was inversely correlated with MTG (r=-0.28, p=0.02). In overweight and obese women, insulin resistance is associated with increased MTG content, cardiac remodelling and reduced diastolic function. ClinicalTrials.gov NCT00956566.

Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects: Relationship to metabolic profile, cardiac function and visceral fat

Article

Jul 2011
INT J OBESITY

To assess epicardial fat volume (EFV), myocardial TG content (MTGC) and metabolic profile in severely obese patients, and to determine whether ectopic fat depots are linked to metabolic disorders or myocardial function. Sixty-three subjects with normal LV function and no coronary artery disease, including 33 lean (BMI: 21.4 ± 2.0 kg m(-2)) and 30 obese (BMI: 41.8 ± 6 kg m(-2)) patients, underwent 3-T cardiovascular MRI, and anthropometric, biological and visceral abdominal fat (VAT) assessments. EFV was measured by short-axis slice imaging and myocardial (intra-myocellular) TG content was measured by proton magnetic resonance spectroscopy. EFV and MTGC were positively correlated (r=0.52, P<0.0001), and were both strongly correlated with age, BMI, waist circumference and VAT, but not with severity of obesity. EFV and MTGC were significantly higher in obese patients than in lean controls (141 ± 18 versus 79 ± 7 ml, P=0.0001; 1.0 ± 0.1 versus 0.6 ± 0.1%, P=0.01, respectively), but some differences were found between the two cardiac depots: EFV was higher in diabetic obese subjects as compared with that in non-diabetic obese subjects (213 ± 34 versus 141 ± 18 ml, P=0.03), and was correlated with parameters of glucose tolerance (fasting plasma glucose, insulin and HOMA-IR), whereas MTGC was not. EFV and MTGC were both associated with parameters of lipid profile or inflammation (TGs, CRP). Remarkably, this was VAT-dependent, as only VAT remained independently associated with metabolic parameters (P<0.01). Concerning myocardial function, MTGC was the only parameter independently associated with stroke volume (β=-0.38, P=0.01), suggesting an impact of cardiac steatosis in cardiac function. These data show that VAT dominates the relationship between EFV, MTGC and metabolic measures, and uncover specific partitioning of cardiac ectopic lipid deposition.

Central Obesity and Survival in Subjects With Coronary Artery Disease

Article

May 2011

The aim of this study was to examine the association of central (waist circumference [WC] and waist-hip ratio [WHR]) and total obesity (body mass index [BMI]) measures with mortality in coronary artery disease (CAD) patients. The question of which measure of obesity better predicts survival in patients with CAD is controversial. We searched OVID/Medline, EMBASE, CENTRAL, and Web of Science from 1980 to 2008 and asked experts in the field for unpublished data meeting inclusion criteria, in which all subjects had: 1) CAD at baseline; 2) measures of WC or WHR; 3) mortality data; and 4) a minimum follow-up of 6 months. From 2,188 studies found, 6 met inclusion criteria. We obtained individual subject data from 4, adding unpublished data from a cardiac rehabilitation cohort. A variable called "central obesity" was created on the basis of tertiles of WHR or WC. Cox-proportional hazards were adjusted for age, sex, and confounders. The final sample consisted of 15,923 subjects. There were 5,696 deaths after a median follow-up of 2.3 (interquartile range 0.5 to 7.4) years. Central obesity was associated with mortality (hazard ratio [HR]: 1.70, 95% confidence interval [CI]: 1.58 to 1.83), whereas BMI was inversely associated with mortality (HR: 0.64, 95% CI: 0.59 to 0.69). Central obesity was also associated with higher mortality in the subset of subjects with normal BMI (HR: 1.70, 95% CI: 1.52 to 1.89) and BMI ≥30 kg/m(2) (HR: 1.93, 95% CI: 1.61 to 2.32). In subjects with CAD, including those with normal and high BMI, central obesity but not BMI is directly associated with mortality.

The Metabolic Syndrome and Cardiovascular Risk: A Systematic Review and Meta-Analysis

Article

Sep 2010

We sought to conduct a systematic review and meta-analysis of the cardiovascular risk associated with the metabolic syndrome as defined by the 2001 National Cholesterol Education Program (NCEP) and 2004 revised National Cholesterol Education Program (rNCEP) definitions. Numerous studies have investigated the cardiovascular risk associated with the NCEP and rNCEP definitions of the metabolic syndrome. There is debate regarding the prognostic significance of the metabolic syndrome for cardiovascular outcomes. We searched the Cochrane Library, EMBASE, and Medline databases through June 2009 for prospective observational studies investigating the cardiovascular effects of the metabolic syndrome. Two reviewers extracted data, which were aggregated using random-effects models. We identified 87 studies, which included 951,083 patients (NCEP: 63 studies, 497,651 patients; rNCEP: 33 studies, 453,432 patients). There was little variation between the cardiovascular risk associated with NCEP and rNCEP definitions. When both definitions were pooled, the metabolic syndrome was associated with an increased risk of cardiovascular disease (CVD) (relative risk [RR]: 2.35; 95% confidence interval [CI]: 2.02 to 2.73), CVD mortality (RR: 2.40; 95% CI: 1.87 to 3.08), all-cause mortality (RR: 1.58; 95% CI: 1.39 to 1.78), myocardial infarction (RR: 1.99; 95% CI: 1.61 to 2.46), and stroke (RR: 2.27; 95% CI: 1.80 to 2.85). Patients with the metabolic syndrome, but without diabetes, maintained a high cardiovascular risk. The metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality. Studies are needed to investigate whether or not the prognostic significance of the metabolic syndrome exceeds the risk associated with the sum of its individual components. Furthermore, studies are needed to elucidate the mechanisms by which the metabolic syndrome increases cardiovascular risk.

Metabolic Syndrome and Risk of Acute Myocardial Infarction A Case-Control Study of 26,903 Subjects From 52 Countries

Article

May 2010

This study examines the risk of acute myocardial infarction (MI) conferred by the metabolic syndrome (MS) and its individual factors in multiple ethnic populations. The risk of the MS on MI has not been well characterized, especially in multiple ethnic groups. Participants in the INTERHEART study (n = 26,903) involving 52 countries were classified using the World Health Organization (WHO) and International Diabetes Federation (IDF) criteria for MS, and their odds ratios (ORs) for MI were compared with the individual MS component factors. The MS is associated with an increased risk of MI, both using the WHO (OR: 2.69; 95% confidence interval [CI]: 2.45 to 2.95) and IDF (OR: 2.20; 95% CI: 2.03 to 2.38) definitions, with corresponding population attributable risks of 14.5% (95% CI: 12.7% to 16.3%) and 16.8% (95% CI: 14.8% to 18.8%), respectively. The associations are directionally similar across all regions and ethnic groups. Using the WHO definition, the association with MI by the MS is similar to that of diabetes mellitus (OR: 2.72; 95% CI: 2.53 to 2.92) and hypertension (OR: 2.60; 95% CI: 2.46 to 2.76), and significantly stronger than that of the other component risk factors. The clustering of > or =3 risk factors with subthreshold values is associated with an increased risk of MI (OR: 1.50; 95% CI: 1.24 to 1.81) compared with having component factors with "normal" values. The IDF definition showed similar results. In this large-scale, multi-ethnic, international investigation, the risk of MS on MI is generally comparable to that conferred by some, but not all, of its component risk factors. The characterization of risk factors, especially continuous variables, as dichotomous will underestimate risk and decrease the magnitude of association between MS and MI.

Myocardial Fat Quantification in Humans: Evaluation by Two-Point Water-Fat Imaging and Localized Proton Spectroscopy

Article

May 2010
MAGN RESON MED

Proton MR spectroscopy ((1)H-MRS) has been used for in vivo quantification of intracellular triglycerides within the sarcolemma. The purpose of this study was to assess whether breath-hold dual-echo in- and out-of-phase MRI at 3.0 T can quantify the fat content of the myocardium. Biases, including T(1), T*(2), and noise, that confound the calculation of the fat fraction were carefully corrected. Thirty-four of 46 participants had both MRI and MRS data. The fat fractions from MRI showed a strong correlation with fat fractions from MRS (r = 0.78; P < 0.05). The mean myocardial fat fraction for all 34 subjects was 0.7 +/- 0.5% (range: 0.11-3%) assessed with MRS and 1.04 +/- 0.4% (range: 0.32-2.44%) assessed with in- and out-of-phase MRI (P < 0.05). Scanning times were less than 15 sec for Dixon imaging, plus an additional minute for the acquisition used for T*(2) calculation, and 15-20 min for MRS. The average postprocessing time for MRS was 3 min and 5 min for MRI including T*(2) measurement. We conclude that the dual echo method provides a rapid means to detect and quantifying myocardial fat content in vivo. Correction/adjustment for field inhomogeneity using three or more echoes seems crucial for the dual echo approach.

The Metabolic Syndrome, Its Component Risk Factors, and Progression of Coronary Atherosclerosis

Article

Mar 2010

The mechanism that confers adverse cardiovascular prognosis in patients with the metabolic syndrome (MetS) remains unclear. We sought to investigate the association of MetS and its component risk factors with progression of coronary atherosclerosis. We performed a systematic review of 3459 patients who participated in 7 clinical trials that monitored coronary atheroma progression with intravascular ultrasonography. Patients with or without MetS were compared with regard to clinical characteristics, coronary atheroma burden at baseline, and change on serial evaluation. Relationships between plaque progression (> or =5% increase in percent atheroma volume [PAV]), MetS, and its component risk factors were investigated. The metabolic syndrome was highly prevalent and was associated with greater progression of PAV (+0.51% +/- 0.23% vs +0.23% +/- 0.24%; P = .003). Multivariable analysis showed that MetS was associated with a greater likelihood of undergoing progression of PAV (adjusted odds ratio [OR], 1.25; 95% confidence interval [CI], 1.05-1.48; P = .01). When the individual components were used in the model instead of MetS, hypertriglyceridemia (OR, 1.26; 95% CI, 1.06-1.49; P = .008) and a body mass index of 30 or higher (1.18, 1.00-1.40; P = .05) predicted progression of PAV. However, after adjusting for its individual components, MetS was no longer an independent predictor (OR, 1.04; 95% CI, 0.79-1.37; P = .79). Although accelerated disease progression is observed in the setting of MetS, this is owing to the presence of individual component risk factors rather than to the presence of the syndrome itself.

Lipotoxicity in the Heart

Article

Oct 2009
Biochim Biophys Acta

Obesity and insulin resistance are associated with ectopic lipid deposition in multiple tissues, including the heart. Excess lipid may be stored as triglycerides, but are also shunted into non-oxidative pathways that disrupt normal cellular signaling leading to organ dysfunction and in some cases apoptosis, a process termed lipotoxicity. Various pathophysiological mechanisms have been proposed to lead to lipotoxic tissue injury, which might vary by cell type. Specific mechanisms by which lipotoxicity alter cardiac structure and function are incompletely understood, but are beginning to be elucidated. This review will focus on mechanisms that have been proposed to lead to lipotoxic injury in the heart and will review the state of knowledge regarding potential causes and correlates of increased myocardial lipid content in animal models and humans. We will seek to highlight those areas where additional research is warranted.

Harmonizing the Metabolic Syndrome: A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity

Article

Oct 2009
CIRCULATION

A cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone, have become known as the metabolic syndrome. The risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. Most recently, these have come from the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute. The main difference concerns the measure for central obesity, with this being an obligatory component in the International Diabetes Federation definition, lower than in the American Heart Association/National Heart, Lung, and Blood Institute criteria, and ethnic specific. The present article represents the outcome of a meeting between several major organizations in an attempt to unify criteria. It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool. Three abnormal findings out of 5 would qualify a person for the metabolic syndrome. A single set of cut points would be used for all components except waist circumference, for which further work is required. In the interim, national or regional cut points for waist circumference can be used.

Prediction of Non-Alcoholic Fatty Liver Disease and Liver Fat Using Metabolic and Genetic Factors

Article

Jul 2009

Our aims were to develop a method to accurately predict non-alcoholic fatty liver disease (NAFLD) and liver fat content based on routinely available clinical and laboratory data and to test whether knowledge of the recently discovered genetic variant in the PNPLA3 gene (rs738409) increases accuracy of the prediction. Liver fat content was measured using proton magnetic resonance spectroscopy in 470 subjects, who were randomly divided into estimation (two thirds of the subjects, n = 313) and validation (one third of the subjects, n = 157) groups. Multivariate logistic and linear regression analyses were used to create an NAFLD liver fat score to diagnose NAFLD and liver fat equation to estimate liver fat percentage in each individual. The presence of the metabolic syndrome and type 2 diabetes, fasting serum (fS) insulin, fS-aspartate aminotransferase (AST), and the AST/alanine aminotransferase ratio were independent predictors of NAFLD. The score had an area under the receiver operating characteristic curve of 0.87 in the estimation and 0.86 in the validation group. The optimal cut-off point of -0.640 predicted increased liver fat content with sensitivity of 86% and specificity of 71%. Addition of the genetic information to the score improved the accuracy of the prediction by only <1%. Using the same variables, we developed a liver fat equation from which liver fat percentage of each individual could be estimated. The NAFLD liver fat score and liver fat equation provide simple and noninvasive tools to predict NAFLD and liver fat content.

Ectopic lipids and organ function

Article

Mar 2009
CURR OPIN LIPIDOL

To summarize recent studies that shed more light on possible mechanisms by which ectopic lipid storage affects organ function. Although ectopic lipids have been considered as biomarkers of lipotoxicity, adaptation of metabolic fluxes and of mitochondrial function seem to be more important than actual cellular fat contents in liver and muscle. Diabetic and obese humans have elevated myocardial lipid contents, which are associated with mitochondrial and contractile dysfunction and could even precede the development of heart failure. Although pancreatic fat content is negatively associated with insulin secretion, [beta]-cell triglycerides are not easily accessible to measurement in humans rendering their role for [beta]-cell function unclear. New approaches to quantify energy metabolism in various organs could help to identify novel biomarkers of organ function in humans. Dietary intake of high-caloric high-fat diets and sedentary lifestyle lead to increased storage of triglycerides not only in adipose tissue but also ectopically in other tissues. Intracellular lipid contents in skeletal muscle and liver have been related to insulin resistance and inflammatory processes. Myocardial fat is increased in heart failure, whereas pancreatic fat could relate to insulin secretion.

Cardiac Adiposity and Global Cardiometabolic Risk - New Concept and Clinical Implication

Article

Jan 2009

Michio Shimabukuro

The obesity epidemic is a global public health concern that increases the likelihood of morbidity and mortality of metabolic and cardiovascular disease (CVD), and threatens to reduce life expectancy around the world. The concept of the metabolic syndrome (MetS) takes into account the essential role that visceral fat plays in the development of metabolic and CVDs, and indicates how waist circumference measurement aids patient identification in the clinical setting. However, MetS cannot be used to assess global CVD risk and is, at best, another modifiable risk factor. Thus, the global cardiometabolic risk (ie, global risk of CVD resulting from traditional risk factors combined with the additional contribution of MetS) should be considered individually. The contribution of abdominal obesity to global cardiometabolic risk is reviewed and also discussed are potential underlying mechanisms including adipocytokine, insulin resistance, lipotoxicity and ectopic fat deposition in the heart components: (1) circulatory and locally recruited fat, (2) intra-and extra-myocellular fat, (3) perivascular fat, and (4) pericardial fat.

Myocardial Steatosis Is an Independent Predictor of Diastolic Dysfunction in Type 2 Diabetes Mellitus

Article

Dec 2008

The purpose of this study was to compare myocardial triglyceride content and function between patients with uncomplicated type 2 diabetes mellitus (T2DM) and healthy subjects within the same range of age and body mass index (BMI), and to study the associations between myocardial triglyceride content and function. T2DM is a major risk factor for cardiovascular disease. Increasing evidence is emerging that lipid oversupply to cardiomyocytes plays a role in the development of diabetic cardiomyopathy, by causing lipotoxic injury and myocardial steatosis. Myocardial triglyceride content and myocardial function were measured in 38 T2DM patients and 28 healthy volunteers in the same range of age and BMI by proton magnetic resonance (MR) spectroscopy and MR imaging, respectively. Myocardial triglyceride content was calculated as a percentage relative to the signal of myocardial water. Myocardial triglyceride content was significantly higher in T2DM patients compared with healthy volunteers (0.96 +/- 0.07% vs. 0.65 +/- 0.05%, p < 0.05). Systolic function did not significantly differ between both groups. Indexes of diastolic function, including the ratio of maximal left ventricular early peak filling rate and the maximal left ventricular atrial peak filling rate (E/A) and E peak deceleration, were significantly impaired in T2DM compared with those in healthy subjects (1.08 +/- 0.04 ml/s(2) x 10(-3) vs. 1.24 +/- 0.06 ml/s(2) x 10(-3) and 3.6 +/- 0.2 ml/s(2) x 10(-3) vs. 4.4 +/- 0.3 ml/s(2) x 10(-3), respectively, p < 0.05). Multivariable analysis indicated that myocardial triglyceride content was associated with E/A and E peak deceleration, independently of diabetic state, age, BMI, heart rate, visceral fat, and diastolic blood pressure. Myocardial triglyceride content is increased in uncomplicated T2DM and is associated with impaired left ventricular diastolic function, independently of age, BMI, heart rate, visceral fat, and diastolic blood pressure.

Left ventricular mass and body size in normotensive children and adults: Assessment of allometric relations and impact of overweight

Article

Nov 1992
J AM COLL CARDIOL

This study was designed to determine the most appropriate method to normalize left ventricular mass for body size. Left ventricular mass has been normalized for body weight, surface area or height in experimental and clinical studies, but it is uncertain which of these approaches is most appropriate. Three normotensive population samples--in New York City (127 adults), Naples, Italy (114 adults) and Cincinnati, Ohio (444 infants to young adults)--were studied by echocardiography. Relations of left ventricular mass to body size were similar in all normal weight groups, as assessed by linear and nonlinear regression analysis, and results were pooled (n = 611). Left ventricular mass was related to body weight to the first power (r = 0.88), to body surface area to the 1.5 power (r = 0.88) and to height to the 2.7 power (r = 0.84), consistent with expected allometric (growth) relations between variables with linear (height), second-power (body surface area) and volumetric (left ventricular mass and body weight) dimensions. Strong residual relations of left ventricular mass/body surface area to body surface area (r = 0.54) and of ventricular mass/height to height (r = 0.72) were markedly reduced by normalization of ventricular mass for height2.7 and body surface area1.5. The variability among subjects of ventricular mass was also reduced (p < 0.01 to p < 0.002) by normalization for body weight, body surface area, body surface area1.5 or height2.7 but not for height. In 20% of adults who were overweight, ventricular mass was 14% higher (p < 0.001) than ideal mass predicted from observed height and ideal weight; this increase was identified as 14% by left ventricular mass/height2.7 and 9% by ventricular mass/height, whereas indexation for body surface area, body surface area1.5 and body weight erroneously identified left ventricular mass as reduced in overweight adults. Normalizations of left ventricular mass for height or body surface area introduce artifactual relations of indexed ventricular mass to body size and errors in estimating the impact of overweight. These problems are avoided and variability among normal subjects is reduced by using left ventricular mass/height2.7. Simple nomograms of the normal relation between height and left ventricular mass allow detection of ventricular hypertrophy in children and adults.

Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, Without Use of the Preparative Ultracentrifuge

Article

Jul 1972

A method for estimating the cholesterol content of the serum low-density lipoprotein fraction (Sf- 0.20)is presented. The method involves measure- ments of fasting plasma total cholesterol, tri- glyceride, and high-density lipoprotein cholesterol concentrations, none of which requires the use of the preparative ultracentrifuge. Cornparison of this suggested procedure with the more direct procedure, in which the ultracentrifuge is used, yielded correlation coefficients of .94 to .99, de- pending on the patient population compared. Additional Keyph rases hyperlipoproteinemia classifi- cation #{149} determination of plasma total cholesterol, tri- glyceride, high-density lipoprotein cholesterol #{149} beta lipo proteins

Improved Method for Accurate and Efficient Quantification of MRS Data with Use of Prior Knowledge

Article

Dec 1997
J MAGN RESON

We introduce AMARES (advanced method for accurate, robust, and efficient spectral fitting), an improved method for accurately and efficiently estimating the parameters of noisy magnetic resonance spectroscopy (MRS) signals in the time domain. As a reference time domain method we take VARPRO. VARPRO uses a simple Levenberg-Marquardt algorithm to minimize the variable projection functional. This variable projection functional is derived from a general functional, which minimizes the sum of squared differences between the data and the model function. AMARES minimizes the general functional which improves the robustness of MRS data quantification. The newly developed method uses a version of NL2SOL, a sophisticated nonlinear least-squares algorithm, to minimize the general functional. In addition, AMARES uses a singlet approach for imposition of prior knowledge instead of the multiplet approach of VARPRO because this greatly extends the possibilities of the kind of prior knowledge that can be invoked. Other new features of AMARES are the possibility of fitting echo signals, choosing a Lorentzian as well as a Gaussian lineshape for each peak, and imposing lower and upper bounds on the parameters. Simulations, as well as in vivo experiments, confirm the better performance of AMARES compared to VARPRO in terms of accuracy, robustness, and flexibility. Copyright 1997 Academic Press. Copyright 1997Academic Press

Java-based graphical user interface for MRUI, a software package for quantitation of in vivo/medical magnetic resonance spectroscopy signals

Article

Aug 2001
COMPUT BIOL MED

This article describes a Java-based graphical user interface for the magnetic resonance user interface (MRUI) quantitation package. This package allows MR spectroscopists to easily perform time-domain analysis of in vivo/medical MR spectroscopy data. We have found that the Java programming language is very well suited for developing highly interactive graphical software applications such as the MRUI system. We also have established that MR quantitation algorithms, programmed in the past in other languages, can easily be embedded into the Java-based MRUI by using the Java native interface (JNI).

Use and abuse of HOMA modelling

Article

Jun 2004
DIABETES CARE

Homeostatic model assessment (HOMA) is a method for assessing β-cell function and insulin resistance (IR) from basal (fasting) glucose and insulin or C-peptide concentrations. It has been reported in >500 publications, 20 times more frequently for the estimation of IR than β-cell function. This article summarizes the physiological basis of HOMA, a structural model of steady-state insulin and glucose domains, constructed from physiological dose responses of glucose uptake and insulin production. Hepatic and peripheral glucose efflux and uptake were modeled to be dependent on plasma glucose and insulin concentrations. Decreases in β-cell function were modeled by changing the β-cell response to plasma glucose concentrations. The original HOMA model was described in 1985 with a formula for approximate estimation. The computer model is available but has not been as widely used as the approximation formulae. HOMA has been validated against a variety of physiological methods. We review the use and reporting of HOMA in the literature and give guidance on its appropriate use (e.g., cohort and epidemiological studies) and inappropriate use (e.g., measuring β-cell function in isolation). The HOMA model compares favorably with other models and has the advantage of requiring only a single plasma sample assayed for insulin and glucose. In conclusion, the HOMA model has become a widely used clinical and epidemiological tool and, when used appropriately, it can yield valuable data. However, as with all models, the primary input data need to be robust, and the data need to be interpreted carefully.

The Metabolic Syndrome

Article

Apr 2005
LANCET

Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss: An Update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease From the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism

Article

Mar 2006
CIRCULATION

Obesity is becoming a global epidemic in both children and adults. It is associated with numerous comorbidities such as cardiovascular diseases (CVD), type 2 diabetes, hypertension, certain cancers, and sleep apnea/sleep-disordered breathing. In fact, obesity is an independent risk factor for CVD, and CVD risks have also been documented in obese children. Obesity is associated with an increased risk of morbidity and mortality as well as reduced life expectancy. Health service use and medical costs associated with obesity and related diseases have risen dramatically and are expected to continue to rise. Besides an altered metabolic profile, a variety of adaptations/alterations in cardiac structure and function occur in the individual as adipose tissue accumulates in excess amounts, even in the absence of comorbidities. Hence, obesity may affect the heart through its influence on known risk factors such as dyslipidemia, hypertension, glucose intolerance, inflammatory markers, obstructive sleep apnea/hypoventilation, and the prothrombotic state, in addition to as-yet-unrecognized mechanisms. On the whole, overweight and obesity predispose to or are associated with numerous cardiac complications such as coronary heart disease, heart failure, and sudden death because of their impact on the cardiovascular system. The pathophysiology of these entities that are linked to obesity will be discussed. However, the cardiovascular clinical evaluation of obese patients may be limited because of the morphology of the individual. In this statement, we review the available evidence of the impact of obesity on CVD with emphasis on the evaluation of cardiac structure and function in obese patients and the effect of weight loss on the cardiovascular system.

Cardiac Steatosis in Diabetes Mellitus A 1H-Magnetic Resonance Spectroscopy Study

Article

Sep 2007
CIRCULATION

The risk of heart failure in type 2 diabetes mellitus is greater than can be accounted for by hypertension and coronary artery disease. Rodent studies indicate that in obesity and type 2 diabetes mellitus, lipid overstorage in cardiac myocytes produces lipotoxic intermediates that cause apoptosis, which leads to heart failure. In humans with diabetes mellitus, cardiac steatosis previously has been demonstrated in explanted hearts of patients with end-stage nonischemic cardiomyopathy. Whether cardiac steatosis precedes the onset of cardiomyopathy in individuals with impaired glucose tolerance or in patients with type 2 diabetes mellitus is unknown. To represent the progressive stages in the natural history of type 2 diabetes mellitus, we stratified 134 individuals (age 45+/-12 years) into 1 of 4 groups: (1) lean normoglycemic (lean), (2) overweight and obese normoglycemic (obese), (3) impaired glucose tolerance, and (4) type 2 diabetes mellitus. Localized (1)H magnetic resonance spectroscopy and cardiac magnetic resonance imaging were used to quantify myocardial triglyceride content and left ventricular function, respectively. Compared with lean subjects, myocardial triglyceride content was 2.3-fold higher in those with impaired glucose tolerance and 2.1-fold higher in those with type 2 diabetes mellitus (P<0.05). Left ventricular ejection fraction was normal and comparable across all groups. In humans, impaired glucose tolerance is accompanied by cardiac steatosis, which precedes the onset of type 2 diabetes mellitus and left ventricular systolic dysfunction. Thus, lipid overstorage in human cardiac myocytes is an early manifestation in the pathogenesis of type 2 diabetes mellitus and is evident in the absence of heart failure.

Forgotten but Not Gone The Rediscovery of Fatty Heart, the Most Common Unrecognized Disease in America

Article

Nov 2007
CIRC RES

Until 60 years ago, fatty heart was an accepted clinical entity. Since then, its very existence has been questioned, despite the fact that 2 of 3 Americans are now obese or overweight and obesity has been shown to be correlated with cardiac functional abnormalities. In 2000, a syndrome of "lipotoxic cardiomyopathy" resembling earlier pathologic descriptions of fatty human hearts was described in rodents, and fatty infiltration of cardiomyocytes was subsequently reported in patients with congestive failure. Now, magnetic resonance spectroscopy has been adapted to permit routine noninvasive screening for fatty heart. The use of this technique in human volunteers indicates that cardiomyocyte fat correlates well with body mass index and is elevated in uncomplicated obesity. It is more severe when glucose tolerance becomes abnormal or diabetes is present. It is associated with impaired diastolic filling, even in seemingly asymptomatic obese volunteers. Because fatty heart can be readily prevented by lifestyle modification and pharmacologic interventions that reduce caloric intake and increase fatty acid oxidation, it seems important to recognize its existence so as to intervene as early as possible.

Abdominal Obesity and the Metabolic Syndrome: Contribution to Global Cardiometabolic Risk

Article

Jul 2008
ARTERIOSCL THROM VAS

There is currently substantial confusion between the conceptual definition of the metabolic syndrome and the clinical screening parameters and cut-off values proposed by various organizations (NCEP-ATP III, IDF, WHO, etc) to identify individuals with the metabolic syndrome. Although it is clear that in vivo insulin resistance is a key abnormality associated with an atherogenic, prothrombotic, and inflammatory profile which has been named by some the "metabolic syndrome" or by others "syndrome X" or "insulin resistance syndrome", it is more and more recognized that the most prevalent form of this constellation of metabolic abnormalities linked to insulin resistance is found in patients with abdominal obesity, especially with an excess of intra-abdominal or visceral adipose tissue. We have previously proposed that visceral obesity may represent a clinical intermediate phenotype reflecting the relative inability of subcutaneous adipose tissue to act as a protective metabolic sink for the clearance and storage of the extra energy derived from dietary triglycerides, leading to ectopic fat deposition in visceral adipose depots, skeletal muscle, liver, heart, etc. Thus, visceral obesity may partly be a marker of a dysmetabolic state and partly a cause of the metabolic syndrome. Although waist circumference is a better marker of abdominal fat accumulation than the body mass index, an elevated waistline alone is not sufficient to diagnose visceral obesity and we have proposed that an elevated fasting triglyceride concentration could represent, when waist circumference is increased, a simple clinical marker of excess visceral/ectopic fat. Finally, a clinical diagnosis of visceral obesity, insulin resistance, or of the metabolic syndrome is not sufficient to assess global risk of cardiovascular disease. To achieve this goal, physicians should first pay attention to the classical risk factors while also considering the additional risk resulting from the presence of abdominal obesity and the metabolic syndrome, such global risk being defined as cardiometabolic risk.

Shedding light on the enigma of myocardial lipotoxicity: the involvement of known and putative regulators of fatty acid storage and mobilization

Jan 2010
897-908

Dn Brindley
Bp Kok
Pc Kienesberger
R Lehner
Jr Dyck

Brindley DN, Kok BP, Kienesberger PC, Lehner R, Dyck JR. Shedding light on the enigma of myocardial lipotoxicity: the involvement of known and putative regulators of fatty acid storage and mobilization. Am J Physiol Endocrinol Metab. 2010;298:E897-E908.

Jan 2011
CARDIOVASC RES
10-18

T Van De Weijer
Vb Schrauwen-Hinderling
P Schrauwen

van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res. 2011; 92:10-18.

Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population

Jan 2005
462-468

Ls Szcepaniak
P Nurenberg
D Leonard

Szcepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288:E462-E468.

Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels

Jan 2006
4689-4695

M Kankaanpää
Hr Lehto
Jp Pä Rkkä

Kankaanpää M, Lehto HR, Pä rkkä JP, et al. Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels. J Clin Endocrinol Metab. 2006;91:4689-4695.

Cardiac Steatosis Associates With Visceral Obesity in Nondiabetic Obese Men

Abstract

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