Cardio-Metabolic Disorders in Non-Alcoholic Fatty Liver Disease.

With the progressive epidemics of obesity, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in adults and children. The increasing prevalence and incidence of NAFLD with advanced fibrosis is concerning because patients appear to experience higher non-liver-related morbidity and mortality than the general population. Recent clinical evidence suggests that NAFLD is directly associated with an increased risk of cardio-metabolic disorders. This mini review describes briefly the current understanding of the pathogenesis of NAFLD, summarizing the link between NAFLD and cardio-metabolic complications, focusing mainly upon ischemic stroke, type 2 diabetes mellitus (DM), hypertension, chronic kidney disease (CKD) and cardiac arrhythmias. In addition, it describes briefly the current understanding of the pathogenesis of NAFLD.

Antioxidant, Anti-Inflammatory, and Metabolic Properties of Tocopherols and Tocotrienols: Clinical Implications for Vitamin E Supplementation in Diabetic Kidney Disease.

Diabetes mellitus is a metabolic disorder characterized by the development of vascular complications associated with high morbidity and mortality and the consequent relevant costs for the public health systems. Diabetic kidney disease is one of these complications that represent the main cause of end-stage renal disease in Western countries. Hyperglycemia, inflammation, and oxidative stress contribute to its physiopathology, and several investigations have been performed to evaluate the role of antioxidant supplementation as a complementary approach for the prevention and control of diabetes and associated disturbances. Vitamin E compounds, including different types of tocopherols and tocotrienols, have been considered as a treatment to tackle major cardiovascular outcomes in diabetic subjects, but often with conflicting or even negative results. However, their effects on diabetic nephropathy are even less clear, despite several intervention studies that showed the improvement of renal parameters after supplementation in patients with diabetic kidney disease. Then we performed a review of the literature about the role of vitamin E supplementation on diabetic nephropathy, also describing the underlying antioxidant, anti-inflammatory, and metabolic mechanisms to evaluate the possible use of tocopherols and tocotrienols in clinical practice.

Systemic and Local Adipose Tissue in Knee Osteoarthritis.

Osteoarthritis is a common chronic joint disorder affecting older people. The knee is the major joint affected. The symptoms of osteoarthritis include limited range of motion, joint swelling, and pain causing disability. There are no disease modifying drugs available, and treatments are mainly focused on pain management. Total knee replacement performed at the end stage of the disease is considered the only cure available. It has been found that obese people have an increased risk to develop not only knee but also hand osteoarthritis. This supports the concept that adipose tissue might be related to osteoarthritis not only through overloading. As matter of fact, obesity induces a low grade systemic inflammatory state characterized by the production and secretion of several adipocytokines that may have a role in osteoarthritis development. Furthermore, hypertension, impaired glucose, and lipid metabolism, which are comorbidities associated with obesity, have been shown to alter the joint tissue homeostasis. Moreover, infrapatellar fat pad in the knee has been demonstrated to be a local source of adipocytokines and potentially contribute to osteoarthritis pathogenesis. Here, we discuss the role of systemic and local adipose tissue in knee osteoarthritis. J. Cell. Physiol. 232: 1971-1978, 2017. © 2016 Wiley Periodicals, Inc.

Infrapatellar fat pad features in osteoarthritis: a histopathological and molecular study.

Objective: The infrapatellar fat pad (IFP) is considered a local producer of adipocytokines, suggesting a potential role in OA. The objective of this study was to evaluate the histopathological and molecular characteristics of OA IFPs compared with controls. Methods: The histopathological characteristics of IFPs were evaluated in patients undergoing total knee replacements and in control patients (without OA), considering the following parameters: presence of inflammatory cells, vascularization, adipose lobules dimension and thickness of the interlobular septa. Immunohistochemistry was performed to evaluate VEGF, monocyte chemotactic protein 1 (MCP-1) and IL-6 proteins. Quantitative real time PCR was performed to evaluate the expression levels of adipocytokines in the OA IFPs. Results: OA IFPs showed an increase in inflammatory infiltration, vascularization and thickness of the interlobular septa compared with controls. VEGF, MCP-1 and IL-6 proteins were higher in OA IFPs compared with in controls. Inflammatory infiltration, hyperplasia, vascularization and fibrosis were increased in OA IFP synovial membranes compared with in those of controls. VEGF protein levels were associated with an increased number of vessels in the OA IFPs, while MCP-1 and IL-6 protein levels were associated with higher grades of inflammatory infiltration. Leptin levels were positively correlated with adiponectin and MCP-1expression, while adiponectin positively correlated with peroxisome proliferative activated receptor gamma, MCP-1 and IFP vascularity. MCP-1 showed a positive correlation with peroxisome proliferative activated receptor gamma. IFP lobules dimensions were positively correlated with IL-6 expression and negatively with thickness of interlobular septa. VEGF mRNA levels were positively correlated with increased synovial vascularity. Conclusions: OA IFPs and synovial membranes are more inflamed, vascularized and fibrous compared with those of control patients (without OA).

Urinary metabolic profiling by 1H NMR spectroscopy in patients with cirrhosis may discriminate overt but not covert hepatic encephalopathy.

To date urinary metabolic profiling has been applied to define a specific metabolic fingerprint of hepatocellular carcinoma on a background of cirrhosis. Its utility for the stratification of other complications of cirrhosis, such as hepatic encephalopathy (HE), remains to be established. Urinary proton nuclear magnetic resonance (1H-NMR) spectra were acquired and NMR data from 52 patients with cirrhosis (35 male; 17 female, median (range) age [60 (18-81) years]) and 17 controls were compared. A sub-set of 45 patients (33 male; 12 female, [60 (18-90) years, median model for end stage liver disease (MELD) score 11 (7-27)]) were fully characterised by West-Haven criteria, Psychometric Hepatic Encephalopathy Score (PHES) and electroencephalogram (EEG), and defined as overt HE (OHE, n = 21), covert HE (cHE, n = 7) or no HE (n = 17). Urinary proton nuclear magnetic resonance (1H-NMR) spectra were analysed by partial-least-squares discriminant analysis (PLS-DA). The results showed good discrimination between patients with cirrhosis (n = 52) and healthy controls (n = 17) (R2X = 0.66, R2Y = 0.47, Q2Y = 0.31, sensitivity-60 %, specificity-100 %) as the cirrhosis group had higher 1-methylnicotinamide with lower hippurate, acetate, phenylacetylglycine and N-methyl nicotinic acid levels. While patients with OHE could be discriminated from those with no HE, with higher histidine, citrate and creatinine levels, the best models lack robust validity (R2X = 0.65, R2Y = 0.48, Q2Y = 0.12, sensitivity-100 %, specificity-64 %) with the sample size used. Urinary 1H-NMR metabolic profiling did not discriminate patients with cHE from those without HE, nor discriminate subjects on the basis of PHES/EEG result or MELD score. In conclusion, patients with cirrhosis showed different urinary 1H-NMR metabolic profiles compared to healthy controls and those with OHE may be distinguished from those with no HE although larger studies are required. However, urinary 1H-NMR metabolic profiling did not discriminate patients with differing grades of HE or according to severity of underlying liver disease.

Hypertrophic, Dilated, and Arrhythmogenic Cardiomyopathy: Where Are We?

Cardiomyopathies are a heterogeneous group of structural, mechanical, and electrical heart muscle disorders which often correlate with life-threatening arrhythmias and progressive heart failure accounting for significant cardiovascular morbidity and mortality. Currently, cardiomyopathies still represent a leading reason for heart transplantation worldwide. The last years have brought remarkable advances in the field of cardiomyopathies especially in terms of understanding the molecular basis as well as the diagnostic evaluation and management. Although most cardiomyopathy treatments had long focused on symptom management, much of the current research efforts aim to identify and act on the disease-driving mechanisms. Regarding risk assessment and primary prevention of sudden cardiac death, additional data are still pending in order to pave the way for a more refined and early patient selection for defibrillator implantation. This review summarizes the current knowledge of hypertrophic, dilated and arrhythmogenic cardiomyopathy with a particular emphasis on their pathophysiology, clinical features, and diagnostic approach. Furthermore, the relevant ongoing studies investigating novel management approaches and main gaps in knowledge are highlighted.

Interrater variability of ML-based CT-FFR during TAVR-planning: influence of image quality and coronary artery calcifications.

Objective: To compare machine learning (ML)-based CT-derived fractional flow reserve (CT-FFR) in patients before transcatheter aortic valve replacement (TAVR) by observers with differing training and to assess influencing factors. Background: Coronary computed tomography angiography (cCTA) can effectively exclude CAD, e.g. prior to TAVR, but remains limited by its specificity. CT-FFR may mitigate this limitation also in patients prior to TAVR. While a high reliability of CT-FFR is presumed, little is known about the reproducibility of ML-based CT-FFR. Methods: Consecutive patients with obstructive CAD on cCTA were evaluated with ML-based CT-FFR by two observers. Categorization into hemodynamically significant CAD was compared against invasive coronary angiography. The influence of image quality and coronary artery calcium score (CAC) was examined. Results: CT-FFR was successfully performed on 214/272 examinations by both observers. The median difference of CT-FFR between both observers was -0.05(-0.12-0.02) (p < 0.001). Differences showed an inverse correlation to the absolute CT-FFR values. Categorization into CAD was different in 37/214 examinations, resulting in net recategorization of Δ13 (13/214) examinations and a difference in accuracy of Δ6.1%. On patient level, correlation of absolute and categorized values was substantial (0.567 and 0.570, p < 0.001). Categorization into CAD showed no correlation to image quality or CAC (p > 0.13). Conclusion: Differences between CT-FFR values increased in values below the cut-off, having little clinical impact. Categorization into CAD differed in several patients, but ultimately only had a moderate influence on diagnostic accuracy. This was independent of image quality or CAC.

Relationship between Heart Disease and Liver Disease: A Two-Way Street.

In clinical practice, combined heart and liver dysfunctions coexist in the setting of the main heart and liver diseases because of complex cardiohepatic interactions. It is becoming increasingly crucial to identify these interactions between heart and liver in order to ensure an effective management of patients with heart or liver disease to provide an improvement in overall prognosis and therapy. In this review, we aim to summarize the cross-talk between heart and liver in the setting of the main pathologic conditions affecting these organs. Accordingly, we present the clinical manifestation, biochemical profiles, and histological findings of cardiogenic ischemic hepatitis and congestive hepatopathy due to acute and chronic heart failure, respectively. In addition, we discuss the main features of cardiac dysfunction in the setting of liver cirrhosis, nonalcoholic fatty liver disease, and those following liver transplantation.

The P2X7 Receptor and NLRP3 Axis in Non-Alcoholic Fatty Liver Disease: A Brief Review.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and its prevalence is reaching epidemic characteristics both in adults and in children. The increase of NAFLD prevalence parallels that of obesity, now representing the major cause of liver inflammation, increasing the risk of cirrhosis and hepatocarcinoma. Furthermore, NAFLD is a risk factor for cardiovascular diseases and type 2 diabetes, two of the major leading causes of morbidity and mortality in western countries. Thus a significant amount of studies have dealt with the evaluation of the possible molecular mechanisms leading to NAFLD and its inflammatory consequences within the liver, the non-alcoholic steatohepatitis, and cirrhosis. The inflammasome is a key player in the inflammation and fibrogenic responses in many different tissues, including the liver. The activation of the NLRP3 inflammasome requires the activation by extracellular adenosine tri-phosphate (ATP) of a specific purinergic receptor named P2X7 located in the target cells, although other pathways have been described. To this regard, extracellular ATP acts as an internal danger signal coming from damaged cells participating in the activation of the inflammatory process, a signaling pathway common to many different tissues. Here, we briefly review the involvement of the P2X7 receptor/inflammasome NLRP3 axis in the pathophysiological events leading to NAFLD and its inflammatory and fibrotic evolutions, reporting the possible therapeutical strategies targeting the P2X7 receptor/NLRP3 inflammasome.

Cardiomyocyte mitochondrial dysfunction in diabetes and its contribution in cardiac arrhythmogenesis.

Cardiovascular disease is the leading cause of diabetes-related morbidity and mortality. It is widely accepted that heart failure risk is increased in diabetic patients even after adjusting for coronary artery disease and hypertension. Mitochondria are the center of fatty acid (FA) and glucose metabolism and thus are likely to be impacted by impaired metabolism associated with diabetes. Although the cause of this increased heart failure risk is multifactorial, increasing evidence points toward a crucial role for cardiomyocyte mitochondria dysfunction. Altered energy metabolism, defects in mitochondrial dynamics, increased oxidative stress, impaired calcium (Ca2+) handling and mitochondria-induced cell death are observed in mitochondria of diabetic myocardium. In addition, mitochondrial dysfunction appears to contribute substantially to the origin of arrhythmias in diabetic hearts. The current review will describe these mitochondrial abnormalities in cardiomyocytes attempting to provide an overview of underlying mechanisms. Finally, we briefly discuss the potential link between mitochondrial malfunction and arrhythmogenesis.

Vitamin E as a Treatment for Nonalcoholic Fatty Liver Disease: Reality or Myth?

Obesity is one of the major epidemics of this millennium, and its incidence is growing worldwide. Following the epidemics of obesity, nonalcoholic fatty liver disease (NAFLD) has become a disease of increasing prevalence and a leading cause of morbidity and mortality closely related to cardiovascular disease, malignancies, and cirrhosis. It is believed that oxidative stress is a main player in the development and progression of NAFLD. Currently, a pharmacological approach has become necessary in NAFLD because of a failure to modify lifestyle and dietary habits in most patients. Vitamin E is a potent antioxidant that has been shown to reduce oxidative stress in NAFLD. This review summarizes the biological activities of vitamin E, with a primary focus on its therapeutic efficacy in NAFLD.

Food Ingredients Involved in White-to-Brown Adipose Tissue Conversion and in Calorie Burning.

Obesity is the consequence of chronic positive energy balance and considered a leading risk factor for cardiovascular and metabolic diseases. Due to its epidemic trends among children and adults, there is an increasing interest in implementing new therapeutic interventions to tackle overweight and obesity. Activation of brown adipose tissue (BAT) represents today a promising strategy to enhance energy expenditure (EE) through heat production. More recently, "browning" of white adipose tissue (WAT) has gained increasing attention in research area as an alternative method in stimulating energy dissipation. This minireview aims to summarize the current knowledge of some dietary compounds that have been shown to promote BAT activation and WAT browning with subsequent beneficial health effects.

Functional imaging of brown adipose tissue in human.

Obesity has become a major public health challenge and an increasing trend is seen in its prevalence worldwide. It is a complex disorder involving an excessive amount of body fat as a result of an energy imbalance leading to caloric overload. Since the discovery of functional brown adipose tissue (BAT) in adult humans, with energy dissipating properties, this thermogenic tissue has thus emerged as an attractive therapeutic target to combat obesity and related cardiometabolic disorders. The advancements in imaging modalities to evaluate organ-specific metabolism in humans is substantially contributing to understand the physiological role of BAT. This review presents an overview of the different imaging approaches implied in BAT assessment, with a special emphasis on adult human BAT. In this context, we also attempted to summarize the developmental origins and physiology of BAT.

Infrared thermography for indirect assessment of activation of brown adipose tissue in lean and obese male subjects.

Brown adipose tissue (BAT) plays a key role in adaptive thermogenesis in mammals, and it has recently been considered as an attractive therapeutic target for tackling human obesity by increasing energy expenditure. Thermal imaging using infrared thermography (IRT) has emerged as a potential safe, rapid and inexpensive technique for detecting BAT in humans. However, little attention has been given to the reliability of this method in obese subjects. To this end, we evaluated the capacity of IRT to detect activated supraclavicular (SCV) BAT in 14 lean and 16 mildly obese young adults after acute cold exposure. Using IRT we measured the temperature of the skin overlying the SCV and sternal areas at baseline and after acute cold stimulation. Additionally, energy expenditure was measured by indirect calorimetry and body composition was estimated using bioelectrical impedance analysis. Energy expenditure and SCV skin temperature significantly increased in lean subjects upon cold exposure, while no significant changes were detected in the obese group. Furthermore, cold-induced variations in SCV skin temperature of obese subjects showed a negative correlation with body mass index. This study suggests that in lean individuals BAT is a rapidly activated thermogenic tissue possibly involved in the regulation of energy balance, and can be indirectly assessed using IRT. In obese subjects, BAT seems less prone to be activated by cold exposure, with the degree of adiposity representing a limiting factor for the indirect detection of BAT activation by measuring the skin temperature overlying BAT.