Circulating total and H-specific GDF15 levels are elevated in subjects with MASLD but not in hyperlipidemic but otherwise metabolically healthy subjects with obesity.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD. METHODS: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed. RESULTS: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders. CONCLUSION: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946.

A Hematoma in the Anterior Abdominal Muscle in a Woman Receiving Venlafaxine: A Literature Review of the Reports on Similar Cases.

INTRODUCTION: Venlafaxine (VEN) is a selective norepinephrine reuptake inhibitor (SNRI) that mainly helps treat major depressive disorder and anxiety and panic disorders. It works by inhibiting the reuptake of serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA) by presynaptic neurons. Additionally, VEN administration has been linked with a bleeding predisposition that may be due to the inhibition of NA and 5-HT uptake by platelets which have their own receptors on their surface and are implicated in platelet aggregation. CASE PRESENTATION: Herein, we report a case of a 54-year-old patient treated with VEN, who presented with a hematoma in the anterior abdominal muscle. We also present the observational studies and case reports highlighting the association of SNRIs use with various hemorrhagic complications ranging from gastrointestinal hemorrhage or vaginal bleeding to bleeding during or after surgery due to either thrombocytopenia or impaired platelet aggregation. CONCLUSION: Given the cases of either reductions in the platelet count or impairment of platelet activity accompanied by bleeding events, every clinician should be aware of these possible adverse effects when prescribing SNRIs.

Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality?

Diabetes mellitus is a major risk factor for cardiovascular morbidity and mortality. Current therapeutic strategies have not provided constant beneficial cardiovascular-related results. Sodium-glucose co-transporters 2 (SGLT-2) inhibitors have emerged as a novel antidiabetic class of drugs that exert favourable results in a variety of other cardiovascular risk factors too, such as increased blood pressure and body weight. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) study was the first trial that evaluated cardiovascular outcomes in patients with diabetes with the use of empagliflozin, a member of this new class of drugs. Empagliflozin was associated with remarkable reduction of cardiovascular morbidity and mortality and all-cause death. On the contrary, stroke incidence was slightly increased, although the result did not reach statistical significance. It could be assumed that a drug providing such beneficial effects on cardiovascular outcomes, would have also the same impact in stroke risk. This finding could theoretically be attributed to 'play of chance'. However, an increase of haematocrit was observed in EMPA-REG and other SGLT-2 inhibitors studies. Accumulating evidence suggests a direct association between increased haematocrit and stroke risk. Could this 'stroke paradox' be a result of the increased haematocrit levels noted with SGLT-2 inhibitors? The aim of this review is to critically assess both possibilities, given that increased stroke rates (if indeed true) should not be neglected and unattended.

Predictive value of the ankle brachial index in patients with acute ischemic stroke.

BACKGROUND: Peripheral arterial disease (PAD) is frequently present in patients with acute ischemic stroke. However, there are limited data regarding the association between ankle brachial index (ABI) ≤ 0.90 (which is diagnostic of PAD) or > 1.40 (suggesting calcified arteries) and the severity of stroke and in-hospital outcome in this population. We aimed to evaluate these associations in patients with acute ischemic stroke. PATIENTS AND METHODS: We prospectively studied 342 consecutive patients admitted for acute ischemic stroke (37.4 % males, mean age 78.8 ± 6.4 years). The severity of stroke was assessed with the National Institutes of Health Stroke Scale (NIHSS)and the modified Rankin scale (mRS) at admission. The outcome was assessed with the mRS and dependency (mRS 2 - 5) at discharge and in-hospital mortality. RESULTS: An ABI ≤ 0.90 was present in 24.6 % of the patients whereas 68.1 % had ABI 0.91 - 1.40 and 7.3 % had ABI > 1.40. At admission, the NIHSS score did not differ between the 3 groups (10.4 ± 10.6, 8.3 ± 9.3 and 9.3 ± 9.4, respectively). The mRS score was also comparable in the 3 groups (3.6 ± 1.7, 3.1 ± 1.8 and 3.5 ± 2.3, respectively). At discharge, the mRS score did not differ between the 3 groups (2.9 ± 2.2, 2.3 ± 2.1 and 2.7 ± 2.5, respectively) and dependency rates were also comparable (59.5, 47.6 and 53.3 %, respectively). In-hospital mortality was almost two-times higher in patients with ABI ≤ 0.90 than in patients with ABI 0.91 - 1.40 or > 1.40 but this difference was not significant (10.9, 6.6 and 6.3 %, respectively). CONCLUSIONS: An ABI ≤ 0.90 or > 1.40 does not appear to be associated with more severe stroke or worse in-hospital outcome in patients with acute ischemic stroke.

Relative Energy Deficiency in sport (REDs): Endocrine manifestations, pathophysiology and treatments.

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on non-pharmacological, behavioral, and lifestyle modifications that target its underlying cause - energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance.

Familial Hypercholesterolemia in the Elderly: An Analysis of Clinical Profile and Atherosclerotic Cardiovascular Disease Burden from the Hellas-FH Registry.

BACKGROUND: Familial hypercholesterolemia (FH) carries a high risk of atherosclerotic cardiovascular disease (ASCVD). As the population ages, the age-related influence on clinical characteristics and outcomes becomes increasingly pertinent. This cross-sectional analysis from the HELLAS-FH registry aims to explore potential differences in clinical characteristics, treatment, ASCVD, and goal achievement between those younger and older than 65 years with FH. RESULTS: A total of 2273 adults with heterozygous FH (51.4% males) were studied. Elderly FH patients (n = 349) had a higher prevalence of ASCVD risk factors, such as hypertension (52.1% vs. 20.9%, p < 0.05) and type 2 diabetes (16.9% vs. 6.0%, p < 0.05), compared to younger patients (n = 1924). They also had a higher prevalence of established ASCVD (38.4% vs. 23.1%, p < 0.001), particularly CAD (33.0% vs. 20.2%, p < 0.001), even after adjusting for major ASCVD risk factors. Elderly patients were more frequently and intensively receiving lipid-lowering treatment than younger ones. Although post-treatment LDL-C levels were lower in elderly than younger patients (125 vs. 146 mg/dL, p < 0.05), both groups had similar attainment of the LDL-C target (3.7% vs. 3.0%). CONCLUSIONS: Elderly FH patients have a higher prevalence of ASCVD, particularly CAD. Despite more aggressive treatment, the achievement of LDL-C targets remains very poor. These results emphasize the importance of early FH diagnosis and treatment in reducing ASCVD.

Obesity and atherosclerotic cardiovascular disease in adults with heterozygous familial hypercholesterolemia: An analysis from HELLAS-FH registry.

BACKGROUND: Familial hypercholesterolemia (FH) and obesity are well-established risk factors of atherosclerotic cardiovascular disease (ASCVD). Despite high prevalence, their joint association with ASCVD remains largely unknown. OBJECTIVE: To investigate the association of obesity with prevalent ASCVD in individuals with heterozygous FH (HeFH) enrolled in the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). METHODS: FH diagnosis was based on Dutch Lipid Clinic Network (DLCN) criteria. Adults with at least possible FH diagnosis (DLCN score ≥3) and available body mass index (BMI) values were included. Homozygous FH individuals were excluded. RESULTS: 1655 HeFH adults (mean age 51.0 ± 14.4 years, 48.6% female) were included; 378 (22.8%) and 430 (26.0%) were diagnosed with probable and definite FH, respectively. Furthermore, 371 participants (22.4%) had obesity and 761 (46.0%) were overweight. Prevalence of ASCVD risk factors increased progressively with BMI. Prevalence of coronary artery disease (CAD) was 23.4% (3.2% for stroke and 2.7% for peripheral artery disease [PAD]), and increased progressively across BMI groups. After adjusting for traditional ASCVD risk factors and lipid-lowering medication, individuals with obesity had higher odds of established CAD (OR: 1.54, 95% CI: 1.04-2.27, p = 0.036) as well as premature CAD (OR: 1.74, 95% CI: 1.17-2.60, p = 0.009) compared with those with normal BMI. No association was found with stroke or PAD. CONCLUSIONS: Over half of adults with HeFH have overweight or obesity. Obesity was independently associated with increased prevalence of CAD in this population.

Physical signs and atherosclerotic cardiovascular disease in familial hypercholesterolemia: the HELLAS-FH Registry.

AIMS: Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals. METHODS: Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD. RESULTS: Adult patients ( n  = 2156, mean age 50 ±â€Š15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets. CONCLUSION: The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD.

Novel Dual Endothelin Inhibitors in the Management of Resistant Hypertension.

Resistant hypertension (RH) is defined as the failure to achieve blood pressure control despite using triple combination therapy with a renin-angiotensin system inhibitor (RAS-i), a calcium antagonist, and a diuretic. The endothelin (ET) system is implicated in the regulation of vascular tone, primarily through vasoconstriction, intervenes in cardiac contractility with inotropic effects, and contributes to water and sodium renal reabsorption. ET inhibitors, currently approved for the treatment of pulmonary hypertension, seem to be also useful for essential hypertension and RH as well. Studies into the development of new dual ET inhibitors, which inhibit both type A and B ET (ETA and ETB) receptors, present initial results of managing RH. Aprocitentan (ACT-132577) is a novel, orally active and well tolerated dual ET receptor antagonist, which has been examined in several experimental studies and clinical trials with promising results for RH control. The recent publication of the large PRECISION study in The Lancet journal provides further reassurance regarding the efficacy and safety of aprocitentan for RH, with the aim of overcoming unmet needs in the management of this difficult group of patients.

Obesity and diabetes.

Obesity, which has currently reached pandemic dimensions, is usually accompanied by diabetes mellitus type 2 (T2DM). These two conditions share common pathophysiological mechanisms. Adipose tissue secretes cytokines which are involved in inflammation and various endocrine functions. As for T2DM, it is characterized also by inflammation, mitochondrial dysfunction, and hyperinsulinemia. These conditions occur also in other diseases related to obesity and T2DM, like cardiovascular disease (CVD) and nonalcoholic fatty liver disease (NAFLD). Thus, management of obesity-related complications with lifestyle modification, anti-obesity drugs, and bariatric surgery, all contribute to improvement in any of these conditions. This review provides an overview of the literature addressing the association between obesity and T2DM, briefly discussing the pathophysiological mechanisms linking these conditions and outlining the management approach at the overlap of obesity and T2DM.

Prevention of cardiovascular disease in young adults: Focus on gender differences. A collaborative review from the EAS Young Fellows.

A steady rise in cardiovascular morbidity and mortality has been observed in young adults within the last decades. This trend corresponds to an increasing prevalence of traditional cardiovascular risk factors such as obesity and diabetes mellitus type 2 among young adults living in developed countries. Moreover, age-specific risk factors, such as substance abuse, contraceptive medication, and pregnancy-related diseases also correlate with an increased incidence of cardiovascular diseases. In this review, we discuss the available data for young adults on the epidemiology and the rationale for the causality of traditional and newly emerging risk factors of atherosclerotic cardiovascular diseases. We focus on gender-related differences in the exposure to these risk factors, investigate the recent data regarding screening and risk stratification in the young adult population, and describe the current state of the art on lifestyle and therapeutic intervention strategies in the primary prevention setting.

A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on.

The WHO just released in May 2022 a report on the state of the obesity pandemic in Europe, stating that 60% of citizens in the area of Europe are either overweight or obese, and highlighting the implications of the obesity pandemic, especially as it interacts with the COVID pandemic to create a twin pandemic, to increase morbidity and mortality. Obesity is a complex disease which has reached pandemic dimensions. The worldwide prevalence of obesity has nearly tripled since 1975, mainly due to the adoption of a progressively more sedentary lifestyle and the consumption of less healthy diets. We first report herein updated prevalence rates of overweight and obesity by sex, age, and region first in Europe, per the WHO report, and then worldwide between 1980 and 2019, as we analyze and present herein the data provided by the Global Burden of Disease Study. The prevalence of obesity is higher in women than in men of any age and the prevalence of both overweight and obesity increases with age and has reached their highest point between the ages of 50 to 65 years showing a slight downward trend afterwards. The age-standardized prevalence of obesity has increased from 4.6% in 1980 to 14.0% in 2019. The American and European region have the highest obesity prevalence and the USA and Russia are the countries with the most obese residents. Given dire implications in terms of comorbidities and mortality, these updated epidemiological findings call for coordinated actions from local and regional governments, the scientific community and individual patients alike, as well as the food industry for the obesity pandemic to be controlled and alleviated. We can hopefully learn from the COVID-19 pandemic, where collaborative efforts worldwide, focused intense work at both the local and global level and well-coordinated leadership have demonstrated that humankind is capable of amazing accomplishments by leveraging science and public health, and that we can finally make strides in terms of understanding and combating the obesity pandemic and its dire comorbidities including diabetes, NAFLD, CVD and obesity associated malignancies.

Humanin and diabetes mellitus: A review of in vitro and in vivo studies.

Humanin (HN) is a 24-amino acid mitochondrial-derived polypeptide with cyto-protective and anti-apoptotic effects that regulates the mitochondrial functions under stress conditions. Accumulating evidence suggests the role of HN against age-related diseases, such as Alzheimer's disease. The decline in insulin action is a metabolic feature of aging and thus, type 2 diabetes mellitus is considered an age-related disease, as well. It has been suggested that HN increases insulin sensitivity, improves the survival of pancreatic beta cells, and delays the onset of diabetes, actions that could be deployed in the treatment of diabetes. The aim of this review is to present the in vitro and in vivo studies that examined the role of HN in insulin resistance and diabetes and to discuss its newly emerging role as a therapeutic option against those conditions.

Statins' efficacy in non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is closely related with the metabolic syndrome and cardiovascular disease. Currently there is no approved medication for NAFLD. Although it has been suggested that statins can be safely used by patients with elevated liver enzymes, their effect on NAFLD has not been clearly defined. The aim of this study is to evaluate the effectiveness of statins on biochemical and histological parameters in patients with NAFLD. METHODS: We searched PubMed, Web of Science, and SCOPUS for clinical trials and observational studies concerning the effects of statins on the development and treatment of NAFLD, regardless of the type or dosage of statin, the duration of treatment or the methods used for the diagnosis of NAFLD (biopsy or imaging technique) up to November 2021. RESULTS: We identified 13 studies. Liver function tests and lipid profile were significantly improved. There was a significant decrease in steatosis grade (standardized mean difference, SMD -1.73, 95% CI -2.11 to -1.35; p < 0.00001; I2 = 98%) and in NAFLD activity score (NAS) (SMD -1.09 (95% CI -1.39 to -0.79; p < 0.00001; I2 = 93%)). CONCLUSIONS: Statins effectively decrease liver enzymes and beneficially affect liver histology in NAFLD patients.

The effect of dietary patterns on non-alcoholic fatty liver disease diagnosed by biopsy or magnetic resonance in adults: a systematic review of randomised controlled trials.

Adhering to specific dietary patterns might hold promise as a lifestyle modification treatment of non-alcoholic fatty liver disease (NAFLD). The aim of this systematic review was to examine the effect of dietary patterns on changes in hepatic fat content, liver enzymes and metabolic syndrome components. We searched Pubmed, Embase, CINAHL and Web of Science for randomised controlled trials published in English until April 2020, comparing a specific dietary pattern with no treatment, usual care, or a different diet in adults with NAFLD. Studies were included if NAFLD had been diagnosed using biopsy, magnetic resonance imaging, or proton magnetic resonance spectroscopy. Data from three trials in adults with NAFLD but without diabetes (n = 128; mean age 49.9 ±â€¯5.0 years, range 42-55 years) were included in the qualitative synthesis; across them, risk of bias was considered low, unclear and high for 33%, 38% and 29% of domains, respectively. There was moderate evidence that a low-carbohydrate, compared to a low-calorie diet (-27%, P = 0.008, one study, n = 18) and the Mediterranean, compared to a low-fat, high-carbohydrate diet (-4.4%, P = 0.030, one study, n = 12) result in greater reductions in hepatic fat content, but no such evidence was found for the Fatty Liver in Obesity dietary pattern (based on the principles of the Mediterranean diet), compared to the American Heart Association diet (-0.6%, P = 0.706, one study, n = 98). No between-group differences were reported for other outcomes across studies. A post hoc analysis, including two eligible studies assessing the effect of the Mediterranean, compared to a low-fat diet, irrespective of baseline presence of diabetes, showed strong evidence that the Mediterranean diet reduces hepatic fat content (-4.1%, 95% CI = -5.8 to -2.3, P < 0.001; I2 = 0%) and triglyceride concentrations (-16.9 mg/dL, 95% CI = -26.3 to -7.7, P < 0.001; I2 = 0%). Well-designed, adequately powered and rigorous randomised controlled trials are needed to provide robust evidence on the effect of these dietary patterns, but also other whole dietary approaches, on NAFLD progression.