Advances in the Pathogenesis of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is both a frequent complication of diabetes mellitus (DM) [...].

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.

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.

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.

Epidemiology and Risk Factors for Stroke in Chronic Kidney Disease: A Narrative Review.

Patients with chronic kidney disease (CKD) have a higher risk ofboth ischemic and hemorrhagic stroke. This association appears to be partly independent from the higher prevalence of established risk factors for stroke in patients with CKD, including hypertension and atrial fibrillation. In the present review we aim to discuss the impact of CKD on the risk of stroke and stroke-related consequences, and explore the pathophysiology underpinning the increased risk of stroke in patients with CKD. We cover the clinical association between renal dysfunction and cerebrovascular disease including stroke, silent brain infarct, cerebral small vessel disease, microbleeds, and white matter hyperintensity, and discuss the underlying mechanisms.

The Role of Histone Modifications in the Pathogenesis of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. The pathogenesis of DKD is multifactorial, with several molecular pathways implicated. Recent data suggest that histone modification plays an important role in the development and progression of DKD. Histone modification appears to induce oxidative stress, inflammation and fibrosis in the diabetic kidney. In the present review, we summarize the current knowledge on the association between histone modification and DKD.

Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Markers of Vascular Damage.

BACKGROUND: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular morbidity and delay the progression of kidney disease in patients with type 2 diabetes mellitus (T2DM). However, the mechanisms underpinning these benefits are not entirely clear. More specifically, it is uncertain whether these agents exert cardiorenal protective effects through a direct action on the vascular wall. The aim of the present study was to evaluate the effects of SGLT2 inhibitors on markers of subclinical vascular damage. METHODS: In total, 40 adult patients with T2DM and glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 and age- and gender-matched patients with T2DM and GFR > 60 mL/min/1.73 m2 were consecutively enrolled. Indices of arterial stiffness (pulse wave velocity, augmentation index (AIx), AIx adjusted to a heart rate of 75 beats/min (Alx@75) and central systolic, diastolic, pulse and mean pressure), carotid atherosclerosis (stenosis, intima-media thickness (cIMT) and maximal plaque thickness) and peripheral arterial disease (ankle brachial index (ABI)) were determined. The chi-squared and Mann-Whitney U-test were used to detect differences in categorical and continuous variables between groups, respectively. RESULTS: In total, 15 patients were treated with SGLT2 inhibitors and 25 patients were not receiving these agents. Serum low-density lipoprotein cholesterol levels were lower in the former whereas other cardiovascular risk factors, the prevalence of established cardiovascular disease, anthropometric and demographic characteristics, and vital signs did not differ between the 2 groups. The AIx was lower in patients treated with SGLT2 inhibitors (21.9 ± 11.3 vs. 29.7 ± 12% in patients not treated with SGLT2 inhibitors; p < 0.05). The AIx@75 was also lower in the former (21.3 ± 10.9 and 32.6 ± 11.3%, respectively, p < 0.005). Other markers of arterial stiffness were similar in the 2 groups. In addition, markers of carotid atherosclerosis and the ABI did not differ between patients treated and not treated with SGLT2 inhibitors. CONCLUSIONS: Treatment with SGLT2 inhibitors appears to reduce arterial stiffness. Accordingly, these agents might improve cardiovascular outcomes not only in patients with T2DM and established cardiorenal disease but also in lower-risk patients.

Microsomal Prostaglandin E Synthase-1 and -2: Emerging Targets in Non-Alcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) affects a substantial proportion of the general population and is even more prevalent in obese and diabetic patients. NAFLD, and particularly the more advanced manifestation of the disease, nonalcoholic steatohepatitis (NASH), increases the risk for both liver-related and cardiovascular morbidity. The pathogenesis of NAFLD is complex and multifactorial, with many molecular pathways implicated. Emerging data suggest that microsomal prostaglandin E synthase-1 and -2 might participate in the development and progression of NAFLD. It also appears that targeting these enzymes might represent a novel therapeutic approach for NAFLD. In the present review, we discuss the association between microsomal prostaglandin E synthase-1 and -2 and NAFLD.

Pharmacological Management of Obesity in Patients with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. A substantial proportion of patients with PCOS are either overweight or obese, and excess body weight aggravates the hormonal, reproductive and metabolic manifestations of PCOS. In recent years, several studies evaluated the role of various pharmacological agents in the management of obesity in this population. Most reports assessed glucagon-like peptide-1 receptor agonists and showed a substantial reduction in body weight. More limited data suggest that sodium-glucose cotransporter-2 inhibitors and phosphodiesterase-4 inhibitors might also be effective in the management of obesity in these patients. In the present review, we discuss the current evidence on the safety and efficacy of these agents in overweight and obese patients with PCOS.

HDL cholesterol efflux capacity and phospholipid content are associated with the severity of acute ischemic stroke and predict its outcome.

BACKGROUND/AIMS: Impaired high-density lipoprotein (HDL) function and composition are more strongly related to cardiovascular morbidity than HDL concentration. However, it is unclear whether HDL function and composition predict ischemic stroke severity and outcome. We aimed to evaluate these associations. METHODS: We prospectively studied 199 consecutive patients who were admitted with acute ischemic stroke. The severity of stroke was evaluated at admission with the National Institutes of Health Stroke Scale (NIHSS). Severe stroke was defined as NIHSS ≥ 5. The outcome was assessed with dependency at discharge (modified Rankin scale 2-5) and in-hospital mortality. Cholesterol efflux capacity (CEC), phospholipid levels, lecithin:cholesterol acyl transferase (LCAT)-phospholipase activity, paraoxonase-1 (PON1)-arylesterase activity and serum amyloid A1 (SAA1) content of HDL were measured. RESULTS: CEC, phospholipid levels and LCAT-phospholipase activity of HDL were lower and SAA1 content of HDL was higher in patients with severe stroke. Patients who were dependent at discharge had lower CEC, PON1-arylesterase activity, phospholipid content and LCAT-phospholipase activity of HDL and higher HDL-SAA1 content. Independent predictors of dependency at discharge were the NIHSS at admission (RR 2.60, 95% CI 1.39-4.87), lipid-lowering treatment (RR 0.17, 95% CI 0.01-0.75), HDL-CEC (RR 0.21, 95% CI 0.05-0.87) and HDL-associated PON1-arylesterase activity (RR 0.95, 95% CI 0.91-0.99). In patients who died during hospitalization, phospholipids, LCAT-phospholipase and PON1-arylesterase activities of HDL were lower. CONCLUSIONS: Changes in CEC and composition of HDL appear to be associated with the severity and outcome of acute ischemic stroke and could represent biomarkers that may inform risk stratification and management strategies in these patients.

Cardiometabolic effects of direct-acting antivirals in patients with hepatitis C / Efectos cardiometabólicos de los antivirales de acción directa en pacientes con hepatitis C

El virus de la hepatitis C (VHC) se ha asociado durante mucho tiempo a varias manifestaciones extrahepáticas, entre ellas el aumento del riesgo cardiovascular. La aparición de los antivirales de acción directa (AAD) ha permitido evaluar la posible reversión de estas manifestaciones tras un tratamiento exitoso. Así, muchos estudios han aportado datos significativos sobre el efecto positivo del tratamiento con AAD en la resistencia a la insulina, la diabetes mellitus de tipo 2, la enfermedad cardiovascular y la aterosclerosis. Por el contrario, los estudios han mostrado efectos perjudiciales sobre el metabolismo de los lípidos y resultados indeterminados respecto a la función renal y el metabolismo del ácido úrico. No obstante, a medida que un mayor número de pacientes logre una respuesta virológica sostenida, se estudiarán ampliamente los efectos de la erradicación del VHC sobre los procesos cardiometabólicos, lo que permitirá obtener conclusiones más fiables sobre el alcance de los resultados extrahepáticos.(AU)

Hepatitis C virus (HCV) has long been associated with several extrahepatic manifestations, including increased cardiovascular risk. The emergence of direct-acting antivirals (DAAs) has allowed us to evaluate the potential reversal of these manifestations after successful treatment. Therefore, many studies have provided significant takeaways regarding the positive effect of DAAs therapy on insulin resistance, type 2 diabetes mellitus, cardiovascular disease and atherosclerosis. In contrast, studies have shown detrimental effects on lipid metabolism and indeterminate results regarding renal function and uric acid metabolism. Nevertheless, as more and more patients achieve sustained virological response, the effects of HCV eradication on cardiometabolic processes will be extensively studied, allowing more reliable conclusions on the extent of extrahepatic outcomes.(AU)

The Role of Novel Antibiotics in the Management of Diabetic Foot Infection.

Diabetic foot infection is a frequent and potentially life-threatening complication of diabetes mellitus. Antibiotic treatment is the cornerstone of management of diabetic foot infection but the rising prevalence of antibiotic resistance has resulted in increasing rates of treatment failure. In this context, the development of several novel antibiotics might represent a useful tool in severe diabetic foot infections caused by multidrug-resistant bacteria. In the present review, we summarize the safety and efficacy of novel antibiotics in patients with diabetic foot infection. Relevant data are limited, and randomized controlled studies that evaluated the role of these agents in this field are lacking. Until more robust data are available, cefiderocol and dalbavancin, which have been studied more extensively in patients with bone infections, might be attractive options in carefully selected patients with severe diabetic foot infection.

Cardiometabolic effects of direct-acting antivirals in patients with hepatitis C.

Hepatitis C virus (HCV) has long been associated with several extrahepatic manifestations, including increased cardiovascular risk. The emergence of direct-acting antivirals (DAAs) has allowed us to evaluate the potential reversal of these manifestations after successful treatment. Therefore, many studies have provided significant takeaways regarding the positive effect of DAAs therapy on insulin resistance, type 2 diabetes mellitus, cardiovascular disease and atherosclerosis. In contrast, studies have shown detrimental effects on lipid metabolism and indeterminate results regarding renal function and uric acid metabolism. Nevertheless, as more and more patients achieve sustained virological response, the effects of HCV eradication on cardiometabolic processes will be extensively studied, allowing more reliable conclusions on the extent of extrahepatic outcomes.

Adiponectin: A player in the pathogenesis of hormone-dependent cancers.

Hormone-dependent cancers are a major cause of morbidity and mortality in both genders. Accumulating evidence suggest that adiponectin, an adipokine with multifaceted functions, is implicated in the pathogenesis of several malignancies. In the present review, we discuss the existing data regarding this relationship. Several observational studies showed that low adiponectin levels are associated with higher risk for breast, cervical, endometrial, ovarian and prostate cancer. A relationship between adiponectin and the aggressiveness of some of these tumors has also been reported. In vitro studies reported that adiponectin inhibits the proliferation and induces apoptosis of breast, cervical, endometrial, ovarian and prostate cancer cells. Given the high prevalence of these cancers and the substantial associated morbidity and mortality, the role of agents that increase adiponectin levels and/or stimulate its activity should be evaluated for the prevention and management of these common tumors.

Considerations for management of patients with diabetes mellitus and acute COVID-19.

Diabetes mellitus (DM) is an independent risk factor for admission to intensive care unit and death in patients with coronavirus disease 2019 (COVID-19). On the other hand, medications used in the management of COVID-19 are potentially associated with increases in blood glucose levels and a higher incidence of infections. Accordingly, care of patients with DM and acute COVID-19 requires careful consideration of both diseases. Hyperglycemia and hypoglycemia are associated with adverse outcomes and therefore frequent measurement of blood glucose levels and a basal-bolus insulin regimen are required in most patients. Regarding the management of COVID-19, dexamethasone increases blood glucose levels and might also increase the risk for infections. On the other hand, limited data suggest that antiviral and immunomodulatory agents used in COVID-19 are not strongly associated with higher incidence of infections in this population. As knowledge evolves in this field, optimization of the management of both DM and COVID-19 will hopefully improve the outcome of these patients.

Hepatic Fibrosis Is a Risk Factor for Greater Severity and Worse Outcome of Acute Ischemic Stroke.

Background: Nonalcoholic fatty liver disease, particularly in the presence of hepatic fibrosis, is associated with an increased risk of cardiovascular events, including ischemic stroke. However, it is unclear whether hepatic fibrosis is associated with the severity and outcome of acute ischemic stroke. Aim: To evaluate the relationship between hepatic fibrosis and the severity at admission and in-hospital outcome of acute ischemic stroke. Patients and methods: We prospectively studied all patients who were admitted to our department with acute ischemic stroke between September 2010 and February 2018 (n = 1107; 42.1% males, age 79.8 ± 7.2 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Severe stroke was defined as NIHSS ≥ 21. The presence of hepatic fibrosis was evaluated with the Fibrosis-4 index (FIB-4). The outcome was assessed with dependency at discharge (modified Rankin Scale between 2 and 5) and with in-hospital mortality. Results: Patients with severe stroke had a higher FIB-4 index than patients with non-severe stroke (2.7 ± 1.7 and 2.3 ± 1.4, respectively; p < 0.05). Independent risk factors for severe IS were age (relative risk (RR) 1.064, 95% confidence interval (CI) 1.030−1.100, p < 0.001), female sex (RR 1.723, 95% CI 1.100−2.698, p = 0.012), atrial fibrillation (RR 1.869, 95% CI 1.234−2.831, p = 0.002), diastolic blood pressure (DBP) (RR 1.019, 95% CI 1.006−1.033, p = 0.001), and the FIB-4 index (RR 1.130, 95% CI 1.007−1.268, p = 0.022). At discharge, 64.2% of patients were dependent. The FIB-4 index did not differ between patients who were dependent and those who were independent at the time of discharge (2.3 ± 1.5 and 2.1 ± 1.2, respectively; p = 0.061). During hospitalization, 9.8% of patients died. Patients who died during hospitalization had a higher FIB-4 index than those who were discharged (2.9 ± 1.8 and 2.3 ± 1.4, respectively; p < 0.005). Independent risk factors for in-hospital mortality were DBP (RR 1.022, 95% CI 1.010−1.034, p < 0.001), serum glucose levels (RR 1.004, 95% CI 1.001−1.007, p = 0.007), serum triglyceride levels (RR 0.993, 95% CI 0.987−0.999, p = 0.023), NIHSS (RR 1.120, 95% CI 1.092−1.149, p < 0.001), and the FIB-4 index (RR 1.169, 95% CI 1.060−1.289, p = 0.002). Conclusions: Hepatic fibrosis, evaluated with the FIB-4 index, appears to be associated with more severe ischemic stroke and might also represent an independent risk factor for in-hospital mortality in patients admitted with acute ischemic stroke.

The role of fibroblast growth factor 19 in the pathogenesis of nonalcoholic fatty liver disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has emerged as the predominant cause of chronic liver injury worldwide. Bile acids and their receptors are profoundly implicated in the pathogenesis of NAFLD and its progression to nonalcoholic steatohepatitis and cirrhosis. AREAS COVERED: We conducted extensive literature search using PubMed database, and we summarized the relevant literature. We provided an overview of the fibroblast growth factor 19 (FGF-19)-farnesoid X receptor (FXR) axis and summarized the latest findings derived from animal and human studies concerning the impact of FGF-19 on NAFLD. EXPERT OPINION: FGF-19, a nutritionally regulated endocrine post-prandial hormone, governs bile acid metabolism, lipid oxidation, lipogenesis, and energy homeostasis. As no approved medication for NAFLD exists, FGF-19 seems to be a propitious therapeutic opportunity for NAFLD, since its administration was associated with ameliorated results in hepatic steatosis, liver inflammation and fibrosis. Furthermore, promising results have been derived from clinical trials concerning the beneficial efficacy of FGF-19 on histological findings and laboratory parameters of NAFLD. However, we should bear in mind the pleiotropic effects of FGF-19 on various metabolically active tissues along with its potential tumorigenic reservoir. Further clinical research is required to determine the clinical application of FGF-19-based therapies on NAFLD.