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Purpose: The glucose hydrogen breath test (GHBT) is commonly used as a noninvasive test to diagnose small bowel bacterial overgrowth (SBBO) but its validity has been questioned. Our aim was to evaluate the lactose-[(13)C]ureide breath test (LUBT) to diagnose SBBO and to compare it with the GHBT, using cultures of intestinal aspirates as a gold standard.Methods: In 22 patients with suspected SBBO (14 male, age range 18-73 years) aspirates were taken from the region of the ligament of Treitz under sterile conditions and cultured for bacterial growth. More than 10(6) colony-forming units/mL fluid or the presence of colonic flora was defined as culture positive (c+). After oral intake of 50 g glucose and 2 g of lactose-[(13)C]ureide, end-expiratory breath samples were obtained up to 120 min. The (13)C/(12)C ratio in breath CO(2) was determined by isotope ratio-mass spectrometry and hydrogen concentration in breath was analyzed electrochemically.Results: After analyzing receiver operating characteristic curves of the LUBT results, total label recovery of >0.88% at 120 min was considered positive. The test had a sensitivity of 66.7% and a specificity of 100% to predict c+. In the GHBT, an increase of the signal of > or =12 ppm from baseline was considered positive. The sensitivity and specificity of the test were 41.7 and 44.4%, respectively.Conclusions: The new stable isotope-labeled LUBT has excellent specificity but suboptimal sensitivity. In contrast, the standard GHBT lacks both high sensitivity and specificity. The LUBT is superior to the GHBT for detecting SBBO. [ABSTRACT FROM AUTHOR]

AIMS: The phosphoenolpyruvate carboxykinase gene (PCK1) is a potential candidate gene in the pathogenesis of Type 2 diabetes mellitus. A -232C/G promoter polymorphism of PCK1 has been associated with an increased risk of Type 2 diabetes in a Canadian population. The purpose of the present study was to examine this association in a German Caucasian population. METHODS: We investigated 397 subjects with Type 2 diabetes [227 men, 170 women, age 63 +/- 11 years, body mass index (BMI) 28.7 +/- 5.1 kg/m2] and 431 control subjects without diabetes (247 men, 184 women, age 64 +/- 7 years, BMI 26.5 +/- 3.7 kg/m2) matched for sex and age. RESULTS: In the diabetic and control groups, the CC genotype frequencies were 18.1 and 18.3%, the CG 48.6 and 48.7% and the GG 33.2 and 32.9%, respectively (P = 0.995). The allelic frequencies were 0.51 and 0.57 for the G allele and 0.49 and 0.43 for the C allele, respectively. In a logistic regression model only BMI and family history, but not the polymorphism, were predictors of Type 2 diabetes. In both the control and diabetic subjects, there were no significant differences in BMI or blood pressure between the groups with or without the polymorphism. The variant also had no significant influence on the presence of atherosclerotic disease, while the influence of other known cardiovascular risk factors was confirmed. CONCLUSIONS: The present data suggest that, in a German Caucasian population, the -232C/G polymorphism of the PEPCK gene is not associated with Type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Resistin, a peptide hormone produced by adipocytes, has been associated with diabetes mellitus type 2 (DM-2) in some rodent models. In humans the exact function of resistin remains unknown. Some, but not all studies have found associations between polymorphisms in the resistin gene with DM-2. Recently a 3'-untranslated region +62G-->A polymorphism of the resistin gene has been associated with decreased risk for DM-2 and for hypertension in diabetics in a Chinese population. Purpose of the present study was to examine for the first time in a German Caucasian population the possible association between this polymorphism and DM-2, hypertension, lipoprotein levels, resistin levels as well as atherosclerosis. DESIGN, SETTING AND SUBJECTS: A total of 818 subjects participated in the study. The presence of the +62G-->A polymorphism of the resistin gene was investigated using polymerase chain reaction-restriction fragment length polymorphism in 384 subjects with DM-2 [224 men, 160 women, age 63.4 +/- 10.6 years, body mass index (BMI) 28.7 +/- 5.1 kg m(-2)] and in 434 nondiabetic age- and sex-matched control subjects (248 men, 186 women, age 64.4 +/- 6.5 years, BMI 26.5 +/- 3.7 kg m(-2)). RESULTS: Thirty-four subjects were found to be carrying the +62G-->A polymorphism in the control and 24 in the diabetic group (allelic frequencies 4% and 3.2% respectively). Subjects with DM-2 were not found to have a different frequency of the genotypes (93.75% and 6.258%, for GG:GA/AA respectively) than the control subjects (92.2% and 7.8% for GG:GA/AA respectively) (OR 0.75, 95% CI 0.44-1.3, P = 0.31). In the total cohort, carriers of the A allele had a higher prevalence of hypertension (OR 1.82, 95% CI 1.03-3.21, P = 0.039). When analysed separately, the control group showed a strong association between the presence of the A allele and hypertension (OR 2.92, 95% CI 1.38-6.15, P = 0.005), whilst no such association could be established in the diabetic group (OR 1.05, 95% CI 0.43-2.54, P = 0.92). Multiple regression analysis confirmed that the presence of the A variant is associated with hypertension in control but not in diabetic subjects, independent of age and BMI. The polymorphism had no significant influence on the presence of atherosclerotic disease, BMI, and on triglyceride, HDL and LDL cholesterol levels, both, in the control and the diabetic groups. There was no difference in the serum resistin levels between the 62G-->A variant carriers and noncarriers. CONCLUSIONS: In conclusion, the present data suggest that in a German Caucasian population the +62G-->A polymorphism of the resistin gene is associated with hypertension but not with DM-2. [ABSTRACT FROM AUTHOR]

BACKGROUND: High intake of soy products has been suggested to prevent breast cancer, osteoporosis, and cardiovascular diseases. AIM OF THE STUDY: To investigate the effects of isoflavone-containing soy on circulating sex hormones, biomarkers of bone turnover, and lipoprotein profiles. METHODS: Fourteen young women received in a randomized crossover design 5 soy cookies (52 mg isoflavones) or 5 soy-free cookies (no isoflavones) per day for one menstrual cycle starting one week before menstruation. Serum and urine analyses were performed on day 3 after onset of menstruation (t(1)), 3 days before ovulation (t(2)), 3 days after ovulation (t(3)), during the midluteal phase (t(4)), and again 3 days after onset of the next menstruation (t(5)). RESULTS: With the exception of higher progesterone levels at t(2), soy supplementation did not affect the physiologic fluctuations in circulating sex hormones. The ratio of C-telopeptide (a bone resorption marker) to osteocalcin (a bone formation marker) was slightly higher at t(4) during the soy period compared to t(4) during the control period (P < 0.05), indicating an uncoupling of bone resorption and formation processes. Serum levels of total cholesterol, LDL cholesterol, and HDL cholesterol were not influenced by soy intake. CONCLUSIONS: High short-term isoflavone-containing soy intake slightly affects physiologic fluctuations in bone turnover, but has no significant effects on most circulating sex hormones and on lipoprotein parameters in young healthy women. [ABSTRACT FROM AUTHOR]

Purpose: Stents coated with hypothrombogenic silicon carbide (a-SiC:H) exhibited low restenosis rates in the rabbit and in an observational study in humans. Thus, the clinical and angiographic outcome was assessed in a large multicenter study.Material and Methods: Four hundred and ninety-seven patients (63.4 +/- 9.8 years) were randomized to either receive the a-SiC:H-coated Tenax stent or the stainless steel Nir stent. Lesions (diameter > or = 2.8 mm, length < 20 mm) were covered with one single stent.Results: Fifty-one of 497 (10.3%) patients were excluded for protocol violation. Three hundred and forty-two of 446 (76.7%) patients presented for scheduled angiographic follow-up after 4.7 +/- 1.2 months and 29 of 446 (6.5%) prematurely. In-hospital complications comprised two deaths (0.8%) (P > 0.99) and one (0.4%) (P > 0.99) CK-elevation in each group, target lesion revascularization in 5 of 250 (2%) of the Tenax and 4 of 244 (1.6%) of the Nir sample (P > 0.99), and subacute thrombosis in 2 of 250 (0.8%) of the Tenax patients (P = 0.5). In the Tenax/Nir patients mean percent diameter stenosis decreased from 82.3 +/- 9.1%/80.7 +/- 8.4% (P = 0.49) to 17.6 +/- 5.5%/17.6 +/- 5.5% (P = 0.99) postprocedure and increased to 34.5 +/- 21.5%/34.2 +/- 23.1% (P = 0.90) at follow-up.Conclusions: Thus, there appears to be no advantage of the silicon carbide coated stent over a stainless steel stent after 4.7 +/- 1.2 months with regard to clinical and angiographic restenosis rates. [ABSTRACT FROM AUTHOR]

Study Objective: s: To determine whether traditional risk factors for cardiovascular disease (CVD) and regional fat distribution, especially the central obesity type and increased parapharyngeal fat pads, are associated with the degree of obstructive sleep apnea (OSA). To determine whether there are interrelationships between body fat, serum leptin levels, and the degree of OSA.Design and Setting: Prospective mono-center cross-sectional study in a university hospital in Germany.Patients: Eighty-five consecutive male patients who were referred for evaluation of suspected OSA.Measurements and Results: The major dependent outcome variable was the apnea-hypopnea index (AHI), the average number of apneas and hypopneas per hour of sleep, determined by overnight polysomnography. Independent measures were anthropometric data, body composition analysis (bioelectrical impedance analysis [BIA]), cardiovascular risk factor evaluation (smoking, hypertension, serum lipoproteins, diabetes or impaired glucose tolerance, uric acid, fibrinogen), and leptin. Adipose tissue quantification of the abdominal and neck regions was performed by nuclear MRI (NMR). Significant linear relationships of AHI with fasting blood glucose, uric acid, fibrinogen, body weight, body mass index (BMI), sum of fat skin folds, and percentage of body fat could be established, whereas there was no correlation with age. The presence of OSA was independent of smoking, hypertension, and lipoproteins. NMR scans showed that AHI was significantly correlated with intra-abdominal fat and subcutaneous abdominal fat, whereas subcutaneous fat in the neck region and parapharyngeal fat in the airway vicinity were not correlated. Leptin concentrations correlated with AHI and with biochemical markers of the metabolic syndrome (lipoproteins, glucose) but were not dependent on AHI. Logistic regression analysis found percentage of body fat (BIA) and BMI as good predictors of AHI > 10 with a sensitivity of 95.5% but a low specificity (46.2%). Multiple regression analysis identified the sum of fat skin folds, body weight, and BMI as good predictors for the degree of OSA.Conclusions: We conclude that OSA is independent from most traditional risk factors for CVD. Regional body fat distribution predicts the presence and degree of OSA, but fat accumulation in the neck and parapharyngeal region are of minor importance. Leptin concentrations when controlled for body fat are not related to the degree of OSA. [ABSTRACT FROM AUTHOR]

BACKGROUND: Elevated plasma total homocysteine (tHcy) is a risk factor for vascular disease and neural tube defects. The polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (FADH(2)) (MTHFR) influences the tHcy concentration and the response to tHcy-lowering therapy. Supplementation with folic acid (FA) decreases plasma tHcy, but limited data are available on the effect of 5-methyltetrahydrofolate (MTHF). OBJECTIVE: We evaluated the tHcy-lowering potential of low-dose FA and of MTHF with respect to the MTHFR genotype. DESIGN: In this randomized, placebo-controlled, double-blind study, 160 women received 400 microg FA, the equimolar amount of MTHF (480 microg, racemic mixture), or a placebo daily during an 8-wk treatment period. Blood samples were collected at baseline and at 4 and 8 wk. RESULTS: Changes in plasma tHcy concentration depended on the supplemented folate derivative and the MTHFR genotype. Supplementation with FA significantly decreased tHcy concentrations by > or = 13% in women of all 3 genotypes after both 4 and 8 wk. The greatest decrease was 20% (P < 0.05) in the women with the TT genotype after 4 wk. MTHF supplementation also decreased tHcy, but only the women with the CT genotype had a significant decrease after 4 wk (7%; P < 0.05). The largest nonsignificant reduction (15%) occurred in the women with the TT genotype after 4 wk of MTHF supplementation. CONCLUSIONS: The response to tHcy-lowering therapy is influenced by MTHFR genotype. Women with the TT genotype seem to benefit the most from supplementation with either FA or MTHF. In women with the CT or CC genotype, FA is more effective than MTHF in lowering plasma tHcy. [ABSTRACT FROM AUTHOR]

Context: Garlic-containing drugs have been used in the treatment of hypercholesterolemia even though their efficacy is not generally established. Little is known about the mechanisms of action of the possible effects on cholesterol in humans.Objective: To estimate the hypocholesterolemic effect of garlic oil and to investigate the possible mechanism of action.Design: Double-blind, randomized, placebo-controlled trial.Setting: Outpatient lipid clinic.Patients: We investigated 25 patients (mean age, 58 years) with moderate hypercholesterolemia.Intervention: Steam-distilled garlic oil preparation (5 mg twice a day) vs placebo each for 12 weeks with wash-out periods of 4 weeks.Main Outcome Measures: Serum lipoprotein concentrations, cholesterol absorption, and cholesterol synthesis.Results: Baseline lipoprotein profiles were (mean [SD]): total cholesterol, 7.53 (0.75) mmol/L (291 [29] mg/dL); low-density lipoprotein cholesterol (LDL-C), 5.35 (0.78) mmol/L (207 [30] mg/dL); high-density lipoprotein cholesterol (HDL-C), 1.50 (0.41) mmol/L (58 [16] mg/dL); and triglycerides, 1.45 (0.73) mmol/L (127 [64] mg/ dL). Lipoprotein levels were virtually unchanged at the end of both treatment periods (mean difference [95% confidence interval]): total cholesterol, 0.085 (-0.201 to 0.372) mmol/L (3.3 [-7.8 to 14.4] mg/dL), P=.54; LDL-C, 0.001 (-0.242 to 0.245) mmol/L (0.04 [-9.4 to 9.5] mg/dL), P=.99; HDL-C, 0.050 (-0.028 to 0.128) mmol/L (1.9 [-1.1 to 4.9] mg/dL), P=.20; triglycerides, 0.047 (-0.229 to 0.135) mmol/L (4.2 [-20.3 to 12.0]) mg/dL, P=.60. Cholesterol absorption (37.5% [10.5%] vs 38.3% [10.7%0], P=.58), cholesterol synthesis (12.7 [6.5] vs 13.4 [6.6] mg/kg of body weight per day, P=.64), mevalonic acid excretion (192 [66] vs 187 [66] microg/d, P=.78), and changes in the ratio of lathosterol to cholesterol in serum (4.4% [24.3%] vs 10.6% [21.1%], P=.62) were not different in garlic and placebo treatment.Conclusions: The commercial garlic oil preparation investigated had no influence on serum lipoproteins, cholesterol absorption, or cholesterol synthesis. Garlic therapy for treatment of hypercholesterolemia cannot be recommended on the basis of this study. [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to evaluate the association between vitamin D status and congestive heart failure (CHF).Background: Impaired intracellular calcium metabolism is an important factor in the pathogenesis of CHF. The etiology of CHF, however, is not well understood.Methods: Twenty patients age <50 years and 34 patients age >/=50 years with New York Heart Association classes >/=2 and 34 control subjects age >/=50 years were recruited. N-terminal pro-atrial natriuretic peptide (NT-proANP), a predictor of CHF severity; vitamin D metabolites; and parameters of calcium metabolism were measured in fasting blood samples collected between November 2000 and March 2001.Results: Both groups of CHF patients had markedly increased serum levels of NT-proANP (p < 0.001), increased serum phosphorus levels (p < 0.001), and reduced circulating levels of both 25-hydroxyvitamin D (p < 0.001) and calcitriol (p < 0.001). Albumin-corrected calcium levels were reduced and parathyroid hormone levels were increased in the younger CHF patients compared with the controls (both p values <0.001). Moreover, parathyroid hormone levels tended to be higher in the elderly CHF patients than in the controls (p = 0.074). In a nonlinear regression analysis 25-hydroxyvitamin D and calcitriol were inversely correlated with NT-proANP (r(2) = 0.16; p < 0.001 and r(2) = 0.12; p < 0.01, respectively). The vitamin D genotype at the BmsI restriction site did not differ between the study groups.Conclusions: The low vitamin D status can explain alterations in mineral metabolism as well as myocardial dysfunction in the CHF patients, and it may therefore be a contributing factor in the pathogenesis of CHF. [ABSTRACT FROM AUTHOR]

Lipid-lowering therapy (LLT) is a cornerstone of atherosclerotic cardiovascular disease prevention. Although LLT might lead to different reductions in low-density lipoprotein cholesterol (LDL-C) levels in women and men, LLT diminishes cardiovascular risk equally effectively in both sexes. Despite similar LLT efficacy, the use of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors is lower in women compared to men. Women achieve the guideline-recommended LDL-C levels less often than men. Greater cholesterol burden is particularly prominent in women with familial hypercholesterolemia. In clinical practice, women and men with dyslipidemia present with different cardiovascular risk profiles and disease manifestations. The concentrations of LDL-C, lipoprotein(a), and other blood lipids differ between women and men over a lifetime. Dissimilar levels of LLT target molecules partially result from sex-specific hormonal and genetic determinants of lipoprotein metabolism. Hence, to evaluate a potential need for sex-specific LLT, this comprehensive review (i) describes the impact of sex on lipoprotein metabolism and lipid profile, (ii) highlights sex differences in cardiovascular risk among patients with dyslipidemia, (iii) presents recent, up-to-date clinical trial and real-world data on LLT efficacy and safety in women, and (iv) discusses the diverse medical needs of women and men with dyslipidemia and increased cardiovascular risk.

Purpose of Review: To provide an insight into the new pharmacological options for the treatment of severe hypertriglyceridemia (sHTG)., Recent Findings: sHTG is difficult to treat. The majority of the traditional pharmacological agents available have limited success in both robustly decreasing triglyceride levels and/or in reducing the incidence of acute pancreatitis (AP), the most severe complication of sHTG. Therapeutic options with novel mechanisms of action have been developed, such as antisense oligonucleotides (ASO) and small interfering RNA (siRNA) targeting APOC3 and ANGPTL3. The review discusses also 2 abandoned drugs for sHTG treatment, evinacumab and vupanorsen. The ASO targeting APOC3, volanesorsen, is approved for use in patients with familial chylomicronemia syndrome (FCS) in Europe. Olezarsen, an N-acetylgalactosamine (GalNAc)-conjugated ASO with the same target, seems to have a better safety and efficacy profile. siRNA targeting APOC3 and ANGPTL3, namely ARO-APOC3 and ARO-ANG3, are also promising for the treatment of sHTG. However, the ultimate clinical goal of any sHTG treatment, the decrease in the risk of AP, has not been definitively achieved till now by any pharmacotherapy, either approved or in development., (© 2023. The Author(s).)

Phytosterols (PSs) have been proposed as dietary means to lower plasma LDL-C. However, concerns are raised that PSs may exert atherogenic effects, which would offset this benefit. Phytosterolemia was thought to mimic increased plasma PSs observed after the consumption of PS-enriched foods. This expert statement examines the possibility of specific atherogenicity of PSs based on sterol metabolism, experimental, animal, and human data. Observational studies show no evidence that plasma PS concentrations would be associated with an increased risk of atherosclerosis or cardiovascular (CV) events. Since variants of the ABCG5/8 transporter affect the absorption of cholesterol and non-cholesterol sterols, Mendelian randomization studies examining the effects of ABCG5/8 polymorphisms cannot support or refute the potential atherogenic effects of PSs due to pleiotropy. In homozygous patients with phytosterolemia, total PS concentrations are ~4000% higher than under physiological conditions. The prevalence of atherosclerosis in these individuals is variable and may mainly relate to concomitant elevated LDL-C. Consuming PS-enriched foods increases PS concentrations by ~35%. Hence, PSs, on a molar basis, would need to have 20-40 times higher atherogenicity than cholesterol to offset their cholesterol reduction benefit. Based on their LDL-C lowering and absence of adverse safety signals, PSs offer a dietary approach to cholesterol management. However, their clinical benefits have not been established in long-term CV endpoint studies.

Purpose of Review: To report on recent data about PCSK9 monoclonal antibodies and to evaluate their relevance in a nucleic acid-based therapy era for lipid lowering and prevention of cardiovascular disease., Recent Findings: New methods of PCSK9 inhibition based on nucleic acid therapeutics such as antisense oligonucleotides, small interfering RNAs, and CRISPR tools for therapeutic gene editing are reported, and interesting new data regarding the clinical relevance of PCSK9 antibodies are discussed. Promising methods of PCSK9 inhibition are in development, and one of them, the siRNA inclisiran targeting PCSK9, has already been approved for clinical use. However, PCSK9-mAb remains the PCSK9-inhibiting tool with the longest safety data and the only one having positive cardiovascular outcome trials. An ongoing cardiovascular outcome trial with inclisiran is planned to be completed in 2026. Other forms of PCSK9 inhibition, such as antisense oligonucleotides targeting PCSK9 and CRISPR base editing of PCSK9, are still in early phases of development, and their potential clinical relevance remains to be established., (© 2022. The Author(s).)

The phosphaturic hormone fibroblast growth factor 23 (FGF23) is a risk marker of cardiovascular and all-cause mortality. We therefore aimed to synthesize the evidence for the effect of vitamin D administration on circulating FGF23 concentrations. We performed a systematic review and meta-analysis of randomized, placebo-controlled trials (RCTs) in several databases from inception to January 2020. A total of 73 records were identified for full-text review, and 21 articles with 23 studies were included in the final analysis. The selected studies included 1925 participants with 8-156 weeks of follow-up. The weighted mean difference in FGF23 in the vitamin D versus placebo group was +21 pg/ml (95% CI: 13-28 pg/ml; P < 0.001) with considerable heterogeneity among studies (I 2  = 99%). The FGF23 increment was higher in patients with end-stage kidney/heart failure than in other individuals (+300 pg/ml [95% CI: 41-558 pg/ml] vs. +20 pg/ml [95% CI: 12-28 pg/ml], P interaction  = 0.03), and if baseline 25-hydroxyvitamin D concentrations were <50 nmol/l instead of ≥50 nmol/l (+34 pg/ml [95% CI: 18-51 pg/ml] vs. +9 pg/ml [95% CI: 3-14 pg/ml]; P interaction  = 0.002). Moreover, the FGF23 increment was influenced by vitamin D dose/type (vitamin D dose equivalent ≤ 2000 IU/day: +2 pg/ml [95% CI: 0-3 pg/ml]; vitamin D dose equivalent > 2000 IU/day: +18 pg/ml [95% CI: 6-30 pg/ml]; administration of activated vitamin D: +67 pg/ml [95% CI: 16-117 pg/ml]; P interaction  = 0.001). Results were not significantly influenced by study duration (P interaction  = 0.14), age class (P interaction  = 0.09), or assay provider (P interaction  = 0.11). In conclusion, this meta-analysis of RCTs demonstrates that vitamin D administration of >2000 IU/d vitamin D or activated vitamin D significantly increased concentrations of the cardiovascular risk marker FGF23, especially in patients with end-stage kidney/heart failure.

In humans, the combination of all sex-specific genetic, epigenetic, and hormonal influences of biologic sex produces different in vivo environments for male and female cells. We dissect how these influences of sex modify the pharmacokinetics and pharmacodynamics of multiple drugs and provide examples for common drugs acting on specific organ systems. We also discuss how gender of physicians and patients may influence the therapeutic response to drugs. We aim to highlight sex as a genetic modifier of the pharmacological response to drugs, which should be considered as a necessary step toward precision medicine that will benefit men and women. SIGNIFICANCE STATEMENT: This study discusses the influences of biologic sex on the pharmacokinetics and pharmacodynamics of drugs and provides examples for common drugs acting on specific organ systems. This study also discusses how gender of physicians and patients influence the therapeutic response to drugs., Competing Interests: Financial disclosure statement No authors have an actual or perceived conflict of interest with the contents of this article., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Vitamin D deficiency has been identified as a potential risk factor for a number of diseases unrelated to the classical skeletal pathophysiology, such as cancer and CVD, but the effects of vitamin D supplementation are less clear. Purpose of this narrative review is to discuss the evidence suggesting an association between vitamin D status and CVD as well as the results of supplementation studies. Vitamin D deficiency has been associated with CVD risk factors such as hypertension, dyslipidemia and diabetes mellitus as well as with cardiovascular events such as myocardial infarction, stroke and heart failure. While vitamin D deficiency might contribute to the development of CVD through its association with risk factors, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells. Moreover, vitamin D has been shown to affect inflammation, cell proliferation and differentiation. While observational studies support an association between low plasma vitamin D levels and increased risk of CVD, Mendelian randomization studies do not support a causal association between the two. At present, high quality randomized trials do not find evidence of significant effects on CVD endpoints and do not support supplementation of vitamin D to decrease CVD events., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Vitamin D supplementation is widely used in the clinical setting, but its effects on mortality and cardiovascular outcomes in patients with heart failure are unclear. This paper reports outcome data that were collected during follow-up of 3 years after closure of the EVITA trial (a 3 year randomized, placebo-controlled, intervention study with 4000 IU vitamin D daily in patients with advanced heart failure), to capture potential latency effects of vitamin D supplementation on clinical outcomes., Methods and Results: The prespecified primary endpoint was overall mortality. Secondary endpoints included hospitalization, mechanical circulatory support implantation, high urgent listing for heart transplantation, and heart transplantation. For group comparisons, we used Cox regression models with a time-dependent categorical covariate. The calculated net difference in circulating 25-hydroxyvitamin D between the vitamin D and placebo groups dropped from 60.9 nmol/L at the end of the active study period to 3.2 nmol/L at the end of the post-intervention period. During the entire 6 year period, 73 patients (36.5%) died in the placebo group and 76 (38.8%) in the vitamin D group. Out of these 149 patients, 36 and 39 died during the first 3 years, and 37 and 37 during the second 3 years, respectively. The hazard ratio (HR) for mortality in the vitamin D versus the placebo group was 1.06 [95% confidence interval (CI): 0.68-1.66] for the first 3 years and 1.07 (95% CI: 0.68-1.70) for the 3 year post-intervention follow-up. Compared with the placebo group, the HRs for hospitalization and for mechanical circulatory support implant were significantly higher in the vitamin D group during vitamin D supplementation (HR = 1.31, 95% CI: 1.01-1.68 and HR = 2.01, 95% CI: 1.08-3.76, respectively) but not after vitamin D discontinuation (HR = 1.10, 95% CI: 0.62-1.94 and HR = 0.99, 95% CI: 0.38-2.56, respectively). There was no significant time-dependent effect on the risk of high urgent listing for heart transplantation and heart transplantation., Conclusions: No beneficial latency effects of vitamin D supplementation on overall mortality could be demonstrated. Instead, the disappearance of unfavourable findings in the vitamin D group (higher HRs for hospitalization and for mechanical circulatory support implant) after vitamin D discontinuation supports the assumption of adverse vitamin D effects on the cardiovascular system at doses of 4000 IU daily., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Purpose: For the prevention of nutritional rickets, 400 IU vitamin D daily and circulating 25-hydroxyvitamin D (25OHD) concentrations > 50 nmol/L are recommended, whereas the toxicity threshold is set at 250 nmol/L. We synthesized the evidence for the effect of vitamin D supplementation on incremental 25OHD in infants up to 1 year of age., Methods: We performed a systematic review and meta-analysis of intervention trials in several databases. A total of 87 records were identified for full-text review and 27 articles with 61 studies were included in the final analysis., Results: The selected 61 studies included 1828 participants. Nineteen cohorts had already mean baseline 25OHD levels ≥ 50 nmol/L. The weighted mean difference in 25OHD following vitamin D supplementation was + 49.4 nmol/L (95% CI 43.6-55.3 nmol/L; P < 0.001). The increment was dose-dependent (P = 0.002), was higher in full-term than in pre-term infants (P < 0.001), was higher in infants with baseline 25OHD < 50 nmol/L as compared to ≥ 50 nmol/L (P = 0.001), and was marginally influenced by the 25OHD test procedure (P = 0.080). Vitamin D 3 doses of 400 IU/day were sufficient to achieve 25OHD concentrations ≥ 50 nmol/L in most full-term infants. A 25OHD level of 250 nmol/L was not exceeded in ≥ 97.5% of infants at doses between 200 and 1200 IU/day, but potentially in ≥ 2.5% of infants at a dose of 1600 IU/day., Conclusions: Vitamin D supplementation of 400 IU/day is sufficient for achieving 25OHD concentrations able to prevent nutritional rickets. A more personalized vitamin D dosing strategy would require 25OHD testing, but also assay standardization.

Background: Non-vitamin K-dependent oral anticoagulants (NOAC) have changed the management of patients with oral anticoagulation. This raises the question of which patients should preferably be anticoagulated with NOAC and which preferably with vitamin K antagonists (VKA). This discussion has so far been insufficiently conducted and often decided on a flat-rate basis in favor of the NOAC., Method: To clarify the question owhich form of anticoagulation - NOAC or VKA - is the best choice for patients with atrial fibrillation, an interdisciplinary team of experts met., Results and Conclusions: The experts discussed essential practical aspects of NOAC and VKA therapy. Based on typical clinical scenarios, they developed assistance, comments and tips on the differentiated use of oral anticoagulants in patients with atrial fibrillation. A criteria served amongst others practicability in daily medical practice, contraindications, side effects and interactions, but also the patient's desire. The advantages and disadvantages of therapy with VKA and NOAC were summarized in a table.

Serum levels of interleukin-6 (IL-6) are increased in patients with type 2 diabetes (T2D). IL-6 exerts its pleiotropic effects via the IL-6 α-receptor (IL-6R), which exists in membrane-bound and soluble (sIL-6R) forms and activates cells via the β-receptor glycoprotein 130 (gp130). The nonsynonymous single-nucleotide polymorphism (SNP) rs2228145 (Asp358Ala) within the IL6R locus is associated with T2D. The aim of this study was to determine whether sIL-6R in combination with soluble gp130 (sgp130) is able to form an IL-6-neutralizing buffer in healthy subjects and whether this is disturbed in T2D. We found that sIL-6R-sgp130 indeed forms an IL-6-neutralizing buffer in the serum of healthy humans, whose capacity is controlled by the SNP of the IL-6R. Circulating sIL-6R-sgp130 levels were lower in T2D subjects ( P < 0.001), whereas IL-6 was high and inversely correlated with sIL-6R ( r  = -0.57, P < 0.001), indicating a severe disturbance of the buffer. This phenomenon is also observed in sex- and age-matched patients with both T2D and atherosclerosis but not in patients with atherosclerosis alone. In conclusion, sIL-6R and sgp130 serum levels were significantly lower in T2D patients compared with healthy subjects or atherosclerosis patients, although IL-6 levels were high. These data suggest that disturbance of the protective buffer may be closely associated with T2D pathophysiology.

Background: Data regarding the effects of vitamin D on cardiac function are inconclusive., Methods: In a post-hoc analysis of the EVITA (Effect of vitamin D on mortality in heart failure) trial, we investigated whether a daily vitamin D 3 supplement of 4000 IU for three years affects echocardiography parameters like left ventricular end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), and LV ejection fraction (LVEF) in patients with advanced heart failure (HF) and 25‑hydroxyvitamin D levels <75 nmol/L. Of 400 patients enrolled, 199 were assigned to vitamin D and 201 to placebo. We assessed time × treatment interaction effects using linear mixed models and analyzed in subgroups vitamin D effects at 12 and 36 months post-randomization using analysis of covariance with adjustments for baseline values., Results: At baseline, values of LVEDD, LVESD, and LVEF were 67.5 ± 10.5 mm, 58.9 ± 12.0 mm, and 30.47 ± 10.2%, respectively. There were no time × treatment interaction effects on LV echocardiographic parameters in the entire study cohort, neither at 12 months nor at 36 months post-randomization (P-values > 0.05). However, in the subgroup of patients aged ≥50 years, vitamin D treatment was associated with an increase in LVEF of 2.73% (95%CI: 0.14 to 5.31%) at 12 months post-randomization (n = 311). The increase was slightly attenuated to 2.60% (95%CI: -2.47 to 7.67%) at 36 months post-randomization (n = 242)., Conclusion: Our data indicate that vitamin D supplementation does not significantly improve cardiac function in all patients with advanced HF. However, vitamin D probably improves LV function in HF patients aged ≥50 years., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Observational studies indicate a positive association between circulating 25-hydroxyvitamin D (25OHD) and testosterone (T) concentrations. Because low 25OHD concentrations and T deficiency are considered to be a generalized phenomenon in patients with advanced heart failure (HF), we aimed to investigate whether vitamin D supplementation has beneficial effects on T indices in these patients., Methods: In a pre-specified secondary analysis of the EVITA (effect of vitamin D on mortality in heart failure) randomized controlled trial, we analyzed in male subjects with 25OHD concentrations < 75 nmol/L the effect of a daily vitamin D 3 supplement of 4000 IU for 3 years (n = 71) vs. placebo (n = 62) on total T (TT), sex hormone-binding globulin (SHBG), free T (fT), and bioactive T (BAT). We assessed changes from baseline until study termination and between-group differences at study termination., Results: 25OHD increased in the placebo group from 36.6 nmol/L by 9.2 nmol/L (95% CI 3.2-15.1 nmol/L; P = 0.003) and in the vitamin D group from 36.5 nmol/L by 63.9 nmol/L (95% CI 52.6-75.3 nmol/L; P < 0.001), with a significant between-group difference at study termination (P < 0.001). TT and SHBG concentrations did not change significantly, neither in the placebo group nor in the vitamin D group (P = 0.845-0.082), but concentrations of fT and BAT declined significantly in both groups (P = 0.025-0.008). At study termination, there were no between-group differences in TT (P = 0.612), SHBG (P = 0.393), fT (P = 0.861), or BAT (P = 0.960)., Conclusions: In male patients with advanced HF and low 25OHD concentrations, a daily vitamin D 3 supplement of 4000 IU for 3 years did not prevent the decline in testosterone indices.

650 millions of adults are obese worldwide - in the US alone, forty percent of the adults are obese. Although the obesity pandemic is constantly expanding at very high costs for health care systems, the currently available options of pharmacotherapy for obesity are rather limited. Despite intensive research efforts, the vast majority of the anti-obesity drugs developed up to now have a rather limited efficacy and/or safety profile. In the last fifty years, various drugs reached advanced states of clinical development but were either never marketed or were initially approved but withdrawn later due to safety issues. However, the understanding of the pathophysiology of obesity has been steadily improving and new, promising drugs targeting various selective obesityassociated and energy-homeostasis-related pathways are now available. When lifestyle changes alone fail to combat, then additional pharmacotherapy with an acceptable efficacy and safety profile could provide a useful therapeutic option., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)