Effects of vitamin D3 on glucose metabolism in patients with severe osteoarthritis: A randomized double-blind trial comparing daily 2000 with 800 IU vitamin D3.

AIM: To investigate the effect of daily 800 versus 2000 IU of vitamin D3 supplementation over 24 months on glycaemic control in older adults after unilateral knee replacement. MATERIALS AND METHODS: The Zurich Multiple Endpoint Vitamin D Trial in Knee OA Patients was a randomized, double-blind trial conducted from 2008 to 2014 in Zurich, Switzerland. Participants were randomly allocated to 800 or 2000 IU vitamin D3 daily for 24 months. This study investigates the predefined secondary endpoints of fasting blood glucose (FBG) and homeostatic model assessment for insulin resistance (HOMA-IR) using linear mixed models adjusted for age, sex, baseline vitamin D deficiency and body mass index. RESULTS: A total of 251 participants (age 70.2 ± 6.5 years; 55.4% women; 39% impaired glucose tolerance, mean 25-hydroxyvitamin D 27.48 ± 12.48 ng/mL, mean FBG 5.49 ± 0.71 mmol/L) were included in this analysis. There was no significant difference in FBG between the group receiving 800 versus 2000 IU after 2 years with a least square mean (95% CI) of 5.32 (5.19; 5.44) versus 5.39 (5.27; 5.51) mmol/L (ptreat = .130) and no difference in HOMA-IR (0.44 [0.37; 0.52] vs. 0.49 [0.41; 0.58]; ptreat = .162), respectively. However, FBG decreased significantly over time independent of vitamin D3 dose (800 IU: 5.54 [5.42; 5.66] to 5.32 [5.19; 5.44], ptime < .001; 2000 IU: 5.5 [5.38; 5.62] to 5.39 [5.27; 5.51] mmol/L, ptime = .019). CONCLUSIONS: There was no clinically meaningful difference between 800 and 2000 IU of vitamin D3 over 2 years in FBG or HOMA-IR in community-dwelling older adults. Glycaemic outcomes improved in both groups.

Randomized trial of vitamin D versus placebo supplementation on markers of systemic inflammation in hypertensive patients.

BACKGROUND AND AIMS: Animal and cell models indicated that vitamin D modulates inflammatory activity, which is considered relevant in the pathogenesis of arterial hypertension and cardiovascular diseases. We therefore aimed to investigate the effect of vitamin D supplementation on systemic markers of inflammation in a cohort of hypertensive patients. METHODS AND RESULTS: The Styrian Vitamin D Hypertension Trial is a single-centre, double-blind, placebo-controlled study conducted from 2011 to 2014 in Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxy-vitamin-D (25(OH)D) concentration below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day or placebo for 8 weeks. The present investigation is a post-hoc analysis using analysis of co-variance (ANCOVA). Outcome measures were biomarkers of inflammation including CRP, leukocytes including subtypes and leukocyte-to-lymphocyte ratio, leucine and kynurenic acid. A total of 187 participants (mean age 60.1 ± 11.3years; 47% women; mean baseline 25(OH)D 21.1 ± 5.6 ng/mL) completed the trial. ANCOVA revealed a mean treatment effect for none of the respective outcomes and no significant results were detected in various subgroup analyses. CONCLUSION: Vitamin D3 supplementation in hypertensive patients with insufficient 25(OH)D concentrations has no significant effect on lowering markers of systemic inflammation. Further studies investigating the effect of vitamin D on other inflammatory pathways and in populations with severe vitamin D deficiency and a significant inflammatory burden are required. REGISTRATION: ClinicalTrials.gov Identifier: NCT02136771; EudraCT No. 2009-018,125-70. Start Date: 2011-04-06.

Associations of Thyroid Hormones and Resting Heart Rate in Patients Referred to Coronary Angiography.

Resting heart rate (RHR) is associated with increased risk of cardiovascular morbidity and mortality. Thyroid hormones exert several effects on the cardiovascular system, but the relation between thyroid function and RHR remains to be further established. We evaluated whether measures of thyroid hormone status are associated with RHR in patients referred to coronary angiography. Thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxin (FT4), and RHR were determined in 2795 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study. Median (25th to 75th percentile) serum concentrations were 1.25 (0.76-1.92) mU/l for TSH, 4.8 (4.2-5.3) pmol/l for FT3 and 17.1 (15.4-19.0) pmol/l for FT4, and mean (±standard deviation) RHR was 68.8 (±11.7) beats/min. Comparing the highest versus the lowest quartile, RHR (beats/min) was significantly higher in the fourth FT4 quartile [3.48, 95% confidence interval (CI): 2.23-4.73; p <0.001] and in the fourth FT3 quartile (2.30, 95% CI: 1.06-3.55; p <0.001), but there was no significant difference for TSH quartiles. In multiple linear regression analyses adjusting for various potential confounders, FT3 and FT4 were significant predictors of RHR (p <0.001 for both). In subgroups restricted to TSH, FT3, and FT4 values within the reference range, both FT3 and FT4 remained significant predictors of RHR (p <0.001 for all). In conclusion, in patients referred to coronary angiography, FT3 and FT4 but not TSH were positively associated with RHR. The relationship between free thyroid hormones and RHR warrants further investigations regarding its diagnostic and therapeutic implications.

Effects of vitamin D supplementation on FGF23: a randomized-controlled trial.

PURPOSE: Fibroblast growth factor-23 (FGF23) is critical for phosphate homeostasis. Considering the high prevalence of vitamin D deficiency and the association of FGF23 with adverse outcomes, we investigated effects of vitamin D3 supplementation on FGF23 concentrations. METHODS: This is a post-hoc analysis of the Styrian Vitamin D Hypertension trial, a single-center, double-blind, randomized, placebo-controlled trial, conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two hundred subjects with 25(OH)D concentrations < 30 ng/mL and arterial hypertension were randomized to receive either 2800 IU of vitamin D3 daily or placebo over 8 weeks. Primary outcome was the between-group difference in FGF23 levels at study end while adjusting for baseline values. RESULTS: Overall, 181 participants (mean ± standard deviation age, 60.1 ± 11.3; 48% women) with available c-term FGF23 concentrations were considered for the present analysis. Mean treatment duration was 54 ± 10 days in the vitamin D3 group and 54 ± 9 days in the placebo group. At baseline, FGF23 was significantly correlated with serum phosphate (r = 0.135; p = 0.002). Vitamin D3 supplementation had no significant effect on FGF23 in the entire cohort (mean treatment effect 0.374 pmol/L; 95% confidence interval - 0.024 to 0.772 pmol/L; p = 0.065), but increased FGF23 concentrations in subgroups with baseline 25(OH)D concentrations below 20 ng/mL (n = 70; mean treatment effect 0.973 pmol/L; 95% confidence interval - 0.032 to 1.979 pmol/L; p = 0.019) and 16 ng/mL (n = 40; mean treatment effect 0.593 pmol/L; 95% confidence interval 0.076 to 1.109; p = 0.022). CONCLUSIONS: Vitamin D3 supplementation had no significant effect on FGF23 in the entire study cohort. We did, however, observe an increase of FGF23 concentrations in subgroups with low baseline 25(OH)D.

Nonejecting Hearts on Femoral Veno-Arterial Extracorporeal Membrane Oxygenation: Aortic Root Blood Stasis and Thrombus Formation-A Case Series and Review of the Literature.

OBJECTIVES: Cardiogenic shock constitutes the final common pathway of cardiac dysfunction associated with tissue hypoperfusion and organ failure. Besides treatment of the underlying cause, temporary mechanical circulatory support serves as a supportive measure. Extracorporeal membrane oxygenation can effectively prevent hypoxemia and end-organ dysfunction, but knowledge about patient selection, risks, and complications remains sparse. DATA SOURCES: Clinical observation. STUDY SELECTION: Case report and review of the literature. DATA EXTRACTION: Relevant clinical information. Online databases, including PubMed, Web of Science, Scopus, and OVID, were searched for previous publications. DATA SYNTHESIS: We report six cases of patients in refractory cardiogenic shock receiving emergency femoral veno-arterial extracorporeal membrane oxygenation support complicated by echocardiographic evidence of absent blood flow, sedimentation, and thrombus formation in the aortic root. CONCLUSIONS: Patients in cardiogenic shock who require femoral veno-arterial extracorporeal membrane oxygenation support are at risk of developing a state of nonejecting heart with thrombus formation in the aortic root. Echocardiography is the cornerstone of diagnosis and documentation of treatment effects. Depending on the likelihood of the presence of clinically relevant thrombotic material in the aortic root, we propose a treatment algorithm for this group of high-risk patients.

Mineralocorticoid Receptor Blockers and Aldosterone to Renin Ratio: A Randomized Controlled Trial and Observational Data.

Current guidelines recommend to withdraw mineralocorticoid receptor (MR) blocker treatment for at least 4 weeks when measuring the aldosterone to renin ratio (ARR) as a screening test for primary aldosteronism (PA). We aimed to evaluate the effect of MR blocker treatment on ARR and its components, plasma aldosterone concentration (PAC), and direct renin concentration (DRC). First, we performed a post-hoc analysis of the effect of eplerenone on parathyroid hormone levels in primary hyperparathyroidism (EPATH) study, a randomized controlled trial (RCT) in 110 patients with primary hyperparathyroidism (pHPT). Patients were 1:1 randomly assigned to receive either 25 mg eplerenone once daily (up-titration after 4 weeks to 50 mg/day) or placebo for 8 weeks. Second, we measured the ARR in 4 PA patients from the Graz Endocrine Causes of Hypertension Study (GECOH) before and after MR blocker treatment. Ninety-seven participants completed the EPATH trial, and the mean treatment effect (95% confidence interval) for log(e)ARR was 0.08 (-0.32 to 0.48) ng/dl/µU/ml (p=0.694). The treatment effect was 0.71 (0.47 to 0.96; p<0.001) ng/dl for log(e)PAC and 0.64 (0.19 to 1.10; p=0.006) µU/ml for log(e)DRC, respectively. In the 4 PA patients, the ARR decreased from 11.24±3.58 at baseline to 2.70±1.03 (p=0.013) ng/dl/µU/ml after MR blocker treatment. In this study with limited sample size, MR blocker treatment did not significantly alter the ARR in pHPT patients but significantly reduced the ARR in PA patients. Diagnostic utility of ARR and its components for PA diagnostics under MR blocker treatment warrants further study.

Vitamin-D concentrations, cardiovascular risk and events - a review of epidemiological evidence.

Vitamin D has long been established as an elemental factor of bone physiology. Beyond mineral metabolism, the expression of the vitamin D receptor has been identified throughout the cardiovascular (CV) system. Experimental studies showed beneficial effects of vitamin D on heart and vessels, but vitamin D intoxication in animals also led to hypercalcemia and vascular calcification. Our knowledge has been extended by epidemiological studies that showed that 25-hydroxyvitamin D (25(OH)D) levels are inversely associated with an increased CV risk itself, but also with established CV risk factors, such as arterial hypertension, endothelial dysfunction and atherosclerosis. Conversely, randomized controlled trials could not document significant and consistent effects of vitamin D supplementation on CV risk or events. Potential explanations may lie in differences in reference ranges or the possibility that low vitamin D in CV disease is only an epiphenomenon. In the latter case, the key question is why low 25(OH)D levels are such a strong predictor of health. While we wait for new data, the current conclusion is that vitamin D is a strong risk marker for CV risk factors and for CV diseases itself.

Low-grade inflammation and tryptophan-kynurenine pathway activation are associated with adverse cardiac remodeling in primary hyperparathyroidism: the EPATH trial.

BACKGROUND: Primary hyperparathyroidism (pHPT) is associated with low-grade inflammation, left ventricular hypertrophy and increased cardiovascular mortality, but the association between inflammatory markers and parameters of adverse cardiac remodeling is unknown. We investigated the relationship between C-reactive protein (CRP), the essential amino acid tryptophan and its pro-inflammatory derivatives kynurenine and quinolinic acid (QUIN) with echocardiographic parameters. METHODS: Cross-sectional baseline data from the "Eplerenone in Primary Hyperparathyroidism" trial were analyzed. Patients with any acute illness were excluded. We assessed associations between CRP, serum levels of tryptophan, kynurenine and QUIN and left ventricular mass index (LVMI), left atrial volume index (LAVI) and E/e'. RESULTS: Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%. Multivariate linear regression analyses with LVMI, LAVI and E/e' as respective dependent variables, and C-reactive protein and tryptophan, kynurenine and QUIN as respective independent variables were performed. Analyses were adjusted for age, sex, blood pressure, parathyroid hormone, calcium and other cardiovascular risk factors. LVMI was independently associated with CRP (adjusted ß-coefficient=0.193, p=0.030) and QUIN (ß=0.270, p=0.007), but not kynurenine. LAVI was related with CRP (ß=0.315, p<0.001), kynurenine (ß=0.256, p=0.005) and QUIN (ß=0.213, p=0.044). E/e' was related with kynurenine (ß=0.221, p=0.022) and QUIN (ß=0.292, p=0.006). Tryptophan was not associated with any of the remodeling parameters. [Correction added after online publication (22 April 2017: The sentence "Among 136 subjects with pHPT (79% females), 100 (73%) had left ventricular hypertrophy." was corrected to "Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%."] Conclusions: Cardiac remodeling is common in pHPT and is associated with low-grade inflammation and activation of the tryptophan-kynurenine pathway. The potential role of kynurenine and QUIN as cardiovascular risk factors may be further investigated in future studies.

Vitamin D and chronic diseases: the current state of the art.

The objective was to provide the current state of the art regarding the role of vitamin D in chronic diseases (osteoporosis, cancer, cardiovascular diseases, dementia, autism, type 1 and type 2 diabetes mellitus, male and female fertility). The document was drawn up by panelists that provided their contribution according to their own scientific expertise. Each scientific expert supplied a first draft manuscript on a specific aspect of the document's topic that was subjected to voting by all experts as "yes" (agreement with the content and/or wording) or "no" (disagreement). The adopted rule was that statements supported by ≥75 % of votes would be immediately accepted, while those with <25 % would be rejected outright. Others would be subjected to further discussion and subsequent voting, where ≥67 % support or, in an eventual third round, a majority of ≥50 % would be needed. This document finds that the current evidence support a role for vitamin D in bone health but not in other health conditions. However, subjects with vitamin D deficiency have been found to be at high risk of developing chronic diseases. Therefore, although at the present time there is not sufficient evidence to recommend vitamin D supplementation as treatment of chronic diseases, the treatment of vitamin D deficiency should be desiderable in order to reduce the risk of developing chronic diseases.

Strain Analysis by Tissue Doppler Imaging: Comparison of Conventional Manual Measurement with a Semiautomated Approach.

PURPOSE: Myocardial strain and strain rate (SR) can be derived from either tissue Doppler (TDI) information or two-dimensional speckle tracking. As conventional TDI analysis (TDI-manual) is time-consuming with poor reproducibility, we developed a faster semiautomated approach (TDI-ST). We aimed to study the comparability of TDI-ST with TDI-manual, an established method for measuring strain and SR. METHODS: Forty healthy subjects (mean age 38.3 ± 12.8 years) and 16 patients with FHL-1 cardiomyopathy (CMP) (36.8 ± 14.2 years) were analyzed with TDI-manual and TDI-ST. TDI-ST was performed with commercial software, using speckle tracking for myocardial tracking and TDI information to derive longitudinal strain and SR from high frame rate TDI recordings. Measurements of longitudinal systolic strain (S) and global S (GLS) made with the two methods were compared with Bland-Altman plots and Deming regression. Receiver operating characteristics (ROC) curves were used to compare discrimination between healthy individuals and patients. RESULTS: Mean S was -20.11 ± 4.85% (healthy) and -16.12 ± 4.44% (CMP) with TDI-ST and -21.15 ± 5.68% (healthy) and -16.27 ± 6.44 (CMP) with TDI-manual. Using all measured segments, the mean bias was 0.78% strain toward less negative S with TDI-ST; the Deming regression slope was 0.7 for S and 0.9 for GLS. Intra- and inter-observer CVs were 5.4% and 7.0%, respectively. ROC curves showed no significant differences between the methods. CONCLUSION: The described S and SR measurements with TDI-ST are comparable to conventional manual analysis. Thus, using TDI-ST, it is possible to quickly and easily extract high-resolution deformation data.

The Renin-Angiotensin-Aldosterone System in Smokers and Non-Smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.

High concentrations of renin and aldosterone are risk factors for cardiovascular diseases (CVD) which are the leading cause of morbidity and mortality worldwide. Enhanced activation of the renin-angiotensin-aldosterone system (RAAS) by cigarette smoking has been reported. The aim of our study was to analyze the effect of cigarette smoking on parameters of the RAAS in active smokers (AS) and life-time non-smokers (NS) of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study as well as the utility of RAAS parameter for risk prediction. We determined the concentration of aldosterone, renin, angiotensin-I and angiotensin-II in participants of the LURIC study. Smoking status was assessed by a questionnaire and the measurement of plasma cotinine concentration. Parameters were log transformed before entering analyses, where appropriate. We used a multivariate Cox regression analysis to assess the effect of parameters on mortality. From the 3316 LURIC participants 777 were AS and 1178 NS. Within a median observation period of 10 years 221 (28.4 %) AS and 302 (25.6 %) NS died. After adjustment for age, gender, and the use of anti-hypertensive medication, only angiotensin-I was significantly different in AS compared to NS with an estimated marginal mean (95 % CI) of 1607 (1541-1673) ng/L and 1719 (1667-1772) ng/L, respectively. For both NS and AS renin and angiotensin-II were directly associated with mortality in the multivariate Cox regression analysis. Angiotensin-I was only associated with increased risk for mortality in NS (HR (95 % CI) of 0.69 (0.53-0.89)). We conclude that increased renin and angiotensin-II are independent predictors of mortality in AS and NS, while angiotensin-I was associated with reduced risk of death in NS only.

Homoarginine in the renal and cardiovascular systems.

Homoarginine (hArg) is an endogenous, nonproteinogenic amino acid which differs from arginine by an additional methylene (CH2) group in the backbone. In this brief narrative review, we summarize the current literature on hArg in the renal and cardiovascular systems. Epidemiological studies have identified low hArg levels as an independent risk marker for cardiovascular, cerebrovascular, and renal diseases as well as for mortality. The relatively low correlation of hArg with established cardiovascular risk factors underlines its great potential as an emerging biomarker to improve risk prediction because plasma hArg concentrations might reflect previously unrecognized pathophysiological processes. hArg may be involved in the pathogenesis of various diseases due to its effects on nitric oxide (NO) and energy metabolism. In view of its structural similarities with arginine, it has been proposed that hArg impacts on arginine metabolism and subsequently also on NO synthesis. The key enzyme for hArg synthesis, arginine:glycine amidinotransferase (AGAT), is involved in the synthesis of energy metabolites including guanidinoacetate, the precursor of creatine. Therefore, the involvement of hArg in energy metabolism could partially explain the close association between hArg and cardiovascular diseases such as heart failure. Whether hArg supplementation or modification of key enzymes of hArg metabolism such as AGAT activity is effective for the treatment of chronic diseases remains to be elucidated.

Role of vitamin D in the development of insulin resistance and type 2 diabetes.

Vitamin D deficiency is mainly a consequence of insufficient sunlight induced vitamin D production in the skin and has been associated with various chronic diseases including type 2 diabetes. Experimental data have shown that vitamin D is important for glucose induced insulin secretion, improves insulin resistance, and exerts anti-inflammatory actions. Epidemiological studies have largely documented that a poor vitamin D status is associated with higher risk of insulin resistance and type 2 diabetes. The majority of randomized controlled trials (RCTs) in healthy or prediabetic individuals have, however, failed to demonstrate relevant vitamin D effects on insulin resistance or diabetes incidence. In patients with type 2 diabetes, a few RCTs reported some moderate effects of vitamin D on glycemic control and insulin resistance. While these findings warrant further in-depth studies, the current evidence is insufficient to recommend vitamin D supplementation for the prevention or treatment of type 2 diabetes.

Vitamin D, arterial hypertension & cerebrovascular disease.

Vitamin D is mainly derived from endogenous ultraviolet-B induced vitamin D synthesis in the skin, and the current high prevalence of vitamin D deficiency can, therefore, largely be attributed to lifestyle related low sunlight exposure. Regulation of bone and mineral metabolism is a classic vitamin D effect, but the identification of the vitamin D receptor (VDR) in almost all human cells suggests a role for vitamin D also in extra-skeletal diseases. Experimental studies demonstrated several antihypertensive and vascular protective effects of vitamin D, such as suppression of the renin angiotensin aldosterone system, beneficial modulation of classic cardiovascular risk factors, and anti-atherosclerotic properties including improvements of endothelial function. Additional neuroprotective actions of vitamin D have also been reported. In line with this, epidemiological studies have largely shown that vitamin D deficiency is an independent risk factor for arterial hypertension and strokes. Data from randomized controlled trials (RCTs) are, however, limited and less promising, with currently no confirmation that vitamin D reduces stroke incidence. Whereas some RCTs suggest that vitamin D supplementation might modestly reduce blood pressure, this has not been consistently observed in all studies. It is, therefore, premature to recommend vitamin D supplementation for the prevention and treatment of arterial hypertension and stroke. Nevertheless, the fact that patients with arterial hypertension and cerebrovascular disease are at a relatively high risk of vitamin D deficiency, and therewith associated musculoskeletal diseases can serve as a rationale for the evaluation, prevention and treatment of vitamin D deficiency in these patients.

A Rare Mechanism for Spontaneous Closure of Muscular Ventricular Septal Defect in Hypertrophic Cardiomyopathy.

In the context of hypertrophic cardiomyopathy (HCM), a ventricular septal defect (VSD) is a rare finding. We present the case of a large spontaneously closed muscular VSD in a patient with HCM. We describe the role of cardiovascular magnetic resonance in the assessment of a VSD and its differential diagnosis in HCM. (Level of Difficulty: Advanced.).

Associations of Parameters of the Tryptophan-Kynurenine Pathway with Cardiovascular Risk Factors in Hypertensive Patients.

Accumulating evidence suggests an association of the tryptophan−kynurenine (TRP-KYN) pathway with atherosclerosis and cardiovascular risk factors. In this cross-sectional analysis we investigated whether TRP-KYN pathway parameters are associated with 24 h blood pressure (BP) and other risk factors in patients with arterial hypertension from a tertiary care centre. In 490 participants, we found no significant and independent association of 24 h systolic and diastolic BP with parameters of the TRP-KYN pathway. However, linear regression analyses of HDL as dependent and TRP, KYN and quinolinic acid (QUIN) as explanatory variables adjusted for BMI and sex showed significant associations. These were found for KYN, BMI and sex (unstandardised beta coefficient −0.182, standard error 0.052, p < 0.001; −0.313 (0.078), p < 0.001; −0.180 (0.024), p < 0.001, respectively) as well as for QUIN, BMI and sex (−0.157 (0.038), p < 0.001; −0.321 (0.079), p < 0.001; −0.193 (0.024), p < 0.001, respectively). Smokers had significantly lower levels of KYN (2.36 µmol/L, IQR 2.01−2.98, versus 2.71 µmol/L, IQR 2.31−3.27, p < 0.001), QUIN (384 nmol/L, IQR 303−448, versus 451 nmol/L, IQR 369−575, p < 0.001) and KYN/TRP ratio (38.2, IQR 33.7−43.2, versus 43.1, IQR 37.5−50.9, p < 0.001) compared to non-smokers. We demonstrated that TRP/KYN pathway metabolites are associated with some cardiovascular risk factors, warranting further studies to elucidate the diagnostic and therapeutic potential of the TRP-KYN pathway for cardiovascular diseases.