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 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.

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.).

Positron Emission Tomography in Heart Failure: From Pathophysiology to Clinical Application.

Imaging modalities are increasingly being used to evaluate the underlying pathophysiology of heart failure. Positron emission tomography (PET) is a non-invasive imaging technique that uses radioactive tracers to visualize and measure biological processes in vivo. PET imaging of the heart uses different radiopharmaceuticals to provide information on myocardial metabolism, perfusion, inflammation, fibrosis, and sympathetic nervous system activity, which are all important contributors to the development and progression of heart failure. This narrative review provides an overview of the use of PET imaging in heart failure, highlighting the different PET tracers and modalities, and discussing fields of present and future clinical application.

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.

Association of branched-chain amino acids with mortality-the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Branched-chain amino acids (BCAAs) are effectors of metabolic diseases, but their impact on mortality is largely unknown. We investigated the association of BCAA with risk factors and mortality in 2,236 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study using linear and Cox regression. Adiponectin, hemoglobin, C-peptide, hemoglobin A1c, and homoarginine showed the strongest association with BCAA concentration (all p < 0.001). During a median follow-up of 10.5 years, 715 participants died, including 450 cardiovascular-related deaths. BCAA concentrations were inversely associated with the risk of all-cause and cardiovascular mortality (HR [95% CI] per 1-SD increase in log-BCAA: 0.75 [0.69-0.82] and 0.72 [0.65-0.80], respectively) after adjustment for potential confounders. BCAAs are directly associated with metabolic risk but inversely with mortality in persons with intermediate-to-high cardiovascular risk. Further studies are warranted to evaluate the diagnostic and therapeutic utility of BCAA in the context of cardiovascular diseases.

The effects of positive end-expiratory pressure on cardiac function: a comparative echocardiography-conductance catheter study.

BACKGROUND: Echocardiographic parameters of diastolic function depend on cardiac loading conditions, which are altered by positive pressure ventilation. The direct effects of positive end-expiratory pressure (PEEP) on cardiac diastolic function are unknown. METHODS: Twenty-five patients without apparent diastolic dysfunction undergoing coronary angiography were ventilated noninvasively at PEEPs of 0, 5, and 10 cmH2O (in randomized order). Echocardiographic diastolic assessment and pressure-volume-loop analysis from conductance catheters were compared. The time constant for pressure decay (τ) was modeled with exponential decay. End-diastolic and end-systolic pressure volume relationships (EDPVRs and ESPVRs, respectively) from temporary caval occlusion were analyzed with generalized linear mixed-effects and linear mixed models. Transmural pressures were calculated using esophageal balloons. RESULTS: τ values for intracavitary cardiac pressure increased with the PEEP (n = 25; no PEEP, 44 ± 5 ms; 5 cmH2O PEEP, 46 ± 6 ms; 10 cmH2O PEEP, 45 ± 6 ms; p < 0.001). This increase disappeared when corrected for transmural pressure and diastole length. The transmural EDPVR was unaffected by PEEP. The ESPVR increased slightly with PEEP. Echocardiographic mitral inflow parameters and tissue Doppler values decreased with PEEP [peak E wave (n = 25): no PEEP, 0.76 ± 0.13 m/s; 5 cmH2O PEEP, 0.74 ± 0.14 m/s; 10 cmH2O PEEP, 0.68 ± 0.13 m/s; p = 0.016; peak A wave (n = 24): no PEEP, 0.74 ± 0.12 m/s; 5 cmH2O PEEP, 0.7 ± 0.11 m/s; 10 cmH2O PEEP, 0.67 ± 0.15 m/s; p = 0.014; E' septal (n = 24): no PEEP, 0.085 ± 0.016 m/s; 5 cmH2O PEEP, 0.08 ± 0.013 m/s; 10 cmH2O PEEP, 0.075 ± 0.012 m/s; p = 0.002]. CONCLUSIONS: PEEP does not affect active diastolic relaxation or passive ventricular filling properties. Dynamic echocardiographic filling parameters may reflect changing loading conditions rather than intrinsic diastolic function. PEEP may have slight positive inotropic effects. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02267291 , registered 17. October 2014.

Critical Appraisal of Large Vitamin D Randomized Controlled Trials.

As a consequence of epidemiological studies showing significant associations of vitamin D deficiency with a variety of adverse extra-skeletal clinical outcomes including cardiovascular diseases, cancer, and mortality, large vitamin D randomized controlled trials (RCTs) have been designed and conducted over the last few years. The vast majority of these trials did not restrict their study populations to individuals with vitamin D deficiency, and some even allowed moderate vitamin D supplementation in the placebo groups. In these RCTs, there were no significant effects on the primary outcomes, including cancer, cardiovascular events, and mortality, but explorative outcome analyses and meta-analyses revealed indications for potential benefits such as reductions in cancer mortality or acute respiratory infections. Importantly, data from RCTs with relatively high doses of vitamin D supplementation did, by the vast majority, not show significant safety issues, except for trials in critically or severely ill patients or in those using very high intermittent vitamin D doses. The recent large vitamin D RCTs did not challenge the beneficial effects of vitamin D regarding rickets and osteomalacia, that therefore continue to provide the scientific basis for nutritional vitamin D guidelines and recommendations. There remains a great need to evaluate the effects of vitamin D treatment in populations with vitamin D deficiency or certain characteristics suggesting a high sensitivity to treatment. Outcomes and limitations of recently published large vitamin D RCTs must inform the design of future vitamin D or nutrition trials that should use more personalized approaches.

Effects of Vitamin D Supplementation on 24-Hour Blood Pressure in Patients with Low 25-Hydroxyvitamin D Levels: A Randomized Controlled Trial.

Accumulating evidence suggests that potential cardiovascular benefits of vitamin D supplementation may be restricted to individuals with very low 25-hydroxyvitamin D (25(OH)D) concentrations; the effect of vitamin D on blood pressure (BP) remains unclear. We addressed this issue in a post hoc analysis of the double-blind, randomized, placebo-controlled Styrian Vitamin D Hypertension Trial (2011−2014) with 200 hypertensive patients with 25(OH)D levels <30 ng/mL. We evaluated whether 2800 IU of vitamin D3/day or placebo (1:1) for 8 weeks affects 24-hour systolic ambulatory BP in patients with 25(OH)D concentrations <20 ng/mL, <16 ng/mL, and <12 ng/mL and whether achieved 25(OH)D concentrations were associated with BP measures. Taking into account correction for multiple testing, p values < 0.0026 were considered significant. No significant treatment effects on 24-hour BP were observed when different baseline 25(OH)D thresholds were used (all p-values > 0.30). However, there was a marginally significant trend towards an inverse association between the achieved 25(OH)D level with 24-hour systolic BP (−0.196 per ng/mL 25(OH)D, 95% CI (−0.325 to −0.067); p = 0.003). In conclusion, we could not document the antihypertensive effects of vitamin D in vitamin D-deficient individuals, but the association between achieved 25(OH)D concentrations and BP warrants further investigations on cardiovascular benefits of vitamin D in severe vitamin D deficiency.

Associations of Serum Cortisol with Cardiovascular Risk and Mortality in Patients Referred to Coronary Angiography.

CONTEXT: Serum cortisol may be associated with cardiovascular risk factors and mortality in patients undergoing coronary angiography, but previous data on this topic are limited and controversial. OBJECTIVE: We evaluated whether morning serum cortisol is associated with cardiovascular risk factors, lymphocyte subtypes, and mortality. METHODS: This is a prospective cohort study performed at a tertiary care centre in south-west Germany between 1997 and 2000. We included 3052 study participants who underwent coronary angiography. The primary outcome measures were cardiovascular risk factors, lymphocyte subtypes, and all-cause and cardiovascular mortality. RESULTS: Serum cortisol was associated with an adverse cardiovascular risk profile, but there was no significant association with coronary artery disease or acute coronary syndrome. In a subsample of 2107 participants, serum cortisol was positively associated with certain lymphocyte subsets, including CD16+CD56+ (natural killer) cells (P < 0.001). Comparing the fourth versus the first serum cortisol quartile, the crude Cox proportional hazard ratios (with 95% CIs) were 1.22 (1.00-1.47) for all-cause and 1.32 (1.04-1.67) for cardiovascular mortality, respectively. After adjustments for various cardiovascular risk factors, these associations were attenuated to 0.93 (0.76-1.14) for all-cause, and 0.97 (0.76-1.25) for cardiovascular mortality, respectively. CONCLUSIONS: Despite significant associations with classic cardiovascular risk factors and natural killer cells, serum cortisol was not a significant and independent predictor of mortality in patients referred to coronary angiography. These findings might reflect that adverse cardiovascular effects of cortisol could be counterbalanced by some cardiovascular protective actions.