Vitamin D supplementation and bone turnover in advanced heart failure: the EVITA trial.

Low vitamin D status is common in patients with heart failure and may influence bone health. A daily vitamin D dose of 4000 IU (moderately high dose) for 3 years had however no effect on parameters of bone metabolism, even in patients with very low vitamin D status. INTRODUCTION: Low vitamin D status is common in patients with heart failure (HF) and has been related to disturbed bone turnover. The present study investigated the effect of a daily vitamin D3 dose of 4000 IU on bone turnover markers (BTMs) in patients with advanced HF and 25-hydroxyvitamin D (25OHD) concentrations < 75 nmol/L. METHODS: In this pre-specified secondary analysis of a randomized controlled trial, we assessed in 158 male HF patients (vitamin D group: n = 80; placebo group: n = 78) between-group differences in calciotropic hormones (25OHD, 1,25-dihydroxyvitamin D [1,25(OH)2D], intact parathyroid hormone [iPTH]), and BTMs (cross-linked C-telopeptide of type I collagen, bone-specific alkaline phosphatase, undercarboxylated osteocalcin). Comparisons were performed at the end of a 3-year vitamin D supplementation period with adjustments for baseline values. RESULTS: Compared with placebo, vitamin D increased 25OHD on average by 54.3 nmol/L. At study termination, 25OHD and 1,25(OH)2D were significantly higher (P < 0.001 and P = 0.007, respectively), whereas iPTH tended to be lower in the vitamin D group than in the placebo group (P = 0.083). BTMs were initially within their reference ranges and did not differ significantly between groups at study termination, neither in the entire study cohort nor when data analysis was restricted to the subgroup of patients with initial 25OHD concentrations < 30 nmol/L (n = 54) or to patients with initial hyperparathyroidism (n = 65) (all P values > 0.05). CONCLUSIONS: A daily vitamin D3 dose of 4000 IU did not influence BTMs. Data indicate that vitamin D supplementation will not lower bone turnover in male patients with heart failure.

Randomized supplementation of 4000 IU vitamin D3 daily vs placebo on the prevalence of anemia in advanced heart failure: the EVITA trial.

BACKGROUND: Low 25-hydroxyvitamin D (25OHD) levels (< 75 nmol/l) are inversely associated with anemia prevalence. Since anemia and low 25OHD levels are common in patients with heart failure (HF), we aimed to investigate whether vitamin D supplementation can reduce anemia prevalence in advanced HF. METHODS: EVITA (Effect of Vitamin D on Mortality in Heart Failure) is a randomized, placebo-controlled clinical trial in patients with initial 25OHD levels < 75 nmol/l. Participants received either 4000 IU vitamin D3 daily or a matching placebo for 36 months. A total of 172 patients (vitamin D group: n = 85; placebo group: n = 87) were investigated in this pre-specified secondary data analysis. Hemoglobin (Hb) and other hematological parameters were measured at baseline and study termination. Assessment of between-group differences in anemia prevalence and Hb concentrations was performed at study termination, while adjusting for baseline differences. RESULTS: In the vitamin D and placebo group, baseline proportions of patients with anemia (Hb < 12.0 g/dL in females and < 13.0 g/dL in males) were 17.2% and 10.6%, respectively (P = 0.19). At study termination, the proportion of patients with anemia in the vitamin D and placebo groups was 32.2% and 31.8%, respectively (P > 0.99). There was no between-group difference in change in the Hb concentrations (- 0.04 g/dL [95%CI:-0.53 to 0.45 g/dL]; P = 0.87). Results regarding anemia risk and Hb concentrations were similar in the subgroup of patients with chronic kidney disease (vitamin D group: n = 26; placebo group: n = 23). Moreover, results did not differ substantially when data analysis was restricted to patients with deficient baseline 25OHD levels. CONCLUSIONS: A daily vitamin D supplement of 4000 IU did not reduce anemia prevalence in patients with advanced HF. Data challenge the clinical relevance of vitamin D supplementation to increase Hb levels. TRIAL REGISTRATION: The study was registered at EudraCT (No. 2010-020793-42) and clinicaltrials.gov ( NCT01326650 ).

Vitamin D metabolites and fibroblast growth factor-23 in patients with left ventricular assist device implants: association with stroke and mortality risk.

PURPOSE: Stroke and mortality risk in patients with left ventricular assist device (LVAD) implants continue to be high. Whether nonclassical cardiovascular risk markers such as vitamin D metabolites and fibroblast growth factor (FGF)-23 contribute to this risk remains to be studied, and this was the objective of our work. METHODS: In 154 LVAD patients (91 HeartWare and 63 HeartMate II implants), we measured circulating 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), parathyroid hormone (PTH) and FGF-23 shortly before LVAD implantation and investigated their association with stroke and mortality risk during 1-year follow-up. RESULTS: Of the study cohort, 34.4 and 92.2%, respectively, had deficient 25OHD (<25 nmol/l) and 1,25(OH)2D3 (<41 pmol/l) values, whereas 42.6 and 98.7%, respectively, had elevated PTH levels (>6.7 pmol/l) and FGF-23 values above the reference range (100 RU/ml). One-year freedom from stroke was 80.9 %, and 1-year survival was 64.3%. The multivariable-adjusted hazard ratio of stroke was 2.44 (95% CI: 1.09-5.45; P = 0.03) for the subgroup of 25OHD levels <25 nmol/l (reference group: 25OHD levels ≥25 nmol/l). The multivariable-adjusted hazard ratio of 1-year mortality was 2.78 (95% CI: 1.52-5.09; P = 0.001) for patients with 25OHD levels <25 nmol/l compared with patients with 25OHD levels ≥25 nmol/l. PTH, FGF-23 and 1,25(OH)2D3 were not associated with stroke or mortality risk. CONCLUSIONS: In LVAD patients, deficient 25OHD levels are independently associated with high stroke and mortality risk. If confirmed in randomized controlled trials, preoperative correction of deficient vitamin D status could be a promising measure to reduce stroke and mortality risk in LVAD patients.

Association between circulating 25-hydroxyvitamin D levels and medication use in patients scheduled for cardiac surgery.

BACKGROUND AND AIM: Low vitamin D status, i.e. circulating 25-hydroxyvitamin D (25OHD) levels <50 nmol/l, is independently associated with increased CVD risk. Medication use may influence 25OHD levels. We therefore investigated the association of circulating 25OHD with medication use in patients scheduled for cardiac surgery. METHODS AND RESULTS: A total of 11,256 patients were included in this cross-sectional study. We compared 25OHD levels of medication users (18 groups of continuously used and 5 groups of intermittently used medications) with levels of non-users. Moreover, we assessed variables (medications, demographic and clinical parameters) that were independently associated with 25OHD levels <50 nmol/l. The prevalence of 25OHD levels <50 nmol/l was 65.7%. The use of statins and immunosuppressive agents was significantly associated with higher 25OHD levels and lower odds ratios of 25OHD levels <50 nmol/l. The use of ACE-inhibitors, catecholamines and antibiotics was associated with lower 25OHD levels and higher odds ratios of 25OHD levels <50 nmol/l. However, only use of antibiotics, immunosuppressive agents and catecholamines showed clinically relevant differences in 25OHD levels, i.e. differences of more than +4 nmol/l or -4 nmol/l, compared with respective non-users. These medications were prescribed either intermittently (antibiotics, catecholamines) and/or infrequently (<2%; immunosuppressive agents, catecholamines) and/or its causal relationship with circulating 25OHD is questionable (antibiotics). Female sex and blood drawing during wintertime were associated with the highest odds ratios of 25OHD levels <50 nmol/l. CONCLUSION: Data indicate that in patients with high cardiovascular risk profile medication use does not substantially contribute to 25OHD levels <50 nmol/l.

Body mass index, cardiac surgery and clinical outcome. A single-center experience with 9125 patients.

BACKGROUND AND AIM: There is evidence for a J-shaped association between Body Mass Index (BMI) and all-cause mortality in general populations. In cardiac surgical patients, the effect of BMI on mortality and major adverse cardiac and cerebrovascular events (MACCE) is not completely clear. METHODS AND RESULTS: We investigated the effect of BMI on MACCE (primary endpoint), as well as intensive care unit (ICU)-related outcomes and mid-term mortality in 9125 consecutive patients who were operated on at our institution between July 2009 and July 2012. Of the study cohort, 3.0% were underweight (BMI < 20 kg/m(2)), 28.0% had a normal BMI (20-24.99 kg/m(2)), 43.1% were overweight (BMI 25-29.99 kg/m(2)), 19.3% were obese (BMI 30-34.99 kg/m(2)), and 6.6% were severely obese (BMI ≥ 35 kg/m(2)). Compared with overweight patients (lowest incidence of MACCE), the multivariable-adjusted odds ratio of MACCE in severely obese patients was 1.39 (95% CI: 1.03-1.87). Underweight and severely obese patients had the longest risk-adjusted duration of mechanical ventilator support and ICU stay (P-values 0.004-0.001). The red blood cell concentrates requirement was highest in underweight patients (P < 0.001). Compared with normal and overweight patients, the multivariable-adjusted hazard ratio of 2-year mortality was higher in underweight patients (1.72 [95% CI: 1.26-2.36] and =2.07 [95% CI: 1.51-2.83], respectively), but did not differ significantly in severely obese patients. CONCLUSION: Data demonstrate that both severe obesity and underweight are independent risk factors for operative complications in cardiac surgical patients. With respect to mid-term survival, special attention should be paid to underweight patients scheduled for cardiac surgery.

Cardiac surgery in Germany during 2013: a report on behalf of the German Society for Thoracic and Cardiovascular Surgery.

On the basis of a voluntary registry of the German Society for Thoracic and Cardiovascular Surgery (GSTCVS), data of all cardiac surgical procedures performed in 79 German cardiac surgical units during the year 2013 are presented. In 2013, a total of 99,128 cardiac surgical procedures (implantable cardioverter defibrillator [ICD] and pacemaker procedures excluded) were submitted to the registry. More than 13.8% of the patients were older than 80 years, which remains equal in comparison to the previous year. In-hospital mortality in 40,410 isolated coronary artery bypass grafting procedures (84.5% on-pump and 15.5% off-pump) was 2.9%. In 29,672 isolated valve procedures (including 7,722 catheter-based procedures), an in-hospital mortality of 4.7% was observed. This long-lasting registry of the GSTCVS will continue to be an important tool for quality control and voluntary public reporting by illustrating current facts and developments of cardiac surgery in Germany.

Determinants of circulating calcitriol in cardiovascular disease.

Circulating calcitriol may contribute to the risk of cardiovascular disease (CVD), but its regulation in patients with CVD is poorly characterized. We therefore aimed to assess determinants of circulating calcitriol in these patients. We analyzed 2183 independent samples from a large cohort of patients scheduled for coronary angiography and 1727 independent samples from different other cohorts from patients with a wide range of CVDs, including heart transplant candidates, to quantify the association of different parameters with circulating calcitriol. We performed univariable and multivariable linear regression analyses using the mathematical function that fitted best with circulating calcitriol. In the multivariable analysis of the large single cohort, nine parameters remained significant, explaining 30.0 % (32.4 % after exclusion of 22 potential outliers) of the variation in circulating calcitriol (r=0.548). Log-transformed 25-hydroxyvitamin D [25(OH)D] and log-transformed glomerular filtration rate were the strongest predictors, explaining 17.6 % and 6.6 %, respectively, of the variation in calcitriol. In the analysis of the combined other cohorts, including heart transplant candidates, the multivariable model explained a total of 42.6 % (46.1 % after exclusion of 21 potential outliers) of the variation in calcitriol (r=0.653) with log-transformed fibroblast growth factor-23 and log-transformed 25(OH)D explaining 29.0 % and 6.2 %, respectively. Circulating 25(OH)D was positively and FGF-23 inversely associated with circulating calcitriol. Although significant, PTH was only a weak predictor of calcitriol in both analyses (<2.5 %). In patients with CVD, FGF-23 and 25(OH)D are important independent determinants of circulating calcitriol. The relative importance of these two parameters may vary according to CVD severity. Future studies should focus on the clinical importance of regulating circulating calcitriol by different parameters.

Future directions in vitamin D and cardiovascular research.

AIMS: Evidence is accumulating that vitamin D status may influence the risk of cardiovascular disease (CVD). Final confirmation for a causal relationship between vitamin D and CVD is however still lacking. The present viewpoint article outlines several future research directions to close this gap. DATA SYNTHESIS: Future directions include the need of performing large randomised controlled supplementation trials with vitamin D in specific risk groups. In addition, large register sets of data on vitamin D supplementation can be used, provided that adequate statistical methods such as propensity score modelled analysis are applied. To better understand vitamin D-mediated effects on CVD risk, the routine measurement of circulating levels of the hormonal vitamin D form, 1,25-dihydroxyvitamin D, is also necessary, in addition to the determination of its precursor 25-hydroxyvitamin D. Further, genetic association studies may help in clarifying the contribution of vitamin D to the development of CVD. Finally, the interrelationship of vitamin D with physical activity should be considered when studying CVD risk. CONCLUSIONS: Overall, it can be expected that the next 10-15 years will provide an increased clarity concerning the role of vitamin D in CVD.

Bosentan effects on hemodynamics and clinical outcome in heart failure patients with pulmonary hypertension awaiting cardiac transplantation.

BACKGROUND: In heart failure (HF) patients, pulmonary hypertension (PH) is associated with a poor prognosis. We assessed whether low dose treatment with the dual endothelin-1 receptor antagonist bosentan is associated with improved hemodynamics and clinical outcome in these patients. METHODS: We performed a retrospective data analysis in 82 end-stage heart failure patients on the waiting list for cardiac transplantation since January 2006. All patients had pulmonary arterial pressure >35 mmHg, pulmonary vascular resistance >240 dyn × s × cm-5, and/or a transpulmonary gradient (TPG) >15 mmHg. Fifty-four patients received a median dose of 125 mg bid bosentan (BOS group), and 28 patients received standard medical treatment (CON group). Data were assessed until June 2009. RESULTS: Hemodynamic parameters improved significantly in the BOS group but remained unchanged in the CON group. The percentage of patients who fell below the thresholds of PAP, PVR, and TPG for cardiac transplantation increased significantly by 20.3%, 34.5%, and 20.8%, respectively (p = 0.007-0.013) in the BOS group, but did not change significantly in the CON group. One-year survival on the waiting list was approximately 20% higher in the BOS group than in the CON group (p = 0.020). Bosentan treatment remained an independent predictor of reduced mortality risk on the waiting list after propensity score adjustment (relative risk = 0.107; 95% CI: 0.013-0.869; p = 0.036). CONCLUSION: Treatment with the endothelin-1 antagonist bosentan is associated with improvements in hemodynamics and clinical outcome in end-stage heart failure patients with PH. If these results can be confirmed by randomized controlled trials, bosentan may represent a treatment option in these patients.

Erdheim-Chester disease in a female cardiac surgery patient.

We report a case of Erdheim-Chester disease (ECD) with isolated cardiac involvement in a 74-year-old female patient. The patient initially presented with superior vena cava syndrome and PET-CT imaging demonstrating an obstructing hypermetabolic lesion in the right atrium, and a distinct nonobstructing hypermetabolic lesion in the left atrium, expected to be malignant. There was no evidence of extracardiac disease. At surgical exploration, consistent with malignancy, the right atrial tumor was found to have grown into the pericardium and was resected to address symptoms and for histological diagnosis which revealed ECD on immunohistochemistry. We conclude that isolated cardiac ECD should be included in the surgical strategy for cardiac tumors showing infiltrative growth.

An Intervention Trial for Strengthening Medical Adherence after Heart Transplantation.

INTRODUCTION: In heart transplant recipients, nonadherence is associated with higher risk of morbidity and mortality. RESEARCH QUESTION: Can a psychoeducational intervention enhance adherence to medical recommendations? DESIGN: We randomized 200 patients awaiting heart transplantation on the high urgency wait list to a manualized psychoeducational intervention or standard care. Follow-up continued to three years after transplantation. Primary endpoint was adherence to immunosuppressive medication, assessed at 3, 6, 12, 24, and 36 months posttransplant. Secondary endpoints were barriers to adherence during follow-up and clinical outcomes, including cardiac rejection within the first postoperative year and postoperative 3-year mortality. RESULTS: Fifty patients died before or within the first 3 months of transplantation. The primary endpoint was analyzed in 66 patients in the intervention group and 66 in the control group. Both study groups showed almost maximal adherence to immunosuppressive medication throughout follow-up, with no significant time x treatment interaction (P>0.99). Likewise, there was no significant time x treatment interaction (P=0.41) on barriers to adherence. The percentage of patients with International Society for Heart and Lung Transplantation standard grade 1 and 2 rejection was in the intervention and control groups 82.5% and 78.7%, respectively, and 8.8% and 13.1%, respectively, without significant differences between study groups (P=0.75). Considering all randomized and transplanted patients in the intervention group (N=85) and control group (N=87), postoperative 3-year mortality was 29.4% and 27.6%, respectively (P=0.82). CONCLUSIONS: Adherence to immunosuppressive medication was high, even without a complex, manualized psychoeducational intervention. The intervention had no significant positive impact on cardiac rejection and mortality.

Cardiac surgery in Germany during 2010: a report on behalf of the German Society for Thoracic and Cardiovascular Surgery.

All cardiac surgical procedures performed in 79 German cardiac surgical units throughout the year 2010 are presented in this report, based on a voluntary registry which is organized by the German Society for Thoracic and Cardiovascular Surgery. In 2010 a total of 95,734 cardiac surgical procedures (ICD and pacemaker procedures excluded) have been collected in this registry. More than 12.4% of the patients were older than 80 years compared to 11.8% in 2009. Hospital mortality in 42,804 isolated CABG procedures (14.2% off-pump procedures) was 2.8%. In 25,127 isolated valve procedures (including 3660 transcatheter-valve implantations) a mortality of 4.9% has been observed. This voluntary registry of the German Society for Thoracic and Cardiovascular Surgery will continue to be an important tool enabling quality control and illustrating the development of cardiac surgery in Germany.

Diffusion-weighted magnetic resonance imaging for the detection of ischemic brain lesions in coronary artery bypass graft surgery: relation to extracorporeal circulation and heparinization.

AIM: Cognitive decline is a well recognized complication after on-pump coronary artery bypass graft (CABG) surgery. We investigated whether the design of extracorporeal circulation (ECC) and the extent of perioperative heparinization have an impact on neurological dysfunction. METHODS: Sixty-three CABG surgery patients were randomly perfused with an uncoated ECC-set (group A) or with two different heparin-coated ECC-sets (groups B and C). In groups A and B, systemic heparin was given in doses of 400 IU/kg body weight, whereas group C received 150 IU/kg body weight. ECC sets in group C included a diagonal pump and low priming as opposed to roller pumps in groups A and B. Furthermore, in group C blood contact to surfaces other than endothelium and heparin coated material was eliminated. Brain lesions were detected by diffusion-weighted magnetic resonance imaging (DWI). Neurological complications were assessed clinically until discharge (manifest motoric, sensitive or cognitive disturbance). Biochemical coagulation and inflammation parameters were measured pre-, peri-, and postoperatively. RESULTS: No major neurological events were observed in either group until discharge. DWIs showed 61 new lesions in 19 of 45 patients who terminated all MRI study procedures. Number and volume of the lesions did not differ between groups (P>0.05). Biochemical and inflammatory parameters showed the expected time courses and variations between groups. CONCLUSION: Ischemic brain lesions are frequently observed in CABG surgery patients but are neither associated with clinically relevant neurological complications nor with ECC set-up and intraoperative heparin dosage. DWI may help in the development of new surgical strategies to reduce postoperative brain damage.

Cardiac surgery in Germany during 2009. A report on behalf of the German Society for Thoracic and Cardiovascular Surgery.

All cardiac surgical procedures performed in 80 German cardiac surgical units throughout the year 2009 are presented in this report, based on a voluntary registry which is organized by the German Society for Thoracic and Cardiovascular Surgery. In 2009 a total of 96 129 cardiac surgical procedures (excluding ICD and pacemaker procedures) were collected in this registry. More than 11.8 % of the patients were older than 80 years compared to 10.3 % in 2008. Hospital mortality in 45 171 isolated CABG procedures (13.1 % off-pump) was 2.8 %. In 23 556 isolated valve procedures (including 2216 catheter-based procedures) a mortality of 4.7 % was observed. This voluntary registry of the German Society for Thoracic and Cardiovascular Surgery continues to be an important tool for quality control and illustrates the development of cardiac surgery in Germany.

Cardiac surgery in Germany during 2008. A report on behalf of the German Society for Thoracic and Cardiovascular Surgery.

All cardiac surgical procedures performed in 79 German cardiac surgical units throughout the year 2008 are illustrated in this report, based on a voluntary registry which is organized by the German Society for Thoracic and Cardiovascular Surgery. In 2008 a total of 99 176 cardiac surgical procedures (ICD and pacemakers procedures excluded) have been collected. More than 10.3 % of the patients were older than 80 years compared to 9.8 % in 2007. Hospital mortality in 47 337 isolated CABG procedures (11.3 % off-pump) was 2.8 %. In 22 243 isolated valve procedures a mortality of 4.7 % has been observed. This voluntary registry of the German Society for Thoracic and Cardiovascular Surgery continues to be an important tool enabling quality control and illustrating the development of cardiac surgery in Germany.

Heart Transplantation in Systemic Sclerosis: New Impulses for Conventional Scleroderma Transplantation Regimen and Scleroderma Diagnostic Monitoring: 2 Case Reports.

BACKGROUND: Although low (but increasing) rates of lung/lung-heart transplantations of scleroderma (systemic sclerosis [SSc]) patients have been reported, exclusive heart transplantation is a rare approach for treatment of heart failure due to SSc. CASES: We report on 2 cases of SSc patients receiving a heart transplantation (HTx) due to severe and progressive right heart failure without pulmonary artery hypertension. One patient received a hepatitis C virus (HCV)-positive donor heart and recovered excellently from viral transmission after administration of a direct-acting antiviral (DAA) regimen. This is the first published case of an SSc patient who underwent HTx using an HCV-positive donor heart. The clinical course of both patients was monitored by different serum SSc biomarkers. Only xylosyltransferase activity proved to be a promising biomarker for disease stage determination and therapeutic monitoring, precisely reflecting fibrotic remodeling and successful organ recovery. CONCLUSIONS: Successful implementation of the 2 cases described here demonstrates that HTx is a safe and effective therapeutic option for defined SSc sub-patient groups despite the progressive character of the underlying disease. In the future, xylosyltransferase activity might be conducive to simplify the identification of patients with low systemic involvement but a strong indication for single heart transplantation. Finally, we demonstrate that treatment of HCV viral transmission from HCV-positive donor to organ recipient using DAA gives us new opportunities to consider HCV-positive donor organs for HTx and might reveal new possibilities to ease the lack of donor organs.

Vitamin D supplementation of 4000 IU daily and cardiac function in patients with advanced heart failure: The EVITA trial.

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 D3 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 25­hydroxyvitamin 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 ±â€¯10.5 mm, 58.9 ±â€¯12.0 mm, and 30.47 ±â€¯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.

Pharmacodynamics of T-cell function for monitoring immunosuppression.

OBJECTIVES: Recent studies show that measuring pharmacodynamic (PD) effects offers a unique possibility to predict immunosuppression. Thus, in this study we have monitored the PD properties of immunosuppressants on diverse T-cell functions in heart transplant (HTx) recipients. MATERIALS: PDs and blood concentrations (PK) of three different basis-immunosuppressive drugs were studied: cyclosporin A (CsA); tacrolimus (TRL) and sirolimus (SRL). T-cell function was analysed by expression of proliferating cell nuclear antigen (PCNA) labelling, expression of cytokines (IL-2, IFN-gamma) and surface antigen (for example, CD25) by FACS analysis. RESULTS: In group I, at time points C0 and C2, increased CsA-PK significantly inhibited expression of IL-2, IFN-gamma, PCNA and CD25 (P < 0.05). Correlations (r(2)) at C2 between inhibition of T-cell functions (PD) with PK and with drug doses were: CsA-PK: 0.71-0.91 and CsA-dose: 0.73-0.87. In group II, increased TRL-PK over time did not further inhibit expression of CD25, but inhibited PCNA expression more on day 3, and IL-2 and IFN-gamma expression was significantly higher on days 2 and 3 compared to PD effects of CsA (P < 0.05). Blood SRL concentrations in C0 group III, increased on day 1 and remained stable at days 3 and 4. Expression of PCNA was not altered in the SRL-PK category, whereas expression of CD25 was higher and expression of cytokines was lower than PD effects of CsA. CONCLUSIONS: Our results show that PD effects on T-cell function can be used to monitor immunosuppression bringing potential to increase the efficacy and safety of immunosuppressive therapy after HTx.

Anastomotic devices for coronary artery bypass grafting: technological options and potential pitfalls.

With the advent of off-pump coronary artery bypass grafting and minimally invasive coronary artery bypass grafting, significant efforts have been made to facilitate construction of the graft to coronary anastomosis. As a result, a number of anastomotic devices have been developed. While the ideal anastomotic device should be easy to use, to produce a geometrically optimal anastomosis with minimal endothelial damage and minimal blood-exposed non-intimal surface, a number of design constraints apply. This review collects the available pre-clinical and clinical data for some of the devices with special regard for surgical outcome, patency rate and the need for additional perioperative anticoagulation treatment.

Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase.

BACKGROUND: In stable coronary artery disease (CAD), exercise training has well-documented positive effects on arterial endothelial function. NO derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. The aim of the present study was to investigate the effects of exercise training on the endothelial function in relation to the expression of eNOS and Akt-dependent eNOS phosphorylation in the left internal mammary artery (LIMA) of patients with stable CAD. METHODS AND RESULTS: In 17 training patients (T) and 18 control patients (C), endothelium-dependent vasodilation and average peak flow velocity (APV) in response to acetylcholine were measured invasively at study beginning and after 4 weeks in the LIMA. In LIMA tissue sampled during bypass surgery, eNOS expression and content of pospho-eNOS-Ser1177, Akt, and phospho-Akt were determined by Western blot and quantitative reverse transcriptase-polymerase chain reaction. After exercise training, LIMA APV in response to acetylcholine was increased by 56+/-8% (from +48+/-8% at beginning to +104+/-11% after 4 weeks, P<0.001). Patients in T had a 2-fold higher eNOS protein expression (T 1.0+/-0.7 versus C 0.5+/-0.3 arbitrary units, P<0.05) and 4-fold higher eNOS Ser1177-phosphorylation levels in LIMA-endothelium (1.2+/-0.9 versus 0.3+/-0.2 arbitrary units, P<0.01). A linear correlation was confirmed between Akt phosphorylation and phospho-eNOS levels (R=0.80, P<0.05) and between phospho-eNOS and Delta APV (R=0.59, P<0.05). CONCLUSIONS: Exercise training in stable CAD leads to an improved agonist-mediated endothelium-dependent vasodilatory capacity. The change in acetylcholine-induced vasodilatation was closely related to a shear stress-induced/Akt-dependent phosphorylation of eNOS on Ser1177.