Gero Tenderich

Low vitamin D status: A contributing factor in the pathogenesis of congestive heart failure?

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.

Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts : Role of late sodium current and intracellular ion accumulation

The goal of this study was to test the hypothesis that the novel anti-ischemic drug ranolazine, which is known to inhibit late I(Na), could reduce intracellular [Na(+)](i) and diastolic [Ca(2+)](i) overload and improve diastolic function. Contractile dysfunction in human heart failure (HF) is associated with increased [Na(+)](i) and elevated diastolic [Ca(2+)](i). Increased Na(+) influx through voltage-gated Na(+) channels (late I(Na)) has been suggested to contribute to elevated [Na(+)](i) in HF. In isometrically contracting ventricular muscle strips from end-stage failing human hearts, ranolazine (10 micromol/L) did not exert negative inotropic effects on twitch force amplitude. However, ranolazine significantly reduced frequency-dependent increase in diastolic tension (i.e., diastolic dysfunction) by approximately 30% without significantly affecting sarcoplasmic reticulum (SR) Ca(2+) loading. To investigate the mechanism of action of this beneficial effect of ranolazine on diastolic tension, Anemonia sulcata toxin II (ATX-II, 40 nmol/L) was used to increase intracellular Na(+) loading in ventricular rabbit myocytes. ATX-II caused a significant rise in [Na(+)](i) typically seen in heart failure via increased late I(Na). In parallel, ATX-II significantly increased diastolic [Ca(2+)](i). In the presence of ranolazine the increases in late I(Na), as well as [Na(+)](i) and diastolic [Ca(2+)](i) were significantly blunted at all stimulation rates without significantly decreasing Ca(2+) transient amplitudes or SR Ca(2+) content. In summary, ranolazine reduced the frequency-dependent increase in diastolic tension without having negative inotropic effects on contractility of muscles from end-stage failing human hearts. Moreover, in rabbit myocytes the increases in late I(Na), [Na(+)](i) and [Ca(2+)](i) caused by ATX-II, were significantly blunted by ranolazine. These results suggest that ranolazine may be of therapeutic benefit in conditions of diastolic dysfunction due to elevated [Na(+)](i) and diastolic [Ca(2+)](i).

Novacor left ventricular assist system versus heartmate vented electric left ventricular assist system as a long-term mechanical circulatory support device in bridging patients: A prospective study

OBJECTIVE Long-term mechanical circulatory support as a bridge-to-transplantation procedure and bridge to recovery is of increasing importance. The implantable left ventricular assist devices, Novacor N100 left ventricular assist system (Baxter Healthcare Corporation, Berkeley, Calif) and TCI HeartMate vented electric left ventricular assist system (Thermo Cardiosystems Inc, Woburn, Mass), have proved to be efficient devices in bridge-to-transplantation settings and for prolonged support. The two systems were compared with regard to reliability and morbidity. METHODS Between October 1996 and March 1998, a prospective, single-center study was done that included 40 patients, 20 of whom were treated with the Novacor system and 20 of whom were treated with the HeartMate device. The diseases were mainly dilated cardiomyopathy (13/9) and ischemic cardiomyopathy (6/10). There were no statistically significant differences between the two groups regarding age, sex, preoperative clinical blood chemistry values, hemodynamic data, or risk factors. RESULTS There were no statistically significant differences between the two groups with regard to postoperative hemodynamics, organ recovery, out-of-hospital support, and survival to heart transplantation. Mean duration of support was 235.3 +/- 210 days for the Novacor group and 174.6 +/- 175 days for the HeartMate group and mean out-of-hospital support was 241 +/- 179 days and 166 +/- 152 days for the two groups, respectively. Neurologic complications occurred significantly more often among the Novacor group, whereas the HeartMate group had a higher prevalence of infections and technical problems, which was statistically significant. Survival to transplantation was 65% for the Novacor group and 60% for the HeartMate group. CONCLUSIONS Most patients had organ recovery with left ventricular assist system support, and a considerable number of patients in both groups underwent transplantation. However, both devices need revision to address the current problems, that is, thromboembolism for the Novacor device and infection and reliability for the HeartMate device.

Poor outcome in end‐stage heart failure patients with low circulating calcitriol levels

Vitamin D receptor knockout mice develop typical signs of congestive heart failure (CHF). In approximately 20% of stable CHF patients, frankly low concentrations of the vitamin D hormone calcitriol are found.

Predictors of survival in patients bridged to transplantation with the Thoratec VAD device: a single-center retrospective study on more than 100 patients

BACKGROUND Careful patient selection markedly influences the outcome of patients who undergo mechanical circulatory support. Therefore, we tried to evaluate predictors of survival after implantation of the Thoratec ventricular assist device (VAD). METHODS Between October 1992 and January 2000, 104 patients (86 men, 18 women, aged 11 to 69 years) received the Thoratec VAD as a bridge to transplant. A total of 51 patients required left ventricular support (LVAD), 50 patients required biventricular support (BVAD), and 3 patients required total artificial heart implantation. We performed univariate analysis of 25 parameters with regard to their effect on survival and then applied a multivariate analysis to evaluate those factors that turned out to be marginally significant. We performed all analysis for the total collective as well as for the LVAD and BVAD sub-group. RESULTS The BVAD patients tended to have worse outcomes than did LVAD patients. We found no significant predictors of survival in either sub-group. In the total collective, however, we found the following pre-implant conditions were independent risk factors for survival after VAD implantation: patient age > 60 years (odds ratio [OR] 3.87, confidence interval [CI] 1.39 to 10.76), pre-implant ventilation (OR, 6.76; CI 2.42 to 18.84), and increased pre-implant total bilirubin (OR, 1.42; CL, 1.19 to 1.69). CONCLUSIONS Transplant candidates on inotropic support should be considered for bridging to transplant as soon as bilirubin values start to increase or before respiratory function deteriorates and ventilation becomes necessary. In elderly patients, careful patient selection, particularly considering potential risk factors, might favorably affect their outcomes.

Mycophenolate and sirolimus as calcineurin inhibitor-free immunosuppression improves renal function better than calcineurin inhibitor-reduction in late cardiac transplant recipients with chronic renal failure.

Background. Calcineurin-inhibitor-(CNI)-induced renal failure is one major cause of morbidity in cardiac transplantation (HTx). In this prospective, randomized, multicenter trial, the impact of immunosuppressive conversion toward CNI-free (mycophenolate mofetil [MMF] and sirolimus) or a CNI-reduced immunosuppressive regimen on renal function, efficacy, and safety was evaluated. Methods. Since 2004, 63 HTx-patients (0.5–18.4 years after HTx) with CNI-based immunosuppression and reduced creatinine clearance less than 60 mL/min (39±15 mL/min) were included in this trial. Patients in the CNI-free-Group (group 1) were converted to sirolimus that was started with 2 mg/day until target trough levels (8–14 ng/mL) were achieved. Subsequently, CNIs were withdrawn. In CNI-reduction-Group (group 2), CNI target trough levels were reduced by 40%. In both groups MMF was continued and trough level adjusted (1.5–4 &mgr;g/mL). Results. Patients demographics and survival (mean follow-up time: 16.7±9 months) was equal (100%). Renal function improved significantly after complete CNI withdrawal while remaining unchanged with CNI-reduction (Creatinine clearance after 12 months: 53±24 mg/dL [group 1] vs. 38±20 mg/dL [group 2], P=0.01). End-stage renal failure (hemodialysis) was avoided by CNI-withdrawal and occurred only after CNI reduction (n=6; P=0.01). Acute rejection episodes were more common in group 2 (4 vs. 2). Graft function remained stable (echocardiography) within both groups. Adverse events were more common in group 1 (65%) than in group 2 (n=40%) and were responsible for discontinuation in 4 and 0 cases, respectively. Conclusions. Conversion toward a CNI-free immunosuppression (Mycophenolate, sirolimus) is superior to CNI-reduced immunosuppression in improving renal failure in late HTx-recipients. However, this benefit is relativized by the increased incidence and severity of sirolimus/MMF-associated side effects.

Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematological parameters in heart transplant recipients

Abstract:  The mTOR (mammalian target of rapamycin) inhibitors sirolimus (SRL) and everolimus (EVL) are potent immunosuppressive agents, which allow reducing the dose of the nephrotoxic calcineurin inhibitors cyclosporin and tacrolimus (TAC) in solid organ transplant recipients. However, there is evidence that mTOR inhibitors may lead to myelosuppression and dyslipidemia/hyperlipidemia. We therefore performed a retrospective analysis in heart transplant recipients with renal insufficiency, who received 3.0 mg/d SRL (SRL group; n = 28) or 1.5 mg/d EVL (EVL group; n = 27) each in combination with a reduced TAC dose for at least one yr. Fewer cardiac rejections, but a similar rate of infections occurred in the EVL group compared with the SRL group indicating that the administered EVL dose resulted in a potent immunosuppression. Serum triglyceride and total cholesterol concentrations rose significantly in the SRL group but not in the EVL group. In the SRL group only, the frequency of statin use increased significantly during follow‐up. The EVL group showed a significant rise in HDL cholesterol levels during follow‐up. There was a slight transient fall in haemoglobin concentrations in the SRL group but not in the EVL group. Leucocyte counts fell significantly in both study groups. However, no cases of leucopenia and also no cases of thrombopenia occurred. In summary, we could demonstrate that in heart transplant recipients with renal insufficiency the introduction of 1.5 mg/d EVL in combination with a reduced TAC dose is effective in preventing cardiac rejections and has less adverse effects on lipid metabolism than the usually prescribed SRL dose, whereas both therapy regimens are not associated with major haematological side‐effects.

Preliminary experience with the lionheart left ventricular assist device in patients with end-stage heart failure

BACKGROUND The Arrow LionHeart LVD 2000 left ventricular assist device is the first fully implantable system designed for destination therapy. We report on 2 years of experience with this device, which we implanted for the first time in October 1999. METHODS Since October 1999, 6 male patients between 55 and 69 years of age (mean 65 +/- 6 years) have received the device at our center; all were in New York Heart Association functional class IV and ineligible for heart transplantation. RESULTS All surgical procedures were uneventful, with a timely extubation in 5 of 6 patients. Duration of support was 17 to 670 (mean 245 +/- 138) days, with a cumulative experience of 4.5 years. Three patients recovered to be discharged from hospital under support and are long-term survivors. Three patients died 17, 31, and 112 days after implantation from multiple organ failure without being discharged to their homes. The survival rate is 50% after 18 months. There were no major system-related problems or any device-related infections, which are otherwise commonly found among vertricular assist device patients. CONCLUSIONS Our preliminary experience demonstrates the reliability and efficacy of the different parts of the system. Nevertheless, further sophistication is needed to reduce the size of its components, which so far still constitutes a limiting factor.

Calcitriol Deficiency and 1-year Mortality in Cardiac Transplant Recipients

Background. Administration of the vitamin D hormone calcitriol improves survival in solid-organ transplanted experimental animals. We investigated whether lower serum calcitriol concentrations are associated with increased 1-year mortality in cardiac transplant recipients. Methods. We prospectively recruited 171 patients who underwent cardiac transplantation at out institution between May 2004 and April 2006. We assessed calciotropic hormones, inflammation markers, and renal function preoperatively and on postoperative days 6 (t1) and 21 (t2). Results. Serum creatinine and C-reactive protein increased, whereas calcitriol decreased significantly after transplantation (P<0.001). As determined by multivariable Cox regression analysis, the calcitriol level at t2 was an independent predictor of 1-year mortality. One-year mortality was 3.7 per 100 person-years in the tertile with the highest calcitriol concentrations at t2 (>18 pg/mL), 13.2 per 100 person-years in the intermediate tertile (11–18 pg/mL), and 32.1 per 100 person-years in the tertile with the lowest calcitriol concentrations at t2 (<11 pg/mL) (P<0.001). 25-hydroxyvitamin D deficiency (serum concentrations below 10 ng/mL), renal insufficiency (serum creatinine ≥1.6 mg/dL), and high serum concentrations of the inflammation markers C-reactive peptide and tumor necrosis factor-&agr; were predictors of a serum calcitriol concentration below 11 pg/mL (P=0.037–0.001). Conclusions. Low postoperative calcitriol concentrations are independently associated with high 1-year mortality in cardiac transplant recipients. A causal relationship has yet to be proven by intervention trials using active vitamin D.

Everolimus exposure in cardiac transplant recipients is influenced by concomitant calcineurin inhibitor.

In two separate pharmacokinetic studies, the drug interaction between immunosuppressive agents was examined in a total of 12 cardiac transplant recipients by conversion of the concomitant immunosuppressant. In six patients under continuous tacrolimus therapy, the concomitant drug azathioprine was converted to everolimus (PK-TAC study). No significant effect on tacrolimus pharmacokinetic parameters was observed. In the second study in which the patients were converted from cyclosporine to tacrolimus under continuous everolimus therapy (PK-EVL study), a significant decrease in everolimus predose concentration (from 4.2 to 2.3 μg/L), maximum concentration (from 9.1 to 5.9 μg/L), and area under the concentration time curve (mean values decreased from 64.2 to 33.7 μg*h/L) was found, indicating a lower everolimus exposure. A pharmacokinetic interaction between cyclosporine and everolimus has been described previously for healthy volunteers after single-dose application and presumably originates from a comparatively greater inhibition of hepatic CYP3A4 or P-glycoprotein efflux transporter with a low-dose cyclosporine regimen. Our results confirm this interaction under clinical conditions and suggest close drug monitoring when converting the calcineurin inhibitor under concomitant mammalian target of rapamycin-inhibitor therapy.