Uwe Fuchs

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.

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.

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.

Immunosuppressive therapy with everolimus can be associated with potentially life-threatening lingual angioedema.

Everolimus has recently received approval for immunosuppressive therapy in heart transplant recipients in Austria and Germany. At our heart center we have treated 114 patients with everolimus since January 2004. Here we describe 6 cases of lingual angioedema (corresponding to 5.3% of the patients). Symptoms occurred within 2 to 41 days after initiation of therapy. In 5 out of the 6 patients, lingual angioedema disappeared with anti-allergic treatment alone. However, in one patient, two severe recurrent episodes of lingual angioedema occurred so that therapy had to be discontinued. We conclude that the potentially life-threatening condition of lingual angioedema should be considered a severe drug reaction after initiation of everolimus therapy in heart transplant recipients.

Patients with congestive heart failure and healthy controls differ in vitamin D-associated lifestyle factors.

We have recently hypothesized that low vitamin D status may contribute to the pathogenesis of congestive heart failure (CHF). This study was aimed at evaluating, in a pilot study, whether CHF patients have indications for a low vitamin D status during earlier periods of their lives. We performed a case-controlled study in 150 CHF patients and 150 controls. Study participants had to answer a questionnaire that included several items concerning vitamin D-associated lifestyle factors during childhood, adolescence, and adulthood. A vitamin D score was constructed. This score takes into consideration that ultraviolet-B (UVB) exposure is the major vitamin D source for humans and that those lifestyle factors, which are associated with regular UVB exposure, can guarantee an adequate vitamin D status at best. The vitamin D score was significantly higher in controls than in patients (p < 0.001). Compared with the controls, more patients lived in large cities (p < 0.001), fewer patients were members of a sport club (p < 0.001), and fewer patients had summer holidays every year (p < 0.01). Patients also reported significantly less alcohol consumption during adulthood than controls (p < 0.001). Our results demonstrate that CHF patients and controls differed in several vitamin D-associated lifestyle factors and in alcohol consumption during earlier periods of their lives.

Heart transplantation in a 68-year-old patient with senile systemic amyloidosis.

Senile systemic amyloidosis (SSA) results from deposition, predominantly in the heart, of amyloid fibrils derived from wild‐type transthyretin (T TR) molecules. Cardiac autopsies indicate that SSA progressively increases in subjects 80 years of age and older. However, only a few cases of patients with SSA and cardiac failure have been recognized by cardiac biopsies during life. Here, we report a case of heart transplantation in a 68‐year‐old male patient with SSA. After cardiopulmonary resuscitation in October 1998, he underwent complete evaluation. Myocardial biopsies revealed the presence of amyloid deposition. Immunohistochemical staining of the amyloid indicated T TR. Genomic DNA analysis of the T TR exons did not result in any identification of a mutation. In 2001, heart transplantation was performed because progressive heart failure occurred. At the 1‐year follow‐up, no amyloid deposits were found in the donor heart. At the 2‐year follow‐up, the patients physical and mental health was excellent. We conclude that heart transplantation can be an effective treatment in progressive heart failure due to SSA.

Effect of vitamin D on all-cause mortality in heart failure (EVITA): a 3-year randomized clinical trial with 4000 IU vitamin D daily

Aims Circulating 25-hydroxyvitamin D (25OHD) levels <75 nmol/L are associated with a nonlinear increase in mortality risk. Such 25OHD levels are common in heart failure (HF). We therefore examined whether oral vitamin D supplementation reduces mortality in patients with advanced HF. Methods and results Four hundred HF patients with 25OHD levels <75 nmol/L were randomized to receive 4000 IU vitamin D daily or matching placebo for 3 years. Primary endpoint was all-cause mortality. Key secondary outcome measures included hospitalization, resuscitation, mechanical circulatory support (MCS) implant, high urgent listing for heart transplantation, heart transplantation, and hypercalcaemia. Initial 25OHD levels were on average <40 nmol/L, remained around 40 nmol/L in patients assigned to placebo and plateaued around 100 nmol/L in patients assigned to vitamin D. Mortality was not different in patients receiving vitamin D (19.6%; n = 39) or placebo (17.9%; n = 36) with a hazard ratio (HR) of 1.09 [95% confidence interval (CI): 0.69-1.71; P = 0.726]. The need for MCS implant was however greater in patients assigned to vitamin D (15.4%, n = 28) vs. placebo [9.0%, n = 15; HR: 1.96 (95% CI: 1.04-3.66); P = 0.031]. Other secondary clinical endpoints were similar between groups. The incidence of hypercalcaemia was 6.2% (n = 10) and 3.1% (n = 5) in patients receiving vitamin D or placebo (P = 0.192). Conclusion A daily vitamin D dose of 4000 IU did not reduce mortality in patients with advanced HF but was associated with a greater need for MCS implants. Data indicate caution regarding long-term supplementation with moderately high vitamin D doses. Trial Registration Information clinicaltrials.gov Idenitfier: NCT01326650.

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.

Parameters of Mineral Metabolism predict Midterm Clinical Outcome in End-Stage Heart Failure Patients

Abstract Objectives. We investigated to which extent disturbances in mineral metabolism predict 90-day clinical outcome in end-stage heart failure patients. Design. Among numerous biochemical parameters, we measured serum levels of sodium and magnesium, the calciotropic hormones parathyroid hormone and 1,25-dihydroxyvitamin D as well as fibroblast growth factor-23 (a phosphaturic hormone) in 305 cardiac transplant candidates. Primary endpoint was a composite of the need of mechanical circulatory support (MCS), transplantation, or death. Results. Of the study cohort, 33.4% reached the primary endpoint. In detail, 19% were transplanted (the vast majority was listed ‘high urgent’), 8.8% died and 5.6% received MCS implants. As determined by logistic regression analysis, all aforementioned biochemical parameters were independently related to the primary endpoint. Results did not change substantially when transplanted patients were censored. A risk score (0–5 points) was developed. Of the patients who scored 5 points 89.5% reached the primary endpoint whereas of the patients with a zero score only 3.8% reached the primary endpoint. Conclusions. Our data demonstrate that in addition to the well-known predictive value of disturbed sodium metabolism, derangements in calcium, phosphate, and magnesium metabolism also predict midterm clinical outcome in end-stage heart failure patients.

Everolimus Plus Dosage Reduction of Cyclosporine in Cardiac Transplant Recipients with Chronic Kidney Disease: A Two-Year Follow-up Study

The calcineurin inhibitor cyclosporine (CSA) displays nephrotoxic side effects. We switched 95 maintenance heart transplant recipients with chronic kidney disease (CKD) stages 3-4 from CSA to everolimus (EVL). The CSA dosage was reduced by 50%. Kidney function, lipid metabolism, and cardiac function investigated during a 2-year follow-up were compared with heart transplant recipients with CKD stages 2-3 who continued to receive CSA (CSA group; n = 84). Whereas 64/95 patients received reduced CSA plus EVL during the entire follow-up period (EVL continued subgroup, ECN), 31 discontinued EVL (EVL discontinued subgroup, EDS) after 4.3 months (median) because of various clinically relevant adverse events. Glomerular filtration rates (estimated using the modification of diet in renal disease formula) increased by 4.0 mL/min/1.73 m(2) in the ECN subgroup but decreased by 2.4 mL/min/1.73 m(2) and 9.0 mL/min/1.73 m(2) in the EDS subgroup and the CSA group, respectively (P < .001). Triglyceride and total cholesterol concentrations increased significantly among the ECN group, but remained constant in the EDS subgroup and the CSA group. Statin use was increased by 15% in the ECN group (P < .01). Mortality and cardiac rejection rates did not differ significantly among the 3 groups. In summary, EVL combined with low-dose CSA had modest beneficial effects on kidney function in heart transplant recipients with CKD stages 3-4. A significant percentage of patients had to stop EVL because of various adverse events.