Circulating calcitriol concentrations and total mortality.

BACKGROUND: Evidence is accumulating that vitamin D supplementation of patients with low 25-hydroxyvitamin D concentrations is associated with lower cardiovascular morbidity and total mortality during long-term follow-up. Little is known, however, about the effect of low concentrations of the vitamin D hormone calcitriol on total mortality. We therefore evaluated the predictive value of circulating calcitriol for midterm mortality in patients of a specialized heart center. METHODS: This prospective cohort study included 510 patients, 67.7% with heart failure (two-thirds in end stage), 64.3% hypertension, 33.7% coronary heart disease, 20.2% diabetes, and 17.3% renal failure. We followed the patients for up to 1 year after blood collection. For data analysis, the study cohort was stratified into quintiles of circulating calcitriol concentrations. RESULTS: Patients in the lowest calcitriol quintile were more likely to have coronary heart disease, heart failure, hypertension, diabetes, and renal failure compared to other patients. They also had low 25-hydroxyvitamin D concentrations and high concentrations of creatinine, C-reactive protein, and tumor necrosis factor alpha. Eighty-two patients (16.0%) died during follow-up. Probability of 1-year survival was 66.7% in the lowest calcitriol quintile, 82.2% in the second quintile, 86.7% in the intermediate quintile, 88.8% in the fourth quintile, and 96.1% in the highest quintile (P < 0.001). Discrimination between survivors and nonsurvivors was best when a cutoff value of 25 ng/L was applied (area under the ROC curve 0.72; 95% CI 0.66-0.78). CONCLUSIONS: Decreased calcitriol levels are linked to excess midterm mortality in patients of a specialized heart center.

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

BACKGROUND: 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. AIMS: We investigated whether serum calcitriol concentrations predict clinical outcome in end-stage CHF. METHODS AND RESULTS: We collected blood samples in 383 end-stage CHF patients who were on a waiting list for cardiac transplantation. We assessed associations of calcitriol with disease severity and freedom from event (death or cardiac transplantation) during 1-year follow-up. In electively listed patients (n=325), 31% had deficient calcitriol levels (<43 pmol/l) compared to 47% in urgently/high urgently listed patients (n=58; P<0.001). As determined by multivariable logistic regression, calcitriol was an independent predictor of the listing status 'urgent/high urgent' (P<0.001). Calcitriol concentrations were also significantly lower in patients with an event (n=233) compared to those who survived on the waiting list (P<0.001). Cox regression analysis revealed that patients in the highest calcitriol tertile had a hazard ratio (95% CI) for an event of 0.506 (0.334-0.767) compared with patients in the lowest calcitriol tertile (P=0.005), after adjustment for potential confounders. CONCLUSION: Data indicate that low serum calcitriol concentrations are independently associated with poor clinical outcome in end-stage CHF.

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.

Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Elevated circulating concentrations of proinflammatory cytokines may contribute to the pathogenesis of congestive heart failure (CHF). In vitro studies suggest that vitamin D suppresses proinflammatory cytokines and increases antiinflammatory cytokines. OBJECTIVE: We evaluated the effect of vitamin D supplementation on the survival rate and different biochemical variables in patients with CHF. DESIGN: One hundred twenty-three patients randomly received either 50 mug vitamin D(3)/d plus 500 mg Ca/d [D(+) group] or placebo plus 500 mg Ca/d [D(-) group] for 9 mo. Biochemical variables were assessed at baseline and after 9 mo. The survival rate was calculated for a follow-up period of 15 mo. RESULTS: Ninety-three patients completed the study. Significant treatment effects were observed on logarithmic-transformed serum concentrations of 25-hydroxyvitamin D (P = 0.001), parathyroid hormone (P = 0.007), tumor necrosis factor alpha (P = 0.006), and interleukin 10 (P = 0.042). 25-Hydroxyvitamin D increased by 26.8 ng/mL in the D(+) group but increased only by 3.6 ng/mL in the D(-) group. Compared with baseline, parathyroid hormone was significantly lower and the antiinflammatory cytokine interleukin 10 was significantly higher in the D(+) group after 9 mo. The proinflammatory cytokine tumor necrosis factor alpha increased in the D(-) group but remained constant in the D(+) group. The survival rate did not differ significantly between the study groups during the follow-up period. CONCLUSIONS: Vitamin D(3) reduces the inflammatory milieu in CHF patients and might serve as a new antiinflammatory agent for the future treatment of the disease. Our data provide evidence for the involvement of an impaired vitamin D-parathyroid hormone axis in the progression of CHF.

Markers of bone metabolism in congestive heart failure.

Congestive heart failure (CHF) is a chronic disease, whose incidence is especially growing in the subpopulation of elderly people. CHF is characterized by dyspnea and fatigue at rest or with exertion, ankle swelling and pulmonary edema. Cardiac transplantation is the ultimate therapeutic measure in patients with end-stage CHF. Some risk factors associated with CHF such as low mobility, renal failure, and prescription of specific drugs may predispose patients to develop osteoporosis. This review article gives an overview about markers of bone metabolism in CHF patients as well as in heart transplant recipients. At first, the physiology of bone metabolism is summarized. Then, a short description of different bone formation and resorption markers is presented. They can be used to characterize actual bone metabolism and can be helpful to explain possible mechanisms of bone loss. Regarding pre-transplant CHF patients, available data indicate that the disturbances in bone metabolism are only subtle. Heart transplant recipients, however, are at increased risk for osteoporotic bone loss due to the use of immunosuppressive agents such as corticosteroids and calcineurin inhibitors. Preventive strategies are able to normalize bone metabolism and to attenuate the high bone loss during the first year after heart transplantation.

[Predictive value of ECG changes for acute cardiac rejections in heart transplant recipients]. / Diagnostische Wertigkeit von EKG-Veränderungen bei akuten kardialen Abstossungsreaktionen nach orthotoper Herztransplantation.

BACKGROUND AND PURPOSE: Currently, endomyocardial biopsy is the most reliable method to detect an acute rejection after heart transplantation. However, as an invasive procedure it is associated with a definite risk for complications. Therefore, it was examined whether changes in QT time and QT dispersion on the surface ECG are able to predict an acute cellular rejection. PATIENTS AND METHODS: During the first 3 months after heart transplantation, QT time, heart rate-corrected QT time (QTc time), QT dispersion, and heart rate-corrected QT dispersion (QTc dispersion) were analyzed in 100 patients with acute cellular rejection grade > or = II according to the International Society for Heart and Lung Transplantation (ZA group), and in 100 patients without or with only mild rejection episodes (< or = grade I; MA group). Results were obtained by determining the difference in the ZA group between the QT interval in the presence of a rejection and the QT interval at other time points, which were then compared with the results of the MA group at matched time points. RESULTS: At the time point of rejection, the ZA group showed a mean prolongation in both QTc time and QTc dispersion of > 40 ms compared with other time points. Such differences were not seen in the MA group (p < 0.001 for comparisons between study groups). If prolongations in QTc time and QTc dispersion of > 25 ms were used as predictors for an acute rejection, sensitivity was 77% and 70%, respectively, and specificity was 96% and 95%, respectively. CONCLUSION: Provided that ECGs are performed regularly, measurements of QTc time and QTc dispersion can reliably be used to detect an acute rejection in the early phase after heart transplantation.

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 > or = 1.6 mg/dL), and high serum concentrations of the inflammation markers C-reactive peptide and tumor necrosis factor-alpha 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.

Vitamin D and vascular calcification.

PURPOSE OF REVIEW: Vascular calcification is frequently found in patients with osteoporosis, atherosclerosis and chronic kidney disease, leading to high morbidity and mortality rates. The effects of vitamin D excess and deficiency on vascular calcification are reviewed in this article. RECENT FINDINGS: There is evidence from experimental studies that mediacalcinosis induced by vitamin D excess is an active and reversible process. Vitamin D excess, however, is rarely seen in the general human population. Experimental data also demonstrate that physiologic vitamin D actions include the inhibition of processes that are important for intimal and medial artery calcification such as pro-inflammatory cytokine release, adhesion molecule release, and proliferation and migration of vascular smooth muscle cells. In uremic rats, low levels of the vitamin D hormone calcitriol are associated with massive vascular and soft tissue calcifications. Whereas retrospective studies already indicate a beneficial effect of active vitamin D on mortality rates in chronic kidney disease, little is yet known about the effect of vitamin D deficiency on cardiovascular morbidity and mortality in the general population. SUMMARY: Available data indicate that vitamin D exerts a biphasic 'dose response' curve on vascular calcification with deleterious consequences not only of vitamin D excess but also of vitamin D deficiency.

Vitamin D insufficiency in congestive heart failure: why and what to do about it?

This article gives an overview of the current knowledge on vitamin D status in patients with congestive heart failure (CHF). A serum 25-hydroxyvitamin D level below 50 nmol/l (20 ng/ml) is generally regarded as insufficient. Available data indicate that the majority of CHF patients have 25-hydroxyvitamin D levels in the insufficiency range. Skin synthesis of vitamin D after solar ultraviolet B exposure is the most important vitamin D source for humans. However, CHF patients have relatively low outdoor activities. Consequently, a disease-related sedentary lifestyle is an important cause for the insufficient vitamin D status in CHF patients. There is also evidence from a recently performed case-controlled study that indicators of ultraviolet B exposure are already reduced in CHF patients during childhood, adolescence, and early adulthood compared to healthy controls. We present results indicating that an insufficient vitamin D status may contribute to the etiology/pathogenesis of CHF. Data include a vitamin D-mediated reduction of elevated blood pressure as well as a vitamin D-mediated prevention of enhanced parathyroid hormone levels, a pathophysiological state that contributes to cardiovascular disease. Based on population attributable risks, hypertension and cardiovascular disease have a high impact, accounting for the majority of CHF events.Theoretically, vitamin D status can be improved by adequate skin synthesis of vitamin D and/or adequate oral vitamin D intake. At present, daily oral intake of 50-100 microg vitamin D seems to be the most effective way to improve vitamin D status in CHF patients.

Putting cardiovascular disease and vitamin D insufficiency into perspective.

The aetiology of CVD is still not completely understood. The present review article summarises data supporting the hypothesis that an insufficient vitamin D status may contribute to the worldwide high prevalence of CVD. Human vitamin D status primarily depends on skin exposure to the UVB spectrum of the sunlight. Epidemiological data indicate that geographic latitude, altitude, season, and the place of residence (urban or rural) are associated with CVD mortality. Interestingly, all these factors also have an influence on human UVB exposure and thus on vitamin D status. Several mechanisms might be responsible for a protective role of vitamin D in CVD. These mechanisms include the inhibition of vascular smooth muscle proliferation, the suppression of vascular calcification, the down regulation of pro-inflammatory cytokines, the up regulation of anti-inflammatory cytokines, and the action of vitamin D as a negative endocrine regulator of the renin-angiotensin system. The first intervention trials indicate that vitamin D may suppress cardiovascular risk markers. However, more controlled clinical trials are needed to investigate whether optimal oral vitamin D supplementation is able to reduce CVD morbidity and mortality.