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CLINICAL STUDY: HEART FAILURE

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

Armin Zittermann, PhD^*,*, Stefanie Schulze Schleithoff^*, Gero Tenderich, MD, Heiner K. Berthold, MD, PhD, Reiner Körfer, MD and Peter Stehle, PhD^*

^* Department of Nutrition Science, University of Bonn, Germany
Heart and Diabetes Center North Rhine-Westfalia, Department of Thoracic and Cardiovascular Surgery, Ruhr-University of Bochum, Bad Oeynhausen, Germany
Center for Cardiovascular Diseases, Department Clinical Pharmacology, Rotenburg a.d. Fulda, Germany

Manuscript received January 25, 2002; revised manuscript received August 19, 2002, accepted September 13, 2002.

^* Reprint requests and correspondence: Dr. Armin Zittermann, Associate Professor, Department of Nutrition Science, University of Bonn, Endenicher Allee 11-13, 53115 Bonn, Germany.
a.zittermann{at}uni-bonn.de

	Abstract

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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 (r² = 0.16; p < 0.001 and r² = 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.

Abbreviations and Acronyms   Ca2+   ionized calcium   CHF   congestive heart failure   CI   cardiac index   LVEF   left ventricular ejection fraction   NT-proANP   N-terminal pro-ANP   NYHA   New York Heart Association   25OHD   25-hydroxyvitamin D   PCWP   pulmonary wedge pressure   PTH   parathyroid hormone   TNF   tumor necrosis factor   UV   ultraviolet   VDR   vitamin D receptor

The etiology of CHF is not well understood. Obviously, an altered intracellular handling of ionized calcium (Ca²⁺) seems to play an important role in the impaired contractility of the myocardium (5). In isolated myocytes from patients with terminal heart failure, systolic Ca²⁺ transients were found to be markedly reduced, diastolic Ca²⁺ levels were increased, and the rate of diastolic decay of Ca²⁺ was slowed compared with heart cells from healthy subjects (6). Consequently, digitalis and beta-blockers are frequently used medications for secondary prevention. They are able to improve contractility by increasing myocardial intracellular Ca²⁺ levels (7) and by improving intracellular Ca²⁺ utilization (8).

In a recent observational study in patients with severe CHF, both vitamin D deficiency and hyperparathyroidism were common findings (9). Interestingly, vitamin D plays a pivotal role in cardiac function. Cardiac muscle cells possess a vitamin D receptor and a calcitriol-dependent Ca²⁺ binding protein (10,11). Moreover, a calcitriol-mediated rapid activation of voltage-dependent Ca²⁺ channels exists in cardiac muscle cells (12). Consequently, calcitriol administration can normalize the impaired contractility of the myocardium that is observed under experimental vitamin D deficiency (13,14). Calcitriol also suppresses synthesis and secretion of the atrial natriuretic peptide (ANP) in cardiac muscle cells (15). Circulating levels of the N-terminal pro-ANP (NT-proANP) are massively increased in CHF patients and are thus a predictor of disease severity (16).

On the basis of these preliminary data, it can be hypothesized that low circulating levels of vitamin D metabolites are contributing to the pathogenesis and/or the symptomatology of CHF. To support this postulate, we performed a case-control study in younger and older CHF patients.

	Methods

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Participants and study design.   Fifty-four patients admitted for investigation or treatment of CHF were recruited at the Heart and Diabetes Center North Rhine-Westfalia (geographic latitude: 52°N) between November 2000 and March 2001. Patients were ambulatory or hospitalized for not longer than two days. They were classified by New York Heart Association (NYHA) functional class according to their cardiac symptoms. Only patients with NYHA classes 2 were included. Moreover, LVEF was determined by echocardiogram. Cardiac index (CI) and pulmonary wedge pressure (PCWP) were assessed using right ventricular cardiac catheterization. Left ventricular ejection fraction values <35%, CI values >2 l/min/m², and PCWP values >20 mm Hg are regarded as clinically unfavorable. Patients were then divided into group I (<50 years; n = 20) and group II (50 years; n = 34) to evaluate possible age-related effects. Control group III consisted of 34 elderly (50 years) free-living subjects. Exercise capacity was assessed by a questionnaire based on NYHA functional classification (17). Subjects were recruited between November 2000 and March 2001 by an advertisement in several senior groups in Bonn, Germany (geographic latitude 51°N). Participants of group III were matched for gender, age, and body mass index with group II (Table 1). All control subjects had an unlimited exercise capacity (NYHA class <2). Exclusion criteria were serum creatinine level >2 mg/dl, serum aspartate aminotransferase level >35 U/l, therapy with glucocorticoids or anticonvulsants, and intake of vitamin D supplements (hospital document/questionnaire).

Biochemical analysis
Blood hormone and cytokine analyses are summarized in Table 2. Serum Ca²⁺ and phosphorus as well as serum albumin concentrations were assessed using atomic absorption spectrometry (Ca²⁺) and colorimetric test kits (phosphorus and albumin; BioMerieux, Nürtingen, Germany), respectively. Coefficients of variation were below 2.5%. Total serum Ca²⁺ was corrected with ±0.32 mg for each 0.5 mg deviation of concomitant serum albumin from a normal mean of 4.14 mg (18). Vitamin D binding protein was measured by single radial immunodiffusion (coefficient of variation = 10.8%; Immundiagnostik, Bensheim, Germany). Serum creatinine was determined enzymatically (test kit: Boehringer, Mannheim, Germany). Creatinine clearance (ml/min) was estimated according to the Crockroft-Gault formula (19):

The restriction fragment length polymorphism for the vitamin D receptor (VDR) gene at the BsmI site was measured with the polymerase chain reaction by using the method and primers described by Morrison et al. (20). The presence of a polymorphic restriction site was designated as b, whereas the absence of this site was designated as B.

Statistics
All statistical evaluations were performed with the Statistical Package for Social Sciences (SPSS), version 10 (Chicago, Illinois). Normal distribution of the data was tested by the Kolmogorov-Smirnov test. Normal distribution was considered if p values were above 0.05. Data were then evaluated using an analysis of variance (ANOVA) (normal distributed data) or by the Kruskall-Wallis test (non-normal data; serum parathyroid hormone, PTH). In the case of significant differences between subgroups, post hoc analyses were based on the Tukey test (normal distributed data) or on the Mann/Whitney U-test. The chi-square test was used to test differences in the genotype of the vitamin D receptor between the study groups. Pearson’s correlation coefficient r (normal distributed data), Spearman’s rank correlation coefficient r_s (non-normal data), and nonlinear regression analyses were used to assess interrelationships. A p value <0.05 (two-tailed test) was considered statistically significant. Data are expressed as mean ± SD.

	Results

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Serum levels of 25-hydroxyvitamin D (25OHD), calcitriol (Fig. 1), Ca²⁺, Ca²⁺C, phosphorus, and PTH (Table 3) revealed highly significant differences between the study groups (ANOVA; all p values <0.001).

View larger version (19K): [in this window] [in a new window]   Figure 1 Circulating concentrations (mean ± SD) of 25-hydoxyvitamin D (A) and calcitriol (B) in congestive heart failure (CHF) patients and in elderly healthy controls (50 years). Main effects of study groups were observed (analysis of variance; p < 0.001). ***Significant differences between CHF patients and elderly controls, p < 0.001 (post hoc Tukey test); **Significant difference between CHF patients and elderly controls, p < 0.025 (post hoc Tukey test).

Both age groups of CHF patients had markedly higher plasma levels of NT-proANP than controls (Fig. 2). Even in the control subjects, however, the NT-proANP levels of 0.96 ± 0.37 nmol/l were slightly higher than the normal values published for healthy adults (0.11 to 0.60 nmol/l, ages 20 to 55 years). Mean serum albumin levels were significantly lower in the CHF patients compared with the controls, but they were still in the normal range of 4.0 to 5.4 g/dl (Table 3). Tumor necrosis factor (TNF)-alpha was significantly increased in the elderly patient group compared with their age-matched controls (p < 0.001). The TNF-alpha levels of the younger patients did not differ from the elderly controls. The levels were, however, markedly higher than the generally accepted mean normal concentrations of 6 pg/ml for healthy middle-aged subjects. Creatinine clearance was highest in the young CHF patients (Table 3).

View larger version (13K): [in this window] [in a new window]   Figure 2 Blood concentrations (mean ± SD) of N-terminal pro-atrial natriuretic peptide (NT-proANP) in congestive heart failure (CHF) patients and in elderly healthy controls (50 years). Main effects of study groups were observed (analysis of variance; p < 0.001). ***Significant differences between CHF patients and elderly controls, p < 0.001 (post hoc Tukey test).

View larger version (15K): [in this window] [in a new window]   Figure 3 Association between serum N-terminal pro-atrial natriuretic peptide (NT-proANP) and serum 25-hydroxyvitamin D values (r2 = 0.16; p < 0.001; regression equation: NT-proANP 4.14·25OHD–0.741).

	Discussion

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We measured serum Ca²⁺ levels by atomic absorption spectrometry, which is regarded as the gold standard. Moreover, our study design allowed samples batching, and the fasting blood drawing guaranteed that serum Ca²⁺ concentrations were unaffected by dietary Ca²⁺ intake. Because sufficient amounts of extracellular activator Ca²⁺ are mandatory for the first step in myocardial contraction (22), adequate influx of activator Ca²⁺ is questionable in the young CHF patients with low serum levels of albumin-corrected Ca²⁺ (Table 3). In addition, the low calcitriol levels of the young and of the elderly CHF patients (Fig. 1) might also impair calcitriol-dependent intracellular genomic actions, such as Ca²⁺ binding protein synthesis (10), and non-genomic actions of Ca²⁺ metabolism, such as calcitriol-dependent activation of adenylate cyclase (23,24). Low adenylat cyclase activity can result in an impaired extracellular Ca²⁺ influx (2,25), decreased Ca²⁺ re-uptake into the sarcoplasmic reticulum (26), and reduced Ca²⁺ liberation from the sarcoplasmic reticulum (27). The latter alteration is considered an important pathogenic factor of the impaired contractility in cardiomyopathy (6,28).

The pathogenesis of low calcitriol levels in CHF patients is uncertain. Some earlier studies brought evidence forward that reduced serum calcitriol levels are the result of low circulating 25OHD levels (29,30). It has recently been suggested that TNF-alpha may also suppress calcitriol synthesis (31). We found an inverse association of TNF-alpha with 25OHD (results section), indicating that low 25OHD levels are involved in activation of the TNF-alpha system. Because the creatinine clearance was highest in the young CHF patients (Table 3), it seems rather unlikely that an impaired kidney function was responsible for a reduced renal 1-alpha hydroxylation of 25OHD in the CHF patients compared with the controls.

25OHD has several independent effects on muscle cells. Uptake of ⁴⁵Ca²⁺into cultured cardiac muscle cells is increased by physiologic concentrations of 25OHD (32). The 25OHD activity in cardiac muscle cells is on a molar basis 222 times lower than that of calcitriol (32). However, at serum concentrations of the two metabolites as those found in our study groups (Fig. 1), these relative molar potencies indicate that from 58% to 64% of the circulating vitamin D activity is contributed by 25OHD. On the basis of the molar potencies of 25OHD and calcitriol and the serum concentrations of the two vitamin D metabolites, the circulating vitamin D activity is 68% in the elderly CHF patients and only 54% in the younger CHF patients compared with the control subjects. Moreover, intracellular Ca²⁺ re-uptake into the sarcoplasmic reticulum is reduced in experimental vitamin D deficiency (33), which is obviously not mediated by calcitriol but probably by 25OHD (27). In addition, intracellular accumulation of phosphate by muscle might be directly increased by 25OHD (34), an effect that may be blunted in the case of low circulating 25OHD levels.

We cannot definitively rule out that diuretic therapy of CHF patients (Table 1) has contributed to the low serum Ca²⁺ levels. A renal Ca²⁺ leak should, however, result in an increased serum calcitriol level. Moreover, some case reports of patients with untreated rickets and with untreated osteomalacia suffering from heart failure (35–37) support our hypothesis that low serum levels of vitamin D metabolites might be an important cause of the reduced serum Ca²⁺ levels and of the cardiac dysfunction. In these earlier case reports a rapid normalization of the hypocalcemia and cardiac symptoms was observed after therapy with Ca²⁺ and vitamin D (metabolites), and in combination with the administration of diuretics such as furosemide and spironolactone (35–37). The inverse nonlinear correlation of 25OHD and calcitriol with NT-proANP (Fig. 3 and Results section) support our hypothesis that the severity of CHF is increased at low serum levels of vitamin D metabolites.

In Europe, circulating levels of 25OHD largely depend on exposure to ultraviolet (UV) light, namely UV B light (38). Normally, serum 25OHD decreases with age (36) because the capability of the skin to produce previtamin D after UV B irradiation declines with age (39). It is thus an unexpected finding that even in the younger CHF patients the vitamin D status is lower than in elderly controls. From the inclusion criteria of our study we can rule out an impaired liver function of the CHF patients (Methods section). Possible explanations for the low circulating 25OHD levels may thus be a genetic abnormality of the hepatic 25-hydroxylase activity, an increased 25OHD catabolism, or an insufficient UV B exposure and/or inadequate dietary vitamin D intake. In this context, it may well be that a disease-related reduction in outdoor activity contributes to the low vitamin D status. Granted the pivotal role of an adequate vitamin D status for the systemic and myocardial Ca²⁺ metabolism, the CHF patients might enter into a circulus vitiosus.

There is growing evidence that circulating 25OHD levels >40 ng/ml are necessary to achieve full physiologic vitamin D actions (40,41). The inverse association between NT-proANP and 25OHD in our study groups (Fig. 3) supports this earlier assumption. Not all subjects with relatively low 25OHD levels, however, had high NT-proANP levels (Fig. 3). Thus, additional factors might increase susceptibility to CHF.

Vitamin D acts through the highly specific vitamin D receptor. The mechanisms by which the receptor protein mediates the cellular vitamin D actions are a subject of intense research. In other vitamin-D-related diseases such as osteoporosis and diabetes mellitus, the genotype of the vitamin D receptor at the BmsI restriction site was associated with disease prevalence (20,42). There is, however, obviously no relationship between the vitamin D genotype at the BmsI restriction site and susceptibility to CHF (Table 3).

Our data of alterations in circulating vitamin D metabolites and in systemic mineral metabolism in CHF patients (Fig. 1 and Table 3) and the cellular alterations in Ca²⁺metabolism found by others (6) are very similar to those observed in essential hypertension (43). Therapy of hypertension has successfully been performed by increasing circulating 25OHD levels through UV B irradiation (44) or by oral vitamin D supplementation (45). Consequently, a clear rationale for interventional trials with vitamin D in combination with a Ca²⁺supplement in chronic CHF would exist.

In conclusion, this case-control study provides evidence for an association between a low vitamin D status and CHF severity. Moreover, data encourage future investigations on the relationship between vitamin D status and the early onset of CHF observed in the subgroup of young patients.

	Footnotes

 
This study was supported by the Pinguin Stiftung, Düsseldorf, Germany.

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				G. Schwalfenberg Not enough vitamin D: Health consequences for Canadians Can Fam Physician, May 1, 2007; 53(5): 841 - 854. [Abstract] [Full Text] [PDF]

				E. D. Michos and R. S. Blumenthal Vitamin D Supplementation and Cardiovascular Disease Risk Circulation, February 20, 2007; 115(7): 827 - 828. [Full Text] [PDF]

				G. M. London, A. P. Guerin, F. H. Verbeke, B. Pannier, P. Boutouyrie, S. J. Marchais, and F. Metivier Mineral Metabolism and Arterial Functions in End-Stage Renal Disease: Potential Role of 25-Hydroxyvitamin D Deficiency J. Am. Soc. Nephrol., February 1, 2007; 18(2): 613 - 620. [Abstract] [Full Text] [PDF]

				Y. Sun, R. A. Ahokas, S. K. Bhattacharya, I. C. Gerling, L. D. Carbone, and K. T. Weber Oxidative stress in aldosteronism Cardiovasc Res, July 15, 2006; 71(2): 300 - 309. [Abstract] [Full Text] [PDF]

				S. S Schleithoff, A. Zittermann, G. Tenderich, H. K Berthold, P. Stehle, and R. Koerfer Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am. J. Clinical Nutrition, April 1, 2006; 83(4): 754 - 759. [Abstract] [Full Text] [PDF]

				S. S. Harris Vitamin D and African Americans J. Nutr., April 1, 2006; 136(4): 1126 - 1129. [Abstract] [Full Text] [PDF]

				C. F. Garland, F. C. Garland, E. D. Gorham, M. Lipkin, H. Newmark, S. B. Mohr, and M. F. Holick The Role of Vitamin D in Cancer Prevention Am J Public Health, February 1, 2006; 96(2): 252 - 261. [Abstract] [Full Text] [PDF]

				M. F. Holick The Vitamin D Epidemic and its Health Consequences J. Nutr., November 1, 2005; 135(11): 2739S - 2748S. [Abstract] [Full Text] [PDF]

				M. Tonelli, F. Sacks, M. Pfeffer, Z. Gao, G. Curhan, and for the Cholesterol And Recurrent Events (CARE) Tr Relation Between Serum Phosphate Level and Cardiovascular Event Rate in People With Coronary Disease Circulation, October 25, 2005; 112(17): 2627 - 2633. [Abstract] [Full Text] [PDF]

				P. H. Law, Y. Sun, S. K. Bhattacharya, V. S. Chhokar, and K. T. Weber Diuretics and Bone Loss in Rats With Aldosteronism J. Am. Coll. Cardiol., July 5, 2005; 46(1): 142 - 146. [Abstract] [Full Text] [PDF]

				R. Vieth, R. Scragg, P.E. Norman, and J.T. Powell Vitamin D Nutrition Does Not Cause Peripheral Artery Disease Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): e41 - e42. [Full Text] [PDF]

				M. Teng, M. Wolf, M. N. Ofsthun, J. M. Lazarus, M. A. Hernan, C. A. Camargo Jr, and R. Thadhani Activated Injectable Vitamin D and Hemodialysis Survival: A Historical Cohort Study J. Am. Soc. Nephrol., April 1, 2005; 16(4): 1115 - 1125. [Abstract] [Full Text] [PDF]

				V. S. Chhokar, Y. Sun, S. K. Bhattacharya, R. A. Ahokas, L. K. Myers, Z. Xing, R. A. Smith, I. C. Gerling, and K. T. Weber Hyperparathyroidism and the Calcium Paradox of Aldosteronism Circulation, February 22, 2005; 111(7): 871 - 878. [Abstract] [Full Text] [PDF]

				V. S. Chhokar, Y. Sun, S. K. Bhattacharya, R. A. Ahokas, L. K. Myers, Z. Xing, R. A. Smith, I. C. Gerling, and K. T. Weber Loss of bone minerals and strength in rats with aldosteronism Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2023 - H2026. [Abstract] [Full Text] [PDF]

				N. Binkley, D. Krueger, C. S. Cowgill, L. Plum, E. Lake, K. E. Hansen, H. F. DeLuca, and M. K. Drezner Assay Variation Confounds the Diagnosis of Hypovitaminosis D: A Call for Standardization J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3152 - 3157. [Abstract] [Full Text] [PDF]

				M. F Holick Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis Am. J. Clinical Nutrition, March 1, 2004; 79(3): 362 - 371. [Abstract] [Full Text] [PDF]

J. Robson What happened to evidence in NICE guidance on heart failure? BMJ, October 18, 20