Andreas Tomaschitz

Vitamin D status and arterial hypertension: a systematic review

Vitamin D deficiency is common and is primarily caused by a lack of ultraviolet-B (UVB) radiation from reduced sun exposure, and the consequent limiting of vitamin D production in the skin. The vitamin D endocrine system regulates about 3% of the human genome. Observational data support the concept that vitamin D is involved in the pathogenesis of cardiovascular diseases and arterial hypertension. The antihypertensive properties of vitamin D include renoprotective effects, suppression of the renin–angiotensin–aldosterone system, direct effects on vascular cells, and effects on calcium metabolism, including prevention of secondary hyperparathyroidism. The results of clinical studies largely, but not consistently, favor the hypothesis that vitamin D sufficiency promotes lowering of arterial blood pressure. Randomized, placebo-controlled trials are greatly needed to clarify and definitively prove the effect of vitamin D on blood pressure. In general, the antihypertensive effects of vitamin D seem to be particularly prominent in vitamin-D-deficient patients with elevated blood pressure. Thus, in view of the relatively safe and inexpensive way in which vitamin D can be supplemented, we believe that vitamin D supplementation should be prescribed to patients with hypertension and 25-hydroxyvitamin D levels below target values.

Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients

Aims Dialysis patients experience an excess mortality, predominantly of sudden cardiac death (SCD). Accumulating evidence suggests a role of vitamin D for myocardial and overall health. This study investigated the impact of vitamin D status on cardiovascular outcomes and fatal infections in haemodialysis patients. Methods and results 25-hydroxyvitamin D [25(OH)D] was measured in 1108 diabetic haemodialysis patients who participated in the German Diabetes and Dialysis Study and were followed up for a median of 4 years. By Cox regression analyses, we determined hazard ratios (HR) for pre-specified, adjudicated endpoints according to baseline 25(OH)D levels: SCD (n = 146), myocardial infarction (MI, n = 174), stroke (n = 89), cardiovascular events (CVE, n = 414), death due to heart failure (n = 37), fatal infection (n = 111), and all-cause mortality (n = 545). Patients had a mean age of 66 ± 8 years (54% male) and median 25(OH)D of 39 nmol/L (interquartile range: 28–55). Patients with severe vitamin D deficiency [25(OH)D of≤ 25 nmol/L] had a 3-fold higher risk of SCD compared with those with sufficient 25(OH)D levels >75 nmol/L [HR: 2.99, 95% confidence interval (CI): 1.39–6.40]. Furthermore, CVE and all-cause mortality were strongly increased (HR: 1.78, 95% CI: 1.18–2.69, and HR: 1.74, 95% CI: 1.22–2.47, respectively), all persisting in multivariate models. There were borderline non-significant associations with stroke and fatal infection while MI and deaths due to heart failure were not meaningfully affected. Conclusion Severe vitamin D deficiency was strongly associated with SCD, CVE, and mortality, and there were borderline associations with stroke and fatal infection. Whether vitamin D supplementation decreases adverse outcomes requires further evaluation.

Vitamin D, cardiovascular disease and mortality

A poor vitamin D status, i.e. low serum levels of 25‐hydroxyvitamin D [25(OH)D], is common in the general population. This finding is of concern not only because of the classic vitamin D effects on musculoskeletal outcomes, but also because expression of the vitamin D receptor (VDR) and vitamin D metabolizing enzymes in the heart and blood vessels suggests a role of vitamin D in the cardiovascular system. VDR‐knockout mice suffer from cardiovascular disease (CVD), and various experimental studies suggest cardiovascular protection by vitamin D, including antiatherosclerotic, anti‐inflammatory and direct cardio‐protective actions, beneficial effects on classic cardiovascular risk factors as well as suppression of parathyroid hormone (PTH) levels. In epidemiological studies, low levels of 25(OH)D are associated with increased risk of CVD and mortality. Data from randomized controlled trials (RCTs) are sparse and have partially, but not consistently, shown some beneficial effects of vitamin D supplementation on cardiovascular risk factors (e.g. arterial hypertension). We have insufficient data on vitamin D effects on cardiovascular events, but meta‐analyses of RCTs indicate that vitamin D may modestly reduce all‐cause mortality. Despite accumulating data suggesting that a sufficient vitamin D status may protect against CVD, we still must wait for results of large‐scale RCTs before raising general recommendations for vitamin D in the prevention and treatment of CVD. In current clinical practice, the overall risks and costs of vitamin D supplementation should be weighed against the potential adverse consequences of untreated vitamin D deficiency.

Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults.

CONTEXT Sclerostin is produced by osteocytes and inhibits bone formation through the Wnt/β-catenin-signaling pathway. Only limited data are available on circulating sclerostin levels in healthy subjects. OBJECTIVE We aimed to evaluate the correlation between sclerostin and physical activity, anthropometric, and biochemical variables. DESIGN, SETTING, AND PARTICIPANTS We conducted a cross-sectional observational study in 161 healthy adult men and premenopausal women aged 19 to 64 yr (mean age, 44 ± 10). INTERVENTION(S) There were no interventions. MAIN OUTCOME MEASURE(S) Serum sclerostin levels were associated with body composition, bone mineral density, physical activity, and various biochemical parameters. RESULTS A positive correlation between age and sclerostin in both men (r = 0.37; P < 0.001) and premenopausal women (r = 0.66; P < 0.001) was found. Men had significantly higher sclerostin levels than women (49.8 ± 17.6 vs. 37.2 ± 15.2 pmol/liter; P < 0.001). However, after adjustment for age, bone mineral content (BMC), physical activity, body mass index (BMI), and renal function, sclerostin levels did not differ (P = 0.543). Partial correlation analysis adjusted for age, gender, and kidney function revealed a significant positive correlation between sclerostin levels and BMC, bone mineral density, BMI, and android/gynoid fat and a significant negative correlation with serum osteocalcin and calcium. The most physically active quartile had significantly lower sclerostin levels compared to the least active quartile in a univariate analysis. CONCLUSIONS In healthy adults, sclerostin serum levels correlate positively with age, BMI, and BMC and negatively with osteocalcin and calcium. Further studies in larger populations are needed to confirm our findings and to better understand their clinical implications.

Independent association between 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and the renin-angiotensin system: The Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

BACKGROUND Antihypertensive and tissue-protective properties of vitamin D metabolites are increasingly attributed to the inhibition of renin synthesis by 1,25-dihydroxyvitamin D [1,25(OH)2D] in the kidney. METHOD We aimed to document a potential association between 25-hydroxyvitamin D [25(OH)D], 1,25(OH)2D and the circulating renin-angiotensin system (RAS) in a large cohort of patients referred (n=3316) to coronary angiography. RESULTS Of the 3316 subjects, 3296 (median age: 63.5 (56.3-70.6)years; 30.2% women) had a baseline measurement of 25(OH)D [median: 15.6(10.1-23.0)microg/L)], 1,25(OH)2D [median: 33.2(25.2-42.9)pg/mL], plasma renin concentration [PRC; median: 11.4(6.0-24.6)pg/mL] and angiotensin 2 [median: 20.0(12.0-35.0)ng/L]. Multivariate adjusted ANCOVA showed a steady increase of PRC values across declining deciles of 25(OH)D and 1,25(OH)2D values (P=0.013 and P=0.045), respectively. Additionally, mean angiotensin 2 values increased significantly across decreasing 25(OH)D and 1,25(OH)2D values (P=0.020 and P=0.024, respectively). In contrast, multivariate adjusted ANCOVA revealed no significant associations between aldosterone, aldosterone-to-renin ratio and 25(OH)D/1,25(OH)2D values. In multivariate stepwise regression analyses both, 25(OH)D and 1,25(OH)2D emerged as independent predictors of plasma renin and angiotensin 2 concentrations. CONCLUSIONS Our data showed for the first time in humans that both, lower 25(OH)D and 1,25(OH)2D values are independently related to an upregulated circulating RAS.

Parathyroid hormone level is associated with mortality and cardiovascular events in patients undergoing coronary angiography

AIMS Elevated parathyroid hormone (PTH) levels have been associated with increased cardiovascular risk in the general population. We aimed to elucidate whether PTH levels are associated with mortality and fatal cardiovascular events in patients referred for coronary angiography. METHODS AND RESULTS Intact PTH was measured in 3232 Caucasian patients from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, who underwent coronary angiography at baseline (1997-2000). During a median follow-up time of 7.7 years, 742 patients died including 467 deaths due to cardiovascular causes. Unadjusted Cox proportional hazard ratios (HRs) (with 95% confidence intervals) in the fourth when compared to the first PTH quartile were 2.13 (1.75-2.60) for all-cause and 2.47 (1.92-3.17) for cardiovascular mortality. After adjustments for common cardiovascular risk factors, these HRs remained significant with 1.71 (1.39-2.10) for all-cause and 2.02 (1.55-2.63) for cardiovascular mortality. Among specific cardiovascular events we observed a particularly strong association of PTH with sudden cardiac death (SCD). The adjusted HR for SCD in the first vs. the fourth PTH quartile was 2.68 (1.71-4.22). CONCLUSION Our results among patients undergoing coronary angiography show that PTH levels are an independent risk factor for mortality and cardiovascular events warranting further studies to evaluate whether PTH modifying treatments reduce cardiovascular risk.

Plasma aldosterone levels are associated with increased cardiovascular mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study

AIMS Evidence has accumulated that elevated aldosterone levels are associated with increased risks of fatal cardiovascular (CV) events. With the present analysis, we aimed at evaluating prospectively whether plasma aldosterone correlates with all-cause and CV disease (CVD) mortality in a large cohort of patients. METHODS AND RESULTS Median plasma aldosterone concentration (PAC) was 79.0 (48.0-124.0) pg/mL (normal range: 30-160) in 3153 patients [median age: 63.5 (56.3-70.6) years; 30.1% women] who had undergone coronary angiography. After a median follow-up of 7.7 (7.2-8.5) years, a total of 716 participants died [22.7%; 454 (14.4%) due to CV causes and 262 (8.3%) due to non-CV causes]. In multivariable Cox proportional hazard analysis, adjusted for age, gender, antihypertensive treatment, and established CV risk factors, PAC levels stratified in quartiles were significantly associated with all-cause and CVD mortality. Compared with the reference (first) PAC quartile, hazard ratios (confidence interval 95%) for the fourth, third, and second PAC quartiles were 1.30 (1.02-1.65, P = 0.033), 1.32 (1.04-1.68, P = 0.021), and 1.20 (0.93-1.54, P = 0.155) for total mortality and 1.58 (1.15-2.16, P = 0.004), 1.39 (1.01-1.90, P = 0.041), and 1.63 (1.20-2.20, P = 0.002) for CVD mortality, respectively. Analyses for specific causes of CV death revealed strong associations between PAC levels and higher risk for fatal stroke and sudden cardiac death. CONCLUSION In a large cohort of patients scheduled for coronary angiography, variation in PAC levels within the normal range is associated with increased all-cause and CVD mortality independent of major established CV risk factors.

Vitamin D deficiency and myocardial diseases

Vitamin D deficiency is common among patients with myocardial diseases because sun-induced vitamin D production in the skin and dietary intake of vitamin D is often insufficient. Knockout mice for the vitamin D receptor develop myocardial hypertrophy and dysfunction. It has also been shown that children with rickets who suffered from severe heart failure could be successfully treated with supplementation of vitamin D plus calcium. In adults, almost all patients with heart failure exhibit reduced 25-hydroxyvitamin D levels, which are used to classify the vitamin D status. In prospective studies, vitamin D deficiency was an independent risk factor for mortality, deaths due to heart failure and sudden cardiac death. Several vitamin D effects on the electrophysiology, contractility, and structure of the heart suggest that vitamin D deficiency might be a causal factor for myocardial diseases. Data from interventional trials, however, are rare and urgently needed to elucidate whether vitamin D supplementation is useful for the treatment of myocardial diseases. In our opinion, the current knowledge of the beneficial effects of vitamin D on myocardial and overall health strongly argue for vitamin D supplementation in all vitamin D-deficient patients with or at high risk for myocardial diseases.

Aldosterone and parathyroid hormone: a precarious couple for cardiovascular disease.

Animal and human studies support a clinically relevant interaction between aldosterone and parathyroid hormone (PTH) levels and suggest an impact of the interaction on cardiovascular (CV) health. This review focuses on mechanisms behind the bidirectional interactions between aldosterone and PTH and their potential impact on the CV system. There is evidence that PTH increases the secretion of aldosterone from the adrenals directly as well as indirectly by activating the renin-angiotensin system. Upregulation of aldosterone synthesis might contribute to the higher risk of arterial hypertension and of CV damage in patients with primary hyperparathyroidism. Furthermore, parathyroidectomy is followed by decreased blood pressure levels and reduced CV morbidity as well as lower renin and aldosterone levels. In chronic heart failure, the aldosterone activity is inappropriately elevated, causing salt retention; it has been argued that the resulting calcium wasting causes secondary hyperparathyroidism. The ensuing intracellular calcium overload and oxidative stress, caused by PTH and amplified by the relative aldosterone excess, may increase the risk of CV events. In the setting of primary aldosteronism, renal and faecal calcium loss triggers increased PTH secretion which in turn aggravates aldosterone secretion and CV damage. This sequence explains why adrenalectomy and blockade of the mineralocorticoid receptor tend to decrease PTH levels in patients with primary aldosteronism. In view of the reciprocal interaction between aldosterone and PTH and the potentially ensuing CV damage, studies are urgently needed to evaluate diagnostic and therapeutic strategies addressing the interaction between the two hormones.

Aldosterone and arterial hypertension

In the setting of primary aldosteronism, elevated aldosterone levels are associated with increased blood pressure. Aldosterone concentrations within the normal range, however, can also alter blood pressure. Furthermore, the aldosterone-to-renin ratio, an indicator of aldosterone excess, is associated with hypertension, even in patients without excessive absolute aldosterone levels. In this Review we assess the data on the role of aldosterone in the development and maintenance of hypertension. We provide an overview of the complex crosstalk between genetic and environmental factors, and about aldosterone-mediated arterial hypertension and target organ damage. The discussion is organized according to major targets of aldosterone action: the collecting duct in the kidney, the vasculature and the central nervous system. The antihypertensive efficacy of mineralocorticoid-receptor blockers, even in patients with aldosterone values in the normal range, supports the evidence that aldosterone plays a part in blood pressure elevation in the absence of primary aldosteronism.