Editorial
The link between vitamin D, parathyroid hormone, and cardiovascular disease Mario Cozzolino J Cardiovasc Med 2015, 16:69–70 Department of Health Sciences, University of Milan, Renal Division, S. Paolo Hospital, Milan, Italy Correspondence to Mario Cozzolino, MD, PhD, FERA, Renal Division, S. Paolo Hospital, University of Milan, Via A. di Rudinı`, 8 – 20142, Milan, Italy Tel: +02 81844381; fax: +02 81844775; e-mail: [email protected] Received 28 February 2014 Revised 21 April 2014 Accepted 30 April 2014
Our understanding of the vitamin D system, the vitamin D receptor (VDR), and the effects of VDR activation in healthy subjects has changed dramatically in recent years, with the publication of several new studies looking at the strong association between vitamin D levels, parathyroid hormone (PTH) levels, and cardiovascular disease.1 In particular, it has been advocated that a potential to change the perspective of VDR activation beyond its role in mineral metabolism and pleiotropic vitamin D effects have come into the focus of interest. The vitamin D–PTH axis and its biological effects have changed dramatically in recent years, identifying 25hydroxyvitamin D (25-D) and 1,25-dihydroxyvitamin D (1,25-D) as ‘real’ hormones, with several effects beyond mineral metabolism effects.2 In fact, new studies have been proposed and realized, looking at either native 25-D or active 1,25-D actions on the cardiovascular and renal systems.3 These advances have the potential to change the perspective of vitamin D beyond its role in mineral metabolism, moving from the bone to the vessels. The several cardiovascular effects of reduced vitamin D include smooth muscle cell calcification, proliferation, and fibrosis, which lead to arterial stiffness, atherosclerosis, and left ventricular hypertrophy.3 In this Issue of the Journal, Chen et al.4 have studied the association between the levels of 25-D, PTH, and coronary artery disease in a Chinese elderly population. Interestingly, both lower serum 25-D levels and higher serum PTH levels were independently associated with increased risk of coronary artery disease, that is, the expected biochemical ‘milieu’ in chronic kidney disease (CKD) patients. I found the manuscript to be of real interest, and I would like to discuss why these results may be important for the clinical point of view, because of the fact that they may generate questions regarding the most appropriate vitamin D serum levels in elderly patients 1558-2027 ß 2015 Italian Federation of Cardiology
and the possible independent association of hyperparathyroidism with cardiovascular risk. One of the more important issues regarding consistency in the field of vitamin D is the recommended target level of 25D, both in the general population and in CKD patients. The debate continues about how much 25D is enough or too much. There is a lack of agreement between various guidelines and experts in what clinical levels of 25D are required and also how much has to be taken as supplements to achieve this. Recommendations and guidelines for optimal vitamin D levels are currently based on epidemiological and observational data, because of the fact that randomized controlled trials related to vitamin D intake and health outcomes are few. Vitamin D deficiency in the general population with normal renal function causes secondary hyperparathyroidism (SHPT), bone loss, and is strongly associated with a higher risk for hypertension, proteinuria, cardiovascular lesions, and higher rates of cardiovascular mortality.5 This exemplifies the broad role that vitamin D has in several biological processes for the maintenance of general health. Nevertheless, various professional groups currently recommend different levels of 25D for optimal efficacy. For example, Medicine of the National Academies (IOM) recently published guidelines on vitamin D supplementation for the general population.6 The IOM stated that, based on available data, almost all individuals have sufficient 25D when their blood levels are >20 ng/ml (50 nmol/l) and that there is little additional benefit above 30 ng/ml (75 nmol/l). In these guidelines, bone health was selected as the indicator to serve as the basis of the Dietary Reference Intake for Ca and vitamin D. Limiting the appropriate vitamin D level to 20 ng/ml of 25D has initiated a vigorous scientific debate in the international literature. Recently, Melamed et al.7 documented all the plausible advantages and problems of further increasing vitamin D levels, acknowledging that the levels of 25-D above 50 ng/ml may be detrimental to health and survival. It should be kept in mind that PTH and vitamin D are two calciotropic hormones that regulate bone and mineral metabolism.2 Increasing evidence suggests a role for mineral metabolism in cardiovascular disease risk. In fact, elevated serum PTH levels, calcium and phosphate disorders, and 25-D deficiency are directly associated with cardiovascular risk factors.8 Clearly, both lower levels of 25-D and higher levels of PTH are associated with high blood pressure, diabetes, insulin resistance, and DOI:10.2459/JCM.0000000000000153
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
70 Journal of Cardiovascular Medicine 2015, Vol 16 No 1
dyslipidemia.9 Furthermore, in a recent analysis of the NHANES study, lower levels of 25-D and higher levels of calcium and PTH appear to be associated with different cardiovascular risk factors and may therefore affect cardiovascular disease through different mechanisms.10 Patients with kidney disease develop a mineral metabolism impairment, in which high levels of PTH and vitamin D deficiency coexist in causing not only a bone pathology, but a severe cardiovascular disease. Recent clinical studies suggested a strong association between vitamin D deficiency and cardiovascular disease in the general population.11 Serum 25-D levels are significantly depleted in most patients with chronic heart failure and may be independently associated with poor clinical outcomes12 and increased risk of myocardial infarction.13 Therefore, a poor vitamin D status in the general population and, in particular, among CKD patients is associated with an increased risk of heart diseases, including cardiovascular mortality and sudden cardiac death. The results from small interventional studies suggest that native (25-D) and active (1,25-D) vitamin D treatment improves cardiovascular outcome. At this time, there is a need for large, randomized clinical trials to specifically evaluate the cardiovascular effects of vitamin D. The key outcomes in these studies should include different cardiovascular risk factors such as blood pressure and left ventricular hypertrophy. Further discussion deserves vitamin D and PTH assays and measurements, from a laboratory perspective. In fact, it has been demonstrated how PTH measurements are far from being accurate, because several different assays are commonly used, giving significantly different results.14 Also, it is important to remember that 1,25-D has a short half-life of minutes, whereas 25-D has a longer half-life of several weeks. Therefore, 25-D is widely used to assess vitamin D status, also because it is less expensive compared with 1,25-D level measurements.15 In conclusion, clinicians should be aware of potential benefit of measuring vitamin D and PTH, independently
by renal function. The ‘optimal’ vitamin D levels remain to be indicated, but at least we should accept the definition of ‘vitamin D deficiency’ when 25-D levels are lower than 20 ng/ml (about 50 nmol/l). Clearly, the two calciotropic hormones, vitamin D and PTH, not only give important information on patients’ bone health, but open a new window to prevent and treat cardiovascular disease in normal population and in CKD patients.
References 1 2 3
4 5 6
7
8
9
10
11 12
13
14 15
Cozzolino M, Ketteler M, Zehnder D. The vitamin D system: a crosstalk between the heart and kidney. Eur J Heart Fail 2010; 12:1031–1041. Cozzolino M. The calciotropic hormones PTH and vitamin D: from bone to blood vessels. J Intern Med 2012; 271:566–568. Ronco C, Cozzolino M. Mineral metabolism abnormalities and vitamin D receptor activation in cardiorenal syndromes. Heart Fail Rev 2012; 17:211–220. Chen, et al. J Cardiovasc Med 2014, accepted for publication. Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab 2010; 95:471–478. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011. p. 1015. Full Report: http://books. nap.edu/openbook.php?record_id¼13050. Brief Report: http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-forCalcium-and- Vitamin-D/Report-Brief.aspx. Melamed ML, Muntner P, Michos ED, et al. Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004. Arterioscler Thromb Vasc Biol 2008; 28:1179– 1185. Snijder MB, Lips P, Seidell JC, et al. Vitamin D status and parathyroid hormone levels in relation to blood pressure: a population-based study in older men and women. J Intern Med 2007; 261:558–565. Zhao G, Ford ES, Li C. Associations of serum concentrations of 25hydroxyvitamin D and parathyroid hormone with surrogate markers of insulin resistance among US. Adults without physician-diagnosed diabetes: NHANES, 2003-2006. Diabetes Care 2010; 33:344–347. Fraser A, Williams D, Lawlor DA. Associations of serum 25-hydroxyvitamin D, parathyroid hormone and calcium with cardiovascular risk factors: analysis of 3 NHANES cycles (2001-2006). PLoS One 2010; 5:e13882. Artaza JN, Mehrotra R, Norris KC. Vitamin D and the cardiovascular system. Clin J Am Soc Nephrol 2009; 4:1515–1522. Zittermann A, Schleithoff SS, Gotting C, et al. Poor outcome in end-stage heart failure patients with low circulating calcitriol levels. Eur J Heart Fail 2008; 10:321–332. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med 2008; 168:1174–1180. La’ulu SL, Roberts WL. Performance characteristics of six intact parathyroid hormone assays. Am J Clin Pathol 2010; 134:930–938. Carter GD. Accuracy of 25-hydroxyvitamin D assays: confronting the issues. Curr Drug Targets 2011; 12:19–28.
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
The link between vitamin D, parathyroid hormone, and cardiovascular disease Mario Cozzolino J Cardiovasc Med 2015, 16:69–70 Department of Health Sciences, University of Milan, Renal Division, S. Paolo Hospital, Milan, Italy Correspondence to Mario Cozzolino, MD, PhD, FERA, Renal Division, S. Paolo Hospital, University of Milan, Via A. di Rudinı`, 8 – 20142, Milan, Italy Tel: +02 81844381; fax: +02 81844775; e-mail: [email protected] Received 28 February 2014 Revised 21 April 2014 Accepted 30 April 2014
Our understanding of the vitamin D system, the vitamin D receptor (VDR), and the effects of VDR activation in healthy subjects has changed dramatically in recent years, with the publication of several new studies looking at the strong association between vitamin D levels, parathyroid hormone (PTH) levels, and cardiovascular disease.1 In particular, it has been advocated that a potential to change the perspective of VDR activation beyond its role in mineral metabolism and pleiotropic vitamin D effects have come into the focus of interest. The vitamin D–PTH axis and its biological effects have changed dramatically in recent years, identifying 25hydroxyvitamin D (25-D) and 1,25-dihydroxyvitamin D (1,25-D) as ‘real’ hormones, with several effects beyond mineral metabolism effects.2 In fact, new studies have been proposed and realized, looking at either native 25-D or active 1,25-D actions on the cardiovascular and renal systems.3 These advances have the potential to change the perspective of vitamin D beyond its role in mineral metabolism, moving from the bone to the vessels. The several cardiovascular effects of reduced vitamin D include smooth muscle cell calcification, proliferation, and fibrosis, which lead to arterial stiffness, atherosclerosis, and left ventricular hypertrophy.3 In this Issue of the Journal, Chen et al.4 have studied the association between the levels of 25-D, PTH, and coronary artery disease in a Chinese elderly population. Interestingly, both lower serum 25-D levels and higher serum PTH levels were independently associated with increased risk of coronary artery disease, that is, the expected biochemical ‘milieu’ in chronic kidney disease (CKD) patients. I found the manuscript to be of real interest, and I would like to discuss why these results may be important for the clinical point of view, because of the fact that they may generate questions regarding the most appropriate vitamin D serum levels in elderly patients 1558-2027 ß 2015 Italian Federation of Cardiology
and the possible independent association of hyperparathyroidism with cardiovascular risk. One of the more important issues regarding consistency in the field of vitamin D is the recommended target level of 25D, both in the general population and in CKD patients. The debate continues about how much 25D is enough or too much. There is a lack of agreement between various guidelines and experts in what clinical levels of 25D are required and also how much has to be taken as supplements to achieve this. Recommendations and guidelines for optimal vitamin D levels are currently based on epidemiological and observational data, because of the fact that randomized controlled trials related to vitamin D intake and health outcomes are few. Vitamin D deficiency in the general population with normal renal function causes secondary hyperparathyroidism (SHPT), bone loss, and is strongly associated with a higher risk for hypertension, proteinuria, cardiovascular lesions, and higher rates of cardiovascular mortality.5 This exemplifies the broad role that vitamin D has in several biological processes for the maintenance of general health. Nevertheless, various professional groups currently recommend different levels of 25D for optimal efficacy. For example, Medicine of the National Academies (IOM) recently published guidelines on vitamin D supplementation for the general population.6 The IOM stated that, based on available data, almost all individuals have sufficient 25D when their blood levels are >20 ng/ml (50 nmol/l) and that there is little additional benefit above 30 ng/ml (75 nmol/l). In these guidelines, bone health was selected as the indicator to serve as the basis of the Dietary Reference Intake for Ca and vitamin D. Limiting the appropriate vitamin D level to 20 ng/ml of 25D has initiated a vigorous scientific debate in the international literature. Recently, Melamed et al.7 documented all the plausible advantages and problems of further increasing vitamin D levels, acknowledging that the levels of 25-D above 50 ng/ml may be detrimental to health and survival. It should be kept in mind that PTH and vitamin D are two calciotropic hormones that regulate bone and mineral metabolism.2 Increasing evidence suggests a role for mineral metabolism in cardiovascular disease risk. In fact, elevated serum PTH levels, calcium and phosphate disorders, and 25-D deficiency are directly associated with cardiovascular risk factors.8 Clearly, both lower levels of 25-D and higher levels of PTH are associated with high blood pressure, diabetes, insulin resistance, and DOI:10.2459/JCM.0000000000000153
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
70 Journal of Cardiovascular Medicine 2015, Vol 16 No 1
dyslipidemia.9 Furthermore, in a recent analysis of the NHANES study, lower levels of 25-D and higher levels of calcium and PTH appear to be associated with different cardiovascular risk factors and may therefore affect cardiovascular disease through different mechanisms.10 Patients with kidney disease develop a mineral metabolism impairment, in which high levels of PTH and vitamin D deficiency coexist in causing not only a bone pathology, but a severe cardiovascular disease. Recent clinical studies suggested a strong association between vitamin D deficiency and cardiovascular disease in the general population.11 Serum 25-D levels are significantly depleted in most patients with chronic heart failure and may be independently associated with poor clinical outcomes12 and increased risk of myocardial infarction.13 Therefore, a poor vitamin D status in the general population and, in particular, among CKD patients is associated with an increased risk of heart diseases, including cardiovascular mortality and sudden cardiac death. The results from small interventional studies suggest that native (25-D) and active (1,25-D) vitamin D treatment improves cardiovascular outcome. At this time, there is a need for large, randomized clinical trials to specifically evaluate the cardiovascular effects of vitamin D. The key outcomes in these studies should include different cardiovascular risk factors such as blood pressure and left ventricular hypertrophy. Further discussion deserves vitamin D and PTH assays and measurements, from a laboratory perspective. In fact, it has been demonstrated how PTH measurements are far from being accurate, because several different assays are commonly used, giving significantly different results.14 Also, it is important to remember that 1,25-D has a short half-life of minutes, whereas 25-D has a longer half-life of several weeks. Therefore, 25-D is widely used to assess vitamin D status, also because it is less expensive compared with 1,25-D level measurements.15 In conclusion, clinicians should be aware of potential benefit of measuring vitamin D and PTH, independently
by renal function. The ‘optimal’ vitamin D levels remain to be indicated, but at least we should accept the definition of ‘vitamin D deficiency’ when 25-D levels are lower than 20 ng/ml (about 50 nmol/l). Clearly, the two calciotropic hormones, vitamin D and PTH, not only give important information on patients’ bone health, but open a new window to prevent and treat cardiovascular disease in normal population and in CKD patients.
References 1 2 3
4 5 6
7
8
9
10
11 12
13
14 15
Cozzolino M, Ketteler M, Zehnder D. The vitamin D system: a crosstalk between the heart and kidney. Eur J Heart Fail 2010; 12:1031–1041. Cozzolino M. The calciotropic hormones PTH and vitamin D: from bone to blood vessels. J Intern Med 2012; 271:566–568. Ronco C, Cozzolino M. Mineral metabolism abnormalities and vitamin D receptor activation in cardiorenal syndromes. Heart Fail Rev 2012; 17:211–220. Chen, et al. J Cardiovasc Med 2014, accepted for publication. Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab 2010; 95:471–478. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011. p. 1015. Full Report: http://books. nap.edu/openbook.php?record_id¼13050. Brief Report: http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-forCalcium-and- Vitamin-D/Report-Brief.aspx. Melamed ML, Muntner P, Michos ED, et al. Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004. Arterioscler Thromb Vasc Biol 2008; 28:1179– 1185. Snijder MB, Lips P, Seidell JC, et al. Vitamin D status and parathyroid hormone levels in relation to blood pressure: a population-based study in older men and women. J Intern Med 2007; 261:558–565. Zhao G, Ford ES, Li C. Associations of serum concentrations of 25hydroxyvitamin D and parathyroid hormone with surrogate markers of insulin resistance among US. Adults without physician-diagnosed diabetes: NHANES, 2003-2006. Diabetes Care 2010; 33:344–347. Fraser A, Williams D, Lawlor DA. Associations of serum 25-hydroxyvitamin D, parathyroid hormone and calcium with cardiovascular risk factors: analysis of 3 NHANES cycles (2001-2006). PLoS One 2010; 5:e13882. Artaza JN, Mehrotra R, Norris KC. Vitamin D and the cardiovascular system. Clin J Am Soc Nephrol 2009; 4:1515–1522. Zittermann A, Schleithoff SS, Gotting C, et al. Poor outcome in end-stage heart failure patients with low circulating calcitriol levels. Eur J Heart Fail 2008; 10:321–332. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med 2008; 168:1174–1180. La’ulu SL, Roberts WL. Performance characteristics of six intact parathyroid hormone assays. Am J Clin Pathol 2010; 134:930–938. Carter GD. Accuracy of 25-hydroxyvitamin D assays: confronting the issues. Curr Drug Targets 2011; 12:19–28.
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
