Vitamin D levels are associated with cardiac autonomic activity in healthy humans

Michelle C Mann, Derek V Exner, Brenda R Hemmelgarn, Darlene Y Sola, Tanvir C Turin, Linda Ellis, Sofia B Ahmed, Michelle C Mann, Derek V Exner, Brenda R Hemmelgarn, Darlene Y Sola, Tanvir C Turin, Linda Ellis, Sofia B Ahmed

Abstract

Vitamin D deficiency (≤50nmol/L 25-hydroxy vitamin D) is a cardiovascular (CV) risk factor that affects approximately one billion people worldwide, particularly those affected by chronic kidney disease (CKD). Individuals with CKD demonstrate abnormal cardiac autonomic nervous system activity, which has been linked to the significant rates of CV-related mortality in this population. Whether vitamin D deficiency has a direct association with regulation of cardiac autonomic activity has never been explored in humans.

Methods: Thirty-four (34) healthy, normotensive subjects were studied and categorized based on 25-hydroxy vitamin D deficiency (deficient vs. non-deficient, n = 7 vs. 27), as well as 1,25-dihydroxy vitamin D levels (above vs. below 25th percentile, n = 8 vs. 26). Power spectral analysis of electrocardiogram recordings provided measures of cardiac autonomic activity across low frequency (LF) and high frequency (HF, representative of vagal contribution) bands, representative of the sympathetic and vagal limbs of the autonomic nervous system when transformed to normalized units (nu), respectively, as well as overall cardiosympathovagal balance (LF:HF) during graded angiotensin II (AngII) challenge (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min).

Results: At baseline, significant suppression of sympathovagal balance was observed in the 25-hydroxy vitamin D-deficient participants (LF:HF, p = 0.02 vs. non-deficient), although no other differences were observed throughout AngII challenge. Participants in the lowest 1,25-dihydroxy VD quartile experienced significant withdrawal of inhibitory vagal control, as well as altered overall sympathovagal balance throughout AngII challenge (HF, mean difference = -6.98 ± 3 nu, p = 0.05; LF:HF, mean difference = 0.34 ± 0.1, p = 0.043 vs. above 25th percentile).

Conclusions: Vitamin D deficiency is associated with suppression of resting cardiac autonomic activity, while low 1,25-dihydroxy vitamin D levels are associated with unfavourable cardiac autonomic activity during an acute AngII stressor, offering a potential pathophysiological mechanism that may be acting to elevate CV risk in in populations with low vitamin D status.

Figures

Figure 1
Figure 1
Cardiosympathovagal modulation during angiotensin II challenge, by vitamin D status LF:HF, low- to high-frequency ratio representative of cardiosympathovagal balance.
Figure 2
Figure 2
Comparison of cardiac vagal autonomic activity between 1,25-dihydroxy vitamin D groups during angiotensin II challenge HF, high-frequency representative of cardiac parasympathetic activity; nu, normalized units.

References

    1. Holick M.F. Vitamin D. N. Engl. J. Med. 2007;357:266–281. doi: 10.1056/NEJMra070553.
    1. Dobnig H., Pilz S., Scharnagl H., Renner W., Seelhorst U., Wellnitz B., Kinkeldi J., Boehm B.O., Weihrauch G., Maerz W. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch. Intern. Med. 2008;168:1340–1349. doi: 10.1001/archinte.168.12.1340.
    1. Deo R., Katz R., Shlipk M.G., Sotoodehnia N., Psaty B.M., Sarnak M.J., Fried L.F., Chonchol M., de Boer I.H., Enquobahrie D., et al. Vitamin D, paraythyroid hormone and sudden cardiac death: Results from the Cardiovascular Health Study. Hypertension. 2011;58:1021–1028. doi: 10.1161/HYPERTENSIONAHA.111.179135.
    1. De Novellis V., Loffreda A., Vitagliano S. Effects of dietary vitamin D deficiency on the cardiovascular system. Res. Commun. Chem. Pathol. Pharmacol. 1994;83:125–144.
    1. Chan C.T., Levin N.W., Chertow G.M., Larive B., Schulman G., Kotanko P., The Frequent Hemodialysis Network Daily Trial Group Determinants of cardiac autonomic dysfunction in ESRD. J. Am. Soc. Nephrol. 2010;5:1821–1827. doi: 10.2215/CJN.03080410.
    1. Kneip C.F., Mallet R.T., Williams A.G., Hamdan M.H., Smith M.L. Vagal modulation of heart rate variability during atrial fibrillation in pigs. Exp. Bil. Med. (Maywood) 2010;235:1007–1014.
    1. Tsuji H., Venditti F.J., Manders E.S., Evans J.C., Feldman C.L., Levy D. Impact of reduced heart rate variability on risk for cardiac events: The framingham heart study. Circulation. 1996;94:2850–2855. doi: 10.1161/01.CIR.94.11.2850.
    1. La Rovere M.T., Pinna G.D., Maestri R., Mortara A., Capomolla S., Febo O., Ferrari R., Franchini M., Gnemmi M., Opasich C., et al. Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients. Circulation. 2003;107:565. doi: 10.1161/01.CIR.0000047275.25795.17.
    1. Ranpuria R., Hall M., Chan C., Unruh M. Heart rate variability (HRV) in kidney failure: Measurement and consequences of HRV. Neph. Dial. Transplant. 2007;23:444–449. doi: 10.1093/ndt/gfm634.
    1. Goldberger J.J., Cain M.E., Hohnloser S.H., Kadish A.H., Knight B.P., Lauer M.S., Maron B.J., Page R.L., Passman R.S., Siscovick D., et al. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society Scientific Statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death. Circulation. 2008;118:1497–1518. doi: 10.1161/CIRCULATIONAHA.107.189375.
    1. Lauer M.S. Autonomic function and prognosis. Cleve Clin. J. Med. 2009;76:S18–S22. doi: 10.3949/ccjm.76.s2.04.
    1. Holick M.F., Binkley N.C., Bischoff-Ferrari H.A., Gordon C.M., Hanley D.A., Heaney R.P., Murad M.H., Weaver C.M. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2011;96:1911–1930. doi: 10.1210/jc.2011-0385.
    1. Forman J.P., Williams J.S., Fisher N.D. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system. Hypertension. 2010;55:1283–1288. doi: 10.1161/HYPERTENSIONAHA.109.148619.
    1. Vaidya A., Forman J.P., Williams J.S. Vitamin D and the vascular sensitivity to angiotensin II in obese Caucasians with hypertension. J. Hum. Hypertens. 2011;25:672–678. doi: 10.1038/jhh.2010.110.
    1. Shoback D.M., Williams G.H., Swartz S.L., Davies R.O., Hollenberg N.K. Time course and effect of sodium intake on vascular and hormonal responses to enalapril (MK 421) in normal subjects. J. Cardiovasc. Pharmacol. 1983;5:1010–1018. doi: 10.1097/00005344-198311000-00015.
    1. Task Force of the European Society of Cardiology. the North American Society of Pacing Electrophysiology Heart rate variability: Standards of measurement, physiological interpretation, and clinical use. Circulation. 1996;93:1043–1065.
    1. Zhong Y., Jan K.M., Ju K.H., Chon K.H. Quantifying cardiac sympathetic and parasympathetic nervous activities using principal dynamic modes analysis of heart rate variability. Am. J. Physiol. Heart Circ. Physiol. 2006;291:H1475–H1483. doi: 10.1152/ajpheart.00005.2006.
    1. Taylor J.A., Carr D.L., Myers C.W., Eckberg D.L. Mechanisms underlying very-low frequency RR-interval oscillations in humans. Circulation. 1998;98:547–555. doi: 10.1161/01.CIR.98.6.547.
    1. Tripathi K.K. Very low frequency oscillations in the power spectra of heart rate variability during dry supine immersion and exposure to non-hypoxic hypobaria. Physiol. Meas. 2011;32:717–729. doi: 10.1088/0967-3334/32/6/008.
    1. Grasso R., Schena F., Gulli G., Cevese A. Does low-frequency variability of heart period reflect a specific parasympathetic mechanism? J. Auton. Nerv. Syst. 1997;63:30–38. doi: 10.1016/S0165-1838(96)00128-2.
    1. Mann M.C., Exner D.V., Hemmelgarn B.R., Sola D.Y., Turin T.C., Ahmed S.B. Impact of gender on the cardiac autonomic response to angiotensin II in healthy humans. J. Appl. Physiol. 2012;112:1001–1007. doi: 10.1152/japplphysiol.01207.2011.
    1. Dreschler C., Pilz S., Obermayer-Pietsch B., Verduijn M., Tomaschitz A., Krane V., Espe K., Dekker F., Brandenburg V., Marz W., et al. Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in hemodialysis patients. Eur. Heart J. 2010;31:2253–2261. doi: 10.1093/eurheartj/ehq246.
    1. Pilz S., Iodice S., Zittermann A., Grant W.B., Gandini S. Vitamin D status and mortality risk in CKD: A meta-analysis of prospective studies. Am. J. Kidney Dis. 2011;58:374–382.
    1. Wang T., Pencina M., Booth S., Jacques P., Ingelsson E., Lanier K., Benjamin E., D’Agostino R., Wolf M., Vasan R. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117:503–511. doi: 10.1161/CIRCULATIONAHA.107.706127.
    1. Scorza F.A., Albuquerque M., Arida R.M., Tera V.C., Machado H.R., Cavalheiro E.A. Benefits of sunlight: Vitamin D deficiency might increase the risk of sudden unexpected death in epilepsy. Med. Hypotheses. 2010;74:158–161. doi: 10.1016/j.mehy.2009.07.009.
    1. Sternberg Z. Autonomic dysfunction: A unifying multiple sclerosis theory, linking chronic cerebrospinal venous insufficiency, vitamin D3 and Epstein-Barr virus. Autoimmun. Rev. 2012;12:250–259. doi: 10.1016/j.autrev.2012.04.004.
    1. Tishkoff D.X., Nibbelink K.A., Holmberg K.H., Dandu L., Simpson R.U. Functional vitamin D receptor (VITAMIN DR) in the t-tubules of cardiac myocytes: VITAMIN DR knockout cardiomyocyte contractility. Endocrinology. 2008;149:558–564.
    1. Brewster U.C., Setaro J.F., Perazella M.A. The renin-angiotensin-aldosterone system: Cardiorenal effects and implications for renal and cardiovascular disease states. Am. J. Med Sci. 2003;326:15–24. doi: 10.1097/00000441-200307000-00003.
    1. Perazella M.A., Setaro J.F. Renin-angiotensin-aldosterone system: Fundamental aspects and clinical implications in renal and cardiovascular disorders. J. Nucl. Cardiol. 2003;10:184–196. doi: 10.1067/mnc.2003.392.
    1. Wolf M., Shah A., Gutierrez O., Ankers E., Monroy M., Tamez H., Steele D., Chang Y., Camargo C.A., Jr., Tonelli M., et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72:1004–1013. doi: 10.1038/sj.ki.5002451.
    1. Kendrick J., Cheung A.K., Kaufman J.S., Green T., Roberta W.L., Smits G., Chonchol M., HOST Study Inventigators Associations of plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations with death and progression to maintenance dialysis in patients with advanced kidney disease. Am. J. Kidney Dis. 2012;60:567–575.
    1. Palmer S.C., Hayen A., Macaskill P., Pellegrini F., Craig J.C., Elder G.J., Strippoli G.F. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis. JAMA. 2011;305:1119–1127. doi: 10.1001/jama.2011.308.
    1. McNeely J.D., Windham B.G., Anderson D.E. Dietary sodium effects on heart rate variability in salt-sensitivity of blood pressure. Psychophysiology. 2007;45:405–411.

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