In addition to its role in bone and calcium metabolism, vitamin D has important prohormone functions in a wide range of clinical processes, including antiproliferative, prodifferentiative and immunomodulatory actions [1
]. Vitamin D deficiency has become the most widespread nutritional disorder in the modern world because of decreased sunlight exposure, increasing obesity, and changes in dietary habits [2
]. Numerous studies have demonstrated that hypovitaminosis D is related to increased risks of cardiovascular diseases (CVD), metabolic dysfunctions, and high all-cause mortality in the general population [3
]. Specifically, vitamin D metabolites and its metabolism gene CYP24A1 are associated with coronary atherosclerosis and calcification [4
]. These observations support the hypothesis that low vitamin D levels influence the activity of the cardiovascular system and result in a dysfunctional cardiac autonomic nervous system (ANS). Chan et al.
reported that patients with chronic kidney disease (impaired vitamin D synthesis) showed poor cardiosympathovagal activity characterized by a withdrawal of inhibitory vagal activity [5
]. However, few studies exploring the association between vitamin D and cardiac autonomic function in healthy people have been reported.
Heart rate interval changes are the result of the ANS dynamically regulating the body’s response to internal and external stimuli. The balance of the ANS activity reflects physiological, hormonal and psychological stability [6
]. Heart rate variability (HRV) analysis is based on the measurement of interval variability between R waves (RR intervals) and qualitative and quantitative assessments that represent the balance of the cardiovascular system via ANS control [7
]. As an established tool in cardiology studies, HRV is used currently for a wide range of clinical conditions from psychiatric illnesses to internal organ pathologies. Increased HRV reflects a healthy ANS able to react appropriately to changing environmental circumstances [8
], whereas decreased HRV is a sign of autonomic inflexibility and heart disease that may precede systemic problems (e.g., inflammatory-mediated atherosclerosis and ventricular fibrillation) [9
]. Recent research has shown that a decreased HRV is associated with risk factors for CVD, heart failure, and sudden cardiac death (SCD) [10
To understand the effects of vitamin D deficiency on the heart, the association between vitamin D deficiency and HRV indices must be examined in terms of clinical importance. To date, few studies have explored the effects of vitamin D on HRV in healthy individuals. Therefore, in the present study we examined the relationship between serum vitamin D levels and HRV and hypothesized that lower serum vitamin D levels are associated with lower HRV parameters.
The present study examined the relationship between serum vitamin D levels and HRV in healthy individuals. The SDNN was low in subjects with 25(OH)D deficiency, and 25(OH)D levels were associated positively with SDNN, and LF. This suggests that low 25(OH)D serum levels are associated with cardiac autonomic dysfunction, which may trigger a pathophysiological mechanism that increases CVD risk in healthy populations with vitamin D deficiency.
Vitamin D has direct effects on numerous cell types via actions on the vitamin D receptor (VDR) [1
]. Although the heart is not considered a traditional target organ, growing evidence suggests that vitamin D plays crucial roles in heart structure and function. In animal studies, 1,25-dihydroxyvitamin D (1,25(OH)2
D) impacted cardiac autonomic activity [19
]. These studies demonstrated that 1,25(OH)2
D deficiency resulted in accelerated rates of cardiac contraction and relaxation. In addition, VDR ablation led to cardiac fibrosis, hypertrophy and dysregulation of the renin-angiotensin system (RAS). The direct applicability of these findings in animals to humans is unclear, but VDR has been found in human cardiac tissue as a 55-kDa protein [21
]. Patients with chronic kidney disease had a reduced capacity for converting 25(OH)D to 1,25(OH)2
D due to decreased 1-α hydroxylase activity. These patients showed chronic RAS upregulation [23
] and altered cardiac autonomic activity defined mainly by extreme vagal insufficiency [5
]. Moreover, Adriana J et al.
reported that 25(OH)D level was cross-sectionally related with higher B-type natriuretic peptide (BNP) in subjects with eGFR < 60 mL/min/1.73 m2
, suggesting low 25(OH)D may be associated with growth and hypertrophy of cardiac cell, therefore may result in stimulated BNP secretion [24
]. Studies of healthy populations have also shown that lower 25(OH)D levels were associated independently with a higher risk of SCD or CVD [3
], suggesting that low vitamin D levels may also be an important and potentially treatable risk factor in populations without established pathologies. However, the molecular mechanisms responsible for the vitamin D deficiency associated with cardiac morbidity and mortality have not been fully elucidated. Our finding of a positive association between 25(OH)D levels and HRV suggests a possible mechanism for this phenomenon.
HRV depends on the sympathetic and parasympathetic effect on the sinus node and reflects changes in ANS activity and function. RMSSD and HF are the predominant responses to variations in parasympathetic tone. By contrast, SDNN and LF are influenced by both adrenergic and cholinergic activities and other physiological inputs. SDNN depends on a change in all HRV parameters and its decrease is associated with reduced function of the left ventricle [27
]. TP level is similar to SDNN by affecting the control of the ANS and is generally decreased in individuals under chronic stress or with disease. Nolan et al.
found prospectively that SDNN was an independently strong prognostic factor for CHF patients [28
]. LF is an indicator of sympathetic activity regulation in the sinus node. Recent research has suggested that the LF component is reduced in patients with CHF; this decrease is related to a higher risk of sudden death, advanced disease, and progression to heart failure [29
]. In our study, 25(OH)D levels were positively related with SDNN and LF, but not HF, indicating diminished sympathetic tone in subjects without pre-existing risk factors for CVD. The sympathetic nervous system has an important role in the regulation of energy homeostasis in humans [30
]. Therefore, differences in sympathetic nervous system activity can cause variations in 24-h energy expenditure among individuals. Reduced activity of sympathetic tone associated with 25(OH)D deficiency may contribute to changes in cardiomyocyte energy expenditure. As mentioned previously, low vitamin D status may result in elevated RAS system activity, causing myocardial hypertrophy and arterial hypertension. In addition, vitamin D affects directly cardiomyocytes, including modulation of contractility, regulation of extracellular matrix turnover and anti-hypertrophic actions [31
]. This may explain the higher risk of CVD in patients with vitamin D deficiency. By contrast, we found no evidence of a significant association between 25(OH)D levels and RMSSD and HF. Parasympathetic effects exert through rapidly dynamic control by acetylcholine influencing muscarinic receptors and are hereby reflected in the HF component of HRV. In cardiac disease, parasympathetic activation and its physiological effects decrease such as attenuation of vagal ganglionic transmission, change of muscarinic receptor composition and density, and reducing of acetylcholinesterase activity [32
]. Because both RMSSD and HF component represent cardiac vagal nerve activity in the sinus node and electronic stability, a decrease in the parasympathetic nerve activity in the heart results in a decrease in RMSSD and HF component [16
]. According to previous studies, decreased parasympathetic tone becomes a significant factor at more advanced stages of heart dysfunction [33
]. Because we excluded patients with established risk factors for CVD, our findings suggest the 25(OH)D levels influence the early stage of pathophysiological changes in the heart. There are several evidences that vitamin D may be important in early process of atherosclerosis disease. Wang et al.
and Giovannucci et al.
reported an increased risk of CVD incidence among subjects with vitamin D deficiency in large prospective studies involving population without pre-existing CVD [15
]. In contrast, prospective studies conducted in patients with stable coronary disease or advanced type 2 diabetes reported that baseline vitamin D levels did not predict cardiovascular events [36
Limited studies of the link between vitamin D and HRV have been published. Only one study examined a relationship between vitamin D metabolites and modulation of the cardiac ANS in a healthy population [39
]. Their findings of a significant association between low 25(OH)D levels and decreased baseline cardiac autonomic activity, low 1,25(OH)2
D levels and unfavorable cardiosympathovagal changes during acute angiotensin II challenge are consistent with our results. Unfortunately, the findings could not be generalized to other studies due to the small sample size (n
= 34). In addition, Metin Cetin et al.
examined the relationship between vitamin D deficiency and autonomic imbalance in patients who had ischemic and non-ischemic dilated cardiomyopathy [40
]. Surprisingly, they reported a stronger association between 25(OH)D levels and HRV, which reflects the activity of the ANS, in patients with non-ischemic rather than ischemic dilated cardiomyopathy. This finding suggests that vitamin D may play an important role in cardiomyocyte pathophysiology and that its deficiency may be more closely associated with the pathogenesis of non-ischemic rather than ischemic myocardial disease.
Our results also suggest that the positive association between 25(OH)D levels and ANS activity is involved in SCD pathogenesis. Interestingly, the association between vitamin D deficiency and risk for SCD was stronger in the population without than with CVD, as reported by Pilz et al.
]. Altered myocardial calcium flux increased the risk of SCD related to vitamin D deficiency, suggesting a link to cardiac arrhythmia [42
]. This hypothesis is supported by the positive association between 25(OH)D levels and corrected QT interval (QTc) in non-ischemic dilated cardiomyopathy patients [41
]. Kim et al.
also reported that calcitriol treatment decreases a prolonged QTc dispersion [42
The present study had several limitations. First, our results do not represent the general population because we enrolled healthy individuals who visited a local university hospital. Secondly, determining the causal relationships between vitamin D and HRV parameters is difficult due to the cross-sectional nature of the study. Additionally, we were unable to assess the serum PTH level, which is an important determinant of vitamin D status. Hyperparathyroidism is linked to hypertrophy of cardiomyocytes and arterial stiffness and vitamin D deficiency may be predisposed to increased BP via elevated PTH and disturbed calcium homeostasis [43
]. Moreover, the analysis of the VLF component could not be used to evaluate clinical implications because we examined HRV parameters only in the short-term (5 min). In such a short-term analysis, VLF does not provide adequate data as this band often reflects meaningless noise signals. HRV has been examined using electrocardiographic signals evaluated during short (2–5 min) and long (24-h) duration periods. We used a short-duration period because long-term electrocardiographic recording inhibits comparison of HRV parameters obtained during various activities such as exercise, sleep, and deep breathing. Finally, we could not apply the standardized forms of autonomic load, such as head-up tilt test, orthoclinostatic or orthostatic tests and deep breathing, in the examination of the HRV component.
Although the interest in vitamin D and its relationship to CVD risk has increased recently, evaluation of the risk of cardiac events in a healthy population with hypovitaminosis D but not established CVD risk factors, such as HTN, DM and dyslipidemia, is easily overlooked. Currently, many commercial devices that automate HRV measurements for research and clinical studies are available. These devices are simple and important tools for assessment of autonomic heart control and autonomic dysfunction.