Abstract
Background
Vitamin D (VitD) has important prohormone functions in a wide range of clinical processes. Although it is known that individuals with VitD deficiency have cardiac autonomic dysfunction, there are no convincing data regarding the effect of VitD replacement. We aimed to evaluate the impact of VitD replacement on cardiac autonomic dysfunction.
Methods
Fifty‐two apparently healthy subjects with VitD deficiency and 50 healthy control subjects were enrolled. Prior to VitD replacement, 24‐hr Holter recordings were obtained, and HRV parameters were recorded. VitD levels were measured 2 months later after replacement, and control 24‐hr Holter recordings were analyzed.
Results
The mean age of the patients was 36.04 ± 7.6 years, and 53.9% were female. SDNN (68.58 ± 13.53 vs. 121.02 ± 27.45 ms, p = .001), SDANN (95.96 ± 22.26 vs. 166.48 ± 32.97 ms, p = .001), RMSSD (23 vs. 59 ms, p < .001), and PNN50 (6.5% vs. 36%, p < .001) were significantly lower in patients with VitD deficiency compared with the control group. HRV parameters were improved after VitD replacement [SDNN (68.58 ± 13.53 to 119.87 ± 28.28 ms, p < .001), SDANN (95.96 ± 22.26 to 164.44 ± 33.90 ms, p < .001), RMSSD (23 to 58 ms, p < .001), and PNN50 (6.5 to 33%, p < .001)].
Conclusion
The present study suggested that VitD deficiency was significantly correlated with impaired cardiac autonomic functions assessed by parameters of HRV, and cardiac autonomic dysfunction improved after VitD replacement in otherwise apparently healthy individuals.
Keywords: cardiac autonomic dysfunction, heart rate variability, vitamin D deficiency
1. INTRODUCTION
Vitamin D (VitD) has important prohormone functions in a wide range of clinical processes, including antiproliferative and immunomodulatory actions, beyond its role in bone and calcium metabolism (Nagpal, Na, & Rathnachalam, 2005). VitD receptors are distributed in most cells and tissues including the vascular smooth cells, endothelium, and cardiomyocytes. VitD deficiency has become a major health problem with dramatically rising trends in its prevalence worldwide because of decreased sunlight exposure, and increasing obesity (Holick, 2007). Many studies demonstrated that VitD deficiency is related to an increased risk of cardiovascular diseases (CVD), autoimmune diseases, and metabolic dysfunctions in the general population (Dobnig et al., 2008).
The two main constituents of the autonomic nervous system, namely the sympathetic and parasympathetic controls, work in a manner opposite to each other, and as a consequence of their net effect, a regulation is achieved on certain physiological parameters such as heart rate (HR). Heart rate variability (HRV) measures have been used as noninvasive assessments of cardiac autonomic tone by quantifying their beat‐to‐beat variations (Dekker et al., 2000). HRV provides a noninvasive assessment of cardiovascular autonomic functions. It has been used as a predictor of sudden cardiac death (SCD) or a marker of the progression of CVD in several high‐risk populations (Kleiger, Stein, & Bigger, 2005; Tsuji et al., 1996).
Until now, only a few studies have investigated the relationship between VitD deficiency and HRV in an otherwise apparently healthy population. Although it is known that individuals with VitD deficiency have cardiac autonomic dysfunction, there are no sufficient data suggesting recovery of following VitD replacement therapy. Thus, we aimed to evaluate the impact of VitD replacement therapy on cardiac autonomic dysfunction in apparently healthy individuals with VitD deficiency.
2. METHODS
2.1. Study population
The study design was an observational prospective cohort. A total of 102 patients were enrolled (52 apparently healthy subjects with VitD deficiency and 50 age‐ and gender‐matched healthy control subjects) who were admitted for routine check‐up and examined at outpatient clinics between April 2018 and September 2018. Patients were excluded from the study if they had hepatic, renal, or gastrointestinal dysfunction, diabetes mellitus, hypertension, hyperlipidemia, alcoholism, ischemic heart disease, valvular heart diseases, arrhythmia, cardiac pacemaker, heart failure, cardiomyopathy, segmental left ventricular wall motion abnormalities, left ventricular ejection fraction (LVEF) <55%, congenital heart disease, malignancy and use of cardiotoxic medication, cardiac depressant drug (B‐blocker, calcium channel blocker, etc.) and any drug that affects the autonomic nervous system, thyroid, and parathyroid dysfunction, and individuals using calcium or VitD supplementation that can interfere with VitD metabolism. The study was approved by the local ethics committee. All patients signed an informed consent form.
2.2. Demographic, clinical, and echocardiographic evaluation of patients
Body mass index (BMI) was calculated as body weight (kg) divided by height squared (m2). Cigarette smoking was defined as smoking ≥1 packet of cigarettes a day. Blood samples were taken from all participants after 12–14 hr of fasting.
All patients underwent 2‐dimensional transthoracic echocardiographic (HD11 XE Ultrasound system, Philips, Canada) evaluation equipped with a 1.5–4.0 MHz transducer. LVEF was obtained by using modified Simpson's method as specified by current guideline of chamber quantification by American Society of Echocardiography (Lang et al., 2015).
2.3. VitD analysis and replacement protocol
The 25‐hydroxyvitamin D (25‐OH VitD) was used as a circulating biomarker of VitD status. 25‐OH VitD was measured in ng/ml by a fully automated electrochemiluminescence assay (Elecsys Vitamin D total II assay; Roche Diagnostics, Mannheim, Germany). VitD deficiency is defined as 25‐OH VitD < 20 ng/ml, and VitD sufficient is defined as 25‐OH VitD ≥ 30 ng/ml according to the latest Endocrinology Society guidelines (Holick et al., 2011). Despite the presence of various treatment modalities for VitD deficiency, there is no consensus on treatment regimens. Both D2 and D3 preparations can be used, but vitamin D3 is the preferred treatment (Adams & Hewison, 2010; Holick et al., 2011). In addition, there is no consensus on the frequency of treatment, as data from different studies suggest that replacement treatment can be given either daily, weekly, or monthly (Sayiner, Arslan, Temizkan, Karabayraktar, & Sargın, 2016). In our study, VitD deficiency group received 300,000 IU vitamin D3 at once, per oral. Target value of serum 25‐OH VitD was between 30 and 50 ng/ml, levels between 50 and 100 ng/ml were considered overdose, and levels more than 100 ng/ml were considered toxic (Płudowski et al., 2013). Before the VitD replacement, 24‐hr Holter recordings were analyzed, and HRV parameters were recorded in subjects with VitD deficiency. Also, 24‐hr Holter records were obtained in the control group. VitD levels were measured 2 months later after replacement, and control 24‐hr Holter recordings were analyzed.
2.4. Assessment of HRV
Twenty four hours Holter recordings were recorded by using three‐channel analogue recorders, using the CardioScan Holter ECG System. HRV was assessed from 24‐hr Holter ECG recordings using previously described and validated methods (La Rovere, Bigger, Marcus, Mortara, & Schwartz, 1998). In the HRV analysis, the standard parameters obtained from the time‐domain analysis of HRV including SDNN [standard deviation (SD) of all NN intervals], SDANN (SD of the averages of NN intervals in all 5‐min segments of the entire recording), RMSSD (square root of the mean of the sum of the squares of differences between adjacent RR intervals), and PNN50 (the proportion of differences in successive NN intervals greater than 50 ms) were used. The total power in the frequency range of 0–0.40 Hz was divided into very low frequency (VLF: <0.04 Hz), low frequency [LF: 0.04–0.15 Hz, modulated by sympathetic nervous system (SNS)], and high frequency [HF: 0.15–0.4 Hz, modulated by parasympathetic nervous system (PNS)]. LF and HF were measured in normalized units (nu), which represent the relative value of each power component in proportion to the total power minus the VLF component. NN or RR intervals mean the time between two successive heartbeats.
2.5. Statistical analysis
SPSS 25.0 (IBM Corp., Armonk, NY, USA) program was used for variable analysis. Normally distributed continuous data were expressed as mean ± standard deviation (minimum–maximum). Continuous variables that are not normally distributed were expressed as median (minimum–maximum), and categorical variables were expressed as n and percentages. The normal distribution of the data was evaluated by the Lilliefors‐corrected Kolmogorov–Smirnov test, and the variance homogeneity was evaluated by the Levene test. The independent‐samples t test was used with the bootstrap results when comparing two independent groups with one according to the quantitative data, and the Mann–Whitney U test was used together with the Monte Carlo results. To compare categorical variables, Pearson chi‐square and Fisher exact tests were tested using exact results. Wilcoxon signed‐rank test and paired‐samples t test were used to compare two repetitive measurements of dependent quantitative variables. Partial correlation test was used to examine the correlations between the 25‐OH VitD levels and SDNN, SDANN, RMSSD, PNN50, HF, and LF values. Variables were examined at 95% confidence level (Cl), and p < .05 was considered to indicate a statistically significant difference.
3. RESULTS
The mean age of the patients was 36.04 ± 7.6 years, and 53.9% were female. Baseline characteristics of the study groups are shown in Table 1. Of all patients, 15.6% were current smokers. None of the study patients were hypertensive, diabetic, or hyperlipidemic. There were no significant differences between groups for age, gender, body mass index, and current smoking. Also, baseline systolic and diastolic blood pressure (BP), LVEF, left atrium diameter, and left ventricular septal wall thickness were similar between groups (Table 1).
Table 1.
Baseline clinical and echocardiographic characteristics
| VitD‐deficient group (n = 52) | Control group (n = 50) | Total (n = 102) | p‐value | |
|---|---|---|---|---|
| Age | 34.6 ± 7.4 | 37.5 ± 7.6 | 36.04 ± 7.6 | .163 |
| Female gender (%) | 28 (53.8) | 27 (54) | 55 (53.9) | .999 |
| BMI (kg/m2) | 28.3 ± 2.1 | 27.2 ± 2.7 | 27.2 ± 2.8 | .978 |
| Smoking (%) | 9 (17.3) | 7 (14) | 16 (15.6) | .838 |
| Systolic BP (mmHg) | 119.7 ± 7.4 | 118.4 ± 8.3 | 119.6 ± 7.3 | .892 |
| Diastolic BP (mmHg) | 75 ± 7.2 | 73.5 ± 6.8 | 74.5 ± 7.1 | .394 |
| LVEF (%) | 64.5 ± 3.5 | 65 ± 3.6 | 64.8 ± 3.8 | .745 |
| Left atrium diameter (mm) | 36.3 ± 3.1 | 35.9 ± 3.6 | 36.1 ± 3.2 | .432 |
| LVSWT (mm) | 10.2 ± 0.9 | 9.4 ± 1.2 | 10.4 ± 0.8 | .371 |
Abbreviations: BMI: body mass index, BP: blood pressure, LVEF: left ventricular ejection fraction, LVSWT: left ventricular septal wall thickness.
Both study groups were similar in regard to fasting glucose, creatinine, electrolytes, cholesterol levels, hemogram, and thyroid status (Table 2).
Table 2.
Laboratory values
| VitD‐deficient group (n = 52) | Control group (n = 50) | Total (n = 102) | p‐value | |
|---|---|---|---|---|
| Fasting glucose (mg/dl) | 96 (69/106) | 90.5 (69/107) | 95 (69/107) | .122 |
| Creatinine (mg/dl) | 0.865 (0.56/1.4) | 0.87 (0.51/1.1) | 0.87 (0.51/1.4) | .238 |
| Na (mmol/L) | 138 (132/143) | 139 (133/142) | 139 (132/143) | .276 |
| K (mmol/L) | 4.2 (3.7/5) | 4.2 (3.4/4.8) | 4.2 (3.4/5) | .695 |
| AST (U/L) | 23 (11/48) | 26 (12/45) | 25 (11/48) | .432 |
| ALT (U/L) | 18.5 (5/40) | 19 (9/46) | 19 (5/46) | .794 |
| TC (mg/dl) | 180.7 ± 22.7 | 175.9 ± 24.2 | 178.4 ± 23.4 | .295 |
| TG (mg/dl) | 155.4 ± 72.1 | 148.6 ± 96.4 | 152.6 ± 73.5 | .216 |
| LDL‐C (mg/dl) | 102.7 ± 21.6 | 95.5 ± 20.09 | 99.2 ± 21.1 | .105 |
| HDL‐C (mg/dl) | 40.3 ± 6.4 | 44.1 ± 7.9 | 42.4 ± 8.4 | .186 |
| Hemoglobin (g/dl) | 14.3 ± 1.4 | 14.1 ± 1.2 | 14.2 ± 1.3 | .425 |
| Platelet (×1,000) (K/µl) | 252 (106/377) | 287 (119/395) | 266 (106/395) | .382 |
| T3 (ng/dl) | 3.1 (2.72/3.84) | 3.09 (2.76/3.93) | 3.1 (2.72/3.93) | .889 |
| T4 (ng/dl) | 1.30 (0.76/1.96) | 1.34 (0.78/1.98) | 1.32 (0.76/1.98) | .845 |
| TSH (mIU/L) | 2.59 (0.96/3.58) | 2.65 (0.94/3.52) | 2.64 (0.94/3.58) | .811 |
| 25‐OH VitD (ng/ml) | 9.2 (5.04/16.2) | 39.35 (33.44/49.8) | 16.2 (5.04/49.8) | <.001 |
Abbreviations: TC, total cholesterol; TG, triglyceride; LDL‐C, low‐density lipoprotein cholesterol; HDL‐C, high‐density lipoprotein cholesterol; TSH, thyroid‐stimulating hormone.
The median 25‐OH VitD level was significantly lower in the VitD‐deficient group than the control group (9.2 vs. 39.35 ng/ml, p < .001) (Table 2).
3.1. HRV parameters
The time‐domain and frequency‐domain parameters of HRV were compared between the VitD‐deficient group and control group. There were no significant differences between groups in terms of mean heart rate and LF. SDNN (68.58 ± 13.53 vs. 121.02 ± 27.45 ms, p = .001), SDANN (95.96 ± 22.26 vs. 166.48 ± 32.97 ms, p = .001), RMSSD (23 vs. 59 ms, p < .001), PNN50 (6.5% vs. 36%, p < .001), and HF (19.6 ± 10.2 vs. 42.1 ± 14.3, p < .001) were significantly lower in patients with VitD deficiency compared with control group (Table 3). HRV parameters were improved after VitD replacement [SDNN (68.58 ± 13.53 to 119.87 ± 28.28 ms, p < .001), SDANN (95.96 ± 22.26 to 164.44 ± 33.90 ms, p < .001), RMSSD (23 to 58 ms, p < .001), PNN50 (6.5 to 33%, p < .001), and HF (19.6 ± 10.2 to 39.4 ± 11.7, p < .001)]. Importantly, following VitD replacement, there were no significant differences regarding HRV parameters in patients with initial VitD deficiency and control group (Table 3).
Table 3.
Comparison of HRV parameters between groups
| VitD‐deficient group (n = 52) | Control group (n = 50) | Total (n = 102) | p‐value | |
|---|---|---|---|---|
| Mean heart rate (bpm) | ||||
| Before replacement | 77.4 ± 6.6 | 79.04 ± 5.9 | 78.2 ± 6.3 | .202 |
| After replacement | 78.08 ± 6.1 | 79.04 ± 5.9 | 78.5 ± 6.03 | .415 |
| p‐value for intragroup | .168 | 1 | – | |
| SDNN (ms) | ||||
| Before replacement | 68.58 ± 13.53 | 121.02 ± 27.45 | 94.28 ± 33.94 | .001 |
| After replacement | 119.87 ± 28.28 | 121.02 ± 27.45 | 120.43 ± 27.75 | .832 |
| p‐value for intragroup | <.001 | 1 | – | |
| SDANN (ms) | ||||
| Before replacement | 95.96 ± 22.26 | 166.48 ± 32.97 | 130.53 ± 45.08 | .001 |
| After replacement | 164.44 ± 33.90 | 166.48 ± 32.97 | 165.44 ± 33.30 | .745 |
| p‐value for intragroup | <.001 | 1 | – | |
| RMSSD (ms) | ||||
| Before replacement | 23 (12/39) | 59 (47/92) | 38.5 (12/92) | <.001 |
| After replacement | 58 (46/92) | 59 (47/92) | 58.5 (46/92) | .638 |
| p‐value for intragroup | <.001 | 1 | – | |
| PNN50 (%) | ||||
| Before replacement | 6.5 (2/15) | 36 (20/55) | 14.5 (2/55) | <.001 |
| After replacement | 33 (17/52) | 36 (20/55) | 35.5 (17/55) | .556 |
| p‐value for intragroup | <.001 | 1 | – | |
| HF (nu) | ||||
| Before replacement | 19.6 ± 10.2 | 42.1 ± 14.3 | 33.4 ± 23.2 | <.001 |
| After replacement | 39.4 ± 11.7 | 42.1 ± 14.3 | 40.8 ± 13.7 | .642 |
| p‐value for intragroup | <.001 | 1 | – | |
| LF (nu) | ||||
| Before replacement | 62.9 ± 15.6 | 61.6 ± 21.7 | 62.5 ± 24.4 | .795 |
| After replacement | 59.4 ± 13.8 | 61.6 ± 21.7 | 59.8 ± 18.8 | .811 |
| p‐value for intragroup | .762 | 1 | ‐ | |
Abbreviations: SDNN, standard deviations of all NN intervals; SDANN, standard deviation of the averages of NN intervals in all 5‐min segments of the entire recording; RMSSD, the square root of the mean of the sum of the squares of differences between adjacent NN intervals; PNN50, the number of pairs of adjacent NN intervals differing by more than 50 ms divided by the total number of all NN intervals; HF, high‐frequency component; LF, low‐frequency component.
In addition, there was significantly positive linear correlation of 25‐OH VitD level with SDNN (r = .658, p < .001), SDANN (r = .676, p < .001), RMSSD (r = .863, p < .001), PNN50 (r = .712, p < .001), and HF (r = .752, p < .001) (Table 4).
Table 4.
Correlation between 25‐OH VitD and HRV parameters
| 25‐OH VitD | ||
|---|---|---|
| r | p | |
| SDNN (ms) | .658 | <.001 |
| SDANN (ms) | .676 | <.001 |
| RMSSD (ms) | .863 | <.001 |
| PNN50 (%) | .712 | <.001 |
| HF (nu) | .752 | <.001 |
Partial correlation test, r: correlation coefficient.
Abbreviations: SDNN, standard deviations of all NN intervals; SDANN, standard deviation of the averages of NN intervals in all 5‐min segments of the entire recording; RMSSD, the square root of the mean of the sum of the squares of differences between adjacent NN intervals; PNN50, the number of pairs of adjacent NN intervals differing by more than 50 ms divided by the total number of all NN intervals; HF, high‐frequency component; HRV, heart rate variability.
4. DISCUSSION
In the present study, we found that otherwise apparently healthy individuals with VitD deficiency had significantly lower SDNN, SDANN, RMSSD, PNN50, and HF values compared with controls. 25‐OH VitD levels were positively correlated with SDNN, SDANN, RMSSD, PNN50, and HF values. Also, HRV parameters have improved following VitD replacement in those with initial VitD deficiency.
VitD deficiency is very common worldwide (Looker et al., 2008). It is associated with a number of nonskeletal diseases including cancer, autoimmune disease, diabetes, and CVD besides its classical hormonal role in bone metabolism (Norman & Powell, 2014).
Autonomic imbalance, characterized by a hyperactive sympathetic system and a hypoactive parasympathetic system, is associated with increased risk of SCD and ventricular arrhythmias (Gerritsen et al., 2001). Therefore, assessment of autonomic tone is a potential method for identifying patients at high risk of sudden death. HRV is noninvasive, simple, and inexpensive method for measurement of cardiac autonomic tone (Lahiri, Kannankeril, & Goldberger, 2008). In the time‐domain analysis, SDNN reflects the general measurement of autonomic nervous system balance and PNN50 predominantly reflects the parasympathetic activity. On the other hand, in the frequency‐domain analysis, HF is modulated predominantly by the parasympathetic nervous system, whereas LF is under the influence of both parasympathetic and sympathetic nervous systems.
The underlying pathways of SCD in patients with VitD deficiency are still unclear. Altered myocardial calcium flux and increased risk of SCD related to a poor VitD status suggest a link to cardiac arrhythmias (Kim et al., 2006; Scragg, Jackson, Holdaway, Lim, & Beaglehole, 1990; Thomasset, Parkes, & Cuisinier‐Gleizes, 1982). Activated VitD is proposed to have the ability to diffuse across the blood–brain barrier, implicating a role for 1,25‐dihydroxy VitD in augmenting autonomic vagal control by binding directly to nuclear VitD receptors in the adrenergic neurons located centrally in the spinal cord and brain tissue (Sternberg, 2012). Association of low levels of VitD with autonomic imbalance might be one of the possible causal mechanisms for the pathogenesis of SCD.
Although previous studies showed that patients with lower VitD levels are at increased risk of CVD and sudden cardiac death (Deo et al., 2011), there is little clinical evidence for the effect of VitD deficiency on cardiac autonomic function. Canpolat et al. reported that cardiac autonomic functions are impaired in patients with VitD deficiency despite the absence of overt cardiac involvement and symptoms (Canpolat et al., 2014). Similarly, in the present study, it has been shown that HRV parameters were significantly decreased in apparently healthy individuals with VitD deficiency compared with control group. However, the design of the other study was cross‐sectional.
Jung et al. found that VitD deficiency was significantly correlated with impaired cardiac autonomic functions assessed by parameters of HRV in patients with type 2 diabetes mellitus (Jung et al., 2015). However, it is difficult to determine any causative relationship between VitD status and diabetic autonomic neuropathy including HRV due to cross‐sectional nature of the study.
Mann et al. reported that VitD supplementation in 13 healthy subjects with VitD deficiency significantly improved sympathovagal balance (Mann et al., 2014). The study results were remarkable for significant effects of VitD deficiency and supplementation on cardiac autonomic functions in healthy subjects. Their study results were in agreement with those from our study. One of the main limitations of their study was very small sample size.
The main strength of our study was the demonstration of recovering of cardiac autonomic dysfunction after VitD replacement in apparently healthy subjects by using HRV which were widely available, simple, inexpensive, and noninvasive technique. Our results suggested that VitD replacement improves cardiac autonomic tone in healthy humans. While larger, prospective studies are required to determine the effect of VitD replacement on clinical outcomes, optimizing VitD levels remains an exciting potential therapeutic target for those populations at high risk of cardiovascular mortality.
5. CONCLUSION
In conclusion, we found that VitD deficiency was significantly correlated with impaired cardiac autonomic functions assessed by parameters of HRV and showed that cardiac autonomic dysfunction has improved after VitD replacement.
6. STUDY LIMITATIONS
The major limitation of our study was a small patient population (102 patients). Further studies with more patients and longer follow‐up periods are needed to evaluate the relationship between VitD deficiency and adverse cardiovascular arrhythmic events.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
Dogdus M, Burhan S, Bozgun Z, et al. Cardiac autonomic dysfunctions are recovered with vitamin D replacement in apparently healthy individuals with vitamin D deficiency. Ann Noninvasive Electrocardiol. 2019;24:e12677 10.1111/anec.12677
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