Corresponding author : Mi Hee Kong, MD, PhD Department of Family Medicine, Jeju National University Hospital, School of University, Jeju National University, 15 Aran 13-gil, Jeju 63241, Korea INTRODUCTION
Heart rate variability (HRV) refers to minute variations in heartbeat cycles. Cardiac impulses are influenced by the autonomic nervous system (ANS), which refers to the interaction between the sympathetic and parasympathetic nervous systems, and minute variations in the heart rate are caused by the interaction between the internal and external environment. Accordingly, the activity and balance of the ANS can be noninvasively determined by analyzing the HRV [1].
The ANS is known to play a fundamental role in human health and disease. Healthy people constantly change and adapt themselves to various environments because of their adequate ANS activity. Conversely, in those individuals with poor ANS activity, various diseases can occur due to reduced internal adaptability to the environment. Accordingly, previous studies have analyzed HRV, which can indicate the level of ANS activity, and found that reduced HRV is associated with poor health, various diseases, and increased mortality rate [2-5].
Death rates have been found to increase when HRV is low regardless of the cause of death, and this risk increases when patients with cardiovascular disease present risk factors such as hypertension and diabetes [4-6]. The risk of death due to cardiovascular diseases also increased in the absence of other underlying diseases when HRV was low, and this risk was even higher in diabetic patients. Furthermore, low HRV itself has been associated with various metabolic and cardiovascular risk factors [7,8]. In this regard, several hypotheses have been proposed explaining that such psychosocial problems can reduce HRV by the same mechanism, ultimately causing diseases.
This study aimed to identify the types of autonomic imbalances in a mono-ethnic South Korean population with low HRV by examining differences in the risk factors of metabolic and cardiovascular diseases regarding each HRV index. In particular, as previous studies have mainly examined the relationship between high levels of low-density lipoprotein(LDL) cholesterol [9,10] and serum lipids among the metabolic indices, the present study investigated the association between high levels of triglyceride and low levels of high-density lipoprotein (HDL) cholesterol.
METHODS
The study was approved by the Institutional Review Board of Jeju National University Hospital, Jeju, Republic of Korea (IRB No. JEJUNUH 2016-01-001). This study was exempted from the obligation to submit the study consent of the subjects because of the very low risk to health of the study subjects due to the retrospective medical records analysis method by the Institutional Review Board of Jeju National University Hospital. In this regard, participants who had a health examination performed at Jeju National University Hospital received on the day of examination a form notifying them that their examination results, excluding personal information, would be used for research purposes.
1. Study subjects
A retrospective review was conducted using the medical records of individuals whose HRV was measured when they underwent anthropometry, electrocardiogram, and blood tests during health examinations between August 2009 and December 2015. During the health examination, a survey was conducted in which participants were asked whether they were diagnosed with and taking medication for hypertension, diabetes, dyslipidemia, and heartbeat irregularities. Those with arrhythmias, such as atrial fibrillation, atrial flutter, atrioventricular block, heart rate <50 bpm or ≥100 bpm, and those previously diagnosed with and currently taking medication for heartbeat irregularities were excluded.
2. Measurement of HRV
HRV was measured with a fingertip pulse wave sensor (BFM-5000P; Medicore Co., Ltd., Seoul, Korea) while participants were in a sitting position without speaking or moving, unless necessary, in a small room. The heart rate was recorded for 5 minutes and the following time-domain measures of HRV were determined: standard deviation of the normal-to-normal intervals (SDNN) and in review frequency-domain variables of HRV, including total power (TP) (0.0-0.4 Hz), high frequency (HF) band (0.15-0.40 Hz), and low frequency (LF) band (0.04-0.15 Hz). Subjects were grouped by quartiles of HRV indices: SDNNs, and 5-minute TP, LF, and HF.
3. Metabolic and cardiovascular risk factors
In this study, the risk factors of metabolic and cardiovascular disorders were analyzed including abdominal obesity, blood pressure elevation, blood glucose elevation, hypertriglyceridemia, and low HDL cholesterolemia. The criteria for abdominal obesity was defined according to the Korean Society for the Study of Obesity [11] and, in this regard, having a waist circumference of ≥90 cm and ≥85 cm in male and female participants, respectively, was considered as abdominal obesity. Blood pressure elevation (high BP) was defined as blood pressure level ≥130 mmHg systolic or ≥85 mmHg diastolic, or a diagnosis of hypertension and currently taking antihypertensive medication. Blood glucose elevation (high FPG) was defined as fasting (≥12 hours) blood glucose level ≥100 mg/dL or a diagnosis of diabetes and currently taking medication. Hypertriglyceridemia (high TG) was defined as fasting (≥12 hours) triglyceride level≥150 mg/dL or a diagnosis of dyslipidemia and currently taking medication. Low HDL cholesterolemia (low HDL) was defined as fasting (≥12 hours) HDL cholesterol level <40 mg/dL for men and <50 mg/dL for women.
4. Statistical analysis
Statistical analyses were performed using SPSS for Windows, version 20.0 (IBM Corp., Armonk, NY, USA). P-values less than 0.05 were considered statistically significant. Regarding the comparison of gender differences in baseline characteristics, age differences were analyzed by t-test and the other variables were age-adjusted using analysis of covariance (ANCOVA). Correlations between HRV parameters and cardiovascular risk factors were analyzed using age-adjusted partial correlation. We compared the prevalence rate of each metabolic and cardiovascular risk factor per quartile group of HRV variables. The odds ratio (OR) and 95% confidence interval (CI) for each metabolic and cardiovascular risk factor per quartile of HRV variables were calculated using logistic regression analysis.
RESULTS
1. Baseline characteristics of the study group
Finally, the total number of participants was 702 (530 men and 172 women). The average age of male participants was 42.8±11.1 years, which was higher than that of female participants (38.9±11.9 years, t=3.913, P<0.001 by t-test). Differences in anthropometric indices, blood pressure, fasting blood glucose, and serum lipids between male and female participants are presented in Table 1. Men had higher body mass index, waist circumference, blood pressure, triglyceride and fasting blood sugar, but lower HDL cholesterol than women (all P<0.001 by ANCOVA after adjustment for age).
The number of male and female participants with abdominal obesity (waist circumferences for men and women of >90 cm and >85 cm, respectively) was 166 (31.3%) and 29 (16.9%). The total number of male and female participants who met the criteria for blood pressure elevation was 275 (51.9%) and 27 (15.7%), respectively. The total number of male and female participants who met the criteria for elevated blood glucose was 121 (22.8%) and 12 (7.0%), respectively. The total number of male and female participants with hypertriglyceridemia was 184 (34.7%) and 14 (8.1%), respectively, and the number of male and female participants with low HDL cholesterolemia was 122 (23.0%) and 46 (26.7%), respectively. Among women, the proportion of elevated blood glucose and hypertriglyceridemia was less than 10%, which was relatively low. Therefore, there was a limitation in analyzing the difference in the OR of elevated blood glucose and hypertriglyceridemia in women with low HRV level compared to those of other groups.
2. Baseline characteristics of HRV parameters in the study group
In terms of gender and age, there were statistically significant inverse correlations between all HRV indices (SDNN, TP, LH, and HF) for men as age increased (r=-0.248, -0.193, -0.226, and -0.239; all P<0.001). Similarly, all HRV indices of female participants showed inverse correlations with increase in age, but statistical significant differences were found only for TP (r=-0.297, P<0.001), LH (r=-0.400, P<0.001), and HF (r=-0.164, P=0.031) indices. The correlation with SDNN was not statistically significant (r=-0.145, P=0.058). A gender-based comparison of HRV indices after controlling for age revealed significant decreases in TP (P=0.016) and LF (P<0.001) indices in female participants compared to male participants. However, there were no statistically significant gender differences for SDNN(P=0.067) and HF (P=0.695), as shown in Table 1.
3. OR of metabolic abnormality among the groups with the lowest and highest HRV indices
Table 2 shows the comparison of the relative risks of metabolic and cardiovascular diseases by each risk factor for the groups with the lowest and highest HRV indices. Each HRV index was categorized into quartiles. Regarding abdominal obesity, the risk of morbidity was significantly increased for women in the lowest SDNN group (OR, 4.51; 95% CI, 1.15-17.72) and for men in the lowest TP group (OR, 1.83; 95% CI, 1.06-3.17). The prevalence of high BP was significantly increased for men in the lowest SDNN (OR, 1.77; 95% CI, 1.06-2.94), TP (OR, 1.74; 95% CI, 1.05-2.88), and LF (OR, 1.82; 95% CI, 1.07-3.11) groups. High FPG morbidity was significantly increased for men in the lowest LF (OR, 2.01; 95% CI, 1.05-3.85) and HF (OR, 2.30; 95% CI, 1.21-4.38) groups, although no relationship with decreased HRV was found in women. The prevalence of high TG was significantly increased for men in the lowest LF group (OR, 1.82; 95% CI, 1.04-3.18) but not in men with other HRV indicators or in women. Low HDL significantly was increased only for women in the lowest SDNN group (OR, 3.01; 95% CI, 1.08-8.33).
DISCUSSION
The results of this study revealed significant increases in the risk of metabolic and cardiovascular diseases with decreases in HRV indices. These findings can be considered to be an extension of previous studies’ results [2-6,7], which have identified a relationship between HRV reduction and cardiovascular diseases.
Specifically, results showed that the risk of contracted abdominal obesity in female participants with low SDNN was 4.51 times higher than that of female participants with high SDNN, while the risk of contracted abdominal obesity in male participants was 1.83 times higher when TP was low. Previous studies have also found that HRV in obese women is lower than in normal-weight women [12]. However, after losing weight, the reduced HRV of these women was recovered [13]. This indicates that the findings of the present study are an extension of research that has studied the relationship between obesity and HRV reduction. Nevertheless, the present study found differences in specific indices. Previous studies have indicated decreases in TP or HF in obese women, however, in the present study, no statistically significant increase in the risk of abdominal obesity was found in those individuals with low TP and HF. Although some differences were identified, variations in HRV were only found with decreases in TP and SDNN for men and women, respectively.
In this study, the risk of blood glucose elevation significantly increased only in men with low LF and HF. Previous studies have also reported significantly lower HRV in patients with diabetes than in people without this health condition, and even in the absence of diabetes, HF or LF was significantly negatively correlated with fasting blood glucose and fasting insulin [14,15].
Furthermore, results revealed that the risk of elevated blood pressure significantly increased in male participants with reduced SDNN, TP, and LF, but not in those who presented reduced HF. However, the nonsignificant association of elevated blood pressure with HF found in the present study is not in line with the results of previous studies, which have reported reduced HF in patients with high blood pressure compared to other groups, as well as a higher risk of future hypertension with reduced HF [16]. Nevertheless, the present findings are consistent with those of a previous study [2], which reported a significant relationship between low LF and incidence of hypertension only in men. Another study[3] reported that the risk of developing hypertension in the future was high when SNDD decreased even when various accompanying risk factors were corrected. This finding is similar to that of the present study, in which the risk of blood pressure elevation morbidity was 1.77 times higher in the low SDNN group compared to other groups.
Additionally, the present study found that the risk of hypertriglyceridemia was higher in men with low LF and, for women, the risk of low HDL cholesterolemia was high when SDNN was low. Research concerning the relationship between HRV and triglyceride or HDL cholesterol is insufficient, but inverse correlations have been found in some studies related to LDL cholesterol, where higher increases in LDL cholesterol were associated with lower SDNN and RMSSD [9].
The correlation analysis of age and HRV in this study revealed inverse correlations for both genders in most of the coefficients between HRV indices and age, except for SDNN in female participants. A previous study [17] also reported low HRV as age increased. Furthermore, lower HF was observed in participants with a family history of hypertension compared to participants without this type of history [18]. In this regard, TP and HF were lower in participants with a family history of diabetes than in participants without such history [19].
Reductions in HRV can be considered as an indication of a decrease in the vagus nerve activity due to autonomic imbalance. Such changes are related to a greater incidence of cardiovascular diseases and death rates. Increases in various inflammatory response levels when HRV decreases [20,21] indicate that lower HRV can deteriorate health.
Chronic pain diseases such as fibromyalgia, irritable bowel syndrome, and functional gastrointestinal disorders, whose underlying mechanisms have been difficult to determine, have been recently explained by the polyvagal theory [22] as generated by an unstable ANS and, in this regard, reduced HRV has been reported in these patients. Smoking can reduce vagal activity and immediate reduction in the average HF has been observed after smoking only one cigarette [23].
Besides, smoking in pregnant women has been reported to reduce HRV in neonates [24]. On the other hand, significantly lower SDNN, LF, and HF have been observed in individuals with insufficient exercise compared to those who regularly exercise [25].
Lifestyle risk factors can be addressed, and increases in HRV have been observed through behavioral changes, such as smoking cessation, weight loss, and increased exercise. In particular, improvement in vagal activity has been observed after smoking cessation for 24 hours, 1 week, and 8 weeks [26-28]. Regarding exercise, regular aerobic exercise for 12 weeks was reported to increase SDNN and HF [29]. With regards to obesity, significant increases in SDNN and HF were observed 1 year after bariatric surgery in participants who were obese and had lower SDNN compared to normal participants [12]. Recent studies have also shown that HRV can be improved using neuroscience equipment.30) This type of equipment has demonstrated to be effective in improving physical symptoms caused by ANS instability such as postmenopausal flushing [31] and post-traumatic stress disorder [32].
The HRV test is a non-invasive method that can be easily administered by being comfortably seated in a quiet room for 5 minutes. Accordingly, careful attention should be paid to the existence of comorbidity revealed through HRV tests, because the threat of risk factors discussed above is higher when HRV decreases. In this regard, it could be a good educational practice to encourage patients to constantly improve their lifestyle habits, because HRV can be easily recovered by changing these habits.
High-risk factors of metabolic and cardiovascular diseases can increase death rates. This can happen specifically if the HRV is low in individuals who present the risk factors mentioned above. In this case, the risk of developing cardiovascular diseases as well as death rates due to these causes can increase. Since many studies have reported the effectiveness of smoking cessation, increased exercise, and weight loss, more thorough education is needed for people whose lifestyle habits need to be modified, and HRV can be used to monitor the results of applying these educational strategies.
However, this study has a limitation in reflecting the current status because the study data collection period has been protracted, and it has a limitation in that it was not amenable to allowing investigation of other factors such as lifestyle, which can affect HRV and cardiovascular risk factors. Therefore, additional research including recent research data and lifestyle conditions that can affect various metabolic and cardiovascular diseases will be needed.
In conclusion, results from this study with South Korean participants revealed that lower HRV in men was associated with a higher risk of abdominal obesity, blood pressure elevation, blood glucose elevation, and hypertriglyceridemia. On the other hand, lower HRV in women was related to a risk of increased low HDL cholesterolemia. In particular, the risk of abdominal obesity in women was 4.51 times higher with low SDNN.
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