DOI: https://doi.org/10.21203/rs.3.rs-2229971/v1
Functional limitations have recently shown in patients with hypertension. However, causes of kinesiophobia remain unknown. The aim was to compare functional exercise capacity (FEC), peripheral muscle strength (MS), level of kinesiophobia, physical activity (PA), fatigue, dyspnea, and quality of life (Qol) in hypertension patients and healthy controls and to investigate relationship between aforementioned outcomes in patients. Fifty-six patients and 45 age/gender-matched controls were included. FEC [6 min. walking test (6MWT)], peripheral MS (Dynamometer), kinesiophobia (Tampa Scale of Kinesiophobia), PA level [International Physical Activity Questionnaire (IPAQ)], perception of dyspnea (Modified Medical Research Council Dyspnea scale), fatigue (Fatigue Severity scale), and Qol (Short Form-36 questionnaire) were evaluated. Demographic characteristics were similar in patients (54.58 ± 11.33y,35M/21F) and healthy controls (51.11 ± 7.42y,33M/12F) (p > 0.05). Peripheral MS (p < 0.05), 6MWT, PA and Qol were significantly lower (p < 0.05); level of kinesiophobia (p < 0.001), perception of dyspnea (p < 0.001), and fatigue (p = 0.001) scores were higher in patients compared with controls. IPAQ (r=-0.556, p < 0.001), quadriceps femoris (r=-0.429, p = 0.001), hip flexor (r=-0.380, p = 0.004), shoulder abductor (r=-0.410,p = 0.002), elbow flexor (r=-0.364,p = 0.006), hand-grip strength (r=-0.355,p = 0.007), fatigue (r = 0.434, p = 0.001), SF-36 physical functioning (r = 0.404, p = 0.002), role limitations due to physical health (r=-0.370,p = 0.005), energy/fatigue (r=-0.357, p = 0.007), general health (r=-0.280, p = 0.036) was related to kinesiophobia in patients. Patients had impaired FEC, peripheral MS, higher level of kinesiophobia, perception of fatigue and dyspnea, reduced PA level, and Qol compared with healthy controls. In addition, a higher degree of kinesiophobia was related to physical inactivity, weakened upper and lower extremity MS, fatigue, impaired Qol in patients. Patients should be directed to cardiopulmonary rehabilitation.
What is known about this topic
Reduced peripheral muscle strength was related to increased cardiovascular mortality in patients with hypertension.
Physical inactivity is one of the factors that cause kinesiophobia in hypertension patients.
However, it is not known whether factors such as muscle strength, fatigue, and quality of life affect kinesiophobia in patients with hypertension.
What this study adds
Patients with hypertension had lower functional exercise capacity, upper and lower extremity muscle strength, higher level of kinesiophobia, fatigue, dyspnea, reduced physical activity level, and quality of life compared with healthy controls.
A higher degree of kinesiophobia was related to physical inactivity, weakened upper and lower extremity muscle strength, fatigue, impaired quality of life.
Hypertension, which affects about 25% of the general population and 65% of the older population, is one of the cause of mortality related to cardiovascular disorders [1]. Therefore, it is important to determine and control target organ damage of hypertension [2]. Decrease in exercise capacity was shown in studies [3, 4]. In addition, exercise intolerance is associated with decreased skeletal muscle strength, physical inactivity, and cardiorespiratory fitness [2]. Reduced muscle strength may cause poor health outcomes, such as the onset of cardiovascular disease and death [5]. Moreover, a recent meta-analysis showed that hypertension patients exhibit lower quality-of-life indicators than normotensives, particularly in the parameters connected to the physical domain [6]. As a result, hypertension has a critical clinical impact.
Reduced physical activity is closely related to kinesiophobia, which has been defined as a natural, irrational, debilitating response to acute injury and clarified by the fear-avoidance model in patients [7]. Kocjan et al. found that a high level of kinesiophobia was significantly correlated with a high level of physical inactivity in patients with hypertension [8]. However, it has not known whether muscle strength, fatigue or quality of life affects kinesiophobia.
Studies investigating the clinical symptoms functional exercise capacity, peripheral muscle strength, physical activity level, kinesiophobia, quality of life and fatigue in hypertension were not clear and insufficient. Therefore, the study's primary objective was to compare functional exercise capacity, peripheral muscle strength, kinesiophobia, fatigue, dyspnea, physical activity, and quality of life in patients with hypertension and healthy controls. The secondary objective was to research the relationship between kinesiophobia, functional exercise capacity, peripheral muscle strength, fatigue, dyspnea, physical activity, and quality of life in patients with hypertension.
Patients
Fifty-six patients were referred to the department for cardiopulmonary rehabilitation between December 2020 and November 2021, and 45 age and gender-matched controls were included in the study. Hypertension patients aged between 18 and 80 years, with no changes in medication during the previous three weeks, and being clinically stable for at least four weeks were included in the study. Patients with severe musculoskeletal, neurological diseases, pulmonary diseases, acute myocardial infarction, malignancies, and complex arrhythmias were excluded.
The study, carried out in conformity with the Declaration of Helsinki, was approved by the Non-interventional Clinic Research Ethics Committee of the University (No:2020/02). Written informed consent was obtained from all patients and controls to participate in the study.
Study design
A cross-sectional study was carried out. Assessment of functional exercise capacity, peripheral muscle strength, kinesiophobia, fatigue, dyspnea, comorbidity, PA level, and Qol patients and control's were tested by physiotherapist. The cardiologist evaluated the patient's clinical assessment. Physical and socio-demographic data were recorded.
The 6-minute walking test (6-MWT) was used to assess functional exercise capacity. The 6-MWT was performed according to ATS guidelines [9]. For comparison, reference values were used [10]. The 6- minute walking work (6-MWw) was calculated as the product of the most significant 6-MWT distance (in kilometers) and weight (in kilograms) [11]. Quadriceps femoris, hip flexors, shoulder abductors, and elbow flexors muscle strength was assessed with a dynamometer (JTECH Power Track Commander, Baltimore, MD, USA). The percentage of predicted values was expressed [12]. Handgrip strength was evaluated with a Jamar analogue hand dynamometer (PowerTrack II, JTECH Medical, Midvale, Utah, USA) [13]. The left and right sides were measured three times. The greatest value was recorded. The Tampa Scale of Kinesiophobia (TSK) was used to asses kinesiophobia. The TSK consists of seventeen items. The scale is scored between 17 and 68 point. Higher scores imply a higher level of kinesiophobia. The score above 37 defines a high level of kinesiophobia [14]. The Fatigue Severity Scale (FSS) was used to evaluate the fatigue. The FSS includes nine items. Each item scores 0 to 7 and maximum score is 63. Scores above 36 indicate severe fatigue [15]. Dyspnea was evaluated with The Modified Medical Research Council (MMRC) dyspnea scale. Dyspnea levels were graded 0–4 [16]. Comorbidity level was assessed using the Charlson Comorbidity Index (CCI). The index contains 19 medical conditions. The total score indicates an index of severity [17]. The International Physical Activity Questionnaire (IPAQ) short-form was used to asses PA level. The IPAQ includes information on walking time, moderate and vigorous-intensity activity, and sedentary activity. Also, the scores were classified as inactive, minimally active, and sufficiently active due to total score [18]. The Qol was evaluated with The Short Form 36 (SF-36) questionnaire. The SF-36 includes eight dimensions: role limitations due to physical health, physical functioning, energy/fatigue, emotional well-being, pain, social functioning, role limitations due to emotional problems, and general health. The score varies from 0 to 100. Higher scores indicate better Qol [19].
Statistical analyses
Statistical analysis was done with SPSS 20.0 statistical analysis program (Armonk, NY: IBM Corp). The G*Power software was used to estimate the sample size. According to the results of a prior study [3], total of 94 individuals was estimated (47 individuals in each group) that would have a power of 80% for an α value of 0.05 (d = 0.530). The Shapiro-Wilk test was used to test normality of data. Normally distrubuted data were expressed as mean (± standard deviation). The Student's t-test was used to compare the groups' characteristics and reported as mean difference and 95%CI. The Mann–Whitney U test was used to compare non-distributed data were showed as median (IQR) and. Nominal data were analysed with the Chi-square test. For calculating correlations between TSK, demographic, and clinical factor, Pearson's and Spearman's rank correlation coefficients were used. The p-value < 0.05 was considered as statistically significant.
Fifty-six patients with HT and 45 healthy controls were included and compared. The distribution of patients and controls were summarized in Fig. 1. Demographics and clinical characteristics of HT patients and healthy controls were similar (p > 0.05) except for CCI (p < 0.001) score (Table 1).
Variables |
Hypertension patients Mean ± SD Median (IQR) |
Control Mean ± SD Median (IQR) |
Mean difference %95 CI |
p |
---|---|---|---|---|
Age (years) |
54.58 ± 11.33 |
51.11 ± 7.42 |
3.47(-0.41-7.36) |
0.079 |
Sex (female/male) |
21/37.5%;35/62.5% |
12/26.7%;33/73.3% |
0.290 |
|
Weight, kg |
81.65 ± 11.74 |
79.91 ± 10.29 |
1.74(-2.67-6.16) |
0.436 |
Height, cm |
168(160.25–173) |
167(165–177) |
0.304 |
|
BMI, kg/m2 |
29.14 ± 4.10 |
27.77 ± 3.20 |
1.36(-0.11-2.85) |
0.070 |
Normal/over weighted/obese, n (%) |
7/12.5%;29/51.8%;20/35.7% |
9/20%;26/57.8%;10/22.2% |
0.275 |
|
Smoking (pack.year) |
3(0-29.50) |
1(0–26) |
0.316 |
|
Smoking (current/ex/non smoker), n (%) |
10/17.9%;21/37.5%;25/44.6% |
10/22.2%;13/28.9%;22/48.9% |
0.642 |
|
CCI score |
2(2–3) |
0(0–0) |
< 0.001* |
|
n/% |
||||
Medical history |
||||
Diabetes mellitus |
24/42.9% |
|||
Hyperlipidemia |
13/23.2% |
|||
Chronic coronary syndrome |
17/30.4% |
|||
BMI: body mass index; CCI: Charlson Comorbidity Index; CI: confidence interval. *p˂0.05. |
The distance covered during 6-MWT, 6-MWT%, and 6MWw were significantly lower in patients than in healthy controls (p ˂ 0.001) (Table 2, Fig. 2). Forty-two (75%) patients’ predicted 6-MWT values were less than 80%. Parameters of 6-MWT are given in Table 2. Measured and predicted quadriceps femoris, hip flexors, shoulder abductors, elbow flexors, and handgrip muscle strength were significantly higher in controls compared with patients (p < 0.05, Table 3). The predicted muscle strength values which is less than 80% were calculated as; in 54 (96.4%) patients for quadriceps femoris, in 21 (37.5%) patients for hip flexors, in 48 (85.7%) patients for shoulder abductors, and in 42 (75%) patients for elbow flexors. The TSK (p < 0.001), FSS (p = 0.001), mMRC (p < 0.001) scores and IPAQ sitting duration (p = 0.005) were statistically significantly higher and IPAQ total PA (p < 0.001), moderate (p = 0.002), and vigorous activity (p < 0.001), SF-36 subscale scores (p < 0.05) except for social functioning, were higher in the controls compared with the patients (Table 4). Forty-four (78.6%) patients had a high level of kinesiophobia (TSK score > 37), and 23 (41.1%) patients reported severe fatigue. Thirty-five (62.5%) of patients were inactive, 19 (33.9%) were minimally active, and 2 (3.6%) of the patients was sufficiently active. On the other hand, 18 (40%) of the controls were inactive, 31 (28.9%) were minimally active, and 14 (31.1%) were sufficiently active (p = 0.001).
6-MWT parameters |
Hypertension patients Mean ± SD Median (IQR) |
Controls Mean ± SD Median (IQR) |
Mean difference %95 CI |
p |
---|---|---|---|---|
6-MWT distance, m |
430.30 (344.40- 488.40) |
604.80 (570–646) |
< 0.001* |
|
6-MWT distance, % predicted |
71.14 (58.98–80.28) |
96.89 (85.66-103.82) |
< 0.001* |
|
6MWw, kg·m |
33281.96 ± 12146.11 |
48431.11 ± 7685.12 |
-15149.14[(-19281.35)-(-11016.94)] |
< 0.001* |
Heart rate, beats/min (resting) |
73(68-84.75) |
79(71–89) |
0.082 |
|
Peak heart rate, beats/min |
101.96 ± 19.44 |
108.68 ± 23.10 |
-6.72 (-15.12-1.67) |
0.115 |
Maximum heart rate,% |
61.76 ± 11.45 |
64.57 ± 14.43 |
-2.80(-7.91-2.30) |
0.278 |
Systolic blood pressure, mmHg (resting) |
130 (120–140) |
120 (110–120) |
< 0.001* |
|
∆ Systolic blood pressure, mmHg |
10(5–20) |
10 (7.50–30) |
0.153 |
|
Diastolic blood pressure, mmHg (resting) |
80 (70-86.75) |
74(70–80) |
0.111 |
|
∆ Diastolic blood pressure, mmHg |
5(0–10) |
6(0–10) |
0.207 |
|
SpO2, % (resting) |
98 (97–98) |
98 (97–98) |
0.986 |
|
∆ SpO2, % |
0 (0–0) |
0 (0–0) |
0.260 |
|
Breathing frequency, breaths/min (resting) |
21.50 (20–24) |
21 (17–24) |
0.188 |
|
∆Breathing frequency, breaths/min |
5.50 (4–8) |
6 (4–8) |
0.765 |
|
Dyspnea, 0–10 (resting) |
0 (0–0) |
0 (0–0) |
0.203 |
|
∆ Dyspnea, 0–10 |
0 (0–2) |
0 (0-1.50) |
0.405 |
|
Fatigue, 0–10 (resting) |
0 (0–0) |
0 (0–0) |
0.154 |
|
∆ Fatigue, 0–10 |
1(0–3) |
0(0–3) |
0.307 |
|
6-MWT: 6-minute walk test, SpO2: Oxygen saturation, 6MWw: 6-minute walk distance x body weight; CI: confidence interval. *p < 0.05. |
Variables |
Hypertension patients Mean ± SD Median (IQR) |
Control Mean ± SD Median (IQR) |
Mean difference %95 CI |
p |
---|---|---|---|---|
Quadriceps femoris (Right), N |
169.60(132-214.75) |
184(168-221.50) |
0.021* |
|
Quadriceps femoris (Left), N |
149.90(112.50-196.75) |
184(160–220) |
0.005* |
|
Quadriceps femoris, % predicted |
35.29(31-44.60) |
43.61(37-50.43) |
0.002* |
|
Hip flexors (Right), N |
143.50(110-178.25) |
200(172.50-218.50) |
< 0.001* |
|
Hip flexors (Left), N |
134(114-179.75) |
182(158-215.50) |
< 0.001* |
|
Hip flexors, % predicted |
95.67 ± 31.89 |
119.40 ± 35.90 |
-23.72[(-37.12)-(-10.32)] |
0.001* |
Shoulder abductors (Right), N |
108.50(84.70–123) |
154(116–193) |
< 0.001* |
|
Shoulder abductors (Left), N |
99(80.65-128.75) |
140(113–176) |
< 0.001* |
|
Shoulder abductors, % predicted |
57.76(43.38–72.27) |
74.14(66.20-91.88) |
< 0.001* |
|
Elbow flexors (Right), N |
129(108.50-181.50) |
169(132–213) |
0.005* |
|
Elbow flexors (Left), N |
130.50(105-183.50) |
158(136-215.50) |
0.008* |
|
Elbow flexors, % predicted |
64.12(43.93–80.86) |
78.47(56.16–94.35) |
0.019* |
|
Hand grip strength (Right), P |
69.30 ± 25.53 |
84.53 ± 22.56 |
-15.22[(-24.86)-(-5.59)] |
0.002* |
Hand grip strength (Left), P |
65.89 ± 22.89 |
79.97 ± 22.20 |
-14.08[(-23.05)-[-5.11)) |
0.002* |
N: Newton; P:Pound; CI: confidence interval. *p˂0.05. |
Variables |
Hypertension patients Mean ± SD Median (IQR) |
Control Mean ± SD Median (IQR) |
Mean difference %95 CI |
p |
---|---|---|---|---|
TSK score (17–68) |
38(35–41) |
19(17–23) |
< 0.001* |
|
FSS score (1–7) |
27.50(14–50) |
12(6–29) |
0.001* |
|
MMRC score (0–4) |
1(0–2) |
0(0–0) |
< 0.001* |
|
IPAQ (MET-min/week) |
||||
Total |
297(165-767.25) |
1140.00(359.25-3421.50) |
< 0.001* |
|
Walking |
272.25(152.62–693) |
462(181.50–1386) |
0.070 |
|
Moderate |
0(0–0) |
0(0-1140) |
0.002* |
|
Vigorous |
0(0–0) |
0(0-720) |
< 0.001* |
|
Sitting (min/day) |
360(300–480) |
240(180–435) |
0.005* |
|
SF-36 subscales (0-100) |
||||
Physical functioning |
80(55–90) |
100(90–100) |
< 0.001* |
|
Role limitations due to physical health |
87.50(0-100) |
100(100–100) |
< 0.001* |
|
Role limitations due to emotional problems |
100(0-100) |
100(100–100) |
< 0.001* |
|
Energy/fatigue |
60(30–80) |
75(60–85) |
0.009* |
|
Emotional well-being |
62.64 ± 21.72 |
75.11 ± 16.75 |
-12.46[(-20.28)-[-4.65)] |
0.002* |
Social functioning |
100(75–100) |
100(81.25–100) |
0.664 |
|
Pain |
78.75(55–100) |
90(77.50–100) |
0.026* |
|
General health |
55(41.25-70) |
85(65–90) |
< 0.001* |
|
TSK: Tampa Scale of Kinesiophobia; FSS: Fatigue Severity Scale; MMRC: Modified Medical Research Council Dyspnea Scale; IPAQ, International Physical Activity Questionnaire; SF-36, Short-Form 36; CI: confidence interval. *p < 0.05. |
Correlations
Kinesiophobia was significantly correlated with total IPAQ score (r=-0.556, p < 0.001), left quadriceps femoris muscle strength (r= -0.429, p = 0.001), left hip flexor muscle strength (r=-0.380, p = 0.004), left shoulder abductor muscle strength (r= -0.410, p = 0.002), right elbow flexor muscle strength (r=-0.364, p = 0.006), left elbow flexor muscle strength (r=-0.293, p = 0.028), left hand-grip strength (r=-0.355, p = 0.007), right hand-grip strength (r=-0.337, p = 0.011), fatigue (r = 0.434, p = 0.001), SF-36 physical functioning (r= -0.404, p = 0.002), role limitations due to physical health (r= -0.370, p = 0.005), energy/fatigue (r=-0.357, p = 0.007), general health (r=-0.280, p = 0.036).
The main findings of the current study are; (1) functional exercise capacity, upper and lower extremity muscle strength are impaired, (2) kinesiophobia, fatigue, dyspnea level are increased, (3) PA level and Qol are reduced in HT patients comparing with healthy controls, (4) physical inactivity, weakened upper and lower extremity muscle strength, fatigue, impaired Qol are associated with a higher degree of kinesiophobia in HT patients.
Kinesiophobia was found a contributing factor for physical inactivity in a various of cardiac diseases [20]. It is known that controlled hypertension is related to decreased adverse events. Also physical activity is one of the key factors to control hypertension [21]. Unfortunately, only 17% of patients with CVD perform the recommended amount of PA [22]. Nair et al., stated that 78% of the patients with HT had kinesiophobia. Also kinesiophobia was found negatively correlated with physical activity [23]. Another study reported that moderate intensity of kinesiophobia was found in patients with HT and kinesiophobia was associated with physical inactivity [8]. In current study, 78.6% of patients had a high level of kinesiophobia consistent with the literature. In addition, to our knowledge we firstly indicated that kinesiophobia was related to not only physical activity but also upper and lower extremity muscle strength, fatigue, Qol in patients. Muscle weakness is crucial in physical activity [24]. Therefore, a reduction in muscle strength may lead to physical inactivity, also both muscle weakness and physical inactivity might cause kinesiophobia. Not only psychological parameters but also physical parameters should take into account for investigation and rehabilitation protocols for kinesiophobia in patients with HT.
It was reported that people reducing mobility are more likely to develop hypertension [4]. A study showed that 6-MWT distance was lower (338.8 ± 112.8 vs. 388.0 ± 66.7) in patients with HT than controls [3]. In the present study, the 6-MWT distance was lower in patients with HT than in controls [430.30 (344.40- 488.40) versus 604.80 (570–646)]. In addition, 6-MWw, which is an alternative method for assessing functional capacity for walking accounts for bodyweight difference [11], was lower in patients with HT than in healthy controls. The 6-MWw was more associated with peakVO2 than the 6-MWT distance in patients with COPD [11]. In the current study, we firstly performed 6-MWw in patients with HT. Improving exercise capacity should be important to prevent or control hypertension.
Lower and upper extremity muscle strength abnormalities were shown in patients with HT [4, 25]. Cardiovascular disease mortality was related to lower levels of muscle strength in patients with HT [26], furthermore, as muscle strength increased, the development of hypertension decreased [27]. In the current study, both lower and upper extremity muscles were weakened in patients with HT. In addition, weakened proximal upper extremity muscles were also demonstrated for the first time. Effects of resistance training on mortality, and peripheral muscle strength should be examined in patients with HT.
Fatigue is a frequent symptom among patients with CVD. It is a major symptom that affects activities of daily living and Qol [28]. A study showed that more than 50% of the patients with CVD (89.2% of the patients had hypertension) reported fatigue [29]. It was stated that fatigue must be assessed in routine evaluation to decrease fatigue in patients with CVD [28]. In the present study, 41.1% of patients with HT reported severe fatigue. Fatigue may be associated with peripheral muscle weakness, sedentary behaviour, and low functional capacity. Fatigue-related factors should be analysed in patients with isolated HT and patients with severe fatigue should be referred to rehabilitation programs.
Dyspnea is reported in patients with HT, however, its origin is complex [30]. Palhares et al., stated that 26.5% of the patients with HT indicated dyspnea [30]. Another study showed that dyspnea was more common in female patients with HT than in male [31]. In the present study patients (66.1% MMRC1-2; 7.1% MMRC 3–4) had higher dyspnea perception than controls. Future studies investigating effect of managing dyspnea perceptions in patient education programs are needed in patients with HT and also gender differences should be take into account in assessment and rehabilitation programs.
A recent study stated that physical inactivity is responsible for up to 8% of deaths and non-communicable diseases assignable to physical inactivity. [32]. On the other way, it is well known that physical activity prevents hypertension and compared with sedentary people, the risk of hypertension was reduced by 6% for people who met the minimum recommended physical activity levels of 150 min/week (10 MET hours/week) [33]. In addition, as the amount of activity increases, the risk decreases [33]. However, patients with HT were found more inactive compared to controls during COVID-19 pandemic [34]. In the current study, 62.5% of patients were inactive, 33.9% were minimally active, and only 3.6% of the patients was sufficiently active. The PA level was lower than healthy controls. Patients should be directed for PA counselling in cardiac rehabilitation programs to control hypertension.
Hypertension was found a contributing factor to decrease quality of life [6]. Impaired quality of life causes barriers to adherence to treatment in patients with HT [35]. Studies showed a reduction in quality of life in patients with HT [6, 35], however, it was firstly stated that impaired quality of life was related to a higher degree of kinesiophobia in patients with HT in current study. Physical inactivity, weakened muscle strength, fatigue might contribute to decrease quality of life. A study stated that 9 months of physical activity interventions improved quality of life and blood pressure control in patients with HT [36]. Factors affecting kinesiophobia should be considered while programming interventions to improve quality of life in patients with HT.
Limitations
The current study had some limitations. Cardiopulmonary exercise testing was not used due to technical difficulties. It should be used in further studies. In addition, patients' anxiety and depression levels that may affect kinesiophobia, were not evaluated. A questionnaire was used to assess PA level. The accelerometer should be used in further studies.
As a result, this study showed that patients with HT had lower functional exercise capacity, upper and lower extremity muscle strength, higher level of kinesiophobia, fatigue, dyspnea, reduced PA level, and Qol compared with healthy controls. In addition, a higher degree of kinesiophobia was related to physical inactivity, weakened upper and lower extremity muscle strength, fatigue, impaired Qol. Patients with HT should be directed to cardiopulmonary rehabilitation, including especially exercise training, PA counselling, and patient education with all other parameters. Further studies are needed to establish the influence of kinesiophobia on the outcomes of cardiopulmonary rehabilitation in patients with HT.
AUTHOR CONTRIBUTIONS
All authors contributed to the study conception and design. Material preparation was performed by NK, Dİ, FY. Data analysis was performed by NK and İH. The first draft of the manuscript was written by NK, and all authors commented on previous versions of the manuscript. The manuscript was read and approved by all authors.
FUNDING
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
ETHICAL APPROVAL
The study, carried out in conformity with the Declaration of Helsinki, was approved by the Ethics Committee of the Hatay Mustafa Kemal University (No:2020/02). All patients and controls obtained written informed consent to participate in the study.
COMPETING INTERESTS
All the authors declare no conflict of interest.