Biomedical Science Letters 2017, 23(2): 118~127 http://dx.doi.org/10.15616/bsl.2017.23.2.118 eissn : 2288-7415 Original Article Clinical Usefulness of Serum Uric Acid and Resting Heart Rate in the Diagnosis of Metabolic Syndrome in Korean Adults Kyung-A Shin Department of Clinical Laboratory Science, Shinsung University, Chungnam 31801, Korea Elevated serum uric acid and resting heart rate are risk factors and predictors of metabolic syndrome. However, few studies have examined the optimal cutoff value for serum uric acid and resting heart rate to predict metabolic syndrome in Korean adults. Subjects for this study were 22,302 adults (average age 45 years old), who underwent health screening examination from January 2010 to December 2012 at the Health Promotion Center of one hospital in Gyeonggi-do for general health check-up. The uric acid and resting heart rate cutoff values were calculated by ROC analysis for metabolic syndrome. Elevated serum uric acid and resting heart rate were associated with an increased prevalence of metabolic syndrome in Korean adults. The optimal cutoff value for uric acid level to predict metabolic syndrome in adults was 4.95 mg/dl (male 6.35, female 4.55) and optimal cutoff value for resting heart rate to predict metabolic syndrome was 68 beats per minute (male 66, female 68). However, serum uric acid and resting heart rate were found to have limitations for the diagnosis of metabolic syndrome. Key Words: Metabolic syndrome, Uric acid, Resting heart rate 서론요산은크산틴 (xanthine) 이크산틴산화효소 (xanthine oxidase) 또는크산틴탈수소효소 (xanthine dehydrogenase) 의활성화에의해생성되는퓨린의최종대사산물로통풍과신장결석의위험요인으로인식되고있다 (Feig et al., 2013). 그러나역학연구를통해혈청요산은대사증후군, 만성신장질환, 심장-뇌혈관질환과관련이있다고보고된다 (Ioachimescu et al., 2008; Tamariz et al., 2011). 특히최근연구들은요산이대사증후군위험인자일뿐만아니라당뇨병, 고혈압, 심혈관질환과관련이있다고제시하고있어요산의역할에관심이집중되고있다 (Tamariz et al., 2011; Feig et al., 2013). 혈중요산이심혈관계에작용하는기전은퓨린대사과 정에서요산과함께생성되는산화효소 (superoxidase) 에의해활성산소 (reactive oxygen species, ROS) 의생성은증가하고, 산화질소 (nitric oxide, NO) 의생성은억제하여혈관저항성을증가시켜결국에는혈관내피세포기능장애를초래한다 (Kanellis and Kang, 2005). 요산에의한혈관내피세포기능장애는대사증후군발생에핵심적인역할을하는인슐린저항성을유발하는기전으로생각된다 (Tomiyama et al., 2011). 고요산혈증은고인슐린혈증발병에선행하여나타나며, 고인슐린혈증은근위세뇨관에서요산을재흡수하여고요산혈증을일으킨다 (Feig et al., 2013; Li et al., 2013). 또한혈청요산은혈소판응집및부착을유도하여혈전생성과저밀도지단백 (low density lipoprotein, LDL) 콜레스테롤의산화를촉진함으로써심혈관질환발생에영향을미친다 (Kanellis and Kang, 2005). Yoo 등 (2004) 은혈청요산치가정상범위에속하더라도혈청요산농도가증가할수 * Received: March 12, 2017 / Revised: March 30, 2017 / Accepted: May 21, 2017 Corresponding author: Kyung-A Shin. Department of Clinical Laboratory Science, Shinsung University, 1 Daehak-Ro, Dangjin-Si, Chungnam 31801, Korea. Tel: +82-41-350-1408, Fax: +82-41-350-1355, e-mail: mobitz2@shinsung.ac.kr C The Korean Society for Biomedical Laboratory Sciences. All rights reserved. CC This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. - 118 -
록대사증후군위험도가비례적으로증가함을보고하였다. 안정시심박수 (resting heart rate) 는 1분동안심장이수축하여혈액을온몸으로박출하는횟수를의미하며 (Diaz et al., 2005), 굴심방결절활동에의해결정되고교감신경과미주신경활성의상호작용에의해영향을받는다 (Menown et al., 2013). 안정시심박수증가는교감신경의과활성과미주신경긴장도 (vagal tone) 감소를나타내는징후이며 (Nanchen et al., 2013), 자율신경계이상을파악할수있는중요한지표이다 (Palatini and Julius, 2004; Bemelmans et al., 2012; Johansen et al., 2013; Menown et al., 2013). 교감신경활성증가에따른안정시심박수증가는인슐린저항성과비만에선행하여나타날수있으며, 교감신경활성화는인슐린저항성의원인이자결과로보고된다 (Bemelmans et al., 2012; Nanchen et al., 2013). 그러므로대사증후군에서는혈압이정상인경우라도교감신경계가항진되고, 자율신경계조절능력이저하되어심박수가증가하는경향을보인다 (Lauer et al., 1996). 한편, 혈중요산농도및안정시심박수의감소가심혈관계질환과대사증후군위험을예방하는것으로보고되고있으나 (Liu et al., 2016), 대사증후군진단을위한요산과안정시심박수의적정절단값설정 (cut-off level) 에대한연구는매우제한적이다. 이에본연구에서는 ROC curve 를이용해한국성인의대사증후군진단을위한요산과안정시심박수의최적절단값을설정하고, 대사증후군진단의유용성에대해알아보고자하였다. 재료및방법실험대상자및대사증후군진단본연구대상자는 2010년 1월부터 2012년 12월까지경기지역일개종합병원에서건강검진을시행한 20세이상의성인남녀를대상으로하였다. 전체대상자총 23,356명중과거력으로당뇨병과고혈압진단을받은환자, 심박수에영향을미치는베타차단제를복용하는환자와결측치를포함하는 1,054명을제외한최종대상자는남성 13,652명, 여성 8,650명으로총 22,302명이었다. 과거력및복용하는약물에대해서는자기기입식문진표를통해조사하였으며, 본연구는경기지역종합병원기관생명윤리위원회의승인을받아시행하였다 (IRB No: D-1205-008-2461). 대사증후군진단기준은 AHA/NHLBI (American Heart Association/National Heart, Lung, and Blood Institute, 2005) 의기준에따라복부비만, 혈압상승, 혈당상승, 중성지방상승, HDL-콜레스테롤감소의 5가지위험요인중 3가지이상만족할경우대사증후군으로정의하였다 (Grundy et al., 2005). 그중혈압상승은수축기혈압이 130 mmhg 이상또는이완기혈압이 85 mmhg 이상인경우, 혈당상승은공복혈당이 100 mg/dl 이상인경우로하였다. 중성지방상승은혈중중성지방이 150 mg/dl 이상, HDL (high density lipoprotein)-콜레스테롤감소는혈중 HDL-콜레스테롤이남성 40 mg/dl 미만, 여성 50 mg/dl 미만으로하였다. 복부비만은 AHA/NHLBI 기준으로남성 102 cm 이상, 여성 88 cm 이상으로정의하고있으나, 본연구에서는동양인의복부비만기준에적합한세계보건기구서태평양지역 International Obesity Task Force에서제시하는남성 90 cm 이상, 여성 80 cm 이상을복부비만으로정의하였다 (WHO, 2000). 신체계측및안정시심박수측정신장과체중은 DS-103M (Jenix, Seoul, Korea) 자동신체계측기를이용하여측정하였으며, 체질량지수 (body mass index, BMI) 는몸무게 (kg) 를키 (m) 의제곱으로나눈식으로추정하였다. 허리둘레는양발을 25~30 cm 벌리고바로선자세에서갈비뼈최하단부위와골반엉덩뼈능선최상단부위의중간지점을측정하였으며, 엉덩이둘레는줄자로엉덩이의가장돌출부위를지나수평이되도록하여측정하였다. 수축기와이완기혈압은 10분이상휴식을취한후앉은자세에서수은혈압계로측정하였다. 안정시심박수는표준 12유도자동심전계 (Cardiocare 2000, Bionet, Korea) 로안정시심전도를기록한후심전도상에기록된심박수를안정시심박수로설정하였다. 혈액검사혈액검사는 8시간이상공복상태로위팔정맥 (antecubital vein) 에서채혈하였으며, TBA-200FR NEO (Toshiba, Tokyo, Japan) 생화학자동분석기로공복혈당, 중성지방, 총콜레스테롤, HDL-콜레스테롤, LDL-콜레스테롤, 요산, 고감도 C-반응단백질 (high sensitivity C-reactive protein, hs-crp) 을측정하였다. 당화혈색소 (hemoglobin A1c, HbA1c) 는 EDTA 전혈검체로 Variant II (Bio Rad, CA, USA) 를이용하여고성능액체크로마토그래피법 (high performance liquid chromatography, HPLC) 으로측정하였다. 인슐린은 Modular Analytics E170 (Roche, Mannheim, Germany) 장비로전기화학발광면역분석법 (electrochemiluminescence immunoassay, ECLIA) 의원리로검사하였으며, 인슐린저항성평가지표인 HOMA- - 119 -
IR (homeostasis model assessment-insulin resistance) 은공복혈당과인슐린농도를이용하여 [ 공복시인슐린 (μiu/ml) 공복시혈당 (mg/dl)] / 405의계산식으로평가하였다 (Moon et al., 2010). 자료처리방법본연구의통계학적분석은 SPSS Windows 21.0 (IBM, Armonk, USA) 프로그램을이용하였으며, 대상자들은혈청요산치와안정시심박수에따라 4등분하여네군으로분류하였다. 혈청요산치사분위수와안정시심박수사분위수에따른대사증후군위험요인의차이를비교하기위하여일원배치분산분석 (one way ANOVA) 을실시하였으며, 차이가있는경우사후검증은 Bonferroni를적용하였다. 또한혈청요산치사분위수와안정시심박수사분위수간의성별및혈압상승, 혈당상승, 중성지방상승, HDL-콜레스테롤감소의 5가지대사증후군위험요인의유병률을비교하기위해카이제곱검정 (chi-square test) 을실시하였다. 혈청요산치와안정시심박수사분위수에따른대사증후군교차비를구하기위해로지스틱회귀분석 (logistic regression) 을시행하였으며, 오즈비 (odds ratio, OR) 와 95% 신뢰구간 (confidence interval, CI) 을제시하였다. 또한로지스틱회귀분석시연령과성별이요산치와안정시심박수에미치는영향을배제하기위해관심독립변수와함께연령과성별을동시에독립변수로고려하여통제한후분석하였다. 요산치와안정시심박수가대사증후군진단을위한정확한지표인지를알아보기위해 ROC 곡선 (Receiver Operating Characteristic Curve) 의면적을비교하였다. 면적은 0과 1사이의값을가지며, 0.5에가까울수록예측력이없고 1이면완벽하게예측하는것으로분류하였다. 대사증후군을진단하기위한혈청요산치와안정시심박수의최적절단값 (optimum cut-off values) 을판단하기위해민감도 (sensitivity) 와특이도 (specificity) 의합이최대가되는지점을혈청요산치와안정시심박수의적정절단값으로채택하였다. 본연구의통계학적으로유의한판정기준은 P<0.05로설정하였다. 결과요산의사분위수에따른대상자의의학적특성혈청요산치를사분위수로나누어인체측정학및의학적지표의차이를비교한결과는 Table 1과같다. 연령은집단간차이를보였다 (P<0.001). 인체측정학적변인중신 장, 체중, 체질량지수, 허리둘레, 엉덩이둘레는 1사분위수보다 2사분위수가높았으며, 1사분위수와 2사분위수보다 3사분위수가높았다. 또한 4사분위수는 1사분위수, 2사분위수, 3사분위수보다높게나타났다 ( 각각 P<0.001). 수축기와이완기혈압은 1사분위수보다 2사분위수가높았으며, 1사분위수와 2사분위수보다 3사분위수가높았다. 또한 4사분위수는 1사분위수, 2사분위수, 3사분위수보다높게나타났다 ( 각각 P<0.001). 총콜레스테롤, LDL-콜레스테롤, 중성지방, 인슐린, 요산은 1사분위수보다 2사분위수가높았으며, 1사분위수와 2사분위수보다 3사분위수가높았다. 또한 1사분위수, 2사분위수, 3사분위수보다 4사분위수가높게나타났다 ( 각각 P<0.001). 안정시심박수는 4사분위수에서 1사분위수, 2사분위수, 3사분위수보다높게나타났다 (P<0.001). hs-crp와 HOMA-IR은 1사분위수보다 3사분위수가높았으며, 4사분위수는 1사분위수와 2사분위수보다높았다 ( 각각 P<0.001). 공복혈당은 1사분위수보다 2사분위수, 3사분위수, 4사분위수에서높았다 (P<0.001). HbA1c는 1사분위수보다 2사분위수와 3사분위수가높았으며, 2사분위수와 3사분위수보다 4사분위수가높았다 (P<0.001). 그러나 HDL-콜레스테롤은 1사분위수보다 2사분위수, 3사분위수, 4사분위수가낮았으며, 3사분위수는 1사분위수와 2사분위수보다낮았다. 또한 4사분위수는 1사분위수, 2사분위수, 3사분위수보다낮게나타났다 (P< 0.001). 대사증후군유병률및대사증후군위험요인은집단간차이를보였으며, 혈압상승, 혈당상승, 중성지방상승, 복부비만및대사증후군유병률은요산의분위수가높아질수록유병률빈도가높게나타났다 ( 각각 P<0.001). 안정시심박수의사분위수에따른대상자의의학적특성안정시심박수를사분위수로나누어인체측정학및의학적지표의차이를비교한결과는 Table 2와같다. 연령은집단간차이를보였다 (P<0.001). 체중은 1사분위수, 2사분위수, 3사분위수보다 4사분위수에서높게나타났다 (P<0.001). 체질량지수는 1사분위수보다 3사분위수, 4사분위수가높았으며, 4사분위수는 2사분위수, 3사분위수보다높았다 (P<0.001). 허리둘레와엉덩이둘레, 수축기혈압, 총콜레스테롤, 공복혈당, HbA1c는 1사분위수보다 2사분위수와 3사분위수, 4사분위수가높았으며, 4사분위수는 2사분위수, 3사분위수보다높게나타났다 ( 각각 P<0.001). 이완기혈압, 안정시심박수, 중성지방, 인슐린은 1사분위수보다 2사분위수, 3사분위수, 4사분위수가높았으며, 2사분위수보다 3사분위수, 4사분위수가높았다. 또한 4사분위 - 120 -
Variables Table 1. The variables characteristics of the different uric acid quartiles Quartile 1 4.19 Uric acid levels quartiles (n=22,302) Quartile 2 4.20~5.29 Quartile 3 5.30~6.29 Quartile 4 6.30 P-value No. of subjects 5,208 5,838 5,361 5,895 Male (%) * 854 (16.4) 2,659 (45.4) 4,471 (83.4) 5,668 (96.1) <0.001 Age (year) 45.43±11.40 46.42±11.72 * 45.62±11.16 44.07±10.55 * <0.001 Height (cm) 160.78±7.30 164.06±8.53 * 169.35±7.93 * 171.46±6.90 * <0.001 Weight (kg) 57.63±9.27 62.83±10.82 * 69.81±10.63 * 74.54±10.70 * <0.001 Body mass index (kg/m 2 ) 22.29±3.17 23.39±6.07 * 24.41±5.86 * 25.35±4.08 * <0.001 Waist circumference (cm) 73.31±8.38 77.42±8.91 * 81.89±8.24 * 84.93±7.60 * <0.001 Hip circumference (cm) 90.85±5.40 92.40±5.56 * 94.46±5.63 * 96.05±5.64 * <0.001 Systolic blood pressure (mmhg) 104.81±14.30 108.01±14.24 * 111.50±13.37 * 113.26±12.89 * <0.001 Diastolic blood pressure (mmhg) 66.87±9.81 69.24±10.12 * 72.20±9.95 * 73.49±10.09 * <0.001 Resting heart rate (bpm) 63.29±8.70 63.12±9.34 63.31±9.33 63.98±9.51 * <0.001 Total cholesterol (mg/dl) 185.28±32.12 191.19±33.36 * 194.26±33.79 * 200.43±34.77 * <0.001 HDL-cholesterol (mg/dl) 62.10±13.88 58.28±13.96 * 53.39±12.57 * 50.75±11.60 * <0.001 LDL-cholesterol (mg/dl) 109.50±29.13 116.40±30.41 * 121.06±30.41 * 126.36±31.32 * <0.001 Triglyceride (mg/dl) 87.89±53.23 107.96±68.86 * 132.77±86.46 * 162.19±104.93 * <0.001 Fasting glucose (mg/dl) 89.23±20.91 90.28±19.28 * 91.01±17.66 * 90.57±15.34 * <0.001 hs-crp (mg/dl) 0.13±0.51 0.15±0.41 0.16±0.37 * 0.17±0.36 * <0.001 HbA1c (%) 5.57±0.83 5.62±0.75 * 5.61±0.67 * 5.56±0.55 <0.001 Insulin (μu/ml) 4.19±2.52 4.69±3.05 * 5.14±3.07 * 5.75±3.46 * <0.001 HOMA-IR 0.20±0.53 0.21±0.58 0.24±0.60 * 0.25±0.63 * <0.001 Uric acid (mg/dl) 3.50±0.50 4.69±0.32 * 5.74±0.28 * 7.23±0.85 * <0.001 Metabolic Syndrome (%) 258 (5.0) 488 (8.4) 578 (10.8) 840 (14.2) <0.001 High blood pressure (%) 466 (8.9) 697 (11.9) 834 (15.6) 1,064 (18.0) <0.001 Low HDL-cholesterol (%) 721 (13.8) 899 (15.4) 774 (14.4) 968 (16.4) 0.001 High fasting glucose (%) 540 (10.4) 831 (14.2) 855 (15.9) 930 (15.8) <0.001 High triglyceride (%) 543 (10.4) 1,094 (18.7) 1,625 (30.3) 2,563 (43.5) <0.001 Abdominal obesity (%) 777 (14.9) 1,070 (18.3) 1,129 (21.1) 1,544 (26.2) <0.001 Calculated by one way ANOVA and Bonferroni test. Values are presented as mean ± SD. ; Calculated by χ 2 -test. Data are presented as number (%). Abbreviations: HDL, high density lipoprotein; LDL, low density lipoprotein; hs-crp, high sensitivity C-reactive protein; HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model assessment-insulin resistance. * ; Significantly different from Quartile 1 at P<0.05, ; Significantly different from Quartile 2 at P<0.05, ; Significantly different from Quartile 3 at P<0.05. 수는 3사분위수보다높게나타났다 ( 각각 P<0.001). LDL- 콜레스테롤은 1사분위수보다 2사분위수, 3사분위수, 4사분위수가높았으며, 4사분위수는 3사분위수보다높았다 (P<0.001). HDL-콜레스테롤은 1사분위수보다 2사분위수, 3사분위수, 4사분위수가낮았으며, 4사분위수는 2사분위수, 3사분위수보다낮았다 (P<0.001). hs-crp는 1사분위수, 2사 분위수보다 3사분위수, 4사분위수가높았으며, 4사분위수는 3사분위수보다높았다 (P<0.001). HOMA-IR은 1사분위수보다 2사분위수, 4사분위수가높았으며, 4사분위수는 2사분위수, 3사분위수보다높았다 (P<0.001). 대사증후군유병률및대사증후군위험요인은집단간차이를보였으며, 혈압상승, 혈당상승및대사증후군유병률은안정시 - 121 -
Variables Table 2. The variables characteristics of the different heart rate quartiles Quartile 1 56.9 Heart rate levels quartiles (n=22,302) Quartile 2 57.0~62.9 Quartile 3 63.0~67.9 Quartile 4 68.0 P-value No. of subjects 4,996 6,146 6,304 4,856 Male (%) * 3,220 (64.5) 3,726 (60.6) 3,685 (58.8) 3,021 (62.6) <0.001 Age (year) 46.55±11.32 45.74±11.16 * 44.64±0.99 * 44.66±11.46 * <0.001 Height (cm) 166.79±8.63 166.61±8.83 166.24±8.80 * 166.49±8.77 0.008 Weight (kg) 65.87±11.35 66.27±12.13 66.16±12.37 67.36±13.01 * <0.001 Body mass index (kg/m 2 ) 23.63±4.37 23.83±5.15 23.91±5.87 * 24.23±4.58 * <0.001 Waist circumference (cm) 78.74±8.83 79.30±9.18 * 79.39±9.47 * 80.77±9.94 * <0.001 Hip circumference (cm) 93.04±5.62 93.41±5.70 * 93.39±5.89 * 94.06±6.37 * <0.001 Systolic blood pressure (mmhg) 107.49±13.54 108.67±13.53 * 109.31±14.04 * 112.80±14.77 * <0.001 Diastolic blood pressure (mmhg) 68.98±9.87 69.94±10.00 * 70.54±10.27 * 72.83±10.85 * <0.001 Resting heart rate (bpm) 52.44±3.30 59.58±1.68 * 65.73±1.98 * 76.64±6.94 * <0.001 Total cholesterol (mg/dl) 190.75±32.66 192.81±33.94 * 193.24±33.47 * 195.20±35.90 * <0.001 HDL-cholesterol (mg/dl) 57.07±14.03 56.14±13.72 * 56.04±13.60 * 54.70±13.48 * <0.001 LDL-cholesterol (mg/dl) 116.80±29.83 118.61±31.02 * 118.53±30.69 * 120.14±32.33 * <0.001 Triglyceride (mg/dl) 109.81±73.29 121.05±80.97 * 125.55±87.46 * 138.37±98.82 * <0.001 Fasting glucose (mg/dl) 87.44±12.92 89.22±15.89 * 89.89±17.30 * 95.07±25.19 * <0.001 hs-crp (mg/dl) 0.12±0.29 0.13±0.31 0.15±0.37 * 0.22±0.63 * <0.001 HbA1c (%) 5.52±0.51 5.56±0.61 * 5.58±0.69 * 5.72±0.93 * <0.001 Insulin (μu/ml) 3.98±2.49 4.59±2.82 * 5.04±2.96 * 5.96±3.62 * <0.001 HOMA-IR 0.16±0.48 0.26±0.59 * 0.15±0.52 0.35±0.72 * <0.001 Uric acid (mg/dl) 5.32±1.41 5.29±1.46 5.31±1.50 5.44±1.52 * <0.001 Metabolic Syndrome (%) 289 (5.8) 526 (8.6) 582 (9.2) 767 (15.8) <0.001 High blood pressure (%) 507 (10.1) 734 (11.9) 839 (13.3) 981 (20.2) <0.001 Low HDL-cholesterol (%) 617 (12.3) 949 (15.4) 955 (15.1) 841 (17.3) <0.001 High fasting glucose (%) 511 (10.2) 752 (12.2) 803 (12.7) 1090 (22.4) <0.001 High triglyceride (%) 988 (19.8) 1,538 (25.0) 1,712 (27.2) 1,587 (32.7) <0.001 Abdominal obesity (%) 780 (15.6) 1,187 (19.3) 1,297 (20.6) 1,256 (25.9) <0.001 Calculated by one way ANOVA and Bonferroni test. Values are presented as mean ± SD. ; Calculated by χ 2 -test. Data are presented as number (%). Abbreviations: HDL, high density lipoprotein; LDL, low density lipoprotein; hs-crp, high sensitivity C-reactive protein; HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model assessment-insulin resistance. * ; Significantly different from Quartile 1 at P<0.05, ; Significantly different from Quartile 2 at P<0.05, ; Significantly different from Quartile 3 at P<0.05. 심박수분위수가높아질수록유병률빈도가높게나타났다 ( 각각 P<0.001). 요산과안정시심박수사분위수에따른대사증후군과의관련성로지스틱회귀분석을통해요산, 안정시심박수의사분 위수에따른대사증후군과의관련성을분석한결과 Table 3과같다. 요산은 1사분위수에비해 2사분위수에서대사증후군발생이 1.7배높았으며 (odds ratio, OR: 1.680, 95% confidence interval, 95% CI: 1.428~1.976), 3사분위수는 2.3 배높았다 (OR: 2.311, 95% CI: 1.943~2.749). 또한 4사분위수는 1사분위수보다대사증후군발생위험도가 3.4배높 - 122 -
Uric acid (mg/dl) Table 3. Independent association between uric acid, resting heart rate and metabolic syndrome Variables Odds ratio (95% confidence interval) for metabolic syndrome Quartile 1 1 Quartile 2 1.680 (1.428~1.976) <0.001 Quartile 3 2.311 (1.943~2.749) <0.001 Quartile 4 3.426 (2.875~4.083) <0.001 Quartile 1 1 Resting heart rate (bpm) Quartile 2 1.636 (1.406~1.904) <0.001 Quartile 3 1.877 (1.617~2.180) <0.001 Quartile 4 3.425 (2.961~3.962) <0.001 Calculated by logistic regression adjusted for gender and age. Values are presented as odds ratio (95% confidence interval). P Table 4. ROC-curve analysis according to uric acid and resting heart rate Variables Cutoff value Sensitivity Specificity AUC (95% confidence interval) Total 4.95 73.0% 44.3% 0.620 (0.607~0.632) Uric acid (mg/dl) Male 6.35 47.7% 62.5% 0.564 (0.548~0.579) Female 4.55 57.1% 69.2% 0.676 (0.652~0.699) Total 67.50 42.7% 73.0% 0.609 (0.597~0.622) Resting heart rate (bpm) Male 65.50 50.1% 66.2% 0.615 (0.600~0.630) Female 67.50 42.9% 72.6% 0.601 (0.577~0.625) Abbreviations: AUC, area under the curve. 은양상을보였다 (OR: 3.426, 95% CI: 2.875~4.083). 안정시심박수는 1사분위수보다 2사분위수에서대사증후군발생이 1.7배높았으며 (OR: 1.636, 95% CI: 1.406~1.904), 3사분위수는 1.9배높았다 (OR: 1.877, 95% CI: 1.617~2.180). 또한 4분위수는 1사분위수보다대사증후군발생위험도가 3.4배높게나타났다 (OR: 3.425, 95% CI: 2.961~3.962). 대사증후군을예측하기위한요산과안정시심박수의절단값 ROC 분석을이용하여대사증후군을진단하기위한요산과안정시심박수의적정절단값을측정한결과는 Table 4와같으며, Fig. 1과 Fig. 2에서는검사항목별 ROC 곡선을나타냈다. 곡선의아래면적인 AUC (area under the ROC curve) 는분류정확도를나타내며, 전체대상자에서요산의 AUC 값은 0.620, 남성은 0.564, 여성은 0.676으로나타났다. 또한대사증후군진단을위한전체대상자의요산절단값은 4.95 mg/dl, 민감도는 73.0%, 특이도는 44.3% 로 나타났다. 여성대상자의경우요산절단값은 4.55 mg/dl, 민감도 57.1%, 특이도 69.2%, 남성대상자는요산절단값은 6.35 mg/dl, 민감도 47.7%, 특이도 62.5% 로나타났다. 전체대상자에서안정시심박수의 AUC 값은 0.609, 남성 0.615, 여성 0.601로나타났다. 대사증후군진단을위한전체대상자의안정시심박수절단값은분당 67.50회에민감도는 42.7%, 특이도는 73.0% 로나타났다. 여성대상자의경우안정시심박수절단값은분당 67.50회에민감도는 42.9%, 특이도는 72.6% 를나타냈으며, 남성의안정시심박수절단값은분당 65.50회에민감도 50.1%, 특이도 66.2% 를보였다. 고찰본연구결과한국성인에서성별, 연령과는독립적으로혈청요산치와안정시심박수가높을수록대사증후군위험도가증가하는것을확인하였다. 또한요산은 4.95 mg/ - 123 -
Fig. 1. ROC curve of uric acid for diagnosis of metabolic syndrome. AUC=0.620, Cutoff value=4.95 mg/dl, Sensitivity= 73.0%, Specificity=44.3% Fig. 2. ROC curve of resting heart rate for diagnosis of metabolic syndrome. AUC=0.609, Cutoff value=67.50 bpm, Sensitivity= 42.7%, Specificity=73.0% dl, 안정시심박수는분당 68회이상일때대사증후군위험이증가하는것으로나타났으며, 대사증후군을진단하는데요산과안정시심박수의 AUC 값은 0.7보다낮은정확도를보여보조적인지표로이용하는것이타당할것으로생각된다. 대사증후군은내당능장애, 복부비만, 고혈압, 중성지방증가와 HDL-콜레스테롤감소의 5가지진단기준중 3가지이상이한개인에게군집화되어나타나는것을말하며, 복부비만과인슐린저항성이핵심역할을한다고알려져있다 (Eckel et al., 2010). 요산은혈관민무늬근육증식을자극하고혈관내피세포기능장애를일으켜산화질소의생체이용률을억제하며, 결국혈관내염증반응과혈소판응집및부착반응에따른혈전생성의증가와같은동맥경화증에서나타나는혈관변화를보인다 (Kanellis and Kang, 2005; Choi and Park, 2015). 요산에의한혈관확장기능과혈관내피세포기능의저하는인슐린저항성의발생기전으로인식되며 (Tomiyama et al., 2011), 인슐린저항성은콩팥에서의요산배설감소와근위세뇨관에서의요산재흡수에의해혈중요산치상승을유도한다 (Feig et al., 2013; Li et al., 2013). Yoo 등 (2004) 은혈중요산농도가고혈압, 인슐린저항성및대사증후군위험요인과상관관계가있으며, 정상범위의혈청요산농 도라할지라도혈청요산농도의증가에비례하여대사증후군위험도가증가한다고보고하였다. 또한여성노인을대상으로고요산혈증인경우대사증후군발병위험이 1.8배증가하였으며 (Zhang et al., 2011), 50세이상남성을대상으로혈청요산농도를 3분위로나누어 5.7년간추적관찰한결과요산농도가가장낮은군보다가장높은군의대사증후군발생이 1.8배높았다 (Sui et al., 2008). 본연구결과요산을사분위수로구분하였을때낮은분위수에서높은분위수로진행할수록대사증후군발생위험이높았으며, 1사분위수보다 3사분위수에서는 2.3배, 4사분위수에서대사증후군발생위험도가 3.4배높게나타났다. 또한혈청요산농도의상한치는남성 7.0 mg/dl, 여성 6.0 mg/dl로제시되며 (Hong et al., 2008), 본연구에서대사증후군위험이증가하는전체대상자의요산적정절단값은 4.95 mg/dl였으며, 여성의경우 4.55 mg/dl, 남성은 6.35 mg/dl 로성별과연령에따라다양한절단값을적용해야할필요성이요구된다. 대사증후군에서는교감신경계의활성화로안정시심박수가증가하며, 대사증후군위험요인의개수가증가함에따라안정시심박수가높게나타나고있어심박수가심혈관질환의위험을예측할수있는대사증후군위험요인의 - 124 -
하나로간주된다 (Shin, 2015). 실제로 8년간 3,527명을대상으로안정시심박수가분당 90회이상인대상자와 70회이하인대상자를비교한결과 90회이상인군의심혈관계질환에의한사망위험이 2.2배높게나타났으며, 심박수가높을수록질환의발병가능성이높고경과도좋지않음을알수있었다 (Kristal-Boneh et al., 2000). 본연구결과안정시심박수를사분위수로구분하였을때낮은분위수에서높은분위수로진행할수록대사증후군발생위험이높았으며, 1사분위수보다 4사분위수의대사증후군발생위험도는 3.4배높게나타났다. 교감신경과활성과미주신경긴장 (vagal tone) 감소를의미하는심박수증가는인슐린저항성과관련이있으며, 인슐린저항성은교감신경계와레닌-안지오텐신시스템을활성화시킴으로써신세뇨관에서나트륨재흡수를증가시켜혈압과심박수의증가를유발하게된다 (Reaven, 2002; Inoue et al., 2008; Nanchen et al., 2013). 심박수가빠를수록대사증후군위험은높아지는데, 심근경색증환자를대상으로베타차단제로심박수를감소시킨결과사망률이감소하는것으로나타났다 (Teo et al., 1993). 안정시심박수는분당 60~ 100회로정의하고있으며 (Jose and Collison, 1970), 본연구에서는대사증후군위험이증가하는안정시심박수의적정절단값은분당 68회로나타났다. 한편, 선행연구에서는안정시심박수가분당 76회이상일경우관상동맥질환에의한사망위험률이높다고제시하고있어심박수를낮게유지하는것이질환발생을예방하는데바람직할것으로사료된다 (Hsia et al., 2009). 그러나심박수는연령증가와함께낮아지는것으로알려져있으며 (Park et al., 2015), 연령대에따라적용가능한심박수의절단값에대한후속연구가필요하겠다. 본연구는단면연구로써원인과결과의인과관계를설명할수없으며, 일개종합병원건강검진센터에서건강검진을실시한성인을대상으로하여결과를일반화하는데제한이있다. 또한음주나흡연, 운동및식이습관등을고려하지못한제한점이있으나, 요산과안정시심박수가대사증후군진단에유용한지를최적절단값설정을통해알아본대규모연구로서의미가있다. 결론적으로본연구결과한국성인에서요산치와안정시심박수가높을수록대사증후군위험도가증가하는것으로나타났다. 대사증후군위험이증가하는요산의최적절단값은 4.95 mg/dl, 안정시심박수의최적절단값은분당 68회로나타나, 정상범위라할지라도낮은수치를유지하는것이바람직하겠다. 또한요산과안정시심박수는 대사증후군을예측하는데독립적으로사용하기에는한계가있으나보조적인지표로는사용가능할것으로생각된다. CONFLICT OF INTEREST The authors have no conflicts of interest to disclose. REFERENCES Bemelmans RH, Wassink AM, van der Graaf Y, Nathoe HM, Vernooij JW, Spiering W, Visseren FL; SMART Study Group. Risk of elevated resting heart rate on the development of type 2 diabetes in patients with clinically manifest vascular diseases. European Journal of Endocrinology. 2012. 166: 717-725. Choi SY, Park JS. The comparison of carotid artery intima-media thickness and plaque characteristics between patients with ST-elevation myocardial infarction and coronary artery chronic total occlusion. Biomedical Science Letters. 2015. 21: 198-207. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. European Heart Journal. 2005. 26: 967-974. Eckel RH, Alberti KG, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2010. 375: 181-183. Feig DI, Madero M, Jalal DI, Sanchez-Lozada LG, Johnson RJ. Uric acid and the origins of hypertension. Journal of Pediatrics. 2013. 162: 896-902. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/ National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005. 112: 2735-2752. Hsia J, Larson JC, Ockene JK, Sarto GE, Allison MA, Hendrix SL, Robinson JG, LaCroix AZ, Manson JE; Women's Health Initiative Research Group. Resting heart rate as a low tech predictor of coronary events in women: prospective cohort study. British Medical Journal. 2009. 338: 219. Hong SP, Lee YS, Bae KR, Chung JW, Kim SY, Lee JB, Ryu JK, Choi JY, Kim KS, Chang SG, Shin IH. Relationship between serum uric acid level and metabolic syndrome according to gender. Korean Circulation Journal. 2008. 38: 152-160. - 125 -
Inoue T, Iseki K, Iseki C, Ohya Y, Kinjo K, Takishita S. Association between heart rate and multiple risk factor syndrome: crosssectional analysis of a screened cohort in Okinawa, Japan. Circulation Journal. 2008. 72: 454-457. Ioachimescu AG, Brennan DM, Hoar BM, Hazen SL, Hoogwerf BJ. Serum uric acid is an independent predictor of all-cause mortality in patients at high risk of cardiovascular disease: a preventive cardiology information system (PreCIS) database cohort study. Arthritis and Rheumatism. 2008. 58: 623-630. Johansen CD, Olsen RH, Pedersen LR, Kumarathurai P, Mouridsen MR, Binici Z, Intzilakis T, Køber L, Sajadieh A. Resting, night-time, and 24 h heart rate as markers of cardiovascular risk in middle-aged and elderly men and women with no apparent heart disease. European Heart Journal. 2013. 34: 1732-1739. Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovascular Research. 1970. 4: 60-167. Kanellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. Seminars in Nephrology. 2005. 25: 39-42. Kristal-Boneh E, Silber H, Harari G, Froom P. The association of resting heart rate with cardiovascular, cancer and all-cause mortality. Eight year follow-up of 3527 male Israeli employees (the CORDIS Study). European Heart Journal. 2000. 21: 116-124. Lauer MS, Okin PM, Larson MG, Evans JC, Levy D. Impaired heart rate response to graded exercise. Prognostic implications of chronotropic incompetence in the Framingham Heart Study. Circulation. 1996. 93: 1520-1526. Li C, Hsieh MC, Chang SJ. Metabolic syndrome, diabetes, and hyperuricemia. Current Opinion in Rheumatology. 2013. 25: 210-216. Liu P, Jiang Y, Meng J. Relationship between serum uric acid, metabolic syndrome and resting heart rate in Chinese elderly. Obesity Research & Clinical Practice. 2016. 10: 159-168. Menown IB, Davies S, Gupta S, Kalra PR, Lang CC, Morley C, Padmanabhan S. Resting heart rate and outcomes in patients with cardiovascular disease: where do we currently stand? Cardiovascular Therapeutics. 2013. 31: 215-223. Moon K, Sung SH, Chang YK, Park IK, Paek YM, Kim SG, Choi TI, Jin YW. The association between Apolipoprotein E genotype and lipid profiles in healthy woman workers. Journal of Preventive Medicine & Public Health. 2010. 43: 213-221. Nanchen D, Stott DJ, Gussekloo J, Mooijaart SP, Westendorp RG, Jukema JW, Macfarlane PW, Cornuz J, Rodondi N, Buckley BM, Ford I, Sattar N, de Craen AJ; PROSPER Group. Resting heart rate and incident heart failure and cardiovascular mortality in older adults: role of inflammation and endothelial dysfunction: the PROSPER study. European Journal of Heart Failure. 2013. 15: 581-588. Palatini P, Julius S. Elevated heart rate: a major risk factor for cardiovascular disease. Clinical and Experimental Hypertension. 2004. 26: 637-644. Park H, Lee J, Kim JY, Kim DI, Jeon JY. The Relationship between resting heart rate and prevalence of metabolic syndrome and type 2 diabetes mellitus in Korean adults: The fifth Korea National Health and Nutrition Examination Survey (2012). Korean Journal of Obesity. 2015. 24: 166-174. Reaven G. Metabolic syndrome: pathophysiology and implications for management of cardiovascular disease. Circulation. 2002. 106: 286-288. Shin KA. Association between resting heart rate and risk factors of metabolic syndrome in Korean men. Journal of Wellness. 2015. 4: 305-316. Sui X, Church TS, Meriwether RA, Lobelo F, Blair SN. Uric acid and the development of metabolic syndrome in women and men. Metabolism. 2008. 57: 845-852. Tamariz L, Agarwal S, Soliman EZ, Chamberlain AM, Prineas R, Folsom AR, Ambrose M, Alonso A. Association of serum uric acid with incident atrial fibrillation. American Journal of Cardiology. 2011. 108: 1272-1276. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction. An overview of results from randomized controlled trials. Journal of the American Medical Association. 1993. 270: 1589-1595. Tomiyama H, Higashi Y, Takase B, Node K, Sata M, Inoue T, Ishibashi Y, Ueda S, Shimada K, Yamashina A. Relationships among hyperuricemia, metabolic syndrome, and endothelial function. American Journal of Hypertension. 2011. 24: 770-774. World Health Organization Western Pacific Region, International Association for the Study of Obesity, and International Obesity Task Force. The Asian-Pacific perspective: redefining obesity and its treatment. Sydney, Australia. Health Communications Australia. 2000. 15-21. Yoo TW, Sung KC, Kim YC, Hwang ST, Oh SY, Shin HS, Kim BJ, Kim BS, Kang JH, Lee MH, Park JR, Kim H, Lee KB, Lhee HY, Ryu SH, Keum DG. The relationship of the hypertension, insulin resistance, and metabolic syndrome in the - 126 -
serum uric acid level. Korean Circulation Journal. 2004. 34: 874-882. Zhang Q, Lou S, Meng Z, Ren X. Gender and age impacts on the correlations between hyperuricemia and metabolic syndrome in Chinese. Clinical Rheumatology. 2011. 30: 777-787. http://dx.doi.org/10.15616/bsl.2017.23.2.118 Cite this article as: Shin KA. Clinical Usefulness of Serum Uric Acid and Resting Heart Rate in the Diagnosis of Metabolic Syndrome in Korean Adults. Biomedical Science Letters. 2017. 23: 118-127. - 127 -