DOI : 10.4093/kdj.2009.33.4.267 REVIEW 무증상제 2 형당뇨병환자에서심혈관질환위험의비침습적방법에의한평가 가톨릭대학교의과대학내과학교실 이지인 손현식 Non-invasive Methods for Cardiovascular Risk Assessment in Asymptomatic Type 2 Diabetes Mellitus Jee In Lee, Hyun Shik Son Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea Abstract Cardiovascular disease (CVD) is the major cause of mortality in type 2 diabetes mellitus. CVD is a clinical manifestation of atherosclerosis, a chronic and progressive inflammatory disease characterized by a long asymptomatic phase. Progression of atherosclerosis can lead to the occurrence of acute cardiovascular events. Atherosclerosis can be identified during the subclinical phase by several methods, including using biomarkers, pulse wave velocity, augmentation index, flow-mediated dilation, carotid ultrasound, and calcium score. The appropriate criteria for identifying asymptomatic patients with type 2 diabetes who should undergo CVD screening and therapeutic intervention remain controversial. Non-invasive methods, such as markers of subclinical atherosclerosis, may aid in risk stratification and the design of tailored therapies for patients with type 2 diabetes mellitus. (Korean Diabetes J 33:267-275, 2009) Key words: Biological markers, Cardiovascular diseases, Diabetes mellitus 서론당뇨병환자의사망원인중에서 65% 는심장질환이나뇌졸증에의한것으로심혈관질환은당뇨병환자의주요한사망원인이다 1-3). 당뇨병에의한미세혈관및대혈관합병증은눈, 신장, 관상동맥, 말초혈관, 뇌혈관과같은표적장기에손상을일으키며, 이러한손상은장기간의무증상시기를거쳐증상이나타날때에는이미합병증이진행된상태로발견된다. 서구화및산업화로인한생활습관의변화및노인인구증가로인해제2형당뇨병의유병률이급속히증가하고있고, 더불어당뇨병의대혈관합병증, 특히동맥경화성혈관합병증의증가가예측된다. 당뇨병환자의심혈관질환의발생빈도는당뇨병이없는성인에비해서 2~5배높고, 기존심혈관질환의과거력이있는비당뇨인의위험도와동일하여당뇨병을관상동맥질환에상응하는위험군 (Coronary heart disease risk equivalent) 으로규정하고있다 4). 심혈관질환은초기에내피세포기능장애의단계를거쳐서서히죽상경화증으로진행하여결국에는심근경색, 불안정협심증및급사와같은급성심혈관사건을일으킨다. 특히죽상경화증은서서히진행하는만성적인염증성질환으로정의할수있다. 당뇨병에서는고혈당, 이상지질혈증, 인슐린저항성등의대사이상이동반되며, 이로인해혈관의정상적인기능이손상되고죽상경화증에취약한상태가된다. 당뇨병이죽상동맥경화의진행을촉진시키는기전은완전히밝혀지지않았으나, 혈관내피세포와혈관평활근세포이상, 혈전혈성경향이원인으로고려되고있다 5). 급성심혈관사건이발생하기전무증상환자에서심혈관질환발병위험도를평가하고조기에정밀검사및적절한치료가행해질수있다면, 당뇨병환자의심혈관질환으로인한이완율과사망률을줄일수있을것이다. 당뇨병환자에서심혈관질환의조기선별을위한여러검사법들이있다 (Table 1). 본란에서는무증상인제2형당뇨병환자에서심 267
Table 1. Various non-invasive cardiovascular risk assessments Global CHD risk scores Framingham risk score UKPDS risk engine Cardiovascular biomarker CRP, lipoprotein (a), homocystein, microalbuminuria, B-type natriuretic peptide, IL-6, serum amyloid A, lipoprotein associated phospholipid A 2 Arterial stiffness Pulse wave velocity, Augmentation index Carotid sonogram Intima-media thickness, plaque Non invasive endothelial function test Flow mediated dilation Coronary calcium scores by EBCT MSCT coronary angiography Exercise ECG Nuclear MPI Stress echocardiography CHD, coronary heart disease; CRP, C-reactive protein; EBCT, Electorn beam computed tomography; ECG, echocardiography; MPI, myocardial perfusion imaging; MSCT, multi-slice computed tomography; UKPDS, United Kindom Prospective Diabetes Study. 혈관질환발병위험도에대해외래에서쉽게이용할수있는비침습적인방법에의한평가법에대해서알아보고자한다. 이없어코호트데이터를기반으로한모델이필요한실정이다. Global CHD Risk Scores United Kingdom Prospective Diabetes Study (UKPDS) 와 Framingham 연구에서심혈관질환의여러전통적인위험인자들을확인하였고, 이를대규모코호트연구결과에근간해만들어진방정식에대입해향후 10년내심혈관질환발생위험률을예측할수있도록하였다. Framingham 위험지수는연령, 성별, 흡연, 혈압, 총콜레스테롤, 고밀도지단백콜레스테롤의위험인자를점수화하여위험도를 % 로표시하였다 6). 그러나 Asia-Pacific Cohort Studies Collaboration (APCSC) 연구에서 Framingham risk score를아시아인에게적용할때심혈관질환의위험예상치가실제관측치보다높게나타나는경향이있음을보고하였고, 이러한평가공식의인종별재조정이필요하다고하였다 7). UKPDS risk engine은나이, 성별, 당뇨병의유병기간, 인종, 흡연여부, 심방세동여부, 당화혈색소수치, 수축기혈압, 총콜레스테롤농도, 고밀도지단백콜레스테롤농도를 UKPDS risk engine v2.0 (www.dtu.org.uk) 에입력하여계산할수있다 8). UKPDS risk engine의장점은전체관상동맥질환, 치명적인관상동맥질환, 뇌졸중, 치명적인뇌졸중의위험도를각각얻을수있다. 아직국내에한국형심혈관예측모델 심혈관계위험인자로서의생체표지자 1. C-reactive Protein (CRP) CRP는펜트락신 (pentraxin) 계의단백질이며대표적인급성기반응성단백 (acute-phase reactant) 중하나이다. CRP는 IL-6에대한반응으로, 주로간에서생성되나, 죽상경화반, 관상동맥평활근세포, 대동맥내피세포, 지방세포에서도발현되는것으로보고되고있다 9-12). 죽상경화조직과관상동맥평활근세포에서 CRP의지속적인생산은만성적인 CRP의상승 (1~3 mg/l) 을초래하고, 심혈관질환발생의위험을예측하는데유용하다. CRP가심혈관질환의원인이지아니면결과의산물인지에대해서는논란의여지가있지만, monomeric CRP가 human coronary artery endothelial cell (HCAEC) 에서부착분자발현을일으키고, 활성화된내피세포에중성구부착을증가시켜혈관에염증을일으키고 13), 또한보체활성화에도직접관여하여심근경색후조직손상을악화시키다. 병변부위에다른 complement 활성화단백과더불어 CRP 단백이축적되어있음이증명되어 CRP가단순히병변의정도를반영하는표지자를지나병을일으키는원인으로고려되고있다 14,15). High sensitivity CRP 검사에대한지침으로 2003년 AHA/CDC에서 global 268
이지인외 1 인 : 무증상제 2 형당뇨병환자에서심혈관질환위험의비침습적방법에의한평가 CHD risk score 평가법에의해 10년 CHD의발병위험도가 10~20% 인중등도위험군에서향후추가평가와심혈관질환일차예방을위한치료여부를결정하는데도움이될수있다고하였고 16), SHAPE (the Screening for Heart Attack Prevention and Education) Task Force에서는무증상의중등도의고위험군에서 CRP를측정하여 4 mg/l를초과한경우에고위험군으로재분류하고철저한검사가필요하다고권고하고있다 17). Women's Health Study에서건강한여성에서심혈관질환발병의예측에대해서다른염증성표지자 (Serum amyloid A, IL-6, Intracellular adhesion molecule 1, homocystein, lipoprotein (a)) 와비교시 CRP가가장강력한예측인자였고, 연구중당뇨병이발생한군에서 CRP 와 IL-6의농도가모두상승되어있어, CRP와 IL-6의농도가동시에높은군에서장기적으로제2형당뇨병의발병률이높은것으로보고하였다 18,19). 경동맥초음파경동맥의동맥경화증정도는뇌졸중과같은뇌혈관질환의표식자일뿐아니라관동맥의협착여부를예측할수있는전신동맥경화증과관련된예측인자로알려져있다. 특히경동맥내중막두께 (Carotid intima-media thickness, CIMT) 는경동맥에동맥경화반이없더라도장기적인뇌졸중혹은허혈성심장질환의발병을예측할수있는것으로알려져있다 20-22). 2008년에발표된미국심장초음파학회의무증상혈관질환과심혈관질환위험도평가를위한경동맥초음파사용에대한권고안에따른검사법은맨먼저횡단면 B방식초음파검사를총경동맥의근위부에서내경동맥의중간부위까지탐촉자를서서히움직이면서시행하여전체적인혈관의방향성, 혈관벽의두께, 플라크와주변의구조물을개괄적으로살펴본다음에도플러검사, 플라크선별스캔을시행하고 CIMT를측정하며, 총경동맥, 팽대부, 내경동맥분절의가까운벽과먼벽을모두살펴야하고, 각분절마다최소한 3개이상의각도에서 3-5박동의 cine-loop 동안관찰하도록권고하고있다. CIMT 영상은대규모역학연구의결과들과접근의용이성, 뛰어난재현성등을바탕으로각총경동맥의먼벽의원위부 1 cm에서영상을얻도록하며, 가까운벽과먼벽에서모두이중선이평행하게보이는원위부총경동맥의깨끗한영상을얻어야실제수직면의스캔이이루어진것이다. 플라크의유무를확인하기위한경동맥의철저한검사가반드시동반이되어야하며, CIMT는플라크가 없는부위에서종축면의총경동맥의먼벽에서측정하는것을권고하고있다 23,24). 두꺼워진 CIMT와달리플라크는동맥내강으로최소 0.5 mm 이상부분적으로침범하였거나, 주변의 CIMT보다 50% 이상증가된경우로구분하고, 중막- 외막으로부터내막 -내강경계까지측정한부분의두께가 1.5 mm를넘는것도플라크의다른기준으로삼고있다. 정상 CIMT치는나이, 성별에따라많은영향을받는다. 상위정상치의기준은임의적이며보통측정치분포상의상위 75% 선을포함하는데, 임상적으로는심혈관계질환의발병률이갑자기증가되는선을 IMT 한계점이라고할수있다 25). 측정방법과인종, 성별간의차이가있지만연령과는관계없이 1.0 mm 이상이면심근경색이나뇌혈관질환의위험이현저하게증가된다고볼수있다 24). 그리고 IMT값중에서평균값이재현성이높고앞으로의심혈관계위험인자를가장잘반영한다고알려져있다. 한국 IMT 연구에서는좌측경동맥평균 IMT는남성 0.65 ± 0.12 mm, 여성 0.64 ± 0.11 mm이고, 비정상과구분하는역치는우측 0.64 mm, 좌측 0.65 mm로외국의경우보다낮게보고하였다 26). 또다른연구에서는당뇨병이없는군에서여성 0.667 ± 0.147 mm, 남성 0.675 ± 0.156 mm이였고, 당뇨병이있는군에서여성 0.866 ± 0.242 mm, 남성 0.856 ± 0.593 mm로당뇨병군에서 CIMT가높았다 27). 하지만이러한수치는연구대상자의수가적고, 건강검진을목적으로방문한사람을대상으로하여서당뇨병환자에서의비정상 CIMT역치기준에대한연령별, 성별, 질환에따른대규모의연구가필요하다. Atherosclerosis Risk in Communities (ARIC) 연구에서중년환자의 CIMT가 1 mm 이상이면 4~7년의추적중관상동맥질환의위험도가남성에서 2배, 여성에서 5배로증가하였고 28), 또 65세이상의노인을대상으로한 Cardiovascular Heart Study에서 CIMT가 1.18 mm면 6년간의추적조사에서급성심근경색증이나뇌졸중이합병될수있는가능성이 4배정도높다고보고하여 CIMT가심혈관질환발생의예측인자로사용될수있음을입증하였다 29). 제2형당뇨병과 CIMT에대한메타분석에서제2형당뇨병환자의 CIMT는정상군에비해서 0.13 mm 증가되어있었고, 이러한차이는당뇨병환자가정상군보다 10년정도혈관의동맥경화가진행되었을것으로보여지며, 심근경색이나뇌졸중의위험이 40% 증가한다고하였다 30). 내피세포의존혈관확장내피세포의기능장애는동맥경화증의가장초기단계에서 269
나타나는현상이며 31), 혈관의구조적인변화가나타나기전이미시작되므로이러한시기를적절히평가할수있는방법이모색되어왔다. 내피세포의존혈관확장의원리는혈관은혈류량증가즉, shear stress의증가에반응하여확장하게되는데이를 flow-mediated vasodilation (FMD) 라한다 32). FMD를일으키는주요한매개체는혈관내피세포에서분비된 NO이다 33). 이외에도 prostanoid나 endothelial-derived hyperpolarizing factor (EDHD) 등도관여한다고알려져있다. 검사방법은안정시의상완동맥의기저영상을얻은후, 미리감아놓은커프의압력을대상자혈압의최소한 50 mm Hg 이상으로높여 5분동안상완부의혈류를차단한후다시커프를이완시키면상완부의산소결핍을보상하기위하여상완동맥의혈류량이증가하는데이를반응성울혈 (reactive hyperemia) 이라한다. 반응성울혈에의한 shear stress의증가는상완동맥의확장을유발하는데이를내피세포의존 FMD라고한다 34). 정상인에서의측정치는 5~10% 이며, 건강한젊은성인에서는 10% 정도이고, 심혈관질환이있는경우에는 0% 까지측정되어 FMD가심혈관질환의존재를예측할수있다고하였다 35). 당뇨병환자에서내피세포기능장애는혈당의최대치와관련되고, 혈당변화폭이클수록내피세포의기능장애가더욱악화되었음을보고하였고, 이는산화스트레스와관련된다고하였다 36). 최근 Multi-Ethnic Study of Atherosclerosis (MESA) 연구에서심혈관질환이없는 3,026명을대상으로 5년간추적한결과대상자의평균 FMD는 4.4% 였고, FMD가심혈관질환발생의예측인자이며 Framingham risk socre와비교시, 저, 중등도, 고위험군의분류를더욱층화시킬수있었다 37). 당뇨병환자는고혈당, 인슐린저항성, NO 가용성감소로인하여내피세포의기능장애가동반된다. 당뇨병환자에서 Epicardial coronary artery의내피세포기능장애가향후관상동맥질환을예측할수있으나 38), FMD 가당뇨병환자에서관상동맥질환을예측할수있을지에대한연구는없는실정으로이에대한추가연구가필요하다. FMD의검사의제한점은검사자의기술능력에따라결과에상당한영향을미칠수있으므로검사자의경험축적과충분한주의가필요하며, 검사치의일중변화가있고, 온도, 스트레스식사, 혈당, 생리주기에영향을받을수있다는것이다. 상완동맥초음파검사를이용한혈류매개혈관확장반응은비침습적인방법으로내피세포의기능장애를평가할수있고, 결국동맥경화증의조기진단및관상동맥질환의예측인자로서유용하게사용되어질수있다. 동맥경직도 (Arterial Stiffness) 경동맥초음파는경동맥내중막두께및플라크를검사하여혈관의구조적인변화를관찰하는반면, 맥파전달속도 (pulse wave velocity, PWV) 나파형증가지수 (augmentation index, AIx) 는동맥경직도를반영하여혈관의기능적인변화를알수있다. 동맥경직도는동맥의탄력성감소에의한단단한정도를의미한다. 동맥경직도의증가원인으로는연령, 고혈압, 당뇨병, 고지혈증, 만성신부전, 흡연이나비만등이있다. 동맥경직도의정도가어떠한질병을진단하는방법이거나치료의대상은아니지만동맥경화의진행정도를의미하고, 이를통해서심혈관질환의발생위험도를예측할수있다 39,40). 1. 맥파전달속도맥파전달속도는혈관에서맥파가전달될때두지점간의맥파가이동하는시간 (ΔT) 과두지점간의거리 (L) 를측정하여혈관의일정구간을통과하는맥파속도를측정하는것이다 (PWV (m/sec or cm/sec) = L/ΔT). 혈관의경직도가증가하여신전성이저하되면 PWV는같은지점을통과하는동안증가하게된다 41). PWV는연령이증가되면서점차증가되어, 20대에는약 4 m/s이지만 80대에는 10 m/s로증가된다. 국내에서성인검진환자를대상으로한 PWV의정상값은 20대는 5.58 ± 0.96 m/sec에서나이에따라점차적으로증가하여, 60대는 8.5 ± 2.36 m/sec의평균값을보였다 42). 그러나이연구는대상자수가적어서이값을한국인정상인의 PWV값으로사용하기에는어렵다. 국내에서도대규모임상연구를통해서정상인의연령별, 질환별 PWV의수치를정립할필요가있다. PWV 검사시주의할점은측정하는조건에따라서측정값의차이가있으므로일정한조건에서측정해야한다. 특히추적검사에서이전에측정한값과비교할때는이전에측정한환경과같은환경에서측정하여야한다. 즉조용한환경, 검사실의쾌적한실내온도, 환자의안정상태, 검사전흡연, 커피, 알코올섭취등을제한해야한다. 2. 맥파형의분석 (Pulse Wave Analysis) 경동맥또는요골동맥에서맥파를기록하여파형을분석해서파형증가지수 (augmentation index, AIx) 와중심대동맥압 (central arterial pressure) 두가지를측정할수있다. 맥파형분석의원리는심장이박출할때전진맥파 (incident wave) 가생겨혈관을따라진행하다가혈관의분지나말초 270
이지인외 1 인 : 무증상제 2 형당뇨병환자에서심혈관질환위험의비침습적방법에의한평가 혈관에서파가되돌아오는데이반사파 (reflected wave) 가대동맥에서전진파와합쳐져대동맥파를이루게된다. 혈관이경직되면서심장에서발생한전진맥파와말초에서심장으로돌아오는반사파의속도가빨라져, 반사파가중심동맥에일찍도착하여중심동맥의수축기압이증가하여수축기혈압이상승한다. 결과적으로좌심실의후부하가증가하고심실의이완기능을저해하고관상동맥의충만이방해를받게되고, 이것은심혈관계질환의위험을예견하는중요한지표가된다. 파형증가지수는반사파에의한맥압크기의변화로반사된파형의강도와타이밍에의해주로결정된다. Coronary Artery Calcium (CAC) Score CAC는체내의총 atheroma burden을확인할수있고 43), 전자선전산화단층촬영 (Electron beam CT, EBCT) 나다검출기전산화단층촬영 (multidetector CT, MDCT) 를이용하여관상동맥의석회화정도를측정할수있다. Agatstone 등은관상동맥석회화의정도를 0, 1~10, 11~100, 101~400, 401 이상의 5등급으로구분하여분류하였고 44), 최근여러연구에서 0, 10, 100, 400, 또는 1,000 등의수치를기준으로위험도를구분하고있으나이러한기준에대해서는좀더많은연구가필요한상태이다. 석회화의정도는연령, 남성, 당뇨병, 고혈압에서증가한다고보고되어있다. 여러단면조사연구들에서당뇨병환자에서비당뇨인에비해 CAC 유병률이높고, 그정도가심하다고보고하였다 44-49). Raggi 등은 903명의당뇨병환자를포함한 10,377명의환자를대상으로 CAC imaging 후약 5년간추적한결과당뇨인과비당뇨인모두에서기저 CAC score가높았던경우에사망률이증가하였고, 비슷한 CAC score를가지더라도당뇨인의사망률이증가되어있다는것을보고하였다. 그리고 CAC score가 0인경우당뇨인과비당뇨인에서생존율이비슷하여, CAC score가당뇨병환자에서심혈관질환의위험도를층화할수있는유용한방법이라고제시하였다 50). 또한 Anand 등은합병증이없는제2형당뇨병환자에서단기간의심혈관질환이나무증상성협심증을예측하는데알려진전통적인심혈관계위험인자보다 CAC score가우월하다고보고하였다 51). 그러나 South Bay Heart Watch Study에서기저 coronary calcium은비당뇨인에서는위험도를예측할수있으나 269 명의당뇨병환자를 6년간추적했을때위험도와관련성이없는것으로보고하여 52), CAC score가심혈관질환의위험도평가및예측인자로사용될수있을지에대해서는대규모전향적인연구가필요하다. 하지만 CAC score는하나의 중요한위험인자임은분명하고 CAC score가높을수록관상동맥질환이있을가능성이높아진다. 그러나칼슘이있는부위와협착이있는부위가서로관련되지는않는다고알려져있으며지질강하제등심혈관질환예방치료를하는경우에도석회화는총동맥경화반양과는상관없이계속남아있기때문에치료성적을추적하는지표로사용할수없다. 일부의심장의컴퓨터단층촬영에대한임상지침에서는 CAC score를전통적인 scoring system에서심혈관질환의위험도가중등도인무증상환자에서 CAC score을권고하고있다 53). 저위험군이나고위험군인무증상환자에서 CAC의진행정도를추적하기위해서시행하는검사는권고하고있지않다 53). Steno-2 연구에서당뇨병환자에서혈당조절만이아니라, 심혈관질환의위험요인을적극적으로조절한경우에심혈관사건을감소킬수있다는결과에서보듯이 54), 무증상당뇨병환자에서심혈관질환의위험요인및예측을통해서적극적인치료를시행한다면향후당뇨병환자의대혈관질환에의한이완율및사망률을더욱줄일수있을것이다. 하지만검사방법이단일화되어있지않거나당뇨병환자에대한심혈관질환의예측도에대한근거자료가아직은부족한실정이다. 향후대규모전향적인임상연구들을통해각검사방법들의평가가필요하다. 참고문헌 1. Beckman JA, Creager MA, Libby P: Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287:2570-81, 2002 2. Creager MA, Luscher TF, Cosentino F, Beckman JA: Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation 108:1527-32, 2003 3. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H: Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 44(Suppl 2):S14-21 4. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339:229-34, 1998 5. Lockhart CJ, Hamilton PK, McVeigh KA, McVeigh 271
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