제 2 형당뇨병환자에서좌심실 이완기장애에영향을미치는 요인들에대한연구 연세대학교대학원 의학과 정지영
감사의글 이논문이완성되기까지항상깊은관심을가지고지도를해주신이현철교수님께진심으로감사드리며. 본연구를위하여세심한조언을아끼지않으신차봉수교수님과조승연교수님께도깊은감사를드립니다. 아울러연구를진행하는데많은도움을주신강사선생님들과내과의국원들에게도감사를드립니다. 사랑하는부모님과남편, 그리고딸서윤이에게고마움을전합니다. 저자씀 ii
차 례 그림및표차례 ⅲ 국문요약 1 Ⅰ. 서론 3 Ⅱ. 재료및방법 5 1. 연구대상 5 2. 연구방법 5 3. 통계및분석 8 Ⅲ. 결과 9 1. 연구대상환자군의임상적특성 9 2. 좌심실이완기장애에따른임상적, 생화학적지표들간의상호관계 11 3. 나이에따른좌심실이완기장애 12 4. 당뇨이환기간에따른좌심실이완기장애 14 5. 좌심실이완기장애유무에따른심초음파및생화학적지표들간의차이 15 6. 알부민뇨증에따른좌심실이완기장애 18 i
Ⅳ. 고찰 19 Ⅴ. 결론 23 참고문헌 24 영문요약 31 ii
그림차례 Figure 1. The incidence of diastolic dysfunction according to diabetes duration 14 iii
표차례 Table 1. Clinical and biochemical characteristics of subjects 10 Table 2. Frequency of microvascular complications 11 Table 3. Relationships between left ventricular diastolic dysfunction and clinical parameters in diabetic patients 12 Table 4. Differences in diastolic parameters according to age 13 Table 5. Echocardiographic parameters according to relaxational abnormality 16 Table 6. Clinical and laboratory data according to relaxational abnormality 17 Table 7. Differences in diastolic parameters according to albuminuria 18 iv
국문요약 제 2 형당뇨병환자에서좌심실이완기장애에 영향을미치는요인들에대한연구 당뇨병성심근병증은관상동맥폐쇄성질환과무관하게좌심실비대를야기하며인슐린저항성과함께고혈당으로인해발생하는고유의질병이며당뇨병환자에서흔히나타난다. 당뇨병성심근병증의조기증상은좌심실의조기이완기채움장애 (early diastolic filling), 동용량성이완장애 (isovolumetric relaxation), 그리고증가된심방채움 (increased atrial filling) 을특징으로하는좌심실이완기장애로나타난다. 본연구의목적은무증상의제 2형한국인당뇨병환자에서좌심실이완기장애에미치는요인들을알아보고자함이다. 제 2형당뇨병환자에서심초음파를시행한환자중관상동맥폐쇄질환, 구조적이상, 예를들면판막질환, 심실중격결손, 심방중격결손이있었던환자를제외하였다. 또한모든환자에서 Valsalva maneuver를시행하여 pseudonormalization을제외하였다. 체질량지수, 허리-엉덩이둘레비, 공복혈당, 공복인슐린, 콜레스테롤, 24시간뇨알부민량등을 1
측정하여상관관계를보았다. 좌심실이완기장애는나이 (r=-0.563, p=0.001), 당뇨이환기간 (r=- 0.301, p=0.005), 알부민뇨 (r=-0.203, p=0.013) 와상관관계를가졌으나, 고혈압유무, 비만, 허리-엉덩이둘레비, 공복혈당, 공복인슐린, 콜레스테롤과는상관관계가없었다. 이완기장애는당뇨병성심근병증의초기증상으로심부전으로의진행을예방하는것은매우중요하다. 따라서, 고령이나이환기간이길거나미세알부민뇨증이있는환자는선별검사로심초음파를시행하여당뇨병성심근병증을조기에진단하고적극적인치료가필요할것으로사료된다. 핵심되는말 : 제 2 형당뇨병, 좌심실이완기장애, 당뇨병성심근병증, 미세알부민뇨 2
제 2 형당뇨병환자에서좌심실이완기 장애에영향을미치는요인들에대한연구 < 지도교수이현철 > 연세대학교대학원의학과 정지영 I. 서론 당뇨병을포함한대사질환은동맥경화증발생에중요한위험인자로잘알려져있다. 역학적연구들에서보고된바와같이당뇨병환자에서주된사인은심혈관질환으로알려져있다. 1, 2. 당뇨병환자에서대사장애가심혈관계에미치는영향은대혈관합병증으로오는허혈성심질환과미세혈관합병증으로오는자율신경병증, 그외에도관상동맥폐쇄와무관한심근병증등이있다 3. 이러한당뇨병성심근기능장애는관상동맥폐쇄성질환, 고혈압, 비만을보정한후에도발생하며당뇨병은임상적심부전증진행의독립인자로알려져있다 4, 5, 6. 제한적심근병증은주로좌심실의이완기장애로나타나며병리학적으로는 3
콜라겐, 단백질, 중성지방, 콜레스테롤등이심근간질에침착하여섬유화로나타나거나소동맥에서내막비후, 유리질축적, 염증성변화등으로나타난다 7. 심근기능장애의기전은잘알려져있지않으나, 그중한기전으로고혈당으로인해 advanced glycosylation end products(ages) 의생성되고 AGEs가 collagen의기능장애를일으켜당뇨성심근병증이발생된다는보고가있고 8, 그외에도미세혈관병증 (microangiopathy), 자율신경병증 (autonomic neuropathy), 세포내칼슘수송결핍, 심근수축단백질의구조적변화, 콜라겐축적등이기전으로제시되고있다 9,10. 또한, 대사장애기전중포도당이용율이떨어지고유리지방산의이용율이증가되면서생기는여러독성물질들에의한심근의구조적변화및생화학적변화등이알려지고있다 11. 제 2 형당뇨병환자에서좌심실이완기에영향을미치는요인들로여러가지가보고되고있는데, 우선고혈압이동반된경우에 12, 비만할수록 13, 당뇨병 의이환기간이길수록 14, 혈당이높을수록 15, 16, 그리고미세알부민뇨가있는 경우에이완기장애가더욱심하였다는보고가있었다 17. 하지만, 우리나라제 2 형당뇨환자에서관상동맥질환과무관한좌심실이완기장애에관한연구는아직보고된바없다. 따라서본연구에서는제 2 형당뇨환자들을대상으로하여좌심실이완기장애에영향을미치는요인들을분석하여이완기장애의발생을조기진단하고진행을개선시키는방법을찾고자한다. 4
Ⅱ. 대상및방법 1. 연구대상 연세대학교세브란스병원당뇨병센터에내원한제2형당뇨병환자 110명을대상으로하였다 ( 남자 60 명과여자 50 명 ; 평균연령, 57.1±10.6년 ; 평균당뇨이환기간, 9.2±7.4년 ). 모든환자는운동과식이요법, sulfonylurea나 metformin, 혹은인슐린을사용하고있었다. 제외대상은다음과같다 : 관상동맥조영술이나 MIBI scan상관상동맥폐쇄질환이있는경우, 심초음파상구조적이상이있는경우, pseudonormalization이있는경우, 크레아티닌이 1.4 mg/dl 이상인경우는연구대상에서제외하였다. 2. 연구방법 가. 당뇨병환자대상모든환자들은체중, 키, 체질량지수, 허리-엉덩이둘레비, 당뇨병의이환기간, 고혈압유무, 흡연력을조사하고, 공복혈당, 공복인슐린, 공복 C-peptide, HbA1c, 혈청크레아티닌, 혈청요산, 혈청총 5
콜레스테롤, 혈청고밀도지단백-콜레스테롤, 혈청중성지방, 혈청저밀도지단백-콜레스테롤, 혈청유리지방산을측정하였다. 허리둘레는 superior iliac crest와늑골최하단사이에서측정하였고, 엉덩이둘레는 maximal greater trochanter protrusion에서측정하였다. 체질량지수는몸무게 (kg) 를키 (m) 의제곱으로나눈계산값으로하였다. Homeostasis model of assessment (HOMA- IR ) 을인슐린저항성의지표로삼았고다음의공식에준해계산하였다. HOMA- IR = [FPG (mmol/l) x fasting serum insulin level (μu/ml)] 22.5. 24 시간뇨알부민량, 신경전도검사, 망막촬영으로당뇨병성신증과 신경병증, 그리고망막병증을확인하였다. 나. 심초음파검사 경흉부초음파는 Sonos 5500(Philips, USA) 을통해이완기장애를측정하였고, 측정은환자를좌측위자세로하고 nipple의좌하방부위에 probe를대면 apical four chamaber view를통해 mitral valve, pulmonary vein flow를보았다. 이완기장애를 grade로나누면, Grade 1은 impaired 6
relaxation, Grade 2는 pseudonormalized pattern, Grade 3는 reversible restrictive pattern, Grade 4는 irreversible restrictive pattern으로나눌수있다. 본연구에서는 Grade 1인 impaired relaxation을이완기장애로정의하였다. 좌심실비대나좌심방확장소견을보이면서 E/A ratio가 1 이상인경우 Valsalva maneuver를시행하게하여 pseudonormalization을감별하였다. 수축기장애를보기위해 ejection fraction, regional wall motion 등을보았고, 이완기장애를보기위해 early diastolic filling velocity (E), late diastolic filling velocity (A), deceleration time (DT) 을측정하였다. 구조적장애를보기위해 posterior wall thickness (PWD), septal wall thickness (ISD), Lt atrial diameter (LAD), Left ventricular end diastolic diameter (LVEDD), Left ventricular end systolic diameter (LVESD), aortic root diameter (AO) 등을측정하였다. LV mass index (LVMI) 는다음과같은공식에준해계산하였다. LVM (g) = 0.8 1.04 [(LVEDD + IVST + PWT) 3 (LVEDD) 3 ] + 0.6 LVM (g) = 0.8 1.04 [(LVEDD + IVST + PWT) 3 (LVEDD) 3 ] + 0.6 LVMI (g/m 2 ) = LVM/BSA Fractional shortening = (LVEDD- LVESD)/LVEDD 100 (%) 7
다. 분석방법공복혈당은 glucose oxidase method로측정하였다. HbA1c는 affinity chromatography로측정하였다. 혈청인슐린농도는 RIA kit (Linco Reaserch, Inc., St. Charles, MO) 를사용하여이중항체방법을이용한 RIA 로측정하였다. 혈청콜레스테롤농도와중성지방농도는자동생화학분석기기인 Hitachi 747 (Hitachi Co, Nagashi, Japan) 을이용하여측정하였다. 3. 통계및분석 모든데이터는 mean + S.D 로표현하였다. 통계학적분석은 SPSS 11.0 software package (SPSS Inc, Chicago) 를사용하여실행하였다. 이완기장애유무에따른비교는 independent t test를사용하여비교하였다. 그룹간의비교는 Scheffe's post hoc test에따라 one-way ANOVA를이용하여실행하였다. 연속변수들사이의비교는 linear relationship으로예측하기위해 Pearson correlation coefficient를사용하였다. p value가 0.05 미만일경우결과값이통계학적으로의미있다고간주하였다.. 8
Ⅲ. 결과 1. 연구대상환자군의임상적특성 고혈압은 110 명중 62명에서있었고, 남자가 60 명이었다. 대상환자들에있어좌심실이완기장애가있는환자는 110 명중 71 명으로 64.5% 였다. 남녀에따른나이의차이는없었다. 평균나이는 57.1±10.6세였으며평균 E/A 비는 0.98±0.43, Deceleration time(dt) 는 212.5±47.6 msec였다. 평균 LVMI는 116.0±31.8 g/m 2 였다 (table 1). 미세혈관합병증의빈도는신경병증 46.9%, 망막병증 45.5%, 신증 40.5% 였다 (table 2) 9
Table 1. Clinical and biochemical characteristics of subjects Mean Age (yr) 57.1±10.6 Height (cm) 162.7±9.2 Weight (kg) 64.9±11.8 Waist circumference (cm) 88.9±10.6 Hip circumference (cm) 94.6±7.8 WHR 0.94±0.08 BMI (kg/ m2 ) 24.5±3.8 SBP (mmhg) 128.2±14.2 DBP (mmhg) 79.3±8.7 Heart rate (/min) 76.6±8.2 Diabetes duration (yr) 9.2±7.4 Fasting glucose (mg/dl) 153.9±54.7 HgA1c (%) 9.1±2.3 Fasting insulin (μu/ ml ) 11.75±22.74 Fasting C-peptide (ng/ ml ) 1.93±1.71 HOMA IR 3.6±4.0 Total cholesterol (mg/dl) 184.0±40.3 Triglyceride (mg/dl) 185.6±154.4 HDL-cholesterol (mg/dl) 43.6±11.9 LDL-cholesterol (mg/dl) 108.6±29.8 Data are means+sd, * p < 0.05 WHR : Waist/Hip ratio, BMI : body mass index SBP : systolic blood pressure, DBP : diastolic blood pressure HOMA IR= fasting insulin(uu/ml) x FPG (mmol/l)/22.5 10
Table 2. Frequency of microvascular complications % retinopathy 30/66(45.5%) neuropathy 23/49(46.9%) nephropathy 37/92(40.2%) 2. 좌심실이완기장애에따른임상적, 생화학적지표들간의상호관계나이와당뇨이환기간이길수록좌심실이완기장애정도와상관관계가있었으나그외공복시혈당, HbA1c, C-peptide, cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, HOMA- IR 와는상관관계가없었다 (Table 3). 11
Table 3. Relationships between left ventricular diastolic dysfunction and clinical parameters in diabetic patients Clinical, laboratory parameters Ejection fraction * E/A ratio r p r p Age (y r) 0.080 0.435-0.563 * 0.000 Body mass index ( kg / m2 ) -0.014 0.904 0.122 0.244 Duration of diabetes (yr) *, -0.276 * 0.014-0.301 * 0.005 Fasting blood sugar ( mg / dl ) -0.124 0.232 0.172 0.84 2-h blood sugar ( mg / dl ) -0.036 0.767 0.122 0.989 Fasting insulin (μu/ ml ) 0.091 0.445 0.071 0.544 Fasting C-peptide (ng/ ml ) 0.064 0.594-0.23 0.838 Homa- IR -0.055 0.649-0.138 0.228 Homa- Beta -0.021 0.864-0.195 0.087 Total cholesterol ( mg / dl ) -0.058 0.585-0.083 0.416 HDL-cholesterol ( mg / dl ) 0.027 0.813-0.133 0.216 LDL-cholesterol ( mg / dl ) -0.080 0.480-0.142 0.188 Triglyceride ( mg / dl ) -0.113 0.300 0.191 0.066 p < 0.05 HOMA IR= fasting insulin(uu/ml) x FPG (mmol/l)/22.5 3. 나이에따른좌심실이완기장애나이는좌심실이완기장애에있어중요한변수로일반적으로나이가들수록좌심실이완기장애가발생하는것으로알려져있다. 65세이상이되면 E velocity가 A velocity와비슷해지고, 70세이상이되면 E/A 비가 1 이하로떨어지게된다. 대상환자에서이완기장애에따른 ROC curve를구하여 49세전후로이완기장애유무의차이가통계학적으로유의하게관찰 12
되었다 (p < 0.001). 49 세전후에따른좌심실이완기변수들의차이는다 음과같다 (Table 4) Table 4. Differences in diastolic parameters according to age < 49 yr (n=28) > 49 yr (n=82) p value E velocity (cm/sec) * 0.75± 0.17 0.63± 0.17 0.01 A velocity (cm/sec) * 0.58 ± 0.21 0.79 ± 0.22 <0.001 E/A ratio * 1.43 ± 0.48 0.83 ±0.27 <0.001 DT (msec) * 185.4 ± 38.1 221.4± 47.3 0.01 * p < 0.05, Data are means+sd E velocity : early diastolic filling velocity A velocity : late diastolic filling velocity DT : deceleration time 13
4. 당뇨병이환기간에따른좌심실이완기장애 당뇨병이환기간이오래될수록좌심실이완기장애의빈도가증가했는 데이환기간에따른 ROC curve 를구하여 6 년전후로이완기장애유무의 차이가통계학적으로유의하게관찰되었다 (p < 0.001) (Figure 1). 50 40 Incidence 30 20 10 이완기장애 무 0 < 6 yr > 6 yr 유 Diabetes duration Figure 1. The incidence of diastolic dysfunction according to diabetes duration 14
5. 좌심실이완기장애유무에따른심초음파및생화학적지표들 간의차이 좌심실이완기장애가있는군에서 posterior wall thickness와 septal wall thickness가통계학적으로의미있게두꺼웠고 LV mass index도의미있게증가되어있었다 (Table 5). 좌심실이완기장애가있는군에서나이, 당뇨이환기간이의미있게많았으며, 체질량지수, 콜레스테롤, 중성지방, 공복시혈당등은유의한차이를보이지않았다 (Table 6). 15
Table 5. Echocardiographic parameters according to relaxational abnormality Relaxational abnormality ( ) ( + ) p value Numbers of Patients 38(34.5%) 72(65.5%) E velocity (cm/s) * 0.74±0.15 0.61±0.17 0.01 A velocity (cm/s) * 0.55±0.14 0.84±0.21 0.000 E/A ratio * 1.40±0.34 0.76±0.28 0.000 DT (msec) * 183.8±25.2 227.5±49.8 0.000 LVEDD (mm) * 49.3±3.6 47.2±5.4 0.02 LVESD (mm) * 32.7±3.6 29.8±4.5 0.002 LAD (mm) 37.1±5.1 38.4±4.8 0.193 ISD (mm) * 8.9±1.6 10.0±1.7 0.002 PWD (mm) * 8.7±1.3 10.4±2.0 0.000 AO (mm) 30.1±3.8 31.1±3.8 0.246 EF (%) * 65.3±7.3 69.6±7.1 0.005 LV mass index (g/m 2 ) * 103.7±22.4 120.0±33.5 0.046 fractional shortening (%) * 33.7±4.9 36.8±5.90 0.011 * p < 0.05, Data are means+sd E velocity : early diastolic filling velocity A velocity : late diastolic filling velocity, DT : deceleration time LVEDD : left ventricular end diastolic dimension LVESD : left ventricular end systolic dimension LAD : left atrial dimension, ISD : interventricular septal thickness PWD : posterior wall thickness, AO : aortic root dimension EF : ejection fraction 16
Table. 6 Clinical and laboratory data according to relaxational abnormality Relaxational abnormality ( ) ( + ) p value Numbners of Patients 38(34.5%) 72(65.5%) Genders(males/females) * 28/10 32/40 0.003 Age (yr) * 50.5±11.5 60.6±8.3 0.000 Body mass index ( kg / m2 ) 24.8±3.4 24.4±3.9 0.64 Diabetes duration (yrs) * 4.9±5.6 10.6±7.3 0.002 Fasting glucose ( mg / dl ) 163.2±67.8 149.0±46.3 0.217 Fasting insulin (μu/ ml ) 17.79±4.66 10.23±1.09 0.529 Fasting C-peptide (ng/ ml ) 1.75±1.06 1.98±1.84 0.643 HgA1c (%) 8.9±2.3 9.2±2.4 0.596 Total cholesterol ( mg / dl ) 177.8±39.6 186.9±40.6 0.305 Triglyceride ( mg / dl ) 194.3±227.3 182.0±114.9 0.729 HDL-cholesterol ( mg / dl ) 43.0±14.2 43.8±11.0 0.779 LDL-cholesterol ( mg / dl ) 109.1±22.9 108.4±32.1 0.920 FFA ( mg / dl ) 595.1±242.0 558.1±280.7 0.666 SBP (mmhg) 128.2±11.7 128.2±14.8 0.989 DBP (mmhg) 81.7±9.3 78.7±8.6 0.222 Heart rate ( /min) * 80.6±13.2 75.8±6.7 0.011 * p < 0.05, Data are means+sd FFA : Free Fatty Acid SBP : systolic blood pressure DBP : diastolic blood pressure 17
6. 알부민뇨증에따른좌심실이완기장애 정상알부민뇨군과미세알부민뇨군, 및거대알부민뇨군간의좌심실 이완기장애차이는있었지만미세알부민뇨군과거대알부민뇨군간에는 통계학적으로이완기장애의차이가없었다.(p= 0.013),(Table 7). Table 7. Differences in diastolic parameters according to albuminuria normoalbuminuria microalbuminuria macroalbuminuria p value Number 56 22 16 E 0.68±0.15 0.69±0.15 0.65±0.25 0.79 A* 0.69±0.20 0.76±0.20 0.88±0.23 0.007 E/A* 1.05±0.34 1.03±0.52 0.76±0.28 0.025 DT 207.7±39.9 214.6±54.0 221.5±66.6 0.599 * p < 0.05, Data are means+sd E velocity : early diastolic filling velocity A velocity : late diastolic filling velocity DT : deceleration time 18
Ⅳ. 고찰 1970년대들어당뇨병환자에서관상동맥질환이없으면서발생하는심부전증이기술되기시작했고이를당뇨성심근병증이라고명명한바있다 18. 당뇨병환자에서심초음파를시행한연구들을통해제1형당뇨병환자에서관상동맥질환없이발생한좌심실이완기장애가보고되었고이는당뇨병이환기간, 고혈당, 미세혈관합병증과의연관성이있다고보고된바있다 19, 20, 21. 최근들어서관상동맥질환이없는제2형당뇨환자에서도비슷한결과들이보고되고있다 22, 23, 24, 25. 좌심실이완기장애란, 조기이완기채움장애, 동용량성이완의연장, 그리고증가된심방채움을특징으로한다 26. 이완기장애를 grade로나누면, Grade 1은 impaired relaxation, Grade 2는 pseudonormalized pattern, Grade 3는 reversible restrictive pattern, Grade 4는 irreversible restrictive pattern으로나눌수있다. 본연구에서는 Grade 1인 impaired relaxation을이완기장애로정의하였다. 이전의혈당이잘조절되는제 2형당뇨환자들에서좌심실이완기장애의유병율은 30% 정도였다 22, 23. 하지만, 이는 standard echocardiography test로시행하여경증조기이완기장애는찾아낼수없었다. 최근엄격한 Doppler method가적용됨에따라 Minnesota주 Olmstead county에서시행한역학조사상당뇨환자중 52% 에서이완기장애가관찰되었고 27, Porier 등 25 은혈당이잘조절되는 19
제 2형당뇨병환자에서좌심실이완기장애가 60%(28%-pseudonormalization, 32%-impaired relaxation) 로보고하였다. 본연구에서는당뇨환자중 64.5% 가 impaired relaxation(grade 1 diastolic dysfunction) 으로정의하였는데이렇게유병율이높은것은대부분의환자가혈당이잘조절되지않았던환자이고고혈압이동반된경우가많았기때문으로생각된다. 이전의연구결과들을보면, 제 2형당뇨병환자에서좌심실비대가많이있으며, Framingham study에서당뇨가없는군에서보다당뇨군에서 10 % 정도 left ventricular mass가더많았던것으로보고한바있다 28. 본연구결과에서도이완기장애가있는군에서 LVMI가통계학적으로의미있게높았다 (p = 0.046). Strong Heart Study에서좌심실이완기장애는 HbA 1c 와직접적인상관관계를가지는데, 그이유로 myocardial AGEs(Advenaced glycosylation end products) 이증가를들고있다. 동물실험에서증가된 myocardial AGE receptor expression은 collagen의 crosslinking을증가시키고심근섬유화를증가시켜좌심실이완기장애를초래한다고한다 8, 29. 또한고혈당은 free radicals 및 oxidants을발생시켜 nitric oxide level을감소시킴으로내피세포장애를유발시키고, poly(adpribose) polymerase-1을자극하여 myocardial inflammation을유발시킨다 30. 고혈당외에도증가된유리지방산에의한 lipotoxicity도 20
당뇨성심근병증의한병인으로설명되고있다 30. 이렇듯고혈당, 고지혈증, 인슐린저항성이좌심실이완기장애에중요한데본연구결과에서는통계학적으로의미가없었다 (table 6). 좌심실이완기장애는나이가증가함에따라더발생하게되는데 Wilkenshoff 등 31 은 53세이상에서부터좌심실이완기장애가관찰됨을보고하였다. 본연구결과에서 49세이상에서그유병율이더높음을알수가있는데이를정상군과비교하지못한한계점을갖고있다. 또한당뇨이환기간이증가할수록좌심실이완기장애가생기는데, 6년이상인군에서좌심실이완기장애가 88.5% 에서관찰되었다. 6년미만과 6년이상인군간의좌심실이완기장애가통계학적으로유의하게달랐다 (p= 0.034). 이와같이무증상의제 2형당뇨병환자에서당뇨성심근, 즉좌심실이완기장애의유병율이높은데, 조기진단하는것이심부전증으로의진행을예방하는데있어서중요하다. 하지만, 모든환자들을선별검사하는데많은비용이들기때문에어려움이많다. 최근연구들에의하면미세알부민뇨의정도에따라이완기장애의정도가비례한다는 보고들이있었고 17, HOPE study 에의하면 32 미세알부민뇨가심부전증의 위험을증가시키는것과연관이있다한다. 본연구에서도미세알부민뇨의정도에따라이완기장애정도가비례하는결과가나왔다 (talbe 7). 따라서미세알부민뇨가있는제 2형당뇨병환자에서좌심실이완기장애를검사한다면조기진단이이루어질수있을것으로 21
생각된다. 좌심실이완기장애가진단되면심부전으로의진행을막기위한치료가시작되어야한다. 우선혈당조절, 특히인슐린저항성을낮추어주는약물이투여되어야하고, β-blockers와 thiazolidinediones(tzd), 즉심근에서유리지방산사용에서포도당으로사용을전환시키는약물이투여될수있다. 즉, 이미동물실험에서 TZD를투여하였을때심근유리지방산과그의독성대사산물의함유율이감소하고좌심실기능이호전됨을보고하였다 33. 초치료로서좌심실비대와심근섬유화를 감소시키고, 내피세포기능을 향상시키며, 인슐린저항성을떨어뜨리는 ACE inhibitor 가투여되어야만하지만, 당뇨가 state 1 heart failure 로 정의됨에따라, β-blockers 의병용사용이도움이될수있다. 3 세대 β- blocker 인 carvedilol 은 α1 blockade 의작용을통해 vasodilation, insulin resistance 를낮추어주어그효과를 증대시킬수있다고 알려지고있다 34.35,36. 그외에도심근에서의항섬유화효과를가지는 spironolactone, eplerenone 등을투여할수있지만, 이들의당뇨성심근에대한효과는입증된바없는실정이다 37. 따라서, 좌심실이완기장애는당뇨병성심근의조기징후로서나이, 당뇨병의이환기간미세알부민뇨와연관성이있으며선별검사로서심초음파는조기진단및치료를가능하게하고심부전으로의진행을예방하는데도움이될수있을것으로생각된다. 22
V. 결론 본연구에서는제2형당뇨병환자에서의관상동맥질환없이발생한좌심실이완기장애의유병율을관찰하였고좌심실이완기장애는나이, 당뇨병이환기간, 미세알부민뇨와연관성이있음을확인하였다. 심부전의조기징후로서좌심실이완기장애를조기진단하고조기치료하는것이당뇨환자에서당뇨성심근병증의진행을예방하는데도움이되며, 고령이거나이환기간이길거나미세알부민뇨가있는환자에서선별검사로서심초음파를시행하여볼수있겠다. 23
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Abstract Clinical parameters of left ventricular diastolic dysfunction in patients with type 2 diabetes mellitus Ji Young Jung Department of Medicine The Graduate School, Yonsei University (Directed by Professor Hyun Chul Lee) Diabetic cardiomyopathy has been accepted as an unique disease entity, resulting in left ventricular hypertrophy due to hyperglycemia and insulin resistance without coronary artery occlusive disease. Early clinial manifestation of Diabetic cardiomyopathy is left ventricular diastolic dysfunction that is characterized by impairment in early diastolic filling, prolongation of isovolumetric relaxation, and increased atrial filling. We intended to investigate factors associated with diastolic dysfunction 31
in Korean asymptomatic type 2 diabetic patients. We investigated diastolic dysfunction in type 2 diabetic patients without coronary artery occlusive disease, structural abnormalities, such as valvular heart disease, ventricular septal defect, atrial septal defect. We ruled out pseudonormalization via Valsalva maneuver. Diastolic dysfunction showed correlation with age, diabetic duration, hypertension and microalbuminuria, but did not with body mass index, waist-hip ratio, fasting glucose, fasting insulin, and cholesterol. Since diastolic dysfunction is on early manifestation of diabetic cardiomyopathy, early detection is important in preventing congestive heart failure. When microalbuminuria is detected, a screening test of diastolic dysfunction could be helpful for early dignosis of diabetic cardiomypopathy, and initiating early treatment. Key Words : type 2 diabetes mellitus, left ventricular diastolic dysfunction, diabetic cardiomyopathy, microalbuminuria 32