Original Articles Korean Circulation J 2001;3111:1171-1184 흰쥐에서심근경색후좌심실재형성에대한 Carvedilol 의영향 이종민 김철민 윤호중 오용석 유기동문건웅 정욱성 최규보 홍순조 The Effects of Carvedilol on Ventricular Remodeling after Myocardial Infarction in Rats Jong-Min Lee, MD, Chul-Min Kim, MD, Ho-Joong Youn, MD, Yong-Seok Oh, MD, Ki-Dong Yoo, MD, Keon-Woong Moon, MD, Wook-Sung Chung, MD, Kyu-Bo Choi, MD and Soon-Jo Hong, MD Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea ABSTRACT Background and ObjectivesVentricular remodeling after acute myocardial infarction can have a strong influence on the function of the ventricle and the prognosis of the patients. The aim of this study was to investigate the effect of carvedilol on the ventricular remodeling with respect to infarct size after myocardial infarction in rats. Materials and MethodsRats were randomly assigned to a carvedilol-treated n24, or untreated group n31 after left coronary artery ligation. Passive pressure-volume relationships of the left ventricle were determined to evaluate ventricular volume and the slopes of this relationship were analyzed to characterize ventricular chamber stiffness at about 6 weeks. ResultsIn the case of infarct size in the range 1034%, ventricular volume indeces indices of the carvedilol-treated rats n5 tended to be decreased to a greater extent than those of the untreated rats n5 as shown in the pressure-volume curve. In the case of infarct size in the range 3549%, there was no significant difference in ventricular volume indices between the carvedilol-treated n6 and the untreated n6 rats. In the case of infarct size greater than 50%, the pressure-volume curve stiffness constant k0 2.530 mmhg of the carvedilol-treated rats n3, 2.130.35 was significantly greater than that of the untreated rats n5, 1.550.16 and the ventricular volumes of left ventricular filling pressure 1030 mmhg were lower in the carvedilol-treated rats than in the untreated rats. ConclusionA leftward shift of the pressure-volume curves was noted in experimentally induced myocardial infarction-induced rats, that treated by carvedilol. Korean Circulation J 2001;3111:1171-1184 KEY WORDSStent Coronary artery disease Intravascular ultrasound. 1171
서론 1172 재료및방법 실험동물및실험군 약제용량의적절성 실험적심근경색의유발 Korean Circulation J 2001;3111:1171-1184
Fig. 1. Plot of competitive b-adrenergic receptor antagonism by carvedilol. Dose-response curve shows the effect of isoproterenol infusion on heart rate. indicates control n5, carvedilol 25 mg/dl group n4, carvedilol 12.5 mg/dl group n5, p0.05, p0.005, BPMbeats per minute. Fig. 2. Examples of M-mode echocardiogram obtained with two-dimensional guidance from a short-axis midventricular view of a sham-operated rat SHAM and a rat with 6-week-old infarction MI. Note increased left ventricular cavitary dimension, hypokinesia, thinning of anterior wall LVAW, and pericardial effusion PE in a rat with MI. Fig. 3. Examples of pulsed-wave Doppler spectra of mitral inflow from a sham-operated rat and a rat with myocardial infarction. Compared with the sham-operated rat SHAM, the mitral inflow pattern from the infarcted rat MI shows an increased peak early filling velocity E, rapid deceleration of the early filling wave, and decreased a wave A. 1173
심초음파 umen catheter(pe-50과 PE-200, 2.9/5.7 Fr, Ha- 심근경색 유발 수술후 6 7주까지 생존한 흰쥐에 대 rvard)를 대동맥을 통하여 좌심실 내로 진입시키고 심 해서 심초음파를 실시하였다. 럼푼(Xylazine, 바이엘코리 장의 방실구를 봉합사로 결찰하여 심실과 도관사이가 폐 아)을 체중 kg당 10 mg과 염산 케타민(Ketamine hy- 쇄된 공간이 되도록 하였다. 우심실 벽을 절개하여 우심 drochloride, 유한 양행) 체중 kg당 100 mg을 복강내 실내 혈액을 배출시켰다. 좌심실에 위치한 PE-200 도 주사하여 마취한 다음, 심초음파(Hewlett Packad, So- 관으로 수액 주입기(Harvard, compact infusion pu- nos 2500, USA) 7.5 MHz 탐촉자를 이용하여 경색부 mp, Model 975)를 사용하여 생리 식염수를 일정한 속 위 및 정상심근부위의 두께를 M-mode 심초음파(Fig. 도(0.59 ml/min)로 주입하였고 PE-50 도관은 변환 2)로 측정하고, 승모판 첨부(Fig. 3)에서 pulsed Do- 기를 통하여 polygraph(san-ei 366, NEC, Japan) ppler 신호를 얻어 이완기 기능을 평가하였고, 좌심실 면 에 연결하였다. 좌심실 내압이 0 30 mmhg 동안의 심 16) 적을 이면성 심초음파(Fig. 4)로 측정하였다. 실 압력-용적 곡선을 얻었다. 기록은 사후 경직이 오기 전인 심정지 이후 10분 이내에 각각 3회씩 시행하여 재 수동적 압력-용적 곡선의 측정 현성을 확인하였다. 심근경색 유발 수술후 6 7주에, 전술한 방법으로 마 압력-용적 곡선의 여러 부위를 분석하기 위해 경직도 취 후 설치류 호흡기로 호흡을 유지하였다. 우측 경정맥 상수를 측정하였다. 심실 내압이 0 3 mmhg까지는 압 을 박리하여 폴리에틸렌관(PE-50, 2.9 Fr, Harvard) 력-용적 곡선이 직선이었고 이때의 경사도가 경직도(k1) 을 삽입하여 정맥을 확보하였다. 수동적 압력-용적 곡 이다. 3 mmhg이상에서는 압력-용적 곡선을 지수 함 선을 얻기 위하여 흉골을 절단하여 상행대동맥을 노출시 수, 즉 p bekv에 맞추어 경직도 상수를 구하였다 k0 킨 후 KCl 1 ml를 우측 경정맥을 통하여 주입하여 심 (2.5 30 mmhg), k1(0 3 mmhg) k2(3 10 mmhg), 실이 이완기에 심정지가 일어나도록 하였다. Doublel- k3(10 20 mmhg), k4(20 30 mmhg).17) A B C D Fig. 4. Examples of two-dimensional echocardiograms from a sham-operated rat (A end systole, B end diastole) and a rat with a large infarction created 6 weeks previously (C end systole, D end diastole). Short-axis images were obtained at the level of the papillary muscles. Note the prominent increases in both left ventricular end-systolic and end-diastolic cavitary areas in the rat with the myocardial infarction. 1174 Korean Circulation J 2001; 31(11): 1171-1184
A B Fig. 5. Histological sections of hearts at apex. Panel A is a heart from sham-operated rat and panel B is a heart from infarcted rat. Note blue-colored thinning of infarcted wall and increased cavity size in infarcted rat (Masson s trichrome stain magnification, 10). 조직표본 제작 및 심근경색 크기의 측정 방법 용하였다. 같은 치료군 내에서의 비교는 ANOVA test와 수동적 압력-용적 곡선을 얻은 후 포르말린을 do- Kruskal Wallis test를 사용하였고 가상 대조군과 비교 ublelumen catheter를 통하여 좌심실 내로 일정 속도 는 t-test 및 Mann-Whitney test를 사용하였다. 같은 (0.59 ml/min)로 주입하고 좌심실 내압이 5 mmhg가 경색 크기 내에서 대조군과 치료군간의 비교는 t-test 및 될 때 three-way stop-cock을 닫아서 좌심실의 압 Mann-Whitney test로 비교하였다. 력을 일정하게 유지하며 심장을 흉곽에서 떼어내어 포 르말린 병에 넣어서 24시간 이상 고정하였다. 좌우심방 결 과 과 대혈관들을 제거하고 우심실을 제거한 후 좌우 심실 의 무게를 측정한 후 좌심실을 파라핀에 고정한다. 조직 총 171마리의 흰쥐에 대해 실험적 심근경색 유발수 은 심장을 방실구에 평행하게 1 mm 두께로 잘라서 Ma- 술을 시행하였고, 유발수술후 하루이상 생존한 쥐는 91 sson씨 trichrome 염색 후에 경색크기를 측정하였다 마리로 사망율은 46.7%이였다. 이중 대조군과 치료군에 (Fig. 5). 심근경색 크기는 조직 슬라이드를 일정 배율 서 6 7주간에 각각 11마리, 19마리가 사망하여 각 군 로 확대하여 면적계를 이용하여 전체 심외막과 심내막 에서 사망율은 21.7%와 41.3%였다. 경색 유발수술후 의 길이와 심근경색이 차지하는 심외막, 심내막의 길이 41일에서 51일에 심초음파와 수동적 압력-용적 곡선 를 측정하여 비율을 평균하였다.18) 경색크기에 따른 심 을 얻었다. 흰쥐의 일일 물 및 약제물의 소비량은 대조 실재형성의 정도를 비교하려고 임의로 경색크기 10 군 약 26 ml, 치료군 27 ml로 차이가 없었다. 34%, 35 49%, 50% 이상으로 구분하였다. 경색이 유 발되지 않았거나 10% 미만의 경색은 가상대조군 또는 검시 결과 및 심근의 질량 비교(Table 1) 가상치료군으로 하였다. 흰쥐의 실험적 심근경색에서 경 가상대조군 10마리, 대조군 21마리, 가상치료군 8마 색크기 20% 미만인 경우의 혈역학적 소견의 변화는 유 리, 치료군 16마리였다. 경색크기 10 34%는 대조군 7 의하지 않으므로 10% 미만은 가상군으로 하였다.3)17) 마리, 치료군 6마리, 경색크기 35 49%는 대조군 9마 리, 치료군 7마리, 그리고 경색크기 50% 이상은 대조군 통 계 모든 실험 결과는 평균표준 편차로 표시하였고, 통계 프로그램은 SPSS for MS Windows Release 7.5를 사 5마리, 치료군 3마리였다. 경색 크기에 따른 경골 길이, 신장의 질량은 차이가 없었지만, 경색크기가 50%이상 인 경우 대조군에 비해 치료군의 체중이 작았다. 1175
M-mode 심초음파상심실벽의두께및내경의변화 Table 1. Autopsy databody weights, left ventricular and right ventricular weights in untreated and carvediloltreated rats Sample size No. Sham Small 1034% Infarct Moderate 3549% Large 50% Untreated 31 10 7 9 5 Carvedilol 24 8 6 7 3 Body weight g Untreated 2431.8 2318.8 2421.3 2500.1 Carvedilol 2492.2 2491.8 2412.1 2211.4 NS Tibial length mm Untreated 40.32.0 40.73.1 39.03.0 42.04.9 Carvedilol 37.92.1 39.61.2 40.33.4 37.32.6 NS Kidney weight g Untreated 1.950.2 1.780.3 1.910.3 1.850.2 Carvedilol 2.110.2 2.180.3 2.090.4 1.920.2 NS Infarct size % Untreated 2.4 3.2 27.64.3 42.63.2 55.95.3 Carvedilol 1.0 2.2 22.58.2 39.25.4 52.91.8 0.001 LV mass mg Untreated 64860 640 83 66888 70083 NS Carvedilol 56643 683153 69070 55395 0.05 LV index mg/g Untreated 2.670.2 2.780.5 2.760.3 2.810.4 NS Carvedilol 2.280.3 2.740.5 2.880.3 2.5 0.5 0.05 RV mass mg Untreated 14836 15249 16933 24595 0.05 Carvedilol 13222 12923 17393 21585 NS RV index mg/g Untreated 0.610.1 0.660.2 0.690.4 0.980.4 0.05 Carvedilol 0.530.1 0.520.1 0.710.3 0.970.4 p value by ANOVAuntreated or carvedilol-treated group. p0.05, Carvedilol-treated compared to untreated rats with infarcts of comparable size. All results are meansd. LVleft ventricular, RVright ventricular, ShamShamoperated rat, NSnot significant, ANOVAanalysis of variances p* 1176 Korean Circulation J 2001;3111:1171-1184
Table 2. Left ventricular size and function 6 weeks after ligation of the left coronary artery in rats by M-mode echocardiography AW thickness, diastole mm Sham Small 1034% Infarct Moderate 3549% Large 50% Untreated 1.9 0.4 1.80.3 1.90.2 2.10.1 Carvedilol 2.1 0.4 2.21.7 2.00.3 2.10.1 NS AW thickness, systole mm Untreated 2.9 0.6 2.30.5 2.30.4 2.90.5 0.05 Carvedilol 3.0 0.6 2.90.4 2.50.5 2.50.3 NS LV dimension, diastole mm Untreated 6.9 0.9 7.40.9 7.70.6 8.80.2 Carvedilol 6.5 0.7 7.30.8 8.21.2 7.80.9 0.05 LV dimension, diatole/body weight mm/kg Untreated 3.5 0.4 4.20.8 4.10.7 4.60.6 Carvedilol 3.1 0.4 3.40.3 4.00.9 4.10.8 0.05 LV dimension, systole mm Untreated 4.1 1.1 5.21.2 5.60.6 6.20.3 Carvedilol 3.6 1.1 4.60.8 5.91.0 5.50.6 0.005 LV dimension, systole/body weight mm/kg Untreated 2.0 0.4 2.90.7 3.00.5 3.30.4 Carvedilol 1.7 0.5 2.10.4 3.00.8 2.90.5 0.05 FS % Untreated 41.610.4 31.39.2 27.86.2 29.64.3 Carvedilol 45.911.3 37.25.3 26.96.2 29.16.4 0.05 PW thickness, diastole mm Untreated 1.9 0.4 1.50.2 1.50.2 1.40.1 Carvedilol 1.6 0.3 1.70.3 1.80.3 1.70.1 NS PW thickness, systole mm Untreated 2.7 0.3 2.20.3 2.60.2 2.20.3 0.05 Carvedilol 2.6 0.4 2.50.3 2.40.1 2.40.6 NS p value by ANOVAbetween untreated or carvedilol-treated group. p0.05, Carvedilol-treated compared to untreated rats with infarcts of comparable size. All results are meansd. AWanterior wall, PWposterior wall, LVleft ventricular, FSfractional shortening, NSnot significant, ANOVAanalysis of variances p* 이면성심초음파상심내막및심외막면적의변화 1177
Table 3. Area change of left ventricle at mid-papillary muscle level by 2 dimensional echocardiography Epicardial area, diastole cm 2 Sham Small 1034% Infarct Moderate 3549% Large 50% Untreated 0.850.3 0.930.1 0.950.1 1.120.1 NS Carvedilol 0.810.2 0.900.2 1.120.1 1.070.1 0.05 Endocardial area, diastole cm 2 Untreated 0.400.2 0.490.1 0.510.1 0.650.1 0.05 Carvedilol 0.340.1 0.470.2 0.620.1 0.610.1 0.005 Endocardial area, systole cm 2 Untreated 0.240.2 0.290.1 0.320.1 0.450.1 0.05 Carvedilol 0.150.1 0.270.1 0.390.1 0.410.1 0.005 FA % Untreated 42.71.2 38.311.2 34.112.7 29.94.4 NS Carvedilol 56.49.8 43.913.4 36.37.2 32.77.8 0.005 p value by ANOVAbetween untreated or carvedilol-treated group. p0.05, Carvedilol-treated compared to untreated rats with infarcts of comparable size. All results are meansd. FAfractional area change and was defined as endocardial area, diastoleendocardial area, systoleendocardial area, diastole 100, NSnot significant, ANOVAanalysis of variances p* Table 4. Diastolic functionpulsed-wave Doppler measurements of mitral inflow E wave velocity cm/s Sham Small 1034% Infarct Moderate 3549% Large 50% Untreated 61.511.9 61.120.4 60.615.6 73.99.5 Carvedilol 54.113.7 52.25.9 62.95.9 67.78.0 NS A wave velocity cm/s Untreated 27.27.7 28.14.1 18.410.1 12.10.1 NS Carvedilol 35.39.5 32.64.7 24.411.1 14.411.8 0.05 E/A ratio Untreated 2.40.7 1.90.4 3.51.3 5.50.1 Carvedilol 1.60.6 1.60.2 3.32.4 4.12.2 0.05 DT msec Untreated 53.311.6 51.916.5 53.910.2 42.77.9 Carvedilol 57.510.0 64.313.3 50.613.7 46.76.1 NS p value by ANOVAbetween untreated or carvedilol-treated group. p0.05, Carvedilol-treated compared to untreated rats with infarcts of comparable size. All results are meansd. Eearly filling, Aatrial filling, DTdeceleration time, NSnot significant, ANOVAanalysis of variances p* 좌심실이완기능의변화 수동적압력-용적곡선의경직도상수 1178 Korean Circulation J 2001;3111:1171-1184
Table 5. Area change of left ventricle at mid-papillary muscle level by 2 dimensional echocardiography Sham Small 1034% Infarct Moderate 3549% Large 50% K0 2.530 mmhg Untreated 2.250.61 2.221.03 2.220.74 1.550.16 n6 n5 n6 n5 NS Carvedilol 3.200.44 2.640.76 2.190.71 2.130.35 n7 n5 n6 n3 0.05 K1 03 mmhg Untreated 7.662.90 8.744.15 4.563.18 2.450.739 0.05 Carvedilol 11.895.27 7.574.75 8.636.01 5.572.54 NS K2 310 mmhg Untreated 3.580.92 2.711.50 2.591.09 1.540.24 0.05 Carvedilol 4.680.96 3.521.24 2.811.09 2.390.71 0.05 K3 1020 mmhg Untreated 2.330.57 2.070.87 2.330.57 1.580.10 NS Carvedilol 2.830.39 2.400.61 1.990.57 2.100.29 0.005 K4 2030 mmhg Untreated 1.670.45 1.760.57 1.670.45 1.390.14 NS Carvedilol 2.130.25 1.740.56 1.610.53 1.750.19 NS p value by ANOVAbetween untreated or carvedilol-treated group. p0.05, Carvedilol-treated compared to untreated rats with infarcts of comparable size. Kventricular chamber stiffness, NSnot significant, ANOVAanalysis of variances p* Fig. 6. The pressure-volume per kg curve of untreated panel A and carvedilol-treated rats panel B. p0.05, p0.005, infarcted rats vs sham-operated rats. Ain the case of infarct size 3549% and above 50%, ventricular volume indeces of untreated rats were increased compared to untreated sham-operated rats. Bin the case of infarcted size 3549% and above 50%, ventricular volume indeces of carvedilol-treated, sham-operated rats. MI myocardial infarction. 1179
Fig. 7. The pressure-volume per kg relation of untreated and carvedilol-treated rats with small panel A, moderate panel B, large panel C infarcts. p0.05, CVDLtreated rats vs untreated rats between large MI group. Ain the case of infarct size 1034%, ventricular volume indeces of carvedilol-treated rats tended to decrease compared to untreated rats and pressure-volume curve tended to shift in parallel to the left. Bin the case of infarcted size 3549%, ventricular volume indeces were no different between carvedilol-treated and untreated rats. Cin the case of infarct size above 50%, pressurevolume curve of carvedilol-treated rats significantly shifted in parallel to the left compared to untreated rats. MImyocardial infarction, CVDLcarvedilol. 이완기말용적지수및압력-용적곡선 1180 Korean Circulation J 2001;3111:1171-1184
고찰 약제용량 심실질량 1181
심초음파 1182 압력-용적곡선 Korean Circulation J 2001;3111:1171-1184
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