2 2
2000000666년년년 222월월월 박
박
박사사사학학학위위위논논논문문문
N N N- - -t t te e er r rm m mi i in n na a al l lp p pr r ro o oB B B- - -t t ty y yp p pe e eN N Na a at t tr r ri i iu u ur r re e et t ti i ic c cP P Pe e ep p pt t ti i id d de e e (
( (N N NT T T- - -p p pr r ro o oB B BN N NP P P) ) )a a an n nd d dt t th h he e ee e ev v va a al l lu u ua a at t ti i io o on n no o of f f C
C
Ca a ar r rd d di i ia a ac c cD D Dy y ys s sf f fu u un n nc c ct t ti i io o on n na a an n nd d dS S Se e ev v ve e er r ri i it t ty y yo o of f f D
D
Di i is s se e ea a as s se e ei i in n nC C Ci i ir r rr r rh h ho o ot t ti i ic c cP P Pa a at t ti i ie e en n nt t ts s s
조 조
조 선 선 선 대 대 대 학 학 학 교 교 교 대 대 대 학 학 학 원 원 원
의
의 의 학 학 학 과 과 과
우
우 우 정 정 정 주 주 주
N N N- - -t t te e er r rm m mi i in n na a al l lp p pr r ro o oB B B- - -t t ty y yp p pe e eN N Na a at t tr r ri i iu u ur r re e et t ti i ic c cP P Pe e ep p pt t ti i id d de e e (
( (N N NT T T- - -p p pr r ro o oB B BN N NP P P) ) )a a an n nd d dt t th h he e ee e ev v va a al l lu u ua a at t ti i io o on n no o of f f C
C
Ca a ar r rd d di i ia a ac c cD D Dy y ys s sf f fu u un n nc c ct t ti i io o on n na a an n nd d dS S Se e ev v ve e er r ri i it t ty y yo o of f f D
D
Di i is s se e ea a as s se e ei i in n nC C Ci i ir r rr r rh h ho o ot t ti i ic c cP P Pa a at t ti i ie e en n nt t ts s s
N N
N- - -T T Te e er r rm m mi i in n na a al l lp p pr r ro o oB B B- - -t t ty y yp p pe e eN N Na a at t tr r ri i iu u ur r re e et t ti i ic c c P P Pe e ep p pt t ti i id d de e e( ( (N N NT T T- - -p p pr r ro o oB B BN N NP P P) ) )를 를 를 이 이 이용 용 용한 한 한 간 간 간경 경 경화 화 화증 증 증
환 환
환자 자 자의 의 의 중 중 중증 증 증도 도 도와 와 와 심 심 심장 장 장 이 이 이상 상 상의 의 의 평 평 평가 가 가
2 2
20 0 00 0 06 6 6년 년 년 2 2 2월 월 월
조 조
조 선 선 선 대 대 대 학 학 학 교 교 교 대 대 대 학 학 학 원 원 원
의
의 의 학 학 학 과 과 과
우
우 우 정 정 정 주 주 주
N N N- - -t t te e er r rm m mi i in n na a al l lp p pr r ro o oB B B- - -t t ty y yp p pe e eN N Na a at t tr r ri i iu u ur r re e et t ti i ic c cP P Pe e ep p pt t ti i id d de e e (
( (N N NT T T- - -p p pr r ro o oB B BN N NP P P) ) )a a an n nd d dt t th h he e ee e ev v va a al l lu u ua a at t ti i io o on n no o of f f C
C
Ca a ar r rd d di i ia a ac c cD D Dy y ys s sf f fu u un n nc c ct t ti i io o on n na a an n nd d dS S Se e ev v ve e er r ri i it t ty y yo o of f f D
D
Di i is s se e ea a as s se e ei i in n nC C Ci i ir r rr r rh h ho o ot t ti i ic c cP P Pa a at t ti i ie e en n nt t ts s s
지 지
지도도도교교교수수수 홍홍홍 순순순 표표표
이 이
이 논논논문문문을을을 의의의학학학박박박사사사 학학학위위위신신신청청청 논논논문문문으으으로로로 제제제출출출함함함...
2 2 20 0 00 0 05 5 5년 년 년 1 1 10 0 0월 월 월 일 일 일
조 조
조 선 선 선 대 대 대 학 학 학 교 교 교 대 대 대 학 학 학 원 원 원
의
의 의 학 학 학 과 과 과
우
우 우 정 정 정 주 주 주
우 우 우정 정 정주 주 주의 의 의 박 박 박사 사 사학 학 학위 위 위 논 논 논문 문 문을 을 을 인 인 인준 준 준함 함 함
위위위원원원장장장 조조조선선선대대대학학학교교교 교교교수수수 정정정 춘춘춘 해해해 인인인 위
위위 원원원 조조조선선선대대대학학학교교교 교교교수수수 홍홍홍 순순순 표표표 인인인 위
위위 원원원 조조조선선선대대대학학학교교교 교교교수수수 장장장 경경경 식식식 인인인 위
위위 원원원 전전전남남남대대대학학학교교교 교교교수수수 조조조 정정정 관관관 인인인 위
위위 원원원 조조조선선선대대대학학학교교교 교교교수수수 고고고 영영영 엽엽엽 인인인
2 2
20 0 00 0 05 5 5년 년 년 1 1 12 2 2월 월 월 일 일 일
조 조 조 선 선 선 대 대 대 학 학 학 교 교 교 대 대 대 학 학 학 원 원 원
C C CO O ON N NT T TE E EN N NT T TS S S
K K
KooorrreeeaaannnAAAbbbssstttrrraaacccttt 444
ⅠⅠⅠ...IIINNNTTTRRROOODDDUUUCCCTTTIIIOOONNN 777
ⅡⅡⅡ...MMMAAATTTEEERRRIIIAAALLLSSS AAANNNDDD MMMEEETTTEEERRRIIIAAALLLSSS 999
ⅢⅢⅢ...RRREEESSSUUULLLTTTSSS 111222
ⅣⅣⅣ...DDDIIISSSCCCUUUSSSSSSIIIOOONNNSSS 111444
ⅤⅤⅤ...SSSUUUMMMMMMAAARRRYYY 222111 R
R
REEEFFFEEERRREEENNNCCCEEESSS 222999
C C CO O ON N NT T TE E EN N NT T TS S S O O OF F F T T TA A AB B BL L LE E ES S S
TTTaaabbbllleee111... 222333 TTTaaabbbllleee222. 222444 TTTaaabbbllleee333... 222555
C C CO O ON N NT T TE E EN N NT T TS S S O O OF F F F F FI I IG G GU U UR R RE E ES S S
FFFiiiggguuurrreee111... 222666 FFFiiiggguuurrreee222... 222777 FFFiiiggguuurrreee333... 222888
< < <국 국 국문 문 문 초 초 초록 록 록> > >
NNN---TTTeeerrrmmmiiinnnaaalllppprrroooBBB---tttyyypppeeeNNNaaatttrrriiiuuurrreeetttiiiccc P
PPeeeppptttiiidddeee(((NNNTTT---ppprrroooBBBNNNPPP)))를를를 이이이용용용한한한 간간간경경경화화화증증증 환환환자자자의의의 중중중증증증도도도와와와 심심심장장장 이이이상상상의의의 평평평가가가
우
우 우 정 정 정 주 주 주 지
지 지도 도 도교 교 교수 수 수 : : :홍 홍 홍 순 순 순 표 표 표
조 조 조선 선 선대 대 대학 학 학교 교 교 대 대 대학 학 학원 원 원 의 의 의학 학 학과 과 과
배경 및 목적 :간경화증 환자에서는 과역동적인 체순환과 심장 이상이 관찰 되는 경우가 흔하다.증가된 심장부하에 반응하여 심실로부터 분비되는 심장 신경호르몬인 BNP (brain natriuretic peptide)와 아미노기 말단 proBNP (NT-proBNP)는 조기 심실 이상을 나타내는 지표이다.따라서 본 연구는 간 경화증 환자에서 NT-proBNP의 혈중 농도,간경화증의 중증도,그리고 심장 이상과의 사이에 어떤 연관 관계가 있는 지 알아보고자 시행되었다.
대상 및 방법 :63명의 간경화증 환자와 (남/녀=40/23,평균연령 55.8세)15명 의 비슷한 연령대의 건강한 대조군을 (남/녀=9/6,평균연령 52.9세)대상으로 하였다. Child-Turcotte-Pugh 분류법에 따라 class A (n=16), class B (n=29),classC (n=18)로 분류되거나,복수를 동반한 3군 (group3,n=35)과 동반하지 않은 2군 (group 2,n=28)으로 각각 분류된 간경화증 환자와 1군 (group 1)으로 분류된 건강대조군에서 심초음파를 시행하고 NT-proBNP의 혈중 농도를 측정하였다.
결과 :NT-proBNP의 혈중 농도는,간경화증 환자인 2군 (155.88 ± 69.75
pg/ml)과 3군 (198.26± 146.69pg/ml)에서 각각 건강대조군 (40.27± 13.58 pg/ml)에 비해 유의하게 증가되어 있었으나 (p< 0.05),복수를 동반하지 않 은 2군과 동반한 3군간에 NT-proBNP의 혈중 농도는 통계적으로 유의한 차 이가 없었다.또한 NT-proBNP의 혈중 농도가 Child 분류 C군 (250.00 ± 176.60 pg/ml)에서 건강대조군은 물론이고,Child 분류 B군 (168.63± 71.34 pg/ml)이나 A군 (119.60± 67.29pg/ml)과 비교하여 각각 유의하게 증가되어 있었으나 (P < 0.05),Child 분류 B군과 A군의 NT-proBNP의 혈중 농도는 통계적으로 유의한 차이가 없었다.심초음파검사상,간경화증 환자 (2군;
39.71±4.75mm,3군;40.51±4.60mm)에서 건강대조군 (35.07±7.39mm) 에 비해 유의하게 좌심방직경이 증가되어 있었다.또한 간경화증 환자에서 심실중격의 두께 (IVSd,2군;10.07± 2.02mm,3군;10.14± 1.70mm)와 좌 심실 후벽의 두께 (LVPWd,2군;9.21± 1.77mm,3군;9.63± 1.22mm)가 건강대조군 (IVSd;8.67± 1.54mm,LVPWd;8.20± 1.66mm)에 비해 각각 유의하게 증가된 소견을 보였다 (P < 0.05).좌심실 구혈률(EF)도 간경화증 환자 (2군;70.50± 7.81% ,3군;71.17± 7.02%)에서 건강대조군 (59.33±
6.17%)에 비해 각각 유의하게 증가된 소견을 보였다 (P < 0.05).한편 도플 러 심초음파검사상,간경화증 환자에서 이완기초 경승모판 혈류 속도와 승모 판륜 속도의 비 (E/E',2군;10.51± 1.93,3군;11.78± 2.25)와 E파의 감속시 간 (EDT,2군;254.29± 60.75msec,3군;271.13± 53.74msec)이 건강대조 군 (E/E;8.81± 1.08,EDT;206.00± 35.32msec)에 비해 각각 유의하게 증 가되어 있는 소견이었다 (P < 0.05).좌심실질량지수는 복수를 동반하지 않은 2군 (110.18±23.06g/㎡)이나 건강대조군 (102.80±23.54g/㎡)에 비해 복수 를 동반한 3군 (123.54± 22.50g/㎡)에서 증가되고,경승모판 혈류 속도의 E 파와 A파의 비 (E/A ratio)는 2군 (1.01 ± 0.37)이나 건강대조군 (1.15 ± 0.37)에 비해 3군 (0.90± 0.32)에서 감소되는 양상이었다 (P < 0.05).간경화 증 환자에서 NT-proBNP의 혈중 농도와 심초음파검사 측정상 좌심실이완기 말직경 (r=0.277,P =0.028)과 E/E'(r=0.450,P =0.01)이 유의한 상관관
계를 보였다.
결론 :간경화증 환자에서 NT-proBNP의 혈중 농도는 상승되어 있었으며,이 것은 간경화증의 중증도가 증가함에 따라 보다 더 밀접한 연관이 있었다.결 론적으로 진행된 간경화증에서 심장의 구조적,기능적 이상이 더욱 진행된 상태였으며,따라서 NT-proBNP의 혈중 농도는 간경화증의 진행과 이와 동 반된 심장 이상을 평가하는데 유용한 예측 인자로 생각된다.
Ⅰ
ⅠⅠ...IIINNNTTTRRROOODDDUUUCCCTTTIIIOOONNN
Relationsbetweencardiovascularpathophysiologyandthecomplicationsof liver disease have been increasingly recognized for half a century (Kowalskietal.,1953;Abelmannetal.,1955).Thesystemiccirculationin patients with cirrhosis is hyperdynamic and is characterized by an increased heartrate and cardiac outputand reduced systemic vascular resistancewith normalordecreased arterialblood pressure(Kowalskiet al.,1953;Abelmann etal.,1955;Schrieretal.,1988; Llach etal.,1988;
Mølleretal.,1995;Mølleretal.,1997;Naschitzetal.,2000).Additionally, cirrhosis is associated with othercardiovascular abnormalities,including portalhypertension,hepatopulmonary syndrome and changes in several different vascular territories, such as, in the renal and cerebral vasculatures (Baik etal.,2004).In cirrhotic patients,cardiac outputis increasedatrest,andithasbeenassumedthatsystolicfunctionisnormal oreven supranormal(Hu etal.,2004;Baik etal.,2004).However,many cirrhotic patients present with dyspnea,fluid retention,and a limited exercise capacity (Mølleretal.,1997;Epstein etal.,1998;Fallon etal., 2000). The new clinical entity of impaired cardiac contractility and performanceincirrhoticpatients,cirrhoticcardiomyopathy,wasintroduced in the middle 1990s. This term implies a condition with defective myocardial contractility, under physical and pharmacological strain, although this disease entity has notyetbeen finally classified and the mechanismsbehindthecardiacabnormalitiesarenotfullyunderstood(Ma etal.,1996;Mølleretal.,2002;Baiketal.,2004).Severalpreviousstudies have shown increased plasma concentrations ofbrain natriuretic peptide (BNP) and N-terminalpro B-type natriuretic peptide (NT-proBNP) in
some patients with cirrhosis,and these findings may suggest cardiac dysfunction (La Villa etal,1992;Bendtsen etal.,1993;La Villa etal., 1995;Bernardietal.,1998;Iwauetal.,2000;Wong etal.,2001;Mølleret al.,2002;Henriksenetal.,2003;Baiketal.,2004).BNP isaneurohormone synthesized in cardiacventricles,and isreleased aspreproBNP and then enzymatically cleaved to NT-proBNP and BNP upon ventricularmyocyte stretching.Moreover,blood measurementsofBNP and NT-proBNP have beenusedtoidentifypatientswithcongestiveheartfailure(McCulloughet al.,2003).BNP measurements are the diagnostic testofchoice because NT-proBNP is influenced by age and renal function. Nevertheless, NT-proBNP wassuggestedrecentlytobeaevenbetterindicatorofearly cardiacdysfunctionduetoitsstabilityandlongerbiologicalhalflife(Hunt etal.,1997;Hughesetal.,1997;Campelletal.,2000;Goetzeetal2001;
McCullough etal.,2003).However,untilnow few study have assessed levelsofcirculating NT-proBNP in patientswith cirrhosis.Therefore,the presentstudy wasundertaken to search forrelationsbetween circulating levels of NT-proBNP and the severities of liver disease and cardiac dysfunction,andfurther,toinvestigatecardiacstructuresandfunctionsby echocardiography,and assesstheircorrelationswith diseaseseverity and cardiacdysfunctionincirrhoticpatients.
ⅡⅡⅡ...MMMAAATTTEEERRRIIIAAALLLSSS AAANNNDDD MMMEEETTTHHHOOODDDSSS
Sixty-three cirrhotic patients were included in the presentstudy.They consistedof40menand23women,withameanageof55.8± 10.1years (range 40-71 years). Diagnoses were based on established clinical, biochemical,and ultrasonography criteria.The cause of cirrhosis was post-hepatic cirrhosis due to hepatitis B virus infection in 32 patients, hepatitis C virus infection in six patients, alcoholic in 19 patients, autoimmunein2patients,andcryptogenicin4patients.According tothe Child-Turcotte-Pughclassification16patientswereinclassA,29inclass B and 18 in class C.The controlgroup (group 1) comprised fifteen healthyadultswithameanageof52.9± 10.5years(range41-67years).
Wedividedthecirrhoticpatientsintoacompensatedgroupwithoutascites (group2,n=28)andadecompensatedgroupwith ascites(group3,n=35).
Thepatientsin group 3 had received diuretictherapy along with a less strictdietary saltrestriction (440 mmolsodium perday),butadditional cardiovascularmedication,including betablockers,wasnotprescribed for any ofthese patients.Seventeen patients had a hepatic encephalopathy history.Exclusion criteria for study subjects were presence ofcardiac, pulmonary,and renal diseases,hypertension,and other major organic diseases.Allpatients and controls received a normalcardiac physical examination,chest X-ray,and electrocardiography (ECG).The baseline clinicaland biochemicalcharacteristics ofthe patients and controls are summarizedinTable1.
Blood was drawn from a forearm vein after at least ten minutes of resting supine, and was collected in standard sampling tubes for NT-proBNP analysis, and in appropriate tubes for other laboratory determinations. A complete blood count, prothrombin time (PT; as reflected by the internationalnormalized ratio (INR)),liver and renal function tests were performed using standard laboratory automated techniques. Serum NT-proBNP levels were determined using a commercially available immunoassay based on the sandwich technique (Elecsys proBNP, Roche Diagnostics); its lower and upper limits of detection were 5pg or 35,000pg/ml,respectively.This is a rapid assay withatesttimeofapproximately18minforasinglesample;testresults are calculated automatically.Allpatients and controls were studied by M-mode, two-dimensional, and Doppler echocardiography via a transthoracicapproach.Cardiacdimensionsandleftventricularhypertrophy were evaluated by measuring echocardiographic parameters including interventricular septum thickness in diastole (IVSd), left ventricular posteriorwallthicknessindiastole(LVPWd),leftventricularend-diastolic diameter (LVEDD),leftventricular end-systolic diameter (LVESD),left ventricularmass index (LVMI),and leftatrialdiameter(LAD).Systolic pumpfunctionoftheleftventricle(LV)wasevaluatedbyejectionfraction (EF).Diastolic function ofthe leftventricle was evaluated by the peak filling velocity ofE (E)andA waves(A)ofDopplermitralvalveinflow velocities,E/A ratio,E wavedecelerationtime(EDT),mitralvalveannular
velocities(E')by Dopplertissueimaging,and E'/E.In addition,LV-Tei index was used as a parameter of combined systolic and diastolic myocardialperformanceoftheLV.
All statistical evaluations were performed using the SPSS statistical package (Version 11,SPSS,Chicago,Illinois).Results are expressed as means ± SD forraw values.One way analysis ofvariance (ANOVA) with Tukey's B posthoc pairwise multiple comparison procedure was used forassessmentofthe between group (1,2,and 3)differences in baselinecharacteristics,echocardiographicparameter,andcirculating levels of NT-proBNP. Correlations were performed by Pearson regression analysis,andP valuesof< 0.05wereconsideredstatisticallysignificant.
Ⅲ
ⅢⅢ...RRREEESSSUUULLLTTTSSS
Echocardiographicparametersaccording to thedecompensation component ofcirrhosisaregiveninTable2.Leftatriaweresignificantlyenlargedin cirrhotic patients (groups 2,3)than in the group (group 1)ofnormal controls(39.71± 4.75mm ingroup2and40.51± 4.60mm ingroup3vs.
35.07 ± 7.39 mm in group 1)and wallthickness ofleftventricles were increasedincirrhoticpatientsthanincontrols(10.07± 2.02mm or9.21±
1.77mm ingroup2and10.14± 1.70mm or9.63± 1.22mm ingroup3 vs.8.67± 1.54mm or8.20± 1.66mm in group 1,IVSd orLVPWd in each group,P < 0.05).EF orE/E'were also increased and EDT was prolonged in patients with cirrhosis versus controls (70.50 ± 7.81 % or 10.51 ± 1.93 or254.29 ± 60.75 msecin group 2 and 71.17 ± 7.02 % or 11.78± 2.25or271.13± 53.74msecingroup3vs.59.33± 6.17% or8.81
± 1.08or206.00± 35.32msecingroup1,respectively,P < 0.05).Onthe other hand, no statistically significant differences were observed for LVEDD and LV-Teiindex between groups1,2 and 3.Increased LVMI and a decreased E/A ratio were noted in the group ofpatients with ascitesascomparedwiththeothergroups(123.54± 22.50g/㎡ or0.90±
0.32 in group 3 vs.110.18 ± 23.06 g/㎡ or1.01 ± 0.37 in group 2 and 102.80 ± 23.54 g/㎡ or1.15 ± 0.37 in group 1,respectively,P < 0.05).
Circulating levels of NT-proBNP were significantly higher in cirrhotic patients than in normalcontrols (155.88 ± 69.75 pg/mlin group 2 and 198.26 ± 146.69 pg/mlin group 3 vs.40.27 ± 13.58 pg/mlin group 1, respectively, P < 0.05), but no significant mean NT-proBNP level difference was observed between groups 2 and 3 (P > 0.05;Figure 1).
When patients were grouped according to the Child-Turcotte-Pugh
classification,circulatinglevelsofNT-proBNP weresignificantlyhigherin Child classC than in classesB and A,and in controls(250.00± 176.60 pg/mlinChildclassC vs.168.63±71.34pg/mlinChildclassB,119.60±
67.29 pg/ml in Child class A,and 40.27 ± 13.58 pg/ml in controls, respectively,P < 0.05),and no significantNT-proBNP leveldifference was observed between Child classes B and A (P > 0.05). When circulating NT-proBNP concentrationsincirrhoticpatientswerecorrelated with echocardiographic parameters,significantpositive correlations were foundwithLVEDD (r= 0.277,P =0.028)andE/E'(r= 0.450,P =0.01) (Table 3, Figure3). However, no significant correlations were found between NT-proBNP levels and EF,LAD,IVSd,LVPWd,LVMI,E/A ratio, EDT, or LV-Tei index (P > 0.05), In addition, circulating NT-proBNP concentrations were notfound to be related to biochemical parameters such as hemoglobin,albumin,INR ofPT,orbilirubin (P >
0.05;Table3).
ⅣⅣⅣ...DDDIIISSSCCCUUUSSSSSSIIIOOONNN
Cardiacdysfunctionincirrhosisliesattheintersectionbetweentwofields ofstudyandisoftenignoredbyhepatologistsandcardiologists.However, cirrhosisisassociatedwith many cardiovascularchangesorabnormalities including hyperdynamic circulation,portalhypertension,hepatopulmonary syndrome,and hepatorenalsyndrome.Themain changeofcardiovascular function in cirrhotic patients, i.e., a hyperdynamic circulation, as manifested by an increased cardiac output and a decreased arterial pressure,has been recognized for a long time (Kowalskietal.,1953;
Abelmann etal.,1955;Schrieretal.,1988; Llach etal.,1988;Mølleret al.,1995;Møller et al.,1997;Naschitz et al.,2000).Increased cardiac outputin cirrhotic patients is associated with severalfactors including increased sympathetic nervous activity,increased blood volume,and the presence of arteriovenous communications (Levy et al., 1988;
Fernandez-Rodriguezetal.,1993;Henriksenetal.,1998).Moreover,dueto thepresenceofincreased cardiacoutputatrest,ittendsto beassumed thatcardiaccontractilefunctionisnormalorevensupranormalincirrhotic patients(Baiketal.,2004).However,manypatientspresentwithdyspnea, fluid retention,and limited exercise capacity thatis suggestive ofearly cardiacdysfunction orovertheartfailure(Mølleretal.,1997;Epstein et al., 1998; Fallon et al., 2000). Thus, there is a need to consider cardiovascular function changes in cirrhotic patients from a different standpoint.From afunctionalpointofview,theheartincirrhosisisboth hyperdynamic and dysfunctional. Experimental and clinical studies of cirrhoticpatientsstronglysuggestthepresenceoflatentheartfailurewith impairedreactionstostandardizedprovocations(Mølleretal.,2002).Inthe
1970s,latentor mild alcoholic cardiomyopathy was presented by some studiesofcardiacfunctioninpatientswithalcoholiccirrhosis,asshowing depressed ventricularresponsivenesstostimulisuch asdrugsorexercise (Gouldetal.,1969;Limasetal.,1974).Forinstance,Gouldandco-workers (Gould etal.,1969)showed thatexercise induced a doubling ofthe left ventricularend-diastolic pressure associated with an insignificantchange incardiacoutputinalcoholicpatientswithchronicliverdisease,indicating amarkedly bluntedcardiacresponse.Overtheintervening period,blunted and depressed ventricular contractile responses to stimuli have been reported in animalmodels and in patients with nonalcoholic cirrhosis (Ahmedetal.,1984;Friedman etal.,1992; Wong etal.,1994;Mølleret al.,1995;Maetal.,1996;Epsteinetal.,1998;Wongetal.,1999;Fallonet al.,2000;Perello etal.,2000).Therefore,in patients with allforms of cirrhosis,concomitant cardiac dysfunction is characterized by baseline hypercontractility.However,depressed contractile response to physiologic or pathophysiologic stimuli has recently been referred to as cirrhotic cardiomyopathy, a clinical entity which is clinically and pathophysiologically differentfrom alcoholic heartmuscledisease(Leeet al.,1989;Maetal.,1996).Leftventricularperformanceisusually reduced in alcoholic heart muscle disease or alcoholic cardiomyopathy.On the other hand, cirrhotic cardiomyopathy comprises compound changes in increased cardiac output related to normal or increased systolic performancewithoutstimuliatrest,butdepressed contractileresponseto various strain,decreased beta-adrenergic receptor function,postreceptor dysfunction,defectiveexcitationcontractioncoupling,andinsomepatients conductance abnormalities (Bernardi et al.,1998; Møller et al.,2002).
Cirrhoticcardiomyopathyhasbeendescribedasanasymptomaticcondition
thatmay assumeclinicalimportanceduring volumeorpressureoverload.
Thatis,clinically significantcardiac dysfunction and latentheartfailure associatedwithimpairedcardiaccontractility during preloadandafterload, may beoutcome(Ahmedetal.1984;Pozzietal.,1997).Thus,itappears that patients with a cirrhotic heart may present with sodium fluid retentionandstrainoftenunmasksthepresenceoflatentheartfailure.No specifictreatmentcan berecommended,and evidentventricularfailurein patients with cirrhotic cardiomyopathy should be treated as having a non-cirrhotic etiology by sodium restriction, diuretics, and afterload reduction,butspecialcaution should be taken during and afterstressful procedures,such as,surgery,shuntimplantation,and livertransplantation (Mølleretal.,2002;Baik etal.,2004).Sinceheartfailureischaracterized by complicated cardiorenal,hemodynamic,and neurohormonalalterations, informationonnumerousvariablesisrequired,e.g.,clinicalstatus,exercise capacity, hemodynamic variables, echocardiographic parameters, several markersofneurohumoralactivation,andbiochemicalmarkersofend-organ dysfunction,to assess and monitorpatients with heartfailure (Mann et al.,1999;Mairetal.,2005).Ingeneral,structuralorfunctionalchangesin thecirrhoticheartareeasily evaluatedby M-mode,two-dimensional,and Doppler echocardiographic studies via the transthoracic approach.Main structuralchangesinthecirrhoticheartareobservedintheleftheart,and include,leftatrium dilatation,and hypertrophy or dilatation ofthe left ventricle.Histologicalchangesincludingmyocardialfibrosis,subendocardial edema,and nuclearand cytoplasmic vacuolation ofcardiomyocytes have been reported by necropsy studies in a patient population limited to alcoholic cirrhosis (Ma etal.,1996;Liu etal.,1999;Mølleretal.,2002;
Baik etal.,2004).In thepresentstudy,leftatrialenlargement,increased
wallthickness and EF ofthe leftventricle,and E/E'ofmitralannulus velocity were noted in cirrhotic patients as compared with controls.In addition,increased LVMIand a decreased E/A ratio were noted in the groupofasciticpatientsascomparedwith pre-asciticpatientsorhealthy controls.On the other hand,no statistically significant difference was observed between these three groups in terms of LVEDD or LV-Tei index.These findings are similarto the structuralchanges reported by previousstudies,itisexpectedthatE/E'measurements,makeupforthe weak points of Doppler transmitralinflow measurement,and that E/E 'may be used as a reliable markerofdiastolic dysfunction in cirrhotic patients. More prevalent left ventricular hypertrophy and relaxation abnormality in decompensated patients with more advanced cirrhosis suggeststhatadvancedcirrhosisisassociatedwithmoreadvancedcardiac dysfunction. Additionally, it has been reported that functional and electrophysiologicalabnormalities also develop in the cirrhotic heart.In cirrhotic patients,systolic function was normalor even supranormalat restwithouta stimulus,butcardiac contractile function in response to strains attenuated these functions compared with healthy controls.
Diastolic dysfunction in thecirrhotic heartappearsto bemoreprevalent than systolic dysfunction,thus echocardiography may reveal abnormal diastolic function under circumstances without strain or even at rest (Kelbaek etal.,1984;Wong etal.,1989;Groseetal.,1995;Finuccietal., 1996;Pozzietal.,1997;Wong etal.,1999).Electrophysiologicalchanges including prolonged repolarization and impaired cardiac excitation-contraction coupling have been demonstrated in cirrhotic patients(Kempleretal.,1993;Bernardietal.,1998;Finuccietal.,1998;
Trevisanietal.,2003;Baletal.,2003).Moreover,thenatriureticpeptides
have been recently highlighted as major markers for the diagnosis, severity,and prognosis ofheart failure.In contrastother conventional cardiacfunction testsaretimeconsuming andoften donotcorrelatewell with symptomatic changes in patients' conditions. B-type natriuretic peptide (BNP) is a neurohormone synthesized with atrial natriuretic peptide (ANP)in cardiac ventricles,and is released as preproBNP and thenenzymatically cleavedtoN-terminal-proBNP (NT-proBNP)andBNP depend upon ventricular myocyte stretching and volume overload (McCullough et al.,2003).In cases of heart failure,ventricular BNP production is markedly elevated,and circulating BNP concentrations are consistently elevated in untreated heart failure (Mair et al., 2001).
Accordingly,blood measurements of BNP and NT-proBNP have been found tobeofdiagnosticvaluein congestiveheartfailure(CHF)related to CHF severity.Moreover,they could be used foradjusting treatment and havebeen shown tobepowerfulprognosticmarkersin both chronic and acute heart failure, independently of standard echocardiographic parameters(Yu etal.,1999;Packeretal.,2003;McCullough etal.,2003;
Hartmanetal.,2004).However,NT-proBNP isinfluencedbyageandthe age-related normaldecline in glomerular filtration rate,and thus,two cutoff points must be used,i.e.,NT-proBNP >125 pg/mL in patients youngerthan 75yearsand > 450pg/mL in patientsolderthan 75years (McCullough etal.,2003).Despite a tightrelationship between age and renalfunction,NT-proBNP,the circulating propeptide ofBNP,has been recently suggested to be an even better marker of early cardiac dysfunction orheartfailurethan BNP,becauseitismorestableandless sensitivetorapid fluctuationscaused by shortterm secretion stimulidue toitsappreciably longerbiologicalhalflife(Huntetal.1997;Hugheset
al.,1999;Campelletal.,2000;Goetze etal.,2001;McCullough etal., 2003;4).A studybyHenriksenetal.,(Henriksenetal.,2003)showedthat circulating proBNP concentrations are significantly increased in patients with advanced cirrhosis and that these are closely related to BNP concentrations,butnosignsofreducedhepaticdegradation ofproBNP or of BNP are present in patients with cirrhosis, which suggests that elevated levels ofproBNP and BNP are related to markers ofcirrhotic severity and indicate the presence of cardiac dysfunction in advanced cirrhosis.In thepresentstudy,circulating NT-proBNP levelswerefound to be significantly higherin cirrhotic patientsthan in controls,and also higherin Child classC patientsthan in Child classB orA patients,or controls.Inaddition,wefoundthatcirculating NT-proBNP concentrations are significantly and positively correlated with the standard echocardiographic parameters LVEDD and E/E'in cirrhotic patients.On theotherhand,circulating NT-proBNP concentrationswerenotfound to berelatedtobiochemicalparameterssuchashemoglobin,albumin,INR of PT, or bilirubin. Importantly, a significant correlation was observed between NT-proBNP and Child class,which suggests that circulating NT-proBNP levelsarelikely toberelatedtotheseverity ofcirrhosis.In addition,the findings thatcirculating NT-proBNP levels increased with thesameincrementaltendencieswithrespecttoLVEDD andE/E'suggest that NT-proBNP provides valuable information about abnormalcardiac function and structural abnormalities in patients with liver cirrhosis.
AscitesisoneoftheparametersoftheChild-Turcotte-Pughclassification thatindicates liverdisease severity.Thus,progressive increases in the ascites ratios in patients from Child Classes A,B and C is expected, however,no significant circulating NT-proBNP level differences were
observed between pre-asciticand asciticcirrhoticpatientsin thepresent study.Thisresultrepresentsastudypitfall,whichmaybeattributableto diuretic therapy before blood sampling in cirrhotic patients with ascites.
DeLemosandhiscolleagues(DeLemosetal.,2003)haveadvocatedthat the net effect of beta-blockers and diuretics is often to reduce BNP concentration.Therefore,furtherpathophysiologicalandclinicalresearchis needed to assess the significance of therapy with diuretics andbeta-blockers.In conclusion,thepresentstudy showsthatcirculating NT-proBNP concentrations,LAD andLVEDD,E/A ratio,EDT,andE/E' may be reliable indicators of the extent of cardiac abnormalities in cirrhoticpatients.Additionally,increasedlevelsofNT-proBNP werefound to be related to disease severity in patients with allforms ofcirrhosis.
Thus,it may be suggested that cardiac dysfunction is related to an increased circulating proBNP concentration, which in turn is more prominentinseveredisease,andthatNT-proBNP haspredictivevaluein casesofconcomitantcardiacdysfunctionandcirrhoticprogression.
V V
V...SSSUUUMMMMMMAAARRRYYY
Background and Objectives :Cardiac dysfunction and a hyperdynamic systemic circulation may be present in cirrhotic patients. B-type natriuretic peptide (BNP) and N-terminal-proBNP (NT-proBNP) are cardiac neurohormones thatreflectearly ventriculardysfunction,and are releasedfrom cardiacventriclesinresponsetoincreasedwalltension.The purposeofthepresentstudy wastoidentify relationsbetweencirculating levels of NT-proBNP and the severity of liver disease and cardiac dysfunctioninpatientswithcirrhosis.
Materialsand Methods:Sixty-threecirrhoticpatients(M/F=40/23,mean age55.8± 10.1years)andfifteenhealthycontrols(M/F=9/6,meanageof 52.9± 10.5years,group1)wereincludedinthepresentstudy.Circulating levelsofNT-proBNP weredetermined in echocardiographically examined patients,whichwereallocatedtooneofthreegroups(16patientsinclass A,29inclassB and18inclassC)accordingtotheChild-Turcotte-Pugh classificationorintotwogroups,i.e.,acompensatedgroupwithoutascites (group2,pre-ascitics,n=28),anddecompensatedgroupwithascites(group 3,ascitics,n=35).
Results : Circulating NT-proBNP levels were significantly higher in cirrhotic patients (groups 2,3)than in normalcontrols (155.88 ± 69.75 pg/mlingroup2and198.26± 146.69pg/mlingroup3vs.40.27± 13.58 pg/ml in group 1,respectively,P < 0.05), but no significant mean NT-proBNP leveldifferencewasobservedbetween groups2and3(P >
0.05).However,NT-proBNP levelsweresignificantlyhigherinChildclass C patientsthan in classesB and A patientsorcontrols(250.00± 176.60 pg/mlinChildclassC vs.168.63±71.34pg/mlinChildclassB,119.60±
67.29 pg/ml in Child class A,and 40.27 ± 13.58 pg/ml in controls, respectively,P < 0.05),and no significantNT-proBNP leveldifference wasobservedbetweenChildclassesB andA (P > 0.05).Leftatriawere significantlyenlargedingroups2and3thaningroup1(39.71±4.75mm ingroup2and40.51± 4.60mm ingroup3vs.35.07± 7.39mm ingroup 1)andwallthicknessofleftventricleswereincreasedincirrhoticpatients thanincontrols(10.07±2.02mm or9.21±1.77mm ingroup2and10.14
± 1.70mm or9.63± 1.22mm ingroup3vs.8.67± 1.54mm or8.20±
1.66 mm in group 1,IVSd orLVPWd in each group,P < 0.05).EF or E/E' were also increased and EDT was prolonged in patients with cirrhosisversuscontrols(70.50± 7.81% or10.51± 1.93or254.29± 60.75 msec in group 2 and 71.17 ± 7.02 % or11.78 ± 2.25 or271.13 ± 53.74 msecingroup3vs.59.33± 6.17% or8.81± 1.08or206.00± 35.32msec in group1,respectively,P < 0.05).IncreasedLVMIandadecreasedE/A ratiowerenoted in thegroup ofpatientswith ascitesascompared with theothergroups(123.54± 22.50g/㎡ or0.90± 0.32ingroup3vs.110.18
± 23.06g/㎡ or1.01± 0.37ingroup2and102.80± 23.54g/㎡ or1.15±
0.37in group1,respectively,P < 0.05).Circulating NT-proBNP levelsof cirrhoticpatientssignificantly and positively correlated with LVEDD (r=
0.277,P =0.028)andE/E'(r=0.450,P=0.01).
Conclusion :Circulating NT-proBNP levels were high in patients with cirrhosis,andarelikelytoberelatedtotheseverityofdiseaseincirrhotic patients. Advanced cirrhosis is associated with an advanced cardiac dysfunction,andNT-proBNP haspredictivevalueforconcomitantcardiac dysfunctionandcirrhosisprogression.
Table1.Baselineclinicalandbiochemicalcharacteristicsofthe cirrhoticpatientsandcontrols
Parameter Control N =15
Cirrhoticgroup Pre-Ascitic
N =28
Ascitic N =35 Age 52.87±10.49 56.68±9.22 54.94±11.01 Sex(male/female) 6/9 18/10 22/13 Hb(g/L) 13.66±1.54 10.76±2.16* 10.31±2.04*
PT (INR) 0.96±0.11 1.34±0.24* 1.62±0.34+*
Album (g/L) 4.13±0.40 3.40±0.55* 2.85±0.43+*
Totalbilirubin(mg/dl) 0.62±0.14 3.05±6.95 4.66±4.11*
Na 143.67±2.35 138.39±4.57* 136.49±5.73*
K 4.31±0.91 3.98±0.71 4.32±0.59 Cr 1.00±0.18 1.04±0.28 1.07±0.30 E
E
Etttiiiooolllooogggyyy
HBV 14 18
HCV 3 3
Alcohol 9 10
Autoimmune 0 2
Cryptogenic 3 1
Hb;Hemoglobin, PT ;Prothrombintime, Cr;Creatinine
*P < 0.05,comparedwithcontrol.+P < 0.05,comparedwithpreasciticgroup.
Parameter Control N =15
Cirrhoticgroup Pre-Ascitic
N =28
Ascitic N =35 EF (%) 59.33±6.17 70.50±7.81 * 71.17±7.02 * LAD (mm) 35.07±7.39 39.71±4.75 * 40.51±4.60 * LVEDD (mm) 46.47±2.56 49.00±3.06 48.23±4.59 IVSd(mm) 8.67±1.54 10.07±2.02 * 10.14±1.70 * LVPWd(mm) 8.20±1.66 9.21±1.77 * 9.63±1.22 * LMI(g/m2) 102.80±23.54 110.18±23.06 123.54±22.50 * E/A ratio 1.15±0.37 1.01±0.37 0.90±0.32 * E/E' 8.81±1.08 10.51±1.93 * 11.78±2.25 * EDT(msec) 206.00±35.32 254.29±60.75 * 271.13±53.74 * LV Teiindex 0.33±0.07 0.34±0.12 0.33±0.13
Table2.Echocardiographicparametersincirrhoticpatientsandcontrols
*P < 0.05,comparedwithcontrol.+P < 0.05,comparedwithpreasciticgroup.
Hb;Hemoglobin, PT ;Prothrombintime, Cr;Creatinine EF ;Ejectionfractionofleftventricle,LAD ;Leftatrium diameter LVEDD ;Leftventricularend-diastolicdiameter
IVSd;Interventricularseptum thicknessindiastole
LVPWd;Leftventricularposteriorwallthicknessindiastole
LVMI;Leftventricularmassindex,E/A ratio;Ratioofvelocity ofE wave tovelocityofA waveofDopplermitralvalveinflow
EDT ;DecelerationtimeofE wave,E';Mitralvalveannularvelocities
Parameter Correlationcoefficients(r) pvalue
Hb(g/L) -0.076 0.556
Albumin(g/L) -0.105 0.415
Totalbilirubin(mg/dl) 0.195 0.127
PT (INR) 0.172 0.178
EF (%) 0.022 0.864
LAD (mm) 0.150 0.239
LVEDD (mm) 0.277 0.028
IVS (mm) 0.111 0.386
LVPWD (mm) 0.124 0.333
LV massindex(g/㎡) 0.080 0.532
E/A ratio 0.058 0.653
E/E' 0.450 0.01
DT (msec) 0.144 0.260
Teiindex 0.099 0.442
EF ;Ejectionfractionofleftventricle,LAD ;Leftatrium diameter LVEDD ;Leftventricularend-diastolicdiameter
IVSd;Interventricularseptum thicknessindiastole
LVPWd;Leftventricularposteriorwallthicknessindiastole
LVMI;Leftventricularmassindex,E/A ratio ;Ratio ofvelocity ofE wavetovelocityofA waveofDopplermitralvalveinflow
EDT ;DecelerationtimeofE wave,E';Mitralvalveannularvelocities Table3.Correlation ofcirculating NT-proBNP concentrationswith echocardiographicparametersincirrhoticpatients
Figure 1. Circulating levels of NT-proBNP in controls and cirrhotic patientsdividedintoacompensatedgroupwithoutascites(pre-ascitic)and adecompensatedgroupwithascites(ascitic).
N T -p ro B N P (p g /m l)
0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0
Control Pre-Ascitic Ascitic P < 0.05
NA
Figure 2. Circulating concentrations of NT-proBNP in controls and cirrhotic patients grouped as class A, B, C according to the Child-Turcotte-Pughclassification.
0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0
N T -p ro B N P (p g /m l)
Control Child A Child B Child C P < 0.05
P < 0.05
NA
Figure 3. Circulating NT-proBNP levels in cirrhotic patients versus echocardiographic parameters.NT-proBNP levels were found to correlate significantlyandpositivelywithLVEDD andE/E'.
0 200 400 600
NT-proBNP, pg/ml
100 300 500 700
16
8 12 14
r = 0.450 p < 0.05
10 6
E /E ' 16
8 12 14
r = 0.450 p < 0.05
10 6
E /E '
8 12 14
r = 0.450 p < 0.05
10 6
E /E ' 60
40
30 50
L V E D D , mm r = 0.277 p < 0.05
60 40
30 50
L V E D D , mm r = 0.277 p < 0.05
RRREEEFFFEEERRREEENNNCCCEEESSS
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