High Prevalence of Atrial Fibrosis in Patients With Dilated Cardiomyopathy

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1 1162 JACC Vl. 25, N. 5 April 1995: High Prevalence f Atrial Fibrsis in Patients With Dilated Cardimypathy KATSUHIKO OHTANI, MD, CHIKAO YUTANI, MD, PHD,* SEIKI NAGATA, MD,* YUKIHIRO KORETSUNE, MD, PHD, FACC,? MASATSUGU HORI, MD, PI-ID,t TAKENOBU KAMADA, MD, PHDt" Kbe and Osaka, Japan Objectives. We examined the extent f fibrtic changes in the left atrium f cardimypathic human hearts and investigated the relatin f mechanical verlad caused by left ventricular dysfunctin t fibrsis f the left atrium. Backgrund. Left atrial dysfunctin in dilated cardimypathy may cntribute t prgressin f heart failure. In cntrast t fibrsis f the left ventricle, atrial fibrsis has nt been extensively studied in cardimypathic hearts. Methds. The extent f fibrsis in the left atrium and left ventricle was determined by an autmatic image analyzer in 38 autpsied hearts btained frm 9 patients wh died f nncardiac illness (cntrl grup), 16 patients with dilated cardimypathy, 6 patients with hypertrphic cardimypathy with features mimicking dilated cardimypathy and 7 patients with a previus mycardial infarctin. Transverse sectins were btained at the upper margins f the framen vale and left auricle in the left atrium and the median level f the left ventricle. Results. There were n significant differences in extent f left atrial dilatin, left ventricular dysfunctin r duratin f illness amng the three grups with cardiac disease. Percent area f left atrial fibrsis (mean ~- SD) was significantly greater in the specimens frm patients with dilated cardimypathy ( %, p < 0.01) and hypertrphic cardimypathy mimicking dilated cardimypathy ( %, p < 0.01) than in thse frm patients with an ld mycardial infarctin (3.8 ± 1.1%). Percent area f left ventricular fibrsis in hearts frm patients with dilated cardimypathy (12.9 ± 8.6%) was significantly smaller than that in hearts frm patients with hypertrphic cardimypathy mimicking dilated cardimypathy ( %, p < 0.01) and a previus mycardial infarctin ( %, p < 0.01). Percent area f atrial fibrsis was significantly crrelated with left ventricular ejectin fractin in the grup with a previus mycardial infarctin but nt in the ther grups. Cnclusins. There was a high degree f fibrtic change in the left atrium in the grups with dilated cardimypathy and hypertrphic cardimypathy mimicking dilated cardimypathy. Our findings suggest that atrial fibrsis in these patients may nt have been related t mechanical verlad f the left atrium but t sme ther, still unknwn mechanisms. (J Am CU Cardil 1995;25:1162-9) Cardiac dilatin and decreased cntractile functin are characteristic f dilated cardimypathy (1). Previus studies (2,3) have demnstrated that fibrsis f the ventricular wall is prminent in dilated cardimypathy; hwever, the crrelatin between the extent f fibrsis and cntractile functin is cntrversial. Fibrsis primarily cntributes t the stiffness f the ventricular wall and thus may accunt fr the elevated end-diastlic pressure f the left ventricle. In stiff, especially failing, hearts, left atrial systlic functin may be imprtant fr ventricular filling during diastle (4,5), and atrial fibrillatin r flutter can prduce atrial failure, with severe detrimental Frm the Department f Internal Medicine, Kbe Ekisaikai Hspital, Kbe; and *Departments f Pathlgy and Internal Medicine, Natinal Cardivascular Center and First Department f Medicine, Osaka University Medical Schl, Suita, Osaka, Japan. This study was supprted in part by a 1994 Research Grant fr Research n Idipathic Cardimypathy frm the Ministry f Health and Welfare, Tky, Japan. Manuscript received January 24, 1994; revised manuscript received Nvember 21, 1994, accepted Nvember 29, Address fr crrespndence: Dr. Yukihir Kretsune. The First Department f Medicine, Osaka University, Medical Schl, 2-2, Yamadaka, Suita, Osaka, 565 Japan. effects n ventricular filling and n the verall pump functin f the heart (6,7). Tripskiadis et al. (8) reprted that depressin f left atrial cntractile functin was significantly greater in patients with dilated cardimypathy than in thse with artic valve disease with cmparable left ventricular dysfunctin. Hwever, left atrial tissue frm cardimypathic hearts has nt undergne extensive histlgic study (9-14). In the present study, we investigated the extent f left atrial fibrsis in autpsied hearts frm patients with dilated cardimypathy and hypertrphic cardimypathy with features mimicking dilated cardimypathy. In an attempt t clarify the effect f mechanical verlad n atrial fibrsis, we als studied the extent f atrial fibrsis in hearts frm patients with a previus mycardial infarctin with left ventricular dysfunctin cmparable t that seen in cardimypathy. Methds Materials. We studied 38 autpsied hearts: 9 frm patients wh died f nncardiac illness (cntrl grup [5 men, 4 wmen]); 6 frm patients with hypertrphic cardimypathy 1995 by the American Cllege f Cardilgy /95/$ (94)00529-Y

2 JACC Vl. 25, N. 5 OHTANI ET AL April 1995: ATRIAL FIBROSIS IN DILATED CARDIOMYOPATHY Table 1. Clinical and Pathlgic Features f 38 Autpsied Hearts Wall Thickness (mm) Case Age (yr)/ Heart N. Gender Weight (g) LA FW LV FW LVS Hypertrphic Cardimypathy Mimicking Dilated Cardimypathy 1 18/M ,q z /F /F /F /M Mean SD _+14' +173 _+0.3 _ LV LA Fibrsis Fibrsis (%) (%) _+9.5:~ Dilated Cardimypathy 1 361F /M /M /M /M /M /M fF /M /M /M /M /M /M /F /M Mean _+SD _+13 _+117 _+0.3 _+2 _~2 _+8.6 _+6.1 Heart LA Wall LV LA Age Weight Thickness Fibrsis Fibrsis (yr) (g) (mm) (%) (%) Previus Mycardial Infarctin (n = 7 [6M/1F]) Range Mean + SD _ _ _+ 8.0:~ 3.8 _+ 1.1 Cntrl Grup (n - 9 [5M/4F]) Range Mean - SD 53 _ _ _ _+ 0.3 *p < 0.05 versus ld mycardial infarctin.?p < 0.01 versus dilated cardimypathy. :~p < 0.01 versus dilated cardimypathy and ld mycardial infarctin. p < 0.01 versus ld mycardial infarctin. F = female; FW = free wall; LA = left atrial; LV = left ventricular; LVS = left ventricular septum; M = male. mimicking dilated cardimypathy (2 men, 4 wmen); 16 frm patients with dilated cardimypathy (13 men, 3 wmen); and 7 frm patients with a previus mycardial infarctin (6 men, 1 wman) (Table 1). Hypertrphic cardimypathy mimicking dilated cardimypathy is a frm f hypertrphic cardimypathy characterized by prgressive dilatin f the left ventricle in the late stage (14-17). The diagnsis f hypertrphic cardimypathy mimicking dilated cardimypathy was made accrding t previusly described criteria (18). In three f the six patients with hypertrphic cardimypathy mimicking dilated cardimyp- athy, prgressin frm typical hypertrphic cardimypathy t dilated cardimypathy-like features was detected by echcardigraphy. In the remaining three patients, dilated cardimypathy was diagnsed n the basis f clinical features, but autpsy shwed extensive mycardial fiber disarray distributed mainly in the ventricular septum. Thus, hypertrphic cardimypathy was diagnsed n the basis f histlgic findings. This diagnsis was als supprted by a familial prevalence f hypertrphic cardimypathy. The clinical diagnsis f dilated cardimypathy was based n the criteria f the Wrld Health Organizatin (19) fr the

3 1164 OHTANI ET AL. JACC Vl. 25, N. 5 ATRIAL FIBROSIS IN DILATED CARDIOMYOPATHY April 1995: definitin and classificatin f cardimypathies. N diffuse disarray f mycytes r marked asymmetric ventricular hypertrphy was bserved in specimens frm patients with dilated eardimypathy. A familial prevalence f dilated cardimypathy was bserved in tw patients. The mean age f the patients with hypertrphic cardimypathy mimicking dilated cardimypathy was significantly yunger than that f patients in the ther tw grups (p < 0.01 vs. patients with dilated cardimypathy and thse with an ld mycardial infarctin). All patients died f severe cngestive heart failure. N cases f sudden death were included in the present study. Mean heart weight was significantly greater in the patients with hypertrphic cardimypathy mimicking dilated cardimypathy than in thse with dilated cardimypatby (p < 0.05). Mean rati f septal/free wall thickness was 1.1 in the grup with dilated cardimypathy and 1.6 in that with hypertrphic cardimypathy mimicking dilated cardimypathy. The left atrial wall was thin in the three grups with cardiac disease cmpared with the cntrl grup (p < 0.05); there was n significant difference in thickness amng the three grups with cardiac disease (Table 1). Lumen diameter f the extramural crnary arteries was <50% in the grups with hypertrphic cardimypathy mimicking dilated cardimypathy and dilated cardimypathy. In the grup with mycardial infarctin, three patients had triplevessel disease, three had prximal left anterir descending crnary artery disease, and ne had left circumflex crnary artery disease. All patients had anterir r lateral mycardial infarctin, r bth. They died f incurable severe cngestive heart failure in the chrnic stage. There was n significant crnary lumen narrwing in the cntrl grup. Histlgic examinatin. Left ventricle. The hearts were weighed and fixed in 10% frmalin and sectined transversely frm base t apex at l-cm intervals. A slice frm the midlevel f the autpsied heart was embedded in paraffin. The whle sectined surface was cut int sectins -5-p,m thick n a glass slide and stained with hematxylin-esin and Massn's triehrme. Each tissue sectin was divided int anterir, lateral, psterir and septal regins. Left atrium. After fixatin, transverse sectins were cut frm the area just abve the left auricle and framen vale (Fig. 1). After staining with hematxylin-esin and Massn's trichrme, each sectin was divided int anterir, lateral, psterir and septal regins. The 5-~m thick preparatins stained with Massn's trichrme were enlarged 10 times with a phtgraphic enlarger. Areas that stained blue, indicating fibrsis, were carefully traced with a fine black pen. The percent area f fibrsis was measured with an autmatic image prcessing system (Olympus Vip-21), as previusly described (20,21). The percent area f fibrsis in the entire ventricular and atrial wall f the transverse slice was btained by dividing the ttal area f fibrsis by the ttal tissue area. T determine the intramural distributin f fibrsis, the reginal percent area f fibrsis in the anterir, lateral, psterir and septal walls f the left atrium and left ventricle was calculated separately. Papil- LA Figure 1. Left, Transverse sectins btained frm area just abve the left auricle (LAA) and framen vale (FO). A = arta; LA = left atrium; MV = mitral valve; P = pulmnary artery; TV = tricuspid valve. Right, Schematic diagram f transverse sectin f the left atrial (LA) wall, divided int anterir (A), lateral (L), psterir (P) and septa[ (S) regins. lary muscles were excluded frm measurement f fibrsis in the ventricular sectin. Endcardium and epicardium were excluded frm measurement f fibrsis in the atrial sectin. T cnfirm the accuracy f measurements, we analyzed the extent f fibrsis in tw transverse sectins btained at 10-ram intervals frm tw hearts in each grup. In all cases, fibrsis was traced and quantified independently by tw mrphlgists. Measurements varied by <7%. ltemdynamic measurements. Hemdynamic measurements determined by cardiac catheterizatin, cntrast r radinuclide left ventriculgraphy and Dppler echcardigraphy (22) were btained within 3 mnths f death. We defined the duratin f illness as the perid frm the first episde f severe cngestive heart failure (New Yrk Heart Assciatin functinal class III) t death. The duratin f illness was nt significantly different amng grups. There were als n significant differences in ejectin fractin r mitral regurgitatin grade. Left ventricular end-diastlic dimensin in the grup with dilated cardimypathy was significantly larger than that in the grups with hypertrphic cardimypathy mimicking dilated cardimypathy and previus mycardial infarctin (p < 0.05, respectively). Left atrial dimensin and mean pulmnary artery wedge pressure did nt differ amng grups (Table 2). The incidence f atrial fibrillatin was 33% in the grup with hypertrphic cardimypathy mimicking dilated cardimypathy, 12.5% in the grup with dilated cardimypathy and 14% in the grup with a previus mycardial infarctin. Statistical analysis. Data are expressed as mean value + SD. Because f the large variance f differences in each grup, nnparametric methds (Wilcxn test with Bnferrni prcedure) were used when apprpriate; p < 0.05 was cnsidered statistically significant. Results Left atrial micrscpic findings. Figure 2 (tp) shws a micrscpic specimen frm the left atrium f a patient with an ld mycardial infarctin. In cntrl hearts and in thse frm patients with a previus mycardial infarctin, fibrus tissue extending frm the perivascular fibrsis was rarely bserved arund the well defined muscle bundles. The extent f fibrsis was minimal, and the mycardium shwed n particular A P

4 JACC Vl. 25, N. 5 OHTANI ET AL April 1995:1 t 62-9 ATRIAL FIBROSIS IN DILATED CARDIOMYOPATHY Table 2. Clinical Curse and Hemdynamic Data Echcardigraphic Family Data Histry Duratin f LVDd LAD mpawp Study Grup (+/-) Illness (m) (mm) (mm) FS (%) (ram Hg) EF (%) MR DCM-like HCM (n = 6) 5/1 32 _ * 39 ± ± ± 9 20 ± _+ 0.6 (n - 5) (n : 5) DCM (n = 16) 2/ _ _ _ _ ± 9 23 ± ± 1.1 (n - 14) (n = 15) OMI (n = 7) ± 8* 40 ± ± ± ± 1.2 (n = 6) *p < 0.05 versus dilated cardimypathy (DCM). DCM-like HCM = hypertrphic cardimypathy with features mimicking dilated cardimypathy; Duratin f illness = perid frm functinal class lii episde t death; EF - ejectin fractin; FS = fractinal shrtening; LAD = left atrial dimensin; LVDd = left ventrieular end-diastlic dimensin; mpawp - mean pulmnary, artery wedge pressure; MR = mitral regurgitatin (grade 0-4); OMI = ld mycardial infarctin; + = presence; - = absence. changes. In hearts with dilated cardimypathy, there was a diffuse netlike fibrsis within the muscle bundles, with mderate disruptin f bundle structure. The muscle mass was relatively well preserved, but sme mycardial fibers shwed vacular degeneratin and a cmbinatin f hypertrphy and attenuatin (Fig. 2, middle). In cntrast, massive fibrsis and marked lss f muscle mass were bserved in the left atrium f hearts with hypertrphic cardimypathy mimicking dilated cardimypathy (Fig. 2, bttm). Muscle bundles were markedly disrupted r assciated with unrecgnizable structures with ccasinal vacular degeneratin and mycardial attenuatin, r bth. Almst cmplete replacement with fibrus tissue was seen in the center f the fibrtic area. The percent area f fibrsis in a transverse sectin f the entire left atrium was % in cntrl hearts, 26.5 _+ 9.5% in hearts with hypertrphic cardimypathy mimicking dilated cardimypathy, 13.1 _+ 6.1% in hearts with dilated cardimypathy and 3.8 _ 1.1% in thse with a previus mycardial infarctin, significantly greater in hearts with hypertrphic cardimypathy mimicking dilated cardimypathy than in thse with dilated cardimypathy (p < 0.01) and a previus mycardial infarctin (p < 0.01) and significantly greater in hearts with dilated cardimypathy than in thse with a previus mycardial infarctin (p < 0.01) (Table 1, Fig. 3). Nne f the grups shwed any significant reginal variatin in the extent f fibrsis (Fig. 4). Percent area f left ventricular fibrsis. The percent area f all left ventricular fibrsis in hearts with dilated cardimypathy (12.9 _+ 8.6%) was significantly smaller than that in hearts with hypertrphic cardimypathy mimicking dilated cardimypathy ( %, p < 0.01) and a previus mycardial infarctin (38.4 _+ 8.0%, p < 0.01). There was n significant reginal variatin in extent f fibrsis in hearts with dilated cardimypathy and hearts with hypertrphic cardimypathy mimicking dilated cardimypathy. Percent area f left ventricular fibrsis did nt crrelate with that in the left atrium in either grup. Relatin f percent area f left atrial fibrsis t ejectin fractin. Extent f left atrial fibrsis was significantly crrelated with left ventricular ejectin fractin (r = -0.82, p < 0.05) in hearts with an ld mycardial infarctin. N crrelatin between extent f fibrsis and ejectin fractin was bserved in the ther grups (Fig. 5). Because the number f patients with chrnic atrial fibrillatin was small, we culd nt detect any trend in the relatin f these tw variables in patients with versus withut sinus rhythm. Discussin Histlgic assessment f atrial fibrsis. Previus studies f atrial fibrsis were limited with regard t quantitative assessment f extent f fibrtic changes (e.g., tissue samples that were t small and sampling sites that were limited t the endcardium [23] r atrial appendage [24]). Bailey et al. (25) bserved extensive atrial tissue fibrsis in patients with chrnic atrial fibrillatin, but this may lead t an incrrect quantitative crrelatin between extent f fibrtic changes and duratin f atrial fibrillatin because bipsied tissue samples may nt reflect histlgic changes in the entire atrium. Histlgic examinatin f entire transverse sectins is necessary t evaluate the distributin and extent f fibrsis f the mycardium. T ur knwledge, the present study is the first t quantitatively assess the extent f fibrsis n transverse slices f the entire left atrium using an autmatic image analyzer. We tested the reliability f using percent fibrsis as an index f the extent f fibrtic changes in the whle atrium by cmparing the percent fibrsis in tw transverse slices btained at 10-mm intervals frm tw hearts in each grup. Percent fibrsis was cmparable in tissue slices btained frm the same heart, suggesting that the percent fibrsis bserved in the transverse slice f the atrium represented the extent f fibrtic changes in the whle atrium. We als cnfirmed that ur measurements f fibrsis were reprducible in the present study. Thus, percent fibrsis appeared t be a reliable index f fibrtic changes in atrial tissue. Fibrsis f the left atrial wall. Aging and mechanical verlad are believed t be tw majr causes f fibrsis in the left atrium. The distributin f fibrsis and adipse tissue in the atrial wall has been fund t increase with age, whereas the prprtin f muscle fibers decreases (26). In the present

5 1166 OHTANI ET AL. JACC Vl. 25, N. 5 ATRIAL FIBROSIS IN DILATED CARDIOMYOPATHY April 1995: (%) 60..a 50 P < i P < O.Ol P < 0.5 i.- ~, 40,~ 't I J!} DCM-like HCM DCM OMI Figure 3. Percent area f left atrial (LA) fibrsis in DCM-like HCM = hypertrphic cardimypathy with features mimicking dilated cardimypathy; DCM = dilated cardimypathy; OMI = ld mycardial infarctin. Vertical bars and pen circles = mean _+ SD. Figure 2. Left atrial wall specimens frm (tp) a patient with an ld mycardial infarctin shwing perivascular fibrsis and cmpact mycardium in muscle bundles; middle a patient with dilated cardimypathy shwing severe interstitial fibrsis and mderate muscle bundle disruptin; and bttm a patient with hypertrphic cardimypathy with features mimicking dilated cardimypathy shwing cmplete replacement fibrsis and marked muscle bundle disruptin. Hematxylinesin and Massn's trichrme stain, x 170, reduced by 30%. study, patients with dilated cardimypathy and hypertrphic cardimypathy mimicking dilated cardimypathy were much yunger than thse with an ld mycardial infarctin. Hwever, percent fibrsis was significantly greater in patients with dilated cardimypathy and hypertrphic cardimypathy mimicking dilated cardimypathy than in thse with a previus mycardial infarctin, suggesting that the marked fibrsis in patients with dilated cardimypathy and hypertrphic cardimypathy mimicking dilated cardimypathy may be related t factrs ther than aging. Mechanical verlad may accunt primarily fr fibrsis f atrial tissue. Tripskiadis et al. (8) reprted that left atrial systlic functin is mre impaired in patients with dilated cardimypathy than in thse with left ventricular dysfunctin caused by valvular abnrmalities, despite cmparable mechanical lads t the atrium in bth diseases. This finding suggests that mechanical verlad itself des nt cause marked fibrtic changes in the atrium. This hypthesis is supprted by the findings f Bailey et al. (25), wh bserved minimal fibrtic changes in the left atrium in patients with nnrheumatic mitral valvular abnrmalities, such as idipathic cardimypathy and papillary muscle dysfunctin. In ur study, there was a clse crrelatin between left ventricular ejectin fractin and percent area f atrial fibrsis in patients with an ld mycardial infarctin. Althugh we did nt determine left atrial pressures in ur patients, it is pssible that the mechanical lad f the left atrium may be inversely crrelated with left ventricular ejectin fractin. If s, the extent f atrial fibrsis in the grup with an ld mycardial infarctin may reflect the mechanical lad f the atrial muscle. Hwever, the lad-dependent fibrtic changes in the grup with an ld mycardial infarctin were significantly smaller than thse bserved in patients with dilated cardimypathy and hypertrphic cardimypathy mimicking dilated cardimypathy, indicating that causes ther than mechanical verlad may be primarily respnsible fr fibrtic changes in idipathic mypathy. Unrecgnized viral mycarditis may be an underlying cause f dilated cardimypathy in a substantially large number f patients (27). Bwles et al. (28) reprted that Cxsaclde B virus RNA was frequently bserved in bipsied ventricular tissue samples frm patients with dilated cardimypathy. Matsumri et al. (29) als reprted that viral mycarditis

6 JACC Vl. 25, N. 5 OHTANI ET AL April 1995: ATRIAL FIBROSIS IN DILATED CARDIOMYOPATHY (%) 70- DCM-like HCM DCM OMI Figure 4. Reginal distributin f left atrial (LA) fibrsis. Vertical bars and pen circles = mean + SD. Abbreviatins as in Figures 1 and 3. L h= a0- E = ccurred in bth the atrium and ventricle in an experimental animal mdel. Thus, it is likely that the marked fibrtic changes in patients with idipathic cardimypathy are related, in part, t previus viral mycarditis. Althugh there was n crrelatin between fibrtic changes in the ventricle and atrium in individual patients, the high prevalence f mycardial fibrsis bserved in patients with idipathic cardimypathy strngly supprts this hypthesis. Fibrsis in patients with dilated cardimypathy and hypertrphic cardimypathy mimicking dilated cardimypa. thy. Percent fibrsis f the left ventricle was significantly higher in patients with hypertrphic cardimypathy mimicking dilated cardimypathy than in thse with dilated cardimypathy (35.8% vs. 12.9%, p < 0.01) despite cmparable left ventricular ejectin fractins and intervals frm the develpment f heart failure symptms t death. Our findings in patients with hypertrphic cardimypathy mimicking dilated cardimypathy are cnsistent with thse previusly reprted (14). A previus study (30) suggested that the transitin frm hypertrphic cardimypathy t hypertrphic cardimypathy mimicking dilated cardimypathy is accmpanied by an increase in ventricular fibrsis. Spirit et al. (31) reprted that 5% t 10% f patients with hypertrphic cardimypathy shw prgressive thinning f the left ventricular wall and dilatin f the left ventricular cavity. This phenmenn has been classified as hypertrphic cardimypathy mimicking dilated cardimypathy (18), which is characterized by extensive left ventricular mycardial fibrsis. Our findings in the hearts frm the grup with an ld mycardial infarctin suggest that fibrtic change itself des nt cause ventricular dilatin, that is, remdeling f the left ventricle. In cardimypathic Syrian hamsters, left ventricular dilatin and wall thinning were assciated with increased cllagenase activity. This degradatin f cllagen may have caused remdeling f the ventricle (32). Such a bichemical mechanism may be present in patients with hypertrphic cardimypathy mimicking dilated cardimypathy, althugh there is n direct evidence t supprt this hypthesis. Mycardial ischemia may als be respnsible fr the tran- sitin frm hypertrphic cardimypathy t hypertrphic cardimypathy mimicking dilated cardimypathy because abnrmal mycardial structures, such as disarray (1438,31,33,34), can impair the crnary micrvascular vasdilatry respnse (35). Hwever, this hypthesis may nt be plausible in the atrium because the atrial chamber, which is like a lw pressure reservir, is nt susceptible t ischemia. Atrial infarctin is extremely rare (36,37). In the present study, three patients with an ld mycardial infarctin had cmplete bstructin f the sinus nde and atrial circumflex arteries in the left atrium. Hwever, nne f these patients had signs f left atrial infarctin, and atrial fibrsis was minimal. There is ften a family link in patients wh prgress frm hypertrphic cardimypathy t hypertrphic cardimypathy mimicking dilated cardimypathy (14), suggesting that genetic factrs may be invlved. The tissue renin-angitensin system and grwth factrs, such as transfrming grwth factr-beta I and basic fibringen grwth factr and cytkines may als play a majr rle in bth ventricular and atrial fibrsis, althugh we bserved n crrelatin between ventricular and atrial fibrsis. Sympathetic activity may als mdulate these prcesses (38). Investigatin f neurhrmnal and immunlgic alteratins in hypertrphic cardimypathy mimicking dilated cardimypathy is needed t clarify the underlying mechanism f mycardial fibrsis. Limitatin f the study. A majr limitatin f this study is that we examined autpsied hearts, and, thus, the present results may represent histlgic changes in severely ill patients nly. Hwever, the mean percent area f fibrsis in the ventricle in patients with dilated cardimypathy (12.9 _+ 8.6%) was cnsistent with that fund in previus studies based n bipsied samples, indicating that the ppulatin bias may nt be excessively large. The hemdynamic data in the present study were btained within 3 mnths f death, and pulmnary artery wedge pressures were btained within 6 mnths f death, cmplicating the relatin between hemdynamic data and histlgic changes at autpsy. Hwever, the interval between the hemdynamic and

7 1168 OHTANI ET AL JACC Vl. 25, N. 5 ATRIAL FIBROSIS IN DILATED CARD1OMYOPATHY April 1995: (4) dilated cardimypathy, especially thse with hypertrphic cardimypathy mimicking dilated cardimypathy. We thank Takashi Shimazu, Shujir Kubri, Shigeru Salt, Masami lmakita and Hatsue Ueda fr their advice (%) ~,~ 30-._m 0 -//, 15 1'6 1'7 1'8 1'9 2'0 2'1 2'2 2'3 2'4 2'5 20- ~ 10- g- (96) 6-.~ 4. "~ 3. E 0. ~ '0 3b ~ 5b 10 2'0 3'0 4'0 5'0 (%) Ejectin fractin Figure 5. Relatin f percent area f left atrial (LA) fibrsis t left ventricular ejectin fractin in patients with hypertrphic cardimypathy mimicking dilated cardimypathy (tp) (r = , p = NS); dilated cardimypathy (middle) (r = 0.516, p = NS); and an ld mycardial infarctin (bttm) (r = , p < 0.05). Slid circles = mitral regurgitatin grade 1 t 2; pen circles = mitral regurgitatin grade 3 t 4. tchrnic atrial fibrillatin. the autpsy studies was cmparable amng the three study grups, and, thus, the difference amng grups may be minimal. We culd nt reach any cnclusin as t whether atrial fibrsis increases the incidince f atrial fibrillatin because the number f patients with chrnic atrial fibrillatin was minimal. Nevertheless, the incidence f atrial fibrillatin was highest in patients with hypertrphic cardimypathy mimicking dilated cardimypathy, indicating that extensive atrial fibrsis may increase the incidence f nnsinus atrial rhythm. Despite these limitatins, t ur knwledge the present study is the first t demnstrate a high prevalence f atrial fibrsis in patients with References 1. Wynne J, Braunwald E. The cardimypathies and mycarditis. In: Braunwald E, editr. Heart Disease. Philadelphia: Saunders, 1980: Baandrup U, Flri RA, Rehahn M, Richardsn PJ, Olsen EGJ. Critical analysis f endmycardial bipsies frm patients suspected f having cardimypathy. II: cmparisn f histlgy and clinical/haemdynamic infrmatin. Br Heart J 1981;45: Schwarz F, Mall G, Zebe H, et al. Quantitative mrphlgic findings f the mycardium in idipathic dilated cardimypathy. Am J Cardil 1983;51: Rahimtla SH, Ehsani A, Sinn MZ, et al. Left atrial transprt functin in mycardial infarct: imprtance f its bster pump functin. Am J Med 1975;59: Manning WJ, Silverman DI, Katz SE, Duglas PS. Atrial ejectin frce: nninvasive assessment f atrial systlic functin. J Am Cil Cardil 1993;22: Braunwald E. Hemdynamic significance f atrial systle. Am J Med 1964;37: Suga H. Imprtance f atrial cmpliance in cardiac perfrmance. Circ Res 1974;35: Tripskiadis F, Pitsavs C, Trikas A, Budulas H, Tutuzas P. Left atrial mypathy in idipathic dilated cardimypathy [abstract]. J Am Cil Cardil 1993;21:198A. 9. Schwartz F, Mall G, Zebe H, et al. Determinants f survival in patients with cngestive cardimypathy--quantitative mrphrgic findings and left ventricular hemdynamics. Circulatin 1984;70: I0. Schwartz F, Mall G, Zebe H, et al. Quantitative mrphlgic findings f the mycardium in idipathic dilated cardimypathy. Am J Cardil 1983;51: Dick MR, Unverferth DV, Baba N. The pattern f mycardial degeneratin in nnischemic cngestive cardimypathy. Hum Pathl 1982;13: Nda S. Histpathlgy f endmycardial bipsies frm patients with idipathic cardimypathy--quantitative evaluatin based n multivaliate statistical analysis. Jpn Circ J 1980;44: Sekiguchi M, Knn S. Diagnsis and classificatin f primary mycardial disease with the aid f endmycardial bipsy. Jpn Circ J 1971;35: Yutani C, Imakita M, Ishibashi-Ueda H, et al Three autpsy cases f prgressin t left ventricular dilatatin in patients with hypertrphic cardimypathy. Am Heart J 1985;109: Nagata S, Park YD, Minamikawa T, et al. Thallium perfusin and cardiac enzyme abnrmalities in patients with familial hypertrphic cardimypathy. Am Heart J 1985;109: Tencate FJ, Relandt J. Prgressin t left ventricular dilatatin in patients with hypertrphic bstructive cardimypathy. Am Heart J 1979;97: Nishimura T, Nagata S, Uehara T, Hayashida K, Mitani I, Kumita S. Assessment f mycardial damage in dilated-phase hypertrphic cardimypathy by using indium-1 ll-antimysin Fab mycardial scintigraphy. J NucI Med 1991;32: Tanaka M, Fujiwara H, Ondera T, et al. Quantitative analysis f narrwings f intramycardial small arteris in nrmal hearts, hypertensive hearts, and hearts with hypertrphic cardimypathy. Circulatin 1987;75: Oakley CM. Reprt f the WHO/ISFC Task Frce n the definitin and classificatin f cardimypathies. Br Heart J 1980;44: Fujiwara H, Ondera T, Tanaka M, Fujiwara T, Kawai C, Hamashima Y. The reliability f the tracing-methd f the fine cardiac fibrsis at a magnificatin f 10--preliminary study fr quantitative analysis f fibrsis in large tissue sectins f hearts with cardimypathy. Heart Vessels 1985;1: Tanaka M, Fujiwara H, Ondera T, Wu D, Hamashima Y, Kawai C. Quantitative analysis f mycardial fibrsis in nrmals, hypertensive hearts, and hypertrphic cardimypathy. Br Heart J 1986;55:

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