Congenital Heart Malformations Associated with Disproportionate Ventricular Septal Thickening

Transcription

1 Congenital Heart Malformations Associated with Disproportionate Ventricular Septal Thickening By BARRY J. MARON, M.D., JESSE E. EDWARDS, M.D., VICTOR J. FERRANS, M. D., Ph. D., CHESTER E. CLARK, M. D., EDWARD A. LEBOWITZ, M.D., WALTER L. HENRY, M.D., AND STEPHEN E. EPSTEIN, M.D. SUMMARY Asymmetric septal hypertrophy, or ASH, is a genetically determined myocardial disorder that is transmitted as an autosomal dominant trait. ASH is characterized by a disproportionately thickened ventricular septum that contains numerous hypertrophied, bizarrely-shaped and disorganized cardiac muscle cells. Disproportionate hypertrophy of the ventricular septum has also been observed in association with certain congenital cardiac malformations. To determine whether such congenital cardiac malformations are part of the disease spectrum of genetically determined ASH, cardiac pathologic observations were made in eight patients with disproportionate septal thickening (ventricular septal to posterobasal left ventricular free wall thickness ratios of 1.5 to 2.5) and the following three categories of associated lesions: 1) parachute deformity of the mitral valve (occurring either as an isolated lesion or with ventricular septal defect, coarctation of the aorta, supravalvular ring of the left atrium, or double outlet right ventricle); 2) complete interruption of the aortic arch; and 3) ventricular septal defect. The arrangement of cardiac muscle cells in the disproportionately thickened ventricular septum was normal in six of the eight patients; in the other two patients (one with parachute deformity of the mitral valve and one with ventricular septal defect) numerous bundles of hypertrophied cardiac muscle cells were interlaced in a disorganized fashion among more normally arranged bundles of cells. First degree relatives of six of the eight patients were studied by echocardiography and found to have normal ventricular wall thicknesses and septal-free wall ratios. It is concluded that disproportionate ventricular septal thickening may occur in patients with a variety of congenital heart malformations, but that such a finding is not necessarily a manifestation of the disease spectrum of genetically determined ASH. ASYMMETRIC SEPTAL HYPERTROPHY (ASH) is a myocardial disorder, transmitted as an autosomal dominant trait,1 that is characterized by disproportionate thickening of the ventricular septum with respect to the left ventricular free wall.2 A disorganized arrangement of hypertrophied cardiac muscle cells is the characteristic histologic feature of the ventricular septum in such patients,-1 and presumably is a morphologic manifestation of the genetically transmitted defect. 9 1 Previous reports have described findings consistent with disproportionate ventricular septal thickening in some patients with a variety of congenital heart malformations.'1-29 However, it is not known whether From the Cardiology Branch and the Section of Pathology, National Heart and Lung Institute, Bethesda, Maryland, and the Department of Pathology, United Hospitals-Miller Division, St. Paul and the Department of Pathology, University of Minnesota, Minneapolis, Minnesota. Supported in part by USPHS Research Grant 5 R1 HL59 and Research Training Grant 5 TO1 HL55 from the National Heart and Lung Institute. Address for reprints: Dr. Barry J. Maron, Cardiology Branch, National Heart and Lung Institute, Bldg. 1, Room B-15, Bethesda, Maryland 21. Received May, 195; revision accepted for publication June 9, the disproportionate septal thickening in such patients is a manifestation of the disease spectrum of genetically determined ASH. To investigate this question, cardiac pathologic observations were made in eight patients with congenital heart malformations who also had disproportionate septal thickening. In addition, first degree relatives of six of these patients were studied by echocardiography to determine whether the disproportionate septal thickening was transmitted genetically. Materials and Methods Selection of Patients The cardiac pathology files of the United Hospitals-Miller Division were reviewed and 1 hearts with "muscular subaortic stenosis" and associated congenital cardiac malformations were initially analyzed. Eight of these 1 specimens were selected for the present study by virtue of: 1) being in satisfactory condition for analysis and 2) meeting our anatomic criteria for disproportionate ventricular septal thickening,5 which will be discussed in detail below. The associated cardiac defects in these eight patients are summarized in table 1 and comprise three categories. The first category consists of five patients (1-5) with single papillary muscle of the left ventricle and parachute deformity of the mitral valvular chordae. In patient 5 the parachute deformity of the mitral valve occurred as an isolated lesion. In patients 1- the parachute deformity of the mitral valve Circulation, Volume 52, November 195

2 DISPROPORTIONATE SEPTAL THICKENING 92 Table 1 Associated Congenital Cardiac Malformations in Eight Patients with Disproportionate Ventricular Septal Thickening Associated cardiac malformations Patient no Age Sex PMV VSD SVRLA DORV COA IAA Others 1 22 yr M * t Bicuspid pulmonic valve; SCA 2 3 mo F 3 2 yr M PDA yr M * Bicuspid aortic valve 5 2 mo F 3 mo F t AMB of RV 5 yr F 2 mo F LSV'C; PDA *Parachute deformity of mitral valve that produced clinically significant mitral valvular obstruction. tlarge ventricular septal defect (as judged by necropsy, angiographic and hemodynamic findings). tsmall ventricular septal defect (as judged by necropsy, angiographic and hemodynamic findings). Abbreviations: AMB = anomalous muscle bundle; COA = coarctation of the aorta; DORV = double outlet right ventricle; IAA = complete interruption of aortic arch; LSVC = left superior vena cava; PDA = patent ductus arteriosus; PMV = parachute mitral valve (single papillary muscle of left ventricle with parachute deformity of the mitral valvular chordae); RV = right ventricle; SCA = single coronary artery (arising from above the posterior aortic sinus); SVRLA = supravalvular ring of the left atrium; VSD = ventricular septal defect (infracristal). was associated with other congenital malformations of the heart. In patients 1 and the association of parachute deformity of the mitral valve, supravalvular ring of the left atrium and coarctation of the aorta comprised a distinctive developmental complex commonly known as "Shone's syndrome. "19 The second category consists of two patients ( and ) with an infracristal ventricular septal defect located cephalad to the subaortic muscular thickening; one of these patients () also had an anomalous muscle bundle of the right ventricle. The third category consists of one patient () with interruption of the aortic arch who also had a small ventricular septal defect and patent ductus arteriosus. The eight patients ranged in age from 2 months to 22 years. Each patient had either hemodynamic or angiographic studies, or both. In no patient was a complete left heart catheterization performed and consequently the degree of left ventricular outflow tract obstruction was not measured. Seven of the eight patients were severely symptomatic (including four with clinical features of congestive heart failure); patient was asymptomatic. Each patient died of complications, either at the time of operation (two patients), during the immediate postoperative period (five patients) or following cardiac catheterization (one patient). Partial descriptions have been presented elsewhere of the clinical and gross pathologic data of patients 1,19,19 52 and. i5 The hearts of two other patients (aged one month and six months) who had parachute deformity of the mitral valve but did not have disproportionate septal thickening were analyzed for comparison. One of these patients also had coarctation of the aorta, ventricular septal defect, and supravalvular ring of the left atrium; the other patient had an associated coarctation of the aorta. Gross Pathology Measurements of ventricular wall thicknesses were made in the following areas: 1) ventricular septum, the maximum thickness of which was usually about one-third to one-half the distance between the aortic valve annulus and left ventricular apex; 2) anterolateral region of the left ventricular free wall, in the same transverse plane as that taken for the ventricular septum; 3) left ventricular posterior wall at Circulation, Volume 52, November 195 several points along a longitudinal plane extending from behind the posterior leaflet of the mitral valve to the left ventricular apex, and ) right ventricular wall in the area of maximum thickness. In making measurements of ventricular wall thicknesses care was taken to avoid including trabeculae, papillary muscles or crista supraventricularis. Histology Multiple blocks of myocardium were taken from the full thickness of the ventricular walls in the following regions of each heart: 1) ventricular septum in the area of maximum thickness; 2) left ventricular posterior wall, one-half the distance between the mitral valve annulus and the left ventricular apex; 3) left ventricular posterobasal wall, directly behind the posterior leaflet of the mitral valve, and ) anterolateral left ventricular wall, about one-half the distance between the mitral valve annulus and left ventricular apex. All tissue specimens were embedded in paraffin, sectioned at a thickness of,u and stained with hematoxylin and eosin. The extent of disorganization of cardiac muscle cells was graded in each tissue block independently by two investigators. The purpose of this assessment was to determine whether cardiac muscle cells in a given area of tissue were normally aligned with respect to each other. Echocardiography Echocardiograms were performed in first degree relatives (siblings or sets of parents, or both) of six of the eight patients (patients 3-) with disproportionate septal thickening and associated congenital heart malformations and of one of the two infants with congenital heart malformations not associated with disproportionate septal thickening. A total of 23 subjects, ranging from seven to 53 years of age, were studied; all were asymptomatic and free of evidence of cardiac disease. Echocardiograms were recorded by use of a modified Ekoline-2 ultrasound unit with an Aerotech gamma transducer.5 The ultrasound signal was transmitted via a custom-built video amplifier to a Honeywell 15 Visicorder and recorded continuously on light sensitive paper. The thickness of the ventricular septum was measured below the tips of the mitral valve leaflets just prior to atrial systole; posterobasal left ventricular wall thickness was measured at

3 92 MARON ET AL. the level of the tips of the mitral valve leaflets during the same phase of the cardiac cycle. Results Gross Pathology The gross pathologic features of the congenital cardiac malformations present in the eight patients with disproportionate septal thickening are summarized in tables 1 and 2. Heart weights ranged from to grams and were heavier than normal3' for the age of each patient. Measurements of ventricular wall thicknesses are summarized in table 2. In seven of the eight patients there was marked thickening of the ventricular septum (1-2 mm). The other patient (), a 2-month-old female infant, had mild ventricular septal thickening ( mm). Each heart showed disproportionate thickening of the ventricular septum with respect to the posterobasal left ventricular free wall (fig. 1). Disproportionate thickening was diagnosed when the ratio between the thickness of the ventricular septum and the posterobasal left ventricular wall equalled or exceeded 1.3L 3 This ratio ranged from 1.5 to 2.5 in the eight patients. In each of the eight hearts the left ventricular free wall showed great variation in thickness. The posterior wall was usually thickest about one-half the distance between the mitral valve annulus and left ventricular apex. When the ratio of ventricular septal to maximum posterior (instead of posterobasal) left ventricular wall thickness was calculated, it was found to be less than 1.3 in patients and. Anterolateral left ventricular wall thickness was equal to or greater than mid-posterior left ventricular wall thickness in each of the eight hearts and actually exceeded ventricular septal thickness in one heart (patient ). Similar findings are present in some patients with genetically determined ASH,' an observation that has led us to the conclusion that ventricular septal thickness must be compared with posterobasal left ventricular wall Figure 1 Heart from a two-month-old infant (patient 5) uwth parachute deformity of the mitral valve. The ventricular septum (VS) is disproportionately hypertrophied with respect to the left ventricular free wall (LV). thickness to ensure that the diagnosis of ASH is not inadvertently missed. Maximum right ventricular wall thickness ranged from 5 to 1 mm and was increased in all patients. Histology Ventricular Septum The observations on the arrangement of cardiac muscle cells in the eight patients with dispropor- able 2 Ventricular Wall Dimensions in Eight Patients with Disproportionate Ventricular Septal Thickening and Associated Congenital Heart Malformations Heart Normal heart Patient no RVSP weight (g) ( ( wseight (g)* s() Max VS PBLV { W all thicknesses (mm) Midposterior Anterolateral LVt LV Max RV 1 1].5 *IUpper limits of niormal heart weight for age of giveni patient.31 tabout onie-half the distance between mitral valve annulus and left ventricuilar apex. Abbreviations: g grams; IV left ventricular; max maximum; mml millimeter; PBLV posteroba.sal left RV - right ventrictular; RVSP right ventricular systolic pressure (mm Hg); VS - ventricular septal. = = VS:PBIV ratio ventriciular; Circulation, Volume 52, November 195

4 DISPROPORTIONATE SEPTAL THICKENING tionate septal thickening and various congenital heart malformations are summarized in table 3. In six of the eight hearts, cardiac muscle cells in the ventricular septum showed normal, parallel alignment (fig. 2). The majority of these cells were hypertrophied. In the other two cases, patient (a 3-month-old girl with ventricular septal defect) and patient 5 (a 2-month-old girl with parachute deformity of the mitral valve), many cardiac muscle cells in the disproportionately thickened ventricular septum were normally arranged; however, numerous other hypertrophied cells showed a disorganized arrangement. This disorganization assumed two patterns: 1) bundles or groups of cardiac muscle cells that interlaced and coursed in various directions among more normally arranged groups of cells (fig. 3) and 2) foci in which adjacent cells did not manifest the normal parallel alignment, but were arranged obliquely and perpendicularly to each other. The disorganized arrangement of cardiac muscle cells in these two infants was similar in appearance but less severe than that present in infants with genetically determined ASH' and is easily distinguished from the normal parallel arrangement of cardiac muscle cells present in infants with normal hearts or with concentric hypertrophy. 929 Table 3 Morphologic Assessment of Cellular Arrangement in Eight Patients with Disproportionate Ventricular Septal Thickening and Associated Congenital Heart Malformations Patient no VS 1 (1 (1 5 ) Grading system: = normal cellular arrangement; mild cellular disorganization; moderate disorganization. Abbreviations: IVFW = left ventricular free wall; VS = ventricular septum. Left Ventricular Free Wall The vast majority of cardiac muscle cells from the anterolateral, mid-posterior and posterobasal regions of the left ventricular free wall were hypertrophied and normally arranged in each patient. In the left ventricular free wall of four of the patients (3-) rare, small areas were observed in which bundles of cells Figure 2 Histologic section from the ventricular septum of a four-year-old child (patient ) with disproportionate septal thickening, parachute deformity of the mitral valve, supravalvular ring of the left atrium and coarctation of the aorta. Cardiac muscle cells are mildly hypertrophied but normally arranged. (X 9) Circulation, Volume 52, November 195 LVFW

5 MARON ET AL. 9 Figure 3 Histologic section from the ventricular septum of the same heart shown in figure 1. Several bundles of cardiac muscle cells are interlaced in a disorganized fashion among more normally arranged groups of cells. This disorganized arrangement of cardiac muscle cells gives a swirling appearance to the myocardium. (X 5) were interlaced in a disorganized fashion among more normally arranged groups of cells or in which adjacent cells were arranged obliquely and perpendicularly to each other. Similar small areas of disorganized cardiac muscle cells were present in the left ventricular free wall of the two patients with congenital cardiac malformations not associated with disproportionate septal thickening; the arrangement of cardiac muscle cells in the ventricular septum of these two patients was normal. Echocardiograms of Family Members Echocardiograms from all first degree relatives studied (including those of patients 5 and, who had disorganized cardiac muscle cells in the ventricular septum) were normal; the thickness of the ventricular septum ranged from to mm and that of the posterobasal left ventricular free wall from to 12 mm; septal-posterobasal wall thickness ratios ranged from.9 to 1.1. Discussion This study confirms the finding that disproportionate thickening of the ventricular septum may occur in association with a variety of congenital heart malformations."29 The major question which this investigation sought to answer, however, was whether such patients with disproportionate septal thickening had the same disease we previously demonstrated to be transmitted as an autosomal dominant trait with a high degree of penetrance; i.e., genetically determined ASH.' That this was probably not the case is demonstrated by the fact that we did not detect, by echocardiography, disproportionate septal thickening in parents or siblings of patients in this investigation. Moreover, six of the eight patients did not have the disorderly arranged cardiac muscle cells in the ventricular septum, a finding characteristic of all patients with genetically determined ASH that we have studied.-1 Nevertheless, we cannot entirely exclude the possibility that some of our patients did have genetically determined ASH in addition to other congenital cardiac malformations (and therefore two independent and coexisting diseases), since the number of first degree relatives studied by echocardiography was relatively small and some affected members could have been overlooked. Furthermore, it is possible that the expression of ASH in some families may have been mild and consequently too subtle to be diagnosed by echocardiography. Circulation, Volume 52, November 195

6 DISPROPORTIONATE SEPTAL THICKENING Of note is our finding that two patients in this study showed disorganization of cardiac muscle cells in the ventricular septum. These observations confirm our previous finding' that this bizarre distortion of myocardial architecture, while characteristic of patients with genetically determined ASH, is also found in other conditions. For example, disorganized cardiac muscle cells similar to those present in patients with ASH have been found in crista supraventricularis muscle of some patients with congenital heart diseases associated with right ventricular outflow tract obstruction.32' 33 The etiology of the disproportionate septal thickening in our patients is unclear. However, all eight patients had right ventricular hypertrophy (as evidenced by increased thickness of the right ventricular wall) and four patients (1, 3, 5 and ) had marked right ventricular hypertension documented by cardiac catheterization. It has been shown that severe right ventricular hypertension may be associated with disproportionate septal thickening;3 this thickening presumably results from increased contribution of the right ventricular component of the septum to ventricular septal hypertrophy. Therefore, the disproportionate septal thickening in our patients may have been a manifestation of this phenomenon. It should be emphasized that this conclusion is based on observations limited to patients with only a few types of congenital cardiac malformations. An association between muscular subaortic obstruction or disproportionate septal thickening and various other congenital cardiac malformations is uncommon, but has been described in patients with secundum type of atrial septal defect,21 23 primum type of atrial septal defect with discrete fibrous subaortic stenosis,2 common atrioventricular canal,25 aortic valvular stenosis,22' 2 discrete fibrous subaortic stenosis,2' 2 situs inversus with dextrocardia,23 pulmonary valvular stenosis22 and ventricular septal defect following pulmonary arterial banding.29 Muscular subaortic obstruction or disproportionate septal thickening are also known to occur in other diseases not associated with congenital cardiac malformations, including Friedreich's ataxia,35' 3 glycogen storage (Pompe's) disease of the heart,3' 3 Turner's phenotype,39 1 hyperthyroidism,2 multiple lentigines3 and systemic hypertension. It is evident that these conditions comprise an extremely heterogeneous group of disorders, and that echocardiographic and detailed anatomic studies will have to be made to determine whether the muscular subaortic obstruction in each of these conditions is a manifestation of the disease spectrum of genetically determined ASH. The following conclusions can be derived from our studies: 1) disproportionate ventricular septal thicken- Circulation, Volume 52, November 195 ing may occur in association with several types of congenital heart malformations; 2) disproportionate septal thickening in these patients does not appear to be a manifestation of the disease spectrum of genetically determined ASH, as shown by echocardiographic study of first degree relatives; and 3) although disproportionate septal thickening and disorganization of cardiac muscle cells constitute characteristic findings of genetically transmitted ASH, they are not specific for this entity and may be present in other cardiac disorders. Acknowledgments 931 We wish to thank Ms. Cora Burn, R.N., Mrs. Joyce McKay, R.N. and Mrs. Estelle Cohen for their fine technical assistance. We are also indebted to Dr. Russell V. Lucas of the University of Minnesota Hospitals for his cooperation in providing clinical information on the patients in this study. 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