Patterns of inheritance in hypertrophic cardiomyopathy: Assessment by m-mode and two-dimensional echocardiography

CARDIOMYOPATHY

Patterns of Inheritance in HypertrophicCardiomyopathy: Assessment by M-Mode and Two-Dimensional Echocardiography BARRY J. MARON, MD, PAUL F. NICHOLS III, MD, LINDA W. PICKLE, PhD, YVONNE E. WESLEY, and JOHN J. MULVIHILL, MD

To determine the mode of inheritance of hypertrophic cardiomyopathy (HC), 367 relatives from 70 families with HC were studied by M-mode and 2dimensional echocardiography (2-D echo). Inspection of individual family pedigrees suggested that HC was genetically transmltted In 39 pedigrees (56%) and probably sporadic In 31 (44%). Of the 39 pedigrees with familial occurrence, 30 had patterns of inheritance that were most consistent with autosomal dominant transmission. A complex mathematical pedigree analysis determined that patterns of genetic transmission observed in the overall study group were not consistent with known models of autosomai dominant, autosomal recessive, or X-linked inheritance and did not support a unified concept of single-gene Mendelian transmission for all families. The proportion of first-degree relatives affected by HC was 22%, with HC most common in fathers of the proband and least common in offspring. About 20 % of the affected relatives (10 of 53) appeared to have inherited a “subclinical” form of HC, in which the sole evidence of HC was the morphologic expression detectable only with echocardiography.

Probands and affected relatives differed distinctly with regard to the expression of HC. Probands most often showed functional llmltatlon (61%), subaortk obstruction at rest (53%), particularly dlffuse distribution of lefl ventricular hypertrophy (59%) and marked septal thickening (mean 23 mm). In contrast, affected relatlves were characterized by absence of functional llmltatlon (72 % ) and subaortic obstruction (94 % ), localized and unusual sites of hypertrophy (60 % ) and only modest septal thlckenlng (mean 17 mm). Probands wlth the familial or sporadic forms of HC did not differ with regard to the phenotypic expression (clinical or morphologic) of their disease. In conclusion, no single mode of Inheritance is typical of HC, although autosomal dominant transmission is most common; a variety of phenotypic expressions occur that appear to have genetic as well as nongenetic causes, suggesting that HC may not be a single etlologically distinct disease entity; and genetic counseling recommendations should be influenced by the particular pattern of Inheritance demonstrated In each family.

Since its initial description by Teare in 1958,’ the cause of hypertrophic cardiomyopathy (HC) has been a source of controversy. During the 1960s both familial (genetically transmitted) and sporadic forms were described, based on information obtained primarily from history and clinical examination or at necropsy.2-12 The ge-

netically transmitted variety of HC comprised about one-third of families,10 with an autosomal dominant pattern of transmission most commonly found.2-12 The application of echocardiography to cardiac diagnosis in the 1970s permitted the identification of many patients with HC who otherwise would have remained undetected clinically.r3J4 Family studies performed with M-mode echocardiography suggested that most, and probably all, patients with HC had a genetic defect that was transmitted as an autosomal dominant trait with a high degree of penetrance.15-LS However, not infrequently, we have evaluated with echocardiography families in which genetic transmission of HC could not be demonstrated.lg Furthermore, the accuracy with which HC may be identified noninvasively has increased

From the Echocardiiaphy Laboratory and Cardiilogy Branch, National Heart, Lung, and Blood Institute, and the Environmental and Clinical Epidemiology Branches, National Cancer Institute. National Institutes of Health, Bethesda, Maryland. Manuscript received September 28, 1983; revised manuscript received December 5, 1983, accepted December 15, 1983. Address for reprints: Barry J. Maron, MD, Senior Investigator, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 7B-15, Bethesda, Maryland 20205.

(Am J Cardlol 1964;53:1067-1094)

1000

INHERITANCEIN HYPERTROPHICCARDIOMYOPATHY

in each family (including probands). No family in this study was included in a previous investigation.i5 There was no evidence of any relationship by blood or marriage among probands. In only 1 family was there an example of consanguinity (the marriage of cousins). M-mode echocardiography: M-mode echocardiograms were performed using a 2.25-MHz, 1.25.cm-diameter, unfocused Aerotech transducer and a Hoffrel201 ultrasonic receiver interfaced with a Honeywell 1856 strip-chart recorder. The methods used for imaging the ventricular septum and posterior left ventricular (LV) free wall have been described.14 Maximal thickness of the ventricular septum was measured just before atria1 systole with the ultrasonic beam directed through or slightly caudal to the mitral leaflets. The thickness of the posterior LV free wall was measured during the same phase of the cardiac cycle, with the ultrasound beam passing through the mitral leaflet tips. In measuring ventricular wall thicknesses the “leading-edge” method was used27 (i.e., the septal dimension was taken between the most anterior edges of both endocardial lines of the septum, and the posterior free wall dimension was taken between the most anterior edges of the endocardium and epicardium). To verify ventricular septal thickness, M-mode echocardiograms were also obtained simultaneously with direct visualization of the cardiac anatomy using a 2-D echo instrument. The relative thicknesses of the ventricular walls were expressed as the ventricular septal to free wall ratio by dividing the value for posterior LV free wall thickness into that for septal thickness.14 Two-dimensional echocardiography: A Varian (V-3400) real-time, phased-array, ultrasonic sector scanner with a hand-held 2.25MHz transducer was used to perform the 2-D echocardiographic studies. 28Images were recorded on either a 0.5-inch (Sanyo) cassette videotape, or l-inch (Sony) reel-

with the improved diagnostic quality of M-mode echocardiograms, greater insights into the interpretation of these tests, the introduction of wide-angle 2dimensional echocardiography (2-D echo), and better appreciation of the broad morphologic spectrum of this disease. Therefore, we studied the relatives of 70 patients with HC utilizing M-mode and 2-D echo, and also applied newly available and sophisticated formal genetic analyses to clarify the patterns of inheritance in HC.

Methods Patients: From February 1979 to October 1979,156 unrelated patients with the characteristic clinical, hemodynamic and echocardiographic features of HC6JoJsJ4Jo-25 were evaluated consecutively in the inpatient and outpatient services of the National Heart, Lung, and Blood Institute. These patients were referred to our institution because of a suspicion or documentation of HC, but no patient was referred solely because of a family history of HC. Each of the 156 patients was interviewed and an extensive family history was obtained. For a pedigree to be included in the study group, the proband was required to have at least 3 first-degree relatives (parents, siblings or offspring)26 who were 5 years of age or older and in whom a technically satisfactory M-mode and Z-D echocardiogram could be obtained. These criteria excluded 86 of the 156 consecutively selected families, and hence, the remaining 70 families constituted the final study group. Finally, 69 of the 70 probands and 298 first-degree relatives were studied by M-mode and 2-D echo and electrocardiography. Four to 11 relatives (range 4 to 11, average 5.4) were studied

A.

fi!? 167) (70) +

(42)

;a*

MO)

(39)

“’ (28)

(25)

(22)

~~~*~*~ (20)

(9)

(52)

(50) (‘@I) (38) ‘-” ” (37) (36)

(34)

(32)

j:::: ::::: (7)

(12)

D.

FIGURE 1. Five family pedigrees selected as examples of different modes of inheritance. A, most consistent with autosomal dominant inheritance showing 5 affected persons (2 males and 3 females) in 3 consecutive generations: B, probable autosomal dominant transmission with 4 affected men in 2 generations; C, large pedigree showing probable autosomal dominant pattern of transmission, but with a relatively small proportion of affected relatives (i.e., 25%); D, familial transmission of hypertrophic cardiomyopathy (HC) in which only the proband and a brother are affected; this pedigree cannot be classified with regard to a particular Mendelian mode of inheritance; E, sporadic (nonfamilial) occurrence of HC. Both parents and each sibling of the proband are unaffected by HC. This pedigree is also compatible with Mendelian modes of inheritance, including autosomal recessive transmission or a new mutation. Solid symbols indicate death due to HC; haMlIed symbols, alive and HC was identified by echocardiography; stippled symbols, echocardiographic studies did not show HC; dagger, noncardiac or nonpremature cardiac death; clear symbols, subject not evaluated by echocardiography; doffed circles, females; dotted squares, males; patient’s age (years) are shown in parentheses below the symbols. Probands are indicated by arrow.

April 1, 1984

THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53

1089

to-reel videotape for subsequent review in real-time, slow motion or stop-action modes. Two-dimensional echocardiographic examination included imaging a number of cross-sectional planes through the heart.2g Serial short-axis LV views were obtained by orienting the sector plane perpendicular to the long axis of the left ventricle from a standard parasternal location. The short-axis sweep was performed by maintaining the transducer in a fixed location on the chest wall and slowly angling the image plane from aorta to apex.30 The long-axis view was obtained by orienting the sector plane parallel to the LV longitudinal axis. The apical 4chamber view was obtained with the transducer placed at the cardiac apex and the tomographic plane directed perpendicular to the ventricular and atria1 septa and through the plane of the mitral and tricuspid valve orifices to permit simultaneous display of both atria and ventricles, atrioventricular valves and cardiac septa.31 The location and distribution of LV hypertrophy could reliably be assessed by 2-D echo in 61 probands and 50 affected relatives. Patients were classified into 4 morphologic types as previously described. 23*32In type I, hypertrophy was confined to the anterior segment of ventricular septum; LV free wall and posterior ventricular septum appeared essentially normal. In type ZZ, hypertrophy involved both the anterior and posterior portions of the septum; the free wall appeared normal. In type ZZZ,hypertrophy involved substantial portions of both septum and anterolateral free wall; often, the only portion of the left ventricle uninvolved by hypertrophy was the posterior free wall. In type IV, hypertrophy was present in regions of the LV wall other than the anterior basal ventricular septum (i.e., posterior segment of septum, anterolateral free wall or septum in its apical one-half). Diagnostic criteria for hypertrophic cardiomyopathy: The basic diagnostic criterion of HC used in this study was a hypertrophied nondilated left ventricle in the absence of another cardiac or systemic disease capable of producing LV hypertrophy.33 Seven probands in the study group had a history of systemic hypertension, but were included because they had clinical or hemodynamic features consistent with HC or because the extent of LV hypertrophy they manifested clearly exceeded that expected from hypertension alone.s4,35 LV hypertrophy was identified by M-mode echocardiography as increased thickness of the ventricular septum alone, or of both the septum and posterior free wall (215 mm in adults or >95% confidence interval in childrenss). In those affected relatives with morphologic type IV (and normal

ventricular wall thicknesses on M-mode echocardiogram), the recognition of hypertrophy in regions of the left ventricle inaccessible to the M-mode ultrasonic beam was achieved by 2-D echo.23v32 Certain first-degree relatives who showed particularly minimal increases in LV mass by echocardiography could not be definitively classified as having HC and were designated as having a borderline morphologic abnormality. These relatives (all of whom were asymptomatic) had ventricular wall thicknesses that were only slightly increased over normal (13 or 14 mm in adults); their alterations in ventricular wall thickness were shown by 2-D echo to be confined to only the anterior ventricular septum. Assessment of hemodynamic state: Probands and affected relatives were categorized with regard to their hemodynamic state. The magnitude of LV outflow tract obstruction under basal conditions was assessed at cardiac catheterization in 46 patients, or was estimated from the M-mode echocardiogram based on the magnitude and duration of systolic anterior motion of the mitral valve25,37+3sin the remaining patients. By our previously described convention,39 outflow obstruction was considered to be present if the measured or estimated subaortic gradient was 130 mm Hg; outflow obstruction was considered absent if the measured or estimated gradient was 0 or <30 mm Hg. Analytic methods: Initially, the 70 pedigrees were inspected and categorized as sporadic (no affected relatives other than the proband) or familial (at least 1 affected relative other than the proband). Pedigrees showing familial occurrence of HC were classified into those with at least 1 affected relative in 2 or more consecutive generations and those with more than 1 affected relative in only 1 generation. Modes of inheritance in the study group were then examined by a simple segregation analysis.40 This method determined the proportion of relatives of probands who were affected by HC. Subsequently, a complex pedigree analysis was performed using the maximal likelihood method of Elston and Stewart41 This procedure tested whether the patterns of transmission observed in the overall study group of 70 pooled families were consistent with mathematical models of single-gene Mendelian inheritance. In addition, the possibility that the occurrence of HC was totally random or sporadic among family members (i.e., the “environmental” nongenetic hypothesis) was tested by this method. Other statistical comparisons were made by Student t test or chi-square test, when appropriate.

FIGURE 2. Prevalence of different modes of inheritance in 70 families with hypertrophic cardiomyopathy, based on inspection of individual pedigrees.

Findings in first-degree relatives: Suruiuors: Of the 298 first-degree relatives studied by echocardiography, 53 met our diagnostic criteria for HC. Another 226 relatives were considered to be definitely unaffected by this disease. Nineteen relatives were classified as neither affected nor unaffected by HC. These subjects had echocardiographic findings suggestive of HC (i.e., increased ventricular wall thicknesses and abnormal septal-free wall ratio of 1.3 or more14). However, the diagnosis remained uncertain because either (1) an associated cardiovascular disease (aortic valvular stenosis or systemic hypertension) obscured the determination of whether cardiac hypertrophy represented a primary manifestation of HC or was secondary to the associated cardiovascular lesion (12 patients),42 or (2) ventricular wall thicknesses were considered borderline (7 patients).

Results

1090

INWWANCE

IN HYPERTROPHIC CARDIOMYOPATHY

Of the 226 relatives considered unaffected by HC (based on echocardiographic studies), 27 (12%) showed distinct abnormalities on the scalar EGG and were younger than 40 years of age. These abnormalities included T-wave alterations in 9, abnormal Q waves in 8, LV hypertrophy in 5, right-axis deviation or left atria1 enlargement in 3 each, and right bundle branch block or Wolff-Parkinson-White pattern in 1 each. Non.suruiuors: A historical review of available clinical and necropsy data disclosed that 11 of the 110 deceased relatives definitely met our diagnostic criteria for HC.6~22~23J3~*2~*s Three other relatives who died suddenly before age 40 years, but had incomplete clinical and necropsy information available, were considered to possibly have had HC. In 95 other relatives, insufficient data were available to determine whether that person had HC (including 66 who ultimately died of noncardiac causes). In 1 patient, available necropsy information definitively excluded HC. Inspection of pedigrees: By inspection, 39 of the 70 pedigrees (56%) revealed familial occurrence of HC with 2 or more affected relatives (including the proband) (Fig. 1 and 2). In 30 of these 39 pedigrees, the pattern of inheritance was consistent with an autosomal dominant trait, i.e., affected relatives were identified in 2 or more consecutive generations (Figure 1, A to C); in 9 other families 2 or more affected relatives were identified in only 1 generation and the precise pattern of inheritance could not be definitively categorized (Fig. 1D).

In the other 31 pedigrees (44%), the proband was the only relative studied who proved to be affected by HC (Fig. 2). For the purposes of this study, these families were considered to represent “sporadic” occurrences of HC. In 9 of these families with sporadic occurrence of HC in the proband, each first-degree relative was studied by echocardiography and HC was definitively excluded (Fig. 1E). Therefore, in these 9 families it was possible to exclude conclusively autosomal dominant inheritance. If surviving relatives with borderline echocardiographic studies and deceased relatives with possible HC were considered to be affected relatives, the proportion of the 70 pedigrees assigned to the familial (59%) or sporadic (41%) groups did not change substantially. Segregation analysis: The proportion of first-degree relatives with HC (i.e., segregation ratio) in the overall study group was 22%. This figure was obtained by considering as affected only those relatives in whom HC was definitely identified, either by echocardiographic study (53 patients) or at necropsy (11 patients). If surviving relatives with borderline echocardiographic studies and those who possibly had died from HC were included among the affected relatives, the segregation ratio (i.e., 24%) was not altered significantly. Furthermore, the proportion of affected relatives did not differ significantly when the data were analyzed either with (23%) or without (22%) the 6 families in which the proband had mild systemic hypertension. Offspring of the probands were less often affected (20 of 139,14%) than were siblings (26 of 112,23%) or par-

906 N =l 8 @3-

PROBANDS

70 -

AFFECTED RELATIVES a

@I

E Y 2

50 N=27 -,-

5 8

40-

N=62

t

z 3O-

20-

10-

01

’

Male

IL

Female

PARENTS

Male

Female

SIBLINGS

Male

Female

OFFSPRING

FffiURE 3. Proportion of relatives affected by hypertrophic cardiomyopathy (segregation ratio), p&ted as mean values with 95% confiiCe intervals. Shown separately by sex for parents, siblings and offspring of the proband.

FUNCTIONAL LIMITATION

LVOT OBSTRUCTION

SEPTUM 5Mmm

DIFFUSE tw*

FIGURE 4. Comparison of probands and affected relatives with regard to functional limitation, left ventricular outflow tract (LVOT) obstruction, marked septal thickening (as assessed by M-mode echocardiography) and distribution of left ventricular hypertrophy (LVH). Aaterfsk indicates ~rp~l~ic type Ill with diffuse hy~~ophy involving substantial portions of ventricular septum and anterolateral free wail.

April 1,1984

ents (18 of 45, 40%; p
THE AMERICAN JOURNAL OF CARDIOLOGY Volunre53

TABLE I

1091

DemographlcData and Ventricular Wall Thicknesses In Probands,Affected Retatives and Unaffected Relatives Relatives Probands

Affected

Unaffected

Characteristics of subjects 226 No. of patients 69’ 41 f 2 37 233 42f 1 Age (yr) 5-83 5-74 Age range 7 28 No. of patients from ‘O-? age 5 to 15 years 64 51 % Male 66 M-mode echo measurements 17 f I+ Septal thickness (mm) Posterior FW thickness (mm) :i $ (: 3 11 f 0.i? ‘: : x,:: 1.8 f 0:05 1.6 $$.!6+1.0 f O:Ol+ VSIFW % VSlFW r 1.3 52+ 7 % VSlFW 11.5 t: All data are expressed as either mean or mean f standard error of the mean. + One proband underwent ventricular septal myotomy-myectomy before the time ec~~rdi~raphy came into diignosic use for hypertrophrc cardtomyopathy. Parameters that, when compared statistically with the proband, have achieved significance at p
ratios than either siblings or parents (Table III). Probands with the familial or sporadic forms of HC did not differ with regard to the clinical and morphologic expression of their disease (Table IV). “Subclinical” expression of hypertrophic cardiomyopathy in relatives: Of the 53 relatives considered to be affected by HC based on echocardiographic findings, 10 bad neither cardiovascular symptoms nor evidence of subaortic obstruction and had attained the age of 50 years (ranging up to 74 years; mean 60). Ventricular septal thicknesses ranged from 15 to 31 mm (mean 19). In 6 of these 7 relatives with technically adequate 2-D echo, hypertrophy was localized to the anterior septum; the other relative had type II distribution of hypertrophy. ECGs were normal in 6 subjects and abnormal in 4. These 10 relatives were considered to have a subclinical trait (i.e., the morphologic features of HC unassociated with an overt clinical expression of the disease). Discussion The data presented in this study demonstrate that an autosomal dominant mode of inheritance is not typical of all patients with HC. Furthermore, no particular pattern of inheritance was characteristic of our entire study group, suggesting that HC may not be a single etiologically distinct disease. A complex pedigree analysis showed that the pooled data for all 70 pedigrees were neither consistent with Mendelian models of autosomal dominant or autosomal recessive inheritance, nor consistent with an environmental (nongenetic) disease model. When the 70 pedigrees were analyzed indi~dually, only 56% had clear evidence of a genetic disease. In pedigrees that showed familial transmission,

1092

INHERITANCE IN HYPERTROPHIC CARDIOMYOPATHY

TABLE II

Distribution of Left Ventricular Hypertrophy (Morphologic Type) in Probands and Affected Relatives

Morphologic Type (2-D Echo)

I

III IV

TABLE Ill

Demographic Data and Ventricular Wall Thicknesses In Probands and in Subgroups of Affected Relatives Affected Relatives

Affected

Probands

Relatives

p Value

10 116%)

17 (34%)

NS

ii3(2i%j 32” I;??) 0

12 {24%j 8 (16%) 13 (26%)


2-D echo = 2-dimensional echocardiography; NS = not significant.

the pattern of inheritance was usually most consistent with an autosomal dominant trait. However, in 44% of our families no relative other than the proband was identified as having HC, and such pedigrees may represent instances of sporadic or isolated occurrence of the disease. Certain methodologic considerations make the study of genetic patterns and interpretation of sporadic OCcurrence of HC difficult. The diagnosis of HC cannot be made reliably from a retrospective history, but USUally requires laboratory tests such as echocardiography or necropsy examination. In our analysis, many relatives who died had not undergone such studies and therefore HC could not be definitvely excluded. Hence, although an isolated case of HC in a pedigree may reflect a nongenetic expression of the disease, alternatively it may also be theoretically consistent with: (1) familial occurrence of HC, which could not be substantiated because of the aforementioned limitations of a retrospective analysis; (2) the initial occurrence of a genetic disease in a family (new mutation); (3) a genetic disease that is not expressed overtly in every generation (reduced penetrance); or (4) autosomal recessive transmission. However, the particularly large proportion of families in this study without apparent genetic transmission (i.e., 44%) support the view that other nongenetic, and therefore etiologically distinct forms of HC, probably occur. Definition of the precise nature of such nongenetic causes is beyond the scope of this investigation. Our conclusions differ importantly from those of previous M-mode echocardiographic studies in families with HC.151s The earlier reports maintained that most, and probably all, patients with this disease have a genetic defect that is transmitted as an autosomal dominant trait with a high degree of penetrance (with a segregation ratio as high as 0.4615). In contrast, our M-mode and 2-D echocardiographic studies showed a substantially smaller proportion of first-degree relatives to be affected by HC. Such discrepancies between the present study and those of previous investigators may be explained largely by advances in the technical and interpretative aspects of echocardiography during the past 10 years, which now permit more accurate assessment of ventricular wall thickening, and minimize falsepositive diagnoses of HC. In particular, real-time 2-D echo affords greater accuracy in defining the right and left surfaces of the ventricular septum, especially when used in conjunction with M-mode echocardiography. However, use of 2-D echo in this study also permitted

Characteristics of subjects No. of pts Age (yr) % Male M-mode echo measurements Serz@&hickness Posterior FW thickness (mm) VSIFW %VSlFW L 1.3 %VS/FW 21.5

Siblings

Offspring

Probands

Parents

69” 41*2+ 66

13 54 f 37 62

41 i24t 64

18 20 f 2 67

23 f

18f

19 f

15f2

1’

13 l 0.3+ 1.8 i4y.l+ 81+

1

11 f 0.4 l.6;2,.l 77t

1’

11 f 0.4: 1.7 i6T.’ 52

10 f 0.4 l.45f60.1 33

All data are expressed as either mean or mean f standard error of the mean. One other proband underwent ventricular septal myotomy-myectomy before the time echocardiography came into diagnostic use for hypertrophic cardiomyopathy. t Variables that, when compared statistically with offspring, have achieved significance (p
the identification of a number of relatives with the morphologic expression of HC who would not have been considered affected family members if studied by Mmode echocardiography alone.32 In such persons (who comprised 25% of all affected relatives), 2-D echo permitted visualization of regions of hypertrophy that were inaccessible to the path of the M-mode beam. When family members were grouped according to their relation to the proband, it was evident that fathers were most frequently affected by HC; offspring were _‘-ast often affected and showed a less severe morphologic expression of the disease. The fact that affected offspring were significantly younger (and fathers older) than other relatives raises the possibility that morphologic expression of HC is not always congenitaIlg and may develop later in life. We can only speculate on this possibility, because our study is a cross-sectional analysis of patients at only a single point in time. Possibly also relevant to such considerations is the fact that about 10% of our first-degree relatives (less than 40 years old) with normal M-mode and 2-D echocardiographic studies had distinct abnormalities on the 12-lead ECG. The significance of these abnormalities is unclear. Although such relatives are probably unaffected by HC, we cannot unequivocably exclude the possibility that their electrocardiographic alterations may precede the actual appearance of LV hypertrophy. The findings of this report are of particular relevance to the issue of genetic counseling. The average “risk” in the study group for transmitting HC to an offspring (empiric recurrence risk) was relatively low (about 20%). However, our data suggest that counseling recommendations should be influenced by the patterns of inheritance shown in each family. For example, families with

April 1.1984 THE AMERICANJOURNALOF CARDlOLOGYVolume53

TABLE IV

Comparisonof Clinlcal and Morphologic Parameters In Probandswlth Familial or Sporadic Forms of Hypertrophlc Car~yopa~y

Clinical Features

Age (yi)

% hiale % With functional limitation % With LVOT obstruction M-mode echo measurements Septal thickness (mm) ~~~ FW thickness (mm)

taining the echocardiographic studies, and to Lynn Goldin, MD, for her helpful advice.

Familial

Sporadic

Value

::

G

0.1 1.0

5:

z;

::t

23f 1 13 f 0.4 1.9fO.l

23f 1 13 f 0.4 1.8 f 0.1

:? 0:2

Distribution of LVH (2-D echo) No. and % of patients with each morphologic iype Ii

References 1. Teare D. Asymmetiical hyp8rtropf1yof the h8art in youngpatients.Br Heart J 1985;20:1-8. 2. Hollman A, Goedwin JF, Tear6 D, Renwkk JW. A family with obstructiw, cardiomyopathy (asymmetrical hypertrophy). Br Heart J 1960;22:449456. 3. Brent LB, Aburano A, Flehef DL, Moran TJ, Myera JD, Taylor WJ. Familial muscular,su~oit!c~stenosis. An unrecognlr+ form 01 “idiopathicheart ci6igo with cltntcal and autopsy observations.Clrcu~t~ 1960;21: 4. Par9 JAG, Freeer RG, Plrozynskl WJ, shanks JA, Btubln9ton D. Her8ditw-y cardiovplscular dysplasia. A form of familial cardiomyopathy. Am J Med 1961:31:37-62. 5. Wood RS, Taykr WJ, Wheat MV, Schlebkr GL Muscularsubaorticstenosis in childhood.Report of occurrence in three siblings. Pediatrics 1Q62Z30: _‘^ _rl 14Y-130.

Ill IV

All data are exoressed as either mean or mean f standard error of themean. ’ LVH = left ventricular hy~rophy; LVOT = left ventricular outflow tract; other abbreviations as in Tables I and ii.

high genetic transmission (i.e., apparent autosomal dominant pattern) have a risk to future offspring that is probably 25 to 50%. Conversely, in families with only a single occurrence of HC, the risk of genetic transmission of the disease is substantially less than 25%. Although we found no examples of HC “skipping” generations, our pedigrees were generally not large enough to unequivocably exclude this possibility. Also of importance to genetic counseling is that about one-fifth of our affected relatives did not have a clinically overt form of HC. In these persons, the morphologic expression of the disease (LV hypertrophy) was identifiable by echo; however, neither symptoms nor subaortic obstruction had appeared by age 50 years. Therefore, it seems reasonable to consider this subgroup of relatives as having a subclinical form of HC that constitutes a dormant morphologic trait rather than a true disease state. If relatives with this subclinical morphologic trait are excluded from consideration, the overall risk for transmission of the clinically overt form of HC from parent to offspring is less than 20%. Proband and affected relatives appeared to differ distinctly with regard to the clinical and morphologic expression of NC. Probands usually showed evidence of significant disease with symptoms and functional limitation, obstruction to LV outflow, marked ventricular septal thickening and diffuse distribution of LV hypertrophy. Indeed, marked symptoms and subaortic obstruction accounted for the referral of most of these patients to our institution. In contrast, affected relatives usually demonstrated no or minimal symptoms, absence of outflow obstruction, modest septal thickening and more unusual and less diffuse patterns of LV hypertrophy. About 70% of affected relatives, including 8 of 10 with subclinical disease, were identified as having a cardiac abnormality only because they participated in this study. Acknowledgment:

1OSS

We extend our appreciation to James

K. Wolfson and Andrew M. Harding for their efforts in ob-

6. BraunwaldE, Lambfew CT, Rookoff SO, Rosa J Jr, Morrow AG. Idiopathic hypertrophic subaoftic stenosis: I. A Description of the disease based upon an analysis of 64 patients. Circulation 1964;3O:suppl iV:IV-3-IV-119. 7. Horllck L, Petkovkh NJ, BoftonCF. Idiopathic hypertrophic subvalvular stenosis. A study of a family involving four nerations. ClInical, hemodynamic and pathologic observations. Am J & diol 1966,17:411-416. 8.~wK,w~JF,~ME,~uRH,H~C,~AD, Genoveee PD. Familial myocardial disease with and without obstruction to left ventricular outflow. Circulation 1967;35:638-652. 9. JOrgeneen 0. Genetische Untersuchungenbel funktionell-obstruktiver subvalvul&erAortenstenosa(irmguliir hypertrophischer Kardiomyopathie). Hum Gsnet 1968;6:13-28. 10. Frank S, BraunwafdE. Idiopathic hypertrophic subaortfc stenosis. Clinical analysis of 128 patients with emphasis on the natural history. Circulation 1960;37:759-760. 11. Emanuel R, Withers R, O’Brlen K. Dominant and recessive modes Of inheritance in idiopathic cardiomyopathy. Lancet 1971;2:1065-1067. 12. Littler WA. Twin studies in hypertrophic cardiomyopathy. Br Heart J 1972;34:1147-1151. 13, Abbeef AS, MecAfpk, RN, Eber LM, Pearce ML Echocardiographic diagnosis of idiopathic hyp8rtrophic cardiomyopathywithout outflow obstructlon. Circulation 1972;46:697-904. 14. Henry WI., Clark CE, Epstein SE. Asymmetric septal hypertrophy (ASH): echocardi aphk identlficatlon of the pathognomonic anatomic abnormality of IH Y S. Circulation 1973;47:225-233. 15. Clark CE, Henry WL, Epet& SE. Familial prevalence and genetic transmission of idiopathic hypertrophic subaortic stenosis. N Engl J M8d 1973;269:709~714. 16. van Dorp WG, ten Cats FJ, Wetter WB, Dohman H, Roelandt J. Familial g;;fF6? of asymmetric septal hypertrophy. Eur J Cardiol 1976;4: 17. ten Cat0FJ, H~~z PG, van Dorp WG, Roelandt J. Prevalence of diagnostic abnormalitl8s in patients wfth Qan8tlcally transmitk! asymmetric septal hypertrophy. Am J Cardiol 1979;43:731-737. 19. Bjamaeon I, Jonsson S, Hardereon T. Mode of inheritance of hypertrophic cardiomyopathy in Iceland. Br Heart J 1982;47: 122- 129. 19. Maron &I. Tajlk AJ, Rultenberg HD, Graham TP, Atwood OF, Vlctorka BE, Lie ST, Robe& WC. ~~0~1~ ~rdi~opa~y in infants: clinical features and natural history. Circulation 1982;65:7-17. 20. GoodwlnJf, Holknan A, Cleland WP, Tears RD. Obstructive cardiomyopathy simulating aortic stenosis. Br Heart J 1960;22:403-414. 21. Wlgle ED, Helmb8cker RO, Gunton RW. Idiopathic ventricular septal hyoertroohv causino muscular subaortic stenosis. Circulation 1962:28: 325$46 ” 22. Epstefn SE, Henry WI., Clark CE, Roberts WC, Maron BJ, Ferrans VJ, Redwood DR, Morrow AG. Asymm8tric septai hypertrophy. Ann Intern Med 1974;81:650-680. 23. Maron BJ, GottdlenerJS, Epstein SE. Patterns and significance of distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy. A wide-anole. twodlmensional echocardiowaphlc study of f25 oatients. Am _ J Cardid 1981;48:418-428. 24. TaJlk A?, Gkdlanl ER. Echocardiographic observations in idiopathic hypertrophlc subaortic stenosis. Mayo Clin Proc 1974;49:89-97. 25. Gllberf BW, Polllck C, Adelman AG, Wfgle ED. Hypertrophic cardiomyopathy: subclassification by M-mode echocardiography. Am J Cardiol 1980:45:861-672. 26. Pfckk LW, Mufvlhlfl JJ. An example of sample size ~te~i~ti~ for family studies. Am J Epldemlol 1981;114:299-303. 27. Safm D, GeMarfa A, Klselo J, Weyman A. Recomm8ndations regarding

29.

2Q. 30. 31.

quantitatlon in M-mod8 echocardiography. Results of a survey of echocardiographic measurements. Circulation 1978;58:1072-1063. Anderson WA, Amokl JI, Clark D, Davkk8WT, Hlllard WJ, Lele WJ, Zftelll LT. A new real-time phasedarray sectw scann8r tar imagingthe entire adult human heart. In: White DN. ed. Ultrasound in Medicine. Vol3B. New York: Plenum press, 1977;1547-1558. Tajlk AJ, Seward JB, Hagfer DJ, Mafr DD, Lfe JT. Twodiisional real-time ultrasonic imaging of the heart and great vessels. Mayo Clin Proc 1976; 53:271-303. Kisefo J, von Ramm 01, Thuretone FL. Cardiac imaging using phased array ultrasound system. II. Clinical technique and appkcation. Circulation 1976:53:262-267. Slfverman NH, Schlller NE. Apex echocardiography. A two-dimensional technique for evaluating congenital heart disease. Circulation 1978;57:

fOS4

INHERITANCE IN HYPERTROPHICCARDtOMYOPATHY

503-5 Il. 32. Yaron GJ, Gottdlener JS, Bonow RG, Epstein SE. Hypertrophic cardiomyopathy with unusuallocatts of left ventricular hyperkophy undetectable by M+node eehocwdttaphy: ~tifi~ii~ by wtdeangle, ~~i~~~l e~~~t~a~y~ ~if~utatton fS61;63:4094fS. 33. Meron &I, Epaetn SE. ~~~o~jc ~Fd&~o~thy: a discussion of nomanclaiure. Am J Cardiot 1979;43:1242-1244. 34. Maron W, Edwards JE, Epstein SE. Prevalence and characterization of disproportionate ventricular septal thickening ifl patients with systemic hvoertension. Chest 1$78:73:466-470. 35. S&age DD, Drayer JIM, itenry WL, UIathewsEC, Ware JH, Gsrdh J1#, C&ten ER. Eps#& SE, Lara& JH. E~di~aphic assessment of cardiac Bnatomy and function in hypertensive subjects. Circulation 1979;59:623-632, 36. Henry WL, Oardin JM,.Ware JH. Echocardiographi?measurementsin no~6~f subtects from infancy to ald age. Circulabon 1980;62:105437. Ret%&WL, Uerk CE, Gtency GL, Epstein SE. Ec~~~Fap~~ measurement of the teft ventricular outftow gradient in idiopathic hypertrophic subaortic stenosis. N Engl J Med 1973;288:989-993.

38. Pollick C, Morgan CD, ‘$Nberl SW, Rakowski H, WlSle ED. Muscular subaortic stenosis: the temporal relattonship between systolic anterior motion of the anterior mitral leaflet and the pressure gradtent. Circulation ~982;66:~067-1634. 39. #few WI., Clark CE, Rotserb WC, Morrow AG, EpaMn SE. Differf~~ces in distributionof myocarrttat abnormalitbs in patients with obstructtve and nonobstructive asymmetric septal hypertrophy (ASH): echocardiographic and gross anatomic findings. Circulation 1974;50:447-455. 40. Elandl-JohnsonRD. ProbabilttyModels and Statistical Methods in Genetics, New York: John Wiley 6 Sons. t971:45a. 41. Et&on RC, Stawart J. A generat model fw theganetiicanalysis of pedttee data. Hum &Fed 1971;21:533-542. 42. Maron RI, EpsteinSE. Kypertrophic cardiomyopathy. Recent obsewations regarding the specificity of three hallmarks of the disease: asymmetFic septal hypertrophy, septat disorganization and systolic anterior motion of the anterior mitraf leaflet. Am J Cardiol 1980;45:141-154. 43. Roberts WC, Femm VJ. Pathotogic anatomy of the ~~orny~~ies. tdkzpathic d&ted and hy~~~ic types, ~n~~attve types, and endomyocardial disease with and withouteosinophiita. Hwnan Pathot 1975;6: 207-342.