JACC Vol. 26, No. 7
December 1995:1699-708
1699
HYPERTROPHIC CARDIOMYOPATHY
Phenotypic Spectrum and Patterns of Left Ventricular Hypertrophy in
Hypertrophic Cardiomyopathy: Morphologic Observations and
Significance As Assessed by Two-Dimensional Echocardiography in
600 Patients
H E I N R I C H G. KLUES, MD, A N D R E A S C H I F F E R S , B A R R Y J. M A R O N , MD, FACC*
Aachen, Germany and Minneapolis, Minnesota
Objectives. This study sought to achieve an understanding of
the true structural heterogeneity of hypertrophic cardiomyopathy.
Background. The diversity and clinical significance of the
morphologic expression of hypertrophic cardiomyopathy have not
been fully defined within this broad disease spectrum.
Methods. Patterns of left ventricnlar hypertrophy were characterized by two-dimensional echocardiography in a large study
cohort of 600 patients (7 to 79 years old, mean age 45; 393 [66%]
men) consecutivelystudied at two referral centers.
Results. Left ventricular wall thickness was 15 to 52 mm (mean
[-SD] 22.3 - 5). A multitude of patterns of asymmetric left
ventricular hypertrophy were identified, with the most common
showing diffuse involvement of substantial portions of both ventricular septum and free wall. Of 16 possible patterns of left
ventricular hypertrophy, 12 (78%) were identified among the 600
patients. Hypertrophy most commonly involved two left ventricnlar segments (228 patients [38%]) or three or more segments (202
patients [34%]), but was also localizedto one segment in a substan-
Hypertrophic cardiomyopathy is a primary, often genetically
transmitted, cardiac disease with a broad clinical and morphologic spectrum that has been the subject of considerable
interest and study (1-7). Of particular note is the phenotypic
variability of hypertrophic cardiomyopathy in which the extent
and distribution of left ventricular hypertrophy may differ
widely among patients (2,3,7-23). However, the frequency with
which different patterns of left ventricular hypertrophy occur in
the hypertrophic cardiomyopathy patient population, as well as
the clinical significance of these phenotypic expressions as they
may relate to patient age, gender, magnitude of symptoms and
left ventricular outflow tract obstruction, have not yet been
From the Medical Clinic 1, Department of Cardiology, University Hospital
Rheinisch-Westf~lische Technische Hochschule, Aachen, Germany; National
Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda,
Maryland; and *Minneapolis Heart Institute Foundation, Minneapolis, Minnesota.
Manuscript received February 13, 1995: revised manuscript received July 14,
1995, accepted July 26, 1995.
Address for correspondence: Dr. Bar n, J. Maron, Cardiovascular Research
Division, Minneapolis Heart Institute Foundation, 920 East 28th Street, Suite 40,
Minneapolis, Minnesota 55407.
©1995 by the Amcriclm (~llc~c o1( ~dioh~e~
tiai number of patients (170 [28%]). The anterior portion of the
ventricular septum was the region of the left ventricle that most
frequently showed thickening (573 patients [96%]), and was also the
predominant site of hypertrophy in most patients (492 patients
[83%]). Patterns of wall thickening that were either concentric (i.e.,
symmetric) or confined to the apex were particularly uncommon (in
1% each).
Conclusions. 1) In hypertrophic cardiomyopathy, the distribution of left ventrieuiar hypertrophy is characteristically asymmet.
tic and particularly heterogeneous, encompassing most possible
patterns of wall thickening, from extensive and diffuse to mild and
segmental, and with no single morphologic expression considered
typical or classic. 2) A greater extent of left ventricular hypertrophy was associated with younger age and more marked mitral
valve systolic anterior motion and outflow obstruction but showed
no relation to either magnitude of symptoms or gender.
(J Am CoU Cardiol 1995;26:1699-708)
completely defined in smaller patient groups (2,3,8,10). Therefore, the availability of a large cohort of 600 patients with
hypertrophic cardiomyopathy studied consecutively with twodimensional echocardiography afforded the opportunity for an
enhanced assessment of the spectrum and importance of these
morphologic forms with respect to selected clinical and demographic features of the disease.
Methods
Study patients. Registries of the echocardiography laboratories were reviewed for the year 1989 at the National Heart,
Lung, and Blood Institute (NHLBI) and for 1989 to 1992 at the
University Hospital RWTH (Aachen, Germany). Complete
transthoracic two-dimensional echocardiographic studies were
available from 671 consecutively studied patients with hypertrophic cardiomyopathy at the two institutions. For each
patient the diagnosis of hypertrophic cardiomyopathy was
established by the echocardiographic demonstration of a hypertrophied, nondilated left ventricle in the absence of another
systemic or cardiovascular disease capable of producing the
magnitude of hypertrophy observed (24). Consequently, pa0735-1097/95/$9.51)
0735-1097(95)00390-P
1700
KLUES ET AL.
LV HYPERTROPHY IN HYPERTROPHIC CARDIOMYOPATHY
tients judged to have left ventricular hypertrophy secondary, to
systemic hypertension were not part of the study group.
Of the 671 patients with hypertrophic cardiomyopathy, 71
were excluded for the following reasons: 1) age <7 or >80
years; 2) echocardiographic studies of technical quality inadequate to reliably assess the distribution of left ventricular
hypertrophy; 3) documented hemodynamically and clinically
significant aortic or mitral valvular or coronary artery disease;
4) availability of echocardiograms obtained only after myotomy-myectomy operation; or 5) evidence of the "end-stage"
phase of hypertrophic cardiomyopathy (25). Consequently, the
remaining 600 patients (500 from the NHLBI, 100 from
University Hospital RWTH) comprised the final study group
(7 to 79 years old, mean age [±SD] 45 _ 17; 49 patients <20
years old [8%], 125 patients >60 years old [21%]; 393 men
[66%]). Of the 600 patients, 182 (30%) had no functional
limitation, 282 (47%) had mild symptoms (New York Heart
Association functional class 1I), and 136 (23%) had moderate
to severe limitations (classes III and IV).
Echocardiograpbic methods. Echocardiographic studies
were performed with commercially available (HewlettPackard, model 77020 AC) ultrasound scanners and 2.5- or
3.5-MHz transducers. Two-dimensional images were obtained
in multiple cross-sectional planes using standard transducer
positions (26). Images were recorded on 0.5- or 0.75-in. format
videotapes to facilitate real-time, slow-motion and freezeframe analysis and to allow serial review and rapid comparison
of studies. M-mode echocardiograms were derived under
direct anatomic visualization from the two-dimensional images
and recorded on a strip chart at 100 mm/s. Chamber dimensions were measured from M-mode echocardiograms according to published recommendations (27).
Magnitude and distribution of left ventricular hypertrophy
was assessed primarily in the parasternal short-axis plane,
although parasternal long-axis and apical views were also used
to integrate the information obtained from the short-axis
images (28). To assess patterns of left ventricular hypertrophy
in the short-axis plane, the ventricle was divided into four
relatively equal segments that comprised the anterior and
posterior ventricular septum and lateral and posterior free wall
(11,28,29). Distribution of left ventricular hypertrophy was also
analyzed in the basal-apical (longitudinal) plane using the
parasternal long-axis and apical views; the ventricle was divided into two segments, the proximal (basal) portion extending from cardiac base to the inferior margins of mitral leaflets,
and the distal (apical) portion visualized caudal to the mitral
leaflets. A segment of the left ventricular wall was judged to be
hypertrophied if >50% of its area was ->15 mm thick at
end-diastole (Fig. 1).
Assessment of left ventricnlar hypertrophy. Patterns of
hypertrophy were described in two ways: 1) Overall extent was
defined with regard to the number of thickened left ventricular
segments: one segment = mild; two segments = moderate;
three or four segments = severe. 2) Alternatively, hypertrophy
was described utilizing our previous classification (8): a)
type I = confined to anterior segment of ventricular septum; b)
JACC Vol. 26, No. 7
December 1995:1699-708
A
R-q--L
P
VS
POSTERIOVS'
R -,
~ANT~_..RIOR
r,/!
~
POSTERIOR
FREEWALL
Figure 1. Segments of left ventricular wall visualized by twodimensional echocardiographyin the short-axis view. The points of
insertion of right ventricle into the left ventricle constitute the
anatomiclandmarksdividingthe ventricularseptum (VS) from the left
ventricular free wall. A = anterior; L = left; P = posterior; R = right.
Reproduced with permission of the AmericanHeart Association.
type H = involved anterior and posterior septum; c) type III =
substantial portions of both septum and free wall; and d)
type/V = regions other than the basal and anterior septum.
Systolic anterior motion of mitral valve. Magnitude of left
ventricular outflow tract obstruction had been measured at
cardiac catheterization or by continuous wave Doppler (30,31)
in close proximity to the time of echocardiographic study in
only a minority of the 600 study patients. Consequently, we
related the distribution of left ventricular hypertrophy directly
to the magnitude and duration of systolic anterior motion of
the mitral valve (32). Magnitude of systolic anterior motion of
mitral valve was assessed using a modification of the grading
system of Gilbert et al. (32): mild --- approached ventricular
septum, but without septal contact; moderate = brief mitralseptal contact; severe = prolonged septal contact, >30% of
echocardiographic systole.
Statistical analysis. Data are expressed as mean value _
SD. Differences between continuous variables were assessed
with the unpaired Student t test and one-way analysis of
variance. A Bonferroni test was applied to correct for multiple
comparisons, where appropriate. Proportions were compared
by the chi-square or Fisher exact tests. Selected variables were
compared using linear regression analysis. Univariate and
multivariate regression analyses (33) were performed to assess
the degree to which the extent of left ventricular hypertrophy
(i.e., number of hypertrophied left ventricular segments) was
associated with gender and age.
Results
Distribution of left ventricular hypertrophy. General analysis. Maximal left ventricular wall thicknesses ranged from 15
to 52 mm (mean 22 -- 5) and were >30 mm in 68 patients
(11%) and -<20 mm in 269 (45%). When analyzed with regard
to the distribution of left ventricular wall thickening, a wide
variety, of patterns were present in the overall study group,
JACC Vol. 26, No. 7
December 1995:1699-708
KLUES ET AL.
I,V HYPERTROPHY IN HYPERTROPHIC CARDIOMYOPATHY
Table 1. Patterns of Left Ventricular Hypertrophyin 600 Patients
With HypertrophicCardiomyopathy
Hypertrophied LV Segment
No. of Pts
Percent of Pts
AVS + PVS
AVS
AVS + PVS + LFW
AVS + PVS + LFW - PFW
AVS + LFW
PVS
Apex
PVS + LFW + PFW
LFW
PFW
PVS + LFW
LFW + PFW
182
150
100
98
43
8
7
4
3
2
2
1
31
25
17
17
7
1
1
0.7
0.5
0.3
0.3
0.2
AVS
AVS
AVS
PVS
+
+
+
+
LFW + PFW
PVS + PFW
PFW
PFW
0
0
0
0
0
0
0
0
AVS : anterior ventricular septum; HCM = hypertrophic cardiomyopathy;
LFW = lateral free wall; LV - left ventricular; PFW : posterior free wall; Pts :
patients; PVS = posterior ventricular septum.
some rather uncommon in frequency (Table 1, Fig. 2 to 5). Of
the 16 possible patterns of hypertrophy, 12 ( 75%) were present
among the 600 study patients (Table 1). Each of the four
patterns not encountered in the present analysis required
thickening of the posterior flee wall, the region least commonly hypertrophied in hypertrophic cardiomyopathy (8).
The anterior ventricular septum was the most frequently
hypertrophied segment of the left ventricle (573 [96%] of 600
patients). Less commonly involved was posterior septum (394
patients [66%]) and lateral free wall (251 patients [42%]); the
posterior free wall was usually preferentially spared from the
hypertrophic process and was thickened in only 105 patients
(18%).
Furthermore, in most patients (492 patients [83%]) the
anterior ventricular septum was the predominant region of
hypertrophy (Fig. 2, A, B and D; Fig. 4, A, C and D); much less
commonly, wall thickening was predominant in the posterior
septum (56 patients [10%]) (Fig. 2F, 4A, 5B), lateral wall (26
patients [4%]) and posterior wall (11 patients [2%]) (Fig. 6).
The prominent asymmetry and heterogeneity of hypertrophy
present in the study patients was evident by such variable
locations of wall thickening within the left ventricle as well as
the sharp, abrupt transitions in wall thickness in which substantially hypertrophied regions were frequently contiguous
with normal areas (Fig. 2, C and E; Fig. 4, A to D and F).
Segmentalanalysis (Table 2, Fig. 7). In 170 (28%) of the 600
study patients, wall thickening was confined to one segment of
the left ventricular wall (Fig. 2E; Fig. 4, A, B, D and F; Fig.
5D). In 150 of these 170 patients only the anterior portion of
the ventricular septum was hypertrophied (morphologic type 1
pattern in the previous classification of Maron et al. [8]); these
included 57 patients in whom hypertrophy discretely involved
only the most basal portion of anterior septum ("septal bump"
in the parasternal long axis) (Fig. 3C).
1701
In the remaining 20 patients, more unusual patterns of wall
thickening sparing the anterior septum were present (posterior
septum in eight patients, lateral free wall in three [Fig. 2El,
posterior free wall in two [Fig. 4F], apex in seven [Fig. 5D]),
with each corresponding to morphologic type IV (8). The latter
seven patients met our strict morphologic criterion for "apical
hypertrophic cardiomyopathy" by virtue of hypertrophy confined to the most apical portion of left ventricle (below
papillary muscle level) (18), as visualized in standard four- and
two-chamber views.
In 228 (38%) of the 600 study patients, wall thickening
involved two segments of the left ventricular wall. Most commonly (in 182 patients), both the anterior and posterior portions
of the ventricular septum were thickened, and the free wall was
spared (Fig. 2G, Fig. 5C), corresponding to the type II pattern (8).
Only the anterior septum and the contiguous portions of the
lateral free wall were involved in 43 patients (Fig. 4B), and the
lateral and posterior free wall in 1 patient. The remaining two
patients showed hypertrophy of two noncontiguous segments,
that is, the posterior septum and lateral free wall (Fig. 5B).
In 202 (34%) of the 600 study patients, wall thickening was
particularly diffuse involving three or all four segments of left
ventricular wall, corresponding to the type III pattern (8) (Fig.
2, A, B and D). Typically, these patients had extensive wall
thickening involving substantial portions of the anterior and
posterior ventricular septum and lateral free wall and preferentially sparing either all of the posterior free wall (100
patients) or only the basal portion of posterior wall (94
patients). Also, this distribution of hypertrophy was often
characterized in the short-axis plane by a "tapered" appearance in which the anterior septum (at the 12 o'clock position)
was predominant, the posterior septum and lateral free wall
less so and posterior free wall (at 6 o'clock) representing the
thinnest portion (34) (Fig. 2, A, B and D). Eight patients with
diffuse hypertrophy were judged to have truly concentric
(symmetric) distribution of hypertrophy in which all hypertrophied segments were thickened to a similar degree (1% of the
600 study patients) (Fig. 5A).
Some portion of the ventricular septum was involved in the
hypertrophic process in 587 patients (98%); in only 13 patients
(2%) (with hypertrophy confined to lateral or posterior free
wall or true apex) was the septum not thickened.
Relation of distribution of hypertrophy to wall thickness.
A direct relation was present between the number of hypertrophied left ventricular segments and maximal wall thickness
(Table 2, Fig. 8). With one, two and three or more left
ventricular segments involved, wall thicknesses were 20 _+ 3,
22 -+ 4 and 25 _ 6 ram, respectively. Similar relations between
distribution of hypertrophy and wall thickness were defined for
morphologic types 1 (20 _+ 3 mm), II (22 _+ 5 mm) and III
(24 _+ 6 ram, p < 0.001).
Areas of massive wall thickening (Fig. 2A, Fig. 3A) (->30 mm)
were present in 47 (23%) of 202 patients with three or more
segments involved, in 18 (8%) of 228 with two segments involved
and in only 3 (2%) of 170 with hypertrophy confined to one
segment. In contrast, relatively mild wall thickening (Fig. 2E;
1702
KLUES ET AL.
LV HYPERTROPHY IN HYPERTROPHIC CARDIOMYOPATHY
JACC Vol. 26, No. 7
December 1995:1699-708
Figure 2. Variabilityof patterns of left ventricular
hypertrophy in patients with hypertrophic cardiomyopathy,shown in a composite of diastolicstopframe imagesin the parasternal short-axisplane. A,
B and D, Wall thickening is diffuse, involving
substantial portions of ventricular septum and free
wall. At the papillarymusclelevel (A),all segments
of the left ventricular wall are hypertrophied, including the posterior free wall (PW), but the
pattern of thickeningis asymmetricwith the anterior portion of ventricular septum (VS) massive
(i.e., 50 mm). B, Hypertrophyis diffuse,involving
three segments of the left ventricle but with the
posterior wall spared and thin (<10 mm) (arrowheads) and with particularlyabrupt changesin wall
thickness evident (arrows). C, Markedhypertrophy
in a pattern distinctlydifferent from that in A, B
and D in which the thickeningof the posteriorwall
is predominant, and the ventricular septum is of
nearly normal thickness. D, Diffusedistributionof
hypertrophy involvingthree segments of the left
ventricle similar to that in B but without sharp
changes in the contour of the wall. E, Hypertrophy
predominantlyof lateral free wall and only a small
portion of contiguousanterior septum (arrows). F,
Hypertrophypredominantlyof posterior ventricular septum (PVS) and, to a lesser extent, the
contiguous portion of the anterior septum. G,
Thickening of anterior and posterior septum to a
similar degree but with sparing of the free wall.
Calibration dots are 1 cm apart. AML = anterior
mitral leaflet; LFW = lateral free wall; PML =
posterior mitral leaflet.
Fig. 3C; Fig. 4, A, B, D and F; Fig. 5D) (---20 rnm) was identified
in 115 patients (68%) with one segment involved, in 99 patients
with two segments involved (43%) and in only 55 patients with
diffuse hypertrophy (27%) in three or more segments.
The 68 study patients with particularly substantial left ventricular hypertrophy (thickness ->30 mm), compared with the 269
patients with relatively mild thickening (-<20 ram), were younger
(31.9 + 16vs. 49.5 _+ 15 years old, p < 0.001) and more frequently
showed systolicanterior motion of mitral valve (53% vs. 25%, p <
0.001) but did not differ with respect to gender (each 68%) or
presence of severe symptoms (16% vs. 22%).
Distribution of hypertrophy in longitudinal plane. Three
patterns of wall thickening were evident in the longitudinal
plane and occurred with similar frequency in the overall study
group. Hypertrophy was predominant in the proximal (basal)
portion of left ventricle in 210 patients (29%) (Fig. 3C), in the
distal (apical) ventricle in 203 patients (Fig. 3, B and D; Fig. 5,
D and E) and relatively equal in the proximal and distal
regions in 217 patients (36%) (Table 2, Fig. 3A). Proximal
hypertrophy was associated with relatively mild wall thickening
(mean 20.7 _+ 3 ram) and occurred in older patients (52 _+ 14
years) compared with distal hypertrophy (24 _+ 6 mm and 39 _+
16 years, p < 0.001).
Distribution of hypertrophy and mitral valve systolic anterior motion. Marked systolic anterior motion of mitral valve
(with prolonged mitral-septal contact) was more common in
patients with diffuse and extensive hypertrophy involving two
to four left ventricular segments (162 [38%] of 430 patients,
p < 0.001) than in patients with only one hypertrophied
segment (42 [25%] of 170) (Table 2, Fig. 9). Similarly, patients
with marked systolic anterior motion of mitral valve had
greater wall thicknesses (24 _+ 5 ram) than those with no or
mild systolic anterior motion of mitral valve (22 _+ 5 mm, p <
0.001). Marked mitral valve systolic anterior motion was also
more commonly associated with predominantly proximal hypertrophy (62 [36%] of 173 patients) than with distal hyper-
JACC Vol. 26, No. 7
December 1995:1699-7(18
KLUES ET AL.
LV HYPERTROPHY IN HYPERTROPHIC CARDIOMYOPATHY
1703
Figure 3. Variability in distribution and extent of ventricular septal
thickeningas shownin a compositeof parasternal long-axisstop-frame
images obtained in diastole. A, Massive asymmetrichypertrophyof
ventricular septum (VS) with wall thickness >50 mm. B, Heterogeneous pattern of septal thickening,with distal portion substantially
thicker than the proximal region at mitral valve level. C, Hypertrophy
sharply confinedto the basal (proximal) septumjust below the aortic
valve (arrows). D, Distal septal thickening (arrows) and particularly
abrupt transitionto thin proximalseptum (<10 mm) (arrowheads).E,
"Inverted" pattern of hypertrophyin which distal anterior ventficular
septum is only mildly thickened, but posterior free wall (PW) is
substantiallythickened (to 40 mm). Calibration dots are 1 cm apart.
Ao = aorta; AML = anterior mitral leaflet; LA = left atrium; LV =
left ventricle.
Distribution of hypertrophy and clinical variables. Age.
The pattern and magnitude of left ventricular hypertrophy was
inversely related to patient age (at the time of the echocardiographic study) (Table 2, Fig. 10). For example, patients were
51 +_ 15, 45 __ 16 and 40 -- 18 years old with one, two or three
or more segments hypertrophied, respectively. Also, linear
regression analysis showed an inverse relation between age and
maximal left ventricular wall thickness (r = 0.343, p < 0.001).
Gender. No differences were identified between male and
female patients with regard to the extent of left ventricular
hypertrophy (Table 2, Fig. 7). Men and women showed similar
maximal wall thickness (22 + 4 vs. 22 +_ 4 ram, p > 0.05) and
number of hypertrophied segments involved (one segment,
30% vs. 26%; two segments, 37% vs. 40%; three or more
segments, 33% vs. 34%, p > 0.05).
Functional class. No relation was evident between magnitude of symptoms and either extent of hypertrophy or maximal
wall thickness (Table 2). Average functional class was 2.0, 1.9
and 2.0 in patients with one, two or three or more hypertrophied segments (p > 0.05). Mean wall thickness was 22 + 5,
23 _~:5 and 22 + 4, in patients in functional classes I, II or III
and IV, respectively (p > 0.05).
Univariate analysis showed extent of left ventrieular hypertrophy to have a significant relation to patient age (p < 0.001)
but not to gender. Multivariate regression analysis showed age to
be the only independent variable associated with extent of
hypertrophy (p < 0.0001).
Discussion
[22%] of 203, p < 0.001). Anomalous direct
insertion of papillary muscle into the anterior leaflet (35) was
judged likely to be present in 26 patients (4%).
t r o p h y (44
Diversity of left ventricular hypertrophy. The findings of
the present detailed echocardiographic analysis of 600 consecutively studied patients with hypertrophic cardiomyopathy
from two major referral institutions underlines the vast diversity of morphologic abnormalities encountered within this
disease spectrum. These observations also support the concept
that no single pattern of left ventricular hypertrophy in hypertrophic cardiomyopathy can be considered "classic" or typical
of the disease. Indeed, we found that our 600 patients encompassed most possible patterns of hypertrophy (1,2,8,10,16-18),
ranging from localized and relatively mild wall thickening
1704
KLUES ET AL.
LV H Y P E R T R O P H Y IN HYPERTROPHIC C A R D I O M Y O P A T H Y
JACC Vol. 26, No. 7
December 1995:1699-708
Figure 4. Illustrationof the broad morphologicspectrum of hypertrophic cardiomyopathy with twodimensionalcross-sectionalechocardiography.A to E,
Parasternal short-axis plane. F, Apical four-chamber
view. In A, B and D, there is substantialvariabilityin
the location of relativelymild segmentalwall thickening within the anterior portion of the ventricular
septum (A and D) and contiguous anterolateral free
wall (B) (arrows). In C, more markedthickeningof the
anterior septum (arrows) is contiguouswith a normal
region of posterior septum, demonstrating a particularly sharp and abrupt transition in wall thickness,
forming a right-angledcontour (arrowheads). E, Predominant and marked hypertrophy of the posterior
ventricular septum (arrows); the adjacent anterior
septum is much thinner. F, Wallthickeningconfinedto
the posterobasal free wall directly behind the mitral
valve (arrowheads). AML = anterior mitral leaflet;
LA = left atrium; LV = left ventricle; VS = ventricular septum.
involving any one of the left ventricular wall segments (or
apex) to marked and diffuse hypertrophy of all portions of the
left ventricle; wall thicknesses averaged >20 mm, and ranged
up to >50 mm, constituting the most extreme form of hypertrophy evident in any cardiac disease (17).
Left ventricular hypertrophy in hypertrophic cardiomyopathy nearly always involves some portion of ventricular septum
and, most frequently, it is the anterior septum that is most
prominently thickened. Furthermore, asymmetry is an almost
invariable feature of wall thickening in hypertrophic cardiomyopathy, in that all regions of the left ventricle are rarely of
identical or similar thickness. Indeed, in -66% of the present
overall patient group, asymmetry was particularly obvious with
wall thickening involving only one or two of the four left
ventricular segments. In patients with more diffuse hypertrophy, the observed asymmetry was frequently due to sparing of
a relatively small portion of the left ventricular wall (usually
the posterior free wall).
Also, in our patients, the pattern of hypertrophy was often
strikingly heterogeneous, showing marked differences in wall
thickness between contiguous segments, or with hypertrophy
involving noncontiguous segments of left ventricle (with interpositioned areas of normal thickness). Transitions between
thickened and nonthickened regions were commonly sharp
and abrupt, not infrequently creating right-angled contours of
the ventricular wall, unique to the degree with which these
findings are present in patients with hypertrophic cardiomyopathy. Conversely, truly symmetric (i.e., concentric) hypertrophy
was also part of the morphologic spectrum of hypertrophic
cardiomyopathy, although present in only a very small minority
of our patients (~1%). Other investigators (3) have reported a
more frequent occurrence of the symmetric form of hypertrophy in hypertrophic cardiomyopathy, apparently due to the use
of alternative morphologic criteria in which diffuse patterns
with only segmental areas of asymmetry were judged to be
concentric. Some patterns of left ventricular hypertrophy (e.g.,
massive and diffuse, involving noncontiguous portions of left
ventricle, or confined to sites such as posterior septum, lateral or
JACC Vol. 26, No. 7
December 1995:1699-708
KLUES ET AL.
LV H Y P E R T R O P H Y IN H Y P E R T R O P H I C C A R D I O M Y O P A T H Y
1705
%)
%)
)
Figure 6. Locationof predominant site of left ventricularwall thickening as assessed in 592 patients with hypertrophic cardiomyopathy
and asymmetricpatterns of hypertrophy(eightpatientswithconcentric
hypertrophy were excluded from this analysis). The predominant
hypertrophied segment was defined as that containing the thickest
portion of the wall or that segment showing the most extensive
involvement (if two or more segments were of the same maximal
thickness). FW = free wall; VS = ventricularseptum.
Figure 5. Heterogeneityin patterns of left ventricular hypertrophyin
five patients with hypertrophiccardiomyopathy.A, B and C, Diastolic
stop-frame imagesobtained in the parasternal short-axisplane. I) and
E, Apical four-chamberviews. In A, relativelymild hypertrophyin a
concentric (symmetric)pattern with each segmentof septum and free
wall havingsimilar or identicalthickness (paired arrows). B, "Butterfly" pattern with prominent indentation (arrow) and localizedarea of
thinning interpositioned at the 11 o'clock position between adjacent
thicker areas of ventricular septum. C, Hypertrophyof entire ventricular septum (VS) and sparing of free wall. D, Myocardialhypertrophy
confined to left ventricular apex (asterisk). E, Image from another
patient with hypertrophyof the apex, but also diffuselyinvolvingthe
ventricular septum and free wall. Calibration marks are 1 cm apart.
AVS = anterior ventricularseptum; LA = left atrium; LFW = lateral
free wall; LV = left ventricle; PVS = posteriorventricular septum.
posterior free wall or apex) are distinctive; they appear unique
to primary hypertrophic cardiomyopathy by virtue of being
uncharacteristic of other cardiac diseases associated with secondary left ventricular hypertrophy such as systemic hypertension (36).
The myriad patterns of left ventricular hypertrophy occurred in our large patient group with differing frequencies.
The most common pattern involved diffuse distribution of wall
thickening in both septum and free wall (i.e., -40%). Although perhaps not generally recognized as part of the hypertrophic cardiomyopathy disease spectrum, localized or segmental patterns of hypertrophy (most commonly of anterior
septum) nevertheless comprised a substantial minority of our
patients (i.e., 28%). Within the latter patient group is a small
subset with wall thickening confined to the most apical portion
of left ventricle ("apical hypertrophic cardiomyopathy") (1215,18,37); that only 1% of our patients had this morphologic
form strongly suggests that it may be much less common
among North American than Japanese patients (5). However,
it is worth emphasizing that this unique distribution of apical
hypertrophy should be distinguished from more common
morphologic patterns in which wall thickening is more prominent in the distal compared to the proximal portion of left
ventricle.
Relevance to clinical features. The magnitude of left ventricular hypertrophy in our patients showed certain clinically
relevant associations compared with demographic features or
disease variables. For example, more extensive left ventricular
hypertrophy was inversely associated with patient age (29). In
younger patients (<30 years old), left ventricular hypertrophy
was more frequently diffuse, involving substantial portions of
septum and free wall, and associated with markedly increased
wall thickness; conversely, older patients more frequently
showed localized and relatively mild wall thickening confined
to one left ventricular segment. Furthermore, a multivariate
stepwise regression analysis showed a strong relation between
wall thickness and age, even after adjusting for other independent variables. The explanation for this inverse relation between age and magnitude of hypertrophy is uncertain but
possibly due to higher rates of premature death in younger
patients with severe hypertrophy (38) or, alternatively, to
progressive wall thinning occurring gradually over a long
period of time in many patients (11,22,25,39). In addition, the
presence of marked systolic anterior motion of mitral valve
(and thereby dynamic outflow obstruction) (32,40-44) was
associated with more marked and proximally located ventricular septal and free wall hypertrophy; these findings are
consistent with the observation that thickening of the anterior
basal septum (associated with reduced left ventricular outflow
tract area) is a morphologic determinant of outflow obstruction (45).
Relation to gender. Men and women with hypertrophic
cardiomyopathy did not differ with respect to the morphologic
expression of their disease, either in terms of maximum wall
thickness, distribution of left ventricular hypertrophy or the
frequency with which the most marked phenotypic disease
1706
KLUES ET AL.
LV HYPERTROPHY
IN HYPERTROPHIC
J A C C V o l . 26, N o . 7
December 1995:1699-708
CARDIOMYOPATHY
Table 2. Comparison of Clinical and Echocardiographic Data in 600 Patients With Hypertrophic Cardiomyopathy Analyzed With Respect to
Number of Hypertrophied Left Ventricular Segments
Age (yr)
Mean _+ SD
Range
Male
Female
Functionalclass
(NYHA)
I
II
Ill/IV
LV wall thickness
(mm)
Mean _- SD
-<20 mm
->30 mm
Degree of SAM*
Absent
Mild/moderate
Severc
Pattern of hypertrophy,
longitudinalplane
Basal > apical
Basal = apical
Apical > basal
Overall Study
Group
[n 600]
One Segment
[n = 170
(28%)1
45.0 _+ 17
7 79
393 (66%)
207 (34%)
50.6 _+ 15
7-78
117 (69%)
53 (32%)
182 (30%)
282 (47%)
136 (.:, ,c )
52 (31%)
76 (45%)
42 (25%)
.~. . . - 5
269 (45%)
68 (11%)
p
Value
(1 vs. 2
segments)
Two Segments
[n = 228
(38%)]
p Value
(2 vs. ->3
segments)
45.0 _+16
7-79
145 (65%)
83 (35%)
< 0.001
NS
NS
NS
78 (34%)
103 (45%)
47 (20%)
20 +_ 3
115 (68%)
3 (2%)
< 0.001
< 0.001
< 0.001
~.~ (38 c)
170 (28%)
204 (34%)
82 (48%)
46 (27%)
42 (25%)
173 (29e~)
217 (36q~)
210 (35%)
83 (49%)
45 (26%=)
42 (25%)
< 0.001
Three or More
Segments
[n = 202
(34%)]
p Value
(l vs. ->3
segments)
40.3 + 18
7-77
131 (65%)
71 (35%)
< 0.001
< 0.05
NS
NS
52 (26%)
103 (51%)
47 (23%)
NS
NS
NS
22 _+4
99 (43%)
18 (8%)
< 0.001
< 0.001
< 0.001
25 -+ 6
55 (27%)
47 (23%)
< 0.00l
< 0.001
< 0.001
< 0.05
NS
< 0.05
89 (39%)
65 (28%)
74 (33%)
< 0.05
NS
< 0.05
55 (27%)
59 (30%)
88 (43%)
< 0.001
NS
< 0.001
< 0.001
< 0.01
< 0.001
54 (24%)
9l (40%)
83 (36%)
NS
NS
NS
36 (18%)
81 (40%)
85 (42%)
< 0.001
< 0.01
< 0.001
NS
NS
NS
*Magnitude of systolicanterior motion of mitral valve (SAM) was asses~d using a modificationof the grading system of Gilbert et al. (32): mild = approaches
ventricular septum, but without mitral valve-septal contact; moderate = brief mitral-septal contact; and severe = prolonged mitral-septal contact, >30% of
echocardiographic systole. Unless otherwise indicated,data presented are number (%) of patients. LV = left ventricular;NYHA = New York Heart Association.
expressions occurred. Given the smaller body size of women,
this finding was somewhat unexpected, and probably largely
reflects the fact that hypertrophic cardiomyopathy is a primary,
genetically determined cardiac disease (1,2,4,6,9,10). Also, we
did not identify in the present study a relation between the
extent of hypertrophy and the magnitude of patient symptoms,
a finding at some variance with earlier cross-sectional analyses
in hypertrophic cardiomyopathy showing mild but statistically
Figure 7. Distribution of left ventricular (LV) hypertrophy as assessed
with echocardiography in 600 patients with hypertrophic cardiomyopathy, shown with respect to the number of hypertrophied left ventricular segments, as well as gender. Solid bars = men; hatched bars
women.
0.05
40
0.001
30
20
10
0
I
/ il
-~
NS
2
No. H y p e r t r o p h i e d I.V S e g m e n t s
significant correlations between greater degrees of hypertrophy and cardiac symptoms (8). These discrepancies are probably explained largely on the basis of the added statistical
power conveyed in this study with a particularly large patient
cohort, or possibly by differences in patient referral patterns.
Study limitations. It should be emphasized that the cohort
with hypertrophic cardiomyopathy evaluated here is tertiary
referral based and, as a consequence, may be subject to
considerable patient selection bias (46,47). Therefore, the
reported frequencies with which different patterns of left
Figure 8. Relation of number of hypertrophied left ventricular (LV)
segments to maximal wall thickness in 600 patients with hypertrophic
cardiomyopathy.
-
>/3
30 --
,
.~E
~
<0.001
,
~--<0.001~<0.001~
20 --
1
2
>/3
No. H y p e r t r o p h i e d L V S e g m e n t s
JACC Vol. 26, No. 7
December 1995:1699-708
KLUES ET AL.
LV HYPERTROPHY IN H Y P E R T R O P H I C C A R D I O M Y O P A T H Y
- -
50
"~o
within individual hypertrophic cardiomyopathy pedigrees having the same genetic substrate (53,54). Therefore, alternatively, it is possible that polymorphism in the form of additional
modifying gene abnormalities, environmental factors or unknown random influences may play a role in the morphologic
expression of hypertrophic cardiomyopathy, including the distribution of hypertrophy evident on echocardiogram.
---
40
~
30
~
20
.~ ~+
~s
~
<0.001
o
1
2
No. Hypertrophied
>/3
LV
Segments
Figure 9,
Relation of distribution of left ventricular (LV) hypertrophy
to the presence of marked systolic anterior motion of the mitral valve
with mitral-septal contact (SAM) in 600 patients with hypertrophic
cardiomyopathy.
ventricular hypertrophy occurred may not be entirely representative of the general patient population and disease spectrum of hypertrophic cardiomyopathy (48). Nevertheless, we
believe that the substantial size of our study group conveys an
important measure of credibility to the overall data and
conclusions.
Relevance to molecular biology. The phenotypic heterogeneity we observed in hypertrophic cardiomyopathy may be
related to a number of possible determinants. Morphoiogic
diversity could be a reflection of the genetic heterogeneity
characteristic of hypertrophic cardiomyopathy (4,6,49,50). For
example, molecular abnormalities in genes encoding for four
proteins of the sarcomere (beta-myosin heavy chain, cardiac
troponin T, alpha-tropomyosin and myosin-binding protein-C)
have been reported to date in families with this disease
(4,6,49-51), and linkage to several other genes is also likely.
Furthermore, many mutations for each of these different gene
abnormalities have been described (49,52), including -35
missense mutations in the beta-myosin heavy-chain gene.
Therefore, ultimately, there may be a particularly substantial
number of genes and mutations responsible for the wide
variety of phenotypes evident in hypertrophic cardiomyopathy.
However, this hypothesis probably cannot completely explain
the phenotypic heterogeneity evident in the present study; for
example, it is also known that a diversity of patterns of left
ventricular hypertrophy may be present in family members
Figure I0.
Relation of number of hypertrophied left ventricular (LV)
segments to patient age in 600 patients with hypertrophic cardiomyopathy.
60
<0.001
,
2
>/3
No. Hypertrophied
I,V Segments
~o 4o
3o,
20 ]
1
1707
References
1. Maron BJ, Bonow RO, Cannon RO, Leon MB, Epstein SE. Hypertrophic
cardiomyopathy: interrelation of clinical manifestations, pathophysiology,
and therapy. N Engl J Med 1987;316:780-9, 844-52.
2. Wigle ED, Sasson Z, Henderson MA, et al. Hypertrophic cardiomyopathy:
the importance of the site and extent of hypertrophy--a review. Prog
Cardiovasc Dis 1985;28:1-83.
3. Shapiro LM, McKenna WJ. Distribution of left ventricular hypertrophy in
hypertrophic cardiomyopathy: a two-dimensional echocardiographic study.
J Am CoU Cardiol 1983;2:437-44.
4. Watkins H, Rosenzweig A, Hwang D-S, et al. Characteristics and prognostic
implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 1992;326:1108-14.
5. Koga Y, Itaya K-I, Toshima H. Prognosis in hypertrophic cardiomyopathy.
Am Heart J 1984;108:351-9.
6. Thierfelder L, Watkins H, MacRae C, et al. a-Tropomyosin and cardiac
troponin T mutations cause familial hypertrophic cardiomyopathy: a disease
of the sarcomere. Cell 1994;77:701-12.
7. Lewis JF, Maron BJ. Elderly patients with hypertrophic cardiomyopathy: a
subset with distinctive left ventricular morphology and progressive clinical
course late in life. J Am Coil Cardiol 1989;13:36-45.
8. Maron BJ, Gottdiener JS, Epstein SE. Patterns and significance of distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a
wide-angle, two-dimensional echocardiographic study of 125 patients. Am J
Cardiol 1981;48:418-28.
9. Maron BJ, Nichols PF, Pickle LW, Wesley YE, Mulvihill JJ. Patterns of
inheritance in hypertrophic cardiomyopathy. Assessment by M-mode and
two-dimensional echocardiography. Am J Cardiol 1984;53:1087-94.
10. Cir6 E, Nichols PF, Maron BJ. Heterogeneous morphologic expression of
genetically transmitted hypertrophic cardiomyopathy: two-dimensional
echocardiographic analysis. Circulation 1983;67:1227-33.
11. Spirito P, Maron BJ, Bonow RO, Epstein SE. Severe functional limitation in
patients with hypertrophic cardiomyopathy and only mild localized left
ventricular hypertrophy. J Am Coil Cardiol 1986;8:537-44.
12. Yamaguchi H, Ishimura T, Nishiyama S, et al. Hypertrophic nonobstructive
cardiomyopathy with giant negative T waves (apical hypertrophy): ventriculographic and echocardiographic features in 30 patients. Am J Cardiol
1979;44:401- 12.
13. Keren G, Belhassen B, Sherez J. et al. Apical hypertrophic cardiomyopathy:
evaluation by noninvasive and invasive techniques in 23 patients. Circulation
1985;71:45-56.
14. Alfonso F, Nihoyannopoulos P, Stewart J, Dickie S, Lemery R, McKenna
WJ. Clinical significance of giant negative Y waves in hypertrophic cardiomyopathy. J Am Coil Cardiol 1990;15:967-71.
15. Webb JG, Sasson Z, Rakowski H, Liu P, Wigle ED. Apical hypertrophic
cardiomyopathy: clinical follow-up and diagnostic correlates. J Am Coil
Cardiol 1990;15:83-90.
16. Lewis JF, Maron BJ. Hypertrophic cardiomyopathy characterized by marked
hypertrophy of the posterior left ventricular free wall: significance and
clinical implications. J Am Coil Cardiol 1991;18:421-8.
17. Louie EK, Maron BJ. Hypertrophic cardiomyopathy with extreme increase
in left ventricular wall thickness: functional and morphologic features and
clinical significance. J Am Coll Cardiol 1986;8:57-65.
18. Ixmie EK, Maron BJ. Apical hypertrophic cardiomyopathy: clinical and
two-dimensional echocardiographic assessment. Ann Intern Med 1987;106:
663-70.
19. Maron BJ, Spirito P, Wesley YE, Arce J. Development and progression of
left ventricular hypertrophy in children with hypertrophic cardiomyopathy.
N Engl J Med 1986;315:610-14.
20. Lever HM. Kuram RF, Currie PJ, et al. Hypertrophic cardiomyopathy in the
1708
KLUES ET AL.
LV HYPERTROPHY IN HYPERTROPHIC CARDIOMYOPATHY
elderly: distinctions from the young based on cardiac shape. Circulation
1989;79:580-9.
21. Hecht GM, Klues HG, Roberts WC, Maron BJ. Coexistence of sudden
cardiac death and end-stage heart failure in familial hypertrophic cardiomyopathy. J Am Coil Cardiol 1993;22:489-97.
22. Spirito P, Lakatos E, Maron BJ. Degree of left ventricular hypertrophy in
chronic atrial fibrillation in hypertrophic cardiomyopathy. Am J Cardiol
1992;69:1217-22.
23. FighaIi S, Krajcer Z, Edelman S, el al. Progression of hypertrophic cardiomyopathy into a hypokinetic left ventricle: higher incidence in patients with
midventricular obstruction. J Am Coil Cardiol 1987:9:288-94.
24. Maron BJ, Epstein SE. Hypertrophic cardiomyopathy: a discussion of
nomenclature. Am J Cardiol 1979;43:1242-4.
25. Spirito P, Maron BJ, Bonow RO, Epstein SE. Occurrence and significance of
progressive left ventricular wall thinning and relative cavity dilatation in
patients with hypertrophic cardiomyopathy. Am J Cardiol 1987;60:123-9.
26. Tajik AJ, Seward JB, Hagler DJ, Mair DD, Lie JT. Two-dimensional
real-time ultrasonic imaging of the heart and great vessels. Mayo Clin Prnc
1978;53:271-303.
27. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding
quantitation in M-mode echocardiography: results of a survey of cchocardiographie measurements. Circulation 1978;58:1072-83.
28. Spirito P, Maron BJ. Relation between extent of left ventricular hypertrnphy
and occurrence of sudden cardiac death in hypertrophic cardiomyopathy.
J Am Coil Cardiol 1990;15:1521-6.
29. Spirito P, Maron BJ. Relation between extent of left ventricular hypertrophy
and age in patients with hypertrophic cardiomyopathy. J Am Coil Cardiol
1989;13:820-3.
30. Sasson Z, Yock PG, Hatle LK, Alderman El_, Popp RL. Doppler echoc:~rdiographic determination of the pressure gradient in hypertrophic cardiomyopathy. J Am Coll Cardiol 1988;11:752-6.
31. Panza JA, Petrone RK, Fananapazir L, Maron BJ. Utility of continuous ~ v c
Doppler in noninvasive assessment of the left ventricular outflow tract
pressure gradient in patients with hypertrophic cardiomyopathy. J Am Coil
Cardiol 1992;19:91-9.
32. Gilbert BW, Pollick C, Adelman AG, Wiglc ED. Hypertrophic cardiomyopathy: subclassification by M-mode echocardiography. Am J Cardiol 1980:45:
861-72.
33. Draper N, Smith H. The stepwise regression procedure. In: Draper N. Smith
H, editors. Applied Regression Analysis, 2nd ed. New York: Wiley, 1981:
307-11.
34. Maron BJ. Asymmetry in hypertrophic cardiomyopathy: the scptal to frec
wall thickness ratio revisited. Am J Cardiol 1985:55:835-8.
35. Klues HG, Roberts WC, Maron BJ. Anomalous insertion of papillary, muscle
directly into anterior mitral leaflet in hypertrophic cardiomyopathy: significance in producing left ventricular outflow obstruction. Circulation 1991:84:
1188 -97.
36. Lewis JF, Maron BJ. Diversity' of patterns of left ventricular wall thickening
in patients with systemic hypertension and marked hypertrophy. Am J
Cardiol 1990;65:874-81.
JACC Vol. 26, No. 7
December 1995:1699-708
37. Maron BJ, Bonow RO, Seshagiri TNR, Roberts WC, Epstein SE. Hypertrophic cardiomyopathy with ventricular septal hypertrophy localized to the
apical region of the left ventricle (apical hypertrophic cardiomyopathy). Am
J Cardiol 1982;49:1838-48.
38. Maron BJ, Roberts WC, Epstein SE. Sudden death in hypertrophic cardiomyopathy: profile of 78 patients. Circulation 1982;65:1388-94.
39. Maron BJ, Epstein SE, Roberts WC. Hypertrophic cardiomyopathy and
transmural myocardial infarction without significant atherosclerosis of the
extramural coronary arteries. Am J Cardiol 1979;43:1086-102.
40. Shah PM, Gramiak R, Kramer DH. Ultrasound location of left ventricular
outflow obstruction in hypertrophic obstructive cardiomyopathy. Circulation
1969;40:3-11.
41. Maron BJ, Epstein SE. Clinical significance and therapeutic implications of
the left ventrieular outflow tract pressure gradient in hypertrophic cardiomyopathy. Am J Cardiol 1986;58:1093-6.
42. Spirito P, Maron BJ. Patterns of systolic anterior motion of the mitral valve
in hypertrophic cardiomyopathy: assessment of two-dimensional echocardiography. Am J Cardiol 1984;54:1039-46.
43. Wigle ED. Hypertrophic cardiomyopathy: a 1987 viewpoint. Circulation
1987;75:311-22.
44. Pollick C, Rakowski H, Wigle ED. Muscular subaortic stenosis: the quantitative relationship between systolic anterior motion and pressure gradient.
Circulation 1984;69:43-9.
45. Spirito P, Maron BJ. Significance of left ventricular outflow tract crosssectional area in hypertrophic cardiomyopathy: a two-dimensional echocardiographic assessment. Circulation 1983;67:1100-8.
46. Spirito P, Chiarella P, Carratino L, Berisso MZ, Bellotti P, Vecchio C.
Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatient population. N Engl J Med 1989;320:749-55.
47. Maron BJ, Spirito P. Impact of patient selection biases on the perception of
hypertrophic cardiomyopathy. Am J Cardiol 1993;72:970-2.
48. Cecchi F. Olivotto l, Montereggi A, Santoro G, Dolara A, Maron BJ.
Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an
unselected regional population. J Am Coll Cardiol (in press).
49. Watkins H, McKenna WJ, Thierfelder L. et al. Mutations in the genes for
cardiac troponin Y and a-tropomyosin in hypertrophic cardiomyopathy.
N Engl J Med 1995;332:1058-64.
50. Solomon SD, Jarcho JA, McKenna WJ, et al. Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease. J Clin Invest 1990;86:
993-9.
51. Watkins H, Conner D, Thieffelder L, et al. Mutations in the cardiac myosin
binding protein-C gene on chromosome It cause familial hypertrophic
cardiomyopathy. Nature Genet. In press.
52. Annan R, Greve G, Yhierfelder L, et al. Prognostic implications of novel/3
cardiac myosin heavy, chain gene mutations that cause familial hypertrophic
cardiomyopathy. J Clin Invest 1994;93:280-5.
53. Hecht GM, Klues HG, Roberts WC, Maron BJ. Coexistence of sudden
cardiac death and end-stage heart failure in familial hypertrophic cardiomyopathy. J Am Coil Cardiol 1993;22:489-97.