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Advances in Cardiovascular Imaging
Imaging Phenotype Versus Genotype in
Hypertrophic Cardiomyopathy
Milind Y. Desai, MD; Steve R. Ommen, MD; William J. McKenna, MD;
Harry M. Lever, MD; Perry M. Elliott, MD
H
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ypertrophic cardiomyopathy (HCM) is a common
monogenetic cardiac disease with a prevalence of 0.2%1
that usually is inherited as an autosomal dominant trait with
variable penetrance and expression. Clinically, HCM is defined by the presence of left ventricular (LV) hypertrophy
(LVH) unexplained by abnormal loading conditions.1 The
natural history varies from an asymptomatic course to drugrefractory angina/dyspnea, sudden cardiac death (SCD), and
end-stage heart failure. The incidence of HCM-related SCD is
approximately 1% to 2% in children and adolescents and
0.5% to 1% in adults.2,3 In this review, we examine the impact
of advanced diagnostic imaging technologies on HCM, with
particular emphasis on the detection of particular genetic
subtypes.
only a single functional copy of a gene, the other being
inactivated by the mutation) also may be important.
It is suggested that hypertrophy results from reduced
contractile function, but studies of myocyte function in
patients with mutations in sarcomere protein genes are
contradictory. Nevertheless, murine models of sarcomeric
mutations show increased calcium sensitivity and altered
calcium cycling between sarcomere and sarcoplasmic reticulum. In vitro studies using purified myosin filaments and
skinned papillary muscle have reported increased calcium
sensitivity of force development that results in impaired
ventricular relaxation in vivo.17,18
Z-discs are lateral boundaries of the sarcomere that play a
fundamental role in mechanical stretch sensing. Several
mutations in genes coding for Z-disc proteins have been
implicated in HCM, including ␣-actinin (mediates the interaction between actin and titin) and telethonin (interacts with
muscle LIM protein and titin).19,20 More recently, melusin, a
muscle-specific signaling protein required for compensatory
hypertrophy response in the pressure-overloaded heart, also
has been implicated.21 A detailed description of metabolic
cardiomyopathies that mimic HCM is described in the later
part of this article.
State-of-the Art in Genetics of HCM
In ⬇60% of cases, HCM is inherited as an autosomal
dominant trait caused by mutations in genes coding for
cardiac sarcomere proteins (Figure 1).4 –7 Mutations in genes
encoding Z-disc proteins and proteins involved in calcium
regulation account for ⬍5% of cases. The absence of sarcomeric gene mutations can be explained by limitations of
current mutation detection techniques or mutations in as yet
unidentified genes, but in some cases, hypertrophy is caused
by other diseases that mimic the phenotype of sarcomeric
protein disease. Table 1 lists genetic disorders associated with
HCM.
State-of-the-Art in Imaging in HCM
In recent years, a comprehensive approach incorporating
multiple imaging modalities has been used to determine
mechanisms of symptoms and prognosis and to plan therapy.
The utility and limitations of each imaging modality are listed
in Table 2; current recommendations for use of different
imaging modalities are listed in Table 3.
Sarcomere and Z-disc Protein Gene Mutations
More than 600 different sarcomeric gene mutations are
reported in patients with HCM.8 –16 The majority are missense
mutations, but nonsense, frameshift, and in-frame insertion/
deletion mutations also occur. Most mutations are characterized by incomplete penetrance and variable clinical expression likely due to locus heterogeneity and the effect of
mutations at different locations within the same gene. Most
mutations probably have a dominant negative effect on
sarcomere function, but in some cases, haploinsufficiency (ie,
Assessment of Morphology
LV Geometry
Echocardiography is the initial modality of choice for evaluation of cardiac morphology. Although asymmetrical upperseptal hypertrophy is the most commonly observed morphological pattern (Figure 2A and 2B),22 midventricular, apical
Received May 5, 2010; accepted November 18, 2010.
From the Heart and Vascular Institute (M.Y.D.), Cleveland Clinic, and Cleveland Clinic Foundation (H.M.L.), Cleveland, OH; Department of
Cardiovascular Medicine (S.R.O.), Mayo Clinic, Rochester, MN; and Department of Cardiovascular Medicine (W.J.M., P.M.E.), The Heart Hospital,
University College, London, England.
The online-only Data Supplement is available at http://circimaging.ahajournals.org/cgi/content/full/CIRCIMAGING/4/2/156/DC1.
Correspondence to Milind Y. Desai, MD, Heart and Vascular Institute, Desk J1–5, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail
[email protected]
(Circ Cardiovasc Imaging. 2011;4:156-168.)
© 2011 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
156
DOI: 10.1161/CIRCIMAGING.110.957936
Desai et al
Hypertrophic Cardiomyopathy
157
Figure 1. A schematic illustration of a
cardiac sarcomere.
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(Figure 3A and 3B), posterolateral, concentric, and biventricular hypertrophy also occur. Three-dimensional echocardiography quantifies and characterizes myocardial hypertrophy,
LV volumes, LV ejection fraction, and LV mass more
accurately than traditional 2D echocardiography.23
Cardiac magnetic resonance (CMR) is especially useful in
identifying the varied phenotypic presentations of HCM,
particularly when hypertrophy involves the anterolateral free
wall24 and apical variant,25 which often are poorly visualized
on echocardiography. In 1 study,24 CMR accurately identified
Table 1.
HCM missed on echocardiography in 6% of the patients.
CMR is the gold standard for measurement of LV mass,
which might have some prognostic utility.26 Recently, a high
prevalence of apical aneurysms, missed by echocardiography
in 43% cases (albeit, without the use of contrast), was
demonstrated using CMR.27
Currently, CMR cannot be used in most patients with
pacemakers or implanted defibrillators; however, this may
change as newer safety data emerge. As an alternative to
CMR, cardiac CT can be used for morphological charac-
Currently Known Genes Implicated in HCM
Protein
Frequency in Patients
With HCM Phenotype
Associated Phenotype
MYH7
␤-myosin heavy chain
25%–35%
Variable
MYBPC3
Variable, late onset
Gene
Sarcomeric mutations
Myosin-bindingproteinC
20%–30%
TNNT2
Troponin T
3%–5%
Sudden death
TNNI3
Troponin I
⬍5%
Extreme heterogeneity
TPM1
Tropomyosin 1␣
⬍5%
Variable prognosis, sudden
death
MYL2
Regulatory myosin light chain 2
⬍5%
Skeletal myopathy
MYL3
Essential myosin light chain 3
Rare
Skeletal myopathy
ACTC
␣-Cardiac actin 1
Rare
Apical hypertrophy
TTN
Titin
Rare
Typical
TNNC1
Troponin C, slow skeletal
and cardiac muscles
Rare
Typical
MYH6
␣-Myosin heavy chain
Rare
Late onset
CSRP3
Muscle LIM protein
Rare
Late onset
MYLK2
Myosin light chain kinase 2
Rare
Early onset
LDB3
LIM binding domain 3
Rare
Mainly sigmoidal
TCAP
Telethonin
Rare
Typical, variable
VCL
Vinculin/metavinculin
Rare
Obstructive midventricular
hypertrophy
Nonsarcomeric mutations
ACTN2
PLN
MYOZ2
JPH2
␣-Actinin 2
Rare
Mainly sigmoidal
Phospholamban
Rare
Typical, variable
Myozenin 2
Rare
Typical
Junctophilin 2
Rare
Typical
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Table 2.
Circ Cardiovasc Imaging
March 2011
Potential Utilities and Pitfalls of Different Imaging Modalities in Diagnosis and Management of HCM
Imaging Technique
Potential Diagnostic Utility
Limitations
TTE (M-mode and 2D)
Assessment of LV thickness, mitral valve, LVOT
gradients, and global and regional LV mechanics
●
●
●
●
3D echocardiography
(TTE and TEE)
Assessment of mitral valve and papillary muscles,
LV volumes, and geometry
● Limited spatial resolution and adequacy of windows (TTE)
● Operator dependent and limited temporal resolution (TTE and TEE)
● Full Doppler capability not available
TEE (2D)
Exercise echocardiography
Assessment of mitral valve and subvalvular pathology
and periprocedural assessment
Assessment of functional capacity, postexercise
LVOT gradients, mitral valve pathology, and blood
pressure response to exercise
Operator dependent
Limited acoustic windows
Suboptimal images limit accuracy and reproducibility of measurements
Suboptimal assessment of subvalvular apparatus
● Semi-invasive
● Operator dependent
● Limited acoustic windows
● Operator dependent
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● Limited availability
● Expensive
● High radiation exposure
PET
Assessment of coronary flow reserve and
microvascular ischemia
CMR
Unlimited imaging planes to assess
anatomy and assessment of LV and
papillary muscle morphology, myocardial
fibrosis, regional myocardial mechanics, and
aortic pathology and flow characteristics
● Limited availability
● Multiple device-related contraindications
● Prognostic value of fibrosis assessment not firmly established
Cardiac CT
Assessment of LV morphology and coronary
artery disease, including myocardial bridging
● Radiation exposure
● Risk of nephrotoxicity due to iodinated contrast
TTE indicates transthoracic echocardiography.
terization and adds the ability to assess coronary artery
anatomy.28
Evaluation of Mitral Valve and Subvalvular Apparatus
Mitral valve abnormalities are common in HCM. The most
frequent is systolic anterior motion (SAM) of the anterior
(less commonly posterior) leaflet of the mitral valve in
systole, but other structural abnormalities frequently are seen,
including calcification of the mitral valve annulus and elongation of 1 or more cusps of either leaflet. Echocardiographic
studies also have demonstrated reduced mobility and length
of the posterior mitral leaflet, leading to a shorter coaptation
length.29 This results in a longer free segment of the anterior
leaflet that is susceptible to drag forces, leading to SAM.30
The direction of MR jet is an important clue in identifying the
underlying mechanism31 because an anteriorly/medially directed jet is most likely due to primary posterior leaflet
pathology, whereas SAM usually results in a posterior jet.
Surface and transesophageal echocardiography (TEE) (including 3D) (online-only Data Supplement Movie 1) may be
required to understand mitral valvular and chordal morphology when the direction of the MR jet is not posteriorly
directed.32
Compared with normal controls, studies using 3D CMR
have demonstrated a higher frequency of papillary muscle
abnormalities (anteroapical displacement and hypermobile
bifid papillary muscles) in patients with HCM.33,34 These
patients have a high prevalence of SAM and elevated LV
outflow tract (LVOT) gradients independent of septal thickness. There is increasing recognition that a subset of patients
with dynamic LVOT obstruction (LVOTO) have normal
thickness or minimal LVH, and the only abnormality noted
involves abnormal orientation and hypermobility of papillary
muscles (online-only Data Supplement Movie 2).33,35
Evaluation of Myocardial Perfusion
The degree of microvascular dysfunction identified by dipyridamole PET is an independent predictor of hard outcomes.36
Following vasodilator challenge, the hyperemic blood flow
response is substantially lower in patients with HCM than in
controls as assessed by CMR.37
Evaluation of Myocardial Fibrosis
Gadolinium-enhanced CMR provides an accurate method for
detection of myocardial fibrosis.38 In patients with HCM,
myocardial fibrosis is patchy, midmyocardial, and most
commonly found in regions of hypertrophy, especially in the
interventricular septum at the right ventricular insertion point
(Figures 2C and 2D and 3C and 3D). The pattern and amount
of fibrosis correlates closely with histopathology39,40 and
coronary arteriole dysplasia.40 Fibrosis, defined by CMR, is
detectable in 75% to 80% of patients with HCM and
correlates with wall thickness and inversely with regional
function.41– 43
The long-term clinical significance of fibrosis is uncertain.
Extent of fibrosis, particularly in patients aged ⬍40 years, is
associated with clinical markers of SCD, whereas in older
patients, it is associated with progressive ventricular dysfunction.44 Furthermore, studies have demonstrated an association
between degree of myocardial fibrosis and ventricular arrhythmia.42,43,45,46 Emerging data demonstrate incremental
prognostic value of myocardial fibrosis assessment in pre-
Desai et al
Table 3. Recommendations for Different Imaging Modalities
in HCM
Modality
Recommendations
TTE
1. Initial detailed morphologic evaluation of patients
with suspected HCM, including assessing severity of
LVOT obstruction and diastolic assessment
2. Screening of first-degree relatives of the affected
proband
3. Periodic follow-up in echocardiography in affected
individuals to assess progression, especially with
change in symptoms
4. Periodic screening of children of patients with HCM,
according to established guideline
5. Assessment of septal perforator anatomy following
contrast administration as an adjunct to alcohol
septal ablation
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6. Differential diagnosis of increased LV wall thickness
Stress
echocardiography
1. Stress echocardiography to assess postexercise LVOT
gradient (stress exercise also helps to assess blood
pressure response at peak stress)
TEE
1. TEE used if TTE is not conclusive
2. TEE for intraoperative guidance of surgery
CMR
1. In patients with suspected HCM in the setting of
inconclusive echocardiography
2. In patients with apical or lateral variants and
suspected apical aneurysms
3. In further evaluation of LV morphology (including
papillary muscles), especially in presence of LVOTO
and absence of significant LVH
4. Emerging role of delayed postgadolinium imaging for
risk stratification of SCD
5. Differential diagnosis of various cardiomyopathies
6. Emerging role in detection of preclinical HCM
Cardiac CT
1. In cases of inconclusive echocardiography where
CMR is contraindicated
2. Assessment of concomitant coronary artery
abnormalities in a symptomatic patient or
preoperatively in lieu of invasive angiography
Myocardial
perfusion
scintigraphy
1. Not recommended for routine assessment of
coronary flow reserve or myocardial ischemia
dicting hard outcomes.47,48 However, long-term prospective
studies establishing the association between fibrosis and SCD
are needed.
Functional Assessment
Evaluation of LV Cavity Obstruction
Approximately 70% of patients with HCM with asymmetrical
septal hypertrophy have evidence of resting or provocable LV
Hypertrophic Cardiomyopathy
159
cavity obstruction,49 which can occur at multiple levels and is
dynamic, varying with changes in heart rate, afterload,
contractility, and intravascular volume.50 LVOTO is associated with worse clinical outcomes, including progression to
heart failure and death.49 LVOTO usually is caused by SAM
of the mitral valve leaflet. The mechanism is complex but
involves narrowing of the LVOT by septal hypertrophy,
elongation of mitral leaflets, and anterior displacement of the
mitral apparatus and papillary muscles. SAM may be complete, incomplete, or chordal. The location and severity of
obstruction is best assessed by pulsed Doppler and
continuous-wave Doppler echocardiography, taking care to
distinguish the Doppler envelope from mitral regurgitation.
Care also should be taken to exclude other causes of LVOTO,
including subaortic membrane and accessory mitral valve
tissue. Obstruction also occurs at the midcavity level and the
ventricular apex. Recently, 3D quantification of LVOT area
has been shown to have added utility in the assessment of
LVOTO.51
Many patients without outflow obstruction at rest develop
it during physiological and pharmacological interventions
that reduce LV end-diastolic volume or increase LV contractility (eg, amyl nitrate inhalation, Valsalva maneuver, and
administration of intravenous inotropic agents). In patients
with exertional symptoms, provocative maneuvers are recommended when the resting LVOT gradient is ⬍30 mm Hg. If
the resting gradient is ⬎50 mm Hg, then provocation may not
be necessary. Valsalva is the simplest maneuver but has low
sensitivity, and pharmacological provocation needs to be
done with careful imaging to ensure that the observed
Doppler signal is not due to cavity obliteration. However,
neither Valsalva nor pharmacological stress reliably reproduce the physiological circumstances in which latent obstruction is likely to occur, and gradients produced during such
maneuvers correlate poorly with those induced by exercise.
Consequently, exercise stress echocardiography is now the
preferred method for provoking gradients. The safety of
exercise stress echocardiography has been established previously.52 It provides crucial information about exerciseinduced LVOT gradient, functional capacity, and blood
pressure response to exercise.53 In very few patients, lowdose infusions of isoproterenol in conjunction with real-time
2D assessment for SAM and dynamic LVOTO, using TEE is
necessary. Identifying and treating provocable obstruction
results in significant overall improvement in patients with
HCM.54
Phase velocity flow mapping on CMR also can be used to
determine the peak LVOT velocity. One study demonstrated
the feasibility of identifying patients with obstructive physiology based on the LVOT area measured by CMR.55 However, because of many technical limitations of CMR, Doppler
echocardiography remains the method of choice for determining LVOT gradients in clinical practice.
Evaluation of Systolic and Diastolic LV Function
Multiple mechanisms, including hypertrophy, myocyte disarray, fibrosis, and abnormal calcium metabolism, contribute to
diastolic dysfunction. Integrated assessment of several echocardiographic diastolic indices, including pulmonary vein
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March 2011
Figure 2. A 27-year-old man with HCM.
A, Two-dimensional echocardiographic
image demonstrating asymmetrical basal
septal hypertrophy. B, Doppler across
the LVOT demonstrating the latepeaking gradient. C, Cine CMR image
confirming severe septal hypertrophy. D,
Delayed hyperenhancement CMR image
demonstrating fibrosis in the hypertrophied septum.
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flow,56 tissue Doppler imaging, and transmitral inflow, can
provide reasonably accurate predictions of filling pressures.56
E/Ea ratio correlates weakly with exercise capacity, and
changes in E/Ea ratio have been demonstrated after alcohol
septal ablation57,58 and cardiac surgery.58 Septal Ea is an
independent predictor of death and ventricular dysrhythmia in
children with HCM.59 Although these observations have been
made in smaller cohorts, larger cross-sectional studies have
failed to significantly correlate Doppler filling patterns,
extent of LVH, and invasive indexes of diastolic function.60,61
Figure 3. A 35-year-old man with HCM.
A, Two-dimensional echocardiographic
image demonstrating severe apical hypertrophy. B, Doppler measurement
across the LVOT demonstrating absence
of obstruction. C, Two-chamber cine
CMR image confirming severe apical
hypertrophy. D, Delayed hyperenhancement CMR image demonstrating fibrosis
in the hypertrophied myocardium.
Desai et al
Although assessment of systolic function generally is
performed by measuring LV ejection fraction (which can be
measured by different imaging techniques), it does not reflect
the true systolic function in HCM. CMR studies have demonstrated reduced circumferential shortening in hypertrophied segments that was inversely related to local thickness,
with most shortening occurring in early systole.62,63 Another
recent study demonstrated reduced LV strain (measured by
speckle tracking echocardiography) in patients with HCM,
even in the absence of fibrosis. Myocardial fibrosis was
associated with further reduction in longitudinal strain.64
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Ventricular-Vascular Interactions
It was demonstrated recently that LVOT and aortic root are
oriented at a steeper angle to the LV in patients with HCM
versus normal controls65 and that the angle is independently
associated with maximal LVOT gradient. Recently,66 pulsewave velocity using phase-contrast CMR demonstrated stiffer
aortas in patients with HCM versus controls and that aortic
stiffness was greater in patients with HCM with myocardial
fibrosis versus those without. Further work has demonstrated
that aortic stiffness is associated with exercise capacity
independent of LV morphology, diastolic function, and
LVOT gradients.67
Risk Stratification for SCD
SCD is a relatively uncommon, but catastrophic complication
of HCM, often occurring during mild-moderate exertion.1,2,4,68 –71 A thorough history (including extended family
history), physical examination, and imaging evaluation are
essential to determine SCD risk. Maximal LV thickness ⱖ3
cm is a major risk factor for SCD.2,70 LVOT gradients
⬎30 mm Hg have been associated with increased risk of
SCD, progression to heart failure, arrhythmia, and stroke.49,72
However, the variable nature of LVOT gradients represents a significant limitation to its use as a risk marker of
SCD. Other major risk factors include an abnormal blood
pressure response during exercise,53 nonsustained ventricular
tachycardia, unexplained syncope, and a family history of
premature SCD. Previous data from CMR studies have
suggested an association between myocardial fibrosis and
ventricular arrhythmia.42,43,45,46 Additionally, emerging data
demonstrate incremental prognostic value of myocardial fibrosis assessment in predicting hard outcomes.47,48
The role of genetic analysis in risk stratification remains
controversial. MYH7-R403Q mutation was associated with
increased mortality, whereas a neutral substitution (V606M)
was associated with normal survival.73 Early data on the
clinical expression from MYBPC mutation indicated a later
onset and milder disease74 and that mutations in TNNT2
(troponin T) were associated with less severe hypertrophy
and fibrosis but severe disarray and a higher incidence of
SCD.75,76 More recently, a larger study has shown an increased risk of composite cardiovascular events with a
positive HCM genetic test involving any sarcomeric genes
compared with patients with a negative test.77 Additionally,
patients with multiple mutations, detected in about 3% to 5%
of genotype-positive patients, had a more severe phenotype
and increased incidence of SCD.78,79 However, family studies
Hypertrophic Cardiomyopathy
161
show that expression of mutations is heterogeneous, even
between individuals within families. Further, the majority of
diseases causing mutations are rare, making it difficult to
determine the SCD risk associated with particular genetic
variants in an adequate number of patients. For these reasons,
detection of specific mutations is insufficient to implant an
implantable cardioverter defibrillator in the absence of other
major risk factors.
Clinical and Imaging-Based Differential Diagnosis
of HCM
In routine clinical practice, a systematic approach to the
assessment of family pedigree, symptoms, and physical
examination in combination with a detailed imaging evaluation and, in some cases, biochemical testing, is central to
differential diagnosis of HCM. In some patients, there may be
clinical clues that suggest a particular etiology (eg, facial
dysmorphia in Noonan syndrome). There also may be clues
on the ECG (ventricular preexcitation in storage diseases and
mitochondrial disorders). There are few, if any, diseasespecific changes on echocardiography, but in context, a
number of features can point to possible diagnoses. For
example, concentric hypertrophy tends to be more common in
metabolic and storage disorders than in patients with sarcomeric gene mutations. Similarly, biatrial dilatation, restrictive
physiology, and an abnormal texture of the interventricular
septum (granular sparkling) should suggest amyloidosis.
Recently, it has been suggested that septal morphology is
preferentially sigmoidal in patients with Z-disc mutations in
contrast to myofilament HCM, which generally has a reverse
septal curvature.80
Metabolic Cardiomyopathies
In ⬍10% of infants and children and an even smaller
proportion of adults, HCM is caused by inborn errors of
metabolism, neuromuscular disorders, and malformation syndromes. Anderson-Fabry disease is an X-linked lysosomal
storage disorder caused by mutations in the ␣-galactosidase A
gene that causes progressive accumulation of glycosphingolipid in various organs, including the heart. Cardiac manifestations include progressive wall thickening (Figure 4), valve
disease, conduction abnormalities, and arrhythmias. Disease
expression typically begins after adolescence.81
Danon disease, an X-linked lysosomal storage disorder
caused by mutations in the gene encoding the lysosomeassociated membrane protein 2,82 is characterized by cardiomyopathy, skeletal myopathy, and developmental delay.
Other features include Wolff-Parkinson-White syndrome,
elevated serum creatine kinase, and retinitis pigmentosa.
Males develop symptoms during childhood and adolescence,
whereas females develop cardiomyopathy during adulthood.
The prognosis is poor, with most patients dying from cardiac
failure, although SCD is reported.
Pompe disease is an autosomal recessive disorder caused
by a deficiency in the lysosomal enzyme acid maltase. The
infantile form presents in the first few months, with severe
skeletal muscle hypotonia, cardiomegaly, hepatomegaly,
and macroglossia, and usually is fatal before 2 years
without treatment. Mutations in the gene encoding the ␥2
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March 2011
Figure 4. A 42-year-old woman with
Fabry disease. A, Two-dimensional
echocardiographic image demonstrating
concentric LVH. B, Doppler measurement demonstrating a late-peaking gradient. C, Four-chamber cine CMR image
confirming concentric LVH. D, Delayed
hyperenhancement CMR image demonstrating inferolateral basal fibrosis.
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subunit of the AMP-activated protein kinase (PRKAG2)
cause a syndrome of HCM, conduction abnormalities, and
Wolff-Parkinson-White syndrome.83
Respiratory chain disorders (mitochondrial cardiomyopathies) are caused by sporadic or inherited mutations in nuclear
or mitochondrial DNA transmitted as autosomal dominant,
recessive, X-linked, or maternal traits.84 These disorders vary
in age at onset, symptoms, and range and severity of organ
involvement. The phenotype usually is concentric LVH
without outflow tract obstruction, often with rapid progression to LV dilatation and heart failure.
Noonan syndrome is characterized by short stature, facial
dysmorphia, skeletal malformations, and a webbed neck.22
Cardiac involvement is present in up to 90% of patients
(pulmonary valve stenosis and HCM). It is inherited as an
autosomal dominant trait with variable penetrance and expression. Mutations in PTPN11 gene, encoding the protein
tyrosine phosphatase SHP-2, account for ⬇50% of cases, but
only 5% to 9% of all individuals with mutations in the
PTPN11 gene have HCM.85 LEOPARD (lentigines, ECG
abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and deafness) syndrome
shares many features with Noonan syndrome and is also
caused by mutations in the PTPN11 gene.23 Noonan syndrome and LEOPARD syndrome are examples of neurocardio-facial-cutaneous syndromes. Many are caused by
germline mutations in key components of the highly conserved RAS-MAPK cascade.86 Missense PTPN11, KRAS,
SOS1, RAF1, MEK1, and BRAF gene mutations have been
associated with HCM.
CMR and Different Cardiomyopathies
Some patterns of myocardial late-gadolinium enhancement
on CMR have been reported more frequently in particular
cardiomyopathies, for example, midmyocardial posterolateral
scarring in the LV (Fabry disease in Figure 4D, glycogen
storage disease)87 and diffuse myocardial pattern in cardiac
amyloidosis.88 However, these patterns are not specific and
must be interpreted in light of the clinical presentation.
Hypertensive Heart Disease
A common clinical dilemma is the diagnosis of HCM in
patients with hypertension. Hypertension typically produces
concentric remodeling of the LV rather than asymmetrical
hypertrophy. Moderate to severe hypertrophy (ⱖ15 mm) is
rare in whites with mild to moderate hypertension, and the
presence of a family history of cardiac hypertrophy in a
nonhypertensive relative or a positive gene test increases the
likelihood of HCM. SAM and LVOTO are recognized but are
less common in hypertensive heart disease. Finally, in hypertension but not HCM, treatment with antihypertensives can
regress LVH. Recently, deformation imaging has been shown
to distinguish between patients with HCM and those with
hypertension.89 In one of the earliest efforts to discern the
morphology of HCM, the septal contour was divided into
reverse curvature, sigmoid shape, apical predominance, and
concentric, although observing that the sigmoid shape was
more predominant in elderly patients with hypertensive heart
disease90 and that this sigmoid shape was less likely to be the
result of an underlying sarcomeric mutation.91
Athlete’s Heart
Differentiation of physiological hypertrophy from HCM in
elite athletes also can pose a problem, but in many cases,
analysis of ECG, echocardiography, and CMR facilitates
accurate diagnosis (Figure 5).92,93 In athletes’ hearts, LV
cavities are typically enlarged, wall thickness is usually
⬍15 mm, and myocardial fibrosis is absent. In contrast,
Desai et al
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163
Figure 5. A 17-year-old subject with an
athlete’s heart. A, Two-dimensional
echocardiographic image demonstrating
absence of LVH. B, Doppler measurement demonstrating normal diastology.
C, Four-chamber cine CMR image confirming absence of LVH. D, Delayed
hyperenhancement CMR image demonstrating no fibrosis.
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patients with HCM usually have normal or reduced LV
dimensions and no cavity dilatation (⬎ 55 mm common in
athletes), except with disease progression and systolic dysfunction. In borderline cases, it is reasonable to recommend
the cessation of exercise with repeat imaging in order to
detect regression of physiological LVH.
State-of-the-Art Imaging in Therapeutic
Decision Making in HCM
In a symptomatic patient with HCM, the goal of imaging is to
characterize the mechanism of obstruction and the feasibility
of different therapeutic interventions. Although 2D echocardiography (and in some cases TEE) are sufficient, 3D
echocardiography and CMR are rapidly emerging as useful
adjuncts, especially for assessment of mitral valve and
papillary muscle morphology.33 In patients with LVOTO and
septal hypertrophy that is not significant (typically ⬍1.8 cm),
an extensive myectomy would not be indicated. In such cases,
alternate surgical options, such as mitral valve repair/replacement and papillary muscle reorientation,94 need to be considered in addition to a minimyectomy (ⱕ5 mm muscle removal). Figure 6 demonstrates the different potential
therapeutic approaches based on septal thickness, mitral
valve, and papillary muscle pathology.94
After the decision has been made to proceed with surgery,
intraoperative TEE plays an invaluable role95 because it helps
to estimate the amount of myocardium that needs to be
removed and the length of the anterior mitral leaflet. It is also
important after surgery to determine whether residual SAM,
LVOTO (measured either directly or with isoproterenol
Figure 6. Potential schemata for management of symptomatic patients with
significant LVOTO. ASA indicates alcohol
septal ablation; MV, mitral valve; PM,
papillary muscle; PMR, papillary muscle
reorientation.
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Circ Cardiovasc Imaging
March 2011
Figure 7. Suggested schemata for
screening of family members in a patient
with documented HCM, incorporating
genetic testing and clinical evaluation.
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provocation), and MR are present, which may necessitate
further intervention. On the other hand, if the decision is
made to proceed with alcohol septal ablation, contrast echocardiography provides essential procedural guidance by identifying the myocardial territory perfused by the target vessel.96 Contrast opacification beyond the area of the basal
anteroseptum precludes ethanol injection. CMR also can be
used to assess the degree and unpredictable nature of septal
regression after alcohol ablation.97 In addition, fibrosis assessment by CMR might have a future role in risk stratification, especially when there is clinical uncertainty about
whether to recommend a defibrillator.
Screening: Family Members and
Asymptomatic Individuals
Because HCM is a genetic disorder in many cases, relatives
of an index case (proband) can be at risk for developing the
disease. The primary aim of family screening, therefore, is to
identify relatives who have the same disease as the proband
in order to prevent complications and inform life choices. In
some cases, assessment of the family also may assist in
diagnosing a borderline clinical phenotype.
There generally are 2 approaches to family screening. The
first is a clinical strategy based on the use of simple
noninvasive tests, such as an ECG and echocardiogram. In
addition to standard echocardiography, tissue Doppler echocardiography has shown reduced myocardial Doppler velocities in genotype-positive subjects without LVH.98 –100 Tagging by CMR also may have a role in early detection of
diastolic dysfunction or morphological changes (prehypertrophic crypts), where LVH has not yet manifested.101,102 In a
recent study, high levels of serum C-terminal propeptide of
type I procollagen (even before presence of overt fibrosis on
CMR) were demonstrated in subjects with HCM mutations
without LVH compared with controls.103 If a relative has tests
consistent with the suspected clinical diagnosis, then screening can be offered to other first-degree relatives (cascade or
stepwise screening). A limitation of this approach is that most
genetic forms of HCM have age-related penetrance (ie, the
HCM phenotype develops during adolescence and adult life),
which means that normal clinical tests cannot exclude future
risk of disease development and must be repeated at regular
intervals throughout life.
An alternative strategy is to identify the causative genetic
abnormality in the proband and then offer genetic testing to
relatives at risk of developing disease.104,105 The advantage of
this approach is that relatives who do not carry the mutation
can be spared from further clinical screening, whereas those
with the mutation can be monitored and advised appropriately. In practice, both strategies are necessary in particular
circumstances. For example, when molecular screening fails
to identify a mutation or demonstrates a genetic variant of
uncertain significance, clinical evaluation of family members
should still be considered.
A suggested schema, incorporating genetic and clinical
screening, based on the current guidelines and position
statements is shown in Figure 7.104,105 There are a couple
caveats that need to be considered. First, in a gene-negative
first-degree relative of a gene-positive proband (who has
multiple risk factors for SCD), it might be prudent to consider
imaging in that relative, irrespective of the genotype status.
Second, imaging generally is more readily (and in most cases,
rapidly) available than genetic testing. It might be prudent to
perform cardiac evaluation (including ECG and echocardiography) in all first-degree relatives of the gene-positive proband while waiting for the results of the genetic test.
Follow-up imaging in such circumstances could be dictated
by the results of the genetic test, as outlined in Figure 7.
Conclusions
Improved cardiac imaging and advances in our understanding
of a genetic basis for HCM have dramatically increased our
ability to diagnose and manage patients with HCM. In the future,
integration of structural and functional information with detailed
Desai et al
molecular analysis will provide the basis for new therapeutic
interventions that improve quality of life and protect patients and
families from disease-related complications.
Disclosures
None.
References
Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017
1. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ,
Seidman CE, Shah PM, Spencer WH, III, Spirito P, Ten Cate FJ, Wigle
ED. American College of Cardiology/European Society of Cardiology
clinical expert consensus document on hypertrophic cardiomyopathy. A
report of the American College of Cardiology Foundation Task Force on
Clinical Expert Consensus Documents and the European Society of
Cardiology Committee for Practice Guidelines J Am Coll Cardiol. 2003;
42:1687–1713.
2. Elliott PM, Poloniecki J, Dickie S, Sharma S, Monserrat L, Varnava A,
Mahon NG, McKenna WJ. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol. 2000;36:
2212–2218.
3. Elliott PM, Gimeno JR, Thaman R, Shah J, Ward D, Dickie S, Tome
Esteban MT, McKenna WJ. Historical trends in reported survival rates
in patients with hypertrophic cardiomyopathy. Heart. 2006;92:785–791.
4. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet. 2004;
363:1881–1891.
5. Seidman JG, Seidman C. The genetic basis for cardiomyopathy: from
mutation identification to mechanistic paradigms. Cell. 2001;104:
557–567.
6. Marian AJ, Roberts R. The molecular genetic basis for hypertrophic
cardiomyopathy. J Mol Cell Cardiol. 2001;33:655– 670.
7. Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ,
Ackerman MJ. Myosin binding protein C mutations and compound
heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol.
2004;44:1903–1910.
8. Jarcho JA, McKenna W, Pare JA, Solomon SD, Holcombe RF, Dickie
S, Levi T, Donis-Keller H, Seidman JG, Seidman CE. Mapping a gene
for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl
J Med. 1989;321:1372–1378.
9. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna
W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene
missense mutation. Cell. 1990;62:999 –1006.
10. Poetter K, Jiang H, Hassanzadeh S, Master SR, Chang A, Dalakas MC,
Rayment I, Sellers JR, Fananapazir L, Epstein ND. Mutations in either
the essential or regulatory light chains of myosin are associated with a
rare myopathy in human heart and skeletal muscle. Nat Genet. 1996;
13:63– 69.
11. Watkins H, Conner D, Thierfelder L, Jarcho JA, MacRae C, McKenna
WJ, Maron BJ, Seidman JG, Seidman CE. Mutations in the cardiac
myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat Genet. 1995;11:434 – 437.
12. Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg
HP, Seidman JG, Seidman CE. Alpha-tropomyosin and cardiac troponin
T mutations cause familial hypertrophic cardiomyopathy: a disease of
the sarcomere. Cell. 1994;77:701–712.
13. Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S,
Sasaoka T, Ohbuchi N, Nakamura T, Koyanagi T, Hwang TH, Choo JA,
Chung KS, Hasegawa A, Nagai R, Okazaki O, Nakamura H, Matsuzaki
M, Sakamoto T, Toshima H, Koga Y, Imaizumi T, Sasazuki T.
Mutations in the cardiac troponin I gene associated with hypertrophic
cardiomyopathy. Nat Genet. 1997;16:379 –382.
14. Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester
DJ, Ommen SR, Potter JD, Ackerman MJ. Molecular and functional
characterization of novel hypertrophic cardiomyopathy susceptibility
mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol. 2008;45:
281–288.
15. Mogensen J, Klausen IC, Pedersen AK, Egeblad H, Bross P, Kruse TA,
Gregersen N, Hansen PS, Baandrup U, Borglum AD. Alpha-cardiac
actin is a novel disease gene in familial hypertrophic cardiomyopathy.
J Clin Invest. 1999;103:R39 – 43.
16. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy.
J Am Coll Cardiol. 2009;54:201–211.
Hypertrophic Cardiomyopathy
165
17. Blanchard E, Seidman C, Seidman JG, LeWinter M, Maughan D.
Altered crossbridge kinetics in the alphaMHC403/⫹ mouse model of
familial hypertrophic cardiomyopathy. Circ Res. 1999;84:475– 483.
18. Miller T, Szczesna D, Housmans PR, Zhao J, de Freitas F, Gomes AV,
Culbreath L, McCue J, Wang Y, Xu Y, Kerrick WG, Potter JD.
Abnormal contractile function in transgenic mice expressing a familial
hypertrophic cardiomyopathy-linked troponin T (I79N) mutation. J Biol
Chem. 2001;276:3743–3755.
19. Gerull B, Gramlich M, Atherton J, McNabb M, Trombitas K, SasseKlaassen S, Seidman JG, Seidman C, Granzier H, Labeit S, Frenneaux
M, Thierfelder L. Mutations of TTN, encoding the giant muscle filament
titin, cause familial dilated cardiomyopathy. Nat Genet. 2002;30:
201–204.
20. Geier C, Perrot A, Ozcelik C, Binner P, Counsell D, Hoffmann K, Pilz
B, Martiniak Y, Gehmlich K, van der Ven PF, Furst DO, Vornwald A,
von Hodenberg E, Nurnberg P, Scheffold T, Dietz R, Osterziel KJ.
Mutations in the human muscle LIM protein gene in families with
hypertrophic cardiomyopathy. Circulation. 2003;107:1390 –1395.
21. Palumbo V, Segat L, Padovan L, Amoroso A, Trimarco B, Izzo R,
Lembo G, Zagrosek VR, Knoll R, Brancaccio M, Tarone G, Crovella S.
Melusin gene (ITGB1BP2) nucleotide variations study in hypertensive
and cardiopathic patients. BMC Med Genet. 2009;10:140.
22. Wigle ED, Sasson Z, Henderson MA, Ruddy TD, Fulop J, Rakowski H,
Williams WG. Hypertrophic cardiomyopathy. The importance of the site
and the extent of hypertrophy. A review. Prog Cardiovasc Dis. 1985;
28:1– 83.
23. Bicudo LS, Tsutsui JM, Shiozaki A, Rochitte CE, Arteaga E, Mady C,
Ramires JA, Mathias W Jr. Value of real time three-dimensional echocardiography in patients with hypertrophic cardiomyopathy: comparison
with two-dimensional echocardiography and magnetic resonance
imaging. Echocardiography. 2008;25:717–726.
24. Rickers C, Wilke NM, Jerosch-Herold M, Casey SA, Panse P, Panse N,
Weil J, Zenovich AG, Maron BJ. Utility of cardiac magnetic resonance
imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation.
2005;112:855– 861.
25. Moon JC, Fisher NG, McKenna WJ, Pennell DJ. Detection of apical
hypertrophic cardiomyopathy by cardiovascular magnetic resonance in
patients with non-diagnostic echocardiography. Heart. 2004;90:
645– 649.
26. Olivotto I, Maron MS, Autore C, Lesser JR, Rega L, Casolo G, De
Santis M, Quarta G, Nistri S, Cecchi F, Salton CJ, Udelson JE, Manning
WJ, Maron BJ. Assessment and significance of left ventricular mass by
cardiovascular magnetic resonance in hypertrophic cardiomyopathy.
J Am Coll Cardiol. 2008;52:559 –566.
27. Maron MS, Finley JJ, Bos JM, Hauser TH, Manning WJ, Haas TS,
Lesser JR, Udelson JE, Ackerman MJ, Maron BJ. Prevalence, clinical
significance, and natural history of left ventricular apical aneurysms in
hypertrophic cardiomyopathy. Circulation. 2008;118:1541–1549.
28. Hendel RC, Patel MR, Kramer CM, Poon M, Hendel RC, Carr JC,
Gerstad NA, Gillam LD, Hodgson JM, Kim RJ, Kramer CM, Lesser JR,
Martin ET, Messer JV, Redberg RF, Rubin GD, Rumsfeld JS, Taylor
AJ, Weigold WG, Woodard PK, Brindis RG, Hendel RC, Douglas PS,
Peterson ED, Wolk MJ, Allen JM, Patel MR. ACCF/ACR/SCCT/
SCMR/ASNC/NASCI/SCAI/SIR 2006 appropriateness criteria for
cardiac computed tomography and cardiac magnetic resonance imaging:
a report of the American College of Cardiology Foundation Quality
Strategic Directions Committee Appropriateness Criteria Working
Group, American College of Radiology, Society of Cardiovascular
Computed Tomography, Society for Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, North American
Society for Cardiac Imaging, Society for Cardiovascular Angiography
and Interventions, and Society of Interventional Radiology. J Am Coll
Cardiol. 2006;48:1475–1497.
29. Schwammenthal E, Nakatani S, He S, Hopmeyer J, Sagie A, Weyman
AE, Lever HM, Yoganathan AP, Thomas JD, Levine RA. Mechanism of
mitral regurgitation in hypertrophic cardiomyopathy: mismatch of posterior to anterior leaflet length and mobility. Circulation. 1998;98:
856 – 865.
30. Flores-Ramirez R, Lakkis NM, Middleton KJ, Killip D, Spencer WH III,
Nagueh SF. Echocardiographic insights into the mechanisms of relief of
left ventricular outflow tract obstruction after nonsurgical septal
reduction therapy in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 2001;37:208 –214.
31. Yu EH, Omran AS, Wigle ED, Williams WG, Siu SC, Rakowski H.
Mitral regurgitation in hypertrophic obstructive cardiomyopathy: rela-
166
32.
33.
34.
35.
36.
Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
Circ Cardiovasc Imaging
March 2011
tionship to obstruction and relief with myectomy. J Am Coll Cardiol.
2000;36:2219 –2225.
Sugeng L, Coon P, Weinert L, Jolly N, Lammertin G, Bednarz JE,
Thiele K, Lang RM. Use of real-time 3-dimensional transthoracic
echocardiography in the evaluation of mitral valve disease. J Am Soc
Echocardiogr. 2006;19:413– 421.
Kwon DH, Setser RM, Thamilarasan M, Popovic ZV, Smedira NG,
Schoenhagen P, Garcia MJ, Lever HM, Desai MY. Abnormal papillary
muscle morphology is independently associated with increased left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.
Heart. 2008;94:1295–1301.
Harrigan CJ, Appelbaum E, Maron BJ, Buros JL, Gibson CM, Lesser
JR, Udelson JE, Manning WJ, Maron MS. Significance of papillary
muscle abnormalities identified by cardiovascular magnetic resonance in
hypertrophic cardiomyopathy. Am J Cardiol. 2008;101:668 – 673.
Austin BA, Kwon DH, Smedira NG, Thamilarasan M, Lever HM, Desai
MY. Abnormally thickened papillary muscle resulting in dynamic left
ventricular outflow tract obstruction: an unusual presentation of hypertrophic cardiomyopathy. J Am Soc Echocardiogr. 2009;22:105.e5– e6.
Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG.
Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med. 2003;349:1027–1035.
Petersen SE, Jerosch-Herold M, Hudsmith LE, Robson MD, Francis JM,
Doll HA, Selvanayagam JB, Neubauer S, Watkins H. Evidence for
microvascular dysfunction in hypertrophic cardiomyopathy: new
insights from multiparametric magnetic resonance imaging. Circulation.
2007;115:2418 –2425.
Simonetti OP, Kim RJ, Fieno DS, Hillenbrand HB, Wu E, Bundy JM,
Finn JP, Judd RM. An improved MR imaging technique for the visualization of myocardial infarction. Radiology. 2001;218:215–223.
Moon JC, Sheppard M, Reed E, Lee P, Elliott PM, Pennell DJ. The
histological basis of late gadolinium enhancement cardiovascular
magnetic resonance in a patient with Anderson-Fabry disease. J Cardiovasc Magn Reson. 2006;8:479 – 482.
Kwon DH, Smedira NG, Rodriguez ER, Tan C, Setser R, Thamilarasan
M, Lytle BW, Lever HM, Desai MY. Cardiac magnetic resonance
detection of myocardial scarring in hypertrophic cardiomyopathy: correlation with histopathology and prevalence of ventricular tachycardia.
J Am Coll Cardiol. 2009;54:242–249.
Choudhury L, Mahrholdt H, Wagner A, Choi KM, Elliott MD, Klocke
FJ, Bonow RO, Judd RM, Kim RJ. Myocardial scarring in asymptomatic
or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am
Coll Cardiol. 2002;40:2156 –2164.
Teraoka K, Hirano M, Ookubo H, Sasaki K, Katsuyama H, Amino M,
Abe Y, Yamashina A. Delayed contrast enhancement of MRI in hypertrophic cardiomyopathy. Magn Reson Imaging. 2004;22:155–161.
Kwon DH, Setser RM, Popovic ZB, Thamilarasan M, Sola S,
Schoenhagen P, Garcia MJ, Flamm SD, Lever HM, Desai MY. Association of myocardial fibrosis, electrocardiography and ventricular
tachyarrhythmia in hypertrophic cardiomyopathy: a delayed contrast
enhanced MRI study. Int J Cardiovasc Imaging. 2008;24:617– 625.
Moon JC, McKenna WJ, McCrohon JA, Elliott PM, Smith GC, Pennell
DJ. Toward clinical risk assessment in hypertrophic cardiomyopathy
with gadolinium cardiovascular magnetic resonance. J Am Coll Cardiol.
2003;41:1561–1567.
Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL, Gibson
CM, Lesser JR, Hanna CA, Udelson JE, Manning WJ, Maron MS.
Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic
resonance. J Am Coll Cardiol. 2008;51:1369 –1374.
Rubinshtein R, Glockner JF, Ommen SR, Araoz PA, Ackerman MJ,
Sorajja P, Bos JM, Tajik AJ, Valeti US, Nishimura RA, Gersh BJ. Characteristics and clinical significance of late gadolinium enhancement by
contrast-enhanced magnetic resonance imaging in patients with hypertrophic cardiomyopathy. Circ Heart Fail. 2009;3:51–58.
O’Hanlon R, Grasso A, Roughton M, Moon JC, Clark S, Wage R, Webb
J, Kulkarni M, Dawson D, Sulaibeekh L, Chandrasekaran B,
Bucciarelli-Ducci C, Pasquale F, Cowie MR, McKenna WJ, Sheppard
MN, Elliott PM, Pennell DJ, Prasad SK. Prognostic significance of
myocardial fibrosis in hypertrophic cardiomyopathy. J Am Coll Cardiol.
2010;56:867– 874.
Bruder O, Wagner A, Jensen CJ, Schneider S, Ong P, Kispert EM,
Nassenstein K, Schlosser T, Sabin GV, Sechtem U, Mahrholdt H.
Myocardial scar visualized by cardiovascular magnetic resonance
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
imaging predicts major adverse events in patients with hypertrophic
cardiomyopathy. J Am Coll Cardiol. 2010;56:875– 887.
Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA,
Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction
on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med.
2003;348:295–303.
Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ,
Seidman CE, Shah PM, Spencer WH III, Spirito P, Ten Cate FJ, Wigle
ED. American College of Cardiology/European Society of Cardiology
Clinical expert consensus document on hypertrophic cardiomyopathy. A
report of the American College of Cardiology Foundation Task Force on
Clinical Expert Consensus Documents and the European Society of
Cardiology Committee for Practice Guidelines. Eur Heart J. 2003;24:
1965–1991.
Fukuda S, Lever HM, Stewart WJ, Tran H, Song JM, Shin MS,
Greenberg NL, Wada N, Matsumura Y, Toyono M, Smedira NG, Thomas JD, Shiota T. Diagnostic value of left ventricular outflow area in
patients with hypertrophic cardiomyopathy: a real-time threedimensional echocardiographic study. J Am Soc Echocardiogr. 2008;
21:789 –795.
Drinko JK, Nash PJ, Lever HM, Asher CR. Safety of stress testing in
patients with hypertrophic cardiomyopathy. Am J Cardiol. 2004;93:
1443–1444, A12.
Olivotto I, Maron BJ, Montereggi A, Mazzuoli F, Dolara A, Cecchi F.
Prognostic value of systemic blood pressure response during exercise in
a community-based patient population with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1999;33:2044 –2051.
Lakkis N, Plana JC, Nagueh S, Killip D, Roberts R, Spencer WH III.
Efficacy of nonsurgical septal reduction therapy in symptomatic patients
with obstructive hypertrophic cardiomyopathy and provocable gradients. Am J Cardiol. 2001;88:583–586.
Schulz-Menger J, Abdel-Aty H, Busjahn A, Wassmuth R, Pilz B, Dietz
R, Friedrich MG. Left ventricular outflow tract planimetry by cardiovascular magnetic resonance differentiates obstructive from nonobstructive hypertrophic cardiomyopathy. J Cardiovasc Magn Reson.
2006;8:741–746.
Nagueh SF, Lakkis NM, Middleton KJ, Spencer WH III, Zoghbi WA,
Quinones MA. Doppler estimation of left ventricular filling pressures in
patients with hypertrophic cardiomyopathy. Circulation. 1999;99:
254 –261.
Nagueh SF, Lakkis NM, Middleton KJ, Killip D, Zoghbi WA, Quinones
MA, Spencer WH III. Changes in left ventricular filling and left atrial
function six months after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 1999;34:
1123–1128.
Sitges M, Shiota T, Lever HM, Qin JX, Bauer F, Drinko JK, Agler DA,
Martin MG, Greenberg NL, Smedira NG, Lytle BW, Tuzcu EM, Garcia
MJ, Thomas JD. Comparison of left ventricular diastolic function in
obstructive hypertrophic cardiomyopathy in patients undergoing percutaneous septal alcohol ablation versus surgical myotomy/myectomy.
Am J Cardiol. 2003;91:817– 821.
McMahon CJ, Nagueh SF, Pignatelli RH, Denfield SW, Dreyer WJ,
Price JF, Clunie S, Bezold LI, Hays AL, Towbin JA, Eidem BW.
Characterization of left ventricular diastolic function by tissue Doppler
imaging and clinical status in children with hypertrophic cardiomyopathy. Circulation. 2004;109:1756 –1762.
Nishimura RA, Appleton CP, Redfield MM, Ilstrup DM, Holmes DR Jr,
Tajik AJ. Noninvasive Doppler echocardiographic evaluation of left
ventricular filling pressures in patients with cardiomyopathies: a simultaneous Doppler echocardiographic and cardiac catheterization study.
J Am Coll Cardiol. 1996;28:1226 –1233.
Geske JB, Sorajja P, Nishimura RA, Ommen SR. Evaluation of left
ventricular filling pressures by Doppler echocardiography in patients
with hypertrophic cardiomyopathy: correlation with direct left atrial
pressure measurement at cardiac catheterization. Circulation. 2007;116:
2702–2708.
Dong SJ, MacGregor JH, Crawley AP, McVeigh E, Belenkie I, Smith
ER, Tyberg JV, Beyar R. Left ventricular wall thickness and regional
systolic function in patients with hypertrophic cardiomyopathy. A threedimensional tagged magnetic resonance imaging study. Circulation.
1994;90:1200 –1209.
Kramer CM, Reichek N, Ferrari VA, Theobald T, Dawson J, Axel L.
Regional heterogeneity of function in hypertrophic cardiomyopathy.
Circulation. 1994;90:186 –194.
Desai et al
Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017
64. Popovic ZB, Kwon DH, Mishra M, Buakhamsri A, Greenberg NL,
Thamilarasan M, Flamm SD, Thomas JD, Lever HM, Desai MY. Association between regional ventricular function and myocardial fibrosis in
hypertrophic cardiomyopathy assessed by speckle tracking echocardiography and delayed hyperenhancement magnetic resonance imaging.
J Am Soc Echocardiogr. 2008;21:1299 –1305.
65. Kwon DH, Smedira NG, Popovic ZB, Lytle BW, Setser R, Thamilarasan
M, Schoenhagen P, Flamm SD, Lever HM, Desai MY. Steep left
ventricle to aortic root angle and hypertrophic obstructive cardiomyopathy: study of a novel association using 3-dimensional multi-modality
imaging. Heart. 2009;95:1784 –1791.
66. Boonyasirinant T, Rajiah P, Setser RM, Lieber ML, Lever HM, Desai
MY, Flamm SD. Aortic stiffness is increased in hypertrophic cardiomyopathy with myocardial fibrosis: novel insights in vascular function
from magnetic resonance imaging. J Am Coll Cardiol. 2009;54:
255–262.
67. Austin BA, Popovic Z, Kwon D, Thamilarasan M, Boonyasirinant T,
Flamm SD, Lever H, Desai MY. Aortic stiffness independently predicts
exercise capacity in hypertrophic cardiomyopathy: a multimodality
imaging study. Heart. 2010;96:1303–1310.
68. Spirito P. The management of hypertrophic cardiomyopathy. N Engl
J Med. 1997;336:775–785.
69. Elliott P. Relation between the severity of left ventricular hypertrophy
and prognosis in patients with hypertrophic cardiomyopathy. Lancet.
2001;357:420 – 424.
70. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ.
Magnitude of left ventricular hypertrophy and risk of sudden death in
hypertrophic cardiomyopathy. N Engl J Med. 2000;342:1778 –1785.
71. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA.
2002;287:1308 –1320.
72. Kofflard MJ, Ten Cate FJ, van der Lee C, van Domburg RT. Hypertrophic cardiomyopathy in a large community-based population: clinical
outcome and identification of risk factors for sudden cardiac death and
clinical deterioration. J Am Coll Cardiol. 2003;41:987–993.
73. Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman
CE, Seidman JG. Characteristics and prognostic implications of myosin
missense mutations in familial hypertrophic cardiomyopathy. N Engl
J Med. 1992;326:1108 –1114.
74. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE,
McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG,
Seidman CE. Mutations in the gene for cardiac myosin-binding protein
C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med.
1998;338:1248 –1257.
75. Moolman JC, Corfield VA, Posen B, Ngumbela K, Seidman C, Brink
PA, Watkins H. Sudden death due to troponin T mutations. J Am Coll
Cardiol. 1997;29:549 –555.
76. Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O’Donoghue
A, Spirito P, Matsumori A, Moravec CS, Seidman JG, Seidman CE.
Mutations in the genes for cardiac troponin T and alpha-tropomyosin in
hypertrophic cardiomyopathy. N Engl J Med. 1995;332:1058 –1064.
77. Olivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E,
Ommen SR, Theis JL, Vaubel RA, Re F, Armentano C, Poggesi C,
Torricelli F, Cecchi F. Myofilament protein gene mutation screening and
outcome of patients with hypertrophic cardiomyopathy. Mayo Clin
Proc. 2008;83:630 – 638.
78. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C.
Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med
Genet. 2005;42:e59.
79. Ho CY, Lever HM, DeSanctis R, Farver CF, Seidman JG, Seidman CE.
Homozygous mutation in cardiac troponin T: implications for hypertrophic cardiomyopathy. Circulation. 2000;102:1950 –1955.
80. Theis JL, Bos JM, Bartleson VB, Will ML, Binder J, Vatta M, Towbin
JA, Gersh BJ, Ommen SR, Ackerman MJ. Echocardiographicdetermined septal morphology in Z-disc hypertrophic cardiomyopathy.
Biochem Biophys Res Commun. 2006;351:896 –902.
81. Linhart A, Kampmann C, Zamorano JL, Sunder-Plassmann G, Beck M,
Mehta A, Elliott PM. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J.
2007;28:1228 –1235.
82. Arad M, Benson DW, Perez-Atayde AR, McKenna WJ, Sparks EA,
Kanter RJ, McGarry K, Seidman JG, Seidman CE. Constitutively active
AMP kinase mutations cause glycogen storage disease mimicking
hypertrophic cardiomyopathy. J Clin Invest. 2002;109:357–362.
Hypertrophic Cardiomyopathy
167
83. Blair E, Redwood C, Ashrafian H, Oliveira M, Broxholme J, Kerr B,
Salmon A, Ostman-Smith I, Watkins H. Mutations in the gamma(2)
subunit of AMP-activated protein kinase cause familial hypertrophic
cardiomyopathy: evidence for the central role of energy compromise in
disease pathogenesis. Hum Mol Genet. 2001;10:1215–1220.
84. DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl
J Med. 2003;348:2656 –2668.
85. Chen B, Bronson RT, Klaman LD, Hampton TG, Wang JF, Green PJ,
Magnuson T, Douglas PS, Morgan JP, Neel BG. Mice mutant for Egfr
and Shp2 have defective cardiac semilunar valvulogenesis. Nat Genet.
2000;24:296 –299.
86. Tidyman WE, Rauen KA. The RASopathies: developmental syndromes
of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009;19:
230 –236.
87. Mahrholdt H, Wagner A, Judd RM, Sechtem U, Kim RJ. Delayed
enhancement cardiovascular magnetic resonance assessment of nonischaemic cardiomyopathies. Eur Heart J. 2005;26:1461–1474.
88. Austin BA, Tang WH, Rodriguez ER, Tan C, Flamm SD, Taylor DO,
Starling RC, Desai MY. Delayed hyper-enhancement magnetic resonance imaging provides incremental diagnostic and prognostic utility
in suspected cardiac amyloidosis. J Am Coll Cardiol Cardiovasc
Imaging. 2009;2:1369 –1377.
89. Kato TS, Noda A, Izawa H, Yamada A, Obata K, Nagata K, Iwase M,
Murohara T, Yokota M. Discrimination of nonobstructive hypertrophic
cardiomyopathy from hypertensive left ventricular hypertrophy on the basis
of strain rate imaging by tissue Doppler ultrasonography. Circulation.
2004;110:3808–3814.
90. Lever HM, Karam RF, Currie PJ, Healy BP. Hypertrophic cardiomyopathy in the elderly. Distinctions from the young based on cardiac shape.
Circulation. 1989;79:580 –589.
91. Binder J, Ommen SR, Gersh BJ, Van Driest SL, Tajik AJ, Nishimura
RA, Ackerman MJ. Echocardiography-guided genetic testing in hypertrophic cardiomyopathy: septal morphological features predict the
presence of myofilament mutations. Mayo Clin Proc. 2006;81:459 – 467.
92. Spirito P, Pelliccia A, Proschan MA, Granata M, Spataro A, Bellone P,
Caselli G, Biffi A, Vecchio C, Maron BJ. Morphology of the “athlete’s
heart” assessed by echocardiography in 947 elite athletes representing
27 sports. Am J Cardiol. 1994;74:802– 806.
93. Scharhag J, Urhausen A, Schneider G, Rochette V, Kramann B, Kindermann W. [Left ventricular mass in endurance-athletes with athlete’s
heart and untrained subjects— comparison between different echocardiographic methods and MRI]. Z Kardiol. 2003;92:309 –318.
94. Kwon DH, Smedira NG, Thamilarasan M, Lytle BW, Lever H, Desai MY.
Characteristics and surgical outcomes of symptomatic patients with hypertrophic cardiomyopathy with abnormal papillary muscle morphology
undergoing papillary muscle reorientation. J Thorac Cardiovasc Surg.
2010;140:317–324.
95. Ommen SR, Park SH, Click RL, Freeman WK, Schaff HV, Tajik AJ.
Impact of intraoperative transesophageal echocardiography in the
surgical management of hypertrophic cardiomyopathy. Am J Cardiol.
2002;90:1022–1024.
96. Nagueh SF, Lakkis NM, He ZX, Middleton KJ, Killip D, Zoghbi WA,
Quinones MA, Roberts R, Verani MS, Kleiman NS, Spencer WH III.
Role of myocardial contrast echocardiography during nonsurgical septal
reduction therapy for hypertrophic obstructive cardiomyopathy. J Am
Coll Cardiol. 1998;32:225–229.
97. Valeti US, Nishimura RA, Holmes DR, Araoz PA, Glockner JF, Breen
JF, Ommen SR, Gersh BJ, Tajik AJ, Rihal CS, Schaff HV, Maron
BJ. Comparison of surgical septal myectomy and alcohol septal ablation
with cardiac magnetic resonance imaging in patients with hypertrophic
obstructive cardiomyopathy. J Am Coll Cardiol. 2007;49:350 –357.
98. Nagueh SF, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW,
Quinones MA, Roberts R, Marian AJ. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic
cardiomyopathy and provides a novel means for an early diagnosis
before and independently of hypertrophy. Circulation. 2001;104:
128 –130.
99. Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman
JG, Seidman CE, Solomon SD. Assessment of diastolic function with
Doppler tissue imaging to predict genotype in preclinical hypertrophic
cardiomyopathy. Circulation. 2002;105:2992–2997.
100. Nagueh SF, McFalls J, Meyer D, Hill R, Zoghbi WA, Tam JW,
Quinones MA, Roberts R, Marian AJ. Tissue Doppler imaging predicts
the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation. 2003;108:395–398.
168
Circ Cardiovasc Imaging
March 2011
101. Ennis DB, Epstein FH, Kellman P, Fananapazir L, McVeigh ER, Arai
AE. Assessment of regional systolic and diastolic dysfunction in familial
hypertrophic cardiomyopathy using MR tagging. Magn Reson Med.
2003;50:638 – 642.
102. Germans T, Wilde AA, van Echteld CJ, Kamp O, Pinto YM, van
Rossum AC. Structural abnormalities of the left ventricle in hypertrophic cardiomyopathy mutation carriers detectable before the development of hypertrophy. Neth Heart J. 2007;15:161–163.
103. Ho CY, Lopez B, Coelho-Filho OR, Lakdawala NK, Cirino AL, Jarolim
P, Kwong R, Gonzalez A, Colan SD, Seidman J, Dietz J, Seidman C.
Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med. 2010:552–563.
104. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR,
Towbin JA. Genetic evaluation of cardiomyopathy—a Heart Failure
Society of America practice guideline. J Card Fail. 2009;15:83–97.
105. Charron P, Arad M, Arbustini E, Basso C, Bilinska Z, Elliott P, Helio T,
Keren A, McKenna W, Monserrat L, Seggewiss H, van Langen I,
Tavazzi L. Genetic counselling and testing in cardiomyopathies: a
position statement of the European Society of Cardiology Working
Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31:
2715–2726.
KEY WORDS: cardiomyopathy
䡲
hypertrophy
䡲
imaging
䡲
genetics
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Imaging Phenotype Versus Genotype in Hypertrophic Cardiomyopathy
Milind Y. Desai, Steve R. Ommen, William J. McKenna, Harry M. Lever and Perry M. Elliott
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Circ Cardiovasc Imaging. 2011;4:156-168
doi: 10.1161/CIRCIMAGING.110.957936
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