The AHA Guidelines and Scientifi c Statements Handbook
population for the disease phenotype recognized by
echocardiography), and probably the most fre-
quently occurring cardiomyopathy. HCM is also the
most common cause of sudden cardiac death in the
young as well as in trained athletes (in the US) and
is an important substrate for heart failure disability
at any age.
HCM is characterized morphologically by virtue of
an otherwise unexplained hypertrophied and nondi-
lated LV in the absence of another cardiac or systemic
disease capable of producing the magnitude of wall
thickening evident (e.g., systemic hypertension, aortic
valve stenosis), independent of whether obstruction
to LV outfl ow is present. Clinical diagnosis is custom-
arily made with two-dimensional echocardiography
(or alternatively with cardiovascular magnetic reso-
nance [CMR] imaging).
HCM demonstrates extreme genetic heterogene-
ity, and is caused by a variety of mutations encod-
ing protein components of the cardiac sarcomere.
Eleven mutated sarcomeric genes are presently asso-
ciated with HCM, most commonly beta-myosin
heavy chain (the fi rst identifi ed) and myosin-binding
protein C. The other nine genes appear to account
for far fewer cases of HCM and include troponin T
and I, regulatory and essential myosin light chains,
titin, α-tropomyosin, α-actin, α-myosin heavy
chain, and muscle LIM protein (MLP). This inter-
genetic diversity displayed in HCM is compounded
by considerable intra-genetic heterogeneity, with
multiple mutations identifi ed in each gene (n = > 400
total individual mutations now). These are most
commonly missense mutations altering only a single
nucleotide (such as with beta-myosin heavy chain
and α-tropomyosin), although other mutations
cause protein truncation (e.g., myosin-binding
protein C and troponin T). The characteristic diver-
sity of the HCM phenotype is attributable to the
disease-causing mutations, but probably also to the
infl uence of modifi er genes and environmental
factors.
A number of other diseases associated with LV
hypertrophy involve prominent thickening of the
LV wall, occurring mostly in infants and children ≤ 4
years of age, which may resemble or mimic typical
HCM due to sarcomere protein mutations. These
cardiomyopathies also include secondary forms
such as Noonan syndrome, an autosomal dominant
cardiofacial condition associated with a variety of
cardiac defects (most commonly, dysplastic pulmo-
nary valve stenosis and atrial septal defect) due to
mutations in PTPN11, a gene encoding the nonre-
ceptor protein tyrosine phosphatase SHP-2 genes.
Other diseases in this category are mitochondrial
myopathies due to mutations encoding mitochon-
drial DNA (including Kearns–Sayre syndrome), or
mitochondrial proteins associated with ATP elec-
tron transport chain enzyme defects which alter
mitochondrial morphology. Also included in these
considerations are metabolic myopathies represent-
ing ATP production and utilization defects involv-
ing abnormalities of fatty acid oxidation (acyl CoA
dehydrogenase defi ciencies) and carnitine defi -
ciency, as well as infi ltrative myopathies – i.e., gly-
cogen storage diseases (type II; autosomal recessive
Pompe disease), Hunter’s and Hurler’s diseases, and
also the transient and nonfamilial cardiomyopathy
as part of generalized organomegaly, recognized in
infants of insulin-dependent diabetic mothers. In
older patients, a number of systemic diseases have
been associated with hypertrophic forms of cardio-
myopathy; these include Friedreich’s ataxia, pheo-
chromocytoma, neurofi bromatosis, lentiginosis,
and tuberous sclerosis.Arrhythmogenic right ventricular cardiomyopathy/
dysplasia (ARVC/D)
ARVC/D is an uncommon form of inheritable heart
muscle disease (estimated 1 : 5000), relatively recent
in its description only about 20 years ago. It is mostly
characterized by myocardial electrical instability and
a risk for life-threatening ventricular arrhythmias.
ARVC/D predominantly involves the right ventricle
with progressive loss of myocytes and fi bro-fatty
tissue replacement, resulting in regional (segmental)
or global abnormalities. Aneurysms of the right ven-
tricle in the triangle of dysplasia (infl ow, apex,
outfl ow) are a specifi c feature. Apoptosis has been
demonstrated as the mode for ongoing death of
myocytes. Although frequently associated with
myocarditis (enterovirus or adenovirus), ARVC/D
is not considered a primary infl ammatory cardio-
myopathy. In addition, evidence of LV involvement
with fi bro-fatty replacement, chamber enlargement
and myocarditis is also reported in up to 50–75% of
patients.
In the majority of cases, ARVC/D shows autoso-
mal dominant inheritance, albeit often with