The n e w e ng l a n d j o u r na l
Case Records of the Massachusetts General Hospital
From the Department of Cardiovascular
Medicine, Mayo Clinic, Rochester, MN
(P.A.P.); the Departments of Medicine
(D.M.D., S.A.L., A.T.-R.) and Pediatrics
(A.K.), Massachusetts General Hospital,
and the Departments of Medicine
(D.M.D., S.A.L., A.T.-R.) and Pediatrics
(A.K.), Harvard Medical School — both
in Boston; and the Division of Cardiology
and Cardiovascular Surgery, University
of British Columbia, Vancouver, Canada
(T.S.M.T.).
N Engl J Med 2022;386:1266-76.
DOI: 10.1056/NEJMcpc2201230
Copyright © 2022 Massachusetts Medical Society.
CME
at NEJM.org
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of m e dic i n e
Founded by Richard C. Cabot
Eric S. Rosenberg, M.D., Editor
David M. Dudzinski, M.D., Meridale V. Baggett, M.D., Kathy M. Tran, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Emily K. McDonald, Tara Corpuz, Production Editors
Case 10-2022: A 78-Year-Old Man
with Marked Ventricular Wall Thickening
Patricia A. Pellikka, M.D., David M. Dudzinski, M.D.,
Steven A. Lubitz, M.D., M.P.H., Teresa S.M. Tsang, M.D.,
Albree Tower‑Rader, M.D., and Amel Karaa, M.D.​​
Pr e sen tat ion of C a se
Dr. David M. Dudzinski: A 78-year-old man was evaluated in the cardiology clinic of
this hospital because of biventricular myocardial wall thickening, progressive mi-
tral regurgitation, and ventricular arrhythmias.
The patient had been a distinguished multisport athlete in high school and col-
lege. However, in his 20s, he found that he was unable to perform competitively,
and he noticed that he did not sweat as much as his teammates. After an episode
of sports-related exertional dizziness, he was evaluated by a physician, and a diag-
nosis of hypertrophic cardiomyopathy was considered.
Twenty-five years before the current evaluation, a transthoracic echocardiogram
(TTE) reportedly showed a symmetric left ventricular wall thickness of 19 mm
(reference value, ≤11), a left ventricular ejection fraction of 74% (reference range,
50 to 75), mitral valve thickening, and trace mitral regurgitation, with no left
ventricular outflow gradient. An electrocardiogram showed sinus rhythm, incom-
plete right bundle-branch block, precordial J-point elevation, and QRS voltage that
met the electrocardiographic criteria for left ventricular hypertrophy (Fig. 1A). The
patient’s blood pressure was 160/90 mm Hg, and he started treatment with meto-
prolol succinate and then also with amlodipine for elevated blood pressure.
During the next 10 years, the patient had intermittent chest discomfort, exer-
tional dyspnea, and leg edema. The chest discomfort and exertional dyspnea were
most likely to occur when he was walking or after he had eaten a meal. He was
evaluated by three cardiologists; treatment with metoprolol succinate and amlo-
dipine was continued, treatment with enalapril was started, and triamterene–
hydrochlorothiazide was administered as needed for leg edema.
A repeat TTE reportedly showed a symmetric left ventricular wall thickness of
20 mm, a normal left ventricular ejection fraction, right ventricular wall thicken-
ing, left atrial enlargement, mitral valve thickening, mild-to-moderate mitral re-
gurgitation, aortic valve thickening, and mild ascending aortic dilatation (39 mm),
with no evidence of left ventricular outflow tract obstruction and no evidence of
systolic anterior motion of the mitral valve. An exercise stress test followed by
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 Case Records of the Massachuset ts Gener al Hospital

A 25 Years before Current Evaluation

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

V1

II

V5

B 9 Years before Current Evaluation

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

V1

II

V5

Figure 1. Electrocardiograms.
An electrocardiogram obtained 25 years before the current evaluation (Panel A) shows sinus rhythm, incomplete
right bundle-branch block, precordial J-point elevation, and QRS voltage that meets the electrocardiographic criteria
for left ventricular hypertrophy. Electrocardiographic tracings obtained during the next 15 years showed similar find-
ings. An electrocardiogram obtained 9 years before the current evaluation (Panel B) shows sinus rhythm with com-
plete heart block and escape rhythm with right bundle-branch block and left-axis deviation.

imaging performed with the use of sestamibi defects. Coronary angiography revealed evidence
(known as a sestamibi stress test) revealed left of chronic total occlusion of the distal left ante-
ventricular wall thickening, with no perfusion rior descending artery, with collateral flow from

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 The n e w e ng l a n d j o u r na l
both the left and right coronary arteries. Left
ventriculography revealed hyperdynamic left ven-
tricular function and 2+ mitral regurgitation (see
Videos showing
Video 1, available with the full text of this article
cardiac imaging
are available at at NEJM.org). The left ventricular end-diastolic
NEJM.org pressure was 28 mm Hg (reference range, 5 to 10),
with no left ventricular intracavitary gradient,
including during ventricular ectopic beats and
during the Valsalva maneuver, and with no evi-
dence of left ventricular outflow tract obstruc-
tion. The blood pressure remained well con-
trolled while the patient was taking metoprolol,
amlodipine, and enalapril.
Nine years before the current evaluation, the
patient had complete heart block with symptom-
atic bradycardia (Fig. 1B), with associated nausea,
dizziness, and chest discomfort. A temporary
transvenous pacing wire was placed; the results
of coronary angiography performed at that
time were unchanged from the previous study.
The creatinine level was 1.2 mg per deciliter
(106 μmol per liter; reference range, 0.6 to 1.5 mg
per deciliter [53 to 133 μmol per liter]); the blood
levels of electrolytes and thyrotropin were nor-
mal, as were the results of serum protein elec-
trophoresis. A dual-chamber implantable cardio-
verter–defibrillator (ICD) was placed. Four months
later, atrial fibrillation developed. Cardioversion
was performed with guidance by transesopha-
geal echocardiography, resulting in sinus rhythm.
However, atrial fibrillation recurred after 3 days.
Treatment with amiodarone and warfarin was
begun.
During the next 5 years, recurrent nonsus-
tained ventricular tachyarrhythmias were detect-
ed on ICD interrogation. A repeat TTE showed a
left ventricular wall thickness of 23 mm and
moderate-to-severe mitral regurgitation.
Four years before the current evaluation, dur-
ing a holiday trip, the patient was hospitalized
in another state because of pulmonary edema
that developed after he had consumed food that
was high in sodium. He was treated with intra-
venous furosemide and discharged with a pre-
scription for oral furosemide. Findings on TTE
were reportedly similar to those observed previ-
ously. Treatment with amlodipine was stopped
because of lightheadedness.
At follow-up appointments during the next
4 years, the patient reported fatigue and exer-
tional dyspnea that occurred after he had climbed
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of m e dic i n e
one flight of stairs or when he was walking on
an incline. In addition, he had nocturia once per
night, slept on two pillows, and had intermittent
wheezing, including episodes that awakened
him from sleep. Treatment with oral furosemide
(administered twice daily) was continued. Recur-
rent nonsustained ventricular tachyarrhythmias
were detected on ICD interrogation. Approxi-
mately 3.5 years before the current evaluation,
the patient sustained a fall that was unrelated to
his cardiac condition. At that time, computed
tomography of the head, performed without the
administration of intravenous contrast material,
did not reveal any evidence of hemorrhage or
stroke but showed periventricular and deep white-
matter hypodensities. Results of pulmonary-
function testing were normal.
The patient presented for the current evalua-
tion at the request of his two teenage grandsons,
who wanted to know about any familial cardiac
risk factors that could influence their participa-
tion in sports. A review of systems was notable
for intermittent palpitations, chronic dry eyes,
reduced hearing, tinnitus in both ears (greater
in the right ear than in the left ear), restless legs,
and constipation. The patient reported no head-
ache, paresthesia, stroke symptoms, diarrhea,
skin changes, or intolerance to heat or cold. His
medical history included cardiomyopathy, coro-
nary artery disease, atrioventricular block and
atrial fibrillation, dyslipidemia, hypertension,
progressive renal insufficiency, cataracts, and
prostatic hypertrophy with carcinoma in situ.
Medications included furosemide, warfarin, amio-
darone, aspirin, atorvastatin, metoprolol, enala-
pril, and tamsulosin, as well as inhaled flutica-
sone. Amiodarone had caused thyroiditis, which
had been treated with a course of prednisone;
there were no other known adverse reactions to
medication.
The patient was a retired executive and lived
with his spouse in Massachusetts. His family
history was notable for brain cancer in his fa-
ther, obstructive lung disease and lung cancer in
his mother, and lung cancer in his sister, who had
died from the disease. There was also a history
of hypertrophic cardiomyopathy in his sister and
in a niece. His family was of Mediterranean origin;
information about other relatives was limited.
His son and grandsons were healthy, and his
son had reportedly had normal results on an
nejm.org March 31, 2022
 Case Records of the Massachuset ts Gener al Hospital
electrocardiogram and echocardiograms. The pa-
tient did not drink alcohol and had never used
tobacco.
On examination, the heart rate was 79 beats
per minute and the blood pressure 106/60 mm Hg.
The weight was 89 kg and the body-mass index
(the weight in kilograms divided by the square
of the height in meters) 26.6. There was a left
ventricular heave. Auscultation revealed splitting
of the S2 heart sound, a grade 3/6 systolic mur-
mur that could be heard throughout the precor-
dium and did not change during the Valsalva
maneuver, and a grade 2/6 holosystolic murmur
at the apex that radiated to the axilla; there was
no S3 heart sound. There was trace leg edema
and mild chronic venous stasis. The rest of the
examination was normal.
Laboratory test results were notable for a cre-
atinine level of 1.5 mg per deciliter (133 μmol
per liter), a urea nitrogen level of 39 mg per
deciliter (13.9 mmol per liter; reference range, 8 to
25 mg per deciliter [2.9 to 8.9 mmol per liter]),
an international normalized ratio of 2.1 (refer-
ence range, 0.9 to 1.1), and an N-terminal pro–
B-type natriuretic peptide level of 2523 pg per
milliliter (reference range, 0 to 1800), as well as
1+ protein on urinalysis. The blood levels of iron,
glycated hemoglobin, thyrotropin, and free thyrox-
ine were normal, and a test for antinuclear anti-
bodies was negative. An electrocardiogram showed
atrial fibrillation with ventricular pacing.
A TTE was obtained, and additional diagnos-
tic tests were performed.
Differ en t i a l Di agnosis
Dr. Patricia A. Pellikka: This 78-year-old man pre-
sented for evaluation of chronic ventricular myo-
cardial wall thickening, mitral regurgitation, and
recurrent ventricular tachyarrhythmias. In deter-
mining the process underlying his cardiomyopa-
thy, it is important to consider the clues from
the echocardiograms in the context of the his-
tory and findings on physical examination. I re-
viewed and interpreted the patient’s most recent
echocardiographic images, which were obtained
at the time of the current evaluation. The images
were remarkable for severe symmetric thicken-
ing of the left ventricular myocardial wall, which
measured 21 mm in end diastole (Fig. 2A and 2B
and Videos 2 and 3). The left ventricular wall
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thickness varies according to sex and body-sur-
face area but is usually 11 mm or less.1 There
was borderline impairment of global systolic
function.
Left Ventricular Wall Thickening
The most common cause of left ventricular wall
thickening is hypertensive heart disease, which
develops in the context of long-standing, poorly
controlled hypertension. Patients with hyperten-
sion can have concentric hypertrophy, eccentric
hypertrophy, or concentric remodeling in the left
ventricle. These types of remodeling are differ-
entiated according to the left ventricular mass
index and relative wall thickness; the presence of
concurrent obesity, valvular or ischemic heart
disease, and genetic factors can influence the
type of remodeling that occurs.2,3 Left ventricu-
lar wall thickening that is associated with hyper-
tension is reversible. This patient had received
treatment for hypertension, and his blood pres-
sure was normal at the time of the current
evaluation. Also, another feature of hypertensive
heart disease, effacement of the sinotubular
junction, was not present (Fig. 2A).
Left ventricular wall thickening can be a con-
sequence of athletic training, depending on the
type of exercise. Athletes can have increases in
the left ventricular diameter, wall thickness, and
mass that are associated with normal systolic
and diastolic function and with sinus bradycar-
dia.4 A left ventricular wall thickness of 13 mm
or greater is uncommon in athletes. The wall
thickness typically decreases with detraining,
although the heart remains enlarged in some
athletes. This patient had an extensive history
of left ventricular wall thickening, which pro-
gressed long after he had stopped participating
in sports; this factor suggests that a different
underlying process was causing his left ventricu-
lar wall thickening.
Left ventricular hypertrophy can be caused by
aortic valve stenosis, subvalvular aortic stenosis,
supravalvular aortic stenosis, or aortic coarcta-
tion, but these abnormalities would have been
detected on echocardiography. The patient had
thickening of the trileaflet aortic valve, but Dop-
pler echocardiography did not reveal clinically
significant aortic valve obstruction (Fig. 2C).
The conditions that have been considered so
far would not explain the concurrent thickening
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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D
52.9 64.8

–52.9
cm/s –64.8
cm/s

E F
52.8 15.0

–52.8 –15.0
cm/s cm/s

of the right ventricular myocardial wall, which is
best visualized in the subcostal view (Video 4).
Thus, conditions associated with biventricular
wall thickening must be considered in this pa-
tient’s differential diagnosis.
Biventricular Wall Thickening
The history of hypertrophic cardiomyopathy in
the patient’s sister and niece is suggestive of a
familial genetic disorder. Conventional hyper-
trophic cardiomyopathy is an autosomal domi-
nant condition that is caused by mutations in
sarcomeric proteins. It has an estimated preva-
lence of 1 in 500 persons, but the prevalence
may be higher than estimated because of undi-
agnosed disease.5 Hypertrophic cardiomyopathy
is most commonly associated with ventricular
hypertrophy involving only the left ventricle.
However, there is considerable phenotypic hetero-
geneity, and right ventricular hypertrophy can
occur, which can make it challenging to estab-
lish the diagnosis. Left ventricular outflow tract
obstruction is present or develops over time in
70% of patients with hypertrophic cardiomyopa-

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 Case Records of the Massachuset ts Gener al Hospital
Figure 2 (facing page). Echocardiograms.
A transthoracic echocardiogram (TTE) in the parasternal
long-axis view (Panel A) shows marked left ventricular
wall thickening, aortic and mitral valve thickening, a trace
pericardial effusion, and left atrial enlargement; the proxi-
mal portion of the aorta is not dilated, and there is no
effacement at the sinotubular junction. A TTE in the
parasternal short-axis view at the level of the mitral valve
(Panel B) shows that the left ventricular wall thickening
is symmetric. A continuous-wave Doppler echocardio-
gram through the aortic valve (Panel C) shows a peak
velocity of 1.5 m per second (reference range at Mayo
Clinic laboratory, 0.8 to 1.8), a finding that indicates the
absence of clinically significant stenosis. A TTE in the
parasternal long-axis view with color Doppler (Panel D)
shows no acceleration of flow in the left ventricular out-
flow tract and no evidence of systolic anterior motion
of the mitral valve; there is moderate mitral regurgita-
tion, which is centrally directed, rather than posteriorly
directed (as typically seen with hypertrophic cardiomy-
opathy). A pulsed-wave Doppler echocardiogram of the
mitral inflow (Panel E) shows an elevated peak velocity
during early diastole (E-wave velocity, 120 cm per second;
reference range, 40 to 88), which is partially due to clin-
ically significant mitral regurgitation, as well as a mark-
edly abbreviated deceleration time, which is suggestive
of a stiff left ventricle and predictive of an increased left
ventricular filling pressure. A tissue Doppler echocardio-
gram of the lateral mitral annulus (Panel F) shows a se-
verely diminished velocity during early diastole (e′ velocity,
5 cm per second; reference value, >9). The markedly in-
creased ratio of E-wave velocity to e′ velocity (E:e′ ratio,
24; reference value, <10), in addition to biatrial enlarge-
ment and an estimated right ventricular systolic pressure
of 56 mm Hg (not shown), is consistent with restrictive
left ventricular diastolic dysfunction.
thy.5 Hypertrophy or displacement of the papil-
lary muscles, anomalous insertion of the papillary
muscles, and elongation of the mitral valve leaf-
lets with systolic anterior motion and posteriorly
directed mitral regurgitation are common echo-
cardiographic features. Although this patient had
papillary muscle hypertrophy, she had mitral
valve thickening and centrally directed mitral
regurgitation (Fig. 2D and Video 5).
Myocardial edema can contribute to ventricu-
lar wall thickening. It can occur in patients who
are in a systemic edematous state due to renal
failure6 or heart failure or in patients with acute
myocarditis.7 However, the degree of myocardial
wall thickening associated with edema or myo-
carditis is milder than that observed in this pa-
tient. His clinical presentation was not consistent
with an edematous state or with acute illness.
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Systemic Diseases Associated with
Ventricular Wall Thickening
Does this patient have a systemic, multiorgan
disorder that is associated with biventricular
wall thickening? He has a history of hypohidro-
sis, reduced hearing, chronic dry eyes, constipa-
tion, and renal insufficiency, all of which may be
features of a systemic disease.
Biventricular wall thickening can be associ-
ated with cardiac amyloidosis, which occurs as
part of a systemic disease — either light chain
(AL) amyloidosis or transthyretin amyloidosis.
Features of cardiac amyloidosis can include
edema, ascites, and dyspnea due to restrictive
cardiomyopathy; fatigue due to low cardiac out-
put; and bradyarrhythmias and heart block. Heart
failure usually progresses rapidly, especially in
patients with cardiac AL amyloidosis. Soft-tissue
involvement is often apparent on physical exami-
nation with either AL amyloidosis or transthyre-
tin amyloidosis.8
AL amyloidosis is caused by underlying plasma-
cell dyscrasia. Transthyretin amyloidosis devel-
ops when a protein made by the liver becomes
unstable, which causes deposits of amyloid fi-
brils to build up in the heart, nerves, and other
organs. There is an autosomal dominant form of
cardiac transthyretin amyloidosis that is most
prevalent in persons of Afro-Caribbean origin,
as well as a sporadic form that can develop in
the elderly.9
A striking feature of cardiac amyloidosis is
the discrepancy between the wall thicknesses
observed on echocardiography and the QRS volt-
age observed on electrocardiography; the QRS
voltage is classically reduced, although a pseudo­
infarct pattern may be present. The feature of
this patient’s disease that makes cardiac amyloid­
osis very unlikely is its indolent nature. The
median survival associated with cardiac amyloid­
osis is less than 4 years among untreated pa-
tients and is even shorter among those with AL
amyloidosis.10 Of note, other systemic diseases
such as hemochromatosis and sarcoidosis are
associated with dilated cardiomyopathy, rather
than with hypertrophic cardiomyopathy.
Genetic Disorders Associated with
Ventricular Wall Thickening
There are various inherited systemic disorders
that are associated with myocardial hypertrophy
nejm.org March 31, 2022 1271
 The n e w e ng l a n d j o u r na l
but also cause other, noncardiac dysmorphisms
and manifest early in life. These include Noonan’s
syndrome and other disorders resulting from
genetic mutations in the RAS–MAPK signaling
pathway (known as RASopathies).11 Mitochon-
drial myopathies can be associated with left
ventricular hypertrophy, but patients typically
present at a younger age with proximal muscle
weakness, ocular myopathy, and heart block;
mitochondrial crisis may be precipitated by
stress.12,13 Friedreich’s ataxia, which is an auto-
somal recessive disease resulting from a defect
in FXN (the gene encoding the mitochondrial
protein frataxin), can cause left ventricular hyper-
trophy,14 but patients usually have ataxia from
nervous system damage. Glycogen storage dis-
ease type III, which results from a deficiency in
glycogen debranching enzyme, can cause left
ventricular hypertrophy, but patients usually
present in childhood with hypoglycemia, short
stature, and hepatomegaly.15
Lysosomal storage disorders that are associ-
ated with myocardial wall thickening include
Danon’s disease, Pompe’s disease, mucopolysac-
charidoses, and Fabry’s disease. Danon’s disease
(or Danon’s cardiomyopathy) is an X-linked
dominant disease resulting from genetic defects
in LAMP2 (the gene encoding lysosomal-associ-
ated membrane protein 2) that causes moderate-
to-severe myocardial wall thickening, skeletal
myopathy, and intellectual disability.16 Pompe’s
disease is an autosomal recessive disorder that
is caused by a deficiency in acid α-glucosidase,
which leads to the intralysosomal accumulation
of glycogen and an increase in myocardial mass.
In both children and adults with this disorder,
skeletal muscle weakness and respiratory muscle
involvement are prominent features. Mucopolysac-
charidoses are caused by defects of intralysosomal
degradation of glycosaminoglycans. In addition
to cardiomyopathy and mitral and aortic valve
thickening, mitral annulus calcification and
coarsening of skin and facial features are prom-
inent findings, and they were not present in this
patient.
Fabry’s Disease
Fabry’s disease is an X-linked inherited disor-
der that is caused by a deficiency in lysosomal
α-galactosidase A, which leads to the accumula-
tion of glycosphingolipids (Fig. 3). The history
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of m e dic i n e
of hypertrophic cardiomyopathy in the patient’s
sister and niece, but not in his son, could be
consistent with an X-linked inherited disorder.
Fabry’s disease is rare, and there is often a delay
between symptom onset and diagnosis, with a
mean delay of 14 years in men.17 A common
clinical manifestation, and a potentially impor-
tant clue in this case, is hypohidrosis. Another
common manifestation is systemic hyperten-
sion, which is often due to coexisting renal
failure. The accumulation of globotriaosylcer­
a­mide in cardiomyocytes, endothelial cells, and
smooth-muscle cells leads to myocardial ische­
mia, valve abnormalities, and myocardial wall
thickening. Diastolic dysfunction (Fig. 2E and
2F) and heart failure can develop. Arrhythmias
and conduction system disease commonly occur
in patients with Fabry’s disease. In this patient,
the prolonged, gradually progressive course of
myocardial wall thickening, the associated ar-
rhythmias and conduction system disease, the
valve thickening, the familial involvement (which
is apparently most severe in the affected male
family member), and the concurrent kidney dis-
ease and hypohidrosis all make Fabry’s disease
the most likely diagnosis.
Cl inic a l Impr e ssion
Dr. Steven A. Lubitz: When we evaluated this pa-
tient, we initially considered hypertrophic car-
diomyopathy to be the most likely diagnosis,
given the degree of ventricular wall thickening,
the ventricular tachyarrhythmias, the atrial fibril-
lation, and the reported family history. Features
that would be atypical of conventional sarco-
meric hypertrophic cardiomyopathy were pres-
ent, including the concentric and biventricular
nature of the wall thickening and, to some ex-
tent, the heart block.
Genetic factors that cause left ventricular wall
thickening can be monogenic (involving genetic
variation in a single gene) or polygenic (influ-
enced by variants involving multiple genes). Ge-
netic testing for left ventricular wall thickening
is typically indicated when there is a high index
of suspicion for hypertrophic cardiomyopathy.
The index of suspicion can be estimated by ob-
taining a detailed family history that includes at
least three generations. In this case, the patient’s
sister and niece had received diagnoses of hyper-
nejm.org March 31, 2022
 Case Records of the Massachuset ts Gener al Hospital

25 years of age ≥69 years of age

X-linked genetic
abnormality White-matter changes

Hearing loss
and tinnitus

Cataracts
Y

Use of pacemaker
and defibrillator
X

Hypohidrosis

Cardiac enlargement
due to myocardial Progression of cardiac
thickening
enlargement

Proteinuria and
renal insufficiency

Figure 3. Longitudinal Clinical Manifestations of Fabry’s Disease in This Patient.

Shown are manifestations of Fabry’s disease that were present when the patient was approximately 25 years of age,
as well as those that were present at the time of his current evaluation.

trophic cardiomyopathy. Although the details Di agnos t ic Te s t ing

are limited, this history raises the index of sus-
picion for a monogenic disorder, perhaps an auto-
Dr. Amel Karaa: The diagnostic test in this case
somal dominant disorder, such as conventional was sequencing of 26 genes that are known to
sarcomeric hypertrophic cardiomyopathy. How- cause hypertrophic cardiomyopathy. Genetic test-
ever, the absence of reported transmission be- ing revealed a missense mutation in GLA (the
tween male family members raises the possibil- gene encoding α-galactosidase A): c.901C→G
ity of an X-linked condition, such as Fabry’s (p.Arg301Gly) in exon 6. This result was consis-
disease. An important caveat is that a family tent with a diagnosis of Fabry’s disease. The di-
evaluation is incomplete without detailed clini-
agnosis was further confirmed with testing for
cal phenotyping. Ultimately, this patient was α-galactosidase A in plasma, which revealed no
referred to a genetic counselor for evaluation,residual activity (0.0001 U per liter; reference
counseling, genetic testing, results disclosure,
range, 0.074 to 0.457).
and post-test counseling. Fabry’s disease results from a deficiency in the
activity of the glycohydrolase enzyme α-galac-
tosidase A. The primary abnormality involves
Cl inic a l Di agnosis
the accumulation of globotriaosylceramide in a
Hypertrophic cardiomyopathy most likely due to variety of cell types, which starts in utero in the
Fabry’s disease. most severe cases. This accumulation of globo-
triaosylceramide progresses over time and leads
to end-organ damage. The organs that are most
Dr . Pat r ici a A . Pel l ik k a’s
Di agnosis often affected include the heart (left ventricular
wall thickening, arrhythmias, and fibrosis), the
Fabry’s disease. kidneys (glomerulosclerosis and proteinuria),

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Key Echocardiographic Features of Fabry’s Disease.

Echocardiographic Technique and Features Present in This Patient

Two-dimensional imaging
Concentric left ventricular wall thickening Yes
Nonconcentric left ventricular wall thickening, including asymmetric No
septal hypertrophy and apical hypertrophy
Right ventricular wall thickening Yes
Valve leaflet thickening Yes
Regional wall abnormalities, especially in an inferior or inferolateral Yes
segment
Biatrial enlargement Yes
Papillary muscle hypertrophy Yes
Doppler imaging
Diastolic dysfunction at various stages, with restrictive dysfunction Yes, restrictive
at advanced stages; regurgitant lesions
Tissue Doppler imaging
Abnormalities suggestive of diastolic dysfunction Yes
Strain imaging
Left ventricular longitudinal strain    
Reduced global longitudinal strain Yes
Segmental longitudinal strain impairment, with a predilection Yes
for the inferolateral wall segment
Left ventricular circumferential strain
Reduced global circumferential strain Not performed
Loss of base-to-apex circumferential strain gradient Not performed
Reduced right ventricular and left atrial strain Not performed

and the central and peripheral nervous system
(white-matter changes, strokes, and neuropa-
thies). If untreated, the accumulation of globo-
triaosylceramide can lead to premature death.18
In classic cases of Fabry’s disease, symptom
onset occurs in childhood and complications
arise in adulthood (Fig. 3).19
Gene t ic Di agnosis
Fabry’s disease.
Echo c a r dio gr a ph y in Fa br y ’s
Dise a se
Dr. Teresa S.M. Tsang: Cardiac imaging is an im-
portant tool in the diagnosis and management
of the cardiac manifestations of Fabry’s disease.
Echocardiography is critical, because the find-
ings may prompt assessment of α-galactosidase
A activity and genetic testing in persons who
have not previously received a diagnosis of
Fabry’s disease. After diagnosis, echocardiogra-
phy is the logical choice of imaging for monitor-
ing disease progression and treatment response.
The main two-dimensional echocardiograph-
ic features observed in this patient with Fabry’s
disease (Table 1) included clinically significant
symmetric left ventricular wall thickening (Fig. 2A
and 2B). Right ventricular wall thickening was
also present (Video 4). Diastolic function was
severely impaired (Fig. 2E and 2F). Although
biventricular systolic function assessed on either
two-dimensional or three-dimensional imaging
is often preserved until later stages, diastolic
abnormalities and biatrial enlargement are com-
mon. Valvular thickening with regurgitation is
also common. Dilatation of the aortic sinus and
ascending aorta has also been described in pa-
tients with Fabry’s disease. None of these echo-

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 Case Records of the Massachuset ts Gener al Hospital
cardiographic findings, alone or in combina-
tion, can confirm or rule out the diagnosis of
Fabry’s disease. The binary sign, which was
previously associated with Fabry’s disease, refers
to the presence of a bright endocardium with an
adjacent hyporeflective subendocardial layer, such
that it can be distinguished from the myocardial
midwall in end diastole. More recent evidence
has shown that this finding is neither sensitive
nor specific for Fabry’s disease.
Strain imaging has an important role in nar-
rowing the differential diagnosis of cardiomy-
opathy. When Fabry’s disease is suspected, strain
imaging can be performed to assess for two
patterns that are suggestive of the disease. The
first pattern is segmental longitudinal strain
impairment involving the basal inferolateral
wall.20,21 This can be accompanied by reduced
global longitudinal strain. Although any seg-
ment can be involved in patients with Fabry’s
disease, there is a predilection for the infero-
lateral wall segment. A retrospective strain
analysis of an echocardiogram obtained from
this patient, which was conducted in preparation
for this conference, showed markedly reduced
global longitudinal strain, at an average level of
−5.6% (reference value, less than −18),22 with the
inferolateral and septal segments most severely
affected (Video 6). This finding highlights the
presence of severe myocardial contractile dys-
function, despite the low normal left ventricular
ejection fraction assessed on two-dimensional
echocardiography. The second pattern to look
for on strain imaging in patients with suspected
Fabry’s disease is a loss of the base-to-apex cir-
cumferential strain gradient.23
A ddi t iona l C a r di ac Im aging
in Fa br y ’s Dise a se
Dr. Albree Tower-Rader: Although this patient did
not undergo cardiac magnetic resonance imag-
ing, this is an important tool for the assessment
of cardiac involvement in patients with Fabry’s
disease, as well as for the evaluation of undif-
ferentiated ventricular wall thickening.24,25 Early
in Fabry’s disease, patients typically have sym-
metric left ventricular wall thickening with a pre-
served left ventricular ejection fraction.26 Later in
the disease process, patients can have either
thinning of the basal inferolateral wall segment
n engl j med 386;13
The New England Journal of Medicine
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Copyright © 2022 Massachusetts Medical Society. All rights reserved.
with corresponding hypokinesis or more diffuse
wall-motion abnormalities with a reduced ejec-
tion fraction.27
Native T1 mapping and delayed imaging after
the administration of gadolinium allow for fur-
ther tissue characterization and aid in the diag-
nosis. Midmyocardial late gadolinium enhance-
ment is typically found within the basal and
middle inferolateral wall segments and may be
present in up to 20% of female patients with
Fabry’s disease who do not have left ventricular
wall thickening.28 Low native T1 times may be
present before the development of left ventricu-
lar wall thickening, leading to the identification
of early cardiac involvement in patients with
Fabry’s disease. In patients with undifferentiated
left ventricular wall thickening, low native T1
times can suggest a diagnosis of Fabry’s disease,
because this finding is present in approximately
90% of patients with Fabry’s disease and left
ventricular wall thickening.29
Discussion of M a nagemen t
Dr. Karaa: The progression of Fabry’s disease fol-
lows a course that is unique to each affected
patient. An individualized approach to manage-
ment starts with a full assessment and monitor-
ing of each organ compartment.30 This patient
was found to have hearing loss, tinnitus, cata-
racts, white-matter changes on imaging, and an
elevated creatinine level with mild proteinuria,
all of which are findings consistent with Fabry’s
disease. Management included symptom-based
interventions for his heart and kidney disease,
annual end-organ assessments, and supportive
care provided by a multidisciplinary team with
experience in treating Fabry’s disease. Therapy
specifically for Fabry’s disease was offered, in-
cluding options to pursue enzyme-replacement
therapy or chaperone therapy. Given the ad-
vanced stage of left ventricular wall thickening
in this patient, such therapy was unlikely to re-
verse the cardiac damage and to stop disease
progression. Although this treatment may have
protected other organs at risk of disease involve-
ment, the patient declined the treatment.31 The
patient was taking amiodarone, which is a com-
petitive inhibitor of phospholipase A2 in the
lysosome and can exacerbate the symptoms of
Fabry’s disease.32 Discontinuation of amiodarone
nejm.org March 31, 2022 1275
 Case Records of the Massachuset ts Gener al Hospital

therapy was discussed, but the benefit of its use He was able to travel and to celebrate a major
in controlling arrhythmias outweighed the po- life milestone with his family.
tential negative additive effects on the progres-
sion of Fabry’s disease. Fina l Di agnosis
Fabry’s disease.
Fol l ow-up
This case was presented at the American Society of Echocar-
Dr. Dudzinski: After 3 years of follow-up, the re- diography 2021 Annual Scientific Sessions.
Disclosure forms provided by the authors are available with
sults on echocardiography were unchanged. The the full text of this article at NEJM.org.
patient had undergone one hospitalization for We thank Drs. Judy Hung, Michael Main, and Michael H.
heart failure. He had ongoing nonsustained ven- Picard for assistance with preparation of the conference and
interpretation of the imaging studies, as well as Dr. Farouc A.
tricular tachycardia events, for which the meto- Jaffer for assistance with interpretation of the ventriculography
prolol and amiodarone regimens were adjusted. studies.

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