J A C C : C A R D I O V A S C U L A R I M A G I N G VO L . 1 1 , N O . 4 , 2 0 1 8

ª 2 0 1 8 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N

P U B L I S H E D B Y E L S E V I E R

IMAGING VIGNETTE

Many Faces of Fabry’s Cardiomyopathy

Renuka Jain, MD,a Lindsey Kalvin, RDCS, BS,a Brandon Johnson, MD,b Lakshmi Muthukumar, MD,a

Bijoy K. Khandheria, MD,a,c A. Jamil Tajik, MDa

ANDERSON-FABRY’S DISEASE, AN X-LINKED INHERITED DEFICIENCY OF ALPHA-GALACTOSIDASE A

(GLA gene) with a birth frequency of 1 in 100,000, results in systemic sphingolipid accumulation withcharacteristic clinical findings. The predominant causes of significant morbidity and mortality are renal,cerebrovascular, and cardiac.

FIGURE 1 Fabry’s Cardiomyopathy Presenting as Hypertrophic Nonobstructive Phenotype

Peak Systolic Strain

ANT_SEPT

I

II

ANT

15

10

5

10

10

5

[cm/s]

-5

-10

-15-1 66.67 mm/s

5

LAT

POST

INF

SEPT

-14

-14

-13

-13 -13

-13

-12

-12

-11

-15-17 -18

-15-12

-19 -16

A B C

E F G

D

On electrocardiography, this 45-year-old man demonstrated a short PR interval (132 ms)–characteristic of Fabry’s disease—and left ventricular

hypertrophy (A). Transthoracic echocardiography demonstrated hypertrophic nonobstructive cardiomyopathy; maximum septal wall thickness

was 20 mm (B). No left ventricular outflow gradient was present at rest (C), during Valsalva maneuver, or during amyl nitrite inhalation. The

patient had diastolic dysfunction (grade II); septal e0 measured 7.6 cm/s (D).Global longitudinal strain (E)was reduced (–14.3%)with preserved

left ventricular ejection fraction (61%). Note the hypertrophic papillarymuscle (arrows) and that the anterior papillarymusclemeasures 2.1 cm

and is more hypertrophic than the posterior papillary muscle; apical displacement of papillary muscles is seen on echocardiography (F) and

cardiac magnetic resonance (G). Hypertrophied papillary muscles are characteristic of Fabry’s disease compared with other hypertrophic car-

diomyopathy phenotypes (1). No delayed enhancement of gadolinium, which would suggest myocardial fibrosis, was noted. ANT ¼ anterior;

ANT_SEPT ¼ anteroseptal; INF ¼ inferior; LAT ¼ lateral; POST ¼ posterior; SEPT ¼ septal.

ISSN 1936-878X/$36.00 https://doi.org/10.1016/j.jcmg.2017.10.018

From the aAurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke’s Medical Centers, Milwaukee, Wisconsin; bRadiology

Department, Aurora Sinai/Aurora St. Luke’s Medical Centers, Milwaukee, Wisconsin; and the cMarcus Family Fund for

Echocardiography Research and Education, Milwaukee, Wisconsin. The authors have reported that they have no relationships

relevant to the contents of this paper to disclose.

Manuscript received September 22, 2017; revised manuscript received October 25, 2017, accepted October 31, 2017.

FIGURE 2 Fabry’s Cardiomyopathy Presenting as Apical-Septal Hypertrophic Phenotype With Midventricular Obstruction

Peak Systolic Strain

5

5

10

5

10

ANT_SEPT

ANT

LAT

POST

INF

SEPT

A B C D

E F G H I

This 61-year-old woman demonstrated a short PR interval (138 ms) and left ventricular hypertrophy on electrocardiogram (A). Transthoracic echocardiography showed

the phenotypic appearance of apical hypertrophic cardiomyopathy (B), with severe apical thickening in diastole (C) and apical obliteration in systole (D). Midventricular

obstruction was present: 15 mm Hg (rest); 65 mm Hg (beat after premature ventricular contraction) (E). Diastolic dysfunction was noted, and global longitudinal strain

was abnormal (–7.0%) (F). Cardiac magnetic resonance demonstrated apical thickening (G) and delayed gadolinium enhancement in a patchy distribution (arrows, H).

Due to the lack of alpha-galactosidase enzyme, excess glycosphingolipids deposit in the myocardium (I). Fat has a lower T1 value, leading to a shortening of T1relaxation; in this patient, the mean T1 value was 859 ms (our laboratory’s abnormal T1 relaxation time is <920 ms). T1 mapping can be assessed without administration

of gadolinium contrast, which is attractive in patients who often have coexisting renal insufficiency. An apical aneurysm phenotype also has been reported (Patient #5 in

Table 1) (2). Abbreviations as in Figure 1.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 1 , N O . 4 , 2 0 1 8 Jain et al.A P R I L 2 0 1 8 : 6 4 4 – 7 Many Faces of Fabry’s Cardiomyopathy

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Cardiac involvement in the disease phenotypically mimics hypertrophic cardiomyopathy, commonly pre-senting in the echocardiography laboratory as a male patient with concentric left ventricular hypertrophy.However, as we describe, the spectrum of Fabry’s cardiomyopathy encompasses all hypertrophic cardiomy-opathy phenotypes. Also, due to selective X-inactivation, both sexes can be severely affected—women are notmerely genetic “carriers.”

Certain imaging features are more likely to be seen in Fabry’s disease than other hypertrophic cardiomy-opathy phenotypes. In this case series (Figures 1 to 4, Table 1), we highlight the characteristic findings onmultimodality imaging that heighten the probability of a diagnosis of Fabry’s cardiomyopathy—the echocar-diographic, electrocardiographic, and cardiac magnetic resonance findings that are unique to the disease.

FIGURE 3 Fabry’s Cardiomyopathy Presenting as Severe Concentric Phenotype

I

II

20

5

10

15

10

61HR

60HR

CTO

ANT_SEPT

ANT

LAT

POST

INF

SEPT

-9

-17-5

-9 -9-19-22

-20

-12 -19-6

-7

-9

-12

-12 7

3

A B C

D E F

A 41-year-old man with Anderson-Fabry’s disease developed both cardiac and renal involvement as a teenager. The electrocardiogram demonstrated the characteristic

short PR interval of Anderson-Fabry’s cardiomyopathy with left ventricular hypertrophy (A). Transthoracic echocardiography demonstrated severely increased left

ventricular wall thickness in a concentric pattern (maximum wall thickness 2.2 cm) (B), and right ventricular wall thickening also was observed (C). No left ventricular

outflow or midventricular obstruction was noted. Grade II diastolic dysfunction was noted and global longitudinal strain was diffusely abnormal (D), with an overall

value of �11.1%. Cardiac magnetic resonance demonstrated delayed cardiac enhancement in the basal inferolateral wall (arrow). Four-chamber cardiac magnetic

resonance images without (E) and with (F) delayed enhancement, respectively, correspond to the same area of scar seen on the global longitudinal strain map (D). This

inferolateral scar is the most common area of delayed gadolinium enhancement in patients with Fabry’s disease. Abbreviations as in Figure 1.

Peak Systolic Strain

ANT_SEPT

ANT

LAT

POST

INF

SEPT

I

II

-7

-13-13

-11

-13-15-18 -18

-16

-16 -13-8

-6

-6

-6

-4

7

A B C

ED

FIGURE 4 Fabry’s Cardiomyopathy Presenting

With Severe Concentric Hypertrophic Phenotype

and Hypertrabeculated Left Ventricular Apex

This 42-year-old man had an electrocardio-

gram (A) that demonstrated sinus rhythm, a

short PR interval (130 ms), and left ventricular

hypertrophy with QRS widening. Trans-

thoracic echocardiography demonstrated

concentrically increased wall thickness

(maximal wall thickness 2.1 cm) with a bilay-

ered myocardium suggestive of hyper-

trabeculation (arrows, B). Grade II diastolic

dysfunction was noted (septal e0 5.2 cm/s),

and global longitudinal strain of –12.5% was

diffusely abnormal throughout the myocar-

dium despite preserved left ventricular

ejection fraction (C). Cardiac magnetic reso-

nance demonstrated a hypertrabeculated left

ventricular apex (arrows, D). Delayed

enhancement was noted particularly in the

inferolateral wall (arrow, E), the most

common location of fibrosis in patients with

Fabry’s disease. Abbreviations as in Figure 1.

Jain et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 1 , N O . 4 , 2 0 1 8

Many Faces of Fabry’s Cardiomyopathy A P R I L 2 0 1 8 : 6 4 4 – 7

646

TABLE 1 Patient Characteristics

Patient #1 Patient #2 Patient #3 Patient #4 Patient #5 (2)

Age, yrs 45 61 41 42 63

Sex Male Female Male Male Male

Phenotype Hypertrophicnonobstructive

Apical-septalhypertrophic

Severe concentrichypertrophy

Severe concentrichypertrophy withhypertrabeculation

Apical-septalhypertrophic withapical aneurysm

Clinical presentation Renal insufficiency,sudden cardiacdeath

Enzyme replacementtherapy

Enzyme replacementtherapy, renaltransplant, atrialfibrillation, CVA

Enzyme replacementtherapy, renaltransplant, atrialfibrillation

Enzyme replacementtherapy, atrialfibrillation, ICD(primary prevention)

GLA mutation c.469C>T (missense) c.469C>T (missense) IVS3þ1G>C (splice-site) c.547G>A c.713G>A

ECG PR interval, ms 132 138 120 130 Pacemaker

LVEF, % 61 77 62 60 60

Maximum thickness, mm 2 2.3 2.2 2.1 2.8

LAVI, ml/m2 60 36 62.3 51.4 50.6

GLS, % �14.3 �7 �11.1 �12.5 *

DD stage 2 1 2 2 2

Septal e0, cm/s 7.6 6.5 2.3 5.2 4

DT, ms 213 201 282 241 196

*Unable to obtain GLS.

CVA ¼ cerebrovascular accident; DD ¼ diastolic dysfunction grade; DT ¼ mitral valve inflow deceleration time; ECG ¼ electrocardiogram; GLS ¼ global longitudinal strain; ICD ¼ implantable cardioverter-defibrillator; LAVI ¼ left atrial volume index; LVEF ¼ left ventricular ejection fraction.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 1 , N O . 4 , 2 0 1 8 Jain et al.A P R I L 2 0 1 8 : 6 4 4 – 7 Many Faces of Fabry’s Cardiomyopathy

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ADDRESS FOR CORRESPONDENCE: Dr. Renuka Jain, Aurora Cardiovascular Services, Aurora St. Luke’sMedical Center, 2801 West Kinnickinnic River Parkway, Suite 840, Milwaukee, Wisconsin 53215. E-mail:publishing159@aurora.org.

R EF E RENCE S

1. Kozor R, Nordin S, Treibel TA, et al. Insight into hy-pertrophied hearts: a cardiovascular magnetic reso-nance study of papillarymusclemass and T1mapping.Eur Heart J Cardiovasc Imaging 2017;18:1034–40.

2. Agarwal A, Malik A, DeFranco AC, Tajik AJ. Leftventricular apical aneurysm: a novel phenotype ofFabry’s disease. Eur Heart J Cardiovasc Imaging2014;15:585.

KEY WORDS Anderson-Fabry disease,echocardiography, hypertrophiccardiomyopathy