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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,aBijoy 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
645
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
647
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
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