Fabry disease affects many parts of the heart and blood vessels. It can cause high blood pressure, an enlarged heart, heart rhythm problems, valve disease, blood vessel damage, heart attack, and sudden cardiac death. These complications are now the leading cause of death in Fabry patients. Advanced imaging techniques like echocardiograms, cardiac MRI, and T1 mapping can detect early heart changes before symptoms appear. Comprehensive screening and treatment of cardiovascular involvement in Fabry disease may allow earlier intervention and reduce morbidity and mortality.

1. Fabry Disease and the Heart
John Lynn Jefferies, MD, MPH,
FACC, FAHA
Director, Cardiomyopathy and Advanced Heart
Failure
Professor, Pediatric Cardiology
Professor, Adult Cardiovascular Diseases
The Heart Institute
Professor, Division of Human Genetics
Cincinnati Children’s Hospital
University of Cincinnati

2. Cardiovascular Findings in Fabry
Disease
 Cardiovascular manifestations in Fabry
are broad and numerous
− Systemic hypertension
− Left ventricular hypertrophy
− Heart rhythm and conduction system
disease
− Valvular heart disease
− Vasculopathy
− Ischemic heart disease
− Sudden cardiac death

3. Cardiovascular Findings in Fabry
Disease
Putko et al. Heart Fail Rev 2014; July 17;epub ahead of print.

4. Cardiovascular Findings in Fabry
Disease
 These findings can progress to more
significant disease over time
− Life-threatening arrhythmias and sudden
cardiac death
− Heart failure
− Myocardial infarction
− Stroke
 All of these conditions can be difficult to
treat and have significant associated
morbidity and mortality

5. Cardiovascular Findings in Fabry
Disease
 Cardiovascular complications are now
the leading cause of death
− Previously was kidney disease
 ~60% of patients have prior signs and
symptoms
 Hypertension and edema most common
 History of a murmur, chest pain, or
shortness of breath
Putko et al. Heart Fail Rev 2014; July 17;epub ahead of print.

6. Predictors of Cardiac Events
 Recent study looked at ~200 patients
 High burden of cardiac morbidity and
mortality
 Adverse cardiac outcomes were
associated with advanced age, overall
Fabry disease severity, and advanced
cardiac disease
 Genetic variants were not predictive of
significant cardiac outcome
Patel et al. Heart 2015;0:1-6.

7. Cardiovascular Findings in Fabry
Disease
 Goal of cardiovascular care should be
directed at preventing these conditions
 Limited data regarding predictors of
onset of disease
− Majority of data are limited to middle-aged
adult males
 Prognosis is negatively impacted once
evidence of ischemic heart disease or
heart failure are diagnosed

8. Cardiovascular Findings in Fabry
Disease
Patel et al. J Am Coll Cardiol 2011;57:1093-9.

9. Arrhythmias in Fabry Disease
 Arrhythmias can be a major cause of
morbidity and mortality in Fabry disease
 Wide range of pathology can be
diagnosed on electrocardiographic
testing
 Bradyarrhythmias and tachyarrhythmias
may be seen requiring additional
therapy
 Electrophysiologic testing may also be
used in some cases

10. Heart Rhythm Abnormalities
Known associated ventricular and atrial
arrhythmias and conduction system
disease
Acharya et al. Card Electrophysiol Clin 2015;7:283-291

11. Heart Rhythm Abnormalities
O’Mahoney et al. Europace 2011.epub ahead of print.

12. Arrhythmias and Conduction
System Disease

13. Noninvasive Imaging
Echocardiography
 Traditional approach to screening
utilizes transthoracic echocardiography
 Echocardiography is widely available
and relatively easy to perform
 Advanced imaging techniques allow for
additional information to be acquired
from standard imaging protocols

14. Pathologic Ventricular
Remodeling
Ventricular Remodeling
Ventricular Remodeling in Diastolic and Systolic HF
Trigger
Expansion of infarct
(hours to days)
Global remodeling
(days to months)
Normal heart
Hypertrophied heart
(diastolic HF)
Dilated heart
(systolic HF)
Jessup M et al. N Engl J Med. 2003;348:2007

15. Myocardial Assessment
Echocardiography

16. Myocardial Assessment
Echocardiography

17. Advanced Imaging Techniques
 Additional information can be gathered
from echocardiography
 Allows for early subclinical systolic and
diastolic function
− Strain and strain rate (SR) imaging
 3D imaging call also be performed that
allows for volume quantification

18. Myocardial Deformation
Abraham et al. Circulation 2007;116:2597-2609.

19. Echocardiographic Strain Imaging

20. Makinkurve-Groothuis et al. Ultrasound in Med&Biol 2010;11:1783-1791.

21. Shanks et al. J Am Soc Echocardiogr 2013;26:1407-14.

22. Cardiac Magnetic Resonance
Imaging (CMR)
 Highly reproducible
 Precise calculation of volumes
 Assessment of arterial and venous
vasculature
 Assessment of ventricular function
 Myocardial characterization
 No radiation exposure

23. Myocardial Characterization

24. T1 Mapping by Cardiac MRI
 T1 mapping can be performed to
assess for pathologic changes in the
myocardium
 Native T1 imaging can be performed
without contrast exposure
 Identifies changes in the intracellular or
extracellular space such as edema or
deposition

25. Clinical Use of Cardiac MRI
Everett et al. Clin Radiol 2016;

26. Utility of Cardiac MRI
Everett et al. Clin Radiol 2016;

27. T1 Mapping in Fabry Disease
Sado et al. Circ Cardiovasc Imaging 2013;6:392-398.

28. Reproducibility of T1 Mapping in
Fabry Disease
Pica et al. J Cardiovasc Magn Reson 2014;16:1-9

29. Cardiac Involvement in Fabry
Disease
Kozor et al. Heart 2016; 102:298-302.

30. Extracellular Volume Assessment
by Cardiac MRI
 Expansion of the extracellular volume
(ECV) in the myocardium is seen in
both systolic and diastolic heart failure
− Expansion seen regardless of the etiology
 Increase in ECV offers prognostic
information
 Recently, MRI techniques have been
developed that allow for quantification
of the ECV (MRI-ECV)
Kammerlander et al. J Am Coll Cardiol Img 2016;9:14-23.

31. Extracellular Volume Using T1
Kammerlander et al. J Am Coll Cardiol Img 2016;9:14-23.

32. Event Free Survival Based on
CMR-ECV
Kammerlander et al. J Am Coll Cardiol Img 2016;9:14-23.

33. Vascular Disease in Fabry Disease
 Concern of ischemic stroke
 Decreased compliance of the aorta
 Increase in thickness of the carotid and
radial arteries
 Reports of aortic dilation and dissection
in Fabry
 Magnetic resonance imaging provides
accurate surveillance of aortic
dimensions

34. Aortic Dilation in Fabry Disease

35. Fabry Disease
Left Ventricular Noncompaction

36. Screening for Cardiovascular
Disease in Fabry Disease
 Established therapies for patients that
have evidence of disease
 May be symptomatic at presentation
 More aggressive approach that
identifies preclinical disease
 Allows for earlier intervention and more
rigorous longitudinal follow-up
− Typically this results in improved outcome

37. Conclusions
 Broad spectrum of cardiovascular
disease in Fabry disease
 Increasingly important cause of
morbidity and mortality
 Historical approach to detection may
result in late diagnosis of cardiovascular
involvement
 This may result in delaying beneficial
therapeutic strategies

38. Comprehensive Cardiovascular
Care In Fabry Disease
 Evaluation of patients of all ages
 Detailed approach to pediatric patients
 Evaluation of female carriers
 Serial follow-up to assess for changes
in findings and institute appropriate
medical and device therapies
 Promote use of existing technologies

39. Comprehensive Cardiovascular
Care In Fabry Disease
 Noninvasive and serologic testing
− Imaging
 Echocardiography
 Cardiac MRI
− EKG and Holter monitoring
− Stress testing
− Blood and urinary biomarker testing
 Offers additional opportunities to
develop prognostic variables and
assess response to therapies

40. Comprehensive Cardiovascular
Care In Fabry Disease
 Additional imaging by ultrasound
− Assess carotid arteries
− Assess stiffness of the aorta
 Noninvasive and simple
 Novel testing that comprises all these
areas
− Extra information from blood tests and
imaging tests that identify preclinical
disease

41. Comprehensive Cardiovascular
Care in Fabry Disease
 Opportunity for “deep phenotyping” in
this unique population
 Increasing amount of literature that
underscores limited understanding of
the cardiovascular phenotype
 Longitudinal care of younger patients
may offer understanding of disease
progression and utility of conventional
treatments

42. Comprehensive Cardiovascular
Care In Fabry Disease
 By taking a more thoughtful and
comprehensive approach:
− Identify cardiovascular disease earlier
− Utilize appropriate therapies
− Potentially reduce morbidity and mortality
− Monitor response to therapies
− Collect data targeting new diagnostic and
treatment strategies