ECG-based score estimates the probability to detect Fabry Disease cardiac involvement
Introduction
Fabry disease (FD) is an X-linked metabolic disorder caused by reduced or absent activity of the lysosomal enzyme α-galactosidase A, leading to intracellular accumulation of globotriaosylceramide (Gb3) [1]. Cardiac involvement represents the main cause of death and it is outlined by left ventricular hypertrophy (LVH) often complicated by myocardial scarring and inflammation. Late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) is associated with adverse outcome and reduced response to enzyme-replacement therapy, (ERT) [2].
FD progression can be slowed by ERT when started before irreversible organ damage [3]. Thus, diagnostic methods of cardiac involvement are key. CMR is the reference non-invasive method to detect and stage FD cardiac involvement [4,5]. CMR allows accurate measurement of LV mass and wall thickness, detecting myocardial fibrosis and inflammation and identifying myocardial glycosphingolipid storage by low native myocardial T1 values [6]. The latter finding is essential in differential diagnosis with other forms of hypertrophic cardiomyopathy. By being detectable from the pre-hypertrophic stages of FD cardiomyopathy, low T1 values also represent an early and non-invasive FD cardiac involvement marker [[6], [7], [8], [9], [10]]. Despite recommendations that all FD patients should undergo CMR [6], high cost and limited availability hinders its widespread application in the “clinical arena”. According to recent literature [11], ECG changes are associated with CMR findings both in early and late FD stages. We aimed to provide a practical ECG-based nomogram estimating the probability to detect CMR markers of cardiac involvement (low T1 values) in FD patients. This tool would improve the identification of FD patients with cardiac involvement.
Section snippets
Study population
This cross-sectional, observational study enrolled consecutive patients with genetically confirmed diagnosis of FD (types of variant 4 and 5) [12] referred for CMR at IRCCS Policlinico San Donato (San Donato Milanese, Italy). Clinical evaluation, CMR and 12‑lead ECG were performed on the same day. Atrial fibrillation, ischemic or valvular heart disease, pacemaker/implantable cardiac defibrillator and CMR contraindications were exclusion criteria.
A cohort of healthy subjects with no
Clinical and CMR findings in the test cohort
Of 121 FD patients and 26 healthy subjects screened from January 2016 to October 2019, 2 FD patients were excluded because of atrial fibrillation and previous myocardial infarction (total population = 145).
The test cohort included 17 healthy volunteers and 71 FD patients, which were divided into three subgroups reflecting progressive stages of FD cardiomyopathy: A) LVH negative, normal T1; B) LVH negative, low T1); C) LVH positive, low T1). All LVH-positive FD patients had low myocardial T1
Discussion
The main strength of this study is developing a practical ECG-based nomogram estimating the probability of detecting low myocardial T1 values by CMR in FD patients.
The potential advantage immediately resulting from the application of the nomogram is a feasible ECG analysis in FD patients to raise the suspicion of cardiac involvement even in the early stages, when ECG is normal according to conventional analysis. By not requiring expert knowledge on non-invasive electrophysiology, the ECG
Conclusions
An ECG-based nomogram accurately estimates the probability of low T1 values by CMR in FD patients, potentially improving early detection of cardiac involvement in daily routine.
Disclosure
Stefano Figliozzi: none related.
Antonia Camporeale: Honoraria for presentations and board meetings from Amicus Therapeutics, Sanofi-Genzyme and Shire. Research grant from Amicus Therapeutics.
Sara Boveri: none related.
Federico Pieruzzi: Honoraria from Sanofi-Genzyme, Shire and Amicus Therapeutics.
Maurizio Pieroni: speaker and advisory board honoraria, and travel support from Sanofi-Genzyme, Amicus Therapeutics and Shire.
Paola Lusardi: travel support from Sanofi-Genzyme and Amicus Therapeutics.
Funding
This study was partially supported by Ricerca Corrente funding from the Italian Ministry of Health to IRCCS Policlinico San Donato.
Declaration of Competing Interest
None.
Acknowledgements
None.
References (30)
- et al.
Cardiac involvement in Fabry disease: JACC review topic of the week
J. Am. Coll. Cardiol.
(2021) - et al.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
Genet. Med.
(2015) - et al.
A human stem cell model of Fabry disease implicates LIMP-2 accumulation in cardiomyocyte pathology
Stem Cell Rep.
(2019) - et al.
Enzymatic defect in Fabry’s disease
N. Engl. J. Med.
(1967) - et al.
Relation of burden of myocardial fibrosis to malignant ventricular arrhythmias and outcomes in fabry disease
Am J Cardiol Published Online First
(2014) - et al.
Fabry disease revisited: management and treatment recommendations for adult patients
Mol. Genet. Metab.
(2018) - et al.
Proposed stages of myocardial phenotype development in Fabry disease
JACC Cardiovasc. Imag.
(2019) - et al.
The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease
J. Cardiovasc. Magn. Reson.
(2006) - et al.
Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2 and extracellular volume: a consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imagin
J. Cardiovasc. Magn. Reson.
(2017) - et al.
Identification and assessment of Anderson-fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping
Circ. Cardiovasc. Imag.
(2013)
Reproducibility of native myocardial T1 mapping in the assessment of Fabry disease and its role in early detection of cardiac involvement by cardiovascular magnetic resonance
J. Cardiovasc. Magn. Reson.
Predictors of clinical evolution in prehypertrophic Fabry disease
Circ. Cardiovasc. Imag.
The myocardial phenotype of Fabry disease pre-hypertrophy and pre-detectable storage
Eur. Heart J. Cardiovasc. Imag.
Multimodality imaging in Fabry cardiomyopathy: from early diagnosis to therapeutic targets
Eur. Heart J. Cardiovasc. Imaging
Left ventricular hypertrophy in Fabry disease: a practical approach to diagnosis
Eur. Heart J.
Cited by (13)
An expert consensus on practical clinical recommendations and guidance for patients with classic Fabry disease
2022, Molecular Genetics and MetabolismCitation Excerpt :A recent study demonstrated that automated ECG analysis may be useful for the identification of patients with FD in the pre-hypertrophic stage [69]. Another recent study found that an ECG-based nomogram may accurately predict the probability of detecting low T1 values by CMR in patients with FD, and thus that the application of this tool in clinical practice could improve early detection of cardiac involvement in FD [70]. As patients with FD may develop bradycardia, atrial fibrillation, and atrioventricular conduction abnormalities, in addition to ECG-Holter as a gold standard, novel cardiac monitoring techniques such as mobile health and digital health technologies (smart watches, etc.) and loop recorders [71] may be useful to detect rhythm disturbances and to assess rate control.
Clinical staging of Anderson-Fabry cardiomyopathy: An operative proposal
2024, Heart Failure ReviewsDifferences Between Two Distinct Hypertrophic Cardiac Conditions: Fabry Disease versus Hypertrophic Cardiomyopathy
2024, Arquivos Brasileiros de CardiologiaFatigue as hallmark of Fabry disease: role of bioenergetic alterations
2024, Frontiers in Cardiovascular MedicineClinical study of left ventricular structure and function in patients with Anderson–Fabry disease before and after enzyme replacement therapy
2024, Journal of Clinical UltrasoundFabry Disease: More than a Phenocopy of Hypertrophic Cardiomyopathy
2023, Journal of Clinical Medicine
- 1
These authors contributed equally as first authors.