Author + information
- Published online December 12, 2018.
- aDepartment of Medical Clinic I, Klinikum Vest, Recklinghausen, Germany
- bDepartment of Medical Clinic II, Klinikum Vest, Marl, Germany
- ↵∗Address for correspondence:
Dr. Frank Weidemann, Medical Clinic I, KLINIKUM VEST, Knappschaftskrankenhaus, Dorstener Straße 151, 45657 Recklinghausen, Germany.
Fabry disease is an X-linked disorder resulting from mutations in the gene that encodes the lysosomal enzyme α-galactosidase A, leading to progressive lysosomal sphingolipid (GL3) accumulation (1). In classic affected male patients, clinical onset occurs in childhood or adolescence and is characterized by several symptoms including kidney failure, cerebrovascular manifestations, heart failure, and eventually premature death (2).
More than 50% of all Fabry patients have cardiac involvement (i.e., Fabry cardiomyopathy), most frequently concentric left ventricular hypertrophy (LVH) (3,4). The intracellular accumulation of GL3 also occurs within myocytes and vascular endothelium cells of the heart (5). Histologically, Fabry cardiomyopathy is characterized by myocyte hypertrophy and vacuolation (6). However, the storage of GL3 alone is insufficient to explain the full extent of myocardial abnormalities seen in Fabry patients. Additionally, the interstitial remodeling appears to be an important feature of Fabry cardiomyopathy (7). The pathophysiology most likely includes a combination of intracellular lysosomal storage of GL3, an increase of trophic factor such as lyso-Gl3, and a neurohormonal activation in the plasma that induces hypertrophic activation (5–7). End-stage Fabry cardiomyopathy is characterized by replacement fibrosis of the left ventricle (LV), which can be detected by the noninvasive gold standard of late gadolinium enhanced magnetic resonance imaging (7).
In this issue of iJACC, Nordin et al. (8) from the United Kingdom proposed a new staging of myocardial phenotype development based on a large cohort of Fabry patients. In general, staging of a disease such as Fabry disease is clinically very useful. However, one must keep in mind that the discussed data are cross-sectional and not longitudinal data. Thus, the pure interpretation of these data is not a final proof for the progression of the disease and the suggested stages. However, the innovative aspect of their proposal is the use of advanced cardiac magnetic resonance (CMR) imaging to describe and understand the pathophysiology. The authors describe storage of GL3 (by pre-contrast T1 mapping), extracellular volume fraction (by post-contrast T1 mapping), and myocardial fibrosis (by late gadolinium enhancement imaging). Furthermore, these advanced morphology assessments were combined with indicators for LVH (by standard CMR), LV electrical repolarization abnormalities (by 12-lead electrocardiography), and blood biomarkers for myocyte death (by high-sensitive troponin T [hsTNT]) as well as for heart failure (by N-terminal pro B-type natriuretic peptide [NT-proBNP]). Combining all of this biological information, 3 pathophysiological phases for the understanding of Fabry cardiomyopathy are proposed:
1. The storage phase: This is the silent phase during childhood in which GL3 storage within the myocytes starts. Patients are mainly asymptomatic and standard clinical and imaging assessment cannot detect abnormalities. However, some hearts already show electrocardiography abnormalities. Although this phase has no major impact on patients’ quality of life, it seems to have a major impact on the developing cardiomyopathy as sphingolipid storage triggers subsequent advanced myocardial pathological processes.
2. The hypertrophy and inflammation phase: In this phase, the pathological response of the LV myocardium to the initial storage trigger can be clinically assessed. Thus, an increasing myocardial mass can be visualized by CMR and also by echocardiography (4). In addition, the inflammation process can indirectly be detected by a pathological elevated hsTNT. This phase is also characterized by sex dimorphism with a balance of sphingolipid storage and myocyte hypertrophy in females, whereas male hearts rapidly progress toward true LVH (9). However, both females and males start to develop myocardial fibrosis, typically in the basal inferolateral wall (4,7). Clinically, patients may suffer from chronic fatigue and less exercise capacity, but usually not from decompensated heart failure.
3. The fibrosis and impairment phase: This is the most advanced cardiomyopathy phase and is mainly characterized during imaging by replacement fibrosis spreading from the basal inferolateral segment toward other basal and mid-myocardial segments of the entire LV. In echocardiography, the hearts are hypertrophied with some thinning and wall motion abnormalities in the basal inferolateral wall (4). Because of the development of fibrosis, the patients have markedly elevated hsTNT levels and, as a biomarker for the failing LV, NT-proBNP is rising. Clinically, patients also suffer from dyspnea and cardiac arrhythmias and may need a pacemaker or implantable cardioverter-defibrillator (10). This fibrosis and impairment stage is more pronounced in male patients (Figure 1).
The understanding and detection of the 3 stages of cardiac involvement in Fabry patients is important for treatment. In the context of enzyme replacement therapy, it might be that long-term treatment success is related to the phase when therapy is started. In addition, as suggested by Nordin et al. (8), all the described pathological processes and pathways might be therapeutic targets for the future.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of iJACC or the American College of Cardiology.
Dr. Reiser has received grants from Abbvie; and has received personal fees from Hitachi and Abbvie. Dr. Weidemann has received grants from Genzyme and Shire; and has received personal fees from Amicus, Genzyme, and Shire.
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