Fabry disease (FD) is an X-linked linked genetic disorder caused by α-galactosidase A deficiency. The typical clinical manifestation is left ventricular hypertrophy, often mimicking hypertrophic cardiomyopathy (HC). In contrast to sarcomeric HC, left ventricular outflow tract obstruction (LVOTO) is less frequent. We describe 6 male patients with genetically confirmed FD and symptomatic LVOTO. All of them underwent a transcatheter alcohol septal ablation with an immediate effect on the obstruction in all cases and without any serious complications. The median LVOT maximal pressure gradient was 85 (60 to 170) mm Hg. The hemodynamic effect persisted during subsequent follow-up (ranging from 6 months to 16 years). Five patients reported substantial symptomatic improvement. Four patients were receiving specific FD therapy before the interventional procedure. In conclusion, alcohol septal ablation appears to be effective in the treatment of LVOTO in patients with FD and appears to be comparable to the limited published experience with surgical septal myectomy. Despite some important differences between FD HC and sarcomeric HC, the recommendation for treating LVOTO should be similar.
Fabry disease (FD) is a rare genetic (X-linked) disorder caused by mutations in the gene encoding α-galactosidase A (AGALA). Deficient AGALA activity leads to intra-lysosomal accumulation of neutral glycosphingolipids, predominantly globotriaosylceramide, in various organ systems. The disease manifests, in its classic variant, with multiple organ involvement with age and gender-dependent manifestations. Several mutations can cause atypical (late-onset) variants affecting a single organ, most frequently the heart. Cardiac involvement consists mainly of ventricular hypertrophy, progressive left ventricle (LV) scarring, heart failure, tachyarrhythmias, bradycardia, and valvular disease. In many cases, the phenotype can mimic sarcomeric hypertrophic cardiomyopathy (HC). , Unlike sarcomeric HC, left ventricular outflow tract obstruction (LVOTO) is relatively rare. Nevertheless, it can be present in a subset of patients and may be unmasked by exercise. Because the underlying pathophysiology in FD is different from sarcomeric HC, there is a concern whether established non-pharmacological treatments of LVOTO in HC would be effective in FD. The literature describes only a small group of patients who have undergone surgical myectomy, , or single myectomy case including discussion of our previous abstract data. However, only a single case report of a successful alcohol septal ablation (ASA) was published previously. Our aim was to assess the feasibility and effectiveness of an ASA in Fabry patients with symptomatic LVOTO.
Methods
Consecutive patients with symptomatic LVOTO, from a cohort of 200 Fabry patients observed and treated in our institution, were included in the study. The diagnosis of FD was confirmed for all patients through the assessment of AGALA activity and genetic testing. In cases carrying a mutation of unknown significance, cardiac involvement was confirmed by histological evidence (i.e., endomyocardial biopsy). The patients with LV hypertrophy were screened for LVOTO.
All patients underwent a clinical examination before the ASA, which confirmed that the symptoms attributable to LVOTO persisted despite maximum tolerated beta-blocker therapy. Electrocardiography, transthoracic echocardiography, and exercise echocardiography were also performed in all patients in whom ASA was planned. The following echocardiographic parameters were used for the analysis: resting and provoked LVOT and the mid-ventricular maximal pressure gradient, interventricular septal and posterior wall thickness, diameter of the left atrium as seen in the parasternal long-axis view, and trans-mitral flow and tissue doppler imaging of the mitral septal annulus. Exercise echocardiography was performed using a dedicated semi-supine bicycle ergometer. The peak pressure gradient in the outflow tract was taken during exercise and at the beginning of the recovery period.
Percutaneous ASA was performed in all patients, using a procedure similar to that used in patients with sarcomeric HC. The reason why these patients underwent ASA were twofold. First, in the experience of our center, Fabry patients have a relatively high cardiac surgery risk and their perioperative care is more complex compared to other cardiac surgery candidates. Secondly, it is our greater experience with ASA than with myectomy. The surgical myectomy is usually reserved for patients with more complex involvement (midventricular obstruction, …) and risk of complete atrioventricular block (left bundle branch block). We were applying small amounts of 96% alcohol (1 to 2 mL) to the proximal septal branch, and the procedure was guided by contrast echocardiography. A temporary pacemaker lead was inserted into the right ventricle before the procedure (except in cases where a pacemaker or automatic implantable defibrillator was already present). Written informed consent for ASA was obtained from all patients; the systematic clinical follow-up of Fabry patients was previously approved by the local ethics committee and performed under a separate written informed consent. All patients received follow-up at regular intervals, including resting echocardiography. The maximal pressure gradient was measured at rest and during the Valsalva maneuver.
Due to the small number of patients in our cohort, the median was used for the statistical descriptions. No further statistical analysis was performed.
Results
From May 2001 through August 2019, 6 unrelated male patients with FD underwent percutaneous ASA at our institution. The median age at the time of intervention was 52 (41 to 54) years. The characteristics of the 6 patients are shown in Table 1 . The diagnosis of FD was confirmed by the presence of a pathogenic mutation in all cases. An extra-cardiac FD manifestation was present in 5 patients at the time of the ASA. Four patients were treated with enzyme replacement therapy before ASA. In the fifth patient, specific therapy was initiated at the same time as ASA, and the sixth patient started receiving treatment 2 years after ASA (our first described case of ASA was in 2001 and enzyme replacement therapy was not available in the Czech Republic at that time). Two patients had received an implantable cardioverter-defibrillator before ASA (one after a cardiac arrest, and the second for primary sudden death prevention). All patients were highly symptomatic – NYHA class III. LVOT obstruction, confirmed by exercise echocardiography, was present in all patients despite pharmacologic therapy (beta-blockers). The median LVOT maximal pressure gradient was 85 (60 to 170) mm Hg. A significant mid-ventricular obstruction was not seen in any of the cases. The median of the maximal ventricular wall thickness was 21 (18 to 25) mm, and the median diameter of the left atrium was 48 (41 to 50) mm. Diastolic function was impaired in all patients; in 4 patients, we observed an impaired relaxation pattern, and 2 patients had a pseudo-normal filling pattern. Electrocardiography showed sinus rhythm, normal PQ interval and slightly prolonged QRS duration 120 (110 to 138) ms. Nobody had left bundle branch block.
| Pt. No. | Age at diagnosis (years) | Age at ASA (years) | Gene mutation | Agalsidase therapy before ASA (age at start [years]) | Max. thickness of IVS (mm) | ICD | Extracardiac manifestation | NYHA before | Class after |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 49 | 53 | c.[901 C>T] | – (56) | 21 | – | Neurologic, PU, cornea vercilata, angiokeratoma | III. | II. |
| 2 | 48 | 51 | c.[973 G>A] | + (49) | 25 | + | RRT, neurologic (TIA) | III. | II. |
| 3 | 48 | 52 | c.[801+ 48T>G] | + (49) | 18 | – | Cornea verticilata | III. | I. |
| 4 | 36 | 41 | c.[902 G>A] | + (37) | 21 | + | Neurologic, PU | III. | III. |
| 5 | 53 | 54 | c.[801+ 48T>G] | – (54) | 21 | – | – | III. | I. |
| 6 | 30 | 46 | c.[950 T>C] | + (30) | 19 | – | RRT, acroparesthesia | III. | II. |
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