The effect of 12‐month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease

Abstract

Fabry disease (McKusick 301500) is an X-linked lysosomal storage disorder secondary to deficient alpha-galactosidase A activity which leads to the widespread accumulation of globotriaosylceramide (Gb(3)) and related glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. We have recently shown that the myocardial perfusion reserve of Fabry patients is significantly decreased. Thus, in the present study we investigated, whether it can be improved with enzyme replacement therapy (ERT). Ten patients (7 male, 3 female; mean age 34, range 19-49 years) with confirmed Fabry disease were approved for this uncontrolled, open-label study. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and radiowater. Myocardial perfusion reserve was calculated as the ratio between maximal and resting perfusion. Perfusion measurements were performed before and after 6 and 12 months of ERT by recombinant human alpha-galactosidase A (Fabrazyme, Genzyme). Plasma Gb(3) concentration decreased significantly and the patients reported that they felt better and suffered less pain after the ERT. However, neither resting or dipyridamole-stimulated myocardial perfusion nor myocardial perfusion reserve changed during the ERT. Pretreatment relative wall thickness correlated negatively with posttreatment changes in flow reserve (r = -0.76, p = 0.05) and positively with posttreatment changes in minimal coronary resistance (r = 0.80, p = 0.03). This study shows that 12 months of ERT does not improve myocardial perfusion reserve, although the plasma Gb(3) concentration decreases. However, individual variation in the response to therapy was large and the results suggest that the success of the therapy may depend on the degree of cardiac hypertrophy.

Angina in Fabry Disease Reflects Coronary Small Vessel Disease

“…It is often associated with electrocardiographic abnormalities of ST-segment and T wave and with impaired myocardial perfusion reserve at positron emission tomography imaging, 3,4 suggesting the existence of myocardial ischemia. However, the site and mechanism of disturbance of coronary circulation have not yet been clarified.…”

“…3 Indeed, in contrast with positron emission tomography imaging suggesting an impaired myocardial perfusion reserve, 3,4 coronary angiography frequently showed normal vessels pointing toward a compromise of coronary microcirculation. However, the mechanisms of microvascular dysfunction are still unclear and may include increased myocardial oxygen demand, increased LV end-diastolic pressure, decreased capillary density, and small vessel disease.…”

Coronary Microvascular Dysfunction in Patients with Cardiomyopathies

“…In addition, Hughes et al 15 reported a 20% mean reduction in myocardial Gb 3 content, as assessed by serial transvenous endomyocardial biopsies, in patients receiving Fabrazyme compared with a 10% mean increase in patients receiving placebo. In the Kalliokoski et al study, 13 plasma Gb 3 concentration decreased significantly, and patients reported symptomatic improvement after treatment with Fabrazyme, although no significant changes in resting or hyperemic blood flow compared with baseline were noted. The latter is consistent with the findings of Elliott et al, 9 who did not find any improvement in resting or hyperemic blood flow in a subgroup of patients with AFD who repeated the PET scan after enzyme replacement therapy.…”

“…12 Different from Chimenti et al, 10 other studies have reported evidence of coronary microvascular dysfunction in AFD in patients both with and without a history of chest pain. 9,13 AFD is a multisystem disorder with widespread structural and functional vascular changes that generally affect different arterial systems. 8 If the presence of angina is a specific indicator of coronary microvascular disease, it would be expected that patients with AFD with a history of angina have significantly more adverse cardiac events at follow-up, similar to patients with dilated or hypertrophic cardiomyopathy in whom the severity of microvascular dysfunction (assessed with PET) predicts major adverse cardiac events.…”

Heart in Fabry Disease

“…In one study, coronary microvascular dysfunction failed to recover in 5 male patients (mean age, 59 years) after 10 months of treatment [36]. A subsequent study of 10 younger patients (mean age, 34 years) also failed to show any effect [40]. Coronary microcirculation dysfunction does not appear to improve on therapy, nor does angina improve despite improvement in LVH however, this may be confounded by the degree of cardiac involvement.…”