Riikka Kalliokoski

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

SummaryFabry disease (McKusick 301500) is an X-linked lysosomal storage disorder secondary to deficient α-galactosidase A activity which leads to the widespread accumulation of globotriaosylceramide (Gb3) 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 α-galactosidase A (Fabrazyme, Genzyme). Plasma Gb3 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 Gb3 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.

Structural and functional changes in peripheral vasculature of Fabry patients

SummaryObjective: Fabry disease is a lysosomal storage disorder due to deficient α-galactosidase A activity, which leads to glycosphingolipid accumulation especially in vascular smooth-muscle and endothelial cells. Little is known about the effects of Fabry disease on peripheral artery function and structure. Therefore, we aimed to further characterize the peripheral vascular structural and functional changes in Fabry disease. Methods and results: We measured structural and functional vascular parameters, including intima-media thickness (IMT) of brachial and carotid arteries and abdominal aorta, carotid and aortic compliance, and brachial artery flow-mediated dilatation (FMD) in 17 Fabry patients and 34 healthy controls matched for age, sex and smoking. Carotid IMT (0.64 ± 0.15 vs 0.57 ± 0.12 mm), brachial IMT (1.02 ± 0.25 vs 0.74 ± 0.18 mm), and aortic IMT (0.31 ± 0.09 vs 0.26 ± 0.04 mm) were significantly increased, and brachial FMD was significantly impaired (6.3 ± 5.0 vs 9.7 ± 3.9%) in Fabry patients compared to healthy controls (p < 0.05 in all comparisons after adjustments for age, LDL-cholesterol, and systolic blood pressure). No differences were observed in arterial compliance between the groups. Conclusions: These data suggest that Fabry disease affects arterial function and structure by disturbing peripheral endothelial function and promoting intima-media thickening.

Impaired myocardial perfusion reserve but preserved peripheral endothelial function in patients with Fabry disease

SummaryFabry disease (McKusick 301500) is an X-linked lysosomal storage disorder due to deficient α-galactosidase A activity, which leads to accumulation of glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. The effect of this accumulation on peripheral and cardiac vascular function is poorly known. We studied 15 Fabry patients (mean age 35 years and mean BMI 24.8 kg/m2) and 30 age- and BMI-matched healthy controls to examine whether myocardial perfusion reserve and peripheral artery endothelial function are altered. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and H215O. Myocardial blood flow reserve was calculated as the ratio between the dipyridamole-induced maximal blood flow and resting blood flow. Peripheral artery endothelial function was assessed by measuring the brachial artery flow-mediated dilatation using ultrasound at rest and during reactive hyperaemia. The myocardial perfusion reserve was significantly lower in Fabry patients than in controls (3.3 ± 1.2 vs 4.4 ± 1.6, p = 0.02), while the brachial artery flow-mediated dilatation was similar (5.9% ± 3.9%vs 4.5% ± 3.6%, p = 0.27). Thus, inFabry disease, myocardial perfusion reserve is reduced while the peripheral artery endothelial function is preserved.

Cardiopulmonary involvement in Fabry's disease

Background — Fabry’s disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipid in different tissues, including endothelial and smooth-muscle cells and cardiomyocytes. Objectives — There is controversial data on cardiopulmonary involvement in Fabry’s disease, because many reports are based on small and selected populations with Fabry’s disease. Furthermore, the aetiology of cardiopulmonary symptoms in Fabry’s disease is poorly understood. Methods — We studied cardiopulmonary involvement in seventeen patients with Fabry’s disease (20-65 years, 6 men) using ECG, bicycle stress, cardiac magnetic resonance imaging, spirometry, diffusing capacity and pulmonary high-resolution computed tomography (HRCT) tests. Cardiopulmonary symptoms were compared to observed parameters in cardiopulmonary tests. Results — Left ventricular hypertrophy (LVH) and reduced exercise capacity are the most apparent cardiac changes in both genders with Fabry’s disease. ECG parameters were normal when excluding changes related to LVH. Spirometry showed mild reduction in vital capacity and forced expiratory volume in one second (FEV1), and mean values in diffusing capacity tests were within normal limits. Generally, only slight morphological pulmonary changes were detected using pulmonary HRCT, and they were not associated with changes in pulmonary function. The self-reported amount of pulmonary symptoms associated only with lower ejection fraction (P < 0.001) and longer QRS-duration (P = 0.04) of all measured cardiopulmonary parameters, whereas cardiac symptoms have no statistically significant association with any of these parameters. Conclusion — LVH and reduced exercise capacity are the most apparent cardiopulmonary changes in Fabry’s disease but they have only a minor association to cardiopulmonary symptoms.Therefore, routine cardiopulmonary evaluation in Fabry’s disease using echocardiography is maybe enough when integrated to counselling for aerobic exercise training.

Increased B-type natriuretic Peptide concentration is associated with reduced coronary vasoreactivity in patients with dilated cardiomyopathy but not in healthy young subjects.

Background/Aims. Natriuretic peptides are associated with the cardiovascular disease risk under a range of different circumstances. However, less is known about whether this association is found also in young healthy subjects. Methods. 9 patients with dilated cardiomyopathy and 26 healthy young subjects were studied. The myocardial blood flow measurements were performed basally and during adenosine infusion using PET. Results. S-proBNP concentrations were significantly higher (2153 ± 1964 versus 28 ± 17 ng/L, P = .000002) and adenosine-stimulated flow lower (1.6 ± 0.8 versus 3.6 ± 1.1 mL·g−1·min−1, P = .00001) in patients with dilated cardiomyopathy when compared to healthy subjects. S-proBNP concentration was inversely associated with adenosine stimulated flow in patients with dilated cardiomyopathy (r = −0.75, P = .019) but not in healthy subjects (r = −0.06, P = .84). Conclusions. Natriuretic peptides are inversely associated with coronary vasoreactivity in patients with dilated cardiomyopathy but not in healthy young subjects. Since reduced coronary vasoreactivity seems to be one of the earliest abnormalities in the development of coronary artery disease, this might indicate that natriuretic peptides are not predictor of cardiovascular disease risk in healthy young subjects.