Enzyme replacement therapy improves cardiovascular responses to orthostatic challenge in Fabry patients.
OBJECTIVE
Fabry patients have autonomic dysfunction but usually do not present clinically overt signs of orthostatic dysregulation. This study evaluated orthostatic regulation and baroreflex sensitivity (BRS) in untreated Fabry patients and possible baroreflex improvement with enzyme replacement therapy (ERT).


METHODS
In 22 Fabry patients (aged 28W8 years), we assessed electrocardiographic RR intervals (RRIs), SBP, DBP and respiratory frequency, in supine and standing position, before and after 18 (11 patients) or 23 months (11 patients) of biweekly alpha-galactosidase A infusions (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetically mediated low-frequency (0.04-0.15 Hz) and parasympathetically mediated high-frequency (0.15-0.5 Hz) RRI fluctuations, and sympathetic low-frequency powers of blood pressure fluctuations. We normalized RRI powers by relating low-frequency and high-frequency powers to total powers (low-frequency + high-frequency powers), assessed the RRI low-frequency/high-frequency ratio reflecting sympathicovagal balance. As a measure of BRS, we used the alpha-index, obtained as square root of the ratio between powers of simultaneous spectral analyses of spontaneous low-frequency variabilities in RRIs and SBP (coherence>0.5). We compared parameters in supine and standing position of untreated and treated patients with those of 15 healthy age-matched (27+/-5 years) men (repeated-measure analysis of variance, significance at P<0.05).


RESULTS
Supine biosignals were similar in all groups. Upon standing, RRIs were lower in controls and patients after ERT than in patients before ERT (P<0.05); normalized RRI high-frequency powers as well as BRS decreased, whereas DBP, low-frequency/high-frequency ratios and sympathetic low-frequency powers of SBP increased in controls and treated patients only (P<0.05).


CONCLUSIONS
Reduced increase in heart rate, blood pressure and sympathetic activation, and limited cardiovagal withdrawal and BRS adjustment seen in untreated Fabry patients upon standing normalized after 18 and 23 months of ERT demonstrating improved baroreflex function, which, in turn, is an established parameter of improved disease prognosis.
Hilz
Max J
MJ
Department of Neurology, New York University School of Medicine, New York, New York 10016, USA. max.hilz@nyumc.org
Marthol
Harald
H
Schwab
Stefan
S
Kolodny
Edwin H
EH
Brys
Miroslaw
M
Stemper
Brigitte
B
D000328:Adult; D017704:Baroreflex / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D004562:Electrocardiography; D056947:Enzyme Replacement Therapy / Q000379:methods*; D000795:Fabry Disease / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D054971:Orthostatic Intolerance / Q000150:complications*; D011994:Recombinant Proteins / Q000627:therapeutic use; D016683:Supine Position / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects; D000519:alpha-Galactosidase / Q000627:therapeutic use*
D011994:Recombinant Proteins; D000519:alpha-Galactosidase