Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease

Abstract

In Fabry disease, there is glycosphingolipid storage in vascular endothelial and smooth muscle cells and neurons of the autonomic nervous system. Vascular or autonomic dysfunction is likely to compromise cerebral blood flow velocities and cerebral autoregulation. This study was performed to evaluate cerebral blood flow velocities and cerebral autoregulation in Fabry patients. In 22 Fabry patients and 24 controls, we monitored resting respiratory frequency, electrocardiographic RR-intervals, blood pressure, and cerebral blood flow velocities (CBFV) in the middle cerebral artery using transcranial Doppler sonography. We assessed the Resistance Index, Pulsatility Index, Cerebrovascular Resistance, and spectral powers of oscillations in RR-intervals, mean blood pressure and mean CBFV in the high (0.15-0.5 Hz) and sympathetically mediated low frequency (0.04-0.15 Hz) ranges using autoregressive analysis. Cerebral autoregulation was determined from the transfer function gain between the low frequency oscillations in mean blood pressure and mean CBFV. Mean CBFV (P < 0.05) and the powers of mean blood pressure (P < 0.01) and mean CBFV oscillations (P < 0.05) in the low frequency range were lower,while RR-intervals, Resistance Index (P < 0.01), Pulsatility Index, Cerebrovascular Resistance (P < 0.05), and the transfer function gain between low frequency oscillations in mean blood pressure and mean CBFV (P < 0.01) were higher in patients than in controls. Mean blood pressure, respiratory frequency and spectral powers of RR-intervals did not differ between the two groups (P > 0.05). The decrease of CBFV might result from downstream stenoses of resistance vessels and dilatation of the insonated segment of the middle cerebral artery due to reduced sympathetic tone and vessel wall pathology with decreased elasticity. The augmented gain between blood pressure and CBFV oscillations indicates inability to dampen blood pressure fluctuations by cerebral autoregulation. Both, reduced CBFV and impaired cerebral autoregulation, are likely to be involved in the increased risk of stroke in patients with Fabry disease.

Autonomic Blockade During Sinusoidal Baroreflex Activation Proves Sympathetic Modulation of Cerebral Blood Flow Velocity

“…We noninvasively monitored mean arterial BP by radial artery tonometry with initial calibration at the brachial artery (Colin Pilot, San Antonio, TX). 18 Mean CBFV of the proximal middle cerebral artery (MCA) was assessed by TCD (Multidop XL, DWL, Germany). The MCA was insonated through the temporal window, approximately 1 cm above the zygomatic arch at a depth of 35 to 55 mm using a 2 MHz Doppler probe.…”

“…Intact CA assures constant cerebral blood flow in the face of BP changes and depends on mechanisms such as the myogenic component, that is, the capacity of vascular smooth muscles to dampen BP fluctuations, on intact endothelial function, and on neurogenic, primarily sympathetic influences. 18,25 The dynamics of autoregulation can be compared with a high-pass filter. 5,26 Rapid BP perturbations are transferred to CBFV, whereas slow BP changes are dampened.…”

“…26 The coherence between BP and CBFV signal oscillations might span from 0 (ie, no association) to 1 (ie, maximal association). 8,18 If coherence is >0.5, the 2 signals are considered to have a stable phase relation for a given frequency of oscillation. 18,27 Before and after pharmacological blockade, we assessed NS-induced changes in transfer function gain and phase shift between BP oscillations and CBFV oscillations at 0.1 Hz, that is, at the frequency that is considered to reflect oscillations mediated by sympathetic outflow.…”

“…5,11,12,26 Such passive phase angle changes have been reported in patients with impaired CA. 17,18,24,26 In these patients, intracranial arterial stenoses, 26 autonomic neuropathy, 17,24 or intracerebral microangiopathy 18 restrict CA and account for the passively driven, BP-dependent changes in CBFV and in phase angles between CBFV and BP oscillations.…”

An In Vitro Model of Fabry Disease

“…More recently, however, associated macrovascular pathology has been appreciated, although the mechanisms related to premature macrovascular events are unknown. Recent studies have reported that Fabry disease is associated with abnormalities of arterial blood flow, including coronary and cerebral arteries (16,17). Additional studies suggest that these changes may be distinct for these vascular beds and absent in other arterial beds, including the radial artery (18).…”