Parasympathetic System Impairment Is Associated with Cerebral Microangiopathy in Adults with Sickle Cell Disease

Background White matter lesions (WML) on brain imaging are common both in children and adults with sickle cell disease (SCD) with no history or symptoms of stroke. Prevalence of silent infarcts can reach 53% of adults with SCD by age 30. These lesions are generally considered to be silent, but studies showed risk of cognitive and intellectual decline in children, testifying to an early cerebral aging.

Autonomic nervous system (ANS) is involved in the homeostasis of cerebral hemodynamic. Impairment of the sympatho-vagal imbalance is described in sickle cell disease patients.

The aim of the study was to evaluate the association between ANS parameters and cerebral microangiopathy in adults with SCD.

Methods In our cohort of SCD patients in Toulouse hospital, adults patients with SCD (S/S, S/C, S/b° and S/b+) were prospectively included to access baroreflex sensitivity (BRS), sympatho-vagal balance (High Frequency HF, Low Frequency LF, LH/HF ratio) and cerebral MRI. Patients with history of stroke were excluded. All patients provided written inform consent. Sympatho-vagal balance and BRS evaluation was based on continuous assessment of cerebral blood flow velocities using trans cranial doppler (TCD) and arterial blood pressure using photo-plethysmograph (Finapres®). Cerebral microangiopathy was defined by the presence of white matter hyperintensities graded with Fazekas score(1) or/and presence of lacunes by 3T MRI allowing to define 2 groups. One group without and one group with cerebral microangiopathy. Sensitivity analysis was performed regarding the phenotype of SCD. Hemolytic phenotype was defined by low level of hemoglobin, high serum lactate dehydrogenase, bilirubin and reticulocytes. Viscous phenotype was defined by high level of hemoglobin and hematocrit. Primary endpoint was to access the association between cerebral microangiopathy and ANS parameters.

Results Forty-one patients were included between January 2017 and April 2021. Median age was 37.5 years (range 19-65). Twenty-nine (70,7%) patients had SS genotype, 7 patients (17,1%) had SC genotype and 5 (12,2%) patients had Sb° genotype. There was 61% of women (n= 25) and 39% of men (n= 16) (Table1).

Among the 41 patients included, 26,8% (n=11) presented cerebral microangiopathy. Patients with cerebral microangiopathy were significantly older (44.5 vs 30.6 years; p<0.001) and had lower High Frequency (HF) (HF 157 ms^2 vs HF 467.6 ms^2; p<0.005). BRS was lower (14,0 ms/mmHg vs 24,2 ms/mmHg) but not significant in the group with cerebral microangiopathy. Velocity blood flow of middle cerebral artery was no significantly different between the two groups.

In univariate analysis, HF was significantly associated with cerebral microangiopathy (OR 0.46; CI 0.21-1.00; p=0.050). Area under the receiver operating characteristic curve for the model with age as a single predictor was estimated at 0.876. For the age and HF model, area under the receiver operating characteristic curve was 0,946.

In sensibility analysis, there was no difference between the hemolytic and viscous phenotypes regarding autonomic nervous system parameters.

Conclusion Our study suggests that impaired parasympathetic system is associated with cerebral microangiopathy in adults with sickle cell disease. These lesions are associated with cerebral aging. Several therapies of cardiovascular prevention including non-drug treatment and physical activity could improve cerebrovascular function and parasympathetic activity. HF monitoring can help assess the cardiovascular impact of such a treatment in aging SCD patients.

References 1. Scheltens P, Erkinjunti T, Leys D, Wahlund LO, Inzitari D, Ser T del, et al. White Matter Changes on CT and MRI: An Overview of Visual Rating Scales. Eur Neurol. 1998;39(2):80-9.

Perrot:Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.