Skeletal and myocardial microvascular blood flow in hydroxycarbamide-treated patients with sickle cell disease

Abstract

In sickle cell disease (SCD), abnormal microvascular function combined with chronic anaemia predisposes patients to perfusion-demand mismatch. We hypothesized that skeletal muscle and myocardial perfusion, normalized to the degree of anaemia, is reduced at basal-state compared to controls, and that this defect is ameliorated by hydroxycarbamide (HC; also termed hydroxyurea) therapy. Twenty-one SCD patients, of whom 15 were treated with HC, and 27 controls underwent contrast-enhanced ultrasound (CEU) perfusion imaging of the forearm as well as the myocardium. HC treatment was associated with lower white cell and reticulocyte counts, and higher fetal haemoglobin and total haemoglobin levels. When corrected for the degree of anaemia in SCD patients, skeletal flow in HC-treated patients was significantly higher than in untreated SCD patients (217·7 ± 125·4 vs. 85·9 ± 40·2, P = 0·018). Similarly, when normalized for both anaemia and increased myocardial work, resting myocardial perfusion was also significantly higher in HC-treated patients compared with untreated SCD patients (0·53 ± 0·47 vs. 0·13 ± 0·07, P = 0·028). Haemoglobin F (HbF) levels correlated with skeletal muscle microvascular flow (r = 0·55, P = 0·01). In conclusion, patients with SCD not on HC therapy have resting flow deficits in both skeletal muscle and myocardial flow. HC therapy normalizes flow and there is a direct correlation with HbF levels. Clinical trial registration ClinicalTrials.gov Identifier: NCT01602809; https://ichgcp.net/clinical-trials-registry/NCT01602809?term=sACHDEV&rank=9.

Keywords: contrast ultrasound; hydroxycarbamide; microvasculature; perfusion imaging; sickle cell disease.

© 2017 John Wiley & Sons Ltd.

Figures

Figure 1. Study Enrolment Diagram

A total of 57 subjects signed consent and completed study procedures. Two had no interpretable contrast data for technical reasons. Six controls were excluded for a BMI > 40 kg/m2. One SCD patient was excluded for a glucose level of > 22.2 mmol/l. There were 48 evaluable patients in the study (27 controls, 21 SCD patients of whom 15 were on HC). BMI: body mass index; HC: hydroxycarbamide; SCD: sickle cell disease.

Figure 2. Brachial artery flow

Calculated brachial artery flow in controls, SCD patients not on HC and SCD patients on HC therapy demonstrates no significant differences between groups. HC: hydroxycarbamide; ns: not significant; SCD: sickle cell disease.

Figure 3. Skeletal Muscle Microvascular Flow

A. Resting contrast-enhanced ultrasound-derived skeletal muscle flow data is shown in controls, SCD patients not on HC and SCD patients on HC therapy. B. Skeletal muscle flow normalized to haemoglobin levels is shown in all three groups. HC: hydroxycarbamide; ns: not significant; SCD: sickle cell disease.

Figure 4. HbF levels and Skeletal Muscle and Myocardial Flow

A. There was a direct correlation between HbF levels and skeletal muscle flow (r=0.55, p=0.01). B. No significant correlation was seen between HbF levels and myocardial flow (r=0.31, p=0.191).

Figure 5. Myocardial Blood Flow

A. Myocardial perfusion data is shown in controls, SCD patients not on HC and SCD patients on HC therapy. B. Myocardial perfusion is normalized to haemoglobin levels. C. Myocardial perfusion is normalized to both haemoglobin and myocardial work. HC: hydroxycarbamide; ns: not significant; SCD: sickle cell disease.