Lipid levels in sickle-cell disease associated with haemolytic severity, vascular dysfunction and pulmonary hypertension

Abstract

Pulmonary hypertension (PH) in sickle cell disease (SCD) is an emerging and important clinical problem. In a single-institution adult cohort of 365 patients, we investigated lipid and lipoprotein levels and their relationship to markers of intravascular haemolysis, vascular dysfunction and PH. In agreement with prior studies, we confirm significantly decreased plasma levels of total cholesterol, high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) in SCD versus ethnically-matched healthy controls. Several cholesterol parameters correlated significantly with markers of anaemia, but not endothelial activation or PH. More importantly, serum triglyceride levels were significantly elevated in SCD compared to controls. Elevated triglyceride levels correlated significantly with markers of haemolysis (lactate dehydrogenase and arginase; both P < 0.0005), endothelial activation (soluble E-selectin, P < 0.0001; soluble P-selectin, P = 0.02; soluble vascular cell adhesion molecule-1, P = 0.01), inflammation (leucocyte count, P = 0.0004; erythrocyte sedimentation rate, P = 0.02) and PH (amino-terminal brain natriuretic peptide, P = 0.002; prevalence of elevated tricuspid regurgitant velocity (TRV), P < 0.001). In a multivariate analysis, triglyceride levels correlated independently with elevated TRV (P = 0.002). Finally, forearm blood flow studies in adult patients with SCD demonstrated a significant association between increased triglyceride/HDL-C ratio and endothelial dysfunction (P < 0.05). These results characterize elevated plasma triglyceride levels as a potential risk factor for PH in SCD.

Fig. 1. Serum Lipid Levels in Sickle Cell Patients Compared with Healthy Controls

Serum lipid levels were determined in either healthy control subjects, patients with mild forms of SCD (SC or Sβ⁺-thalassemia) or patients with more severe forms of SCD (SS or Sβ⁰-thalassemia). (A) Serum total cholesterol levels were determined for 39 control subjects 78 patients with SC or Sβ⁺-thalassemia, or 249 patients with SS or Sβ⁰-thalassemia. (B) Serum HDL-cholesterol levels were determined for 39 control subjects, 78 patients with SC or Sβ⁺-thalassemia, or 249 patients with SS or Sβ⁰-thalassemia. (C) Serum LDL-cholesterol levels were determined for 39 control subjects, 78 patients with SC or Sβ⁺-thalassemia, or 250 patients with SS or Sβ⁰-thalassemia. (D) Serum triglyceride levels were determined for 32 control subjects, 77 patients with SC or Sβ⁺-thalassemia, or 245 patients with SS or Sβ⁰-thalassemia. Only those patients with genotypes determined by nucleotide sequencing (n=328, total) were included in this analysis. p values were determined from ANOVA F test of difference in means between sickle cell groups and controls.

Fig. 2. Serum triglycerides and pulmonary hypertension

(A) Mean serum triglyceride levels were determined for sickle cell patients (all phenotypes) with pulmonary pressures that were normal (TRV<2.5 m/sec), mildly elevated (2.5 ≤ TRV ≤ 2.9 m/sec) or highly elevated (TRV ≥ 3 m/sec). Statistical significance was determined from ANOVA F test of difference in means between TRV groups. (B) Prevalence of highly elevated pulmonary pressures by triglyceride level among sickle cell patients. Patients were divided into quartiles according to their serum triglyceride levels and the percentage of patients in each quartile with highly elevated pulmonary pressure (TRV ≥ 3 m/sec) was determined. p-values were determined by Cohran-Armitage χ² test for trend.

Fig. 3. High TG/HDL-C ratio is a marker for endothelial dysfunction

Forearm blood flow was measured in 20 patients with SCD with venous occlusion plethysmography following test doses of (A) acetylcholine (ACh) and (B) sodium nitroprusside (SNP) infused into the brachial artery. (A) Patients with lower than median TG/HDL-C values (median = 2.0) demonstrated dose-dependent vasodilation to ACh close to previously published normal values (solid line). In sharp contrast, those with higher than median TG/HDL-C values (dashed line) had markedly blunted responses, measured as absolute blood flow (P < .05, 2-way ANOVA). (B) The absolute blood flow at baseline and all doses of SNP did not differ by TG/HDL-C status.