Tricuspid regurgitant jet velocity and myocardial tissue Doppler parameters predict mortality in a cohort of patients with sickle cell disease spanning from pediatric to adult age groups ‐ revisiting this controversial concept after 16 years of additional evidence

Abstract Pulmonary hypertension (PHT) has emerged as a frequent cause of increased morbidity and mortality in adults with sickle cell disease (SCD). However, the incidence, prevalence and etiology of PHT in children with SCD are currently unknown. An elevated tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/sec on Doppler echocardiogram (ECHO) in adults may predict PHT usually diagnosed by traditional cardiac catheterization. We hypothesized that routinely measuring TRJV in children and young adults with SCD was feasible and that TRJV correlated with degree of baseline hemolysis. Methods Using a standard protocol, we prospectively measured steady state TRJV in a convenience, cross-sectional sample of 43 patients (mean age 14.2±2.8 years, range 10 to 20) with hemoglobin (Hb) SS, SC or S-β0 thalassemia at our institution as part of a PHT screening initiative beginning December 2005. Patients on chronic transfusions were excluded. The relationship between TRJV and same day laboratory studies and clinical data obtained from patient charts was examined. Results TRJV was not measurable in 5 of 43 (12%) patients, due presumably to normal pulmonary artery systolic pressures. Neither right ventricular hypertrophy nor decreased septal wall motion, both suggestive of PHT, was present when TRJV could not be determined. In the remaining 38 studies in which TRJV could be quantified (mean 2.34 m/sec±0.44), TRJV was ≥ 2.5 m/sec in 13 patients. Using Pearson’s correlation coefficient, we found a significant correlation between TRJV and LDH (r=0.54, p=0.01), with higher TRJV associated with higher LDH. There were also significant, though more modest, positive correlations between TRJV and WBC (r=0.37, p=0.05) and reticulocyte count (r=0.40, p=0.05) and a significant negative correlation between TRJV and Hb (r= -0.46, p=0.01). Using t-test for independent samples, we found a significant difference in mean LDH (458 IU/L±192 vs. 338 IU/L±144, p=0.037), Hb (8.7 g/dL±1.3 vs. 10.2 g/dL±1.6, p=0.008) and reticulocyte count (17.3%±10.3 vs. 10.7%±6.9, p=0.027) between patients with TRJV ≥ 2.5 and <2.5 m/sec. A difference approaching significance in total WBC (11.4 x103/μL±5.3 vs. 8.3 x103/μL ±3.2, p=0.075) was also observed between the two groups. We found neither a significant difference in mean values between the two groups nor significant relationships with TRJV when we examined platelet count, plasma free Hb, percent fetal Hb or total bilirubin. Using Fisher’s Exact Test, we did not demonstrate in our small cohort a difference in the proportion of patients with TRJV ≥ 2.5 or < 2.5 m/sec who had a history of hydroxyurea use, acute chest syndrome, frequent pain, asthma, splenectomy, gallstones, priapism, exchange transfusion, heart disease or tonsilloadenoidectomy. Conclusions We conclude that TRJV by ECHO is quantifiable in most children and young adults being evaluated for PHT and that a higher LDH and reticulocyte count and a lower Hb at baseline are observed more frequently with elevated TRJV. Larger cohort studies are needed to test the predictive value of one or more of these markers of hemolysis. Although long term outcomes associated with elevated TRJV, as an indication of PHT, in children with SCD remains unclear, decreasing hemolysis in this population may represent an early therapeutic target in the prevention of future clinically significant PHT.

Download Full-text

An Elevated Tricuspid Regurgitant Jet Velocity in Sickle Cell Disease Is Associated with Polymorphisms in Genes Impacting Innate Immunity

Blood ◽

10.1182/blood.v118.21.514.514 ◽

2011 ◽

Vol 118 (21) ◽

pp. 514-514

Author(s):

Harold T. Bae ◽

Clinton T. Baldwin ◽

Mark T Gladwin ◽

Allison E Ashley-Koch ◽

Melanie Garrett ◽

...

Keyword(s):

Innate Immunity ◽

Sickle Cell Disease ◽

Candidate Gene ◽

Sickle Cell ◽

P Value ◽

Cell Disease ◽

A Genome ◽

Candidate Gene Studies ◽

Jet Velocity ◽

Tricuspid Regurgitant Jet Velocity

Abstract Abstract 514 An elevated tricuspid regurgitant jet velocity (TRV) by echocardiography, associated with increased mortality risk, may be reflective of pulmonary and systemic vasculopathy in sickle cell disease (SCD). The epidemiologic associations between an elevated TRV and other sub-phenotypes of SCD, such as leg ulcers, priapism, proteinuria and increased rate of hemolysis, suggest a common pathogenic link across vascular beds. We were interested in identifying genetic modifiers of SCD and hypothesized that an elevated TRV is, in part, genetically determined. Previous candidate gene studies identified single nucleotide polymorphisms (SNPs) in activin A receptor, type II-like 1 (ACVRL1), bone morphogenetic receptor 2 (BMPR2) and bone morphogenetic protein 6 (BMP6) associated with an elevated TRV suggesting a role for the TGF-b pathway in pathogenesis. We performed a genome-wide association study (GWAS) to identify novel genes and pathways that might be associated with an elevated TRV. We first used Illumina 610K arrays in a GWAS on 340 sickle cell disease patients recruited as part of the observational arm of the Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) clinical trial (discovery set) and then validated these results using a replication set consisting of 56 patients enrolled in the studies of TRV and SCD at Duke and Boston Universities. All subjects were 17 years or older and had the HbS only phenotype. We analyzed the data using TRV as a continuous variable and we adjusted for potential confounding effects of age and gender. In addition, as there were 9 different clinical centers in the discovery set, we used center-adjusted TRV values for the analysis. We identified 3 SNPs in CUB and sushi multiple domains 1 (CSMD1) (rs12674750, p=9.5 × 10−6, rs7008391, p=1.8×10−5, rs4433172, p=4.1×10−5) and 1 in sorting nexin 31 (SNX31) (rs1609, p=8.2×10−5), also on chromosome 8q, which were also identified in our replication set (p=0.04 for CSMD1 SNPs and 0.01 for SNX31). CSMD1 is a very large gene of more than 2 Mb and the 610 array includes 1710 SNPs in this gene. However, the probability that we observe 3 SNPs replicated in this gene in a sample size of 56 by chance is only 0.0005. Additionally, 2 SNPs in the mediator of innate immunity, lymphocyte antigen 86 (LY86) (rs3827783, p=3.89×10−6, rs9502483, p=1.02×10−5), were identified in our discovery set. We evaluated the top 5 SNPs originally identified in the candidate gene studies and found that 4 were not present on the 610K arrays. The remaining one had a p-value of 0.17 but is in linkage dysequilibrium with another SNP in BMP6 (rs7450930), a rare variant, with a p-value of 2.5 × 10−5. CSMD1 inhibits the classical pathway of complement activation and complement-mediated hemolysis in rats. This is of interest in SCD because of recent data linking cell-free heme and immune modulation. These findings suggest that sickle cell disease patients with an elevated TRV have altered innate immunity and that sickle vasculopathy may be associated with dysregulation of inflammation. Disclosures: No relevant conflicts of interest to declare.

Download Full-text