Cardiovascular biomarkers in sickle cell disease− clinical and echocardiographic correlations in a cross-sectional study with 126 patients

INTRODUCTION: Cardiac biomarkers can be useful in understanding the systemic and heart manifestations of sickle cell disease (SCD). Biomarkers reflect various aspects of heart disease (remodeling, injury and myocardial strain), with discriminatory potential for non-cardiac complications. Patients and METHODS: SCD patients (SS/Sß0) in steady state, were studied, correlating clinical manifestations and echo parameters (myocardial work - MW and speckle tracking), pre-MSCD severity score (integrating clinical and echo data), and cardiac biomarkers (high-sensitivity troponins ­ hs-cTn I and T, NT-pro-BNP, ST2s, and galectin-3 - GAL3). Quantitative characteristics were analyzed by Spearman tests, and qualitative characteristics by Mann-Whitney test. Hemolytic Index (HI) was calculated through Principal Component Analysis. Generalized linear Poisson models were generated for hs-cTn, and γ-distribution models were employed for other markers, with final models selected through the Stepwise Backward method. RESULTS: We studied 126 patients (mean age 37.2 ± 11.6 years), 42.1% male, and 80.2% SS. 47% were on hydroxyurea treatment and 30.2% on a chronic transfusion. NT-pro-BNP was elevated in 44% (> 160 ng/mL in 37%), correlated with female gender (p < 0.001), severity score (p = 0.001), uric acid (p = 0.017), HI (p < 0.001), Global Work Index (GWI) (p = 0.003), left atrial (LA) stiffness (p = 0.003), and ventricular mass (VM) (p = 0.02). ST2s were elevated in 11% and correlated with male gender (p > 0.001), HI (p > 0.001), cardiac index (p = 0.015), and LA strain reservoir function (p = 0.034). GAL3 was elevated in 42.8%, correlated with E/e'ratio (p = 0.006), uric acid (p = 0.005), and absence of chronic pain (p = 0.046). hs-cTn correlated with age (c-TnI p = 0.004; c-TnT p > 0.001), HI (p > 0.001), diastolic dysfunction (p > 0.001), left VM (p < 0.001), increased GWI (p < 0.001), and reduced MW efficiency (p < 0.001). hs-cTn I also correlated with increased LA reservoir function (p < 0.001) with reduced conduit function (p < 0.001). hs-cTn T correlated with uric acid (p = 0.001), and in univariate analysis was also correlated with severity score. The values of both hs-cTn correlated with increased GWI (p < 0.001) and reduced MW efficiency (p < 0.001). DISCUSSION: The biomarkers demonstrated various clinical and pathophysiological aspects of SCD. NT-pro-BNP is a routine marker with correlations similar to literature, except for higher values in females, also observed in non-SCD population. ST2 and GAL3 had limited correlations with echo findings, likely due to their production in extracardiac tissues affected by inflammation/vaso-occlusion. Both were linked to the HI, and the decrease in GAL3 in chronic pain can be attributed to chronic opioid use causing reduced synthesis of it. The elevation of hs-cTn was expected due to the analytical characteristics of high-sensitivity assays, but low in terms of the extent of heart involvement. hs-cTnT was more associated with general severity, like in the general population, where it is associated with overall mortality, while hs-cTnI is more connected to heart disease. MW in SCD is optimized to the maximum with a very low Global Work Wasted, and hs-cTn elevation is associated with reduced MW efficiency, indicating mecano-energetic uncoupling and subtle systolic dysfunction. CONCLUSION: Our study demonstrates that cardiac biomarkers can be used for clinical and pathophysiological evaluation, with NT-pro-BNP confirming its role in clinical stratification. ST2s and GAL3 may reveal new pathophysiological pathways in hemolysis and the interaction of opioids and chronic pain. Troponins are promising as prospective tool and may unveil ischemic damage resulting from myocardial mecano-energetic dissociation.

Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease.

Recent studies have recognised the importance of pulmonary hypertension (PH) in sickle cell disease (SCD). The aim of this study was to determine the prevalence and prognostic impact of PH and its features in patients with SCD. 80 patients with SCD underwent baseline clinical evaluation, laboratory testing, 6-min walk tests (6MWTs) and echocardiography. Patients with a peak tricuspid regurgitant jet velocity (TRV) of ≥ 2.5 m·s(-1) were further evaluated through right heart catheterisation (RHC) to assure the diagnosis of PH. Our study evidenced a 40% prevalence of patients with elevated TRV at echocardiography. RHC (performed in 25 out of 32 patients) confirmed PH in 10% (95% CI 3.4-16.5%) of all patients, with a prevalence of post-capillary PH of 6.25% (95% CI 0.95-11.55%) and pre-capillary PH of 3.75% (95% CI -0.4-7.9%). Patients with PH were older, had worse performance in 6MWTs, and more pronounced anaemia, haemolysis and renal dysfunction. Survival was shorter in patients with PH. Our study reinforced the use of echocardiography as a screening tool for PH in SCD and the mandatory role of RHC for proper diagnosis. Our findings confirmed the prognostic significance of PH in SCD as its association to pronounced haemolytic profile.

Polymorphism of the human platelet antigen-5 system is a risk factor for occlusive vascular complications in patients with sickle cell anemia.

BACKGROUND: Polymorphisms of platelet membrane glycoproteins such as human platelet antigen (HPA)-1b, HPA-2b, the -5T/C Kozak sequence and C807T have been described as risk factors for vascular disease. Vaso-occlusion episodes are a common feature of sickle cell anaemia (SCA), leading to complications such as stroke, acute chest syndrome, avascular head femur necrosis and priapism. Complex interactions are involved in vaso-occlusion, and activated platelets may play an important role. These data raised the question of whether platelet polymorphisms could be implicated in occlusive vascular complications (OVC) of SCA. MATERIALS AND METHODS: In this study, 97 patients with SCA were analysed in two groups: 34 patients presenting with OVC (SCA-VC) and 63 without these complications (SCA-N). The distribution of the HPA-1, -2 and -5 systems, as well as C807T dimorphism and -5T/C Kozak sequence alleles, was evaluated using DNA-based methods. RESULTS: Patients of the SCA-VC group showed a higher frequency of the HPA-5b allele (0.324) compared with those of the SCA-N group (0.111) (chi2 = 13.19, P = 0.0002). None of the other polymorphisms, isolated or associated as haplotypes, demonstrated any correlation with the development of OVC in these patients. CONCLUSIONS: The findings of this study suggest that the HPA-5b allele is a genetic risk factor for the development of OVC in patients with SCA. This allele could be explored as a target for the development of new therapeutic approaches.