Protection Against Coronary Atherosclerosis in High Cardiovascular Risk Sickle Cell Disease Patients: A Beneficial Role of Intravascular Hemolysis?

Background: Sickle Cell Disease (SCD) is linked to various cardiac and systemic vascular disorders, which significantly contribute to both morbidity and mortality. Despite numerous cardiovascular (CV) risk factors, chronic inflammation and endothelial dysfunction, pre-clinical studies suggest a paradoxical protection against atherosclerosis in this population.

Purpose: This study aimed to assess the prevalence of coronary artery disease in homozygous sickle cell disease (SCD) patients - also known as sickle cell anemia (SCA) – at high CV risk, to further identify potential determinants or protective factors.

Methods: From January 2019 to December 2023, consecutive adult patients with SCD were prospectively included in the DREPACOEUR registry at Henri Mondor hospital (Créteil, France), to specifically analyze cardiac structure and function. They all had a comprehensive CV evaluation at steady-state in daycare hospital including clinical exam, cardiac imaging, rhythm monitoring along with biological analysis. For the present study, only SCA patients that underwent coronary imaging (computed tomography (CT) coronary angiogram) were included. Coronary artery disease was defined using coronary calcium score (CS) and CT coronary angiogram score for coronary artery disease (CAD-RADS). For the reader’s information, a CAD-RADS=0 stands for no coronary stenosis while a score >2 refers to a stenosis above 50% and ≥4 to a severe stenosis justifying functional assessment, medical therapy and possibly coronary revascularization. A sample of DREPACOEUR population was then age-matched to a non-SCD population from the same center. Control patients were prospectively enrolled, they had low CV risk, controlled CV risk factors, no type 2 diabetes and no history of coronary artery disease. The entire control cohort underwent CT coronary angiogram using the same equipment, during the same timeframe and with identical acquisition protocol.

Results: Overall, 113 SCA (SS or Sβ0) patients from DREPACOEUR were included. Mean age was 44±12, 48% were male with a high prevalence of systemic hypertension (57%), obstructive sleep apnea (21%) and 12% active smokers. Only one patient had a history of diabetes, and no dyslipidemia (or lipid lowering therapy) was reported. Heart function was mainly preserved with a mean left ventricular ejection fraction (LVEF) of 58±6%. Expectedly, patients displayed low hemoglobin level 8,7±1.4g/dL with high hemolysis markers. Glomerular filtration rate was 109 [62; 122] mL/min/m² with 21% showing chronic kidney disease. Plasmatic LDLc level was surprisingly low (0.7±0.3g/L, with 20% <0.5g/l). Strikingly, no patient showed signs of significant coronary artery disease, with 87% presenting a calcium CS of 0, 77% had CAD-RADS of 0 while no patient was higher than 2 (i.e. coronary stenosis >50%).

Comparison of a subgroup of this cohort with an age-matched non-SCD population (n=62 vs. 82, mean age of 52 years) showed a more extended coronary atherosclerosis in the control group (CS=0 for 77% vs. 52%, p=0.002; CAD-RADS ≥2 for 9 vs. 23%, p=0.02). Coronary angioplasty following CT-scan was performed in 6% of the control group vs. 0% of SCA patients (p=0.046). Multivariate analysis showed that SCA patients were more likely to have systemic hypertension and chronic kidney disease, while the control group showed more obesity (28±5 vs. 24±5kg/m² of BMI) and treated dyslipidemia.

These results prompted us to further explore the determinants of such low LDLc among the DREPACOEUR cohort (n=113). Multivariate linear regression revealed that Age, BMI and total Bilirubin were independently associated with LDLc. Interestingly, only Bilirubin was negatively associated with LDLc (r=-0.35, p<0.001).

Conclusion: Despite multiple CV risk factors, systemic vasculopathy and chronic inflammation, ageing SCA population showed no significant coronary artery disease. These findings align with preclinical studies that suggest bilirubin's lipid-lowering role and its protective effect against atherosclerosis. Furthermore, this study initiates a crucial discussion on the potential impact of hemolysis reduction therapy on atherosclerosis development in SCA patients. Ultimately, these data open new avenues in coronary artery disease pathophysiology understanding, extending far beyond sickle cell disease.