Haptoglobin phenotypes and coronary artery disease: unlocking a new marker for cardiovascular risk

Abstract Background Haptoglobin (HP) is a plasma protein that prevents iron-mediated oxidative tissue damage. Some HP isoforms (i.e., Hp 2-2) have been previously related to a reduced anti-oxidant activity and therefore to unfavourable evolution of myocardial infarction and to higher risk of CAD. Purpose The present study aimed to evaluate the possible associations between HP phenotypes and CAD severity. In particular, we explored the possibility that HP 2-2 isoform could act as a novel cardiovascular risk factor and could therefore help in CAD risk stratification. Methods We prospectively enrolled 150 consecutive patients with unknown coronary anatomy (mean age 62±10.5 years; 59% men) with a clinical indication for CCTA. These patients simultaneously underwent HP phenotyping and CCTA at our Center. The risk factor-weighted clinical likelihood score of obstructive CAD (RF-CL score) proposed by the recent guidelines of the European Society of Cardiology (ESC) was calculated for each patient. Moreover, a complete qualitative and quantitative plaque analysis including pericoronary adipose tissue attenuation was performed by expert cardio-radiologist using a dedicated commercial post-processing software. Results Among the 150 patients of our cohort, we included the 113/150 patients (75%) who exhibited a CAD-RADS score 0 at CCTA. The population was subdivided in carriers of a high-risk HP isoform (Hp 2-2, 49 patients, defined as HR group) and carriers of intermediate-low risk HP isoforms (Hp 1.1 and 2-1, 64 patients defined as LR group). No statistically significant differences in terms of modifiable and non-modifiable cardiovascular risk factors and therapy were present between the two groups. CCTA characteristics of the two groups are depicted in Figure 1. Patients from the HR group showed a higher prevalence of obstructive CAD (defined as 50%, 37.5% vs 22.4% in the HR and LR group, respectively, p= 0.047) and, even more specifically, of LAD obstructive disease (33 vs 15%, in the HR and LR group, respectively, p=0.017) and a higher prevalence of high degree CAD-RADS scores (49% vs 24% of patients showing CAD-RADS 3-4 in the HR and LR group, respectively, p=0.009). Moreover, significantly more HR group patients showed qualitative high-risk plaque (HRP) features at CCTA (14 vs 3% in the HR and LR group, respectively, p=0.03). Multivariate analysis confirmed Hp 2-2 isoform as an independent predictor of obstructive CAD (OR: 5.09 95% confidence interval [CI: 1.0 to 25.89; p 0.049]) and of HRP feature presence (OR: 3.02 95% CI: 1.20 to 7.58; p 0.019) at CCTA (see Figure 2). Conclusion HP phenotype is an independent predictor of the presence of obstructive CAD and of HRP features at CCTA and shows additional predictive power on top of the most comprehensive clinical and risk factor weighted score proposed by the last ESC guidelines. Hp phenotyping will possibly be proposed as a new tool for personalized CAD risk stratification.