Research Article: Role of the APOE polymorphism in carotid and lower limb revascularization: A prospective study from Southern Italy

Date Published: March 1, 2017

Publisher: Public Library of Science

Author(s): Sandra Mastroianno, Giuseppe Di Stolfo, Davide Seripa, Michele Antonio Pacilli, Giulia Paroni, Carlo Coli, Maria Urbano, Carmela d’Arienzo, Carolina Gravina, Domenico Rosario Potenza, Giovanni De Luca, Antonio Greco, Aldo Russo, Ornit Chiba-Falek.


Atherosclerosis is a complex multifactorial disease and the apolipoprotein E (APOE) polymorphism has been associated to vascular complications of atherosclerosis.

To investigate the relationship between the APOE genotypes and advanced peripheral vascular disease.

258 consecutive patients (201 males and 57 females, mean age 70.83 ± 7.89 years) with severe PVD were enrolled in a 42-months longitudinal study (mean 31.65 ± 21.11 months) for major adverse cardiovascular events. At follow-up genotypes of the APOE polymorphism were investigated in blinded fashion.

As compared with ε3/ε3, in ε4-carriers a significant higher incidence of major adverse cardiovascular events (35.58% vs. 20.79%; p = 0.025) and total peripheral revascularization (22.64% vs. 5.06%; p < 0.001) was observed. Prospective analysis, showed that ε4-carriers have an increased hazard ratio for major adverse cardiovascular events (adjusted HR 1.829, 95% CI 1.017–3.287; p = 0.044) and total peripheral revascularization (adjusted HR = 5.916, 95% CI 2.405–14.554, p <0.001). The ε4 allele seems to be risk factor for major adverse cardiovascular events, and in particular for total peripheral revascularization in patients with advanced atherosclerotic vascular disease.

Partial Text

Atherosclerosis and associated cardiovascular diseases (CVD) represent the major cause of death and comorbidities in Western and developing countries [1, 2]. The Global Burden of Disease Study estimated that about 32% of all deaths worldwide in 2013 were caused by CVD, with about 80% of these deaths occurring in low-and middle-income countries [3]. In 2011, CVD still had a significant social burden in the US with annual costs for disease treating estimated about US$320.1 billion [4, 5]. Some manifestations of CVD as stroke, heart attack, limb ischemia, peripheral revascularization or amputation, have a decisive weight on health-related quality of life and disability, for which the long-term care costs tend to exceed health spending [6].

Demographic and clinical characteristics of patients at baseline according to the APOE genotypes were reported in Table 1. In respect to ε3, we found ε2-patients significantly more obese (BMI 29.81 ± 2.52 Kg/m2 vs. 28.63 ± 4.13 Kg/m2; p = 0.046), have lower levels of 25-OH-Vit D (10.78 ± 6.45 ng/ml vs. 17.02 ± 14.08 ng/ml; p = 0.001), greater arterial stiffness as PWV (17.00 ± 3.60 m/sec vs. 14.45 ± 4.17 m/sec; p = 0.001), and an increased LVMI (89.69 ± 25.35 gr/m2 vs. 76.52 ± 19.80 gr/m2; p = 0.017). Statistical trend towards a greater waist-hip ratio (0.99 ± 0.06 vs. 0.96 ± 0.06; p = 0.053) and a lower level of LDL-Ch (81.80 ± 48.52 mg/dl vs. 96.28 ± 33.21 mg/dl; p = 0.050) were also observed. Even in respect to ε3, we found ε4-patients significantly less obese (BMI 27.23 ± 3.63 Kg/m2 vs. 28.63 ±4.13 Kg/m2; p = 0.029), and with minor inflammatory indexes as ESR (21.21 ± 13.02 mm/h vs. 26.66 ± 18.52 mm/h; p = 0.026) and hs-CRP (0.42 ± 0.35 mg/dl vs. 0.80 ± 2.69 mg/dl; p = 0.016). Statistical trend towards a minor level of fibrinogen (327.98 ± 68.37 mg/dl vs. 352.26 ± 78.68 mg/dl; p = 0.054) was also observed.

The present study analyzed the association of the APOE polymorphism with the incidence of cardiovascular events and death occurred in a short-term follow-up study of a cohort of 258 patients affected by advanced atherosclerosis. Our results showed that the ε4 allele seems to be risk factor for MACE, and in particular for total peripheral revascularizations in these patients.

In our cohort of patients at very high-risk of cardiovascular events the APOE4 may be used for a further prognostic stratification for MACE and peripheral revascularization, adding more information useful for individual residual risk determination. Prospectively, this finding would improve pharmacogenetics, leading to the “best marriage” between individualized medicine and health system cost-effectiveness. Clearly APOE polymorphisms represent just a brick in the Great Wall of atherosclerosis building, yet still having a definite weight in the physiopathology of this complex disease.




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