Association between cholesterol efflux capacity and peripheral artery disease in coronary heart disease patients with and without type 2 diabetes: from the CORDIOPREV study

Elena M Yubero-Serrano, Juan F Alcalá-Diaz, Francisco M Gutierrez-Mariscal, Antonio P Arenas-de Larriva, Patricia J Peña-Orihuela, Ruth Blanco-Rojo, Javier Martinez-Botas, Jose D Torres-Peña, Pablo Perez-Martinez, Jose M Ordovas, Javier Delgado-Lista, Diego Gómez-Coronado, Jose Lopez-Miranda, Elena M Yubero-Serrano, Juan F Alcalá-Diaz, Francisco M Gutierrez-Mariscal, Antonio P Arenas-de Larriva, Patricia J Peña-Orihuela, Ruth Blanco-Rojo, Javier Martinez-Botas, Jose D Torres-Peña, Pablo Perez-Martinez, Jose M Ordovas, Javier Delgado-Lista, Diego Gómez-Coronado, Jose Lopez-Miranda

Abstract

Background: Peripheral artery disease (PAD) is recognized as a significant predictor of mortality and adverse cardiovascular outcomes in patients with coronary heart disease (CHD). In fact, coexisting PAD and CHD is strongly associated with a greater coronary event recurrence compared with either one of them alone. High-density lipoprotein (HDL)-mediated cholesterol efflux capacity (CEC) is found to be inversely associated with an increased risk of incident CHD. However, this association is not established in patients with PAD in the context of secondary prevention. In this sense, our main aim was to evaluate the association between CEC and PAD in patients with CHD and whether the concurrent presence of PAD and T2DM influences this association.

Methods: CHD patients (n = 1002) from the CORDIOPREV study were classified according to the presence or absence of PAD (ankle-brachial index, ABI ≤ 0.9 and ABI > 0.9 and < 1.4, respectively) and T2DM status. CEC was quantified by incubation of cholesterol-loaded THP-1 cells with the participants' apoB-depleted plasma was performed.

Results: The presence of PAD determined low CEC in non-T2DM and newly-diagnosed T2DM patients. Coexisting PAD and newly-diagnosed T2DM provided and additive effect providing an impaired CEC compared to non-T2DM patients with PAD. In established T2DM patients, the presence of PAD did not determine differences in CEC, compared to those without PAD, which may be restored by glucose-lowering treatment.

Conclusions: Our findings suggest an inverse relationship between CEC and PAD in CHD patients. These results support the importance of identifying underlying mechanisms of PAD, in the context of secondary prevention, that provide potential therapeutic targets, that is the case of CEC, and establishing strategies to prevent or reduce the high risk of cardiovascular events of these patients. Trial registration https://ichgcp.net/clinical-trials-registry/NCT00924937 . Unique Identifier: NCT00924937.

Keywords: Cholesterol efflux capacity; Coronary heart disease; Peripheral artery disease; Secondary prevention; Type 2 diabetes mellitus.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Cholesterol efflux capacity in patients with CHD. A) According to the presence or absence of PAD and B) According to the presence or absence of PAD and diabetes status * Significant differences between PAD and no PAD in each diabetes status s group. Different common letter superscripts denote significant differences among non-T2DM, newly-diagnosed T2DM and established T2DM. p1, effect of presence or absence of PAD; p2, effect of diabetes status; p3, interaction between presence of absence of PAD and diabetes status. CHD, coronary heart disease; PAD, peripheral artery disease; T2DM, type 2 diabetes mellitus Analyses were adjusted age, smoking habit, hypertension, eGFR, and medications—glucose-lowering treatment, lipid-lowering therapy, and anti-hypertensive drugs
Fig. 2
Fig. 2
Multiple logistic regression analysis for the presence of PAD in patients with CHD. Squares denote hazard ratios; horizontal lines represent 95% confidence intervals. R2 = 0.201, constant = − 4.493 (p = 0.000). Predictive variables tested by backward (conditional) method: age (years), diabetes status (non-T2DM, newly-diagnosed T2DM and established T2DM), HbA1c (%), Fasting glucose (mg/dL), hypertension, HDL-cholesterol (mg/dL), Triglycerides (mg/dL), Cholesterol efflux (%), hsCRP (mg/mL), eGFR (mL/min/1.73 m2), oral antidiabetics use (%) and lipid-lowering therapy (%). HbA1c (%), Fasting glucose (mg/dL), HDL-cholesterol (mg/dL), eGFR (mL/min/1.73 m2), oral antidiabetics use (%), lipid-lowering therapy (%) have been eliminated from the model (p > 0.05). CHD, cardiovascular heart disease; T2DM, type2 diabetes mellitus; hsCRP, high sensitive C-reactive protein; eGFR, estimated glomerular filtration rate. HDL, high-density lipoprotein; HbA1c, glycated haemoglobin

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