Lack of protective role of HDL-C in patients with coronary artery disease undergoing elective coronary artery bypass grafting.

Angeloni E, Paneni F, Landmesser U et al.
Eur Heart J. 2013 May 22.

Background

Although low HDL-C levels are an independent predictor of cardiovascular (CV) risk [1], recent translational studies strongly suggest that vascular effects of HDL-C can be highly heterogeneous in different clinical conditions [2,3]. HDL-C isolated from patients with coronary artery disease (CAD) showed less anti-inflammatory activity than HDL-C obtained from healthy controls. Also the capacity of HDL-C to stimulate endothelial NO production and endothelial repair was reduced in the case of CAD and diabetes. The term ‘dysfunctional HDL-C’ indicates the loss of its anti-inflammatory and vasoprotective effects [4].
Since therapies aimed to raise HDL-C levels are being investigated for the treatment of CAD patients, it is urgent to assess whether an increase in dysfunctional HDL-C is less beneficial than expected or even detrimental. The present prospective study therefore evaluates the protective effect of HDL-C in a large cohort of CAD patients undergoing elective coronary artery bypass grafting (CABG). Propensity matching yielded two cohorts of 502 patients each, with high (group A) or low (group B) pre-operative HDL-C.

Main results

• After a median follow-up time of 32 months, 44 out of 502 (8.8%) of patients with high HDL-C had died, as opposed to 36 deaths in the low HDL-C group  (HR: 1.19, P=0.42).
• Incidence of major adverse cardiac events (MACE) was 165 out of 502 (32.9%) in group A and 120 out of 502 (23.9%) in group B (P=0.04). Kaplan-Meier analysis confirmed the difference between the two groups (HR: 1.32, P=0.017, for freedom from MACE at 3 years: 57.0 +2.8% for group A vs. 67.9% +2.6% for group B).
• Pre-operative HDL-C levels were non-statistically significantly correlated to mortality (HR: 1.33, P=0.13, Cox proportional-hazards regression model). Age, diabetes, chronic obstructive pulmonary disease and pre-operative renal dysfunction were significantly and independently correlated to survival.
• Pre-operative HDL-C levels had a negative effect on the occurrence of MACE, although this effect did not reach statistical significance (HR: 1.43, P=0.11, Cox proportional-hazards regression model). Age, diabetes, pre-operative LV dysfunction and pre-operative stroke were independently correlated to MACE-free survival.
• In univariate analysis in the total cohort, HDL-C was not significantly associated with mortality or MACE (β=0.06, 95%CI: -0.11 - 0.27, P=0.24), while other common risk factors were.

Conclusion

Recent translational studies have challenged the inverse predictive role of HDL-C on CV events. Indeed, this study shows the lack of a protective effect of HDL-C in CAD patients undergoing isolated first-time elective CABG, and tendencies towards correlations between HDL-C levels and mortality and MACE. Higher HDL-C levels were not associated with a reduced CV risk in patients with CAD, suggesting that in these patients HDL-C functionality is impaired. Improving HDL-C function rather than increasing its levels may be a more promising therapeutic strategy.

References

1. Arsenault BJ, Barter P, DeMicco DA et al. Prediction of cardiovascular events in statin-treated stable coronary patients by lipid and nonlipid biomarkers. J Am Coll Cardiol 2011;57:63–69.
2. Ansell BJ, Navab M, Hama S, et al. Inflammatory/anti-inflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 2003;108:2751–2756.
3. Besler C, Heinrich K, Rohrer L et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 2011;121:2693–2708.
4. Besler C, Luscher TF, Landmesser U. Molecular mechanisms of vascular effects of High-density lipoprotein: alterations in cardiovascular disease. EMBO Mol Med 2012;4:251–268.

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