Strong evidence is available to support the use of statins to reduce LDL levels and improve the outcomes of patients recovering from CABG [2–4]. Less is known, however, regarding the influence of HDL on the outcomes of patients after CABG. Previous research has suggested that a relationship exists between lower HDL levels and higher risk of atherosclerosis progression and adverse events following surgery [12–14]. Nevertheless, these studies were conducted in an earlier era, before the routine use of postoperative statins and antiplatelet agents. With a growing interest in the study of HDL therapies in the cardiology community [5, 7–9], we sought to evaluate the relevance of HDL levels on the process of SVG disease within a cohort of contemporary CABG patients who were treated aggressively with secondary preventative therapies.
In this exploratory analysis of the CASCADE trial, we assessed graft occlusion rates and vein intimal hyperplasia 12 months after CABG, comparing the degree of SVG disease between patients with low HDL levels to those with higher and more ideal levels. Using an established cut-off of increased risk (<40 mg/dL) [10, 11], we noted slightly more SVG occlusions amongst patients with HDL levels <40 mg/dL (6.8%) compared to those with HDL levels >40 mg/dL (4.0%), although statistical significance was not seen (P = 0.54). After adjustment in multivariate analysis, HDL level <40 mg/dL was associated with a trend towards more SVG occlusions (OR: 3.2; P = 0.12). Lower HDL level was also associated with a trend towards more intimal hyperplasia on IVUS. Interestingly, patients with ideal levels of HDL >60 mg/dL had the least amount of intimal hyperplasia, significantly less compared to the rest of the cohort (P = 0.01).
Lower levels of HDL are well-known to be associated with worse clinical outcomes amongst CAD patients [5, 6, 10, 11]. Some of the earliest data on the subject became available from the Framingham Heart Study, whereby low HDL was found to be a more potent CAD risk factor than high LDL . Recent studies from the current era have shown that HDL levels are inversely related to cardiovascular events, even amongst patients receiving statin therapy and those with LDL levels aggressively treated to <70 mg/dL [5, 11]. In addition, moderate increases in HDL appear to be associated with regression of coronary atherosclerosis .
Given the risk for adverse events that remains despite statin treatment [5, 6], several research groups have focused their attention on the evaluation of therapies to increase HDL and thereby improve clinical outcomes in patents already treated with preventative medications [7–9, 18]. A number of pharmacological interventions have been shown to improve HDL levels in clinical trials, including niacin [7, 8], gemfibrozil , bezafibrate , fenofibrate , and torcetrapib . While some studies have demonstrated modest biological effects, such as the reduction of either carotid artery intimal thickness  or angiographic CAD progression [14, 19, 20], the majority of the studies in the field have produced negative clinical results [7, 18]. Casting doubt on the HDL theory, no therapy to date has been shown to increase HDL levels and improve outcomes in a clinical trial enrolling CAD patients already treated with statins [7, 18].
In contrast to the attention that HDL has captured in the cardiology community, few studies have evaluated the influence of HDL levels on the outcomes of patients following cardiac surgery. Previous work from the Cleveland Clinic has demonstrated associations between lower HDL and both worse long-term survival and higher risk of adverse events after CABG [12, 13]. In the only prospective randomized study in the field, the Lopid Coronary Angiography Trial (LOCAT) enrolled 395 men with HDL levels <42.5 mg/dL who had undergone CABG on average 2 years earlier. From an era prior to the routine use of statins after CABG, patients were randomized to receive either slow-release gemfibrozil 1200 mg per day or matching placebo. Coronary angiography was performed at baseline and after a mean of 32 months of therapy. Gemfibrozil therapy led to significant increases in HDL levels (P < 0.001) and slowed the progression of native CAD (P = 0.009). Moreover, gemfibrozil significantly reduced the risk of developing new lesions in bypass grafts on follow-up angiography (2% versus 14%, gemfibrozil versus placebo, P < 0.001) . Despite the notable results of LOCAT, gemfibrozil never became incorporated into the routine care of CABG patients. This is likely a reflection of the impressive data published that same year promoting the use of statins after CABG , as well as the high risk of side effects associated with gemfibrozil when combined with statin therapy .
Similar to LOCAT, our exploratory study provides support, albeit modest, to the concept that low HDL levels negatively influence the outcomes of patients following CABG. Whereas the current study focused on the process of SVG disease within the first postoperative year, LOCAT patients were enrolled years after surgery, when many had already developed SVG disease at the time of the baseline angiography. We were limited by a smaller sample size and shorter follow-up period in our study, but we found that a relationship existed between HDL levels and SVG disease using both conventional angiography as well as using more sophisticated graft imaging with IVUS. We believe our data highlights the relevance of HDL as a factor influencing the development of SVG disease, even in the current era when nearly all patients receive antiplatelet and statin therapies after surgery.
Multiple mechanisms may explain the link between HDL and the development of SVG disease. HDL particles reduce LDL oxidation and reverse cholesterol transport, promoting cholesterol efflux from macrophages and preventing foam cell development in a vessel wall [6, 8]. Moreover, higher levels of HDL are profoundly anti-atherogenic and may favorably impact graft patency by preventing a procoagulant milieu [1, 6]. Independent from their involvement in cholesterol metabolism, HDL also improves endothelial function and promotes endothelial repair . By reducing vascular inflammation and thrombosis , it is possible that higher levels of HDL particles may slow the process of SVG disease, ultimately decreasing the risk of adverse outcome following surgery. Regardless of the exact mechanism of action, the biological signal demonstrated in this analysis highlights the need for further research in this area. The modulation of HDL with medical therapy may represent a valuable future strategy for the prevention of SVG disease after CABG.
The current study is the first to date to evaluate the impact of HDL levels on graft occlusion rates and vein intimal hyperplasia early after CABG. Nevertheless, the results presented must be interpreted within the context of several limitations. The CASCADE Trial was designed to assess the impact of antiplatelet therapy on the process of SVG disease 12 months after surgery . Patients were not randomized to different postoperative lipid modification strategies, as these decisions were left to the discretion of physicians who were following established clinical guidelines . Moreover, we acknowledge that the findings of this post-hoc analysis must be viewed as exploratory in nature. Given the modest results, we believe our findings are hypothesis-generating and require confirmation from future studies, perhaps with longer follow-up periods and larger sample sizes. Post-hoc power calculations revealed that we would have required more than 350 vein grafts in each group to have demonstrated a significant difference in the patency rate between patients who did or did not have HDL levels <40 mg/dL 12 months after surgery, assuming a statistical power of 50%.