CANHEART: Is HDL cholesterol a cardiovascular specific risk factor?

Initial observational studies have identified high-density lipoprotein cholesterol (HDL-C) as an independent predictor of cardiovascular (CV) risk, even in patients on optimal statin therapy. However, the notion that higher HDL-C is better, has been seriously challenged by the results from several recent clinical and genetic trials. Data from the CANHEART study serve to clarify the relation between HDL-C and cause-specific mortality. Individuals with lower HDL-C levels were independently associated with higher risk of CV, cancer, and non-CV/non-cancer mortality compared with individuals in the reference ranges of HDL-C levels. Given the similarities in associations between HDL-C and CV as swell as non-CV outcomes, it is likely that HDL-C level serve as a marker of risk rather than a causal CV specific risk factor.


INTRODUCTION
HDL particles have several biological functions (Fig. 1), the most important is the ability of HDL to promotes cellular cholesterol efflux and drive the process of reverse cholesterol transport from lipid laden macrophages. Initial observational studies have identified high density lipoprotein cholesterol (HDL-C) as an independent predictor of cardiovascular (CV) risk, even in patients on optimal statin therapy [2][3][4][5] . A linear inverse relation has been reported between plasma HDL-C level and incident coronary heart disease (CHD) events, with a plateau effect at HDL-C values >90 mg/dL in men and 75 mg/dL in women 2 . A 1-mg/dl increment in plasma HDL-C level was associated with 2-3% decrement in CHD risk, and 3.7-4.7% decrement in CV mortality rates 3 .
The notion that higher HDL-C is better, has been seriously challenged by the results from several recent clinical trials [6][7][8] . In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITIR) trial cohort, HDL-C concentrations were not predictive of residual CV risk among patients treated with rosuvastatin therapy who attain very low concentrations of LDL-C 9 . Silbernagel et al. have also reported a strong association between plasma HDL-C levels and CV mortality in people without coronary artery disease (CAD), but not in patients with stable or unstable CAD 6 . In addition, higher HDL-C levels were not associated with reduced risk of vascular events in CAD patients undergoing CABG 7 . Table 1 summarizes most of the studies that examined the relation between HDL-C, CV risk, and mortality.
Recent genetic Mendelian randomization studies have also questioned the causality of inverse relationship between HDL-C and CHD risk while reaffirming the relationship of LDL-C levels and CHD risk 8 . Carriers of the endothelial lipase gene (LIPG) 396Ser allele (2.6% frequency, and have high plasma HDL-C levels) were expected to decrease the risk of myocardial infarction (MI) by 13% (odds ratio [OR] = 0.87, 95% confidence interval (CI) = 0.84-0.91), however no decrease in the risk of MI was detected in 396Ser allele carriers (OR = 0.99, 95% CI 0.88-1.11, p = 0.85) 8 . Furthermore, a 1 standard deviation (SD) increase in HDL-C due to genetic score was not associated with significant decrease in the risk of MI (OR = 0.93, 95% CI = 0.68-1.26, p = 0.63), which is discordant with that estimated from observational epidemiology (OR 0.62, 95% CI 0.58-0.66) 8 . In contrast,  Pre-operative higher HDL-C levels were not associated with reduced but rather increased MACE occurrence during follow-up.
(continued on next page)  9 17,802 JUPITIR trial HDL-C concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who attain very low concentrations of LDL-C. a 1 SD increase in LDL-C due to genetic score was associated with significant decrease in the risk of MI (OR = 2.13, 95% CI = 1.69-2.69, p = 2 × 10 −10 ) 8 , which is concordant with that estimated from observational epidemiology (OR = 1.54, 95% CI = 1.45-1.63) 10 . The string of failures for HDL therapies confirms the results obtained from observational and genetic studies. All existing HDL-C boosting drugs by inhibiting cholesteryl ester transfer protein (CETP), or by using extended release niacin consistently failed to have an impact on clinical outcomes in several large randomized clinical trials [13][14][15][16] . Data from the CANHEART study serves to clarify the relation between HDL-C and cause specific mortality.

CANHEART STUDY
The Cardiovascular Health in Ambulatory Care Research Team (CANHEART) study was an observational cohort study that was conducted by merging 17 different individuallevel data sources. The essential data sources for this study included: (1)  The study has been published recently in the Journal of the American College of Cardiology in November 2016 17 . The primary outcome for the study was cause-specific mortality. The cause of death was identified to be CV, cancer, or non-CV/non-cancer. A total of 631,762 individuals with a mean age of 57.2 years were included. The all-cause mortality rate was 8.1 per 1,000 person-years for men, and 6.6 per 1,000 person-years for women during a mean follow up of 4.9 ± 0.4 years. Individuals with lower HDL-C levels were more likely to have low incomes, unhealthy lifestyle, and higher triglycerides levels.

DISCUSSION
HDL particles have several protective anti-atherosclerotic properties, including the ability to mediate macrophage cholesterol efflux, antioxidant and anti-inflammatory properties, and nitric oxide promoting activity 1 . However, It is unclear whether HDL-C concentration plays a causal role in protecting against atherosclerosis. CAD may modulate the association of HDL-C with CV mortality 6 . It seems that once LDL-C is well controlled, HDL-C may be less relevant for risk assessment and risk mitigation. These findings are in keeping with the analysis of the JUPITIR trial 9 , but contradict findings from the TNT trial 5 . This could also explain the negative results of raising HDL-C with niacin or dalcetrapib in patients pre-treated with high intensity statin therapy [13][14][15][16] .
In contrast to the results of four prospective American studies that showed no significant effect of HDL-C level on non-CV mortality 3 , the CANHEART study demonstrated higher non-CV mortality in Individuals with HDL-C level ≤30 mg/dl compared to those with higher HDL-C levels. Given the similarities in associations between HDL-C and CV as well as non-CV outcomes, it is not likely that HDL-C level represents a CV-specific risk factor.
HDL-C level may not be a reliable indicator of vascular protective function of HDL. HDL particles are very complex and heterogeneous in composition and function. Moreover, the composition and function of HDLs might have been altered in patients with established CV disease. It has been reported recently that Low HDL 3 cholesterol, but not HDL 2 cholesterol, is associated with increased risk of death and MI 13 . Indeed, changes in HDL-C levels may not reflect changes in the physiologic functions of HDLs 14 . High HDL-C efflux capacity ''the ability of HDL to accept cholesterol from macrophages'', but not HDL-C level, has been associated with a significant reduction in CV risk 12 . Furthermore, measuring HDL particle numbers and small pre-beta HDL (lipid-poor particles considered to be the major acceptors of free cholesterol from macrophages has been suggested to be a better indicator of the association between HDL and CHD risk 18 . Acute and chronic inflammatory states may render HDL depleted of atheroprotective molecules such as Apo A-1, paraoxonase (PON), clusterin (Apo J), and sphingosine 1 phosphate (S1P), and enriched in pro-inflammatory pro-atherogenic molecules such as serum amyloid A (SAA), haemoglobin-haemopexin complex, caeruloplasmin, symmetrical dimethylarginine (SMDA), and, importantly, Apo CIII, making the HDL particles more pro-oxidant and pro-inflammatory (so-called dysfunctional HDL) (Fig. 3) [19][20][21] . Indeed, the failure of the CETP torcetrapib, while often attributed to activation of the aldosterone pathway, may also have resulted from production of dysfunctional HDL 22 . The two new CETP inhibitors, evacetrapib and anacetrapib, that produce larger increases in HDL-C (>100%) and reductions (>20%) in LDL-C and do not Figure 3. Changes in the composition of HDL in various conditions could result in non-functional or dysfunctional HDL which loses vascular protective effects or create a superfunctional HDL containing a mutant of Apo A-1. CAD, coronary artery disease; Hgb, haemo-globin; MPO, myeloperoxidase; RA, rheumatoid arthritis; SAA, serum amyloid A; SLE, systemic lupus erythematosus; SMDA, symmetric dimethy-larginine; S1P, sphingosine 1 phosphate. Adapted from [1].