Featured Commentary

Issue No. 2, 2013

HDL function and cardiovascular risk: debate continues…

Measurement of high-density lipoprotein (HDL) cholesterol is highly relevant in the context of estimating global cardiovascular risk based on SCORE.1 Based on animal models showing that HDL have a number of properties that are potentially atheroprotective, it has been suggested that assessment of HDL function may offer advantages over measurement of plasma concentration of HDL cholesterol. However, given the complexity of HDL biology, there are still uncertainties about what assays of HDL function represent.

The ability of HDL to promote cholesterol efflux from cells, including lipid-laden macrophages in the arterial wall, is the best known of the potentially atheroprotective effects of HDL, and is therefore a logical focus for study. Recent work has shown cholesterol efflux capacity to be inversely associated with prevalent coronary artery disease (CAD), independent of HDL cholesterol concentration. Each 1-standard deviation increase in cholesterol efflux capacity was associated with 30% decrease (95% CI 17-41%) in risk of prevalent CAD (p<0.001).2 However, a recent report questions whether cholesterol efflux capacity is predictive for risk of cardiovascular events.3

This study aimed to confirm previous findings of the relationship between cholesterol efflux capacity and prevalent coronary artery disease (CAD). Another important objective of the study was to provide information about the potential association between cholesterol efflux capacity and risk of incident major cardiovascular events (death, myocardial infarction and stroke). Thus, the study aimed to bridge a gap in knowledge about the clinical relevance of cholesterol efflux capacity as a prognostic indicator of cardiovascular risk.

The investigators measured cholesterol efflux capacity from free cholesterol-enriched macrophages to apolipoprotein B (apoB)-depleted serum as the cholesterol acceptor, in two case-control cohorts: one cohort (A) included subjects with stable CAD undergoing elective coronary angiography (871 with angiographic CAD versus 279 controls), and the second (B) included an outpatient cohort (146 with CAD versus 431 controls). As anticipated, the prevalence of diabetes, hypertension, smoking and obesity was higher in subjects with CAD than in controls. Additionally, in each cohort, subjects with CAD had lower plasma HDL cholesterol concentration than controls (median 33 mg/dL versus 39 mg/dL in Cohort A, and 44 mg/dL versus 53 mg/dL in cohort B).

In each cohort, ATP-binding cassette transporter A1 (ABCA1)-stimulated cholesterol efflux capacity was inversely associated with prevalent CAD (Table 1). Adjustment for conventional cardiovascular risk factors attenuated this association in cohort A but not in cohort B. Thus, subjects with the highest cholesterol efflux capacity had the lowest risk of prevalent CAD, consistent with previous findings.2

Table 1. Association between cholesterol efflux capacity and risk of prevalent CAD
 Cohort

   Unadjusted odds ratio (95% CI)*  
 
 p-value  
A (angiographic CAD versus control) 
0,60 (0.42-0.85)
<0,01
B (outpatients with CAD versus control)
0,11 (0.06-0.20) <0,01
*comparing tertiles with the lowest versus highest cholesterol efflux capacity

In contrast, the reverse was shown for the association between cholesterol efflux capacity and incident risk of major cardiovascular events over 3 years. In cohort A, subjects with the highest cholesterol efflux capacity also had the highest risk (unadjusted hazard ratio 1.66, 95% CI 1.07-2.58, p<0.05 versus subjects in the lowest tertile). Furthermore, this association was strengthened after adjustment for conventional cardiovascular risk factors (hazard ratio 1.85, 95% CI 1.11-3.06, p<0.05). There were also issues as to what this assay was measuring, as most of the radiolabelled cholesterol from macrophages was not detected in HDL particles, although 75% did interact with apoA-I as the cholesterol acceptor.

The authors of this report suggest that their paradoxical findings might relate to the ABCA1-dependent cholesterol efflux pathway. Lipid-poor pre-beta1 HDL particles are known to be primary acceptors of cholesterol from the ABCA1 transporter in macrophages.4,5 Previous studies report that ABCA1-dependent cholesterol efflux is correlated with the concentration of pre-beta HDL,6 and further, that pre-beta-HDL is positively correlated with coronary heart disease.7

HDL biology is still inadequately understood. The changing focus of HDL measurement, from HDL cholesterol to HDL function, is an evolving area. Additionally, it needs to be recognised that potentially atheroprotective properties of HDL are actually conferred by other molecules that HDL transports. Therefore, further understanding of HDL biology is clearly indicated before such assays can be used as a predictive tool for cardiovascular risk.

Key Points• This study reported a direct association between cholesterol efflux capacity and prospective risk of major cardiovascular events. This contrasts with evidence of an inverse association between cholesterol efflux capacity and prevalent CAD.

• These paradoxical findings underline the fact that HDL biology is complex and not fully understood. Further study is needed before such research tools can be adapted as prognostic markers in clinical trials or beyond.

Statin confers benefit across the spectrum of CKD

Chronic kidney disease (CKD) is a major public health problem. Individuals with CKD are known to be at high risk of cardiovascular events; independent of other risk factors, the risk of cardiovascular death is 2-4-fold higher in individuals with stage 4–5 CKD than the general population.8 Moreover, CKD has a substantial economic impact, highly relevant when resources for healthcare are increasingly finite. Diabetes is a key driver of end-stage renal disease; consequently, the escalation in diabetes prevalence will undoubtedly impact the socioeconomic cost of CKD.

Low-density lipoprotein (LDL) cholesterol lowering with a statin is recommended by guidelines as the cornerstone for dyslipidaemia management.1 However, there is uncertainty about the role of statin therapy in patients with severe CKD. This uncertainty is reflected by recent meta-analyses, with one concluding that benefit was confined to individuals with earlier stages of disease.9,10 There are also emerging data that the underlying pathology of cardiovascular disease may differ in individuals with and without severe CKD.11 Furthermore, trials in CKD patients have shown conflicting results.12-14

A recent meta-analysis15 of 31 randomised, controlled trials of 48,429 patients with CKD (mean age 42-73 years) treated with a statin (atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin and lovastatin) aimed to resolve this controversy. Ten of these trials (n=4,503) were solely in dialysis patients, 18 were in non-dialysis patients (n=33,252) and three included both dialysis and non-dialysis patients. The database included 6,690 major cardiovascular events and 6,653 deaths.

Overall, statin therapy was associated with a 23% (95% CI 15-30%) reduction in the risk of major cardiovascular events, comparable to risk reductions reported by the Cholesterol Treatment Trialists’ Collaboration.16 Consistent with findings in patients without CKD, there was greater reduction in risk with intensive versus less intensive regimens. The benefit of statin therapy was modified by renal function, with greater reduction in risk in individuals with less severe CKD than those with more severe disease (Table 2). In patients not receiving dialysis, there was a 27% (95% CI 17-35%, p<0.001) reduction in the risk of cardiovascular events per 1 mmol/L reduction in LDL cholesterol.

Similarly, statin therapy reduced the risk of major coronary events by 22% (95% CI 12-31%), cardiovascular mortality by 9% (95% CI 1-16%) and all-cause mortality by 8% (95% CI 1-15%).

There was no clear evidence that statin treatment reduced the risk of renal failure events, defined as a 25% reduction in estimated glomerular filtration rate, doubling of serum creatinine, or end-stage renal disease (relative risk 0.95, 95% CI 0.90-1.01).

Table 2. Effect of statin therapy according to CKD stage
 CKD stage

Statin-treated
No. with event/Total N  

 
Placebo
No. with event/Total N  

Relative risk (95% CI) of
major CV event
Stage 5 - dialysis
866/3639
934/3650
0.93 (0.86 -1.00) 
Stage 5 - no dialysis
67/614 81/607
0.82 (0.60-1.11) 
Stage 4 134/1263   179/1335 0.78 (0.63-0.96) 
Stage 2-3 504/6194   764/6211 0.69 (0.63-0.77) 

In conclusion, the results of this meta-analysis reaffirm the benefit of statin therapy across a broad spectrum of renal impairment. Kidney function was an important modifier of the benefit derived from statin therapy. Thus, consistent with previous analysis,10 the magnitude of benefit was lower in patients with the most severe disease (CKD stage 5 on dialysis treatment). Despite this, there were clinically meaningful reductions in cardiovascular events in every stage of renal disease. These findings therefore support guideline recommendations for statin therapy to reduce cardiovascular risk in patients with CKD. 1

Key Points• This meta-analysis reaffirms the value of LDL lowering with a statin as the cornerstone of dyslipidaemia management in CKD, as recommended by the joint European Society of Cardiology/European Atherosclerosis Society guidelines for dyslipidaemia management.

• Although renal function is a modifier of this benefit, there are clinically meaningful reductions in cardiovascular risk across the spectrum of renal dysfunction.

• Statin therapy had no benefit on renal events.

Lifestyle: potential benefit comparable to statins?

Current guidelines clearly focus on lifestyle as the important first step in preventing cardiovascular disease. Considering the evolution of atherosclerosis it is clearly more relevant to target intervention to an earlier pre-clinical stage rather than the later phase associated with clinical events. Optimal risk factor management from an early age would be expected to translate to reduction in life-time risk for cardiovascular events, as supported by evidence from a recent analysis.17

Recent data from the PREDIMED study18 indicates that in high-risk primary prevention patients, dietary intervention has important benefit. The study included 7,447 subjects (mean age ~67 years, 54-60% of each group female) with at least three major cardiovascular risk factors (smoking, hypertension, elevated LDL cholesterol, low HDL cholesterol, obesity or family history of premature coronary heart disease). These subjects were randomly allocated (1:1:1) to a Mediterranean diet supplemented with extra-virgin olive-oil (~1 litre per week), a Mediterranean diet supplemented with nuts (15 g of walnuts, 7.5 g of hazelnuts and 7.5 g of almonds) or a control diet. No advice on total calorie restriction, or physical activity was given. The study protocol was amended to allow for follow-up every 3 months in each group.

Subjects in the Mediterranean diet groups completed a self-report 14-item food frequency dietary questionnaire at each visit, and those in the control group completed a 9-point questionnaire. A general medical questionnaire, a 137-point food frequency questionnaire and The Minnesota Leisure Time Physical Activity Questionnaire were also completed by all individuals every year. Compliance was assessed by measurement of urinary hydroxytyrosol levels for the group receiving extra-virgin olive oil, and plasma alpha-linolenic acid for the group receiving nuts. Both intervention groups had good dietary adherence.

The primary endpoint was cardiovascular events, a composite of myocardial infarction (MI), stroke and cardiovascular death. After a median follow-up of 4.8 years, there was substantial reduction in the risk of cardiovascular events in subjects receiving a Mediterranean diet supplemented with extra-virgin olive oil (hazard ratio 0.70, 95% CI 0.54-0.92, p=0.01) or nuts (hazard ratio 0.72, 95% CI 0.54-0.96, p=0.03). This benefit was wholly due to significant reduction in stroke with no effect on coronary events or cardiovascular death (Table 3). When the Mediterranean dietary intervention groups were combined, there was a 29% reduction in risk of cardiovascular events compared with control (hazard ratio 0.71, 95% CI 0.56–0.90, p=0.005), with similar magnitude of benefit on stroke (hazard ratio 0.61 95% CI 0.44–0.86, p=0.005).

Table 3. Effect of Mediterranean diet on cardiovascular events
 Outcome
Control
Mediterranean diet +
extra-virgin olive oil
                    
Mediterranean diet +
nuts

                                
Adjusted HR
p-value
Adjusted HR
(95% CI)
p-value
Adjusted HR
(95% CI)
p-value
CV events
1 (reference)

0.70 (0.54-0.92)
0.01
0.72(0.54-0.96)
0.03
Stroke 1 (reference) 
0.67 (0.46-0.98)
0.04
 0.54 (0.35-0.84)
 0.006
MI 1 (reference) 
0.80 (0.51-1.26)
0.34
 0.74 (0.46-1.19)
 0.22
CV death
1 (reference)
0.69 (0.41-1.16)
0.17
 1.01 (0.61-1.66)
 0.98
All-cause death
1 (reference)    0.82 (0.64-1.07)
 0.15  0.97 (0.74-1.26)
 0.82
CV cardiovascular; HR hazard ratio; MI myocardial infarction;

These findings are consistent with other studies showing the benefit of a Mediterranean diet including olive oil19,20 or nuts21 in preventing cardiovascular disease, notably stroke.20 While intervention was intended to improve the overall dietary pattern, the main between-group differences related to the supplemental items. Thus, it is likely that extra-virgin olive oil and nuts were probably responsible for most of the observed benefits. Indeed, evidence from a substudy of PREDIMED indicates that the diet plus extra-virgin olive oil or nuts reduced oxidative damage to lipids in subjects with metabolic syndrome.22

The magnitude of the reduction in cardiovascular risk compares with that observed with statin therapy in high-risk individuals in a primary prevention setting.23 Thus, the findings from the PREDIMED study reinforce the value of dietary intervention, as part of a healthy lifestyle, as a core strategy for preventing cardiovascular disease. Thus, it is therefore worrying that there is suggestion from ongoing studies, such as the Moli-sani Project,24 that changing economic factors may have a detrimental effect on adoption of the Mediterranean diet.

Key Points• High risk primary prevention subjects derived ~30% reduction in the risk of cardiovascular events, specifically stroke, by adoption of a Mediterranean diet including either extra-virgin virgin olive oil or nuts.

• These data reinforce the value of dietary strategies as a key component of lifestyle intervention for preventing cardiovascular disease, as recommended by guidelines.1


References

1. Catapano AL, Reiner Z, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011;217:3-46.

2. Khera AV, Cuchel M, de la Llera-Moya M et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-35.

3. Li X-M, Tang WHW, Mosior MK et al. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risk. Arterioscler Thromb Vasc Biol 2013. Epub ahead of print.

4. Asztalos BF, Cupples LA, Demissie S et al. High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants of the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 2004;24:2181–7.

5. Favari E, Lee M, Calabresi L et al. Depletion of pre-beta-high density lipoprotein by human chymase impairs ATP-binding cassette transporter A1- but not scavenger receptor class B type I-mediated lipid efflux to high density lipoprotein. J Biol Chem 2004;279:9930–6.

6. de la Llera-Moya M, Drazul-Schrader D, Asztalos BF et al. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler Thromb Vasc Biol 2010;30:796–801.

7. Kane JP, Malloy MJ. Prebeta-1 HDL and coronary heart disease. Curr Opin Lipidol 2012;23:367–71.

8. Baigent C, Burbury K, Wheeler D. Premature cardiovascular disease in chronic renal failure. Lancet 2000;356:147-152.

9. Palmer SC, Craig JC, Navaneethan SD et al. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and analysis. Ann Intern Med 2012;157:263-75.

10. Upadhyay A, Earley A, Lamont JL et al. Lipid-lowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012;157:251-62.

11. Liu Y, Coresh J, Eustace JA et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 2004;291:451–9.

12. Baigent C, Landray MJ, Reith C et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181–92.

13. Fellstrom BC, Jardine AG, Schmieder RE et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395–1407.

14. Wanner C, Krane V, Marz W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238–48.

15. Hou W, Lv J, Perkovic V et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Eur Heart 2013;Epub ahead of print March 6, 2013.

16. Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.

17. Wilkins JT, Ning H, Berry J, Zhao L, Dyer AR, Lloyd-Jones DM. Lifetime risk and years lived free of total cardiovascular disease. JAMA 2012;308:1795-801.

18. Estruch R, Ros E, Salas-Salvado J; PREDIMED Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;Epub ahead of print 25 February, 2013.

19. Bendinelli B, Masala G, Saieva C, et al. Fruit, vegetables, and olive oil and risk of coronary heart disease in Italian women: the EPICOR Study. Am J Clin Nutr 2011; 93:275-83.

20. Samieri C, Féart C, Proust-Lima C, et al. Olive oil consumption, plasma oleic acid, and stroke incidence: the Three-City Study. Neurology 2011;77:418-25.

21. Ros E, Tapsell LC, Sabaté J. Nuts and berries for heart health. Curr Atheroscler Rep 2010;12:397-406.

22. Mitjavila MT, Eandos M, Salas-Salvado J et al. The Mediterranean diet improves systemic lipid and DNA oxidative damage in metabolic syndrome individuals. A randomized, controlled, trial. Clin Nutr 2013;32:172-8.

23. Taylor F, Huffman MD, Macedo AF et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD004816. DOI:10.1002/14651858.CD004816.pub5.

24. Iacoviello L, Bonanni A, Costanzo S et al. The Moli-sani project, a randomized, prospective cohort study in the Molise region in Italy; design, rationale and objectives. Italian J Public Health 2007; DOI: 10.2427/5886.