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EAS 2017 April 24: The smoking gun in atherosclerosis– LDL or immune cells?

25 April 2017   (0 Comments)
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Monday Plenary focused on whether atherosclerosis is a cholesterol or immune disease.

Professor Chris Packard (University of Glasgow, UK) presented the evidence against LDL using validated criteria for causality (Table 1). Taking each criterion in turn, he made a watertight case for the prosecution. His evidence was provided by the new EAS Consensus Panel Statement published in the European Heart Journal on Monday 24th April, which analyzed all the evidence in one paper and concluded that LDL causes atherosclerotic cardiovascular disease (ASCVD).1 This paper should be regarded as a landmark statement in the field of atherosclerosis and cardiovascular disease. Unlike other papers which have purported to be ‘meta-analyses’ investigating this question, this new Statement evaluated the totality of evidence from epidemiologic studies, Mendelian randomization and genetic studies, and randomized controlled trials of LDL- lowering therapies, including evidence from the first of the PCSK9 cardiovascular outcomes studies, FOURIER and SPIRE-2. This analysis included data from more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events, thus obviating potential criticism due to selection bias.

Table 1. Bradford Hill criteria for causality

Is there a plausible pathologic mechanism?

Is there a strong graded relationship to the disease?

Does elevation in the risk factor precede disease?

Is the risk factor independent of other risk factors?

Is the effect consistent across studies?

Is there coherence in the evidence across different approaches?

Do genetic findings provide support?

Does reduction in the risk factor uniformly lead to decreased risk of disease?

 

There is biological plausibility that LDL has a key role in the biology of atherosclerosis via a number of mechanisms. While atherosclerosis is undoubtedly a chronic inflammatory disease, it is the retention and accumulation in the artery wall of apolipoprotein B-containing lipoproteins that drives this process. Given that LDL account for more than 90% of circulating apoB-containing lipoproteins, it is clearly the main suspect. Indeed, the connection with a saturated fat–rich diet, which raises LDL cholesterol and enhances uptake of LDL into the artery wall, clogging the artery, has been validated in numerous studies and reaffirms that the cumulative LDL arterial burden is a central determinant for the initiation and progression of coronary artery disease and cardiovascular atherosclerosis.

What is the relationship between LDL and ASCVD? According to this new EAS Consensus Panel Statement, the totality of evidence shows a dose-dependent, log-linear association between the absolute magnitude of exposure to LDL and the risk of ASCVD. Indeed, familial hypercholesterolaemia (FH, inherited high cholesterol), in which mutations in the LDL receptor predominate, provides the ultimate paradigm for this association. Exposure to high LDL levels from birth precede the onset of ASCVD events, which can occur as early as childhood in the case of homozygous FH.

Importantly, the EAS Consensus Panel Statement showed that this dose-dependent, log-linear association between the absolute magnitude of exposure to LDL and risk of ASCVD was independent of other risk factors consistent across multiple lines of evidence.

Furthermore, there was clear consistency of benefit from more than 30 randomized trials involving over 200,000 individuals and 30,000 cardiovascular events evaluating treatments specifically designed to lower LDL. There did not appear to be a threshold for LDL-C, as evident in the FOURIER and GLAGOV studies, in which treatment with the PCSK9 inhibitor reduced LDL cholesterol levels far below recommended goals. Irrespective of the underlying mechanism, i.e. cholesterol absorption, or effects on cholesterol production or LDL receptor number, the reduction in coronary heart disease risk was consistent.

In his summing up, Professor Packard made the case for LDL as the guilty party in ASCVD. There are important implications for prevention. Exposure is the key; the risk reduction in studies of genetic variants associated with low LDL cholesterol is much greater than that observed in clinical trials given the difference in duration of exposure (lifetime versus an average of about 5 years in clinical trials). As age is a major determinant of cardiovascular risk, it stands to reason that the risk level of young individuals is much lower than observed in clinical trials, where the average age of subjects is usually in the region of about 65 years. The recent data from FOURIER also implies the need for lower LDL cholesterol goals in very high risk patients.

The ramifications for primary prevention are clear: we need to consider earlier intervention, lowering LDL cholesterol in individuals at high cardiovascular risk earlier rather than later to gain a legacy benefit. This strategy is the crux of the EAS Consensus Panel Statement on the management of paediatric FH; treating earlier can help to gain decades of healthy years of life.2

Finally, effective strategy-based primary preventive strategies are the main challenge for healthcare systems. A biomarker that can predict the risk of coronary heart disease over time would offer value. Indeed, emerging research suggests that high sensitivity troponin I concentration, a specific marker of myocardial injury, may reflect subclinical coronary artery disease and identify those at greatest risk, supported by evidence from the WOSCOPS study. Although further work is needed, serial high-sensitivity troponin concentrations may be one approach to this challenge.3

On the opposing bench, Professor Peter Libby (Brigham and Women’s Hospital, Harvard Medical School, Boston, USA) started his case. However, he first qualified his argument to the part that the monocyte plays in ASCVD. There has been a revision of the role of monocytes in the healing of myocardial infarction, with an initial demolition phase (characterized by inflammation and proteolysis) followed by a reconstructive phase (characterized by angiogenesis and collagen deposition). He suggested that there is an echo of systemic inflammation in the early period post MI, as evident by a ‘cardiosplenic axis’ of inflammation.

Since the early 20th century there has been a link between leukocytosis and atherothrombosis. In the 21st century, studies have demonstrated an association between white cell count and both short- and long-term motality.4  Pro-inflammatory actions of interleukin-1 beta, a soluble danger signal, may explain this link, supported by experimental evidence that anti IL-1 beta antibody treatment dampens the post-MI increase in hematopoietic stem cell proliferation, mutes the inflammatory leukocytes during MI, and improves left ventricular function post-MI. We await the results of the CANTOS study to determine whether this therapeutic approach translates to the prevention of recurrent cardiovascular events.

In his summing up, Professor Libby concluded that both speakers have made their case. Inflammation does not supplant or demote conventional risk factors such as LDL, but instead provides a mechanism that links them to altered arterial wall function.

And echoing this in his KeyNote lecture, Professor Göran K. Hansson (Karolinska Institute, Karolinska University Hospital and the Center for Molecular Medicine, Stockholm Sweden) commented that both Anitschkow and Virchow were right; LDL induces inflammation in the artery wall. Atherosclerosis is a chronic inflammation at the sites of cholesterol accumulation in the artery wall, with LDL and its contents acting as the driver of both innate and adaptive immunity mechanisms.

References

1. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA,. Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgozoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic and clinical studies. A Consensus Statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal. doi:10.1093/eurheartj/ehx144.

Available at: https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehx144.

2. Wiegman A, Gidding SS, Watts GF et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425-37.

3.  Ford I, Shah AS, Zhang R et al. High-Sensitivity cardiac troponin, statin therapy, and risk of coronary heart disease. J Am Coll Cardiol 2016;68:2719-28.

4. Shah AD, Thornley S, Chung SC et al. White cell count in the normal range and short-term and long-term mortality: international comparisons of electronic health record cohorts in England and New Zealand. BMJ Open 2017;7(2):e013100.


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