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R3i EDITORIAL

2 June 2020

Triglyceride-rich remnant lipoproteins: a new therapeutic target in aortic valve stenosis?

Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

Given that aortic valve stenosis is a chronic and multifactorial process, initiated many years before the onset of clinical symptoms, implies an atherosclerotic-like evolution with the involvement of atherogenic lipoproteins. Indeed, there is evidence from observational and genetic studies that low-density lipoprotein (LDL) cholesterol from standard LDLs, is one contributing factor 5. However, studies evaluating the effect of interventions that lower LDL cholesterol have proved largely inconclusive. For example, in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, the combination of simvastatin and ezetimibe did not reduce the primary study endpoint, a composite of aortic valve events and ischemic events, and had no significant effect on events related to aortic valve stenosis 6.

By contrast, other atherogenic lipoproteins show promise as potential targets for intervention. Lipoprotein(a), a LDL modified by attachment of an apolipoprotein(a), is one candidate, supported by Mendelian randomization studies which showed that among the general population, elevated lipoprotein(a) levels were associated with an increased risk of aortic valve stenosis 7. Although the underlying mechanisms remain unclear, oxidized phospholipids which are carried by lipoprotein(a), may act as a pivotal player in driving valve calcification and disease progression 8.

Added to this, there is also new evidence suggesting a role for triglyceride (TG)-rich lipoproteins and their remnants, the focus of this month’s Landmark study 9. Using Mendelian randomization and data from the Copenhagen General Population Study, Kaltoft and co-workers investigated whether higher levels of plasma TG and remnant cholesterol are associated with an increased risk for aortic valve stenosis. The advantages of this approach are that both observational and genetic risk were evaluated, using instrumental variable analysis to avoid confounding and measurement error in the assessment of causality. Sixteen of the most appropriate genetic variants for proteins that play key roles in TG metabolism were used in the development of a genetic score.

The findings of this study are indeed novel. Higher levels of plasma TG and remnant cholesterol were observationally and genetically associated with a higher risk of aortic valve stenosis, providing a rationale that elevated TG-rich remnant lipoproteins may act as a potential driver of aortic valve stenosis. Although the study does not provide information into the underlying mechanisms, the authors suggest that these most likely involve pro-inflammatory effects, based on prior preclinical findings (10).

In conclusion, this important study provides a rationale for future randomized clinical trials to investigate whether therapeutic intervention against elevated TG, a surrogate for TG-rich remnant lipoproteins, can prevent and/or reduce progression of aortic valve stenosis. This study offers a basis for such trials to address this unmet clinical need for novel preventive approaches in aortic valve stenosis.

References

1. Joseph J, Naqvi SY, Giri J, Goldberg S. Aortic stenosis: pathophysiology, diagnosis, and therapy. Am J Med 2017;130:253-63.
2. Osnabrugge RL, Mylotte D, Head SJ, et al. Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J Am Coll Cardiol 2013;62:1002-12.
3. Baumgartner H, Falk V, Bax JJ, et al. ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91.
4. Sharma UC, Barenbrug P, Pokharel S, et al. Systematic review of the outcome of aortic valve replacement in patients with aortic stenosis. Ann Thorac Surg 2004;78:90–9.
5. Stritzke J, Linsel-Nitschke P, Markus MRP, et al. Association between degenerative aortic valve disease and long-term exposure to cardiovascular risk factors: results of the longitudinal
population-based KORA/MONICA survey. Eur Heart J 2009;30:2044–53.
6. Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–56.
7. Zheng KH, Tsimikas S, Pawade T, et al. Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis. J Am Coll Cardiol 2019;73:2150-62.
8. Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 2014;63:470-7.
9. Kaltoft M, Langsted A, Nordestgaard BG. Triglycerides and remnant cholesterol associated with risk of aortic valve stenosis: Mendelian randomization in the Copenhagen General Population Study. Eur Heart J 2020. doi: 10.1093/eurheartj/ehaa172.
10. Varbo A, Benn M, Tybjærg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013;128:1298–309.