Remnant lipoproteins are associated with risk of aortic stenosis

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Macrovascular Residual Risk Studies

2 June 2020

Data from the Copenhagen General Population Study show that increased levels of triglycerides (TG) and remnant cholesterol increase the risk of aortic stenosis.

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

STUDY SUMMARY

Objective:

To investigate whether higher levels of plasma TG and remnant cholesterol are observationally and genetically associated with increased risk of aortic valve stenosis.

Study design:

Mendelian randomization study

Study population:

This study used data from 108,559 individuals from the Copenhagen General Population Study.

Study outcome:

The primary outcome was incident aortic valve stenosis. Individuals with known congenital aortic valve malformation were excluded.

Methods:

Plasma TG, remnant cholesterol (total cholesterol minus low-density lipoprotein [LDL] and high-density lipoprotein cholesterol) were determined. Sixteen variants of the ANGPTL3, ANGPTL4, APOA5, APOC3, LPL and TRIB1 genes causing increased or decreased levels of plasma TG and remnant cholesterol were used to create an allele score. Observational associations of TG and remnant cholesterol with aortic valve stenosis were calculated using Cox proportional hazards regression adjusted for age and sex or multifactorially for age, sex, smoking status, pack-years smoked, systolic blood pressure, LDL cholesterol, lipoprotein(a), and years of education. TG were categorized into six groups of 1 mmol/L change:<1.0 mmol/L (<89 mg/dL), 1.0–1.9 mmol/L (89–176 mg/dL), 2.0–2.9 mmol/L (177–265 mg/dL), 3.0–3.9 mmol/L (266–353 mg/dL), 4.0–4.9 mmol/L (354–442 mg/dL), and ≥5.0 mmol/L (≥443 mg/dL). Remnant cholesterol was categorized into five groups of 0.5 mmol/L change: <0.5 mmol/L (<19 mg/dL), 0.5–0.9 mmol/L (19–38 mg/dL), 1.0–1.4 mmol/L (39–57 mg/dL), 1.5–1.9 mmol/L (58– 76 mg/dL), and ≥2.0 mmol/L(≥77 mg/dL). Genetic allele score associations were calculated by logistic regression with age and sex as covariates. Instrumental variable analysis with allele score as the instrumental variable was performed to quantify a causal effect.

Results:

Incident aortic valve stenosis occurred in 1593 individuals over a median follow-up of 8.7 years (range 0–14 years).

Observational risk

Increasing levels of TG and remnant cholesterol were associated with an increased risk of aortic stenosis (Table 1). Compared to individuals with TG <2.0 mmol/L (<177 mg/ dL), the risk for aortic valve stenosis increased by 31% for individuals with TG of 2.0–4.9 mmol/L (177– 442 mg/dL) and by 64% for those with TG ≥5 mmol/L (≥443 mg/dL). Risk increased similarly with increasing levels of remnant cholesterol.

Table 1. Observational association of plasma triglycerides and remnant cholesterol with risk of aortic valve stenosis

Variable	mmol/L (mg/dL)	Hazard ratio (95% CI)
TG	<1 (<89)	Reference
	1.0-1.9 (89-176)	1.02 (0.87 - 1.19)
	2.0-2.9 (177-265)	1.22 (1.02 -1.46)
	3.0-3.9 (266-353)	1.40 (1.11 – 1.77)
	4.0-4.9 (354-442)	1.29 (0.88 – 1.90)
	≥5 (≥443)	1.52 (1.02 – 2.27)

Remnant cholesterol	<0.5 (<19)	Reference
	0.5-0.9 (19-38)	1.06 (0.92 – 1.22)
	1.0-1.4 (39-57)	1.31 (1.11 - 1.56)
	1.5-1.9 (58-76)	1.43 (1.12 – 1.84)
	≥2.0 (≥77)	1.48 (0.91 – 2.43)

For each 1 mmol/L (89 mg/dL) increase in TG, and 0.39 mmol/L (15 mg/dL) increase in remnant cholesterol, there was 1.1-fold increase in the observational risk of aortic stenosis (Hazard ratios of 1.09, 95% 1.05-1.14 and 1.10, 95% CI 1.05-1.15, respectively).

Genetic risk

The genetic risk for aortic stenosis increased as the allele score increased (Table 2).

Table 2. Genetic association of plasma triglycerides and remnant cholesterol with risk of aortic valve stenosis

Weighted allele score group	% increase in TG (% increase in remnant cholesterol)	Hazard ratio (95% CI)
1	Reference
2	20 (18)	1.11 (1.02 - 1.21)
3	35 (31)	1.21 (1.13 - 1.31)
4	63 (55)	1.31 (1.06 - 1.60)

For each 1 mmol/L (89 mg/dL) increase in TG, and 0.39 mmol/L (15 mg/dL) increase in remnant cholesterol, there was 1.6-fold increase in the genetic risk of aortic stenosis (risk ratios of 1.62, 95% 1.15-2.29 and 1.62, 95% CI 1.15-2.29, respectively).

Conclusion:

Higher TG and remnant cholesterol were observationally and genetically associated with increased risk of aortic valve stenosis.

COMMENT

Aortic valve stenosis is increasingly common as the population ages, affecting up to 10% of 80-year olds. Once symptomatic, treatment options are limited, and prognosis is poor. Therefore, understanding the risk factors for aortic valve stenosis is critical to improving management strategies. Although these risk factors may be similar to those implicated in other vascular diseases, randomized trials of treatments to lower LDL cholesterol showed minimal impact on disease progression (2-4).

With recognition of the causal role of TG-rich remnant lipoproteins in atherosclerotic cardiovascular disease (5,6), it is possible that these lipoproteins may also be implicated in aortic valve stenosis. This question was addressed in the current study. The investigators used a Mendelian randomization approach using data from the Copenhagen General Population Study to test for an association of remnant lipoproteins with aortic valve stenosis. They showed that higher plasma TG and remnant cholesterol were observationally and genetically associated with a higher risk of aortic valve stenosis, implying a potential role for elevated TG-rich remnant lipoproteins in the evolution of this cardiovascular disease. The study does not provide insights into the underlying mechanisms, although these are likely to include facilitation of inflammation, as has been shown in atherosclerotic cardiovascular disease (7).

References

1. Joseph J, Naqvi SY, Giri J, Goldberg S. Aortic stenosis: pathophysiology, diagnosis, and therapy. Am J Med 2017;130:253-63.

2. Cowell SJ, Newby DE, Prescott RJ, et al. A Randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389–97.

3. 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.

4. Chan KL, Teo K, Dumesnil JG, et al. Effect

of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121:306–14.

5. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626–35.

6. Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J 2020;41:99-109c.

7. 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.

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