Abstract
Importance
A more precise identification of patients at “high cardiovascular risk” is preeminent in cardiovascular risk stratification.
Objective
To investigate the relationships between markers of cholesterol homeostasis, cardiovascular events and all-cause mortality.
Design, setting and participants
We quantified markers of cholesterol homeostasis by gas chromatography–mass spectrometry in 377 subjects with suspected coronary artery disease, who were not on lipid-lowering drugs at baseline. All patients were followed for occurrence of cardiovascular events and mortality over a period of 4.9 +/− 1.7 years. The standardized mortality ratio (SMR) was calculated as the ratio of the observed and the expected deaths based on the death rates of the Regional Databases Germany, and Poisson regression (rate ratio, RR) was used to compare subgroups. The SMR and RR were standardized for sex, age category and calendar period. In addition, Cox regression (Hazard ratio, HR) was used to determine the effect of co-variables on (cardiovascular) mortality within the cohort.
Main outcomes
Cardiovascular events, cardiovascular mortality and all-cause mortality.
Results
A total of 42 deaths were observed in 1818 person-years corresponding with an SMR of 0.99 (95% CI 0.71–1.33; p = 0.556). A fatal cardiovascular event occurred in 26 patients. Lower levels of lathosterol were associated with increased cardiovascular mortality (HR 1.59; 95% CI: 1.16–2.17; p = 0.004) and excess all-cause mortality (HR 1.41; 95% CI: 1.09–1.85; p = 0.011). Lower lathosterol tertile compared to the adjacent higher tertile was associated with 1.6 times higher all-cause mortality risk (RR 1.60; 95% CI 1.07–2.40; p for trend = 0.022). This corresponded with a 2.3 times higher mortality risk of a lathosterol–LDL ratio equal to or below the median (RR 2.29; 95% CI 1.19–4.43; p = 0.013). None of the other cholesterol homeostasis markers were associated with cardiovascular and all-cause mortality.
Conclusions
In patients not on lipid-lowering agents, low serum lathosterol correlated with increased risk of cardiovascular events and excess all-cause mortality.
Similar content being viewed by others
References
Ference BA, Ginsberg HN, Graham I et al (2017) 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. Eur Heart J 38(32):2459–2472
Fulcher J, O’Connell R, Voysey M et al (2015) Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 385(9976):1397–1405
Weingärtner O, Lütjohann D, Böhm M, Laufs U (2010) Relationship between cholesterol synthesis and intestinal absorption is associated with cardiovascular risk. Atherosclerosis. 210:362–365
Miettinen TA, Gylling H, Strandberg T, Sarna S (1998) Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. Finnish 4S Investigators. BMJ 316(7138):1127–1130
Weingärtner O, Weingärtner N, Scheller B et al (2009) Alterations in cholesterol homeostasis are associated with coronary heart disease in patients with aortic stenosis. Coron Artery Dis 2009:276–282
Matthan NR, Pencina M, LaRocque JM et al (2009) Alterations in cholesterol absorption/synthesis markers characterize Framingham offspring study participants with CHD. J Lipid Res 50(9):1927–1935
Silbernagel G, Fauler G, Hoffmann MM et al (2010) The associations of cholesterol metabolism and plasma plant sterols with all-cause and cardiovascular mortality. J Lipid Res 51(8):2384–2393
Rogacev KS, Cremers B, Zawada AM et al (2012) CD14++ CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography. J Am Coll Cardiol 60(16):1512–1520
van Himbergen TM, Matthan NR, Resteghini NA et al (2009) Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers. J Lipid Res 50(4):730–739
Mackay DS, Jones PJ, Myrie SB, Plat J, Lutjohann D (2014) Methodological considerations for the harmonization of non-cholesterol sterol bio-analysis. J Chromatogr B Anal Technol Biomed Life Sci. 957:116–122
Thelen KM, Rentsch KM, Gutteck U et al (2006) Brain cholesterol synthesis in mice is affected by high dose of simvastatin but not of pravastatin. J Pharmacol Exp Ther 316(3):1146–1152
Brown MS, Dana SE, Goldstein JL (1973) Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts by lipoproteins. Proc Natl Acad Sci USA 70(7):2162–2166
Weingärtner O, Lütjohann D, Elsässer A (2016) Personalize and optimize lipid-lowering therapies. J Am Coll Cardiol. 68(3):325–326
Lorenzi M, Ambegaonkar B, Baxter CA et al (2018) Ezetimibe in high-risk, previously treated statin patients: a systemic review and network meta-analysis of lipid efficacy. Clin Res Cardiol. https://doi.org/10.1007/s00392-018-1379
Yamaguchi J, Kawada-Watanabe E, Koyanagi R et al (2018) Baseline serum sitosterol level as predictor of adverse clinical events in acute coronary syndrome patients with dyslipidaemia: a sub-analysis of HIJ-PROPER. Atherosclerosis. 274:139–145
Acknowledgements
This study was supported by an unrestricted research grant from Unilever, Vlaardingen, the Netherlands.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Weingärtner, O., Lütjohann, D., Meyer, S. et al. Low serum lathosterol levels associate with fatal cardiovascular disease and excess all-cause mortality: a prospective cohort study. Clin Res Cardiol 108, 1381–1385 (2019). https://doi.org/10.1007/s00392-019-01474-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00392-019-01474-2