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Open Access 01-12-2024 | Research

APOE ε4 carriage associates with improved myocardial performance from adolescence to older age

Authors: Constantin-Cristian Topriceanu, Mit Shah, Matthew Webber, Fiona Chan, Hunain Shiwani, Marcus Richards, Jonathan Schott, Nishi Chaturvedi, James C. Moon, Alun D. Hughes, Aroon D. Hingorani, Declan P. O’Regan, Gabriella Captur

Published in: BMC Cardiovascular Disorders | Issue 1/2024

Abstract

Background

Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy).

Methods

Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR).

Results

Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e’, posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1–7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0–1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged < 24 years had a 2% higher MCF (95% CI 0–5%, p = 0.059).

Conclusions

By triangulating results in four independent cohorts, across imaging modalities (echocardiography and CMR), and in ~ 37,000 individuals, our results point towards an association between ε4 carriage and improved cardiac performance in terms of LV MCF. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to the pleiotropic effects APOE ε4 carriage that might collectively explain its persistence in human populations.

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Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science (American Association for the Advancement of Science). 1988;240:622–30. https://doi.org/10.1126/science.3283935.ADSCrossRef

Yamazaki Y, Zhao N, Caulfield TR, Liu C-C, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15:501–18. https://doi.org/10.1038/s41582-019-0228-7.CrossRefPubMedPubMedCentral

Neu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, Wang L-S, Romero K, Arneric SP, Redolfi A, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a Meta-analysis. JAMA neurology. 2017;74:1178–89. https://doi.org/10.1001/jamaneurol.2017.2188.CrossRefPubMedPubMedCentral

Skoog I, Horder H, Frandin K, Johansson L, Ostling S, Blennow K, Zetterberg H, Zettergren A. Association between APOE genotype and change in physical function in a population-based Swedish cohort of older individuals followed over four years; 2016.CrossRef

Nao J, Sun H, Wang Q, Ma S, Zhang S, Dong X, Ma Y, Wang X, Zheng D. Adverse effects of the apolipoprotein E ε4 allele on episodic memory, task switching and gray matter volume in healthy young adults. Front Hum Neurosci. 2017;11:346–6. https://doi.org/10.3389/fnhum.2017.00346.CrossRefPubMedPubMedCentral

Tuminello ER, Han SD. The Apolipoprotein E antagonistic pleiotropy hypothesis: review and recommendations. Int J Alzheimers Dis. 2011;2011:726197–12. https://doi.org/10.4061/2011/726197.CrossRefPubMedPubMedCentral

Smith CJ, Ashford JW, Perfetti TA. Putative survival advantages in Young Apolipoprotein ɛ4 carriers are associated with increased neural stress. J Alzheimers Dis. 2019;68:885–923. https://doi.org/10.3233/JAD-181089.CrossRefPubMedPubMedCentral

Jasienska G, Ellison PT, Galbarczyk A, Jasienski M, Kalemba-Drozdz M, Kapiszewska M, Nenko I, Thune I, Ziomkiewicz A. Apolipoprotein E (ApoE) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy? Proc R Soc B Biol Sci. 2015;282:20142395–5. https://doi.org/10.1098/rspb.2014.2395.CrossRef

Lumsden AL, Mulugeta A, Zhou A, Hyppönen E. Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK biobank. EBioMedicine. 2020;59:102954–4. https://doi.org/10.1016/j.ebiom.2020.102954.CrossRefPubMedPubMedCentral

10.

Wolk DA, Dickerson BC. Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional—executive network function in Alzheimer's disease. Proceedings of the National Academy of Sciences - PNAS. 2010;107:10256–61. https://doi.org/10.1073/pnas.1001412107.ADSCrossRef

11.

Zhao QR, Lei YY, Li J, Jiang N, Shi JP. Association between apolipoprotein E polymorphisms and premature coronary artery disease: a meta-analysis. Clin Chem Lab Med. 2017;55:284–98. https://doi.org/10.1515/cclm-2016-0145.CrossRefPubMed

12.

Shi J, Liu Y, Liu Y, Li Y, Qiu S, Bai Y, Gu Y, Luo J, Cui H, Li Y, et al. Association between ApoE polymorphism and hypertension: a meta-analysis of 28 studies including 5898 cases and 7518 controls. GENE. 2018;675:197–207. https://doi.org/10.1016/j.gene.2018.06.097.CrossRefPubMed

13.

Chen DW, Shi JK, Li Y, Yang Y, Ren SP. Association between ApoE polymorphism and type 2 diabetes: a Meta-analysis of 59 studies. Biomed Environ Sci. 2019;32:823–38. https://doi.org/10.3967/bes2019.104.CrossRefPubMed

14.

Khan TA, Shah T, Prieto D, Zhang W, Price J, Fowkes GR, Cooper J, Talmud PJ, Humphries SE, Sundstrom J, et al. Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals. Int J Epidemiol. 2013;42:475–92. https://doi.org/10.1093/ije/dyt034.CrossRefPubMedPubMedCentral

15.

Mueller K, Thiel F, Beutner F, Teren A, Frisch S, Ballarini T, Möller HE, Ihle K, Thiery J, Schuler G, et al. Brain damage with heart failure: cardiac biomarker alterations and gray matter decline. Circ Res. 2020;126:750–64. https://doi.org/10.1161/CIRCRESAHA.119.315813.CrossRefPubMedPubMedCentral

16.

Golding J, Pembrey M, Jones J. ALSPAC - the Avon longitudinal study of parents and children I. Study methodology Paediatric and perinatal epidemiology. 2001;15:74–87. https://doi.org/10.1046/j.1365-3016.2001.00325.x.CrossRefPubMed

17.

Kuh D, Pierce M, Adams J, Deanfield J, Ekelund U, Friberg P, Ghosh AK, Harwood N, Hughes A, Macfarlane PW, et al. Cohort profile: updating the cohort profile for the MRC National Survey of health and development: a new clinic-based data collection for ageing research. Int J Epidemiol. 2011;40(1):e1–9.CrossRefPubMedPubMedCentral

18.

Tillin T, Forouhi NG, McKeigue PM, Chaturvedi N. Southall and Brent REvisited: cohort profile of SABRE, a UK population-based comparison of cardiovascular disease and diabetes in people of European, Indian Asian and African Caribbean origins. Int J Epidemiol. 2012;41:33–42. https://doi.org/10.1093/ije/dyq175.CrossRefPubMed

19.

Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, Downey P, Elliott P, Green J, Landray M, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12:e1001779–9. https://doi.org/10.1371/journal.pmed.1001779.CrossRefPubMedPubMedCentral

20.

Timpka S, Macdonald-Wallis C, Hughes AD, Chaturvedi N, Franks PW, Lawlor DA, Fraser A. Hypertensive Disorders of Pregnancy and Offspring Cardiac Structure and Function in Adolescence; 2016.CrossRef

21.

Cromer BA, Tarnowski KJ. Noncompliance in adolescents: a review. J Dev Behav Pediatr. 1989;10:207–15. https://doi.org/10.1097/00004703-198908000-00010.CrossRefPubMed

22.

Ghosh AK, Hardy RJ, Francis DP, Chaturvedi N, Pellerin D, Deanfield J, Kuh D, Mayet J, Hughes AD. Medical Research Council National Survey of health and development scientific and data collection T. Midlife blood pressure change and left ventricular mass and remodelling in older age in the 1946 British birth cohort study. Eur Heart J. 2014;35(46):3287–95.CrossRefPubMedPubMedCentral

23.

Al Saikhan L, Park C, Tillin T, Lloyd G, Mayet J, Chaturvedi N, Hughes AD. Relationship between image quality and Bias in 3D echocardiographic measures: data from the SABRE (Southall and Brent Revisited) study. J Am Heart Assoc. 2022;11:e019183–3. https://doi.org/10.1161/JAHA.120.019183.CrossRefPubMedPubMedCentral

24.

Chirinos JA, Segers P, De Buyzere ML, Kronmal RA, Raja MW, De Bacquer D, Claessens T, Gillebert TC, St. John-Sutton M, Rietzschel ER. Left ventricular mass: Allometric scaling, normative values, effect of obesity, and prognostic performance. Hypertension (Dallas, Tex 1979). 2010;56:91–8. https://doi.org/10.1161/HYPERTENSIONAHA.110.150250.CrossRefPubMed

25.

Petersen SE, Matthews PM, Francis JM, Robson MD, Zemrak F, Boubertakh R, Young AA, Hudson S, Weale P, Garratt S, et al. UK Biobank's cardiovascular magnetic resonance protocol. J Cardiovasc Magn Reson. 2016;18:8–8. https://doi.org/10.1186/s12968-016-0227-4.CrossRefPubMedPubMedCentral

26.

Bai W, Sinclair M, Tarroni G, Oktay O, Rajchl M, Vaillant G, Lee AM, Aung N, Lukaschuk E, Sanghvi MM, et al. Automated cardiovascular magnetic resonance image analysis with fully convolutional networks. J Cardiovasc Magn Reson. 2018;20:65–5. https://doi.org/10.1186/s12968-018-0471-x.CrossRefPubMedPubMedCentral

27.

Schulz-Menger J, Bluemke DA, Bremerich J, Flamm SD, Fogel MA, Friedrich MG, Kim RJ, Von Knobelsdorff-Brenkenhoff F, Kramer CM, Pennell DJ, et al. Standardized image interpretation and post-processing in cardiovascular magnetic resonance - 2020 update: Society for Cardiovascular Magnetic Resonance (SCMR): Board of Trustees Task Force on standardized post-processing. J Cardiovasc Magn Reson. 2020;22:19–9. https://doi.org/10.1186/s12968-020-00610-6.CrossRefPubMedPubMedCentral

28.

Cerqueira MD, Weissman NJ, Dilsizian JAK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart - a statement for healthcare professionals from the cardiac imaging Committee of the Council on clinical cardiology of the American Heart Association. Circulation (New York, NY). 2002;105:539–42. https://doi.org/10.1161/hc0402.102975.CrossRef

29.

Thanaj M, Mielke J, McGurk KA, Bai W, Savioli N, de Marvao A, Meyer HV, Zeng L, Sohler F, Lumbers RT, et al. Genetic and environmental determinants of diastolic heart function. 2022.CrossRef

30.

Taylor AE, Guthrie PAI, Smith GD, Golding J, Sattar N, Hingorani AD, Deanfield JE, Day INM. IQ, educational attainment, memory and plasma lipids: associations with Apolipoprotein E genotype in 5995 children. Biol Psychiatry. 1969;2011(70):152–8. https://doi.org/10.1016/j.biopsych.2010.10.033.CrossRef

31.

Rousseau K, Vinall LE, Butterworth SL, Hardy RJ, Holloway J, Wadsworth MEJ, Swallow DM. MUC7 haplotype analysis: results from a longitudinal birth cohort support protective effect of the MUC7 5 allele on respiratory function. Ann Hum Genet. 2006;70:417–27. https://doi.org/10.1111/j.1469-1809.2006.00250.x.CrossRefPubMed

32.

Rawle M, Davis D, Bendayan R, Wong A, Kuh D, Richards M. Apolipoprotein-E (ApoE) ε4 and cognitive decline over the adult life course; 2018.CrossRef

33.

Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, Motyer A, Vukcevic D, Delaneau O, O’Connell J, et al. The UK biobank resource with deep phenotyping and genomic data. Nature (London). 2018;562:203–9. https://doi.org/10.1038/s41586-018-0579-z.ADSCrossRefPubMed

34.

Townsend P, Beattie A, Phillimore P. Health and deprivation : inequality and the north / Peter Townsend, Peter Phillimore and Alastair Beattie. London: Routledge; 1989.

35.

The R programming language and software. In. 2014:71–117.

36.

Xu H, Li H, Liu J, Zhu D, Wang Z, Chen A, Zhao Q. Meta-analysis of apolipoprotein e gene polymorphism and susceptibility of myocardial infarction. PLoS One. 2014;9:e104608–8. https://doi.org/10.1371/journal.pone.0104608.ADSCrossRefPubMedPubMedCentral

37.

Torres-Perez E, Ledesma M, Garcia-Sobreviela MP, Leon-Latre M, Arbones-Mainar JM. Apolipoprotein E4 association with metabolic syndrome depends on body fatness. ATHEROSCLEROSIS. 2015;245:35–42. https://doi.org/10.1016/j.atherosclerosis.2015.11.029.CrossRefPubMed

38.

Griffin BA, Walker CG, Jebb SA, Moore C, Frost GS, Goff L, Sanders TAB, Lewis F, Griffin M, Gitau R, et al. APOE4 genotype exerts greater benefit in lowering plasma cholesterol and Apolipoprotein B than wild type (E3/E3), after replacement of dietary saturated fats with low Glycaemic index carbohydrates. NUTRIENTS. 2018;10:1524. https://doi.org/10.3390/nu10101524.CrossRefPubMedPubMedCentral

39.

Richardson TG, Sanderson E, Palmer TM, Ala-Korpela M, Ference BA, Smith GD, Holmes MV. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable Mendelian randomisation analysis. PLoS Med. 2020;17:e1003062–2. https://doi.org/10.1371/JOURNAL.PMED.1003062.CrossRefPubMedPubMedCentral

40.

Tejedor MT, Garcia-Sobreviela MP, Ledesma M, Arbones-Mainar JM. The apolipoprotein e polymorphism rs7412 associates with body fatness independently of plasma lipids in middle aged men. PLoS One. 2014;9:e108605–5. https://doi.org/10.1371/journal.pone.0108605.ADSCrossRefPubMedPubMedCentral

41.

Arbones-Mainar JM, Johnson LA, Altenburg MK, Maeda N. Differential modulation of diet-induced obesity and adipocyte functionality by human apolipoprotein E3 and E4 in mice. INT J OBESITY. 2008;32:1595–605. https://doi.org/10.1038/ijo.2008.143.CrossRef

42.

King DL, El-Khoury Coffin L, Maurer MS. Myocardial contraction fraction: a volumetric index of myocardial shortening by freehand three-dimensional echocardiography. J Am Coll Cardiol. 2002;40:325–9. https://doi.org/10.1016/s0735-1097(02)01944-7.CrossRefPubMed

43.

Chuang MLMD, Gona PP, Salton CJBA, Yeon SBMDJD, Kissinger KVBSRTMR, Blease SJMPH, Levy DMD, O'Donnell CJMDMPH, Manning WJMD. Usefulness of the left ventricular myocardial contraction fraction in healthy men and women to predict cardiovascular morbidity and mortality. Am J Cardiol. 2012;109:1454–8. https://doi.org/10.1016/j.amjcard.2012.01.357.CrossRefPubMedPubMedCentral

44.

Rubin J, Steidley DE, Carlsson M, Ong M-L, Maurer MS. Myocardial contraction fraction by M-mode echocardiography is superior to ejection fraction in predicting mortality in transthyretin amyloidosis. J Card Fail. 2018;24:504–11. https://doi.org/10.1016/j.cardfail.2018.07.001.CrossRefPubMedPubMedCentral

45.

Zhao D, Quill GM, Gilbert K, Wang VY, Houle HC, Legget ME, Ruygrok PN, Doughty RN, Pedrosa J, D'Hooge J, et al. Systematic comparison of left ventricular geometry between 3D-echocardiography and cardiac magnetic resonance imaging. Frontiers in cardiovascular medicine. 2021;8:728205–5. https://doi.org/10.3389/fcvm.2021.728205.CrossRefPubMedPubMedCentral

46.

Žofková I, Zajíčková K, Hill M, Hořínek A. Apolipoprotein E gene determines serum testosterone and dehydroepiandrosterone levels in postmenopausal women. Eur J Endocrinol. 2002;147:503–6. https://doi.org/10.1530/eje.0.1470503.CrossRefPubMed

47.

Ayaz O, Howlett SE. Testosterone modulates cardiac contraction and calcium homeostasis: cellular and molecular mechanisms. Biol Sex Differ. 2015;6:9–9. https://doi.org/10.1186/s13293-015-0027-9.CrossRefPubMedPubMedCentral

48.

Gharbi-Meliani A, Dugravot A, Sabia S, Regy M, Fayosse A, Schnitzler A, Kivimäki M, Singh-Manoux A, Dumurgier J. The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study; 2021.

49.

Park J-H, Marwick TH. Use and limitations of E/e' to assess left ventricular filling pressure by echocardiography. Journal of cardiovascular ultrasound. 2011;19:169. https://doi.org/10.4250/jcu.2011.19.4.169.CrossRefPubMedPubMedCentral

50.

Weverling-Rijnsburger AWE, Blauw GJ, Lagaay AM, Knock DL, Meinders AE, Westendorp RGJ. Total cholesterol and risk of mortality in the oldest old. The Lancet (British edition). 1997;350:1119–23. https://doi.org/10.1016/S0140-6736(97)04430-9.CrossRef

51.

Glinge C, Lahrouchi N, Jabbari R, Tfelt-Hansen J, Bezzina CR. Genome-wide association studies of cardiac electrical phenotypes. Cardiovasc Res. 2020;116:1620–34. https://doi.org/10.1093/cvr/cvaa144.CrossRefPubMedPubMedCentral

52.

Shah S, Henry A, Roselli C, Lin H, Sveinbjörnsson G, Fatemifar G, Hedman Å, Wilk JB, Morley MP, Chaffin MD, et al. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. 2020.CrossRef

53.

Warren HR, Cabrera CP, Ren M, Kraja AT, Nos F, Loh M, Karaman I, MPS L, Said MA, Farrall M, et al. Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat Genet. 2017;49:403–15. https://doi.org/10.1038/ng.3768.CrossRefPubMedPubMedCentral

54.

Lewis CM, Vassos E. Polygenic risk scores: from research tools to clinical instruments. Genome medicine. 2020;12:44–4. https://doi.org/10.1186/s13073-020-00742-5.CrossRefPubMedPubMedCentral

Title: APOE ε4 carriage associates with improved myocardial performance from adolescence to older age
Authors: Constantin-Cristian Topriceanu
Mit Shah
Matthew Webber
Fiona Chan
Hunain Shiwani
Marcus Richards
Jonathan Schott
Nishi Chaturvedi
James C. Moon
Alun D. Hughes
Aroon D. Hingorani
Declan P. O’Regan
Gabriella Captur
Publication date: 01-12-2024
Publisher: BioMed Central
Published in: BMC Cardiovascular Disorders / Issue 1/2024
Electronic ISSN: 1471-2261
DOI: https://doi.org/10.1186/s12872-024-03808-z

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APOE ε4 carriage associates with improved myocardial performance from adolescence to older age

Abstract

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