Genetic and environmental determinants of diastolic heart function

Thanaj, Marjola; Mielke, Johanna; Ka, McGurk; Bai, Wenjia; Savioli, Nicoló; Marvao, Antonio de; Hv, Meyer; Zeng, Lingyao; Sohler, Florian; Wilkins, Martin R.; Ware, JS; Bender, Christian; Rueckert, Daniel; MacNamara, Aidan; Df, Freitag; O’Regan, Declan P

doi:10.1101/2021.06.07.21257302

Cited by 9 publications

(10 citation statements)

References 77 publications

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“…All analyses in this study can be found here https://github.com/ImperialCollegeLondon/diastolic_genetics/ 43 and were conducted with R version > 3.6.0.…”

Section: Methodsmentioning

confidence: 99%

Genetic and environmental determinants of diastolic heart function

et al. 2022

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Diastole is the sequence of physiological events that occur in the heart during ventricular filling and principally depends on myocardial relaxation and chamber stiffness. Abnormal diastolic function is related to many cardiovascular disease processes and is predictive of health outcomes, but its genetic architecture is largely unknown. Here, we use machine-learning cardiac motion analysis to measure diastolic functional traits in 39,559 participants of the UK Biobank and perform a genome-wide association study. We identified nine significant, independent loci near genes that are associated with maintaining sarcomeric function under biomechanical stress and genes implicated in the development of cardiomyopathy. Age, sex and diabetes were independent predictors of diastolic function and we found a causal relationship between genetically determined ventricular stiffness and incident heart failure. Our results provide insights into the genetic and environmental factors influencing diastolic function that are relevant for identifying causal relationships and potential tractable targets.

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“…All analyses in this study can be found here https://github.com/ImperialCollegeLondon/diastolic_genetics/ 43 and were conducted with R version > 3.6.0.…”

Section: Methodsmentioning

confidence: 99%

Genetic and environmental determinants of diastolic heart function

et al. 2022

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“…13 Diastolic function, which is a key feature of the ageing heart, was assessed using motion analysis to derive end diastolic strain rates. 6 We assessed diffuse myocardial fibrosis, an early feature of natural ageing, 14 using native T1 mapping of the interventricular septum. 15 Central vascular function was assessed by measuring aortic distensibility from central blood pressure estimates and dynamic aortic imaging.…”

Section: Image Phenotypingmentioning

confidence: 99%

“…5 A final common pathway of cardiovascular ageing is loss of tissue compliance which is manifest through diastolic dysfunction, interstitial fibrosis and vascular remodelling. 6,7 Such changes can be assessed though non-invasive imaging and enable an estimate of how an individual's cardiovascular system has aged relative to a normative population. 8 An equivalent calculation of "age gap" has been shown to be a promising neuro-imaging marker for modelling dynamic lifespan trajectories of brain ageing.…”

Section: Introductionmentioning

confidence: 99%

Environmental and genetic predictors of human cardiovascular ageing

Shah

Inácio

et al. 2022

Preprint

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Cardiovascular ageing is a process that begins early in life and leads to a progressive change in structure and decline in function due to accumulated damage across diverse cell types, tissues and organs contributing to multi-morbidity. Damaging biophysical, metabolic and immunological factors exceed endogenous repair mechanisms resulting in a pro-fibrotic state, cellular senescence and end-organ damage, however the genetic architecture of cardiovascular ageing is not known. Here we used machine learning approaches to quantify cardiovascular ageing from image-derived traits of vascular function, cardiac motion and myocardial fibrosis, as well as conduction traits from electrocardiograms, in 39,559 participants of UK Biobank. Cardiovascular ageing was found to be significantly associated with common or rare variants in genes regulating sarcomere homeostasis, myocardial immunomodulation, and tissue responses to biophysical stress. Ageing is accelerated by cardiometabolic risk factors and we also identified prescribed medications that were potential modifiers of ageing. Through large-scale modelling of ageing across multiple traits our results reveal insights into the mechanisms driving premature cardiovascular ageing and reveal potential molecular targets to attenuate age-related processes.

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“…Thickness of the IVS was calculated as the mean wall thickness of segments 2, 3, 8, 9 and 14, while PWT was taken as the mean of segments 5,6, 11, 12, and 16. To compute longitudinal and radial peak diastolic strain rates, non-rigid image co-registration was performed between successive frames to enable dynamic motion tracking of the heart during the cardiac cycle 26 . Unindexed CMR metrics were used in all subsequent analyses as discussed above.…”

Section: Methodsmentioning

confidence: 99%

APOE ε4 carriage associates with improved myocardial performance in older age

Topriceanu

Shah

Webber

et al. 2022

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IntroductionAlthough APOE ε4 allele carriage confers a risk of coronary disease, its persistence in human populations might be explained by certain survival advantages (antagonistic pleiotropy).HypothesisCombining data from three British cohorts–1946 National Survey of Health and Development (NSHD), Southall and Brent Revised (SABRE) and UK Biobank–we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional parameters by echocardiography and cardiovascular magnetic resonance (CMR) in older age.MethodsBased on the presence of APOE ε4, genotypes were divided into: APOE ε4 (ε2ε4, ε3ε4, ε4ε4) and non-APOE ε4 carriers. Echocardiographic data included: LV ejection fraction, E/e’, systolic and diastolic posterior wall and interventricular septal thickness (LVPWTs/d, IVSs/d), LV mass and the ratio of the LV stroke volume to the LV myocardial volume called myocardial contraction fraction (MCF). CMR data additionally included longitudinal and radial peak diastolic strain rates (PDSR). Generalized linear models explored associations between APOE ε4 genotypes as exposures and echocardiographic/CMR biomarkers as outcomes. As APOE genotype is a genetic instrumental variable (unconfounded), Model 1 was unadjusted; Model 2 was adjusted for factors associated with the outcome (age, sex, and socio-economic position) to yield more precise estimates; and subsequent models were individually adjusted for mediators (body mass index, cardiovascular disease [CVD], high cholesterol and hypertension) to explore mechanistic pathways.Results35,568 participants were included. Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac echocardiographic phenotypes in terms of LV EF, E/e’, LVPWTs/d, IVSs/d and LV mass but had a 4% higher MCF (95% confidence interval [CI]: 1–7%, p=0.016) which persisted in Model 2 (95% CI 1–7%, p=0.008) but was attenuated to 3% after adjustment for CVD, diabetes and hypertension (all 95% CI 0–6%; all p<0.070). This was replicated in UK Biobank using CMR data, where APOE ε4 carriers had a 1% higher MCF (95% CI 0-1%, p=0.020) which was attenuated only after adjusting for BMI or diabetes.ConclusionsAPOE ε4 carriage associates with improved myocardial performance in older age resulting in greater LV stroke volume generation per 1 mL of myocardium and better longitudinal strain rates compared to non APOE ε4 carriers. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to APOE ε4 carriage that might collectively explain its persistence in humans.

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Genetic and environmental determinants of diastolic heart function

Cited by 9 publications

References 77 publications

Genetic and environmental determinants of diastolic heart function

Genetic and environmental determinants of diastolic heart function

Environmental and genetic predictors of human cardiovascular ageing

APOE ε4 carriage associates with improved myocardial performance in older age

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