Genetic and environmental determinants of diastolic heart function

Abstract

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.

Identification of an increased lifetime risk of major adverse cardiovascular events in UK Biobank participants with scoliosis

“…PDSR is a diastolic function trait, that has been previously associated with MACEs, increased mortality, increased blood pressure, and altered left atrial function. 21 For example, decreased PDSR rr corresponds to stiffer ventricle, impairing relaxation and increasing the risk of heart failure. 21 No additional significant associations were found with other CMR measures available for analysis and no association was observed between scoliosis and diabetes ( table 2 ).…”

Identification of an increased lifetime risk of major adverse cardiovascular events in UK Biobank participants with scoliosis

“…PDSR is a diastolic function trait, that has been previously associated with major adverse cardiovascular events, increased mortality, increased blood pressure and altered left atrial function [21]. For example, decreased PDRS rr corresponds to stiffer ventricle, impairing its relaxation and increasing the risk of heart failure[21]. No additional significant associations were found with the other CMR measures available for analysis and no association was observed between scoliosis and diabetes ( Table 1 ).…”

“…Adequate diastolic function is essential during ventricular filling and maintenance of optimum stroke volume. PDSR is a diastolic function trait, that has been previously associated with major adverse cardiovascular events, increased mortality, increased blood pressure and altered left atrial function [21]. For example, decreased PDRS rr corresponds to stiffer ventricle, impairing its relaxation and increasing the risk of heart failure [21].…”

Cardiac age prediction using graph neural networks

“…Cardiac ageing culminates in a final common pathway involving loss of tissue compliance which is manifest through diastolic dysfunction, tissue fibrosis and structural remodelling. 13,14 While conventional image-derived phenotypes characterising these processes are associated with ageing, 6,15,16 they rely on pre-defined parameters that may be weak estimators of the underlying biology and do not take advantage of the rich three dimensional structural and functional information encoded by cardiac imaging. Precision models of cardiac motion minimise information loss but pose challenges for how to efficiently predict an outcome from such high-dimensional inputs.…”

“…27 Circumferential (𝐸 cc ) and radial (𝐸 rr ) strains were calculated on the short axis cines by the change in length of respective line segments. 13 Peak strain for each segment and global peak strain were then calculated. Strain rate was estimated as the first derivative of strain and peak early diastolic strain rate in radial (PDSR rr ) and longitudinal (PDSR ll ) directions were detected using local maxima.…”