From DNA to clinical practice: integrating genetics into cardiovascular prevention

The field of Preventive Cardiology continues to expand, with novel biomarkers, imaging modalities, and therapeutics, aimed at improving risk stratification and delaying the onset and progression of cardiovascular disease (CVD). Similar advancements in genetics have furthered the understanding of heritable and acquired CVDs. The current issue of the European Journal of Preventive Cardiology focuses on the integration of genetics into CVD prevention. The biological contributions of sex-based differences in CVD risk factors and outcomes remain unexplored. In the narrative review ‘Sex chromosomes and cardiovascular disease’, Spiering et al.1 from the Netherlands and USA review basic science and several recent population-based studies exploring mechanisms of sex chromosomes and CVD risk, including mosaic loss of the Y chromosome and X-chromosome inactivation escape. The review marks a key shift in understanding of sex chromosomes beyond just reproductive biology and to their critical role in CVD. In another review, ‘Impact of genetic risk information for cardiovascular disease on behavioural changes, psychological responses and risk factor modification: a systematic review’, Chen et al.2 from Australia investigate how disclosing CVD genetic risk information to patients influence behavioural, psychological, and CVD risk factor outcomes. A total of 11 randomized control trials from 2004 to 2021 were included in the analysis. Overall, patients who received monogenic or polygenic CVD risk data had no significant changes in health behaviours, psychological responses, or modifiable cardiovascular risk factors. The authors did find a trend towards positive dietary changes with sharing of genetic CVD risk data. This review underscores the need for further research on optimal communication methods for delivery of genetic CVD risk information to best tailor prevention efforts. Furthermore, in ‘Exploring gene-activity interplay in cardiovascular disease: is feasible to mitigate genetic risk through physical activity?’ Núñez-Cortés et al.3 explore the interplay between CVD genetic susceptibility, physical activity, and CVD risk. Overall, physical activity significantly attenuated genetically determined CVD risk, with increasing benefit in those at greatest risk, lending credence to personalized physical activity interventions. Next in the issue are three important manuscripts that focus on genetics in familial hypercholesterolaemia (FH), a condition that leads to high lifetime exposure of low-density lipoprotein-cholesterol (LDL-C) due to impaired clearance. In a genome-wide analysis ‘Variants in LPA are associated with familial hypercholesterolemia: whole genome sequencing analysis in the 10 000 genomes project’, Bird et al.4 from the UK and France provide a comprehensive assessment of genetic causes of FH, identifying the lipoprotein(a) [Lp(a)] gene (LPA) as a key player. LDL-C and Lp(a) polygenic risk scores were significantly higher in FH variant-negative and monogenic FH participants, compared to controls (Figure 1). These findings support Lp(a) and LDL-C testing in FH individuals to guide diagnostic and treatment strategies. Violin plot of lipoprotein(a) polygenic risk score (PRS) in controls, familial hypercholesterolaemia variant-negative (FH/M−) and monogenic familial hypercholesterolaemia (FH/M+) individuals. Reproduced from Bird et al.4 Diagnosing FH, especially early in childhood to mitigate lifetime CVD risk from LDL-C exposure remains a clinical challenge. In ‘Clinical scores fail to sufficiently identify children with familial hypercholesterolemia’, Schmieder et al.5 from Germany compare the performance of three clinical scoring systems with genetic testing in 1337 children. All three scoring systems showed high specificity for FH diagnosis, ranging from 0.91 to 0.97; however, the sensitivity was quite low, ranging from 0.44 to 0.54. These data highlight the need for routine genetic testing to improve FH detection, as clinical scores did not identify about half of genetically confirmed FH cases. Timely identification of FH patients allows for earlier and more aggressive interventions; however, limited data exist analysing the CVD-related costs associated with FH. In ‘Ten-year costs of cardiovascular disease in genetically verified familial hypercholesterolemia compared with age- and sex-matched controls’, Wisløff et al.6 from Norway and Denmark examine healthcare costs in 5585 genetically confirmed FH patients. Compared with age- and sex-matched controls, hospital costs and pharmaceutical costs were approximately 3 and 10 times greater in FH patients, respectively. This well-conducted analysis will aid in informing policy discussions on FH management. The role of inflammation, including interleukin-6 (IL-6) pathways, is of emerging interest in the field of CVD prevention. In ‘Genetic interleukin-6 receptor blockade, chronic disease risk, and longevity: results from the women’s health initiative’, Wissel et al.7 investigate the association of genetic IL-6 receptor blockade with chronic disease risk in 38 807 individuals from the Women’s Health Initiative. Interestingly, genetic IL-6 receptor blockade was associated with reduced systemic inflammation, but not with lower risk of coronary heart disease, heart failure, stroke, survival to old age, or cancer. With the development of anti-IL-6 therapies, further research is essential to understand how mechanisms of genetic IL-6 receptor blockade impact chronic diseases across diverse populations and subgroups. In ‘Genetically predicted iron status and cardiovascular function and structure: a Mendelian randomization study’, Quezada-Pinedo et al.8 found genetically predicted serum iron was associated with reduced left ventricular end diastolic and systolic volumes. Additionally, the authors found genetically determined transferrin saturation was associated with higher left ventricular mass-to-end-diastolic volume ratio (Figure 2). The influence of iron status on cardiac structure may help to refine screening strategies and personalized treatment interventions for those at risk of iron deficiency and iron overload. Mendelian randomization results for the effect of iron status and cardiac function and structure by inverse variance weighted method (IVW). Values reflect the SD change in cardiac outcomes with 95% confidence interval (95% CI) per SD increase in iron biomarkers, derived from Inverse Variance Weighted (IVW) methods. TSAT, transferrin saturation; TIBC, total iron binding capacity; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEF, left ventricular ejection fraction; LVM, left ventricular mass; LVMVR, left ventricular mass to end-diastolic volume ratio. Reproduced from Quezada-Pinedo et al.8 Polygenic risk scores (PRSs) provide a quantitative assessment of CVD genetic variants to guide risk prediction, which is central for tailoring CVD prevention strategies. In ‘Assessing the role of polygenic risk scores in cardiovascular risk prediction: a cross-sectional analysis from the Paracelsus 10 000 cohort’, Wernly et al.9 from Austria examined the added value of PRS to SCORE2 in predicting coronary artery calcium (CAC) >100. In 1420 participants, the authors found that integrating PRS to SCORE2 improved the overall prediction of subclinical atherosclerosis, increasing the area under the curve in women from 0.662 to 0.738 and in men from 0.659 to 0.714. Collectively, these data suggest the addition of PRS to SCORE2 aid in identifying individuals who may benefit from more aggressive primary prevention interventions. While PRSs allow for improved risk stratification, most developed PRSs have predominantly been derived from European populations; and thus, generalizability to other populations is not clear. In ‘Polygenic prediction of coronary heart disease among 130 000 Mexican adults’ Liu et al.10 from the UK and Mexico compared the performance of eight PRSs, five derived from European populations and three from multi-ancestry groups, in 133 207 Mexican adults. The authors found all eight PRSs to be associated with coronary heart disease independent of traditional CVD risk factors, with odds ratios ranging from 1.05 to 1.29 for each standard deviation increase in PRS. The PRSs derived from multi-ancestry populations performed better than PRSs derived from European populations, illustrating the need for developing genetic instruments that capture the genetic architecture in diverse populations. In ‘A family-based strategy to identify and prevent premature cardiovascular disease: a feasibility pilot study’, Charleux et al.11 from France investigate the feasibility of CVD risk assessment in first-degree relatives of participants with premature coronary artery disease. The authors identified 137 individuals with premature coronary artery disease. A total of 352 siblings and offspring of the indexed patients were identified, with 13.7% having established CVD and 19.3% already receiving primary prevention care. Only a total of 25 of the eligible 226 remaining individuals (11.1%) initiated primary prevention screening. Identifying barriers to primary prevention screening among family members of individuals with premature coronary artery disease may help to increase adherence. The last full research paper in the issue, ‘Influence of age and sex on the diagnostic yield of inherited cardiac conditions in sudden arrhythmic death syndrome decedents’, Gray et al.12 from the UK and Australia explore aetiologies of sudden death through familial evaluation and molecular autopsy. A total of 760 sudden death decedents were included in the study, and the diagnostic yield for an inherited cardiac disease through familial evaluation was 37%, molecular autopsy was 8.8%, and combination of both familial evaluation and molecular autopsy was 45%. This is the largest cohort of autopsy negative sudden unexplained deaths and emphasizes the need for familial and post-mortem DNA evaluation to help identify, risk stratify, and treat family members with inherited cardiac conditions. This issue of the European Journal of Preventive Cardiology shares the multi-faceted role of genetics shaping the field of CVD prevention with improved diagnostics and cascade screening, with FH demonstrating the most mature example. The field is ripe for continued advancements for improved risk stratification, such as with PRSs, and personalized treatment. We believe this issue will enhance clinical practice and be a valuable addition to all providers and researchers with an interest in CVD prevention. Victor Aboyans (MD PhD (Writing—review & editing [supporting])) and Rishi R. Rikhi (Writing—original draft [lead]) There are no new data associated with this article.