An update on the ESC Council on Cardiovascular Genomics: out from the niche into the open

Medicine—in particular, the field of cardiology—has undergone remarkable transformations over the past few decades by achieving milestones in disease understanding, technology, and medical therapy. In this wealth of achievements, genetics and genomic medicine play a rapidly growing role and have now entered the clinical scene. While the potential of genomic medicine to improve patient outcomes is huge, its implementation in routine cardiovascular care remains challenging. Several problems must be addressed to fully realize the benefits of genomic medicine today and to pave the way for genetically stratified patient treatment in the future. Historically, the understanding of cardiovascular diseases (CVD) was primarily based on environmental and lifestyle factors. However, the late 20th century marked a pivotal shift as research began to uncover the genetic underpinnings of various heart conditions. The identification of familial hypercholesterolaemia and the discovery of genes associated with hypertrophic cardiomyopathy were among the earliest landmarks that stressed the role of genetics in CVD. The Human Genome Project further accelerated this momentum by providing a first comprehensive map of human genes in 2003. This monumental achievement laid the groundwork for the exploration of genetic variants associated with CVD, which opened vast opportunities for genomic medicine in cardiology. Today, genomic medicine is increasingly being integrated into cardiology guidelines, offering new avenues for diagnosis, risk assessment, and treatment.1–5 Genetic testing and counselling are now routinely recommended to identify inherited cardiovascular conditions, allowing for early intervention and family screening. For instance, a patient with a young-onset myocardial infarction on the basis of familial hypercholesterolaemia should trigger appropriate diagnosis and family screening to allow for proactive counselling and management. In a similar fashion, cardiomyopathy in a patient should trigger attention to family history and prescription for a genetic test under the guidance of multidisciplinary experts followed again by family cascade screening and counselling for preventive measures. In addition to these classical genetic approaches, the advent of genome-wide association studies and next-generation sequencing has revolutionized the ability to analyse large volumes of genetic data quickly and cost-effectively. These technologies and bioinformatics have facilitated the identification of both rare and common genetic variants that contribute to complex cardiovascular phenotypes, enhancing our understanding of disease mechanisms and pointing to the potential for personalized risk assessment and treatment in selected conditions.6 Despite those achievements affecting all fields of cardiology and concerning all ESC Associations, Working Groups, and Councils, several hurdles remain to implement genomic medicine into routine cardiovascular care. The ESC Council on Cardiovascular Genomics was founded in 2020 with a mandate to shape the ‘cardiologist of tomorrow’ by bundling multidisciplinary expertise, harmonizing recommendations, identifying gaps in knowledge, making genetic and genomic medicine accessible, and—most importantly—structuring and promoting education in this rapidly evolving field. In the meantime, the ESC Council on Cardiovascular Genomics has established a regular educational series called ‘Cardiovascular Genomics Insight’ (https://www.escardio.org/Councils/Council-on-Cardiovascular-Genomics/Cardiovascular-Genomics-Insight) and has made substantial contributions to guidelines and consensus statements. The Council on Cardiovascular Genomics is committed to serving the cardiology community and building a bridge among all ESC bodies, Councils, and Working Groups in a multidisciplinary approach that invites free membership (https://www.escardio.org/Councils/Council-on-Cardiovascular-Genomics/Membership#:∼:text=Sign%20up%20for%20Council%20on,login%20via%20%E2%80%9CMY%20ESC%E2%80%9D). To reach the goal of personalized medicine in a widely accessible, safe, and sustainable way that keeps up with established standards of evidence-based medicine, we have established 10 rules for the implementation of genomic medicine in cardiology: Be aware of a possible genetic contribution (with variable effect size). Do not overestimate the diagnostic power of genetic testing, but keep in mind that knowledge of specific gene variants may change patient management and prognosis. Look for a positive familial history, although its absence does not rule out an inherited cardiac condition. Establish a standardized and comprehensive family history (three-generation family tree). Select or refer preferentially the index case(s) to the geneticist—i.e. the patient(s) with the most pronounced and the most characterized phenotype to maximize the likelihood of identifying a pathogenic variant. Respect confidentiality and ethical rules. Use ACMG guidelines to classify variants and (re-)challenge variants pathogenicity in light of the actual knowledge in a dynamic fashion. Genetic testing for clinically actionable variants should be offered to relatives through a cascade approach considering and anticipating the benefit/risk ratio of getting this genetic result, including testing in asymptomatic patients, in children, and in the setting of prenatal or pre-implantation genetic diagnosis in case of potentially severe or life-threatening disease according to national laws and regulations. If no affected patient is available for testing, cardiac phenotyping may be reasonable—including electrocardiogram, imaging, exercise stress testing, and more, followed by targeted sequencing of first-degree relatives. Blood and/or tissue samples should be collected and stored from sudden-death deceased with suspected or confirmed inherited conditions in order to allow genetic study (‘molecular autopsy’). Keep educating yourself and your multidisciplinary team about cardiogenetics, including variants classification, methodology, and database registries combining clinical and genomic information. One significant challenge among many is the appropriate interpretation of genetic variants.3,6 The clinical significance of many identified variants frequently remains uncertain, leading to potential misinterpretation and anxiety for patients and families. The clinical significance of polygenic risk scores needs to be established and validated following rules of evidence-based medicine in order to achieve broad acceptance. Additionally, the integration of genomic data into electronic health records poses logistical challenges for healthcare providers who must be equipped to interpret and act upon this information. Personalized medicine tailors treatment strategies to individual patients based on their own genetic makeup, while stratified medicine categorizes patients into subgroups based on shared genetic and phenotypic characteristics. Both approaches hold the promise of improving patient outcomes by ensuring therapies that are more effective and better tolerated. Gene-based therapeutic approaches are at the forefront of this evolution.7 The development of gene-editing technologies, such as CRISPR-Cas9, offers the potential to correct genetic variants responsible for certain CVD. Furthermore, pharmacogenomics—the study of how genes affect a person’s response to drugs—can optimize drug selection and dosing in cardiovascular patients. To facilitate the integration of genomic medicine into routine clinical practice and to promote its safe use, cardiologists and a multidisciplinary team of healthcare providers must be equipped with the knowledge and skills to generate, interpret, and communicate genetic data. The ESC Council on Cardiovascular Genomics is committed to coordinating and providing guidance to reach this goal of transforming expert knowledge into common knowledge (Figure 1). Out from the niche into the open! The ESC Cardiogenomics Conference in December 2024 in Antwerp, Belgium: bringing together a multidisciplinary community. Nothing to declare.