Cancer therapy has dramatically changed over the past many decades, not only in efficacy but also complexity, with targeted therapeutics that have novel mechanisms of action. As a direct result of these remarkable treatments that have extended the lives of many patients, the increased recognition of cancer therapy-related cardiac dysfunction as well as the broader description of cancer therapy-related cardiovascular toxicity (CTR-CVT) has become obvious. The discipline of cardio-oncology has accepted the challenge to provide excellent cardiovascular (CV) protection for our patients being treated for cancer in order to achieve the best overall outcomes. The successful application of optimal CV protection by cardio-oncology needs to incorporate basic principles to realise these improved overall outcomes. Critical paradigm principles include: (1) using effective CV therapy; (2) targeting the likely mechanisms of action responsible for CTR-CVT; and (3) documenting cancers and cancer therapies associated with high CTR-CVT. Such a CV protection paradigm is likely to have the biggest impact and confirm an improved overall outcome. In addition, it is important to emphasise that knowing those cancers with high CTR-CVT risk requires careful comparative study of CV endpoints during exploratory cancer trials. Furthermore, astute clinical observations of specific CTR-CVT should be routinely reported to allow the development of strategies that minimise the negative impact of CTR-CVT. Lastly, coordinated efforts that allow realistic goals of cancer treatment while minimising the impact of CTR-CVT are the end goal in order to eliminate CV disease as a barrier to effective cancer treatment.

Congenital heart disease (CHD) is the most common congenital anomaly, with lifelong implications as survival into adulthood becomes the norm. Despite advances in prenatal detection, surgical care and long-term follow-up, the aetiology of CHD remains incompletely understood. This narrative review synthesises current evidence across genetic, epigenetic and environmental domains, with particular attention to their interplay.Growing evidence indicates that genetic susceptibility in combination with environmental exposures may shape CHD risk. While chromosomal anomalies and single-gene defects explain a minority of cases, polygenic contributions and emerging evidence on epigenetic programming suggest additional layers of complexity in CHD aetiology. Maternal health conditions, such as diabetes, autoimmune disease and infections together with medication use, play critical roles in determining fetal cardiac development and contribute to modifiable risk pathways. Lifestyle, reproductive and external environmental factors, including smoking, assisted reproductive technology and air pollution, further underscore the need for proactive counselling and early risk mitigation. Emerging evidence also points to gene-environment interactions as a key mechanism through which genetic susceptibility modulates the impact of external exposures, offering new avenues for precision prevention.Looking ahead, progress will depend on integrating multi-omic data with longitudinal cohorts, multinational registries and interoperable data infrastructures. Such efforts must be coupled with implementation research to translate mechanistic insights into predictive tools and scalable interventions. Framing CHD within this bench-to-bedside-to-policy continuum positions it as both a model for precision prevention and lifelong, multidisciplinary care and a test case for approaches that could be extended to other multifactorial conditions with major population-health impact.