A focus on two rapidly expanding fields: cardio-oncology and genetics

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on cardio-oncology, genetics, ischaemic heart disease contains a State of the Art Review entitled ‘Genetic testing in early-onset atrial fibrillation’ by Shinwan Kany from the Broad Institute of MIT and Harvard in Cambridge, MA (USA), and colleagues.1 The role of genetics in the management of cardiovascular diseases is expanding.2–8 The authors note that a prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%–11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pre-test counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European-descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research—mechanistic, translational, and clinical—is urgently needed. Multivessel coronary artery disease is present in ∼50% of patients with acute coronary syndrome and, compared with single-vessel disease, entails a higher risk of new ischaemic events and a worse prognosis. In a State of the Art Review article entitled ‘Coronary bypass surgery for multivessel disease after percutaneous coronary intervention in acute coronary syndromes: why, for whom, how early?’, Laura Besola from the University of Pisa in Italy, and colleagues note that randomized controlled trials have shown the superiority of ‘complete revascularization’ over culprit lesion-only treatment.9 Trials, however, only included patients treated with percutaneous coronary intervention (PCI), and evidence regarding complete revascularization with coronary artery bypass graft (CABG) surgery after culprit lesion-only PCI (‘hybrid revascularization’) is lacking. The CABG after PCI is an open, non-negligible therapeutic option for patients with non-culprit left main and/or left anterior descending coronary artery disease where evidence in chronic coronary syndrome patients points in several cases to a preference of CABG over PCI. This valuable but poorly studied ‘PCI first–CABG later’ option presents, however, relevant challenges, mostly in the need to interrupt post-stenting dual antiplatelet therapy (DAPT) for surgery to prevent excess bleeding. Depending on patients’ clinical characteristics and coronary anatomical features, either deferring surgery after a safe interruption of DAPT or bridging DAPT interruption with intravenous short-acting antithrombotic agents appears to be a suitable option. Off-pump minimally invasive surgical revascularization, associated with less operative bleeding than open-chest surgery, may be an adjunctive strategy when revascularization cannot be safely deferred and DAPT is not interrupted. Here, the rationale, patient selection, optimal timing, and adjunctive strategies are reviewed for an ideal approach to hybrid revascularization in post-acute coronary syndrome patients to support physicians’ choices in a case-by-case patient-tailored approach. In a Viewpoint article entitled ‘Iron replacement in anthracycline-related cardiac dysfunction: fuel on the fire?’, Muhummad Sohaib Nazir from King’s College London in the United Kingdom, and colleagues note that while anthracycline cardiotoxicity causing cancer therapy-related cardiac dysfunction has a complex multifactorial pathology incorporating topoisomerase IIα inhibition, inflammation, microvascular injury, and senescence, anthracyclines also have a profound effect on cardiac iron handling.10 Not only do anthracyclines liberate intracellular iron from aconitase, but by inactivating iron regulatory proteins 1 and 2, they upregulate myocyte transferrin receptor expression to increase iron uptake while downregulating mitochondrial ferritin expression and inactivating the mitochondrial iron exporter ATP-binding cassette subfamily member 8. As such, they increase cardiac (and specifically mitochondrial) iron uptake while simultaneously decreasing mitochondrial capacity to either store or excrete it. This elevated labile iron can then complex with anthracyclines in the cytoplasm to redox cycle via NADPH oxidase or with cardiolipin-anchored anthracyclines in the inner mitochondrial membrane to redox cycle in the electron transport chain to transform superoxide and hydrogen peroxide to more damaging hydroxyl free radicals and iron–peroxo complexes, causing oxidative stress, ferroptosis, and mitochondrial dysfunction. Experimental elevation of cardiac iron has been shown to exacerbate anthracycline cardiotoxicity in animal studies, and genetic predisposition to cardiac iron overload in conditions like haemochromatosis is known to lead to increased incidence of anthracycline cardiotoxicity in cancer patients. While research in this arena continues, the authors would advise that careful consideration should be given when supplementing iron during anthracycline administration, particularly in patients with acute or early left ventricular systolic dysfunction secondary to anthracyclines. Nevertheless, given the large clinical benefits of intravenous iron that have been shown in randomized controlled trials,11–14 the authors’ viewpoint is that it would not be logical to consider intravenous iron replacement until after completion of anthracycline chemotherapy, clearance of anthracyclines and their metabolites from the heart, and a period of recovery from any acute anthracycline-related cardiac dysfunction. In a Viewpoint entitled ‘Cardiac wasting and cancer’, Markus Anker from Charité—University Medicine Berlin in Germany, and colleagues note that in the classical cardiotoxicity inspired approach to cardio-oncology, most preclinical and clinical research is focusing on a better understanding of the precise effects of anti-cancer therapy on the heart in patients with cancer and how this may cause increased inflammatory and oxidative stress on cardiomyocytes.15 They argue, however, that cardiac wasting occurs also independent of cardiotoxic cancer therapy and may lead to cardiac dysfunction resembling heart failure. They also indicate that preventing or reversal of cancer-related cardiac wasting requires dedicated attention in future trials given its detrimental effects on quality of life and mortality. To be of value, mechanistic/surrogate endpoints need to portray an important aspect of pathophysiology, should be related to patient prognosis, and potentially undergo sizeable changes in reasonably short periods of time. In addition, such endpoints should be readily assessable in standardized ways with high precision, which is also the case for LV mass when assessed by echocardiography or cardiac magnetic resonance imaging. Such endpoints need to be responsive to appropriate therapy and predict clinical benefits well. Further research is imperative to identify the development and stages of cardiac cachexia in cancer patients and delineate it from cachexia due to chronic illnesses. Ongoing trials (like EMPATICC, NCT05636774) and future trials should help to build knowledge on how predictive changes in LV mass are for the clinical benefit of patients regarding symptoms, quality of life, exercise capacity, and mortality. In a Clinical Research article entitled ‘Bleeding risk prediction after acute myocardial infarction-integrating cancer data: the updated PRECISE-DAPT cancer score’, Mohamed Dafaalla from Keele University in Stoke-on-Trent in the United Kingdom, and colleagues assessed the impact of incorporating cancer as a predictor on performance of the PRECISE-DAPT score.16 A nationally linked cohort of ST-elevation myocardial infarction (STEMI) patients between 1 January 2005 and 31 March 2019 was derived from the UK Myocardial Ischaemia National Audit Project and the UK Hospital Episode Statistics Admitted Patient Care registries. The primary outcome was major bleeding at 1 year. A new modified score was generated by adding cancer as a binary variable to the PRECISE-DAPT score using a Cox regression model and comparing its performance with the original PRECISE-DAPT score. A total of about 217 000 STEMI patients were included, of whom 4569 had cancer. The original score showed moderate accuracy (C-statistics .60), and the modified score showed modestly higher discrimination (C-statistics .64; hazard ratio 1.03) even in patients without cancer (C-statistics .63; hazard ratio 1.03). The net reclassification index was .07. The bleeding rates of the modified score risk categories (high, moderate, low, and very low bleeding risk) were 6.3%, 3.8%, 2.9%, and 2.2%, respectively. According to the original score, 65% of cancer patients were classified as high bleeding risk (HBR) and 22% were low or very low bleeding risk. According to the modified score, 94% of cancer patients were HBR, 6.0% were moderate bleeding risk, and no cancer patient was classified as low or very low bleeding risk (Figure 1). Generation and validation of an updated PRECISE-DAPT cancer score. HBR, high bleeding risk; HES, Hospital Episode Statistics; MINAP, Myocardial Ischaemia National Audit Project; ONS, Office for National Statistics; STEMI, ST-elevation myocardial infarction16 The authors conclude that adding cancer to the PRECISE-DAPT score identifies most patients with cancer as HBR and can improve its discrimination ability without undermining its performance in patients without cancer. This manuscript is accompanied by an Editorial by Alfonso Jurado-Román from the La Paz University Hospital and Pilar Agudo-Quílez from the University Hospital Ramón y Cajal in Madrid, Spain.17 The authors highlight that further studies are required to generate more accurate tools for risk assessment of bleeding events in cancer patients. In this sense and considering that some scores are probably not used in daily practice as much as recommended, it will be necessary to maintain a balance between the improved accuracy of the new scores and their applicability (adding only those variables that significantly improve their performance). For this aim, artificial intelligence might be useful. Our challenge in the coming years will be to take advantage of all these tools and new technologies, while maintaining clinical judgement and common sense as a basic pillar in decision-making, especially in complex patients such as oncological patients with myocardial infarction. A cardiovascular disease polygenic risk score (CVD-PRS) can stratify individuals into different categories of cardiovascular risk,18–20 but whether the addition of a CVD-PRS to clinical risk scores improves the identification of individuals at increased risk in a real-world clinical setting is unknown. In a Clinical Research article entitled ‘Polygenic risk score adds to a clinical risk score in the prediction of cardiovascular disease in a clinical setting’, Nilesh Samani from the University of Leicester in the United Kingdom, and colleagues investigated just this question.21 The Genetics and the Vascular Health Check study (GENVASC) was embedded within the UK National Health Service Health Check (NHSHC) programme, which invites individuals between 40 and 74 years of age without known CVD to attend an assessment in a UK general practice where CVD risk factors are measured and a CVD risk score (QRISK2) is calculated. Between 2012 and 2020, about 44 000 individuals (56% females, 16% non-white) who attended an NHSHC in 147 participating practices across two counties in England were recruited and followed. When 195 individuals (cases) had suffered a major CVD event (CVD death, myocardial infarction or acute coronary syndrome, coronary revascularization, stroke), 396 propensity-matched controls with a similar risk profile were identified, and a nested case-control genetic study undertaken to see if the addition of a CVD-PRS to QRISK2 in the form of an integrated risk tool (IRT) combined with QRISK2 would have identified more individuals at the time of their NHSHC as at high risk (QRISK2 10-year CVD risk of ≥10%), compared with QRISK2 alone. QRISK2 identified 61% of individuals who subsequently developed a major CVD event as being at high risk at their NHSHC, while the combination of QRISK2 and IRT identified 69%, a relative increase of 11.7% (P = 1 × 10−4).The combination of QRISK2 and IRT increased the proportion of additional cases identified similarly in both women and men, and in non-white ethnicities compared with white ethnicity. The findings were similar when the CVD-PRS was added to the atherosclerotic cardiovascular disease pooled cohort equations (ASCVD-PCE) or SCORE2 clinical scores. The authors conclude that in a clinical setting, the addition of genetic information to clinical risk assessment significantly improves the identification of individuals who go on to have a major CVD event as being at high risk, especially among younger individuals. The findings provide important real-world evidence of the potential value of implementing a CVD-PRS into health systems. The contribution is accompanied by an Editorial by Virimchi Pillutla and Krishna Aragam from Broad Institute of MIT and Harvard in Cambridge, MA (USA).22 The authors note that following a decade of investigations to develop, test, and refine CVD-PRSs in research cohorts, the current study represents a pivotal shift towards their real-world application. Future efforts will need to pursue CVD-PRS implementation in various clinical scenarios, health economic assessments, evaluations of behavioural change in response to PRS disclosure, and studies of real-world patient outcomes to determine the optimal integration and impact of PRSs in routine practice. Samani et al. take a crucial step in this direction, as final judgements on the utility of CVD-PRSs may lie in their evaluation in the context of clinical care. The spleen serves as an important relay organ that releases cardioprotective factor(s) upon vagal activation during remote ischaemic conditioning (RIC) in rats and pigs. In a Translational Research article entitled ‘Vago-splenic signal transduction of cardioprotection in humans’, Helmut Raphael Lieder from the University of Essen Medical School in Germany, and colleagues attempted the translation of these findings to humans.23 Remote ischaemic conditioning or electrical auricular tragus stimulation (ATS) were performed in 10 healthy young volunteers, 10 volunteers with splenectomy, and 20 matched controls. Venous blood samples were taken before and after RIC/ATS or placebo, and a plasma dialysate was infused into isolated perfused rat hearts subjected to global ischaemia/reperfusion. Neither left nor right RIC or ATS altered heart rate and heart rate variability in the study cohorts. With the plasma dialysate prepared before RIC or ATS, respectively, infarct size (% ventricular mass) in the recipient rat heart was 36 ± 6% (left RIC), 34 ± 3% (right RIC) or 31 ± 5% (left ATS), 35 ± 5% (right ATS), and decreased with the plasma dialysate from healthy volunteers after RIC or ATS to 20 ± 4% (left RIC), 23 ± 6% (right RIC) or to 19 ± 4% (left ATS), 26 ± 9% (right ATS); infarct size was still reduced with plasma dialysate 4 days after ATS and 9 days after RIC. In a subgroup of six healthy volunteers, such infarct size reduction was abrogated by intravenous atropine. Infarct size reduction by RIC or ATS was also abrogated in 10 volunteers with splenectomy, but not in their 20 matched controls (Figure 2). In healthy humans, remote ischaemic conditioning (RIC) by cycles of arm ischaemia/reperfusion and electrical auricular tragus stimulation (ATS) does not alter heart rate and heart rate variability (HRV) but induces the release of circulating cardioprotective factor(s), which, when transferred to an isolated perfused rat heart with global ischaemia/reperfusion, reduce infarct size. This release of cardioprotective factors requires vagal innervation and is abrogated by atropine. The cardioprotective factor(s) are released from the spleen and are absent in humans with prior splenectomy. Both RIC and ATS activate vago-splenic signal transduction for cardioprotection. ECG, electrocardiogram23 The authors conclude that in humans, vagal innervation and the spleen as a relay organ are decisive for the cardioprotective signal transduction of RIC and ATS. The manuscript is accompanied by an Editorial by Lina Badimon from the Hospital de la Santa Creu i Sant Pau in Barcelona, Spain, and Attila Kiss and Bruno Podesser from the Medical University in Vienna, Austria.24 The authors note that the protection of the myocardium during ischaemia and infarction is an unmet need and many approaches are presently being investigated. They hope that the application of strict research protocols with few confounders and the utilization of state-of-the-art technologies will generate a rapid development of new options and approaches with successful translation into the clinical arena. In the meantime, the authors should be commended for designing a translational research study to clearly show the vago-splenic in the of of RIC. cardiac represents a major health for a proportion of cardiovascular are by coronary artery disease however, the are not particularly in patients without In a contribution entitled coronary and cardiac in patients with coronary artery from the University School of Medicine in and colleagues further study this This study included 23 patients who and coronary and was identified in while and were in patients and respectively. were in which with such as and However, 10 patients in the of or was identified in two as by elevation and by patients were to have coronary following a response to the in all but patient with coronary The authors conclude that their results that is in patients from without coronary accompanied by coronary The is also by a In a entitled for and cardiovascular further evidence is and from the University School of Medicine in and colleagues on the recent benefits after coronary for acute coronary syndromes: the by from University of London in the United The hope that this of the Heart will be of to its from the With to and for help with of this