Cardio-oncology: a new specialty moves to centre stage

For the podcast associated with this article, please visit https://academic. oup.com/eurheartj/pages/Podcasts. The treatment of malignant disease has made impressive progress over the last two decades. With novel compounds such as trastuzumab, novel kinase and checkpoint inhibitors, just to mention a few, the survival of patients with many types of tumour can now be markedly prolonged. However, most of these substances, both older compounds such as anthracycline and the newer molecules, are associated with unfavourable side effects on the cardiovascular system, in both the short and the long term.1–5 Of particular importance are reductions in pump function, arrythmias, coagulation disorders, and coronary artery disease. Thus, novel and interdisciplinary services are urgently needed in order to manage such patients, as outlined by Patrizio Lancellotti from the University Hospital of Liège in Belgium and colleagues in their Special Article ‘Cardio-Oncology Services: rationale, organization, and implementation: a report from the ESC Cardio-Oncology council’.6 They point out that cardiotoxicity may occur both early and late after treatment initiation or termination. The extent is variable, depending on the type of drug used, combination with other drugs, mediastinal radiotherapy, the presence of cardiovascular risk factors, as well as comorbidities. A position paper of the European Society of Cardiology addressed the management of such patients, while this article focuses on Cardio-Oncology Services, their rationale, organization, and implementation. Such services require a multidisciplinary approach, with the aim of promoting cardiovascular health and facilitating effective cancer therapy. The growing volume of patients with cancer at risk of developing or worsening cardiovascular disease, the advent of new technological opportunities to refine diagnosis, and the necessity of early recognition of cancer therapy-related toxicity mandate an integrative multidisciplinary approach and care in a specialized environment. The cardiotoxic effects of chemotherapy are further pursued in a review article entitled ‘Cancer therapy-induced cardiomyopathy: can human induced pluripotent stem cell modelling help prevent it?’ by Joseph C. Wu and colleagues from Stanford University in California, USA.7 Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-cardiomyocytes) are increasingly being used as instruments for disease modelling,8 drug discovery,9,10 and mechanistic toxicity studies.11,12 Promising results with hiPSC-cardiomyocyte chemotherapy studies are raising hopes for improving cancer therapies through personalized medicine and safer drug development, as outlined extensively in this review. Of note, cardiotoxic effects of any, not just oncological, drug may affect the cardiovascular system, as reviewed by Rainer Schulz and colleagues from the Institute of Pathophysiology in Essen, Germany in their article ‘Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications’.13 They remind us that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, ATP-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Drugs may exert unwanted effects on the diseased and treated heart that are hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of ‘hidden cardiotoxicity’, defined as cardiotoxicity of a drug that manifests only in the diseased heart with, for example, ischaemia/reperfusion injury and/or in the presence of its major comorbidities. As little is known about the mechanism of hidden cardiotoxicity, there is a need for a novel cardiac safety platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or co-treatments. A common comorbidity of both cardiac and cancer patients is hyperuricaemia.14 A FAST TRACK entitled ‘Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy’ by Sunao Kojima and colleagues from the Kumamoto University at Okayama, Japan compared the occurrence of cerebral, cardiovascular, and renal events in patients with hyperuricaemia treated with febuxostat or conventional therapy with lifestyle modification in a multicentre, prospective, randomized open-label, blinded endpoint study involving 1070 patients.15 Serum uric acid at the endpoint in the febuxostat and non-febuxostat groups was 4.5 ± 1.5 mg/dL and 6.8 ± 1.5 mg/dL, respectively. Composite events were significantly lower with febuxostat than in controls, with a hazard ratio of 0.75. The most frequent event was renal impairment, which occurred in 16.2% with febuxostat and in 20.5% in controls. Thus, febuxostat lowers uric acid and delays the progression of renal dysfunction compared with convention therapy with lifestyle changes. However, compared with allupurinol, the drug looks less favourable.16 These findings are further discussed in a comprehensive Editorial by Franz Messerli from the University Hospital Bern in Switzerland.17 Due to comorbidities, cancer patients increasingly undergo cardiac procedures. In their article ‘Percutaneous coronary intervention in cancer patients: a report of the prevalence and outcomes in the United States’, Chun Shing Kwok and colleagues from the Fuwai Hospital in Beijing, China examined the temporal trends and outcomes in patients who underwent percutaneous coronary intervention (PCI) with a previous or current diagnosis of cancer, according to cancer type and the presence of metastases.18 In the 6 571 034 PCIs analysed, current and previous cancer rates were 1.8% and 5.8%, respectively. Both rates increased over time, and the four most common malignancies were prostate, breast, colon, and lung cancer (Figure 1). Patients with a current lung cancer had greater in-hospital mortality, with an odds ratio (OR) of 2.81 and any in-hospital complication with an OR of 1.21, while current colon cancer was associated with complication (OR 2.17) and bleeding (OR 3.65), but not mortality. A current diagnosis of breast cancer was not significantly associated with either in-hospital mortality or any of the complications studied, and prostate cancer was only associated with increased risk of bleeding (OR 1.41). Further, a prior diagnosis of lung cancer was also associated with increased odds of in-hospital mortality (OR 1.65). Thus, cancer is not rare among patients undergoing PCI, and the prognostic impact of cancer is specific for the type of cancer, presence of metastases, and with a past or current diagnosis. These clinically most important findings are put into context in an informative Editorial by Anju Nohria from the Brigham and Women’s Hospital in Boston, USA.19 Percentages of top 10 prevalent current cancer diagnoses, along with historical prevalence of each type of cancer (from Potts JE, Iliescu CA, Lopez Mattei JC, Martinez SC, Holmvang L, Ludman P, De Belder MA, Kwok CS, Rashid M, Fischman DL, Mamas MA. Percutaneous coronary intervention in cancer patients: a report of the prevalence and outcomes in the United States. See pages 1790–1800). Multimorbid patients are prone to complications and bad outcomes after acute events and procedures. During the first 6–12 h of intensive care unit (ICU) stay, post-cardiac arrest patients treated with a mean arterial blood pressure target of 65 mmHg experience a drop of the cerebral oxygenation that may cause additional cerebral damage. In their FAST TRACK ‘Early goal-directed haemodynamic optimization of cerebral oxygenation in comatose survivors after cardiac arrest: the Neuroprotect post-cardiac arrest trial’, Koen Ameloot and colleagues from the Ziekenhuis Oost-Limburg in Zonhoven, Belgium investigated 112 out-of-hospital cardiac arrest patients to determine whether an early goal-directed haemodynamic optimization strategy (EGDHO) aiming at a mean arterial pressure of 85–100 mmHg and mixed venous oxygen saturation of 65–75% would be safe and would optimize cerebral oxygenation, reduce anoxic brain damage, and improve outcome to a pressure target of 65 mmHg.20 With EGDHO, mean arterial pressure and cerebral oxygenation during the first 12 h of ICU stay were significantly higher (Figure 2). However, the percentage of voxels below an apparent diffusion coefficient score did not differ between both groups. Also, the number of patients with favourable neurological outcome at 180 days was similar. However, the number of serious adverse events was lower in patients assigned to EGDHO. Thus, targeting a higher mean arterial pressure in post-cardiac arrest patients is safe and improves cerebral oxygenation, but does not improve the extent of anoxic brain damage or neurological outcome. Daily evolution of troponin, neuron specific enolase, and kidney function (diuresis and creatinine). The figures present the marginal means and their 95% confidence intervals obtained using a GEE model with normal distribution and identity link that included the following factors: stratum, randomized group, time and the interaction between randomized group and time. An exchangeable working correlation matrix was used to account for interdependencies between the timepoints. EGDHO, early goal directed haemodynamic optimization strategy; MAP, mean arterial pressure (from Ameloot K, De Deyne C, Eertmans W, Ferdinande B, Dupont M, Palmers P-J, Petit T, Nuyens P, Maeremans J, Vundelinckx J, Vanhaverbeke M, Belmans A, Peeters R, Demaerel P, Lemmens R, Dens J, Janssens S. Early goal-directed haemodynamic optimization of cerebral oxygenation in comatose survivors after cardiac arrest: the Neuroprotect post-cardiac arrest trial. See pages 1804–1814). This issue is complemented by two Discussion Forum pieces. In a contribution entitled ‘What to do with the equipoise?’, Wiebe G. Knol and colleagues from the Erasmus MC in Rotterdam, The Netherlands comment on the previously published paper entitled ‘Coronary computed tomography angiography for heart team decision-making in multivessel coronary artery disease’ by Patrick W Serruys and colleagues from Imperial College in London, UK.21,22 Serruys et al. respond to the contribution in a separate Discussion Forum article.23 The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.