Innovative therapeutic targets in cardio-oncology and a Great Debate in heart failure

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on cardio-oncology, ischaemic heart disease, and heart failure contains a contribution entitled ‘Great Debate: SGLT2 inhibitors should be first-line treatment in heart failure with reduced ejection fraction’ introduced by the EHJ Editor Johan. Bauersachs.1 He notes that evidence-based medical therapy of heart failure (HF) is well established using a combination of angiotensin receptor–neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium–glucose co-transporter 2 (SGLT2) inhibitors. The recent 2021 ESC guidelines for the treatment of HF have abandoned the paradigm of sequential therapy (i.e. installing one treatment after the other), instead advocating early installation of all four live-saving treatments already during the hospitalization phase in patients after a HF decompensation.2 In clinical practice, however, both for patients with stable chronic HF and also for patients with acutely decompensated HF, there is uncertainty as to how to implement all of these therapies. In particular for patients not pre-treated with an angiotensin-converting enzyme (ACE) inhibitor or a beta-blocker, the question often arises of whether one of these long-established HF treatments should be initiated first, or whether, even without knowledge of the left ventricular ejection fraction, it would be preferable to initiate an SGLT2 inhibitor. However, it is still not evidence based whether SGLT2 inhibition should precede other guideline-recommended medical therapy drugs in patients with de novo HF or in patients with stable chronic HF. In this Great Debate the authors of the Pro propose that in patients with heart failure with reduced ejection fraction (HFrEF) there is enough evidence to advocate for the primordial start of SGLT2 inhibitors instead of other HF drugs first. The authors of the Contra provide arguments which challenge this approach. There is growing interest in cardio-oncology.3–7 In a Viewpoint article entitled ‘The year in cardiovascular medicine 2023: the top 10 papers in cardio-oncology’, EHJ Editors Joerg Herrmann, Teresa López-Fernández, and Alexander R. Lyon indicate that over the past year, there have been many outstanding contributions to the field of cardio-oncology, and these are carefully analysed and put into perspective.8 Coexisting atrial fibrillation (AF) and cancer challenge the management of both. In a Clinical Research article entitled ‘Coexisting atrial fibrillation and cancer: time trends and associations with mortality in a nationwide Dutch study’, Qingui Chen from the Leiden University Medical Center in the Netherlands, and colleagues seek to comprehensively provide the epidemiology of coexisting AF and cancer.9 Using Dutch nationwide statistics, individuals with incident AF (n = 320 139) or cancer (n = 472 745) were identified during the period 2015–19. Dutch inhabitants without a history of AF (n = 320 135) or cancer (n = 472 741) were matched as control cohorts by demographic characteristics. Prevalence of cancer/AF at baseline and 1-year risk of cancer/AF diagnosis were determined. The association of cancer/AF diagnosis with all-cause mortality among those with AF/cancer was estimated by using time-dependent Cox regression. The rate of prevalence of cancer in the AF cohort was 12.6% compared with 5.6% in the controls; 1-year cancer risk was 2.5% compared with 1.8% in the controls [adjusted hazard ratio (aHR) 1.52], which was similar by cancer type. The rate of prevalence of AF in the cancer cohort was 7.5% compared with 4.3% in the controls; 1-year AF risk was 2.8% compared with 1.2% in the controls (aHR 2.78), but cancers of the oesophagus, lung, and stomach, myeloma, and lymphoma were associated with higher hazards of AF than other cancer types. Both cancer diagnosed after incident AF (aHR 7.77) and AF diagnosed after incident cancer (aHR 2.55) were associated with all-cause mortality, but the strength of the association varied by cancer type (Figure 1). Prevalence, incidence, time trend, and association with all-cause mortality of coexisting atrial fibrillation and cancer in the Netherlands. AF, atrial fibrillation; aHR, adjusted hazard ratio; CI, confidence interval.9 The authors conclude that AF and cancer are associated bidirectionally, and AF risk varies by cancer type. Coexisting AF and cancer are negatively associated with survival. This manuscript is accompanied by an Editorial by Dimitrios Farmakis and Gerasimos Filippatos from the National and Kapodistrian University of Athens Medical School in Greece.10 The authors note that the 2022 European Society of Cardiology guidelines on cardio-oncology recommend, largely based on expert consensus, to guide decision-making on anticoagulation in patients with active cancer by periodic assessment of the risk of thrombosis and bleeding, drug–drug interactions, and patient preferences, as summarized in the acronym TBIP (T for thrombosis, B for bleeding, I for interactions and P for patients). Finally, the management of AF in terms of rhythm or rate control should follow the general guideline recommendations, taking into consideration two additional factors, the stage and prognosis of cancer and again the potential drug–drug interactions. As cancer prognosis continuously improves by virtue of modern therapeutics, patients should not be a priori deprived of any available treatment options for the management of AF. Platelet–fibrin clot strength is linked to major adverse cardiovascular event (MACE) risk. However, the association between platelet–fibrin clot strength and platelet reactivity and their prognostic implication remains uncertain in patients undergoing percutaneous coronary intervention (PCI). In another Clinical Research article entitled ‘Platelet–fibrin clot strength and platelet reactivity predicting cardiovascular events after percutaneous coronary interventions’, Osung Kwon from the Catholic University of Korea in Seoul, South Korea, and colleagues researched this matter.11 In ∼2500 PCI-treated patients, platelet–fibrin clot strength using thromboelastography and platelet reactivity using VerifyNow were measured. MACE [all-cause death, myocardial infarction (MI), or stroke] and major bleeding were followed up to 4 years. High platelet reactivity and high platelet–fibrin clot strength showed an additive effect for clinical outcomes (log-rank test, P < .001). Individuals with normal platelet reactivity and normal platelet–fibrin clot strength, normal platelet reactivity and high platelet–fibrin clot strength, high platelet reactivity and normal platelet–fibrin clot strength, or alterations of both parameters exhibited MACE incidences of 7.5, 12.6, 13.4, and 19.3%, respectively. Kwon and colleagues conclude that in PCI patients, platelet–fibrin clot strength and platelet reactivity demonstrate important relationships in predicting MACE. Their combined assessment may enhance post-PCI risk stratification for personalized antithrombotic therapy. The contribution is accompanied by an Editorial by Diana Gorog from Imperial College in London, UK.12 Gorog notes that the present study suggests that antiplatelet therapy may not be sufficient to mitigate against ischaemic events in patients undergoing PCI, and pharmacological therapies that specifically target fibrin clot formation, in addition to high platelet reactivity, may be desirable in a number of patients. This will require future trials of tailored pharmacotherapy, a direction supported by this year’s ESC 2024 meeting Spotlight on ‘Personalizing Cardiovascular Care’. Patients with acute myeloid leukaemia (AML) suffer from severe myocardial injury during daunorubicin (DNR)-based chemotherapy and are at high risk of cardiac mortality. The cross-talk between tumour cells and cardiomyocytes might play an important role in chemotherapy-related cardiotoxicity, but this has yet to be demonstrated. In a Translational Research article entitled ‘Rescue of cardiac dysfunction during chemotherapy in acute myeloid leukaemia by blocking IL-1α’, Xingliang Zhou from the Shanghai Jiaotong University School of Medicine in China, and colleagues aimed to identify its underlying mechanism and explore potential therapeutic targets.13 Cardiac tissues were harvested from an AML patient after DNR-based chemotherapy and were subjected to single-nucleus RNA sequencing. Cardiac metabolism and function were evaluated in AML mice after DNR treatment by using positron emission tomography, magnetic resonance imaging, and stable-isotope tracing metabolomics. Plasma cytokines were screened in AML mice after DNR treatment. Genetically modified mice and cell lines were used to validate the central role of the identified cytokine and explore its downstream effectors. In the AML patient, disruption of cardiac metabolic homeostasis was associated with heart dysfunction after DNR-based chemotherapy. In AML mice, cardiac fatty acid utilization was attenuated, resulting in cardiac dysfunction after DNR treatment, while these alterations were not observed in similarly treated tumour-free mice. Furthermore, tumour cell-derived interleukin (IL)-1α was identified as a primary factor leading to DNR-induced cardiac dysfunction, and administration of an anti-IL-1α neutralizing antibody improved cardiac functions in AML mice after DNR treatment. The authors conclude that this study reveals that cross-talk between tumour cells and cardiomyocytes during chemotherapy could disturb cardiac energetic metabolism and impair heart function. IL-1α neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients. The manuscript is accompanied by an Editorial by Carlo Gabriele Tocchetti from the University of Naples in Italy, and colleagues.14 The authors highlight that the previous experience of IL-1β blockade with canakinumab in the CANTOS trial points out that identifying crucial players in the inflammatory response is essential to tackle both cancer and cardiovascular disease. Thus, targeting IL-1α might be a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients. More in general, this intriguing finding feeds the evidence that inflammation is indeed at the crossroads between cancer, cardiotoxicity of anticancer therapies, and HF. In a Rapid Communications contribution entitled ‘Cardiac biomarkers for diagnosing Takotsubo syndrome’, Victor Schweiger from the University of Zurich in Switzerland, and colleagues note that Takotsubo syndrome (TTS) is marked by temporary left ventricular wall motion abnormalities due to coronary microvascular dysfunction, without blockage in the main coronary arteries.15 The authors enrolled 1060 patients with TTS and 2435 all-comer patients with either ST-elevation MI or non-ST-elevation MI. Patients with TTS exhibited comparable admission troponin values, but lower peak troponin values than patients with MI. Admission and peak brain natriuretic peptide (BNP) levels were significantly higher in TTS compared with MI patients. The BNP/troponin ratio at admission exhibited an area under the curve (AUC) of 0.62 (9.8% sensitivity at 90% specificity) for the diagnosis of TTS, while the BNP/troponin ratio at peak achieved an AUC of 0.70 (25.9% sensitivity at 90% specificity). The authors conclude that in this study, involving patients from the world’s largest cohort of TTS patients, the efficacy of biomarker ratios in distinguishing TTS from acute coronary syndrome (ACS) is only moderately successful. Despite previous claims that these ratios could accurately differentiate between TTS and MI, the originally anticipated excellent diagnostic accuracies could not be replicated in this international cohort of TTS patients. Thus, this study highlights the critical necessity for discovering novel biomarkers to enhance the diagnosis of TTS. The issue also contains a Rapid Communications contribution entitled ‘Atherosclerosis in ancient mummified humans: the global HORUS study’ by Randall Thompson from the University of Missouri-Kansas City from the USA, and colleagues. The authors note that atherosclerosis is usually thought of as a disease of modern times. However, atherosclerosis has been found in the remains of ancient people, suggesting that the disease has been present in humans in some form for many millennia. In this study, the authors significantly expanded the previous experience of computed tomography (CT) scanning to systematically identify atherosclerosis in the mummified remains of people from around the world and explored its presence in seven different cultures.16 CT scans from 237 adult mummies were analysed. Of these, 38% were females. Mean estimated age at death was 40 years. Atherosclerosis was found in all cultures. Definite or probable atherosclerosis was seen in 38% of mummies. The aorta was the most involved vascular bed, followed by the ilio-femoral, the popliteal-tibial, the carotid, and the coronary arteries. The authors conclude that atherosclerosis is ubiquitous in human populations since ancient times. Atherosclerotic calcifications are found in similar frequencies in Egyptian and non-Egyptian mummies and in men and women. These findings support the existence of an innate human predisposition to atherosclerosis. Modern cardiovascular risk factors superimposed on an underlying, inherent risk may drive the extent and impact, of atherosclerosis. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Percutaneous stellate ganglion block for electrical storm treatment: the new rising STAR?’, Roberto Scacciavillani from the Policlinico A Gemelli: Policlinico Universitario Agostino Gemelli in Rome, Italy comments on the recent publication ‘Electrical storm treatment by percutaneous stellate ganglion block: the STAR study’ by Simone Savastano from the Fondazione IRCCS Policlinico San Matteo in Pavia, Italy.17,18 Savastano et al. respond in a separate comment.19 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.