Open AccessReview Cancer as a Hidden Catalyst: Rethinking Postoperative Atrial Fibrillation After Cardiac Surgery by Sotiris Kyriakou Sotiris Kyriakou Scilit Preprints.org Google Scholar 1,†, Marios Markantonis Marios Markantonis Scilit Preprints.org Google Scholar 2,†, Panos Georghiou Panos Georghiou Scilit Preprints.org Google Scholar 1, Filippos Triposkiadis Filippos Triposkiadis Scilit Preprints.org Google Scholar 2, Amalia Georgiou Amalia Georgiou Scilit Preprints.org Google Scholar 3, Konstantinos Lampropoulos Konstantinos Lampropoulos Scilit Preprints.org Google Scholar 2, Argyris Kyriakou Argyris Kyriakou Scilit Preprints.org Google Scholar 4, Nikolas Iosif Nikolas Iosif Scilit Preprints.org Google Scholar 5 and Georgios P. Georghiou Georgios P. Georghiou Scilit Preprints.org Google Scholar 2,6,* 1 Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AD London, UK 2 School of Medicine, European University Cyprus, 2404 Nicosia, Cyprus 3 Department of Cardiology, Marien Hospital Düsseldorf, 40479 Düsseldorf, Germany 4 Barking, Havering and Redbridge University Hospitals NHS Trust, RM1 2BA London, UK 5 Faculty of Medicine & Surgery, University of Turin, 10126 Turin, Italy 6 Department of Surgery, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel * Author to whom correspondence should be addressed. † These authors contributed equally to this work. J. Clin. Med. 2026, 15(12), 4456; https://doi.org/10.3390/jcm15124456 (registering DOI) Submission received: 29 April 2026 / Revised: 18 May 2026 / Accepted: 6 June 2026 / Published: 9 June 2026 Abstract Postoperative atrial fibrillation (POAF) is the most frequent post-cardiac surgical arrhythmia and is associated with haemodynamic instability, longer hospital stays, higher healthcare utilisation, stroke and adverse long-term outcomes. Conventional models of POAF focus on advancing age, pre-existing atrial substrate, increasing operative complexity, inflammatory responses related to cardiopulmonary bypass, disturbances in autonomic balance, and acute metabolic insults during the perioperative period. Although these explanations are important, they may be incomplete. Malignancy and the cancer-associated systemic environment involve biological processes potentially relevant to postoperative atrial vulnerability, such as chronic inflammation, oxidative stress, impaired vascular function, hypercoagulability, altered immune response, frailty, and treatment-related myocardial, pericardial, or conduction-system injury. This review assesses whether malignancy should be regarded as an underrecognised modifier of susceptibility rather than as a coincidental comorbidity. Most available data are extrapolated from cardio-oncology and thoracic oncology studies or general studies related to atrial fibrillation (AF) rather than studies focused on cardiac surgery. While malignancy cannot be dismissed as irrelevant to the generation of POAF, it also does not permit causal inference. Future studies should move beyond binary cancer status and incorporate cancer activity, treatment exposures, biomarker profiles, and atrial substrate measures to determine whether malignancy improves perioperative POAF risk stratification. Two prior publications from our group have addressed related aspects of this topic and warrant explicit distinction. Georghiou GP et al. conducted a prospective clinical study reporting POAF incidence in relation to cancer status after cardiac surgery, providing preliminary observational data but not a mechanistic synthesis [ 6]. A subsequent narrative overview introduced the conceptual framework linking cancer-associated biology to perioperative atrial vulnerability [ 7]. The present review extends both prior works in several substantive ways. It proposes a structured mechanistic hierarchy that distinguishes substrate-based from trigger-based POAF, introduces an explicit evidence hierarchy across cancer therapy classes, and presents a candidate biomarker and phenotyping panel for future prospective studies. It also provides dedicated analysis of competing explanations, including frailty, multimorbidity, and surveillance bias. Crucially, it distinguishes between active malignancy, prior inactive disease, and definitively cured cancer, a distinction that was incompletely addressed in earlier work. Taken together, this review aims to move the conversation from observational association toward a framework that can guide future study design. 2. POAF as a Substrate-Trigger Syndrome After Cardiac Surgery While conventional models for predicting POAF remain clinically useful, they are biologically incomplete. These models identify age, type of operation, atrial size, prior heart disease, and standard perioperative variables as predictors. However, they account poorly for chronic inflammatory burden, treatment-induced myocardial damage, occult radiation-induced fibrosis, cancer-related endothelial dysfunction, and diminished physiological reserve as represented by frailty and sarcopenia [ 8, 9]. If malignancy is relevant, it will likely be because current models inadequately capture how oncologic biology and treatment history influence the biological substrate on which postoperative triggers act. 3. Malignancy as a Systemic Modifier of Atrial Vulnerability 4. Shared Mechanistic Pathways Between Cancer and POAF Frailty, cachexia, sarcopenia, and autonomic dysregulation can be conceptualised either as confounders or as mechanisms, since they are not exclusive to malignancy and may each contribute independently to AF risk. Nevertheless, they remain relevant when assessing cancer’s role in perioperative susceptibility, regardless of whether malignancy exerts its effects through these intermediaries or through more tumour-specific pathways. For perioperative assessment, the key issue is not simply whether cancer is present, but which oncological consequences the patient brings into the operating room. Atrial myopathy represents an additional mechanistic concept that is particularly relevant to this discussion. Defined by structural and functional alterations of the left atrium—including impaired reservoir and conduit strain, left atrial enlargement, P-wave abnormalities, and elevated NT-proBNP—atrial myopathy shares key pathophysiological cascades with both AF and cancer, including chronic inflammation, extracellular matrix remodelling, oxidative stress, and fibrosis [ 28]. Importantly, markers of left atrial (LA) myopathy have been shown to carry prognostic value for adverse outcomes, including stroke and dementia, even in patients in sinus rhythm, suggesting that structural atrial vulnerability can exist and be quantified before AF becomes clinically overt [ 28]. In the perioperative context, cancer-associated chronic inflammation and treatment-related cardiac injury may accelerate the development or progression of atrial myopathy, thereby establishing the atrial substrate on which surgical triggers act. This raises an important hypothesis for future investigation: whether preoperative markers of LA myopathy—specifically LA volume index, reservoir strain, and NT-proBNP—measured in patients with malignancy who are in sinus rhythm prior to cardiac surgery, carry independent prognostic value for the development of POAF. A prospective study incorporating such measures alongside cancer activity classification and treatment exposure data would directly test this hypothesis and could refine preoperative risk stratification in this population. illustrates how malignancy-related vulnerability and acute cardiac-surgical stressors may converge to promote POAF. 5. POAF as Marker, Mediator, or Both 6. Cancer Therapy Exposures Anthracyclines are particularly important because of their well-established cardiotoxic effects, although their impact on AF may occur indirectly. For example, anthracyclines can produce oxidative injury to the myocardium, impair mitochondrial function with reduced ATP production, promote myocardial fibrosis, and result in impaired left ventricular function. These structural and metabolic changes may render hearts previously exposed to anthracyclines vulnerable to ischaemia–reperfusion injury, catecholamine surges, and mechanical stress during cardiac surgery, and thus potentially more susceptible to POAF [ 34 Bruton tyrosine kinase (BTK) inhibitors represent the most direct therapy class for which a demonstrable link with increased risk of POAF has been reported. Specifically, BTK inhibitors, especially ibrutinib, have been associated with pro-arrhythmic effects through multiple lines of evidence [ 35, 36]. This distinction is important because it suggests that cancer therapy may increase POAF risk through mechanisms more specific than a generalised comorbidity burden. However, this observation should not be extrapolated broadly across all classes of cancer therapy. Rather, it is more appropriate to conclude that patients who are taking BTK inhibitors, or who have been exposed to them recently, and are undergoing major cardiac interventions warrant particular attention. summarises the major anticancer therapy classes with potential relevance to perioperative atrial vulnerability and POAF susceptibility. Evidence categories reflect the consistency, directness, and volume of published data in relation to POAF after cardiac surgery specifically. High: consistent signal from multiple prospective or randomised studies with a direct AF or POAF endpoint. Moderate: supportive observational or mechanistic data, without prospective cardiac surgical evidence. Low-moderate: indirect, limited, or heterogeneous data with biological plausibility but no direct POAF signal. Low: predominantly indirect evidence via cardiometabolic or vascular pathways with no established atrial-specific mechanism. 7. Perioperative Stressors in the Cancer-Exposed Patient summarises how cancer-related vulnerability may amplify established cardiac-surgical triggers and lower the threshold for POAF. 8. Clinical Evidence It should be noted at the outset that direct, high-quality clinical evidence specifically linking malignancy to POAF after cardiac surgery remains sparse; much of what follows is derived from registry data, indirect oncological surgery literature, and mechanistic extrapolation. There are few prospective clinical studies examining the specific relationship between cancer and POAF after cardiac surgery. Georghiou et al. provided one of the earliest prospective assessments of POAF incidence in relation to cancer status. Their findings support the possibility that malignancy and operative stress may interact in arrhythmogenic ways; however, the evidence remains preliminary and does not establish independence from operative stress, comorbidity burden, or baseline atrial vulnerability [ 6 summarises the principal published studies directly or indirectly examining POAF in cancer-exposed surgical populations. 9. Methodological Limitations of the Current Evidence Base Several limitations in the current literature should shape interpretation and they include (1) crude definitions of cancer exposure, (2) incomplete documentation of both disease activity and disease stage at diagnosis, (3) inadequate detail regarding prior treatment exposures, (4) significant variability among institutions and providers regarding their use of rhythm monitoring and (5) lack of distinction between pre-existing AF and truly de novo AF that occurred after surgery. Survivorship bias may also complicate direct comparison between patients with active malignancy and those with prior cancer. Patients with very advanced malignancies are frequently unable to undergo evaluation for cardiac surgery. Thus, while cohorts of patients with a history of cancer may provide some insight into potential risks associated with undergoing cardiac surgery, they are unlikely to accurately represent the risk experienced by cohorts of patients who have active systemic malignancy, unless future studies clearly distinguish these states. 10. Toward More Informative Risk Stratification Cancer is likely to inform clinical decision-making meaningfully if it is used as something more than a simple binary variable. As such, a history of cancer typically provides little additional mechanistic insight beyond that provided by a patient’s age, comorbidities, and functional reserve. A potentially more meaningful way to stratify risk based on cancer would be to incorporate more granular variables to better characterise both the status of the patient’s cancer and the nature of their previous treatments. This requires documenting cancer activity status, tumour type, disease stage, and time since diagnosis. Treatment exposures should be recorded with enough specificity to distinguish limited historical exposure from ongoing cardiovascular injury. If incorporated into a model predicting POAF, cancer is more likely to enhance discrimination through the refinement of phenotypic characterization rather than through binary classification. 11. Candidate Biomarkers and Phenotypic Markers outlines candidate biomarker, imaging, and phenotypic measures that could support future prospective studies of cancer-related POAF susceptibility. 12. Implications for Perioperative Assessment and Management 13. Limitations and Alternative Explanations Frailty deserves particular attention as a standalone competing explanation. Frailty is an independent predictor of POAF after cardiac surgery and is simultaneously over-represented in cancer populations [ 52]. If the association between malignancy and POAF attenuates substantially after adjustment for validated frailty indices, this would suggest that cancer’s apparent effect is mediated principally through reduced physiological reserve rather than tumour-specific biology. Current observational studies have not performed this adjustment with sufficient granularity to settle this question. Multimorbidity represents a closely related alternative. Patients with a cancer history disproportionately accumulate hypertension, diabetes, renal dysfunction, and anaemia—each of which independently predicts POAF and atrial remodelling. If these comorbidities are incompletely captured or adjusted for, the residual cancer effect may reflect comorbidity clustering rather than oncologic biology per se. Future registry-based and prospective studies should apply comorbidity burden scores alongside cancer classification to disentangle these contributions. Treatment burden, including polypharmacy, prior hospitalisations, nutritional depletion, and deconditioning from chemotherapy or prolonged illness, may also contribute to perioperative vulnerability independently of the biological effects of cancer itself. Patients with treatment-heavy histories may have impaired autonomic regulation, reduced functional capacity, and diminished cardiopulmonary reserve that are not captured by standard preoperative risk scores and that would lower the threshold for postoperative arrhythmia regardless of the tumour’s direct biological influence. Adequately accounting for this dimension will require more granular treatment history documentation than is currently standard in cardiac surgical databases. summarises competing explanations for the observed association between cancer and POAF, highlighting the need for refined clinical phenotyping. 14. Distinguishing Active from Prior Malignancy A critical distinction must be made between individuals with active metastatic disease and/or recent systemic therapy for their cancer and those with previously treated and now definitively cured cancer. Many databases currently collapse these two categories together. Such practices tend to diminish the gradient of biological relevance that this area of investigation seeks to understand. Future studies must distinguish cancer activity status (e.g., active, inactive), stage (e.g., localised, regional) and treatment timing (e.g., past year vs. years ago) to effectively assess the biological impact of cancer on POAF. 15. Overall Interpretation of the Evidence Taken together, the available evidence supports malignancy as a plausible modifier of POAF susceptibility, but not yet as an independently validated determinant of perioperative risk. The main unresolved issue is whether cancer-related biology adds predictive value beyond the comorbidities and frailty with which it commonly clusters. The most appropriate way to investigate this question is within existing POAF frameworks. Current data suggest that cancer and its treatments may augment inflammation, oxidative stress, endothelial dysfunction, immune activation, and reserve depletion, thereby intensifying mechanisms already known to promote AF after surgery. Future studies should determine whether malignancy acts chiefly as a chronic biological preconditioner of the atrium, a marker of diminished systemic resilience, or both. 16. Future Directions Malignancy should not yet be regarded as an independently validated determinant of POAF after cardiac surgery, but it should not be dismissed as a passive background comorbidity. Current evidence supports a biologically plausible framework in which cancer activity, treatment-related cardiotoxicity, systemic inflammation, endothelial dysfunction, hypercoagulability, frailty, and reduced physiological reserve may converge with established perioperative triggers to increase susceptibility to postoperative arrhythmia. However, the evidence remains insufficient to support causal inference, cancer-specific prophylactic protocols, or automated treatment decisions. The immediate clinical value of this framework lies in reframing cancer history as a clinically informative risk domain rather than a binary variable. Future prospective studies should distinguish active from prior malignancy, capture treatment timing and cardiotoxic exposures, and test whether biomarkers, frailty measures, and atrial structural markers improve POAF prediction beyond existing models. Until such data is available, malignancy is best understood as a potential vulnerability state that may lower the threshold for POAF by amplifying established perioperative mechanisms, rather than as a distinct arrhythmogenic pathway. Author Contributions Conceptualization, M.M., S.K., F.T. and G.P.G.; investigation (literature search), S.K. and M.M.; formal analysis, S.K., M.M., F.T., N.I., P.G., A.G., K.L., A.K. and G.P.G.; validation, P.G., A.G., K.L., A.K., N.I. and G.P.G.; methodology, G.P.G.; data curation, G.P.G.; software, G.P.G.; writing—original draft preparation, S.K.; writing—review and editing, S.K., M.M., F.T., P.G., A.G., K.L., A.K., N.I. and G.P.G.; visualization, S.K. and M.M.; supervision, G.P.G. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Institutional Review Board Statement Not applicable. This review did not involve original studies with human participants or animals. Informed Consent Statement Not applicable. Data Availability Statement No new data were created or analysed in this study. Data sharing is not applicable to this article. Acknowledgments During the preparation of this manuscript, the authors used OpenAI ChatGPT-5 Images 2.0 for editorial formatting assistance and support in developing graphical elements. No generative AI tool was used to generate primary data, perform analyses, or replace author interpretation. The authors reviewed and edited all outputs and take full responsibility for the content of this publication. Conflicts of Interest The authors declare no conflicts of interest. Abbreviations The following abbreviations are used in this manuscript: AF Atrial fibrillation POAF Post-operative atrial fibrillation SA Sinoatrial BNP B-type natriuretic peptide NT-proBNP N-terminal pro-B-type natriuretic peptide BTK Bruton tyrosine kinase HER2 Human epidermal growth factor receptor 2 ICU Intensive care unit LV Left ventricular References McIntyre, W.F.; Devereaux, P.J.; Belley-Côte, E.P.; Spence, J.D.; Zhao, R.; Chan, M.T.V.; Lomivorotov, V.V.; Landoni, G.; Paparella, D.; Hillis, G.S.; et al. New-onset postoperative atrial fibrillation management and outcomes: The VISION Cardiac Surgery cohort. Eur. Heart J. 2026, ehag236. [ Google Scholar] [ CrossRef] Eikelboom, R.; Sanjanwala, R.; Le, M.L.; Yamashita, M.H.; Arora, R.C. Postoperative atrial fibrillation after cardiac surgery: A systematic review and meta-analysis. Ann. Thorac. Surg. 2021, 111, 544–554. [ Google Scholar] [ CrossRef] Woldendorp, K.; Farag, J.; Khadra, S.; Black, D.; Robinson, B.; Bannon, P. Postoperative atrial fibrillation after cardiac surgery: A meta-analysis. Ann. Thorac. Surg. 2021, 112, 2084–2093. [ Google Scholar] [ CrossRef] [ PubMed] Caldonazo, T.; Kirov, H.; Rahouma, M.; Robinson, N.B.; Demetres, M.; Gaudino, M.; Doenst, T.; Dobrev, D.; Borger, M.A.; Kiehntopf, M.; et al. Atrial fibrillation after cardiac surgery: A systematic review and meta-analysis. J. Thorac. Cardiovasc. Surg. 2023, 165, 94–103.e24. [ Google Scholar] [ CrossRef] [ PubMed] Wang, M.K.; Meyre, P.B.; Heo, R.; Devereaux, P.J.; Birchenough, L.; Whitlock, R.; McIntyre, W.F.; Chen, Y.C.P.; Ali, M.Z.; Biancari, F.; et al. Short-term and long-term risk of stroke in patients with perioperative atrial fibrillation after cardiac surgery: Systematic review and meta-analysis. CJC Open 2022, 4, 85–93. [ Google Scholar] [ CrossRef] [ PubMed] Georghiou, G.P.; Xanthopoulos, A.; Kanellopoulos, G.; Georghiou, P.; Georgiou, A.; Skoularigis, J.; Giamouzis, G.; Lampropoulos, K.; Patrikios, I.; Triposkiadis, F. Cancer Is a Major Determinant of Postoperative Atrial Fibrillation After Cardiac Surgery. J. Clin. Med. 2025, 14, 2117. [ Google Scholar] [ CrossRef] Georghiou, G.P.; Georghiou, P.; Georgiou, A.; Triposkiadis, F. Cardiac Surgery and Postoperative Atrial Fibrillation: The Role of Cancer. Medicina 2025, 61, 1815. [ Google Scholar] [ CrossRef] Pandey, A.; Okaj, I.; Ichhpuniani, S.; Tao, B.; Kaur, H.; Spence, J.D.; Young, J.; Healey, J.S.; Devereaux, P.J.; Um, K.J.; et al. Risk scores for prediction of postoperative atrial fibrillation after cardiac surgery: A systematic review and meta-analysis. Am. J. Cardiol. 2023, 209, 232–240. [ Google Scholar] [ CrossRef] Mathew, J.P.; Fontes, M.L.; Tudor, I.C.; Ramsay, J.; Duke, P.; Mazer, C.D.; Barash, P.G.; Hsu, P.H.; Mangano, D.T.; Investigators of the Ischemia Research and Education Foundation; et al. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 2004, 291, 1720–1729. [ Google Scholar] [ CrossRef] Villareal, R.P.; Hariharan, R.; Liu, B.C.; Kar, B.; Lee, V.V.; Elayda, M.; Lopez, J.A.; Rasekh, A.; Wilson, J.M.; Massumi, A. Postoperative atrial fibrillation and mortality after coronary artery bypass surgery. J. Am. Coll. Cardiol. 2004, 43, 742–748. [ Google Scholar] [ CrossRef] Ahlsson, A.; Fengsrud, E.; Bodin, L.; Englund, A. Postoperative atrial fibrillation in patients undergoing aortocoronary bypass surgery carries an eightfold risk of future atrial fibrillation and a doubled cardiovascular mortality. Eur. J. Cardiothorac. Surg. 2010, 37, 1353–1359. [ Google Scholar] [ CrossRef] Horwich, P.; Buth, K.J.; Légaré, J.-F. New-onset postoperative atrial fibrillation is associated with a long-term risk for stroke and death following cardiac surgery. J. Card. Surg. 2013, 28, 8–13. [ Google Scholar] [ CrossRef] [ PubMed] Butt, J.H.; Xian, Y.; Peterson, E.D.; Olsen, P.S.; Rørth, R.; Gundlund, A.; Olesen, J.B.; Gislason, G.H.; Torp-Pedersen, C.; Køber, L.; et al. Long-term thromboembolic risk in patients with postoperative atrial fibrillation after coronary artery bypass graft surgery and patients with nonvalvular atrial fibrillation. JAMA Cardiol. 2018, 3, 417–424. [ Google Scholar] [ CrossRef] [ PubMed] Wilcox, N.S.; Amit, U.; Reibel, J.B.; Berlin, E.; Howell, K.; Ky, B. Cardiovascular disease and cancer: Shared risk factors and mechanisms. Nat. Rev. Cardiol. 2024, 21, 617–631. [ Google Scholar] [ CrossRef] [ PubMed] Davis, N.E.; Prasitlumkum, N.; Tan, N.Y. Atrial fibrillation and cancer—Epidemiology, mechanisms, and management. J. Clin. Med. 2024, 13, 7753. [ Google Scholar] [ CrossRef] Fradley, M.G.; Beckie, T.M.; Brown, S.A.; Cheng, R.K.; Dent, S.F.; Nohria, A.; Patton, K.K.; Singh, J.P.; Olshansky, B. Recognition, prevention, and management of arrhythmias and autonomic disorders in cardio-oncology: A scientific statement from the American Heart Association. Circulation 2021, 144, e41–e55. [ Google Scholar] [ CrossRef] Lyon, A.R.; López-Fernández, T.; Couch, L.S.; Asteggiano, R.; Aznar, M.C.; Bergler-Klein, J.; Boriani, G.; Cardinale, D.; Cordoba, R.; Cosyns, B.; et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association, the European Society for Therapeutic Radiology and Oncology, and the International Cardio-Oncology Society. Eur. Heart J. 2022, 43, 4229–4361. [ Google Scholar] [ CrossRef] Keramida, K.; Kariki, O.; Angelopoulou, E.; Kalafatis, I.; Lafaras, C.; Letsas, K.P.; Michalopoulou, H.; Saplaouras, A.; Tampakis, K.; Tsekoura, D.; et al. Arrhythmias, conduction disorders and sudden cardiac death in cancer patients and survivors: Expert opinion of the working groups on cardio-oncology and on electrophysiology of the Hellenic Cardiac Society. Cardio-Oncology 2025, 11, 19. [ Google Scholar] [ CrossRef] Farmakis, D.; Parissis, J.; Filippatos, G. Insights into onco-cardiology: Atrial fibrillation in cancer. J. Am. Coll. Cardiol. 2014, 63, 945–953. [ Google Scholar] [ CrossRef] Palmieri, V.; Vietri, M.T.; Montalto, A.; Montisci, A.; Donatelli, F.; Coscioni, E.; Napoli, C. Cardiotoxicity, cardioprotection, and prognosis in survivors of anticancer treatment undergoing cardiac surgery: Unmet needs. Cancers 2023, 15, 2224. [ Google Scholar] [ CrossRef] Heijman, J.; Muna, A.P.; Veleva, T.; Molina, C.E.; Sutanto, H.; Tekook, M.; Wang, Q.; Abu-Taha, I.H.; Gorka, M.; Künzel, S.; et al. Atrial myocyte NLRP3/CaMKII nexus forms a substrate for postoperative atrial fibrillation. Circ. Res. 2020, 127, 1036–1055. [ Google Scholar] [ CrossRef] [ PubMed] Zaman, J.A.B.; Harling, L.; Ashrafian, H.; Darzi, A.; Gooderham, N.; Athanasiou, T.; Peters, N.S. Post-operative atrial fibrillation is associated with a pre-existing structural and electrical substrate in human right atrial myocardium. Int. J. Cardiol. 2016, 220, 580–588. [ Google Scholar] [ CrossRef] [ PubMed] Zakkar, M.; Ascione, R.; James, A.F.; Angelini, G.D.; Suleiman, M.-S. Inflammation, oxidative stress and postoperative atrial fibrillation in cardiac surgery. Pharmacol. Ther. 2015, 154, 13–20. [ Google Scholar] [ CrossRef] [ PubMed] Hassanabad, A.F.; Deniset, J.F.; Fedak, P.W.M. Pericardial inflammatory mediators that can drive postoperative atrial fibrillation in cardiac surgery patients. Can. J. Cardiol. 2023, 39, 1090–1102. [ Google Scholar] [ CrossRef] Squiccimarro, E.; Stasi, A.; Lorusso, R.; Paparella, D. Narrative review of the systemic inflammatory reaction to cardiac surgery and cardiopulmonary bypass. Artif. Organs 2022, 46, 568–577. [ Google Scholar] [ CrossRef] Shaaban, A.; Scott, S.S.; Greenlee, A.N.; Binda, N.; Noor, A.; Webb, A.; Guo, S.; Purdy, N.; Pennza, N.; Habib, A.; et al. Atrial fibrillation in cancer, anticancer therapies, and underlying mechanisms. J. Mol. Cell. Cardiol. 2024, 194, 118–132. [ Google Scholar] [ CrossRef] Van Linthout, S. Shared mechanisms in cancer and cardiovascular disease: S100A8/9 and the NLRP3 inflammasome: JACC: CardioOncology state-of-the-art review. JACC CardioOncol. 2025, 7, 501–513. [ Google Scholar] [ CrossRef] Masini, G.; Wang, W.; Ji, Y.; Eaton, A.; Inciardi, R.M.; Soliman, E.Z.; Passman, R.S.; Solomon, S.D.; Shah, A.M.; De Caterina, R.; et al. Markers of Left Atrial Myopathy: Prognostic Usefulness for Ischemic Stroke and Dementia in People in Sinus Rhythm. Stroke 2025, 56, 858–867. [ Google Scholar] [ CrossRef] Hu, Y.-F.; Chen, Y.-J.; Lin, Y.-J.; Chen, S.-A. Inflammation and the pathogenesis of atrial fibrillation. Nat. Rev. Cardiol. 2015, 12, 230–243. [ Google Scholar] [ CrossRef] Chen, Q.; van Rein, N.; van der Hulle, T.; Heemelaar, J.C.; Trines, S.A.; Versteeg, H.H.; Klok, F.A.; Cannegieter, S.C. Coexisting atrial fibrillation and cancer: Time trends and associations with all-cause mortality in a nationwide study. Eur. Heart J. 2024, 45, 2201–2213. [ Google Scholar] [ CrossRef] Khan, M.Z.; Gupta, A.; Patel, K.; Abraham, A.; Franklin, S.; Kim, D.Y.; Patel, K.; Hussian, I.; Zarak, M.S.; Figueredo, V.; et al. Association of atrial fibrillation and various cancer subtypes. J. Arrhythm. 2021, 37, 1205–1214. [ Google Scholar] [ CrossRef] Liao, K.-M.; Yu, C.-H.; Wu, Y.-C.; Wang, J.-J.; Liang, F.-W.; Ho, C.-H. Risk of atrial fibrillation in patients with different cancer types in Taiwan. Life 2024, 14, 621. [ Google Scholar] [ CrossRef] [ PubMed] Oh, M.J.; Choi, Y.J.; Jung, J.-H.; Lee, S.; Han, K.; Cho, S.-J. Atrial fibrillation risk in relation to the clinical staging of gastric cancer: A nationwide population-based cohort study. Cancers 2025, 17, 2054. [ Google Scholar] [ CrossRef] [ PubMed] Dean, Y.E.; Dahshan, H.; Motawea, K.R.; Khalifa, Z.; Tanas, Y.; Rakha, I.; Hasan, W.; Kishk, M.; Mahmoud, A.; Elsayed, A.; et al. Anthracyclines and the risk of arrhythmias: A systematic review and meta-analysis. Medicine 2023, 102, e35770. [ Google Scholar] [ CrossRef] [ PubMed] Caldeira, D.; Alves, D.; Costa, J.; Ferreira, J.J.; Pinto, F.J. Ibrutinib increases the risk of hypertension and atrial fibrillation: Systematic review and meta-analysis. PLoS ONE 2019, 14, e0211228. [ Google Scholar] [ CrossRef] Gambril, J.A.; Ghazi, S.M.; Sansoterra, S.; Ferdousi, M.; Kola-Kehinde, O.; Ruz, P.; Kittai, A.S.; Rogers, K.; Grever, M.; Bhat, S.; et al. Atrial fibrillation burden and clinical outcomes following BTK inhibitor initiation. Leukemia 2024, 38, 1454–1463. [ Google Scholar] [ CrossRef] Nielsen, D.L.; Juhl, C.B.; Nielsen, O.H.; Chen, I.M.; Herrmann, J. Immune checkpoint inhibitor-induced cardiotoxicity: A systematic review and meta-analysis. JAMA Oncol. 2024, 10, 1390–1399. [ Google Scholar] [ CrossRef] Zalaquett, Z.; Shukla, N.; Hajj, J.; Chedid El Helou, M.; Moudgil, R.; Collier, P. Cardiovascular toxicity of fluoropyrimidines: What we know. Mayo Clin. Proc. 2025, 101, 136–155. [ Google Scholar] [ CrossRef] Reiss, A.B.; Vasalani, S.; Albert, J.; Drewes, W.; Li, K.; Srivastava, A.; De Leon, J.; Katz, A.E. The effect of androgen deprivation therapy on the cardiovascular system in advanced prostate cancer. Medicina 2024, 60, 1727. [ Google Scholar] [ CrossRef] Kim, K.H.; Oh, J.; Yang, G.; Lee, J.; Kim, J.; Gwak, S.Y.; Cho, I.; Lee, S.H.; Byun, H.K.; Choi, H.K.; et al. Association of sinoatrial node radiation dose with atrial fibrillation and mortality in patients with lung cancer. JAMA Oncol. 2022, 8, 1624–1634. [ Google Scholar] [ CrossRef] Butler, S.; No, H.; Guo, F.; Merchant, G.; Park, N.J.; Jackson, S.; Clark, D.E.; Vitzthum, L.; Chin, A.; Horst, K.; et al. Predictors of atrial fibrillation after thoracic radiotherapy. JACC CardioOncol. 2024, 6, 935–945. [ Google Scholar] [ CrossRef] [ PubMed] Mennander, A.A.; Nielsen, S.J.; Huhtala, H.; Dellgren, G.; Hansson, E.C.; Jeppsson, A. History of cancer and survival after coronary artery bypass grafting: Experiences from the SWEDEHEART registry. J. Thorac. Cardiovasc. Surg. 2022, 164, 107–114.e1. [ Google Scholar] [ CrossRef] [ PubMed] Lorusso, R.; Vizzardi, E.; Johnson, D.M.; Mariscalco, G.; Sciatti, E.; Maessen, J.; Bidar, E.; Gelsomino, S. Cardiac surgery in adult patients with remitted or active malignancies: A review of preoperative screening, surgical management and short- and long-term postoperative results. Eur. J. Cardiothorac. Surg. 2018, 54, 10–18. [ Google Scholar] [ CrossRef] [ PubMed] Chan, J.; Rosenfeldt, F.; Chaudhuri, K.; Marasco, S. Cardiac surgery in patients with a history of malignancy. Heart Lung Circ. 2012, 21, 255–259. [ Google Scholar] [ CrossRef] Higuchi, S.; Kabeya, Y.; Matsushita, K.; Arai, N.; Tachibana, K.; Tanaka, R.; Kawachi, R.; Takei, H.; Suzuki, Y.; Kogure, M.; et al. Incidence and complications of perioperative atrial fibrillation after non-cardiac surgery for malignancy. PLoS ONE 2019, 14, e0216239. [ Google Scholar] [ CrossRef] Higuchi, S.; Kabeya, Y.; Matsushita, K.; Arai, N.; Tachibana, K.; Tanaka, R.; Kawachi, R.; Takei, H.; Suzuki, Y.; Kogure, M.; et al. Perioperative atrial fibrillation in noncardiac surgeries for malignancies and one-year recurrence. Can. J. Cardiol. 2019, 35, 1449–1456. [ Google Scholar] [ CrossRef] Inoue, K.; Tajiri, K.; Xu, D.; Murakoshi, N.; Ieda, M. Risk factors and in-hospital outcomes of perioperative atrial fibrillation for patients with cancer: A meta-analysis. Ann. Surg. Oncol. 2023, 30, 711–721. [ Google Scholar] [ CrossRef] Semeraro, G.C.; Meroni, C.A.; Cipolla, C.M.; Cardinale, D.M. Atrial fibrillation after lung cancer surgery: Prediction, prevention and anticoagulation management. Cancers 2021, 13, 4012. [ Google Scholar] [ CrossRef] Rosati, F.; Baudo, M.; Tomasi, C.; Scotti, G.; Pirola, S.; Mastroiacovo, G.; Polvani, G.; Bisleri, G.; Benussi, S.; Di Bacco, L.; et al. Prediction model for postoperative atrial fibrillation in cardiac surgery patients: The POLARIS score. J. Clin. Med. 2025, 14, 650. [ Google Scholar] [ CrossRef] Pastore, M.C.; Degiovanni, A.; Grisafi, L.; Renda, G.; Sozzani, M.; Giordano, A.; Salvatici, C.; Lorenz, V.; Pierfelice, F.; Cappelli, C.; et al. Left atrial strain to predict postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting. Circ. Cardiovasc. Imaging 2024, 17, e015969. [ Google Scholar] [ CrossRef] Thet, M.S.; Hlwar, K.E.; Thet, K.S.; Han, K.P.P.; Oo, A.Y. Preoperative B-type natriuretic peptides to predict postoperative atrial fibrillation in cardiac surgery: A systematic review and meta-analysis. Heart Lung Circ. 2024, 33, 597–607. [ Google Scholar] [ CrossRef] Dorey, T.W.; Bohne, L.J.; Hassanabad, A.F.; Duttchen, K.; Wilton, S.B.; Chun, R. The Relationship between Frailty and Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis. J. Card. Surg. 2025, 2025, 1336346. [ Google Scholar] [ CrossRef] Liblik, K.; Zucker, J.; Baranchuk, A.; Fernandez, A.L.; Zhang, S.; El Diasty, M.E. The role of pericardial fluid biomarkers in predicting post-operative atrial fibrillation: A comprehensive review of current literature. Trends Cardiovasc. Med. 2024, 34, 244–247. [ Google Scholar] [ CrossRef] Gulizia, M.M.; Turazza, F.M.; Ameri, P.; Alings, M.; Collins, R.; De Luca, L.; Di Nisio, M.; Lucci, D.; Gabrielli, D.; Janssens, S.; et al. Characteristics and management of patients with cancer and atrial fibrillation: The BLITZ-AF Cancer Registry. JACC Adv. 2024, 3, 100991. [ Google Scholar] [ CrossRef] Farkowski, M.M.; Szmit, S.; Boriani, G.; Castrejon, S.; Fradley, M.; Guha, A.; Merino, J.L.; Mugnai, G.; Lee, G.A.; Lyon, A.R.; et al. Contemporary management of atrial fibrillation in patients with cancer—The 2025 European Heart Rhythm Association survey. Europace 2026, 28, euaf325. [ Google Scholar] [ CrossRef] Monsour, R.; Seo, A.; Wilcox, N.; Fradley, M.G. Diagnosis and management of atrial arrhythmias in cancer patients. Curr. Cardiol. Rep. 2025, 27, 103. [ Google Scholar] [ CrossRef] Sorigue, M.; Miljkovic, M.D. Atrial fibrillation and stroke risk in patients with cancer: A primer for oncologists. J. Oncol. Pract. 2019, 15, 641–650. [ Google Scholar] [ CrossRef] Conen, D.; Wong, J.A.; Sandhu, R.K.; Cook, N.R.; Lee, I.-M.; Buring, J.E.; Albert, C.M. Risk of malignant cancer among women with new-onset atrial fibrillation. JAMA Cardiol. 2016, 1, 389–396. [ Google Scholar] [ CrossRef] Vinter, N.; Christesen, A.M.; Fenger-Grøn, M.; Frost, L. Atrial fibrillation and risk of cancer: A Danish population-based cohort study. J. Am. Heart Assoc. 2018, 7, e009543. [ Google Scholar] [ CrossRef] Yoshimura, H.; Zakkak, N.; Lyratzopoulos, G.; Lip, G.Y.H.; Schmidt, F.; Providência, R. Risk of cancer following presentation with new-onset atrial fibrillation using data from UK national databases. Europace 2025, 27, euaf319. [ Google Scholar] [ CrossRef] Li, W.; Huang, M.; Wang, R.; Wang, W. Impact of genetically predicted atrial fibrillation on cancer risks: A large cardio-oncology Mendelian randomization study using UK Biobank. Front. Cardiovasc. Med. 2023, 9, 974402. [ Google Scholar] [ CrossRef] Gong, Z.; Hu, M.; Yang, Y.; Yin, C. Causal associations between atrial fibrillation and breast cancer: A bidirectional Mendelian randomization analysis. Cancer Med. 2024, 13, e7067. [ Google Scholar] [ CrossRef] Van Gelder, I.C.; Kotecha, D.; Rienstra, M.; Bunting, K.V.; Casado-Arroyo, R.; Caso, V.; Crijns, H.J.G.M.; De Potter, T.J.R.; Dwight, J.; Guasti, L.; et al. 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery. Eur. Heart J. 2024, 45, 3314–3414. [ Google Scholar] [ CrossRef] Malignancy-related substrate-trigger model of POAF. This figure represents a proposed conceptual framework illustrating how malignancy-related biological factors may converge with acute surgical stressors to promote POAF. It does not imply established causal relationships. Malignancy-related substrate-trigger model of POAF. This figure represents a proposed conceptual framework illustrating how malignancy-related biological factors may converge with acute surgical stressors to promote POAF. It does not imply established causal relationships. Cancer as an amplifier of POAF susceptibility. This figure is a proposed conceptual model and reflects biological plausibility rather than proven mechanistic pathways. Cancer as an amplifier of POAF susceptibility. This figure is a proposed conceptual model and reflects biological plausibility rather than proven mechanistic pathways. Competing explanations for cancer–POAF associations. This figure summarises alternative interpretations of the observed association and is intended to highlight the need for refined clinical phenotyping rather than to imply definitive causal conclusions. Competing explanations for cancer–POAF associations. This figure summarises alternative interpretations of the observed association and is intended to highlight the need for refined clinical phenotyping rather than to imply definitive causal conclusions. Anticancer therapies and POAF susceptibility. Anticancer therapies and POAF susceptibility. Therapy Class Key Cardiovascular/Atrial Effects Relevance to POAF After Cardiac Surgery Evidence Anthracyclines Oxidative injury, fibrosis, left ventricular (LV) dysfunction Indirect: reduced myocardial reserve and structural vulnerability Moderate BTK inhibitors Direct atrial pro-arrhythmia, hypertension, bleeding issues High: strongest therapy-specific AF signal, especially if recent or ongoing High Immune checkpoint inhibitors Myocarditis, pericarditis, conduction disease, immune activation Moderate: more relevant if prior cardiotoxicity or persistent inflammation Moderate Fluoropyrimidines Vasospasm, ischaemia, arrhythmias, haemodynamic stress Modest/indirect: broader cardiotoxic stress rather than specific atrial effect Low-moderate HER2-targeted therapies Ventricular dysfunction, reduced cardiac reserve Indirect: mainly relevant when reserve is impaired Low-moderate Androgen deprivation/AR pathway inhibitors Metabolic dysfunction, hypertension, vascular risk, QT effects Indirect: mainly via cardiometabolic burden Low Thoracic radiotherapy Atrial/sinoatrial (SA) node fibrosis, pericardial and conduction injury, microvascular damage Potentially high in selected patients, especially with mediastinal exposure Moderate Published clinical studies examining POAF in cancer patients undergoing cardiac or oncological surgery. Published clinical studies examining POAF in cancer patients undergoing cardiac or oncological surgery. Study Design Cancer Definition POAF Incidence/Key Finding Limitations Proposed perioperative phenotyping panel. Proposed perioperative phenotyping panel. Domain Candidate Measure Rationale Suggested Timing Atrial structure and function Left atrial volume index; reservoir, conduit, and contractile strain Defines latent atrial remodelling more directly than comorbidity burden Preoperative echocardiography Ventricular/haemodynamic stress B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) Reflects wall stress, filling pressure, and reduced myocardial reserve Preoperative; postoperative day 1 Myocardial injury High-sensitivity troponin Helps separate perioperative injury from pre-existing reserve limitation Preoperative baseline; early postoperative Systemic inflammation C-reactive protein; interleukin-6; neutrophil-based indices Quantifies inflammatory burden relevant to both cancer and POAF Preoperative; intensive care unit (ICU) arrival; postoperative day 1–2 Thrombo-inflammatory state Fibrinogen; D-dimer; platelet count/derived ratios Captures coagulation activation and perioperative haemostatic disturbance Preoperative; postoperative day 1 Frailty/nutritional status Clinical frailty scale; gait-based or standardised frailty score; albumin; sarcopenia surrogate Operationalises reserve depletion that may mediate part of the cancer signal Preoperative Local cardiac inflammatory milieu Selected pericardial fluid cytokines or myeloperoxidase May identify a distinct pericardial inflammatory signature in cancer-exposed patients Intraoperative or immediate postoperative research sampling Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Share and Cite MDPI and ACS Style Kyriakou, S.; Markantonis, M.; Georghiou, P.; Triposkiadis, F.; Georgiou, A.; Lampropoulos, K.; Kyriakou, A.; Iosif, N.; Georghiou, G.P. Cancer as a Hidden Catalyst: Rethinking Postoperative Atrial Fibrillation After Cardiac Surgery. J. Clin. Med. 2026, 15, 4456. https://doi.org/10.3390/jcm15124456 AMA Style Kyriakou S, Markantonis M, Georghiou P, Triposkiadis F, Georgiou A, Lampropoulos K, Kyriakou A, Iosif N, Georghiou GP. Cancer as a Hidden Catalyst: Rethinking Postoperative Atrial Fibrillation After Cardiac Surgery. Journal of Clinical Medicine. 2026; 15(12):4456. https://doi.org/10.3390/jcm15124456 Chicago/Turabian Style Kyriakou, Sotiris, Marios Markantonis, Panos Georghiou, Filippos Triposkiadis, Amalia Georgiou, Konstantinos Lampropoulos, Argyris Kyriakou, Nikolas Iosif, and Georgios P. Georghiou. 2026. "Cancer as a Hidden Catalyst: Rethinking Postoperative Atrial Fibrillation After Cardiac Surgery" Journal of Clinical Medicine 15, no. 12: 4456. https://doi.org/10.3390/jcm15124456 APA Style Kyriakou, S., Markantonis, M., Georghiou, P., Triposkiadis, F., Georgiou, A., Lampropoulos, K., Kyriakou, A., Iosif, N., & Georghiou, G. P. (2026). Cancer as a Hidden Catalyst: Rethinking Postoperative Atrial Fibrillation After Cardiac Surgery. Journal of Clinical Medicine, 15(12), 4456. https://doi.org/10.3390/jcm15124456 Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here. Article Metrics Article metric data becomes available approximately 24 hours after publication online.
