Trastuzumab increases pulmonary vein arrhythmogenesis through modulating pulmonary vein electrical and conduction properties via phosphatidylinositol 3-kinase signaling

Document Type: Original Article


1 Department of Medical, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei, Taiwan

2 Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan

3 Department of Cardiology, Chi-Mei Medical Center, Tainan, Taiwan

4 Division of Cardiology, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei City, Taiwan

5 School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan

6 Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

7 Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

8 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan


Objective(s): Drug-induced atrial fibrillation (AF) is considered an adverse effect of chemotherapeutic drugs. AF is a crucial risk factor for stroke, heart failure, myocardial infarction, and mortality. Pulmonary veins (PVs) are considered triggers inducing AF, and the sinoatrial node (SAN) may modulate PV activity and participate in AF genesis. AF was associated with early discontinuation of trastuzumab in patients with breast cancer. However, whether trastuzumab directly modulates the electrophysiological characteristics of PV and SAN remains unclear.
Materials and Methods: ECG and conventional microelectrode system were used to record rabbit heart rhythm in vivo and electrical activities in vitro from isolated SAN, PV, and SAN-PV preparations.
Results: Trastuzumab reduced the beating rate in isolated PV and SAN preparations at 1, 10, and 30 μM (particularly in isolated SAN preparations) and induced burst firings in isolated PV preparations at 10 μΜ. In addition, trastuzumab (10 μM) induced SAN-PV conduction block and burst firings, which were blocked by wortmannin (a PI3K inhibitor, 100 nM). Similarly, ECG recordings showed that acute intravenous administration of trastuzumab (10 mg/kg) reduced rabbit heart rates.
Conclusion: Trastuzumab increased PV arrhythmogenesis through interfering with PI3K signaling, which may contribute to the genesis of AF.


1. Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation 2011;124:2264-2274.
2. Guo Y, Tian Y, Wang H, Si Q, Wang Y, Lip GYH. Prevalence, incidence, and lifetime risk of atrial fibrillation in China: new insights into the global burden of atrial fibrillation. Chest 2015;147:109-119.
3. Khan MA, Ahmed F, Neyses L, Mamas MA. Atrial fibrillation in heart failure: The sword of Damocles revisited. World J Cardiol 2013;5:215-227.
4. Schmitt J, Duray G, Gersh BJ, Hohnloser SH. Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J 2009;30:1038-1045.
5.    Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A. Atrial fibrillation and dementia in a population-based study. The Rotterdam Study Stroke 1997;28:316-321.
6.    Cheng WL, Kao YH, Chen SA, Chen YJ. Pathophysiology of cancer therapy-provoked atrial fibrillation. Int J Cardiol 2016;219:186-194.
7.    Farmakis D, Parissis J, Filippatos G. Insights into onco-cardiology: atrial fibrillation in cancer. J Am Coll Cardiol 2014;63:945-953.
8.    Melloni C, Shrader P, Carver J, Piccini JP, Thomas L, Fonarow GC, et al. Management and outcomes of patients with atrial fibrillation and a history of cancer: the ORBIT-AF registry. E Eur Heart J Qual Care Clin Outcomes 2017;3:192-197.
9.    Ording AG, Horvath-Puho E, Adelborg K, Pedersen L, Prandoni P, Sorensen HT. Thromboembolic and bleeding complications during oral anticoagulation therapy in cancer patients with atrial fibrillation: a Danish nationwide population-based cohort study. Cancer Med 2017;6:1165-1172.
10.    Adão R, de Keulenaer G, Leite-Moreira A, Brás-Silva C. Cardiotoxicity associated with cancer therapy: pathophysiology and prevention strategies. Rev Port Cardiol 2013;32:395-409.
11.    Tamargo J, Caballero R, Delpon E. Drug-induced atrial fibrillation: does it matter? Discov Med 2012;14:295-299.
12.    Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst 2010;102:14-25.
13.    Soo Park J, Youn JC, Shim CY, Hong GR, Lee CK, Kim JH, et al. Cardiotoxicity of trastuzumab in patients with HER2-positive gastric cancer. Oncotarget 2017;8:61837-61845.
14.    Coughlin SS, Ekwueme DU. Breast cancer as a global health concern. Cancer Epidemiol 2009;33:315-318.
15.    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-1684.
16.    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-792.
17.    Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007;369:29-36.
18.    Bregni G, Galli G, Gevorgyan A, de Braud F, Di Cosimo S. Trastuzumab cardiac toxicity: a problem we put our heart into. Tumori 2016;102:1-5.
19.    Denegri A, Moccetti T, Moccetti M, Spallarossa P, Brunelli C, Ameri P. Cardiac toxicity of trastuzumab in elderly patients with breast cancer. J Geriatr Cardiol 2016;13:355-363.
20.    Hamirani Y, Fanous I, Kramer CM, Wong A, Salerno M, Dillon P. Anthracycline- and trastuzumab-induced cardiotoxicity: a retrospective study. Med Oncol 2016;33:82-89.
21.    Jain D, Russell RR, Schwartz RG, Panjrath GS, Aronow W. Cardiac Complications of Cancer Therapy: Pathophysiology, Identification, Prevention, Treatment, and Future Directions. Curr Cardiol Rep 2017;19:36-47.
22.    Leung HW, Chan AL. Trastuzumab-induced cardiotoxicity in elderly women with HER-2-positive breast cancer: a meta-analysis of real-world data. Expert Opin Drug Saf 2015;14:1661-1671.
23.    Mantarro S, Rossi M, Bonifazi M, D’Amico R, Blandizzi C, La Vecchia C, et al. Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer. Intern Emerg Med 2016;11:123-140.
24.    Maurea N, Coppola C, Piscopo G, Galletta F, Riccio G, Esposito E, et al. Pathophysiology of cardiotoxicity from target therapy and angiogenesis inhibitors. J Cardiovasc Med (Hagerstown) 2016;17 Suppl 1 Special issue on Cardiotoxicity from Antiblastic Drugs and Cardioprotection:e19-e26.
25.    Tang GH, Acuna SA, Sevick L, Yan AT, Brezden-Masley C. Incidence and identification of risk factors for trastuzumab-induced cardiotoxicity in breast cancer patients: an audit of a single “real-world” setting. Med Oncol 2017;34:154.
26.    Ezaz G, Long JB, Gross CP, Chen J. Risk prediction model for heart failure and cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Heart Assoc 2014;3:e000472.
27.    Wang SY, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP, et al. Cardiovascular events, early discontinuation of trastuzumab, and their impact on survival. Breast Cancer Res Treat 2014;146:411-419.
28.    Martinello R, Becco P, Vici P, Airoldi M, Del Mastro L, Garrone O, et al. Trastuzumab-related cardiotoxicity in patients with nonlimiting cardiac comorbidity. Breast J 2019;25:444-449.
29.    Yuan M, Tse G, Zhang Z, Han X, Wu WKK, Li G, et al. The incidence of atrial fibrillation with trastuzumab treatment: A systematic review and meta-analysis. Cardiovasc Ther 2018;36:e12475.
30.    Fu YF, Gui R, Liu J. HER-2-induced PI3K signaling pathway was involved in the pathogenesis of gastric cancer. Cancer Gene Ther 2015;22:145-153.
31.    Nanni P, Nicoletti G, Palladini A, Croci S, Murgo A, Ianzano ML, et al. Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor. PLoS One 2012;7:e39626.
32.    Pretorius L, Du XJ, Woodcock EA, Kiriazis H, Lin RC, Marasco S, et al. Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation. Am J Pathol 2009;175:998-1009.
33. Fink RI, Kolterman OG, Griffin J, Olefsky JM. Mechanisms of insulin resistance in aging. J Clin Invest. 1983;71:1523–1535.
34. Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM. Preconditioning the diabetic heart: the importance of Akt phosphorylation. Diabetes. 2005;54:2360–2364.
35. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106:473–481.
36.    Riccio G, Esposito G, Leoncini E, Contu R, Condorelli G, Chiariello M, et al. Cardiotoxic effects, or lack thereof, of anti-ErbB2 immunoagents. FASEB J 2009;23:3171-3178.
37.    Zeglinski M, Ludke A, Jassal DS, Singal PK. Trastuzumab-induced cardiac dysfunction: A ‘dual-hit’. Exp Clin Cardiol 2011;16:70-74.
38.    Nattel S. New ideas about atrial fibrillation 50 years on. Nature 2002;415:219-226.
39.    Chen SA, Hsieh MH, Tai CT, Tsai CF, Prakash VS, Yu WC, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999;100:1879-1886.
40.    Pappone C, Oreto G, Rosanio S, Vicedomini G, Tocchi M, Gugliotta F, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001;104:2539-2544.
41.    Chen YC, Lu YY, Cheng CC, Lin YK, Chen SA, Chen YJ. Sinoatrial node electrical activity modulates pulmonary vein arrhythmogenesis. Int J Cardiol 2014;173:447-452.
42.    Tsai CF, Chen YC, Lin YK, Chen SA, Chen YJ. Electromechanical effects of the direct renin inhibitor (aliskiren) on the pulmonary vein and atrium. Basic Res Cardiol 2011;106:979-993.
43.    Chang CJ, Chen YC, Kao YH, Lin YK, Chen SA, Chen YJ. Dabigatran and thrombin modulate electrophysiological characteristics of pulmonary vein and left atrium. Circ Arrhythm Electrophysiol 2012;5:1176-1183.
44.    Lo LW, Chen YC, Chen YJ, Wongcharoen W, Lin CI, Chen SA. Calmodulin kinase II inhibition prevents arrhythmic activity induced by alpha and beta adrenergic agonists in rabbit pulmonary veins. Eur J Pharmacol 2007;571:197-208.
45.    Quartino AL, Hillenbach C, Li J, Li H, Wada RD, Visich J, et al. Population pharmacokinetic and exposure-response analysis for trastuzumab administered using a subcutaneous “manual syringe” injection or intravenously in women with HER2-positive early breast cancer. Cancer Chemother Pharmacol 2016;77:77-88.
46.    Olin RL, Desai SS, Fox K, Davidson R. Non-myopathic cardiac events in two patients treated with trastuzumab. Breast J 2007;13:211-212.
47.    McMullen JR, Amirahmadi F, Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, et al. Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A 2007;104:612-617.
48.    McMullen JR, Boey EJ, Ooi JY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood 2014;124:3829-3830.
49.    Yang KC, Tseng YT, Nerbonne JM. Exercise training and PI3Kalpha-induced electrical remodeling is independent of cellular hypertrophy and Akt signaling. J Mol Cell Cardiol 2012;53:532-541.
50.    Schluter KD, Goldberg Y, Taimor G, Schafer M, Piper HM. Role of phosphatidylinositol 3-kinase activation in the hypertrophic growth of adult ventricular cardiomyocytes. Cardiovasc Res 1998;40:174-181.
51. Yano N, Tseng A, Zhao TC, Robbins J, Padbury JF, Tseng YT. Temporally controlled overexpression of cardiac-specific PI3Kalpha induces enhanced myocardial contractility--a new transgenic model. Am J Physiol Heart Circ Physiol 2008;295:H1690-1694.
52.    Lu Z, Jiang YP, Wang W, Xu XH, Mathias RT, Entcheva E, et al. Loss of cardiac phosphoinositide 3-kinase p110 alpha results in contractile dysfunction. Circulation 2009;120:318-325.
53. Blazek M, Santisteban TS, Zengerle R, Meier M. Analysis of fast protein phosphorylation kinetics in single cells on a microfluidic chip. Lab Chip 2015;15:726-734.
54. Prabakaran SL, Lippens G, Steen H, Gunawardena J. Post-translational modification: nature’s escape from genetic imprisonment and the basis for dynamic information encoding. Wiley Interdiscip Rev Syst Biol Med 2012;4:565-583.
55. Zhu S, Cawley SM, Bloch KD, Huang PL. Trastuzumab and lapatinib differ in effects on calcium cycling and HER2 expression in human embryonic stem cell-derived cardiomyocytes. Cardio Vasc Syst 2013; 1:10.