The impact of antiarrhythmics on human pulmonary arteries: Ex vivo characterization
Background & aim: The safety and efficacy of the anti-arrhythmic agents, amiodarone and digoxin, in patients with pulmonary hypertension is not described well in literature although their use is common practice. Our study aims to investigate the effect of these drugs on pulmonary arteries which may have implications for their use in patients with pulmonary hypertension.
Methods: Human pulmonary arteries were obtained from consenting patients undergoing lobectomies. Arterials rings (N=40 from 10 patients) were dissected form the tissue and mounted onto a multiwire myograph. The rings were preconstricted using prostaglandin F2α before the addition of additive dilutions of amiodarone and digoxin. Finally, the reagents were washed out and the arterial rings’ viability was confirmed using acetylcholine and potassium chloride.
Results: Amiodarone had a slightly vasodilatory effect on the arterial rings, whereas digoxin had a relatively neutral effect. Amiodarone caused the greatest vasodilatory response at 100 μM with an active tension of -0.494 gf with an EC50 of 9.42 μM. Digoxin produced no significant vasodilatory or vasoconstrictive response.
Conclusions: This study demonstrated the ex vivo effects of amiodarone and digoxin on human pulmonary arterial tension. The results of the study showed that neither amiodarone nor digoxin had any vasoconstrictive effects. Amiodarone also exhibited vasodilatory properties and therefore may be used preferentially as it could help reduce the impact of PH. However, more studies need to be conducted before we can confirm the safety of these drugs.
Relevance for patients: The ambivalence surrounding treatment of postoperative arrhythmias in patients with pulmonary hypertension results is a significant disparity between individual cases. Our study takes the first step in elucidating which drugs may be a safer treatment for patients with the aim to resolve the doubts clinicians may have about using these treatments. The principal goal of our work is to ensure that we are providing patients with the most effective and, more importantly, safest treatment.
[1] Echahidi N, Pibarot P, O’Hara G, Mathieu P. Mechanisms, Prevention, and Treatment of Atrial Fibrillation After Cardiac Surgery. J Am Coll Cardiol 2008;51:793-801.
[2] Yadava M, Hughey AB, Crawford TC. Postoperative Atrial Fibrillation. Incidence, Mechanisms, and Clinical Correlates. Heart Failure Clinics 2016;12:299-308.
[3] Hiram R, Provencher S. Pulmonary Disease, Pulmonary Hypertension and Atrial Fibrillation. Cardiac Electrophysiol Clin 2021;13:141-53.
[4] Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and Molecular Pathobiology of Pulmonary Arterial Hypertension. J Am Coll Cardiol 2004;43:S13-24.
[5] Rajdev A, Garan H, Biviano A. Arrhythmias in Pulmonary Arterial Hypertension. Prog Cardiovasc Dis 2012;55: 180-6.
[6] Ruiz-Cano MJ, Gonzalez-Mansilla A, Escribano P, Delgado J, Arribas F, Torres J, et al. Clinical Implications of Supraventricular Arrhythmias in Patients with Severe Pulmonary Arterial Hypertension. Int J Cardiol 2011;146:105-6.
[7] Tongers J, Schwerdtfeger B, Klein G, Kempf T, SchaeferA, Knapp JM, et al. Incidence and Clinical Relevance of Supraventricular Tachyarrhythmias in Pulmonary Hypertension. Am Heart J 2007;153:127-32.
[8] Olsson KM, Nickel NP, Tongers J, Hoeper MM. Atrial Flutter and Fibrillation in Patients with Pulmonary Hypertension. Int J Cardiol 2013;167:2300-5.
[9] Minai OA, Yared JP, Kaw R, Subramaniam K, Hill NS. Perioperative Risk and Management in Patients with Pulmonary Hypertension. Chest 2013;144:329-40.
[10] Wanamaker B, Cascino T, McLaughlin V, Oral H, Latchamsetty R, Siontis KC. Atrial Arrhythmias in Pulmonary Hypertension: Pathogenesis, Prognosis and Management. Arrhythmia Electrophysiol Rev 2018;7: 43-8.
[11] Gillinov AM, Bagiella E, Moskowitz AJ, Raiten JM, Groh MA, Bowdish ME, et al. Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery. N Engl J Med 2016;374:1911-21.
[12] Greenberg JW, Lancaster TS, Schuessler RB, Melby SJ. Postoperative Atrial Fibrillation Following Cardiac Surgery: A Persistent Complication. Eur J Cardiothorac Surg 2017;52:665-72.
[13] Zhu J, Wang C, Gao D, Zhang C, Zhang Y, Lu Y, et al. Meta-analysis of Amiodarone Versus Beta-blocker as a Prophylactic Therapy Against Atrial Fibrillation Following Cardiac Surgery. Intern Med J 2012;42:1078-87.
[14] Burgess DC, Kilborn MJ, Keech AC. Interventions for Prevention of Post-operative Atrial Fibrillation and its Complications After Cardiac Surgery: A Meta-analysis. Eur Heart J 2006;27:2846-57.
[15] Mayson SE, Greenspon AJ, Adams S, DeCaro MV, Sheth M, Weitz HH, et al. The Changing Face of Postoperative Atrial Fibrillation Prevention: A Review of Current Medical Therapy. Cardiol Rev 2007;15:231-41.
[16] Boriani G, Fauchier L, Aguinaga L, Beattie JM, Blomstrom Lundqvist C, Cohen A, et al. European Heart Rhythm Association (EHRA) Consensus Document on Management of Arrhythmias and Cardiac Electronic Devices in the Critically ill and Post-surgery Patient, Endorsed by Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Cardiac Arrhythmia Society of Southern Africa (CASSA), and Latin American Heart Rhythm Society (LAHRS). Europace 2019;21:7-8.
[17] Reddy SA, Nethercott SL, Khialani BV, Grace AA, Martin CA. Management of Arrhythmias in Pulmonary Hypertension. J Interv Cardiac Electrophysiol 2021;62: 219-29.
[18] Rich S, Seidlitz M, Dodin E, Osimani D, Judd D, Genthner D, et al. The Short-term Effects of Digoxin in Patients with Right Ventricular Dysfunction from Pulmonary Hypertension. Chest 1998;114:787-92.
[19] Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. Eur Heart J 2016;37:67-119.
[20] Hussain A, Bennett RT, Chaudhry MA, Qadri SS, Cowen M, Morice AH, et al. Characterization of Optimal Resting Tension in Human Pulmonary Arteries. World J Cardiol 2016;8:553.
[21] Hussain A, Bennett R, Haqzad Y, Qadri S, Chaudhry M, Cowen M, et al. The Differential Effects of Systemic Vasoconstrictors on Human Pulmonary Artery Tension. Eur J Cardiothorac Surg 2017;51:880-6.
[22] Afzal A, Jafri S, Borzak S. Role of Amiodarone in Heart Failure. Heart Failure Rev 1997;2:3-10.
[23] Marck PV, Pierre SV. Na/K-ATPase Signaling and Cardiac Pre/Post conditioning with Cardiotonic Steroids. Int J Mol Sci 2018;19:2336.
[24] Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, et al. Amiodarone in Patients with Congestive Heart Failure and Asymptomatic Ventricular Arrhythmia. N Engl J Med 1995;333:77-82.
[25] NICE. Recommendations Chronic Heart Failure in Adults: Diagnosis and Management Guidance. NICE; 2018. Available from: https://www.nice.org.uk/guidance/ng106/ resources/chronic-heart-failure-in-adults-diagnosis-andmanagement-pdf-66141541311685 [Last accessed on 2019 Dec 10].
[26] Feduska ET, Thoma BN, Torjman MC, Goldhammer JE. Acute Amiodarone Pulmonary Toxicity. J Cardiothorac Vasc Anesthesia 2021;35:1485-94.
[27] Patocka J, Nepovimova E, Wu W, Kuca K. Digoxin: Pharmacology and toxicology-A review. Environ Toxicol Pharmacol 2020;79:103400.
[28] Goldschlager N, Epstein AE, Naccarelli G, Olshansky B, Singh B. Practical Guidelines for Clinicians Who Treat Patients with Amiodarone. Arch Internal Med 2000;160:1741-8.
[29] Goldberger ZD, Goldberger AL. Therapeutic Ranges of Serum Digoxin Concentrations in Patients With Heart Failure. Am J Cardiol 2012;109:1818.
[30] Mubarak KK. A Review of Prostaglandin Analogs in the Management of Patients with Pulmonary Arterial Hypertension. Respir Med 2010;104:9-21.