Site-specific prolongation of repolarization prevents postmyocardial infarction tachycardia

Key Findings▪Prolongation of repolarization in myocardium adjacent to infarcted myocardium mitigates reentry and prevents postinfarction ventricular tachycardia.▪Local injection of sotalol does not cause conduction delay or myocardial injury.▪We speculate that site-specific targeted antiarrhythmic therapy will provide a nondestructive, mechanism-based treatment of arrhythmic substrates, to a degree not attained with drugs or ablation and without their side effects. ▪Prolongation of repolarization in myocardium adjacent to infarcted myocardium mitigates reentry and prevents postinfarction ventricular tachycardia.▪Local injection of sotalol does not cause conduction delay or myocardial injury.▪We speculate that site-specific targeted antiarrhythmic therapy will provide a nondestructive, mechanism-based treatment of arrhythmic substrates, to a degree not attained with drugs or ablation and without their side effects. Antiarrhythmic drugs that aim to prolong refractoriness by reducing repolarizing are often used to treat postinfarction ventricular tachycardia (VT). However, these drugs prolong action potential duration throughout the heart and may trigger polymorphic VT by prolonging repolarization in areas where it already is long. Here we investigate whether site-specific prolongation of repolarization in myocardium adjacent to the infarcted myocardium mitigates reentry and prevents postinfarction VT. We generated myocardial infarction in a 2-year-old male pig by 90-minute occlusion of the left anterior descending coronary artery. Six weeks later, we performed epicardial mapping during Langendorff perfusion as reported previously (Figure 1).1Boukens B.J. Meijborg V.M.F. Belterman C.N. et al.Local transmural action potential gradients are absent in the isolated, intact dog heart but present in the corresponding coronary-perfused wedge.Physiol Rep. 2017; 5e13251Crossref Scopus (13) Google Scholar Programmed stimulation induced reentry and monomorphic VT. We locally injected 0.5 mL sotalol (10 μM) at the site with fractionated electrograms to prolong repolarization. Direct injection of sotalol into the myocardium did not cause injury as evidenced by the absence of ST elevation in the local electrograms and was further supported by similar epicardial activation patterns before and after sotalol injection. Fifteen minutes after sotalol injection, VT could no longer be induced. Next, we used a digital twin heart model from a patient with postmyocardial infarction arrhythmias (Figures 1D–1F) based on preablation cardiac late gadolinium enhanced magnetic resonance imaging, and gray zone myocardium with remodeled ionic current properties and slowed conduction.2Prakosa A. Arevalo H.J. Deng D. et al.Personalized virtual-heart technology for guiding the ablation of infarct-related ventricular tachycardia.Nat Biomed Eng. 2018; 2: 732-740Crossref PubMed Scopus (140) Google Scholar Core scar was made inexcitable. VT was induced by programmed stimulation to identify the exit site of the arrhythmia. Next, we prolonged repolarization of the nonscarred myocardium adjacent to the exit site by 50 ms and repeated the stimulation protocol for VT induction. This only resulted in a single spontaneous premature ventricular beat, after which arrhythmic quiescence ensued. Our findings show the potential of local prolongation of repolarization as a novel antiarrhythmic therapy in postmyocardial infarction patients. In the isolated heart and in the virtual patient heart, local prolongation of repolarization in myocardium with fractionated potentials or containing the VT exit site was effective in preventing VT. If multiple exit sites had been present, our intervention would have been inconclusive because the arrhythmias could have been sustained by a different exit site. When multiple exit sites are present, multiple regions need to be selectively targeted. Site-specific therapy may prevent off-target effects of systemic therapy or unnecessary ablation of viable myocardium or the induction of new scars. Local delivery of repolarization prolonging drugs could be achieved by materials that support drug release, such as bioresorbable adhesive devices.3Yang Q. Wei T. Yin R.T. et al.Photocurable bioresorbable adhesives as functional interfaces between flexible bioelectronic devices and soft biological tissues.Nat Mater. 2021; 20: 1559-1570Crossref PubMed Scopus (0) Google Scholar Alternatively, long-term local prolongation of repolarization could be achieved using cardiac gene therapy.4Kelemen K. Greener I.D. Wan X. et al.Heterogeneous repolarization creates ventricular tachycardia circuits in healed myocardial infarction scar.Nat Commun. 2022; 13: 830Crossref PubMed Scopus (9) Google Scholar The latter has evolved into a high-potential therapeutic strategy targeting various disorders. For long-term gene delivery, adeno-associated virus vectors have emerged as the most potent system and are now being tested in various clinical trials primarily targeting heart failure.5Sasano T. McDonald A.D. Kikuchi K. Donahue J.K. Molecular ablation of ventricular tachycardia after myocardial infarction.Nat Med. 2006; 12: 1256-1258Crossref PubMed Scopus (103) Google Scholar Our study is limited by the results of a single experiment and a single in silico observation. Thus, it can be argued that the outcome of the experiment was coincidental. However, we have shown that a pig heart is very stable during Langendorff perfusion and that the heart can serve as its own control for interventions such as infusion of sotalol. Second, we showed that the effect of sotalol was mediated by repolarization prolongation. Also, the results are confirmed by the patient-specific simulations, in which confounding variability is absent, thus providing translational value. Thus, a single experiment can be valuable to establish proof of concept. Future studies should test our intervention in the setting of more complex reentrant pathways with multiple exit sites. In conclusion, site-specific targeted antiarrhythmic therapy carries promise for nondestructive, mechanism-based treatment of arrhythmic substrates, to a degree not attained with drugs or ablation and without their side effects. This work was supported by the RHYTHM Leducq Grant (16CVD02) and GALANT (ZonMW) (116004202). Mr O’Hara was supported by a National Science Foundation Graduate Research Fellowship (DGE-1746891). Dr Boink was supported by European Research Council Starting Grant 714866 and associated proof-of-concept Grants 899422 and 101081921; Health Holland LentiPace II; Horizon 2020 Eurostars E114245 and E115484; and the Dutch Research Council Open Technology Program 18485.