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Open Access 19-09-2023 | Tetralogy of Fallot | Original Paper

Disease severity, arrhythmogenesis, and fibrosis are related to longer action potentials in tetralogy of Fallot

Authors: Hannah E. Fürniss, Eike M. Wülfers, Pia Iaconianni, Ursula Ravens, Johannes Kroll, Brigitte Stiller, Peter Kohl, Eva A. Rog-Zielinska, Rémi Peyronnet

Published in: Clinical Research in Cardiology | Issue 5/2024

Abstract

Background

Arrhythmias may originate from surgically unaffected right ventricular (RV) regions in patients with tetralogy of Fallot (TOF). We aimed to investigate action potential (AP) remodelling and arrhythmia susceptibility in RV myocardium of patients with repaired and with unrepaired TOF, identify possible correlations with clinical phenotype and myocardial fibrosis, and compare findings with data from patients with atrial septal defect (ASD), a less severe congenital heart disease.

Methods

Intracellular AP were recorded ex vivo in RV outflow tract samples from 22 TOF and three ASD patients. Arrhythmias were provoked by superfusion with solutions containing reduced potassium and barium chloride, or isoprenaline. Myocardial fibrosis was quantified histologically and associations between clinical phenotype, AP shape, tissue arrhythmia propensity, and fibrosis were examined.

Results

Electrophysiological abnormalities (arrhythmias, AP duration [APD] alternans, impaired APD shortening at increased stimulation frequencies) were generally present in TOF tissue, even from infants, but rare or absent in ASD samples. More severely diseased and acyanotic patients, pronounced tissue susceptibility to arrhythmogenesis, and greater fibrosis extent were associated with longer APD. In contrast, APD was shorter in tissue from patients with pre-operative cyanosis. Increased fibrosis and repaired-TOF status were linked to tissue arrhythmia inducibility.

Conclusions

Functional and structural tissue remodelling may explain arrhythmic activity in TOF patients, even at a very young age. Surprisingly, clinical acyanosis appears to be associated with more severe arrhythmogenic remodelling. Further research into the clinical drivers of structural and electrical myocardial alterations, and the relation between them, is needed to identify predictive factors for patients at risk.

Graphical Abstract

Central illustration: summary diagram of essential study results. Note that not all results are depicted here. For more detail, see text. APA action potential amplitude, APD action potential duration, AUC area under the curve, TOF tetralogy of Fallot.

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Arya S, Kovach J, Singh H, Karpawich PP (2014) Arrhythmias and sudden death among older children and young adults following tetralogy of Fallot repair in the current era: are previously reported risk factors still applicable? Congenit Heart Dis 9(5):407–414. https://doi.org/10.1111/chd.12153CrossRefPubMed

Mouws EMJP, Roos-Hesselink JW, Bogers AJJC, de Groot NMS (2018) Coexistence of tachyarrhythmias in patients with tetralogy of Fallot. Heart Rhythm 15(4):503–511. https://doi.org/10.1016/j.hrthm.2017.11.021CrossRefPubMed

Brouwer C, Kapel GFL, Jongbloed MRM, Schalij MJ, de Riva Silva M, Zeppenfeld K (2018) Noninvasive identification of ventricular tachycardia-related anatomical isthmuses in repaired tetralogy of Fallot. JACC Clin Electrophysiol 4(10):1308–1318. https://doi.org/10.1016/j.jacep.2018.06.017CrossRefPubMed

Kapel GFL, Sacher F, Dekkers OM et al (2017) Arrhythmogenic anatomical isthmuses identified by electroanatomical mapping are the substrate for ventricular tachycardia in repaired Tetralogy of Fallot. Eur Heart J 38(4):268–276. https://doi.org/10.1093/eurheartj/ehw202CrossRefPubMed

Drago F, Pazzano V, Di Mambro C et al (2016) Role of right ventricular three-dimensional electroanatomic voltage mapping for arrhythmic risk stratification of patients with corrected tetralogy of Fallot or other congenital heart disease involving the right ventricular outflow tract. Int J Cardiol 222:422–429. https://doi.org/10.1016/j.ijcard.2016.07.231CrossRefPubMed

Jalal Z, Sacher F, Fournier E et al (2019) Right ventricular electrical activation in patients with repaired tetralogy of Fallot. Circ Arrhythm Electrophysiol 12(6):e007141. https://doi.org/10.1161/CIRCEP.119.007141CrossRefPubMed

Balkhi RA, Beghetti M, Friedli B (2004) Time course of appearance of markers of arrhythmia in patients with tetralogy of Fallot before and after surgery. Cardiol Young 14(4):360–366. https://doi.org/10.1017/S1047951104004020CrossRefPubMed

Bokma JP, Winter MM, Vehmeijer JT et al (2017) QRS fragmentation is superior to QRS duration in predicting mortality in adults with tetralogy of Fallot. Heart 103(9):666–671. https://doi.org/10.1136/heartjnl-2016-310068CrossRefPubMed

Pelzmann B, Schaffer P, Bernhart E et al (1998) L-type calcium current in human ventricular myocytes at a physiological temperature from children with tetralogy of Fallot. Cardiovasc Res 38(2):424–432. https://doi.org/10.1016/s0008-6363(98)00002-9CrossRefPubMed

10.

Schaffer P, Pelzmann B, Bernhart E et al (1999) Repolarizing currents in ventricular myocytes from young patients with tetralogy of Fallot. Cardiovasc Res 43(2):332–343. https://doi.org/10.1016/S0008-6363(99)00118-2CrossRefPubMed

11.

Benoist D, Dubes V, Roubertie F et al (2017) Proarrhythmic remodelling of the right ventricle in a porcine model of repaired tetralogy of Fallot. Heart 103(5):347–354. https://doi.org/10.1136/heartjnl-2016-309730CrossRefPubMed

12.

Gatzoulis MA, Till JA, Redington AN (1997) Depolarization-repolarization inhomogeneity after repair of tetralogy of Fallot. Circulation 95(2):401–404. https://doi.org/10.1161/01.CIR.95.2.401CrossRefPubMed

13.

Agha HM, El-Saiedi SA, Shaltout MF et al (2015) Incomplete RV remodeling after transcatheter ASD closure in pediatric age. Pediatr Cardiol 36(7):1523–1531. https://doi.org/10.1007/s00246-015-1196-3CrossRefPubMed

14.

Martin SS, Shapiro EP, Mukherjee M (2014) Atrial septal defects—clinical manifestations, echo assessment, and intervention. Clin Med Insights Cardiol. https://doi.org/10.4137/CMC.S15715CrossRefPubMed

15.

Rücklová K, Koubský K, Tomek V, Kubuš P, Janoušek J (2016) Prolonged repolarization in atrial septal defect: an example of mechanoelectrical feedback due to right ventricular volume overload. Heart Rhythm 13(6):1303–1308. https://doi.org/10.1016/j.hrthm.2016.01.032CrossRefPubMed

16.

Wülfers EM, Greiner J, Giese M et al (2021) Quantitative collagen assessment in right ventricular myectomies from patients with tetralogy of Fallot. Europace 23(Suppl 1):i38–i47. https://doi.org/10.1093/europace/euaa389CrossRefPubMedPubMedCentral

17.

Pradegan N, Vida VL, Geva T et al (2016) Myocardial histopathology in late-repaired and unrepaired adults with tetralogy of Fallot. Cardiovasc Pathol 25(3):225–231. https://doi.org/10.1016/j.carpath.2016.02.001CrossRefPubMed

18.

Chowdhury UK, Sathia S, Ray R, Singh R, Pradeep KK, Venugopal P (2006) Histopathology of the right ventricular outflow tract and its relationship to clinical outcomes and arrhythmias in patients with tetralogy of Fallot. J Thorac Cardiovasc Surg 132(2):270-277.e4. https://doi.org/10.1016/j.jtcvs.2006.04.001CrossRefPubMed

19.

Yim D, Riesenkampff E, Caro-Dominguez P, Yoo SJ, Seed M, Grosse-Wortmann L (2017) Assessment of diffuse ventricular myocardial fibrosis using native T1 in children with repaired tetralogy of Fallot. Circ Cardiovasc Imaging 10(3):e005695. https://doi.org/10.1161/CIRCIMAGING.116.005695CrossRefPubMed

20.

Kozak MF, Redington A, Yoo SJ, Seed M, Greiser A, Grosse-Wortmann L (2014) Diffuse myocardial fibrosis following tetralogy of Fallot repair: a T1 mapping cardiac magnetic resonance study. Pediatr Radiol 44(4):403–409. https://doi.org/10.1007/s00247-013-2840-9CrossRefPubMed

21.

Kido T, Ueno T, Taira M et al (2018) Clinical predictors of right ventricular myocardial fibrosis in patients with repaired tetralogy of Fallot. Circ J 82(4):1149–1154. https://doi.org/10.1253/circj.CJ-17-1088CrossRefPubMed

22.

Cochet H, Iriart X, Allain-Nicolaï A et al (2019) Focal scar and diffuse myocardial fibrosis are independent imaging markers in repaired tetralogy of Fallot. Eur Heart J Cardiovasc Imaging 20(9):990–1003. https://doi.org/10.1093/ehjci/jez068CrossRefPubMedPubMedCentral

23.

Bove T, Alipour Symakani R, Verbeke J et al (2020) Study of the time-relationship of the mechano-electrical interaction in an animal model of tetralogy of Fallot: implications for the risk assessment of ventricular arrhythmias. Interact Cardiovasc Thorac Surg 31(1):129–137. https://doi.org/10.1093/icvts/ivaa047CrossRefPubMed

24.

Kohl P, Sachs F, Franz MR (2011) Cardiac mechano-electric coupling and arrhythmias. OUP, OxfordCrossRef

25.

Timmermann V, McCulloch AD (2020) Mechano-electric coupling and arrhythmogenic current generation in a computational model of coupled myocytes. Front Physiol 11:519951. https://doi.org/10.3389/fphys.2020.519951CrossRefPubMedPubMedCentral

26.

Wülfers EM (2022) APAnalysis. Zenodo. https://doi.org/10.5281/zenodo.7127601

27.

Davignon A, Rautaharju P, Boisselle E, Soumis F, Mégélas M, Choquette A (1980) Normal ECG standards for infants and children. Pediatr Cardiol 1(2):123–131. https://doi.org/10.1007/BF02083144CrossRef

28.

Surawicz B, Childers R, Deal BJ, Gettes LS (2009) AHA/ACCF/HRS Recommendations for the standardization and interpretation of the electrocardiogram. Circulation 119(10):e235–e240. https://doi.org/10.1161/CIRCULATIONAHA.108.191095CrossRefPubMed

29.

Vehmeijer JT, Koyak Z, Bokma JP et al (2018) Sudden cardiac death in adults with congenital heart disease: does QRS-complex fragmentation discriminate in structurally abnormal hearts? EP Eur 20(FI1):f122–f128. https://doi.org/10.1093/europace/eux044CrossRef

30.

Beurskens NEG, Hagdorn QAJ, Gorter TM et al (2019) Risk of cardiac tachyarrhythmia in patients with repaired tetralogy of Fallot: a multicenter cardiac MRI based study. Int J Cardiovasc Imaging 35(1):143–151. https://doi.org/10.1007/s10554-018-1435-9CrossRefPubMed

31.

Varro A, Tomek J, Nagy N et al (2021) Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior. Physiol Rev 101(3):1083–1176. https://doi.org/10.1152/physrev.00024.2019CrossRefPubMed

32.

Okutucu S, Sabanoglu C, Yetis Sayin B, Aksoy H, Bursa N, Oto A (2020) Switching from ramipril to sacubitril/valsartan favorably alters electrocardiographic indices of ventricular repolarization in heart failure with reduced ejection fraction. Acta Cardiol 75(1):20–25. https://doi.org/10.1080/00015385.2018.1535818CrossRefPubMed

33.

Lou Q, Janks DL, Holzem KM et al (2012) Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling. Am J Physiol 303(12):H1426–H1434. https://doi.org/10.1152/ajpheart.00457.2012CrossRef

34.

Li GR, Lau CP, Leung TK, Nattel S (2004) Ionic current abnormalities associated with prolonged action potentials in cardiomyocytes from diseased human right ventricles. Heart Rhythm 1(4):460–468. https://doi.org/10.1016/j.hrthm.2004.06.003CrossRefPubMed

35.

Lu YY, Cheng CC, Tsai CF et al (2017) Discrepant effects of heart failure on electrophysiological property in right ventricular outflow tract and left ventricular outflow tract cardiomyocytes. Clin Sci 131(12):1317–1327. https://doi.org/10.1042/CS20170121CrossRef

36.

Wilson LD, Jeyaraj D, Wan X et al (2009) Heart failure enhances susceptibility to arrhythmogenic cardiac alternans. Heart Rhythm 6(2):251–259. https://doi.org/10.1016/j.hrthm.2008.11.008CrossRefPubMed

37.

Husti Z, Varró A, Baczkó I (2021) Arrhythmogenic remodeling in the failing heart. Cells 10(11):3203. https://doi.org/10.3390/cells10113203CrossRefPubMedPubMedCentral

38.

Gatzoulis MA, Till JA, Somerville J, Redington AN (1995) Mechanoelectrical interaction in tetralogy of Fallot: QRS prolongation relates to right ventricular size and predicts malignant ventricular arrhythmias and sudden death. Circulation 92(2):231–237. https://doi.org/10.1161/01.CIR.92.2.231CrossRefPubMed

39.

Valente AM, Gauvreau K, Assenza GE et al (2014) Contemporary predictors of death and sustained ventricular tachycardia in patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort. Heart 100(3):247–253. https://doi.org/10.1136/heartjnl-2013-304958CrossRefPubMed

40.

Liu CM, Lin FZ, Chen YC et al (2020) Concurrent increases in post-pacing action potential duration and contractility predict occurrence of ventricular arrhythmia. Pflugers Arch 472(12):1783–1791. https://doi.org/10.1007/s00424-020-02445-7CrossRefPubMed

41.

Yabek SM, Kato R, Singh BN (1985) Effects of hypoxia on the cellular electrical activity of adult and neonatal canine ventricular myocardium. Pediatr Res 19(12):1263–1267. https://doi.org/10.1203/00006450-198512000-00008CrossRefPubMed

42.

Romanowicz J, Guerrelli D, Dhari Z et al (2021) Chronic perinatal hypoxia delays cardiac maturation in a mouse model for cyanotic congenital heart disease. Am J Physiol 320(5):H1873–H1886. https://doi.org/10.1152/ajpheart.00870.2020CrossRef

43.

Reddy S, Zhao M, Hu DQ et al (2013) Physiologic and molecular characterization of a murine model of right ventricular volume overload. Am J Physiol 304(10):H1314–H1327. https://doi.org/10.1152/ajpheart.00776.2012CrossRef

44.

Possner M, Tseng SY, Alahdab F et al (2020) Risk factors for mortality and ventricular tachycardia in patients with repaired tetralogy of Fallot: a systematic review and meta-analysis. Can J Cardiol 36(11):1815–1825. https://doi.org/10.1016/j.cjca.2020.01.023CrossRefPubMed

Title: Disease severity, arrhythmogenesis, and fibrosis are related to longer action potentials in tetralogy of Fallot
Authors: Hannah E. Fürniss
Eike M. Wülfers
Pia Iaconianni
Ursula Ravens
Johannes Kroll
Brigitte Stiller
Peter Kohl
Eva A. Rog-Zielinska
Rémi Peyronnet
Publication date: 19-09-2023
Publisher: Springer Berlin Heidelberg
Keywords: Tetralogy of Fallot
Tetralogy of Fallot
Atrial Septal Defect
Atrial Septal Defect
Cyanosis
Cyanosis
Published in: Clinical Research in Cardiology / Issue 5/2024
Print ISSN: 1861-0684
Electronic ISSN: 1861-0692
DOI: https://doi.org/10.1007/s00392-023-02288-z

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Disease severity, arrhythmogenesis, and fibrosis are related to longer action potentials in tetralogy of Fallot

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

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