Congenital EP Featured Articles of June 2017

 

Congenital and Pediatric Cardiac EP Reviews of June 2017 Manuscripts

 

Prospective Study of Adenosine on Atrioventricular Nodal Conduction in Pediatric and Young Adult Patients After Heart Transplantation.

Flyer JN, Zuckerman WA, Richmond ME, Anderson BR, Mendelsberg TG, McAllister JM, Liberman L, Addonizio LJ, Silver ES.

Circulation. 2017 Jun 20;135(25):2485-2493. doi: 10.1161/CIRCULATIONAHA.117.028087. Epub 2017 Apr 27.

PMID: 28450351

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Take Home Points:

  • Supraventricular tachycardia can be seen in up to 50% of children and adults after heart transplantation.
  • Adenosine, a endogenous nucleoside that results in sinus slowing and AV block, has been considered relatively contraindicated in heart transplant recipients due to post-transplant denervation
  • Adenosine use at low doses of 25 μg/kg or 1.5 mg were found to be effective in causing AV block in healthy heart transplant patients in sinus rhythm
  • AV block was seen in 96% of patients with escalating adenosine administration up to maximal dose of 200 μg/kg or 12 mg
  • There were no adverse events seen after adenosine administration including no clinically significant asystole (≥ 12 seconds) requiring rescue ventricular pacing
  • The use of adenosine during supraventricular tachycardia in post-heart transplants patients was not evaluated and therefore, the dosing, response and safety of adenosine in that scenario cannot be commented on based on this study.

 

A PatelComment from Dr. Akash Patel (San Francisco), section editor of Congenital Electrophysiology Journal Watch:  Previous limited data has suggested heart transplant patients are at adverse risk to adenosine in the setting of cardiac denervation after transplantation. In particular, adenosine exposure in this setting has been thought to lead to excessive AV block and bradycardia. Due to this concern, adenosine is relatively contraindicated in post-heart transplant patients and thus uncommonly used. However, up to 50% of children and adults with heart transplantation can be affected by supraventricular tachycardia with adenosine potentially providing a therapeutic and/or diagnostic option.  This single center prospective study from New York Presbyterian/Morgan Stanley Children’s Hospital, Columbia University Medical Center aimed to improve our understanding of the safety and efficacy of adenosine in pediatric and young adult patients who have undergone heart transplantation with hopes to reconsider its use in this population.

 

All healthy patients ≥ 2 weeks post-cardiac transplantation were included if they agreed to consent and were excluded if there was evidence of rejection (clinical/humeral/cellular), graft vasculopathy, concurrent use of intravenous inotropic medication, concurrent treatment for rejection, conduction disease (first-, second-, or third-degree AV block, preexisting sinus node dysfunction), or systolic ventricular dysfunction. At the time of routine post-cardiac transplant catheterization, eligible patients underwent adenosine testing.

The study group included 80 patients (55% male) with a median age of 13.6 years (Range: 1.1 – 24 year). The median weight was 50.4 kg (Range: 7.8 – 120 kg). The indications for transplantation included cardiomyopathy (60%), congenital heart disease (30%), retransplantation (7.5%), and other (2.5%). The most common type of transplantation was bicaval (71%) followed by biatrial (28%). Prior history of rejection was seen in 49%. There was use of dipyridamole in 53% which is a medication known to effect adenosine metabolism. This medication was stopped 3 days before catheterization in all patients. There was use of antiarrhythmic drugs – beta-blocker (24%) and digoxin (2.5%)- but no data on indications or prior arrhythmia status. The cardiac catheterization procedures were done under general anesthesia in 64%.

After catheterization and biopsy were complete but before the removal of central access, a 4F quadripolar pacing catheter was introduced into the right ventricle with pacing thresholds tested and outputs set appropriately. Adenosine was given via central access in serial escalating doses based on weight until AV block or clinically significant asystole (either a sinus pause or AV block ≥ 12 seconds which were the predetermined criterion to initiate ventricular pacing) were seen. If patients weighed <60 kg, patients were given 12.5, 25, 50, 100, and 200 μg/kg of adenosine. If patients weighed ≥ 60 kg, patients were given 0.8, 1.5, 3, 6, and 12 mg.  See below.  The median maximal dose of adenosine given was 3.6 mg (IQR: 2.0 – 6.0 mg).

June EP v1

The primary outcome of the study was to assess the safety of adenosine.  There were no patients (0%) who had clinically significant asystole requiring rescue ventricular pacing after adenosine administration during the escalating adenosine protocol. See below.

 June EP V2

 

The secondary objective was to assess the efficacy of adenosine in the post-heart transplant patient. There was AV block seen in 77/80 (96%) of the cohort (see above).  There was sinus pause > 2 seconds seen in 4 (5%). The effect of AV nodal blockade was seen at doses as low as 25 μg/kg (< 60 kg) or 1.5 mg (≥ 60kg) in 12%. As expected, incremental escalations in dosing increased the percent of patients demonstrating AV nodal block. At up to initial standard dosing of 100 μg/kg (< 60 kg) or 6 mg (≥ 60kg), there was AV nodal blockade seen in 72%.  See Below.

June EP V3The AV nodal effects of adenosine varied in duration. The median longest R-R interval during AV block was 1.9 seconds (IQR: 1.4 – 3.2 seconds) (Example See Figure Below (A)) The mean total adenosine effect was 4.3 seconds (SD: ±2.0 seconds)  (Example: See Figure Below (B)). The absolute longest R-R interval and total adenosine effect in any patient was 8.4 seconds. The median consecutive non-conducted P waves during the longest pause were 2 (IQR, 1–3). The authors stated no variable predicted adenosine effect including prior rejection, maximal dose, weight, or time from transplant.

June EP v6

The use of adenosine was well tolerated with typical symptoms reported in the non-anesthetized group including shortness of breath, discomfort, chest pain, headache, and flushing. There were no adverse symptoms that resulted in premature termination of the protocol.

This study demonstrates the safety of adenosine use in a large healthy pediatric and young adult post-cardiac transplant cohort with no adverse effects including no clinically significant asystole requiring rescue ventricular pacing.  The authors conclude that adenosine is effective in causing AV node blockade at much lower doses – 25 μg/kg (< 60kg) or 1.5mg (≥ 60 kg) –  than PALS or ACLS standard dosing. As the effect is dose-dependent, gradual dose escalation can be considered up to maximal doses of 200 μg/kg (< the 60kg) or 12 mg (≥60kg) until AV blockade is achieved.

This study however does not address if and why lower doses are required and if there is an exaggerated response with adenosine use in post-transplant patients. In particular, it is unclear if the same lower doses given centrally in healthy age-based controls would have resulted in the same effect. In addition, in 1990 Ellenbogen et al (Circulation 1990;81: 821-828  PMID: 2306833) demonstrated there was evidence of a supersensitivity effect in adult patients. Since the dose escalation was terminated once AV block was seen, it is unclear if maximal dosing in all 80 patients would have resulted in an exaggerated response. The study design did not allow for answering these important questions but did show safety with their adenosine dose escalation protocol.  The authors discuss the roles of cardiac denervation and reinnervation as it may play a factor in these issues, but interesting the study showed safe adenosine effect as early as 25 days post-transplant and overall no correlation between time of transplant and effective adenosine dose suggesting other factors may play a role.

Clearly there are limitations to this study with the most notable being that patients are known to be healthy, were not in supraventricular tachycardia at the time of adenosine administration, and the route of adenosine administration was via central access. From a practical standpoint, adenosine is often given peripherally and used in an acute setting. Therefore, the effect of adenosine in the “healthy patient” is a less likely scenario as their rejection status and function may not be known and they may be on antiarrhythmics or other medications that may affect the response to adenosine. Nevertheless, this study demonstrates that adenosine may be used safely in this population but a cautious approach using low doses should be undertaken.

 

Additional EP Articles Worth Reading.

 

Intraoperative arrhythmias in children with congenital heart disease: transient, innocent events? Houck CA, Ramdjan TTTK, Yaksh A, Teuwen CP, Lanters EAH, Bogers AJJC, de Groot NMS.Europace. 2017 Jun 28. doi: 10.1093/europace/eux072. [Epub ahead of print]

PMID: 28666343

 

Cardiac Fibroblast Transcriptome Analyses Support a Role for Interferogenic, Profibrotic and Inflammatory Genes in Anti-SSA/Ro-Associated Congenital Heart Block.

Clancy RM, Markham AJ, Jackson T, Rasmussen SE, Blumenberg M, Buyon JP.

Am J Physiol Heart Circ Physiol. 2017 Jun 16:ajpheart.00256.2017. doi: 10.1152/ajpheart.00256.2017. [Epub ahead of print]

PMID: 28626076

 

Cardiac Arrhythmias in Adults with Congenital Heart Disease.

Balaji S, Mandapati R, Shivkumar K.

Card Electrophysiol Clin. 2017 Jun;9(2):xv-xvi. doi: 10.1016/j.ccep.2017.04.001. No abstract available.

PMID: 28457248

 

Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome: A Japanese Multicenter Registry.

Yamagata K, Horie M, Aiba T, Ogawa S, Aizawa Y, Ohe T, Yamagishi M, Makita N, Sakurada H, Tanaka T, Shimizu A, Hagiwara N, Kishi R, Nakano Y, Takagi M, Makiyama T, Ohno S, Fukuda K, Watanabe H, Morita H, Hayashi K, Kusano K, Kamakura S, Yasuda S, Ogawa H, Miyamoto Y, Kapplinger JD, Ackerman MJ, Shimizu W.

Circulation. 2017 Jun 6;135(23):2255-2270. doi: 10.1161/CIRCULATIONAHA.117.027983. Epub 2017 Mar 24.

PMID: 28341781

 

 

CHD EP June 2017

 

  1. Intraoperative arrhythmias in children with congenital heart disease: transient, innocent events?

Houck CA, Ramdjan TTTK, Yaksh A, Teuwen CP, Lanters EAH, Bogers AJJC, de Groot NMS.

Europace. 2017 Jun 28. doi: 10.1093/europace/eux072. [Epub ahead of print]

PMID: 28666343

 

Select item 28660303

 

  1. Cardiac Fibroblast Transcriptome Analyses Support a Role for Interferogenic, Profibrotic and Inflammatory Genes in Anti-SSA/Ro-Associated Congenital Heart Block.

Clancy RM, Markham AJ, Jackson T, Rasmussen SE, Blumenberg M, Buyon JP.

Am J Physiol Heart Circ Physiol. 2017 Jun 16:ajpheart.00256.2017. doi: 10.1152/ajpheart.00256.2017. [Epub ahead of print]

PMID: 28626076

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  1. Sudden cardiac death in the young: Epidemiology and overview.

Link MS.

Congenit Heart Dis. 2017 Jun 15. doi: 10.1111/chd.12494. [Epub ahead of print]

PMID: 28618149

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  1. Sudden death in athletes.

Corrado D, Zorzi A.

Int J Cardiol. 2017 Jun 15;237:67-70. doi: 10.1016/j.ijcard.2017.03.034. Epub 2017 Mar 10.

PMID: 28318658

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  1. <i>Nkx2.5</i> is Essential to Establish Normal Heart Rate Variability in the Zebrafish Embryo.

Harrington JK, Sorabella R, Tercek A, Isler JR, Targoff KL.

Am J Physiol Regul Integr Comp Physiol. 2017 Jun 14:ajpregu.00223.2016. doi: 10.1152/ajpregu.00223.2016. [Epub ahead of print]

PMID: 28615160

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  1. Calcium Signaling and Cardiac Arrhythmias.

Landstrom AP, Dobrev D, Wehrens XHT.

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PMID: 28596175

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  1. Permanent chronotropic impairment after closure of atrial or ventricular septal defect.

Heiberg J, Nyboe C, Hjortdal VE.

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PMID: 28457248

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Deal BJ, Mavroudis C.

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Card Electrophysiol Clin. 2017 Jun;9(2):319-328. doi: 10.1016/j.ccep.2017.02.013. Epub 2017 Mar 31. Review.

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  1. Catheter Ablation: General Principles and Advances.

Ernst S.

Card Electrophysiol Clin. 2017 Jun;9(2):311-317. doi: 10.1016/j.ccep.2017.02.012. Epub 2017 Mar 14. Review.

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  1. Drug Therapy in Adult Congenital Heart Disease.

Contractor T, Levin V, Mandapati R.

Card Electrophysiol Clin. 2017 Jun;9(2):295-309. doi: 10.1016/j.ccep.2017.02.011. Review.

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Sathananthan G, Harris L, Nair K.

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  1. Supraventricular Tachycardia in Adult Congenital Heart Disease: Mechanisms, Diagnosis, and Clinical Aspects.

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Carlson SK, Patel AR, Chang PM.

Card Electrophysiol Clin. 2017 Jun;9(2):177-187. doi: 10.1016/j.ccep.2017.02.002. Epub 2017 Mar 22. Review.

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  1. Introduction to the Congenital Heart Defects: Anatomy of the Conduction System.

Moore JP, Aboulhosn JA.

Card Electrophysiol Clin. 2017 Jun;9(2):167-175. doi: 10.1016/j.ccep.2017.02.001. Epub 2017 Mar 14. Review.

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Bulic A, Zimmerman FJ, Ceresnak SR, Shetty I, Motonaga KS, Freter A, Trela AV, Hanisch D, Russo L, Avasarala K, Dubin AM.

Heart Rhythm. 2017 Jun;14(6):853-857. doi: 10.1016/j.hrthm.2017.03.035.

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Pacing Clin Electrophysiol. 2017 Jun;40(6):735-737. doi: 10.1111/pace.13089. Epub 2017 May 16. No abstract available.

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  1. Lone Pediatric Atrial Fibrillation in the United States: Analysis of Over 1500 Cases.

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  1. Measures of and changes in heart rate variability in pediatric heart transplant recipients.

Williams T, Tang X, Gilmore G, Gossett J, Knecht KR.

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  1. [News techniques of pacing in congenital heart diseases].

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  1. Postnatal Outcomes of Fetal Supraventricular Tachycardia: a Multicenter Study.

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  1. Prospective Study of Adenosine on Atrioventricular Nodal Conduction in Pediatric and Young Adult Patients After Heart Transplantation.

Flyer JN, Zuckerman WA, Richmond ME, Anderson BR, Mendelsberg TG, McAllister JM, Liberman L, Addonizio LJ, Silver ES.

Circulation. 2017 Jun 20;135(25):2485-2493. doi: 10.1161/CIRCULATIONAHA.117.028087. Epub 2017 Apr 27.

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Indian Pediatr. 2017 Jun 15;54(6):503-504.

PMID: 28667725

 

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  1. Variation in Pediatric Post-Ablation Care: A Survey of the Pediatric and Congenital Electrophysiology Society (PACES).

Dechert BE, Dick M 2nd, Bradley DJ, LaPage MJ.

Pediatr Cardiol. 2017 Jun 15. doi: 10.1007/s00246-017-1654-1. [Epub ahead of print]

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  1. Comparison of 6-mm Versus 8-mm-Tip Cryoablation Catheter for the Treatment of Atrioventricular Nodal Reentrant Tachycardia in Children: A Prospective Study.

Tuzcu V, Gul EE, Karacan M, Kamali H, Celik N, Akdeniz C.

Pediatr Cardiol. 2017 Jun 13. doi: 10.1007/s00246-017-1648-z. [Epub ahead of print]

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Yamagata K, Horie M, Aiba T, Ogawa S, Aizawa Y, Ohe T, Yamagishi M, Makita N, Sakurada H, Tanaka T, Shimizu A, Hagiwara N, Kishi R, Nakano Y, Takagi M, Makiyama T, Ohno S, Fukuda K, Watanabe H, Morita H, Hayashi K, Kusano K, Kamakura S, Yasuda S, Ogawa H, Miyamoto Y, Kapplinger JD, Ackerman MJ, Shimizu W.

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PMID: 28341781

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  1. Cost Analysis of Patients Referred for Inherited Heart Rhythm Disorder Evaluation.

Janzen ML, Cheung C, Sanatani S, Cunningham T, Kerr C, Steinberg C, Sherwin E, Arbour L, Deyell MW, Andrade JG, Lehman AM, Gula LJ, Krahn AD.

Can J Cardiol. 2017 Jun;33(6):814-821. doi: 10.1016/j.cjca.2016.12.009. Epub 2016 Dec 20.

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  1. Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death.

Lahrouchi N, Lodder EM, Mansouri M, Tadros R, Zniber L, Adadi N, Clur SB, van Spaendonck-Zwarts KY, Postma AV, Sefiani A, Ratbi I, Bezzina CR.

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  1. Vectorcardiography identifies patients with electrocardiographically concealed long QT syndrome.

Cortez D, Bos JM, Ackerman MJ.

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  1. Single-incision percutaneous pericardial ICD lead placement in a piglet model.

Clark BC, Opfermann JD, Davis TD, Krieger A, Berul CI.

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