John Papagiannis

Late enlargement of radiofrequency lesions in infant lambs. Implications for ablation procedures in small children.

Despite the current clinical use of radiofrequency (RF) catheter ablation in infants, the acute and late effects of RF lesion production in immature myocardium remain unknown. This study was specifically designed to investigate the pathology of RF lesions in developing sheep myocardium. Methods and ResultsIn study 1, RF lesions were made on the epicardial left ventricular surface of the beating heart in 15 sheep, 5 approximately 4 weeks of age (11.0±1.0 kg) and 10 approximately 8 weeks of age (23.8±3.4 kg), to assess the effects of RF application duration (10 to 90 seconds) and electrode tip temperature (45° to 90°C) on lesion size in immature myocardium. Lesion width and depth increased asymptotically with RF duration, to 7.0±0.7 and 4.8±1.0 mm at 90 seconds, respectively. The time to reach one-half lesion size was 6.5 seconds for width and 12.0 seconds for depth. Lesion width increased nearly linearly with tip temperature above 50°C, but depth followed a sigmoid relation, with no increase above 80°C. In study 2, RF lesions were made in all four cardiac chambers under fluoroscopic guidance in 19 infant sheep (10.9±1.4 kg). Lesion sizes and histological characteristics were assessed acutely (acute, n=5), at 1.07±0.02 months (1 month, n=5), and at 8.5±0.5 months (late, n=9). Atrial and ventricular lesions but not atrioventricular groove lesions apparently increased in size during the follow-up period. Atrial lesions width increased from 5.3±0.5 to 8.7±0.7 mm at 1 month (164%) but did not increase further at late follow-up, while ventricular lesion width increased from 5.9±0.8 to 10.1±0.7 mm (171%) at late follow-up but was not significantly changed at 1 month. Histological evaluation revealed replacement of normal myocytes with fibrous and elastic tissue at 1 month and late follow-up in all locations but also demonstrated a poorly delineated border with multiple extensions of fibrous and elastic tissue into surrounding normal myocardium in late ventricular lesions. ConclusionsRF lesion formation in immature sheep myocardium is similar to that in adult myocardium acutely but is associated with late lesion enlargement and fibrous tissue invasion of normal myocardium. These findings may have implications for clinical RF ablation procedures in infants.

Calmodulin Mutations Associated With Recurrent Cardiac Arrest in Infants

Background— Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results— We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity. Conclusions— Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.

Cardiac resynchronisation therapy in paediatric and congenital heart disease: differential effects in various anatomical and functional substrates

Background: Cardiac resynchronisation therapy (CRT) is increasingly used in children in a variety of anatomical and pathophysiological conditions, but published data are scarce. Objective: To record current practice and results of CRT in paediatric and congenital heart disease. Design: Retrospective multicentre European survey. Setting: Paediatric cardiology and cardiac surgery centres. Patients: One hundred and nine patients aged 0.24–73.8 (median 16.9) years with structural congenital heart disease (n = 87), congenital atrioventricular block (n = 12) and dilated cardiomyopathy (n = 10) with systemic left (n = 69), right (n = 36) or single (n = 4) ventricular dysfunction and ventricular dyssynchrony during sinus rhythm (n = 25) or associated with pacing (n = 84). Interventions: CRT for a median period of 7.5 months (concurrent cardiac surgery in 16/109). Main outcome measures: Functional improvement and echocardiographic change in systemic ventricular function. Results: The z score of the systemic ventricular end-diastolic dimension decreased by median 1.1 (p<0.001). Ejection fraction (EF) or fractional area of change increased by a mean (SD) of 11.5 (14.3)% (p<0.001) and New York Heart Association (NYHA) class improved by median 1.0 grade (p<0.001). Non-response to CRT (18.5%) was multivariably predicted by the presence of primary dilated cardiomyopathy (p = 0.002) and poor NYHA class (p = 0.003). Presence of a systemic left ventricle was the strongest multivariable predictor of improvement in EF/fractional area of change (p<0.001). Results were independent of the number of patients treated in each contributing centre. Conclusion: Heart failure associated with ventricular pacing is the largest indication for CRT in paediatric and congenital heart disease. CRT efficacy varies widely with the underlying anatomical and pathophysiological substrate.

Pathologic anatomy of corrected transposition of the great arteries: Medical and surgical implications

BACKGROUND Because the double-switch operation (atrial switch plus arterial switch) has recently become feasible in selected patients with congenitally physiologically corrected transposition of the great arteries, a detailed understanding of the pathologic anatomy is now mandatory for cardiologists, radiologists, and surgeons. METHODS A detailed study of the pathologic anatomy, the clinical implications, and the surgical implications was undertaken on 33 postmortem cases with two ventricles. A companion study was also performed of 44 postmortem cases with functionally only one ventricle. Hence this was an investigation of 77 postmortem cases. RESULTS Three main anatomic types of corrected transposition of the great arteries (TGA) with two ventricles were found: (1) TGA with solitus atria (S), L-loop ventricles (L), and L-TGA (L), that is, TGA [S,L,L] in 31 cases (94%); (2) TGA with solitus atria (S), L-loop ventricles (L), and D-TGA (D), that is, TGA [S,L,D] in 1 case (3%); and (3) TGA with inverted atria (I), D-loop ventricles (D), and D-TGA (D), that is, TGA [I,D,D] in 1 case (3%). Associated malformations resulted in 13 anatomic subtypes. In classical corrected TGA [S,L,L] with two ventricles, anomalies of the left-sided systemic tricuspid valve were present in 97%, with malformations of the left-sided systemic right ventricle in 91%. CONCLUSIONS The findings in corrected TGA with two ventricles and in cases with single ventricle support the view that anatomic repair such as the double-switch procedure, or left-sided right ventricle bypass such as the modified Norwood procedure followed by the modified Fontan procedure, is indicated in selected patients.

Permanent Cardiac Pacing in Children: Choosing the Optimal Pacing Site A Multicenter Study

Background— We evaluated the effects of the site of ventricular pacing on left ventricular (LV) synchrony and function in children requiring permanent pacing. Methods and Results— One hundred seventy-eight children (aged <18 years) from 21 centers with atrioventricular block and a structurally normal heart undergoing permanent pacing were studied cross-sectionally. Median age at evaluation was 11.2 (interquartile range, 6.3–15.0) years. Median pacing duration was 5.4 (interquartile range, 3.1–8.8) years. Pacing sites were the free wall of the right ventricular (RV) outflow tract (n=8), lateral RV (n=44), RV apex (n=61), RV septum (n=29), LV apex (n=12), LV midlateral wall (n=17), and LV base (n=7). LV synchrony, pump function, and contraction efficiency were significantly affected by pacing site and were superior in children paced at the LV apex/LV midlateral wall. LV dyssynchrony correlated inversely with LV ejection fraction (R=0.80, P=0.031). Pacing from the RV outflow tract/lateral RV predicted significantly decreased LV function (LV ejection fraction <45%; odds ratio, 10.72; confidence interval, 2.07–55.60; P=0.005), whereas LV apex/LV midlateral wall pacing was associated with preserved LV function (LV ejection fraction ≥55%; odds ratio, 8.26; confidence interval, 1.46–47.62; P=0.018). Presence of maternal autoantibodies, gender, age at implantation, duration of pacing, DDD mode, and QRS duration had no significant impact on LV ejection fraction. Conclusions— The site of ventricular pacing has a major impact on LV mechanical synchrony, efficiency, and pump function in children who require lifelong pacing. Of the sites studied, LV apex/LV midlateral wall pacing has the greatest potential to prevent pacing-induced reduction of cardiac pump function.

Impact of the permanent ventricular pacing site on left ventricular function in children: a retrospective multicentre survey.

Background Chronic right ventricular (RV) pacing is associated with deleterious effects on cardiac function. Objective In an observational multicentre study in children with isolated atrioventricular (AV) block receiving chronic ventricular pacing, the importance of the ventricular pacing site on left ventricular (LV) function was investigated. Methods Demographics, maternal autoantibody status and echocardiographic measurements on LV end-diastolic and end-systolic dimensions and volumes at age <18 years were retrospectively collected from patients undergoing chronic ventricular pacing (>1 year) for isolated AV block. LV fractional shortening (LVFS) and, if possible LV ejection fraction (LVEF) were calculated. Linear regression analyses were adjusted for patient characteristics. Results From 27 centres, 297 children were included, in whom pacing was applied at the RV epicardium (RVepi, n=147), RV endocardium (RVendo, n=113) or LV epicardium (LVepi, n=37). LVFS was significantly affected by pacing site (p=0.001), and not by maternal autoantibody status (p=0.266). LVFS in LVepi (39±5%) was significantly higher than in RVendo (33±7%, p<0.001) and RVepi (35±8%, p=0.001; no significant difference between RV-paced groups, p=0.275). Subnormal LVFS (LVFS<28%) was seen in 16/113 (14%) RVendo-paced and 21/147 (14%) RVepi-paced children, while LVFS was normal (LVFS≥28%) in all LVepi-paced children (p=0.049). These results are supported by the findings for LVEF (n=122): LVEF was <50% in 17/69 (25%) RVendo- and in 10/35 (29%) RVepi-paced patients, while LVEF was ≥50% in 17/18 (94%) LVepi-paced patients. Conclusion In children with isolated AV block, permanent ventricular pacing site is an important determinant of LV function, with LVFS being significantly higher with LV pacing than with RV pacing.

Early results after transatrial/transpulmonary repair of tetralogy of Fallot.

OBJECTIVES Right ventricular (RV) dysfunction is a significant cause of morbidity and mortality after surgical correction of tetralogy of Fallot (TOF). Transatrial/transpulmonary repair avoids a ventriculotomy (in contrast to the transventricular approach) emphasizing maximal preservation of RV structure and function. We have adopted this technique as less traumatic for the right ventricle. This study evaluates the early surgical results of our approach. METHODS Between September 1997 and July 2001, 110 consecutive patients with TOF were referred to our unit for surgical therapy. Of these, 14 were unsuitable for repair and underwent aortopulmonary shunting+/-pulmonary artery patching. In the remaining 96 patients (median age 1.4 years), complete transatrial/transpulmonary repair was performed. Previously placed shunts (ten patients) were taken down and any secondary stenoses or branch pulmonary artery distortion repaired. In all cases, subpulmonary resection and ventricular septal defect (VSD) closure were accomplished transatrially. Whenever pulmonary valvotomy and valve ring widening were necessary, it was achieved through a pulmonary arteriotomy. In 84 patients the main pulmonary artery was augmented with an autologous pericardial patch, and in 23 the patch was extended to pulmonary artery branch(es). A limited (<1cm ) or extended (>1cm, but <or=length of RV infundibulum) transannular incision was necessary in 59 and 18 patients, respectively, in order to achieve an adequate residual RV outflow tract diameter. A monocusp autologous pericardial valve was placed in 13 patients. RESULTS There was no death in this series. No patient required permanent pacemaker. In one case, early reoperation for residual RV outflow tract obstruction was needed. Median ICU and hospital stay were 3.5 and 10 days, respectively. At median follow up of 26 (mean 25+/-12) months, all patients are asymptomatic, with no significant residual lesion. CONCLUSIONS Transatrial/transpulmonary repair of TOF is associated with remarkably low morbidity and mortality in our early experience.

Permanent junctional reciprocating tachycardia in children: A multicenter experience

BACKGROUND Permanent junctional reciprocating tachycardia (PJRT) is an uncommon form of supraventricular tachycardia in children. Treatment of this arrhythmia has been considered difficult because of a high medication failure rate and risk of cardiomyopathy. Outcomes in the current era of interventional treatment with catheter ablation have not been published. OBJECTIVE To describe the presentation and clinical course of PJRT in children. METHODS This is a retrospective review of 194 pediatric patients with PJRT managed at 11 institutions between January 2000 and December 2010. RESULTS The median age at diagnosis was 3.2 months, including 110 infants (57%; aged <1 year). PJRT was incessant in 47%. The ratio of RP interval to cycle length was higher with incessant than with nonincessant tachycardia. Tachycardia-induced cardiomyopathy was observed in 18%. Antiarrhythmic medications were used for initial management in 76%, while catheter ablation was used initially in only 10%. Medications achieved complete resolution in 23% with clinical benefit in an additional 47%. Overall, 140 patients underwent 175 catheter ablation procedures with a success rate of 90%. There were complications in 9% with no major complications reported. Patients were followed for a median of 45.1 months. Regardless of treatment modality, normal sinus rhythm was present in 90% at last follow-up. Spontaneous resolution occurred in 12% of the patients. CONCLUSION PJRT in children is frequently incessant at the time of diagnosis and may be associated with tachycardia-induced cardiomyopathy. Antiarrhythmic medications result in complete control in few patients. Catheter ablation is effective, and serious complications are rare.

Preservation of right ventricular structure and function following transatrial-transpulmonary repair of tetralogy of Fallot

OBJECTIVES Management strategy of patients with tetralogy of Fallot (TOF)-including timing, as well as surgical technique-remains a controversial topic. We sought to analyse both early and late results of our consistent policy of non-neonatal transatrial/transpulmonary (TA/TP) repair of TOF over almost 14 years, in order to assess preservation or possible deterioration of right ventricular (RV) function. METHODS All 245 consecutive patients with TOF, referred to our group for repair between September 1997 and December 2010, have been prospectively followed up. Their clinical and echocardiographic data were retrospectively analysed. All underwent complete TA/TP repair at a median age of 1.6 years (range 0.2 to 55.6 years). RESULTS Follow-up (median 8.5 years, range 0.5 to 14.6 years) was 100% completed. There was no operative death. There were three early re-operations: one for residual right ventricular outflow tract obstruction (RVOTO), one for intractable arrhythmias and one for remote second ventricular septal defect (VSD). There were three non-cardiac-related late deaths. Actuarial survival at 14 years was 98.8% (242/245). Twenty five patients required late re-operation, including 23 patients (9.4%, 23/245) who had pulmonary valve replacement (PVR). All other patients remained asymptomatic at follow-up. Mean residual right ventricular outflow tract (RVOT) pressure gradients have remained stable (6.8 ± 6.6 mmHg, 95% CI 5.9-7.6, early postoperatively, versus 7.6 ± 7.5 mmHg, 95% CI 6.6-8.6 at follow-up; P = 0.015). The mean qualitative grade of pulmonary valve insufficiency (PVI) increased (from 1.4 ± 0.9, 95% CI 1.3-1.5 at discharge to 2.1 ± 1.2, 95% CI 2-2.3 at follow-up; P < 0.001). Similarly, mean qualitative grade of tricuspid valve insufficiency (TVI) also increased (from 1 ± 0.7, 95% CI 0.9-1 at discharge to 1.5 ± 0.8, 95% CI 1.4-1.6 at follow-up; P < 0.001). However, RV function has remained normal in most patients. No significant arrhythmias have been noted. CONCLUSIONS Our management strategy of non-neonatal TA/TP repair for all patients with TOF is associated with minimal early and late mortality and morbidity, relatively low re-operation rate, preserved RV function and excellent clinical outcomes at follow-up over almost 14 years. Since many patients demonstrated progressive increase in PVI and TVI, a much longer follow-up is necessary to determine the ultimate rates of late re-operation for pulmonary valve replacement (PVR).

Extracorporeal membrane oxygenation support for intractable primary arrhythmias and complete congenital heart block in newborns and infants: Short-term and medium-term outcomes

Objectives: To describe the experience with extracorporeal membrane oxygenation support for intractable primary arrhythmias in newborns and infants. Design: Retrospective study. Setting: A tertiary care pediatric hospital. Patients: Patients younger than 1 yr supported with extracorporeal membrane oxygenation for primary cardiac arrhythmias were identified from the institutional extracorporeal membrane oxygenation registry. Interventions: Extracorporeal membrane oxygenation support. Measurements and Main Results: Clinical characteristics and outcomes were investigated for patients with primary cardiac arrhythmia supported with extracorporeal membrane oxygenation. Outcomes investigated were time from initiation of extracorporeal membrane oxygenation support to arrhythmia control, duration of extracorporeal membrane oxygenation support, and results of interventions performed while supported with extracorporeal membrane oxygenation. We summarized the independent categorical and continuous variables using frequencies, percentages, and medians and ranges, respectively. Extracorporeal membrane oxygenation support was used in nine patients for rescue therapy for primary tachyarrhythmia and bradycardia. The primary arrhythmias were: focal atrial tachycardia (n = 2); reentrant supraventricular tachycardia (n = 3); junctional ectopic tachycardia (n = 2); and congenital complete atrioventricular block (n = 2) patients. Seven patients presented with severe hemodynamic compromise, with six patients requiring extracorporeal cardiopulmonary resuscitation. All patients required extracorporeal membrane oxygenation within 24 hrs of initial presentation. Balloon atrial septostomy was performed in three patients and ablation was performed in two patients. Sinus rhythm was achieved in all reentrant supraventricular tachycardia and rate control was established in both patients with focal atrial tachycardia and in one patient with junctional ectopic tachycardia while using extracorporeal membrane oxygenation support. All patients survived to hospital discharge, and median follow-up for the cohort was 5 yrs. There was one late death; all survivors had good overall and neurologic outcomes. Conclusions: The requirement of extracorporeal membrane oxygenation support in newborns and infants with intractable arrhythmia is rare. Extracorporeal membrane oxygenation support does potentially carry morbidity; however, to prevent arrhythmia-related mortality, extracorporeal membrane oxygenation support and/or extracorporeal cardiopulmonary resuscitation should be considered in the management of hemodynamically unstable primary arrhythmias as an emergent lifesaving procedure.