Anita Hiippala

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.

Junctional ectopic tachycardia after surgery for congenital heart disease: incidence, risk factors and outcome

OBJECTIVES Junctional ectopic tachycardia (JET) is a serious, haemodynamically compromising tachyarrhythmia associated with paediatric cardiac surgery, with a reported mortality up to 14%. The incidence, risk factors and outcome of this tachyarrhythmia were evaluated in this population-based, case-control patient cohort. METHODS A total of 1001 children, who underwent open-heart surgery during a 5-year period, were retrospectively analysed. The patients with haemodynamically significant tachycardia were identified, and their postoperative electrocardiograms were analysed. Three controls matched with the same type of surgery were selected for each patient with JET. RESULTS JET was diagnosed in 51 patients (5.0%). These patients had longer cardiopulmonary bypass time (138 vs 119 min, p=0.002), higher body temperature (38.0 vs 37.4 °C, p=0.013) and higher level of postoperative troponin-T (3.7 vs 2.1 μg l(-1), p<0.001) compared with controls. They also needed longer ventilatory support (3 vs 2 days, p=0.004) and intensive care stay (7 vs 5 days, p<0.001) as well as use of noradrenaline (23/51 vs 35/130, p=0.019). Ventricular septal defect (VSD) closure was part of the surgery in 33/51 (64.7%) of these patients. The mortality was 8% in the JET group and 5% in the controls (p=0.066). In the logistic regression model, JET was not an independent risk factor for death (p=0.557). CONCLUSIONS The incidence of JET was 5.0% in this large paediatric open-heart surgery patient group. Compared with controls, these patients had longer cardiopulmonary bypass time and higher level of troponin-T, possibly reflecting the extent of surgical trauma. However, the tachycardia was not an independent risk factor for death.

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.

New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies

Background:We report a new mutation in the human DNAJC19 gene that causes early onset dilated cardiomyopathy syndrome (DCMA).Methods:Two brothers of Finnish origin presented with an unusual combination of early onset dilated cardiomyopathy syndrome, a disease which was associated with cardiac noncompaction, microcytic anemia, ataxia, male genital anomalies and methylglutaconic aciduria type V. Suspicion of a DCMA syndrome prompted sequencing of the human DNAJC19 gene.Results:Sequencing of the human DNAJC19 gene showed a homozygous single nucleotide (A) deletion in alanine 63 coding triplet in exon 6, which does not immediately cause amino acid change but leads 11 amino acids later to a stop codon and to premature termination of the peptide. This DNAJC19 protein is located in the inner mitochondrial membrane and has been shown to function as a mitochondrial chaperone.Conclusion:This is the first clinical report of DCMA syndrome, a human DNAJC19 deficiency, that is related to cases of severe dilated cardiomyopathy diagnosed in Europe. DNAJC19 deficiency causes a relatively specific finding in urinary organic acid analysis (methylglutaconic aciduria type V), which together with the clinical features of the ensuing cardiac disease, allows for effective screening before undertaking molecular genetic analysis.

Intravenous epinephrine infusion test in diagnosis of catecholaminergic polymorphic ventricular tachycardia.

Epinephrine Infusion in Diagnosis of CPVT. Introduction: A test involving intravenous infusion of epinephrine has been proposed as a method alternative to exercise stress test in diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). We aimed at estimating the predictive value of intravenous epinephrine administration in CPVT patients with frequent exercise‐induced ventricular ectopy.

Expanding the phenotype of Timothy syndrome type 2: An adolescent with ventricular fibrillation but normal development

Timothy syndrome is a rare multiorgan disorder with prolonged QTc interval, congenital heart defects, syndactyly, typical facial features and neurodevelopmental problems. Ventricular tachyarrhythmia is the leading cause of death at early age. Classical Timothy syndrome type 1 (TS1) results from a recurrent de novo CACNA1C mutation, G406R in exon 8 A. An atypical form of Timothy syndrome type 2 (TS2) is caused by mutations in G406R and G402S in the alternatively spliced exon 8. Only one individual for each exon 8 mutations has been described. In contrast to multiorgan disease caused by the mutation in G406R either in exon 8 A or 8, the G402S carrier manifested only an isolated cardiac phenotype with LQTS and cardiac arrest. We describe a teenage patient resuscitated from ventricular fibrillation and treated with an implantable cardioverter defibrillator. She has no other organ manifestations, no syndactyly, normal neurodevelopment and her QTc has ranged between 440–480 ms. There is no family history of arrhythmias or sudden death. Targeted oligonucleotide‐selective sequencing (OS‐Seq) of channelopathy genes revealed a de novo substitution, G402S in exon 8 of CACNA1C. Direct sequencing of blood and saliva derived DNA showed an identical mutation peak suggesting ubiquitous expression in different tissues. The phenotype of our patient and the previously described patient show an isolated arrhythmia disease with no other organ manifestations of classical Timothy syndrome.

Follow-up of 316 Molecularly Defined Pediatric Long QT Syndrome Patients - Clinical Course, Treatments and Side Effects

Background—Inherited long-QT syndrome (LQTS) is associated with risk of sudden death. We assessed the clinical course and the fulfillment of current treatment strategies in molecularly defined pediatric LQTS type 1 and (LQT1) and type 2 (LQT2) patients. Methods and Results—Follow-up data covering a mean of 12 years were collected for 316 genotyped LQT1 and LQT2 patients aged 0 to 18 years. No arrhythmic deaths occurred during the follow-up. Finnish KCNQ1 and KCNH2 founder mutations were associated with fewer cardiac events than other KCNQ1 and KCNH2 mutations (hazard ratio [HR], 0.33; P=0.03 and HR, 0.16; P=0.01, respectively). QTc interval ≥500 ms increased the risk of cardiac events compared with QTc <470 ms (HR, 3.32; P=0.001). Treatment with &bgr;-blocker medication was associated with reduced risk of first cardiac event (HR, 0.23; P=0.001). Noncompliant LQT2 patients were more often symptomatic than compliant LQT2 patients (18% and 0%, respectively; P=0.03). Treatment with implantable cardioverter defibrillator was rare (3%) and resulted in reinterventions in 44% of cases. Conclusions—Severe cardiac events are uncommon in molecularly defined and appropriately treated pediatric LQTS mutation carriers. &bgr;-Blocker medication reduces the risk of cardiac events and is generally well tolerated in this age group of LQTS patients.

Population‐Based Single‐Center Outcome for Pediatric Catheter Ablation of Common Supraventricular Tachycardias

Catheter ablation has become the preferred treatment for common supraventricular tachycardia (SVT) in children and adolescents, but long‐term follow‐up data on pediatric patients remain limited.

The rare Costello variant HRAS c.173C>T (p.T58I) with severe neonatal hypertrophic cardiomyopathy

We report a 10‐year‐old girl presenting with severe neonatal hypertrophic cardiomyopathy (HCM), feeding difficulties, mildly abnormal facial features, and progressive skeletal muscle symptoms but with normal cognitive development. Targeted oligonucleotide‐selective sequencing of 101 cardiomyopathy genes revealed the genetic diagnosis, and the mutation was verified by Sanger sequencing in the patient and her parents. To offer insights into the potential mechanism of patient mutation, protein structural analysis was performed using the resolved structure of human activated HRAS protein with bound GTP analogue (PDB id 5P21) in Discovery Studio 4.5 (Dassault Systèmes Biovia, San Diego, CA). The patient with hypertrophic cardiomyopathy and normal cognitive development was diagnosed with an HRAS mutation c.173C>T (p.T58I), a milder variant of Costello syndrome affecting a highly conserved amino acid, threonine 58. Our analysis suggests that the p.G12 mutations slow GTP hydrolysis rendering HRAS unresponsive to GTPase activating proteins, and resulting in permanently active state. The p.T58I mutation likely affects binding of guanidine‐nucleotide‐exchange factors, thereby promoting the active state but also allowing for slow inactivation. Patients with the HRAS mutation c.173C>T (p.T58I) might go undiagnosed because of the milder phenotype compared with other mutations causing Costello syndrome. We expand the clinical and molecular picture of the rare HRAS mutation by reporting the first case in Europe and the fourth case in the literature. Our protein structure analysis offers insights into the mechanism of the mildly activating p.T58I mutation.

Permanent Cardiac Pacing in Children

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.