Freek van den Heuvel

Not all Beta-Blockers are Equal in the Management of Long QT Syndrome Types 1 and 2: Higher Recurrence of Events under Metoprolol

OBJECTIVES The purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS). BACKGROUND Beta-blockers are the mainstay in managing LQTS. Studies comparing the efficacy of commonly used beta-blockers are lacking, and clinicians generally assume they are equally effective. METHODS Electrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients <1 year of age at beta-blocker initiation. Symptoms before therapy and the first breakthrough cardiac events (BCEs) were documented. RESULTS Patients (56% female, 27% symptomatic, heart rate 76 ± 16 beats/min, QTc 472 ± 46 ms) were started on beta-blocker therapy at a median age of 14 years (interquartile range: 8 to 32 years). The QTc shortening with propranolol was significantly greater than with other beta-blockers in the total cohort and in the subset with QTc >480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol. CONCLUSIONS Propranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients.

Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene

BACKGROUND Desmin-related myopathy is a clinically heterogenous group of disorders encompassing myopathies, cardiomyopathies, conduction disease, and combinations of these disorders. Mutations in the gene encoding desmin (DES), a major intermediate filament protein, can underlie this phenotype. OBJECTIVE The purpose of this study was to investigate the clinical and pathologic characteristics of 27 patients from five families with an identical mutation in the head domain region (p.S13F) of desmin. METHODS/RESULTS All 27 carriers or obligate carriers of a p.S13F DES founder mutation demonstrated a fully penetrant yet variable phenotype. All patients demonstrated cardiac involvement characterized by high-grade AV block at young ages and important right ventricular (RV) involvement. RV predominance was demonstrated by the presence of right bundle branch block in 10 patients (sometimes as a first manifestation) and by RV heart failure in 6 patients, including 2 patients who fulfilled the diagnostic criteria for arrhythmogenic RV cardiomyopathy. Because of this clinical overlap with desmosome cardiomyopathies, we also studied the organization of the intercalated disks, particularly the distribution of desmosomal proteins. Normal amounts of the major desmosomal proteins were found, but the intercalated disks were more convoluted and elongated and had a zigzag appearance. CONCLUSION In this largest series to date of individuals with a single head domain DES mutation, patients show a variable yet predominantly cardiologic phenotype characterized by conduction disease at an early age and RV involvement including right bundle branch block and/or RV tachycardias and arrhythmogenic RV cardiomyopathy phenocopies. A localized effect of desmin on the structure of the cardiac intercalated disks might contribute to disease pathogenesis.

Familial evaluation in catecholaminergic polymorphic ventricular tachycardia disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives

Background— Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with mutations in the cardiac ryanodine receptor gene ( Ryr2 ) in the majority of patients. Previous studies of CPVT patients mainly involved probands, so current insight into disease penetrance, expression, genotype-phenotype correlations, and arrhythmic event rates in relatives carrying the Ryr2 mutation is limited. Methods and Results— One-hundred sixteen relatives carrying the Ryr2 mutation from 15 families who were identified by cascade screening of the Ryr2 mutation causing CPVT in the proband were clinically characterized, including 61 relatives from 1 family. Fifty-four of 108 antiarrhythmic drug-free relatives (50%) had a CPVT phenotype at the first cardiological examination, including 27 (25%) with nonsustained ventricular tachycardia. Relatives carrying a Ryr2 mutation in the C-terminal channel-forming domain showed an increased odds of nonsustained ventricular tachycardia (odds ratio, 4.1; 95% CI, 1.5–11.5; P =0.007, compared with N-terminal domain) compared with N-terminal domain. Sinus bradycardia was observed in 19% of relatives, whereas other supraventricular dysrhythmias were present in 16%. Ninety-eight (most actively treated) relatives (84%) were followed up for a median of 4.7 years (range, 0.3–19.0 years). During follow-up, 2 asymptomatic relatives experienced exercise-induced syncope. One relative was not being treated, whereas the other was noncompliant. None of the 116 relatives died of CPVT during a 6.7-year follow-up (range, 1.4–20.9 years). Conclusions— Relatives carrying an Ryr2 mutation show a marked phenotypic diversity. The vast majority do not have signs of supraventricular disease manifestations. Mutation location may be associated with severity of the phenotype. The arrhythmic event rate during follow-up was low.Background— Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with mutations in the cardiac ryanodine receptor gene (Ryr2) in the majority of patients. Previous studies of CPVT patients mainly involved probands, so current insight into disease penetrance, expression, genotype-phenotype correlations, and arrhythmic event rates in relatives carrying the Ryr2 mutation is limited. Methods and Results— One-hundred sixteen relatives carrying the Ryr2 mutation from 15 families who were identified by cascade screening of the Ryr2 mutation causing CPVT in the proband were clinically characterized, including 61 relatives from 1 family. Fifty-four of 108 antiarrhythmic drug-free relatives (50%) had a CPVT phenotype at the first cardiological examination, including 27 (25%) with nonsustained ventricular tachycardia. Relatives carrying a Ryr2 mutation in the C-terminal channel-forming domain showed an increased odds of nonsustained ventricular tachycardia (odds ratio, 4.1; 95% CI, 1.5–11.5; P=0.007, compared with N-terminal domain) compared with N-terminal domain. Sinus bradycardia was observed in 19% of relatives, whereas other supraventricular dysrhythmias were present in 16%. Ninety-eight (most actively treated) relatives (84%) were followed up for a median of 4.7 years (range, 0.3–19.0 years). During follow-up, 2 asymptomatic relatives experienced exercise-induced syncope. One relative was not being treated, whereas the other was noncompliant. None of the 116 relatives died of CPVT during a 6.7-year follow-up (range, 1.4–20.9 years). Conclusions— Relatives carrying an Ryr2 mutation show a marked phenotypic diversity. The vast majority do not have signs of supraventricular disease manifestations. Mutation location may be associated with severity of the phenotype. The arrhythmic event rate during follow-up was low.

Physical Activity in Pediatric Pulmonary Arterial Hypertension Measured by Accelerometry. A Candidate Clinical Endpoint

&NA; Rationale: The development of evidence‐based treatment guidelines for pediatric pulmonary arterial hypertension (PAH) is hampered by lack of pediatric clinical trials. Trial design is hampered by lack of a feasible clinical endpoint in this population. Objectives: To evaluate the use of accelerometry for measuring physical activity (PA) in pediatric PAH and to investigate its correlation with clinical disease severity markers. Methods: We included children from the Dutch National Network for Pediatric Pulmonary Hypertension. Control patients were recruited from the outpatient cardiology clinic of the Beatrix Childrens Hospital. Children were asked to wear the accelerometer for 7 days. Vector magnitude counts per minute (VM CPM) and time per day spent in different PA intensity levels were defined as accelerometer outcomes. Measurements and Main Results: VM CPM was lower in children with PAH (n = 29) than in controls (n = 60; 647 vs. 921; P < 0.001). Children with PAH spent less time in moderate and vigorous PA (13 vs. 29 min/d and 2 vs. 13 min/d, respectively; P < 0.001). Time spent in moderate and vigorous PA correlated inversely with World Health Organization functional class. Time spent in moderate PA correlated positively with 6‐minute‐walk distance. In post hoc analyses, VM CPM and time spent in moderate/vigorous combined and vigorous PA were associated with outcome (P ≤ 0.044). Conclusions: PA is markedly decreased in children with PAH. Accelerometer output correlated with clinical disease severity markers and may predict outcome. We showed an exciting potential of PA as a meaningful endpoint for clinical trials in pediatric PAH, although its clinical utility and prognostic value need to be further validated.

Off-pump connection of the hepatic to the azygos vein through a lateral thoracotomy for relief of arterio-venous fistulas after a Kawashima procedure

OBJECTIVE To connect the hepatic veins to the azygos venous system through a lateral thoracotomy, and without the use of extracorporeal circulation, so as to relieve arteriovenous fistulas after a previous Kawashima operation. METHODS Description of the operative technique by which the hepatic veins are anastomosed to the hepatic venous system. RESULTS The surgical approach was successfully applied in 3 patients, all of whom showed an excellent rise of saturations of oxygen after redirection of the hepatic venous blood. CONCLUSION The operative method presented is an elegant means of redirecting the hepatic venous blood to the pulmonary circulation without the disadvantages of extracorporeal circulation and resternotomy.

Drug management of fetal tachyarrhythmias : Are we ready for a systematic and evidence-based approach?

Fetal tachyarrhythmias are a life‐threatening condition complicating a small proportion of normal pregnancies. Despite major advances in the (intrauterine) pharmacologic treatment of these arrhythmias over the last years major uncertainties remain. Among these are controversies in the choice of agents in relation to arrhythmia type, and timing and duration of treatment. Currently, no evidence‐based approach to the management of fetal tachyarrhythmias is available. An international registry is proposed as an important step toward obtaining the necessary data to develop evidence‐based management strategies.

Arrhythmias from neonate to adult, Part II

In October 2006, the second international congress on “Arrhythmias from Neonate to Adult” took place in Groningen, The Netherlands. Almost 10 years after the first edition of this congress, Groningen again turned into “the place to be” for professionals involved in the field of arrhythmias in pediatric and congenital heart diseases. A broad faculty of internationally recognized experts in diagnosis and management of arrhythmias in this specific patient population gathered for 2 days and shared their experiences and ideas with an interested audience. Arrhythmias in congenital heart disease is a continuously evolving field, crossing the borders between pediatric and adult cardiology and characterized by growing insights in the long-term effects of complex cardiac surgery early in life and of chronic abnormal loading conditions of the heart. Also the knowledge on pediatric and heritable “electrical” and functional diseases of the heart is expanding rapidly. The meeting was completely devoted to new developments and perspectives in this field. In these two days, numerous state-of-the art lectures were presented by experts in the field on current highlights, including “presentation and treatment modalities in arrhythmias after congenital cardiac surgery,” “developments and concepts in pacing and ICD therapy in congenital heart disease,” “new perspectives in genetics of arrhythmias and myocardial diseases,” and “arrhythmias during pregnancy and its perinatal management.” In our opinion, the presentations during this congress formed a beautiful and valuable synopsis and overview of the current state of the art in arrhythmias, from neonate to adult. We therefore thank the faculty members that they were prepared to write a short communication on the topic of their presentation and that we got the opportunity to publish these manuscripts, all collected in this supplement of PACE. We feel this issue provides a concise overview of the current state of the art in the field of arrhythmias in pediatric and congenital heart diseases and we hope that it will prove to be useful to all professionals involved in the care of these patients. This second international congress on arrhythmias from neonate to adult was dedicated to Dr. Margreet Bink-Boelkens, pediatric cardiologist and acknowledged expert in arrhythmias from neonate to adult, in recognition of her valuable contributions to the field of congenital cardiology and arrhythmias during a career of almost 40 years. Dr. Bink-Boelkens retired as a pediatric cardiologist directly after this congress. From this place we thank her for all her efforts and achievements during her career, always in benefit for her patients. We foresee that Dr. Bink-Boelkens will be actively present at and contributing to the future third international congress on “Arrhythmias from Neonate to Adult” in Groningen!

Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. OBJECTIVE The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. METHODS We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. RESULTS Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. CONCLUSION Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.

Vein of Galen Aneurysmal Malformation in Neonates Presenting With Congestive Heart Failure

The authors report the case of a neonate presenting with signs of a congenital cardiac disease. Echocardiography showed a structural normal heart, right-to-left ductal flow, a dilated superior caval vein, and reversed diastolic flow in the proximal descending aorta. Brain magnetic resonance imaging showed a vein of Galen arteriovenous malformation. This highlights the importance of considering an intracranial cause in the differential diagnosis of neonatal congestive heart failure.

Lusoria Flap for the Management of Aortic Coarctation in an Eight-Year-Old Child

Anomalous origin of right subclavian artery arising from the descending aorta is known as “arteria lusoria.” The diagnosis in asymptomatic children is usually the by-product of other symptomatic-associated anomalies, such as aortic coarctation. We describe a case of an eight-year-old boy with juxtaductal aortic coarctation and rare origin of the arteria lusoria proximal to the aortic coarctation. The anomalous arteria lusoria was used as a flap to repair the aortic coarctation. To the authors’ knowledge, this is the first reported application of lusoria flap in a young child (not newborn) with ductal aortic coarctation.