Current Pharmaceutical Design - Volume 14, Issue 8, 2008

In pediatric age supraventricular tachiarrhythmias represent one of the most common cause of admission in cardiology units. Supraventricular arrhythmias may significantly influence the normal growth of a child with significant psycho-social implications. Pediatric cardiologists should be aware about the arrhythmias they face in their clinical practice. Moreover, they should know the possible risks related to specific arrhythmias and use the most efficacious therapeutic strategy with a correct knowledge of antiarrhythmic drugs. In this issue of Current Pharmacological Design the most recent knowledges on pathophysiology, diagnosis and treatment of supraventricular tachyarrhythmias in pediatric age are reviewed and discussed by recognized opinion leaders in the field. Calabro et al. [1] and Vignati et al. [2] carefully analyze the complex pathophysiological mechanisms responsible for arrythmias in pediatric age focusing on the diagnostic tools to be used for a correct characterization of sopraventricular tachycardia (e.g. accessory or doubles pathways) even before birth. Mongiovi et al. [3], based on their sound clinical experience, report the diagnostic and therapeutic guidelines to be used in fetus with supraventricular tachycardia. Karpawich et al. [4] define a general profile of the possible therapeutic solutions according to the natural history of supraventricular arrhythmias in pediatric age. Ratnasamy et al. [5] report the therapeutic algorythms regarding the atrio-ventricular reentry (the most common cause of supraventricular thachycardia in children), whereas Pappone et al. [6] discuss about the need to treat asymptomatic children with ventricular preexcitation at risk for sudden death and on the need to revise the current guidelines, even on the basis of an international survey performed among 111 electrophysiologic centers worldwide. Bouhouch et al. [7] define the principal therapeutic guidelines for nodal reentry tachycardia, the incidence of which may increase in the first years of life. The authors discuss about the need of a long-term pharmacological treatment considering the low mortality risk in the patients affected by this arrhythmia. Fazio et al. [8] analyze the pathophysiological mechanisms of atrial fibrillation and atrial flutter, which are uncommon arrhythmias in pediatric age, defining the principal clinical and therapeutic guidelines. Maid et al. [9] and Sulafa [10] analyze the important problem of the use of antiarrhythmics in pediatric age. Maid et al. focus on the problem of experimentation of new antiarrhythmics and on the written consent to use these drugs in children, with related ethical and clinical implications. Sulafa describes the principal collateral effects of antiarrhythmics in pediatric age, with a careful analysis of the interaction among drugs. Finally, De Santis et al. [11] analyze the nonpharmacological therapy in children with supraventricular tachycardia, comparing the different techniques of ablation (radiofrequency, cryoablation) and their correct use in pediatric age. We would like to thank all the authors for their contributions by providing significant insights based on their clinical experience in pediatric cardiology. It's our hope that the issue be helpful for the scientific and clinical community working in this area. References [1] Calabro M, Cerrito M, Luzza F, Oreto G. Supraventricular tachycardia in infants: epidemiology and clinical management. Curr Pharm Des 2008; 14(8): 723-728. [2] Vignati G, Annoni G. Chacaterization of tachycardia in infants: clinical and instrumental diagnosis. Curr Pharm Des 2008; 14(8): 729-735. [3] Mongiovi M, Pipitone S. Supraventricular tachycardia in fetus: how can we treat? Curr Pharm Des 2008; 14(8): 736-742. [4] Karpawich P, Pettersen M, Gupta P, Shah N. Infants and children with tachycardia: natural history and drug administration. Curr Pharm Des 2008; 14(8): 743-752. [5] Ratnasamy C, Rossique-Gonzalez M,Young ML. Pharmacological therapy in children with atrioventricular reentry: which drug? Curr Pharm Des 2008; 14(8): 753-761. [6] Pappone C, Radinovic A, Santinelli V. Sudden death and ventricular preexcitation: is it necessary to treat the asymptomatic patients? Curr Pharm Des 2008; 14(8): 762-765. [7] Bouhouch R, El Houari T, Fellat I,Arharbi M. Pharmacological therapy in children with nodal reentry tachycardia: when, how and how long to treat the affected patients? Curr Pharm Des 2008; 14(8): 766-769. [8] Fazio G, Visconti C, D'Angelo L, Novo G,Barbaro G, Novo S. Pharmacological therapy in children with atrial fibrillation and atrial flutter. Curr Pharm Des 2008; 14(8): 770-775. [9] Maid G,Guerchicoff M, Falconi M, de Arenaza D. Written consent to use the drug in children. The problem of off-label drugs. Curr Pharm Des 2008; 14(8): 776-781. [10] Sulafa AK. Collateral effects of antiarrhythmics in paediatric age. Curr Pharm Des 2008; 14(8): 782-787. [11] De Santis A, Fazio G, Silvetti MS,Drago F. Transcatheter ablation of supraventricular tachycardias in pediatric patients. Curr Pharm Des 2008; 14(8): 788-793.

Supraventricular tachycardias (SVTs) are observed in 0,1-0,4% of the paediatric population and represent an important clinical problem with related significant health and social issues. Most tachycardias are paroxysmal, being associated with sudden onset and termination, and only a relatively small number of them is permanent, namely chronic. Paroxysmal tachycardias, in addition, can be either sustained (lasting > 30 seconds) or non-sustained whenever their duration is less. Most SVTs are due to re-entry, and only atrial tachycardia and and junctional ectopic tachycardia are caused by enhanced automaticity. Atrial tachycardia, however, can also be due, although rarely, to re-entry or to triggered activity. A prompt recognition of these arrthmias in children by pediatric cardiologist is essential for a correct clinical managemet of the patients. In this review, the epidemiologic data regarding the SVTs in pediatric age are reported along with the description of the pathophysiological mechanisms and the analysis of electrocardiographic findings to be considered for a correct clinical diagnosis and a rational therapeutic approach to these arrhythmias.

Supraventricular tachycardia (SVT) is the most common symptomatic arrhythmias in children. Re-entry tachycardias are the most common form, on the contrary automatic tachycardias are relatively rare. There are four types or re-entry: along anomalous pathway with bi-directional (Wolff-Parkinson-White) or unidirectional conduction, intranodal re-entry, intra-atrial re-entry that is common after surgical procedure, and finally the uncommon sinus node re-entry. Automatic tachycardias may be atrial or junctional. The different types of tachycardia have a different incidence according to the age: in the first year of age re-entry along anomalous pathway is the dominant form, while intranodal reentry becomes common during adolescence. The age at the beginning of tachycardia is important for long term prognosis. When SVT starts in the first months of life it disappears in 80% of cases within the first year of life; on the contrary, if tachycardia starts later spontaneous remission is detected in only 15%-20% of patients. In infancy heart failure is the more common presenting symptom, thereafter palpitations become the principal cause of recognition of SVT. Syncope is reported in about 8% of cases and in another 15% usually neonates and infants, the SVT has an occasional detection. Electrocardiogram (ecg) usually allows the precise diagnosis of various types of SVT, and every effort should be made to record ecg during tachycardia. The parameters that should be evaluated are: heart rate, P wave axis, PR and RP interval, and finally presence or absence of AV block. Short lasting episodes should be difficult to be recorded; in these cases cardio-call and trans-telephonic transmission represent useful techniques to obtain SVT demonstration. Patients with SVT require a complete evaluation with others diagnostic techniques: echocardiogram, Holter monitoring, stress test, that should be chosen according the type of tachycardia. Electrophysiologic evaluation is now rarely performed for diagnostic purpose; trans-esophageal atrial stimulation being less invasive than intracardiac evaluation is more extensively employed when diagnosis of SVT is uncertain. Transesophageal stimulation is useful in the following situations: 1) evaluation of patients with symptoms suggestive of paroxistic tachycardia but without ecg documentation, 2) to assess the mechanism responsible for re-entry tachycardia: macro re-entry versus intranodal re-entry 3) to evaluate characteristics of anomalous pathway with bi-directional conduction, and 4)to terminate re-entrant SVT.

The normal fetal cardiac rhythm is characterized by a regular heart rate ranging between 100 and 160 -180 beats/min with a normal 1: 1 atrioventricular electromechanical relationship during each cardiac cycle. Fetal tachycardia occurring in approximately 0.5% of all pregnancies and it is an important cause of fetal morbidity and mortality. A fetal tachycardic heart is at risk for developing low cardiac output, hydrops and ultimately fetal death or significant neurological morbidity. Different conditions can play a role to determine the natural history of tachycardic fetus as gestational age, underlying pathophysiology of the arrhythmia, fetal heart rate, duration of the tachyarrhythmia, and presence or absence of cardiac dysfunction. Reliable diagnosis in utero of fetal arrhythmia is possible by ultrasound examination of the fetal heart. In fact pulsed wave Doppler guided by two-dimensional echocardiography provided important information on cardiac rhythm as it study the blood flow from different chambers. With the introduction of the latest myocardial deformation methodology, the fetal tachyarrhythmias can be diagnosed more accurately. Precise diagnosis of cardiac arrhythmias in the fetus is crucial for a managed therapeutic approach. The choice of management is correlated to many factors: gestational age, underlying pathophysiology of the arrhythmia, fetal heart rate, duration of the tachyarrhythmia, and presence or absence of cardiac dysfunction. A large review of fetal arrhythmias was been reported in our work.

Tachyarrhythmias can occur at any age from the developing fetus through adulthood. However, in deference to adult-onset ischemic cardiac issues, abnormal heart rhythms occurring in the young are often due to developmental alterations of the cardiac conduction tissue, genetically-inherited changes of myocardial cellular ion membrane properties and both pre- and post-surgical repair of associated structural congenital heart anatomical defects. And different from adults, abnormal rhythms occurring in the young can spontaneously disappear with progressive patient growth. Both supra- and ventricular tachyarrhythmias occur in the young although atrial rhythm abnormalities far exceed those of the ventricle. In both, pharmacologic therapies to alter tissue conduction and refractoriness remain the mainstay for initial intervention in the infant and young child, reserving more invasive and potentially harmful ablation therapies for drug-refractory cases. The purpose of the review is to present common and uncommon tachyarrhythmias which can occur in the fetus and throughout infancy. Emphasis will be placed on their electrocardiographic identification, recognition of any associated structural congenital heart defects and recommended pharmacologic management. Drug therapies will be divided according to mechanism of action and discussions of which particular agent is potentially best-suited to treat which specific tachyarrhythmia. A listing of current pharmacologic agents used in the young with appropriate dosages is included.

Atrioventricular reentrant tachycardia (AVRT) is the most common cause of supraventricular tachycardia in young children. In nearly 70% of cases, there is manifest preexcitation on electrocardiogram. In the rest, the accessory pathway is concealed. Drugs control AVRT by affecting conduction through the atrioventricular node (beta-blockers, digoxin, verapamil) or accessory pathway (flecainide, propafenone) or both (sotalol, amiodarone). Adenosine is the drug of choice in acute management of AVRT in hemodynamically stable children. In adenosine-resistant cases, intravenous flecainide, procainamide, esmolol, propafenone and amiodarone are other treatment options. Hypotension and bradycardia can occur during administration of these drugs. Verapamil may be used to treat AVRT using a concealed pathway. Verapamil should be avoided in infants and in patients with decreased cardiac function. In chronic management, catheter ablation is the preferred treatment in older children with frequent AVRT. In infants and small children, ablation is associated with higher risk, and pharmacologic management is recommended. Beta-blockers are the preferred first line drugs for chronic management. In patients with concealed accessory pathway, digoxin and calcium channel blockers are alternative options. Sotalol, flecainide, propafenone and amiodarone can be prescribed in resistant cases. Flecainide and propafenone should be avoided in children with structurally abnormal hearts because of a higher risk of proarrhythmia. The initiation of flecainide, propafenone and sotalol therapy is recommended in an inpatient setting to monitor for proarrhythmias.

Currently, asymptomatic ventricular preexcitation, which has been put at rest for many decades, remains a clinical challenge as there are no predictors of sudden death, which can be the first clinical presentation of the syndrome. Identification of risk factors for sudden death is important, considering the availability of a definitive treatment. Now, as radiofrequency catheter ablation of accessory pathways has reported success rates approaching 100 percent without major complications in many centers worldwide, it becomes unacceptable that even one asymptomatic individual with WPW will die or will experience life-threatening arrhythmic events. In our extensive experience a short anterograde refractory period of accessory pathways, inducibility of sustained tachyarrhythmias and the presence of multiple accessory pathways are the strongest predictors of life-threatening arrhythmias and sudden death. Therefore, it is not yet justified that, after an incidental diagnosis of WPW syndrome has been made, no risk stratification by invasive testing is done. Subjects at high risk, particularly if young or adolescent, should be identified and then ablated in the same session as they can develop lethal arrhythmic events within a few years and this is our current practice. Recently, we sent a questionnaire to investigate clinical practices over a large number of centers around the world about asymptomatic ventricular preexcitation. A total of 100 replies were received and the results demonstrate that there is worldwide agreement in performing invasive electrophysiologic testing and prophylactic ablation in selected subjects. These findings provide strong evidence to revisit current guidelines, which appropriately in the absence of evidence had been conservative.

Atrio-ventricular nodal reentrant tachycardia (AVNRT) is a rare supra-ventricular tachycardia (SVT) in children and becomes more frequent in adolescents. Most of children with an AVNRT have a healthy heart thus rarely experiencing severe symptoms. Because of haemodynamic instability or risk of complications, recurrences of SVT may require a chronic therapy. Interruption of dual atrioventricular nodal physiology is the basic mechanism to terminate AVNRT. This may be achieved by using anti-arrhythmic drugs or through Radiofrequency catheter ablation (RF). We aim to review the literature on the use of anti-arrhythmic drugs for the management of AVNRT in children aged more than 1 year and discuss the recommended dosages and the duration of a long term therapy. In the absence of comparative trials of risks and benefits between pharmacological therapy and RF and because of a greater clinical experience with anti-arrhythmic drugs, these last but not the least continue to be first-line therapy in the management of most SVT in children. Trials on pharmacotherapy in children with SVT in general and AVNRT in particular are lacking, use of anti-arrhythmic drugs being extrapolated from adult literature. Although Adenosine is becoming more used since it is the safest and effective drug in the acute setting, Digoxin continue to be the drug of first choice. Beta-blockers and Class I anti-arrhythmic are the second choice drugs with Flecainide being the preferred anti-arrhythmic drug for treatment failures. Amiodarone is rarely used as a chronic therapy in resistant cases. With the new advances in the RF technology, this therapy is becoming more safe and effective for AVNRT in children. Therefore, additional welldesigned controlled trials are needed to further evaluate the comparative efficacy of anti-arrhythmic drugs in the management of AVNRT in children, as well as to evaluate dosing and toxicity in various age groups and determine the duration of a chronic therapy as compared to a potential RF.

Heart rhythm disorders in children are not different, on electrocardiographic trace, from heart rhythm disorders in adults with the exception of incidence which is different according to the age. Paticularly, atrial flutter (FlA) and fibrillation (FA) are very uncommon arrhythmias in the general pediatric population. Generally atrial fibrillation and atrial flutter, in our experience, is a temporary heart rhythm disturbance connected to specifical and resovable reasons with the exception of Fontain's surgical correction of congenital heart diseases or cardiopathies with dilatation of both atria. Presenting symptoms, symptom history (e.g., frequency, duration, and severity), risk assessment, previous response to alternative treatment options, convenience and patient preference for a specific treatment option, and costeffectiveness of a treatment option are among the many factors that should be considered. Treatment of atrial flutter and fibrillation in pediatric age involves several options: Pharmacological therapy, Transoesophageal atrial pacing (TEAP), Electrical cardioversion and Catheter ablation. In this review we evaluated the physiopathology, the clinical features and the current terapeutical strategies for these arrythmias in paediatric age.

Cardiac arrhythmias in pediatric patients have different mechanisms and frequencies compared to adult patients. There are many physiological differences between children and adults that may affect the pharmacodynamic and pharmacokinetic of the antiarrhythmic drugs in pediatric population. Children, and specially breast feeding children, cannot be considered low weighted adults to select antiarrhythmic drug doses. Although radiofrequency ablation has experienced great technological advances, it is performed in selected pediatric patients. Therefore, the main therapeutic strategy is the use of antiarrhythmic drugs in children. The medical management of arrhythmias in pediatric patients is challenging and complex. There are few clinical guidelines. There is scarce and incomplete information about the efficacy and safety of antiarrhythmic drugs in pediatric population. Most of the doses and drug administration intervals are extrapolated from adult population and applied to children. Antiarrhythmic drug doses have been extensively studied in adult population. However, in pediatric population, there are very few clinical trials and the safety of these drugs is not well known. In general, dose regimens are based on small uncontrolled studies, extrapolation of drug doses from studies performed in the adult population or physician experience. As a consequence, there is a need for further studies to assess the most effective antiarrhythmic drug regimens in children reducing the risk of side effects. Evidence suggests that medical research in pediatric population is necessary and morally valuable. But investigators involved must take care of moral and ethical values, including the respect for the child-subject and his parents or legal representatives, and this respect compels them to consider the patient and family in the decision making process. The participation request and the informed consent must be obtained according to the competitions the patient exhibits, trying to anticipate information about benefits and possible damages derived from the investigation in an understandable language for him. In our opinion the pharmacologic clinical investigation of antiarrhythmic treatments in pediatrics is necessary. More clinical studies must be carried out under rigorous scientific rules that contemplate the particular ethical dilemmas this population faces.

Although there are numerous reports of antiarrhythmic use in children, controlled, comparison trials of antiarrhythmic agents in children are virtually nonexistent and most data are obtained from case series of children treated. Effective and safe pharmacological therapy requires that the physicians attempt to identify a drug with the most appropriate profile to attack the most vulnerable parameter of the mechanisms of the cardiac arrhythmia with the least pro arrhythmic/collateral effects. Digoxin in patients with Wolf-Parkinson -White syndrome, verapamil in infants and intravenous quinidine should be avoided as there is clear evidence that they can cause serious side effects. Collateral effects of other antiarrhythmic drugs are discussed in details in this review. Well-designed, controlled trials are needed to further evaluate the comparative efficacy of antiarrhythmics in children, as well as to evaluate dosing and toxicity in various age groups.

Ablation has become an important treatment for many pediatric patients with common supraventricular tachycardias (SVTs). Many multicenter studies have documented that radiofrequency (RF) catheter ablation is a safe and effective procedure for treatment of a large variety of SVTs in children and adults with a high success rate and minimal complications. Novel electrophysiology technologies such as electroanatomic mapping and sophisticated ablating catheters have improved success rates and decreased complications of transcatheter ablation. Moreover, within the last several years, a new energy source using cryoenergy has evolved as a safe and effective alternative for catheter ablation for arrhythmogenic substrates traditionally associated with increased risk when using RF ablation. In this review pediatric transcatheter ablation practice is analysed and discussed with reference to current clinical guidelines.

Many currently available drugs show unfavourable physicochemical properties for delivery into or across the skin and temporary chemical modulation of the penetrant is one option to achieve improved delivery properties. Pro-drugs are chemical derivatives of an active drug which is covalently bonded to an inactive pro-moiety in order to overcome pharmaceutical and pharmacokinetic barriers. A pro-drug relies upon conversion within the body to release the parent active drug (and pro-moiety) to elicit its pharmacological effect. The main drawback of this approach is that the pro-moiety is essentially an unwanted ballast which, when released, can lead to adverse effects. The term ‘co-drug’ refers to two or more therapeutic compounds active against the same disease bonded via a covalent chemical linkage and it is this approach which is reviewed for the first time in the current article. For topically applied co-drugs, each moiety is liberated in situ, either chemically or enzymatically, once the stratum corneum barrier has been overcome by the co-drug. Advantages include synergistic modulation of the disease process, enhancement of drug delivery and pharmacokinetic properties and the potential to enhance stability by masking of labile functional groups. The amount of published work on co-drugs is limited but the available data suggest the co-drug concept could provide a significant therapeutic improvement in dermatological diseases. However, the applicability of the co-drug approach is subject to strict limitations pertaining mainly to the availability of compatible moieties and physicochemical properties of the overall molecule.

Histone deacetylase (HDAC) inhibitors are a new family of anti-cancer agents currently undergoing clinical investigations for various oncology indications. Their anti-inflammatory activities had been well documented and they appear to be potential therapeutic strategies for various inflammatory diseases. In this review, the anti-inflammatory activities of HDAC inhibitors with emphasis on their potential applications in rheumatoid arthritis (RA) will be summarized. The possible anti-rheumatic mechanisms, including growth arrest in rheumatoid arthritis synovial fibroblasts (RASFs), suppression of pro-inflammatory cytokines or chemokines, anti-angiogenesis as well as protective effects on bone and cartilage destruction will also be discussed. Current literatures strongly imply HDAC inhibitors as innovative anti-rheumatic drug candidates. However, long-term safety is a major concern. Future investigations should focus on identification of molecular anti-rheumatic mechanisms, development of new classes of HDAC inhibitors with better safety and selectivity profiles, combination of HDAC inhibitors with disease modifying anti-rheumatic drugs (DMARDs) and establishment of topical or intraarticular formulations.