Sudden death in the young is a tragic and devastating event for families and communities. Characterization of the population that suffers sudden death would assist in understanding the scope and nature of the problem, and could potentially inform strategies targeting prevention. We conducted a population-based retrospective cohort study of sudden death cases involving persons aged 2-40 years identified from the 2008 comprehensive database of the Office of the Chief Coroner, which contains data on all cases reported to and investigated by coroners in Ontario. Coroner's reports including autopsy findings, description of circumstances and decedent medical history were reviewed and coded to establish cause of death. Of 1,741 coroner's cases, 376 were considered potential sudden cardiac death cases and underwent further review. There were 174 cases of presumed sudden death from a population of 6,602,680 persons aged 2-40 years. Structural heart disease was present in 126 cases (72%), 78% of which was unrecognized (n=98). There was no identifiable cause of death in 48 cases (28%), representing definite primary arrhythmia syndromes. The majority of decedents were male (76%) over the age of 18 (90%). The overall incidence of sudden death was 2.6/100,000 person-years, increasing with age from 0.7/100,000 (2-18 years) to 2.4/100,000 (19-29 years) and 5.3/100,000 person-years (30-40 years). Persons experiencing sudden death under age 30 were more likely to have a primary arrhythmia syndrome than those 30 and older (OR=3.17, 95% CI=1.60-6.28; p<0.001). The majority of events occurred in the home (72%); 33% of events in children/adolescents and 9% of events in adults occurred during reported moderate or vigorous exercise (9% and 33%, respectively, p=0.02). Organized, competitive sporting activity was not associated with SCD in this analysis. Premonitory symptoms were more frequent in females (61% vs. 41%, p=0.007), and in cases with underlying heart disease (54% vs. 25%, p<0.0001). The incidence of sudden cardiac death increases with age. Death typically occurs in a male at rest in the home with unrecognized underlying heart disease or a primary arrhythmia syndrome. Prevention strategies should consider targeting identification of unrecognized structural heart disease and primary arrhythmia syndromes.

Hair analyses for exogenous compounds, specifically drugs of abuse, have been a useful tool in detecting long-term drug exposure. More recently, studies have delved into the exposure of endogenous compounds in hair. Cortisol is synthesized in the adrenal cortex in response to stress-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis. While catecholamines generally indicate acute stress, cortisol can be used as an indicator for sub-acute and chronic stress. Studies on the effects of chronic stress are most often subjective in nature, relying on questionnaires asking the participant to recall on past stressors. This can lead to the issue of recall and reporting bias. A new objective measure of chronic stress is needed for a more accurate understanding of the effects of chronic stress on the body. This review uses emerging evidence to describe the usefulness of hair analysis for cortisol and discusses the current methods used.

OBJECTIVE:Studies in rodent models have suggested that reduction in renal transforming growth factor (TGF)-beta1 may underlie the renoprotective effects of the renin-angiotensin system (RAS) blockade. However, the role of the RAS blockade in abrogating TGF-beta in human disease is unknown. Accordingly, we sought to examine TGF-beta gene expression and biological activity in human renal biopsies, before and after ACE inhibition.RESEARCH DESIGN AND METHODS:RNA was extracted from renal biopsies taken from participants in the Diabiopsies study, a randomized controlled 2-year trial of 4 mg/day perindopril versus placebo that reported a reduction in proteinuria and cortical matrix expansion in type 2 diabetic nephropathy. Biopsies taken at study entry and at 2 years were obtained in 12 patients (6 placebo and 6 taking perindopril). TGF-beta1 and its receptor mRNA were quantified by real-time PCR, and its biological activity was assessed by examining the activation of its intracellular signaling pathway (phosphorylated Smad2) and the expression TGF-beta-inducible gene H3 (betaig-H3).RESULTS:At baseline, TGF-beta1 expression was similar in both placebo- and perindopril-treated groups and was unchanged over a 2-year period in biopsies of placebo-treated subjects. In contrast, perindopril treatment led to a substantial diminution in TGF-beta1 mRNA (mean 83% reduction, P < 0.05). Phosphorylated Smad2 immunolabeling and betaig-H3 mRNA were similarly reduced with ACE inhibition (P < 0.05) but unchanged in the placebo group. No differences were noted in the gene expression of TGF-beta receptor II in biopsies of either placebo- or perindopril-treated subjects.CONCLUSIONS:This study demonstrates that over a 2-year period, treatment with perindopril in patients with type 2 diabetes and nephropathy leads to a reduction in both renal TGF-beta1 gene expression and its downstream activation.

Pulsed Doppler evaluation of pulmonary venous flow was performed in three groups of patients who had undergone either a Mustard or Senning procedure. Group I consisted of 43 patients in sinus rhythm who had undergone the Mustard procedure 9 months or more before the Doppler examination and 16 who were evaluated immediately after surgery. Group II consisted of 12 patients in sinus rhythm who had undergone the Senning procedure 9 months or more before the Doppler evaluation. Group III consisted of eight patients with mid baffle obstruction of the pulmonary venous atrium and seven with isolated stenosis of the pulmonary vein of which all but one had previously had associated mid baffle obstruction. In those without obstruction, the pulmonary venous flow pattern mirrored the left atrial pressure trace, with peak forward flow occurring during the x and y descent. Obstruction produced a specific high-velocity turbulent pattern, whether at the mid baffle or pulmonary venous level. This technique provides reliable noninvasive information about pulmonary venous flow after the Mustard or Senning procedure. Circulation 73, No. 4, 765-774, 1986. INTERATRIAL REROUTING of pulmonary and systemic venous blood by the Mustard or Senning procedure is still the most common operation for patients with simple transposition of the great arteries. In the former the pericardium is used to form the baffle, while in the latter the native atrial tissue is used.' The theoretical advantages of the Senning procedure is that it preserves normal atrial function and growth of the pathways.t Both procedures may be complicated by systemic or pulmonary venous obstruction (PVO), and more rarely by isolated stenosis of the pulmonary veins.'-"1 Unless PVO is severe, clinical recognition is difficult and diagnosis necessitates cardiac catheterization.' 1-7 Recently cross-sectional echocardiography has been From the Department of Pediatrics, Division of Cardiology and Cardiovascular Surgery, The Hospital for Sick Children, Toronto, Ontario, the Montreal Children's Hospital, Quebec, and the Ottawa Children's Hospital, Ontario. Dr. Gow was supported by the Ontario Heart Foundation, grant No. 9511. Address for correspondence: Jeffrey Smallhom, M.D., Department of Cardiology, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Received July 22, 1985; revision accepted Dec. 5, 1985. Vol. 73, No. 4, April 1986 used to assess the midportion of the pulmonary venous atrium after the Senning procedure.'8' 9 However, problems may occur in the older patient in whom a reliable window is absent. Furthermore, this technique does not identify those patients with stenosis of the pulmonary veins.11 The left atrium acts as a reservoir for pulmonary venous return and augments left ventricular filling during atrial contraction. Pulmonary venous flow measured experimentally appears to mirror left atrial pressure events, particularly the slope of the x and y descent.2'22 More recently it has been possible to assess pulmonary venous flow by pulsed Doppler echocardiography.2324 The purpose of this study was to compare pressure and flow profiles in patients who have undergone the Mustard Senning procedure with normal subjects and those with PVO either at mid baffle or pulmonary venous level. Materials and methods Three groups of patients were studied. Group I consisted of 59 patients who had undergone the Mustard procedure and were evaluated at the Hospital for Sick Children. In 43, the surgery had been performed more than 9 months before the study. In

Pathologic fibrosis is a key feature of progressive renal disease that correlates closely with kidney dysfunction and in which the prosclerotic growth factor TGF-beta has been consistently implicated. Tranilast (n-[3,4-dimethoxycinnamoyl] anthranilic acid), an antifibrotic agent that is used to treat hypertrophic scars and scleroderma, has also been shown to inhibit TGF-beta-induced extracellular matrix synthesis in a range of cell types, including those of renal origin. Therefore, the effects of tranilast on kidney fibrosis and dysfunction were examined in the subtotal nephrectomy model of progressive renal injury. Subtotal nephrectomy led to proteinuria and renal dysfunction in association with glomerulosclerosis, tubulointerstitial fibrosis, and macrophage accumulation. Despite persistent hypertension, treatment with tranilast led to a reduction in albuminuria (61.7 (x)/(/) 1.2 versus 20.5 (x)/(/) 1.3 mg/d; P < 0.01) and plasma creatinine (0.16 versus 0.08 mmol/L; P < 0.01) in subtotally nephrectomized rats. In addition, features suggestive of TGF-beta activation, including glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy, and macrophage accumulation, all were significantly attenuated by tranilast in association with evidence of reduced TGF-beta signaling in vivo. In the context of a recent pilot study in humans, the findings of the present report suggest that tranilast may provide a novel strategy for the treatment of progressive kidney disease characterized by fibrotic scarring.

The value of the electrocardiogram (ECG) in children with supraventricular tachycardia (SVT) is unclear. The noninvasive differentiation of typical atrioventricular node reentrant tachycardia (AVNRT) and atrioventricular reciprocating tachycardia (AVRT) mediated by concealed accessory pathway conduction is clinically important, as it helps in counseling and potentially facilitates ablation procedures. One hundred forty-eight ECGs showing narrow QRS complex SVT were obtained from children before successful radiofrequency catheter ablation. An initial 102 ECGs were analyzed by 3 blinded observers to assess the utility of various electrocardiographic findings. No electrocardiographic criteria were found to discriminate between SVT mechanisms on 1- to 3-channel Holter/event recorder tracings (n = 32); their interpretation mainly (55%) resulted in an incorrect SVT diagnosis. On 12-lead ECGs (n = 70), the 2 arrhythmias were accurately diagnosed in 76% of patients; 5 findings were found to be discriminators of tachycardia mechanism. Predictors of AVRT were visible P waves in 74% of cases (sensitivity 92%; specificity 64%), RP intervals of ≥100 ms in 91% (sensitivity 84%; specificity 91%), and ST-segment depression of ≥2 mm in 73% of cases (sensitivity 52%; specificity 82%). Pseudo r′ waves in lead V1 and pseudo S waves in the inferior leads during tachycardia predicted AVNRT in 100% of cases (sensitivity 55% and 20%, respectively; specificity 100% for both). Based on these results, we developed a new diagnostic 12-lead electrocardiographic algorithm for pseudo r′/S waves, RP duration, and ST-segment depression during tachycardia. Two observers tested the algorithm in 46 (21 AVNRT; 25 AVRT) additional cases; they correctly diagnosed the SVT mechanism in 91% and 87%, respectively. Thus, the stepwise use of diagnostically relevant 12-lead electrocardiographic parameters helps to more accurately differentiate mechanisms of reentrant SVT.

Clomipramine, haloperidol, and placebo were compared with baseline in the treatment of autism, and overall outcome, specific symptoms, and side effects were examined. It was hypothesized that clomipramine would be better tolerated than haloperidol and prove superior on a measure of stereotypy. Individuals with a DSM-IV diagnosis of autistic disorder (mean age, 16.3 years; range, 10–36 years) were randomly assigned, by using a Latin square design, to the following 7-week trials: placebo, clomipramine (mean daily dose, 128.4 mg; range, 100–150 mg), or haloperidol (mean daily dose, 1.3 mg; range, 1–1.5 mg). Data on 36 subjects were analyzed and taken together; the results favored haloperidol. In those patients who were able to complete a full therapeutic trial, clomipramine proved comparable to haloperidol in terms of improvement compared with baseline. However, significantly fewer individuals receiving clomipramine versus haloperidol were able to complete the trial (37.5% vs. 69.7%, respectively) for reasons related to both side effects and efficacy or behavior problems. In the intent-to-treat sample, which is perhaps more clinically relevant, only haloperidol proved superior to baseline on a global measure of autistic symptom severity, as well as specific measures for irritability and hyperactivity. Clomipramine did not seem more effective on a measure of stereotypy, nor was it better tolerated.

Adenosine has become the preferred acute treatment for common types of supraventricular tachycardia because of its efficacy and safety. There have been a few reports of serious proarrhythmic events associated with its use, including the induction of atrial fibrillation in adult patients. Three instances of adenosine-induced atrial proarrhythmia (two atrial fibrillation and one atrial flutter) have been observed in children with manifest or concealed Wolff-Parkinson-White syndrome at the Hospital for Sick Children, Toronto, Ontario since 1990, which indicates a previously unreported risk of atrial arrhythmia for children as well. Because adenosine may enhance antegrade bypass tract conduction, its use carries a risk of ventricular acceleration, including progression to ventricular fibrillation. Because of such rare and potentially life-threatening adverse effects, appropriate monitoring and precautions are required during the administration of the drug to children and adults.

To elucidate contribution of an active metabolite to overall clinical responses to propafenone, steady‐state disposition of propafenone and its active metabolite and the clinical responses to treatment were examined in pediatric patients receiving intravenous or oral propafenone. There were more than ten‐fold interindividual differences in apparent clearance, resulting in a wide range of the steady‐state trough plasma concentrations of propafenone. The active metabolite, 5‐hydroxypropafenone, was detected in four of the six patients receiving oral propafenone; however, two neonates receiving oral propafenone and all eight receiving intravenous propafenone had no detectable levels of 5‐hydroxypropafenone in plasma. In nine patients for whom electrocardiographic (ECG) data were available, the PQ interval was significantly increased, whereas the QRS duration and the QTc interval were not. There was no close relationship between plasma concentrations of propafenone or 5‐hydroxypropafenone and ECG parameters. Lack of good correlation between serum concentrations and clinical response precludes using a serum‐concentration targeting strategy with propafenone therapy.

BACKGROUND:Myocardial bridging may cause compression of a coronary artery, and it has been suggested that myocardial ischemia may result. The clinical significance and prognostic value of myocardial bridging of the left anterior descending coronary artery in children with hypertrophic cardiomyopathy are unknown. We sought to determine the prevalence and clinical effects of myocardial bridging in children with hypertrophic cardiomyopathy who underwent cardiac catheterization.METHODS:Angiograms from 36 children with hypertrophic cardiomyopathy were reviewed to determine whether myocardial bridging was present and, if so, to assess the characteristics of systolic narrowing of the left anterior descending coronary artery caused by myocardial bridging and the duration of residual diastolic compression. We also reviewed clinical data on these patients.RESULTS:Myocardial bridging was present in 10 (28 percent) of the patients. Compression of the left anterior descending coronary artery persisted for a mean (+/-SD) of 50+/-17 percent of diastole. As compared with patients without bridging, patients with bridging had a greater incidence of chest pain (60 percent vs. 19 percent, P=0.04), cardiac arrest with subsequent resuscitation (50 percent vs. 4 percent, P=0.004), and ventricular tachycardia (80 percent vs. 8 percent, P<0.001). On average, the patients with bridging had a reduction in systolic blood pressure with exercise of 17+/-27 mm Hg, as compared with an elevation of 43+/-31 mm Hg in those without bridging (P<0.001). The patients with bridging also had greater ST-segment depression with exercise (median, 5 vs. 0 mm, P=0.004) and a shorter duration of exercise (mean, 6.6+/-2.4 vs. 9.1+/-1.4 minutes, P=0.008). The degree of dispersion of the QT interval corrected for heart rate on the electrocardiogram was greater in patients with bridging than in those without bridging (104+/-46 vs. 48+/-31 msec, P=0.002). Kaplan-Meier estimates of the proportions of patients who had not died or had cardiac arrest with subsequent resuscitation five years after the diagnosis of hypertrophic cardiomyopathy were 67 percent among patients with bridging and 94 percent among those without bridging (P=0.004).CONCLUSIONS:Myocardial bridging is associated with a poor outcome in children with hypertrophic cardiomyopathy. Our observations suggest that bridging is associated with myocardial ischemia

BACKGROUND:Dolasetron mesylate is a selective 5-HT3 receptor antagonist under investigation as an antiemetic in children. Published studies indicate that its antiemetic activity results from the active metabolite (MDL 74,156), which is produced within 10 minutes of administration of dolasetron mesylate. METHODS:The pharmacokinetics of MDL 74,156 and the safety and tolerability of dolasetron mesylate were studied after a single oral or intravenous dose of 1.2 mg.kg-1 dolasetron mesylate to healthy children from 2 to 12 years of age. Oral dolasetron was administered to 12 children 1 to 2 hours before anesthesia. Intravenous dolasteron was administered to 18 children at induction of anesthesia. Serial blood samples were collected for 24 hours after dosing to measure the plasma concentration of MDL 74,156. Indexes of liver and kidney function were determined, and electrocardiograms and adverse events were recorded.

The trend to perform early primary repair of tetralogy of Fallot prompted us to review our experience in the current era with the traditional protocol consisting of palliation during infancy, if required, and repair after infancy. During a 10-year period, 270 infants with tetralogy of Fallot presented aged less than 18 months. Thirteen infants (4.8%) had major noncardiac lesions that precluded definitive care for their congenital heart disease. Twenty infants (7.4%) had major associated cardiac lesions (atrioventricular septal defect or absent pulmonary valve syndrome, or both). Survival in this group was poor, with only 58% +/- 12% reaching the age of 10 years. Four of the seven deaths occurred before intracardiac repair was performed. The remaining 237 infants presented with isolated tetralogy of Fallot. Eight-nine percent +/- 2.3% survived to age 10 years. Sixty percent of these infants required palliation, and survival in these infants did not differ from that in those who never required palliation. However, 19 infants (8%) required palliation in the first month of life. In these children, survival to age 10 years was significantly lower (77%), secondary palliation was frequently required (n = 11), and a transannular patch or conduit at the time of repair (10 of 14 patients) was more likely needed than it was in children who had not undergone a palliative procedure during the neonatal period. The survival in infants with tetralogy of Fallot is unlikely to be different, regardless of whether primary repair or a staged repair is carried out. The quality of survival, including the exercise capability and absence of arrhythmias, must be assessed to determine which protocol is superior.

The Wolff-Parkinson-White syndrome is caused by a congenital accessory connection between the atrium and ventricle. We describe a case of symptomatic Wolff-Parkinson-White syndrome that arose after a Björk modification of the Fontan operation. Invasive electrophysiologic and intraoperative mapping indicated that the surgically created atrioventricular connection was functioning as an accessory pathway. Surgical dissection and cryoablation abolished the symptoms and the preexcitation.

Twenty patients (aged 50 +/- 21 years and mean left ventricular ejection fraction 37 +/- 17%) with recurrent ventricular arrhythmias were treated with an investigational, implantable combined antitachycardia-pacing cardioverter defibrillator. The device's telemetry capabilities include both stored (1-second snapshots) and real-time display of endocardial and device-circuit signals. The device can store these before, during and after up to 50 tachycardia and antitachycardia pacing episodes. All stored events are indexed to a 24-hour internal clock. During 10.1 +/- 5.1 months of follow-up, the device was used in 11 of 20 patients. In the entire group, antitachycardia pacing was activated on 44 +/- 14 occasions per patient (total 874) and shock delivery occurred on 8 +/- 14 occasions per patient (total 156). Reconstruction by stored telemetry of all device-therapy episodes was possible. Twenty-six percent of all shocks delivered were not appropriate and were due to atrial arrhythmias in 2 patients and dysfunction of the sensing lead in 3. The absence of a relation between symptoms and appropriate shock delivery was documented in 1 patient. Antitachycardia pace acceleration occurred in 5.3% of cases; 7% of attempts at pacing were unsuccessful and needed shock therapy. It is concluded that the enhanced telemetry available in newer antitachycardia devices enables more accurate assessment of device use and enhances diagnosis of inappropriate therapy delivery.

From 1986 to 1991, we evaluated the clinical use of three new epicardial lead designs incorporating a steroid-eluting electrode. Medtronic models SP2114 (bipolar high profile), 10320 (bipolar low profile), 10295A/4965 (unipolar low profile) steroid epicardial (SE) leads were used on either atrium or ventricle for a total of 21 lead placements in 17 patients. Energy thresholds (T) were calculated and compared with our most recent 16 nonsteroid epicardial (NE) Medtronic model 4951 lead implants for which T was available. SE leads demonstrated no acute T rise and continued T improvements at 1 year of follow-up. We conclude that epicardial application of SE lead technology offers a major improvement in pacing lead function and potential pacemaker longevity over NE leads in pediatric patients in whom endocardial pacing is precluded by size or anatomy.

Paret, Gideon; Gow, Robert; Zalzstein, Eli; Mofada, Saleh Al; Bohn, Desmond; Barker, Geoffrey Author Information