IMPORTANCE Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM), but there is no validated algorithm to identify those at highest risk. OBJECTIVE To develop and validate an SCD risk prediction model that provides individualized risk estimates. DESIGN, SETTING, AND PARTICIPANTS A prognostic model was developed from a retrospective, multicenter, longitudinal cohort study of 1024 consecutively evaluated patients aged 16 years or younger with HCM. The study was conducted from January 1, 1970, to December 31, 2017. EXPOSURES The model was developed using preselected predictor variables (unexplained syncope, maximal left-ventricular wall thickness, left atrial diameter, left-ventricular outflow tract gradient, and nonsustained ventricular tachycardia) identified from the literature and internally validated using bootstrapping. MAIN OUTCOMES AND MEASURES A composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia associated with hemodynamic compromise). RESULTS Of the 1024 patients included in the study, 699 were boys (68.3%); mean (interquartile range [IQR]) age was 11 (7-14) years. Over a median follow-up of 5.3 years (IQR, 2.6-8.3; total patient years, 5984), 89 patients (8.7%) died suddenly or had an equivalent event (annual event rate, 1.49; 95% CI, 1.15-1.92). The pediatric model was developed using preselected variables to predict the risk of SCD. The model's ability to predict risk at 5 years was validated; the C statistic was 0.69 (95% CI, 0.66-0.72), and the calibration slope was 0.98 (95% CI, 0.59-1.38). For every 10 implantable cardioverter defibrillators implanted in patients with 6% or more of a 5-year SCD risk, 1 patient may potentially be saved from SCD at 5 years. CONCLUSIONS AND RELEVANCE This new, validated risk stratification model for SCD in childhood HCM may provide individualized estimates of risk at 5 years using readily obtained clinical risk factors. External validation studies are required to demonstrate the accuracy of this model's predictions in diverse patient populations.

Abstract-Upregulation of the sympathetic nervous system plays a key role in the pathogenesis of insulin resistance.Although the heart is a target organ of insulin, few studies have examined the mechanisms by which ␤-adrenergic stimulation affects insulin sensitivity in cardiac muscle. In this study, we explored the molecular mechanisms involved in the regulation of the cross-talk between ␤ adrenergic and insulin receptors in neonatal rat cardiomyocytes and in transgenic mice with cardiac overexpression of a constitutively active mutant of Akt (E40K Tg). The results of this study show that ␤-adrenergic receptor stimulation has a biphasic effect on insulin-stimulated glucose uptake. Short-term stimulation induces an additive effect on insulin-induced glucose uptake, and this effect is mediated by phosphorylation of Akt in threonine 308 through PKA/Ca 2ϩ -dependent and PI3K-independent pathway, whereas insulin-evoked threonine phosphorylation of Akt is exclusively PI3K-dependent. On the other hand, long-term stimulation of ␤-adrenergic receptors inhibits both insulin-stimulated glucose uptake and insulin-induced autophosphorylation of the insulin receptor, and at the same time promotes threonine phosphorylation of the insulin receptor. This is mediated by serine 473 phosphorylation of Akt through PKA/Ca 2ϩ and PI3K-dependent pathways. Under basal conditions, E40K Tg mice show increased levels of threonine phosphorylation of the ␤ subunit of the insulin receptor and blunted tyrosine autophosphorylation of the ␤-subunit of the insulin receptor after insulin stimulation. These results indicate that, in cardiomyocytes, ␤-adrenergic receptor stimulation impairs insulin signaling transduction machinery through an Akt-dependent pathway, suggesting that Akt is critically involved in the regulation of insulin sensitivity.

Percutaneous AD stenting is as effective as MBTS in promoting a global PA growth in CHD-DPC. In addition, it ensures an even distribution of the pulmonary blood flow, thereby promoting a more balanced pulmonary vascular development than MBTS.

The benefits of prophylactic anticoagulation or antiplatelet therapy for patients undergoing extracardiac conduit (ECC) Fontan procedure still are a matter of debate. Through a systematic review and meta-analysis, this study aimed to determine the incidence of thromboembolism among patients undergoing ECC Fontan who received anticoagulation or antiplatelet therapy. Until February 2010, MEDLINE studies describing the incidence of thromboembolic events after ECC Fontan were reviewed. Information on type of drugs and clinical outcome was extracted. The 20 studies analyzed involved 1,075 patients: 220 (20.4%) in the antiplatelet group and 855 (79.5%) in the anticoagulation group. The mean follow-up period ranged from 2 to 144 months. The overall thromboembolism rate was 5.2% (95% confidence interval [CI], 3.8-7%; I(2) = 0%; p(het) = 0.32). The effect of different therapeutic strategies on the occurrence of thromboembolic and bleeding events was analyzed. Interestingly, the anticoagulation therapy compared with the antiplatelet therapy was not associated with a significant reduction in the incidence of overall thromboembolic complications (5% vs 4.5%, respectively; I(2) = 0%; p(het) = 0.80). Only two cases of bleeding were observed among patients receiving anticoagulant therapy at the time of the event. For patients undergoing ECC Fontan, the rate of thromboembolic and bleeding events associated with antiplatelet therapy is similar to that associated with anticoagulation therapy.

Activation of the endocytosis machinery is required for activation of Akt, which, in turn, critically mediates beta1-AR-induced cardiac hypertrophy.