Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.
BACKGROUND Despite estimates that waste constitutes up to 20% of healthcare expenditures in the United States, overuse of tests and therapies is significantly under‐recognized in medicine, particularly in pediatrics. The American Board of Internal Medicine Foundation developed the Choosing Wisely campaign, which challenged medical societies to develop a list of 5 things physicians and patients should question. The Society of Hospital Medicine (SHM) joined this effort in the spring of 2012. This report provides the pediatric workgroup's results. METHODS A workgroup of experienced and geographically dispersed pediatric hospitalists was convened by the Quality and Safety Committee of the SHM. This group developed an initial list of 20 recommendations, which was pared down through a modified Delphi process to the final 5 listed below. RESULTS The top 5 recommendations proposed for pediatric hospital medicine are: (1) Do not order chest radiographs in children with asthma or bronchiolitis. (2) Do not use systemic corticosteroids in children under 2 years of age with a lower respiratory tract infection. (3) Do not use bronchodilators in children with bronchiolitis. (4) Do not treat gastroesophageal reflux in infants routinely with acid suppression therapy. (5) Do not use continuous pulse oximetry routinely in children with acute respiratory illness unless they are on supplemental oxygen. CONCLUSION We recommend that pediatric hospitalists use this list to prioritize quality improvement efforts and include issues of waste and overuse in their efforts to improve patient care. Journal of Hospital Medicine 2013;8:479–485. © 2013 Society of Hospital Medicine
Rationale: Voltage-gated sodium channels initiate action potentials in excitable tissues. Mice in which Scn5A (the predominant sodium channel gene in heart) has been knocked out die early in development with cardiac malformations by mechanisms which have yet to be determined. Objective: Here we addressed this question by investigating the role of cardiac sodium channels in zebrafish heart development. Methods and Results: Transcripts of the functionally-conserved Scn5a homologs scn5Laa and scn5Lab were detected in the gastrulating zebrafish embryo and subsequently in the embryonic myocardium. Antisense knockdown of either channel resulted in marked cardiac chamber dysmorphogenesis and perturbed looping. These abnormalities were associated with decreased expression of the myocardial precursor genes nkx2.5, gata4, and hand2 in anterior lateral mesoderm and significant deficits in the production of cardiomyocyte progenitors. These early defects did not appear to result from altered membrane electrophysiology, as prolonged pharmacological blockade of sodium current failed to phenocopy channel knockdown. Moreover, embryos grown in calcium channel blocker-containing medium had hearts that did not beat but developed normally. Conclusions: These findings identify a novel and possibly nonelectrogenic role for cardiac sodium channels in heart development. (Circ Res. 2010;106:1342-1350.)Key Words: ion channels Ⅲ heart development Ⅲ zebrafish Ⅲ scn5La T he Na v 1 family of voltage-gated sodium channels are multi-protein complexes that account for the initial upstroke (phase 0) of the action potential in neurons, myocytes, and other excitable cells by permitting a rapid influx of Na ϩ ions. 1 Ten distinct pore-forming (␣) subunit genes (SCNxA) have been cloned, 1-3 and SCN5A encodes Na v 1.5, the predominant sodium channel isoform in myocardium. 4 Perturbed expression or function of Na v 1.5 in patients can cause a range of phenotypes including the long QT syndrome, Brugada syndrome, progressive cardiac conduction system disease, and atrial arrhythmias. 5,6 Mice heterozygous for Scn5a deletion display slow conduction and susceptibility to ventricular tachycardia. 7 By contrast, Scn5a Ϫ/Ϫ homozygotes die between embryonic day (E)10 and E11 with abnormalities of ventricular morphogenesis, indicating that Scn5a is also required for normal development. 7 The mechanisms underlying these defects have not been determined.Here, we used zebrafish to examine the role of sodium channels in the developing heart. Zebrafish embryos are optically transparent and externally fertilized, facilitating the study of early organ formation. Genetic manipulation is readily achieved using antisense morpholinos, and embryos are also permeable to small molecule drugs placed in their medium. The stages of zebrafish cardiac development have been welldelineated: cardiac precursors are located at the blastula margin at 5 hours postfertilization (hpf). 8 These bilateral precursors undergo a complex series of movements that result in the formation of a ...
Organ development is a highly regulated process involving the coordinated proliferation and differentiation of diverse cellular populations. The pathways regulating cell proliferation and their effects on organ growth are complex and for many organs incompletely understood. In all vertebrate species, the cardiac natriuretic peptides (ANP and BNP) are produced by cardiomyocytes in the developing heart. However, their role during cardiogenesis is not defined. Using the embryonic zebrafish and neonatal mammalian cardiomyocytes we explored the natriuretic peptide signaling network during myocardial development. We observed that the cardiac natriuretic peptides ANP and BNP and the guanylate cyclase-linked natriuretic peptide receptors Npr1 and Npr2 are functionally redundant during early cardiovascular development. In addition, we demonstrate that low levels of the natriuretic peptides preferentially activate Npr3, a receptor with Gi activator sequences, and increase cardiomyocyte proliferation through inhibition of adenylate cyclase. Conversely, high concentrations of natriuretic peptides reduce cardiomyocyte proliferation through activation of the particulate guanylate cyclase-linked natriuretic peptide receptors Npr1 and Npr2, and activation of protein kinase G. These data link the cardiac natriuretic peptides in a complex hierarchy modulating cardiomyocyte numbers during development through opposing effects on cardiomyocyte proliferation mediated through distinct cyclic nucleotide signaling pathways.
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