SADS Foundation Quarterly Review of Literature

A. Drewes 10:00:00 AM
Connexin43 mutation causes heterogeneous gap junction loss and sudden infant death.

An estimated 10% to 15% of sudden infant death syndrome (SIDS) cases may stem from channelopathy-mediated lethal arrhythmias. Loss of the GJA1-encoded gap junction channel protein connexin43 is known to underlie formation of lethal arrhythmias. GJA1 mutations have been associated with cardiac diseases, including atrial fibrillation. Therefore, GJA1 is a plausible candidate gene for premature sudden death.  This study provides the first molecular and functional evidence implicating a GJA1 mutation as a novel pathogenic substrate for SIDS. E42K-connexin43 demonstrated a trafficking-independent reduction in junctional coupling in vitro and a mosaic pattern of mutational DNA distribution in deceased cardiac tissue, suggesting a novel mechanism of connexin43-associated sudden death.

Van Norstrand DW, Asimaki A, Rubinos C, Dolmatova E, Srinivas M, Tester DJ, Saffitz JE, Duffy HS, Ackerman MJ.
Circulation. 2012 Jan 24;125(3):474-81. Epub 2011 Dec 16.
PMID: 22179534
 

Nadolol Block of Nav1.5 Does Not Explain Its Efficacy in the Long QT Syndrome.

Beta-adrenergic receptor antagonists (β-blockers) are the therapy of choice for the long QT syndrome but their efficacy is not homogeneous: propranolol and nadolol are the most effective, whereas metoprolol is associated with more treatment failures. Propranolol has a blocking effect on the sodium current ("membrane-stabilizing" effect), and it has been hypothesized that the efficacy of nadolol might be due to a similar effect. Accordingly, we used whole-cell patch-clamp recording to assess propranolol, nadolol, and metoprolol block of wild-type or mutant cardiac sodium channels (Nav1.5) coexpressed with β1 subunit in tsA201 cells. Nadolol had a ∼20% non-use-dependent blocking effect on peak sodium current and no effect on the persistent current evoked by the LQT3 mutant A1330D, whereas propranolol blocked Nav1.5 in a use-dependent manner and reduced A1330D persistent current. Metoprolol had no effect on either the peak or persistent current. Analysis of the biophysical properties of the channel revealed that both nadolol and propranolol cause hyperpolarizing shifts on voltage dependence of activation and steady-state inactivation, whereas metoprolol shifts only the activation curve. These results provide partial explanation for the differences between nadolol and metoprolol but do not explain the similar clinical efficacy of nadolol and propranolol.    

Besana A, Wang DW, George AL Jr, Schwartz PJ.
J Cardiovasc Pharmacol. 2012 Mar;59(3):249-253.
PMID: 22030895
 

Incidence of and risk factors for sudden cardiac death in children with dilated cardiomyopathy: a report from the Pediatric Cardiomyopathy Registry.   

The purpose of this study was to establish the incidence of and risk factors for sudden cardiac death (SCD) in pediatric dilated cardiomyopathy (DCM). The cohort was 1,803 children in the PCMR (Pediatric Cardiomyopathy Registry) with a diagnosis of DCM from 1990 to 2009. Cumulative incidence competing-risks event rates were estimated. We achieved risk stratification using Classification and Regression Tree methodology. The 5-year incidence rate of SCD in children with DCM is 3%. A risk stratification rule (86% sensitivity) included age at diagnosis younger than 14.3 years, LV dilation, and LV posterior wall thinning. Patients who consistently meet these criteria should be considered for implantable cardioverter-defibrillator placement.   

Pahl E, Sleeper LA, Canter CE, Hsu DT, Lu M, Webber SA, Colan SD, Kantor PF, Everitt MD, Towbin JA, Jefferies JL, Kaufman BD, Wilkinson JD, Lipshultz SE; Pediatric Cardiomyopathy Registry Investigators.
J Am Coll Cardiol. 2012 Feb 7;59(6):607-15.
PMID: 22300696 
   

Cardiac screening prior to stimulant treatment of ADHD: a survey of US-based pediatricians.
A survey of 1600 randomly selected, practicing US pediatricians with American Academy of Pediatrics membership was conducted. Multivariate models were created for 3 screening practices: (1) performing an in-depth cardiac history and physical (H & P) examination, (2) discussing potential stimulant-related cardiac risks, and (3) ordering an electrocardiogram (ECG).  This has indicated that ≥1 of these screening practices were associated with physicians' attitudes about SCD risk, legal liability, their responsibility to inform about risk, their ability to perform an in-depth cardiac H & P, and family concerns about risk. In conclusion, variable pediatrician attitudes and cardiac screening practices reflect the limited evidence base and conflicting guidelines regarding cardiac screening. Barriers to identifying cardiac disorders influence practice.

Leslie LK, Rodday AM, Saunders TS, Cohen JT, Wong JB, Parsons SK.
Pediatrics. 2012 Feb;129(2):222-30. Epub 2012 Jan 16.
PMID: 22250023

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Expanding the benefits of implantable cardioverter-defibrillator therapy: "is less more"?

Implantable cardioverter-defibrillator (ICD) therapy improves survival in patients with significant left ventricular systolic dysfunction. Although this lifesaving therapy has many benefits, inappropriate ICD shocks may increase morbidity and mortality. With rates of inappropriate therapy quoted as high as 35% at 3 years after device implantation, numerous strategies have been evaluated to decrease the overall incidence of inappropriate therapy. Changes in programming algorithms, which allow for longer detection windows for rhythm analysis, extended the use of antitachycardia pacing, and improved supraventricular tachycardia discriminators, hold promise for decreasing inappropriate ICD therapy. In this review, we discuss the data summarizing the adverse effects of ICD shocks on outcomes, clinical trial-based programming algorithms to decrease inappropriate shocks, and the expanded role of antitachycardia pacing in ventricular arrhythmia management.

Jackson LR 2nd, Daubert JP, Thomas KL.
Prog Cardiovasc Dis. 2012 Jan-Feb;54(4):372-8. Review.
PMID: 22226007 


Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry.

The PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) prospective registry was designed to assess the predictive accuracy of sustained ventricular tachycardia/ventricular fibrillation (VTs/VF) inducibility and to identify additional predictors of arrhythmic events in Brugada syndrome patients without history of VT/VF.  The data show that VT/VF inducibility is unable to identify high-risk patients, whereas the presence of a spontaneous type I ECG, history of syncope, ventricular effective refractory period <200 ms, and QRS fragmentation seem useful to identify candidates for prophylactic implantable cardioverter defibrillator.

Priori SG, Gasparini M, Napolitano C, Della Bella P, Ottonelli AG, Sassone B, Giordano U, Pappone C, Mascioli G, Rossetti G, De Nardis R, Colombo M.
J Am Coll Cardiol. 2012 Jan 3;59(1):37-45.
PMID: 22192666

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A. Drewes

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