SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome.

BACKGROUND: Congenital long-QT syndrome (LQTS) is potentially lethal secondary to malignant ventricular arrhythmias and is caused predominantly by mutations in genes that encode cardiac ion channels. Nearly 25% of patients remain without a genetic diagnosis, and genes that encode cardiac channel regulatory proteins represent attractive candidates. Voltage-gated sodium channels have a pore-forming alpha-subunit associated with 1 or more auxiliary beta-subunits. Four different beta-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome. METHODS AND RESULTS: We present a case of a 21-month-old Mexican-mestizo female with intermittent 2:1 atrioventricular block and a corrected QT interval of 712 ms. Comprehensive open reading frame/splice mutational analysis of the 9 established LQTS-susceptibility genes proved negative, and complete mutational analysis of the 4 Na(vbeta)-subunits revealed a L179F (C535T) missense mutation in SCN4B that cosegregated properly throughout a 3-generation pedigree and was absent in 800 reference alleles. After this discovery, SCN4B was analyzed in 262 genotype-negative LQTS patients (96% white), but no further mutations were found. L179F was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells that contained the stably expressed SCN5A-encoded sodium channel alpha-subunit (hNa(V)1.5). Compared with the wild-type, L179F-beta4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-beta4) increase in late sodium current consistent with the molecular/electrophysiological phenotype previously shown for LQTS-associated mutations. CONCLUSIONS: We provide the seminal report of SCN4B-encoded Na(vbeta)4 as a novel LQT3-susceptibility gene.

Cardiocerebral resuscitation improves out-of-hospital survival in older adults.

OBJECTIVES: To compare the survival and neurological status of people aged 65 and older receiving cardiocerebral resuscitation (CCR) with that of those receiving standard advanced life support (Std-ALS), as well as predictors of survival. DESIGN: Historical prospective cohort study. SETTING: The Save Hearts in Arizona Registry (SHARE). PARTICIPANTS: Persons who had experienced cardiac arrest receiving CCR or Std-ALS. MEASUREMENTS: Patient demographics, emergency medical service events, survival to hospital discharge, and out-of-hospital cardiac arrest (OHCA) outcomes were obtained from Arizona hospital records and Bureau of Public Health Statistics from 2005 to 2008. RESULTS: People receiving CCR were twice as likely to survive as those receiving Std-ALS (adjusted odds ratio=2.0, P=.005). An additional 20 per 1,000 older adults would survive, above the background survival rate of Std-ALS, if given CCR. More than 96% of those receiving CCR had good or moderate neurological outcomes, compared with 89% of those receiving Std.-ALS (P=.41). CONCLUSION: CCR is associated with superior survival outcomes than Std-ALS for OHCAs in people aged 65 and older. Use of CCR in older adults without known do-not-resuscitate status is warranted. These findings should be understood within the broader context of the essential role of comprehensive advance care planning in providing care consistent with patient goals and values.

Cardiocerebral resuscitation is associated with improved survival and neurologic outcome from out-of-hospital cardiac arrest in elders.

BACKGROUND: Recent studies have shown that a new emergency medical services (EMS) protocol for treating patients who suffer out-of-hospital cardiac arrest (OHCA), cardiocerebral resuscitation (CCR), significantly improves survival compared to standard advanced life support (ALS). However, due to their different physiology, it is unclear if all elders, or any subsets of elders who are OHCA victims, would benefit from the CCR protocol. OBJECTIVES: The objectives of this analysis were to compare survival by age group for patients receiving CCR and ALS, to evaluate their neurologic outcome, and to determine what other factors affect survival in the subset of patients who do receive CCR. METHODS: An analysis was performed of 3,515 OHCAs occurring between January 2005 and September 2008 in the Save Hearts in Arizona Registry. A total of 1,024 of these patients received CCR. Pediatric patients and arrests due to drowning, respiratory, or traumatic causes were excluded. The registry included data from 62 EMS agencies, some of which instituted CCR. Outcome measures included survival to hospital discharge and cerebral performance category (CPC) scores. Logistic regression evaluated outcomes in patients who received CCR versus standard ALS across age groups, adjusted for known potential confounders, including bystander cardiopulmonary resuscitation (CPR), witnessed arrest, EMS dispatch-to-arrival time, ventricular fibrillation (Vfib), and agonal respirations on EMS arrival. Predictors of survival evaluated included age, sex, location, bystander CPR, witnessed arrest, Vfib/ventricular tachycardia (Vtach), response time, and agonal breathing, based on bivariate results. Backward stepwise selection was used to confirm predictors of survival. These predictors were then analyzed with logistic regression by age category per 10 years of age. RESULTS: Individuals who received CCR had better outcomes across age groups. The increase in survival for the subgroup with a witnessed Vfib was most prominent on those<40 years of age (3.7% for standard ALS patients vs. 19% for CCR patients, odds ratio [OR]=5.94, 95% confidence interval [CI]=1.82 to 19.26). This mortality benefit declined with age until the >or=80 years age group, which regained the benefit (1.8% vs. 4.6%, OR=2.56, 95% CI=1.10 to 5.97). Neurologic outcomes were also better in the patients who received CCR (OR=6.64, 95% CI=1.31 to 32.8). Within the subgroup that received CCR, the factors most predictive of improved survival included witnessed arrest, initial rhythm of Vfib/Vtach, agonal respirations upon arrival, EMS response time, and age. Neurologic outcome was not adversely affected by age. CONCLUSIONS: Cardiocerebral resuscitation is associated with better survival from OHCA in most age groups. The majority of patients in all age groups who survived to hospital discharge and who could be reached for follow-up had good neurologic outcome. Among patients receiving CCR for OHCA, witnessed arrest, Vfib/Vtach, agonal respirations, and early response time are significant predictors of survival, and these do not change significantly based on age.