Background—: In recent years, a wider use of automated external defibrillators (AEDs) to treat out-of-hospital cardiac arrest was advocated in The Netherlands. We aimed to establish whether survival with favorable neurologic outcome after out-of-hospital cardiac arrest has significantly increased, and, if so, whether this is attributable to AED use. Methods and Results—: We performed a population-based cohort study, including patients with out-of-hospital cardiac arrest from cardiac causes between 2006 and 2012, excluding emergency medical service–witnessed arrests. We determined survival status at each stage (to emergency department, to admission, and to discharge) and examined temporal trends using logistic regression analysis with year of resuscitation as an independent variable. By adding each covariable subsequently to the regression model, we investigated their impact on the odds ratio of year of resuscitation. Analyses were performed according to initial rhythm (shockable versus nonshockable) and AED use. Rates of survival with favorable neurologic outcome after out-of-hospital cardiac arrest increased significantly (N=6133, 16.2% to 19.7%; P for trend=0.021), although solely in patients presenting with a shockable initial rhythm (N=2823; 29.1% to 41.4%; P for trend<0.001). In this group, survival increased at each stage but was strongest in the prehospital phase (odds ratio, 1.11 [95% CI, 1.06–1.16]). Rates of AED use almost tripled during the study period (21.4% to 59.3%; P for trend <0.001), thereby decreasing time from emergency call to defibrillation-device connection (median, 9.9 to 8.0 minutes; P <0.001). AED use statistically explained increased survival with favorable neurologic outcome by decreasing the odds ratio of year of resuscitation to a nonsignificant 1.04. Conclusions—: Increased AED use is associated with increased survival in patients with a shockable initial rhythm. We recommend continuous efforts to introduce or extend AED programs.

Cardiac sodium channel are protein complexes that are expressed in the sarcolemma of cardiomyocytes to carry a large inward depolarizing current (I_Na) during phase 0 of the cardiac action potential. The importance of I_Na for normal cardiac electrical activity is reflected by the high incidence of arrhythmias in cardiac sodium channelopathies, i.e., arrhythmogenic diseases in patients with mutations in SCN5A, the gene responsible for the pore-forming ion-conducting α-subunit, or in genes that encode the ancillary β-subunits or regulatory proteins of the cardiac sodium channel. While clinical and genetic studies have laid the foundation for our understanding of cardiac sodium channelopathies by establishing links between arrhythmogenic diseases and mutations in genes that encode various subunits of the cardiac sodium channel, biophysical studies (particularly in heterologous expression systems and transgenic mouse models) have provided insights into the mechanisms by which I_Na dysfunction causes disease in such channelopathies. It is now recognized that mutations that increase I_Na delay cardiac repolarization, prolong action potential duration, and cause long QT syndrome, while mutations that reduce I_Na decrease cardiac excitability, reduce electrical conduction velocity, and induce Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, or combinations thereof. Recently, mutation-induced I_Na dysfunction was also linked to dilated cardiomyopathy, atrial fibrillation, and sudden infant death syndrome. This review describes the structure and function of the cardiac sodium channel and its various subunits, summarizes major cardiac sodium channelopathies and the current knowledge concerning their genetic background and underlying molecular mechanisms, and discusses recent advances in the discovery of mutation-specific therapies in the management of these channelopathies.

Previous studies on sex differences in out-of-hospital cardiac arrest (OHCA) had limited scope and yielded conflicting results. We aimed to provide a comprehensive overall view on sex differences in care utilization, and outcome of OHCA. We performed a population-based cohort-study, analysing all emergency medical service (EMS) treated resuscitation attempts in one province of the Netherlands (2006–2012). We calculated odds ratios (ORs) for the association of sex and chance of a resuscitation attempt by EMS, shockable initial rhythm (SIR), and in-hospital treatment using logistic regression analysis. Additionally, we provided an overview of sex differences in overall survival and survival at successive stages of care, in the entire study population and in patients with SIR. We identified 5717 EMS-treated OHCAs (28.0% female). Women with OHCA were less likely than men to receive a resuscitation attempt by a bystander (67.9% vs. 72.7%; P < 0.001), even when OHCA was witnessed (69.2% vs. 73.9%; P < 0.001). Women who were resuscitated had lower odds than men for overall survival to hospital discharge [OR 0.57; 95% confidence interval (CI) 0.48–0.67; 12.5% vs. 20.1%; P < 0.001], survival from OHCA to hospital admission (OR 0.88; 95% CI 0.78–0.99; 33.6% vs. 36.6%; P = 0.033), and survival from hospital admission to discharge (OR 0.49, 95% CI 0.40–0.60; 33.1% vs. 51.7%). This was explained by a lower rate of SIR in women (33.7% vs. 52.7%; P < 0.001). After adjustment for resuscitation parameters, female sex remained independently associated with lower SIR rate. In case of OHCA, women are less often resuscitated by bystanders than men. When resuscitation is attempted, women have lower survival rates at each successive stage of care. These sex gaps are likely explained by lower rate of SIR in women, which can only partly be explained by resuscitation characteristics.

Background— Although Brugada syndrome revolves around reduced net depolarizing force, the electrophysiological mechanisms of its defining features (right precordial ST-segment elevation and ventricular tachyarrhythmias) remain unresolved. Two proposed mechanisms are (1) right ventricular (RV) conduction delay and (2) selective and significant RV subepicardial action potential shortening. Both mechanisms must cause disparate contractile changes: delay in RV contraction and reduction of contractile force, respectively. We aimed to establish the electrophysiological mechanism of Brugada syndrome by studying the timing and force of RV contraction. Methods and Results— Using tissue Doppler echocardiography, we studied how these contractile variables change on induction of the characteristic ST-segment changes of Brugada syndrome by flecainide challenge. Accordingly, we studied patients in whom flecainide induced these changes (inducible) and those in whom these changes were not induced (control). We found that (1) the occurrence of a positive response (coved-type ST elevation) after flecainide coincides with delay in the onset of contraction between the RV and left ventricle (LV); (2) the extent of contraction delay between RV and LV correlates with the magnitude of ST elevation; and (3) RV ejection time (duration of RV ejection phase) shortens as the Brugada ECG pattern emerges. Conclusions— These results indicate that both proposed mechanisms of Brugada syndrome may be operative.

Animal studies revealed that the hyperpolarization-activated pacemaker current, I_f, contributes to action potential (AP) generation in sinoatrial node (SAN) and significantly determines heart rate. I_f is becoming a novel therapy target to modulate heart rate. Yet, no studies have demonstrated that I_f is functionally present and contributes to pacemaking in human SAN. We aimed to study I_f properties in human SAN. In a patient undergoing SAN excision, we identified SAN using epicardial activation mapping. From here, we isolated myocytes and recorded APs and I_f using patch-clamp techniques. Pacemaker cells generated spontaneous APs (cycle length 828 ± 15 ms) following slow diastolic depolarization, maximal diastolic potential − 61.7 ± 4.3 mV, and maximal AP upstroke velocity 4.6 ± 1.2 V/s. They exhibited an hyperpolarization-activated inward current, blocked by external Cs⁺ (2 mmol/L), characterizing it as I_f. Fully-activated conductance was 75.2 ± 3.8 pS/pF, reversal potential − 22.1 ± 2.4 mV, and half-maximal activation voltage and slope factor of steady-state activation − 96.9 ± 2.7 and − 8.8 ± 0.5 mV. Activation time constant ranged from ∼350 ms (−130 mV) to ∼1 s (−100 mV), deactivation time constant 156 ± 45 ms (−40 mV). The role of I_f in pacemaker activity was demonstrated by slowing of pacemaker cell diastolic depolarization and beating rate by Cs⁺. I_f is functionally expressed in human SAN and probably contributes to pacemaking in human SAN.

Sodium ion (Na) influx through cardiac Na channels triggers the action potential in cells of the working myocardium and the specialized conduction system. Na channels thus act as key molecular determinants of cardiac excitability and impulse propagation. Na channel dysfunction may cause life-threatening arrhythmias. Here, we review the ways in which Na channel function can be aberrant due to genetic changes. We discuss how biophysical studies of mutant Na channels combined with precise clinical phenotyping may improve our understanding of Na channel function in health and disease and may be useful as a model from which to derive improved treatment strategies for common disease.