C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3ϵ

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Improved Clinical Risk Stratification in Patients with Long QT Syndrome? Novel Insights from Multi-Channel ECGs.

BACKGROUND:We investigated whether multichannel ECG-recordings are useful to risk-stratify patients with congenital long-QT syndrome (LQTS) for risk of sudden cardiac death under optimized medical treatment. METHODS:In 34 LQTS-patients (11 male; age 31±13 years, QTc 478±51ms; LQT1 n = 8, LQT2 n = 15) we performed a standard 12-channel ECG and a 120-channel body surface potential mapping. The occurrence of clinical events (CE; syncope, torsade de pointes (TdP), sudden cardiac arrest (SCA)) was documented and correlated with different ECG-parameters in all lead positions. RESULTS:Seven patients developed TdP, four survived SCA and 12 experienced syncope. 12/34 had at least one CE. CE was associated with a longer QTc-interval (519±43ms vs. 458±42ms; p = 0.001), a lower T-wave integral (TWI) on the left upper chest (-1.2±74.4mV*ms vs. 63.0±29.7mV*ms; p = 0.001), a lower range of T-wave amplitude (TWA) in the region of chest lead V8 (0.10±0.08mV vs. 0.18±0.07mV; p = 0.008) and a longer T-peak-T-end time (TpTe) in lead V1 (98±23ms vs. 78±26ms; p = 0.04). Receiver-operating-characteristic (ROC) analyses revealed a sensitivity of 96% and a specificity of 75% (area under curve (AUC) 0.89±0.06, p = 0.001) at a cut-off value of 26.8mV*ms for prediction of CE by TWI, a sensitivity of 86% and a specificity of 83% at a cut-off value of 0.11mV (AUC 0.83±0.09, p = 0.002) for prediction of CE by TWA and a sensitivity of 83% and a specificity of 73% at a cut-off value of 87ms (AUC 0.80±0.07, p = 0.005) for prediction of CE by TpTe. CONCLUSIONS:Occurrence of CE in LQTS-patients seems to be associated with a prolonged, low-amplitude T-wave

Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca 2+ exchanger overexpression:whole heart and cellular mechanisms

The cardiac Na(+)/Ca(2+) exchanger (NCX) generates an inward electrical current during SR-Ca(2+) release, thus possibly promoting afterdepolarizations of the action potential (AP). We used transgenic mice 12.5 weeks or younger with cardiomyocyte-directed overexpression of NCX (NCX-Tg) to study the proarrhythmic potential and mechanisms of enhanced NCX activity. NCX-Tg exhibited normal echocardiographic left ventricular function and heart/body weight ratio, while the QT interval was prolonged in surface ECG recordings. Langendorff-perfused NCX-Tg, but not wild-type (WT) hearts, developed ventricular tachycardia. APs and ionic currents were measured in isolated cardiomyocytes. Cell capacitance was unaltered between groups. APs were prolonged in NCX-Tg versus WT myocytes along with voltage-activated K(+) currents (K(v)) not being reduced but even increased in amplitude. During abrupt changes in pacing cycle length, early afterdepolarizations (EADs) were frequently recorded in NCX-Tg but not in WT myocytes. Next to EADs, delayed afterdepolarizations (DAD) triggering spontaneous APs (sAPs) occurred in NCX-Tg but not in WT myocytes. To test whether sAPs were associated with spontaneous Ca(2+) release (sCR), Ca(2+) transients were recorded. Despite the absence of sAPs in WT, sCR was observed in myocytes of both genotypes suggesting a facilitated translation of sCR into DADs in NCX-Tg. Moreover, sCR was more frequent in NCX-Tg as compared to WT. Myocardial protein levels of Ca(2+)-handling proteins were not different between groups except the ryanodine receptor (RyR), which was increased in NCX-Tg versus WT. We conclude that NCX overexpression is proarrhythmic in a non-failing environment even in the absence of reduced K(V). The underlying mechanisms are: (1) occurrence of EADs due to delayed repolarization; (2) facilitated translation from sCR into DADs; (3) proneness to sCR possibly caused by altered Ca(2+) handling and/or increased RyR expression