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Background It has been postulated that long QT syndrome (LQTS) can cause fetal loss through putative adverse effects of the channelopathy on placenta and myometrial function. The authors aimed to describe the fetal death rate in a population of pregnant women with long QT syndrome and investigate whether women with more severe phenotype had worse fetal outcomes. Methods and Results The authors retrospectively evaluated fetal outcomes of 64 pregnancies from 23 women with long QT syndrome followed during pregnancy in a tertiary pregnancy and heart disease program. Thirteen of 64 pregnancies (20%) resulted in a fetal loss, 12 miscarriages (19%), and 1 stillbirth (1.6%). Baseline maternal characteristics, including age and use of β‐blockers, did not differ between women who experienced a fetal death or not. Maternal corrected QT interval (QTc) was significantly longer in pregnancies that resulted in fetal death compared with live births (median, 518 ms [interquartile range (IQR), 482‐519 ms] versus 479 ms [IQR, 454–496 ms], P500 ms was significantly lower compared with women with QTc 500 ms is lower, suggesting that patients with more marked phenotype may experience worse fetal outcomes.

Background Patients with hypertrophic cardiomyopathy (HCM) are at risk of ventricular arrhythmia (VA) attributed to abnormal electrical activation arising from myocardial fibrosis and myocyte disarray. We sought to quantify intra‐QRS peaks (QRSp) in high‐resolution ECGs as a measure of abnormal activation to predict late VA in patients with HCM. Methods and Results Prospectively enrolled patients with HCM (n=143, age 53±14 years) with prophylactic implantable cardioverter‐defibrillators had 3‐minute, high‐resolution (1024 Hz), digital 12‐lead ECGs recorded during intrinsic rhythm. For each precordial lead, QRSp was defined as the total number of peaks detected in the QRS complex that deviated from a smoothing filtered version of the QRS. The VA end point was appropriate implantable cardioverter‐defibrillator therapy during 5‐year prospective follow‐up. After 5 years, 21 (16%) patients had VA. Patients who were VA positive had greater QRSp (6.0 [4.0–7.0] versus 4.0 [2.0–5.0]; P

Background Unlike T‐wave alternans (TWA), the relation between QRS alternans (QRSA) and ventricular arrhythmia (VA) risk has not been evaluated in hypertrophic cardiomyopathy (HCM). We assessed microvolt QRSA/TWA in relation to HCM risk factors and late VA outcomes in HCM. Methods and Results Prospectively enrolled patients with HCM (n=130) with prophylactic implantable cardioverter‐defibrillators underwent digital 12‐lead ECG recordings during ventricular pacing (100–120 beats/min). QRSA/TWA was quantified using the spectral method. Patients were categorized as QRSA+ and/or TWA+ if sustained alternans was present in ≥2 precordial leads. The VA end point was appropriate implantable cardioverter‐defibrillator therapy over 5 years of follow‐up. QRSA+ and TWA+ occurred together in 28% of patients and alone in 7% and 7% of patients, respectively. QRSA magnitude increased with pacing rate (1.9±0.6 versus 6.2±2.0 µV; P=0.006). Left ventricular thickness was greater in QRSA+ than in QRSA− patients (22±7 versus 20±6 mm; P=0.035). Over 5 years follow‐up, 17% of patients had VA. The annual VA rate was greater in QRSA+ versus QRSA− patients (5.8% versus 2.0%; P=0.006), with the QRSA+/TWA− subgroup having the greatest rate (13.3% versus 2.6%; P

Pregnancy is not contraindicated and generally safe in women with IA. Vaginal delivery is generally well tolerated and operative delivery should be reserved to patients with heart failure, recurrent arrhythmia, or obstetric indications. Maternal risk stratification is mandatory to identify women at higher risk of cardiac events during pregnancy and labor. This is ideally considered as part of pre-conception counselling. Beta-blockers are the first line therapy in many IAs and should be continued through pregnancy. Consultation with a multidisciplinary team with experience in high-risk obstetrics, anesthesia, cardiology, electrophysiology, pediatrics, and genetics is key to the successful management of women with inherited arrhythmia conditions through their reproductive years.

BACKGROUND:The SCN5A mutation, P1332L, is linked to a malignant form of congenital long QT syndrome, type 3 (LQT3), and affected patients are highly responsive to the Na+ channel blocking drug, mexiletine. In contrast, A647D is an atypical SCN5A mutation causing Brugada syndrome. An asymptomatic male with both P1332L and A647D presented with varying P wave/QRS aberrancy and mild QTc prolongation which did not shorten measurably with mexiletine. OBJECTIVE:We characterized the biophysical properties of P1332L, A647D and wild-type (WT) Na+ channels as well as their combinations in order to understand our proband's phenotype and to guide mexilitine therapy. METHODS:Na+ channel biophysics and mexilitine-binding kinetics were assessed using heterologous expression studies in CHO-K1 cells and human ventricular myocyte modeling. RESULTS:Compared to WT, P1332L channels displayed a hyperpolarizing shift in inactivation, slower inactivation and prominent late Na+ currents (INa). While A647D had no effect on the biophysical properties of INa, it reduced peak and late INa density when co-expressed with either WT or P1332L. Additionally, while P1332L channels had greater sensitivity to block by mexiletine compared to WT, this was reduced in the presence of A647D. Modelling studies revealed that mixing P1332L with A647D channels, action potential durations were shortened compared to P1332L, while peak INa was reduced compared to either A647D coexpressing with WT or WT alone. CONCLUSIONS:While A647D mitigates the lethal LQT3 phenotype seen with P1332L, it also reduces mexilitine sensitivity and decreases INa density. These results explain our proband's mild repolarization abnormality and prominent conduction defect in the atria and ventricles, but also suggest that expression of P1332L with A647D yields a novel disease phenotype for which mexiletine pharmacotherapy is no longer suitable.

BackgroundThe cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio‐oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life‐threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario. Methods and ResultsIn this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta‐Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare. ConclusionsOur systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.