Susan Conacher

Early repolarization is associated with symptoms in patients with type 1 and type 2 long QT syndrome

BACKGROUND Early repolarization (ER) is associated with an increased risk for death from cardiac causes. Recent evidence supports ERs role as a modifier and/or predictor of risk in many cardiac conditions. OBJECTIVE The purpose of this study was to determine the prevalence of ER among genotype-positive patients with long QT syndrome (LQTS) and evaluate its utility in predicting the risk of symptoms. METHODS ER was defined as QRS slurring and/or notching associated with ≥1-mV QRS-ST junction (J-point) elevation in at least 2 contiguous leads, excluding the anterior precordial leads. The ECG with the most prominent ER was used for analysis. Major ER was defined as ≥ 2-mm J-point elevation. Symptoms of LQTS included cardiac syncope, documented polymorphic ventricular tachycardia (VT), and resuscitated cardiac arrest. RESULTS One hundred thirteen patients (mean age 41 ± 19 years; 63 female) were reviewed, among whom 414 (mean 3.7 ± 1.5) ECGs were analyzed. Of these, 30 patients (27%) with a history of symptoms. Fifty patients (44%) had ER, and 19 patients (17%) had major ER. Patients with major ER were not different from patients without major ER with respect to age, sex, long QT type, longest QTc recorded, number of patients with QTc >500 ms, or use of beta-blockade. Univariate and independent predictors of symptom status included the presence of major ER, longest QTc recorded >500 ms, and female sex. CONCLUSION ER ≥2 mm was the strongest independent predictor of symptom status related to LQTS, along with female sex and QTc >500 ms.

A Detailed Description and Assessment of Outcomes of Patients With Hospital Recorded QTc Prolongation

Corrected QT (QTc) interval prolongation has been shown to be an independent predictor of mortality in many clinical settings and is a common finding in hospitalized patients. The causes and outcomes of patients with extreme QTc interval prolongation during a hospital admission are poorly described. The aim of this study was to prospectively identify patients with automated readings of QTc intervals >550 ms at 1 academic tertiary hospital. One hundred seventy-two patients with dramatic QTc interval prolongation (574 ± 53 ms) were identified (mean age 67.6 ± 15.1 years, 48% women). Most patients had underlying heart disease (60%), predominantly ischemic cardiomyopathy (43%). At lease 1 credible and presumed reversible cause associated with QTc interval prolongation was identified in 98% of patients. The most common culprits were QTc interval-prolonging medications, which were deemed most responsible in 48% of patients, with 25% of these patients taking ≥2 offending drugs. Two patients were diagnosed with congenital long-QT syndrome. Patients with electrocardiograms available before and after hospital admission demonstrated significantly lower preadmission and postdischarge QTc intervals compared with the QTc intervals recorded in the hospital. In conclusion, in-hospital mortality was high in the study population (29%), with only 4% of patients experiencing arrhythmic deaths, all of which were attributed to secondary causes.

Loss-of-Function KCNE2 Variants: True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation?

Background— Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel &bgr;-subunit, is limited. We sought to further characterize its clinical phenotype. Methods and Results— Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype–phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the KCNE2 variant was not the underlying culprit. The collective frequency of KCNE2 variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4%, in comparison with a 0.0005% estimated clinical prevalence for LQT6. Conclusions— On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype–phenotype segregation, our findings suggest that many KCNE2 variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, KCNE2 variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.

Arrhythmogenic Right Ventricular Cardiomyopathy With Recessive Inheritance Related to a New Homozygous Desmocollin-2 Mutation

Arrhythmogenic right ventricular cardiomyopathy/dysplasia is an inherited cardiomyopathy that is transmitted in autosomal dominant and autosomal recessive forms and involves mutations in desmosomal and extradesmosomal genes. We present a case of arrhythmogenic right ventricular cardiomyopathy that cosegregates in a Lebanese family with a previously unreported desmocollin-2 mutation (c.712_714delGAT). We believe this newly described genetic variant displays autosomal recessive inheritance without the cutaneous manifestations expected in recessive genotypes, and represents the latest addition to the compendium of desmosomal mutations with pathogenic potential.

KCNJ2 variant of unknown significance reclassified as long QT syndrome causing ventricular fibrillation.

KCNJ2 is the only gene implicated in Andersen-Tawil syndrome. Sudden cardiac arrest is rare in Andersen-Tawil syndrome. However, sudden cardiac arrest is often the index presentation in other forms of long QT syndrome. We present an unreported variant in the KCNJ2 gene, associated with long QT syndrome, that presented with ventricular fibrillation. Exercise testing and adrenaline infusion were useful in assigning pathogenicity to this variant of unknown significance.

End-Recovery QTc: A Useful Metric for Assessing Genetic Variants of Unknown Significance in Long-QT syndrome

QTc for Assessing Significance of LQT Variants.

A large familial pathogenic Plakophilin-2 gene (PKP2) deletion manifesting with sudden cardiac death and lone atrial fibrillation: Evidence for alternating atrial and ventricular phenotypes

The increased prevalence of AF observed in genetic ventricular cardiomyopathies may be secondary to a common underlying genetic culprit. Introduction A single genetic culprit giving rise to varied forms of ventricular cardiomyopathy is a well-documented phenomenon and likely arises, at least in part, secondary to a combination of genetic modifiers and environmental factors. Recent work has begun to implicate cardiomyopathy genes in “lone” atrial fibrillation (AF), suggesting that atrial cardiomyopathy may be a subphenotype of the arrhythmia. It is conceivable that within certain patients and families, cardiomyopathy gene mutations may preferentially manifest with atrial rather than ventricular phenotypes. In the current report, we describe a family with a large pathogenic PKP2 deletion, implicated as the probable cause of sudden death in the proband, that appeared to manifest with predominant atrial phenotypes in other family members.