An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis.

BACKGROUND: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. OBJECTIVES: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. METHODS: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied. RESULTS: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died. CONCLUSIONS: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.

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 ß-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.

Variabilidad de la respuesta plaquetaria a la aspirina / Assessing platelet response to aspirin

Introducción y objetivos: A pesar de que el estudio Antiplatelet Trialists' Collaboration demostró una reducción del 25% de los eventos mayores con el uso de aspirina en enfermos de alto riesgo, un porcentaje de pacientes presentan eventos isquémicos recurrentes. Esto ha llevado a la descripción de la "resistencia a la aspirina" con una tasa muy variable, de 0.4% a 83%. Este estudio evaluó la variabiliad en la función plaquetaria basal, la prevalencia de la resistencia a la aspirina, y la efectividad y reproducibilidad de los estudios de función plaquetaria. Materiales y métodos: Se llevó a cabo un estudio aleatorizado y cruzado de mediciones repetidas, con sujetos saludables de entre 18 y 60 años. Luego de firmar el consentimiento informado, los pacientes fueron distribuidos en forma aleatorizada a recibir aspirina en dosis de 75 mg o 300 mg; fueron evaluados al inicio y luego de cuatro períodos de tres semanas mediante diferentes técnicas: Optical Platelet Aggregation (OPA), PFA-100™, VerifyNow™, y los niveles séricos y urinarios de tromboxano B2 (TXB2). Se obtuvo la aprobación del comité de ética local. El análisis estadístico fue realizado con el programa SPSS17. Resultados: El índice global de resistencia a la aspirina fue variable, entre 2.4% y 63.5% en función de la técnica utilizada. Se demostró una variabilidad interindividual e intraindividual significativa al inicio y con la administración de placebo en las diferentes técnicas. La sensibilidad de los ensayos varió entre 24% (OPA ADP10) y 87.8% (tromboxano sérico), y la especificidad varió entre 81% (PFA-100™) y 97.4% (tromboxano). La selección de "valores de corte" alternativos provocó tasas de prevalencia diferentes de resistencia bioquímica a la aspirina, con un mecanismo de compensación entre la sensibilidad y la especificidad. Conclusiones: La respuesta a la aspirina mostró una marcada variabilidad interensayo, interindividual y temporal. Se requieren varias evaluaciones con diferentes técnicas para diagnosticar en forma confiable la resistencia a la aspirina. La selección de valores discriminativos alternativos debería considerarse al evaluar formalmente esta entidad

Introduction: Despite the 25% reduction in major events with aspirin in high-risk patients reported by the Antiplatelet Trialists' Collaboration, a proportion of patients develop recurrent ischaemic events. This has led to the emergence of 'aspirin resistance' with rates between 0.4% and 83% reported. This study assessed variability in baseline platelet function, prevalence of aspirin resistance, and the performance and reproducibility of platelet function testing methods. Materials and Methods: A repeated-measures randomised crossover study was performed in healthy individuals aged 18-60 years. After informed consent, patients were randomised to aspirin dose (75 mg or 300 mg) and treatment sequence with testing at baseline and after each four 3-week treatment period via Optical Platelet Aggregation (OPA), PFA-100™, VerifyNow™, and serum and urinary thromboxane (TXB2) levels. Local ethical approval was granted. Statistical analysis was performed using SPSS17. Results: The overall rate of aspirin resistance varied from 2.4% to 63.5% depending on the assay used. Significant inter- and intra-individual variability existed at baseline and on placebo testing between assays. Assay sensitivities ranged from 24.0% (OPA ADP10) to 87.8% (serum TXB2), and specificities from 81.0% (PFA-100™) to 97.4% (serum TXB2). Selection of alternative "cut-off" values resulted in differing prevalence rates of biochemical aspirin resistance with a trade-off between sensitivity and specificity. Conclusions: Response to aspirin shows marked inter-assay, inter-individual and temporal variability. Testing on multiple occasions using several assays is necessary to reliably diagnose aspirin resistance. Selection of alternative assay "cut-off" values should be considered when formally assessing aspirin response

ST segment elevation in lead aVR during exercise testing is associated with LAD stenosis.

PURPOSE: To evaluate, in patients with chest pain, the diagnostic value of ST elevation (STE) in lead aVR during stress testing prior to (99m) Tc-sestamibi scanning correlating ischaemic territory with angiographic findings. METHODS: Consecutive patients attending for (99m) Tc-sestamibi myocardial perfusion imaging (MPI) completed a treadmill protocol. Peak exercise ECGs were coded. STE >or=0.05 mV in lead aVR was considered significant. Gated perfusion images and findings at angiography were assessed. RESULTS: STE in lead aVR occurred in 25% (138/557) of the patients. More patients with STE in aVR had a reversible defect on imaging compared with those who had no STE in aVR (41%, 56/138 vs 27%, 114/419, p=0.003). Defects indicating a left anterior descending artery (LAD) culprit lesion were more common in the STE in aVR group (20%, 27/138 vs 9%, 39/419, p=0.001). There was a trend towards coronary artery stenosis (>70%) in a double vessel distribution involving the LAD in those patients who had STE in aVR compared with those who did not (22%, 8/37 vs 5%, 4/77, p=0.06). Logistic regression analysis demonstrated that STE in aVR (OR 1.36, p=0.233) is not an independent predictor of inducible abnormality when adjusted for STD >0.1 mV (OR 1.69, p=0.026). However, using anterior wall defect as an end-point, STE in aVR (OR 2.77, p=0.008) was a predictor even after adjustment for STD (OR 1.43, p=0.281). CONCLUSION: STE in lead aVR during exercise does not diagnose more inducible abnormalities than STD alone. However, unlike STD, which is not predictive of a territory of ischaemia, STE in aVR may indicate an anterior wall defect.