Characterization of a novel KCNQ1 mutation for type 1 long QT syndrome and assessment of the therapeutic potential of a novel IKs activator using patient-specific induced pluripotent stem cell-derived cardiomyocytes.

INTRODUCTION: Type 1 long QT syndrome (LQT1) is a common type of cardiac channelopathy associated with loss-of-function mutations of KCNQ1. Currently there is a lack of drugs that target the defected slowly activating delayed rectifier potassium channel (IKs). With LQT1 patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs), we tested the effects of a selective IKs activator ML277 on reversing the disease phenotypes. METHODS: A LQT1 family with a novel heterozygous exon 7 deletion in the KCNQ1 gene was identified. Dermal fibroblasts from the proband and her healthy father were reprogrammed to hiPSCs and subsequently differentiated into hiPSC-CMs. RESULTS: Compared with the control, LQT1 patient hiPSC-CMs showed reduced levels of wild type KCNQ1 mRNA accompanied by multiple exon skipping mRNAs and a ~50% reduction of the full length Kv7.1 protein. Patient hiPSC-CMs showed reduced IKs current (tail current density at 30 mV: 0.33±0.02 vs. 0.92±0.21, P<0.05) and prolonged action potential duration (APD) (APD 50 and APD90: 603.9±39.2 vs. 319.3±13.8 ms, P<0.005; and 671.0±41.1 vs. 372.9±14.2 ms, P<0.005). ML277, a small molecule recently identified to selectively activate KV7.1, reversed the decreased IKs and partially restored APDs in patient hiPSC-CMs. CONCLUSIONS: From a LQT1 patient carrying a novel heterozygous exon7 deletion mutation of KCNQ1, we generated hiPSC-CMs that faithfully recapitulated the LQT1 phenotypes that are likely associated with haploinsufficiency and trafficking defect of KCNQ1/Kv7.1. The small molecule ML277 restored IKs function in hiPSC-CMs and could have therapeutic value for LQT1 patients.

Assessment of left ventricular preload by cardiac magnetic resonance imaging predicts exercise capacity in adult operated tetralogy of Fallot: a retrospective study.

BACKGROUND: The optimal timing of pulmonary homograft valve replacement (PVR) is uncertain. Cardiopulmonary exercise testing (CPET) and cardiac magnetic resonance (CMR) are often used to guide the clinical decision for PVR in operated tetralogy of Fallot (TOF) patients with significant pulmonary regurgitation (PR). We aim to study the relationship between exercise capacity and CMR in these patients. METHODS: The study is a single-centre retrospective analysis of 36 operated TOF patients [median 21.4 (interquartile range 16.4, 26.4) years post-repair; 30 NYHA I, 6 NYHA II; median age 25.2 (interquartile range 19.5-31.7) years, 29 males] with significant PR on CMR who underwent CPET within 15 [median 2.0 (interquartile range 0.8-7.2)] months from CMR. CPET parameters were compared with 30 age- and sex-matched healthy controls [median age 27.8 (interquartile range 21.0-32.8) years; 24 males]. RESULTS: Peak systolic blood pressure (177 versus 192 mmHg, p = 0.007), Mets (7.3 versus 9.9, p < 0.001), peak oxygen consumption (VO2max) (29.2 versus 34.5 ml/kg/min, p < 0.001) and peak oxygen pulse (11.0 versus 13.7 ml/beat, p = 0.003) were significantly lower in TOF group versus control. Univariate analyses showed negative correlation between PR fraction and anaerobic threshold. There was a positive correlation between indexed left (LV) and right (RV) ventricular end-diastolic volumes, as well as indexed LV and effective RV stroke volumes, on CMR and VO2max and Mets achieved on CPET. These remained significant after adjustment for age and sex. CONCLUSIONS: TOF subjects have near normal exercise capacity but significantly lower Mets, VO2max and peak oygen pulse achieved compared to controls. Increased PR fraction in TOF subjects was associated with lower anaerobic threshold. Higher indexed effective RV stroke volume, a measure of LV preload, was associated with higher VO2max and Mets achieved, and may potentially be used as a predictor of exercise capacity.

The implantable loop recorder-an important addition to the armentarium in the management of unexplained syncope.

INTRODUCTION: Unexplained syncope is a common condition with a significant impact both on the patient and on healthcare expenditure. Often, the diagnosis is hampered due to the temporary sporadic nature of the symptoms. Conventional monitoring methods have a low yield for identifying an abnormality during a spontaneous event. The implantable loop recorder (ILR), often underutilised, is an important diagnostic device that may fi ll this void in the early assessment of patients presenting with syncope. MATERIALS AND METHODS: This article begins with 2 case vignettes which highlight the clinical utility of ILRs in making a definitive diagnosis and guiding subsequent management. This is followed by a review of the existing evidence for ILRs, including the recent international guidelines, underpinning the role of ILRs in the present management algorithm of patients presenting with unexplained syncope. The technical aspects and cost implications will also be reviewed. RESULTS: Present evidence-based international guidelines have recommended the early use of ILRs in the management of patients with unexplained syncope. Furthermore, there may also be an important role for ILR use in patients with presumed epilepsy refractory to treatment and in the neurally mediated syncope cohort with recurrent symptoms. Cost benefit analysis also demonstrates advantages with early ILR use. CONCLUSION: The early use of ILR in selected patients remains an accurate, cost-effective, high yield tool for diagnosis and management of patients with unexplained syncope. However, its use should not detract from the importance of taking a detailed medical history and physical examination in the initial assessment to facilitate identification of the aetiology and risk stratification of patients.