AimsSudden cardiac death (SCD) is challenging to predict. Electrocardiogram (ECG)-derived heart rate-corrected QT-interval (QTc) is used for SCD-risk assessment. QTc is preferably determined... Show moreAimsSudden cardiac death (SCD) is challenging to predict. Electrocardiogram (ECG)-derived heart rate-corrected QT-interval (QTc) is used for SCD-risk assessment. QTc is preferably determined manually, but vendor-provided automatic results from ECG recorders are convenient. Agreement between manual and automatic assessments is unclear for populations with aberrant QTc. We aimed to systematically assess pairwise agreement of automatic and manual QT-intervals and QTc.Methods and resultsA multi-centre cohort enriching aberrant QTc comprised ECGs of healthy controls and long-QT syndrome (LQTS) patients. Manual QT-intervals and QTc were determined by the tangent and threshold methods and compared to automatically generated, vendor-provided values. We assessed agreement globally by intra-class correlation coefficients and pairwise by Bland–Altman analyses and 95% limits of agreement (LoA). Further, manual results were compared to a novel automatic QT-interval algorithm. ECGs of 1263 participants (720 LQTS patients; 543 controls) were available [median age 34 (inter-quartile range 35) years, 55% women]. Comparing cohort means, automatic and manual QT-intervals and QTc were similar. However, pairwise Bland–Altman-based agreement was highly discrepant. For QT-interval, LoAs spanned 95 (tangent) and 92 ms (threshold), respectively. For QTc, the spread was 108 and 105 ms, respectively. LQTS patients exhibited more pronounced differences. For automatic QTc results from 440–540 ms (tangent) and 430–530 ms (threshold), misassessment risk was highest. Novel automatic QT-interval algorithms may narrow this range.ConclusionPairwise vendor-provided automatic and manual QT-interval and QTc results can be highly discrepant. Novel automatic algorithms may improve agreement. Within the above ranges, automatic QT-interval and QTc results require manual confirmation, particularly if T-wave morphology is challenging. Show less
One of the main challenges in the clinical management of patients with monogenic cardiac disease patients is the clinical heterogeneity in disease severity. Clinical manifestation of congenital... Show moreOne of the main challenges in the clinical management of patients with monogenic cardiac disease patients is the clinical heterogeneity in disease severity. Clinical manifestation of congenital long QT syndrome type 2 (LQT2) can range from the absence of symptoms to life-threatening arrhythmia episodes. Insight into the genetic etiology could advance clinical-decision making and guide the development of tailored medicine strategies. The focus of this thesis was twofold, 1) to validate technical procedures to store hiPSC-CMs and 2) to investigate genetic variant pathogenicity and unravel variable disease expressivity in genetically-matched hiPSC-CM models with LQT2-associated variants. First we established cryopreservation as an opportune method to store hiPSC-CMs with molecular and functional characteristics being retained after thaw and recovery. Second, we demonstrate the potential of hiPSC-CMs to reveal the inherent severity of KCNH2 mutations when using genetically-matched lines with KCNH2 mutations either located in different regions of the affected cardiac ion channel, in conjunction with a common single nucleotide, or a compound heterozygous mutation. Show less
