Andrew Krahn

Cardiogenetics encompasses a diverse group of heart conditions unified by their inherited nature. Sex-differences in cardiogenetics are understood to varying degrees; while a mechanism underlying sex-differences in Long-QT Syndrome (LQTS) is well-established, disease prevalence and severity by sex is inconsistent across different Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) cohorts. This thesis explores sex-differences in cardiogenetics by posing three hypotheses: (1) high precordial leads increase the detection of ARVC with sex-specific implications, (2) sex-stratification of a diagnostic treadmill testing algorithm will aid in the diagnosis of LQTS, and (3) the menstrual cycle affects the QT-interval in LQTS. The first study showed clear differences in high leads of ARVC and healthy controls, with no Type 1 or 2 Brugada pattern or sex-differences. The second study suggested that the 3-step algorithm is a valid and simple screening method for detecting LQTS, while a sex-specific approach offers additional insight for LQTS1/2 and should be used in the interpretation of exercise testing. The preliminary result of the third study suggests the menstrual cycle has a clear differential effect in controls, but not in LQTS patients, which will be clarified using a larger sample size. Ultimately, it is evident that sex-differences in cardiogenetic conditions remains a complicated and multifaceted area.

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Anorexia nervosa (AN) is a complex psychiatric disorder with the highest mortality rate of any eating disorder. A subset of these deaths may be sudden and attributed to cardiac rhythm changes which may be present during acute AN. Specifically, the repolarization phase of each heartbeat, as visualized by the QT interval on electrocardiogram (ECG), has been suggested as a potential prognostic tool. In addition, many AN patients are prescribed psychopharmacotherapy to treat concurrent depression and/or anxiety which may accentuate ECG changes.Through four research studies, this thesis explored three hypotheses:1. Comprehensive cardiac testing is an effective and cost-efficient means of evaluation.2. Psychopharmacotherapy will alter the ECG in eating disorders3. Cardiac repolarization in AN will differ from healthy controls at rest and during exercise.In the first study, Hypothesis 1 was tested by means of a cost analysis of patients referred for inherited heart rhythm disorder evaluation. Analyses revealed multidisciplinary cardiac testing was effective and did not incur unreasonably high costs. Secondly, a retrospective case-control ECG review was conducted to evaluate Hypotheses 2 and 3. The QT interval was not clinically different between eating disorder patients and healthy controls, but patients were more likely to show T-wave flattening or inversion on ECG, which have been previously associated with SUD risk. Thirdly, Hypothesis 3 was further analyzed through a systematic review and meta-analysis of the current literature surrounding the resting QT interval in AN. Again, there was no difference in the QT interval, but AN patients had greater QT dispersion (interlead difference on ECG) compared to controls. QT dispersion has also been linked to increased SUD risk.Finally, we are prospectively assessing the ECG during modified exercise in eating disorder patients to further explore Hypothesis 3. Preliminary data suggest QT dynamics as heartrate increases may be abnormal.Overall, it appears that the resting QT interval may not be a direct marker of SUD risk in AN. However, more subtle markers of repolarization abnormality such as T-wave changes and QT dispersion may be superior at rest. During exercise, QT interval dynamics may regain relevance in assessing SUD risk.

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Background: The Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) enrolls patients with apparently unexplained cardiac arrest and no evident cardiac disease, and aims to identify the underlying conditions responsible for the cardiac arrest through systematic clinical testing. A combination of exercise testing, drug provocation, electrophysiological testing, advanced cardiac imaging, and targeted genetic testing may unmask the cause of cardiac arrest when a cause is not apparent.Methods and Results: The first 200 survivors (48.6 ± 14.7 years, 41% female) of unexplained cardiac arrest from CASPER, from 14 centers across Canada were evaluated to determine the results of investigation and follow-up risk of recurrence. Patients were free of evidence of coronary artery disease, left ventricular dysfunction or evident repolarization syndromes. Advanced testing determined a probable or definite diagnosis in 41% of patients. During a median follow-up of 3.15±2.34 years, 23% of patients had either a shock from their ICD or appropriate anti-tachycardia pacing or both. The annual ICD appropriate intervention rate was 0.16 per year (SEM=0.14), with no clear difference in intervention rate between diagnosed and undiagnosed subjects, or between those diagnosed with a primary electrical versus structural etiology.Conclusions: Obtaining a diagnosis in previously unexplained cardiac arrest patients requires systematic clinical testing and regular follow-up to unmask the cause of cardiac arrest. Nearly half of apparent unexplained cardiac arrest patients ultimately received a diagnosis, allowing for improved treatment and family screening. A substantial proportion of patients received appropriate ICD therapy during follow-up.

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