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Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. Although recent advances in cell-based models, including human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM), are contributing to our understanding of electrophysiology and arrhythmia mechanisms, preclinical animal studies of cardiovascular disease remain a mainstay. Over the past several decades, animal models of cardiovascular disease have advanced our understanding of pathological remodeling, arrhythmia mechanisms, and drug effects and have led to major improvements in pacing and defibrillation therapies. There exist a variety of methodological approaches for the assessment of cardiac electrophysiology and a plethora of parameters may be assessed with each approach. This guidelines article will provide an overview of the strengths and limitations of several common techniques used to assess electrophysiology and arrhythmia mechanisms at the whole animal, whole heart, and tissue level with a focus on small animal models. We also define key electrophysiological parameters that should be assessed, along with their physiological underpinnings, and the best methods with which to assess these parameters. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-cardiac-electrophysiology/ .

Cardiac electrophysiological studies demonstrate that restricting the feeding of mice to the light cycle (time restricted feeding or TRF) causes a pronounced change in heart rate and ventricular repolarization as measured by the RR- and QT-interval, respectively. TRF slows heart rate and shifts the peak (acrophase) of the day/night rhythms in the RR- and QT-intervals from the light to the dark cycle. This study tested the hypothesis that these changes in cardiac electrophysiology are driven by the cardiomyocyte circadian clock mechanism. We determined the impact that TRF had on RR- and QT-intervals in control mice or mice that had the cardiomyocyte circadian clock mechanism disrupted by inducing the deletion of Bmal1 in adult cardiomyocytes (iCSΔBmal1(−/−) mice). In control and iCSΔBmal1(−/−) mice, TRF increased the RR-intervals measured during the dark cycle and shifted the acrophase of the day/night rhythm in the RR-interval from the light to the dark cycle. Compared to control mice, TRF caused a larger prolongation of the QT-interval measured from iCSΔBmal1(−/−) mice during the dark cycle. The larger QT-interval prolongation in the iCSΔBmal1(−/−) mice caused an increased mean and amplitude in the day/night rhythm of the QT-interval. There was not a difference in the TRF-induced shift in the day/night rhythm of the QT-interval measured from control or iCSΔBmal1(−/−) mice. We conclude that the cardiomyocyte circadian clock does not drive the changes in heart rate or ventricular repolarization with TRF. However, TRF unmasks an important role for the cardiomyocyte circadian clock to prevent excessive QT-interval prolongation, especially at slow heart rates.

Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common sustained supraventricular arrhythmias. An understanding of gender-related differences in AVNRT epidemiology, diagnosis, treatment, outcome, and complications can help guide a more effective diagnosis and treatment of the condition. The study aimed to perform a review of the available literature regarding all aspects of gender-related differences of AVNRT. We focused on all aspects of gender-related differences regarding AVNRT between men and women. A literature search was performed using Google Scholar, PubMed, Springer, Ovid, and Science Direct. Many investigations have demonstrated that the prevalence of AVNRT exhibited a twofold women-to-men predominance. The potential mechanism behind this difference due to sex hormones and autonomic tone. Despite being more common in women, there is a delay in offering and performing the first-line therapy (catheter ablation) compared to men. There were no significant gender-related discrepancies in patients who underwent ablation therapy for AVNRT, regarding the acute success rate of the procedure, long-term success rate, and recurrence of AVNRT. AVNRT is more common in women due to physiological factors such as sex hormones and autonomic tone. Catheter ablation is equally safe and efficacious in men and women; however, the time between the onset of symptoms and ablation is significantly prolonged in women. It is important for the medical community to be aware of this discrepancy and to strive to eliminate such disparities that are not related to patients' choices.

The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano-Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in

SUMMARYCellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence supports age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profiled the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in 3 age groups. We found age-dependent and tissue-specific clock output changes. Aging reduced the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. Many genes gained rhythmicity in old tissues, reflecting an adaptive response. REGs were enriched for the hallmarks of aging, adding a new dimension to our understanding of aging. Differential gene expression analysis found that there were temporally distinct clusters of genes in tissue-specific manner. Increased daily gene expression variability is a common feature of aged tissues. This novel analysis extends the landscape of the understanding of aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.HIGHLIGHTS- Rhythmically expressed genes (REGs) in Young, but not Old mice, are enriched for the aging hallmarks across all tissues.- The numbers of REGs decline across all tissues with age implicating the circadian clock in altered homeostasis.- Age- and tissue-specific differentially expressed genes (DEGs) cluster at specific times of the day.- Increase in gene expression variability over a day is a common feature of aging tissues.

Sudden cardiac death (SCD) and arrhythmias represent a global public health problem, accounting for 15–20% of all deaths [...]

Daily variations in cardiac electrophysiology and the incidence for different types of arrhythmias reflect ≈24-hour changes in the environment, behavior, and internal circadian rhythms. This article focuses on studies that use animal models to separate the impact that circadian rhythms, as well as changes in the environment and behavior, have on 24-hour rhythms in heart rate and ventricular repolarization. Circadian rhythms are initiated at the cellular level by circadian clocks, transcription-translation feedback loops that cycle with a periodicity of 24-hours. Several studies now show the circadian clock in cardiomyocytes regulates the expression of cardiac ion channels by multiple mechanisms; underlies time-of-day changes in sinoatrial node excitability/intrinsic heart rate; and limits the duration of the ventricular action potential waveform. However, the 24-hour rhythms in heart rate and ventricular repolarization are primarily driven by autonomic signaling. A functional role for the cardiomyocyte circadian clock appears to buffer the heart against perturbations. For example, the cardiomyocyte circadian clock limits QT-interval prolongation (especially at slower heart rates), and it may facilitate the realignment of the 24-hour rhythm in heart rate to abrupt changes in the light cycle. Additional studies show modifying rhythmic behaviors (including feeding behavior) can dramatically impact the 24-hour rhythms in heart rate and ventricular repolarization. If these mechanisms are conserved, these studies suggest targeting endogenous circadian mechanisms in the heart, as well as modifying the timing of certain rhythmic behaviors, could emerge as therapeutic strategies to support heart function against perturbations and regulate 24-hour rhythms in cardiac electrophysiology.

Introduction: Initiation of QTc-prolonging medications may lead to the rare but potentially catastrophic event, torsades de pointes (TDP). At present, no adequate, generalizable tools exist to predict drug-induced long QTc (LQT); machine learning from ECG data is a promising approach. Hypothesis: Prediction of drug-induced LQT using an ECG-based machine learning model is feasible, and outperforms a model trained on baseline QTc, age, and sex alone. Methods: We identified baseline 12-lead ECGs with QTc values < 500 ms for patients who had not received any known, conditional, or possible QTc prolonging medication per CredibleMeds at the time of ECG or within the past 90 days. We matched these with ECGs from the same patients while they were taking at least one CredibleMeds drug (“on-drug” ECGs). Using 5-fold cross-validation, we trained and tested two machine learning models using the baseline ECGs of the 92,848 resulting pairs to predict drug-induced LQT (≥500 ms) in the on-drug ECGs: a deep neural network using ECG voltage data, and a gradient-boosted tree using the baseline QTc. Age and sex were also inputs to both models. Results: On-drug LQT prevalence was 16%. The ECG model demonstrated superior performance in predicting on-drug LQT (area under the receiver operating characteristic curve (AUC) = 0.756) compared to the QTc model (0.710). At a potential operating point (Figure), the ECG model had 89% sensitivity and 95% negative predictive value. Even in the subset of patients with baseline QTc < 470/480 ms (male/female; post-drug LQT prevalence = 14%), the ECG model demonstrated good performance (AUC = 0.736). Conclusions: An ECG-based machine learning model can stratify patients by risk of developing drug-induced LQT better than a model using baseline QTc alone. This model may have clinical value to identify high-risk drug starts that would benefit from closer monitoring and others who are at low risk of drug-induced LQT.

Sudden cardiac death (SCD) is the sudden, unexpected death due to abrupt loss of heart function secondary to cardiovascular disease. In certain populations living with cardiovascular disease, SCD follows a distinct 24-hour pattern in occurrence, suggesting day/night rhythms in behavior, the environment, and endogenous circadian rhythms result in daily spans of increased vulnerability. The National Heart, Lung, and Blood Institute convened a workshop, Understanding Circadian Mechanisms of Sudden Cardiac Death to identify fundamental questions regarding the role of the circadian rhythms in SCD. Part 2 summarizes research gaps and opportunities in the areas of population and clinical research identified in the workshop. Established research supports a complex interaction between circadian rhythms and physiological responses that increase the risk for SCD. Moreover, these physiological responses themselves are influenced by several biological variables, including the type of cardiovascular disease, sex, age, and genetics, as well as environmental factors. The emergence of new noninvasive biotechnological tools that continuously measure key cardiovascular variables, as well as the identification of biomarkers to assess circadian rhythms, hold promise for generating large-scale human data sets that will delineate which subsets of individuals are most vulnerable to SCD. Additionally, these data will improve our understanding of how people who suffer from circadian disruptions develop cardiovascular diseases that increase the risk for SCD. Emerging strategies to identify new biomarkers that can quantify circadian health (eg, environmental, behavioral, and internal misalignment) may lead to new interventions and therapeutic targets to prevent the progression of cardiovascular diseases that cause SCD.

Sudden cardiac death (SCD), the unexpected death due to acquired or genetic cardiovascular disease, follows distinct 24-hour patterns in occurrence. These 24-hour patterns likely reflect daily changes in arrhythmogenic triggers and the myocardial substrate caused by day/night rhythms in behavior, the environment, and endogenous circadian mechanisms. To better address fundamental questions regarding the circadian mechanisms, the National Heart, Lung, and Blood Institute convened a workshop, Understanding Circadian Mechanisms of Sudden Cardiac Death. We present a 2-part report of findings from this workshop. Part 1 summarizes the workshop and serves to identify research gaps and opportunities in the areas of basic and translational research. Among the gaps was the lack of standardization in animal studies for reporting environmental conditions (eg, timing of experiments relative to the light dark cycle or animal housing temperatures) that can impair rigor and reproducibility. Workshop participants also pointed to uncertainty regarding the importance of maintaining normal circadian rhythmic synchrony and the potential pathological impact of desynchrony on SCD risk. One related question raised was whether circadian mechanisms can be targeted to reduce SCD risk. Finally, the experts underscored the need for studies aimed at determining the physiological importance of circadian clocks in the many different cell types important to normal heart function and SCD. Addressing these gaps could lead to new therapeutic approaches/molecular targets that can mitigate the risk of SCD not only at certain times but over the entire 24-hour period.

Loss-of-function (LOF) variants in the K(V)11.1 potassium channel cause long QT syndrome (LQTS). Most variants disrupt intracellular channel transport (trafficking) to the cell membrane. Since some channel inhibitors improve trafficking of K(V)11.1 variants, a high-throughput screening (HTS) assay to detect trafficking enhancement would be valuable to the identification of drug candidates. The thallium (Tl(+)) flux assay technique, widely used for drug screening, was optimized using human embryonic kidney (HEK-293) cells expressing a trafficking-deficient K(V)11.1 variant in 384-well plates. Assay quality was assessed using Z prime (Z’) scores comparing vehicle to E-4031, a drug that increases K(V)11.1 membrane trafficking. The optimized assay was validated by immunoblot, electrophysiology experiments, and a pilot drug screen. The combination of: 1) truncating the trafficking-deficient variant K(V)11.1-G601S (K(V)11.1-G601S-G965*X) with the addition of 2) K(V)11.1 channel activator (VU0405601) and 3) cesium (Cs(+)) to the Tl(+) flux assay buffer resulted in an outstanding Z’ of 0.83. To validate the optimized trafficking assay, we carried out a pilot screen that identified three drugs (ibutilide, azaperone, and azelastine) that increase K(V)11.1 trafficking. The new assay exhibited 100% sensitivity and specificity. Immunoblot and voltage-clamp experiments confirmed that all three drugs identified by the new assay improved membrane trafficking of two additional LQTS K(V)11.1 variants. We report two new ways to increase target-specific activity in trafficking assays—genetic modification and channel activation—that yielded a novel HTS assay for identifying drugs that improve membrane expression of pathogenic K(V)11.1 variants. SIGNIFICANCE STATEMENT: This manuscript reports the development of a high-throughput assay (thallium flux) to identify drugs that can increase function in K(V)11.1 variants that are trafficking-deficient. Two key aspects that improved the resolving power of the assay and could be transferable to other ion channel trafficking–related assays include genetic modification and channel activation.

Mortality associated with prescription opioids has significantly increased over the past few decades and is considered a global pandemic. Prescribed opioids can cause cardiac arrhythmias, leading to fatal outcomes and unexpected death, even in the absence of structural cardiac disease. Despite the extent of cardiac toxicity and death associated with these medications, there is limited data to suggest their influences on cardiac electrophysiology and arrhythmias, with the exception of methadone. The goal of our review is to describe the possible mechanisms and to review the different ECG changes and arrhythmias that have been reported. A literature search was performed using Google Scholar, PubMed, Springer, Ovid, and Science Direct to identify studies that demonstrated the use of prescription opioids leading to electrocardiogram (ECG) changes and cardiac arrhythmias. Many of the commonly prescribed opioid medications can uniquely effect the ECG, and can lead to the development of various cardiac arrhythmias. One of the most significant side effects of these drugs is QTc interval prolongation, especially when administered to patients with a baseline risk for QTc prolongation. A prolonged QTc interval can cause lethal torsades de pointes and ventricular fibrillation. Obtaining an ECG at baseline, following a dosage increase, or after switching an opioid medication, is appropriate in patients taking certain prescribed opioids. Opioids are often used first line for the treatment of acute and chronic pain, procedural sedation, medication opioid use disorders, and maintenance therapy. To reduce the risk of cardiac arrhythmias and to improve patient outcomes, consideration of accurate patient selection, concomitant medications, electrolyte monitoring, and vigilant ECG monitoring should be considered.

This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed.

Ventriculoatrial (VA) conduction is a critical component in many arrhythmias, has a diagnostic value in electrophysiology study (EPS), and is implicated in pacemaker-mediated arrhythmias. This study sought to characterize retrograde conduction during EPS and to utilize it as a diagnostic tool in patients without AV block. Patients with intact AV conduction undergoing EPS were included in this study to systematically evaluate baseline VA conduction. If absent, parahisian pacing was used to determine the level of block (nodal or infranodal). Recovery of VA conduction with increased sympathetic activity was assessed with isoproterenol infusion. Baseline characteristics and electrophysiological data were collected and analyzed. Among the 801 patients studied, VA conduction was present in 98% (81% at baseline and 17% after isoproterenol infusion). Parahisian pacing demonstrated that the block was at the AV node level among 150 patients with VA dissociation at baseline. Among patients presenting with supraventricular tachycardia (SVT), 98.7% with atrioventricular nodal reentrant tachycardia (AVNRT) had VA conduction at baseline versus 82.7% presenting with other SVT (atrial fibrillation excluded), P < 0.001. Thus, the absence of VA conduction at baseline during an EPS for SVT carries a negative predictive value (NPV) of 96.9% for AVNRT. VA conduction is present in most patients (98%) with intact AV conduction. The level of VA dissociation when present at baseline is always at the level of the AV node. Patients with SVT presenting for EPS that lacked VA conduction at baseline were unlikely to have AVNRT.

BACKGROUND Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common type of supraventricular tachycardia (SVT). Similar to other cardiac tests and interventions, gender bias may influence clinical decision making in providing appropriate care for AVNRT patients. We assessed for gender differences in the diagnosis and management of AVNRT patients who underwent catheter ablation. METHODS Patients who underwent catheter ablation for AVNRT were included. We explored the gender difference on various clinical parameters such as the time from SVT symptoms, SVT diagnosis, and first electrophysiology consult to time of catheter ablation. RESULTS Among 140 patients screened, 116 patients met the inclusion criteria, including 67.2% women. Median time from symptoms onset to SVT diagnosis was 18.5 months (interquartile range [IQR] 4.0-58.5) in women versus 4.0 months (0.75-34.7) in men, P = .005. Once SVT was diagnosed, women took a median of 12.5 months (IQR 3.0-57.0) to proceed with ablation versus 3.0 months (1.0-7.0) for men, P ≤ .001. It took a longer time from the first electrophysiology consultation to ablation: 54.5 days (20.75-144.75) for women versus 20.5 days (6.0-46.25) for men, P = .008. Overall, it took 60.0 months (IQR 12.8-132.0) for women to have an ablation from initial symptoms onset versus 15 months (IQR 4.6-48.0) for men, P = .001. Prior to ablation, women had 3.78 ± 3.79 (mean ± SD) emergency department visits for SVT versus men 1.52 ± 1.72 and women tried 1.28 ± 0.82 medications versus men 0.76 ± 0.68, P

Background: Cardiac gene expression and arrhythmia occurrence have time-of-day variation; however, daily changes in cardiac electrophysiology, arrhythmia susceptibility, and Ca 2+ handling have not been characterized. Furthermore, how these patterns change with age is unknown. Methods: Hearts were isolated during the light (zeitgeber time [ZT] 4 and ZT9) and dark cycle (ZT14 and ZT21) from adult (12–18 weeks) male mice. Hearts from aged (18–20 months) male mice were isolated at ZT4 and ZT14. All hearts were Langendorff-perfused for optical mapping with voltage- and Ca 2+ -sensitive dyes (n=4–7/group). Cardiac gene and protein expression were assessed with real-time polymerase chain reaction (n=4–6/group) and Western blot (n=3–4/group). Results: Adult hearts had the shortest action potential duration (APD) and Ca 2+ transient duration (CaTD) at ZT14 (APD 80 : ZT4: 45.4±4.1 ms; ZT9: 45.1±8.6 ms; ZT14: 34.7±4.2 ms; ZT21: 49.2±7.6 ms, P 80 : ZT4: 70.1±3.3 ms; ZT9: 72.7±2.7 ms; ZT14: 64.3±3.3 ms; ZT21: 74.4±1.2 ms, P P 80 : ZT4: 39.7±1.9 ms versus ZT14: 33.8±3.1 ms, P KCNA5 (potassium voltage-gated channel subfamily A member 5; encoding Kv1.5) was increased, whereas gene expression of ADRB1 (encoding β1-adrenergic receptors) was decreased at ZT14 versus ZT4 in adult hearts. No time-of-day changes in expression or phosphorylation of Ca 2+ handling proteins (SERCA2 [sarco/endoplasmic reticulum Ca 2+ -ATPase], RyR2 [ryanodine receptor 2], and PLB [phospholamban]) was found in ex vivo perfused adult isolated hearts. Conclusions: Isolated adult hearts have strong time-of-day variation in cardiac electrophysiology, Ca 2+ handling, and adrenergic responsiveness, which is disrupted with age.

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the KCNH2 gene (also known as the human ether-à-go-go-related gene or hERG). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies suggest that about 90% of these mutations disrupt the intracellular transport, or trafficking, of the KCNH2-encoded Kv11.1 channel protein to the cell surface membrane. In this review, we discuss emerging strategies that improve the trafficking and functional expression of trafficking-deficient LQT2 Kv11.1 channel proteins to the cell surface membrane and how new insights into the structure of the Kv11.1 channel protein will lead to computational approaches that identify which KCNH2 missense variants confer a high-risk for LQT2.

Kv11.1 (hERG) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 channel densities. Although class III antiarrhythmics, e.g. dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use due to their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a Kv11.1 allosteric modulator/activator, to rescue Kv11.1 trafficking and produce functional Kv11.1 current. LUF7244 treatment by itself did not disturb or rescue WT or G601S Kv11.1 trafficking as shown by western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT Kv11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S Kv11.1 cells, dofetilide (10 μM) or dofetilide+LUF7244 (10+5 μM) restored Kv11.1 trafficking also, as demonstrated by western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased IKv11.1 despite the presence of dofetilide (1 μM) in WT Kv11.1 cells. In G601S expressing cells, long-term treatment (24-48 h) with LUF7244 (10 μM) and dofetilide (1 μM) increased IKv11.1 compared to non-treated, or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues Kv11.1 trafficking and produces functional IKv11.1. Thus, combined administration of LUF7244 and an IKV11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced Kv11.1 trafficking defects.

Background Ablation is an effective treatment for atrioventricular nodal reentrant tachycardia (AVNRT). The occurrence of junctional ectopic rhythm (JER), including junctional ectopic tachycardia, following AVNRT ablation has been described as an extremely rare phenomenon, but may be underestimated. We aimed to determine the incidence of JER following AVNRT ablation within our institution, as well as that reported in the literature via an extensive review. Methods We reviewed our adult ablation institutional experience for the occurrence of JER after AVNRT ablation from 2009 to 2016. Additionally, we conducted an extensive literature search using different databases looking for AVNRT ablation case series. The individually reported complications of these studies were reviewed, with a primary endpoint defined as the occurrence of JER shortly after AVNRT ablation. The study was approved by our institutional review board. Results Our institutional data revealed 6/126 patients (prevalence 4.8%) developed non-preexisting JER post-AVNRT ablation. Four patients were asymptomatic. Two patients had persistent symptoms lasting over a year, with one patient requiring repeat ablation. The literature review included 149 adult and pediatric studies. There were three cases of reported JER, out of a total of 37,541 patients (31,768 adults and 5,773 pediatric; prevalence 0.008%). The three JER patients were pediatric, and all required further therapeutic intervention. Conclusion JER might be an underreported complication of AVNRT ablation. It seems most often to be transient and self-limited, occurring days to weeks after ablation, but may also be debilitating, requiring more aggressive management.

Voltage-gated potassium 11.1 (K

The electrocardiogram (ECG) is a widely used medical test, consisting of voltage versus time traces collected from surface recordings over the heart1. Here we hypothesized that a deep neural network (DNN) can predict an important future clinical event, 1-year all-cause mortality, from ECG voltage–time traces. By using ECGs collected over a 34-year period in a large regional health system, we trained a DNN with 1,169,662 12-lead resting ECGs obtained from 253,397 patients, in which 99,371 events occurred. The model achieved an area under the curve (AUC) of 0.88 on a held-out test set of 168,914 patients, in which 14,207 events occurred. Even within the large subset of patients (n = 45,285) with ECGs interpreted as ‘normal’ by a physician, the performance of the model in predicting 1-year mortality remained high (AUC = 0.85). A blinded survey of cardiologists demonstrated that many of the discriminating features of these normal ECGs were not apparent to expert reviewers. Finally, a Cox proportional-hazard model revealed a hazard ratio of 9.5 (P

This paper is the outcome of the fourth UC Davis Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias Symposium, a biannual event that aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2016 symposium was 'K+ Channels and Regulation'. Experts in the field contributed their experimental and mathematical modelling perspectives and discussed emerging questions, controversies and challenges on the topic of cardiac K+ channels. This paper summarizes the topics of formal presentations and informal discussions from the symposium on the structural basis of voltage-gated K+ channel function, as well as the mechanisms involved in regulation of K+ channel gating, expression and membrane localization. Given the critical role for K+ channels in determining the rate of cardiac repolarization, it is hardly surprising that essentially every aspect of K+ channel function is exquisitely regulated in cardiac myocytes. This regulation is complex and highly interrelated to other aspects of myocardial function. K+ channel regulatory mechanisms alter, and are altered by, physiological challenges, pathophysiological conditions, and pharmacological agents. An accompanying paper focuses on the integrative role of K+ channels in cardiac electrophysiology, i.e. how K+ currents shape the cardiac action potential, and how their dysfunction can lead to arrhythmias, and discusses K+ channel-based therapeutics. A fundamental understanding of K+ channel regulatory mechanisms and disease processes is fundamental to reveal new targets for human therapy.

We illustrate the work necessary to reverse course after identification of a KCNQ1 variant interpreted erroneously as causing long QT syndrome (LQTS) and to identify the true cause of a case of sudden death in the young. Surrogate genetic testing of a decedent's living brother identified a rare KCNQ1-V133I variant, which prompted an implantable cardioverter defibrillator and subsequent diagnosis of LQTS in other family members. Subsequently, this presumed LQT1 family came to our institution for further clinical evaluation and research-based investigations, including KCNQ1-V133I variant-specific analysis of the decedent, heterologous expression studies of KCNQ1-V133I, and a whole-exome molecular autopsy along with genomic triangulation using his unaffected parents' DNA. After evaluating several V133I-positive family members, clinical doubt was cast on the veracity of the previously levied diagnosis of LQT1, resulting in a re-opening of the case and an intense pursuit of the lethal substrate. Furthermore, the decedent tested negative for V133I, and heterologous expression studies demonstrated a normal cellular phenotype for V133I-containing Kv7.1 channels. Instead, after whole-exome molecular autopsy, a de novo pathogenic variant (p.R454W) in DES-encoded desmin was identified. As detailed herein, the forensic evaluation of sudden death in the young requires meticulous focus on the decedent followed by a careful and deliberate assessment of the decedent's relatives. Surrogate genetic testing can have disastrous consequences and should be avoided. Genetic test results require careful scrutiny to avoid unintended and potentially devastating repercussions. Although the root cause of the decedent's tragic death would have remained a mystery, the unintended consequences for the living relatives described herein might have been avoided based on clinical grounds alone. All family members had electrocardiograms with normal QT intervals, making the diagnosis of familial LQTS unlikely. As such, if the clinicians caring for these patients had focused solely on clinical data from the survivors, there might have been no reason to embark on a path of inappropriate treatment based on genetic testing.

Background The safety of digoxin has been a subject of debate for decades, most recently among patients with atrial fibrillation (AF). Digoxin has been used during the acute phase of ST elevation myocardial infarction (STEMI) complicated with AF or heart failure. Data about digoxin in this setting are scarce. Hypothesis We hypothesize that digoxin maybe associated with increased mortality when used during the acute phase of ST segment myocardial infarction. Methods We investigated the association between digoxin and mortality in patients enrolled in the MAGnesium In Coronaries (MAGIC) study, which evaluated the efficacy of early magnesium administration in STEMI. Multiple Cox proportional hazards models were examined to assess the aforementioned association after correction for clinical characteristics and comorbidities. Results After excluding 639 (10.3%) patients for missing data, we analyzed the remaining 5574 patients. There were 852 (15.3%) deaths during the one month follow-up and 170 (3.0%) patients on digoxin concomitantly, among which 42 patients (24.7%) died. There was a statistically significant association between digoxin and increased mortality in the unadjusted statistical analysis; however, this association disappeared after correction for clinical characteristics and comorbidities in the primary multivariable analysis (estimated hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.62–1.19, p=0.372) and in three additional multivariable analyses. Conclusion Digoxin use as a new or preexisting medication during the acute phase of STEMI in the MAGIC trial was not associated with a significant increase in mortality after correcting for clinical characteristics and comorbidities.

In this article, we provide a brief summary of work by us and others to discover the molecular underpinnings of early conduction system development and function. We focus on how the multifunctional protein Tbx3 contributes to acquisition and homeostasis of the tissue-specific properties of the sinoatrial and atrioventricular nodes. We also provide unpublished, preliminary findings supporting the role of Tbx3-regulated alternative RNA processing in the developing conduction system.

Frequent premature ventricular contractions (PVCs) can cause disabling symptoms and decrease left ventricular ejection fraction. PVC burden, typically quantified by a 24-hour monitor, is one of the factors that determines the clinical management of PVCs.The purpose of this study was to evaluate the extent of variability in 24-hour PVC burden during 14-day ambulatory cardiac monitoring in patients with significant PVC burden.All patients referred for PVC evaluation received a 14-day ambulatory cardiac monitor. Parameters of interest included mean 14-day PVC burden, minimum and maximum 24-hour PVC burden, and absolute change in 24-hour PVC burden (maximum minus minimum). We included only patients with a mean 14-day PVC burden of more than 5%.Fifty-nine patients were included in the study. The median of mean 14-day PVC burden, maximum 24-hour PVC burden, and minimum 24-hour PVC burden were 9.0% (IQR 6.4%-17.9%), 16.2% (IQR 11.7%-26.2%), and 4.5% (IQR 2.6%-11.2%) respectively (P.001). The median of the absolute 24-hour PVC burden change was 9.9% (IQR 5.4%-14.5%). There was a 2.45-fold (IQR 1.68- to 5.55-fold) median difference between maximum 24-hour PVC burden and minimum 24-hour burden in the same patient. When categorized by low (10%), intermediate (10%-20%), and high (20%) 24-hour PVC burden, 72.9% patients fell into at least 2 categories depending on the 24-hour period considered.There is a significant variation in 24-hour PVC burden when measured over a 14-day period in patients with of PVC burden of more than 5%. This variation might impact critical clinical decisions in a significant proportion of such patients.

Introduction: The autosomal dominant long QT syndrome type 3 (LQT3) is caused by gain-of-function mutations in the pore-forming cardiac sodium channel α-subunit Na V 1.5 ( Scn5a ). A major challenge for treating LQT3 patients is predicting when or if a potentially life-threatening cardiac event (syncope or cardiac arrest) will strike. For example, longitudinal data from five LQT3 families with the Δ1505-1507KPQ mutation show only 33% of patients are symptomatic, and most symptomatic patients suffered only a single event (n = 46 patients; average age = 41 ± 23 years; average QTc interval = 510 ± 50 ms). The data suggest external stressors play a key role for triggering cardiac events in LQT3. Hypothesis: Disruptions in circadian rhythms can act as an external stressor to trigger LQT3-releated cardiac events. Methods: We disrupted the circadian rhythms in older wild type (WT) or Scn5a +/ΔKPQ mice using an established model of chronic jet lag (chronic light phase advance or CPA). The light cycle was advanced 6 hours every 4 days for 65 days. Mice were monitored using in vivo telemetry before and during CPA. Heart size and cardiac fibrosis were measured using immunohistochemistry. Results and Conclusions: Actograms for both WT and Scn5a +/ΔKPQ mice showed that CPA disrupted diurnal activity patterns. Before starting CPA, the Scn5a +/ΔKPQ mice had longer heart rate corrected QT (QTc) intervals compared to WT mice (Pre-WT = 45 ± 2 ms vs. Pre- Scn5a +/ΔKPQ = 54 ± 7 ms, n = 5, pScn5a +/ΔKPQ mice became even longer (CPA-WT = 47 ± 2 ms vs. CPA- Scn5a +/ΔKPQ = 63 ± 6 ms, pScn5a +/ΔKPQ ). Shockingly, all 5 of the Scn5a +/ΔKPQ mice undergoing CPA died within 65 days. Most deaths occurred after repeating patterns of premature contractions or prolonged episodes of bradycardia. In contrast, none of the age-matched control Scn5a +/ΔKPQ mice died (n = 5). Compared to the hearts of control Scn5a +/ΔKPQ mice, the hearts from CPA Scn5a +/ΔKPQ mice did not show changes in size or thickness but had more fibrosis (control = 9 ± 2%, CPA = 15 ± 2%; pScn5a +/ΔKPQ mice exacerbates QTc prolongation, increases arrhythmias, and causes premature mortality.

Background: Heterologous functional validation studies of putative long-QT syndrome subtype 2–associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous KCNH2 variants seemingly associated with sudden infant death syndrome. Methods: Genetic testing of 292 sudden infant death syndrome cases identified 9 KCNH2 variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R. Previous studies show R181Q-, P967L-, and R1047L-Kv11.1 channels function similar to wild-type Kv11.1 channels, whereas Q1068R-Kv11.1 channels accelerate inactivation gating. We studied the biochemical and biophysical properties for E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels expressed in human embryonic kidney 293 cells; examined the electronic health records of patients who were genotype positive for the sudden infant death syndrome–linked KCNH2 variants; and simulated their functional impact using computational models of the human ventricular action potential. RESULTS: Western blot and voltage-clamping analyses of cells expressing E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels demonstrated these variants express and generate peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels, but R791W- and R1005W-Kv11.1 channels accelerated deactivation and activation gating, respectively. Electronic health records of patients with the sudden infant death syndrome–linked KCNH2 variants showed that the patients had median heart rate–corrected QT intervals Conclusions: We conclude that these rare Kv11.1 missense variants are not long-QT syndrome subtype 2–causative variants and therefore do not represent the pathogenic substrate for sudden infant death syndrome in the variant-positive infants.