Circadian Regulation of Cardiac Arrhythmias and Electrophysiology.

Circadian rhythms in physiology and behavior are ≈24-hour biological cycles regulated by internal biological clocks (ie, circadian clocks) that optimize organismal homeostasis in response to predictable environmental changes. These clocks are present in virtually all cells in the body, including cardiomyocytes. Many decades ago, clinicians and researchers became interested in studying daily patterns of triggers for sudden cardiac death, the incidence of sudden cardiac death, and cardiac arrhythmias. This review highlights historical and contemporary studies examining the role of day/night rhythms in the timing of cardiovascular events, delves into changes in the timing of these events over the last few decades, and discusses cardiovascular disease-specific differences in the timing of cardiovascular events. The current understanding of the environmental, behavioral, and circadian mechanisms that regulate cardiac electrophysiology is examined with a focus on the circadian regulation of cardiac ion channels and ion channel regulatory genes. Understanding the contribution of environmental, behavioral, and circadian rhythms on arrhythmia susceptibility and the incidence of sudden cardiac death will be essential in developing future chronotherapies.

Feeding behavior modifies the circadian variation in RR and QT intervals by distinct mechanisms in mice.

Rhythmic feeding behavior is critical for regulating phase and amplitude in the ≈24-h variation of heart rate (RR intervals), ventricular repolarization (QT intervals), and core body temperature in mice. We hypothesized changes in cardiac electrophysiology associated with feeding behavior were secondary to changes in core body temperature. Telemetry was used to record electrocardiograms and core body temperature in mice during ad libitum-fed conditions and after inverting normal feeding behavior by restricting food access to the light cycle. Light cycle-restricted feeding modified the phase and amplitude of 24-h rhythms in RR and QT intervals, and core body temperature to realign with the new feeding time. Changes in core body temperature alone could not account for changes in phase and amplitude in the ≈24-h variation of the RR intervals. Heart rate variability analysis and inhibiting ß-adrenergic and muscarinic receptors suggested that changes in the phase and amplitude of 24-h rhythms in RR intervals were secondary to changes in autonomic signaling. In contrast, changes in QT intervals closely mirrored changes in core body temperature. Studies at thermoneutrality confirmed that the daily variation in QT interval, but not RR interval, primarily reflected daily changes in core body temperature (even in ad libitum-fed conditions). Correcting the QT interval for differences in core body temperature helped unmask QT interval prolongation after starting light cycle-restricted feeding and in a mouse model of long QT syndrome. We conclude feeding behavior alters autonomic signaling and core body temperature to regulate phase and amplitude in RR and QT intervals, respectively.NEW & NOTEWORTHY We used time-restricted feeding and thermoneutrality to demonstrate that different mechanisms regulate the 24-h rhythms in heart rate and ventricular repolarization. The daily rhythm in heart rate reflects changes in autonomic input, whereas daily rhythms in ventricular repolarization reflect changes in core body temperature. This novel finding has major implications for understanding 24-h rhythms in mouse cardiac electrophysiology, arrhythmia susceptibility in transgenic mouse models, and interpretability of cardiac electrophysiological data acquired in thermoneutrality.

Prediction of Kv11.1 potassium channel PAS-domain variants trafficking via machine learning.

Congenital long QT syndrome (LQTS) is characterized by a prolonged QT-interval on an electrocardiogram (ECG). An abnormal prolongation in the QT-interval increases the risk for fatal arrhythmias. Genetic variants in several different cardiac ion channel genes, including KCNH2, are known to cause LQTS. Here, we evaluated whether structure-based molecular dynamics (MD) simulations and machine learning (ML) could improve the identification of missense variants in LQTS-linked genes. To do this, we investigated KCNH2 missense variants in the Kv11.1 channel protein shown to have wild type (WT) like or class II (trafficking-deficient) phenotypes in vitro. We focused on KCNH2 missense variants that disrupt normal Kv11.1 channel protein trafficking, as it is the most common phenotype for LQTS-associated variants. Specifically, we used computational techniques to correlate structural and dynamic changes in the Kv11.1 channel protein PAS domain (PASD) with Kv11.1 channel protein trafficking phenotypes. These simulations unveiled several molecular features, including the numbers of hydrating waters and hydrogen bonding pairs, as well as folding free energy scores, that are predictive of trafficking. We then used statistical and machine learning (ML) (Decision tree (DT), Random forest (RF), and Support vector machine (SVM)) techniques to classify variants using these simulation-derived features. Together with bioinformatics data, such as sequence conservation and folding energies, we were able to predict with reasonable accuracy (≈75%) which KCNH2 variants do not traffic normally. We conclude that structure-based simulations of KCNH2 variants localized to the Kv11.1 channel PASD led to an improvement in classification accuracy. Therefore, this approach should be considered to complement the classification of variant of unknown significance (VUS) in the Kv11.1 channel PASD.

A stepwise external cardioversion protocol for atrial fibrillation to maximize acute success rate.

AIMS: Cardioversion is a very commonly performed procedure for persistent atrial fibrillation (AF). However, there is no well-defined protocol to address failed external electrical direct current cardioversion. The aim of the study is to test the efficacy of a pre-defined stepwise cardioversion protocol for patients with persistent AF of ≤12 months. Success was the achievement of sinus rhythm. METHODS AND RESULTS: The study population included patients with persistent AF of ≤12 months duration requiring rhythm management. Patients were offered cardioversion using a pre-defined stepwise protocol using different electrode placement locations, applying compression at end of expiration, and higher energy delivered simultaneously through two defibrillators. : A total of 414 patients were included in the study, of which 362 (87.4%) required a single successful cardioversion. The remaining 52 (12.5%) patients required additional cardioversion attempts using the stepwise cardioversion protocol with an overall success rate of 99.3%. Two simultaneous defibrillators were required in 14 patients (3.4%). Patients with multiple cardioversions (13.5%) experienced more local skin irritation and pain compared with patients with single cardioversion (13.5% vs. 3.5%, P = 0.004). The predictor for the need for multiple cardioversion attempts is high body mass index, while high transthoracic impedance is associated with failed cardioversion. No major complications were observed during the study. CONCLUSION: The stepwise cardioversion protocol has a high success rate of >99% and can be safely performed in outpatient or inpatient settings.

New Insights into Cardiac Ion Channel Regulation 2.0.

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

A High-Throughput Screening Assay to Identify Drugs that Can Treat Long QT Syndrome Caused by Trafficking-Deficient KV11.1 (hERG) Variants.

Loss-of-function (LOF) variants in the KV11.1 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 KV11.1 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 KV11.1 variant in 384-well plates. Assay quality was assessed using Z prime (Z') scores comparing vehicle to E-4031, a drug that increases KV11.1 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 KV11.1-G601S (KV11.1-G601S-G965*X) with the addition of 2) KV11.1 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 KV11.1 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 KV11.1 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 KV11.1 variants. SIGNIFICANCE STATEMENT: This manuscript reports the development of a high-throughput assay (thallium flux) to identify drugs that can increase function in KV11.1 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.

The role of the cardiomyocyte circadian clocks in ion channel regulation and cardiac electrophysiology.

Daily variations in cardiac electrophysiology and the incidence for different types of arrhythmias reflect ≈24 h changes in the environment, behaviour 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 behaviour, have on 24 h 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 h. Several studies now show that 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 h rhythms in heart rate and ventricular repolarization are primarily driven by autonomic signalling. 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 h rhythm in heart rate to abrupt changes in the light cycle. Additional studies show that modifying rhythmic behaviours (including feeding behaviour) can dramatically impact the 24 h rhythms in heart rate and ventricular repolarization. If these mechanisms are conserved, these studies suggest that targeting endogenous circadian mechanisms in the heart, as well as modifying the timing of certain rhythmic behaviours, could emerge as therapeutic strategies to support heart function against perturbations and regulate 24 h rhythms in cardiac electrophysiology.

Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals.

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.

Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes.

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 KCNQ1 (LQT1) and KCNH2 (LQT2). We move beyond the "benign" to a "pathogenic" binary classification scheme for different KCNQ1 and KCNH2 missense variants and discuss gene- and mutation-specific differences in K+ channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of KCNQ1 and KCNH2 variants, with the goal of realizing a layered precision medicine approach focused on individuals.

Gender associated disparities in atrioventricular nodal reentrant tachycardia: A review article.

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.

LUF7244 plus Dofetilide Rescues Aberrant Kv11.1 Trafficking and Produces Functional IKv11.1.

Voltage-gated potassium 11.1 (Kv11.1) 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 because of 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 wild type (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) also restored Kv11.1 trafficking, as demonstrated by Western blot and immunofluorescence microscopy. LUF7244 (10 µM) increased IKv 11.1 despite the presence of dofetilide (1 µM) in WT Kv11.1 cells. In G601S-expressing cells, long-term treatment (24-48 hour) with LUF7244 (10 µM) and dofetilide (1 µM) increased IKv11.1 compared with nontreated 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. SIGNIFICANCE STATEMENT: Decreased levels of functional Kv11.1 potassium channel at the plasma membrane of cardiomyocytes prolongs action potential repolarization, which associates with cardiac arrhythmia. Defective forward trafficking of Kv11.1 channel protein is an important factor in acquired and congenital long QT syndrome. LUF7244 as a negative allosteric modulator/activator in combination with dofetilide corrected both congenital and acquired Kv11.1 trafficking defects, resulting in functional Kv11.1 current.

A rapid solubility assay of protein domain misfolding for pathogenicity assessment of rare DNA sequence variants.

PURPOSE: DNA sequencing technology has unmasked a vast number of uncharacterized single-nucleotide variants in disease-associated genes, and efficient methods are needed to determine pathogenicity and enable clinical care. METHODS: We report an E. coli-based solubility assay for assessing the effects of variants on protein domain stability for three disease-associated proteins. RESULTS: First, we examined variants in the Kv11.1 channel PAS domain (PASD) associated with inherited long QT syndrome type 2 and found that protein solubility correlated well with reported in vitro protein stabilities. A comprehensive solubility analysis of 56 Kv11.1 PASD variants revealed that disruption of membrane trafficking, the dominant loss-of-function disease mechanism, is largely determined by domain stability. We further validated this assay by using it to identify second-site suppressor PASD variants that improve domain stability and Kv11.1 protein trafficking. Finally, we applied this assay to several cancer-linked P53 tumor suppressor DNA-binding domain and myopathy-linked Lamin A/C Ig-like domain variants, which also correlated well with reported protein stabilities and functional analyses. CONCLUSION: This simple solubility assay can aid in determining the likelihood of pathogenicity for sequence variants due to protein misfolding in structured domains of disease-associated genes as well as provide insights into the structural basis of disease.

Gender differences in management of patients undergoing catheter ablation of atrioventricular nodal reentry tachycardia.

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 < .001 and .001, respectively. CONCLUSIONS: This study demonstrates significant and multifactorial gender-related disparities in AVNRT diagnosis and treatment. Larger studies are needed to confirm these results.

Tbx3-Mediated Regulation of Cardiac Conduction System Development and Function: Potential Contributions of Alternative RNA Processing.

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.

Junctional ectopic rhythm after AVNRT ablation: An underrecognized complication.

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.

Potassium channels in the heart: structure, function and regulation.

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.

Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing.

PurposeArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained.MethodsIndividuals (n = 30,716) underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFß3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes.ResultsEighteen subjects had pLOF variants; none of these had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram, one had a minor diagnostic criterion; the rest were normal. A total of 184 subjects had VUS, none of whom had an ARVC diagnosis. The proportion of subjects with VUS with major (4%) or minor (13%) electrocardiogram diagnostic criteria did not differ from that of variant-negative controls. ICD-9 codes showed no difference in defibrillator use, electrophysiologic abnormalities or nonischemic cardiomyopathies in patients with pLOF or VUSs compared with controls.ConclusionpLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain.

A Practical ECG Criterion to Unmask Left Accessory AV Connections in Patients With Subtle Preexcitation.

BACKGROUND: Accessory AV-connections capable of antegrade conduction need to be recognized because of the potential for life-threatening arrhythmias. However, the preexcited ECG pattern may be subtle, especially among left-sided AV-connections. We explored whether additional ECG criteria might help identify left-sided AV-connections. METHODS: We analyzed 156 patients who underwent an electrophysiology study (EPS) and ablation for paroxysmal supraventricular tachycardias (PSVT). Patients were divided into 2 groups: those with left-sided AV-connections (Group 1) and all other PSVT (Group 2). Various ECG parameters were compared before and after ablation in both groups. RESULTS: The EPS identified left-sided AV-connections among 43 patients (Group 1) and excluded it among 113 (Group 2). Baseline ECG in Group 1 demonstrated obvious preexcitation among 24/43 patients (55.8%), the remaining 19/43 missing obvious preexcitation. R/S ratio > 0.5 in V1 was noted in 38/43 (88.4%) patients in Group 1 before ablation (median 1.00; IQR 0.58-2.20), including 16/19 (84.2%) patients lacking obvious left-sided AVconnections. Conversely, only 10/113 (8.8%) patients in Group 2 had R/S ratios in V1 ≥ 0.5 (0.20; 0.10-0.31), P < 0.0001. After ablation, the R/S ratio decreased significantly in Group 1 (0.29; 0.17-0.45), P < 0.0001. Thus, a combined criterion of classic preexcitation or R/S ratio ≥ 0.5 on ECG identified 40/43 left-sided AV-connections (sensitivity 93.0%). The negative predictive value of this combined criterion was 103/106 (97.2%). CONCLUSIONS: In symptomatic patients, combining the R/S ratio (≥ 0.5) in lead V1 with the classic preexcitation pattern on ECG markedly improved the sensitivity to diagnose left-sided AV-connections. This ratio may be particularly useful among patients lacking obvious preexcitation.

Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice.

Long QT syndrome type 3 (LQT3) is caused by mutations in the SCN5A-encoded Nav1.5 channel. LQT3 patients exhibit time of day-associated abnormal increases in their heart rate-corrected QT (QTc) intervals and risk for life-threatening episodes. This study determines the effects of uncoupling environmental time cues that entrain circadian rhythms (time of light and time of feeding) on heart rate and ventricular repolarization in wild-type (WT) or transgenic LQT3 mice (Scn5a(+/ΔKPQ)). We used an established light phase-restricted feeding paradigm that disrupts the alignment among the circadian rhythms in the central pacemaker of the suprachiasmatic nucleus and peripheral tissues including heart. Circadian analysis of the RR and QT intervals showed the Scn5a(+/ΔKPQ) mice had QT rhythms with larger amplitudes and 24-h midline means and a more pronounced slowing of the heart rate. For both WT and Scn5a(+/ΔKPQ) mice, light phase-restricted feeding shifted the RR and QT rhythms ~12 h, increased their amplitudes greater than twofold, and raised the 24-h midline mean by ~10%. In contrast to WT mice, the QTc interval in Scn5a(+/ΔKPQ) mice exhibited time-of-day prolongation that was flipped after light phase-restricted feeding. The time-of-day changes in the QTc intervals of Scn5a(+/ΔKPQ) mice were secondary to a steeper power relation between their QT and RR intervals. We conclude that uncoupling time of feeding from normal light cues can dramatically slow heart rate to unmask genotype-specific differences in the QT intervals and aggravate the LQT3-related phenotype.