Acute alcohol exposure and electrocardiographic changes: Finding from the HOLIDAY trial.

BACKGROUND: Alcohol consumption is associated with a higher increased risk of atrial fibrillation (AF), but the acute effects on cardiac electrophysiology in humans remain poorly understood. The HOw ALcohol InDuces Atrial TachYarrhythmias (HOLIDAY) Trial revealed that alcohol shortened pulmonary vein atrial effective refractory periods, but more global electrophysiologic changes gleaned from the surface ECG have not yet been reported. METHODS: This was a secondary analysis of the HOLIDAY Trial. During AF ablation procedures, 100 adults were randomized to intravenous alcohol titrated to 0.08% blood alcohol concentration versus a volume and osmolarity-matched, masked, placebo. Intervals measured from 12­lead ECGs were compared between pre infusion and at infusion steady state (20 min). RESULTS: The average age was 60 years and 11% were female. No significant differences in the P-wave duration, PR, QRS or QT intervals, were present between alcohol and placebo arms. However, infusion of alcohol was associated with a statistically significant relative shortening of the JT interval (r: -14.73, p = 0.048) after multivariable adjustment. CONCLUSION: Acute exposure to alcohol was associated with a relative reduction in the JT interval, reflecting shortening of ventricular repolarization. These acute changes may reflect a more global shortening of refractoriness, suggesting immediate proarrhythmic effects pertinent to the atria and ventricles.

Epigenetic Regulation of Cardiomyocyte Maturation by Arginine Methyltransferase CARM1.

BACKGROUND: During the neonatal stage, the cardiomyocyte undergoes a constellation of molecular, cytoarchitectural, and functional changes known collectively as cardiomyocyte maturation to increase myocardial contractility and cardiac output. Despite the importance of cardiomyocyte maturation, the molecular mechanisms governing this critical process remain largely unexplored. METHODS: We leveraged an in vivo mosaic knockout system to characterize the role of Carm1, the founding member of protein arginine methyltransferase, in cardiomyocyte maturation. Using a battery of assays, including immunohistochemistry, immuno-electron microscopy imaging, and action potential recording, we assessed the effect of loss of Carm1 function on cardiomyocyte cell growth, myofibril expansion, T-tubule formation, and electrophysiological maturation. Genome-wide transcriptome profiling, H3R17me2a chromatin immunoprecipitation followed by sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing were used to investigate the mechanisms by which CARM1 (coactivator-associated arginine methyltransferase 1) regulates cardiomyocyte maturation. Finally, we interrogated the human syntenic region to the H3R17me2a chromatin immunoprecipitation followed by sequencing peaks for single-nucleotide polymorphisms associated with human heart diseases. RESULTS: We report that mosaic ablation of Carm1 disrupts multiple aspects of cardiomyocyte maturation cell autonomously, leading to reduced cardiomyocyte size and sarcomere thickness, severe loss and disorganization of T tubules, and compromised electrophysiological maturation. Genomics study demonstrates that CARM1 directly activates genes that underlie cardiomyocyte cytoarchitectural and electrophysiological maturation. Moreover, our study reveals significant enrichment of human heart disease-associated single-nucleotide polymorphisms in the human genomic region syntenic to the H3R17me2a chromatin immunoprecipitation followed by sequencing peaks. CONCLUSIONS: This study establishes a critical and multifaceted role for CARM1 in regulating cardiomyocyte maturation and demonstrates that deregulation of CARM1-dependent cardiomyocyte maturation gene expression may contribute to human heart diseases.

Single Cell Multi-Omics of an iPSC Model of Human Sinoatrial Node Development Reveals Genetic Determinants of Heart Rate and Arrhythmia Susceptibility.

Cellular heterogeneity within the sinoatrial node (SAN) is functionally important but has been difficult to model in vitro , presenting a major obstacle to studies of heart rate regulation and arrhythmias. Here we describe a scalable method to derive sinoatrial node pacemaker cardiomyocytes (PCs) from human induced pluripotent stem cells that recapitulates differentiation into distinct PC subtypes, including SAN Head, SAN Tail, transitional zone cells, and sinus venosus myocardium. Single cell (sc) RNA-sequencing, sc-ATAC-sequencing, and trajectory analyses were used to define epigenetic and transcriptomic signatures of each cell type, and to identify novel transcriptional pathways important for PC subtype differentiation. Integration of our multi-omics datasets with genome wide association studies uncovered cell type-specific regulatory elements that associated with heart rate regulation and susceptibility to atrial fibrillation. Taken together, these datasets validate a novel, robust, and realistic in vitro platform that will enable deeper mechanistic exploration of human cardiac automaticity and arrhythmia.

A Randomized Trial of High vs Standard Power Radiofrequency Ablation for Pulmonary Vein Isolation: SHORT-AF.

BACKGROUND: High-power, short duration (HPSD) radiofrequency ablation (RFA) is a commonly used strategy for pulmonary vein isolation (PVI). OBJECTIVES: This study sought to compare HPSD with standard power, standard duration (SPSD) RFA in patients undergoing PVI. METHODS: Patients with paroxysmal or persistent (<1 year) atrial fibrillation (AF) were randomized to HPSD (50 W) or SPSD (25-30 W) RFA to achieve PVI. Outcomes assessed included time to achieve PVI (primary), left atrial dwell time, total procedure time, first-pass isolation, PV reconnection with adenosine, procedure complications including asymptomatic cerebral emboli (ACE), and freedom from atrial arrhythmias. RESULTS: Sixty patients (median age 66 years; 75% male) with paroxysmal (57%) or persistent (43%) AF were randomized to HPSD (n = 29) or SPSD (n = 31). Median time to achieve PVI was shorter with HPSD vs SPSD (87 minutes vs 126 minutes; P = 0.003), as was left atrial dwell time (157 minutes vs 180 minutes; P = 0.04). There were no differences in first-pass isolation (79% vs 76%; P = 0.65) or PV reconnection with adenosine (12% vs 20%; P = 0.26) between groups. At 12 months, recurrent atrial arrhythmias occurred less in the HPSD group compared with the SPSD group (n = 3 of 29 [10%] vs n = 11 of 31 [35%]; HR: 0.26; P = 0.027). There was a trend toward more ACE with HPSD RFA (40% HPSD vs 17% SPSD; P = 0.053). CONCLUSIONS: In patients undergoing AF ablation, HPSD compared with SPSD RFA results in shorter time to achieve PVI, greater freedom from AF at 12 months, and a trend toward increased ACE.

Risk of Adverse Outcomes Associated With Cardiac Sarcoidosis Diagnostic Schemes.

BACKGROUND: Multiple cardiac sarcoidosis (CS) diagnostic schemes have been published. OBJECTIVES: This study aims to evaluate the association of different CS diagnostic schemes with adverse outcomes. The diagnostic schemes evaluated were 1993, 2006, and 2017 Japanese criteria and the 2014 Heart Rhythm Society criteria. METHODS: Data were collected from the Cardiac Sarcoidosis Consortium, an international registry of CS patients. Outcome events were any of the following: all-cause mortality, left ventricular assist device placement, heart transplantation, and appropriate implantable cardioverter-defibrillator therapy. Logistic regression analysis evaluated the association of outcomes with each CS diagnostic scheme. RESULTS: A total of 587 subjects met the following criteria: 1993 Japanese (n = 310, 52.8%), 2006 Japanese (n = 312, 53.2%), 2014 Heart Rhythm Society (n = 480, 81.8%), and 2017 Japanese (n = 112, 19.1%). Patients who met the 1993 criteria were more likely to experience an event than patients who did not (n = 109 of 310, 35.2% vs n = 59 of 277, 21.3%; OR: 2.00; 95% CI: 1.38-2.90; P < 0.001). Similarly, patients who met the 2006 criteria were more likely to have an event than patients who did not (n = 116 of 312, 37.2% vs n = 52 of 275, 18.9%; OR: 2.54; 95% CI: 1.74-3.71; P < 0.001). There was no statistically significant association between the occurrence of an event and whether a patient met the 2014 or the 2017 criteria (OR: 1.39; 95% CI: 0.85-2.27; P = 0.18 or OR: 1.51; 95% CI: 0.97-2.33; P = 0.067, respectively). CONCLUSIONS: CS patients who met the 1993 and the 2006 criteria had higher odds of adverse clinical outcomes. Future research is needed to prospectively evaluate existing diagnostic schemes and develop new risk models for this complex disease.

The Value of Programmed Ventricular Extrastimuli From the Right Ventricular Basal Septum During Supraventricular Tachycardia.

BACKGROUND: The difference between the right ventricular (RV) apical stimulus-atrial electrogram (SA) interval during resetting of supraventricular tachycardia (SVT) versus the ventriculoatrial (VA) interval during SVT (ΔSA-VAapex) is an established technique for discerning SVT mechanisms but is limited by a significant diagnostic overlap. OBJECTIVES: This study hypothesized that the difference between the RV SA interval during resetting of SVTs versus the VA interval during SVTs (ΔSA-VA) would yield a more robust differentiation of atrioventricular nodal re-entrant tachycardia (AVNRT) from atrioventricular reciprocating tachycardia (AVRT) when using the RV basal septal stimulation (ΔSA-VAbase) as compared to the RV apical stimulation (ΔSA-VAapex). Moreover, it was predicted that the ΔSA-VAbase might distinguish septal from free wall accessory pathways (APs) effectively. METHODS: In this prospective study, 105 patients with AVNRTs (age 48 ± 20 years, 44% male) and 130 with AVRTs (age 26 ± 18 years, 54% male) underwent programmed ventricular extrastimuli delivered from both the RV basal septum and RV apex. The ΔSA-VA values were compared between the 2 sites. RESULTS: The ΔSA-VAbase was shorter than the ΔSA-VAapex during AVRT (44 ± 30 ms vs 58 ± 29 ms; P < 0.001), and the opposite occurred during AVNRT (133 ± 31 ms vs 125 ± 25 ms; P = 0.03). A ΔSA-VAbase of ≧85 milliseconds had a sensitivity of 97% and specificity of 96% for identifying AVNRT. Furthermore, a ΔSA-VAbase of 45-85 milliseconds identified AVRT with left free wall APs (sensitivity 86%, specificity 95%), 20-45 milliseconds for posterior septal APs (sensitivity 72%, specificity 96%), and <20 milliseconds for right free wall or anterior/mid septal APs (sensitivity 86%, specificity 98%). CONCLUSIONS: The ΔSA-VAbase during programmed ventricular extrastimuli produced a robust differentiation between AVNRT and AVRT regardless of the AP location with ≧85 milliseconds as an excellent cutoff point. This straightforward technique further allowed localizing 4 general AP sites.

Cholecystokinin-A Signaling Regulates Automaticity of Pacemaker Cardiomyocytes.

Aims: The behavior of pacemaker cardiomyocytes (PCs) in the sinoatrial node (SAN) is modulated by neurohormonal and paracrine factors, many of which signal through G-protein coupled receptors (GPCRs). The aims of the present study are to catalog GPCRs that are differentially expressed in the mammalian SAN and to define the acute physiological consequences of activating the cholecystokinin-A signaling system in isolated PCs. Methods and Results: Using bulk and single cell RNA sequencing datasets, we identify a set of GPCRs that are differentially expressed between SAN and right atrial tissue, including several whose roles in PCs and in the SAN have not been thoroughly characterized. Focusing on one such GPCR, Cholecystokinin-A receptor (CCK A R), we demonstrate expression of Cckar mRNA specifically in mouse PCs, and further demonstrate that subsets of SAN fibroblasts and neurons within the cardiac intrinsic nervous system express cholecystokinin, the ligand for CCK A R. Using mouse models, we find that while baseline SAN function is not dramatically affected by loss of CCK A R, the firing rate of individual PCs is slowed by exposure to sulfated cholecystokinin-8 (sCCK-8), the high affinity ligand for CCK A R. The effect of sCCK-8 on firing rate is mediated by reduction in the rate of spontaneous phase 4 depolarization of PCs and is mitigated by activation of beta-adrenergic signaling. Conclusions: (1) PCs express many GPCRs whose specific roles in SAN function have not been characterized, (2) Activation of the the cholecystokinin-A signaling pathway regulates PC automaticity.

Randomized Comparison of a Radiofrequency Wire Versus a Radiofrequency Needle System for Transseptal Puncture.

BACKGROUND: Transseptal puncture is a necessary component of many electrophysiology and structural heart procedures. Improving this technique has broad ramifications for the overall efficiency and safety of these interventions. A new technology uses a specialized introducer wire to cross the septum with radiofrequency (RF) energy, eliminating the need for a transseptal needle and wire/needle exchanges. OBJECTIVES: This study sought to compare the efficacy and safety of an RF needle versus RF wire approach for transseptal puncture. METHODS: Individuals ≥18 years of age undergoing double transseptal puncture for atrial fibrillation or left atrial flutter ablation were randomized to a transseptal approach with either an RF needle or RF wire. The primary outcome was time to achieve first transseptal puncture. Secondary outcomes included second and combined transseptal puncture time, fluoroscopy time, number of equipment exchanges, and complications. RESULTS: A total of 75 participants were enrolled (36 RF needle, 39 RF wire). No crossovers occurred. Randomization to the RF wire resulted in a significant reduction in first transseptal time compared with the RF needle (median 9.2 [IQR: 5.7-11.2] minutes vs 6.9 [IQR: 5.2-8.4] minutes, P = 0.03). Second and combined transseptal times, and number of equipment exchanges, were also reduced with the RF wire. One participant in the RF needle group experienced transient atrioventricular block due to mechanical trauma from the sheath/dilator assembly. There were no complications in the RF wire group. CONCLUSIONS: The RF wire technique resulted in faster time to transseptal puncture and fewer equipment exchanges compared with an RF needle with no difference in complications.

Cholecystokinin-A signaling regulates automaticity of pacemaker cardiomyocytes.

Aims: The behavior of pacemaker cardiomyocytes (PCs) in the sinoatrial node (SAN) is modulated by neurohormonal and paracrine factors, many of which signal through G-protein coupled receptors (GPCRs). The aims of the present study are to catalog GPCRs that are differentially expressed in the mammalian SAN and to define the acute physiological consequences of activating the cholecystokinin-A signaling system in isolated PCs. Methods and results: Using bulk and single cell RNA sequencing datasets, we identify a set of GPCRs that are differentially expressed between SAN and right atrial tissue, including several whose roles in PCs and in the SAN have not been thoroughly characterized. Focusing on one such GPCR, Cholecystokinin-A receptor (CCKAR), we demonstrate expression of Cckar mRNA specifically in mouse PCs, and further demonstrate that subsets of SAN fibroblasts and neurons within the cardiac intrinsic nervous system express cholecystokinin, the ligand for CCKAR. Using mouse models, we find that while baseline SAN function is not dramatically affected by loss of CCKAR, the firing rate of individual PCs is slowed by exposure to sulfated cholecystokinin-8 (sCCK-8), the high affinity ligand for CCKAR. The effect of sCCK-8 on firing rate is mediated by reduction in the rate of spontaneous phase 4 depolarization of PCs and is mitigated by activation of beta-adrenergic signaling. Conclusion: (1) PCs express many GPCRs whose specific roles in SAN function have not been characterized, (2) Activation of the cholecystokinin-A signaling pathway regulates PC automaticity.

Transcription Factor GATA4 Regulates Cell Type-Specific Splicing Through Direct Interaction With RNA in Human Induced Pluripotent Stem Cell-Derived Cardiac Progenitors.

BACKGROUND: GATA4 (GATA-binding protein 4), a zinc finger-containing, DNA-binding transcription factor, is essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Defects in alternative splicing are associated with many heart diseases, yet relatively little is known about how cell type- or cell state-specific alternative splicing is achieved in the heart. Here, we show that GATA4 regulates cell type-specific splicing through direct interaction with RNA and the spliceosome in human induced pluripotent stem cell-derived cardiac progenitors. METHODS: We leveraged a combination of unbiased approaches including affinity purification of GATA4 and mass spectrometry, enhanced cross-linking with immunoprecipitation, electrophoretic mobility shift assays, in vitro splicing assays, and unbiased transcriptomic analysis to uncover GATA4's novel function as a splicing regulator in human induced pluripotent stem cell-derived cardiac progenitors. RESULTS: We found that GATA4 interacts with many members of the spliceosome complex in human induced pluripotent stem cell-derived cardiac progenitors. Enhanced cross-linking with immunoprecipitation demonstrated that GATA4 also directly binds to a large number of mRNAs through defined RNA motifs in a sequence-specific manner. In vitro splicing assays indicated that GATA4 regulates alternative splicing through direct RNA binding, resulting in functionally distinct protein products. Correspondingly, knockdown of GATA4 in human induced pluripotent stem cell-derived cardiac progenitors resulted in differential alternative splicing of genes involved in cytoskeleton organization and calcium ion import, with functional consequences associated with the protein isoforms. CONCLUSIONS: This study shows that in addition to its well described transcriptional function, GATA4 interacts with members of the spliceosome complex and regulates cell type-specific alternative splicing via sequence-specific interactions with RNA. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.

Outcomes Associated With Catheter Ablation of Ventricular Tachycardia in Patients With Cardiac Sarcoidosis.

Importance: Ventricular tachycardia (VT) is associated with high mortality in patients with cardiac sarcoidosis (CS), and medical management of CS-associated VT is limited by high failure rates. The role of catheter ablation has been investigated in small, single-center studies. Objective: To investigate outcomes associated with VT ablation in patients with CS. Design, Setting, and Participants: This cohort study from the Cardiac Sarcoidosis Consortium registry (2003-2019) included 16 tertiary referral centers in the US, Europe, and Asia. A total of 158 consecutive patients with CS and VT were included (33% female; mean [SD] age, 52 [11] years; 53% with ejection fraction [EF] <50%). Exposures: Catheter ablation of CS-associated VT and, as appropriate, medical treatment. Main Outcomes and Measures: Immediate and short-term outcomes included procedural success, elimination of VT storm, and reduction in defibrillator shocks. The primary long-term outcome was the composite of VT recurrence, heart transplant (HT), or death. Results: Complete procedural success (no inducible VT postablation) was achieved in 85 patients (54%). Sixty-five patients (41%) had preablation VT storm that did not recur postablation in 53 (82%). Defibrillator shocks were significantly reduced from a median (IQR) of 2 (1-5) to 0 (0-0) in the 30 days before and after ablation (P < .001). During median (IQR) follow-up of 2.5 (1.1-4.9) years, 73 patients (46%) experienced VT recurrence and 81 (51%) experienced the composite primary outcome. One- and 2-year rates of survival free of VT recurrence, HT, or death were 60% and 52%, respectively. EF less than 50% and myocardial inflammation on preprocedural 18F-fluorodeoxyglucose positron emission tomography were significantly associated with adverse prognosis in multivariable analysis for the primary outcome (HR, 2.24; 95% CI, 1.37-3.64; P = .001 and HR, 2.93; 95% CI, 1.31-6.55; P = .009, respectively). History of hypertension was associated with a favorable long-term outcome (adjusted HR, 0.51; 95% CI, 0.28-0.92; P = .02). Conclusions and Relevance: In this observational study of selected patients with CS and VT, catheter ablation was associated with reductions in defibrillator shocks and recurrent VT storm. Preablation LV dysfunction and myocardial inflammation were associated with adverse long-term prognosis. These data support the role of catheter ablation in conjunction with medical therapy in the management of CS-associated VT.

Transcriptional and Epigenetic Landscape of Cardiac Pacemaker Cells: Insights Into Cellular Specialization in the Sinoatrial Node.

Cardiac pacemaker cells differentiate and functionally specialize early in embryonic development through activation of critical gene regulatory networks. In general, cellular specification and differentiation require that combinations of cell type-specific transcriptional regulators activate expression of key effector genes by binding to DNA regulatory elements including enhancers and promoters. However, because genomic DNA is tightly packaged by histones that must be covalently modified in order to render DNA regulatory elements and promoters accessible for transcription, the process of development and differentiation is intimately connected to the epigenetic regulation of chromatin accessibility. Although the difficulty of obtaining sufficient quantities of pure populations of pacemaker cells has limited progress in this field, the advent of low-input genomic technologies has the potential to catalyze a rapid growth of knowledge in this important area. The goal of this review is to outline the key transcriptional networks that control pacemaker cell development, with particular attention to our emerging understanding of how chromatin accessibility is modified and regulated during pacemaker cell differentiation. In addition, we will discuss the relevance of these findings to adult sinus node function, sinus node diseases, and origins of genetic variation in heart rhythm. Lastly, we will outline the current challenges facing this field and promising directions for future investigation.

Acute Consumption of Alcohol and Discrete Atrial Fibrillation Events.

BACKGROUND: Patients' self-reports suggest that acute alcohol consumption may trigger a discrete atrial fibrillation (AF) event. OBJECTIVE: To objectively ascertain whether alcohol consumption heightens risk for an AF episode. DESIGN: A prospective, case-crossover analysis. SETTING: Ambulatory persons in their natural environments. PARTICIPANTS: Consenting patients with paroxysmal AF. MEASUREMENTS: Participants were fitted with a continuous electrocardiogram (ECG) monitor and an ankle-worn transdermal ethanol sensor for 4 weeks. Real-time documentation of each alcoholic drink consumed was self-recorded using a button on the ECG recording device. Fingerstick blood tests for phosphatidylethanol (PEth) were used to corroborate ascertainments of drinking events. RESULTS: Of 100 participants (mean age, 64 years [SD, 15]; 79% male; 85% White), 56 had at least 1 episode of AF. Results of PEth testing correlated with the number of real-time recorded drinks and with events detected by the transdermal alcohol sensor. An AF episode was associated with 2-fold higher odds of 1 alcoholic drink (odds ratio [OR], 2.02 [95% CI, 1.38 to 3.17]) and greater than 3-fold higher odds of at least 2 drinks (OR, 3.58 [CI, 1.63 to 7.89]) in the preceding 4 hours. Episodes of AF were also associated with higher odds of peak blood alcohol concentration (OR, 1.38 [CI, 1.04 to 1.83] per 0.1% increase in blood alcohol concentration) and the total area under the curve of alcohol exposure (OR, 1.14 [CI, 1.06 to 1.22] per 4.7% increase in alcohol exposure) inferred from the transdermal ethanol sensor in the preceding 12 hours. LIMITATION: Confounding by other time-varying exposures that may accompany alcohol consumption cannot be excluded, and the findings from the current study of patients with AF consuming alcohol may not apply to the general population. CONCLUSION: Individual AF episodes were associated with higher odds of recent alcohol consumption, providing objective evidence that a modifiable behavior may influence the probability that a discrete AF event will occur. PRIMARY FUNDING SOURCE: National Institute on Alcohol Abuse and Alcoholism.

Predictors of long-term success after catheter ablation of premature ventricular complexes.

INTRODUCTION: Some patients have late recurrence after acutely successful radiofrequency catheter ablation (RFCA) of premature ventricular complexes (PVCs). The aim of this study was to evaluate predictors of long-term success following acutely successful PVC RFCA. METHODS: We identified consecutive patients at our institution with frequent PVCs undergoing RFCA and reviewed procedural data and medical records. Acute success was defined as elimination of targeted PVCs for at least 30-min after RFCA. Long-term success was defined as absence of targeted PVCs during all follow-up visits and PVC-burden <5% on follow-up monitoring. RESULTS: Among 241 patients (mean age 57 ± 15 years, 58% male), 161 (66.8%) had long-term success with median follow-up of 17.7 (IQR, 12.2-29.8) months. Unadjusted predictors of late PVC recurrence were increasing age, diabetes mellitus and alcohol use, while female-sex, shorter ablation-time, right ventricular PVC-origin, single PVC morphology, and earliest bipolar activation ≥24 ms pre-QRS were predictors of long-term success. In multivariate-analysis, female-sex, single-PVC morphology and earliest-onset of PVC ≥ 24 ms pre-QRS were independent predictors for long-term success. The positive-predictive value of earliest-bipolar onset of PVC ≥ 24 ms pre-QRS for long-term success was 0.77 (p < .001). Negative-predictive value of PVC < 15 ms pre-QRS for long-term success was 0.86 (p = .003), suggesting that RFCA when the bipolar electrogram preceded QRS by <15 ms was unlikely to result in long-term success. CONCLUSIONS: Female-sex, single-PVC morphology, and earliest-onset of bipolar electrogram ≥24 ms pre-QRS were multivariable predictors of long-term success in patients with PVCs undergoing RFCA. RFCA at sites with local onset <15 ms pre-QRS are unlikely to be successful.

Heart Failure, Atrioventricular Block, and Ventricular Tachycardia in Sarcoidosis.

Background Sarcoidosis is a granulomatous disease usually affecting the lungs, although cardiac morbidity may be common. The risk of these outcomes and the characteristics that predict them remain largely unknown. This study investigates the epidemiology of heart failure, atrioventricular block, and ventricular tachycardia among patients with and without sarcoidosis. Methods and Results We identified California residents aged ≥21 years using the Office of Statewide Health Planning and Development ambulatory surgery, emergency, or inpatient databases from 2005 to 2015. The risk of sarcoidosis on incident heart failure, atrioventricular block, and ventricular tachycardia were each determined. Linkage to the Social Security Death Index was used to ascertain overall mortality. Among 22 527 964 California residents, 19 762 patients with sarcoidosis (0.09%) were identified. Sarcoidosis was the strongest predictor of heart failure (hazard ratio [HR], 11.2; 95% CI, 10.7-11.7), atrioventricular block (HR, 117.7; 95% CI, 103.3-134.0), and ventricular tachycardia (HR, 26.1; 95% CI, 24.2-28.1) identified among all risk factors. The presence of any cardiac involvement best predicted each outcome. Approximately 22% (95% CI, 18%-26%) of the relationship between sarcoidosis and increased mortality was explained by the presence of at least 1 of these cardiovascular outcomes. Conclusions The magnitude of risk associated with sarcoidosis as a predictor of heart failure, atrioventricular block, and ventricular tachycardia, exceeds all established risk factors. Surveillance for and anticipation of these outcomes among patients with sarcoidosis is indicated, and consideration of a sarcoidosis diagnosis may be prudent among patients with heart failure, atrioventricular block, or ventricular tachycardia.

The Role of the Left Septal Fascicle in Fascicular Arrhythmias: Clinical Presentation and Laboratory Evaluation.

OBJECTIVES: This study describes a series of cases best explained by invoking the left septal fascicle (LSF) as a critical component of the arrhythmia circuit. BACKGROUND: Numerous anatomic studies have shown evidence of the LSF, but its precise role in the onset of arrhythmia is unclear. METHODS: This paper presents 5 cases that implicated the LSF as a critical component of arrhythmogenesis. RESULTS: The first case had ventricular fibrillation repeatedly documented after a single premature atrial complex, produced left-sided conduction delay and simultaneous earliest activation of the left anterior fascicle (LAF) and left posterior fascicle (LPF). The LSF was ablated, resulting in an arrhythmia cure. The second case showed narrow QRS morphology during fascicular re-entrant tachycardia. The earliest mid-septal diastolic potentials had distal-to-proximal activation suggesting an LSF as a retrograde common pathway. The third case, with multiple ectopic Purkinje-related premature complexes exhibited earliest Purkinje potentials in the mid-septum, with subsequent anterograde activation of the LAF and LPF. Ablation of the LSF eliminated the premature ventricular complexes (PVCs). The fourth case demonstrated LPF and LAF PVCs. The His-left bundle activation showed earliest potentials at the proximal insertion of the left bundle during LPF PVCs, as well as a distal-to-proximal activation pattern during LAF PVC, suggestive of LSF involvement. The fifth case had focal non-re-entrant fascicular beats successfully ablated over the LSF. CONCLUSIONS: Involvement of the LSF is suspected with presentation of multiform fascicular and narrow QRS complex ventricular episodes of arrhythmia. Diagnoses and ablation require detailed mapping of the entire left sided conduction system.