Human Arrhythmia Research Articles

Identification and Functional Investigation of SOX4 as a Novel Gene Underpinning Familial Atrial Fibrillation

Background: Atrial fibrillation (AF) signifies the most prevalent supraventricular arrhythmia in humans and may lead to cerebral stroke, cardiac failure, and even premature demise. Aggregating strong evidence points to genetic components as a cornerstone in the etiopathogenesis of familial AF. However, the genetic determinants for AF in most patients remain elusive. Methods: A 4-generation pedigree with idiopathic AF and another cohort of 196 unrelated patients with idiopathic AF as well as 278 unrelated healthy volunteers were recruited from the Chinese population of Han ethnicity. A family-based whole-exome sequencing examination followed by a Sanger sequencing assay in all research subjects was implemented. The functional impacts of the identified SOX4 mutations were explored via a dual-reporter assay. Results: Two new heterozygous SOX4 mutations, NM_003107.3: c.211C>T; p.(Gln71*) and NM_003107.3: c.290G>A; p.(Trp97*), were observed in the family and 1 of 196 patients with idiopathic AF, respectively. The two mutations were absent in the 278 control individuals. The biochemical measurements revealed that both Gln71*- and Trp97*-mutant SOX4 failed to transactivate GJA1 (Cx43). Moreover, the two mutations nullified the synergistic activation of SCN5A by SOX4 and TBX5. Conclusions: The findings first indicate SOX4 as a gene predisposing to AF, providing a novel target for antenatal genetic screening, individualized prophylaxis, and precision treatment of AF.

An endogenous cholinergic system controls electrical conduction in the heart.

The cholinergic system is distributed in the nervous system, mediating electrical conduction through acetylcholine (ACh). This study aims to identify whether the heart possesses an intact endogenous cholinergic system and to explore its electrophysiological functions and relationship with arrhythmias in both humans and animals. The components of the heart's endogenous cholinergic system were identified by a combination of multiple molecular cell biology techniques. The relationship of this system with cardiac electrical conduction and arrhythmias was analysed through electrophysiological techniques. An intact cholinergic system including ACh, ACh transmitter vesicles, ACh transporters, ACh metabolic enzymes, and ACh receptors was identified in both human and mouse ventricular cardiomyocytes (VCs). The key components of the system significantly regulated the conductivity of electrical excitation among VCs. The influence of this system on electrical excitation conduction was further confirmed both in the mice with α4 or α7 nicotinic ACh receptors (nAChRs) knockouts and in the monolayers of human induced pluripotent stem cell-derived cardiomyocytes. Mechanistically, ACh induced an inward current through nAChRs to reduce the minimum threshold current required to generate an action potential in VCs, thereby enhancing the excitability that acts as a prerequisite for electrical conduction. Importantly, defects in this system were associated with fatal ventricular arrhythmias in both patients and mice. This study identifies an integrated cholinergic system inherent to the heart, rather than external nerves that can effectively control cardiac electrical conduction. The discovery reveals arrhythmia mechanisms beyond classical theories and opens new directions for arrhythmia research.

Cardiac arrhythmias in fish induced by natural and anthropogenic changes in environmental conditions.

A regular heartbeat is essential for maintaining the homeostasis of the vertebrate body. However, environmental pollutants, oxygen deficiency and extreme temperatures can impair heart function in fish. In this Review, we provide an integrative view of the molecular origins of cardiac arrhythmias and their functional consequences, from the level of ion channels to cardiac electrical activity in living fish. First, we describe the current knowledge of the cardiac excitation-contraction coupling of fish, as the electrical activity of the heart and intracellular Ca2+ regulation act as a platform for cardiac arrhythmias. Then, we compile findings on cardiac arrhythmias in fish. Although fish can experience several types of cardiac arrhythmia under stressful conditions, the most typical arrhythmia in fish - both under heat stress and in the presence of toxic substances - is atrioventricular block, which is the inability of the action potential to progress from the atrium to the ventricle. Early and delayed afterdepolarizations are less common in fish hearts than in the hearts of endotherms, perhaps owing to the excitation-contraction coupling properties of the fish heart. In fish hearts, Ca2+-induced Ca2+ release from the sarcoplasmic reticulum plays a smaller role than Ca2+ influx through the sarcolemma. Environmental changes and ion channel toxins can induce arrhythmias in fish and weaken their tolerance to environmental stresses. Although different from endotherm hearts in many respects, fish hearts can serve as a translational model for studying human cardiac arrhythmias, especially for human neonates.

Abstract Mo055: CHD4 Interacts With TBX5 to Maintain the Gene Regulatory Network of Postnatal Atrial Cardiomyocytes

Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, leading to increased mortality due to increased incidence of stroke and heart failure. Over 200 genes are associated with AF by GWAS studies, suggesting a nuanced gene regulatory network (GRN) is required to maintain atrial cardiomyocyte (aCM) function and rhythm. Among these genes is the transcription factor TBX5, which we and others have shown is a master regulator of aCM identity that is essential for atrial rhythm homeostasis. We showed that TBX5 is required to maintain the chromatin looping, accessibility, and activity of atrial enhancers. Chromodomain helicase DNA binding protein 4 (CHD4), a chromatin remodeling protein that interacts with TBX5, is canonically thought to repress transcription as a component of the NuRD complex. Here, we investigated the contribution of CHD4 to TBX5 regulation of aCM gene expression. Methods: We inactivated CHD4 specifically within atrial cardiomyocytes using Cre recombinase driven by the aCM-specific Nppa promoter delivered postnatally with AAV9. Atrial remodeling, transcriptomic changes and AF susceptibility were examined. Results: We show that inactivating CHD4 in postnatal aCMs resulted in fibrotic atrial remodeling, spontaneous AF in a subset of mice, and increased AF susceptibility and burden after electrical pacing. Transcriptomic profiling of CHD4 aCM KO atria revealed gene expression changes that were highly correlated to altered gene expression downstream of TBX5 inactivation. Mechanistically, we show TBX5 recruits CHD4 to 33,170 genomic regions that are important for aCM gene regulation, whose expression is concordantly regulated downstream of TBX5 and CHD4. Together, these data reveal that CHD4 is required by TBX5 to promote accessibility of enhancers and activate many TBX5 target genes to maintain atrial rhythm.

Loss of pitx2c causes early alterations in atrial calcium handling in zebrafish

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science, Innovation and Universities, Spain (PID2019-111456RB-100); Consejería de Educación, Cultura y Deportes, Junta de Comunidades de Castilla-La Mancha (SBPLY/19/180501/000223, co-funded by EU FEDER-ERDF) and grants for research groups from University of Castilla-La Mancha (2019-GRIN-27019, 2020-GRIN-29186 and 2022-GRIN-34301, co-funded by EU FEDER-ERDF) Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia in humans. Genome-wide association studies revealed that AF is related to sequence variants in chromosomic regions in close proximity to the transcription factor PITX2, involved in cardiac development and asymmetry, and in morphogenesis of pacemaker regions such as the sinoatrial region and the atrioventricular canal, which receive significant input from the autonomic nervous system. AF patients showed reduced PITX2 mRNA levels. PITX2-/- atrial tissue showed lower expression of CACNA1C accompanied by lower L-type Ca2+ current density. A recent study revealed AF-like phenotypes, including fibrosis, structural and metabolic alterations, arrhythmia, and cardiac conduction defects in adult pitx2c -/- zebrafish. Nevertheless, Ca2+ handling alterations remain unexplored in this zebrafish model. Purpose In this study we investigated cardiac Ca2+ handling in pitx2c deficient zebrafish. Methods We used the transgenic zebrafish line Tg(myl7:Twitch-4) expressing a fluorescent Ca2+ indicator in the heart. We outcrossed pitx2c+/- fish with Tg(myl7:Twitch-4) pitx2c+/- and studied Ca2+ dynamics and cardiac function by videomicroscopy in the beating hearts of 5 days post fertilization (dpf) larvae. Larvae were treated with 100 µM carbachol to assess differential response to parasympathetic stimulation in pitx2c deficient larvae. Results We observed sinoatrial pauses in 40 % of pitx2c+/- larvae accompanied by an increase in heart rate variability. In addition, pitx2c+/- and pitx2c-/- larvae at 5 dpf showed differential response to carbachol, a cholinergic agonist, compared to their wild-type siblings. Moreover, carbachol significantly decreased heart rate in pitx2c+/- and pitx2c-/- 5dpf larvae compared to siblings. Furthermore, we also observed a reduction of the amplitude of Ca2+ transients due to a decrease in the systolic Ca2+ levels in the atrium of pitx2c+/- larvae. The rise time of the atrial Ca2+ transient was prolonged, with a decrease in the rise slope. These data suggest a lower Ca2+ entry in the atrium. Interestingly, pitx2c+/- and wild-type larvae showed similar ventricular Ca2+ handling and contractility. Conclusion These results suggest that loss of pitx2c induce early Ca2+ alterations in the atrium as well as sinoatrial dysfunction in zebrafish during embryogenesis. Furthermore, pitx2c deficiency in zebrafish larvae possibly alters autonomic innervation leading to differentiated cardiac response to carbachol.

The role of the pulmonary veins on left atrial flow patterns and thrombus formation.

Atrial fibrillation (AF) is the most common human arrhythmia, forming thrombi mostly in the left atrial appendage (LAA). However, the relation between LAA morphology, blood patterns and clot formation is not yet fully understood. Furthermore, the impact of anatomical structures like the pulmonary veins (PVs) have not been thoroughly studied due to data acquisition difficulties. In-silico studies with flow simulations provide a detailed analysis of blood flow patterns under different boundary conditions, but a limited number of cases have been reported in the literature. To address these gaps, we investigated the influence of PVs on LA blood flow patterns and thrombus formation risk through computational fluid dynamics simulations conducted on a sizeable cohort of 130 patients, establishing the largest cohort of patient-specific LA fluid simulations reported to date. The investigation encompassed an in-depth analysis of several parameters, including pulmonary vein orientation (e.g., angles) and configuration (e.g., number), LAA and LA volumes as well as their ratio, flow, and mass-less particles. Our findings highlight the total number of particles within the LAA as a key parameter for distinguishing between the thrombus and non-thrombus groups. Moreover, the angles between the different PVs play an important role to determine the flow going inside the LAA and consequently the risk of thrombus formation. The alignment between the LAA and the main direction of the left superior pulmonary vein, or the position of the right pulmonary vein when it exhibits greater inclination, had an impact to distinguish the control group vs. the thrombus group. These insights shed light on the intricate relationship between PV configuration, LAA morphology, and thrombus formation, underscoring the importance of comprehensive blood flow pattern analyses.

DNA Methylation and Telomeres-Their Impact on the Occurrence of Atrial Fibrillation during Cardiac Aging.

Atrial fibrillation (AF) is the most common arrhythmia in humans. AF is characterized by irregular and increased atrial muscle activation. This high-frequency activation obliterates the synchronous work of the atria and ventricles, reducing myocardial performance, which can lead to severe heart failure or stroke. The risk of developing atrial fibrillation depends largely on the patient's history. Cardiovascular diseases are considered aging-related pathologies; therefore, deciphering the role of telomeres and DNA methylation (mDNA), two hallmarks of aging, is likely to contribute to a better understanding and prophylaxis of AF. In honor of Prof. Elizabeth Blackburn's 75th birthday, we dedicate this review to the discovery of telomeres and her contribution to research on aging.

In Vitro Models for Improved Therapeutic Interventions in Atrial Fibrillation.

Atrial fibrillation is the most common type of cardiac arrhythmias in humans, mostly caused by hyper excitation of specific areas in the atrium resulting in dyssynchronous atrial contractions, leading to severe consequences such as heart failure and stroke. Current therapeutics aim to target this condition through both pharmacological and non-pharmacological approaches. To test and validate any of these treatments, an appropriate preclinical model must be carefully chosen to refine and optimise the therapy features to correctly reverse this condition. A broad range of preclinical models have been developed over the years, with specific features and advantages to closely mimic the pathophysiology of atrial fibrillation. In this review, currently available models are described, from traditional animal models and in vitro cell cultures to state-of-the-art organoids and organs-on-a-chip. The advantages, applications and limitations of each model are discussed, providing the information to select the appropriate model for each research application.

Abstract P1144: Single-cell RNA-Sequencing Of The Murine Cardiac Conduction System Reveals Transcriptional Regulators Associated With Conduction Development And Disease

Rhythmic beating of the heart is driven by a small subset of heart cells, altogether known as the cardiac conduction system (CCS). The CCS consists of unique components including the sinoatrial node (SAN), the atrioventricular node (AVN), the bundle of His, bundle branches and Purkinje fiber (PF) system. Due to obstacles inherent in studying the CCS, including small cell numbers, large cell-type heterogeneity and complex anatomy, our understanding of the transcriptional networks driving CCS development remains limited. Here, we harnessed single-cell RNA-sequencing (scRNAseq) and bioinformatic analyses to uncover putative DNA-binding transcription factors (TFs) as well as transcriptional co-regulators enriched within the entire developing murine CCS. Comparison of multiple independent prior datasets, spanning all major components of the CCS, revealed previously known TFs necessary for conduction development including, Islet 1 ( Isl1 ; avg log fold change 0.34, p= 1E-192) in the SAN; T-box transcription factor 5 (Tbx5 ; avg log fold change 0.54, p= 2.1E-110) in the AVN; and ETS variant transcription factor 1 ( Etv1; avg log fold change 0.89, p= 6.7E-105) in the PFs, among others. Notably, an additional 16 novel DNA-binding transcription factors and 40 transcription co-regulators were enriched within specific CCS components at statistical significance. To further evaluate the transcriptional landscape of individual subcomponents within the SAN (compact versus transitional cells), we also performed scRNAseq on FACS-isolated SAN cells from embryonic day 16.5 Hcn4 -GFP transgenic mice revealing differential expression of a host of TFs, both established and novel. Finally, our murine findings were then cross-referenced to over 15 human GWAS studies related to cardiac rhythm abnormalities, revealing an association of a subset of these murine CCS-enriched transcription factors and cardiac arrhythmias in humans. In conclusion, this study provides a comprehensive gene expression atlas of transcription factors and transcriptional co-regulators within individual CCS components at single-cell resolution, laying the groundwork for future studies into the transcriptional regulation of cardiac conduction development and disease.

The Possible Influence of Vitamin D Levels on the Development of Atrial Fibrillation-An Update.

Atrial fibrillation (AF) is a severe and most common supraventricular arrhythmia in humans, which, if left untreated or treated ineffectively, can lead to ischemic stroke or heart failure. It has been suggested that serum vitamin D (VitD) deficiency may be one of the critical factors influencing the onset of AF, especially in the period after cardiac surgery, such as coronary artery bypass grafting. Several papers have indicated that VitD supplementation reduces the risk of AF, significantly reducing the proportion of patients between the control and study groups in both the pre- and postoperative periods. Factors that increase the risk of AF from VitD deficiency are also further indicated, and these are age, gender, weight, season or comorbidities. In addition, the cardiodepressive mechanism of VitD is not fully understood; however, it is suggested that it acts through at least two pathways. The first indicates a direct effect of VitD on atrial muscle degradation, while the second is related to the modulation of cardiovascular depression factors. Despite many reports showing correlations between no VitD concentrations on the development of AF, this topic is still widely debated and the results from these papers are still subject to doubt. Therefore, this review aims at describing in detail the problem of correlation between VitD deficiency and the development of AF associated mainly with the postoperative period, i.e., after cardiac surgery, especially pathogenesis, and results of this correlation, taking into account recent studies, limitations and future perspectives. Due to the fact that this is still a topical problem, we believe that the collection of the latest reports and a detailed description of the problem is most appropriate in this case.

Impact of stress on cardiac phenotypes in mice harboring an ankyrin-B disease variant

Encoded by ANK2, ankyrin-B (AnkB) is a multifunctional adapter protein critical for the expression and targeting of key cardiac ion channels, transporters, cytoskeletal-associated proteins, and signaling molecules. Mice deficient for AnkB expression are neonatal lethal, and mice heterozygous for AnkB expression display cardiac structural and electrical phenotypes. Human ANK2 loss-of-function variants are associated with diverse cardiac manifestations; however, human clinical 'AnkB syndrome' displays incomplete penetrance. To date, animal models for human arrhythmias have generally been knock-out or transgenic overexpression models and thus the direct impact of ANK2 variants on cardiac structure and function invivo is not clearly defined. Here, we directly tested the relationship of a single human ANK2 disease-associated variant with cardiac phenotypes utilizing a novel invivo animal model. At baseline, young AnkBp.E1458G+/+ mice lacked significant structural or electrical abnormalities. However, aged AnkBp.E1458G+/+ mice displayed both electrical and structural phenotypes at baseline including bradycardia and aberrant heart rate variability, structural remodeling, and fibrosis. Young and old AnkBp.E1458G+/+ mice displayed ventricular arrhythmias following acute (adrenergic) stress. In addition, young AnkBp.E1458G+/+ mice displayed structural remodeling following chronic (transverse aortic constriction) stress. Finally, AnkBp.E1458G+/+ myocytes harbored alterations in expression and/or localization of key AnkB-associated partners, consistent with the underlying disease mechanism. In summary, our findings illustrate the critical role of AnkB in invivo cardiac function as well as the impact of single AnkB loss-of-function variants invivo. However, our findings illustrate the contribution and in fact necessity of secondary factors (aging, adrenergic challenge, pressure-overload) to phenotype penetrance and severity.

The Acute Effects Of ATP-Sensitive Potassium Channel Opener (Pinacidil) And Blocker (Glimepride) On the Ischemia or Reperfusion-Induced Arrhythmias

Introduction: Myocardial ischemia due to coronary obstruction and reperfusion due to the opening of the coronary vessel occurring in the acute stage of myocardial infarction leads to lethal arrhythmia and sudden death in humans. That is why pharmacological drug research to decrease these arrhythmias have been researched intensively. In this study, the effect of acute administration of pinacidil and glimepride, on ischemia or reperfusion-induced arrhythmia was aimed to be researched. Methods: Two groups were produced; In the first group, only ischemia was produced by the ligation of the left coronary artery in 20 minutes, and in the second group 6 minutes of ischemia by the ligation of the artery and the subsequent 15 minutes of reperfusion were produced by the opening of the occluded artery. Drugs were administered intravenously at 2 minutes of ischemia in the first group and just following the reperfusion in the second group. The ECG and blood pressure were recorded during ischemia and reperfusion. The type, duration, incidence of arrhythmia, heart rate, blood pressure, and the death rate from the recording were determined. All data were first compared by one-way ANOVA. Then, the drug groups with their control, and control and drug groups with each other were compared by a one-tailed student t-test. The incidence of arrhythmia and the death rate between groups was compared by the Ki square test. Results: Pinacidil significantly decreased the arrhythmia score both in the ischemia and reperfusion period but glimepiride was not effective when they were given intravenously in the acute stage of ischemia or reperfusion. Discussion and Conclusion: This study suggests that pinacidil might be a candidate for drugs that can be used to decrease arrhythmia in the acute stage of myocardial infarction but more study is needed to reveal the antiarrhythmic or proarrhythmic effect of glimepride in the acute stage of myocardial infarction.

Overview of programmed electrical stimulation to assess atrial fibrillation susceptibility in mice.

Atrial fibrillation (AF) is the most common human arrhythmia and is associated with increased risk of stroke, dementia, heart failure, and death. Among several animal models that have been used to investigate the molecular determinants of AF, mouse models have become the most prevalent due to low cost, ease of genetic manipulation, and similarity to human disease. Programmed electrical stimulation (PES) using intracardiac or transesophageal atrial pacing is used to induce AF as most mouse models do not develop spontaneous AF. However, there is a lack of standardized methodology resulting in numerous PES protocols in the literature that differ with respect to multiple parameters, including pacing protocol and duration, stimulus amplitude, pulse width, and even the definition of AF. Given this complexity, the selection of the appropriate atrial pacing protocol for a specific model has been arbitrary. Herein we review the development of intracardiac and transesophageal PES, including commonly used protocols, selected experimental models, and advantages and disadvantages of both techniques. We also emphasize detection of artifactual AF induction due to unintended parasympathetic stimulation, which should be excluded from results. We recommend that the optimal pacing protocol to elicit an AF phenotype should be individualized to the specific model of genetic or acquired risk factors, with an analysis using several definitions of AF as an endpoint.

Prolonged Piezo1 Activation Induces Cardiac Arrhythmia

The rhythmical nature of the cardiovascular system constantly generates dynamic mechanical forces. At the centre of this system is the heart, which must detect these changes and adjust its performance accordingly. Mechanoelectric feedback provides a rapid mechanism for detecting even subtle changes in the mechanical environment and transducing these signals into electrical responses, which can adjust a variety of cardiac parameters such as heart rate and contractility. However, pathological conditions can disrupt this intricate mechanosensory system and manifest as potentially life-threatening cardiac arrhythmias. Mechanosensitive ion channels are thought to be the main proponents of mechanoelectric feedback as they provide a rapid response to mechanical stimulation and can directly affect cardiac electrical activity. Here, we demonstrate that the mechanosensitive ion channel PIEZO1 is expressed in zebrafish cardiomyocytes. Furthermore, chemically prolonging PIEZO1 activation in zebrafish results in cardiac arrhythmias. indicating that this ion channel plays an important role in mechanoelectric feedback. This also raises the possibility that PIEZO1 gain of function mutations could be linked to heritable cardiac arrhythmias in humans.

Long-Term Impact of the Great Chinese Famine on the Risks of Specific Arrhythmias and Severe Hypertension in the Offspring at an Early Stage of Aging.

Perinatal malnutrition affects postnatal cardiovascular functions. This study used the Great Chinese Famine (GCF) to determine the long-term impact of perinatal undernutrition on hypertension and arrhythmias in older offspring. Subjects (n = 10,065) were divided into an exposed group whose fetal life was in the GCF and an unexposed group. The exposed group showed higher systolic/diastolic pressure, heart rate, and total cholesterol. Perinatal exposure to the GCF was a significant risk to Grade 2 and Grade 3 hypertension (OR = 1.724, 95%CI: 1.441-2.064, p < 0.001; OR = 1.480, 95%CI: 1.050-2.086, p < 0.05) compared to the control. The GCF also increased risks for myocardial ischemia (OR = 1.301, 95%CI: 1.135-1.490, p < 0.001), bradycardia (OR = 1.383, 95%CI: 1.154-1.657, p < 0.001), atrial fibrillation (OR = 1.931, 95%CI: 1.033-3.610, p < 0.05), and atrioventricular block (OR = 1.333, 95%CI: 1.034-1.719, p < 0.05). Total cholesterol, diabetes, and metabolic syndrome were associated with Grade 2 or Grade 3 hypertension after exposure to the GCF; high cholesterol, high BMI, diabetes, metabolic syndrome, and elevated blood pressure were linked to certain types of arrhythmias in exposed offspring. The results first demonstrated perinatal undernutrition was a significant risk factor for the development of Grade 2-3 hypertension and certain arrhythmias in humans. Perinatal undernutrition still significantly impacted cardiovascular systems of the aged offspring even 50 years after the GCF. The results also provided information to a specific population with a history of prenatal undernutrition for early prevention against cardiovascular diseases before aging.

Gastric Perforation Due to Yellow Oleander Poisoning: First Case Report in Humans

Yellow oleander (Thevetia peruviana) is a commonly found shrub in India which produces multiple alkaloidswhich are cardiotoxic. Numerous cases of yellow oleander poisoning have been reported in humans. The spectrumof toxicity due to this plant ranges from nausea, vomiting, diarrhoea, electrolyte abnormalities and arrhythmiasin humans. No case of bowel necrosis due to yellow oleander has been reported in humans to the best of ourknowledge.We present a case of 45-year-old female with suicidal consumption of crushed yellow oleander seeds. The patientwas admitted and observed for arrhythmias. On day 2 of admission, she developed bloody stools, hematemesisand abdominal pain. Abdominal examination showed rigidity and per rectal examination showed blood-stainedmucoid stools. A CECT was done which showed findings suggestive of gastric necrosis with perforation. Thepatient was taken up for surgery and stomach was found to be gangrenous with a perforation at the greatercurvature. Total gastrectomy was performed. The post operative biopsy showed extensive transmural coagulativenecrosis of the stomach and lymphoplasmacytic infiltration of the submucosa.Necrosis of bowel has been reported in experimental settings in animals and in cattle poisoning but no reportedcase of stomach necrosis and perforation due to yellow oleander has been reported in humans. As yellow oleanderis a commonly used suicidal poison in Southern Asia, an eye needs to be kept out for gastrointestinal symptoms.We conclude with recommendations on management of yellow oleander poisoning in the light of these newmanifestations.

Abstract 13503: Assessment of Automatic Measurement of Short-Term Variability of Repolarization for Arrhythmic Risk Monitoring in a Porcine Model of Ischemic Ventricular Fibrillation

Background: Short-term variability of repolarization derived from the QT-interval (STV-QT) has previously been demonstrated to increase prior to arrhythmias in both humans and animals. To continuously monitor the arrhythmic risk by a cardiovascular implantable electronic device (CIED), a fully automatic method to determine STV on intracardiac electrograms (STV-EGM auto ) has been developed. This method demonstrated high effectiveness in monitoring and predicting Torsade de Pointes arrhythmias in the CAVB dog model. However, this technique has not been evaluated in arrhythmias related to ischemia yet. Purpose: To assess the novel automatic method of arrhythmic risk monitoring by CIEDs through STV-EGM auto measurements in a porcine model of ischemia-induced ventricular fibrillation (VF). Methods: Myocardial infarction was induced in 8 anesthetized pigs by balloon occlusion of the left anterior descending coronary artery for 75 minutes, followed by reperfusion. Monitoring included a 12-lead ECG and a duodecapolar EGM catheter in the right ventricle. STV-EGM auto and STV-QT, our gold standard calculated by the method of fiducial segment averaging, were assessed at baseline, occlusion, one minute before VF and just before VF. The STV values and the percentual changes from baseline to the successive three timepoints were compared between STV-EGM auto and STV-QT. Results: VF occurred 21±8.8 minutes after occlusion. Both STV-EGM auto and STV-QT increased significantly from baseline to VF (1.1±0.8 ms vs 2.4±1.5 ms, p&lt;0.05; 1.0±0.5 ms vs 2.2±0.9 ms, p&lt;0.05, respectively). The percentual change in STV-EGM auto from baseline to occlusion, one minute before VF and VF showed an excellent correlation with the changes in STV-QT from baseline to the successive timepoints (r 2 = 0.94; p&lt;0.001). Bland-Altman analysis of the values showed a small bias of 0.26 ms and 95% limits of agreement between -1.1 and 1.6 ms. Conclusion: The STV values derived from the fully-automatic method for continuous STV measurements on intracardiac EGM signals (STV-EGM auto ) show values and trends similar to the clinically validated STV-QT in a porcine model of ischemia-related VF. Future integration of this technique in CIEDs can furnish continuous monitoring of arrhythmic risk.

Atrial fibrillation: Insights from animal models, computational modeling, and clinical studies.

Atrial fibrillation (AF) is the most common human arrhythmia, affecting millions of patients worldwide. A combination of risk factors and comorbidities results in complex atrial remodeling, which increases AF vulnerability and persistence. Insights from animal models, clinical studies, and computational modeling have advanced the understanding of the mechanisms and pathophysiology of AF. Areas of heterogeneous pathological remodeling, as well as altered electrophysiological properties, serve as a substrate for AF drivers and spontaneous activations. The complex and individualized presentation of this arrhythmia suggests that mechanisms-based personalized approaches will likely be needed to overcome current challenges in AF management. In this paper, we review the insights on the mechanisms of AF obtained from animal models and clinical studies and how computational models integrate this knowledge to advance AF clinical management. We also assess the challenges that need to be overcome to implement these mechanistic models in clinical practice.

Successful Typical AVNRT Ablation

AVNRT is the most common regular arrhythmia in humans, and therefore the most commonly encountered during ablation attempts for regular tachycardias. Case Summary: We present a 41-year-old female patient with chest palpitations in the last 10 years, but prior to hospitalization felt heavy sensation on her chest and hospitalized due to heavy chest palpitations and documented SVT. She had no history of hypertension, diabetes mellitus, coronary heart conditions, or stroke. Physical examination showed fair general condition with GCS E4V5M6, blood pressure 130/80, pulse rate 96x / minute, breath rate 18 x / minute and saturation of 99%. Physical examinations are within normal limits. Discussion: Catheter ablation for AVNRT is the current treatment of choice in symptomatic patients. It reduces arrhythmia-related hospitalizations and costs, and substantially improves quality of life. Catheter ablation approaches aimed at the fast pathway have been abandoned; slow pathway ablation, using a combined anatomical and mapping approach, is now the method of choice. This approach offers a success rate of 95 %, has a recurrence rate of approximately 1.3 – 4.0 %, and has been associated with a low risk of atrioventricular (AV) block.

The hemodynamic effect of simulated atrial fibrillation on left ventricular function.

Atrial fibrillation (AF) is the most common sustained arrhythmia in humans. The onset of the arrhythmia can significantly impair cardiac function. This hemodynamic deterioration has been explained by several mechanisms such as the loss of atrial contraction, shortening of ventricular filling, or heart rhythm irregularity. This study sought to evaluate the relative hemodynamic contribution of each of these components during in vivo simulated human AF. Twelve patients undergoing catheter ablation for paroxysmal AF were paced simultaneously from the proximal coronary sinus and the His bundle region according to prescribed sequences of irregular R-R intervals with the average rate of 90and 130 bpm, which were extracted from the database of digital ECG recordings of AF from other patients. The simulated AF was compared to regular atrial pacing with spontaneous atrioventricular conduction and regular simultaneous atrioventricular pacing at the same heart rate. Beat-by-beat left atrial and left ventricular pressures, including LV dP/dT and Tau index were assessed by direct invasive measurement; beat-by-beat stroke volume and cardiac output (index) were assessed by simultaneous pulse-wave doppler intracardiac echocardiography. Simulated AF led to significant impairment of left ventricular systolic and diastolic function. Both loss of atrial contraction and heart rate irregularity significantly contributed to hemodynamic impairment. This effect was pronounced with increasing heart rate. Our findings strengthen the rationale for therapeutic strategies aiming at rhythm control and heart rate regularization in patients with AF.