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JACC. Clinical Electrophysiology Dec 2023Despite evidence that women are at higher risk of drug-induced torsade de pointes and sudden cardiac death, female sex is vastly underrepresented in cardiovascular... (Review)
Review
Despite evidence that women are at higher risk of drug-induced torsade de pointes and sudden cardiac death, female sex is vastly underrepresented in cardiovascular research, thus limiting our fundamental understanding of sex-specific arrhythmia mechanisms and our ability to predict arrhythmia propensity. To address this urgent clinical and preclinical need, we developed a quantitative tool that predicts the electrophysiological response to drug administration in female cardiomyocytes starting from data collected in males. We demonstrate the suitability of our translator for sex-specific cardiac safety assessment and include proof-of-concept application of our translator to in vitro and in vivo data.
Topics: Humans; Male; Female; Long QT Syndrome; Pharmaceutical Preparations; Electrocardiography; Heart; Arrhythmias, Cardiac
PubMed: 37768254
DOI: 10.1016/j.jacep.2023.08.016 -
Methodist DeBakey Cardiovascular Journal 2024Cardiovascular disease significantly jeopardizes pregnancies in the United States, impacting 1% to 4% of pregnancies annually. Among complications, cardiac arrhythmias... (Review)
Review
Cardiovascular disease significantly jeopardizes pregnancies in the United States, impacting 1% to 4% of pregnancies annually. Among complications, cardiac arrhythmias are prevalent, posing concerns for maternal and fetal health. The incidence of arrhythmias during pregnancy is rising, partly due to advances in congenital heart surgery and a growing population of women with structural heart disease. While most arrhythmias are benign, the increasing prevalence of more serious arrhythmias warrants a proactive approach. Guidance and reassurance suffice in many cases, but persistent symptoms require cautious use of antiarrhythmic drugs or other therapies for a safe outcome. Managing more serious arrhythmias requires a comprehensive, multidisciplinary approach involving specialists, including maternal-fetal medicine physicians, cardiologists, electrophysiologists, and anesthesiologists.
Topics: Pregnancy; Female; Humans; United States; Arrhythmias, Cardiac; Anti-Arrhythmia Agents
PubMed: 38495654
DOI: 10.14797/mdcvj.1325 -
American Journal of Physiology. Heart... Sep 2023Although cardiac action potential (AP) generation and propagation have traditionally been attributed exclusively to cardiomyocytes (CM), other cell types in the heart... (Review)
Review
Although cardiac action potential (AP) generation and propagation have traditionally been attributed exclusively to cardiomyocytes (CM), other cell types in the heart are also capable of forming electrically conducting junctions. Interactions between CM and nonmyocytes (NM) enable and modulate each other's activity. This review provides an overview of the current understanding of heterocellular electrical communication in the heart. Although cardiac fibroblasts were initially thought to be electrical insulators, recent studies have demonstrated that they form functional electrical connections with CM in situ. Other NM, such as macrophages, have also been recognized as contributing to cardiac electrophysiology and arrhythmogenesis. Novel experimental tools have enabled the investigation of cell-specific activity patterns in native cardiac tissue, which is expected to yield exciting new insights into the development of novel or improved diagnostic and therapeutic strategies.
Topics: Humans; Myocytes, Cardiac; Fibroblasts; Arrhythmias, Cardiac; Action Potentials; Electrophysiological Phenomena
PubMed: 37417876
DOI: 10.1152/ajpheart.00184.2023 -
Biomedicine & Pharmacotherapy =... Dec 2023Arrhythmia is one of the most common cardiovascular diseases. The search for new drugs to suppress various types of cardiac arrhythmias has always been the focus of... (Review)
Review
Arrhythmia is one of the most common cardiovascular diseases. The search for new drugs to suppress various types of cardiac arrhythmias has always been the focus of attention. In the past decade, the screening of antiarrhythmic active substances from plants has received extensive attention. These natural compounds have obvious antiarrhythmic effects, and chemical modifications based on natural compounds have greatly increased their pharmacological properties. The chemical modification of botanical antiarrhythmic drugs is closely related to the development of new and promising drugs. Therefore, the structural characteristics and action targets of natural compounds with antiarrhythmic effects are reviewed in this paper, so that pharmacologists can select antiarrhythmic lead compounds from natural compounds based on the disease target - chemical structural characteristics.
Topics: Humans; Anti-Arrhythmia Agents; Biological Products; Arrhythmias, Cardiac
PubMed: 37897974
DOI: 10.1016/j.biopha.2023.115762 -
Europace : European Pacing,... Aug 2023In the last 25 years, EP Europace has published more than 300 basic and translational science articles covering different arrhythmia types (ranging from atrial... (Review)
Review
In the last 25 years, EP Europace has published more than 300 basic and translational science articles covering different arrhythmia types (ranging from atrial fibrillation to ventricular tachyarrhythmias), different diseases predisposing to arrhythmia formation (such as genetic arrhythmia disorders and heart failure), and different interventional and pharmacological anti-arrhythmic treatment strategies (ranging from pacing and defibrillation to different ablation approaches and novel drug-therapies). These studies have been conducted in cellular models, small and large animal models, and in the last couple of years increasingly in silico using computational approaches. In sum, these articles have contributed substantially to our pathophysiological understanding of arrhythmia mechanisms and treatment options; many of which have made their way into clinical applications. This review discusses a representative selection of EP Europace manuscripts covering the topics of pacing and ablation, atrial fibrillation, heart failure and pro-arrhythmic ventricular remodelling, ion channel (dys)function and pharmacology, inherited arrhythmia syndromes, and arrhythmogenic cardiomyopathies, highlighting some of the advances of the past 25 years. Given the increasingly recognized complexity and multidisciplinary nature of arrhythmogenesis and continued technological developments, basic and translational electrophysiological research is key advancing the field. EP Europace aims to further increase its contribution to the discovery of arrhythmia mechanisms and the implementation of mechanism-based precision therapy approaches in arrhythmia management.
Topics: Animals; Atrial Fibrillation; Translational Science, Biomedical; Tachycardia, Ventricular; Anti-Arrhythmia Agents; Heart Failure
PubMed: 37622575
DOI: 10.1093/europace/euad210 -
PLoS Medicine Oct 2023Although previous evidence has suggested an increased risk of cardiovascular disease (CVD) in patients with inflammatory bowel disease (IBD), its association with...
BACKGROUND
Although previous evidence has suggested an increased risk of cardiovascular disease (CVD) in patients with inflammatory bowel disease (IBD), its association with arrhythmias is inconclusive. In this study, we aimed to explore the long-term risk of arrhythmias in patients with IBD.
METHODS AND FINDINGS
Through a nationwide histopathology cohort, we identified patients with biopsy-confirmed IBD in Sweden during 1969 to 2017, including Crohn's disease (CD: n = 24,954; median age at diagnosis: 38.4 years; female: 52.2%), ulcerative colitis (UC: n = 46,856; 42.1 years; 46.3%), and IBD-unclassified (IBD-U: n = 12,067; 43.8 years; 49.6%), as well as their matched reference individuals and IBD-free full siblings. Outcomes included overall and specific arrhythmias (e.g., atrial fibrillation/flutter, bradyarrhythmias, other supraventricular arrhythmias, and ventricular arrhythmias/cardiac arrest). Flexible parametric survival models estimated hazard ratios (aHR) with 95% confidence intervals (95% CIs), after adjustment for birth year, sex, county of residence, calendar year, country of birth, educational attainment, number of healthcare visits, and cardiovascular-related comorbidities. Over a median of approximately 10 years of follow-up, 1,904 (7.6%) patients with CD, 4,154 (8.9%) patients with UC, and 990 (8.2%) patients with IBD-U developed arrhythmias, compared with 6.7%, 7.5%, and 6.0% in reference individuals, respectively. Compared with reference individuals, overall arrhythmias were increased in patients with CD [54.6 versus 46.1 per 10,000 person-years; aHR = 1.15 (95% CI [1.09, 1.21], P < 0.001)], patients with UC [64.7 versus 53.3 per 10,000 person-years; aHR = 1.14 (95% CI [1.10, 1.18], P < 0.001)], and patients with IBD-U [78.1 versus 53.5 per 10,000 person-years; aHR = 1.30 (95% CI [1.20, 1.41], P < 0.001)]. The increased risk persisted 25 years after diagnosis, corresponding to 1 extra arrhythmia case per 80 CD, 58 UC, and 29 IBD-U cases over the same period. Patients with IBD also had a significantly increased risk of specific arrhythmias, except for bradyarrhythmias. Sibling comparison analyses confirmed the main findings. Study limitations include lack of clinical data to define IBD activity, not considering the potential role of IBD medications and disease activity, and the potential residual confounding from unmeasured factors for arrhythmias.
CONCLUSIONS
In this study, we observed that patients with IBD were at an increased risk of developing arrhythmias. The excess risk persisted even 25 years after IBD diagnosis. Our findings indicate a need for awareness of this excess risk among healthcare professionals.
Topics: Humans; Female; Adult; Siblings; Cohort Studies; Bradycardia; Inflammatory Bowel Diseases; Atrial Fibrillation
PubMed: 37856566
DOI: 10.1371/journal.pmed.1004305 -
Circulation Research Dec 2023Nitric oxide (NO) has been identified as a signaling molecule generated during β-adrenergic receptor stimulation in the heart. Furthermore, a role for NO in triggering...
BACKGROUND
Nitric oxide (NO) has been identified as a signaling molecule generated during β-adrenergic receptor stimulation in the heart. Furthermore, a role for NO in triggering spontaneous Ca release via -nitrosylation of CaMKIIδ (Ca/calmodulin kinase II delta) is emerging. NO donors are routinely used clinically for their cardioprotective effects on the heart, but it is unknown how NO donors modulate the proarrhythmic CaMKII to alter cardiac arrhythmia incidence. We test the role of -nitrosylation of CaMKIIδ at the Cysteine-273 inhibitory site and cysteine-290 activating site in cardiac Ca handling and arrhythmogenesis before and during β-adrenergic receptor stimulation.
METHODS
We measured Ca-handling in isolated cardiomyocytes from C57BL/6J wild-type (WT) mice and mice lacking CaMKIIδ expression (CaMKIIδ-KO) or with deletion of the -nitrosylation site on CaMKIIδ at cysteine-273 or cysteine-290 (CaMKIIδ-C273S and -C290A knock-in mice). Cardiomyocytes were exposed to NO donors, -nitrosoglutathione (GSNO; 150 μM), sodium nitroprusside (200 μM), and β-adrenergic agonist isoproterenol (100 nmol/L).
RESULTS
Both WT and CaMKIIδ-KO cardiomyocytes responded to isoproterenol with a full inotropic and lusitropic Ca transient response as well as increased Ca spark frequency. However, the increase in Ca spark frequency was significantly attenuated in CaMKIIδ-KO cardiomyocytes. The protection from isoproterenol-induced Ca sparks and waves was mimicked by GSNO pretreatment in WT cardiomyocytes but lost in CaMKIIδ-C273S cardiomyocytes. When GSNO was applied after isoproterenol, this protection was not observed in WT or CaMKIIδ-C273S but was apparent in CaMKIIδ-C290A. In Langendorff-perfused isolated hearts, GSNO pretreatment limited isoproterenol-induced arrhythmias in WT but not CaMKIIδ-C273S hearts, while GSNO exposure after isoproterenol sustained or exacerbated arrhythmic events.
CONCLUSIONS
We conclude that prior -nitrosylation of CaMKIIδ at cysteine-273 can limit subsequent β-adrenergic receptor-induced arrhythmias, but that -nitrosylation at cysteine-290 might worsen or sustain β-adrenergic receptor-induced arrhythmias. This has important implications for the administration of NO donors in the clinical setting.
Topics: Mice; Animals; Isoproterenol; Nitric Oxide; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cysteine; Mice, Inbred C57BL; Arrhythmias, Cardiac; Myocytes, Cardiac; Phosphorylation; Receptors, Adrenergic, beta; Calcium; Sarcoplasmic Reticulum
PubMed: 37961889
DOI: 10.1161/CIRCRESAHA.123.323571 -
EuroIntervention : Journal of EuroPCR... Nov 2023The GORE CARDIOFORM atrial septal defect (ASD) Occluder (GCA) is composed of a platinum-filled nitinol wire frame covered with expanded polytetrafluoroethylene, making... (Review)
Review
The GORE CARDIOFORM atrial septal defect (ASD) Occluder (GCA) is composed of a platinum-filled nitinol wire frame covered with expanded polytetrafluoroethylene, making it softer and more conformable compared with nitinol mesh devices. After the ASSURED clinical study confirmed the efficacy and safety of the device, it received U.S. Food and Drug Administration approval and a European conformity mark. Our aim was to understand the learning curve implicated in using the GCA for ASD closure in paediatric and adult patients as well as to study the early outcomes. To this end, a review of ASD device closures with GCA in 4 UK centres was conducted between January 2020 and January 2023. Implantation success was the primary outcome; the secondary outcomes were serious adverse events, including new onset arrhythmia. In all, 135 patients were included, and 128 (95%) had successful ASD device closure with GCA. The median patient age was 49 years, the median defect size was 18 mm, and the median device size was 37 mm. The median follow-up time was 6 months (interquartile range 1-14). One device embolisation occurred, and 15 patients (12% of GCA implantations) developed new onset arrhythmia - this was not related to patient age, defect diameter or device oversizing but was positively associated with device size. With growing experience using GCA, the device can be applied to a wide variety of ASD sizes and morphologies. Given the number of successful implantations with an absence of aortic erosion, as well as the ability to perforate through the device should procedures be required in the left atrium, the GCA device is an important addition for interventionists who close atrial septal defects.
Topics: Adult; Child; Humans; Middle Aged; Prosthesis Design; Septal Occluder Device; Treatment Outcome; Time Factors; Cardiac Catheterization; Heart Septal Defects, Atrial; Arrhythmias, Cardiac
PubMed: 37609882
DOI: 10.4244/EIJ-D-23-00378 -
Journal of the American College of... Jul 2023Implantable cardioverter-defibrillators (ICDs) represent transformational technology, arguably the most significant advance in cardiovascular medicine in 50 years. The... (Review)
Review
Implantable cardioverter-defibrillators (ICDs) represent transformational technology, arguably the most significant advance in cardiovascular medicine in 50 years. The vision and determination of pioneers Mirowski and Mower was fundamental to this monumental achievement, working with limited resources and confronted by skepticism/criticism from medical establishment. The inventors were followed >35 years in which a multitude of innovative clinical scientists and engineers introduced technological advances leading to the sophisticated devices in practice today. A pivotal patient experiment with automated termination of ventricular fibrillation (1980) led to U.S. Food and Drug Administration approval. Transvenous lead systems converted ICDs from thoracotomy-based secondary prevention to primary prevention of sudden death devices in countless patients worldwide. ICD acceptance was solidified by prospective randomized controlled trials showing reduced mortality superior to antiarrhythmic drugs. ICDs eventually expanded from coronary disease to inherited arrhythmia conditions (eg, hypertrophic cardiomyopathy). The ICD breakthrough story demonstrates how significant progress is possible in medicine against all odds, given fearless imagination to pursue novel ideas that conflict with accepted wisdom.
Topics: Humans; Defibrillators, Implantable; Prospective Studies; Death, Sudden, Cardiac; Ventricular Fibrillation; Arrhythmias, Cardiac
PubMed: 37468191
DOI: 10.1016/j.jacc.2023.04.056 -
International Journal of Molecular... Dec 2023Dysrhythmia is a term referring to the occurrence of spontaneous and repetitive changes in potentials with parameters deviating from those considered normal. The term... (Review)
Review
Dysrhythmia is a term referring to the occurrence of spontaneous and repetitive changes in potentials with parameters deviating from those considered normal. The term refers to heart anomalies but has a broader meaning. Dysrhythmias may concern the heart, neurological system, digestive system, and sensory organs. Ion currents conducted through ion channels are a universal phenomenon. The occurrence of channel abnormalities will therefore result in disorders with clinical manifestations depending on the affected tissue, but phenomena from other tissues and organs may also manifest themselves. A similar problem concerns the implementation of pharmacotherapy, the mechanism of which is related to the impact on various ion currents. Treatment in this case may cause unfavorable effects on other tissues and organs. Drugs acting through the modulation of ion currents are characterized by relatively low tissue specificity. To assess a therapy's efficacy and safety, the risk of occurrences in other tissues with similar mechanisms of action must be considered. In the present review, the focus is shifted prominently onto a comparison of abnormal electrical activity within different tissues and organs. This review includes an overview of the types of dysrhythmias and the basic techniques of clinical examination of electrophysiological disorders. It also presents a concise overview of the available pharmacotherapy in particular diseases. In addition, the authors review the relevant ion channels and their research technique based on patch clumping.
Topics: Humans; Arrhythmias, Cardiac; Heart; Ion Transport; Research Design; Ion Channels
PubMed: 38203440
DOI: 10.3390/ijms25010263