ArticleCirculation research2008
Sex, age, and regional differences in L-type calcium current are important determinants of arrhythmia phenotype in rabbit hearts with drug-induced long QT type 2.
Article in Circulation research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 123 citations in OpenAlex.
- T-World Virtual Human Cardiomyocyte. I. Development, Validation, and Cell Arrhythmogenesis.Circulation research · 2026Article
- Digital twin for sex-specific identification of class III antiarrhythmic drugs based on in vitro measurements, computer models, and machine learning tools.PLoS computational biology · 2025Article
- Antiarrhythmic effects of mirabegron on ventricular fibrillation in Langendorff-perfused rabbit ventricles.The Journal of physiology · 2025Article
- Exploring the mechanisms of sex-specific proarrhythmia in long QT syndrome through computational modeling.American journal of physiology. Heart and circulatory physiology · 2025Article
- T-World: A highly general computational model of a human ventricular myocyte.bioRxiv : the preprint server for biology · 2025Article
- Sex differences in cardiac dynamics during myocardial ischemia using a single cell approach.Scientific reports · 2025Article
- Sex Differences in Cardiac Tolerance to Oxygen Deprivation - 40 Years of Cardiovascular Research.Physiological research · 2024Review
- The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block.Cardiovascular research · 2024Article
- Sex and age affect depot expression of Ca2+ channels in rat white fat adipocytes.Journal of molecular endocrinology · 2024Article
- Burden of Purkinje ectopies associated with sex hormone levels.HeartRhythm case reports · 2023Article
- Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle.International journal of molecular sciences · 2023Review
- Whole-heart multiparametric optical imaging reveals sex-dependent heterogeneity in cAMP signaling and repolarization kinetics.Science advances · 2023Article
- The effect of sex and age on ex vivo cardiac electrophysiology: insight from a guinea pig model.American journal of physiology. Heart and circulatory physiology · 2023Article
- Sex differences in heart: from basics to clinics.European journal of medical research · 2022Review
- Why Is Only Type 1 Electrocardiogram Diagnostic of Brugada Syndrome? Mechanistic Insights From Computer Modeling.Circulation. Arrhythmia and electrophysiology · 2022Article
- Sex-Specific Classification of Drug-Induced Torsade de Pointes Susceptibility Using Cardiac Simulations and Machine Learning.Clinical pharmacology and therapeutics · 2021Article
- Amylin deposition activates HIF1α and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates.Communications biology · 2021Article
- TdP Incidence in Methoxamine-Sensitized Rabbit Model Is Reduced With Age but Not Influenced by Hypercholesterolemia.Frontiers in physiology · 2021Article
- The Link Between Sex Hormones and Susceptibility to Cardiac Arrhythmias: From Molecular Basis to Clinical Implications.Frontiers in cardiovascular medicine · 2021Review
- Sex-specific IHeart rhythm · 2021Article
4 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
In congenital and acquired long QT type 2, women are more vulnerable than men to torsade de pointes. In prepubertal rabbits (and children), the arrhythmia phenotype is reversed; however, females still have longer action potential durations than males. Thus, sex differences in K(+) channels and action potential durations alone cannot account for sex-dependent arrhythmia phenotypes. The L-type calcium current (I(Ca,L)) is another determinant of action potential duration, Ca(2+) overload, early afterdepolarizations (EADs), and torsade de pointes. Therefore, sex, age, and regional differences in I(Ca,L) density and in EAD susceptibility were analyzed in epicardial left ventricular myocytes isolated from the apex and base of prepubertal and adult rabbit hearts. In prepubertal rabbits, peak I(Ca,L) at the base was 22% higher in males than females (6.4+/-0.5 versus 5.0+/-0.2 pA/pF; P<0.03) and higher than at the apex (6.4+/-0.5 versus 5.0+/-0.3 pA/pF; P<0.02). Sex differences were reversed in adults: I(Ca,L) at the base was 32% higher in females than males (9.5+/-0.7 versus 6.4+/-0.6 pA/pF; P<0.002) and 28% higher than the apex (9.5+/-0.7 versus 6.9+/-0.5 pA/pF; P<0.01). Apex-base differences in I(Ca,L) were not significant in adult male and prepubertal female hearts. Western blot analysis showed that Ca(v)1.2alpha levels varied with sex, maturity, and apex-base, with differences similar to variations in I(Ca,L); optical mapping revealed that the earliest EADs fired at the base. Single myocyte experiments and Luo-Rudy simulations concur that I(Ca,L) elevation promotes EADs and is an important determinant of long QT type 2 arrhythmia phenotype, most likely by reducing repolarization reserve and by enhancing Ca(2+) overload and the propensity for I(Ca,L) reactivation.
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