Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles

Xiao, Langtao; Zhang, Liming; Han, Wei; Wang, Zhiguo; Nattel, Stanley

doi:10.1152/ajpheart.01288.2005

Cited by 71 publications

(68 citation statements)

References 37 publications

(56 reference statements)

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“…Also, concentrations of galactin‐3 levels have been shown to be higher in women compared with men in population‐based studies, whereas soluble ST2 and growth differentiation factor‐15 have been shown to be lower in women compared with men 28. Although the exact role sex plays in cardiac diseases remains to be fully understood, what is known is that there are fundamental intrinsic sex differences in cardiac tissue 29. These differences may include variable ion channel expression and diverse responses to sex hormonal regulations via long term genomic and acute non‐genomic pathways 29, 30.…”

Section: Discussionmentioning

confidence: 99%

Differentiating heart failure phenotypes using sex‐specific transcriptomic and proteomic biomarker panels

et al. 2017

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AimsHeart failure with preserved ejection fraction (HFpEF) accounts for 30–50% of patients with heart failure (HF). A major obstacle in HF management is the difficulty in differentiating between HFpEF and heart failure with reduced ejection fraction (HFrEF) using conventional clinical and laboratory investigations. The aim of this study is to develop robust transcriptomic and proteomic biomarker signatures that can differentiate HFpEF from HFrEF.Methods and resultsA total of 210 HF patients were recruited in participating institutions from the Alberta HEART study. An expert clinical adjudicating panel differentiated between patients with HFpEF and HFrEF. The discovery cohort consisted of 61 patients, and the replication cohort consisted of 70 patients. Transcriptomic and proteomic data were analysed to find panels of differentiating HFpEF from HFrEF. In the discovery cohort, a 22‐transcript panel was found to differentiate HFpEF from HFrEF in male patients with a cross‐validation AUC of 0.74, as compared with 0.70 for N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) in those same patients. An ensemble of the transcript panel and NT‐pro‐BNP yielded a cross‐validation AUC of 0.80. This performance improvement was also observed in the replication cohort. An ensemble of the transcriptomic panel with NT‐proBNP produced a replication AUC of 0.90, as compared with 0.74 for NT‐proBNP alone and 0.73 for the transcriptomic panel.ConclusionsWe have identified a male‐specific transcriptomic biomarker panel that can differentiate between HFpEF and HFrEF. These biosignatures could be further replicated on other patients and potentially be developed into a blood test for better management of HF patients.

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Section: Discussionmentioning

confidence: 99%

Differentiating heart failure phenotypes using sex‐specific transcriptomic and proteomic biomarker panels

et al. 2017

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“…20 In contrast to rabbit hearts, a study on mongrel dogs found uniformly higher levels of I Ca,L in female than male hearts across the left ventricular wall. 41 In guinea pig hearts, the opposite result was obtained, where I Ca,L was significantly higher in males than females even when the female current density was measured at different phases of the estrus cycle. 42 Moreover, in mouse and rat hearts, no significant differences were found in I Ca,L between males and females.…”

Section: Sex Differences In I Calmentioning

confidence: 95%

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

Sims

Reisenweber

Viswanathan

et al. 2008

Circulation Research

103

121

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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 ϩ 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 2ϩ 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 (6.4Ϯ0.5 versus 5.0Ϯ0.2 pA/pF; PϽ0.03) and higher than at the apex (6.4Ϯ0.5 versus 5.0Ϯ0.3 pA/pF; PϽ0.02). Sex differences were reversed in adults: I Ca,L at the base was 32% higher in females than males (9.5Ϯ0.7 versus 6.4Ϯ0.6 pA/pF; PϽ0.002) and 28% higher than the apex (9.5Ϯ0.7 versus 6.9Ϯ0.5 pA/pF; PϽ0.01). Apex-base differences in I Ca,L were not significant in adult male and prepubertal female hearts. Western blot analysis showed that Ca v 1.2␣ 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 2ϩ overload and the propensity for I Ca,L reactivation. (Circ Res. 2008;102:e86 -e100.)

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“…Such variability may even exist among nearby cells and regions (Schram et al, 2002). It is also possible that AP properties may depend on other factors, including age (Jeck and Boyden, 1992) and gender (Tanabe et al, 1999;Xiao L et al, 2006).…”

Section: Agreement Between the Two Modelsmentioning

confidence: 99%

Dynamics of human atrial cell models: Restitution, memory, and intracellular calcium dynamics in single cells

Cherry

Hastings

Evans

2008

Progress in Biophysics and Molecular Biology

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Mathematical models of cardiac cells have become important tools for investigating the electrophysiological properties and behavior of the heart. As the number of published models increases, it becomes more difficult to choose a model appropriate for the conditions to be studied, especially when multiple models describing the species and region of the heart of interest are available. In this paper, we will review and compare two detailed ionic models of human atrial myocytes, the Nygren et al. model (NM) and the Courtemanche et al. model (CM). Although both models include the same transmembrane currents and are largely based on the same experimental data from human atrial cells, the two models exhibit vastly different properties, especially in their dynamical behavior, including restitution and memory effects. The CM produces pronounced rate adaptation of action potential duration (APD) with limited memory effects, while the NM exhibits strong rate dependence of resting membrane potential (RMP), limited APD restitution, and stronger memory, as well as delayed afterdepolarizations and auto-oscillatory behavior upon cessation of rapid pacing. Channel conductance modifications based on experimentally measured changes during atrial fibrillation modify rate adaptation and memory in both models, but do not change the primary rate-dependent properties of APD and RMP for the CM and NM, respectively. Two sets of proposed changes to the NM that yield a spike-and-dome action potential morphology qualitatively similar to the CM at slow pacing rates similarly do not change the underlying dynamics of the model. Moreover, interchanging the formulations of all transmembrane currents between the two models while leaving calcium handling and ionic concentrations intact indicates that the currents strongly influence memory and the rate adaptation of RMP, while intracellular calcium dynamics primarily determine APD rate adaptation. Our results suggest that differences in intracellular calcium handling between the two human atrial myocyte models are responsible for marked dynamical differences and may prevent reconciliation between the models by straightforward channel conductance modifications.

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Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles

Cited by 71 publications

References 37 publications

Differentiating heart failure phenotypes using sex‐specific transcriptomic and proteomic biomarker panels

Differentiating heart failure phenotypes using sex‐specific transcriptomic and proteomic biomarker panels

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

Dynamics of human atrial cell models: Restitution, memory, and intracellular calcium dynamics in single cells

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