Gender differences in electrophysiological gene expression in failing and non-failing human hearts

Abstract

The increasing availability of human cardiac tissues for study are critically important in increasing our understanding of the impact of gender, age, and other parameters, such as medications and cardiac disease, on arrhythmia susceptibility. In this study, we aimed to compare the mRNA expression of 89 ion channel subunits, calcium handling proteins, and transcription factors important in cardiac conduction and arrhythmogenesis in the left atria (LA) and ventricles (LV) of failing and nonfailing human hearts of both genders. Total RNA samples, prepared from failing male (n = 9) and female (n = 7), and from nonfailing male (n = 9) and female (n = 9) hearts, were probed using custom-designed Taqman gene arrays. Analyses were performed to explore the relationships between gender, failure state, and chamber expression. Hierarchical cluster analysis revealed chamber specific expression patterns, but failed to identify disease- or gender-dependent clustering. Gender-specific analysis showed lower expression levels in transcripts encoding for K(v)4.3, KChIP2, K(v)1.5, and K(ir)3.1 in the failing female as compared with the male LA. Analysis of LV transcripts, however, did not reveal significant differences based on gender. Overall, our data highlight the differential expression and transcriptional remodeling of ion channel subunits in the human heart as a function of gender and cardiac disease. Furthermore, the availability of such data sets will allow for the development of disease-, gender-, and, most importantly, patient-specific cardiac models, with the ability to utilize such information as mRNA expression to predict cardiac phenotype.

Figure 1. Study population (n = 34).

Figure 2. Ventricular remodeling in heart failure.

(A) Ventricular remodeling of major ion channel subunits and accessory proteins in heart failure. (B) Regional specificity of targets in failing and nonfailing hearts of both genders.

Figure 3. Gender dependent comparison of relative expression levels of all genes.

(A) Nonfailing male versus female LA. (B) Failing male versus female LA showing a distinct male bias. (C) Nonfailing male versus female LV. (D) Failing female versus male LV. The dotted diagonal line represents equal expression levels between genders.

Figure 4. Gender dependent remodeling in the LA.

(A) Gender dependent atrial remodeling of major ion channel subunits and accessory proteins in failing and nonfailing hearts of both genders. (B) Relative expression levels of failing LA samples of both genders. The white data points indicate the patient with a documented history of AF.

Figure 5. Gender dependent remodeling of adrenergic receptors.

(A) Gender dependent atrial remodeling of adrenergic receptors in failing and nonfailing hearts of both genders. (B) Relative expression levels of adrenergic receptors in failing LA samples of both genders. The white data points indicate the patient with a documented history of AF.

Figure 6. Gender dependent ventricular remodeling of major repolarizing ion channel subunits and accessory proteins in failing and nonfailing hearts of both genders.

Figure 7. Relative expression levels of failing LV samples of both genders.

The white data points indicate patients with a documented history of ventricular tachyarrhythmias.

Figure 8. Average ratios of epicardial to endocardial expression of repolarization targets in failing and nonfailing hearts of both genders.

The dotted back line represents a ratio of one.