Identifying Sex-Dependent Markers Of Heart Failure And Atrial Myopathy

Heart failure (HF) with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) each represent approximately ½ of current HF cases. HFrEF is a cardiac-centric syndrome, driven by cell loss and dysfunction leading to dilated cardiomyopathy. HFpEF, alternatively, is a systemic syndrome characterized by accumulated risk factors, comorbidities, and a stiff heart with diastolic dysfunction, sometimes clinically presenting as restrictive cardiomyopathy. Recent studies have established that women constitute the majority of patients with HFpEF and that female sex is one of the strongest distinguishing features of HFpEF versus HFrEF. Comorbidities in females include obesity, hypertension, and diabetes. HFrEF or systolic HF is more common in males, and risk factors include smoking and heart attack. While numerous devices and pharmacological agents reduce mortality in HFrEF, no current medications are similarly effective for HFpEF; thus, the un-responsive HFpEF proportion is rising. Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with HF and also demonstrates sex differences in incidence. Both AF and HFpEF have shared risk factors and confer increased risks for adverse cardiovascular outcomes. Since sex-specific variables that contribute to HF development and progression are largely unknown, increasing our knowledge about molecular mechanisms involved in metabolic and structural changes in the male versus female failing heart will allow us to pinpoint possible targets for safer and more effective sex-specific therapeutic strategies. We haves recently developed a mouse model that recapitulates this sexual dimorphism in HF and atrial susceptibility. In this model, female mice only exhibit continuous left ventricular hypertrophy, diastolic dysfunction, preserved ejection fraction, pulmonary congestion, arrhythmia, and reduced exercise tolerance, mimicking the clinical symptoms of restrictive cardiomyopathy. Thus, this mouse line represents a novel tool to interrogate sex differences in cardiac remodeling at the functional, structural, and biochemical level at baseline or with coordinate cardiac or metabolic stress. These mice were generated by crossing the βARKnt line (residues 50-145) with the βARKct line, peptide fragments of the prototypical G protein-coupled receptor (GPCR) kinase (GRK) GRK2 (βARK1). Breeding of βARKnt (NT) with βARKct (M27) single-transgenic mice results in a combination of all four possible genotypes, non-transgenic littermate controls (NLC)/NLC, NT/NLC (TG/NLC), NLC/M27 (NLC/TG), and NT/M27 (TG/TG), born as littermate controls. Heart weight normalized to tibia length (HW/TL) was significantly increased in 9-12 week old female and male TG/NLC and TG/TG mice, but left atrial weight was enhanced only in the TG/TG mice and to a greater extent in females that males. Despite no difference in ventricular myocyte area, ventricular fibrosis, atrial myocyte area, and atrial fibrosis were significantly increased in female NT/M27 mice only. Further, this was accompanied by a significant increase in mitral valve E/A (ventricular relaxation/atrial contraction) ratio in these mice.