A female-specific rabbit model of heart failure with preserved ejection fraction.

Abstract

BACKGROUND: Women had a higher risk of heart failure with preserved ejection fraction (HFpEF) and diastolic dysfunction than men. OBJECTIVES: We hypothesize that (1) the high cholesterol (HC) diet causes HFpEF in female but not male hearts, and (2) adding salt to the HC diet worsens HFpEF. METHODS: We fed rabbits an HC diet (4 males and 4 females) or a high salt (HS)-HC diet (4 males and 4 females) for 14 weeks. The hearts were Langendorff-perfused for optical mapping. RESULTS: The HC diet and female sex were associated with increased E/e' ratios at sacrifice (P < .001 for both). The E/e' ratios were higher in the HC than in the HS-HC group (P < .001). Females had a larger left atrial diameter (P = .002) and more atrial fibrosis than males (P < .001). There was more ventricular fibrosis in HC than in HS-HC (P < .001). Apamin, a specific blocker of apamin-sensitive small conductance calcium-activated potassium current (I), lengthened action potential duration more in females than males (by 8 &#xb1; 2 ms, P = .002) in the absence of isoproterenol. Apamin reduced intracellular calcium amplitudes (P < .001) and conduction velocity (P = .008), the phase singularities during ventricular fibrillation (VF) (P = .002), and dominant frequency during VF (P = .016) more in females. HC females (but not HC males or any HS-HC rabbits) showed significant increases in N-terminal pro-B-type natriuretic peptide levels at sacrifice (P < .001). CONCLUSION: The HC rabbit is a female-specific model of HFpEF. Adding salt to the HC diet improved rather than worsened the HFpEF. Apamin modulates this HFpEF model's electrophysiological parameters and VF patterns.