Exposure to 10% O2 for 2 weeks worsened diastolic dysfunction in HFpEF mice, whereas moderate hyperoxia (40% O2) normalized E/A ratio and global longitudinal strain.
In preclinical models of HFpEF, lung capillary rarefaction leads to systemic hypoxemia which exacerbates LV diastolic dysfunction, a process that can be mitigated by moderate hyperoxia.
Abstract Rationale Heart failure with preserved ejection fraction (HFpEF) is characterized by systemic hypoxemia at rest and during exercise, and may ultimately progress from left ventricular (LV) disease to right ventricular (RV) dysfunction and failure. Previous studies suggest that impaired alveolo-capillary diffusion may contribute to hypoxemia in HFpEF, yet underlying structural and functional changes remain unclear. We hypothesized that HFpEF may be associated with lung capillary rarefaction resulting in systemic hypoxemia which may in turn exacerbate LV and RV dysfunction in a positive feedback loop. Methods We applied three distinct animal models of heart failure: 1) a rat model of surgically-induced supracoronary aortic banding (AoB) as a model of congestive heart failure; 2) ZSF1 obese rats treated with the VEGF receptor antagonist SU5416 as a model of HFpEF; and 3) C57BL/6J mice receiving high fat diet and Nω-nitro-l-arginine methyl ester over 12 weeks as a model of HFpEF. LV and RV functions were evaluated by hemodynamic assessment. Lung microvascular rarefaction was determined by micro-computed tomography (micro-CT) and stereology, and lung endothelial cells were quantified by flow cytometry. Hypoxemia was evaluated by arterial blood gas analysis (AoB rats) and mouseOx (HFpEF mice). Results All models showed preserved LV ejection fraction (LVEF) with diastolic dysfunction indicated by impaired E/A ratios and reduced LV global longitudinal strain (GLS). Micro-CT revealed decreased pulmonary vascular volume in both rat models that was most prominent in vessels 250 µm in diameter. Stereology in HFpEF mice confirmed a significant reduction in total pulmonary capillary number. Lung microvascular endothelial cell counts were markedly reduced in AoB rats and HFpEF mice. Systemic hypoxemia was evident in AoB rats (reduced arterial oxygen partial pressures and oxygen saturation) and in HFpEF mice both at rest and after exercise.To assess cardiac effects of hypoxemia in HFpEF, HFpEF mice were exposed to 10% O2 for 2 weeks, which worsened diastolic dysfunction while preserving LVEF. Conversely, restoration of normoxemia by exposure to moderate hyperoxia (40% O2) normalized E/A ratio and GLS and as such, mitigated LV diastolic dysfunction in HFpEF mice. Conclusions Our findings identify lung microvascular rarefaction in three different preclinical models of heart failure. Capillary rarefaction is associated with systemic hypoxemia which further exacerbates LV dysfunction, while moderate hyperoxia protects LV function in HFpEF. These findings highlight the critical interplay between lung vascular remodeling and ventricular dysfunction in HFpEF. This abstract is funded by: the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 437531118 – SFB 1470
Kocana et al. (Fri,) conducted a other in Heart failure with preserved ejection fraction (HFpEF). Hypoxia and hyperoxia exposure vs. Normoxemia was evaluated on LV and RV functions, lung microvascular rarefaction. Exposure to 10% O2 for 2 weeks worsened diastolic dysfunction in HFpEF mice, whereas moderate hyperoxia (40% O2) normalized E/A ratio and global longitudinal strain.
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