Lung capillary rarefaction in systemic hypoxemia in HFpEF

Ceren Koçana (Berlin)1, L. Jäschke (Berlin)2, N. Hegemann (Berlin)3, M. Kucherenko (Berlin)4, K. Kräker (Berlin)5, P.-L. Perret (Berlin)3, A. Winkler (Berlin)4, D. Faidel (Berlin)4, L. von der Ohe (Berlin)4, C. Knosalla (Berlin)4, R. Dechend (Berlin)6, C. Brandenberger (Berlin)7, S. Simmons (Berlin)8, J. Grune (Berlin)4, W. Kübler (Berlin)1

1Charité - Universitätsmedizin Berlin Institut für Physiologie Berlin, Deutschland; 2Institut für Phyiologie / Charité-Universitätsmedizin Berlin Berlin, Deutschland; 3Charité - Universitätsmedizin Berlin CC2: Institut für Physiologie, CCO Berlin, Deutschland; 4Deutsches Herzzentrum der Charite (DHZC) Klinik für Herz-, Thorax- und Gefäßchirurgie Berlin, Deutschland; 5Max-Delbrück-Centrum für Molekulare Medizin Berlin, Deutschland; 6HELIOS Klinikum Berlin-Buch Klinik und Poliklinik für Kardiologie und Nephrologie Berlin, Deutschland; 7Charité – Universitätsmedizin Berlin Institut für Funktionelle Anatomie Berlin, Deutschland; 8Institut für Physiologie, Charité - Universitätsmedizin Berlin Labor für Lungenkreislaufforschung, Nachwuchsgruppe Immunodynamik Berlin, Deutschland


Systemic hypoxemia at rest and during exercise is a hallmark of patients with heart failure with preserved ejection fraction (HFpEF). This effect cannot be attributed to reduced left ventricular (LV) function per se but implies secondary effects of HFpEF on pulmonary gas exchange. Indeed, HFpEF patients often develop lung vascular remodeling and secondary pulmonary hypertension (PH-HFpEF). Previous studies identified lung vascular maladaptation in HFpEF that may contribute to impaired alveolo-capillary diffusion, yet structural alterations and cellular mechanisms behind these remain unclear. Recently, we identified capillary rarefaction due to apoptotic cell death of lung microvascular endothelial cells as a key feature of vascular remodeling in pulmonary arterial hypertension. As such, we considered that a similar scenario may contributes to impaired gas exchange in PH-HFpEF. Analogously, we here hypothesize that HFpEF may be associated with lung capillary rarefaction causing impaired pulmonary oxygen uptake. The ensuing hypoxemia may in turn aggravate right ventricular and LV dysfunction, thereby propagating HFpEF deterioration in a positive feedback loop.
To test this hypothesis, we used three different animal models of heart failure namely i) a rat model of surgically-induced supracoronary aortic banding (AoB) as an established model of congestive heart failure and secondary PH, ii) ZSF1 obese rats treated with the vascular endothelial growth factor receptor antagonist SU5416 as a model of PH-HFpEF, and iii) C57BL/6J mice receiving high fat diet and N[ω]-nitro-l-arginine methyl ester (L-NAME) over 12 weeks, and additional exposure to hypoxia (10% O2) for the final 2 weeks as a model of severe murine PH-HFpEF. Similar to clinical HFpEF, all animal models presented with a preserved LV EF, increased E/e’ ratio and elevated LV mass as assessed by echocardiography with ZSF1 rats and PH-HFpEF mice also showing reduced LV global longitudinal strain. Pulmonary microangiography by micro-computed tomography indicated a decline in lung vascular surface area and vascular volume in PH-HFpEF vs. control lungs in both rat models. Similarly, preliminary data from PH-HFpEF mice indicated a trend towards a reduced capillary number as determined by design-based stereology. Flow cytometric analyses revealed reduced lung microvascular endothelial cell counts in AoB rats and PH-HFpEF mice relative to corresponding controls. Finally, AoB animals had systemic hypoxemia with reduced arterial oxygen partial pressures and saturation, yet no change in venous oxygenation compared to sham-operated controls pointing to impaired pulmonary gas exchange as underlying mechanism.
Our findings demonstrate lung vascular rarefaction in three different preclinical models of heart failure with PH, respectively. AoB rats also showed relevant systemic hypoxemia similar to the clinical HFpEF phenotype, a finding that remains to be validated in the other models. Lung vascular rarefaction is expected to contribute to the observed systemic hypoxemia in PH-HFpEF, which in turn may negatively impact on the progression of ventricular dysfunction. Our findings highlight the potential relevance of lung vascular maladaptation on the development of PH and hypoxemia in HFpEF, and as such on the progression of biventricular heart disease.
This study is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)–SFB-1470–subproject A04.
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