Dyspnea and hypoxemia are common clinical findings in patients with heart failure with preserved ejection fraction (HFpEF), who frequently present with pulmonary hypertension (type II PH). Relevant intermittent or chronic oxygen desaturation is often present at rest and even more pronounced during physical exercise, and poses an additional negative impact on global cardiac function. Arterial hypoxemia in HF patients is commonly attributed to reduced cardiac outputs, yet unaltered venous saturation points instead to an impaired pulmonary gas exchange. Here, we hypothesize that hypoxemia in HFpEF is attributable to a decrease in lung vascular surface area. Lung capillary rarefaction is present in patients suffering from pulmonary arterial hypertension, but so far, has not been addressed in HFpEF and type II PH.

To test this hypothesis, we employed the well-established rat model of surgically-induced supracoronary aortic banding (AoB) to induce congestive heart failure and type II PH associated with pulmonary vascular remodeling. In line with clinical HFpEF, AoB rats present with a preserved left-ventricular (LV) ejection fraction of 50-55%, increased E/e’ ratio, elevated echocardiographically-assessed LV mass as well as profound lung vascular remodeling. Systemic hypoxemia was detected in AoB animals with reduced arterial oxygen partial pressure and saturation while venous oxygenation remained unchanged compared to SHAM-operated controls. Flow cytometric analysis revealed reduced lung microvascular endothelial cell counts, suggestive of capillary loss. Assessment of capillary surface area by measuring dextran blue efflux confirmed a reduction in absolute capillary surface area in AoB lungs compared to SHAM controls. To corroborate our findings, we performed pulmonary angiography in AoB lungs using micro computed tomography (µCT). Preliminary data show a 23% decline in lung vascular surface area and a significantly lower lung vascular volume in HFpEF vs. control lungs.

In conclusion, the AoB HFpEF model displays relevant systemic hypoxemia, mimicking the clinical phenotype, and shows characteristic signs of pulmonary vascular rarefaction including loss of endothelial cells, vascular surface area and volume. As such, vascular rarefaction is expected to contribute relevantly to the observed systemic hypoxemia in HFpEF. Our findings underscore the importance of maintaining physiological lung vascular structure and function in HFpEF to decelerate disease progression. The project is funded by the CRC1470.