Nitric Oxide in Pulmonary Vein Stenosis: Lower Pulmonary Vascular Resistance at the Expense of Oxygenation
Authors: van Duin Richard Willem Benjamin , Stam Kelly , Garcia‐Alvarez Ana , Pereda Daniel , Ibanez Borja , Duncker Dirk Jan , Reiss Irwin Karl Marcel , Merkus Daphne 
Published: November 2023

Background

Pulmonary vein stenosis (PVS) can occur as a result of a congenital anomaly or as a complication of radiofrequency ablation in treatment of atrial fibrillation. PVS impairs outflow to the left atrium, which produces a passive pressure increase in consecutively the pulmonary veins, capillaries and pulmonary arteries, ultimately leading to pulmonary hypertension (PH).

PH, defined as a chronic elevation of pulmonary artery pressure >25 mmHg, is characterized by remodeling of the pulmonary arterioles, that produces a further increase in pulmonary vascular resistance, thereby sustaining a vicious cycle of elevations in pressure, resistance and vascular remodeling. The resultant progressive increase in right ventricular (RV) after load leads to an impaired exercise capacity and eventually results in overt right heart failure and death.

Here we test the hypothesis that vasoconstriction and vascular remodeling in PH is a result of decreased production of the vasodilator and anti‐proliferative factor nitric‐oxide (NO).

Methods

Swine either underwent non‐restrictive banding of the confluent of both inferior pulmonary veins (PVB group n=7), or sham operation (SH group n=6). Four weeks after surgery, all animals were chronically instrumented to longitudinally assess hemodynamics at rest and during exercise for an additional 8 weeks (week 5–12). To determine whether the contribution of endogenous NO‐production in regulation of pulmonary vascular resistance was reduced, the NO‐synthase inhibitor Nω‐nitro‐L‐arginine (NLA) was administered, and hemodynamic responses to exercise were re‐assessed. At sacrifice, the heart was excised to assess RV hypertrophy.

Results

PVB swine developed a gradual elevation of mean pulmonary artery pressure (mPAP) compared to SH group 41±7 vs 19±4 mmHg (p<0.01) and increased total pulmonary vascular resistance index (tPVRi) of 250±62 vs 105±15 mmHg·L−1·min·kg (p<0.01). Both PVB and SH groups showed similar increase in pulmonary resistance and pressure after NO‐synthase inhibition with NLA at rest and during exercise, indicating preserved NO‐production in banded swine. Interestingly, NO‐synthase inhibition improved oxygenation in exercising PVB swine, as arterial pO2 was significantly increased by NLA (Figure). Right ventricular hypertrophy was evident from the increased RV/LV ratio of 0.59±0.03 vs 0.44±0.01 g/g, and the RV/Bodyweight ratio of 1.74±0.11 vs 1.29±0.06 g/kg (both p<0.01).

Conclusion

Banded swine gradually developed pulmonary hypertension which eventually resulted in RV hypertrophy. At this stage of the disease, increased pulmonary artery pressure and resistance are not due to NO‐deficiency. Interestingly, the observed improvement of oxygenation upon NO‐synthase inhibition suggests that at this stage, maintaining low RV after load has priority over optimal oxygenation, possibly in an attempt to prevent excessive RV hypertrophy.

Support or Funding Information

CVON2012‐08 (PHAEDRA), Sophia Foundation S13‐12