Multi-scale Structure-Function Relationships in Right Ventricular Failure Due to Pressure Overload

Right ventricular failure (RVF) is the major cause of death in pulmonary hypertension. Recent studies have characterized changes in RV structure in RVF, including hypertrophy, fibrosis and abnormalities in mitochondria. Few if any studies have explored the relationships between these multi-scale structural changes and functional changes in RVF. Pulmonary artery banding (PAB) was used to induce RVF due to pressure overload in male rats. Eight-weeks post-surgery, terminal invasive measurements demonstrated RVF with decreased ejection fraction (70{plus minus}10% vs 45{plus minus}15%, Sham vs. PAB, p<0.005) and cardiac output (126{plus minus}40 mL/min vs. 67{plus minus}32 mL/min, Sham vs. PAB, p<0.05). At the organ level, RV hypertrophy was directly correlated with increased contractility, which was insufficient to maintin ventricular-vascular coupling. At the tissue level, there was a 90% increase in fibrosis that had a direct correlation with diastolic dysfunction measured by reduced chamber compliance (R2=0.43, p=0.008). At the organelle level, transmission electron microscopy demonstrated an abundance of small-sized mitochondria. Increased mitochondria was associated with increased ventricular oxygen consumption and reduced mechanical efficiency (p<0.05). These results demonstrate an association between alterations in mitochondria and RV oxygen consumption and mechanical inefficiency in RVF, and, a link between fibrosis and in vivo diastolic dysfunction. Overall, this work provides key insights into multi-scale RV remodeling in RVF due to pressure overload.