Long-chain fatty acid utilization in Eisenmenger syndrome

Morbidity and mortality in idiopathic pulmonary arterial hypertension (iPAH) are linked to right ventricular failure (RVF), a condition characterized by a metabolic shift from fatty acid oxidation (FAO) to glycolysis. Eisenmenger Syndrome (ES), a unique form of PAH, is associated with a mortality paradox, yet the mechanism for better survival in this condition remains poorly understood.

We postulated that beneficial changes in long chain fatty acid (LCFA) utilization may support right ventricular (RV) adaptations in ES, and therefore ssupport favorable RV function and improved morbidity and mortality when compared to iPAH.

We examined clinical and metabolomic data to identify potential mechanistic clues about RV function and morbidity/mortality in controls, iPAH, and ES subjects.

In a small cohort with iPAH (n = 3) or ES (n = 3) clinical data demonstrated worse hemodynamic disease in ES (mean pulmonary artery/mPA pressure 90 ± 6 vs. 50 ± 4 mmHg, p < 0.001), with better clinical compensation (resting heart rate 81 ± 6 vs. 105 ± 6 bpm, p ≤ 0.05 and lower brain natriuretic peptide levels 11 ± 6 pg/dL vs. 71 ± 18 pg/dL, p < 0.01). Metabolomic analysis demonstrated that 97 circulating lipids were significantly different between iPAH and ES. Plasma concentration of LCFAs (Stearate, Palmitate, Oleate, Lineolate) were significantly reduced in ES compared to iPAH, and all but Lineolate were also reduced when compared to non-PAH control samples, suggesting there may be an advantageous compensatory increase in LCFA utilization (FAO) in ES. Plasma tricarboxylic acid (TCA) cycle metabolites were significantly increased in ES compared to iPAH, supporting that compensatory augmentation of FAO occurs in ES, but not likely in RV failure from iPAH.

Our preliminary data in ES differs importantly and unexpectedly from left ventricular and RV failure, in that circulating LCFA utilization appears to be increased. Further, TCA cycle activity is increased in ES, supporting that mechanisms which preserve or enhance LCFA utilization may ultimately preferentially support FAO for energy production. Further study of the impact of LCFA utilization on RV function in ES and other cohorts will be important to determine the role that metabolic substrates may play in long-term preservation of heart function in unique groups.