Clinical and Mechanistic Understanding of Right Ventricular Steatosis in Pulmonary Arterial Hypertension

ABSTRACT
Most patients with pulmonary arterial hypertension (PAH) die from right ventricular (RV) failure and all
experience exercise limitation. No RV-specific therapies exist because the mechanisms underlying RV failure
are poorly understood. The discovery of novel, potentially treatable causes of RV failure and exercise limitation
would be an important advance in the treatment of PAH. RV steatosis may be a novel mechanism of RV failure
in human PAH. We and others reported a high prevalence of insulin resistance in patients with PAH. We
recently published that insulin resistance in PAH manifests primarily as abnormalities in lipid metabolism.
Patients with PAH had elevated circulating free fatty acids and long-chain acylcarnitines and we found
impaired mitochondrial fatty acid oxidation and RV lipid accumulation (steatosis) in a rodent model of PAH. We
used proton magnetic resonance spectroscopy (MRS) to quantify RV lipid in vivo and showed that RV lipid
content is over 10-fold higher in humans with PAH compared with matched controls and may be modifiable
with metformin. In autopsy RV specimens, we found increased ceramide, a mediator of lipotoxicity, and
identified candidate plasma surrogates for RV steatosis. Finally, we present new evidence of skeletal muscle
steatosis in humans to demonstrate that insulin resistance is a systemic feature of PAH. The clinical relevance
of RV steatosis in human PAH is unknown. RV steatosis is common in both heritable and idiopathic PAH and
is not an end-stage phenomenon, which suggests potential for therapeutic intervention. We hypothesize that
abnormal lipid metabolism in PAH leads to delivery of fatty acids in excess of RV oxidative capacity, resulting
in steatosis and lipotoxicity. Our objectives are to: 1) Define the relationships between RV steatosis, RV
function, and exercise capacity; 2) Identify mechanistic drivers of RV steatosis including BMPR2 expression
and lipid metabolism; 3) Examine lipid metabolism in PAH skeletal muscle as a potential driver of reduced
functional capacity; and 4) test the response of RV and skeletal muscle steatosis to metformin. In Aim 1
(clinical relevance) we will measure RV and LV lipid in participants with heritable, idiopathic, and scleroderma-
associated PAH. Participants will undergo the 6-minute walk test, cardiopulmonary exercise testing, and will be
followed for clinical events. A subgroup will undergo repeat MRS at four timepoints over three years to
determine the natural history of steatosis. We will measure RV lipid in participants before and after metformin
therapy in a separate on-going study. In Aim 2 (mechanism), we will perform metabolomic/lipidomic profiling of
peripheral and coronary sinus plasma and measure BMPR2 expression to identify potential drivers of
steatosis. In Aim 3 (specificity), we will perform MRS on skeletal muscle in Aim 1 participants and matched
healthy controls to clarify the systemic effects of lipid metabolic defects in PAH. We will also test the effect of
metformin on skeletal muscle lipid content and fatigue. The proposed studies address an important knowledge
gap in PAH pathophysiology by interrogating a newly discovered, novel mechanism of RV failure in humans.

Grant Number: 5R01HL155278-04
NIH Institute/Center: NIH
Principal Investigator: Evan Brittain