Abstract 13007: Ketone Bodies for Right Ventricular Failure: A Unique Therapeutic Opportunity

Abstract

Introduction: Right ventricular failure (RVF) is the leading cause of death in pulmonary arterial hypertension (PAH), but effective therapies for RVF are lacking. Ketones exert therapeutic effects through suppression of the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome and exhibit favorable metabolic properties in LVF. However, the relationships among serum ketone bodies, RV inflammasome activation, and RV function in preclinical and human RVF are unexplored. Hypothesis: Serum ketones correlate with RV function and induction of therapeutic ketosis ameliorates RV dysfunction. Methods: 51 PAH patients were dichotomized into preserved or impaired RV function based on a cardiac index of 2.2 L/min/m 2 . Serum ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (BOHB) were quantified using ultra performance liquid chromatography and mass spectrometry. The relationships between AcAc and BOHB and clinical measures of RV function were evaluated. In rodent studies, male Sprague Dawley rats were assigned to three groups: control (saline injection), monocrotaline (MCT) standard chow diet (MCT-SD), and MCT ketogenic diet (MCT-KD). Immunoblots and confocal microscopy probed macrophage NLRP3 activation in RV extracts and sections. RV fibrosis was determined by Picrosirus Red. Echocardiography evaluated RV function. Results: Human RVF patients lacked a compensatory ketosis as serum AcAc and BOHB levels were not associated with hemodynamic or echocardiographic measures of RV function. In rodent studies, AcAc and BOHB levels were also not elevated in MCT-mediated RVF, but the ketogenic diet significantly increased AcAc and BOHB levels. MCT-KD exhibited suppressed NLRP3 activation with a reduction in NLRP3, ASC (apoptosis-associated speck-like protein), pro-caspase-1, and interleukin-1 beta on immunoblots. Moreover, the number of ASC-positive macrophage in RV sections was reduced, RV fibrosis was blunted, and RV function was augmented in MCT-KD rats. Conclusions: Our preclinical and clinical data suggests therapeutic ketosis could combat RVF, and patients with RVF are uniquely primed for ketogenic interventions due to a lack of effective ketosis.