Modulating Cardiac Energetics in Cardio-Metabolic Syndromes: A mechanistic, hyperpolarized MR Trial of Ninerafaxstat Treatment

Background Type 2 diabetes (T2D) and obesity are key contributors for heart failure (HF)- development, especially for HF with a preserved ejection fraction (HFpEF). On a molecular basis, excessive use of fatty acids (FA) induces lipotoxicity which in turn promotes inflammation, reduces mitochondrial pyruvate dehydrogenase (PDH) activity and impairs myocardial energetics and -function. Harnessing in-vivo, real time measurement of cellular metabolism via hyperpolarized pyruvate MR, we aimed to assess the effects of ninerafaxstat, a selective FA oxidation inhibitor, on cardiac energetics, metabolism & diastolic function in patients with cardio-metabolic syndromes. Methods IMPROVE-DiCE was an open-label, mechanistic phase 2a trial. 21 participants received 200mg ninerafaxstat twice daily for four (n=5) or eight weeks (n=16). Myocardial energetics (phosphocreatine to adenosine triphosphate ratio, PCr/ATP), metabolism and function were assessed pre-& post-treatment using magnetic resonance imaging (MRI), 31P- and 1H-MR spectroscopy (MRS). We utilised hyperpolarized [1-13C]pyruvate MRS to assess in-vivo PDH-flux (n=9) and plasma metabolomics and proteomics to assess whole body metabolism. Results Patients presented with impaired PCr/ATP, (median 1.6 [IQR 1.4, 2.1]), myocardial steatosis (2.2 % [IQR 1.5, 3.2]) and LV diastolic dysfunction (peak circumferential diastolic strain rate 0.86/s [IQR 0.82, 1.06]) at baseline. Ninerafaxstat treatment improved myocardial energetics by 32% ( p <0.01), reduced myocardial triglyceride content by 34% ( p =0.03) and showed a trend towards improved PDH-flux (mean 45% increase, p =0.08). Diastolic function was significantly improved post-treatment (peak diastolic strain rate by 10%, peak LV filling rate by 11%, both p <0.05). Conclusions Metabolic modulation with ninerafaxstat significantly improved myocardial energetics, reduced myocardial steatosis and improved LV diastolic filling. Combining hyperpolarized MRS and metabolomics, is a powerful approach to examine the mechanism of action of novel metabolic modulators. REGISTRATION URL: ; Unique identifier: [NCT04826159][1] ![Figure][2] ### Competing Interest Statement The authors have declared no competing interest. * ### List of Nonstandard Abbreviations and Acronyms 1H-MRS : proton magnetic resonance spectroscopy 31P-MRS : phosphorus magnetic resonance spectroscopy AE : adverse event ACE-I : angiotensin converting enzyme inhibitor ALAT : alanine aminotransferase ARB : angiotensin II receptor blocker ATP : adenosine triphosphate BID : twice daily BMI : body mass index CMR : cardiovascular magnetic resonance DbCM : diabetic cardiomyopathy EDV : end-diastolic volume EOT : end of trial FFA : free fatty acids FAO : fatty acid oxidation FT-CMR : feature tracking CMR GLS : global longitudinal strain HbA1c : glycated haemoglobin A1c HLA : horizontal long axis HF : heart failure HFpEF : heart failure with preserved ejection fraction HFrEF : heart failure with reduced ejection fraction HOMA : homeostasis model assessment Hs-cTn : high-sensitivity cardiac troponin IQR : interquartile range LDH : lactate dehydrogenase LV : left ventricular LVEDV : left ventricular end-diastolic volume LVEF : left ventricular ejection fraction LVOT : left ventricular outflow tract MRI : magnetic resonance imaging MRS : magnetic resonance spectroscopy MTG : myocardial triglyceride NAD+ : nicotinamide adenine dinucleotide NT-proBNP : n-terminal pro b-type natriuretic peptide NYHA : New York Heart Association PCr/ATP : phosphocreatine to adenosine triphosphate ratio PDH : pyruvate dehydrogenase PDSR : peak diastolic strain rate QUICKI : quantitative insulin sensitivity check ROS : reactive oxygen species SAE : serious adverse event SCMR : Society for Cardiovascular Magnetic Resonance SGLT2i : sodium glucose co-transporter 2 inhibitor SV : stroke volume T2D : type 2 diabetes TMZ : trimetazidine UTE : ultra-short echo time VLA : vertical long axis VLED : very low energy diet [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04826159&atom=%2Fbiorxiv%2Fearly%2F2024%2F04%2F25%2F2024.04.24.591019.atom [2]: pending:yes