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

Hundertmark, M. J.; Siu, A. G.; Matthews, V.; Lewis, A. J.; Grist, J. T.; Patel, J.; Chamberlin, P.; Sarwar, R.; Yavari, A.; Dehbi, H.-M.; Rao, P.; Shi, X.; Zheng, S.; Robbins, J. M.; Gerszten, R. E.; Frenneaux, M. P.; Valkovic, L.; Miller, J. J.; Neubauer, S.; Tyler, D. J.; Rider, O. J.

doi:10.1101/2024.04.24.591019

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bioRxiv · 10.1101/2024.04.24.591019

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

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Abstract

BackgroundType 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. MethodsIMPROVE-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. ResultsPatients 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). ConclusionsMetabolic 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. REGISTRATIONURL: https://clinicaltrials.gov; Unique identifier: NCT04826159 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/591019v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@86fae1org.highwire.dtl.DTLVardef@1c1037eorg.highwire.dtl.DTLVardef@cc5ca9org.highwire.dtl.DTLVardef@d789d1_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Hundertmark, M. J., Siu, A. G., Matthews, V., Lewis, A. J., Grist, J. T., Patel, J., Chamberlin, P., Sarwar, R., Yavari, A., Dehbi, H.-M., Rao, P., Shi, X., Zheng, S., Robbins, J. M., Gerszten, R. E., Frenneaux, M. P., Valkovic, L., Miller, J. J., Neubauer, S., Tyler, D. J., Rider, O. J.. 2024-04-25. Modulating Cardiac Energetics in Cardio-Metabolic Syndromes: A mechanistic, hyperpolarized MR Trial of Ninerafaxstat Treatment. https://doi.org/10.1101/2024.04.24.591019

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