Investigation of skeletal and cardiac muscle metabolism in patients with cardiovascular disease

Thesis

Despite advances in treatment, heart failure (HF) remains a leading cause of morbidity and mortality worldwide. This thesis demonstrates the use of magnetic resonance imaging (MRI) and multinuclear magnetic resonance spectroscopy (³¹P, ¹H, ¹³C MRS) techniques to examine three structurally and metabolic different phenotypes of HF: non-ischaemic cardiomyopathy with reduced ejection fraction and iron deficiency (Chapter 3 IRON HEART), metabolic HF with preserved ejection fraction (Chapter 4 DICE), and pressure overload induced HF (Chapter 5 HYPER HEART). The overarching aim was to characterise myocardial and skeletal muscle energetics in each phenotype and examine the effect of three targeted interventions – intravenous iron, Ninerafaxstat, and aortic valve intervention, on substrate metabolism, mitochondrial function and functional outcomes.

Chapter 3 described the first study (IRON HEART) combing cardiac and skeletal muscle energetic assessment following intravenous ferric carboxymaltose in non-ischaemic cardiomyopathy and iron deficiency. Intravenous iron has shown benefits in large trials, reducing symptoms, improving exercise capacity, and lowering hospitalisation rates, though mechanisms remain unclear. The results demonstrated a significant improvement in ejection fraction, exercise capacity, and skeletal muscle mitochondrial capacity without an improvement in myocardial energetics. These findings suggest a combined benefit of iron on cardiac and skeletal muscle, warranting larger trials.
Chapter 4 (DICE) demonstrates a proof of concept for metabolic modulation in HFpEF and the potential for cardiac mitotropes to become an additional pillar in the treatment of metabolic HFpEF. The novel mitotrope, Ninerafaxstat, as a partial fatty acid inhibitor, was safe and improved cardiac energetics by restoring metabolic flexibility. The energetic improvement was linked to increased exercise capacity and symptoms. It is the first of its kind and might offer potential as a targeted therapy in a phenotype with limited treatment options.
Chapter 5 (HYPER HEART) explored the metabolic adaptations before and after pressure unloading in severe aortic stenosis. The study revealed a dissociation between structural and metabolic recovery post valve intervention. It highlighted the potential role of multinuclear magnetic resonance spectroscopy and imaging to guide timing of valve intervention, in particularly in asymptomatic patients who already display structural remodelling.

Authors: Birkhoelzer, SM

• DOI: 10.5287/ora-pyerg0oxx
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: aortic stenosis; multinuclear magnetic resonance spectroscopy; cardiac energetics; heart failure; metabolic modulation
• Subjects: Nuclear magnetic resonance; Iron; Aortic valve; Energy metabolism; Magnetic resonance imaging; Heart failure; Type 2 diabetes; Cardiovascular system