Exploring Intramyocellular Magnesium Augmentation: Implications for Myocardial and Skeletal Muscle Metabolism in Individuals With Heart Failure With Preserved Ejection Fraction

Hypomagnesaemia is prevalent among patients suffering from heart failure with preserved ejection fraction (HFpEF), and in those with predisposing risk factors such as obesity and diabetes. The intricate link between hypomagnesaemia and the pathophysiological processes of HFpEF remains to be fully elucidated. However, its notable prevalence suggests a significant role in the onset and advancement of the disease. Serum magnesium (S-Mg) is commonly used to evaluate Mg status, however, it does not accurately reflect true intracellular Mg concentrations ([Mg2+]i), where this essential ion exerts its beneficial effects. Thus, previous literature lacks a thorough evaluation of [Mg2+]i in HFpEF, and specifically the potential impact of Mg replete physiology.

The research hypothesis is that [Mg2+]i is related to myocardial and skeletal muscle (SM) energetics and performance in patients with HFpEF. The study aims to explore the role of [Mg2+]i at a functional and cellular level in cardiac and SM, symptomatology, and insulin sensitivity; comparing a HFpEF population with healthy and matched controls.

Using the chemical shift difference in the resonance frequencies of the α- and β- phosphate resonances in magnetic resonance spectroscopy (MRS), [Mg2+]i will be measured, comparing it to S-Mg. Blood samples for cardiac biomarkers, electrolytes, and markers of HFpEF risk factors (such as lipid profile, HbA1C and TSH) will be taken and a calf leg raise performed. Advanced imaging techniques at rest and stress including cardiac magnetic resonance imaging (CMR), MRS and echocardiography will be performed. MRS measurements include cellular energetics (Phosphocreatine [PCr]/ATP), rate of myocardial ATP delivery (CK flux and KfCK) and skeletal muscle energetics (PCr recovery Tau). At two time points post-Mg augmentation (immediate and delayed [7-15 days]), investigations will be repeated.

This study aspires to quantify [Mg2+]i in the HFpEF population compared with healthy and matched controls, juxtapose its levels with S-Mg, and examine its significance in the pathophysiology, functional and cellular performance, and symptom presentation of HFpEF. The study aims to recruit 45 individuals with HFpEF, 20 healthy controls and 20 age-and sex-matched individuals over a 2-year period.