Diabetes mellitus is a major cause of death and disability and a large economic burden on health care systems across the world. Globally, 1 in 12 all-cause deaths in adults have been attributed to diabetes and its complications. Epidemiological data suggest that diabetes may in itself give rise to a specific cardiomyopathy characterized by progressively impaired left ventricular (LV) diastolic function and, in humans, a predominant phenotype of heart failure with preserved ejection fraction (HFpEF). Despite current glucose lowering therapies, diabetic patients are still at higher risk of developing heart disease.
Excessive production of reactive oxygen species, metabolic disturbances (eg alterations in substrate supply or utilisation), remodelling of the extracellular matrix, and mitochondrial dysfunction have been advocated as main determinants of both vascular and myocardial dysfunction in diabetes. However, a unifying mechanism upstream of the observed LV functional changes is still missing.
I have investigated the molecular signature of diabetes in heart cells/muscle of patients and animal models and discovered that cardiac dysfunction is prevented by increasing the myocardial level of tetrahydrobiopterin (BH4). BH4 is a key cofactor of nitric oxide synthase (NOS), and is responsible for maintaining the enzyme’s function in the presence of oxidative stress. These findings open the possibility that BH4 supplementation may provide a novel therapeutic tool in the management of patients with diabetes and HFpEF.
The aim of my research is to elucidate the mechanisms by which BH4 protects the cardiovascular system in diabetes. We are currently assessing the antioxidant properties of BH4 as well as its effects on metabolism and the inflammatory responses at different stages of the disease.
Tetrahydrobiopterin Protects Against Hypertrophic Heart Disease Independent of Myocardial Nitric Oxide Synthase Coupling.
Hashimoto T. et al, (2016), J Am Heart Assoc, 5
Nitric oxide synthase regulation of cardiac excitation-contraction coupling in health and disease.
Simon JN. et al, (2014), J Mol Cell Cardiol, 73, 80 - 91
Cardiomyocyte GTP cyclohydrolase 1 and tetrahydrobiopterin increase NOS1 activity and accelerate myocardial relaxation
Carnicer R. et al, (2012), Circulation Research, 111, 718 - 727
Multi-organ single-cell RNA-sequencing reveals early hyperglycaemia responses that converge on fibroblast dysregulation
Braithwaite AT. et al, (2023)
Atrial nitroso-redox balance and refractoriness following on-pump cardiac surgery: a randomized trial of atorvastatin.
Jayaram R. et al, (2022), Cardiovasc Res, 118, 184 - 195
Hyperglycaemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis.
Edgar L. et al, (2021), Circulation
BH4 Increases nNOS Activity and Preserves Left Ventricular Function in Diabetes.
Carnicer R. et al, (2021), Circ Res, 128, 585 - 601
Inducibility, but not stability, of atrial fibrillation is increased by NOX2 overexpression in mice.
Mighiu AS. et al, (2021), Cardiovasc Res