Ricardo Carnicer
Associate Professor
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.
Key publications
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Tetrahydrobiopterin Protects Against Hypertrophic Heart Disease Independent of Myocardial Nitric Oxide Synthase Coupling.
Journal article
Hashimoto T. et al, (2016), J Am Heart Assoc, 5
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Nitric oxide synthase regulation of cardiac excitation-contraction coupling in health and disease.
Other
Simon JN. et al, (2014), J Mol Cell Cardiol, 73, 80 - 91
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Cardiomyocyte GTP cyclohydrolase 1 and tetrahydrobiopterin increase NOS1 activity and accelerate myocardial relaxation
Journal article
Carnicer R. et al, (2012), Circulation Research, 111, 718 - 727
Recent publications
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Hyperglycaemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis.
Journal article
Edgar L. et al, (2021), Circulation
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BH4 Increases nNOS Activity and Preserves Left Ventricular Function in Diabetes.
Journal article
Carnicer Hijazo R. et al, (2021), Circulation research
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Inducibility, but not stability, of atrial fibrillation is increased by NOX2 overexpression in mice.
Journal article
Mighiu AS. et al, (2021), Cardiovasc Res
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Atrial nitroso-redox balance and refractoriness following on-pump cardiac surgery: A randomised trial of atorvastatin.
Journal article
Jayaram R. et al, (2020), Cardiovasc Res
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Improved cellular uptake of perfluorocarbon nanoparticles for in vivo murine cardiac 19F MRS/MRI and temporal tracking of progenitor cells.
Journal article
Constantinides C. et al, (2019), Nanomedicine, 18, 391 - 401