FWF - HHcy - Cardiovascular function and biomechanics in HHcy

Cardiovascular disease is the leading cause of death worldwide. In the majority of cases it is caused by atherosclerosis. Due to the development of atherosclerotic plaques as well as changes in the vessel wall, atherosclerosis can lead to narrowing and stiffening of the aorta and, because of this, to its reduced ability to transport blood. Understanding of the risk factors for atherosclerosis and cardiac dysfunction is thus important to prevent, diagnose and treat cardiovascular disease. Today, only a half of all cases of atherosclerosis can be explained by established risk factors including hypercholesterolemia (HCL). Risk factors for cardiac dysfunction are also not sufficiently resolved. Hyperhomocysteinemia (HHcy) is a common pathological condition characterized by an accumulation of homocysteine, a sulfur-containing, non-proteinogenic amino acid involved in intermediary metabolism of methionine, in the blood. HHcy is an independent risk factor for atherosclerosis and is also linked to cardiac pathology. It (i) increases cardiovascular risk in combination with HCL, (ii) strongly correlates with cardiovascular mortality, and (iii) is associated with cardiac dysfunction, cardiomyopathy, heart failure and sudden death. HHcy is present in 5-10% of the general population and up to 30% of the elderly. While severe and moderate HHcy are caused by genetic defects in homocysteine degradation, mild HHcy is caused by deficiency of vitamins required for homocysteine degradation and accounts for 2/3 of HHcy incidence. Accumulation of fibrotic, collagen-rich tissue in the aorta and the myocardium, leading to loss of their biomechanical properties, may be a central mechanism how HHcy contributes or even triggers cardiovascular disease. This as well as other pathological mechanisms induced by elevated homocysteine may together or independently lead and/or contribute to aortic and/or cardiac dysfunction in the absence and presence of HCL. In a collaborative project between the University of Graz, the Medical University of Graz and the Graz University of Technology we aim to understand whether and how HHcy can contribute or even trigger atherosclerosis and cardiac dysfunction as well as the mechanisms involved. We will combine different approaches and use cutting-edge technologies including magnetic resonance imaging, biomechanical testing, second harmonic generation and two-photon excited fluorescence microscopy, coherent anti-Stokes Raman scattering spectroscopy, mass spectrometry based lipidomics and proteomics as well as mathematical modeling and numerical simulations. Knowledge gained in this project will help to better understand the link between HHcy and cardiovascular disease and enable development of therapeutic interventions to treat HHcy-associated consequences.