Group leader: Xabier Arana Achaga, M.D., Ph.D.

Donostialdea IHO xabier.aranaachaga@osakidetza.eus

Strategic Objectives

Primary: 

• To study the degree of involvement of myocardial fibrosis in systolic and diastolic dysfunction of the left ventricle in patients with arterial hypertension and with aortic stenosis.
• To analyse the quantitative and qualitative aspects of myocardial collagen and their influence on the left ventricle function.
• To determine whether the circulating levels of the peptids involved in the turnover of collagen are related to the magnitude of the fibrosis directly determined in the myocardium of those patients and whether their origin is essentially cardiac (coronary sinus-peripheral blood gradient).
• To determine the capacity of the MMP-1/TIMP-1 ratio measure in peripheral blood to differentiate the patients with systolic HF from those with diastolic HF (stages C and D of the new HF classification (NYHA functional classes II to IV)).
• To analyse the implication of emerging biomarkers such as Cardiotrophin-1 and Osteopontin in the development of myocardial fibrosis.
• To analyse any association that may exist between inappropriate left ventricular hypertrophy and the systolic-diastolic function, with the degree of fibrosis and the levels of circulating substances derived from neurohumoral hyperactivation.
• To study whether the expression of the different isoforms of the PLC?, in particular of the PLC?₄, is different in patients with appropriate and inappropriate left ventricular hypertrophy.

Secondary:

• To assess whether the MMP-1/TIMP-1 ratio in peripheral blood allows patients with systolic and diastolic HF to be more accurately distinguished than with other myocardium structural damage markers related to the collagen deposit (PICP), with the loss of cardiac muscle cells via apoptosis (annexin V, cardiotrophin-1) or more accurately than cardiac muscle cell stress biomarkers (proBNP).
• To analyse the myocardial interstitial collagen both in quantitative and qualitative terms: Soluble versus insoluble collagen (cross-linked) and relative deposit of Collagen I and III.
• To take a more in-depth look at the physiopathological mechanisms that lead to systolic dysfunction and to identify new targets in the pharmacological treatment of HF.
• To establish whether the alterations of the left ventricle myocardial extracellular matrix differ significantly in the biopsy samples obtained from the basal interventricular septum with regard to those observed in the left ventricle free wall in patients with aortic stenosis.
• To determine which of the two locations for the biopsy show alterations that better relate to systolic and diastolic ventricular function variables.
• To thus establish the left ventricle region that should be studied in future research projects.
• To create a method for human fibroblast cell culture by means of a biopsy of the right atrial appendage for in vitro studies (in collaboration with the CIMA [Centre for Applied Medical Research]).

Main lines of research

• Myocardial fibrosis in Heart Failure Stages A, B and C caused by hypertension.
  • Influence of the quantity and quality of myocardial collagen in the ventricular function in patients with heart failure caused by hypertension (in collaboration with the CIMA).
  • Relative importance of the levels of myocardial Cardiotrophin-1 as regards Aldosterone and TGF-beta.
  • To study the possible association of myocardial collagen in hypertensive heart disease stages A, B and C with the appearance of major clinical events. Follow-up higher than 8-10 years: Analysis using the “Net Reclassification Improvement” and “Integrated Discrimination Improvement” methods.
• Myocardial fibrosis associated with ageing in severe degenerative aortic stenosis in the elderly.
  • Myocardial fibrosis and inappropriate left ventricular hypertrophy in severe degenerative aortic stenosis. Study of the implication of the different isoenzymes of the PLC? (1-4) in the development of hypertrophy.
  • Influence of the quantity, quality and location of collagen in the left ventricular myocardium in the ventricular function in patients with severe aortic stenosis.
  • Histological validation of a new method for the quantification of diffuse myocardial fibrosis by magnetic resonance in patients with severe degenerative aortic stenosis.