Heart Failure with Hypertension and Valvular Causes

Group leader: Ramón Querejeta, M.D., Ph.D.

Donostialdea IHO ramon.querejetairaola@osakidetza.eus

Strategic Objectives


  • 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.


  • 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.

Team Members

Name Surname Center E-mail
Daniel Cea Primo Donostialdea IHO
Francisco De La Cuesta Arzamendi Donostialdea IHO
Cristina del Bosque Martín Donostialdea IHO
Kattalin Echegaray Ibañez Donostialdea IHO kattalin.echegarayibanez@osakidetza.eus
Tomás Echeverría García Donostialdea IHO tomas.echeverriagarcia@osakidetza.eus
Mikel Asier Garro Beristain UPV – EHU
Alberto Eizaguirre Yarza Donostialdea IHO
Mariano Larman Tellechea Donostialdea IHO mariano.larmantellechea@osakidetza.eus
Ainhoa Rengel Jimenez Donostialdea IHO
Eva Robledo Mansilla Donostialdea IHO  eva.robledomansilla@osakidetza.eus
Itziar Solla Ruiz Donostialdea IHO itziar.sollaruiz@osakidetza.eus
Iñaki Villanueva Benito Donostialdea IHO
Elena Zubillaga Azpiroz Goierri – Alto Urola IHO elena.zubillagaazpiroz@osakidetza.eus


Scientific Output


Published: 10 / 18

Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease.

White HD, Held C, Stewart R, Tarka E, Brown R, Davies RY, Budaj A, Harrington RA, Steg PG, Ardis-Sino D, Armstrong PW, Avezum A, Aylward PE, Bryce A, Chen H, Chen MF, Corbalan R, Dalby AJ, Danchin N, De Winter RJ, Denchev S, Diaz R, Elisaf M, Flather MD, Goudev AR, Granger CB, Grinfeld L, Hochman JS, Husted S, Kim HS, Koenig W, Linhart A, Lonn E, Lopez-Sendon J, Manolis AJ, Mohler III, Emile R, Nicolau JC, Pais P, Parkhomenko A, Pedersen TR, Pella D, Ramos-Corrales MA, Ruda M, Sereg M, Siddique S, Sinnaeve P, Smith P, Sritara P, Swart HP, Sy RG, Teramoto T, Tse HF, Watson D, Weaver WD, Weiss R, Viigimaa M, Vinereanu D, Zhu J, Cannon CP, Wallentin L.

N. Engl. J. Med. 2014; 370: 1702-1711. FI: 54.420 (Q1).

ALTITUDE Investigators. Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes.

Parving HH, Brenner BM, McMurray JJV, De Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA,

N. Engl. J. Med. 2012; 367: 2204-2213. FI: 53.298 (Q1).

Circulating Biomarkers of Myocardial Fibrosis The Need for a Reappraisal.

Lopez B, Gonzalez A, Ravassa S, Beaumont J, Moreno MU, San Jose G, Querejeta R, Diez J.

J. Am. Coll. Cardiol. 2015; 65: 2449-2456. FI: 16.503 (Q1).

Association of osteopontin with cardiac fibrosis and diastolic dysfunction in heart failure of hypertensive origin. A role for lysyl oxidase?

López Salazar B, González Miqueo A, Querejeta Iraola R, Beaumont Ezcurra J, Ravassa Albeniz S, Diez Martinez J.

Eur. Heart J. 2012; 33: 35-0. FI: 10.478 (Q1).

Association of Cardiotrophin-1 With Myocardial Fibrosis in Hypertensive Patients With Heart Failure.

Lopez B, Gonzalez A, Querejeta R, Larman M, Rabago G, Diez J.

Hypertension. 2014; 63: 483-489. FI: 7.632 (Q1).

Short- and Medium-term Prognosis in Patients Hospitalized for COPD Exacerbation The CODEX Index.

lmagro P, Soriano JB, Cabrera FJ, Boixeda R, Alonso-Ortiz MB, Barreiro B, Diez-Manglano J, Murio C, Heredia JL, Spanish Soc Internal Med.

Chest. 2014; 145: 972-980. FI: 7.132 (Q1).

Galectin-3 and histological, molecular and biochemical aspects of myocardial fibrosis in heart failure of hypertensive origin.

Lopez B, Gonzalez A, Querejeta R, Zubillaga E, Larman M, Diez J.

Eur. J. Heart Fail. 2015; 17: 385-392. FI: 6.526 (Q1).

Collagen Cross-Linking But Not Collagen Amount Associates With Elevated Filling Pressures in Hypertensive Patients With Stage C Heart Failure Potential Role of Lysyl Oxidase.

López B, Querejeta R, González A, Larman M, Diez J.

Hypertension. 2012; 60: 677-683. FI: 6.207 (Q1).

Osteopontin-mediated myocardial fibrosis in heart failure: a role for lysyl oxidase?.

Lopez Begon A, Gonzalez A, Lindner D, Westermann D, Ravassa S, Beaumont J, Gallego I, Zudaire A, Brugnolaro C, Querejeta R, Larman M, Tschoepe C, Diez J.

Cardiovasc. Res. 2013; 99: 111-120. FI: 5.940 (Q1).

Lack of association of galectin-3 with myocardial fibrosis in patients with chronic stable heart failure of hypertensive origin.

Lopez B, Gonzalez Miqueo A, Querejeta Iraola R, Larman Tellechea M, Diez Martinez J.

CARDIOVASC RES. 2014; 103: -0. FI: 5.808 (Q1).


Published: 0 / 0


Published: 0 / 0


Published: 2 / 2

Transcatheter aortic valve replacement with Lotus valve: initial experience.

Larman M, Telleria M, Lasa G, Sanmartin JC, Gaviria K.

Rev Esp Cardiol (Engl Ed). 2014; 67: 956-958. FI: 0.000 (Q0).

Initial experience and valve-in-valve implantation with the balloon-expandable SAPIEN 3 transcatheter prosthesis.

Ochoa V, Amat-Santos IJ, Castrodeza J, Larman M, Gutiérrez H, Gimeno F.

Archivos De Cardiología De México. 2016; 86: 88-90.


Published: 0 / 0


Projects 1 / 1

Papel de la Fibrosis Miocárdica y de la Hipertrofia Inapropiada del Ventrículo Izquierdo (VI) en el desarrollo de disfunción sistólica en la Estenosis Aórtica (EAO) Severa.

Investigador principal: Elena Zubillaga Azpiroz. Entidad financiadora: Gobierno Vasco, Departamento de Salud. Año inicio: 2011. Año final: 2014.