Pathophysiology of heart failure with preserved ejection fraction. Extracellular matrix

Transcription

1 Pathophysiology of heart failure with preserved ejection fraction Extracellular matrix Javier Díez, MD, PhD. Full Professor of Cardiovascular Medicine and Director Division of Cardiovascular Sciences Centre of Applied Medical Research and University Clinic School of Medicine, University of Navarra Pamplona, Spain cima No conflict of interest

2 ALTERATIONS OF THE CARDIAC ECM IN HEART FAILURE Diastolic HF Systolic HF Advanced age OSTEOPONTIN Female Arterial hypertension DD > LVMI LVEDV = EF DD > LVMI > LVEDV < EF Diabetes mellitus Obesity Total amount of collagen fibers Relative abundance of collagen types Physical properties of collagen fibers Excessive non-physiological (interstitial & perivascular) collagen deposition Excessive physiological (endomysial & perimysial) collagen disruption (Díez J et al, Nature Clin Pract Cardiovasc Med 2005;2: Borlaug BA & Paulus WJ, Eur Heart J 2011; 32: )

3 ROLE OF MYOCARDIAL FIBROSIS IN DISEASES EVOLVING WITH LV DIASTOLIC DYSFUNCTION/FAILURE Advanced age Female Arterial hypertension Diabetes mellitus Obesity >Insoluble (cross-linked) >Myocardial <LV chamber >LV filling collagen type I fibers stiffness compliance pressure Clinically overt diastolic HF (Díez J et al, Nature Clin Pract Cardiovasc Med 2005;2: )

4 Collagen volume fractino (%) MYOCARDIAL FIBROSIS IN DIASTOLIC HEART FAILURE Sirius red staining * Controls DHF patients * P<0.001 vs Controls (Querejeta R et al, Circulation 2004;110: )

5 INCREASED COLLAGEN TYPE I DEPOSITION IN DIASTOLIC HEART FAILURE Controls DHF patients Anti-collagen type I staining 17% 5% 83% 95% P<0.05 II (Querejeta R et al, Circulation 2004;110: )

6 Collagen cross-linking % of total collagen INCREASED ACCUMULATION OF STIFF COLLAGEN IN DIASTOLIC HEART FAILURE Insoluble collagen Soluble collagen * * * Controls DHF patients Controls DHF patients 0 * P<0.001 vs Controls (López B et al, Hypertension 2009;53: )

7 ASSOCIATIONS OF MYOCARDIAL COLLAGEN WITH DOPPLER INDICES OF DIASTOLIC DYSFUNCTION IN DIASTOLIC HEART FAILURE Parameters Total collagen Insoluble collagen E (<0.001) (<0.001) (0.031) E/E 0.48 (<0.001) 0.46 (<0.001) 0.55 (0.007) Data are expressed as Pearson correlation coefficient (P value for N=23) (Kassner M et al, J Am Coll Cardiol 2011;57: )

8 GENERAL MECHANISMS OF MYOCARDIAL FIBROSIS Access to the myocardium of systemic inmune-inflammatory cells and profibrotic substances Response of cardiomyocytes and cardiac fibroblasts to local injury (mechanical, chemical) Activation of the endocardium (End-Mes Transition) and the epicardium (Epit-Mes Transition) Physical stretching Vasoconstrictor factors Pro-inflammatory cytokines Pro-oxidant factors Mineralocorticoids Other factors Profibrotic factors Antifibrotic factors Vasodilatory factors Ant-inflammatory cytokines Anti-oxidant systems Glucocorticoids Other factors Altered (insoluble) collagen (type I) turnover Synthesis Degradation and >>>> and deposition removal (Díez J et al, Nature Clin Pract Cardiovasc Med 2005;2: )

9 COLLAGEN TYPE I TURNOVER IN HYPERTENSIVE HEART DISEASE Myofibroblast Fibroblast Interstitial and perivascular space N-propeptide Procollagen type I Procollagen proteinases C-propeptide Synthesis of procollagen Generation of mature collagen Synthesis Lysyl oxidase fibers Formation of collagen fibers Collagenase Small telopeptide TIMPs Big telopeptide Degradation Gelatinases Matrikines (López B et al, J Hypertens 2005;23: )

10 EXTRACELLULAR FORMATION OF COLLAGEN TYPE I FIBERS LOX Fibril LOX Fiber LOX Lysyl oxidase (López B et al, Am J Physiol Heart Circ Physiol 2010;299:H1-H9)

11 LOX protein (A.D.U.) INCREASED MYOCARDIAL LYSYL OXIDASE IN DIASTOLIC HEART FAILURE Control heart Diastolic failing heart * kDa Controls DHF patients * P<0.01 vs Controls (López B et al, Hypertension 2009;52: )

12 Collagen cross-linking ASSOCIATIONS OF MYOCARDIAL LOX IN DIASTOLIC HEART FAILURE 6 Parameters Collagen cross-linking LOX 5 4 E (0.010) (0.018) r=0.63 P= LOX protein (A.D.U.) E/E 0.72 (<0.001) 0.71 (0.003) Data are expressed as Pearson correlation coefficient (P value) (Kassner M et al, J Am Coll Cardiol 2011;57: )

13 EFFECTS OF LOOP DIURETICS * ON MYOCARDIAL LOX IN HEART FAILURE PATIENTS Torasemide group Furosemide group P<0.05 NS Lysyl oxidase (A.D.U.) Lysyl oxidase (.AD.U.) Baseline After TX 0 Baseline After TX (* On top of BB+ACEI or ARB) (López B et al, Hypertension 2009;52: )

14 EFFECTS OF LOOP DIURETICS * ON MYOCARDIAL COLLAGEN AND STIFFNESS IN HEART FAILURE PATIENTS Torasemide group Furosemide group Baseline After TX Baseline After TX Collagen 3.27± ±1.00 (P<0.05) 3.66± ±1.14 (NS) crosslinking Insoluble 8.88± ±2.26 (P<0.05) 9.10± ±0.99 (NS) collagen (µg/mg) LV stiffness 0.18± ±0.02 (P<0.05) 0.17± ±0.02 (NS) (mm Hg/ml) (* On top of BB+ACEI or ARB) (López B et al, Hypertension 2009;52: )

15 LYSYL OXIDASE: A NOVEL TARGET FOR ANTI-FIBROSIS THERAPIES IN DIASTOLIC HEART FAILURE? Ischemia, pressure overload, metabolic alterations >HIF-1α Does >TGF-β torasemide Does > procollagen torasemide >ROS > AGEs C-proteinase interfere with this pathway? interfere with this pathway? Veraveedu PT et al. Eur J Pharmacol López B et al. J Am Coll Cardiol Synthesis of Synthesis of Conversion to Stimulation 2008;581: ;50: LOX mrna LOX precursor LOX active form of active LOX LOX activity (López B et al, Am J Physiol Heart Circ Physiol 2010;299:H1-H9)

16 A CRITICAL ROLE FOR EXTRACELLULAR STIFF COLLAGEN TYPE I SYNTHESIS IN DIASTOLIC HEART FAILURE? Procollagen type I Overt diastolic HF > PCP/PCPE > Synthesis > Mature collagen type I > LOX > Assembly and cross-linking > fibers < MMP-1:TIMP-1 < Degradation Fibrosis Diastolic dysfunction

17 ACKNOWLEDGEMENT University Clinic & Centre of Applied Medical Research University of Navarra Pamplona, Spain Charité-Universitaetsmedizin Campus Benjamin Franklin Berlin, Germany Teresa Arias, PhD Javier Beaumont, PhD Idoia Gallego, BSc María González, T Ignacio García-Bolao, MD, PhD Ana Huerta, MD Laura Martínez, BSc María Basagoiti, T Ana Egea, BSc Arantxa González, PhD Nerea Hermida, PhD Begoña López, PhD Sonia Martínez, T Mika Matsumoto, MD, PhD Ramón Querejeta, MD, PhD Susana Ravassa, PhD Amaia Zudaire, BSc Javier Díez, MD, PhD Mario Kasner, MD, MSc Dirk Westermann, MD Regina Gaub, MD Felicitas Escher, MD Uwe Kühl, MD Heinz-Peter Schultheiss, MD Carsten Tschöpe, MD