Abstract
Given the importance of fibrous tissue in leading to myocardial dysfunction, non-invasive assessment of fibrosis could prove a clinically useful tool in heart failure (HF) patients. Biomarkers may be used for early detection of otherwise subclinical disease, diagnostic assessment of an acute or chronic clinical syndrome, risk stratification of patients with a suspected or confirmed diagnosis, selection of an appropriate therapeutic intervention and monitoring the response to therapy. Extracellular matrix (ECM) biomarkers in HF are promising biomarkers. They are able to detect early changes in heart and large vessel structure and function and transition to HF. High ECM biomarker levels have been associated with poor outcome. The ability of treatment to reduce myocardial fibrosis in HF patients may be monitored by the measurement of various serum peptides arising from the metabolism of collagen types. Biomarkers may be selectively influenced by pharmacological agents.
Similar content being viewed by others
Abbreviations
- ACE:
-
Angiotensin converting enzyme
- baPWV:
-
Brachial-ankle pulse wave velocity
- BNP:
-
Brain natriuretic peptide
- CHF:
-
Congestive heart failure
- DCT:
-
Deceleration time of the mitral E wave
- ECM:
-
Extracellular matrix
- HD:
-
Patients with Hypertension and type II Diabetes
- ICTP:
-
Type I pyridinoline cross-linked C-terminal telopeptide
- LV:
-
Left ventricular
- LVH:
-
Left ventricular hypertrophy
- LVM:
-
Left ventricular mass
- LVMI:
-
Left ventricular mass index
- MMPs:
-
Matrix MetalloProteinases
- PICP:
-
Procollagen type I C-terminal propeptide
- PINP:
-
Procollagen type I N-terminal propeptide
- PIIINP:
-
N terminal type III collagen peptide
- SHR:
-
Spontaneously hypertensive rats
- TIMP:
-
Tissue inhibitor of matrix metalloproteinases
References
Bishop JE, Laurent GJ (1995) Collagen turnover and its regulation in the normal and hypertrophying heart. Eur Heart J 16(Suppl C):38–44
Zannad F, Dousset B, Alla F (2001) Treatment of congestive heart failure: interfering the aldosterone-cardiac extracellular matrix relationship. Hypertension 38:1227–1232. doi:10.1161/hy1101.099484
D’Armiento J (2002) Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction. Trends Cardiovasc Med 12:97–101. doi:10.1016/S1050-1738(01)00160-8
Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92:827–839. doi:10.1161/01.RES.0000070112.80711.3D
Laviades C, Varo N, Fernandez J et al (1998) Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 98:535–540
Weber KT (1997) Monitoring tissue repair and fibrosis from a distance. Circulation 96:2488–2492
Lopez B, Gonzalez A, Querejeta R et al (2005) The use of collagen-derived serum peptides for the clinical assessment of hypertensive heart disease. J Hypertens 23:1445–1451
Risteli J, Risteli L (1995) Analysing connective tissue metabolites in human serum. Biochemical, physiological and methodological aspects. Journal of Hepatology 22:77–81. doi:10.1016/0270-9139(95)94132-0
Jensen LT, Horslev-Petersen K, Toft P et al (1990) Serum aminoterminal type III procollagen peptide reflects repair after acute myocardial infarction. Circulation 81:52–57
Querejeta R, Varo N, Lopez B et al (2000) Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 101:1729–1735
Querejeta R, Lopez B, Gonzalez A et al (2004) Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis. Circulation 110:1263–1268. doi:10.1161/01.CIR.0000140973.60992.9A
Diez J, Querejeta R, Lopez B et al (2002) Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 105:2512–2517. doi:10.1161/01.CIR.0000017264.66561.3D
Izawa H, Murohara T, Nagata K et al (2005) Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: a pilot study. Circulation 112:2940–2945
Lopez B, Gonzalez A, Querejeta R et al (2006) Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure. J Am Coll Cardiol 48:89–96. doi:10.1016/j.jacc.2006.01.077
Diez J (2007) Mechanisms of cardiac fibrosis in hypertension. J Clin Hypertens (Greenwich) 9:546–550. doi:10.1111/j.1524-6175.2007.06626.x
Diez J, Panizo A, Gil MJ et al (1996) Serum markers of collagen type I metabolism in spontaneously hypertensive rats: relation to myocardial fibrosis. Circulation 93:1026–1032
Varo N, Etayo JC, Zalba G et al (1999) Losartan inhibits the post-transcriptional synthesis of collagen type I and reverses left ventricular fibrosis in spontaneously hypertensive rats. J Hypertens 17:107–114. doi:10.1097/00004872-199917010-00016
Diez J, Laviades C, Mayor G et al (1995) Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations. Circulation 91:1450–1456
Carver W, Nagpal ML, Nachtigal M et al (1991) Collagen expression in mechanically stimulated cardiac fibroblasts. Circ Res 69:116–122
Chapman D, Weber KT, Eghbali M (1990) Regulation of fibrillar collagen types I and III and basement membrane type IV collagen gene expression in pressure overloaded rat myocardium. Circ Res 67:787–794
Mukherjee D, Sen S (1990) Collagen phenotypes during development and regression of myocardial hypertrophy in spontaneously hypertensive rats. Circ Res 67:1474–1480
Nakahara T, Takata Y, Hirayama Y et al (2007) Left ventricular hypertrophy and geometry in untreated essential hypertension is associated with blood levels of aldosterone and procollagen type III amino-terminal peptide. Circ J 71:716–721. doi:10.1253/circj.71.716
Ahmed SH, Clark LL, Pennington WR et al (2006) Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 113:2089–2096. doi:10.1161/CIRCULATIONAHA.105.573865
Martos R, Baugh J, Ledwidge M et al (2007) Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 115:888–895. doi:10.1161/CIRCULATIONAHA.106.638569
Lindsay MM, Maxwell P, Dunn FG (2002) TIMP-1: a marker of left ventricular diastolic dysfunction and fibrosis in hypertension. Hypertension 40:136–141. doi:10.1161/01.HYP.0000024573.17293.23
Diez J (2007) Arterial stiffness and extracellular matrix. Adv Cardiol 44:76–95. doi:10.1159/000096722
Ishikawa J, Kario K, Matsui Y et al (2005) Collagen metabolism in extracellular matrix may be involved in arterial stiffness in older hypertensive patients with left ventricular hypertrophy. Hypertens Res 28:995–1001. doi:10.1291/hypres.28.995
Jugdutt BI (2003) Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation 108:1395–1403. doi:10.1161/01.CIR.0000085658.98621.49
Jugdutt BI (2003) Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways. Curr Drug Targets Cardiovasc Haematol Disord 3:1–30. doi:10.2174/1568006033337276
Radauceanu A, Moulin F, Djaballah W et al (2007) Residual stress ischaemia is associated with blood markers of myocardial structural remodelling. Eur J Heart Fail 9:370–376. doi:10.1016/j.ejheart.2006.09.010
Uusimaa P, Risteli J, Niemela M et al (1997) Collagen scar formation after acute myocardial infarction: relationships to infarct size, left ventricular function, and coronary artery patency. Circulation 96:2565–2572
Poulsen SH, Host NB, Jensen SE et al (2000) Relationship between serum amino-terminal propeptide of type III procollagen and changes of left ventricular function after acute myocardial infarction. Circulation 101:1527–1532
Papadopoulos DP, Moyssakis I, Makris TK et al (2005) Clinical significance of matrix metalloproteinases activity in acute myocardial infarction. Eur Cytokine Netw 16:152–160
Zannad F, Alla F, Dousset B et al (2000) Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 102:2700–2706
Li H, Simon H, Bocan TM et al (2000) MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE- and MMP-inhibition. Cardiovasc Res 46:298–306. doi:10.1016/S0008-6363(00)00028-6
Medeiros DM, Velleman SG, Jarrold BB et al (2002) Ontogeny of enhanced decorin levels and distribution within myocardium of failing hearts. Connect Tissue Res 43:32–43. doi:10.1080/713713431
Muller-Brunotte R, Kahan T, Lopez B et al (2007) Myocardial fibrosis and diastolic dysfunction in patients with hypertension: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA). J Hypertens 25:1958–1966. doi:10.1097/HJH.0b013e3282170ada
Poulsen SH, Andersen NH, Heickendorff L et al (2005) Relation between plasma amino-terminal propeptide of procollagen type III and left ventricular longitudinal strain in essential hypertension. Heart 91:624–629. doi:10.1136/hrt.2003.029702
Alla F, Kearney-Schwartz A, Radauceanu A et al (2006) Early changes in serum markers of cardiac extra-cellular matrix turnover in patients with uncomplicated hypertension and type II diabetes. Eur J Heart Fail 8:147–153. doi:10.1016/j.ejheart.2005.06.008
Quilliot D, Alla F, Bohme P et al (2005) Myocardial collagen turnover in normotensive obese patients: relation to insulin resistance. Int J Obes (Lond) 29:1321–1328. doi:10.1038/sj.ijo.0803022
Mukherjee D, Sen S (1991) Alteration of collagen phenotypes in ischemic cardiomyopathy. J Clin Invest 88:1141–1146. doi:10.1172/JCI115414
Klappacher G, Franzen P, Haab D et al (1995) Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol 75:913–918. doi:10.1016/S0002-9149(99)80686-9
Radauceanu A, Ducki C, Virion JM et al (2008) Extracellular matrix turnover and inflammatory markers independently predict functional status and outcome in chronic heart failure. J Card Fail 14:467–474. doi:10.1016/j.cardfail.2008.02.014
Iraqi W, Rossignol P, Fay R, Nuée J, Ketelslegers JM, Vincent J, Pitt B, Zannad F (2009) Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: insights from the EPHESUS study. Circulation (in press)
Murakami T, Kusachi S, Murakami M et al (1998) Time-dependent changes of serum carboxy-terminal peptide of type I procollagen and carboxy-terminal telopeptide of type I collagen concentrations in patients with acute myocardial infarction after successful reperfusion: correlation with left ventricular volume indices. Clin Chem 44:2453–2461
Cerisano G, Pucci PD, Sulla A et al (2007) Relation between plasma brain natriuretic peptide, serum indexes of collagen type I turnover, and left ventricular remodeling after reperfused acute myocardial infarction. Am J Cardiol 99:651–656. doi:10.1016/j.amjcard.2006.09.114
Blangy H, Sadoul N, Dousset B et al (2007) Serum BNP, hs-C-reactive protein, procollagen to assess the risk of ventricular tachycardia in ICD recipients after myocardial infarction. Europace 9:724–729. doi:10.1093/europace/eum102
Albaladejo P, Bouaziz H, Duriez M et al (1994) Angiotensin converting enzyme inhibition prevents the increase in aortic collagen in rats. Hypertension 23:74–82
Weber KT (1997) Extracellular matrix remodeling in heart failure: a role for de novo angiotensin II generation. Circulation 96:4065–4082
Ciulla MM, Paliotti R, Esposito A et al (2004) Different effects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial fibrosis: results of a randomized trial. Circulation 110:552–557. doi:10.1161/01.CIR.0000137118.47943.5C
Briest W, Holzl A, Rassler B et al (2001) Cardiac remodeling after long term norepinephrine treatment in rats. Cardiovasc Res 52:265–273. doi:10.1016/S0008-6363(01)00398-4
Kobayashi N, Mori Y, Nakano S et al (2001) Celiprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in deoxycorticosterone acetate-salt hypertensive rats. J Hypertens 19:795–801. doi:10.1097/00004872-200104000-00017
Grimm D, Huber M, Jabusch HC et al (2001) Extracellular matrix proteins in cardiac fibroblasts derived from rat hearts with chronic pressure overload: effects of beta-receptor blockade. J Mol Cell Cardiol 33:487–501. doi:10.1006/jmcc.2000.1321
Wei S, Chow LT, Sanderson JE (2000) Effect of carvedilol in comparison with metoprolol on myocardial collagen postinfarction. J Am Coll Cardiol 36:276–281. doi:10.1016/S0735-1097(00)00671-9
Funder JW (2006) Minireview: aldosterone and the cardiovascular system: genomic and nongenomic effects. Endocrinology 147:5564–5567. doi:10.1210/en.2006-0826
Young MJ (2008) Mechanisms of mineralocorticoid receptor-mediated cardiac fibrosis and vascular inflammation. Curr Opin Nephrol Hypertens 17:174–180. doi:10.1097/MNH.0b013e3282f56854
Pitt B, Reichek N, Willenbrock R et al (2003) Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 108:1831–1838. doi:10.1161/01.CIR.0000091405.00772.6E
Sato A, Takane H, Saruta T (2001) High serum level of procollagen type III amino-terminal peptide contributes to the efficacy of spironolactone and angiotensin-converting enzyme inhibitor therapy on left ventricular hypertrophy in essential hypertensive patients. Hypertens Res 24:99–104. doi:10.1291/hypres.24.99
Zannad F, Radauceanu A (2005) Effect of MR blockade on collagen formation and cardiovascular disease with a specific emphasis on heart failure. Heart Fail Rev 10:71–78. doi:10.1007/s10741-005-2351-3
Hayashi M, Tsutamoto T, Wada A et al (2003) Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation 107:2559–2565. doi:10.1161/01.CIR.0000068340.96506.0F
Loch D, Levick S, Hoey A et al (2006) Rosuvastatin attenuates hypertension-induced cardiovascular remodeling without affecting blood pressure in DOCA-salt hypertensive rats. J Cardiovasc Pharmacol 47:396–404
Majima T, Komatsu Y, Fukao A et al (2007) Short-term effects of atorvastatin on bone turnover in male patients with hypercholesterolemia. Endocr J 54:145–151. doi:10.1507/endocrj.K06-127
Rajagopalan S, Zannad F, Radauceanu A et al (2007) Effects of valsartan alone versus valsartan/simvastatin combination on ambulatory blood pressure, C-reactive protein, lipoproteins, and monocyte chemoattractant protein-1 in patients with hyperlipidemia and hypertension. Am J Cardiol 100:222–226. doi:10.1016/j.amjcard.2007.02.085
Zucker S, Hymowitz M, Conner C et al (1999) Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. Ann N Y Acad Sci 878:212–227. doi:10.1111/j.1749-6632.1999.tb07687.x
Garnero P, Bianchi F, Carlier MC et al (2000) Biochemical markers of bone remodeling: pre-analytical variations and guidelines for their use. SFBC (Societe Francaise de Biologie Clinique) Work Group. Biochemical markers of bone remodeling. Annales de Biologie Clinique 58:683–704
Fontaine V, Jacob MP, Houard X et al (2002) Involvement of the mural thrombus as a site of protease release and activation in human aortic aneurysms. Am J Pathol 161:1701–1710
Jung K, Nowak L, Lein M et al (1996) Role of specimen collection in preanalytical variation of metalloproteinases and their inhibitors in blood. Clin Chem 42:2043–2045
Zucker S, Doshi K, Cao J (2004) Measurement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) in blood and urine: potential clinical applications. Adv Clin Chem 38:37–85. doi:10.1016/S0065-2423(04)38002-9
Cremers S, Garnero P (2006) Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls. Drugs 66:2031–2058. doi:10.2165/00003495-200666160-00001
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zannad, F., Rossignol, P. & Iraqi, W. Extracellular matrix fibrotic markers in heart failure. Heart Fail Rev 15, 319–329 (2010). https://doi.org/10.1007/s10741-009-9143-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10741-009-9143-0