Heart Failure - Markers of Collagen Turnover

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Circ J. 2007 Dec;71(12):1893-7.
Transient enhancement of oxidant stress and collagen turnover in patients with acute worsening of congestive heart failure.
Kunishige M, Kijima Y, Sakai T, Akutagawa O, Matsuo A, Nishibe A, Nakagawa Y, Hata T.
Department of Cardiology, Higashi-osaka City General Hospital, Osaka, Japan.

BACKGROUND: Myocardial remodeling is a crucial step for progression of heart failure (HF). Free radical generation by the failing myocardium has been proposed as linked to myocardial remodeling. The aim of this study was to evaluate the urinary excretion of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a reliable marker for oxidant stress in vivo, and collagen turnover in patients with acute worsening of congestive HF. METHODS AND RESULTS: Enrolled were 43 patients with acute worsening of congestive HF of various etiologies. On admission (acute phase) and after approximately 2 weeks of conventional treatment (chronic phase), the following were measured: (1) immunoreactive urinary 8-iso-PGF2alpha, (2) serum total antioxidant status (TAS); and (3) serum levels of procollagen type I carboxyterminal peptide (PIP) and carboxyterminal collagen type I telopeptide (CITP), biochemical markers for collagen synthesis and degradation, respectively. From the acute to the chronic phase the parameters changed as follows: 335.1+/-245.4 to 205.3+/-107.4 pg/mg creatinine for urinary 8-iso-PGF2alpha (p<0.0001); 0.92+/-0.16 to 0.98+/-0.13 mmol/L for TAS (p<0.01); 171.4+/-72.5 to 93.7+/-33.9 ng/ml for PIP (p<0.0001); and 7.2+/-3.6 to 12.6+/-8.4 ng/ml for CITP (p<0.0001). CONCLUSIONS: Acute worsening of congestive HF promotes free radical generation and collagen synthesis.

Congest Heart Fail. 2007 Sep-Oct;13(5):275-9.
Markers of cardiac collagen turnover are similar in patients with mild and more severe symptoms of heart failure.
Cavallari LH, Groo VL, Momary KM, Stamos TD, Vaitkus PT.
Department of Pharmacy Practice, College of Pharmacy University of Illinois at Chicago, Chicago, IL 60612-7230, USA. humma@uic.edu

Cardiac fibrosis plays an important role in the pathophysiology of heart failure. The authors sought to determine whether biomarkers of cardiac fibrosis for milder clinical degrees of heart failure are comparable to those of more advanced disease. Procollagen types I and III amino-terminal peptides (PINP and PIIINP) and type I collagen telopeptide (ICTP) were compared between aldosterone-antagonistnaive patients with heart failure and New York Heart Association class I or II (n=22/23) and class III or IV (n=42/3) symptoms. Median (interquartile) range concentrations of PINP (63.3 [44.2-88.8] vs 48.6 [37.8-74.9] microg/L), ICTP (7.0 [5.4-16.8] vs 6.5 [4.7-12.7] microg/L), and PIIINP (4.7 [3.2-7.0] vs 4.7 [2.9-7.3] microg/L) were comparable between patients with mild and moderate to severe disease, respectively. These data suggest that patients with mild heart failure may have similar degrees of cardiac fibrosis to patients with more severe disease and support the examination of antifibrotic therapy, including aldosterone antagonists, in milder degrees of heart failure.

J Cardiovasc Med (Hagerstown). 2007 Sep;8(9):683-91.
Baseline characteristics of patients recruited in the AREA IN-CHF study (Antiremodelling Effect of Aldosterone Receptors Blockade with Canrenone in Mild Chronic Heart Failure).
Boccanelli A, Cacciatore G, Mureddu GF, de Simone G, Clemenza F, De Maria R, Di Lenarda A, Gavazzi A, Latini R, Masson S, Porcu M,
Vanasia M, Gonzini L, Maggioni AP.
Department of Cardiology, San Giovanni Addolorata Hospital, Rome, Italy. centro_studi@anmco.it

OBJECTIVE: Excess aldosterone activity contributes to the pathogenesis and progression of heart failure (HF). Aldosterone antagonists improve clinical outcome in patients with severe HF or left ventricular (LV) dysfunction after myocardial infarction, but knowledge of their impact in mild chronic HF is sparse. AREA IN-CHF was planned to investigate the effects of canrenone on progression of LV remodelling in mild HF. METHODS: AREA IN-CHF is a multicentre, randomised, double-blind, parallel group comparison of canrenone (up to 50 mg/day) versus placebo in mild stable HF. The primary endpoint is change in echocardiographic LV end-diastolic volume over 12 months. Patients had New York Heart Association class II HF, LV ejection fraction < or =45%, stable standard therapy, creatinine < or =2.5 mg/dl, potassium < or =5.0 mmol/l. Follow-up examinations were scheduled monthly for the first 3 months and every 3 months thereafter. Aldosterone was measured at baseline, brain natriuretic peptide and procollagen type III amino-terminal peptide (PIIINP) at baseline and at 6 months. Echocardiography was performed at baseline, at 6 and 12 months. RESULTS: Among 467 patients, median age 64 years (interquartile range (IQR) 56-70 years), 84% were men, 52% had ischaemic HF, 96% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 79% beta-blockers. Brain natriuretic peptide, aldosterone and PIIINP were 88 pg/ml (IQR 35-185 pg/ml), 118 pg/ml (IQR 75-177 pg/ml), and 5.38 microg/l (IQR 3.98-7.14 microg/l), respectively. LV end-diastolic volume was 79 ml/m (IQR 64-105 ml/m) and LV ejection fraction was 40% (IQR 33-45%). CONCLUSIONS: The role of aldosterone blockade in patients with mild HF remains to be established. AREA IN-CHF is addressing this issue in a large population on optimal medical therapy.

J Am Coll Cardiol. 2004 Jan 7;43(1):68-76.
The cardiac atria are chambers of active remodeling and dynamic collagen turnover during evolving heart failure.
Khan A, Moe GW, Nili N, Rezaei E, Eskandarian M, Butany J, Strauss BH.
Roy and Ann Foss Interventional Cardiology Research Program, Terrence Donnelly Heart Center, St. Michael's Hospital, Toronto, Ontario, Canada.

OBJECTIVES: The role of atrial myocytes and extracellular matrix (ECM) changes in atrial chamber remodeling was studied in a canine model of heart failure (HF). BACKGROUND: Cardiac remodeling is a key process mediating the progression of HF. Studies of the structural mechanisms of cardiac remodeling have been limited to the left ventricle. The structural alterations associated with atrial chamber remodeling in evolving HF have not been studied. METHODS: Age- and weight-matched dogs were subjected to right ventricular pacing (240 beats/min) for one and three weeks to produce early and severe HF, respectively. Atrial tissues were assessed for myocyte and ECM changes. RESULTS: Right atrial and left atrial (LA) pressures were significantly increased in early and severe HF. The LA wall tension index was significantly increased at both HF stages by 116% and 443%, respectively. Atrial collagen synthesis and degradation were significantly increased in severe HF. Gelatinase activity was significantly increased at both early and severe stages of HF. Gelatin zymography showed increased matrix metalloproteinases (MMP)-9 with early HF and increased MMP-2 with severe HF. The LA wall tension index was significantly correlated with gelatinase activity and collagen synthesis. Although total atrial collagen content was not changed, disarray of collagen fibers was observed. Atrial myocyte hypertrophy without evidence of apoptosis was also present in severe HF. CONCLUSIONS: There is marked atrial chamber remodeling in canine pacing-induced HF, which is characterized by myocyte hypertrophy and dynamic collagen turnover. Atrial remodeling may contribute to the development of atrial arrhythmias and pulmonary hypertension and could offer a novel therapeutic target.

Treatment of Congestive Heart Failure: Interfering the Aldosterone-Cardiac Extracellular Matrix Relationship.
Fourth International Seminar on Cardiovascular Biology and Medicine
Hypertension. 38(5):1227-1232, November 2001.
Zannad, Faiez; Dousset, Brigitte; Alla, Francois

Cardiac extracellular matrix undergoes extensive and continuous turnover involved in the lesion-reparation process, such as in cardiac remodeling, in hypertensive cardiac hypertrophy, in dilated cardiomyopathy, after myocardial infarction in the transition to heart failure, and during the progression of left ventricular dysfunction. Cardiac fibrosis is a major determinant of diastolic dysfunction and pumping capacity, and it may provide the structural substrate for arrhythmogenicity, thus potentially contributing the to progression of heart failure and sudden death. Aldosterone was shown to promote cardiac fibrosis in various experimental models. It was demonstrated that spironolactone may oppose the effect of aldosterone in promoting cardiac fibrosis. Measurement of cardiac collagen turnover by use of serological markers is a useful tool for monitoring cardiac tissue repair and fibrosis in experimental models or clinical conditions. We found that high serum levels of a marker of collagen turnover (procollagen type III N-terminal peptide ) in patients with chronic heart failure receiving conventional therapy, including ACE inhibitors, was associated with high mortality and hospitalization rates. In RALES (Randomized Aldactone Evaluation Study), in patients randomized to placebo, markers continued to increase or remained unchanged after 6-month follow-up. On the contrary, adding spironolactone 25 mg daily significantly decreased the levels of these serum markers during the same period. Most importantly, the spironolactone-related morbidity and mortality benefit was most predominant in subgroups with highest baseline levels of serum markers. These results suggest that limitation of the aldosterone-related excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with chronic heart failure.

Cardiovasc Res. 1997 Jul;35(1):30-4.
Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients.
MacFadyen RJ, Barr CS, Struthers AD.
Department of Clinical Pharmacology, University of Dundee, Ninewells Hospital and Medical School, UK. macfadyen@clinpharm.dundee.ac.uk

BACKGROUND: Experimental data suggest that aldosterone has harmful effects promoting myocardial fibrosis and disturbing autonomic balance. There has been no evidence of these potential effects in intact man. METHODS AND RESULTS: We report the findings in 31 patients with stable chronic heart failure (CHF) who were treated with spironolactone (50-100 mg/day) or placebo in addition to diuretics and angiotensin converting enzyme (ACE) inhibition. In a controlled randomised double-blind study, we found that spironolactone treatment reduced circulating levels of procollagen type III N-terminal amino peptide, a marker of vascular collagen turnover, and in addition increased time-domain parameters of heart rate variability (n = 24). These latter parameters suggest a parasympathomimetic effect for additional spironolactone. Spironolactone significantly reduced heart rate (prolonged RR interval) particularly during the dawn hours (06.00-09.00 h). In this unbalanced study it was not possible to provide a detailed diurnal assessment of the impact of spironolactone on heart rate variability, but the preliminary data suggest that there may be an interaction with the autonomic nervous system which varies in time. CONCLUSIONS: These are the first human data to show that use of the aldosterone antagonist, spironolactone, can positively improve time-domain heart rate variability and reduce myocardial collagen turnover, as reflected by further reductions in serum procollagen peptide, despite concurrent ACE inhibitor treatment. Residual aldosterone after ACE inhibitor treatment may therefore have a role promoting arrhythmia and cardiac death by two mechanisms. Effects of additional spironolactone on slowing heart rate (and potentially the detrimental effect of aldosterone) were most prominent between 6 a.m. and 10 a.m. when cardiac death is also known to be most prominent.

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