Treatment of Congestive Heart Failure

Abstract

Abstract-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. Key Words: aldosterone Ⅲ renin-angiotensin system Ⅲ collagen Ⅲ extracellular matrix Ⅲ heart failure I n the myocardium, the role of collagen fibers was thought to be limited to providing a supporting framework for myocytes and blood vessels and acting as lateral connections between muscle bundles. Far from being an inert collection of macromolecules that serves as a scaffold for cells, cardiac extracellular matrix (ECM) undergoes extensive and continuous turnover involved in cardiac remodeling, in hypertensive cardiac hypertrophy, in dilated cardiomyopathy, and after myocardial infarction, as well as in the transition to heart failure and during the progression of left ventricular dysfunction. ECM controls numerous cellular functions and serves as a substrate for cell adhesion, a source of anti-apoptotic signals, a reservoir for growth factors, and a determinant of tissue mechanics.Collagen biosynthesis is regulated at different levels of transcription and translation. Type I and type III are the 2 major types of collagen present in the myocardium in both normal and diseased myocardial tissue. Fibrillar collagens within the...

Sustained Reduction of Aldosterone in Response to the Angiotensin Receptor Blocker Valsartan in Patients With Chronic Heart Failure

“…9 In addition to angiotensin II, aldosterone production is under the control of other factors such as potassium and corticotropins, and these may assume greater importance during aldosterone escape. 18 Although it has long been known that aldosterone is important in edema formation, 19 its role in the progression of HF remains unclear. The remarkable result of the RALES trial, which showed a 30% reduction in mortality with the addition of spironolactone in patients with class III and IV HF receiving ACE-I, has renewed interest in the possible pathogenetic role of aldosterone in HF.…”

Analytical, physiologic, and clinical validation of a radioimmunoassay for measurement of procollagen type III amino terminal propeptide in serum and bronchoalveolar lavage fluid obtained from dogs

“…16 In patients with severe congestive heart failure, serum PIIINP concentration is closely correlated with clinical stage and outcome. 17 Serum and urinary PIIINP concentrations have been studied in humans with various renal diseases 18,19 as well as in patients after renal transplantation 20 and have been shown to correlate with the extent of organ fibrosis. In interstitial pulmonary conditions including pulmonary fibrosis, 5 acute respiratory distress syndrome 21 and sarcoidosis, 22 PIIINP concentrations in both serum and BALF are significantly increased, compared with values in samples from healthy individuals.…”

Improvement in collagen metabolism after 12 weeks’ cardiac resynchronization therapy in patients with ischaemic cardiomyopathy

“…ACEi/ARB and spironolactone therapy have been shown to partly reverse the abnormal metabolism of cardiac collagen tissue and enhance cardiac function in ICM patients. 16,19,[22][23][24] Improvements in haemodynamics and electromechanical synchronization after CRT appear to be related to corrected collagen metabolism. 25,26 However, no clinical observations of the effect of CRT on collagen metabolism in ICM have previously been reported.…”

“…However, noninvasive ways of assessing collagen metabolism (by measuring the biomarkers MMP and TIMP) have been developed and may replace myocardial biopsy. 6,10,11,[17][18][19] In the present study, MMP-9 and its inhibitor TIMP-1 were chosen as markers of collagen haemostasis in ischaemic myocardium. 20 Due to the antagonistic relationship between MMP-9 and TIMP-1, the ratio of MMP-9 to TIMP-1 can reflect MMP hydrolyzing ability and activity, and can also indirectly estimate the balance between collagen synthesis and degradation.…”