Anca Radauceanu

Extracellular Matrix Turnover and Inflammatory Markers Independently Predict Functional Status and Outcome in Chronic Heart Failure

BACKGROUND Inflammatory pathways may promote extracellular matrix (ECM) remodeling and chronic heart failure (CHF) progression. The relationship between markers of inflammation and of ECM remodeling, and their influence on functional status and outcomes has not been examined in a large cohort of CHF patients. METHODS AND RESULTS We measured baseline blood serum collagen (amino-terminal propeptide of collagen III [PIIINP], metalloproteinase 1 [MMP-1], tissue inhibitor of metalloproteinase 1 [TIMP-1]), and inflammatory (high-sensitivity C-reactive protein [(hsCRP], interleukin [IL]-18, IL-10) markers in 1009 patients enrolled in the Research into Etanercept Cytokine Antagonism in Ventricular Dysfunction (RECOVER) trial. A positive correlation was detected between the 2 classes of markers (PIIINP to IL-18, MMP-1 and TIMP-1 to CRP, TIMP-1 to IL-18, MMP-1 to IL-10). In the adjusted multivariable model including all biomarkers, only PIIINP (P = .03) and MMP-1 (P = .048) were independent predictors of 6-minute walk test (6-MWT), whereas in another model including only inflammatory biomarkers, IL-18 was an independent predictor. PIIINP (P = .001) was the only biomarker independently associated with death and CHF hospitalization. CONCLUSIONS The independent associations of PIIINP and MMP-1 with 6-MWT and PIIINP with CHF morbi-mortality suggest that excessive ECM turnover may be associated with functional capacity deterioration and poor outcome.

Effect of MR Blockade on Collagen Formation and Cardiovascular Disease with a Specific Emphasis on Heart Failure

Collagen is the major extracellular matrix protein in the heart and represents a crucial target for anti-remodeling and cardioprotective therapy. Collagen quantity and quality have been shown to be regulated under various physiological and pathologic conditions. Excessive deposition of collagen, leading to cardiac fibrosis, is a major determinant of cardiac dysfunction and arrhythmogenecity associated with sudden death. Serological markers of collagen turnover were proven as a noninvasive reliable tool for monitoring from a distance cardiac tissue repair and fibrosis, both in experimental and clinical conditions. Some markers of collagen synthesis and degradation were shown to have a prognostic significance in myocardial infarction, cardiomyopathy and heart failure, and were reported as independent predictors of mortality. Aldosterone represents the end-product of the renin angiotensin aldosterone system and may play a role in cardiac collagen deposition independent of its effect on blood pressure. Production of aldosterone is mainly regulated by angiotensin II and is activated in the failing human ventricle in proportion to heart failure severity. Circulating or locally produced aldosterone stimulates fibrillar collagen accumulation in the heart directly via mineralocorticoid receptors or, indirectly, modifying angiotensine II receptors number and/or function. The use of mineralocorticoid receptor antagonists counters collagen deposition, even when used on top of classical RAAS inhibitors, such as ACE inhibitors and angiotensine II receptor blockers. There is now accumulating evidence from experimental and clinical studies showing antifibrotic and cardioprotective effect for aldosterone antagonists, spironolactone and eplerenone. In chronic heart failure and post myocardial infarction patients, aldosterone receptor blockade benefit was associated with decreased serum levels of collagen synthesis marker PIIINP (procollagen type III amino-terminal peptide), without affecting collagen degradation.Understanding various autocrine/paracrine mechanisms involved in extracellular matrix remodeling in heart failure represents a major challenge, essential for developing new cardioreparative and cardioprotective strategies.

Early changes in serum markers of cardiac extra-cellular matrix turnover in patients with uncomplicated hypertension and type II diabetes.

Extracellular matrix (ECM) turnover is a major determinant of diastolic dysfunction and pumping capacity, thus potentially contributing to the progression of congestive heart failure (CHF). Patients with both arterial hypertension and diabetes have a high risk of heart failure. Whether these patients have changes in cardiac ECM has not been studied previously. Our objective was to compare blood markers of collagen turnover among patients with CHF, patients with hypertension and type II diabetes (HD), and healthy individuals.

The prognostic value of circulating markers of collagen turnover after acute myocardial infarction.

BACKGROUND We assessed the time profiles and prognostic utility of circulating markers of collagen turnover (CTO) following acute myocardial infarction (MI). In contrast to previous studies, no patient had been pre-treated with inhibitors of the renin-angiotensin-aldosterone system (RAAS) at the time of initial assessment. METHODS Plasma levels of N-terminal fragment of type I collagen (PINP), carboxy-terminal telopeptide of type I collagen (ICTP), N-terminal fragment of type III collagen (PIIINP), matrix metalloproteinase-1(MMP-1) and tissue inhibitor of MMPs type-1 (TIMP-1) were assessed in 233 patients following acute MI. The CTO markers were initially assessed prior to treatment by either captopril or losartan, at a median of 3 days following MI. In addition, blood samples were acquired at 1 month, 1 year and 2 years following MI. Development of heart failure symptoms, all-cause and cardiovascular death were recorded as endpoints during two years of follow-up. RESULTS With the exception of PIIINP, all CTO markers demonstrated significant longitudinal changes following MI. At baseline, ICTP (p<0.0001) and TIMP-1 (p=0.01) levels were significantly elevated in patients who later died compared with survivors. In multivariable analysis only ICTP reached statistical significance as predictor of all cause death (p=0.048). In patients developing symptoms of heart failure during follow-up, ICTP was the only significantly elevated CTO marker (p<0.01). CONCLUSION The present study supports a prognostic role for ICTP in both the acute and chronic phase following MI.

Residual stress ischaemia is associated with blood markers of myocardial structural remodelling.

Long‐term prognosis of coronary artery disease (CAD) patients is worsened when stress ischemia persists on treatment, but the relationship with adverse cardiac remodelling had never been investigated.

Differential time effect profiles of amlodipine, as compared to valsartan, revealed by ambulatory blood pressure monitoring, self blood pressure measurements and dose omission protocol

Amlodipine and valsartan are once‐daily antihypertensive agents. To date, no comparison between these agents given as monotherapies was reported. This study was aimed to evaluate the therapeutic coverage and safety of amlodipine and valsartan in mild‐to‐moderate hypertensive patients. Multicenter, double‐blind, randomized, comparative study. After a 4‐week placebo wash‐out period, 246 outpatients with office diastolic blood pressure 95 ≤ DBP ≤110 mmHg and systolic blood pressure (SBP) < 180 mmHg, in addition to a mean daytime SBP and/or DBP > 135/85 mmHg on 24‐h ambulatory blood pressure monitoring (ABPM), were randomly allocated to once‐daily amlodipine 5–10 mg or valsartan 40–80 mg, for 12 weeks. In a subgroup of patients, 48‐h ABPM were performed at the end of the treatment period. Dose omission was simulated by a single‐blind placebo dosing. The primary efficacy end‐point was the 24‐h trough office BP after 12 weeks of active therapy. The reductions in 24‐h trough BP were more pronounced in amlodipine compared with valsartan group as well in office [SBP: −17.8 ± 10.9 vs. −14.6 ± 11.2, P = 0.025, DBP: −12.7 ± 7.2 vs. −10.9 ± 7.8 mmHg, P = 0.06) as in ambulatory BP (SBP/DBP: −13.0 ± 13.7/−10.8 ± 9.1 vs. −7.2 ± 19.4/−4.9 ± 13.4 mmHg, P < 0.05). Forty‐eight hours after the last active dose, the slope of the morning BP surge (4–9 h) was less steep with amlodipine vs. valsartan [DBP (P < 0.04), SBP (n.s.)]. Ankle edema were more often reported in amlodipine group. These results suggest a superior BP lowering and a longer duration of action with amlodipine compared with valsartan.

Time-effect profile of antihypertensive agents assessed with trough/peak ratio, smoothness index and dose omission: an ambulatory blood pressure monitoring study with trandolapril vs. quinapril1

The duration of action of antihypertensive drugs may be assessed by several methods using ambulatory blood pressure monitoring (ABPM).