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Background Fibroblast growth factor 23 (FGF23) is a regulator of mineral metabolism, that has been linked to myocardial remodeling including development of left ventricular (LV) hypertrophy and myocardial fibrosis. The aim of this study was to investigate the relationship between intact FGF23 (iFGF23), myocardial infarct size and LV remodeling following a first acute ST-elevation myocardial infarction (STEMI). Methods and results Forty-two consecutive patients with first-time STEMI, single vessel disease, successfully treated with primary percutaneous coronary intervention were included. Cardiac magnetic resonance (CMR) imaging was performed at day 2, 1 week, 2 months and 1 year post MI, and blood samples were drawn at admittance and at the same time points as the CMRs. The cohort was divided according to the presence or not of heart failure post MI. In the total cohort, iFGF23 (mean ± SD) was significantly lower at day 0 (33.7 ± 20.6 pg/ml) and day 2 (31.5 ± 23.4 pg/ml) compared with a reference interval based on 8 healthy adults (43.9 pg/ml ± 19.0 pg/ml). iFGF23 increased to normal levels (55.8 ± 23.4 pg/ml) seven days post MI. In the subset of patients with signs of acute heart failure, FGF23 was higher at all measured timepoints, reaching significantly higher FGF23 levels at 2 months and 1 year following revascularization. Conclusion There was a reduction in iFGF23 levels during the acute phase of MI, with a normalization at seven days following revascularization. During one-year follow-up, there was a gradual increase in iFGF23 levels in patients with heart failure.

Objectives: Galectin-3 (Gal-3) is involved in cardiac inflammation and fibrosis, and is in use as a biomarker that indicates increased risk in heart failure. This study examined the relationship between Gal-3 levels and acute and old myocardial infarction (MI) in patients assessed by cardiac magnetic resonance (CMR) imaging. Methods: Group 1 consisted of 38 patients with ST-elevation MI and single-vessel disease treated with primary percutaneous coronary intervention (PCI). Group 2 consisted of 52 patients with prior complicated MI. Twenty-two controls were included. CMR was performed in group 1 at 2 days, 1 week, 2 months and 1 year following PCI and in group 2 at >4 years after MI. Results: Median Gal-3 was elevated in patients compared with controls, group 1: 11.93 ng/ml (IQR 6.34-17.52, p = 0.03), group 2: 12.96 (IQR 6.33-19.29, p = 0.03) and controls: 10.16 (IQR 5.59-14.73). Gal-3 levels did not change during acute MI, and there was no relationship between Gal-3 and infarct size, troponin-T, high-sensitivity C-reactive protein, left-ventricular (LV) volumes or LV ejection fraction (LVEF) in group 1. In group 2, Gal-3 correlated modestly with MI size (r = 0.28, p < 0.05), LV end-diastolic volume index (r = 0.40, p < 0.01), LV end-systolic volume index (r = 0.43, p < 0.01) and LVEF (r = -0.39, p < 0.01). Conclusion: There was no relationship between Gal-3 levels and acute ischemic myocardial injury. A significant, modest relationship between Gal-3 levels, MI size and LV remodeling was only found in patients with old MI.

Aims We investigated the temporal changes in circulating levels of markers of extracellular cardiac matrix (ECCM) turnover and their relationship with infarct size (IS), ejection fraction (EF), and left ventricular (LV) volumes, determined by serial cardiac magnetic resonance (CMR) imaging in patients with first-time ST-elevation myocardial infarction (STEMI). Methods and results Forty-two patients with a first-time STEMI, successfully revascularized by primary percutaneous coronary intervention (pPCI) had serum samples taken prior to pPCI, 2, 7 days, 2 months, and 1 year following STEMI for the analysis of the markers of collagen synthesis, and collagen degradation. Late enhancement and cine CMR was performed on Days 2, 7, 2 months, and 1-year post-STEMI. There was a significant increase in type I collagen degradation following STEMI that was not accompanied by an increase in collagen type I synthesis until 2 months and 1 year. In contrast to the delay in type I collagen synthesis, there was an immediate increase in type III collagen synthesis that was sustained for 1 year. N-terminal procollagen type I levels assessed prior to pPCI were predictive of adverse LV remodelling at all CMR time-points. Conclusions Our findings indicate a net type I collagen breakdown in the first week following STEMI compensated by an early increase in collagen type III synthesis. There is an increase in both type I and III collagen synthesis markers at 2 months and 1 year, indicating a persistent increase in collagen turnover even in these apparently successfully treated patients. Clinical study no. NCT 00465868.

Background: The objective of this study was to elucidate the complex interactions between families of circulating biomarkers representing different biochemical responses to the pathophysiology following complicated acute myocardial infarction (AMI).Methods: Blood samples, drawn at a median of 3 days post AMI were obtained from 236 patients with complicated AMI and evidence of heart failure or left ventricular dysfunction. Using exploratory factor analysis, 37 biomarkers were grouped according to their collinearity to each other into clusters. The clusters were used as a model to elucidate interdependencies between individual biomarkers. Each cluster defines a specific pathophysiological process, called factor. These factors were used as covariates in multivariable Cox-proportional hazard regression analyses for prediction of all-cause death and the combined endpoint of cardiovascular death and re-infarction.Results: Exploratory factor analysis grouped the biomarkers under 5 factors. The composition of these groups was partially unexpected but biological plausible. In multivariable analysis, only 1 factor proved to be an independent predictor of outcome. Major contributions (factor loadings>0.50) in this cluster came from: midregional pro-adrenomedullin, tumor necrosis factor receptor, pro-endothelin-1, growth differentiation factor 15, C-terminal pro arginine vasopressin, uric acid, chromogranin A and procollagen type III N-terminal.Conclusion: Clustering of multiple biomarkers by exploratory factor analysis might prove useful in exploring the biological interactions between different biomarkers in cardiovascular disease and thus increase our understanding of the complicated orchestral interplay at the molecular level. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Objectives To assess the relationship between interleukin (IL)-1-related molecules, infarct size and left ventricular (LV) remodelling following acute myocardial infarction (MI). Methods Forty-two patients with first-time diagnosis of ST segment elevation MI (STEMI), with a single occluded vessel successfully revascularized by primary percutaneous coronary intervention (PCI), were recruited to this observational study conducted at a university teaching hospital and followed for 1 year. Main outcome measures Plasma levels of IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-18 and caspase-1 were analysed before and 2 days, 1 week and 2 months after PCI. Serial cardiac magnetic resonance imaging (CMR) was used for the assessment of infarct size and LV remodelling. CMR findings at 1 year was the primary outcome variable. Results Univariate analysis showed that IL-1-related mediators were strongly (IL-1 β), moderately (caspase-1) and weakly (IL-1Ra) associated with impaired myocardial function and noninfarct mass, but not infarct size, 1 year after reperfused STEMI. In multivariate analyses, troponin T predicted LV ejection fraction (LVEF), infarct size and LV end-diastolic (LVEDVi) and end-systolic volume index (LVESVi). However, significant additional variance was explained by IL-1β, IL-18 and caspase-1. IL-1β levels at 2 months, IL-18 at 2 days and pre-PCI caspase-1 were predictors of LVEF. Caspase-1 and in particular IL-1β at 2 days were the only predictors of noninfarct mass. IL-1β and IL-18 at 2 days were predictors of LVEDVi, whilst pre-PCI levels of IL-1β contributed to prediction of LVESVi. By contrast, pro-B-type natriuretic peptide, C-reactive protein, IL-6 and transforming growth factor-β1 (TGF-β1) had no or only a weak (TGF-β1) association with these CMR parameters in multivariate analyses. Conclusions IL-1β levels after STEMI were strongly associated with impaired myocardial function and noninfarct LV mass after 1 year, suggesting a potential role for IL-1β as a predictor of maladaptive myocardial remodelling following reperfused MI.

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.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.With the exception of PIIINP, all CTO markers demonstrated significant longitudinal changes following MI. At baseline, ICTP (p0.0001) 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 (p0.01).The present study supports a prognostic role for ICTP in both the acute and chronic phase following MI.

Aims We studied the time-dependent relationships between microvascular obstruction (MO), infarct size, and left ventricular (LV) remodelling after acute myocardial infarction (MI). Methods and results Forty-two consecutive patients with first-time ST-elevation MI, single-vessel disease, successfully treated with primary percutaneous coronary intervention (PCI) were included. Microvascular obstruction, infarct size, and LV remodelling were assessed by cardiac magnetic resonance. Cardiac magnetic resonance was performed at: 2 days, 1 week, 2 months, and 1 year following PCI. Microvascular obstruction was assessed by first-pass perfusion. Patients were divided into three groups according to the presence or absence of MO at 2 days and 1 week: no detectable MO at any time point (11 patients), MO detectable only at 2 days (16 patients), and MO detectable both at 2 days and 1 week (15 patients). In multivariable analysis adjusting for infarct size at 2 days, detectable MO at 1 week was an independent predictor ( P = 0.003) of infarct size at 1 year follow-up, associated with adverse infarct healing, adverse LV remodelling, increased LV volumes, and lower ejection fractions when compared with the rest of the cohort. Conclusion Microvascular obstruction is an important determinant of infarct healing. The effect of MO on infarct size translated into distinct patterns of LV remodelling during long-term follow-up. Clinical study no.: NCT 00465868

Aims This study assessed the relationship between inflammatory mediators and indices of infarct size and left-ventricular (LV) remodelling following successful primary percutaneous coronary intervention (PCI) in patients with first time ST elevation myocardial infarction (MI). Methods and results Forty-two patients admitted with an occluded single vessel were recruited consecutively. Cardiac magnetic resonance was used for serial assessment (2 days, 1 week, 2 months) of infarct size, microvascular obstruction (MO), and LV remodelling. Inflammatory mediators were analysed before and after PCI. Our major findings were: (1) Following PCI, there was a marked increase in plasma levels of C-reactive protein, closely correlated with an increase in interleukin-6 and terminal complement complex, reaching maximum 2 days after PCI; (2) C-reactive protein 2 days after PCI was significantly correlated with infarct size and parameters of LV remodelling 2 months after PCI; (3) Patients with persistent MO had significantly higher C-reactive protein levels 2 days following PCI. Conclusion We suggest that the rapid increase in C-reactive protein levels in this model of successful revascularization of a single, totally occluded vessel reflects the degree of inflammation within the infarcted area. Our findings support a role for C-reactive protein-mediated complement activation as both a marker and mediator of myocardial damage following MI. Clinical study no.: NCT 00465868.

Background Altered activity of the matrix metalloproteinases (MMP-2 and -9), has been implicated in the left ventricular (LV) remodeling process occurring after myocardial infarction (MI). In the acute phase, a relation between plasma MMP-9 levels and parameters of LV dysfunction has been demonstrated. The relationship in long-term survivors has not been investigated. We studied the relationships of these biochemical markers, and N-terminal pro-B-type natriuretic peptide (N-BNP), with measures of long-term LV remodeling. Methods and Results Plasma levels of N-BNP, MMP-2, and MMP-9 were measured at randomization, 1 month, 1 year, and >4 years after complicated AMI. Contrast-enhanced cardiac magnetic resonance (CMR) was performed at 4.4 (±0.4) years in 52 clinically stable long-term survivors of the index AMI. We assessed the relationships of plasma N-BNP, MMP-2, and MMP-9 with myocardial scarring, and measures of long-term LV remodeling. Compared with a reference population, N-BNP and MMP-9 levels were increased at all time points from the acute phase until >4 years after MI. Plasma N-BNP and MMP-9 correlated only in the subacute phase (randomization, mean 3.3 days after MI) days after acute MI ( r = 0.38, P = .006). At CMR assessment ≥4 years, log MMP-9 level was inversely related to LV ejection fraction ( P = .002) and nonscarred myocardial mass ( P = .008). This relationship was independent of MMP-2. Log N-BNP was related to end diastolic volume index ( P = .0002). There was no correlation between log MMP-9 and LV volumes. Conclusion There is a time-dependent relationship between plasma N-BNP and MMP-9 levels, these peptides correlating only in the acute phase after MI. In long-term follow-up, plasma MMP-9 and N-BNP levels were related to different parameters of LV remodeling. These findings suggest that in long-term survivors of complicated MI, different mechanisms modulate plasma levels of MMP-9 and N-BNP.

Background Few studies have compared the relative prognostic value of different natriuretic peptides after acute myocardial infarction (AMI). None has described peptide levels beyond the early post-AMI period. This study describes temporal profiles of 4 natriuretic peptides to 2 years after AMI and relationship with outcome. Methods and Results We assessed profiles of N-terminal proANP (N-ANP), B-type natriuretic peptide (BNP), N-terminal proBNP (N-BNP), and C-type natriuretic peptide (CNP) (study entry, 1 month, 1 year, and 2 years) in 236 patients with AMI complicated by clinical or radiologic evidence of heart failure. We assessed the prognostic value for baseline levels of each peptide for death or reinfarction. We observed distinct natriuretic peptide profiles. BNP and N-BNP levels were highest at baseline and fell thereafter. N-ANP levels increased from baseline to 30 days and fell thereafter. During follow-up (mean 938 days), 34 patients died and a further 25 suffered nonfatal AMI. Baseline natriuretic peptide levels did not have independent predictive power for outcome. N-BNP levels fell from baseline to 30 days in patients surviving to the end of follow-up ( P = .005) but were similar at both times ( P = .76) for those dying after 30 days. Age ( P P = .026) had independent predictive value for death after 30 days. Conclusion N-ANP, BNP, N-BNP, and CNP show distinct plasma profiles after AMI. Failure of plasma N-BNP to fall in the 30 days after AMI indicates adverse prognosis.

Background: β-Blockade usually causes a slight reduction in exercise capacity among healthy subjects, while more variable results have been observed in chronic heart failure (CHF), probably related to patients studied, methods and agent used. The effect of metoprolol controlled release/extended release (CR/XL) on peak oxygen uptake (peak VO2) in this patient population has not previously been investigated. Aims: We examined the effect of long-term treatment with the selective β1-receptor blocker metoprolol CR/XL once daily on exercise capacity in patients with CHF. Methods: Ninety-four patients (70 males and 24 females; mean age 63.6±10.6 years) with chronic symptomatic heart failure in New York Heart Association (NYHA) functional class II–IV, and with ejection fraction ≤40%, stabilized on optimum standard therapy were randomized to metoprolol CR/XL or placebo in a double-blind trial. Exercise capacity was evaluated by peak VO2 at baseline, after 3 months and at the end of study (mean follow-up 11.4±0.4 months). Results: Compared with placebo metoprolol CR/XL produced a significant decrease in heart rate by 11 beats/min at rest and 18 beats/min at peak exercise. There was a tendency for a temporal decline in peak VO2 after 3 months of therapy in both groups, but altogether peak VO2 remained unchanged from baseline with no difference between the groups at 1 year. Conclusions: In patients with moderate to severe CHF, 11.4 months of β1-blockade with metoprolol CR/XL had no effect on exercise capacity when compared with placebo or baseline.

Congestive heart failure (CHF) is characterized by elevated plasma norepinephrine (PNE) associated with a poor prognosis. Moxonidine selectively stimulates medullary imidazoline receptors which centrally inhibit sympathetic outflow and potently suppress levels of circulating PNE. This study was designed to evaluate the effects of central sympathetic inhibition on clinical and neurohumoral status in patients with CHF.This study evaluated 25 patients (age=69+/-7 years, 20 males) with symptomatic CHF (NYHA II-III), stabilized on standard therapy. The mean ejection fraction was 28+/-7% at baseline. Patients were titrated in a double-blind fashion to 11 weeks of oral therapy with placebo (n=9) or sustained-release (SR) moxonidine 0.9 mg bid (n=16). Clinical and neurohumoral status were evaluated at baseline, on chronic therapy at the target dose, and during cessation of therapy. All patients completed the trial and reached the target dose. Dry mouth, symptomatic hypotension, and asthenia were more frequent in the moxonidine SR-treated group. PNE was substantially reduced after 6 weeks at the maximum dose (0.9 mg bid) by 50% vs. placebo (P0. 0005). A reduction in 24-h mean heart rate (P0.01) was correlated to the reduction in PNE (r=0.70, P0.05). A 36% increase in the standard deviation of normal-to-normal intervals (SDNN) was observed in the moxonidine SR group vs. a 2% decrease for placebo (P=0.06); for the root mean square of successive differences (rMSSD), there was a 21% increase for moxonidine SR vs. a 19% decrease for placebo (P0.05). Abrupt cessation of chronic therapy resulted in substantial increases in PNE, blood pressure, and heart rate.Chronic therapy with a sustained-release formulation of moxonidine in patients with CHF was well tolerated, with substantial and sustained reductions in PNE. The tachyarrhythmias were attenuated, with evidence of improved autonomic tone. Due to the observed effects following moxonidine discontinuation, tapering of therapy is recommended.

Elevated plasma norepinephrine (PNE) has been shown to be an important predictor of morbidity and mortality in patients with congestive heart failure (CHF). Moxonidine selectively stimulates imidazoline receptors located in the medulla, which centrally inhibit sympathetic outflow. PNE is suppressed and peripheral vasodilation reduces systemic blood pressure. This study evaluated the acute neurohumoral and hemodynamic effects of a single dose of oral moxonidine in 32 patients (22 men, mean +/- SD age 66 +/- 10 years) with CHF. All patients were in New York Heart Association functional class III and stabilized on chronic therapy with diuretics, digitalis, and angiotensin-converting enzyme inhibitors. The mean PNE concentration was 509 +/- 304 pg/ml at baseline. Patients underwent invasive hemodynamic monitoring after double-blind randomization to either placebo (n = 12), moxonidine 0.4 mg (n = 9), or moxonidine 0.6 mg (n = 11). Moxonidine produced a dose-dependent, vasodilator response compared with placebo. Analysis of the time-averaged change from baseline over 6 hours demonstrated that moxonidine 0.6 mg caused significant reductions in mean systemic arterial pressure (p

Aims: Myocardial CCN2/CTGF is induced in heart failure of various etiologies. However, its role in the pathophysiology of left ventricular (LV) remodeling after myocardial infarction (MI) remains unresolved. The current study explores the role of CTGF in infarct healing and LV remodeling in an animal model and in patients admitted for acute ST-elevation MI. Methods and Results: Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate controls (NLC) were subjected to permanent ligation of the left anterior descending coronary artery. Despite similar infarct size (area of infarction relative to area at risk) 24 hours after ligation of the coronary artery in Tg-CTGF and NLC mice, Tg-CTGF mice disclosed smaller area of scar tissue, smaller increase of cardiac hypertrophy, and less LV dilatation and deterioration of LV function 4 weeks after MI. Tg-CTGF mice also revealed substantially reduced mortality after MI. Remote/peri-infarct tissue of Tg-CTGF mice contained reduced numbers of leucocytes, macrophages, and cells undergoing apoptosis as compared with NLC mice. In a cohort of patients with acute ST-elevation MI (n = 42) admitted to hospital for percutaneous coronary intervention (PCI) serum-CTGF levels (s-CTGF) were monitored and related to infarct size and LV function assessed by cardiac MRI. Increase in s-CTGF levels after MI was associated with reduced infarct size and improved LV ejection fraction one year after MI, as well as attenuated levels of CRP and GDF-15. Conclusion: Increased myocardial CTGF activities after MI are associated with attenuation of LV remodeling and improved LV function mediated by attenuation of inflammatory responses and inhibition of apoptosis. publishedVersion

Increased circulating chemokines have been reported during acute myocardial infarction and might give prognostic information about future ischemic events. However, data on the chemokine network in relation to infarct size and measures of left ventricular remodeling after successful percutaneous coronary intervention (PCI) are lacking. A total of 42 patients with first-time ST-segment elevation acute myocardial infarction with a single occluded vessel were recruited, and cardiac magnetic resonance was used for serial assessment (2, 7, and 60 days) of infarct size and left ventricular remodeling. The chemokines were analyzed before and after PCI. After PCI, high levels of CCL4, CXCL16, CXCL10, and, in particular, CXCL8 within the first week after PCI correlated positively with the degree of myocardial damage, as reflected by correlations with the maximum troponin T levels and infarct size after 2 months, as assessed by cardiac magnetic resonance, and with impaired myocardial function after 2 months as assessed by cardiac magnetic resonance and neurohormonal methods. In contrast, the plasma levels of CCL3 and CXCL7 during the first week correlated negatively with myocardial dysfunction after 2 months. In conclusion, our findings suggest a role for chemokines in both adaptive and maladaptive responses after myocardial infarction and might support a role for CCL4, CXCL16, CXCL10, and, in particular, CXCL8 in postmyocardial infarction reperfusion and remodeling.

Acute myocarditis is a serious condition that is challenging to diagnose. Recent developments in contrast-enhanced cardiac magnetic resonance imaging (ce-MRI) enable visualization of myocardial damage in patients with myocarditis. The objective of this study was to identify patients in whom ce-MRI could be useful to reach such a diagnosis.We reviewed data from 37 patients referred to ce-MRI with suspected acute myocarditis at Stavanger University Hospital from July 2004 to May 2007.20 patients had epicardial contrast enhancement compatible with myocarditis. The contrast enhancement was focal and most frequently localized to the inferolateral wall (n = 12). No patient with Troponin T0.1 microg/L (n = 7) showed epicardial contrast enhancement. It was not possible to distinguish patients with acute myocarditis from the other patients on the basis of clinical signs, symptoms, C-reactive protein levels, ECG- or echocardiography.Ce-cardiac MRI is important in the diagnosis of acute myocarditis. If troponin T levels are0.1 microg/L during the acute phase, it is unlikely that a contrast enhancement pattern will be compatible with myocarditis.