Cord Manhenke

Microvascular obstruction is a major determinant of infarct healing and subsequent left ventricular remodelling following primary percutaneous coronary intervention

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.

C-reactive protein, infarct size, microvascular obstruction, and left-ventricular remodelling following acute myocardial infarction

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.

Myocardial Connective Tissue Growth Factor (CCN2/CTGF) Attenuates Left Ventricular Remodeling after Myocardial Infarction

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.

Increased interleukin-1β levels are associated with left ventricular hypertrophy and remodelling following acute ST segment elevation myocardial infarction treated by primary percutaneous coronary intervention

Abstract.  Ørn S, Ueland T, Manhenke C, Sandanger Ø, Godang K, Yndestad A, Mollnes TE, Dickstein K, Aukrust P (Stavanger University Hospital, Stavanger; Oslo University Hospital Rikshospitalet; University of Bergen, Bergen; University of Oslo; Oslo; Norway). Increased interleukin‐1β levels are associated with left ventricular hypertrophy and remodelling following acute ST segment elevation myocardial infarction treated by primary percutaneous coronary intervention. J Intern Med 2012; 272: 267–276.

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.

The effects of chronic, sustained-release moxonidine therapy on clinical and neurohumoral status in patients with heart failure

AIMS 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. METHODS AND RESULTS 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 (P<0. 0005). A reduction in 24-h mean heart rate (P<0.01) was correlated to the reduction in PNE (r=0.70, P<0.05). 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 (P<0.05). Abrupt cessation of chronic therapy resulted in substantial increases in PNE, blood pressure, and heart rate. CONCLUSIONS 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.

Clustering of 37 circulating biomarkers by exploratory factor analysis in patients following complicated acute myocardial infarction

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: mid-regional 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.

The Chemokine Network in Relation to Infarct Size and Left Ventricular Remodeling Following Acute Myocardial Infarction

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 hemodynamic and neurohumoral effects of moxonidine in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

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 <0.0001), mean pulmonary arterial pressure (p <0.005), systemic vascular resistance (p <0.05), pulmonary vascular resistance (p <0.01), and heart rate (p <0.05). Stroke volume was unchanged. PNE was reduced substantially (-180 pg/ml at 4 hours, p <0.005) and the reduction was highly correlated with the baseline level (r = -0.968). Moxonidine was well tolerated in this single-dose study and resulted in a modest, dose-dependent, vasodilator response, with substantial reductions in systemic and pulmonary arterial blood pressure. Trials designed to evaluate the clinical efficacy of chronic moxonidine therapy in CHF added to conventional therapy would be appropriate.

The relationship between markers of extracellular cardiac matrix turnover: infarct healing and left ventricular remodelling following primary PCI in patients with first-time STEMI

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.