Search

Background: Rivaroxaban 2.5 mg twice daily with aspirin 100 mg daily was shown to be better than aspirin 100 mg daily for preventing cardiovascular (CV) death, stroke or myocardial infarction in patients with either stable coronary artery disease (CAD) or peripheral artery disease (PAD). The cost-effectiveness of this regimen in this population is essential for decision-makers to know., Methods: US direct healthcare system costs (in USD) were applied to hospitalized events, procedures and study drugs utilized by all patients. We determined the mean cost per participant for the full duration of the trial (mean follow-up of 23 months) plus quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) over a lifetime using a two-state Markov model with 1-year cycle length. Sensitivity analyses were performed on the price of rivaroxaban and the annual discontinuation rate., Results: The costs of events and procedures were reduced for Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) patients who received rivaroxaban 2.5 mg orally (BID) plus acetylsalicylic acid (ASA) compared with ASA alone. Total costs were higher for the combination group ($7426 versus $4173) after considering acquisition costs of the study drug. Over a lifetime, patients receiving rivaroxaban plus ASA incurred $27,255 more and gained 1.17 QALYs compared with those receiving ASA alone resulting in an ICER of $23,295/QALY. ICERs for PAD only and polyvascular disease subgroups were lower., Conclusion: Rivaroxaban 2.5 mg BID plus ASA compared with ASA alone was cost-effective (high value) in the USA. COMPASS ClinicalTrials.gov identifier: NCT01776424., (© 2023. The Author(s).)

Aims: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long-term open-label extension (LTOLE)., Methods and Results: Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination., Conclusion: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period., Methods and Results: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants., Conclusion: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms., Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Acute myocardial infarction (MI) is the major cause of chronic heart failure. The activity of blood coagulation factor XIII (FXIIIa) plays an important role in rodents as a healing factor after MI, whereas its role in healing and remodelling processes in humans remains unclear. We prospectively evaluated the relevance of FXIIIa after acute MI as a potential early prognostic marker for adequate healing., Methods and Results: This monocentric prospective cohort study investigated cardiac remodelling in patients with ST-elevation MI and followed them up for 1 year. Serum FXIIIa was serially assessed during the first 9 days after MI and after 2, 6, and 12 months. Cardiac magnetic resonance imaging was performed within 4 days after MI (Scan 1), after 7 to 9 days (Scan 2), and after 12 months (Scan 3). The FXIII valine-to-leucine (V34L) single-nucleotide polymorphism rs5985 was genotyped. One hundred forty-six patients were investigated (mean age 58 ± 11 years, 13% women). Median FXIIIa was 118% (quartiles, 102-132%) and dropped to a trough on the second day after MI: 109% (98-109%; P < 0.001). FXIIIa recovered slowly over time, reaching the baseline level after 2 to 6 months and surpassed baseline levels only after 12 months: 124% (110-142%). The development of FXIIIa after MI was independent of the genotype. FXIIIa on Day 2 was strongly and inversely associated with the relative size of MI in Scan 1 (Spearman's ρ = -0.31; P = 0.01) and Scan 3 (ρ = -0.39; P < 0.01) and positively associated with left ventricular ejection fraction: ρ = 0.32 (P < 0.01) and ρ = 0.24 (P = 0.04), respectively., Conclusions: FXIII activity after MI is highly dynamic, exhibiting a significant decline in the early healing period, with reconstitution 6 months later. Depressed FXIIIa early after MI predicted a greater size of MI and lower left ventricular ejection fraction after 1 year. The clinical relevance of these findings awaits to be tested in a randomized trial., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Heart failure remains a frequent cause of death and is the leading reason for hospitalization in Germany although therapeutic options have significantly increased over the past years particularly in heart failure with reduced ejection fraction. Clinical symptoms are usually preceded by cardiac remodeling, which was originally defined only by left ventricular dilatation and depressed function but is also associated with typical cellular and molecular processes. Healing after acute myocardial infarction is characterized by inflammation, cellular migration and scar formation. Cardiac remodeling is accompanied by adaptive changes of the peripheral cardiovascular system. Since prevention is the primary goal, rapid diagnosis and treatment of myocardial infarction are mandatory. Early reperfusion therapy limits infarct size and enables the best possible preservation of left ventricular function. Standard pharmacotherapy includes angiotensin-converting enzyme inhibitors, angiotensin-1-receptor blockers and beta blockers. In addition, mineralocorticoid receptor antagonists have proven beneficial. Compounds specifically targeting infarct healing processes are currently under development.

Background: There is information suggesting differences and underuse of invasive coronary diagnostic and therapeutic procedures in women compared to men., Methods: Data from consecutive patients (pts) which were enrolled in the Coronary Angiography and PCI Registry of the German Society of Cardiology were analyzed. We compared gender-related differences in diagnosis and therapeutic recommendation of pts undergoing coronary angiography (XA) for stable coronary artery disease (CAD), non-ST elevation acute coronary syndromes (NSTE-ACS) and ST elevation myocardial infarction (STEMI)., Results: From 2004 until the end of 2009, data of 1,060,542 invasive procedures in 1,014,996 pts were prospectively registered. One-third (34.6%) of them were female. Women less often had significant CAD, irrespective of the indication for XA. In pts with relevant CAD, percutaneous coronary interventions (PCI) were recommended in 87.1% of women versus 89.1% of men with STEMI [age-adjusted OR (aOR) 0.98, 95% CI 0.93-1.04], in 67.1 vs. 66.8% in NSTE-ACS (aOR 1.10, 1.07-1.12), and in 50.3 vs 49.4% in stable CAD (aOR 1.07, 1.05-1.09)., Conclusions: In pts with significant CAD, there was no difference in recommendation for PCI between the genders in stable CAD, whereas in STEMI and NSTE-ACS women were treated even more often with PCI. There were only minor differences in referral for CABG between women and men. Hence, our data provide strong evidence against a gender bias in use of invasive therapeutic procedures once the diagnosis of significant CAD has been confirmed.

Purpose: To develop and validate a fast cardiac magnetic resonance imaging T1 mapping technique with high spatial resolution based on a radial inversion-recovery (IR) spoiled gradient-echo acquisition., Materials and Methods: Approval for the study was granted by the local institutional review board, and all subjects gave written informed consent. An electrocardiographically triggered radial single-shot IR (TRASSI) sequence was developed in conjunction with a custom-written fitting algorithm. The proposed imaging technique was validated in phantom measurements and then used for cardiac T1 mapping in 62 subjects with or without cardiac disease. The study population included 51 healthy subjects, three patients with arrhythmia, and eight patients with myocardial infarction. The potential heart rate dependency of the TRASSI method was tested by using linear regression analysis. Statistically significant differences between the sexes and various section orientations were analyzed with a Student t test for independent groups and a repeated-measures analysis of variance for dependent groups., Results: High-spatial-resolution T1 maps (1.17 × 1.17 mm) without motion artifacts and without heart rate dependency (slope = -0.0303, R(2) = 0.0000887, P = .899) were acquired with an acquisition time of less than 6 seconds in all subjects. The mean T1 of healthy left ventricular myocardium across all examined subjects was 1031 msec ± 33 (standard deviation). Testing for reproducibility in three individuals with 34 repetitive measurements revealed a mean standard deviation of 4.1 msec (0.412%). Subacute and chronic myocardial infarction could be detected in all eight patients. T1 disturbances due to arrhythmia proved to be minimal in three patients (standard deviation, <1.2%)., Conclusion: Fast and accurate cardiac T1 mapping is feasible within a single-shot IR experiment.

Myocardial infarction (MI) leads to necrosis and uncontrolled release of cellular content. Binucleated and polyploid cardiomyocytes contain high amounts of chromatin, a DNA polymer of histones which are cytotoxic. We hypothesized that chromatin from necrotic cells accumulates in the non-perfused, ischemic infarct region, causing local high concentrations of cytotoxic histones, thereby potentiating damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion which could lead to a decrease in local histone concentrations and cytotoxicity. It was confirmed that after permanent coronary artery ligation in mice, extracellular histones accumulated within the infarcted myocardium. In vitro, histones caused myocyte cytotoxicity. For protection against histone-mediated cytotoxicity after MI in vivo, DNase1 was administered within the first 6 h after induction. Indeed, DNase1 accumulation in the infarcted region of the heart was observed, as well as effective disruption of extracellular cytotoxic chromatin and subsequent reduction of high local histone concentrations. Functionally, acute DNase1 treatment resulted in significantly improved left ventricular remodeling in mice as measured by serial echocardiography, while mortality, infarct size and inflammatory parameters were unaffected. Notably, improved cardiomyocyte survival within the infarct region was observed and might account for the protective effects in acutely DNase1-treated animals. Disruption of extracellular cytotoxic chromatin within the infarcted heart by acute DNase1 treatment is a promising approach to protect myocytes from histone-induced cell death and subsequent left ventricular dysfunction after MI.

Background: Activation of innate immunity, especially infiltration of monocytes, is critical for proper wound healing and scar formation after myocardial infarction (MI). Therefore, we tested the hypothesis that interleukin-13 (IL-13), which influences the differentiation of monocytes/macrophages and has profibrotic properties, modulates wound healing and remodeling after MI., Methods and Results: MI was induced by permanent ligation of the left coronary artery in both male and female wild-type (WT)/IL-13(-/-) mice. Real-time polymerase chain reaction demonstrated that expression of IL-13 was induced in left and right ventricular myocardium of WT mice within days in response to MI. Fifty-six-day survival was significantly impaired (65% in WT versus 34% in IL-13(-/-)) in male but not female IL-13(-/-) (55% in WT versus 54% in IL-13(-/-)) mice. Serial echocardiography showed significantly increased left ventricular dilation in male IL-13(-/-) compared with WT mice starting from day 1 after MI, despite comparable infarct size. Fluorescence-activated cell sorter analysis revealed less leukocyte infiltration in male IL-13(-/-) mice on day 3. Real-time polymerase chain reaction analysis demonstrated reduced expression of marker genes of alternative activation in monocytes sorted from the infarct zone of male IL-13(-/-) in comparison with WT mice on day 3 after MI., Conclusions: Genetic deficiency of IL-13 worsens outcome after MI in male mice. Our data indicate that IL-13 regulates leukocyte recruitment and induces M2-like monocyte/macrophage differentiation, which modifies wound healing within the infarct zone., (© 2014 American Heart Association, Inc.)

Rationale: An exaggerated or persistent inflammatory activation after myocardial infarction (MI) leads to maladaptive healing and subsequent remodeling of the left ventricle. Foxp3(+) CD4(+) regulatory T cells (Treg cells) contribute to inflammation resolution. Therefore, Treg cells might influence cardiac healing post-MI., Objective: Our aim was to study the functional role of Treg cells in wound healing post-MI in a mouse model of permanent left coronary artery ligation., Methods and Results: Using a model of genetic Treg-cell ablation (Foxp3(DTR) mice), we depleted the Treg-cell compartment before MI induction, resulting in aggravated cardiac inflammation and deteriorated clinical outcome. Mechanistically, Treg-cell depletion was associated with M1-like macrophage polarization, characterized by decreased expression of inflammation-resolving and healing-promoting factors. The phenotype of exacerbated cardiac inflammation and outcome in Treg-cell-ablated mice could be confirmed in a mouse model of anti-CD25 monoclonal antibody-mediated depletion. In contrast, therapeutic Treg-cell activation by superagonistic anti-CD28 monoclonal antibody administration 2 days after MI led to improved healing and survival. Compared with control animals, CD28-SA-treated mice showed increased collagen de novo expression within the scar, correlating with decreased rates of left ventricular ruptures. Therapeutic Treg-cell activation induced an M2-like macrophage differentiation within the healing myocardium, associated with myofibroblast activation and increased expression of monocyte/macrophage-derived proteins fostering wound healing., Conclusions: Our data indicate that Treg cells beneficially influence wound healing after MI by modulating monocyte/macrophage differentiation. Moreover, therapeutic activation of Treg cells constitutes a novel approach to improve healing post-MI., (© 2014 American Heart Association, Inc.)

Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined., Methods and Results: Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality., Conclusion: Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium.

Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX(-/-) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX(-/-) bone marrow in 5-LOX(-/-) animals), indicating that an altered function of 5-LOX(-/-) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX(-/-) mice in vivo after MI. This might be due to an impaired migration of 5-LOX(-/-) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function.

Myocardial infarction (MI) leads to rapid necrosis of cardiac myocytes. To achieve tissue integrity and function, inflammatory cells are activated, including monocytes/macrophages. However, the effect of monocyte/macrophage recruitment after MI remains poorly defined. After experimental MI, monocytes and macrophages were depleted through serial injections of clodronate-containing liposomes. Monocyte/macrophage infiltration was reduced in the myocardium after MI by active treatment. Mortality was increased due to thromboembolic events in monocyte- and macrophage-depleted animals (92 vs. 33%; P<0.01). Left ventricular thrombi were detectable as early as 24 h after MI; this was reproduced in a genetic model of monocyte/macrophage ablation. A general prothrombotic state, increased infarct expansion, and deficient neovascularization were not observed. Severely compromised extracellular matrix remodeling (collagen I, placebo liposome vs. clodronate liposome, 2.4 ± 0.2 vs. 0.8 ± 0.2 arbitrary units; P<0.001) and locally lost integrity of the endocardium after MI are potential mechanisms. Patients with a left ventricular thrombus had a relative decrease of CD14CD16 monocyte/macrophage subsets in the peripheral blood after MI (no thrombus vs. thrombus, 14.2 ± 0.9 vs. 7.80 ± 0.4%; P<0.05). In summary, monocytes/macrophages are of central importance for healing after MI. Impaired monocyte/macrophage function appears to be an unrecognized new pathophysiological mechanism for left ventricular thrombus development after MI.

Background: Noninvasive echocardiographic differentiation between old and fresh left ventricular thrombi after myocardial infarction would be of clinical importance to estimate the risk for embolization and the necessity of anticoagulation., Methods and Results: Fifty-two patients, aged 41 to 87 years, with a thrombus after myocardial infarction were included in this 2-part study: In substudy-I, 20 patients, 10 each with a definite diagnosis of fresh or old thrombus, were included. In the subsequent prospective substudy-II, 32 consecutive patients with an incident thrombus after myocardial infarction but unknown thrombus age were started on phenprocoumon and followed for 6 months. Data on medical history, standard echocardiography, strain-rate (SR) imaging and magnetic resonance tomography were analyzed. In substudy-I, analysis of thrombus deformation revealed the most rapid change in SR during the isovolumetric relaxation period when cavity pressure decreases rapidly. Fresh (range: 5-27 days) and old thrombi (4-26 months) could be discriminated without overlap by peak SR during the isovolumetric relaxation period, using a cutoff value of 1 s(-1). Applying this threshold value in substudy-II, 17 thrombi were echocardiographically classified as fresh (=SR ≥1 s(-1)) and 15 as old. After 6 months in the fresh thrombus group, 16 of 17 thrombi had disappeared (94%), and in 1 patient the thrombus size was diminished by >50% (now presenting an old thrombus SR pattern). In contrast, 14 of the 15 old thrombi remained unchanged in size and deformation (1 thrombus disappeared)., Conclusions: Fresh and old intracavitary thrombi can be reliably differentiated by deformation imaging. In fresh thrombi, anticoagulation with phenprocoumon results in thrombus resolution in most patients.

Background: The role of adaptive immunity, especially CD4(+) T-helper cells, has not yet been systematically investigated in wound healing and remodeling after myocardial infarction (MI). Therefore, we studied whether CD4(+) T cells become activated and influence wound healing after experimental MI in mice., Methods and Results: When we compared sham versus MI in wild-type (WT) mice, T-cell receptor-dependent activation of both conventional Foxp3(-) and regulatory Foxp3(+) CD4(+) T cells could be demonstrated in heart-draining lymph nodes within the first week after MI. Concomitantly, we found infiltration of CD4(+) T cells in infarcted myocardium. To study the role of CD4(+) T cells in wound healing and remodeling, CD4(+) T-cell-deficient mice (CD4 knockout [KO], MHCII(Δ/Δ)) and T-cell receptor-transgenic OT-II mice recognizing an irrelevant ovalbumin-derived peptide were studied. Serial echocardiography up to day 56 after MI revealed increased left ventricular dilation in CD4 KO compared with WT mice. Within the infarcted myocardium, CD4 KO mice displayed higher total numbers of leukocytes and proinflammatory monocytes (18.3±3.0 10(4)/mg WT versus 75.7±17.0 10(4)/mg CD4 KO, P<0.05). MHCII(Δ/Δ) and OT-II mice displayed significantly greater mortality (21% WT versus 48% OT-II, P<0.05, and WT 22% versus 52% MHCII(Δ/Δ), P<0.05) and myocardial rupture rates than WT mice. Collagen matrix formation in the infarct zone was severely disturbed in CD4 KO and MHCII(Δ/Δ) mice, as well as in OT-II mice., Conclusions: The present study provides the first evidence that CD4(+) T cells become activated after MI, presumably driven by recognition of cardiac autoantigens, and facilitate wound healing of the myocardium.

Collagen breakdown and de novo synthesis are important processes during early wound healing after myocardial infarction (MI). We tested the hypothesis that collagen I, the main constituent of the extracellular matrix, affects wound healing after MI. The osteogenesis imperfecta mouse (OIM), lacking procollagen-α2(I) expression, represents a model of the type III form of the disease in humans. Homozygous (OIM/OIM), heterozygous (OIM/WT), and wild-type (WT/WT) mice were subjected to a permanent myocardial infarction protocol or sham surgery. Baseline functional and geometrical parameters determined by echocardiography did not differ between genotypes. After MI but not after sham surgery, OIM/OIM animals exhibited significantly increased mortality, due to early ventricular rupture between day 3 and 7. Echocardiography at day 1 demonstrated increased left ventricular dilation in OIM/OIM animals. Less collagen I mRNA within the infarct area was found in OIM/OIM animals. At 2 days after MI, MMP-9 expression in the infarct border zone was higher in OIM/OIM than in WT/WT animals. Increased granulocyte infiltration into the infarct border zone occurred in OIM/OIM animals. Neither granulocyte depletion nor MMP inhibition reduced mortality in OIM/OIM animals. In this murine model, deficiency of collagen I leads to a myocardial wound-healing defect. Both structural alterations within pre-existing collagen matrix and impaired collagen de novo expression contribute to a high rate of early myocardial rupture after MI., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Object: To analyze the remodeling processes of the infarct territory in the time course of infarct healing., Materials and Methods: Serial late enhancement (LE) studies were performed in 30 patients following reperfused myocardial infarction (MI) in the first and second week post-MI and after 3 months. To characterize infarct remodeling over time, the following variables were derived and analyzed in a blinded fashion: Infarct size (IS, in mm(3)), maximum infarct thickness (IT(max), mm), mean infarct thickness (IT(mean), mm) and the variability of infarct thickness (VIT=IT(max)/IT(mean)). Further, a new parameter for the assessment of infarct remodeling, the infarct extent (IE, mm(2)) was computed. IE quantifies IS in two dimensions along the heart's circumferential and longitudinal directions. IS was divided by the IE to obtain IT(mean)., Results: Overall infarct thickness was highly variable. Infarct shrinkage due to infarct thinning and IE reduction was found in the first months of healing. IS, IT(mean) and IT(max) significantly decreased during follow-up. There was a less consistent change of the IE: IE decreased in 75% of all infarcts from the first week up to 3 months post-MI, whereas 25% of infarcts expanded. Infarct thinning was found in almost all patients (92%), hence occurring in patients with infarct expansion and in patients without infarct expansion., Conclusion: Infarct thinning and-to a lesser extent-IE reduction, contribute to infarct shrinkage in the time course of infarct healing. Infarct thinning may occur without infarct expansion.

Background: Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood., Methods and Results: Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival., Conclusions: Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesis and is suitable for therapeutic intervention in the setting of ischemic heart disease.

The role of estrogens during myocardial ischemia has been extensively studied. However, effects of a standard hormone replacement therapy including 17β-estradiol (E2) combined with medroxyprogesterone acetate (MPA) have not been assessed, and this combination could have contributed to the negative outcomes of the clinical studies on hormone replacement. We hypothesized that adding MPA to an E2 treatment would aggravate chronic heart failure after experimental myocardial infarction (MI). To address this issue, we evaluated clinical signs of heart failure as well as left ventricular (LV) dysfunction and remodeling in ovariectomized rats subjected to chronic MI receiving E2 or E2 plus MPA. After eight weeks MI E2 showed no effects. Adding MPA to E2 aggravated LV remodeling and dysfunction as judged by increased heart weight, elevated myocyte cross-sectional areas, increased elevated left ventricle end diastolic pressure, and decreased LV fractional shortening. Impaired LV function in rats receiving MPA plus E2 was associated with increased cardiac reactive oxygen species generation and myocardial expression levels of NADPH oxidase subunits. These results support the interpretation that adding MPA to an E2 treatment complicates cardiovascular injury damage post-MI and therefore contributes to explain the adverse outcome of prospective clinical studies.

Background: TOPSTAR was a randomized, placebo-controlled trial studying the effects of adding the glycoprotein IIb/IIIa inhibitor tirofiban to conventional treatment with aspirin and clopidogrel in patients undergoing elective percutaneous coronary interventions (PCI). TOPSTAR demonstrated a lower periprocedural troponin release and a reduced 6-month mortality risk following PCI. The present study analyzed the corresponding long-term effects., Methods: All 96 patients who were initially included were followed for a minimum of 4 years (median follow-up time, 4.3 years). The prespecified endpoints were: 1) all-cause mortality and 2) the combined endpoint of all-cause death, myocardial infarction and target vessel revascularization by intention-to-treat analysis in patients randomly assigned to elective PCI. Survival analyses were carried out using Kaplan-Meier analysis and Cox proportional hazard regression., Results: After 4 years of follow up, no differences were observed between the two groups with respect to medical therapy, NYHA classification and number of reinterventions and target vessel revascularizations. All-cause mortality was still higher in the placebo group (10.9%; 5/46) compared with the tirofiban group (0%; 0/50; Kaplan-Meier log rank = 0.017). The combined endpoint occurred in 21.7% (10/46) in the placebo group versus 8.0% (4/50) in the tirofiban group (Kaplan-Meier log rank = 0.056)., Conclusions: The reduced 6-month mortality risk after elective PCI in the TOPSTAR trial persisted after 4 years of follow up. Even in this relatively small study, periprocedural effective platelet inhibition had a sustained impact on long-term mortality risk.

Background: Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR(MLCCre)) that were generated with a conditional MR allele (MR(flox)) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter., Methods and Results: Control (MR(flox/flox), MR(flox/wt)) and MR(MLCCre) mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR(MLCCre) mice. Chronically infarcted MR(MLCCre) mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O(2)(·-) production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR(MLCCre) mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-κB and reduced apoptosis early after myocardial infarction., Conclusion: Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression.

Aims: Evidence for a pathophysiologic relevance of autoimmunity in human heart disease has substantially increased over the past years. Conformational autoantibodies stimulating the cardiac beta1-adrenoceptor (beta1-aabs) are considered of importance in heart failure development and clinical pilot studies have shown their prognostic significance in human 'idiopathic' cardiomyopathy., Methods: We recently developed a novel highly sensitive fluorescence-based functional assay to detect stimulating beta1-aabs. We will use this method to assess Etiology, Titre-Course, and effect on Survival (ETiCS) of beta1-aabs in a prospective multicentre study with serial follow-up of patients after a first acute myocarditis or myocardial infarction. Several European core laboratories will jointly study the hypothesis that both disorders may trigger autoimmune reactions leading to the generation of beta1-aabs and/or other heart-directed aabs. Further, sera from healthy controls and well-characterized patient cohorts with dilated, ischaemic, or hypertensive cardiomyopathy will be analysed retrospectively for beta1-aab prevalence, incidence, persistence, and/or clearance., Conclusion: ETiCS is so far the largest clinical diagnostic study projected to address cardiac autoimmunity. It attempts to unravel the pathophysiology of cardiac autoantibody formation and persistence/clearance. ETiCS will enhance current knowledge on autoimmunity in human heart disease and promote endeavours to develop novel therapies targeting cardiac aabs.

Background and Purpose: Our recent experiments demonstrated that the Sphingosine-1-phosphate (S1P) receptor agonist FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride) improves recovery of function after myocardial ischaemia-reperfusion ex vivo. Therefore, we tested the hypothesis that pharmacological post-conditioning with FTY720 reduces infarct size after myocardial ischaemia-reperfusion in vivo., Experimental Approach: Myocardial ischaemia was induced in Wistar rats by ligation of the left coronary artery for 45 min. FTY720 (0.5 mg kg(-1)) was applied i.p. either once, before reperfusion, or twice, 24 h before myocardial ischaemia and before reperfusion. After 24 h reperfusion, we determined infarct size by triphenyltetrazolium chloride staining and granulocyte infiltration by immunohistochemistry. Tumour necrosis factor-alpha (TNF)-alpha concentration was determined by elisa. S1P receptor expression was studied by Western blot. Calcium transients were evaluated in Indo-1-loaded cardiomyocytes., Key Results: In both groups, FTY720 significantly reduced lymphocyte count in peripheral blood. FTY720 treatment attenuated granulocyte infiltration and TNF-alpha protein expression in reperfused myocardium. However, both treatment regimens were not able to reduce infarct size. FTY720 increased mortality due to induction of fatal ventricular tachyarrhythmias when administered once before reperfusion, but protected against reperfusion arrhythmias when given 24 h prior to ischaemia. Pretreatment selectively down-regulated S1P(1) receptor expression within the myocardium. S1P receptor agonists did not induce calcium deregulation in cardiomyocytes., Conclusions and Implications: FTY720 applied during reperfusion did not reduce infarct size but increased mortality during myocardial ischaemia-reperfusion due to induction of arrhythmias. Pretreatment with FTY720 before ischaemia abrogated the deleterious pro-arrhythmic effects without reducing infarct size.

In human and experimental myocardial infarction (MI), cessation of blood supply leads to rapid necrosis of cardiac myocytes in the ischaemic heart. Immediately after injury, various intra- and intercellular pathways contribute to healing the myocardial wound in order to achieve tissue integrity and function. MI and the consequent loss of myocardium are the major aetiology for heart failure. Despite aggressive primary therapy, prognosis remains poor in patients with large infarction and severe left ventricular dysfunction. Thus, it would be highly desirable to improve healing of the cardiac wound to maintain structure and function of the heart. Healing in the heart occurs in overlapping phases. Herein, we review the inflammatory phase as a trigger of tissue formation.

Background: Transforming growth factor (TGF)-beta is a locally generated cytokine involved in healing processes and tissue fibrosis, all relevant for cardiac remodeling and the development of heart failure after myocardial infarction (MI). However, data regarding the function of TGF-beta after ischemic injury are inconclusive., Methods and Results: We tested the effect of TGF-beta inhibition by application of a blocking antibody in mice with MI. Starting 1 week before or 5 days after coronary artery ligation mice were treated with intraperitoneal injections of an anti-TGF-beta (5 mg/kg bodyweight 1D11, Genzyme) or control antibody. Mortality over 8 weeks was significantly higher in the groups treated with the anti-TGF-beta antibody. Both, pre or post MI treatments were associated with increased left ventricular dilatation after MI as determined by serial echocardiography. In anti-TGF-beta treated mice collagen production decreased and matrix-metalloproteinase expression increased. However, the expression of TGF pro-inflammatory cytokine TNF-alpha was not altered by the treatment. Anti-TGF-beta treatment before or after coronary artery ligation increases mortality and worsens left ventricular remodeling in mice with non-reperfused MI. The detrimental effects of TGF-beta inhibition may be mediated by alterations in extracellular matrix remodeling.

Background: Reduced endothelial nitric oxide (NO) bioavailability contributes to the progression of heart failure. In this study, we investigated whether the transcription enhancer of endothelial NO synthase (eNOS) AVE9488 improves cardiac remodeling and heart failure after experimental myocardial infarction (MI)., Methods and Results: Starting 7 days after coronary artery ligation, rats with MI were treated with placebo or AVE9488 (25 ppm) as a dietary supplement for 9 weeks. AVE9488 therapy versus placebo substantially improved left ventricular (LV) function, reduced LV filling pressure, and prevented the rightward shift of the pressure-volume curve. AVE9488 also attenuated the extent of pulmonary edema, reduced LV fibrosis and myocyte cross-sectional area, and prevented the increases in LV gene expression of atrial natriuretic factor, brain natriuretic peptide, and endothelin-1. eNOS protein levels and calcium-dependent NOS activity were decreased in the surviving LV myocardium from placebo MI rats and normalized by AVE9488. The beneficial effects of AVE9488 on LV dysfunction and remodeling after MI were abrogated in eNOS-deficient mice. Aortic eNOS protein expression and endothelium-dependent NO-mediated vasorelaxation were significantly enhanced by AVE9488 treatment after infarction, whereas increased vascular superoxide anion formation was reduced. Moreover, AVE9488 prevented the marked depression of circulating endothelial progenitor cell levels in rats with heart failure after MI., Conclusions: Long-term treatment with the eNOS enhancer AVE9488 improved LV remodeling and contractile dysfunction after MI. Molecular alterations, circulating endothelial progenitor cell levels, and endothelial vasomotor dysfunction were improved by AVE9488. Pharmacological interventions designed to increase eNOS-derived NO constitute a promising therapeutic approach for the amelioration of postinfarction ventricular remodeling and heart failure.

Mineralocorticoid receptor (MR) blockade reduces morbidity and mortality after acute myocardial infarction; however, the underlying mechanisms are still under investigation. This study examined whether MR antagonism promotes healing of the infarcted myocardium. Starting immediately after coronary ligation, male Wistar rats were treated with the selective MR antagonist eplerenone (100 mg/kg per day by gavage) or placebo for 2 to 7 days. At 7 days, eplerenone therapy versus placebo significantly reduced thinning and dilatation of the infarcted wall, improved left ventricular function, and enhanced neovessel formation in the injured myocardium. At 2 days, eplerenone-treated rats displayed lower plasma corticosterone levels, higher circulating blood monocytes, and more macrophages infiltrating the infarcted myocardium. MR blockade led to a transient upregulation (at days 2 and 3 but not at day 7) of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interleukin-10, and interleukin-4 and an increase in factor XIIIa protein expression in the healing myocardium. Prevention of macrophage accumulation into the infarct zone by treatment with liposome-encapsulated clodronate almost abrogated the protein expression of factor XIIIa and the beneficial effects of eplerenone on infarct expansion. In conclusion, selective MR blockade immediately after myocardial infarction accelerated macrophage infiltration and transiently increased the expression of healing promoting cytokines and factor XIIIa in the injured myocardium resulting in enhanced infarct neovascularization and reduced early LV dilation and dysfunction.

History and Clinical Findings: A 60-year-old man had a workup for atypical angina. Noninvasive investigations, including computed tomography, showed no evidence for coronary artery disease. A few months later the patient was hospitalized because of severe epileptic seizures. Thyrotoxicosis was diagnosed and emergency thyroidectomy was performed. Two months after discharge the patient was again referred because of exercise-induced angina pectoris., Investigations and Diagnosis: Echocardiography and cardiac magnetic resonance imaging (MRI) showed a large aneurysm of the lateral wall of the left ventricle with a thrombus adhering to the wall. Coronary angiography and levocardiography confirmed the aneurysm and detected an occlusion of the distal part of the circumflex artery., Treatment and Course: Surgical aneurysm resection with thrombectomy and endoventricular circular plasty (Dor procedure) was performed without postoperative complications. Six months after surgery the patient was in good general condition without any angina. Follow-up echocardiography as well as cardiac MRI gave proof of an excellent postoperative result., Conclusions: Noninvasive preoperative diagnosis and documentation as well as postoperative monitoring with modern imaging modalities, such as echocardiography and MRI are of great value in patients with left ventricular aneurysm.

Objective: Bone marrow (BM)-derived haematopoietic stem cells have been proposed as a potential cell source to functionally engraft the myocardium and to improve cardiac function after myocardial infarction (MI). However, experimental and clinical data are inconsistent. Since the specific characteristics of different BM cell subsets could influence their therapeutic potential we determined the effect of different BM cell populations on left ventricular remodelling after MI., Methods and Results: MI was induced in female mice by coronary artery ligation. Surviving mice were randomised to receive either: total BM, mature Lin(+) or primitive Lin(-) cells from male mice, or saline, via intracardiac injection. Injected cells were detected in the infarct and border zone by PCR for Y-chromosomal sequences. Serial transthoracic echocardiography was performed 1, 21, and 42 days after MI. Over a period of 6 weeks, mortality was not different between the groups. After MI, animals exhibited left ventricular dilatation, as expected. Left ventricular remodelling was not influenced by Lin(+) or Lin(-) BM cells but was partially improved by unfractionated BM cell injection. Paracrine secretion of cytokines (e.g. IL-6, GM-CSF) was differentially regulated in supernatants of cultured BM cells., Summary: Treatment with unfractionated BM cells, but not Lin(+), or Lin(-) cells partially improved cardiac remodelling and function after MI. This may be mediated by paracrine effects.

Objectives: Left ventricular (LV) remodeling after myocardial infarction (MI) is characterized by myocyte hypertrophy and a disproportional capillary growth. We developed a hypothetical model of capillary remodeling mechanisms based on quantitative data of microcirculation determined by magnetic resonance (MR) imaging techniques and histology., Methods: Perfusion and regional capillary blood volume (RBV) were quantified 8 and 16 weeks after MI (mean 27.0+/-2.9% of the left ventricle 16 weeks post MI) or sham operation in rats using MR imaging and were correlated with morphometric data., Results: Maximum perfusion (ml/(g min)) in the remote area decreased from 5.69+/-0.63 to 3.48+/-0.48 compared to sham animals (5.33+/-0.31, p

Clinical data suggest an association of increased serum androgens with cardiovascular mortality in females, but not in males. Therefore, we examined effects of chronic anabolic testosterone administration on left ventricular remodeling after myocardial infarction in female rats. Ovariectomized adult female rats were treated with placebo, supraphysiologic testosterone undecanoate (T), estradiol (E(2)), or T+E(2). Two weeks after ovarcectomy, animals underwent sham-operation or coronary artery ligation. Left ventricular remodeling and function were assessed by echocardiography and hemodynamic investigation. In sham operated animals T administration increased serum T levels and led to cardiac hypertrophy, with an increase in the beta/alpha-MHC-ratio and in IGF-1 expression. After coronary artery ligation, infarct size and mortality were similar among the groups. T treatment aggravated left ventricular hypertrophy and chamber dilatation (end-diastolic diameter, E(2) vs. T vs. E(2)+T, 8.6 +/- 0.6 vs. 9.9 +/- 0.3 vs. 9.8 +/- 0.3 mm, p<0.05) and reduced fractional shortening 8 weeks after myocardial infarction. Extracellular matrix remodeling was not altered by hormonal treatment. In conclusion, chronic anabolic T treatment causes myocardial hypertrophy under basal conditions and adversely affects left ventricular remodeling following myocardial infarction in female rats.

Mineralocorticoid receptor blockade improves mortality early after myocardial infarction (MI). This study investigated the vascular effects of mineralocorticoid receptor blockade in the early phase postinfarction in rats. Starting immediately after coronary ligation, male Wistar rats were treated with placebo or eplerenone (100 mg/kg/d). After 7 days, hemodynamic assessment was performed and endothelial function was determined. Maximum acetylcholine-induced relaxation was significantly attenuated in aortic rings from rats with heart failure after MI, and ameliorated by eplerenone treatment. Endothelium-independent relaxation by DEA-NONOate was similar among the groups. Endothelial NO synthase phosphorylation was reduced in the aorta of MI rats and restored by eplerenone therapy. Angiotensin I-induced vasoconstriction as well as angiotensin-converting enzyme protein levels were enhanced in aortas from MI placebo rats, and reduced by mineralocorticoid receptor inhibition. Aortic reactive oxygen species formation as well as the expression of the NAD(P)H oxidase subunit p22(phox) were increased after MI and normalized in eplerenone treated rats. In conclusion, mineralocorticoid receptor antagonism improved endothelial dysfunction in the early phase post-MI. Underlying mechanisms involve inhibition of vascular angiotensin-converting enzyme upregulation and improvement of endothelial NO synthase-derived NO bioavailability.

Myocardial ischemia induces 5-lipoxygenase (LOX) translocation and leukotriene production in the heart. Leukotrienes increase inflammatory responses and could thereby aggravate ischemic injury. However, the role of lipoxygenase and leukotrienes in cardiac ischemia/reperfusion damage has not been well defined. Therefore, we tested the effect of ischemia reperfusion in mice with targeted deletion of 5-lipoxygenase, the enzyme converting arachidonic acid in leukotrienes. 5-LOX deficient (KO) and wild-type (WT) mice underwent 30 min of coronary artery ligation and 24 h of reperfusion in vivo. In mice with equivalent area at risk, infarct size was not significantly different between WT and KO mice (infarct/area at risk 61.7+/-3.9 vs. 55.8+/-6.6%, WT vs. KO, P=n.s.). However, neutrophil infiltration as well as tumor necrosis factor expression were increased in 5-lipoxygenase deficient mice. In summary, inhibition of 5-lipoxygenase does not affect cardiac ischemia-reperfusion injury but the post-ischemic inflammatory response.

Nuclear factor kappaB (NF-kappaB) is a ubiquitous transcription factor activated by various stimuli implicated in ischemia-reperfusion injury. However, the role of NF-kappaB in cardiac ischemia-reperfusion injury has not yet been well defined. Therefore, we investigated reperfusion damage in mice with targeted deletion of the NF-kappaB subunit p50. Electrophoretic mobility shift assays validated NF-kappaB activation in wild-type (WT) but not p50 knockout (KO) mice. KO and WT animals underwent 30 minutes of coronary artery ligation and 24 hours of reperfusion in vivo. Ischemia-reperfusion damage was significantly reduced in the p50 KO when compared with matching WT mice. Although adhesion molecules such as intercellular adhesion molecule were up-regulated in left ventricles of p50 KO animals, fewer neutrophils infiltrated the infarct area, suggesting leukocytes as a potential mediator of the protection observed in the p50 KO. This was confirmed in adoptive transfer experiments: whereas transplantation of KO bone marrow in KO animals sustained the protective effect on ischemia-reperfusion injury, transplantation of WT bone marrow in KO animals abolished it. Thus, deletion of the NF-kappaB subunit p50 reduces ischemia-reperfusion injury in vivo, associated with less neutrophil infiltration. Bone marrow transplantation experiments indicate that impaired NF-kappaB activation in p50 KO leukocytes attenuates cardiac damage.

Background: Proinflammatory proteins like inflammatory cytokines are implicated in myocardial depression and left ventricular remodeling after myocardial infarction. High-dose aspirin inhibits cytokine activation. Therefore, we tested the influence of high-dose aspirin treatment on left ventricular remodeling in mice after myocardial infarction., Methods and Results: Mice were treated for 4 weeks with placebo or aspirin (120 mg/kg per day) by Alzet mini-osmotic pumps after ligation of the left anterior descending coronary artery. Serial transthoracic echocardiography was performed at days 1, 7, and 28. Over the 4 weeks, mortality was not different between the groups (placebo 30.8%, aspirin 30.8%). On echocardiography, animals after myocardial infarction exhibited left ventricular dilatation (week 4, end-systolic area, placebo sham 8.9 +/- 1.7 vs. placebo MI 15.9 +/- 2.5 mm(2)), which was not changed by aspirin treatment (week 4, end-systolic area, aspirin MI 14.5 +/- 1.3 mm(2), p= ns vs. placebo MI). The expression of the proinflammatory cytokines TNF and IL-1beta were markedly upregulated in mice with myocardial infarction on placebo. Cytokine expression was significantly reduced by aspirin treatment while collagen deposition was not influenced., Conclusion: Continuous aspirin treatment (120 mg/kg/d) reduces the expression of proinflammatory cytokines after myocardial infarction, but does not affect post-infarct cardiac remodeling and cardiac function.

Objectives: Prognosis of heart failure remains poor despite therapeutic advances, such as angiotensin converting enzyme inhibition or beta-receptor blockade. Thus, more effective forms of treatment are urgently needed. Since estrogens have been shown to modulate migration and proliferation of cardiac fibroblasts and to modulate the expression of estrogen receptors of cardiomyocytes we examined whether high-dose estrogen treatment can affect post-myocardial infarction left ventricular remodeling., Methods: Female rats were treated with 17beta-estradiol (7.5 mg/90 d) or placebo for ten weeks, starting two weeks prior to experimental myocardial infarction. Eight weeks after infarction, in vivo echocardiographic and hemodynamic measurements as well as isolated heart perfusion were performed., Results: In vivo, chronic estrogen treatment almost completely prevented the development of all signs of heart failure that occur in untreated infarcted hearts, such as increased left ventricular diameters (dilatation), reduced fractional shortening (systolic dysfunction) or increased left ventricular end-diastolic pressure (diastolic dysfunction). In vitro, the right- (indicating structural dilatation) and downward (indicating left ventricular dysfunction) shift of left ventricular pressure-volume curves occurring in untreated infarcted hearts was completely prevented by estrogen., Conclusions: High dose estradiol treatment prevented development of post-MI remodeling, as assessed by in vivo and in vitro parameters of LV dysfunction. Estrogen may hold the potential of becoming a new form of heart failure treatment.However, the mechanisms responsible for this striking and unexpected beneficial action of estrogen in heart failure remain to be elucidated.

Inadequate healing of myocardial infarction may contribute to local expansion of the infarct, frequently leading to chamber dilation, heart failure, or myocardial rupture. Experimental evidence in mouse models suggests that Factor XIII might play a key role in wound healing, and low persistent values lead to increased incidence of cardiac rupture following myocardial infarction. Here we would like to share our initial clinical experiences with strikingly similar observations in patients with this grave disease, and compare these observations to experimental findings.

Aims: To characterize the relationship between known and newly diagnosed atrial fibrillation (AF) and the risk of death and major cardiovascular (CV) events in patients with acute myocardial infarction (MI) complicated by heart failure (HF) and/or left ventricular systolic dysfunction (LVSD)., Methods: The VALIANT trial enrolled 14,703 individuals with acute MI complicated by HF and/or LVSD. AF was assessed at presentation and at randomization (median 4.9 days after symptom onset). Primary outcomes were risk of death and major CV events 3 years following acute MI., Results: A total of 1812 with current AF (AF between presentation and randomization), 339 patients with prior AF (history of AF without current AF), and 12,509 without AF were enrolled. Patients with AF were older; had more prior HF, angina, and MI, and received beta-blockers and thrombolytics less often than those without AF. Three-year mortality estimates were 20% in those without AF, 37% with current AF, and 38% with prior AF. Compared with patients without AF, the multivariable adjusted HR of death was 1.25 (1.03-1.52; p=0.03) for prior AF and 1.32 (1.20-1.45; p<0.0001) for current AF. HR for major CV events was 1.15 (0.98-1.35; p=0.08) and 1.21 (1.12-1.31; p<0.0001)., Conclusion: AF is associated with greater long-term mortality and adverse CV events with acute MI complicated by HF or LVSD.

Background: NF kappa B (NF-kappaB) is a ubiquitous transcription factor activated by various stimuli implicated in heart failure progression including reactive oxygen species (ROS), hypoxia, and inflammatory cytokines. Although NF-kappaB is involved in ischemic preconditioning, unstable angina pectoris, and atherogenesis, its role in heart failure has not been determined. Therefore, we investigated left ventricular remodeling in mice with a targeted deletion of the NF-kappaB subunit p50/NF-kappaB1 after myocardial infarction., Methods and Results: p50 knockout (KO) and wild-type (WT) animals underwent coronary artery ligation. Transthoracic echocardiography was performed at days 0, 21, and 56 at midpapillary levels. Early mortality was significantly lower in KO than in WT animals. Moreover, p50 KOs exhibited significantly reduced ventricular dilatation over 8 wk compared to WT controls (end-systolic diameters by transthoracic echocardiography, WT vs. KO, 0.55+/-0.04 vs. 0.34+/-0.03 cm) and preserved left ventricular contractility. Collagen content and matrixmetalloproteinase (MMP) -9 expression were significantly lower in KO mice after myocardial infarction and may account for improved left ventricular remodeling., Conclusions: Absence of the NF-kappaB subunit p50 improves early survival and reduces left ventricular dilatation after myocardial infarction. NF-kappaB might therefore be an attractive target to treat heart failure.

Objective: The aim of this prospective clinical study was to follow up patients with acute myocardial infarction from the ischemic event, over the primary coronary intervention (PCI), up to the chronic phase after survived myocardial infarction by noninvasive strain rate (SR) imaging and to determine its role in the assessment of transmurality of infarction., Methods: In all, 41 patients with acute S-T elevation infarction were examined immediately before, 3 days after, and 5 months after PCI. Regional myocardial function was assessed by the use of ultrasonic SR imaging and peak systolic SR and systolic strain were extracted. In addition, late-enhancement (LE) imaging with magnetic resonance imaging was done after 5 months to assess the transmurality of residual scar distribution., Results: Magnetic resonance imaging showed that 8 patients had no LE (complete recovery = no-scar group), 16 patients had subendocardial LE (nontransmural infarction = NT group), and 17 patients had a transmural LE (transmural infarction = T group) in the region of interest. Before PCI both SR and strain were markedly reduced in the ischemic segments compared with the nonischemic remote region in all 3 groups (SR: ischemia = -0.6 +/- 0.3 s(-1); remote = -1.3 +/- 0.4 s(-1), P < .001). Three days after PCI, systolic SR only increased significantly in the regions that were not transmurally infarcted. After 5 months the measurement of systolic strain could accurately distinguish the different groups. (no-scar group = -24 +/- 5%, NT group = -13 +/- 4%, T group = -1 +/- 3%)., Conclusions: This clinical study shows that with SR imaging: (1) the ischemic segment can be precisely detected; (2) the absence of transmurality early after coronary intervention can be predicted; and (3) in the chronic phase the transmurality of scar distribution can be assessed.

Background: Based on the RALES study, in patients with moderate to severe chronic heart failure and reduced left ventricular function, the nonselective aldosterone antagonist spironolactone has a well-established role in combination with ACE inhibition, beta-blockade and diuretics. This indication was recently reinforced by the guideline for chronic heart failure therapy of the German Cardiac Society, although there is no formal approval for spironolactone for this indication in Germany., New Clinical Studies: Heart failure after acute myocardial infarction represents a new indication for aldosterone receptor blockade. In the EPHESUS trial of patients with acute myocardial infarction, reduced ejection fraction, and clinical signs of heart failure, the selective aldosterone antagonist eplerenone in combination with ACE inhibition and beta-blockade significantly reduced mortality. The best benefit was achieved by early treatment, i. e., starting 3-7 days post myocardial infarction. In addition, as early as after 30 days, eplerenone-treated patients had significantly reduced mortality and hospitalization. Eplerenone was approved for the indication heart failure after acute myocardial infarction in late 2004 in Germany., Purpose of This Study: The present review summarizes the pathophysiological basis, the experimental and clinical trials that constitute the rationale for therapy with aldosterone antagonists in patients with acute myocardial infarction and heart failure. Tips for use in clinical practice are given which allow to profit from the effective potential for mortality and morbidity reduction of aldosterone receptor blockade and to minimize the risk of serious hyperkalemia.

Endocannabinoids have been implicated in protective effects in the heart and brain, but the mechanism of possible infarct-size-reducing effects remains controversial. Using a model of delayed preconditioning (PC), rats received the nitric oxide (NO) donor nitroglycerin (0.15 mg/h/kg) for 24 hours via transdermal application. Two days later, rat isolated perfused hearts were subjected to global, no-flow ischemia (20 min), and reperfusion (120 min). Cannabinoid receptor antagonists were given before no-flow throughout the protocol. Endocannabinoids were detected by liquid chromatography and mass spectrometry. NO-induced PC reduced the left ventricular infarct size from 40.9 +/- 3.9% to 27.5 +/- 3.8% (P < 0.05). Treatment with the specific CB1 cannabinoid receptor antagonist AM-251 (0.3 microM) prevented the protective effect of PC on infarct size (40.2 +/- 4.7%, P > 0.05 vs. controls). On the contrary, the specific CB2 receptor antagonist AM-630 (0.3 microM) did not alter infarct size (31.6 +/- 6.3%, P > 0.05 vs. PC alone). Recovery of left ventricular developed pressure and coronary flow was incomplete in control and NO-pretreated hearts and not consistently altered by cannabinoid receptor antagonists. PC increased the heart tissue content of the endocannabinoid 2-arachidonylglycerol (2-AG) from 4.6 +/- 1.0 nmol/g in controls to 12.0 +/- 2.1 nmol/g (P < 0.05). Tissue levels of the endocannabinoid arachidonylethanolamide (anandamide) remained unchanged (19.8 +/- 3.9 pmol/g vs. 19.5 +/- 4.8 pmol/g). 2-AG (1 microM) or its metabolically stable derivative noladinether (0.1 microM), given 30 minutes before ischemia/reperfusion in unpreconditioned hearts, mimicked the cardioprotective effects of PC and reduced infarct size. We conclude that delayed PC through transdermal nitroglycerin application increases the production of the endocannabinoid 2-AG which elicits protective effects against myocardial infarction via CB1 cannabinoid receptors which represents one new mechanism of NO-mediated PC.

Nuclear factor kappaB (NF-kappaB) is a ubiquitous transcription factor activated by various stimuli implicated in heart failure progression. However, its activation in heart failure has not been well defined yet. Therefore, we investigated activation of NF-kappaB after myocardial infarction. For the first time, we performed serial, non-invasive in vivo molecular imaging of transcription factor activation in the heart. We used mice expressing a luciferase reporter whose transcription is dependent upon NF-kappaB activation for up to 8 weeks after myocardial infarction. There was a significant increase of NF-kappaB activity with a maximum at day 3 after myocardial infarction when compared to sham controls. Thus, in vivo measurement of the activation of NF-kappaB is feasible. NF-kappaB activity might play an important role for the remodeling process.

Objective: Standard drugs post-myocardial infarction (MI) such as angiotensin converting enzyme (ACE) and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) increase levels of endothelial progenitor cells (EPC). However, potential underlying mechanisms have not yet been investigated., Methods and Results: We studied the effects of ACE inhibition or statin treatment on EPC levels and on bone marrow molecular pathways involved in EPC mobilization after MI in rats. Three days post-infarction, acetylated LDL (acLDL)+/Ulex europeus-1 (UEA-1)+/VEGF receptor-2+/eNOS+ EPC levels and formation of endothelial colony forming units (CFU) were reduced to 60+/-12% (p < 0.05) and 68+/-7% (p < 0.05). In bone marrow, extracellular signal-regulated kinase (ERK) phosphorylation and matrix metalloproteinase (MMP)-9 activity were repressed. Endothelial nitric oxide synthase (eNOS) activity was unchanged, whereas reactive oxygen species (ROS) were increased two-fold in bone marrow. ACE or HMG-CoA reductase inhibition resulted in significant increases in EPC levels. ACE inhibition increased bone marrow ERK phosphorylation and MMP-9 activity. Statin therapy enhanced bone marrow VEGF protein levels, Akt phosphorylation, eNOS activity and normalized increased ROS levels. Augmented EPC levels in the early post-infarction phase by ACE inhibition or statin treatment were associated with improved cardiac function and increased capillary density in the peri-infarct area 7 days after MI. Moreover, increased EPC levels in response to ACE inhibition or statin treatment were sustained 10 weeks post-infarction., Conclusions: Increased ROS and impaired MMP-9 activity in bone marrow likely contribute to reduced EPC mobilization in the early post-infarction phase. ACE inhibition or statin treatment increased EPC levels with distinct drug-specific effects on bone marrow molecular alterations.