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Background: Infarct-related artery (IRA) patency after acute myocardial infarction (AMI) is associated with a more favourable clinical course, in particular in patients with high-risk features. As it has been recently reported that IRA patency is associated with a reduced postinfarction apoptotic rate (AR), the aim of our study was to assess whether IRA status late after AMI had a different impact on AR in high- vs. low-risk patients. Methods and results: Co-localization of TUNEL and caspase-3 was used to calculate the AR at the site of infarction at the time of death in 30 subjects. The Norris coronary prognostic index (NI) was calculated (computing age, presence of pulmonary congestion, heart size and history of previous additional AMI) in order to define the patients' individual risk at the time of hospitalization. According to the NI (≤ 7 vs. > 7), subjects were divided into low and high risk, as NI > 7 carries an approximate threefold higher risk of death. The NI was significantly correlated with the AR at the time of death both in infarct and remote areas. Twenty subjects had IRA occlusion at the time of death, and in these patients AR was significantly higher both in infarct and remote areas (P < 0.001 and P = 0.009 vs. the others, respectively). However the impact of IRA occlusion on AR was significantly different comparing high- vs. low-risk subjects. In particular, AR at the infarct site was 10-fold higher in the high-risk subjects with IRA occlusion (26-1% [20.4-28.7%]) vs. those with open IRA (2.3% [0.6-3.5%]; P = 0.002) and was nonsignificantly different in the low-risk subjects vs. those without IRA occlusion (8.2% [2.5-17.5%] vs. 5.4% [1.5-7.9%]; P = 0.48). Similarly, in the high-risk subjects, AR in remote areas was significantly greater in cases with occluded vs. open IRA (0.7% [0.4-0.9%] vs. 0.3% [0.3-0.32%]; P = 0.009). Conclusion: A significantly higher AR is associated with IRA occlusion late post AMI in subjects with high-risk clinical features, and not in low-risk patients. The diverse impact of IRA occlusion on AR in subjects with different risk profiles may explain the greater benefit associated with coronary reperfusion in high-risk subjects. The overall lower AR in low-risk subjects, independently from the IRA status, may be correlated with the better long-term prognosis after AMI in this case.

We believe that sIL-2R levels should be regarded as markers of LV dysfunction independently from its cause. Moreover, we believe that in the current effort to understand and appraise fully the role of inflammatory mechanism in cardiac remodelling and failure, sIL-2R levels should be determined in the active phases of the disease when LV dysfunction ensues, rather than in its advanced phase.

"BACKGROUND: Percutaneous dilatational tracheostomy (PDT) is a common procedure in intensive care units and the identification of the best technique is very important. We performed a systematic review and meta-analysis of randomized studies comparing different PDT techniques in critically ill adult patients to investigate if one technique is superior to the others with regard to major and minor intraprocedural complications.. . METHODS: BioMedCentral and other database of clinical trials were searched for pertinent studies. Inclusion criterion was random allocation to at least two PDT techniques. Exclusion criteria were duplicate publications, nonadult studies, and absence of outcome data.. . STUDY DESIGN: Population, clinical setting, and complications were extracted.. . RESULTS: Data from 1130 patients in 13 randomized trials were analyzed. Multiple dilators, single-step dilatation, guide wire dilating forceps, rotational dilation, retrograde tracheostomy, and balloon dilation techniques were always performed in the intensive care unit. The different techniques and devices appeared largely equivalent, with the exception of retrograde tracheostomy, which was associated with more severe complications and more frequent need of conversion to other techniques when compared with guide wire dilating forceps and single-step dilatation techniques. Single-step dilatation technique was associated with fewer failures than rotational dilation, and fewer mild complications in comparison with balloon dilation and guide wire dilating forceps (all P

Cardiac remodeling after acute myocardial infarction (AMI) is characterized by molecular and cellular mechanisms involving both the left (LV) and right ventricular (RV) walls. Cardiomyoycte apoptosis in the peri-infarct and remote LV myocardium has a central role in cardiac remodeling. Whether apoptosis also occurs in the right ventricle of patients with ischemic heart disease has not been investigated. The aim of the present study was to investigate the presence of cardiomyocyte apoptosis in the right ventricle in patients with AMI. We assessed the number of apoptotic cardiomyocytes using multiple samplings in the LV and RV walls of 12 patients selected at autopsy who died 4 to 42 days after AMI. Five patients without cardiac disease were also selected at autopsy as controls. Apoptotic rates were calculated from the number of cardiomyocytes showing double positive staining for in situ end-labeling of DNA fragmentation (TUNEL) and for activated caspase-3. Potentially false-positive results (DNA synthesis and RNA splicing) were excluded from cell counts. The apoptotic rate in the right ventricle in patients with AMI was significantly higher than in control hearts (median 0.8%, interquartile range 0.3 to 1.0 vs median 0.01%, interquartile range 0.01 to 0.03, p

Background: Multivessel coronary disease after myocardial infarction is a major risk factor for unfavorable cardiac remodeling and death due to pump failure, but underlying pathophysiologic mechanisms are still uncompletely established. Post-infarction myocardial apoptosis has been recently implicated as a cause of ongoing cell loss leading to cardiac failure. Our aim was to assess the role of post-infarction myocardial apoptosis and pro-apoptotic factor expression in the non-infarcted remote myocardium of subjects with multivessel coronary disease. Methods: Twenty-one males dying after recent myocardial infarction with permanent occlusion of the infarct-related artery were selected at autopsy. Apoptosis was assessed at viable myocardial regions remote from infarction by co-staining for in situ end-labeling of DNA fragmentation and cleaved caspase-3. Expression of pro-apoptotic factor bax and hypoxia-induced factor-1alpha was evaluated by immunohistochemistry. Results: Subjects with multivessel disease (N = 11) showed a significantly two-fold higher myocardial apoptosis in comparison to subjects with single vessel disease (N = 10) (0.9% vs. 0.5%, p = 0.013). Similarly, myocardial bax expression was increased in patients with multivessel disease (3.0% vs. 1.4%, p = 0.029). Stratification for the number of diseased coronary vessels confirmed the association between extent of coronary disease and apoptotic rates (p = 0.022). Even in subjects dying over 30 days after infarction multivessel disease remained predictive of enhanced myocardiocyte apoptosis at remote regions (p = 0.033). Conclusions: Post-infarction myocardial apoptosis and bax expression in remote left ventricular regions are significantly increased in male patients with multivessel coronary disease in comparison to those with isolated infarct-related artery occlusion. These findings suggest that apoptotic cell loss in the viable non-infarcted myocardium, possibly due ongoing ischemia, may play a relevant role in the unfavorable clinical course typical of multivessel disease after myocardial infarction. © 2004 Published by Elsevier Ireland Ltd.

The open-artery hypothesis states that myocardial reperfusion, even if late for myocardial salvage, provides benefits and prevents adverse cardiac remodeling. While observational data in humans regarding the deleterious impact of a permanent infarct-related artery occlusion and the benefits of spontaneous reperfusion are quite consistent, the reports regarding late revascularization are inconclusive in order to prove such a hypothesis. The observational studies tend to have selection biases, while randomized trials to date are too small to be conclusive. Moreover, the pathophysiological mechanisms underlying presumed benefits of reperfusion are still unclear. However, although the open-artery hypothesis remains unproven, the current evidence suggesting benefits calls for additional studies. Limitations of ischemic left ventricular dilatation and myopathy could markedly reduce cardiovascular morbidity and mortality after acute myocardial infarction. Copyright © 2003 S. Karger AG, Basel.

Left ventricular (LV) remodeling and heart failure (HF) complicate acute myocardial infarction (AMI) even weeks to months after the initial insult. Apoptosis may represent an important pathophysiologic mechanism causing progressive myocardiocyte loss and LV dilatation even late after AMI. This review will discuss the role of apoptosis according to findings in animal experimental data and observational studies in humans in order to assess clinical relevance, determinants, and mechanisms of myocardial apoptosis and potential therapeutic implications. More complete definition of the impact of myocardiocyte loss on prognosis and of the mechanisms involved may lead to improved understanding of cardiac remodeling and possibly improved patients' care. Mitochondrial damage and bcl-2 to bax balance play a central role in ischemia-dependent apoptosis while angiotensin II and β1-adrenergic-stimulation may be major causes of receptormediated apoptosis. Benefits due to treatment with ACE-inhibitors and β-blockers appear to be in part due to reduced myocardial apoptosis. Moreover, infarct-related artery patency late after AMI may be a major determinant of myocardial apoptosis and clinical benefits deriving from an open artery late post AMI (the "open artery hypothesis") may be, at least in part, due to reduced myocardiocyte loss. © 2002 Wiley-Liss, Inc.

Heart failure is a complex syndrome characterized by impaired emptying and/or impaired filling of the heart chambers. The use of parameters of diastolic function has provided novel tools for risk stratification and management of patients with heart failure. This study evaluated the potential correlation between apoptosis at time of death and left ventricular (LV) diastolic function after acute myocardial infarction. We selected, at routine postmortem examination, 14 subjects who died 10 to 62 days after an acute myocardial infarction and had an available echocardiographic report from the most recent hospital admission. The apoptotic rate was calculated at the region bordering the infarct, using co-localization of in situ end-labeling for deoxyribonucleic acid fragmentation and immunohistochemistry for caspase-3. Transthoracic echocardiographic studies were retrospectively reevaluated and pulse-wave Doppler spectra of mitral inflow were analyzed. LV diastolic function was assessed by measuring the ratio of E peak velocity to A peak velocity and E-wave deceleration time; a ratio of E peak velocity to A peak velocity ≥2 and deceleration time

Objective: The authors conducted a review of randomized studies to determine whether there were any advantages for clinically relevant outcomes by adding epidural analgesia in patients undergoing cardiac surgery under general anesthesia. Design: Meta-analysis. Setting: Hospitals. Participants: A total of 2366 patients from 33 randomized trials. Interventions: None. Measurements and Main Results: Data sources and study selection: PubMed, BioMedCentral, CENTRAL, EMBASE, Cochrane Central Register of Controlled Trials, and conference proceedings were searched (updated January 2008) for randomized trials that compared general anesthesia with an anesthetic plan including general anesthesia and epidural analgesia in cardiac surgery. Two independent reviewers appraised study quality, with divergences resolved by consensus. Overall analysis showed that epidural analgesia reduced the risk of the composite endpoint mortality and myocardial infarction (30/1125 [2.7%] in the epidural group v 64/1241 [5.2%] in the control arm, odds ratio [OR] = 0.61 [0.40-0.95], p=0.03 number needed to treat [NNT] = 40), the risk of acute renal failure (35/590 [5.9%] in the epidural group v 54/618 [8.7%] in the control arm, OR = 0.56 [0.34-0.93], p = 0.02, NNT = 36), and the time of mechanical ventilation (weighted mean differences = -2.48 hours [-2.64, 2.32], p < 0.001). Conclusions: This analysis suggested that epidural analgesia on top of general anesthesia reduced the incidence of perioperative acute renal failure, the time on mechanical ventilation, and the composite endpoint of mortality and myocardial infarction in patients undergoing cardiac surgery. (C) 2010 Elsevier Inc. All rights reserved.

Objective: Controversial results exist on the effects of spinal analgesia in cardiac surgery. The authors conducted a review of randomized studies to show whether there are any advantages in clinically relevant outcomes using spinal analgesia in patients undergoing cardiac surgery. Design: Meta-analysis. Setting: Multiple hospitals. Participants: A total of 1,106 patients from 25 randomized trials. Interventions: None. Measurements and Main Result: Pub Med, BioMedCentral, CENTRAL, EMBASE, Cochrane Central Register of Controlled Trials, and conference proceedings were searched (updated January 2009) for randomized trials that compared general anesthesia with an anesthetic plan including spinal analgesia in cardiac surgery. Four independent reviewers performed data extraction, with divergences resolved by consensus. A total of 1,106 patients from 25 randomized studies were included in the analysis. Overall analysis showed that there were no differences in terms of mortality (2/562 [0.4%] in the spinal group v2/514 [0.4%] in the control arm [risk difference (RD) = 0.00 [-0.02, +0.02], p = 1.01, perioperative myocardial infarction (9/421 [2.1%] in the spinal group v 11/407 [2.7%] in the control arm [RD = 0.00, (0.03, +0.02), p = 0.77), and the length of hospital stay (WMD = -0.28 days [-0.68, -0.13], p = 0.18, with 419 included patients). Conclusions: This analysis indicated that spinal analgesia does not improve clinically relevant outcomes in patients undergoing cardiac surgery, discouraging further randomized controlled trials on this topic even if changes in techniques, devices, and drugs could modify the outlook of the comparison between spinal and standard anesthesia in this setting. (C) 2009 Elsevier Inc. All rights reserved.

Acute myocarditis is an acute inflammatory syndrome characterized by acute myocardial damage and dysfunction followed by a variable recovery over time with some patients progressing toward severe dilated cardiomyopathy. Cardiomyocyte apoptosis, a key pathologic feature of heart failure, may play a critical role in functional recovery in patients with acute myocarditis. The aim of the study was to investigate whether apoptosis predicts functional recovery in patients with acute myocarditis. Sixteen patients with biopsy-documented acute myocarditis were followed for 1 year with serial transthoracic echocardiography. Functional recovery was defined as 12-month left ventricular ejection fraction >40%. Cardiomyocyte apoptosis, leukocyte infiltration, and cell proliferation was assessed in all samples. A group of cases in which the diagnosis of acute myocarditis was made after death was also selected for comparison, and morphologically normal hearts from patients who died from a noncardiac cause were selected as controls. Six patients (38%) had functional recovery at 12 months, whereas 10 (62%) did not. The 2 groups had similar characteristics except for lower baseline left ventricular ejection fraction in the group with functional recovery. Apoptotic rate was found to be significantly higher in patients with acute myocarditis than in control hearts, and, unexpectedly, patients with functional recovery had significantly higher apoptotic rates than patients without recovery (3.2% vs 0.5%, p = 0.001). None of the patients with apoptotic rates below the median had functional recovery versus 86% of patients with apoptotic rates above the median (p

the past decade has been characterized by unprecedented progress in cardiac cell biology and pathophysiology. The dogma of the heart being a terminally differentiated organ has been challenged by compelling evidence generated in several different laboratories around the world ([6][1]). These

Background— Experimental interleukin-1 receptor antagonist gene overexpression has shown that interleukin-1 receptor antagonist is cardioprotective during global cardiac ischemia. The aim of the present study was to test the impact of an exogenous recombinant human interleukin-1 receptor antagonist (anakinra) in experimental acute myocardial infarction. Methods and Results— Two animal studies were conducted: one of immediate anakinra administration during ischemia in the mouse and one of delayed anakinra administration 24 hours after ischemia in the rat. Seventy-eight Institute of Cancer Research mice and 20 Wistar rats underwent surgical coronary artery ligation (or sham operation) and were treated with either anakinra 1 mg/kg or NaCl 0.9% (saline). Treatment was administered during surgery and then daily for 6 doses in the mice and starting on day 2 daily for 5 doses in the rats. Twenty-eight mice underwent infarct size assessment 24 hours after surgery, 6 saline-treated mice and 22 mice treated with increasing doses of anakinra (1 mg/kg [n=6], 10 mg/kg [n=6], and 100 mg/kg [n=10]); 6 mice were euthanized at 7 days for protein expression analysis. The remaining animals underwent transthoracic echocardiography before surgery and 7 days later just before death. Cardiomyocyte apoptosis was measured in the peri-infarct regions. The antiapoptotic effect of anakinra was tested in a primary rat cardiomyocyte culture during simulated ischemia and in vitro on caspase-1 and -9 activities. At 7 days, 15 of the 16 mice (94%) treated with anakinra were alive versus 11 of the 20 mice (55%) treated with saline ( P =0.013). No differences in infarct size at 24 hours compared with saline were observed with the 1- and 10-mg/kg doses, whereas a 13% reduction in infarct size was found with the 100-mg/kg dose ( P =0.015). Treatment with anakinra was associated with a significant reduction in cardiomyocyte apoptosis in both the immediate and delayed treatment groups (3.1±0.2% versus 0.5±0.3% [ P P Conclusions— Administration of anakinra within 24 hours of acute myocardial infarction significantly ameliorates the remodeling process by inhibiting cardiomyocyte apoptosis in 2 different experimental animal models of AMI. This may open the door for using anakinra to prevent postischemic cardiac remodeling and heart failure.

OBJECTIVE: Selective cyclo-oxygenase-2 (COX-2) inhibitors have been shown to preserve hemodynamic performance in experimental models of acute myocardial infarction (AMI) in rodents. The impact of COX-2 inhibition on apoptosis, vascular density, and postinfarction remodeling has not yet been fully characterized. The aim of the present study was to evaluate the effects of parecoxib, a selective COX-2 inhibitor, in an experimental AMI model in the rat. METHODS: Twenty-four male Wistar rats (10 weeks of age, weighing 350-500 g) underwent surgical left coronary artery ligation. Four animals died within 24 hours. Starting on day 2, 10 rats received parecoxib (0.75 mg/kg intraperitoneal) daily for 5 days and the remaining 10 received NaCl-0.9%. Animals underwent transthoracic echocardiography before surgery and 7 days later for the measurement of end-diastolic and end-systolic diameter and wall thickness; thereafter, animals were sacrificed and histological analysis was performed to evaluate cardiomyocyte apoptosis and small arteriolar density. Data are expressed as mean and standard error. RESULTS: Three saline-treated (30%) and zero parecoxib-treated animals died before day 7. Compared with saline-treated animals, rats treated with parecoxib had a smaller end-diastolic diameter (6.3 ± 0.1 vs. 7.0 ± 0.1 mm, P = 0.018) and end-systolic diameter (2.7 ± 0.1 vs. 3.9 ± 0.1 mm, P = 0.027), and had a greater fractional shortening (57 ± 1 vs. 45 ± 2%, P = 0.050). Systolic thickness in the anterior (infarct) wall was also significantly greater in the parecoxib-treated animals (3.2 ± 0.1 vs. 2.7 ± 0.1 mm, P = 0.008), while the posterior wall was not significantly affected (P = 0.08). Aneurysmal dilatation of the left ventricle was more frequent in saline-treated versus parecoxib-treated animals (43 vs. 0%, P = 0.025). Parecoxib treatment was associated with lower apoptotic rates (1.0 ± 0.2 vs. 4.0 ± 0.4%, P < 0.001) and preservation of arteriolar density (20 ± 5 vs. 8 ± 2 mm/mm, P = 0.018) in the peri-infarct area, without differences in circulating interleukin-1β, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma levels. CONCLUSION: Administration of parecoxib significantly ameliorates the remodeling process after AMI, possibly through prevention of apoptosis and preservation of myocardial vascularity. These findings aid in the understanding of the role of COX-2 in ischemic damage and remodeling. © 2007 Lippincott Williams & Wilkins, Inc.

Objective: To test the hypothesis that impaired coronary and myocardial blood flow are linked with increased myocyte apoptosis, thus establishing a link between pressure overload and left ventricular (LV) remodelling. Methods and results: Peak diastolic coronary blood flow velocity (CBFV) was evaluated at transthoracic Doppler echocardiography, and signal intensity (SI) and the rate of SI rise (β) were measured at myocardial contrast echocardiography in 11 patients with severe aortic stenosis and LV hypertrophy. In the same patients, biopsies were obtained from the anterolateral LV free wall during surgery and analysed for cardiomyocyte apoptosis. LV mass corrected CBFV (CBFVI) was significantly lower in patients than in controls (median 0.100 cm·g/s (interquartile range 0.07–0.115) v 0.130 cm·g/s (0.130–0.160), p = 0.002). Similarly, SI*β was significantly lower in patients than in controls (11 1/s (8–66) v 83 1/s (73–95), p = 0.001). Apoptotic rate was increased in aortic stenosis more than 100-fold versus controls (1.2% (0.8–1.4) v 0.01% (0.01–0.01), p r = −0.77, p = 0.001 for both). Conclusions: Patients with severe aortic stenosis and LV hypertrophy have impaired myocardial perfusion, which is associated with enhanced cardiomyocyte apoptosis. Impaired myocardial perfusion and the ensuing oxygen demand–supply imbalance may, at least partially, be responsible for increased apoptosis and possible transition to heart failure, thus establishing a link between pressure overload, LV remodelling, and heart failure.

Heart failure (HF) is less prevalent and has a better prognosis in women than in men. Also, the outlook after acute myocardial infarction (AMI) is more favourable in elderly women.1 Such sex related differences are probably related to sex specific cardiac remodelling processes.2 However, despite several hypothetical pathogenetic mechanisms, there are no established explanations. Myocardial apoptosis is a pivotal determinant of left ventricular (LV) dysfunction and cardiac failure in experimental and clinical studies, including after AMI. Sex may indeed influence apoptosis, as shown in normal aging and in end stage HF.3 However, little is known about the role of sex in post-infarction apoptosis. We thus evaluated the influence of sex on expression of pro-apoptotic mediators and myocardiocyte apoptotic index (AI) in subjects dying after AMI. Using established methods,4 we selected six females who had died after AMI with permanent infarct related artery occlusion at necropsy (< 30 hours after death); 15 males with similar characteristics were selected during the same period. Three men and one woman dying from non-cardiac causes were included as controls. Re-infarction was excluded on clinicopathologic grounds in all cases. Infarct size was quantified at gross pathology on a four grade scale (small, moderate, moderate to extensive, and extensive). Tissue specimens were obtained at peri-infarct and remote sites. In situ end labelling of DNA fragmentation by transferase-mediated biotinylated UTP nick end labelling (TUNEL) was performed (Apoptag, Oncor) and sections were stained with antibodies against muscle actin (DAKO-Carpintera; dilution 1:50), and activated caspase-3 (Cell …

We report hypoxia-inducible factor-1 (HIF-1) expression in myocardium of patients with recent acute myocardial infarction (AMI), supporting the hypothesis of HIF-1 as a possible mediator of response to ischemia. A potential diagnostic role of determining tissue expression of HIF-1 as a marker of ischemia, and potential therapeutic implications by trying to modulate HIF-1 activity in order to promote beneficial effects of HIF-1 related genes (e.g. expression of vascular endothelial growth factor (VEGF)) may derive. © 2004 Elsevier Ireland Ltd. All rights reserved.

Aims: Unfavourable cardiac remodelling often complicates acute myocardial infarction (AMI) as a result of increased cardiomyocyte apoptosis. It is currently unclear whether ongoing or recurrent ischaemia is an independent determinant for increased apoptosis in peri-infarct viable myocardium. Methods and results: In order to assess the link between infarct-related artery (IRA) occlusion, ischaemia, and apoptosis, 30 subjects dying 7-120 days after AMI (16 with IRA occlusion and 14 with patent IRA) and five control subjects were selected at autopsy. Cardiomyocytes were defined as apoptotic if co-expressing TUNEL and activated caspase-3. Expression of both hypoxia-inducible factor-1 and cyclo-oxygenase-2 was assessed in the peri-infarct myocardium and considered as tissue markers of ischaemia. Evidence of ischaemia was significantly more frequent in cases with IRA occlusion (53%) than in cases with patent IRA (15%) or control hearts (0%, P = 0.026). The finding of IRA occlusion and markers of ischaemia identified cases with higher apoptotic rates (ARs) in the peri-infarct viable myocardium [12.2% (8.2-14.0), P < 0.001 vs. others], whereas IRA occlusion without ischaemia was associated with lower AR, not significantly different from patent IRA [3.0% (1.0-7.9) vs. 2.2% (1.0-5.8), respectively, P = 0.42] Conclusion: Ischaemia in the peri-infarct viable myocardium is present in over 50% of subjects dying late after AMI with IRA occlusion, and it is associated with increased apoptosis. Relief of ischaemia after AMI may prove of benefit in preventing apoptosis and its consequences. © The European Society of Cardiology 2005. All rights reserved.

BACKGROUND: Diffuse coronary artery ectasiae (DCE) are occasionally found at necropsy or at angiography. Pathogenetic mechanisms of DCE are still poorly known. Matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and vascular endothelial growth factor (VEGF) are involved in vascular remodeling and may play a role in DCE.METHODS: A total of 1280 consecutive coronary angiograms performed in a single institution in 1 year were screened. DCE were found in 15 patients. Diagnosis at hospital admission was acute coronary syndromes in all of them. Two patients died during initial admission and 1 refused blood sampling; the remaining 12 patients were enrolled in the study. No patient with DCE exhibited coronary stenoses. Plasma levels of VEGF, MMP-2, TIMP-1, TIMP-2 and C-reactive protein (CRP) were measured in these 12 patients 12 months after discharge during a silent clinical phase, in 12 age- and sex-matched patients with stable angina (SA) and coronary artery disease, and in 12 age- and sex-matched patients with normal coronary arteries (NCA).RESULTS: VEGF levels were higher in patients with DCE than in SA or NCA (151.6 pg/ml [36.2-252.9] vs. 66.6 pg/ml [36.4-93.3] and 54.8 pg/ml [14.5-87.1], respectively, p = 0.012]. TIMP-2 levels were lower in DCE and SA than in NCA (5.9 ng/ml [0-33.6] and 5.0 [0-17.4] vs. 139.3 ng/ml [114.4-237.4], respectively, p < 0.001). TIMP-1 and MMP-2 plasma levels were similar in all groups (p = NS), and CRP levels were within normal limits (< 3 mg/L) in most patients, irrespective of their coronary anatomy (75% for DCE, 66% for SA, and 84% for NCA [p = NS]).CONCLUSIONS: Symptomatic patients with DCE typically present with an acute coronary syndrome and exhibit lack of obstructive stenosis at angiography, decreased plasma levels of TIMP-2 and raised plasma levels of VEGF. The simultaneous occurrence of reduced MMPs inhibition and increased angiogenetic activity suggests an accelerated and persistent extracellular matrix remodeling process favouring arterial remodeling and aneurysms formation which is likely to enhance the risk of thrombosis because of low shear stress.

Background— Diffuse coronary vascular inflammation is associated with acute coronary syndromes. However, it is unknown whether inflammation also occurs within the myocardium. Therefore, this study was aimed at assessing the presence of activated cells in unaffected remote myocardium of patients with acute myocardial infarction (AMI), in comparison to the peri-infarct region from the same cases, and in comparison to myocardial specimens from control hearts. Methods and Results— Sixteen patients dying 1 to 12 weeks after AMI and 16 control subjects were selected at autopsy. Myocardial specimens were taken at remote unaffected viable regions and at peri-infarct regions in cases with AMI. Confocal microscopy was performed to measure the number of activated cells (DR+), T-lymphocytes (CD3+), and activated T-lymphocytes (CD3+/DR+). Activated cells and activated T-lymphocytes were found in remote unaffected regions in 11 of 16 cases (69%), in peri-infarct zone in all cases (100%), and in none of the control hearts (0%, P P Conclusions— This study for the first time shows the presence of activated T-lymphocytes in remote unaffected myocardial regions in approximately two thirds of patients with recent AMI. Because these cells are associated with persistent infarct-related artery occlusion, our data may suggest that an antigenic stimulus present also in the myocardium triggers an immune response that may be critical to precipitate artery occlusion. (Circulation. 2004;110:46-50.)

Background: Cyclo-oxygenase-2 (COX-2) is induced in cardiomyocytes only in response to stress, such as ischaemia. Objective: To assess COX-2 expression at the site of recent myocardial infarction. Methods: COX-2 expression was evaluated by specific immunostaining in cardiomyocytes from 23 subjects who died 10–60 days after acute myocardial infarction. The relation between COX-2 myocardial expression and apoptotic rate was investigated. Cardiomyocyte apoptotic rate was defined as the number of cells co-expressing in situ end labelling of DNA fragmentation (TUNEL) and immunostaining for activated caspase-3. Results: COX-2 expression was found in cardiomyocytes at the site of infarction in nine of 23 cases (39%). It was associated with fivefold higher apoptotic rates (median 17.9% (interquartile range 11.0–25.4%) v 3.7% (0.6–12.8%); p = 0.016), and apoptotic rate increased progressively from mild to intense COX-2 staining (p for trend 0.009). COX-2 expression co-localised with TUNEL nuclear staining in myocytes, and there was a high concordance between COX-2 and hypoxia induced factor 1-α staining (78%, p = 0.021) and between COX-2 and bax (83%, p = 0.014). Subjects showing myocardial COX-2 expression were more likely to have enlarged hearts (p = 0.050), and intense COX-2 staining was strictly associated with symptomatic heart failure (p = 0.035). Conclusions: COX-2 is expressed in cardiomyocytes in nearly 40% of cases at the site of recent acute myocardial infarction, even late after the index event. Its expression was associated with extremely high apoptotic rates. These findings suggest a potential cause–effect link between COX-2 expression and enhanced myocardial apoptosis in ischaemic cardiomyopathy.

While demonstration of cells with DNA synthesis is common in postinfarction models, the true significance of these cells is questionable. As we find that these markers are closely linked to apoptosis and unfavorable cardiac remodeling, they are likely to represent either early or late events in the mitotic failure leading to cell death. Because the differentiation of dying myocardiocytes in oncotic, apoptotic and mitotic deaths is mostly academical, these markers should be considered unfavorable prognostic markers for cell loss, unless true demonstration of effective cell replication is presented. © 2003 Elsevier Ireland Ltd. All rights reserved.

OBJECTIVES: The purpose of this study was to evaluate a potential correlation between apoptotic rate (AR), post-infarction left ventricular (LV) remodeling, and clinical characteristics in subjects who died late (≥10 days) after an acute myocardial infarction (AMI) with evidence of persistent occlusion of the infarct-related artery at autopsy. BACKGROUND: Apoptosis contributes to myocardiocyte loss in cardiac disease and may have a pathophysiologic role in post-infarction LV remodeling. METHODS: The AR was calculated at the site of infarction and in remote unaffected LV regions, using co-localization of in situ end labeling for deoxyribonucleic acid fragmentation and immunohistochemistry for caspase-3, in 14 subjects who died within two months after AMI. Correlation between AR and clinical characteristics such as age, site of AMI, transmural extension, multivessel coronary disease, and signs and/or symptoms of heart failure (HF), at the time of initial hospitalization for AMI or subsequently before death, was assessed using non-parametric statistical tests. Parameters of LV remodeling including diameters, free wall thickness, diameter-to-wall-thickness ratio, and mass were measured at gross examination at autopsy. Values are expressed as median (interquartile range). RESULTS: Among clinical variables, early symptomatic post-infarction HF (9 cases, 64%) was associated with nearly fourfold increased AR at the site of infarction (26.2% [24.5% to 28.8%] vs. 6.4% [1.9% to 13.3%], p = 0.001). Moreover, AR both at the site of infarction and in unaffected regions was significantly correlated with parameters of progressive LV remodeling (p < 0.05). CONCLUSIONS: Our data show that in patients dying ≥10 days after AMI, myocardial apoptosis is strongly associated with and may be a major determinant of unfavorable LV remodeling and early symptomatic post-infarction HF. © 2003 by the American College of Cardiology Foundation.

Background: Cardiac remodelling after acute myocardial infarction (AMI) is characterised by molecular and cellular mechanisms involving both left and right ventricles, and biventricular failure identifies patients with an extremely unfavourable prognosis. Aims: To assess whether a link exists between increased myocardial apoptotic rates (AR) at sites of recent infarction and patterns of unfavourable cardiac remodelling, such as biventricular enlargement after left ventricular (LV) infarction. Methods: Twelve patients with recent AMI involving the LV and not the right ventricle (RV) and with permanent infarct related artery occlusion were selected at necropsy. Gross pathological characteristics, such as LV and RV dilatation, and AR at site of infarction were assessed. Potential false positive results (DNA synthesis and RNA splicing) were excluded from the cell count. Results: RV enlargement, defined as a tricuspidal ring greater than 120 mm, was found in five cases and was associated with LV dilatation. These patients showed significantly higher AR than the others. When the subjects were divided into three groups according to progressive cardiac remodelling (absence of cardiac dilatation, isolated LV dilatation, and biventricular enlargement), the last group had significantly higher ARs than the other two groups, showing that myocardiocyte apoptosis is increased in more unfavourable forms of cardiac remodelling. Conclusion: Patients with severely unfavourable cardiac remodelling, such as biventricular enlargement, have extremely high myocardiocyte apoptosis at necropsy, even late after LV myocardial infarction, supporting the role of myocardiocyte loss in determining post-infarction adverse remodelling.

Background— Myocardial apoptosis persists beyond the acute phases of acute myocardial infarction (AMI) and is associated with left ventricular (LV) remodeling. Infarct-related artery (IRA) patency is considered a favorable prognostic factor after AMI and may be associated with more favorable LV remodeling because of reduced apoptosis at the site of AMI. The aim of this study was to assess the influence of IRA status on apoptotic rate (AR) in the hearts of subjects dying late after AMI. Methods and Results— We used colocalization for in situ end-labeling of DNA fragmentation and immunohistochemistry for caspase-3 to calculate the AR at time of death (12 to 62 days after AMI) in 16 hearts with persistently occluded IRAs and in 8 hearts with patent IRAs. No significant differences were found when comparing the clinical characteristics of the 2 groups. Occluded IRA was associated with significantly higher AR at site of infarction (25.8% [interquartile range 20.9% to 28.5%] versus 2.3% [interquartile range 0.6% to 5.0%], P P =0.003). Conclusions— A significantly higher AR was associated with persistent IRA occlusion late post-AMI. These data may suggest that the post-AMI benefits observed with a patent IRA (the “open-artery hypothesis”) may in part be due to reduced myocardial apoptosis.