Myocardial Infarction Scar Research Articles

Amplified Bioactive Signaling and Proteolytic Enzymes Following Ischemia Reperfusion and Aging

Left ventricular (LV) remodeling, defined as changes in myocardial structure and geometry, is considered to be a fundamental milestone in the progression to heart failure. This is particularly true in the clinical context of a myocardial infarction (MI) whereby adverse LV remodeling is directly associated with the progression to heart failure and increased morbidity and mortality.1 LV remodeling is a multifactorial process which includes changes within the myocardial, vascular and extracellular matrix (ECM). However, in terms of post-MI remodeling, changes in myocardial growth/viability and ECM structure/composition are ubiquitous events, and occur in a heterogeneous fashion within the remote viable myocardium, the myocardial region surrounding the MI (borderzone), and the MI scar itself. It is the summation of the alterations within both the cellular and extracellular compartments, which occur in all these regions post-MI, which promulgate adverse LV remodeling and ultimately the progression to heart failure. Through the use of animal models and clinical translational studies, certain signaling and proteolytic events have been identified to uniformly occur following an MI, and likely induce the cascade of events which yield changes in myocardial structure and function.2–8 In this issue of Circulation, Jugdutt and colleagues report how activation of a specific signaling pathway, the angiotensin-II receptor, influences a number of critical cellular signaling and ECM proteolytic events which can contribute to adverse LV remodeling.2 These investigators examined a number of critical pathways following a period of ischemia and reperfusion, which resulted in a significant and relevant MI. These investigators not only examined these signaling/proteolytic events in a clinically relevant model of MI, but more importantly examined the post-MI remodeling process within the aging myocardium. The findings from this study are important for 2 reasons. First, this study clearly demonstrated that important interactions occurred between the angiotensin-II receptor and the induction of bioactive molecules and proteases following an acute MI. Second, this study demonstrated that an amplified response occurs between these intersecting pathways within the aging myocardium following an acute MI. Taken together, the findings by Jugdutt and colleagues provide mechanistic evidence that the elderly myocardium is a more vulnerable substrate to an ischemic insult, and that this is likely due to enhanced/amplified induction of signaling cascades and proteolytic events that would directly contribute to a more advanced and accelerated LV remodeling process.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Detection and Quantification of Myocardial Scars by Contrast-Enhanced 3D Echocardiography

Background— Myocardial infarct scars are usually imaged by delayed-enhanced cardiac magnetic resonance (DE-cMR). In this study, we tested the hypothesis that the detection and quantification of myocardial scars can be evaluated by 3D echocardiography (3D-echo). Methods and Results— Fifty patients with a healed myocardial infarction (&gt;3 months) and 10 controls underwent 3D echo and DE-cMR within 2 weeks. 3D-echo images were acquired with different settings, with or without contrast. The highest contrast-to-noise ratio was obtained with second-harmonic imaging (1.6/3.2 MHz), at a mechanical index of 0.5, in the presence of contrast. Using this modality, we calculated the sensitivity and specificity of the 3D-echo detection of cMR scars on a segmental basis to be 78% and 99%, respectively. On a per-patient basis, they were 96% and 90%, respectively. Good correlation and limits of agreement were found between the assessment of scar mass by 3D echo and DE-cMR ( r =0.93, P &lt;0.001; bias, 1.4±3.6 g), and the concordance between both techniques for the assessment of scar transmurality was good. Intraobserver, interobserver, and day-to-day reproducibility was comparable between 3D echo and DE-cMR for both the detection and quantification of scars. Conclusions— Contrast-enhanced 3D echo is a promising new tool for the detection and quantification of myocardial infarct scars.

Long-Term Localized High-Frequency Electric Stimulation Within the Myocardial Infarct

Disruption of the balance between matrix metalloproteinases (MMP) and MMP inhibitors (TIMPs) within a myocardial infarct (MI) contributes to left ventricular wall thinning and changes in regional stiffness at the MI region. This study tested the hypothesis that a targeted regional approach through localized high-frequency stimulation (LHFS) using low-amplitude electric pulses instituted within a formed MI scar would alter MMP/TIMP levels and prevent MI thinning. At 3 weeks after MI, pigs were randomized for LHFS (n=7; 240 bpm, 0.8 V, 0.05-ms pulses) or were left unstimulated (UNSTIM; n=10). At 4 weeks after MI, left ventricular wall thickness (echocardiography; 0.89+/-0.07 versus 0.67+/-0.08 cm; P<0.05) and regional stiffness (piezoelectric crystals; 14.70+/-2.08 versus 9.11+/-1.24; P<0.05) were higher with LHFS than in UNSTIM. In vivo interstitial MMP activity (fluorescent substrate cleavage; 943+/-59 versus 1210+/-72 U; P<0.05) in the MI region was lower with LHFS than in UNSTIM. In the MI region, MMP-2 levels were lower and TIMP-1 and collagen levels were higher with LHFS than in UNSTIM (all P<0.05). Transforming growth factor-beta receptor 1 and phosphorylated SMAD-2/3 levels within the MI region were higher with LHFS than in UNSTIM. Electric stimulation (4 Hz) of isolated fibroblasts resulted in reduced MMP-2 and MT1-MMP levels but increased TIMP-1 levels compared with unstimulated fibroblasts. These unique findings demonstrate that LHFS of the MI region altered left ventricular wall thickness and material properties, likely as a result of reduced regional MMP activity. Thus, LHFS may provide a novel means to favorably modify left ventricular remodeling after MI.

Can We Prevent Sudden Cardiac Death in Athletes? In Search of Evidence-Based, Cost-Effective Screening

Purpose of a New Project: To develop a novel screening strategy to prospectively establish predictors and to prevent sudden cardiac death (SCD) in athletes. Most cases of SCD are related to preexisting high-risk cardiovascular conditions (hr-CVC) - predominantly coronary artery anomalies (CAAs) and cardiomyopathies that are readily diagnosed with advanced imaging. Currently, there is considerable debate about the need and extent for cardiovascular preparticipation screening of physical training and athletes. At Texas Heart Institute, we recently founded a Center for Coronary Artery Anomalies (CCAA) with a purpose to investigate hr-CVCs and prevent SCD. METHODS: We are currently conducting two coordinated projects: 1) The MRI study - involving cardiac magnetic resonance imaging (cMRI) screening for hr-CVC in 10,000 middle-school children to identify carriers of hr-CVC. This is the first prospective MRI imaging screening study ever performed in a general population, aimed at establishing the prevalence of hr-CVC, while including a large and representative population, from various subgroups. Such program will use a simple clinical information form for cardiovascular symptoms, a modified screening protocol cMRI (no contrast/intravenous access, 5-7 min acquisition time) and a resting electrocardiogram. The subjects with hr-CVC will be referred to specialized centers, for final evaluation and disposition, according to agreed protocols, at 3 local institutions. 2) The Necropsy study - continuous series of 6,000 autopsies carried out over a 2-years period at the Harris County Forensic Center, referral center for the 4 million inhabitants in the Houston, Texas area. This project will be used to collect information about the incidence of the same hr-CVC and all different causes and modes of death in such population. This study will combine clinical data at the time of death (ECG, type of physical activity, previous participation in sports activities) and specific anatomic markers of severity of the hr-CVC. Initial rhythm at time of SCD (ventricular fibrillation, asystole or pulseless electrical activity) will be correlated with anatomical findings and evidence of acute myocardial infarction or previous myocardial scarring. Mortality at 5 years follow-up, in the screened general population and hr-CVC students, will be evaluated and compared to historical mortality databases. CONCLUSIONS: The ultimate purposes of the 2 studies are to establish: 1) prevalence of hr-CVC in different subgroups; 2) cost/efficiency of such screening, in the different subgroups; and 3) effect of instituting such pre-certification screening and work-up for prevention of SCD.

Clinical Summaries

Clinical Summaries

Intracoronary Administration of Cardiac Progenitor Cells Alleviates Left Ventricular Dysfunction in Rats With a 30-Day-Old Infarction

Administration of cardiac progenitor cells (CPCs) 4 hours after reperfusion ameliorates left ventricular function in rats with acute myocardial infarction (MI). Clinically, however, this approach is not feasible, because expansion of autologous CPCs after acute MI requires several weeks. Therefore, we sought to determine whether CPCs are beneficial in the more clinically relevant setting of an old MI (scar). One month after coronary occlusion/reperfusion, rats received an intracoronary infusion of vehicle or enhanced green fluorescent protein-labeled CPCs. Thirty-five days later, CPC-treated rats exhibited more viable myocardium in the risk region, less fibrosis in the noninfarcted region, and improved left ventricular function. Cells that stained positive for enhanced green fluorescent protein that expressed cardiomyocyte, endothelial, and vascular smooth muscle cell markers were observed only in 7 of 17 treated rats and occupied only 2.6% and 1.1% of the risk and noninfarcted regions, respectively. Transplantation of CPCs was associated with increased proliferation and expression of cardiac proteins by endogenous CPCs. Intracoronary administration of CPCs in the setting of an old MI produces beneficial structural and functional effects. Although exogenous CPCs can differentiate into new cardiac cells, this mechanism is not sufficient to explain the benefits, which suggests paracrine effects; among these, the present data identify activation of endogenous CPCs. This is the first report that CPCs are beneficial in the setting of an old MI when given by intracoronary infusion, the most widely applicable therapeutic approach in patients. Furthermore, this is the first evidence that exogenous CPC administration activates endogenous CPCs. These results open the door to new therapeutic applications for the use of autologous CPCs in patients with old MI and chronic ischemic cardiomyopathy.

Usefulness of Fragmented QRS on a 12-Lead Electrocardiogram in Acute Coronary Syndrome for Predicting Mortality

Electrocardiographic signs of a non-ST elevation myocardial infarction (NSTEMI) are nonspecific, and therefore the diagnosis of NSTEMI during acute coronary syndromes (ACS) depends mainly on cardiac biomarker levels. Fragmented QRS (fQRS) represents myocardial conduction abnormalities due to myocardial infarction (MI) scars in patients with coronary artery disease. However, the time of appearance of fQRS during ACS has not been investigated. It was postulated that in patients with ACS, fQRS on 12-lead electrocardiography occurs within 48 hours of presentation with NSTEMI as well as ST elevation MI and that fQRS predicts mortality. Serial electrocardiograms from 896 patients with ACS (mean age 62 +/- 11 years, 98% men) who underwent cardiac catheterization were studied. Four hundred forty-one patients had MIs, including 337 patients with NSTEMIs, and 455 patients had unstable angina (the control group). Serial electrocardiograms were obtained every 6 to 8 hours during the first 24 hours after the diagnosis of MI and the next day (<48 hours). Fragmented QRS on 12-lead electrocardiography was defined by the presence of single or multiple notches in the R or S wave, without a typical bundle branch block, in > or =2 contiguous leads in 1 of the major coronary artery territories. Fragmented QRS developed in 224 patients (51%) in the MI group and only 17 (3.7%) in the control group (p <0.001). New Q waves developed in 122 (28%), 76 (23%), and 2 (0.4%) patients in the MI, NSTEMI, and control groups, respectively. The sensitivity values of fQRS for ST elevation MI and NSTEMI were 55% and 50%, respectively. The specificity of fQRS was 96%. Kaplan-Meier survival analysis revealed that patients with fQRS had significantly decreased times to death compared to those without fQRS. Fragmented QRS, T-wave inversion, and ST depression were independent predictors of mortality during a mean follow-up period of 34 +/- 16 months. In conclusion, fQRS on 12-lead electrocardiography is a moderately sensitive but highly specific sign for ST elevation MI and NSTEMI. Fragmented QRS is an independent predictor of mortality in patients with ACS.

Evolution of scar structure, mechanics, and ventricular function after myocardial infarction in the rat

The mechanical properties of the healing scar are an important determinant of heart function following myocardial infarction. Yet the relationship between scar structure, scar mechanics, and ventricular function remains poorly understood, in part because no published study has tracked all of these factors simultaneously in any animal model. We therefore studied the temporal evolution of scar structure, scar mechanics, and left ventricular (LV) function in large anterior myocardial infarcts in rats. At 1, 2, 3, and 6 wk after left anterior descending coronary ligation, we examined LV function using sonomicrometry, infarct mechanical properties using biaxial mechanical testing, infarct structure using polarized light microscopy, and scar collagen content and cross-linking using biochemical assays. Healing infarcts in the rat were structurally and mechanically isotropic at all time points. Collagen content increased with time and was the primary determinant of scar mechanical properties. The presence of healing infarcts influenced systolic LV function through a rightward shift of the end-systolic pressure-volume relationship (ESPVR) that depended on infarct size, infarct collagen content, and LV dilation. We conclude that in sharp contrast to previous reports in large animal models, healing infarcts are structurally and mechanically isotropic in the standard rat model of myocardial infarction. On the basis of the regional strain patterns we observed in healing rat infarcts in this study and in healing pig infarcts in previous studies, we hypothesize that the local pattern of stretching determines collagen alignment in healing myocardial infarct scars.

Heart Failure: the Commonest Reason for Hospitalization in Germany—Medical and Economic Perspectives: Primary Diseases Need to Be Considered

Neumann et al, worried by data from the Federal Statistical Office, report on diagnoses, mortality, and of which, they say, currently one of the most common and most cost-intensive of the chronic diseases. The authors reflect generally on the costs associated with in Germany in 2006 and thinking about trends. However, we wish to point out that is not a chronic disease but a clinical syndrome with characteristic symptoms that can have very diverse underlying disease causes. Heart failure should not be the general term used when writing about a chronic form of and if a concrete nosological classification of the presented heterogeneous statistical columns of figures is not possible. Acute and chronic left as well as acute and chronic right have different symptoms, although they all comprise classic symptoms. These indicate manifold changes and diseases of the right and left and the pericardium, which constitute the three groups of causes of failure: decompensated cardiac hypertrophy, myogenic and pericardial changes. If new concepts for prevention and treatment [of failure] will be needed in the near future (1) because the population is ageing, the manifold etiologies of will have to be borne in mind. Non-smoking prevents chronic obstructive pulmonary disease (COPD) with right due to decompensated cor pulmonale. Blood pressure control and physical exercise prevent myocardial infarction and infarction related scarring as a result of coronary disease (2, 3). Fighting chronic alcoholism prevents some of the cardiomyopathies. These and many other diseases result in heart failure, which is not obvious from the reported global statistic for this individual diagnosis (1). Considering the primary diseases for seems indicated when medical and economic aspects of the most common reason for hospitalization are being discussed.

Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy

The ability of mesenchymal stem cells (MSCs) to heal the chronically injured heart remains controversial. Here we tested the hypothesis that autologous MSCs can be safely injected into a chronic myocardial infarct scar, reduce its size, and improve ventricular function. Female adult Göttingen swine (n = 15) underwent left anterior descending coronary artery balloon occlusion to create reproducible ischaemia-reperfusion infarctions. Bone-marrow-derived MSCs were isolated and expanded from each animal. Twelve weeks post-myocardial infarction (MI), animals were randomized to receive surgical injection of either phosphate buffered saline (placebo, n = 6), 20 million (low dose, n = 3), or 200 million (high dose, n = 6) autologous MSCs in the infarct and border zone. Injections were administered to the beating heart via left anterior thoracotomy. Serial cardiac magnetic resonance imaging was performed to evaluate infarct size, myocardial blood flow (MBF), and left ventricular (LV) function. There was no difference in mortality, post-injection arrhythmias, cardiac enzyme release, or systemic inflammatory markers between groups. Whereas MI size remained constant in placebo and exhibited a trend towards reduction in low dose, high-dose MSC therapy reduced infarct size from 18.2 +/- 0.9 to 14.4 +/- 1.0% (P = 0.02) of LV mass. In addition, both low and high-dose treatments increased regional contractility and MBF in both infarct and border zones. Ectopic tissue formation was not observed with MSCs. Together these data demonstrate that autologous MSCs can be safely delivered in an adult heart failure model, producing substantial structural and functional reverse remodelling. These findings demonstrate the safety and efficacy of autologous MSC therapy and support clinical trials of MSC therapy in patients with chronic ischaemic cardiomyopathy.

Signal intensity of myocardial scars at delayed-enhanced mri

Traditionally, unrecognized myocardial infarction (UMI) is defined as the appearance, in a non-acute setting, of a new diagnostic Q wave. In the recent past, delayed-enhanced magnetic resonance imaging (DE-MRI) has provided a new imaging method for evaluating myocardial viability and to detect myocardial scars. To investigate differences in tissue characteristics between UMI and recognized myocardial infarction (RMI) scars, by assessing the signal intensity (SI) detected by DE-MRI. A randomized subgroup of 259 subjects from the Prospective Investigation of the Vasculature of Uppsala Seniors (PIVUS) study was submitted to cardiac magnetic resonance imaging (MRI). DE-MRI-detected myocardial scars were divided in two groups, UMI and RMI, according to the hospital medical records. The scars detected by DE-MRI were analyzed by measuring SI ratio of scar tissue to normal myocardium. The mean SI ratio in the UMI group (4.5+/-3.0, mean+/-SD) was lower than in the RMI group 8.9+/-5.1 (P-value = 0.001). This difference was still significant (P<0.0001) after adjustment for gender, body mass index, time of image acquisition after gadolinium administration, scar transmurality, or total myocardial infarction mass. The difference in the SI ratio of the scars between the two groups most likely reflects a different contrast distribution volume of the tissues, which might indicate that UMI and RMI tissues diverge in tissue composition.

Association of electrostimulation with cell transplantation in ischemic heart disease

Until now, cell therapy has constituted a passive therapeutic approach; the only effects seem to be related to the reduction of the myocardial fibrosis and the limitation of the adverse ventricular remodeling. Cardiac resynchronization therapy is indicated in patients with heart failure to correct conduction disorders associated with chronic systolic and diastolic dysfunction. The association of electrostimulation with cellular cardiomyoplasty could be a way to transform passive cell therapy into "dynamic cellular support." Electrostimulation of ventricles following skeletal myoblast implantation should induce the contraction of the transplanted cells and a higher expression of slow myosin, which is better adapted for chronic ventricular assistance. The purpose of this study is to evaluate myogenic cell transplantation in an ischemic heart model associated with cardiac resynchronization therapy. Twenty two sheep were included. All animals underwent myocardial infarction by ligation of 2 coronary artery branches (distal left anterior descending artery and D2). After 4 weeks, autologous cultured myoblasts were injected in the infarcted areas with or without pacemaker implantation. Atrial synchronized biventricular pacing was performed using epicardial electrodes. Echocardiography was performed at 4 weeks (baseline) and 12 weeks after infarction. Echocardiography showed a significant improvement in ejection fraction and limitation of left ventricular dilatation in cell therapy with cardiac resynchronization therapy as compared with the other groups. Viable cells were identified in the infarcted areas. Differentiation of myoblasts into myotubes and enhanced expression of slow myosin heavy chain was observed in the electrostimulated group. Transplantation of cells with cardiac resynchronization therapy caused an increase in diastolic wall thickening in the infarcted zone relative to cells-only group and cardiac resynchronization therapy-only group. Biventricular pacing seems to induce synchronous contraction of transplanted myoblasts and the host myocardium, thus improving ventricular function. Electrostimulation was related with enhanced expression of slow myosin and the organization of myoblasts in myotubes, which are better adapted at performing cardiac work. Patients with heart failure presenting myocardial infarct scars and indication for cardiac resynchronization therapy might benefit from simultaneous cardiac pacing and cell therapy.

Ventricular tachycardia from the healed myocardial infarction scar: Validation of an animal model and utility of gene therapy

Life-threatening ventricular arrhythmias generally occur in the setting of structural heart disease. Current clinical options for patients at risk for these rhythm disturbances are limited. We developed a porcine model of inducible ventricular tachycardia originating in the border region of a healed myocardial infarction scar. After validating the model, we assessed gene transfer techniques, focusing on local modification of border zone tissues. We found that gene transfer of the dominant negative KCNH2-G628S mutation to the anteroseptal infarct border caused localized prolongation of effective refractory period in the target region and eliminated all ventricular arrhythmia inducibility. In this work, we characterize the animal model and review the gene transfer results.

Invited Commentary

Progressive dilation of the left ventricle (LV) and deterioration of LV pump performance often occur after myocardial infarction (MI). A number of pharmacological or nonpharmacological interventions, or both, have been used to attenuate or even reverse these progressive adverse changes in LV geometry and function. However, mechanisms that contribute to these changes, especially the role of the changes in the material properties of the MI region, remain largely unexplored. In this article, Pilla and colleagues [1Pilla J.J. Gorman III, J.H. Gorman R.C. et al.Theoretical impact of infarct compliance on left ventricular function.Ann Thorac Surg. 2009; 87: 803-811Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] describe a mathematical simulation for changes in hemodynamics and LV geometry as a function of changing the compliance (or stiffness) of a hypothesized MI region. The authors refer to the mathematical model as a “lumped parameter” simulation, which comprised of resistive, capacitive, and unidirectional flow (diode) components. This model was first used to simulate normal hemodynamics and LV geometry based on database records of normal ovine physiology. An important component of this model was the inclusion of a compensatory element that accounted for maintenance of stroke volume through a feedback input that altered total blood volume. Next, this model was used to simulate LV pressures and volumes while incorporating a noncontributing portion of the LV (the MI region) at a set compliance value for the MI region. The authors report that the simulated LV pressure-volume curves closely approximated recorded values in an ovine MI model. A significant finding from this model was the attenuation in LV dilation and oxygen consumption with a stiffer (noncompliant) infarct region. An important implication of this finding with respect to remodeling of the infarct region is that modification of the composition and content of the MI scar can provide a means to prevent the almost inevitable LV dilation and deterioration in pump function after MI. Moreover, these findings provide a mathematical basis for the attenuation in post-MI LV dilation that has been reported in prior studies where biocompatible scaffolding/matrix was injected into the MI region. However, it must be recognized that any mathematical model is built on a series of assumptions and that these conditions are even more difficult to apply to the heterogeneous “border” region between the viable myocardium and the MI region. It has been postulated that the differential stress and strain patterns at the transition between viable myocardium and the border zone, as well as the interface between the border zone and the MI region, likely exacerbate expansion of the MI region. The relative paucity of critical basic science detailing of myocardial material properties, in particular at the border region, precludes more comprehensive mathematical modeling of LV remodeling post-MI. An important consideration for any model is its clinical applicability or application of the model, or both, to better understand where and when a certain therapeutic modality may confer clinical benefit. For example, if a hypothesized intervention were known to provide a specific time-dependent effect on the material properties of the MI region, then this model could be implemented to determine long-term effects of the intervention on LV dilation post-MI. In this light, further validation from complementary in vivo studies in which the relationship between compliance and the extent of LV dilation post-MI are warranted. Nevertheless, the findings from the mathematical model developed by Pilla and colleagues [1Pilla J.J. Gorman III, J.H. Gorman R.C. et al.Theoretical impact of infarct compliance on left ventricular function.Ann Thorac Surg. 2009; 87: 803-811Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] form an important first step to further understanding the role of changes in myocardial material properties and pathologic remodeling after MI. Theoretic Impact of Infarct Compliance on Left Ventricular FunctionThe Annals of Thoracic SurgeryVol. 87Issue 3PreviewAfter coronary occlusion, the infarct region loses contractile function immediately and then undergoes a progressive healing process. This causes complex and time-dependent changes in infarct material properties that have not been well described experimentally. We used a theoretic approach to assess how infarct compliance effects left ventricular (LV) size and function after myocardial infarction. Full-Text PDF

Infarct architecture and characteristics on delayed enhanced magnetic resonance imaging and electroanatomic mapping in patients with postinfarction ventricular arrhythmia

Delayed enhanced magnetic resonance imaging (DE-MRI) can be used for the exact assessment of myocardial infarct scar. Electroanatomic (EA) mapping can identify the subendocardial extension of infarcts and is used to identify and eliminate areas critical for postinfarction ventricular arrhythmias. The purpose of this study was to correlate DE-MRI with EA mapping in postinfarction patients with ventricular arrhythmias to assess myocardial infarct architecture and its relationship to postinfarction ventricular arrhythmias. EA mapping during sinus rhythm was performed in 14 postinfarction patients (10 men; age 64 +/- 10 years; ejection fraction 0.33 +/- 0.12) referred for ablation of ventricular arrhythmias. All patients underwent prior DE-MRI. Both DE-MRI and EA mapping data were registered in three-dimensional space. Presence of scar and its transmurality as well as scar core versus gray zone were assessed on DE-MRI and correlated with EA maps; furthermore, the electrogram characteristics of the EA map were correlated with the DE-MRI. Scar areas as assessed by bipolar and unipolar voltages in the EA map both correlated well with the scar as defined by DE-MRI. The best cutoff value to differentiate subendocardial scar from normal myocardium was 1.0 mV for bipolar voltage and 5.8 mV for unipolar voltage. Areas with DE had distinct electrophysiologic characteristics compared with nonenhancing sites. All identified sites that were critical for postinfarction ventricular tachycardia (31/31) and premature ventricular complexes (5/5) were located within areas of DE, with most (71%) being located in the core area of the scar. DE-MRI can accurately predict the EA characteristics of corresponding subendocardial locations. Critical sites of postinfarction arrhythmias were confined to areas of DE. The scar information on MRI can be selectively imported into an EA mapping system to facilitate the mapping and ablation procedure.

Morpho-pathological alterations of the cardio-vascular system in violent death cases

Our study focuses on the main indicators of cardio-vascular disease (main cause of death in middle-aged and older adults) in all cases of violent deaths autopsied in our institute over a specific period of time. We studied 1620 autopsy reports on violent death adult cases, autopsied over a five-year period in our institute. We focused on the associations of the following morpho-pathological alterations: atherosclerotic (ATS) alterations of the coronaries (CA), of the aorta (Ao), left ventricle hypertrophy (LVH), myocardial infarction (MI) scars, fibrosis of the valve and chordae tendineae, myocardial fibrosis (MF), cardiac hypertrophy (CHT). Our data shows that the thickness of the LV wall is proportionally decreasing with the increase of the gravity of the coronary lesions. 91.5% of the cases with MF, presented ATS plaques on the aorta, 56% on the coronaries, 11.5% MI scars and 33.5% LVH. The association of valvular fibrosis and fibrosis of the cordae tendineae appeared in 31% cases - 48% of cases with MF. Only 1% of cases with LVH had normal coronaries. In 33% of our caseload CHT was present, all of them presented coronary and aortic ATS and MF. Only 18% of cases had MI scars. LVH appeared in 47% of CHT cases. MI scars were found 8% cases.

Abstract 816: Low-Amplitude, High Frequency Electrical Stimulation of the Infarct Region Decreases Matrix Metalloproteinase Abundance and Increases Levels of Tissue Inhibitors of the Metalloproteinases and Collagen Content

Discordant alterations in the balance between matrix metalloproteinases (MMP) and endogenous MMP inhibitors (TIMPs) within a myocardial infarct (MI) contribute to alterations in LV geometry and ultrastructure, which lead to LV wall thinning at the MI region. While systemic pharmacological approaches can globally alter LV remodeling post-MI, a targeted regional approachto modify MMP/TIMP balance and MI structure has not been explored. We tested the hypothesis that application of localized high frequency stimulation (LHFS) using low amplitude electrical pulses within a formed MI scar would alter MMP/TIMP levels and prevent MI thinning. A uniform and discrete MI was surgically induced in pigs (n=17). At 3 wks post-MI, pigs were randomized for LHFS (n=7, electrical stimulation at 240 bpm, using 0.8V, 0.05ms pulses at the center of the MI region) or unstimulated (UNSTIM, n=10). At 4 wks post-MI, LV wall thickness (echo), and stiffness (piezoelectric crystals with LV preload reduction) were measured. MMP-2, MMP-9, TIMP-1 (zymography or immunoblotting) levels, and fibrillar collagen content (COLL, histology) in the remote and MI regions were determined and normalized to values in LV samples obtained from non-MI pigs (n=5, 100%). LV wall thickness at the MI region was higher with LHFS than UNSTIM (0.89±0.07 vs 0.67±0.08 cm, p&lt;0.05). With LHFS, MMP-2 levels were lower, and TIMP-1 and COLL levels higher than UNSTIM values in the MI region (TABLE ). Myocardial stiffness in the MI region was higher with LHFS than UNSTIM (14.70±2.08 vs 9.11±1.24, respectively, p&lt;0.05). These findings, for the first time, demonstrate that sub-threshold electrical stimulation of the MI region altered MMP/TIMP balance and collagen content, which directly affected LV wall thickness and stiffness. Thus, LHFS may represent a novel, selective means to favorably modify MI scar remodeling and attenuate the progressive LV wall thinning that occurs post-MI.

Abstract 6087: Fragmented QRS Complex on 12-lead ECG Developed During the First 48 Hours after Acute Myocardial Infarction Predicts Mortality

Fragmented QRS complex (fQRS) signifies myocardial infarction (MI) scar. Myocardial scar acts as a substrate for ventricular arrhythmias and a risk for death. We postulated that the development of new fQRS during the first 48 hours after an acute MI signifies mortality. Serial ECGs of 896 pts with acute coronary syndrome (ACS) and their mortality during follow-up were studied. MI was diagnosed by history, ECG and elevated cardiac enzymes. Serial ECGs were recorded at presentation, 8 hours, 16 hours and 24 – 48 hours. The fQRS on 12-lead ECG was defined by the presence of fragmented QRS, notched R or S wave, or RSR′ pattern without any bundle branch block, in at least 2 contiguous leads in one of the coronary artery territories (LAD: lead V1 to V6, LCx: lead I, aVL and V6, and RCA: lead II, III and aVF). The MI group (n =441, 98.4% males, age 63±11 yrs) and the control (unstable angina) group (n=455, 97.1% males, age 61±11 yrs, P=NS). 104 (24%) patients had STMI and 337 (76%) patients had NSTMI. fQRS developed in a significantly higher number of patients in the MI group as compared to the control group (224 [50.8%] vs. 17 [3.7%], p&lt;0.001), respectively. New Q-waves developed in 122 (27.7%) and 2 (0.4%) patients in MI group and control group, respectively. fQRS was a multivariate predictor of mortality in ACS group as well as in the MI group, whereas Q wave did not predict mortality during a 23+/−17 months of follow-up. Kaplan-Meier survival curve revealed a significantly higher mortality in fQRS vs. non-fQRS group (p=0.001),. The development of fQRS within the first 48 hours of ACS patients predicts mortality during follow-up in patients with MI.

IGF-II/mannose 6-phosphate receptor activation induces metalloproteinase-9 matrix activity and increases plasminogen activator expression in H9c2 cardiomyoblast cells

The IGF-II/mannose 6-phosphate receptor (IGF2R) function in extracellular matrix (ECM) remodeling is known to occur as a result of transforming growth factor-beta (TGF-beta) activation and plasmin in the proteolytic cleavage level caused by the interaction between latent TGF-beta and urokinase plasminogen activator receptor (uPAR) respectively. In one of our previous studies, we found IGF-II and IGF2R dose-dependently correlated with the progression of pathological hypertrophy remodeling following complete abdominal aorta ligation. However, how this IGF2R signaling pathway responds specifically to IGF-II and regulates the myocardial ECM remodeling process is unclear. We found that IGF2R was aberrantly expressed in myocardial infarction scars. The matrix metalloproteinase-9 (MMP-9) zymographic activity was elevated in H9c2 cardiomyoblast cells treated with IGF-II, but not IGF-I. Treatment with Leu27IGF-II, an IGF2R specifically binding IGF-II analog, resulted in significant time-dependent increases in the MMP-9, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA); and a reduction in the tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) protein expression. Furthermore, IGF2R expression inhibition by siRNA blocked the IGF-II-induced MMP-9 activity. We hypothesize that after IGF-II is bound with IGF2R, the resulting signal disrupts the balance in the MMP-9/TIMP-2 expression level and increases plasminogen activator (PAs) expression involved in the development of myocardial remodeling. If so, IGF2R signaling inhibition may have potential use in the development of therapies preventing heart fibrosis progression.