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The global incidence of coronary artery diseases (CADs), especially myocardial infarction (MI), has drastically increased in recent years. Even though the conventional therapies have improved the outcomes, the post-MI complications and the increased rate of recurrence among the survivors are still alarming. Molecular events associated with the pathogenesis and the adaptive responses of the surviving myocardium are largely unknown. Focus on exosome-mediated signaling for cell-cell/matrix communications at the infarct zone reflects an emerging opportunity in cardiac regeneration. Also, cardiac tissue engineering provides promising insights for the next generation of therapeutic approaches in the management of CADs. In this article, we critically reviewed the current understanding on the biology of cardiac exosomes, therapeutic potential of exosomes, and recent developments in cardiac tissue engineering and discussed novel translational approaches based on tissue engineering and exosomes for cardiac regeneration and CADs.

Infarct extension involves necrosis of healthy myocardium in the border zone (BZ), progressively enlarging the infarct zone (IZ) and recruiting the remote zone (RZ) into the BZ, eventually leading to heart failure. The mechanisms underlying infarct extension remain unclear, but myocyte stretching has been suggested as the most likely cause. Using human patient-specific left-ventricular (LV) numerical simulations established from cardiac magnetic resonance imaging (MRI) of myocardial infarction (MI) patients, the correlation between infarct extension and regional mechanics abnormality was investigated by analysing the fibre stress-strain loops (FSSLs). FSSL abnormality was characterised using the directional regional external work (DREW) index, which measures FSSL area and loop direction. Sensitivity studies were also performed to investigate the effect of infarct stiffness on regional myocardial mechanics and potential for infarct extension. We found that infarct extension was correlated to severely abnormal FSSL in the form of counter-clockwise loop at the RZ close to the infarct, as indicated by negative DREW values. In regions demonstrating negative DREW values, we observed substantial fibre stretching in the isovolumic relaxation (IVR) phase accompanied by a reduced rate of systolic shortening. Such stretching in IVR phase in part of the RZ was due to its inability to withstand the high LV pressure that was still present and possibly caused by regional myocardial stiffness inhomogeneity. Further analysis revealed that the occurrence of severely abnormal FSSL due to IVR fibre stretching near the RZ-BZ boundary was due to a large amount of surrounding infarcted tissue, or an excessively stiff IZ.

BACKGROUND: In vivo imaging of oxidative stress can facilitate the understanding and treatment of cardiovascular diseases. We evaluated nitroxide-enhanced MRI with 3-carbamoyl-proxyl (3CP) for the detection of myocardial oxidative stress. METHODS: Three mouse models of cardiac oxidative stress were imaged, namely angiotensin II (Ang II) infusion, myocardial infarction (MI), and high-fat high-sucrose (HFHS) diet-induced obesity (DIO). For the Ang II model, mice underwent MRI at baseline and after 7 days of Ang II (n = 8) or saline infusion (n = 8). For the MI model, mice underwent MRI at baseline (n = 10) and at 1 (n = 8), 4 (n = 9), and 21 (n = 8) days after MI. For the HFHS-DIO model, mice underwent MRI at baseline (n = 20) and 18 weeks (n = 13) after diet initiation. The 3CP reduction rate, K(red), computed using a tracer kinetic model, was used as a metric of oxidative stress. Dihydroethidium (DHE) staining of tissue sections was performed on Day 1 after MI. RESULTS: For the Ang II model, K(red) was higher after 7 days of Ang II versus other groups (p < 0.05). For the MI model, K(red), in the infarct region was significantly elevated on Days 1 and 4 after MI (p < 0.05), whereas K(red) in the noninfarcted region did not change after MI. DHE confirmed elevated oxidative stress in the infarct zone on Day 1 after MI. After 18 weeks of HFHS diet, K(red) was higher in mice after diet versus baseline (p < 0.05). CONCLUSIONS: Nitroxide-enhanced MRI noninvasively quantifies tissue oxidative stress as one component of a multiparametric preclinical MRI examination. These methods may facilitate investigations of oxidative stress in cardiovascular disease and related therapies.

Visual Abstract, Highlights • A drop in eosinophil blood count is associated with recruitment of eosinophils to the heart during repair following clinical and experimental MI. • Genetic and pharmacological eosinophil depletion leads to increased adverse remodeling in experimental MI. • Eosinophils are required for acquisition of an anti-inflammatory macrophage phenotype, a shift to resolution of inflammation and mature scar formation during infarct repair. • IL-4 therapy is able to rescue the adverse remodeling phenotype in conditions of eosinophil deficiency., Summary In ST-segment elevation myocardial infarction of both patients and mice, there was a decline in blood eosinophil count, with activated eosinophils recruited to the infarct zone. Eosinophil deficiency resulted in attenuated anti-inflammatory macrophage polarization, enhanced myocardial inflammation, increased scar size, and deterioration of myocardial structure and function. Adverse cardiac remodeling in the setting of eosinophil deficiency was prevented by interleukin-4 therapy.

Background Delivering therapeutic materials, like stem cells or gene vectors, to the myocardium is difficult in the setting of ischemic heart failure because of decreased coronary flow and impaired microvascular perfusion ( MP ). The aim of this study was to determine if mechanical left ventricular ( LV ) unloading with the Impella increases coronary flow and MP in a subacute myocardial infarction. Methods and Results Anterior transmural myocardial infarction (infarct size, 26.0±3.4%) was induced in Yorkshire pigs. At 2 weeks after myocardial infarction, 6 animals underwent mechanical LV unloading by Impella, whereas 4 animals underwent pharmacological LV unloading using sodium nitroprusside for 2 hours. LV unloading with Impella significantly reduced end‐diastolic volume (−16±11%, P =0.02) and end‐diastolic pressure (EDP; −32±23%, P =0.03), resulting in a significant decrease in LV end‐diastolic wall stress ( EDWS ) (infarct: 71.6±14.7 to 43.3±10.8 kdynes/cm 2 [ P =0.02]; remote: 66.6±20.9 to 40.6±13.3 kdynes/cm 2 [ P =0.02]). Coronary flow increased immediately and remained elevated after 2 hours in Impella‐treated pigs. Compared with the baseline, MP measured by fluorescent microspheres significantly increased within the infarct zone (109±81%, P =0.003), but not in the remote zone. Although sodium nitroprusside effectively reduced LV ‐ EDWS , 2 (50%) of sodium nitroprusside–treated pigs developed profound systemic hypotension. A significant correlation was observed between the infarct MP and EDWS ( r 2 =0.43, P =0.03), suggesting an important role of EDWS in regulating MP during LV unloading in the infarcted myocardium. Conclusions LV unloading using an Impella decreased EDWS and increased infarct MP without hemodynamic decompensation. Mechanical LV unloading is a novel and efficient approach to increase infarct MP in patients with subacute myocardial infarction.

Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of molecular, cellular, and functional alterations that are both part of the wound healing response to form a scar in the infarct region and the consequence of that response. Using the laws of thermodynamics as an analogy, we present here three laws for categorizing the post-MI LV remodeling process. The first law is that the LV will attempt to maintain equilibrium and compensate as a way to maximize function, the second law is that remodeling is progressive and unidirectional, and the third law is that the final goal is (ideally, but not always achievable) a stable, equilibrated scar. This comparison helps to define the boundaries of the system, whether it be the infarct zone, the LV, the heart, or the entire body. This review provides an overview for those not directly in the field and establishes a framework to help prioritize future research directions.

Background Hemorrhage is a frequent complication in acute myocardial infarction (AMI) and is speculated to be an independent predictor of adverse outcomes [1]. In addition to infarct zone remodeling, the distal remote myocardium may experience alterations vasodilator dysfunction, edema, and extracellular matrix (ECM) expansion [2-4]. The aim of our study was to understand the impact of hemorrhage on infarct as well as remote myocardial remodeling following an ischemic event. To this end, we employed quantitative T1 and T2 mapping to probe the underlying tissue alterations in a novel hemorrhagic model of AMI.

Purpose: To study the effect of exercise training on the myocardial perfusion in the postinfarct myocardium. Materials and Methods: Twenty-nine patients with stable chronic myocardial infarction were randomly assigned to either a training group (N = 17) or a control group (N = 12). The training group received a 3-month exercise program. Cardiovascular MR was first performed before the training to establish a baseline, and subsequently performed once again upon conclusion of the program. Late gadolinium enhancement was used both to define the infarct and remote zones and to quantify the ratio of the residual viable myocardium (VMR) within the infarct zone. The myocardium was divided into subendocardial and subepicardial layers with equal thickness. The interval change of myocardial perfusion reserve (MPR) was computed for each zone and layer. The association between the exercise-induced perfusion change and VMR was analyzed for layers of the infarct zone. Results: In the training group, the remote zone showed significantly increased MPR. The infarct zone showed no perfusion change in the subendocardial layer, but it demonstrated significantly increased MPR in the subepicardial layer. In the infarct zone, the change in MPR was associated with VMR. Conclusion: In chronic myocardial infarction, the exercise-induced perfusion change in the infarct zone is proportional to the amount of residual viable myocardium. J. Magn. Reson. Imaging 2011;. © 2011 Wiley-Liss, Inc.

Microvascular obstruction (MVO) is usually seen in a proportion of patients with acute myocardial infarction following reperfusion therapy of an occluded coronary artery. It is characterized by damage and dysfunction of the myocardial microvasculature with a no-reflow phenomenon within the infarct zone. While MVO may be demonstrated via a number of different imaging modalities, cardiac MR (CMR) enables accurate identification of MVO and also permits assessment of infarct extent and overall left ventricular function during the same imaging examination. We present a pictorial review of the characteristic appearances of MVO on CMR and highlight the importance of this imaging diagnosis for patient outcome following acute myocardial infarction.

We compared two routes for myocardial delivery of therapeutics, transendocardial (TE) delivery with an intramyocardial injection catheter, and retrograde coronary venous (RCV) delivery with a balloon occlusion catheter in the interventricular vein. Methods: TE and RCV injection of 15 mu m, neutron-activatable microspheres was compared in healthy pigs (Group I, n = 3), pigs with a 1-week-old myocardial infarction (MI; group II, n = 5), and pigs with a 2-weeks-old MI (group III, n = 4). The MI was induced by a 1-hr balloon occlusion in the LAD. Both methods were compared in the same animal using different microspheres. The RCV catheter allowed for continuous measurement of distal pressure and 2.5 x 10(6) microspheres were injected in 10 ml at 300 mmHg above balloon occlusion pressure. The TE injections were targeted to the infarct zone and 2.5 x 10(6) microspheres were distributed over 10 injections of 200 mu l. Results: The retention of microspheres decreased with increase in MI age, but was comparable between devices within the groups. RCV delivery resulted in (14.3 +/- 0.9)% microsphere retention in Group I, (10.3 +/- 0.2)% in Group II, and (6.4 +/- 0.1)% in group III (P less than 0.05 versus group I). Microsphere retention after TE was (15.1 +/- 0.7)% in group I, (18.9 +/- 0.6)% in group II, (4.1 +/- 0.1)% in Group III (P less than 0.05 versus groups I and II). The RCV catheter delivered primarily to midventricular, antero-septal segments, whereas TE targeted apical areas predominantly. Conclusions: Delivery efficacy was comparable between devices in each group however RCV targeted midventricular areas whereas TE targeted apical areas.

Introduction: In acute coronary syndromes, the extent of myocardial injury can be substantially greater than the infarct zone. Existing imaging methods identify the infarct zone but do not assess “global myocardial injury” (GMI), which measures the total area of myocardium that sustained injuries including and beyond the infarct zone per se. Hypothesis: GMI can be detected based on changes in cellular membrane organization as a surrogate marker, using Tc-99m-duramycin. Methods: Balloon angioplasty was used for coronary occlusion in a pig model of myocardial ischemia and reperfusion (n = 9). Tc-99m-duramycin scans were acquired on a SPECT/CT scanner on day 1. On day 2, the infarct zone was assessed with Tc-99m-tetrofosmin. In an open-chest pig model of myocardial ischemia/reperfusion (n = 4) we used Evans Blue dye to facilitate the measurement of area-at-risk (AAR). Tc-99m-duramycin uptake was measured by gamma counting after tetrazolium (TTC) staining and physically dissecting the AAR, infarct zone and the noninfarcted-but-ischemically-damaged tissues. Histopathology was used to document cellular damages. Results: Quantitatively, Tc-99m-duramycin uptake delineated an area of myocardium that included but was substantially more extensive than the infarct zone. Under the current experimental condition, this area accounted for 81.0 ± 9.6% of the AAR, whereas the infarct zone was 25.5 ± 14.0% of the AAR. This was consistent with in vivo imaging, where the size of Tc-99m-duramycin positive tissue was visually larger than the perfusion defect in the Tc-99m-tetrofosmin scan. By histopathology, the noninfarcted-but-ischemically-damaged tissues contained features associated with cellular damages, and a heterogeneous mix of viable and dead cells. Conclusions: Tc-99m-duramycin has significant uptake in infarcted as well as noninfarcted-but-ischemically-damaged myocardium, thus reflecting global myocardial injury. The data support GMI as a new criterion independent of infarct size and AAR. The noninfarcted-but-ischemically-damaged myocardium is pathologically heterogeneous, thus a potential substrate for ventricular arrhythmias. The ability to detect such tissues may have important diagnostic and prognostic value.

The purpose of this study was to assess the value of technetium 99m sestamibi gated single photon emission computed tomography (SPECT) in predicting the evolution of left ventricular volumes in patients treated successfully in the acute phase of a myocardial infarction (MI).Twenty-nine patients with acute MI and early percutaneous transluminal coronary angioplasty (PTCA) were included in this study. A rest Tc-99m sestamibi electrocardiography (ECG)-gated SPECT study was performed 21 +/- 5 days after PTCA. The myocardial perfusion index was calculated by use of a semiautomatic sectorial analysis. All patients had contrast ventriculography performed during the acute phase and 6 months later. The patients were separated into two groups according to the absence (group I, n = 21) or presence (group II, n = 8) of end-systolic enlargement. The perfusion index in the infarct sectors was -2.29 +/- 2.90 SD in group I and -6.40 +/- 2.85 SD in group II ( P.01). With a cutoff value of -2.46 SD, the sensitivity and specificity of Tc-99m sestamibi SPECT for the prediction of end-systolic volume enlargement were 100% and 62%, respectively. When the functional data from ECG-gated acquisitions were added, specificity increased to 86%.Despite successful PTCA in the acute phase of MI, an increase in end-systolic volume was observed at 6 months in 28% of patients. Tc-99m sestamibi ECG-gated SPECT performed 3 weeks after the acute phase could predict this enlargement with a high accuracy.

Purpose To characterize the extent and distribution of left ventricular myocardial scar in delayed enhancement magnetic resonance imaging (MRI). Materials and Methods Delayed enhancement images from 18 patients were categorized into three groups based on myocardial scar appearance: discrete myocardial infarction (N = 10), diffuse fibrosis (N = 4), and circumferential endocardial scarring (N = 4). Images were segmented manually by two observers (twice by one observer) to identify nonviable myocardium. Scar was characterized by the following morphologic parameters: the relative area of nonviable myocardium (Percent Scar); a measure of scar cohesion (Patchiness); and the extent to which scar traversed the ventricle wall (Trans>50). Results The three scar parameters successfully discriminated between patient groups, although no one parameter was able to differentiate between all groups. The average bias between readers was approximately 3% for each parameter, and the average bias between repeated measurements was 1%. In addition, five patients exhibited regions of nonhyperenhanced nonviable myocardium that were expected to show hyperenhancement based upon their location within the infarct zone and appearance on cine images. Conclusion Quantitative characterization of myocardial scar showed good interobserver and intraobserver agreement. However, the appearance of nonhyperenhanced scar in chronic ischemia is problematic for segmentation of delayed enhancement images. J. Magn. Reson. Imaging 2003;18:434–441. © 2003 Wiley-Liss, Inc.

GOAL Comparison between a fluid-sensitive (HASTE-TIRM)-sequence and delayed contrast-enhancement in patients with acute myocardial infarct (AMI) in MRI. MATERIAL AND METHODS 32 patients with AMI were imaged 7 +/- 4 days after the time of infarction with a 1.5 T unit using a T2 HASTE-TIRM and a contrast-enhanced (CE) T1 turbo FLASH sequence. A threshold method (>2 SD in comparison with normal myocardium) was used to quantify the hyperintense zones in both sequences. The transmurality of the hyperintense regions was measured on a segmental basis. RESULTS The hyperintense areas were larger on the HASTE-TIRM sequence with 29.6 +/- 13.2 % of the left ventricular (LV) area as compared to the CE-MRI with 19.2 +/- 10 % of the LV area (p < 0.0001). The measured transmurality was higher with the HASTE-TIRM sequence than with the CE-MRI (p < 0.0001). While the correlation between CE-MRI and peak creatine kinase (CK max) was good (r = 0.59, p < 0.001), no correlation was found between the HASTE-TIRM sequence and CK max (r = 0.29, p = ns). CONCLUSIONS The peri-infarct edema can be depicted with a HASTE-TIRM sequence in addition to the non-viable infarct zone. The HASTE-TIRM sequence shows a higher transmurality of the hyperintense regions than the CE-MRI. The additional area depicted by the HASTE-TIRM sequence could represent functionally impaired but viable myocardium).

Acute coronary occlusion causes ST-segment elevation on the body surface ECG and on the epicardial electrogram in the territory supplied by that artery. The occurrence and significance of endocardial ST changes have not been studied. The NOGA electromechanical mapping was performed on eight anesthetized dogs at baseline, immediately after occlusion of the LAD, and again at 5 hours to assess regional changes in the ST segment. At 3 days and 4 weeks the ventricles were remapped for comparison. Regional unipolar ST-segment elevation was measured for each zone from NOGA maps at 0, 80, and 120 ms after the J point. ST segments rose immediately in the infarct zones, as demarcated by echocardiography, compared to remote zones, but by 3 days had dropped below, and at 4 weeks returned to baseline values. Immediately postocclusion, ST elevation at 120 ms best differentiated between normal versus abnormal echo scores (concordance = 0.80), probably by correcting for pressure induced ST elevation. In conclusion, acute endocardial ST-segment changes occur in the infarct zone in the dog, showing a distinctive temporal evolution.

Increased myocardial structural heterogeneity in response to ischemic injury following myocardial infarction (MI) is purported as the mechanism of ventricular arrhythmogenesis. Current modalities for in vivo assessment of structural heterogeneity for identification of arrhythmogenic substrate are limited due to the complex nature of the structural microenvironment post-MI. We investigated the utility of in vivo bio-impedance spectroscopy (BIS) in a large post-infarct animal model for differentiation between normal and infarcted tissue. We also investigated the quantitative effects of adipose and collagen on BIS assessment of myocardium. The results indicate that the degree of myocardial injury following chronic post-infarction remodeling could be reliably quantified (performed in triplicates) using BIS. Furthermore, the presence of intramyocardial adipose tissue that develops in conjunction with collagen within the infarct zone had a greater and significant influence on BIS then collagen tissue alone. These preliminary results indicate a potential role of BIS for quantitative assessment and characterization of complex arrhythmogenic substrates in ischemic cardiomyopathy.

Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. We have developed a therapeutic materials strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructures to mechanically alter the microenvironment. Polymeric microstructures were fabricated using photolithographic techniques and studied in a three-dimensional culture model of the fibrotic environment and by direct injection into the infarct zone of adult rats. Here, we show dose-dependent down-regulation of expression of genes associated with the mechanical fibrotic response in the presence of microstructures. Injection of this microstructured material into the infarct zone decreased levels of collagen and TGF-β, increased elastin deposition and vascularization in the infarcted region, and improved functional outcomes after six weeks. Our results demonstrate the efficacy of these discrete anti-fibrotic microstructures and suggest a potential therapeutic materials approach for combatting pathologic fibrosis.

We recently reported that compared to Primary Reperfusion (PR), first reducing myocardial oxygen demand by activating an acute mechanical circulatory support (AMCS) pump while delaying coronary reperfusion (Primary Unloading; PU) reduces myocardial damage in models of acute myocardial infarction (

Background —The aim of the present study was to characterize temporal changes in cyclic variation of ultrasonic integrated backscatter (IBS), which reflects intrinsic contractile performance, in patients with reperfused acute myocardial infarction (AMI) and to elucidate the clinical value of tissue characterization in predicting myocardial viability. Methods and Results —We recorded short-axis IBS images before and 3, 7, and 21 days after reperfusion in 26 patients with AMI and obtained the cyclic variation of IBS in the normal and infarct zones. When cyclic variation showed synchrony and asynchrony, we expressed its magnitude as positive and negative values, respectively, called the phase-corrected magnitude. We also measured average wall motion score (dyskinesis, 4; normal, 0) of the infarct segments. The phase-corrected magnitude was lower in the infarct zone than in the normal zone before reperfusion (0.3±2.5 versus 5.2±1.7 dB, P P Conclusions —In patients with AMI, cyclic variation of IBS is blunted during ischemia but recovers much faster after reperfusion than the improvement in wall motion. The greater phase-corrected magnitude at day 3 may be a predictor of better functional improvement.

The goal of reperfusion strategies in patients with acute myocardial infarction is to salvage myocardium within the infarct zone at risk from the acute occlusion. The status of wall motion and thickening within the infarct zone is an imprecise guide to the extent of salvage and viability within the infarct zone, based on the well-described phenomenon of myocardial stunning. However, knowledge of significant salvage and preserved viability within an infarct zone soon after infarction has important implications regarding clinical decision making for catheterization and potential revascularization: given preserved viability, restoration of normal coronary flow in the setting of a severe residual stenosis or occlusion would be expected to result in significant recovery of regional, and possibly global left ventricular function, with attendant implications for prognosis and outcome.

Background Sympathetic hyperactivity is linked with several adverse cardiovascular events in patients with acute coronary syndrome (ACS). Sympathetic activity increases early in the process of ischemia through 2 mechanisms. One originates from the central nervous system and leads to enhanced sympathetic activity. The other mechanism originates at the infarct zone and leads to B receptor up-regulation and catecholamine supersensitivity. Nevertheless, sympathetic hyperactivity accompanied by an underlying myocardial structural damage is likely to increase the ventricular repolarization duration measured as QT interval on the body surface electrocardiogram. Purpose The aims of the current review of the literature were to examine the physiological processes underlying the use of long QT interval as a risk prediction tool in patients with ACS and to critically review and critique the existing evidence related to this matter. Conclusion The available evidence is contradictory and includes serious limitations in design and QT measurement and correction. Until accurate and reliable data are available, it is difficult to determine the additional clinical value and prognostic significance of long QT interval in patients with ACS beyond that in other patients. Clinical implications Long QT interval is not uncommon among patients with ACS. Automated continuous QT interval monitoring is superior to manual QT interval measurement with the standard 10-second electrocardiogram. Optimum care for patients with ACS requires nurses to keep monitoring the QT interval several days after the initial event.

Background The natural history of persistent myocardial oedema after ST-elevation myocardial infarction (STEMI) is uncertain. Methods and ResultsPatients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI; ClinicalTrials.gov: NCT02072850). Cardiac magnetic resonance (CMR) imaging with T2-mapping of myocardial oedema was performed at 1.5 Tesla 2 days and 6 months post-MI. Myocardial oedema was defined as infarct signal intensity (S. I.) >2 standard deviations from the mean S. I. within a remote reference region. 283 STEMI patients (mean (SD) age 59 (12) years, 75% male) were enrolled. Infarct size was 18 (13)% of left ventricular (LV) mass. At 2 days, infarct zone T2 (ms) was higher than remote zone T2 (62.9 (5.2) vs. 49.7 (2.1); p Conclusion Persistence of oedema within the infarct zone affected the majority of patients at 6 months post-STEMI, and was associated with the initial severity of STEMI and adverse LV remodelling.

Summary A cardiac-tailored framework for 3D Diffusion Tensor MRI tractography is developed and used to characterize myofiber architecture in normal and remodeled myocardium. We show that myofibers in the subepicardium of the remote infarct zone become less oblique (more circumferential) as the heart dilates and remodels. This fiber realignment may play an important role in the loss of contractile function in the remote zone over time. Background

In acute myocardial infarction (AMI), the aim of any therapeutic intervention is to reduce the infarct size and attenuate adverse remodeling. The type and extent of infarction encountered clinically [transmural, hemorrhagic, heterogeneous, with microvascular obstruction (MVO)], is primarily determined by the severity of the initial ischemic insult. Understanding the in-vivo pathophysiological mechanisms after AMI as a function of severity will be key in predicting functional recovery, prognosis and assessing the efficacy of novel therapies.

To evaluate the role of dobutamine echocardiography for early assessment of myocardial viability and ischemia in acute myocardial infarction (MI), 59 patients with thrombolyzed acute MI underwent low- (5-10 micrograms/kg/min, 8 patients) and high-dose (20-40 micrograms/kg/min, 51 patients) dobutamine echocardiography at a mean of 8 +/- 4 days after acute MI. Myocardial viability in the infarct zone was documented in 43 of 59 (73%) patients (group 1), in whom mean asynergy score index decreased from 1.6 +/- 0.3 at baseline to 1.3 +/- 0.2 (p0.001), after low-dose dobutamine. No viability was present in 16 of 59 (27%) patients (group 2). At follow-up, recovery of regional contractile function was observed in group 1 (asynergy score index decreased from 1.6 +/- 0.3 to 1.4 +/- 0.3; p0.001), but not in group 2 patients. Sensitivity, specificity, and negative and positive predictive values of low-dose dobutamine echocardiography in predicting spontaneous recovery of function were 79%, 68%, 50%, and 89%, respectively. Of the 51 patients who underwent high-dose dobutamine, 26 of 36 (72%) group 1 patients showed a deterioration of contractility in the infarct zone indicative of myocardial ischemia compared with only 1 of 15 (7%) group 2 patients. At follow-up, recovery of regional function was greater in patients with no evidence of myocardial ischemia at high doses than in those with an ischemic response.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess regional myocardial perfusion in patients with chronic myocardial infarction (MI) in relationship to the extent of residual viable myocardium.The study was approved by the local ethics committee; written informed consent was obtained from each participant. Twenty-nine patients with first onset of MI who underwent successful primary percutaneous coronary intervention at least 6 months thereafter were studied. Delayed enhancement magnetic resonance (MR) imaging was performed to define the infarct zone and its viable myocardial ratio (VMR), quantified by the percentage of the nonscarred pixels relative to the total pixels in the infarct zone. First-pass contrast material-enhanced MR imaging was performed to estimate regional perfusion and myocardial perfusion reserve (MPR) in the infarct region. Paired comparisons in perfusion and MPR were tested with nonparametric Wilcoxon matched-pairs test. A difference with P.05 was considered significant. Correlation was tested with Pearson analysis.The infarct region showed significant impairment of regional perfusion at rest (mean, 0.966 [mL x min(-1)]/g +/- 0.271 [standard deviation] vs 1.151 [mL x min(-1)]/g +/- 0.282; P = .024) and during stress (mean, 1.789 [mL x min(-1)]/g +/- 0.732 vs 2.753 [mL x min(-1)]/g +/- 0.806; P.0001) and a reduced MPR (mean, 1.923 +/- 0.678 vs 2.486 +/- 0.836; P.0001) as compared with remote myocardium. The estimated perfusion, with stress, of the residual viable myocardium was preserved (2.993 [mL x min(-1)]/g +/- 1.451 vs 2.753 [mL x min(-1)]/g +/- 0.806), and the difference was not significant. Furthermore, stress perfusion (R = 0.385; P = .039) and MPR (R = 0.434; P = .018) in the infarct zone were significantly correlated with VMR, suggesting that preservation of myocardial perfusion in the infarct region reflects the amount of viable myocardium.Reduced perfusion in the infarct zone is related to the extent of the viable myocardium.

Background A variety of CMR methods for detecting intramyocardial haemorrhage (IMH) has been proposed, including T2-weighted imaging (T2w), T2-mapping and T2* mapping. IMH detected by T2w imaging is associated with adverse LV remodelling and adverse outcome post acute myocardial infarction (MI). We compare the sensitivity, specificity, CNR and SNR of the three IMH imaging techniques. Methods Twenty patients underwent CMR at 3T (Achieva TX system, Philips Healthcare, Best, The Netherlands) within 3 days following reperfused ST-elevation MI. Black blood, cine, T2w, T2-mapping, T2*-mapping and LGE imaging (0.1 mmol/kg gadolinium DTPA) were performed in identical short axis locations using the ‘3 of 5’ approach. Data were evaluated offline using commercial software (cvi42 v4.1.5, Circle Cardiovascular Imaging Inc., Calgary, Canada). On the LGE images showing the largest infarct volume, infarct size was determined by using a semi-automated histogram-based thresholding method. This slice was evaluated for visual presence of IMH by the three methods. Signal intensity (SI) and respective standard deviation of SI (SD) were measured for the infarcted myocardium, remote myocardium and any IMH (if present). SNR was computed for each using the formula = 0.655((SI)/(SD)). CNR was determined comparing contrast-to-noise of infarcted myocardium to IMH (SNRi-SNRIMH). Results Of the twenty patients, 55% (n = 11) had IMH on T2w-imaging. The mean (±standard deviation) SNR and CNR values are listed in Table 1. The visual assessment of T2w imaging correlated strongly to T2-maps (r = 0.69; p = 0.001) and to the T2*-maps (r = 0.60; p = 0.005). The SNR for IMH and infarct zone were significantly different for only T2w imaging (Figure 1). Quantitative CNR for T2w imaging correlated strongly to visual assessment of all three imaging modalities (T2w- r = 0.650; p = 0.002, T2-map- r = 0.454; p = 0.04, T2*-map- r = 0.603; p = 0.005). The CNR for T2-maps and T2*-maps did not show similar correlation to the visual assessment. Conclusion Quantitative and qualitative T2w-imaging assessment for IMH is superior to T2-mapping and T2*mapping.

Left ventricular (LV) remodeling after myocardial infarction (MI) may lead to congestive heart failure, disability and death. It consists of expansion of the infarct zone and dilatation of the non-infarcted myocardium, causing shape distortion and ventricular enlargement. Experimental studies have shown that treatment with growth hormone (GH) stimulates cardiac repair, resulting in increased infarct zone collagen scar formation and possibly enhanced proteinosynthesis. These actions may ameliorate the process of LV remodeling. We hypothesize that these beneficial effects may be more prominent, if GH is delivered selectively in the infarct area, during the early phase of acute MI. Experimental and clinical studies are necessary to validate this hypothesis.

Background Inflammation following myocardial infarction has detrimental effects on reperfusion, myocardial remodelling and left ventricular function. MRI using ultrasmall superparamagnetic particles of iron oxide (USPIO) can be used to detect cellular inflammation in tissues. Methods 15 patients were recruited up to 5 days after ST-segment elevation myocardial infarction. Nine patients underwent cardiac MRI (3 Tesla) at baseline, and at 24 and 48 h following infusion of USPIO (4 mg/kg; Ferumoxytol, AMAG). Six control patients underwent the same scanning protocol without infusion of USPIO. T2*-weighted multi-gradient-echo sequences were acquired and R2* maps (inverse of T2*) were generated to assess USPIO accumulation. Baseline scans were registered to subsequent 24 and 48 h scans and the infarct zone was defined on Gadolinium-enhanced T2-weighted images. An “object map” was created that defined corresponding regions of interest (ROI) on all scans for each subject. The ROIs included infarct zone, peri-infarct zone, remote myocardium, liver, blood pool and skeletal muscle. The R2* values for each ROI was calculated. Results In the control group, the R2* value in the infarct zone remained constant: baseline, 0.047 s −1 (95% CI 0.034 to 0.059); 24 h, 0.043 s −1 (95% CI 0.035 to 0.052) and 48 h, 0.040 s −1 (95% CI 0.024 to 0.056). In the infarct zone, the R2* value increased from a baseline of 0.041 s −1 (95% CI 0.029 to 0.053) to 0.164 s −1 (95% CI 0.125 to 0.204) at 24 h and 0.128 s −1 (95% CI 0.097 to 0.158) at 48 h following USPIO administration (p Conclusion USPIO are taken up into the infarcted myocardium following acute myocardial infarction and can be quantified by MRI. This approach appears to image infarct-related cellular inflammation and represents an important novel method of assessing recovery following acute myocardial infarction.

Because they are terminally differentiated cells, adult cardiomyocytes cannot regenerate and there is no myocardial pool of stem cells to replace those which have suffered irreversible ischaemic injury. The responses to such an injury involve evolution of the infarct zone toward a fibrous noncontractile scar and hypertrophy of cells harboured in the still-viable segments of the heart. At best, these compensatory responses can temporarily maintain an adequate contractile function. At worst, the combination of interstitial fibrosis and inappropriate remodelling promote deterioration of systolic and diastolic functions and lead to heart failure.

Large myocardial infarction (MI) in the left ventricle (LV) leads not only to expansion of the necrotic infarct zone, but also to compensatory remodeling throughout the remainder of the LV. This is shown in the Figure (left), which was acquired from a 73-year-old man who presented with NYHA class II congestive heart failure 7 years after an anterior MI. Cardiac MRI, as described in the legend, revealed a thin-walled pseudoaneurysm of the apical anterior wall and severe systolic dysfunction in the rest of the myocardium. These findings were confirmed at surgery (pseudoaneurysm repair and 2 coronary artery bypass grafts). Long-axis cardiac MR images …

Left ventricular (LV) remodeling after acute myocardial infarction (MI) is strongly related to infarct size. The contribution of viability in the infarct zone and the presence of multivessel disease remains unknown. Because dobutamine stress echocardiography (DSE) can estimate infarct size and detect myocardial viability and multivessel disease, we postulated that DSE can accurately predict LV remodeling after acute MI.To test this hypothesis, 30 patients age 59 +/- 15 years, 21 men, 14 with anterior MI, underwent multistage DSE (low dose, 5 to 10 microg, and peak dose) during the first week after MI occurred. Follow-up echocardiography was performed at/=1 year. LV remodeling (2 SD increase in LV volume) occurred in 17 of 30 patients. Remodeling occurred in 12 (92%) of 13 patients with large nonviable infarct and in 1 (13%) of 8 patients with large viable infarct (P.001). Univariate predictors of LV remodeling were baseline ejection infarct (P.01), infarct size (number of akinetic segments at low dose P.01), age (P.05), and multivessel coronary disease (P. 01). The only multivariate predictor of remodeling was infarct size. Viability of infarct zone was a negative predictor of LV remodeling.DSE performed during the first week after acute MI predicts subsequent LV remodeling. Infarct size, nonviability of the infarct zone, and age are independent predictors of LV remodeling. Myocardial viability is a strong negative predictor of LV remodeling.

In a patient with acute myocardial infarction, clinical, electrocardiographic and angiographic information may be inadequate for determining the presence of viable tissue. If wall thickening is present, the myocardium is viable; if wall thickening is absent, the myocardium may or may not be viable [1]. The basis for the underlying myocardial dysfunction may be multifactorial in a single patient or even in a single myocardial segment. Myocardial contrast echocardiography (MCE) can define regions of viability within the infarct zone based on its ability to demonstrate the spatial distribution of microvascular perfusion [2]. The magnitude and spatial extent of microvascular perfusion within the infarct zone is the predominant determinant of the extent of myocellular viability.

We sought to investigate the effects of revascularization on the contractile reserve of dysfunctional myocardium.The improvement in dysfunctional but viable myocardium after revascularization is frequently less than expected from the amount of contractile reserve detected on dobutamine stress echocardiography. The fate of the contractile reserve, when it does not result in an adequate contractile recovery, is unknown.Basal contraction and contractile reserve of infarct zones were assessed by dobutamine stress echocardiography in 21 postinfarction male patients before and3 months after revascularization (30 infarct zones; mean +/- SD left ventricular ejection fraction 35 +/- 8%). An infarct zone wall motion score index (WMSI) was calculated.Before revascularization, contractile reserve was present in 14 infarct zones (12 patients) and absent in 16 (9 patients). After revascularization, ejection fraction increased by 5 +/- 4% (p0.01) in patients classified as positive for contractile reserve and remained unchanged in those classified as negative. New York Heart Association classification improved in 58.3% and 22.2% of patients, respectively. Basal contraction improved in eight zones with previous contractile reserve (57.1%) and in one zone without (6.3%) (p0.01). Contractile reserve was still evident in 13 zones with previous contractile reserve (93%; 8 with contractile recovery), and it developed in 6 zones without (38%; none with contractile recovery). WMSI values after revascularization were decreased from values before revascularization during low dose dobutamine in zones with and without previous contractile reserve (p0.01 and0.05, respectively).After revascularization, contractile reserve is maintained or even increases in viable infarct zones that do not recover as expected. It may also develop in some infarct zones judged not to be viable before revascularization. This increased contractile reserve may play a role in the functional improvement of patients after revascularization.

The importance, implications, and potential value of pharmacologic interventions during healing of the wound of myocardial infarction have become apparent as a result of recent advances in pathophysiology of healing and ventricular remodeling post-infarction. Over the last three decades, therapeutic efforts after myocardial infarction have centered around minimizing the loss of myocardium and function. Therapy focused on acute reduction of myocardial infarct size in the mid-seventies and on restoration of perfusion in the infarct zone in the mid-eighties. Over the last decade, chronic therapies have been developed for prevention of ventricular remodeling, progressive ventricular dilation and ventricular dysfunction [1, 2]. It became evident during the last 30 years that some pharmacologic therapies aimed at salvaging ischemic myocardium also exerted other effects on infarct healing, and those with clearly adverse effects were best avoided [3–7]. Recognition that the substrate for ventricular remodeling changes during infarct healing led to the suggestion that timing and duration of specific antiremodeling interventions should be based on knowledge of the natural pathophysiologic stage of healing in order to maximize therapeutic benefits [2, 8, 9]. To date, therapies have not been primarily targeted at improving the healing process post-infarction. This chapter will review current and potential pharmacologic interventions in post-infarction wound healing.

A sudden reduction in luminal diameter or a complete occlusion of a coronary artery triggers a cascade of metabolic events leading to myocardial ischemia. These events may differ from the slowly progressing narrowing of the coronary lumen due to developing atherosclerosis which allows for formation of collateral vessels. Yet, both situations are interrelated. They lead to an impairment of contractile function and to metabolic changes in the dependent myocardium. Considerable research has focused on elucidating mechanisms underlying the ischemia related changes in metabolism. Yet, the study of metabolism, especially in humans, has been limited. Tissue sampling for measurements of metabolites is highly invasive and provides only very regional information. Alternatively, collection of blood draining from the coronary sinus provides information on only average but not regional changes.

Little is known regarding the prognostic implications of exercise myocardial perfusion scans in patients late after myocardial infarction (MI). Thus, we studied 399 patients who underwent rest TI-201/exercise sestamibi SPECT more than one year after MI (mean 9 ± 7, range 2–37 years) who were followed up for more than 1 year (mean follow-up 21 ±6 months). Exercise and rest scans were visually assessed in 20 myocardial segments using a 5 point scale (0 = normal, 4 = no uptake). An infarct zone was defined as a region within a vascular territory with a rest score of g 1. A difference ≥1 between stress and rest scores for a segment was defined as ischemic. All patients were followed up for at least one year after their test. 25 hard events (HE; cardiac death or repeat MI) occurred (6.3% HE rate). A large proportion of patients had ischemia by scan (66%, 263/399) or subendocardial MI (no fixed defects; 44%, 177/399). Patients with ischemia outside an infarct zone (n = 209) and inside an infarct zone (n = 85) both had an event rate of 7%. HE rates were as follows. Reversible Defects g 2 6/66 (9%) 3/51 (6%) 4/53 (7.5%) 1–2 3/31 (10%) 0/19 (0%) 4/45 (9%) 0 2/80 (2.5%) 0/15 (0%) 3/39 (8%) Fixed Defects 0 1–2 g 2 There was no difference in HE rates between patients with only large fixed defects and only reversible defects. Conclusions (1) In patients with temporally remote infarction, the presence of large fixed defects confers high HE rates similar to reversible defects (possibly due to the risks of late infarct remodeling). (2) Ischemia within and outside infarct zones denotes similar high risk for adverse outcomes.

Objectives. This study used myocardial contrast echocardiography to investigate the extent of residual perfusion within the infarct zone in a select group of patients with recently reperfused myocardial infarction and evaluated its influence on the ultimate infarct size. Background. Limited information is available on the status of myocardial perfusion within postischemic dysfunctional segments at predischarge and on its influence on late regional and global functional recovery. Methods. Twenty patients with acute myocardial infarction were selected for the study. Patients met the following inclusion criteria: 1) single-vessel coronary artery disease; 2) patency of infarct-related artery with persistent postischemic dysfunctional segments at predischarge; 3) stable clinical condition up to 6 months after hospital discharge. All selected patients underwent coronary angiography and myocardial contrast echocardiography before hospital discharge and repeated the echocardiographic examination 6 months later. Patients were grouped according to the pattern of contrast enhancement in predischarge dysfunctional segments. Results. In nine patients (group I), the length of segments showing abnormal contraction coincided with that of the contrast defect segments. In the remaining 11 patients (group II), postischemic dysfunctional segments were partly or completely reperfused. There was no difference between the two groups in asynergic segment length at predischarge (7.3 ± 2.5 vs. 7.2 ± 4.3 cm, p = NS). At follow-up study, asynergic segment length was significantly reduced in group II patients, whereas no changes were observed in group I patients (from 7.2 ± 4.3 to 4.7 ± 3.7 cm, p < 0.005; and from 7.3 ± 2.5 to 7.5 ± 2.9 cm, p = NS, respectively). Conclusions. Among patients with a predischarge patent infarct-related artery, further improvement in regional and global function may be expected during follow-up when residual perfusion in the infarct zone is present.

Thrombolytic therapy has been convincingly demonstrated to open occluded coronary arteries, limit infarct size, preserve left ventricular function and reduce mortality when given within the first six hours of acute myocardial infarction (1). It is generally accepted that the closer to the onset of symptoms the thrombolytic agent is administered, the greater the amount of myocardium that is salvaged and the greater the clinical benefit (2). Because until recently it was felt that the primary mechanism of the clinical benefit of reperfusion was entirely through myocardial salvage, the maximum length of time following symptom onset that thrombolytic treatment should remain beneficial has been controversial.

I read with great interest the article by Turschner et al. 1 describing the echocardiographic observation of experimentally induced myocardial infarction and subsequent reperfusion in the pig model. They have demonstrated an increase in regional wall thickness in the reperfused infarct zone due to ‘oedema associated with reperfusion injury’. The phenomenon of ‘reperfusion injury’ (first described by Tennant and Wiggers2) comes entirely from experimental laboratories; there are a number of experimental observations showing the deleter-ious effects of reperfusion leading to further progression of already existing ischaemic damage. Data from human studies are, however, in discrepancy with …

PreviewIn patients experiencing transmural infarction, early reperfusion of the infarct zone offers the best hope of preserving myocardial function. Dr Vetrovec reviews methods of recanalization and details a procedure—intracoronary thrombolysis—that has received much attention and is widely applied, alone or with angioplasty. Intravenous use of streptokinase is also discussed.

To characterize the pattern of pacemaker dominance in the ventricular specialized conduction system (VSCS), escape ventricular pacemakers were localized and quantified in vivo and in virto, in normal hearts and in hearts 24 hours after myocardial infarction. Excape pacemaker foci were localized in vivo during vagally induced atrial arrest by means of electrograms recorded from the His bundle and proximal bundle branches and standard electrocardiographic limb leads. The VSCS was isolated using a modified Elizari preparation or preparations of each bundle branch. Peacemakers were located by extra- and intracellular recordings. Escape pacemaker foci in vivo were always in the proximal conduction system, usually the left bundle branch. The rate was 43+/-11 (mean+/-SD) beats/min. After beta-adrenergic blockade, the mean rate fell to 31+/-10 beats/min, but there were no shifts in pacemaker location. In the infarcted hearts, pacemakers were located in the peripheral left bundle branch. The mean rate was 146+/-20 beats/min. In isolated normal preparations, the dominant pacemakers usually were in the His bundle, firing at a mean rate of 43+/-10 beats/min. The rates of pacemakers diminished with distal progression. In infarcted hearts, the pacemakers invariably were in the infarct zone. The mean firing rates were not influenced by beta-adrenergic blockade. The results indicate that the dominant pacemakers are normally in the very proximal VSCS, but after myocardial infarction pacemaker dominance is shifted into the infarct. Distribution of pacemaker dominance is independent of sympathetic influence.

The experiments investigated the hypothesis that the occurrence of repetitive ventricular responses elicited by the ventricular extrasystole (VES) technique are an indicator of ventricular vulnerability to fibrillation. A comparison was made between the incidence of repetitive responses elicited by the VES technique and the minimum electrical energy (VFT technique) necessary to elicit repetitive responses and ventricular fibrillation in normal dogs, dogs with acute infarction, and dogs with chronic infarction. The VES technique produced repetitive responses in 14 of 46 sites. Responses were of at least three types: (1) bundle branch re-entry; (2) activation at the pacing site, and (3) activation at the infarct zone. In contrast repetitive responses and the onset of fibrillation produced by the VFT technique appeared to be a single type with earliest activation at the pacing site. There were no differences in the ventricular fibrillation thresholds between dogs with and without repetitive responses produced by the VES technique. Thus the incidence of VES technique-induced repetitive responses is not a reasonable predictor of ventricular vulnerability to fibrillation. However, in 2 dogs with lower ventricular fibrillation thresholds, repetitive responses originating at the infarct zone were induced by the VES technique. Occurrence of these repetitive responses may be indicative of ventricular vulnerability to fibrillation.

We studied two forms of post-infarction angina: ischemia at a distance (angina with new electrocardiographic changes distant from the acute infarct) and ischemia in the infarct zone (angina with new electrocardiographic changes limited to the leads originally involved by the acute infarct). Seventy patients with early post-infarction angina were followed for an average of six months; 43 had ischemia at a distance, and 27 had ischemia in the infarct zone. Mortality in the entire group was 56 per cent, but it was 72 per cent (31 of 43 patients) among those with ischemia at a distance and 33 per cent (nine of 27) among those with ischemia in the infarct zone (P less than 0.005). Post-infarction angina identifies patients with high mortality; among such patients, ischemia at a distance may represent an especially high-risk subset of patients with large areas of viable but jeopardized myocardium who could benefit from aggressive intervention.

To determine the effect of thrombolytic therapy and/or immediate coronary angioplasty (PTCA) on left ventricularfunction. 129 patients with acute transmural myocardial infarction were retrospectively studied. Treatment strategies included thrombolytic therapy alone (n = 29), PTCA alone (n = 41), and combined thrombolytic therapy and PTCA (n = 59). Left ventricular ejection fraction (LVEF) and infarct zone regional wall motion (R WM) were determined from contrast ventriculography obtained acutely and at day 7-10. In the overall group, there was a 2 & 9% increase in LVEF (p < 0.02) and a 0.7 f 1.2 SD/chord increase in R WM (p < 0.0001) between day 1 and day 7-10. Patients with a patent infarct vessel at day 7-10 had a more significant change (A) in LVEF (3 f 8 vs -5 & 996, p = 0.0002) and RWM (0.8 f 1.2 vs 0.1 A 1.0 SD/chord, p < 0.02) than patients with .an occluded vessel. Patients with a residual stenosis < 70% at day 7-10 manifested a greater MVEF (3 f 8 vs -5 f 9%. p < 0.01) and ARWW (0.9 k 1.2 vs 0.1 1.0 SD/ chord, p < 0.05) than patients who were occluded. There was a negative correlation between residual

The effect of infarct maturation on the temporal sequence of contraction within infarct zones has not previously been described. Accordingly, the time-varying pattern of contraction within ischemic/infarct zones was studied with use of cross-sectional echocardiography in 17 dogs at 10 min to 6 weeks after acute experimental myocardial infarction.Left ventricular short-axis images were digitized from end-diastole to end-systole and endocardial fractional radial change along 36 evenly spaced rays was calculated. The circumferential extent of dyskinesia and the number of rays that exhibited maximal dyskinesia were determined for each decile of the normalized contraction sequence. Between 10 min and 1 week after infarction, the greatest circumferential extent of dyskinesia occurred between the 3rd and 4th deciles of the normalized contraction sequence. However, as the infarct matured, the greatest spatial expanse of dyskinesia was noted to occur progressively earlier in the contraction sequence (second decile at 6 weeks), and the extent of mid- to late-systolic dyskinesia decreased markedly. Whereas end-systolic dyskinesia was present in 30% to 50% of ischemic/infarct zone rays from 10 min to 48 h, end-systolic dyskinesia was no longer observed at 6 weeks. Similarly, the maximal amplitude of dyskinesia was most commonly observed during midsystole from 10 min to 48 h, but occurred progressively earlier as the infarct matured, falling during the first decile at 6 weeks after infarction.These data suggest that maximal circumferential extent and amplitude of dyskinesia occur progressively earlier in the systolic contraction sequence as the infarct matures. An awareness of these temporal variations in the contraction pattern is important in the use of wall motion as a marker of left ventricular dysfunction after myocardial infarction.