Infarct Zone Research Articles

Etiopathology, Clinical and Imaging Characteristics of Border Zone Strokes.

A border zone infarct (BI) is defined as an infarction that is localized to watersheds or border zones in the brain. BI is further classified into cortical border zone infarct (CBZ) and internal border zone infarct (IBZ). This study was conducted to explore the clinical and radiological characteristics of BI. The study was conducted on eligible 400 acute ischemic stroke patients out of which 52 BI patients (diagnosed by the radiologist on DWI MRI images), patients >18 yrs of age were selected and divided into two groups of IBZ and CBZ infarct patients. The degree of intracranial and extracranial stenosis and characteristics on clinical presentation were assessed. The data were collected and analyzed using SPSS version 20.0 software at significance level p-value <0.05. 25% and 75% of CBZ and IBZ patients, respectively, had history of presyncope or syncope before stroke. On vascular evaluation, 3.9% and 51.9% were in MCA and ICA stenosis group, respectively. Evidence of cardio embolism was found in 17.3% of patients. 53.3% of CBZ and 53.8% of IBZ patients were in ICA stenosis group, and 6.7% of CBZ and 7.7% of IBZ patients were in MCA stenosis group, with a statistically insignificant relation (p-value >0.05). Association of BI with events causing hypotension or hypovolemia is well-established in our study, association of BI with large vessel atherosclerosis is common, and its contribution to CBZ and IBZ seems to be equal.

Ischemia reperfusion myocardium injuries in type 2 diabetic rats: Effects of ketamine and insulin on LC3-II and mTOR expression.

Objectives: Myocardiopathy occurs in ischemia-induced injury caused by dysregulation of autophagy of cardiac tissues. The present report evaluates the protective effect of ketamine and insulin against myocardial injury in type 2 diabetic rats (T2DM).Methods: The effects of ketamine and its combination with insulin on biochemical parameters and inflammatory cytokines in the serum of I/R-induced myocardial injury in T2DM rats were evaluated. The parameters of reactive oxygen species and the expression of autophagosome signaling pathway proteins were also determined. Using transmission electron microscopy, we investigated autophagosomes. Western blots were used to detect autophagy-associated signaling pathways. Myocardial function was determined by echocardiography and histopathological changes in myocardial tissues were also determined in I/R-induced myocardial injury in type 2 diabetic rats.Results: There was a significant reduction in glucose, AST, LDH, and CK-MB levels and cytokines (IL-1β, IL-6, and TNF-α) in serum of the ketamine (p < .05) and ketamine + insulin (p < .01) groups than in the diabetic + I/R. MDA and ROS levels were reduced with a substantial (p < .05) increase in GSH levels through improved cardiac function in the ketamine (p < .05) and ketamine + insulin (p < .01) groups than the diabetic + I/R group. There was an increase in mature autophagosomes in diabetic+I/R+Kt+In compared to diabetic+I/R+Kt alone in infarction and marginal zones. It should be noted that the significant increase (p < .01) in protein levels of the autophagy-associated intracellular signaling pathways AMPK and mTOR, as well as an increase in LC3-II and BECLIN-1, suggests that ketamine combined with insulin-activated autophagy-associated intracellular signaling AMPK and mTOR.Conclusion: The findings of the study suggest that ketamine combined with insulin administration remarkably protects I/R-induced myocardial injury in rats with T2DM by reducing the dysregulation of autophagy.

Novel Approach for Assessing Postinfarct Myocardial Injury and Inflammation Using Hybrid Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging.

Novel Approach for Assessing Postinfarct Myocardial Injury and Inflammation Using Hybrid Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging.

Diabetes mellitus — metabolic preconditioning in protecting the heart from ischemic damage?

The negative impact of diabetes mellitus (DM) on the cardiovascular system has been confirmed by numerous clinical studies. However, there are experimental studies that show an increase in the resistance of the heart to ischemic and reperfusion damage in animals with DM. This phenomenon is characterized by a smaller size of the infarct zone, better preservation of the contractile function of the myocardium, and a lower incidence of ischemic and reperfusion arrhythmias. It is assumed that at a certain stage in the development of DM, a “metabolic window” is formed, in which metabolic alterations at the cellular level trigger adaptive mechanisms that increase the viability of cardiomyocytes. Published data confirm that the magnitude of the protective effect induced by DM is comparable to, and in some cases even exceeds, the effect of the preconditioning phenomenon. It is recognized that the mechanisms that protect the heart from ischemic and reperfusion damage against the background of DM are universal and are associated with the modulation of the antioxidant system, apoptosis factors, pro-inflammatory cytokines, and signaling systems that ensure cell survival. The one of the main pathogenic factor in DM is hyperglycemia, but under stress it plays the role of an adaptive mechanism aimed at meeting the increased energy demand in pathological conditions. Probably, at a certain stage of DM, hyperglycemia becomes a trigger for the development of protective effects and activates not only signaling pathways, but also the restructuring of energy metabolism, which makes it possible to maintain ATP production at a sufficient level to maintain the vital activity of heart cells under ischemia/reperfusion conditions. It is possible that an increased level of glucose, accompanied by the activation of insulin-independent mechanisms of its entry into cells, as well as the availability of this energy substrate, will contribute to a better restoration of energy production in heart cells after a infarction, which, in turn, will significantly reduce the degree of myocardial damage and will help preserve the contractile function of the heart. Identification of the conditions and mechanisms of the cardioprotective phenomenon induced by DM will make it possible to simulate the metabolic state in which the protection of cardiomyocytes from damaging factors is realized.

Defining the timeline of periostin upregulation in cardiac fibrosis following acute myocardial infarction in mice

After myocardial infarction (MI), the heart's reparative response to the ischemic insult and the related loss of cardiomyocytes involves cardiac fibrosis, in which the damaged tissue is replaced with a fibrous scar. Although the scar is essential to prevent ventricular wall rupture in the infarction zone, it expands over time to remote, non-infarct areas, significantly increasing the extent of fibrosis and markedly altering cardiac structure. Cardiac function in this scenario deteriorates, thereby increasing the probability of heart failure and the risk of death. Recent works have suggested that the matricellular protein periostin, known to be involved in fibrosis, is a candidate therapeutic target for the regulation of MI-induced fibrosis and remodeling. Different strategies for the genetic manipulation of periostin have been proposed previously, yet those works did not properly address the time dependency between periostin activity and cardiac fibrosis. Our study aimed to fill that gap in knowledge and fully elucidate the explicit timing of cellular periostin upregulation in the infarcted heart to enable the safer and more effective post-MI targeting of periostin-producing cells. Surgical MI was performed in C57BL/6J and BALB/c mice by ligation of the left anterior descending coronary artery. Flow cytometry analyses of cells derived from the infarcted hearts and quantitative real-time PCR of the total cellular RNA revealed that periostin expression increased during days 2–7 and peaked on day 7 post-infarct, regardless of mouse strain. The established timeline for cellular periostin expression in the post-MI heart is a significant milestone toward the development of optimal periostin-targeted gene therapy.

267 EFFECTS OF PIRFENIDONE ON SCAR SIZE AND VENTRICULAR REMODELING AFTER MYOCARDIAL INFARCTION: A PRECLINICAL STUDY

Abstract Background An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling, increasing the risk for ventricular arrhythmias and heart failure. Pirfenidone is a drug currently approved for the treatment of idiopathic pulmonary fibrosis, and reduces LV fibrosis in patients with heart failure and preserved ejection fraction. We aimed to characterize the different profiles or protein expression in the infarct zone in rats receiving or not receiving pirfenidone on top of standard therapy for MI. Methods Male Wistar rats were randomized to: sham procedure (group 1; n=13), reperfused MI induced by surgical ligation of the left anterior descending artery (LAD) for 45 minutes (group 2; n=17), reperfused MI plus standard therapy (aspirin, angiotensin-converting enzyme inhibitor, beta-blocker, and also mineralocorticoid receptor antagonist [MRA]) (group 3; n=17), reperfused MI plus pirfenidone alone (group 4; n=17), reperfused MI plus standard therapy and pirfenidone (group 5; n=17). Rats surviving LAD ligation and reperfusion underwent cardiac magnetic resonance (CMR) after 72 hours and 30 days from MI, and were sacrificed the day after the second CMR exam. The primary endpoint was the change in late gadolinium enhancement (LGE) mass as a percentage of LV mass. Results Forty-six rats survived until the second CMR. Percent changes in LV end-diastolic and end-systolic volume (p=0.370 and 0.423, respectively), ejection fraction (p=0.236) and mass (p=0.815) did not differ significantly between rats on pirfenidone plus standard therapy compared with those receiving standard therapy alone. The decrease in LGE mass was significantly greater in rats on pirfenidone plus standard therapy vs. those on standard therapy alone: -22.0% (interquartile range, -37.1 to -5.7, range -51.1 to +37.5) vs. +1.9% (-7.7 to +12.5, range -19.8 to +56.5), p=0.029. Conclusions Pirfenidone had additive effects to standard therapy for MI (including an MRA) in reducing LV fibrosis in a rat model of reperfused MI, while it did not further improve LV function, volumes or mass.

Association of monomeric C-Reactive Protein (m-CRP) with hypothalamic neurons after CRP hippo-campal administration in a model of dementia.

The ensuing ischemia due to the disruption of blood supply to the brain is one of the most common causes of stroke. Evidence suggests a clear association of the ischemic injury with vascular dementia and Alzheimer's disease (AD). In response to the brain ischemia, a cascade reaction starts leading to neuronal damage due to oxidative stress and other inflammatory mediators. A pilot study was done, which showed that following stroke, monomeric-C-reactive protein (mCRP) is expressed in large quantities around the infarcted zone and this CRP is able to induce neurodegeneration and inflammation potentially perpetuating dementia. We examined both patient brain samples and excised mouse brain tissue, previously injected with 1.75 mg/mL mCRP into the CA1 area of the hippocampus through the stereotactic surgical procedures and followed them over a period of over 6 months. The distribution of mCRP was examined through immunohistochemistry (mouse anti-human mCRP-specific antibodies 8C10). We observed a novel finding: those micro vessels close to the injection location were strongly stained with mCRP only in the mice that had been injected with mCRP, indicating that this small blood vessel can spread it throughout the brain. mCRP found in the brain after a hemorrhagic stroke promotes damage over a large area via the induction of inflammation and degeneration of perivascular compartments.

Novel Approaches to Program Cells to Differentiate into Cardiomyocytes in Myocardial Regeneration.

With heart failure (HF) being one of the leading causes of hospitalization and death worldwide, multiple stem cell therapies have been attempted to accelerate the regeneration of the infarct zone. Versatile strategies have emerged to establish the cell candidates of cardiomyocyte lineage for regenerative cardiology. This article illustrates critical insights into the emerging technologies, current approaches, and translational promises on the programming of diverse cell types for cardiac regeneration.

Insight into Heart-Tailored Architectures of Hydrogel to Restore Cardiac Functions after Myocardial Infarction.

With permanent heart muscle injury or death, myocardial infarction (MI) is complicated by inflammatory, proliferation and remodeling phases from both the early ischemic period and subsequent infarct expansion. Though in situ re-establishment of blood flow to the infarct zone and delays of the ventricular remodeling process are current treatment options of MI, they fail to address massive loss of viable cardiomyocytes while transplanting stem cells to regenerate heart is hindered by their poor retention in the infarct bed. Equipped with heart-specific mimicry and extracellular matrix (ECM)-like functionality on the network structure, hydrogels leveraging tissue-matching biomechanics and biocompatibility can mechanically constrain the infarct and act as localized transport of bioactive ingredients to refresh the dysfunctional heart under the constant cyclic stress. Given diverse characteristics of hydrogel including conductivity, anisotropy, adhesiveness, biodegradability, self-healing and mechanical properties driving local cardiac repair, we aim to investigate and conclude the dynamic balance between ordered architectures of hydrogels and the post-MI pathological milieu. Additionally, our review summarizes advantages of heart-tailored architectures of hydrogels in cardiac repair following MI. Finally, we propose challenges and prospects in clinical translation of hydrogels to draw theoretical guidance on cardiac repair and regeneration after MI.

Single-cell and spatial transcriptomics of the infarcted heart define the dynamic onset of the border zone in response to mechanical destabilization.

The border zone (BZ) of the infarcted heart is a geographically complex and biologically enigmatic interface separating poorly perfused infarct zones (IZs) from remote zones (RZs). The cellular and molecular mechanisms of myocardial BZs are not well understood because microdissection inevitably combines them with uncontrolled amounts of RZs and IZs. Here, we use single-cell/nucleus RNA sequencing, spatial transcriptomics and multiplexed RNA fluorescence in situ hybridization to redefine the BZ based on cardiomyocyte transcriptomes. BZ1 (Nppa + Xirp2 -) forms a hundreds-of-micrometer-thick layer of morphologically intact cells adjacent to RZs that are detectable within an hour of injury. Meanwhile, BZ2 (Nppa + Xirp2 +) forms a near-single-cell-thick layer of morphologically distorted cardiomyocytes at the IZ edge that colocalize with matricellular protein-expressing myofibroblasts and express predominantly mechanotransduction genes. Surprisingly, mechanical injury alone is sufficient to induce BZ genes. We propose a 'loss of neighbor' hypothesis to explain how ischemic cell death mechanically destabilizes the BZ to induce its transcriptional response.

Contractile Adaptation of the Left Ventricle Post-myocardial Infarction: Predictions by Rodent-Specific Computational Modeling.

Myocardial infarction (MI) results in cardiac myocyte death and the formation of a fibrotic scar in the left ventricular free wall (LVFW). Following an acute MI, LVFW remodeling takes place consisting of several alterations in the structure and properties of cellular and extracellular components with a heterogeneous pattern across the LVFW. The normal function of the heart is strongly influenced by the passive and active biomechanical behavior of the LVFW, and progressive myocardial structural remodeling can have a detrimental effect on both diastolic and systolic functions of the LV leading to heart failure. Despite important advances in understanding LVFW passive remodeling in the setting of MI, heterogeneous remodeling in the LVFW active properties and its relationship to organ-level LV function remain understudied. To address these gaps, we developed high-fidelity finite-element (FE) rodent computational cardiac models (RCCMs) of MI using extensive datasets from MI rat hearts representing the heart remodeling from one-week (1-wk) to four-week (4-wk) post-MI timepoints. The rat-specific models (n = 2 for each timepoint) integrate detailed imaging data of the heart geometry, myocardial fiber architecture, and infarct zone determined using late gadolinium enhancement prior to terminal measurements. The computational models predicted a significantly higher level of active tension in remote myocardium in early post-MI hearts (1-wk post-MI) followed by a return to near the control level in late-stage MI (3- and 4-wk post-MI). The late-stage MI rats showed smaller myofiber ranges in the remote region and in-silico experiments using RCCMs suggested that the smaller fiber helicity is consistent with lower contractile forces needed to meet the measured ejection fractions in late-stage MI. In contrast, in-silico experiments predicted that collagen fiber transmural orientation in the infarct region has little influence on organ-level function. In addition, our MI RCCMs indicated that reduced and potentially positive circumferential strains in the infarct region at end-systole can be used to infer information about the time-varying properties of the infarct region. The detailed description of regional passive and active remodeling patterns can complement and enhance the traditional measures of LV anatomy and function that often lead to a gross and limited assessment of cardiac performance. The translation and implementation of our model in patient-specific organ-level simulations offer to advance the investigation of individualized prognosis and intervention for MI.

Predictive Value of Cardiac Magnetic Resonance for Left Ventricular Remodeling of Patients with Acute Anterior Myocardial Infarction.

Background: Heart failure is a serious complication resulting from left ventricular remodeling (LVR), especially in patients experiencing acute anterior myocardial infarction (AAMI). It is crucial to explore the predictive parameters for LVR following primary percutaneous coronary intervention (PPCI) in patients with AAMI. Methods: A total of 128 AAMI patients who were reperfused successfully by PPCI were enrolled sequentially from June 2018 to December 2019. Cardiovascular magnetic resonance (CMR) was performed at the early stage (<7 days) and after the 6-month follow-up. The patients were divided into LVR and non-LVR groups according to the increase of left ventricular end diastolic volume (LVEDV) measured by the second cardiac magnetic resonance examination ≥20% from baseline. (3) Results: The left ventricular ejection fraction (LVEF), the global longitudinal strain (GLS), the peak circumferential strain in infarcted segments, and the infarct size (IS) remained significantly different in the multivariate logistic regression analysis (all p < 0.05). The area under the receiver operating characteristic curve of Model 1, wherein the GLS was added to the LVEF, was 0.832 (95% CI 0.758−0.907, p < 0.001). The C-statistics for Model 2, which included the infarct-related regional parameters (IS and the peak circumferential strain in infarcted segments)was 0.917 (95% CI 0.870−0.965, p < 0.001). Model 2 was statistically superior to Model 1 in predicting LVR (IDI: 0.190, p = 0.002). (4) Conclusions: Both the global and regional CMR parameters were valuable in predicting LVR in patients with AAMI following the PPCI. The local parameters of the infarct zones were superior to those of the global ones.

Abstract 15385: Integrin Alpha 11 is a Critical Regulator of Cardiac Remodelling, Fibrosis and Infarct Formation Following Myocardial Infarction

Cardiac fibrosis (CF), a key feature of cardiac remodelling, defined as the accumulation of excessive amounts of extracellular matrix (ECM), in response to injuries such as myocardial infarction (MI). Cardiac fibroblasts within and surrounding the injured area respond to biochemical and mechanical stimuli transforming into myofibroblasts and begin to secrete collagen. Long term collagen production reduces ventricular compliance and ultimately results in further cardiac dysfunction leading to heart failure. Mechanical activation of collagen production is understood to be a significant mediator of cardiac fibrosis. However, the mechanisms via which mechanical stimuli initiate cardiac fibroblast activation are not well understood. Therefore, we sort to investigate the role of Integrin ⍺11, a collagen binding integrin which preferentially binds to type I collagen, in response to cardiac injury. Fibroblast conditional ⍺11 knockout (KO) mice demonstrated similar cardiac function to that of Wildtype littermates (WT). However, interstitial collagen I (P&lt;0.05) and III (P&lt;0.0001) content was reduce along with cardiac myocyte size (P&lt;0.0001). In response to ligation of the left anterior descending aorta ⍺11 KO mice had significantly increased Infarct size 24 hours post MI (WT=39%, ⍺11KO=64% P&lt;0.05). Larger MI’s resulted in increased mortality in ⍺11 KO mice (22% v’s 57%, P&lt;0.05) due to rupture. Cardiac function 2 days following MI measured by echo demonstrated that Fractional Area Change (FAC) (23% ±1.812 v’s 16%±2.311, P&lt;0.05) and Cardiac Output (8.53ml±1.045 v’s 4.98ml±0.67, P&lt;0.05) were significantly worse in ⍺11 KO compared to WT mice. In the later remodelling response 4 weeks post MI, FAC was again significantly worse for ⍺11 KO mice (~9% ±1.659%, P&lt;0.0001) compared to WT (~19% ± 0.9810%). Moreover, ⍺11 KO mice that survived MI had significantly more collagen I (P&lt;0.0001) content in the remote, peri-infarct and infarct zone’s than that of WT along with, a lack of hypertrophic response. In conclusion, the loss ⍺11 results in increased ventricular dilation, impairs cardiac function and, was associated with increased mortality due to rupture following MI. In mice which survived MI ⍺11 deletion led to increased CF and blunted cardiac myocyte hypertrophy.

Abstract 13180: Trans-Valvular Unloading Reduces Anaerobic Glycolysis Before Reperfusion and Preserves Energy Substrate Utilization After Reperfusion in Models of Acute Myocardial Infarction

Background: The impact of mechanical left ventricular (LV) unloading before reperfusion on myocardial energetics in acute myocardial infarction (AMI) is unknown. We hypothesized that LV unloading reduces anaerobic glycolysis in models of ischemia reperfusion injury (IRI). Methods: Myocardial ischemia was induced by percutaneous occlusion of the left anterior descending (LAD) artery for 90 minutes in adult swine. In Groups A and B, an additional 120 minutes of LAD occlusion without reperfusion was performed in the presence or absence of a trans-valvular pump (TVP). In Group C and D, an additional 120 minutes of reperfusion was performed in the presence or absence TVP (Fig. 1A). Untargeted Metabolomics was performed on the tissues from the infarct zones. Results: Compared to Group A, infarct size normalized to the area at risk (IS/AAR) was significantly smaller with LV unloading after ischemia alone (Group B; Fig 1B) and reperfusion (Group D; Fig 1B). Principal component analysis analysis of 800 metabolites identified 5 distinct clusters corresponding to the 4 study groups and sham controls (Fig 1C). LV unloading without reperfusion reduced lactate by 30±4% (p&lt;0.006), glucose by 25±5% (p&lt;0.02), and intermediates of glucose metabolism, Fructose 1,6-diphosphate by 9.3%, p&lt;0.008) and ATP by 14±5% (p&lt;0.04) consistent with decreased anaerobic glycolysis and reduced myocardial oxygen demand (Fig 1D Groups A and B). LV unloading followed by reperfusion increased lactate and glucose levels by 30±5% and 75±30% (p&lt;0.05). Consistent with reduced glycolytic metabolites during ischemia with unloading, we observed significantly reduced levels of genes and proteins associated with glycolysis including mRNA expression of Glut1 and PDK1 within the infarct zone.We report for the first time that LV unloading during coronary occlusion reduces anaerobic glycolysis, energy substrate utilization and ATP production before reperfusion.

Abstract 12329: Checkpoint Kinase 1 Protein Therapy Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair in a Porcine Model of Myocardial Ischemia/Reperfusion Injury

Objective: To investigate the impact of recombinant human checkpoint kinase 1 (rhCHK1) on cardiomyocyte renewal and myocardial repair after myocardial ischemia/reperfusion (I/R) injury in swine. Methods: Quantitative phosphoproteomics profiling was performed on infarct border zone of neonatal myocardium, and kinase-substrate network analysis using iGPS algorithm revealed CHK1 kinase with enriched substrates and upregulated phosphorylation levels. Swine myocardial ischemia/reperfusion injury was induced by ligating the left anterior descending coronary artery for 60 minutes, and followed by reperfusion. Immediately after reperfusion, rhCHK1 protein (1mg/kg) dissolved in hydrogel or equivalent hydrogel was injected into the infarcted border zone. The therapeutic efficacy of rhCHK1 post I/R injury was evaluated by ECG, echocardiography, MRI, hematological indices and immunofluorescence. Results: Intramyocardial injection of rhCHK1-hydrogel efficiently delivered rhCHK1 to the cardiomyocytes surrounding the infarcted area of pig hearts without affecting other organs. A single administration of rhCHK1 protein (1mg/kg) prominently stimulated cardiomyocytes proliferation, reduced cardiac inflammation and improved vascularity 3 days after I/R. At 28-days post rhCHK1-hydrogel therapy, improved cardiac function, reduced infarct size and cardiac scar area, and attenuated ventricular remodeling were evidenced in I/R swine. Mechanistically, rhCHK1 stimulated CMs renewal and cardiac repair by activating mTOR/CTHRC1/P70S6K signaling pathways. Conclusion: Our study demonstrates that myocardial injection of rhCHK1 could promote cardiomyocyte proliferation, inhibit local myocardial inflammation and promote angiogenesis to facilitate myocardial repair and cardiac function after I/R injury in adult pigs through activating mTOR/CTHRC1/P70S6K signaling pathways.

Abstract 12655: Lipomatous Metaplasia in Chronic Infarcts is Associated With Prolonged Activation Recovery Interval Within Ventricular Tachycardia Corridors

Introduction: We studied the association of infarct scar versus lipomatous metaplasia (LM) with the activation recovery interval (ARI) in putative ventricular tachycardia (VT) corridors traversing the infarct zone. Methods: The cohort included 32 patients from the prospective Intra-Myocardial Fat Deposition and Ventricular Tachycardia in Ischemic Cardiomyopathy (INFINITY) study. We defined myocardial scar, border zone (BZ) and potential viable corridors through infarct by late gadolinium enhancement (LGE)-cardiac magnetic resonance (CMR), and LM by computed tomography (CT). The images were registered with electroanatomic maps wherein the ARI of each point (1,530 within LM, 4,946 within scar) was calculated using a custom Python code as the time interval from the minimum derivative within the QRS to the maximum derivative within the T wave. ARI dispersion was defined as the standard deviation (SD) of ARI per AHA segment. Multilevel random effects linear regression models, clustered by patient, were used to evaluate the association between ARI (or ARI dispersion) with tissue types. Results: LM exhibited higher myocardial ARI than normal myocardium, BZ, scar [regression coefficient: 35.5 vs. 0, 11.4, and 25.4, P &lt;0.001]. Of 100 corridors computed from LGE-CMR and electrophysiologically confirmed to participate in VT reentry, 97 traversed through or near LM, and displayed prolonged ARI compared to 123 non-critical corridors distant from LM [356 (319, 396) vs. 283 (266, 316) ms, P &lt;0.001, Figure 1]. The association of LM with Log(ARI SD ) was more robust than that of scar (likelihood ratio χ 2 47.5 vs. 23.4, and 5.9% vs. 1.6% increase in Log(ARI SD ) /1 cm 2 increase per AHA segment, respectively). Additionally, LM and scar exhibited interaction (p&lt;0.001) in their association with Log(ARI SD ). Conclusion: LM is closely associated with prolonged local action potential duration of corridors and ARI dispersion, which may facilitate the propensity of VT circuit reentry.

Abstract 14991: Local Prolongation of Repolarization Prevents Post Myocardial Infarction Ventricular Tachycardia

Introduction: Reentry is the predominant mechanism underlying ventricular arrhythmias in chronic myocardial infarction patients. Reentry can be prevented by prolonging effective refractory period, thereby blocking reexcitation of recently activated tissue. This is currently achieved with systemically administered class III antiarrhythmic drugs. These therapies are limited by their risk of provoking ventricular arrhythmias by off-target effects. Hypothesis: Local prolongation of repolarization in healthy myocardium adjacent to the exit site attenuates reentry and postinfarction arrhythmias. Method and results: We used a pig model and generated myocardial infarction by balloon occlusion of the left anterior descending coronary artery and performed epicardial mapping 6 weeks later during Langendorff-perfusion. Programmed stimulation induced reentry leading to ventricular premature beats and sustained ventricular tachycardia (VT). Local injection of Sotalol adjacent to the infarcted myocardium prolonged repolarization and prevented VT after programmed stimulation. To translate these experimental findings to the patient situation we used a virtual heart based on data from a patient suffering from postmyocardial infarction VTs. The patient underwent pre-ablation cardiac late gadolinium enhanced- magnetic resonance imaging followed by geometrical reconstruction of the left ventricle and computational electrophysiological modelling of VT induction. We used a rapid pacing protocol to induce VT and determined the site where the activation front exited the infarct zone and reactivated the adjacent normal myocardium. Next, we prolonged repolarization of the normal myocardium adjacent to the exit site with 50 ms and performed rapid pacing to induce VT. This only resulted in a single premature ventricular beat after which sinus rhythm restored. Conclusion: Our experimental and in silico findings show the potential of local prolongation of repolarization a novel potentially genetic anti-arrhythmic therapy in post-infarction patients.

Abstract 11403: Systemic Administration of High Mobility Group Box 1 Fragment Improves Cardiac Functions via Activating Tissue Healing Pathway of Bone-Marrow Mesenchymal Stem Cell in a Porcine Ischemic Cardiomyopathy Model

Introduction : Regenerative therapy for heart failure (HF) points to bone marrow mesenchymal stem cell (BM-MSC) as a promising cell source. High mobility group box 1 (HMGB1) is a nuclear protein involved in tissue homeostasis. In this study, we developed an HMGB1 fragment containing a BM-MSC mobilization domain. Hypothesis: We hypothesize that the HMGB1 fragment improves cardiac function by activating a tissue healing pathway of BM-MSC within a porcine ischemic cardiomyopathy (ICM) model as a pre-clinical study. Methods: Gottingen mini pigs weighing 15-25 kg were used. An ICM model was generated by placing an ameroid constrictor ring (internal diameter; 3.5 mm) on the left anterior descending artery (LAD). After 4 weeks, either the HMGB1 fragment (HMGB1 group; 3 mg/kg, n=6) or normal saline (control group; n=5) was administered intravenously with one dose every 48 h for five times. We examined cardiac function before and 8 weeks post treatment through echocardiography, cardiac magnetic resonance imaging (cMRI) with late gadolinium enhancement (LGE), and a fluoroscopy-guided pressure wire study. Then, histological analysis was performed. Results: In echocardiography, ejection fraction significantly improved in the HMGB1 group compared with the control (+11.1% vs -4.8%, p=0.0003). cMRI with LGE demonstrated that the areas of damaged myocardium (core infarct zone + border zone) in the LAD region was reduced in the HMGB1 group compared with the control group (-11.9% vs +17.9%, p=0.0090). Coronary flow reserve (CFR) and resistive reserve ratio (RRR) were evaluated through pressure wire study; they improved in the HMGB1 group compared with the control group (ΔCFR; +0.38 vs +0.01, p=0.0249, ΔRRR; +0.42 vs +0.07, p=0.0275). Histological analysis showed that cardiomyocyte size (26.6 μm vs 38.0 μm, p=0.0339) and areas of fibrosis were smaller (9.8% vs 11.6%, p=0.1649), and the density of CD31-positive endothelial cells was higher (1033/mm 2 vs 640/mm 2 , p=0.0339) in the HMGB1 group than in the control group. Conclusions: Systemic administration of the HMGB1 fragment improved cardiac function, coronary flow reserve, and reduced cardiac fibrosis in an ICM model. This drug-induced activation of inner tissue repair and regeneration is a novel approach to treat HF.

Abstract 15273: Impact of Lipid Lowering Therapy on Progenitor Endothelial Cell Phenotype and Function in Coronary Artery Disease

Introduction: Early revascularization of infarcted zone is crucial to improve patient′s outcomes. Despite their primary actions, major lipid-lowering drugs may also reduce cardiovascular events by pleiotropic mechanisms. Hypothesis: Conventional (statin) and novel lipid-lowering therapies [(PSCK9-inhibitor (PCSK9i) and eicosatetraenoic acid (EPA)] can improve endothelial progenitor cells (EPC) phenotype and favor neovascularization. Methods: EPC were isolated from peripheral blood of patients with acute coronary syndrome (n=62) who were statin-naïve (n=34) or chronic statin treatment (n=28) at time of inclusion. A set of statin-naïve EPC and mature endothelial cells (HUVEC) were treated in vitro with statin (20nM), PCSKi (1μM) and EPA (3μM). EPC phenotype was determined as EPC colony number and time of appearance, proliferative rate, and ability to form capillary-like structures. Serum PCSK9 and markers of angiogenesis and endothelial function were determined by multiplexed protein assay. Results: Frequency of EPC appearance was higher in samples of statin group (78%) compared to naïve group (66%) (Fig A). They also appeared much earlier (Fig B), in greater quantity (4.7 vs 2.1 colony, p = 0.0009) and had higher proliferative rate than EPCs of naïve group. Besides they had increased potential of tube formation and shaped more branched vessel-like structures (Fig C). No differences in serum levels of biomarkers were found. In vitro treatment of EPC with statin, PCSK9i and EPA did not modify colonies behavior (Fig D). PCSK9 levels showed negative correlation with EPC proliferation (r -0.4150, p=0.004), and PCSK9i treatment increased angiogenic potential of HUVEC (Fig E). Conclusions: Statin and PCSK9i have pleiotropic effects on EPC, boosting their potential to form endothelial cells colonies and to induce angiogenesis. These effects could contribute to the progression and outcomes of coronary artery disease. Funding: ISCIII - FEDER-ERDF (PI19/00264)

Abstract 11288: Conduction Velocity is Slower in Corridors Traversing Lipomatous Metaplasia Than in Corridors Traversing Scar in Chronic Infarcts

Introduction: We sought to examine the association of infarct scar versus lipomatous metaplasia (LM) with impulse conduction velocity (CV) in putative ventricular tachycardia (VT) corridors that traverse the infarct zone in patients with prior myocardial infarction (MI). Methods: The cohort included 31 patients from the prospective In tra-Myocardial F at Deposition and Ventricular Tachycardia in Ischemic Card i omyopa t h y (INFINITY) study. CV was calculated as the mean CV between that point and five adjacent points along the activation wavefront using an automated Python script in myocardial scar, border zone (BZ), and potential viable corridors defined by late gadolinium enhancement (LGE)-cardiac magnetic resonance (CMR), and LM identified by computed tomography (CT). Both image sets were registered with electroanatomic maps (EAM). Results: Regions with LM exhibited lower myocardial CV than scar (median 12.0 vs. 13.5 cm/s, P &lt;0.001). Of 96 corridors computed from LGE-CMR and electrophysiologically confirmed to participate in VT reentry, 95 traversed through or near LM identified on CT. These critical corridors displayed slower CV {median 8.8 [interquartile range (IQR) 6.0, 15.4] vs. 39.0 (IQR 27.8, 56.5) cm/s, P &lt;0.001, Figure 1}, and demonstrated low-peripheral-high-center (mountain-shaped, 25%), or mean low level (45.7%) CV patterns, when compared to 122 non-critical corridors distant from LM that displayed high-peripheral-low-center (valley-shaped, 20.5%) or mean high level (59%) CV patterns. Conclusion: Myocardial LM is a crucial contributor to VT propensity. Corridors traversing through or near LM exhibit significantly slower CV, which likely facilitate the presence and stability of the VT circuit reentry.