Similar Infarct Size Research Articles

Delayed Reperfusion-Coronary Artery Reperfusion Close to Complete Myocardial Necrosis Benefits Remote Myocardium and Is Enhanced by Exercise.

The present study aimed to analyze the effects of reperfusion of a distant coronary artery on cardiac function, the ultrastructure, and the molecular environment of the remote myocardium immediately after the completion of myocardial regional necrosis: delayed reperfusion (DR). Additionally, the effects of prior exercise on the outcomes of DR were investigated. Female rats with permanent occlusion or delayed reperfusion were randomly assigned to an exercise (swimming, 1 h/day, 5 days/week for 8 weeks) or sedentary protocol. Thus, the study included the following four groups: sedentary permanent occlusion, exercise permanent occlusion, sedentary delayed reperfusion, and exercise delayed reperfusion. The descending coronary artery was occluded for 1 h. Reperfusion was confirmed by contrast echocardiography, and the rats were observed for 4 weeks. Permanent occlusion and DR caused similar myocardial infarction sizes among the four groups. Interestingly, exercise significantly decreased the mortality rate. Delayed reperfusion resulted in significant benefits, including enhanced hemodynamics and papillary muscle contraction, as well as reduced apoptosis and collagen content. Protein calcium kinetics did not change. Meanwhile, developed tension and the Frank–Starling mechanism were enhanced, suggesting that calcium sensitivity was intensified in myofilaments. Remarkable remote myocardial benefits occurred after distant DR, and prior exercise intensified cardiac recovery. Our findings provide valuable information about DR. Our data might explain the better clinical outcomes in recent studies showing that late reperfusion could improve heart failure in patients with myocardial infarction. In conclusion, DR has remote myocardial benefits, including inotropism enhancement, pulmonary congestion reduction, and collagen and apoptosis attenuation, which are enhanced by prior exercise.

Estimation of Acute Infarct Volume with Reference Maps: A Simple Visual Tool for Decision Making in Thrombectomy Cases.

Background and PurposeThrombectomy within 24 hours can improve outcomes in selected patients with a clinical-infarct mismatch. We devised an easy-to-use visual estimation tool that allows infarct volume estimation in centers with limited resources. MethodsWe identified 1,031 patients with cardioembolic or large-artery atherosclerosis infarction on diffusion-weighted images (DWIs) obtained before recanalization therapy and within 24 hours of onset, and occlusion of the internal carotid or middle cerebral artery. Acute DWIs were mapped onto a standard template and used to create visual reference maps with known lesion volumes, which were then used in a validation study (with 130 cases) against software estimates of infarct volume. ResultsThe DWI reference map chart comprises 144 maps corresponding to 12 different infarct volumes (0.5, 1, 2, 3, 5, 7, 9, 11, 13, 15, 17, and 19 mL) in each of 12 template slices (Montreal Neurological Institute z-axis –15 to 51 mm). Infarct volume in a patient is estimated by selecting a slice with a similar infarct size at the corresponding z-axis level on the reference maps and then adding up over all slices. The method yielded good correlations to software volumetrics and was easily learned by both experienced and junior physicians, with approximately 1 to 2 minutes spent per case. The sensitivity, specificity, and accuracy for detecting threshold infarct volumes (<21, <31, and <51 mL) were very high (all about >90%). ConclusionsWe developed easy-to-use reference maps that allow prompt and reliable visual estimation of infarct volumes for triaging patients to thrombectomy in acute stroke.

Brain renin-angiotensin system blockade with orally active aminopeptidase A inhibitor prevents cardiac dysfunction after myocardial infarction in mice

Brain renin-angiotensin system (RAS) hyperactivity has been implicated in sympathetic hyperactivity and progressive left ventricular (LV) dysfunction after myocardial infarction (MI). Angiotensin III, generated by aminopeptidase A (APA), is one of the main effector peptides of the brain RAS in the control of cardiac function. We hypothesized that orally administered firibastat (previously named RB150), an APA inhibitor prodrug, would attenuate heart failure (HF) development after MI in mice, by blocking brain RAS hyperactivity. Two days after MI, adult male CD1 mice were randomized to three groups, for four to eight weeks of oral treatment with vehicle (MI + vehicle), firibastat (150 mg/kg; MI + firibastat) or the angiotensin I converting enzyme inhibitor enalapril (1 mg/kg; MI + enalapril) as a positive control. From one to four weeks post-MI, brain APA hyperactivity occurred, contributing to brain RAS hyperactivity. Firibastat treatment normalized brain APA hyperactivity, with a return to the control values measured in sham group two weeks after MI. Four and six weeks after MI, MI + firibastat mice had a significant lower LV end-diastolic pressure, LV end-systolic diameter and volume, and a higher LV ejection fraction than MI + vehicle mice. Moreover, the mRNA levels of biomarkers of HF (Myh7, Bnp and Anf) were significantly lower following firibastat treatment. For a similar infarct size, the peri-infarct area of MI + firibastat mice displayed lower levels of mRNA for Ctgf and collagen types I and III (markers of fibrosis) than MI + vehicle mice. Thus, chronic oral firibastat administration after MI in mice prevents cardiac dysfunction by normalizing brain APA hyperactivity, and attenuates cardiac hypertrophy and fibrosis.

Abstract 16750: Angiogenesis/Arteriogenesis, the Mechanism for Cardioprotection, in Secreted Frizzled Related Protein 2 Transgenic Mice

Secreted frizzled related protein 2 (sFRP2) has been shown to protect against myocardial ischemia primarily mediated by reducing fibrosis. Our hypothesis is that sFRP2 myocardial ischemic protection induced by permanent coronary artery occlusion (CAO) must involve a primary angiogenesis/arteriogenesis mechanism in order to protect the heart in the chronic absence of blood flow. To test this hypothesis, we induced permanent CAO for 1 week in cardiac specific sFRP2 transgenic (TG) mice (n=12), which exhibited reduced infarct size vs. their wild type littermates (WTL; n=13) (16±1 vs. 25±2%) and improved left ventricular ejection fraction (LVEF) (61±6 vs. 45±6%). These salutary effects were accompanied by angiogenesis (170% increase in capillary proliferation and a 54% increase in capillary density) and arteriogenesis (106% increase in arteriole proliferation). sFRP2 increased in vitro tubule formation in HUVEC cells by 46% (p&lt;0.05), compared to vehicle. As expected, sFRP2 TG mice also exhibited decreased remote fibrosis, compared to WTL (1.6±0.1 vs.± 3.7±0.3%; n=4-6/group). ATF6, an ER stress response transcription factor, was upregulated in sFRP2 TG mice. When ATF6 was blocked with AEBSF, sFRP2 TG mice no longer demonstrated cardioprotection with permanent CAO, as reflected by similar infarct size, LV EF, capillary and arteriolar proliferation observed in WTL. cTGF, a pro-angiogenic factor, was also upregulated in sFRP2 TG mice. Blocking cTGF with a cTGF antibody, eliminated the increased tubule formation with sFRP2 treatment. AEBSF also eliminated the increased cTGF in sFRP2 TG, confirming ATF6 as the upstream regulator of cTGF, responsible for the angiogenesis and arteriogenesis observed in the sFRP2 TG mice. To determine if angiogenesis/arteriogenesis was the initiating mechanism inducing cardioprotection, blood flow, measured ultrasonically at 1 day following CAO, was increased significantly more, p&lt;0.05, in the ischemic zone of sFRP2 TG mice (2.1±0.46 A.U.) compared with blood flow in WTL (0.4 ±0.09 A.U.). Thus, angiogenesis/arteriogenesis appears to be the primary cardioprotective mechanism induced by sFRP2, with reduced fibrosis playing a secondary role.

The factor Xa inhibitor rivaroxaban reduces cardiac dysfunction in a mouse model of myocardial infarction

IntroductionRivaroxaban selectively inhibits factor Xa (FXa), which plays a central role in blood coagulation. In addition, FXa activates protease-activated receptor-2 (PAR-2). We have shown that PAR-2−/− mice exhibit less cardiac dysfunction after cardiac injury. Material and methodsWild-type (WT) and PAR-2−/− mice were subjected to left anterior descending artery (LAD) ligation to induce cardiac injury and heart failure. Mice received either placebo or rivaroxaban chow either starting at the time of surgery or 3 days after surgery and continued up to 28 days. Cardiac function was measured by echocardiography pre-surgery and 3, 7 and 28 days after LAD ligation. We also measured anticoagulation, intravascular thrombi, infarct size, cardiac hypertrophy and inflammation at various times. ResultsRivaroxaban increased the prothrombin time and inhibited the formation of intravascular thrombi in mice subjected to LAD ligation. WT mice receiving rivaroxaban immediately after surgery had similar infarct sizes at day 1 as controls but exhibited significantly less impairment of cardiac function at day 3 and beyond compared to the placebo group. Rivaroxaban also inhibited the expansion of the infarct at day 28. Rivaroxaban did not significantly affect the expression of inflammatory mediators or a neutrophil marker at day 2 after LAD ligation. Delaying the start of rivaroxaban administration until 3 days after surgery failed to preserve cardiac function. In addition, rivaroxaban did not reduce cardiac dysfunction in PAR-2−/− mice. ConclusionsEarly administration of rivaroxaban preserves cardiac function in mice after LAD ligation.

Cardioprotection induced by a brief exposure to acetaldehyde: role of aldehyde dehydrogenase 2.

We previously demonstrated that acute ethanol administration protects the heart from ischaemia/reperfusion (I/R) injury thorough activation of aldehyde dehydrogenase 2 (ALDH2). Here, we characterized the role of acetaldehyde, an intermediate product from ethanol metabolism, and its metabolizing enzyme, ALDH2, in an ex vivo model of cardiac I/R injury. We used a combination of homozygous knock-in mice (ALDH2*2), carrying the human inactivating point mutation ALDH2 (E487K), and a direct activator of ALDH2, Alda-1, to investigate the cardiac effect of acetaldehyde. The ALDH2*2 mice have impaired acetaldehyde clearance, recapitulating the human phenotype. Yet, we found a similar infarct size in wild type (WT) and ALDH2*2 mice. Similar to ethanol-induced preconditioning, pre-treatment with 50 μM acetaldehyde increased ALDH2 activity and reduced cardiac injury in hearts of WT mice without affecting cardiac acetaldehyde levels. However, acetaldehyde pre-treatment of hearts of ALDH2*2 mice resulted in a three-fold increase in cardiac acetaldehyde levels and exacerbated I/R injury. Therefore, exogenous acetaldehyde appears to have a bimodal effect in I/R, depending on the ALDH2 genotype. Further supporting an ALDH2 role in cardiac preconditioning, pharmacological ALDH2 inhibition abolished ethanol-induced cardioprotection in hearts of WT mice, whereas a selective activator, Alda-1, protected ALDH2*2 against ethanol-induced cardiotoxicity. Finally, either genetic or pharmacological inhibition of ALDH2 mitigated ischaemic preconditioning. Taken together, our findings suggest that low levels of acetaldehyde are cardioprotective whereas high levels are damaging in an ex vivo model of I/R injury and that ALDH2 is a major, but not the only, regulator of cardiac acetaldehyde levels and protection from I/R.

Prognostic significance of QRS fragmentation and correlation with infarct size in patients with anterior ST-segment elevation myocardial infarction treated with percutaneous coronary intervention: Insights from the INFUSE-AMI trial

BackgroundQRS fragmentation (fQRS) is believed to reflect myocardial scar formation in patients with coronary disease. Whether early formation of fQRS in patients with ST-segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) is correlated with infarct size and prognosis is unknown. We assessed the prognostic value of fQRS at 60min post-PCI and its correlation with infarct size in patients with anterior STEMI managed with primary PCI. MethodsThe INFUSE-AMI trial enrolled 452 patients with anterior STEMI undergoing primary PCI. Electrocardiograms (ECGs) were performed at baseline and 60min post-PCI. Infarct size was evaluated using cardiac magnetic resonance imaging at 30days post-PCI. Target vessel failure (TVF) was defined as the composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target vessel revascularization. Study groups were defined as patients with versus without fQRS at 60min post-PCI. ResultsOut of 421 patients with ECG data 60min post-PCI, 68 patients (16.2%) had fQRS. Patients with versus without fQRS had similar baseline characteristics and infarct size (16.9%±8.7% vs. 16.1%±10.5%, p=0.62), but patients with fQRS had higher adjusted risk of 1-year TVF (adjusted HR 2.27, 95% CI 1.06–4.89, p=0.036) and a trend toward a higher risk of the composite cardiac death or target vessel myocardial infarction (9.0% vs. 4.1%, p=0.08) at 1year. ConclusionfQRS in patients with STEMI is associated with TVF but does not correlate with infarct size.

Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho-kinase signalling in infarcted rats.

We have demonstrated that ATP‐sensitive potassium (KATP) channel agonists attenuated fibrosis; however, the mechanism remained unclear. Since RhoA has been identified as a mediator of cardiac fibrosis, we sought to determine whether the anti‐fibrotic effects of KATP channel agonists were mediated via regulating macrophage phenotype and fibroblast differentiation by a RhoA/RhoA‐kinase‐dependent pathway. Wistar male rats after induction of myocardial infarction were randomized to either vehicle, nicorandil, an antagonist of KATP channel glibenclamide, an antagonist of ROCK fasudil, or a combination of nicorandil and glibenclamide or fasudil and glibenclamide starting 24 hrs after infarction. There were similar infarct sizes among the infarcted groups. At day 3 after infarction, post‐infarction was associated with increased RhoA/ROCK activation, which can be inhibited by administering nicorandil. Nicorandil significantly increased myocardial IL‐10 levels and the percentage of regulatory M2 macrophages assessed by immunohistochemical staining, Western blot, and RT‐PCR compared with vehicle. An IL‐10 receptor antibody increased myofibroblast infiltration compared with nicorandil alone. At day 28 after infarction, nicorandil was associated with attenuated cardiac fibrosis. These effects of nicorandil were functionally translated in improved echocardiographically derived cardiac performance. Fasudil showed similarly increased expression of M2 macrophages as nicorandil. The beneficial effects of nicorandil on fibroblast differentiation were blocked by adding glibenclamide. However, glibenclamide cannot abolish the attenuated fibrosis of fasudil, implying that RhoA/RhoA‐kinase is a downstream effector of KATP channel activation. Nicorandil polarized macrophages into M2 phenotype by inhibiting RhoA/RhoA‐kinase pathway, which leads to attenuated myofibroblast‐induced cardiac fibrosis after myocardial infarction.

Lack of Contribution of p66shc and Its Mitochondrial Translocation to Ischemia-Reperfusion Injury and Cardioprotection by Ischemic Preconditioning.

Whereas high amounts of reactive oxygen species (ROS) contribute to cardiac damage following ischemia and reperfusion (IR), low amounts function as trigger molecules in the cardioprotection by ischemic preconditioning (IPC). The mitochondrial translocation and contribution of the hydrogen peroxide-generating protein p66shc in the cardioprotection by IPC is unclear yet. In the present study, we investigated the mitochondrial translocation of p66shc, addressed the impact of p66shc on ROS formation after IR, and characterized the role of p66shc in IR injury per se and in the cardioprotection by IPC. The amount of p66shc in subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) isolated from wildtype mouse left ventricles (LV) was determined after 40 min normoxic perfusion and after 30 min ischemia and 10 min reperfusion without and with IPC. The p66shc content in SSM (in % of normoxic controls, n = 5) was 174 ± 16% (n = 6, p < 0.05) after IR, and was reduced to 128 ± 13% after IPC (n = 6, p = ns). In IFM, the amount of p66shc remained unchanged (IR: 81 ± 7%, n = 6; IPC: 110 ± 5%, n = 6, p = ns). IR induced an increase in ROS formation in SSM and IFM isolated from mouse wildtype LV, which was more pronounced in SSM than in IFM (1.18 ± 0.18 vs. 0.81 ± 0.16, n = 6, p < 0.05). In mitochondria from p66shc-knockout mice (p66shc-KO), the increase in ROS formation by IR was not different between SSM and IFM (0.90 ± 0.11 vs. 0.73 ± 0.08, n = 6, p = ns). Infarct size (in % of the left ventricle) was 51.7 ± 2.9% in wildtype and 59.7 ± 3.8% in p66shc-KO hearts in vitro and was significantly reduced to 35.8 ± 4.4% (wildtype) and 34.7 ± 5.6% (p66shc-KO) by IPC, respectively. In vivo, infarct size was 57.8 ± 2.9% following IR (n = 9) and was reduced to 40.3 ± 3.5% by IPC (n = 11, p < 0.05) in wildtype mice. In p66shc-knockout mice, infarct sizes were similar to those measured in wildtype animals (IR: 56.2 ± 4.3%, n = 11; IPC: 42.1 ± 3.9%, n = 13, p < 0.05). Taken together, the mitochondrial translocation of p66shc following IR and IPC differs between mitochondrial populations. However, similar infarct sizes after IR and preserved infarct size reductions by IPC in p66shc-KO mice suggest that p66shc-derived ROS are not involved in the cardioprotection by IPC nor do they contribute to IR injury per se.

Abstract 299: Cardioprotection from Ischemia/Reperfusion Injury by β-Arrestin-Biased β2-Adrenergic Receptor Activation

β-Adrenergic receptors (βAR) are important regulators of cardiac function in the normal and failing heart. Activation of the β1AR subtype increases contractility and cardiomyocyte death whereas the β2AR can promote survival. In response to cardiac injury, increased catecholamines activate and downregulate β1AR thus, β-adrenergic receptor antagonists or β-blockers are commonly prescribed in to restore β1AR expression and preserve contractility. However, promoting the pro-survival effects of β2AR, which are known to occur in part through β-arrestin (ARR)-dependent signaling, may be a beneficial therapeutic strategy. Pepducins have been developed based on the intracellular loop (ICL) domains of β2AR to activate either Gαs- or βARR-dependent β2AR signaling pathways. We hypothesized that pepducin-mediated engagement of βARR-dependent β2AR signaling in the heart would be therapeutically advantageous following ischemia/reperfusion (I/R) injury. To test this, wild-type (WT) C57BL/6 mice received three intracardiac injections of either a βARR-biased pepducin (ICL1-9) or a scrambled control pepducin at the time of ischemia (30 min) followed by reperfusion. Assessment of cardiomyocyte death 24h post-I/R using TUNEL staining showed a decrease in cell death in animals treated with ICL1-9 when compared to scrambled pepducin, correlating with decreased infarct size and improved cardiac function as measured by echocardiography. Assessment of cardiac function at later time points showed that the cardioprotective effects of ICL1-9 were preserved over time and resulted in decreased cardiac remodeling. Although βARR1KO mice displayed similar cell death, infarct size, and contractility changes following I/R as their WT counterparts, they did not manifest a cardioprotective response from ICL1-9 treatment, indicating that βARR signaling is essential in relaying ICL1-9-dependent cardioprotection. These results demonstrate that pharmacologically-mediated activation of βARR-biased β2AR signaling provides a therapeutic benefit in the context of I/R-induced injury and may provide an improved strategy for the treatment of acute cardiac injury.

9-cis retinoic acid induces neurorepair in stroke brain

The purpose of this study was to examine the neurorestorative effect of delayed 9 cis retinoic acid (9cRA) treatment for stroke. Adult male rats received a 90-min right distal middle cerebral artery occlusion (dMCAo). Animals were separated into two groups with similar infarction sizes, based on magnetic resonance imaging on day 2 after dMCAo. 9cRA or vehicle was given via an intranasal route daily starting from day 3. Stroke rats receiving 9cRA post-treatment showed an increase in brain 9cRA levels and greater recovery in motor function. 9cRA enhanced the proliferation of bromodeoxyuridine (+) cells in the subventricular zone (SVZ) and lesioned cortex in the stroke brain. Using subventricular neurosphere and matrigel cultures, we demonstrated that proliferation and migration of SVZ neuroprogenitor cells were enhanced by 9cRA. Our data support a delayed and non-invasive drug therapy for stroke. Intranasal 9cRA can facilitate the functional recovery and endogenous repair in the ischemic brain.

Abstract WP119: Transcriptome Analysis of Motor Cortex Network Responses in Spontaneously Recovered Stroke Mice

Introduction: Spontaneous recovery after stroke occurs in both human and animals. However, the underlying molecular mechanisms driving spontaneous recovery are still unclear. This study investigates the molecular mechanisms driving spontaneous recovery after unilateral experimental stroke using RNA sequencing (RNAseq). Methods: Ischemic stroke was induced in C57BL/6J adult male mice by transient MCAO. Neurological score, vertical pole, and rotating horizontal beam test were performed at baseline and post stroke days (PD) 4, 8, and 14. All mice were sacrificed at PD15 and processed for immunohistochemistry or Hi-seq. Infarcts were visualized by T2WI at PD2 using 7T MR scanner or histology at PD15. All stroke mice included in the study have comparable cortico-striatal infarcts and exhibit similar prestroke baseline performance and PD4 deficits. These mice were further categorized into spontaneously recovered and non-recovered groups based on their rotating beam performance during recovery. Results: Out of 35 stroke mice with abovementioned similar conditions, 9 (26%) were categorized into spontaneously recovered group and 26 (74%) were categorized into non-recovered group. Hierarchical clustering analysis supported this categorization. At PD14, the spontaneously recovered group exhibited significant improvement in beam performance in distance traveled and speed (p&lt;0.001). Using Ingenuity Pathway Analysis, the comparison of RNAseq transcriptome between ipsilesional and contralesional primary motor cortex (iM1 and cM1) in spontaneously recovered and non-recovered stroke mice revealed significant differential molecular pathways, including glutamate, calcium, and neurotrophin signaling pathways. Conclusions: Our study demonstrates that stroke mice with similar cortico-striatal infarct size can exhibit significant differences in their behavioral recovery outcome. The transcriptome profile in iM1-cM1 network at 2 weeks post-stroke highlighted several molecular pathways that were significantly different between spontaneously recovered and non-recovered mice. Validation of key molecular candidates from the RNAseq data would provide insights into the molecular mechanisms mediating spontaneous recovery after stroke.

Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts

During myocardial infarction, infiltrated macrophages have pivotal roles in cardiac remodeling and delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3-dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I-201 (a STAT3 inhibitor), or phlorizin + S3I-201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post-infarction was associated with increased levels of superoxide and nitrotyrosine, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Although phlorizin decreased myofibroblast infiltration, the effect of dapagliflozin on attenuated myofibroblast infiltration was significantly higher than phlorizin. The effects of SGLT2 inhibitors on cardiac fibrosis were nullified by adding S3I-201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL-10 levels can be reversed by 3-morpholinosydnonimine, a peroxynitrite generator. Taken together, these observations provide a novel mechanism of SGLT2 inhibitors-mediated M2 polarization through a RONS-dependent STAT3-mediated pathway and selective SGLT2 inhibitors are more effective in attenuating myofibroblast infiltration during postinfarction remodeling.

Abstract 12654: PBI-4050 Therapy Selectively Improves Pulmonary Hypertension, Lung Remodeling and Right Ventricular Function in Heart Failure With Reduced Ejection Fraction

Introduction: There is currently no approved treatment for the most prevalent form of PH that is associated with left heart disease (Group II PH). Heart failure with reduced ejection fraction (HFrEF) causes lung remodeling characterized by myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome contributing to PH and RV dysfunction. Hypothesis: We evaluated PBI-4050, a novel first-in-class agent with anti-fibrotic and anti-proliferative actions, for the treatment of PH in a model of HFrEF. Methods: HFrEF was induced by myocardial infarction (MI) after coronary artery ligation in rats. Two weeks after surgery, sham-operated and MI groups were treated with PBI-4050 (200 mg/kg/day by gavage) or with saline for 3 weeks. Animals were analyzed according to pathological infarct size into large MI (≥35% LV) and small to medium MI (&lt; 35%). Hemodynamic evaluation was performed with microtip cathethers and lung function testing evaluated with a Flexivent respirator. Cardiac ultrasound was performed at 2 weeks and at 5 weeks. Scar size and lung fibrosis were quantified by histology. Results: Pathological infarct size correlated with echocardiographic wall motion score index (r 2 =0.73, p&lt;0.001). Large MI (≥35% LV) resulted in PH and RVH with a restrictive lung syndrome. For a similar infarct size, PBI-4050 did not affect LV function but markedly reduced PH and RVH. The compensatory increase in RV contractility was normalized by PBI-4050. PBI-4050 reduced lung remodeling evidenced by a reduction in lung weight and improved respiratory compliance. Finally, lung fibrosis was reduced by PBI-4050 with histological evidence of reduced alveolar wall cellular proliferation. Conclusions: PBI-4050 effectively reduces PH and RVH in HFrEF by reducing lung fibrosis and remodeling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function without affecting LV function. PBI-4050 is a promising therapy for group II PH.

Impact of Non-Infarct-Related Artery Disease on Infarct Size and Outcomes (from the CRISP-AMI Trial)

BackgroundNon-infarct-related artery (non-IRA) disease is prevalent in patients with ST-segment elevation myocardial infarction (STEMI). We aimed to assess the impact of non-IRA disease on infarct size and clinical outcomes in patients with acute STEMI. MethodsThe Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP-AMI) trial randomized patients to intra-aortic balloon counterpulsation (IABC) vs no IABC prior to percutaneous coronary intervention in patients with acute STEMI. Infarct size (% left ventricular mass) at 3-5 days post percutaneous coronary intervention and 6-month clinical outcomes were compared between patients with and without non-IRA disease (defined as ≥50% stenosis in at least one non-IRA). ResultsA total of 324 (96.1%) patients had anterior STEMI, of whom 34.9% had non-IRA disease. There was no difference in infarct size (% left ventricular mass) between patients with and without non-IRA disease (median 39% vs 39%; P = .73). At 6 months, there was no difference in rates of recurrent myocardial infarction (0.9% vs 0.9%; P = .78), major Thrombolysis In Myocardial Infarction bleeding (0.9% vs 0.5%; P = .77), or all-cause death (3.5% vs 2.4%; P = .61) in patients with and without non-IRA disease, respectively. Patients with non-IRA disease had a higher rate of new/worsening heart failure with hospitalization (8.8% vs 1.9%; P = .0050). ConclusionsMore than one-third of patients with anterior STEMI in the CRISP-AMI study had non-IRA disease. These patients had similar infarct sizes and rates of recurrent myocardial infarction, major bleeding, and all-cause death. Patients with non-IRA disease did have a higher rate of new/worsening heart failure with hospitalization. Further study is needed to understand the mechanisms of outcomes of patients with non-IRA disease.

Functional Effects of Delivering Human Mesenchymal Stem Cell-Seeded Biological Sutures to an Infarcted Heart.

Stem cell therapy has the potential to improve cardiac function after myocardial infarction (MI); however, existing methods to deliver cells to the myocardium, including intramyocardial injection, suffer from low engraftment rates. In this study, we used a rat model of acute MI to assess the effects of human mesenchymal stem cell (hMSC)-seeded fibrin biological sutures on cardiac function at 1 week after implant. Biological sutures were seeded with quantum dot (Qdot)-loaded hMSCs for 24 h before implantation. At 1 week postinfarct, the heart was imaged to assess mechanical function in the infarct region. Regional parameters assessed were regional stroke work (RSW) and systolic area of contraction (SAC) and global parameters derived from the pressure waveform. MI (n = 6) significantly decreased RSW (0.026 ± 0.011) and SAC (0.022 ± 0.015) when compared with sham operation (RSW: 0.141 ± 0.009; SAC: 0.166 ± 0.005, n = 6) (p < 0.05). The delivery of unseeded biological sutures to the infarcted hearts did not change regional mechanical function compared with the infarcted hearts (RSW: 0.032 ± 0.004, SAC: 0.037 ± 0.008, n = 6). The delivery of hMSC-seeded sutures exerted a trend toward increase of regional mechanical function compared with the infarcted heart (RSW: 0.057 ± 0.011; SAC: 0.051 ± 0.014, n = 6). Global function showed no significant differences between any group (p > 0.05); however, there was a trend toward improved function with the addition of either unseeded or seeded biological suture. Histology demonstrated that Qdot-loaded hMSCs remained present in the infarcted myocardium after 1 week. Analysis of serial sections of Masson's trichrome staining revealed that the greatest infarct size was in the infarct group (7.0% ± 2.2%), where unseeded (3.8% ± 0.6%) and hMSC-seeded (3.7% ± 0.8%) suture groups maintained similar infarct sizes. Furthermore, the remaining suture area was significantly decreased in the unseeded group compared with that in the hMSC-seeded group (p < 0.05). This study demonstrated that hMSC-seeded biological sutures are a method to deliver cells to the infarcted myocardium and have treatment potential.

Post-treatment with cocaine- and amphetamine-regulated transcript enhances infarct resolution, reinnervation, and angiogenesis in stroke rats - an MRI study.

Recent studies have shown that post-treatment with cocaine- and amphetamine-regulated transcript (CART) has neuroregenerative effects in animal models of stroke. The purpose of this study was to characterize CART-mediated neuronal and vascular repairments using non-invasive MRI techniques. Adult male rats were subjected to a 90 min middle cerebral artery occlusion (MCAo). Animals were separated into two groups with similar infarction sizes, measured by T2 -weighted MRI on Day 2 after MCAo, and were treated with CART or vehicle intranasally from Day 3 to Day 12. Diffusion tensor imaging was used to examine changes in plasticity of white matter elements. Susceptibility-weighted imaging (SWI) was used to measure angiogenesis. Post-treatment with CART significantly increased fractional anisotropy (FA) in lesioned cortex on Days 10 and 25 post stroke. A significant correlation between the behavioral recovery in body asymmetry and the change in FA was shown, suggesting that behavioral recovery was associated with reinnervation to the lesioned hemisphere. CART also increased the intensity of SWI and the immunoreactivity of the vascular marker alpha-smooth muscle actin in lesioned cortex. Together, our data support a non-invasive treatment strategy for stroke through angiogenesis and reinnervation by CART. Copyright © 2016 John Wiley & Sons, Ltd.

Abstract 14122: Myeloid Cell mPGES-1 Depletion Attenuates Mortality After Myocardial Infarction in Mice

Selective depletion of microsomal PGE2 synthase (mPGES) -1 in myeloid cells retards atherogenesis and suppresses the vascular proliferative response to injury, while it does not predispose to thrombogenesis or hypertension. However, studies using bone marrow transplants from irradiated mice suggest that myeloid cell mPGES-1 facilitates cardiac remodeling and prolongs survival after experimental myocardial infarction (MI). Here we addressed this question using mice lacking mPGES-1 in myeloid cells, particularly macrophages (Mac-mPGES-1 KO), generated by crossing mPGES-1 floxed mice with LysMCre mice, and subjecting them to coronary artery ligation. Cardiac structure and function were assessed by morphometric analysis, echocardiography, and invasive hemodynamics 7 and 28 days after MI. Despite a similar infarct size, in contrast to the prior report, the post-MI survival rate was markedly improved in the Mac-mPGES-1 KO mice compared to WT controls (92.9% vs. 55.6%, p=0.03). Left ventricular systolic (reflected by ejection fraction, fractional shortening, end systolic pressure, and +dP/dt) and diastolic function (reflected by end diastolic pressure, -dP/dt, and Tau), cardiac hypertrophy (reflected by LV dimensions) and staining for fibrosis did not differ between the groups. In conclusion, Cre-loxP mediated deletion of mPGES-1 in myeloid cells has favorable effects on post-MI survival, with no detectable adverse influence on post-MI remodeling. These results add to evidence that targeting macrophage mPGES-1 may represent a safe and efficacious approach to the treatment and prevention of cardiovascular inflammatory disease.

Abstract 9950: Patients With Depressive Symptoms Experienced Substantial Adverse Cardiac Remodeling After Myocardial Infarction

Background: Mechanisms underlying post-MI depression and cardiac events in CAD patients remain poorly understood. The OMEGA-REMODEL Study is a randomized double-blind trial assessing for any benefical effects of post-MI LV remodeling by high-dose Omega-3 fatty acids (n-3 FAs). As a post-hoc analysis, we tested the hypothesis that patients with higher depression scores experienced more severe adverse post-MI remodeling. Methods: 358 patients with acute MI were randomized to placebo or 4g/d n-3 FAs with 2-4 weeks post-MI. All patients underwent Hamilton Depression Scale, cardiac MRI, inflammatory biomarkers, and red cell n-3 index at baseline and after 6 months of study drug. Patients were stratified by median depression score as DEP and non-DEP. Results: Demographics and baseline LV measurements are shown in Table 1. N-3 FAs assignment resulted in significant improvement in LVESV compared to placebo. Compared to patients without DEP at baseline, those with DEP had slightly smaller LVEDV but similar LVESV, LVEF and infarct size. However, patients with DEP experienced marked expansion of LVEDV and LVESV compared to patients without DEP during the 6 months study period (P=0.007 and 0.02, respectively). N-3 FAs appeared to benefit LV remodeling of patients with or without DEP. Inflammatory markers did not correlate with the severity of the adverse LV remodeling. Conclusion: In conclusion, patients with DEP were substantially more likely to experience adverse cardiac remodeling which may account for the adverse cardiac outcomes of post MI depression. Table 1: Baseline Features and Changes in Cardiac Parameters

Abstract 18200: Intracoronary Delivery of Bioabsorbable Alginate Matrix (IK-5001) Ameliorates Adverse Post-infarction Left Ventricular Remodeling and Improves Left Ventricular Function in a Porcine Model of Reperfused Myocardial Infarction

Background: Adverse cardiac remodeling after MI is associated with excessive degradation of the extracellular matrix (ECM). IK-5001 is a low viscosity injectable solution that provides the polysaccharide alginate. After intracoronary injection into the MI area it undergoes phase transition forming a hydrogel which can support the ECM. We hypothesized that administration of alginate post-MI would provide a temporary scaffold and attenuate adverse LV remodeling. Methods: Acute MI was induced in 16 pigs by balloon occlusion of the proximal LAD for 2 hours. Animals randomly received intracoronary alginate or saline 4 days post-MI. LV function and remodeling were evaluated with cardiac MRI, 3D-echo and pressure-volume loops at 1 and 2 months post-MI. Histology and Western blot analysis were performed after 2 months. Results: Both groups had similar LVEF and infarct size 4 days post-MI. Coronary angiography immediately after alginate injection showed no impairment in coronary flow. However, 2 months post-MI, alginate-treated pigs exhibited reduced LV remodeling compared with controls demonstrated by reduced LV end-systolic volume, LV mass and sphericity (Table). Alginate-treated pigs had less cardiomyocyte hypertrophy and decreased interstitial fibrosis. Consistent with this, chronic activation of Akt and ERK was reduced. Alginate pigs also showed lower plasma levels of BNP and aldosterone. Interestingly, after 2 months, alginate pigs showed better systolic LV function: higher LVEF, better contractile reserve with dobutamine, and higher dP/dt. Conclusions: Intracoronary administration of alginate ameliorates adverse post-MI LV remodeling at the anatomical, histological and molecular level, and mitigates neurohormonal activation in a porcine model of MI. Alginate also improves systolic LV function. Intracoronary injection of alginate represents an exciting novel treatment option to reduce post-MI remodeling that merits assessment in clinical studies.