Similar Infarct Size Research Articles

Endogenous complement 1q binding protein (C1qbp) regulates mitochondrial permeability transition and post-myocardial infarction remodeling and dysfunction

The mitochondrial permeability transition (MPT) pore regulates necrotic cell death following diverse cardiac insults. While the componentry of the pore itself remains controversial, Cyclophilin D (CypD) has been well-established as a positive regulator of pore opening. We have previously identified Complement 1q-binding protein (C1qbp) as a novel CypD-interacting molecule and a negative regulator of MPT-dependent cell death in vitro. However, its effects on the MPT pore and sensitivity to cell death in the heart remain untested. We therefore hypothesized that C1qbp would inhibit MPT in cardiac mitochondria and protect cardiac myocytes against cell death in vivo. To investigate the effects of C1qbp in the myocardium we generated gain- and loss-of-function mice. Transgenic C1qbp overexpression resulted in decreased complex protein expression and reduced mitochondrial respiration and ATP production but MPT was unaffected. In contrast, while C1qbp+/− mice did not exhibit any changes in mitochondrial protein expression, respiration, or ATP, the MPT pore was markedly sensitized to Ca2+ in these animals. Neither overexpression nor depletion of C1qbp significantly affected baseline heart morphology or function at 3 months of age. When subjected to myocardial infarction, C1qbp transgenic mice exhibited similar infarct sizes and cardiac remodeling to non-transgenic mice, consistent with the lack of an effect on MPT. In contrast, cardiac scar formation and dysfunction were significantly increased in the C1qbp+/− mice compared to C1qbp+/+ controls. Our results suggest that C1qbp is required for normal regulation of the MPT pore and mitochondrial function, and influences cardiac remodeling following MI, the latter more likely being independent of C1qbp effects on the MPT pore.

Exacerbated cardiac dysfunction after myocardial infarction in offspring from obese parents

The prevalence of obesity in women of reproductive age is increasing rapidly, and children from obese mothers are at higher risk of developing cardiovascular diseases in adulthood. Acute myocardial infarction (MI) is one of the leading causes of death worldwide with more than one million deaths per year in the U.S. alone. Using a model of parental obesity with male and female Sprague-Dawley rats fed a high fat diet (HFD) prior to mating, and dams maintained on the HFD during gestation and lactation, we found that male and female offspring from these obese parents have multiple metabolic abnormalities early in life (3 weeks old), and that male, but not female, offspring have impaired diastolic function associated with reduced cardiac SIRT3 expression and mitochondrial biogenesis. At 24 weeks of age, male offspring from obese parents exhibit increased blood pressure. To examine if offspring from obese parents are at greater risk of death and worse cardiac function after MI, male and female lean offspring fed a normal diet (ND) born from ND fed lean parents (ND-Offs, n=5-6/sex) and lean offspring fed ND born from HFD fed obese parents (HFD-Offs, n=6-11/sex) were submitted to a permanent left descending coronary artery ligation to induce MI at 12 weeks of age. Twenty-four-hour survival rate post-MI surgery was examined and cardiac function was measured by intraventricular catheterization with a Millar catheter on day 7 post-MI. Compared to ND-Offs, male and female HFD-Off born from obese HFD-fed parents exhibited reduced survival rate (male: 60% vs 100% and female: 55% vs. 83% for HFD-Offs and ND-Offs, respectively) and increased ventricular fibrillation post-MI. At day 7 post-MI, we observed reduced +dP/dtmax in male, but not female, HFD-Offs compared to ND-Offs (6,554±25 vs. 8,253±440 mmHg/sec in males and 7,962±557 vs. 7,668±890 mmHg/sec in females, for HFD-Offs and ND-Offs, respectively) despite similar infarct size in all groups (~40% of the total left ventricle circumference). We found no major differences in -dP/dtmin or tau (indices of diastolic function) between groups. Thus, parental obesity is associated with increased mortality rate in their offspring after induction of MI and worse systolic function in male, but not female, offspring even when offspring are fed a healthy diet after weaning and remain lean. NIDDK 1R01121411 (do Carmo), HL1630376 (da Silva/do Carmo), NIGMS P20GM104357 (Hall), P30GM149404 (Hall) and U54GM115428 (Hall). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Foxo3a and cardiac myofibroblast transdifferentiation after myocardial infarction

Abstract Background Fibroblast/ myofibroblast differentiation following acute myocardial infarction (MI) is important for myocardial scar formation but also causes adverse remodeling and stiffening of the myocardium leading to cardiac dysfunction and heart failure. Transdifferentiation of myofibroblasts are characterized by periostin, and extracellular matrix protein expression. The transcription factor forkhead box O 3 (FOXO3a) has been recently shown to inhibit hypertrophic cardiac remodeling. Purpose We hypothesized that FOXO3a, a key regulator of cell size, immunity, and cell differentiation, might inhibit transdifferentiation of fibroblasts into myofibroblasts and therefore cardiac fibrosis after MI. Methods Acute MI was induced in Foxo3a-/- mice and wild-type littermates by permanent LAD ligation. Cardiac function was determined by transthoracic echocardiography (TTE) at baseline as well as on days 4 and 14 post-MI. Immune histochemistry was performed with collagen and periostin. Finally, fibroblast differentiation was investigated by single nucleus RNA-sequencing (snRNA-seq). Results Foxo3a-/- mice showed significantly improved survival despite similar infarct size post-MI (p<0.01). The survival advantage was in part due to reduced cardiac ruptures on autopsy. TTE showed reduced LV function, cardiac output, and global strain 4 days post-MI that did not differ between both groups of animals. However, systolic LV function was significantly attenuated in Foxo3a-/- mice 14 days post-MI indicating enhanced wall stiffness. In line with these findings, sn-RNAseq on day 4 post-MI revealed significantly increased numbers of periostin positive myofibroblasts (Myo) (p<0.05) important for stabilizing matrix interactions that transdifferentiated mainly from progenitor-like state fibroblasts (PLS) and homeostatic epicardial derived fibroblasts (HEpiD) in Foxo3a-/- mice. Myo differentially expressed, i.e. upregulated genes important for extracellular matrix structure and organization, cell migration and collagen organization. Moreover, an upregulation of pro-fibrotic genes was observed in other fibroblast clusters such as in HEpiD (i.e., Col1a1, Col1a2, Col3a1), PLS (i.e., fgf10, il1r1), late response fibroblasts (LR-F) (i.e., Col14a1, Rin2) and in activated fibroblasts (F-ACT) (i.e., Gpc6, Slt2) in Foxo3a-/- mice. These changes were corroborated by significantly elevated collagen type 1 and 3 as well as periostin protein expression in Foxo3a-/- mice. Cell chat analysis indicated enhanced number of interactions and interaction strength of myeloid cells with fibroblasts in Foxo3a-/- mice. Conclusion Our data identify Foxo3a as a master regulator of cardiac remodeling attenuating myofibroblast transdifferentiation after acute MI. These findings suggest that deficiency of Foxo3a promotes early scar formation preventing rupture but also contributes to adverse remodeling in later stages resulting in impaired cardiac function and enhanced fibrosis after MI.

Pharmacoinvasive Strategy in Elderly Up to 75 Years or Non-Elderly: Analysis of Biochemical and Cardiac Magnetic Resonance Imaging Parameters.

Pharmacoinvasive strategy is an alternative when primary percutaneous coronary intervention (PCI) is not feasible. This study aimed to evaluate the effects of early pharmacoinvasive strategy on the infarct size and left ventricular ejection fraction in elderly and non-elderly patients. The role of inflammatory markers was also examined. Patients (n=223) with ST segment elevation myocardial infarction (STEMI) were prospectively included and submitted to pharmacological thrombolysis in the first six hours, and underwent coronary angiogram and PCI when necessary, in the first 24 hours. Blood samples were collected in the first day (D1) and after 30 days (D30). Cardiac magnetic resonance imaging (cMRI) was performed at D30. Significance was set at p<0.05. Elderly and non-elderly patients showed similar percentage of infarcted mass (13.7 [6.9-17.0] vs. 14.0 [7.3-26.0], respectively, p=0.13) (median [interquartile range]). However, elderly patients had better left ventricular ejection fraction (53 [45-62] vs. 49 [39-58], p=0.025). Titers of interleukin (IL)1beta, IL-4, IL-6, and IL-10 did not differ between D1 and D30, but elderly patients had higher titers for IL-18 at D1 and D30. Absolute numbers of B and T lymphocytes were similar in both groups at D1 and D30, but elderly patients had higher neutrophil/lymphocyte ratio at D30. Multivariate linear regression analysis of cMRI outcomes in the whole population showed that the independent predictors were not different between elderly and non-elderly patients. Pharmacoinvasive strategy in elderly patients was associated with small differences in inflammatory parameters, similar infarct size and better left ventricular function than non-elderly patients.

Endogenous Modulation of Extracellular Matrix Collagen during Scar Formation after Myocardial Infarction

Myocardial infarction is remains the leading cause of death in developed countries. Recent data show that the composition of the extracellular matrix might differ despite similar heart function and infarction sizes. Because collagen is the main component of the extracellular matrix, we hypothesized that changes in inflammatory cell recruitment influence the synthesis of different collagen subtypes in myofibroblasts, thus changing the composition of the scar. We found that neutrophils sustain the proliferation of fibroblasts, remodeling, differentiation, migration and inflammation, predominantly by IL-1 and PPARγ pathways (n = 3). They also significantly inhibit the mRNA expression of fibrillar collagen, maintaining a reduced stiffness in isolated myofibroblasts (n = 4-5). Reducing the neutrophil infiltration in CCR1-/- resulted in increased mRNA expression of collagen 11, moderate expression of collagen 19 and low expression of collagen 13 and 26 in the scar 4 weeks post infarction compared with other groups (n = 3). Mononuclear cells increased the synthesis of all collagen subtypes and upregulated the NF-kB, angiotensin II and PPARδ pathways (n = 3). They increased the synthesis of collagen subtypes 1, 3, 5, 16 and 23 but reduced the expression of collagens 5 and 16 (n = 3). CCR2-/- scar tissue showed higher levels of collagen 13 (n = 3), in association with a significant reduction in stiffness (n = 4-5). Upregulation of the inflammation-related genes in myofibroblasts mostly modulated the fibrillar collagen subtypes, with less effect on the FACIT, network-forming and globular subtypes (n = 3). The upregulation of proliferation and differentiation genes in myofibroblasts seemed to be associated only with the fibrillar collagen subtype, whereas angiogenesis-related genes are associated with fibrillar, network-forming and multiplexin subtypes. In conclusion, although we intend for our findings to deepen the understanding of the mechanism of healing after myocardial infarction and scar formation, the process of collagen synthesis is highly complex, and further intensive investigation is needed to put together all the missing puzzle pieces in this still incipient knowledge process.

Abstract 12050: Ketone Ester Supplementation Reduces Cardiac Inflammation and Enhances Cardiac Energetics in Acute Myocardial Infarction

Introduction: Myocardial infarction (MI) is a major risk factor for the development of heart failure with reduce ejection fraction (HFrEF). While previous studies have focused on HFrEF, the role of ketone bodies in MI is unclear. Hypothesis: K etone may exert some cardioprotective effects following MI. Methods: Male Yorkshire pigs underwent percutaneous balloon occlusion of the LAD for 80 minutes followed by 72 hours reperfusion period. Oral ketone ester (BHB-butanediol monoester, KE, 550 mg/kg) or vehicle was administered during reperfusion and continued during the follow-up period. Simultaneous blood sampling from coronary sinus and artery was obtained to quantify the extraction fraction of major cardiac substrates. Scar size was measured by LGE CMR and molecular markers were assessed in the LV. The study was approved by the IACUC at the Massachusetts General Hospital. Results: KE induced ketosis within 30 min after ingestion. KE increased β-hydroxybutyrate (βOHB) extraction in healthy swine without affecting glucose and fatty acid (FA) consumption. Despite similar infarct size in both MI and MI-KE groups, cardiac expression of proinflammatory cytokines TNF-⍺, IL-1, IL-6, and cardiac injury TTNI3 alongside with plasma hs-cTnI were reduced by KE. The untreated MI hearts consumed less FA with no changes in glucose uptake, whereas hearts from KE-treated animals consumed more βOHB and FA. KE increased cardiac expression of genes involved in ketone utilization MCT1 and SCOT after MI (p&lt;0.05 for all), indicating that cardiac uptake and utilization of βOHB as fuel were augmented. Together these metabolic changes were associated with an increase in cardiac ATP production. RNA-seq analysis identified differentially expressed genes related to mitochondrial energy metabolism. Conclusions: Oral KE induced ketosis and enhanced cardiac βOHB extraction in both healthy and infarcted hearts. Although infarct size was unchanged 72h after MI, acute oral supplementation with KE supressed cardiac inflammation and injury, altered cardiac substrate uptake and enhanced cardiac energetics following acute MI. Evaluating the potential chronic benefits of these changes on long-term remodeling after MI will be an exciting direction for future studies.

Circadian dependence of microvascular obstruction during ST-segment elevation myocardial infarction

BackgroundMicrovascular obstruction (MVO) contributes significantly to adverse left-ventricular remodeling and mortality following ST-segment elevation myocardial infarction (STEMI). Because circadian processes contribute significantly to the timing and degree of ischemic injury in STEMI we hypothesized that the occurrence of MVO may also exhibit circadian behavior. Methods and resultsA single center cohort trial of 336 STEMI patients (273 M 63 F) with their first STEMI who were reperfused with primary percutaneous coronary intervention (PCI) and referred for cardiac MRI prior to discharge. The time of onset of chest pain was recorded from the patients chart and used to stratify patients with MVO over a 24-h cycle to analyze for circadian behavior. Subjects with MVO (n = 200) had greater infarct size by cMRI (45 vs. 20 g; p < 0.001), had reduced ejection fraction (LVEF = 50 vs 45%; p = 0.008) and significantly greater LV end-diastolic (LVEDVI) and end-systolic (LVESVI) volume index compared to subject without MVO (n = 136). The frequency of patients with MVO was compared against the frequency of patients without MVO at each 1-h and 3-h period over a 24-h cycle. A clear peak in patients with MVO (MVO + / MVO –) was seen at the 0700 h interval where 26 out of 27 patients had MVO (p = 0.0038) although MVO mass was not increased. This observation remained significant at the 06–09 time interval when 3-h segments were analyzed. Through 2021, mortality in patients with MVO was significantly greater compared to patients without MVO (n = 20 vs. 5, p < 0.03). ConclusionsThis analysis reveals for the first time a circadian dependence of the frequency of MVO in the setting of STEMI which could explain in part, the wide variation in MVO seen in STEMI patients with similar ischemic times and infarct size.

Patients with rheumatic disease experiencing ST-elevation myocardial infarction have increased inflammatory- and neurohormonal response and higher 1-year mortality

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by Righospitalets Forskningsfond (Grant number: 07IO). Lundbeck Foundation (R186-2015-2132). Background Patients with rheumatoid diseases have been reported to have increased risk of ST-elevation myocardial infarction (STEMI). However, little is known about mortality risk following STEMI in these patients. Furthermore, STEMI patients with increased neurohormonal- and inflammatory response have higher mortality compared to patients with low response. Purpose We sought to assess whether patients with a rheumatic disease (RD) have an increased inflammatory- and neurohormonal response to a STEMI and whether 1-year mortality was higher in these patients compared to patients without rheumatic disease. Methods In 1700 consecutive STEMI patients (comatose cardiac arrest- and cardiogenic shock patients were excluded) from two Danish tertiary heart centres were studied. Biomarkers reflecting neurohormonal activation (pro-atrial natriuretic peptide (proANP), copeptin, and mid-regional pro-adrenomedullin (MRproADM)) and inflammatory response (C-reactive protein (CRP) and ST2) were measured at in the catheterization laboratorium before the acute coronary angiogram was performed. Patients were stratified according to known RD or not. Results In total, 88 (5.2%) STEMI patients had a RD diagnosis. From these 28 (32%) had RA, 9 (10%) had psoriasis arthritis, and 23 (26%) had gout, while 28 (32%) had other RDs. Patients in the two groups were similar of age (no RD vs. RD, mean (SD): 63 (13) vs. 65 (14) years, p=0.22), mostly male (n (%) 1194 (74) vs 57 (66), p=0.08) with similar number of comorbidities, same LVEF (median (IQR) 50 (40-55) vs. 50 (40-55), p=0.58), and similar infarct size (maximum troponin T concentration 3050 (1150-6885) vs. 3030 (1500-7260) ng/L, p=0.79). In RD patients, admission concentration of MRproADM (median (IQR) 0.77 (0.63-0.98) vs. 0.71 (0.58-0.90) nmol/L, p=0.04), ST2 (43 (33-64) vs 39 (29-55) ng/ml, p=0.04), and CRP (6.8 (2.9-14) vs 3.3 (1.4-8.2) mg/L, p&amp;lt;0.0001) was higher compared to patients without RD. No difference in proANP and copeptin was detected. One-year all-cause mortality was higher in patients with RD (11% vs. 5.5%, p=0.02). When including patients with CS and patients comatose after cardiac arrest, the signal remained intact. Conclusion STEMI patients with RD have higher admission inflammatory response and neurohormonal activation compared to patients without. Furthermore, patients with RD have higher 1-year all-cause mortality.

Ischemic ST-Segment Depression Maximal in V1-V4 (Versus V5-V6) of Any Amplitude Is Specific for Occlusion Myocardial Infarction (Versus Nonocclusive Ischemia).

BackgroundOcclusion myocardial infarctions (OMIs) of the posterolateral walls are commonly missed by ST‐segment–elevation myocardial infarction (STEMI) criteria, with >50% of patients with circumflex occlusion not receiving emergent reperfusion and experiencing increased mortality. ST‐segment depression maximal in leads V1–V4 (STDmaxV1–4) has been suggested as an indicator of posterior OMI.Methods and ResultsWe retrospectively reviewed a high‐risk population with acute coronary syndrome. OMI was defined from prior studies as a culprit lesion with TIMI (Thrombolysis in Myocardial Infarction) 0 to 2 flow or TIMI 3 flow plus peak troponin T >1.0 ng/mL or troponin I >10 ng/mL. STEMI was defined by the Fourth Universal Definition of Myocardial Infarction. ECGs were interpreted blinded to outcomes. Among 808 patients, there were 265 OMIs, 108 (41%) meeting STEMI criteria. A total of 118 (15%) patients had “suspected ischemic” STDmaxV1–4, of whom 106 (90%) had an acute culprit lesion, 99 (84%) had OMI, and 95 (81%) underwent percutaneous coronary intervention. Suspected ischemic STDmaxV1–4 had 97% specificity and 37% sensitivity for OMI. Of the 99 OMIs detected by STDmaxV1–4, 34% had <1 mm ST‐segment depression, and only 47 (47%) had accompanying STEMI criteria, of which 17 (36%) were identified a median 1.00 hour earlier by STDmaxV1–4 than STEMI criteria. Despite similar infarct size, TIMI flow, and coronary interventions, patients with STEMI(−) OMI and STDmaxV1–4 were less likely than STEMI(+) patients to undergo catheterization within 90 minutes (46% versus 68%; P=0.028).ConclusionsAmong patients with high‐risk acute coronary syndrome, the specificity of ischemic STDmaxV1–4 was 97% for OMI and 96% for OMI requiring emergent percutaneous coronary intervention. STEMI criteria missed half of OMIs detected by STDmaxV1–4. Ischemic STDmaxV1–V4 in acute coronary syndrome should be considered OMI until proven otherwise.

Cardiac Thyrotropin-releasing Hormone Inhibition Improves Ventricular Function and Reduces Hypertrophy and Fibrosis After Myocardial Infarction in Rats

BackgroundCardiac thyrotropin-releasing hormone (TRH) is a tripeptide with still unknown functions. We demonstrated that the left ventricle (LV) TRH system is hyperactivated in spontaneously hypertensive rats and its inhibition prevented cardiac hypertrophy and fibrosis. Therefore, we evaluated whether in vivo cardiac TRH inhibition could improve myocardial function and attenuate ventricular remodeling in a rat model of myocardial infarction (MI). Methods and ResultsIn Wistar rats, MI was induced by a permanent left anterior descending coronary artery ligation. A coronary injection of a specific small interfering RNA against TRH was applied simultaneously. The control group received a scrambled small interfering RNA. Cardiac remodeling variables were evaluated one week later. In MI rats, TRH inhibition decreased LV end-diastolic (1.049 ± 0.102 mL vs 1.339 ± 0.102 mL, P < .05), and end-systolic volumes (0.282 ± 0.043 mL vs 0.515 ± 0.037 mL, P < .001), and increased LV ejection fraction (71.89 ± 2.80% vs 65.69 ± 2.85%, P < .05). Although both MI groups presented similar infarct size, small interfering RNA against TRH treatment attenuated the cardiac hypertrophy index and myocardial interstitial collagen deposition in the peri-infarct myocardium. These effects were accompanied by attenuation in the rise of transforming growth factor-β, collagen I, and collagen III, as well as the fetal genes (atrial natriuretic peptide, B-type natriuretic peptide, and beta myosin heavy chain) expression in the peri-infarct region. In addition, the expression of Hif1α and vascular endothelial growth factor significantly increased compared with all groups. ConclusionsCardiac TRH inhibition improves LV systolic function and attenuates ventricular remodeling after MI. These novel findings support the idea that TRH inhibition may serve as a new therapeutic strategy against the progression of heart failure.

Accuracy of OMI ECG findings versus STEMI criteria for diagnosis of acute coronary occlusion myocardial infarction.

In the STEMI paradigm of Acute Myocardial Infarction (AMI), many NSTEMI patients have unrecognized acute coronary occlusion MI (OMI), may not receive emergent reperfusion, and have higher mortality than NSTEMI patients without occlusion. We have proposed a new OMI vs. Non-Occlusion MI (NOMI) paradigm shift. We sought to compare the diagnostic accuracy of OMI ECG findings vs. formal STEMI criteria for the diagnosis of OMI. We hypothesized that blinded interpretation for predefined OMI ECG findings would be more accurate than STEMI criteria for the diagnosis of OMI. We performed a retrospective case-control study of patients with suspected acute coronary syndrome. The primary definition of OMI was either 1) acute TIMI 0-2 flow culprit or 2) TIMI 3 flow culprit with peak troponin T 1.0ng/mL or I 10.0ng/mL. 808 patients were included, of whom 49% had AMI (33% OMI; 16% NOMI). Sensitivity, specificity, and accuracy of STEMI criteria vs Interpreter 1 using OMI ECG findings among 808 patients were 41% vs 86%, 94% vs 91%, and 77% vs 89%, and for Interpreter 2 among 250 patients were 36% vs 80%, 91% vs 92%, and 76% vs 89%. STEMI(-) OMI patients had similar infarct size and mortality as STEMI(+) OMI patients, but greater delays to angiography. Blinded interpretation using predefined OMI ECG findings was superior to STEMI criteria for the ECG diagnosis of Occlusion MI. These data support further investigation into the OMI vs. NOMI paradigm and suggest that STEMI(-) OMI patients could be identified rapidly and noninvasively for emergent reperfusion using more accurate ECG interpretation.

Abstract 12682: Accuracy of Expert Electrocardiography versus ST-Segment Elevation Myocardial Infarction Criteria for Diagnosis of Acute Coronary Occlusion Myocardial Infarction

Introduction: In the current STEMI paradigm of Acute Myocardial Infarction (AMI), many NonSTEMI patients have unrecognized acute coronary occlusion. Such patients do not receive emergent reperfusion and are known to have higher mortality than NSTEMI patients without occlusion. Thus, we have proposed a new Occlusion MI vs. Non-Occlusion MI (OMI vs. NOMI) paradigm. We sought to compare the diagnostic accuracy for OMI of blinded expert ECG interpretation vs. STEMI criteria advocated in the fourth Universal Definition of MI. We hypothesized that blinded expert ECG interpretation would be more accurate than STEMI criteria for the diagnosis of OMI, and that STEMI(-) OMI patients would have similar characteristics to STEMI(+) OMI but greater delays to cardiac catheterization. Methods: Retrospective case-control study of patients with suspected acute coronary syndrome, collecting demographics, laboratory results, ECGs, angiographic data, and outcomes. The primary definition of OMI was defined as either 1) acute TIMI 0-2 flow culprit or 2) TIMI 3 flow culprit with peak troponin T &gt;1.0 ng/mL or troponin I &gt;10.0 ng/mL. Results: 808 patients were included, of whom 49% had AMI (33% OMI; 16% NOMI). Sensitivity, specificity, and accuracy of STEMI criteria vs Expert 1 for OMI among all 808 patients were 41% vs 86%, 94% vs 91%, and 77% vs 89%, and for Expert 2 among 250 patients were 36% vs 80%, 91% vs 92%, and 76% vs 89%. When experts outperformed STEMI criteria (55% of OMI), they diagnosed OMI a median of 1.5 hours earlier than STEMI criteria. Seven key ECG findings were identified by experts as important signs of OMI in STEMI(-) cases. STEMI(-) OMI patients had similar infarct size and mortality as STEMI(+) OMI patients, but greater delays to angiography. Conclusions: Blinded expert ECG interpretation was superior to STEMI criteria for the ECG diagnosis of Occlusion MI. STEMI(-) OMI patients had greater delays to catheterization but similar outcomes to STEMI(+) OMI patients. These data support the OMI vs. NOMI paradigm and suggest that STEMI(-) OMI patients could be identified rapidly and noninvasively for emergent reperfusion using expert ECG interpretation.

Abstract 13871: Plasmacytoid Dendritic Cell-derived Interferons Mediate Myocardial Ischemia-reperfusion Injury by Activating Type I Interferon Receptor

Introduction: We have previously demonstrated type I interferon (IFN-I) is elevated during and mediates myocardial ischemia-reperfusion injury (IRI). Hypothesis: Plasmacytoid dendritic cells (pDCs) secrete IFN-I to exacerbate myocardial IRI by activating IFN-I receptor (IFNAR). Methods: C57BL/6 (WT) and IFNAR1 knockout (KO) mice underwent 40 minutes of left coronary artery occlusion followed by 60 minutes of reperfusion. At the end of reperfusion, plasma was obtained and hearts were harvested for TTC-Phthalo-blue staining to calculate infarct size (IS), denoted as a percentage of the ischemic risk region (RR). In pDC-depleted mice, WT mice were treated with PDCA-1 antibody (250 μg via intraperitoneal injection) on days 1, 3, 5, 7 prior to undergoing IRI on day 11. Control mice were treated with isotype IgG. For IFNAR blockade, IFNAR1 antibody (MAR1-5A3 2.0 μg/g) was administered as an IV bolus to WT mice 5 minutes before reperfusion. Results: Flow cytometry demonstrated that PDCA-1 antibody treatment had no effect on the number of splenic conventional dendritic cells (1.87±0.33% vs. 1.55±0.12% in IgG control, p=NS), but significantly reduced splenic pDCs by 60% (0.47±0.01% vs. 1.41±0.29% in IgG control, p&lt;0.05. Figure). pDC-depleted mice had significantly smaller IS compared to control after IRI (31.4±2.8 vs. 51.1±6.0, p&lt;0.05. Figure). At the end of reperfusion, plasma levels of IFNα and IFNβ were significantly elevated in IgG control but not in pDC-depleted mice. RRs were comparable in WT mice with/without IFNAR1 blockade and congenic IFNAR1 KO mice following IRI. WT control and IgG control mice had similar IS (53±4 vs. 49±4, p=NS). IS was significantly reduced by greater than 30% in IFNAR1 mAb-treated mice and IFNAR1 KO mice (p&lt;0.05 vs. controls). Conclusions: pDCs are activated during myocardial IRI and secrete IFN-I, which subsequently activates IFNARs and exacerbates IS. This pathway presents potential new therapeutic targets to attenuate myocardial IRI.

Investigating the potential effects of selective histone deacetylase 6 inhibitor ACY1215 on infarct size in rats with cardiac ischemia-reperfusion injury

BackgroundDespite the fact that histone deacetylase (HDAC) inhibitors have been tested to treat various cardiovascular diseases, the effects of selective HDAC6 inhibitor ACY1215 on infarct size during cardiac ischemia-reperfusion (IR) injury still remain unknown. In the present study we aimed to investigate the effects of ACY1215 on infarct size in rats with cardiac IR injury, as well as to examine the association between HDAC6 inhibitors and the gene expression of hypoxia inducible factor-1α (HIF-1α), a key regulator of cellular responses to hypoxia.MethodsBy using computational analysis of high-throughput expression profiling dataset, the association between HDAC inhibitors (pan-HDAC inhibitors panobinostat and vorinostat, and HDAC6 inhibitor ISOX) and their effects on HIF-1α gene-expression were evaluated. The male Wistar rats treated with ligation of left coronary artery followed by reperfusion were used as a cardiac IR model. ACY1215 (50 mg/kg), pan-HDAC inhibitor MPT0E028 (25 mg/kg), and vehicle were intraperitoneally injected within 5 min before reperfusion. The infarct size in rat myocardium was determined by 2,3,5-triphenyltetrazolium chloride staining. The serum levels of transforming growth factor-β (TGF-β) and C-reactive protein (CRP) were also determined.ResultsThe high-throughput gene expression assay showed that treatment of ISOX was associated with a more decreased gene expression of HIF-1α than that of panobinostat and vorinostat. Compared to control rats, ACY1215-treated rats had a smaller infarct size (49.75 ± 9.36% vs. 19.22 ± 1.70%, p < 0.05), while MPT0E028-treated rats had a similar infarct size to control rats. ACY-1215- and MPT0E028-treated rats had a trend in decreased serum TGF-β levels, but not statistically significant. ACY1215-treated rats also had higher serum CRP levels compared to control rats (641.6 μg/mL vs. 961.37 ± 64.94 μg/mL, p < 0.05).ConclusionsOur research indicated that HDAC6 inhibition by ACY1215 might reduce infarct size in rats with cardiac IR injury possibly through modulating HIF-1α expression. TGF-β and CRP should be useful biomarkers to monitor the use of ACY1215 in cardiac IR injury.

Characteristics of Dexmedetomidine Postconditioning in the Field of Myocardial Ischemia-Reperfusion Injury.

Timing and onset of myocardial ischemia are mostly unpredictable. Therefore, postconditioning could be an effective cardioprotective intervention. Because ischemic postconditioning is an invasive and not practicable treatment, pharmacological postconditioning would be a more suitable alternative cardioprotective measure. For the α2-adrenoreceptor agonist, dexmedetomidine postconditioning has been shown. However, data on a concentration-dependent effect of dexmedetomidine are lacking. Furthermore, it is unclear whether the time point and/or duration of dexmedetomidine administration in the reperfusion period is of relevance. We set out to determine whether infarct size reduction by dexmedetomidine is concentration dependent and whether time point and/or duration of dexmedetomidine application has an impact on the effect size of cardio protection. Hearts of male Wistar rats were randomized and placed on a Langendorff system perfused with Krebs-Henseleit buffer at a constant pressure of 80 mm Hg. All hearts were subjected to 33 minutes of global ischemia and 60 minutes of reperfusion. In part I of the study, a concentration-response effect was determined by perfusing hearts with various concentrations of dexmedetomidine (0.3-100 nM) at the onset of reperfusion. Based on these results, part II of the study was conducted with 3 nM dexmedetomidine. Application of dexmedetomidine started directly at the onset of reperfusion (Dex60) and 15 minutes (Dex15), 30 minutes (Dex30), or 45 minutes (Dex45) after the start of reperfusion and lasted always until the end of the reperfusion period. Infarct size was determined by triphenyltetrazolium chloride staining. In part I, infarct size in control (Con) hearts was 62% ± 4%. Three-nanometer dexmedetomidine was the lowest most effective cardioprotective concentration and reduced infarct size to 24% ± 7% (P < .0001 versus Con). Higher concentrations did not confer stronger protection. Infarct size in control hearts from part II was 66% ± 6%. Different starting times and/or durations of application resulted in similar infarct size reduction (all P < .0001 versus Con). Postconditioning by dexmedetomidine is concentration dependent in ranges between 0.3 and 3 nM. Increased concentrations above 3 nM do not further enhance this cardioprotective effect. This cardioprotective effect is independent of time point and length of application in the reperfusion period.

P4473Brain renin-angiotensin system blockade with firibastat, an orally active, central acting aminopeptidase A inhibitor prodrug prevents cardiac dysfunction after myocardial infarction in mice

Abstract Introduction Brain renin-angiotensin system (RAS) hyperactivity has been implicated in sympathetic hyperactivity and progressive left ventricular (LV) dysfunction after myocardial infarction (MI). Brain angiotensin III, generated by aminopeptidase A (APA), is one of the main effector peptides of the brain RAS in the control of cardiac function. Purpose We hypothesized that orally administered firibastat (previously named RB150), an orally central acting APA inhibitor prodrug, would attenuate heart failure (HF) development after MI in mice, by blocking brain RAS hyperactivity. Methods Two days after MI induced by the left anterior descending artery ligation, 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. Results From one to four weeks post-MI, brain APA hyperactivity occurred, contributing to brain RAS hyperactivity. Firibastat treatment during four weeks after MI normalized brain APA hyperactivity, with a return to the control values measured in the sham group. 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 markers of fibrosis such Ctgf and collagen types I and III than MI+vehicle mice. Conclusions Chronic oral firibastat administration after MI in mice normalizes brain APA hyperactivity, thereby normalizing brain RAS hyperactivity, whilst preventing cardiac dysfunction and attenuating cardiac hypertrophy and fibrosis. Acknowledgement/Funding INSERM, College de France, ANR LabCom, and Quantum Genomics

Abstract P2005: Antioxidant Resveratrol Attenuates Cardiac Fibrosis and Reduces Matrix Metalloproteinase-2 Activity in Heart Failure Rats

Increased reactive oxygen species activate matrix metalloproteinases (MMP) playing a critical role in cardiovascular remodeling after myocardial infarction (MI). We evaluated the antioxidant effect of resveratrol (RESV) on cardiac remodeling and MMP-2 activity in heart failure (HF) rats. Wistar rats were divided into the following groups: Control; Control+RESV; HF; HF+RESV (10mg/kg/day, p.o., 4 wk). The MI was elicited by ligation of the coronary artery. After four weeks, the animals were anesthetized to evaluate the cardiac function and to collect the hearts and blood samples. Heart weight/body weight (HW/BW, mg/g) ratio and the infarct size were calculated. Histological assessment of the left ventricle was carried out with hematoxylin/eosin, and fibrosis was quantified with Masson trichrome-staining. Cardiac and plasma MMP-2 activities were determined by gel zymography. The oxidative stress was assessed measuring the thiobarbituric acid reactive substances (TBARS) from plasma. HF and HF+RESV showed similar infarct size. The HW/BW ratio increased (3.7±0.2 vs 3.8±0.2 vs 3.0±0.05). RESV improved the maximal slope of the systolic increment of left ventricular pressure in HF animals (9004±1120 vs 5849±595 vs 7181±533 mmHg/s) and reduced the end diastolic pressure (4±1 vs 18±4 vs 7±1 mmHg). HF increased TBARS, whereas RESV produced an antioxidant effect in HF+RESV group (11.2±0.9 vs 21.7±3 vs 8.2±1.4 μmol/L). HF augmented cardiac fibrosis (30,8±1,3 vs 8,8±0,5%) and myocyte hypertrophy (12,2±0,7 vs 8,8±0,3μm). RESV reduced collagen deposition in HF hearts (22,7±1,9%), but did not reduce the myocyte hypertrophy (11,7±0,6 μm). Cardiac and plasma MMP-2 activity were higher in HF animals (plasma: 1344±39 vs. 1164±47; heart: 536±54 vs. 262±18). RESV decreased plasma MMP-2 activity in control (992±27) and HF animals (1200±49) and reduced cardiac MMP-2 activity only in HF+RESV group (426±42). In conclusion, the antioxidant effect of RESV improved cardiac function and fibrosis and reduced MMP-2 levels in the heart and plasma from HF rats.

Iron deficiency in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

BackgroundIron deficiency (ID) is a known co-morbidity and a potential therapeutic target in heart failure. Whether ID is frequent also in ST-segment elevation acute myocardial infarction (STEMI) patients and is associated with worse in-hospital outcomes has never been evaluated. MethodsWe defined ID as a serum ferritin < 100 μg/L or transferrin saturation < 20% at hospital admission. We assessed the association between ID and the primary endpoint (a composite of in-hospital mortality and Killip class ≥ 3). We explored the potential association between ID, circulating cell-free mitochondrial DNA (mtDNA), and cardiac magnetic resonance (CMR) parameters. ResultsFour-hundred-twenty STEMI patients undergoing primary percutaneous coronary intervention (pPCI) were included. Of them, 237 (56%) had ID. They had significantly higher admission high-sensitivity troponin and mtDNA levels as compared to non-ID patients (145 ± 35 vs. 231 ± 66 ng/L, P < 0.001; 917 [404–1748] vs. 1368 [908–4260] copies/μL; P < 0.003, respectively). A lower incidence of the primary endpoint (10% vs. 18%, P = 0.01) was observed in ID patients (adjusted OR 0.50 [95% CI 0.27–0.93]; P = 0.02). At CMR (n = 192), ID patients had a similar infarct size (21 ± 18 vs. 21 ± 19 g; P = 0.95), but a higher myocardial salvage index (0.56 ± 0.30 vs. 0.43 ± 0.27; P = 0.002), and a smaller microvascular obstruction extent (3.6 ± 2.2 vs. 6.9 ± 3.9 g; P < 0.001). ConclusionsIron deficiency is frequent in STEMI patients, it is coupled with mitochondrial injury, and, paradoxically, with a better in-hospital outcome. This unexpected clinical result seems to be associated with a smaller myocardial reperfusion injury. The mechanisms underlying our findings and their potential clinical implications warrant further investigation.

Targeting the PI3K/STAT3 axis modulates age-related differences in macrophage phenotype in rats with myocardial infarction.

Ageing is associated with impaired repair mechanisms in cardiovascular diseases. Macrophages contribute to cardiac fibrosis after myocardial infarction (MI). The phosphatidyl‐inositol‐3‐kinase (PI3K) pathway has been shown to play a role in cardiac remodelling after MI. It remained unclear whether n‐butylidenephthalide, a major component of Angelica sinensis, can attenuate cardiac fibrosis by regulating the PI3K/signal transducer and activator of transcription 3 (STAT3)‐mediated macrophage phenotypes in ageing rats after MI. Twenty‐four hours after ligation of the left anterior descending artery, young (2‐month‐old) and ageing (18‐month‐old) male Wistar rats were treated with either vehicle or n‐butylidenephthalide for 4 weeks. There were similar infarct sizes in both age groups. Compared with young rats, ageing rats exhibited significant increased cardiac fibrosis after MI, which can be attenuated after administering n‐butylidenephthalide. MI was associated with decreased activities of PI3K and STAT3 in ageing rats compared with young rats. In both age groups, n‐butylidenephthalide effectively provided a significant increase of STAT3 phosphorylation, STAT3 activity, STAT3 nuclear translocation, myocardial IL‐10 levels and the percentage of M2c macrophage and a decrease of myofibroblast infiltration. The effects of n‐butylidenephthalide on increased IL‐10 levels were reversed by LY294002 or S3I‐201. Furthermore, LY294002 abolished the STAT3 phosphorylation, whereas PI3K activity was not affected following the inhibition of STAT3. In conclusions, the host environment is responsible for ageing‐related myofibroblast dysregulation in response to MI which can be improved by administering n‐butylidenephthalide via macrophage differentiation towards M2 phenotype by targeting the PI3K/STAT3 axis.

Myeloid Cell mPges-1 Deletion Attenuates Mortality Without Affecting Remodeling After Acute Myocardial Infarction in Mice.

Selective deletion of microsomal prostaglandin E2 synthase-1 (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-knockout (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 3, 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 with wild-type controls. Left ventricular systolic (reflected by ejection fraction, fractional shortness end systolic volume, and +dP/dt) and diastolic function (reflected by end diastolic volume, -dP/dt, and Tau), cardiac hypertrophy (reflected by left ventricular dimensions), and staining for fibrosis did not differ between the groups. In conclusion, we found that 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.