Increased Infarct Size Research Articles

Mitigating the risk of flow deterioration by deferring stent optimization in STEMI patients with large thrombus burden: Insights from a prospective cohort study

ObjectivesIt is uncertain, if omitting post-dilatation and stent oversizing (stent optimization) is safe and may decrease the risk for distal thrombus embolization (DTE) in STEMI patients with large thrombus burden (LTB).BackgroundIn patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) with stenting, (DTE) and flow deterioration are common and increase infarct size leading to worse outcomes.MethodsFrom a prospective registry, 74 consecutive STEMI patients with LTB undergoing pPCI with stenting and intentionally deferred stent optimization were analyzed. Imaging data and outcomes up to 2 years follow-up were analyzed.ResultsOverall, 74 patients (18% females) underwent deferred stent optimization. Direct stenting was performed in 13 (18%) patients. No major complications occurred during pPCI. Staged stent optimization was performed after a median of 4 (interquartile range (IQR) 3; 7) days. On optical coherence tomography, under-expansion and residual thrombus were present in 59 (80%) and 27 (36%) cases, respectively. During deferred stent optimization, we encountered no case of flow deterioration (slow or no-reflow) or side branch occlusion. Minimal lumen area (mm2) and stent expansion (%) were corrected from 4.87±1.86mm to 6.82±2.36mm (p<0.05) and from 69±18% to 91±12% (p<0.001), respectively. During follow-up, 1 patient (1.4%) required target lesion revascularization and 1 (1.4%) patient succumbed from cardiovascular death.ConclusionsAmong STEMI patients with LTB, deferring stent optimization in the setting of pPCI appears safe and potentially mitigates the risk of DTE. The impact of this approach on infarct size and clinical outcomes warrants further investigation in a dedicated trial.

Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans.

The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing. In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels. Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI.

Microvascular Obstruction in Acute Myocardial Infarction, a Potential Therapeutic Target.

Microvascular obstruction (MVO) is a recognised phenomenon following mechanical reperfusion in patients presenting with ST-segment elevation myocardial infarction (STEMI). Invasive and non-invasive modalities to detect and measure the extent of MVO vary in their accuracy, suggesting that this phenomenon may reflect a spectrum of pathophysiological changes at the level of coronary microcirculation. The importance of detecting MVO lies in the observation that its presence adds incremental risk to patients following STEMI treatment. This increased risk is associated with adverse cardiac remodelling seen on cardiac imaging, increased infarct size, and worse patient outcomes. This review provides an outline of the pathophysiology, clinical implications, and prognosis of MVO in STEMI. It describes historic and novel pharmacological and non-pharmacological therapies to address this phenomenon in conjunction with primary PCI.

NKRF in Cardiac Fibroblasts Protects against Cardiac Remodeling Post-Myocardial Infarction via Human Antigen R.

Myocardial infarction (MI) remains the leading cause of death worldwide. Cardiac fibroblasts (CFs) are abundant in the heart and are responsible for cardiac repair post-MI. NF-κB-repressing factor (NKRF) plays a significant role in the transcriptional inhibition of various specific genes. However, the NKRF action mechanism in CFs remains unclear in cardiac repair post-MI. This study investigates the NKRF mechanism in cardiac remodeling and dysfunction post-MI by establishing a CF-specific NKRF-knockout (NKRF-CKO) mouse model. NKRF expression is downregulated in CFs in response to pathological cardiac remodeling in vivo and TNF-α in vitro. NKRF-CKO mice demonstrate worse cardiac function and survival and increased infarct size, heart weight, and MMP2 and MMP9 expression post-MI compared with littermates. NKRF inhibits CF migration and invasion in vitro by downregulating MMP2 and MMP9 expression. Mechanistically, NKRF inhibits human antigen R (HuR) transcription by binding to the classical negative regulatory element within the HuR promoter via an NF-κB-dependent mechanism. This decreases HuR-targeted Mmp2 and Mmp9 mRNA stability. This study suggests that NKRF is a therapeutic target for pathological cardiac remodeling.

Abstract GS.08: Cardiolipin Is A Novel Target Of Therapy To Mitigate Myocardial Injury Due To Veno-arterial Extracorporeal Membrane Oxygenation (va-ecmo)

Cardiolipin (CL) is a mitochondrial specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia-reperfusion injury. VA-ECMO use to provide hemodynamic support for acute myocardial infarction (AMI) has grown exponentially; is associated with poor outcomes; and is the subject of active clinical trials, yet the mechanistic impact of VA-ECMO on myocardial damage in AMI remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial CL and promotes myocardial damage in AMI. We first report that levels of CL and tafazzin, a key enzyme required for CL synthesis, are significantly reduced in the left ventricles (LV) of human subjects requiring VA-ECMO compared to subjects without VA-ECMO prior to heart transplantation. Six hours of exposure to VA-ECMO also decreased LV levels of CL and tafazzin in healthy swine compared to sham controls. To explore whether CL depletion by VA-ECMO increases infarct size, we performed left anterior descending artery (LAD) occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with CL to stabilize the inner mitochondrial membrane. Compared to reperfusion alone, VA-ECMO activation beginning after 90 minutes of LAD occlusion increased infarct size (33±11% vs 48±7%, p&lt;0.001). VA-ECMO also decreased CL and tafazzin levels, disrupted mitochondrial structural integrity, reduced ETC function and promoted oxidative stress. Compared to reperfusion alone or VA-ECMO before reperfusion, intracoronary delivery of MTP-131 five minutes before VA-ECMO activation reduced infarct size (22±8%, p=0.03 vs IRI and p&lt;0.001 vs VA-ECMO). Treatment with MTP-131 also restored CL and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the LV. Our results identify a novel mechanism by which VA-ECMO promotes myocardial dysfunction and further identify cardiolipin as an important target of therapy to reduce infarct size and preserve mitochondrial function for patients requiring VA-ECMO for acute myocardial infarction. Future clinical studies are required to test the translational utility of this approach.

Abstract P3207: Mitoregulin Microprotein Influences Mitochondrial Membrane Integrity And Myocardial Ischemia-Reperfusion Injury

Microproteins have emerged as a class of proteins often found to be encoded by misannotated long noncoding RNAs (lncRNAs). We and others discovered that a ubiquitously-expressed “lncRNA” ( LINC00116 ) encodes for a highly-conserved mitochondrial transmembrane microprotein that regulates beta-oxidation; we named this protein Mitoregulin (Mtln). In cells and mice, we found that Mtln increases mitochondrial respiratory efficiencies and Ca 2+ retention capacities, while reducing ROS. To date, the molecular function of Mtln remains unclear, with instances of conflicting data across papers. Recently, we found that mitochondria from Mtln-knockout (KO) mice are susceptible to membrane freeze-damage, leading to matrix protein leak during mitochondrial isolation. This appears not to be a distal downstream consequence of chronic Mtln loss, as we have confirmed these findings in cells after acute Mtln knockdown and in a mouse model of inducible cardiac-specific KO of Mtln (AAV-based CRISPR in aMHC-Cas9 mice; ~90% reduction in Mtln). Furthermore, acute re-expression of Mtln using AAV in Mtln-KO mice rescues the membrane deficit. Transmission electron microscopy revealed that acute Mtln knockdown in cells disrupts mitochondrial cristae integrity / density. Given that we previously found that Mtln strongly binds cardiolipin, we assessed the effects of synthetic Mtln peptide on membrane dynamics in mitochondrial-simulated lipid monolayers and found that Mtln modulates lipid packing and mixing and increases monolayer elasticity. Whether these potential direct effects mediate Mltn’s broad positive impact on mitochondria remain unknown. To further explore a role for Mtln in cardiac disease, we subjected Mtln-KO and AAV-Mtln overexpression mice to myocardial ischemia-reperfusion (IR), given Mtln’s influence on mitochondrial Ca 2+ buffering and ROS. Mtln-KO mice showed significantly worse outcomes (increased infarct size, cardiac dilation, and decreased ejection fraction) at 72 h post-IR, whereas AAV-Mtln mice were protected (decreased infarct size and increased ejection fraction), each compared to control littermates. Overall, this work points to new molecular functions for Mtln and highlights its protective (therapeutic) role in IR injury.

Abstract P2124: Trans-valvular Unloading Protects Against Post-reperfusion Injury Via Hif-1a In Preclinical Models Of Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is a major cause of heart failure and mortality worldwide. Reducing left ventricular (LV) workload using a trans-valvular pump (TVP) and delaying reperfusion for 30 minutes reduces infarct size by 50% in preclinical models and is currently under clinical investigation. We hypothesized that LV unloading limits myocardial injury by activating hypoxia inducible factor 1-α (HIF-1α). Myocardial ischemia was induced by percutaneous balloon occlusion of the left anterior descending (LAD) artery for 90 minutes in adult male swine. The detailed study design is shown in Fig A. In Group A and B, no infarct was observed with or without TVP. In Groups C and D, infarct size was significantly lower with TVP activation (Fig B). During LAD occlusion without reperfusion, HIF-1α levels increased within the infarct zone (Group A), but were significantly lower with TVP activation (Group B). After reperfusion, HIF-1α levels decreased in Group C, but paradoxically, increased with TVP support (Group D; Fig C). To test whether HIF1α mediates cardioprotection with LV unloading, adult swine were treated with intracoronary delivery of a HIF-1α inhibitor (2-methoxyestradiol; 2ME) before reperfusion. Compared to DMSO-treated controls, 2ME increased infarct size despite LV unloading (Fig D). Conversely, compared to reperfusion alone, intracoronary delivery of a HIF-1α stabilizing agent (Roxadustat) before reperfusion significantly decreased infarct size both in the presence and absence of a TVP (Fig E). We identified a novel functional role for HIF-1α as a critical mediator of the cardioprotective effects associated with trans-valvular unloading before reperfusion.

Deficiency of olfactory receptor 2 worsens cardiac function and increases infarct size after myocardial infarction

Deficiency of olfactory receptor 2 worsens cardiac function and increases infarct size after myocardial infarction

Heart rate reduction after genetic ablation of L-type Cav1.3 channels induces cardioprotection against ischemia-reperfusion injury.

Acute myocardial infarction (AMI) is the major cause of cardiovascular mortality worldwide. Most ischemic episodes are triggered by an increase in heart rate, which induces an imbalance between myocardial oxygen delivery and consumption. Developing drugs that selectively reduce heart rate by inhibiting ion channels involved in heart rate control could provide more clinical benefits. The Cav1.3-mediated L-type Ca2+ current (ICav1.3) play important roles in the generation of heart rate. Therefore, they can constitute relevant targets for selective control of heart rate and cardioprotection during AMI. We aimed to investigate the relationship between heart rate and infarct size using mouse strains knockout for Cav1.3 (Cav1.3-/-) L-type calcium channel and of the cardiac G protein gated potassium channel (Girk4-/-) in association with the funny (f)-channel inhibitor ivabradine. Wild-type (WT), Cav1.3+/-, Cav1.3-/- and Girk4-/- mice were used as models of respectively normal heart rate, moderate heart rate reduction, bradycardia, and mild tachycardia, respectively. Mice underwent a surgical protocol of myocardial IR (40 min ischemia and 60 min reperfusion). Heart rate was recorded by one-lead surface ECG recording, and infarct size measured by triphenyl tetrazolium chloride staining. In addition, Cav1.3-/- and WT hearts perfused on a Langendorff system were subjected to the same ischemia-reperfusion protocol ex vivo, without or with atrial pacing, and the coronary flow was recorded. Cav1.3-/- mice presented reduced infarct size (-29%), while Girk4-/- displayed increased infarct size (+30%) compared to WT mice. Consistently, heart rate reduction in Cav1.3+/- or by the f-channel blocker ivabradine was associated with significant decrease in infarct size (-27% and -32%, respectively) in comparison to WT mice. Our results show that decreasing heart rate allows to protect the myocardium against IR injury in vivo and reveal a close relationship between basal heart rate and IR injury. In addition, this study suggests that targeting Cav1.3 channels could constitute a relevant target for reducing infarct size, since maximal heart rate dependent cardioprotective effect is already observed in Cav1.3+/- mice.

Sarcospan Deficiency Increases Oxidative Stress and Arrhythmias in Hearts after Acute Ischemia-Reperfusion Injury.

The protein sarcospan (SSPN) is an integral member of the dystrophin-glycoprotein complex (DGC) and has been shown to be important in the heart during the development and the response to acute stress. In this study, we investigated the role of SSPN in the cardiac response to acute ischemia-reperfusion (IR) injury in SSPN-deficient (SSPN-/-) mice. First, the hemodynamic response of SSPN-/- mice was tested and was similar to SSPN+/+ (wild-type) mice after isoproterenol injection. Using the in situ Langendorff perfusion method, SSPN-/- hearts were subjected to IR injury and found to have increased infarct size and arrhythmia susceptibility compared to SSPN+/+. Ca2+ handling was assessed in single cardiomyocytes and diastolic Ca2+ levels were increased after acute β-AR stimulation in SSPN+/+ but not SSPN-/-. It was also found that SSPN-/- cardiomyocytes had reduced Ca2+ SR content compared to SSPN+/+ but similar SR Ca2+ release. Next, we used qRT-PCR to examine gene expression of Ca2+ handling proteins after acute IR injury. SSPN-/- hearts showed a significant decrease in L-type Ca2+ channels and a significant increase in Ca2+ release channel (RyR2) expression. Interestingly, under oxidizing conditions reminiscent of IR, SSPN-/- cardiomyocytes, had increased H2O2-induced reactive oxygen species production compared to SSPN+/+. Examination of oxidative stress proteins indicated that NADPH oxidase 4 and oxidized CAMKII were increased in SSPN-/- hearts after acute IR injury. These results suggest that increased arrhythmia susceptibility in SSPN-/- hearts post-IR injury may arise from alterations in Ca2+ handling and a reduced capacity to regulate oxidative stress pathways.

Acute Low Dose Naltrexone Increases β-Endorphin and Promotes Neuronal Recovery Following Hypoxia-Ischemic Stroke in Type-2 Diabetic Mice.

Diabetic patients experience significant mortality and poor recovery following ischemic stroke. Our clinical and basic science studies demonstrate an overall immune suppression in the periphery of diabetic stroke patients, as well as within the central nervous system (CNS) of type-2 diabetic mice following hypoxia-ischemia (HI). Low doses of naltrexone (LDN) improved clinical outcomes in many autoimmune diseases by acting on opioid receptors to release β-endorphin which in turn balances inflammatory cytokines and modulates the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) pathway. We hypothesized that in our model of diabetic mice, LDN treatment will induce the release of β-endorphin and improve CNS response by promoting neuronal recovery post HI. To test this hypothesis, we induced HI in 10week old male db/db and db/ + mice, collected tissue at 24 and 72h post HI, and measured OGF levels in plasma and brain tissue. The infarct size and number of OGF + neurons in the motor cortex, caudate and hippocampus (CA3) were measured. Following HI, db/db mice had significant increases in brain OGF expression, increased infarct size and neurological deficits, and loss of OGFr + neurons in several different brain regions. In the second experiment, we injected LDN (1mg/kg) intraperitoneally into db/db and db/ + mice at 4, 24, and 48h post HI, and collected brain tissue and blood at 72h. Acute LDN treatment increased β-endorphin and OGF levels in plasma and promoted neuronal recovery in db/db mice compared to phosphate buffer saline (PBS)-treated diabetic mice suggesting a protective or regenerative effect of LDN.

Transvalvular Unloading Mitigates Ventricular Injury Due to Venoarterial Extracorporeal Membrane Oxygenation in Acute Myocardial Infarction

Whether extracorporeal membrane oxygenation (ECMO) with Impella, known as EC-Pella, limits cardiac damage in acute myocardial infarction remains unknown. The authors now report that the combination of transvalvular unloading and ECMO (EC-Pella) initiated before reperfusion reduced infarct size compared with ECMO alone before reperfusion in a preclinical model of acute myocardial infarction. EC-Pella also reduced left ventricular pressure-volume area when transvalvular unloading was applied before, not after, activation of ECMO. The authors further observed that EC-Pella increased cardioprotective signaling but failed to rescue mitochondrial dysfunction compared with ECMO alone. These findings suggest that ECMO can increase infarct size in acute myocardial infarction and that EC-Pella can mitigate this effect but also suggest that left ventricular unloading and myocardial salvage may be uncoupled in the presence of ECMO in acute myocardial infarction. These observations implicate mechanisms beyond hemodynamic load as part of the injury cascade associated with ECMO in acute myocardial infarction.

Propofol inhibits myocardial injury induced by microvesicles derived from hypoxia-reoxygenated endothelial cells via lncCCT4-2/CCT4 signaling

BackgroundIschemia-reperfusion (IR) induces increased release of extracellular vesicles in the heart and exacerbates myocardial IR injury. We have previously shown that propofol attenuates hypoxia/reoxygenation (HR)-induced injury in human umbilical vein endothelial cells (HUVECs) and that microvesicles derived from propofol-treated HUVECs inhibit oxidative stress in endothelial cells. However, the role of microvesicles derived from propofol post-treated HUVECs ((HR + P)-EMVs) in IR-injured cardiomyocytes is unclear. In this study, we aimed to investigate the role of (HR + P)-EMVs in cardiac IR injury compared to microvesicles derived from hypoxic/reoxygenated HUVECs (HR-EMVs) and to elucidate the underlying mechanisms.MethodsHypoxia/reoxygenation (HR) models of HUVECs and AC16 cells and a mouse cardiac IR model were established. Microvesicles from HR-injured HUVECs, DMSO post-treated HUVECs and propofol post-treated HUVECs were extracted by ultra-high speed centrifugation, respectively. The above EMVs were co-cultured with HR-injured AC16 cells or injected intracardially into IR mice. Flow cytometry and immunofluorescence were used to determine the levels of oxidative stress and apoptosis in cardiomyocytes. Apoptosis related proteins were detected by Western blot. Echocardiography for cardiac function and Evans blue-TTC staining for myocardial infarct size. Expression of lncCCT4-2 in EMVs and AC16 cells was analysed by whole transcriptome sequencing of EMVs and RT-qPCR. The molecular mechanism of inhibition of myocardial injury by (HR + P)-EMVs was elucidated by lentiviral knockdown of lncCCT4-2, plasmid overexpression or knockdown of CCT4, and actinomycin D assay.ResultsIn vitro and in vivo experiments confirmed that HR-EMVs exacerbated oxidative stress and apoptosis in IR-injured cardiomyocytes, leading to increased infarct size and worsened cardiac function. Notably, (HR + P)-EMVs induced significantly less oxidative stress and apoptosis in IR-injured cardiomyocytes compared to HR-EMVs. Mechanistically, RNA sequencing of EMVs and RT-qPCR showed that lncCCT4-2 was significantly upregulated in (HR + P)-EMVs and cardiomyocytes co-cultured with (HR + P)-EMVs. Reduction of lncCCT4-2 in (HR + P)-EMVs enhanced oxidative stress and apoptosis in IR-injured cardiomyocytes. Furthermore, the anti-apoptotic activity of lncCCT4-2 from (HR + P)-EMVs was achieved by increasing the stability of CCT4 mRNA and promoting the expression of CCT4 protein in cardiomyocytes.ConclusionsOur study showed that (HR + P)-EMVs uptake by IR-injured cardiomyocytes upregulated lncCCT4-2 in cardiomyocytes and promoted CCT4 expression, thereby inhibiting HR-EMVs induced oxidative stress and apoptosis.

Inhibition of MALT1 reduces ferroptosis in rat hearts following ischemia/reperfusion via enhancing the Nrf2/SLC7A11 pathway

The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in the hearts suffered ischemia/reperfusion (I/R), but the mechanisms behind the dysregulation of them are not fully elucidated. Mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) can function as a paracaspase to cleave specified substrates and it is predicted to interact with Nrf2. This study aims to explore whether targeting MALT1 can reduce I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion to establish the I/R injury model, which showed myocardial injuries (increase in infarct size and creatine kinase release) and up-regulation of MALT1 while downregulation of Nrf2 and SLC7A11 concomitant with the increased ferroptosis, reflecting by an increase in glutathione peroxidase 4 (GPX4) level while decreases in the levels of acyl-CoA synthetase long chain family member 4 (ACSL4), total iron, Fe2+ and lipid peroxidation (LPO); these phenomena were reversed in the presence of MI-2, a specific inhibitor of MALT1. Consistently, similar results were achieved in the cultured cardiomyocytes subjected to 8h-hypoxia plus 12h-reoxygenation. Furthermore, micafungin, an antifungal drug, could also exert beneficial effect on mitigating myocardial I/R injury via inhibition of MALT1. Based on these observations, we conclud that inhibition of MALT1 can reduce I/R-induced myocardial ferroptosis through enhancing the Nrf2/SLC7A11 pathway; and MALT1 may be used as a potential target to seek novel or existing drugs (such as micafungin) for treating myocardial infarction.

RETROSPECTIVE STUDY ON CLINICAL OUTCOME OF STROKE IN RELATION TO ADMISSION DAY GLYCEMIC STATUS IN A TERTIARY CARE HOSPITAL

Stroke or cerebrovascular accident is an abrupt onset of a neurological decit lasting for more than 24hrs that is attributable to a focal vascular cause. Hyperglycemia and stroke appear to be related in two ways. First incidence of stroke is known to be higher in diabetics than non diabetics. Second it has been suggested that even in non diabetics relatively mild degree of hyperglycemia early in stroke might increase infarct size and lead to poor prognosis. A record based retrospective study was conducted at a tertiary care hospital to determine the admission day glycemic status of patients with cerebrovascular accident and to record the outcome. Datas of 30 patients admitted with cerebrovascular accident in the past year was obtained and analysed for demographic and clinical features. It was observed that hyperglycemia was noticed in 63% of patients in general and hyperglycaemia is positively associated with poor functional outcome. Hence, there is an urgent need to conrm the improvement in these patients by normalizing blood sugar

P38 MAPK activated ADAM17 mediates ACE2 shedding and promotes cardiac remodeling and heart failure after myocardial infarction

BackgroundHeart failure (HF) after myocardial infarction (MI) is a prevalent disease with a poor prognosis. Relieving pathological cardiac remodeling and preserving cardiac function is a critical link in the treatment of post-MI HF. Thus, more new therapeutic targets are urgently needed. The expression of ADAM17 is increased in patients with acute MI, but its functional role in post-MI HF remains unclear.MethodsTo address this question, we examined the effects of ADAM17 on the severity and prognosis of HF within 1 year of MI in 152 MI patients with or without HF. In mechanistic studies, the effects of ADAM17 on ventricular remodeling and systolic function were extensively assessed at the tissue and cellular levels by establishing animal model of post-MI HF and in vitro hypoxic cell model.ResultsHigh levels of ADAM17 predicted a higher incidence of post-MI HF, poorer cardiac function and higher mortality. Animal studies demonstrated that ADAM17 promoted the occurrence of post-MI HF, as indicated by increased infarct size, cardiomyocyte hypertrophy, myocardial interstitial collagen deposition and cardiac failure. ADAM17 knock down significantly improved pathological cardiac remodeling and cardiac function in mice with MI. Mechanistically, activated ADAM17 inhibited the cardioprotective effects of ACE2 by promoting hydrolytic shedding of the transmembrane protein ACE2 in cardiomyocytes, which subsequently mediated the occurrence of cardiac remodeling and the progression of heart failure. Moreover, the activation of ADAM17 in hypoxic cardiomyocytes was dependent on p38 MAPK phosphorylation at threonine 735.ConclusionsThese data highlight a novel and important mechanism for ADAM17 to cause post-MI HF, which will hopefully be a new potential target for early prediction or intervention of post-MI HF.1TH-7ttE8r63zZ3UeeV3ZMVideo abstract

Platelet-Derived MicroRNAs Regulate Cardiac Remodeling After Myocardial Ischemia.

Platelets can infiltrate ischemic myocardium and are increasingly recognized as critical regulators of inflammatory processes during myocardial ischemia and reperfusion (I/R). Platelets contain a broad repertoire of microRNAs (miRNAs), which, under certain conditions such as myocardial ischemia, may be transferred to surrounding cells or released into the microenvironment. Recent studies could demonstrate that platelets contribute substantially to the circulating miRNA pool holding the potential for so far undiscovered regulatory functions. The present study aimed to determine the role of platelet-derived miRNAs in myocardial injury and repair following myocardial I/R. In vivo model of myocardial I/R, multimodal in vivo and ex vivo imaging approaches (light-sheet fluorescence microscopy, positron emission tomography and magnetic resonance imaging, speckle-tracking echocardiography) of myocardial inflammation and remodeling, and next-generation deep sequencing analysis of platelet miRNA expression. In mice with a megakaryocyte/platelet-specific knockout of pre-miRNA processing ribonuclease Dicer, the present study discloses a key role of platelet-derived miRNAs in the tightly regulated cellular processes orchestrating left ventricular remodeling after myocardial I/R following transient left coronary artery ligation. Disruption of the miRNA processing machinery in platelets by deletion of Dicer resulted in increased myocardial inflammation, impaired angiogenesis, and accelerated development of cardiac fibrosis, culminating in an increased infarct size by d7 that persisted through d28 of myocardial I/R. Worsened cardiac remodeling after myocardial infarction in mice with a platelet-specific Dicer deletion resulted in an increased fibrotic scar formation and distinguishably increased perfusion defect of the apical and anterolateral wall at day 28 post-myocardial infarction. Altogether, these observations culminated in an impaired left ventricular function and hampered long-term cardiac recovery after experimental myocardial infarction and reperfusion therapy. Treatment with the P2Y12 (P2Y purinoceptor 12) antagonist ticagrelor completely reversed increased myocardial damage and adverse cardiac remodeling observed in DicerPf4∆/Pf4∆ mice. The present study discloses a critical role of platelet-derived miRNA in myocardial inflammation and structural remodeling processes following myocardial I/R.

CLINICAL PROFILE OF ISCHEMIC STROKE AND ITS OUTCOME IN RELATION TO GLYCEMIC STATUS ON PRESENTATION AT A TERTIARY CARE CENTRE: A PROSPECTIVE OBSERVATIONAL STUDY

Background: Stroke, also known as a cerebrovascular accident, is common in patients and can be a major cause of morbidity and mortality. Stroke and hyperglycemia appear to be linked in two ways. Diabetics are known to have a greater stroke rate than non-diabetics. Even in non-diabetics, a mild degree of hyperglycemia early in a stroke has been reported to increase infarct size and lead to a bad prognosis. Aim: To study the clinical prole, infarct size on CT scan, and clinical outcome of cerebral infraction in relation to glycemic status at presentation. Material and Methodology: This prospective observational study was conducted in the medicine department of Jhalawar Medical College, Jhalawar, a tertiary care center in south-east Rajasthan, from January 2020 to June 2021. The study included all ischemic stroke patients. Data were analyzed in SPSS 21. Independent t-tests and Chi-square tests were applied. A p value of &lt; 0.05 was considered statistically signicant. Results: The current study revealed that out of 100 participants, 39 were euglycemic, 27 had stress hyperglycemia, and 34 had diabetes; a small, medium, or large infarct was present in 39, 27, and 34 patients, respectively. Diabetes patients had a statistically signicant high NIHSS score, blood sugar level, and deaths, followed by stress hyperglycemia, and euglycemic patients had the lowest. Conclusion: Hyperglycemia, including stress hyperglycemia and diabetes, was a common nding in patients with ischemic stroke, and NIHSS, blood sugar, and death were associated with hyperglycemia in ischemic stroke patients.

Brain-Derived Neurotrophic Factor Precursor Contributes to a Proinflammatory Program in Monocytes/Macrophages After Acute Myocardial Infarction.

Background The imbalance of monocyte/macrophage polarization toward the preferential proinflammatory phenotype and a lack of normal inflammation resolution are present in acute myocardial infarction (AMI). Our previous study showed that upregulation of brain-derived neurotrophic factor precursor (proBDNF) in M2-like monocytes may contribute to the proinflammatory response in the Stanford type-A acute aortic dissection. The present study aimed to investigate the role of proBDNF signaling in monocytes/macrophages in the progress of AMI. Methods and Results We observed the upregulation of proBDNF in the proinflammatory monocytes of patients with AMI. The upregulation of proBDNF was also observed in the circulating proinflammatory Ly6Chigh monocytes and cardiac F4/80+CD86+ macrophages 3 days after AMI in a mice model. To neutralize proBDNF, the mice subjected to AMI were injected intraperitoneally with a monoclonal anti-proBDNF antibody. Echocardiography, 2,3,5-triphenyltetrazolium chloride staining, and positron emission tomography/computed tomography results demonstrate that monoclonal anti-proBDNF antibody treatment further impaired cardiac functions, increased infarct size, and exacerbated the proinflammatory state. Moreover, the level of proinflammatory Ly6Chigh in the blood and F4/80+CD86+ in the heart was further increased in monoclonal anti-proBDNF antibody mice. RNA sequencing revealed that matrix metalloprotease-9 protein level was dramatically increased, along with the activated proinflammatory-related cytokines. Matrix metalloprotease-9 inhibitor treatment attenuated the deteriorated effect of monoclonal anti-proBDNF antibody on cardiac function and infarct areas. Conclusions Our study shows that endogenous proBDNF in monocytes/macrophages may exert protective roles in cardiac remodeling after AMI by regulating matrix metalloprotease-9 activity.

Development of an ischemia/reperfusion injury model in the living myocardial slice.

The most effective treatment for acute myocardial infarction is reperfusion; however, reperfusion injury can increase infarct size by 50%. Although many benchtop studies have had success treating or preventing ischemia/reperfusion (I/R) injury these results have failed to translate into the clinic. One proposed reason for this failure is the simplicity of in vitro models. We have developed an in vitro I/R model using the living myocardial slice (LMS) which bridges the gap between the flexibility of cell studies and the in vivo complexity of animal models. LMS from Lewis rats (250-400 g) are initially cultured for 1.5 hours in a hypoxic environment (1% O2). Afterwards, the media is slowly reoxygenated over the course of 1 hour and the LMS are cultured for an additional 19-23 hours. After culture we quantify functional changes in the LMS by measuring contractility at physiological load and by quantifying changes in the Frank-Starling relationship. The active force in the I/R group decreased by 57% compared to the control group (p<0.05). Additionally, the slope of the Frank-Starling curve decreased in the I/R group by 48% compared to the control group (p<0.05). We also applied the I/R model to LMS made from rejected donor hearts and biopsies from failing heart tissue. In human tissue the active force also decreased in the I/R group. The I/R model in the LMS captures a decrease in function in response to hypoxia. This model can be used to further characterise the I/R response in heart tissue and be more effective for testing new treatments in vitro.