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European Heart Journal Jun 2024Acute ST-elevation myocardial infarction (STEMI) and acute ischaemic stroke (AIS) share a number of similarities. However, important differences in pathophysiology...
Acute ST-elevation myocardial infarction (STEMI) and acute ischaemic stroke (AIS) share a number of similarities. However, important differences in pathophysiology demand a disease-tailored approach. In both conditions, fast treatment plays a crucial role as ischaemia and eventually infarction develop rapidly. Furthermore, in both fields, the introduction of fibrinolytic treatments historically preceded the implementation of endovascular techniques. However, in contrast to STEMI, only a minority of AIS patients will eventually be considered eligible for reperfusion treatment. Non-invasive cerebral imaging always precedes cerebral angiography and thrombectomy, whereas coronary angiography is not routinely preceded by non-invasive cardiac imaging in patients with STEMI. In the late or unknown time window, the presence of specific patterns on brain imaging may help identify AIS patients who benefit most from reperfusion treatment. For STEMI, a uniform time window for reperfusion up to 12 h after symptom onset, based on old placebo-controlled trials, is still recommended in guidelines and generally applied. Bridging fibrinolysis preceding endovascular treatment still remains the mainstay of reperfusion treatment in AIS, while primary percutaneous coronary intervention is the strategy of choice in STEMI. Shortening ischaemic times by fine-tuning collaboration networks between ambulances, community hospitals, and tertiary care hospitals, optimizing bridging fibrinolysis, and reducing ischaemia-reperfusion injury are important topics for further research. The aim of this review is to provide insights into the common as well as diverging pathophysiology behind current reperfusion strategies and to explore new ways to enhance their clinical benefit.
PubMed: 38941344
DOI: 10.1093/eurheartj/ehae371 -
JACC. Advances Jul 2023Portable, smartphone-sized electrocardiography (ECG) has the potential to reduce time to treatment for patients suffering acute cardiac ischemia, thereby lowering the...
BACKGROUND
Portable, smartphone-sized electrocardiography (ECG) has the potential to reduce time to treatment for patients suffering acute cardiac ischemia, thereby lowering the morbidity and mortality. In the UMC Utrecht, a portable, smartphone-sized, multi-lead precordial ECG recording device (miniECG 1.0, UMC Utrecht) was developed.
OBJECTIVES
The purpose of this study was to investigate the ability of the miniECG to capture ischemic ECG changes in a porcine coronary occlusion model.
METHODS
In 8 animals, antero-septal myocardial infarction was induced by 75-minute occlusion of the left anterior descending artery, after the first or second diagonal. MiniECG and 12-lead ECG recordings were acquired simultaneously before, during and after coronary artery occlusion and ST-segment deviation was evaluated.
RESULTS
During the complete occlusion and reperfusion period, miniECG showed large ST-segment deviation in comparison to 12-lead ECG. MiniECG ST-segment deviation was observed within 1 minute for most animals. The miniECG was positive for ischemia (ie, ST-segment deviation ≥1 mm) for 99.7% (Q1-Q3: 99.6%-99.9%) of the occlusion time, while the 12-lead was only positive for 79.8% (Q1-Q3: 81.1%-98.7%) of the time ( = 0.018). ST-segment deviation reached maxima of 10.5 mm [95% CI: 6.5-14.5 mm] vs 5.0 mm [95% CI: 2.0-8.0 mm] for the miniECG vs 12-lead ECG, respectively.
CONCLUSIONS
MiniECG ST-segment deviation was observed early and was of large magnitude during 75 minutes of porcine transmural antero-septal infarction. The miniECG was positive for ischemia for the complete occlusion period. These findings demonstrate the potential of the miniECG in the detection of cardiac ischemia. Although clinical research is required, data suggests that the miniECG is a promising tool for the detection of cardiac ischemia.
PubMed: 38939006
DOI: 10.1016/j.jacadv.2023.100410 -
Molecular Nutrition & Food Research Jun 2024Perinatal nutritional disturbances may "program" an increased cardio-metabolic risk in adulthood; however, few experimental studies have explored their effects on mature...
SCOPE
Perinatal nutritional disturbances may "program" an increased cardio-metabolic risk in adulthood; however, few experimental studies have explored their effects on mature and/or old animal. This study aims to investigate the influence of postnatal overfeeding (PNOF) on cardiac function, sensitivity to ischemia-reperfusion (I-R) injury in vivo, glucose metabolism, and metabolic profile of pericardial adipose tissue (PAT) in young (4 months), adult (6 months), old (12 months), and very old (18 months) male mice.
METHODS AND RESULTS
Two days after birth, PNOF is induced by adjusting the litter size of C57BL/6 male mice to three pups/mother, while the normally fed (NF) control group is normalized to nine pups/mother. After weaning, all mice have free access to standard diet. Glucose/insulin tests and in vivo myocardial I-R injury are conducted on mice aged from 2 to 12 months, while echocardiography is performed at all ages up to 18 months. PNOF mice exhibit an early and persistent 10-20% increase in body weight and a 10% decrease in left ventricular ejection fraction throughout their lifespan. In PNOF mice aged 4, 6, and 12 months, glucose intolerance and insulin resistance are observed, as well as a 27-34% increase in infarct size. This is accompanied by a higher PAT mass with increased inflammatory status.
CONCLUSION
Short-term PNOF results in nutritional programming, inducing long-lasting alterations in glucose metabolism and cardiac vulnerability in male mice, lasting up to 12 months.
PubMed: 38937861
DOI: 10.1002/mnfr.202400136 -
Asian Journal of Surgery Jun 2024
PubMed: 38937244
DOI: 10.1016/j.asjsur.2024.06.019 -
Archives of Biochemistry and Biophysics Jun 2024It has been previously demonstrated that the maintenance of ischemic acidic pH or the delay of intracellular pH recovery at the onset of reperfusion decreases...
BACKGROUND
It has been previously demonstrated that the maintenance of ischemic acidic pH or the delay of intracellular pH recovery at the onset of reperfusion decreases ischemic-induced cardiomyocyte death.
OBJECTIVE
To examine the role played by nitric oxide synthase (NOS)/NO-dependent pathways in the effects of acidic reperfusion in a regional ischemia model METHODS: Isolated rat hearts perfused by Langendorff technique were submitted to 40 min of left coronary artery occlusion followed by 60 min of reperfusion (IC). A group of hearts received an acid solution (pH=6.4) during the first 2 min of reperfusion (AR) in absence or in presence of L-NAME (NOS inhibitor). Infarct size (IS) and myocardial function were determined. In cardiac homogenates, the expression of P-Akt, P-endothelial and inducible isoforms of NOS (P-eNOS and iNOS) and the level of 3-nitrotyrosine were measured. In isolated cardiomyocytes, the intracellular NO production was assessed by confocal microscopy, under control and acidic conditions. Mitochondrial swelling after Ca addition and mitochondrial membrane potential (Δψ) were also determined under control and acidosis RESULTS: AR decreased IS, improved postischemic myocardial function recovery, increased P-Akt and P-eNOS, and decreased iNOS and 3-nitrotyrosine. NO production increased while mitochondrial swelling and Δψ decreased in acidic conditions. L-NAME prevented the beneficial effects of AR CONCLUSIONS: Our data strongly supports that a brief acidic reperfusion protects the myocardium against the ischemia-reperfusion injury through eNOS/NO-dependent pathways.
PubMed: 38936683
DOI: 10.1016/j.abb.2024.110059 -
Prostaglandins & Other Lipid Mediators Jun 2024Myocardial ischemia/reperfusion (MI/R) injury is a detrimental disease with high mortality worldwide. We aimed to explore the role of G protein-coupled receptor 4 (GPR4)...
Interference with GPR4 inactivates NLRP3 inflammasome signaling by inhibiting LPAR1 expression to ameliorate oxygen-glucose deprivation/reoxygenation-induced inflammation and apoptosis of cardiomyocytes.
Myocardial ischemia/reperfusion (MI/R) injury is a detrimental disease with high mortality worldwide. We aimed to explore the role of G protein-coupled receptor 4 (GPR4) and lysophosphatidic acid receptor 1 (LPAR1) in MI/R injury in vitro. H9c2 cells were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) conditions to simulate the MI/R injury and GPR4 expression was detected. Then, GPR4 was knocked down and cell viability was examined with a CCK-8 assay. The activities of LDH, CK and CK-MB were detected to evaluate the damage of OGD/R-induced H9c2 cells. ELISA kits and TUNEL staining were used to examine the inflammation and apoptosis of H9c2 cells exposed to OGD/R conditions. Western blot was employed to detect the expression of proteins related to apoptosis and NLRP3 inflammasome signaling. Additionally, Co-IP analyzed the binding between GPR4 and LPAR1. Finally, LPAR1 was overexpressed to conduct the rescue experiments. Results revealed that GPR4 was upregulated in OGD/R-treated H9c2 cells and GPR4 knockdown attenuated the damage of H9c2 cells. OGD/R induced inflammation and apoptosis were markedly inhibited by GPR4 silencing, as evidenced by the decreased TNF-α, IL-6 and IL-8 levels as well as the elevated Bcl-2 expression and reduced Bax and cleaved caspase3 expression. Moreover, GPR4 bound to LPAR1 and upregulated LPAR1 expression. Interference with GPR4 inactivated the NLRP3 inflammasome signaling. Besides, LPAR1 overexpression abrogated the effects of GPR4 silencing on the damage, inflammation and apoptosis of H9c2 cells induced by OGD/R. Particularly, LPAR1 upregulation promoted the activation of NLRP3 inflammasome signaling in GPR4-silenced H9c2 cells induced by OGD/R. To be concluded, GPR4 deficiency inactivates NLRP3 inflammasome signaling by inhibiting LPAR1 expression to ameliorate OGD/R -induced inflammation and apoptosis of cardiomyocytes.
PubMed: 38936540
DOI: 10.1016/j.prostaglandins.2024.106863 -
PloS One 2024Myocardial ischemia-reperfusion injury (MIRI) refers to the secondary damage to myocardial tissue that occurs when blood perfusion is rapidly restored following...
Myocardial ischemia-reperfusion injury (MIRI) refers to the secondary damage to myocardial tissue that occurs when blood perfusion is rapidly restored following myocardial ischemia. This process often exacerbates the injury to myocardial fiber structure and function. The activation mechanism of angiogenesis is closely related to MIRI and plays a significant role in the occurrence and progression of ischemic injury. In this study, we utilized sequencing data from the GEO database and employed WGCNA, Mfuzz cluster analysis, and protein interaction network to identify Stat3, Rela, and Ubb as hub genes involved in MIRI-angiogenesis. Additionally, the GO and KEGG analysis of differentially expressed genes highlighted their broad participation in inflammatory responses and associated signaling pathways. Moreover, the analysis of sequencing data and hub genes revealed a notable increase in the infiltration ratio of monocytes and activated mast cells. By establishing key cell ROC curves, using independent datasets, and validating the expression of hub genes, we demonstrated their high diagnostic value. Moreover, by scrutinizing single-cell sequencing data alongside trajectory analysis, it has come to light that Stat3 and Rela exhibit predominant expression within Dendritic cells. In contrast, Ubb demonstrates expression across multiple cell types, with all three genes being expressed at distinct stages of cellular development. Lastly, leveraging the CMap database, we predicted potential small molecule compounds for the identified hub genes and validated their binding activity through molecular docking. Ultimately, our research provides valuable evidence and references for the early diagnosis and treatment of MIRI from the perspective of angiogenesis.
Topics: Myocardial Reperfusion Injury; Humans; STAT3 Transcription Factor; Biomarkers; Transcription Factor RelA; Protein Interaction Maps; Neovascularization, Pathologic; Gene Expression Profiling; Angiogenesis
PubMed: 38935597
DOI: 10.1371/journal.pone.0300790 -
Journal of the American Heart... Jun 2024The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This...
Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.
BACKGROUND
The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine.
METHODS AND RESULTS
Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming.
CONCLUSIONS
This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.
PubMed: 38934866
DOI: 10.1161/JAHA.124.034805 -
Health Science Reports Jun 2024Although the clinical benefit of percutaneous coronary intervention (PCI) on cardiovascular outcomes has been widely investigated, the impact of this revascularization...
BACKGROUND AND AIMS
Although the clinical benefit of percutaneous coronary intervention (PCI) on cardiovascular outcomes has been widely investigated, the impact of this revascularization strategy compared to other alternatives on the degree of left ventricular function recovery is poorly demonstrated. In this regard, we investigated whether time delays between the presentation of ST-segment elevation myocardial infarction (STEMI) and PCI in reperfusion strategies have different impacts on left ventricular function recovery.
METHODS
In this single-center study, all the patients who presented with STEMI and a reduced left ventricular ejection fraction (LVEF ≤ 40%) were enrolled. Included patients were subjected to four different treatment groups of primary, rescue (immediate transfer for angioplasty due to failed fibrinolytic therapy), facilitated (fibrinolytic therapy followed by angioplasty within 24 h), and deferred (successful fibrinolytic therapy and PCI after 24 h) PCI based on hospital facilities. Echocardiography was performed for all the patients at the time of hospitalization and 6 months later.
RESULTS
A total of 128 patients were included in this study. The LVEF improved by 15.3 ± 6.3%, 11.5 ± 3.61%, 4.0 ± 1.0%, and -1.3 ± 7.0% in primary, rescue, facilitated, and deferred PCI groups, respectively ( < 0.001). Patients undergoing deferred PCI experienced a significantly lower improvement in LVEF compared with primary and rescue PCI ( < 0.001).
CONCLUSION
Primary PCI demonstrated the most promising recovery in left ventricular function following STEMI compared to other alternative strategies. Performing PCI as soon as possible provides better recovery of LVEF.
PubMed: 38933425
DOI: 10.1002/hsr2.2220 -
Antioxidants (Basel, Switzerland) May 2024Ischemic conditionings (ICon) were intensively investigated and several protective signaling pathways were identified. Previously, we have shown the role of matrix...
INTRODUCTION
Ischemic conditionings (ICon) were intensively investigated and several protective signaling pathways were identified. Previously, we have shown the role of matrix metalloproteinases (MMP) in myocardial ischemia/reperfusion injury (MIRI) and the cardioprotective role of biglycan (BGN), a small leucine-rich proteoglycan in vitro. Here, we hypothesized that cardiac MMP and BGN signaling are involved in the protective effects of ICon.
METHODS
A reverse target-microRNA prediction was performed by using the miRNAtarget™ 2.0 software to identify human microRNAs with a possible regulatory effect on MMP and BGN, such as on related genes. To validate the identified 1289 miRNAs in the predicted network, we compared them to two cardioprotective miRNA omics datasets derived from pig and rat models of MIRI in the presence of ICons.
RESULTS
Among the experimentally measured miRNAs, we found 100% sequence identity to human predicted regulatory miRNAs in the case of 37 porcine and 24 rat miRNAs. Upon further analysis, 42 miRNAs were identified as MIRI-associated miRNAs, from which 24 miRNAs were counter-regulated due to ICons.
CONCLUSIONS
Our findings highlight 24 miRNAs that potentially regulate cardioprotective therapeutic targets associated with MMPs and BGN in a highly translatable porcine model of acute myocardial infarction.
PubMed: 38929113
DOI: 10.3390/antiox13060674