The Clinical and Economic Impact of Delayed Reperfusion Therapy: Real-World Evidence. / O Impacto Clínico e Econômico do Atraso na Terapia de Reperfusão: Evidências do Mundo Real.

BACKGROUND: Early reperfusion therapy is acknowledged as the most effective approach for reducing case fatality rates in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVE: Estimate the clinical and economic consequences of delaying reperfusion in patients with STEMI. METHODS: This retrospective cohort study evaluated mortality rates and the total expenses incurred by delaying reperfusion therapy among 2622 individuals with STEMI. Costs of in-hospital care and lost productivity due to death or disability were estimated from the perspective of the Brazilian Unified Health System indexed in international dollars (Int$) adjusted by purchase power parity. A p < 0.05 was considered statistically significant. RESULTS: Each additional hour of delay in reperfusion therapy was associated with a 6.2% increase (95% CI: 0.3% to 11.8%, p = 0.032) in the risk of in-hospital mortality. The overall expenses were 45% higher among individuals who received treatment after 9 hours compared to those who were treated within the first 3 hours, primarily driven by in-hospital costs (p = 0.005). A multivariate linear regression model indicated that for every 3-hour delay in thrombolysis, there was an increase in in-hospital costs of Int$497 ± 286 (p = 0.003). CONCLUSIONS: The findings of our study offer further evidence that emphasizes the crucial role of prompt reperfusion therapy in saving lives and preserving public health resources. These results underscore the urgent need for implementing a network to manage STEMI cases.

FUNDAMENTO: A terapia de reperfusão precoce é reconhecida como a abordagem mais eficaz para reduzir as taxas de letalidade de casos em pacientes com infarto do miocárdio com supradesnivelamento do segmento ST (IAMCSST). OBJETIVO: Estimar as consequências clínicas e econômicas do atraso da reperfusão em pacientes com IAMCSST. MÉTODOS: O presente estudo de coorte retrospectivo avaliou as taxas de mortalidade e as despesas totais decorrentes do atraso na terapia de reperfusão em 2.622 indivíduos com IAMCSST. Os custos de cuidados hospitalares e perda de produtividade por morte ou incapacidade foram estimados sob a perspectiva do Sistema Único de Saúde indexado em dólares internacionais (Int$) ajustados pela paridade do poder de compra. Foi considerado estatisticamente significativo p < 0,05. RESULTADOS: Cada hora adicional de atraso na terapia de reperfusão foi associada a um aumento de 6,2% (intervalo de confiança de 95%: 0,3% a 11,8%, p = 0,032) no risco de mortalidade hospitalar. As despesas gerais foram 45% maiores entre os indivíduos que receberam tratamento após 9 horas em comparação com aqueles que foram tratados nas primeiras 3 horas, impulsionados principalmente pelos custos hospitalares (p = 0,005). Um modelo de regressão linear multivariada indicou que para cada 3 horas de atraso na trombólise, houve um aumento nos custos hospitalares de Int$ 497 ± 286 (p = 0,003). CONCLUSÕES: Os achados do nosso estudo oferecem mais evidências que enfatizam o papel crucial da terapia de reperfusão imediata no salvamento de vidas e na preservação dos recursos de saúde pública. Estes resultados enfatizam a necessidade urgente de implementação de uma rede para gerir casos de IAMCSST.

Intracoronary microcatheter indwelling for continuous pumping of low-dose thrombolytic drugs: A new approach to reperfusion in acute myocardial infarction.

Reperfusion therapy of acute myocardial infarction (AMI) refers to physical or chemical recanalization and restoration of blood flow to an occluded coronary artery, and current techniques for reperfusion therapy include intravenous thrombolysis, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). The number of patients receiving emergency CABG in the real world is decreasing due to the disadvantages of CABG and the improvement in PCI procedures. Thrombolytic therapy has some disadvantages such as low recanalization rate, high risk of reocclusion and bleeding, and short time window. On the other hand, intracoronary interventional therapy may meet the requirements of "early, complete and persistent" patency of coronary arteries at different time points. However, in the emergency PCI, although thrombus aspiration via a catheter or balloon dilation is performed, residual thrombus with heavy or low TIMI (thrombolysis in myocardial infarction) myocardial perfusion grading is still observed in some patients, suggesting disordered microcirculation. Currently, the treatment of microcirculatory disturbance in emergency PCI mainly employed injection of tirofiban, adenosine, thrombolytic agent or other drugs into the local area via a microcatheter in a short time, all of which can significantly reduce the thrombus load and improve TIMI perfusion. Herein, we report that a microcatheter was indwelled in the coronary artery for continuous pumping of low-dose thrombolytic drugs as reperfusion therapy in 12 patients with acute and subacute MI.

[Features of the Reperfusion Therapy for ST-Segment Elevation Myocardial Infarction According to the Russian Registry of Acute Myocardial Infarction - REGION-IM].

AIM: Based on data from the Russian REGION-IM registry, to study the features of reperfusion therapy in patients with ST-segment elevation myocardial infarction (STEMI) in real-life clinical practice. MATERIAL AND METHODS: REGION-IM is a multicenter prospective observational study. The observational period is divided into 3 stages: during the stay in the hospital and at 6 and 12 months after inclusion in the registry. The patient's records contain demographic and history data; information about the present case of MI, including the time of the first symptom onset, first contact with medical personnel, and admission to the hospital; coronary angiography (CAG) data, percutaneous coronary intervention (PCI) data, and information about the thrombolytic therapy (TLT). RESULTS: Reperfusion therapy was performed in 88.9 % of patients with STEMI. Primary PCI (pPCI) was performed in 60.6 % of patients. The median time from the onset of symptoms to pPCI was 315 minutes [195; 720]. The median time from ECG to pPCI was 110 minutes [84;150]. Isolated TLT was performed in 7.4 %, pharmaco-invasive treatment tactics were used only in 20.9 % of cases. The median time from ECG to TLT (prehospital and in-hospital) was 30 minutes [10; 59], whereas the median time from ECG to prehospital TLT was 18 minutes [10; 39], and in 63 % of patients, TLT was performed more than 10 minutes after diagnosis. PCI followed TLT in 73 % of patients. CONCLUSION: The frequency of reperfusion therapy for STEMI in the Russian Federation has increased considerably in recent years. The high frequency of pPCI is noteworthy, but the timing of pPCI does not always comply with clinical guidelines. The results of this registry confirm the high demand for pharmaco-invasive strategies in real-life clinical practice. Taking into account geographical and logistical features, implementing timely myocardial reperfusion requires prehospital TLT. However, the TLT frequency in the Russian Federation is still insufficient despite its proven maximum effectiveness in the shortest possible time from the detection of acute MI.

Spontaneous reperfusion in STEMI: Its mechanisms and possible modulation.

Patients with transient ST-segment elevation myocardial infarction or spontaneous reperfusion, which occurs in approximately 20% of patients with ST-segment elevation myocardial infarction (STEMI), have smaller infarcts and more favorable clinical outcomes than patients without spontaneous reperfusion. Understanding the mechanisms underlying spontaneous reperfusion is therefore important since this may identify possible novel therapeutic targets to improve outcomes in patients with STEMI. In this review, we discuss some of the possible determinants of spontaneous reperfusion including pro-thrombotic profile, endogenous fibrinolytic status, lipoprotein(a) (Lp[a]), inflammatory markers, and neutrophil extracellular traps (NETs). Effective (rapid) endogenous fibrinolysis, as assessed in whole blood in vitro, using a point-of-care technique assessment of global thrombotic status, has been strongly linked to spontaneous reperfusion. Lp(a), which has a high degree of homology to plasminogen, may impair fibrinolysis through competitive inhibition of tissue plasminogen activator-mediated plasminogen activation as well as tissue plasminogen activator-mediated clot lysis and contribute to pathogenic clot properties by decreasing fibrin clot permeation. NETs appear to negatively modulate clot lysis by increasing thrombin fiber diameter and inhibiting plasmin-driven lysis of plasma clots. There are limited data that oral anticoagulation may modulate endogenous fibrinolysis but antiplatelet agents currently appear to have no impact. Phase III trials involving subcutaneous P2Y12 or glycoprotein IIb/IIIa inhibitors, oral factor XIa inhibitors, interleukin-6 inhibitors, and apolipoprotein(a) antisense oligonucleotides in patients with cardiovascular disease are ongoing. Future studies will be needed to determine the impact of these novel antithrombotic, anti-inflammatory, and lipid-lowering therapies on endogenous fibrinolysis and spontaneous reperfusion.

Exploring variation in timely reperfusion treatment in ST-segment elevation myocardial infarction in Norway: a national register-based cohort study.

OBJECTIVES: This study aimed to investigate determinants of reperfusion within recommended time limits (timely reperfusion) for ST-segment elevation myocardial infarction patients, exploring the impact of geography, patient characteristics and socio-economy. DESIGN: National register-based cohort study. SETTING: Multilevel logistic regression models were applied to examine the associations between timely reperfusion and residency in hospital referral areas and municipalities, patient characteristics, and socio-economy. PARTICIPANTS: 7607 Norwegian ST-segment elevation myocardial infarction patients registered in the Norwegian Registry of Myocardial Infarction during 2015-2018. MAIN OUTCOME MEASURES: The odds of timely reperfusion by primary percutaneous coronary intervention (PCI) or fibrinolysis. RESULTS: Among 7607 ST-segment elevation myocardial infarction patients in Norway, 56% received timely reperfusion. The Norwegian goal is 85%. While 81% of the patients living in the Oslo hospital referral area received timely reperfusion, only 13% of the patients living in Finnmark did so.Patients aged 75-84 years had lower odds of timely reperfusion than patients below 55 years of age (OR 0.73, 95% CI 0.61 to 0.87). Patients with moderate or high comorbidity had lower odds than patients without (OR 0.81, 95% CI 0.68 to 0.95 and OR 0.61, 95% CI 0.44 to 0.84). More than 2 hours from symptom onset to first medical contact gave lower odds than less than 30 min (OR 0.63, 95% CI 0.54 to 0.72). 1-2 hours of travel time to a PCI centre (OR 0.39, 95% CI 0.31 to 0.49) and more than 2 hours (OR 0.22, 95% CI 0.16 to 0.30) gave substantially lower odds than less than 1 hour of travel time. CONCLUSIONS: The varying proportion of patients receiving timely reperfusion across hospital referral areas implies inequity in fundamental healthcare services, not compatible with established Norwegian health policy. The importance of travel time to PCI centre points at the expanded use of prehospital pharmacoinvasive strategy to obtain the goals of timely reperfusion in Norway.

Comparative Analysis of Infarct-Limiting Activity of Peptide and Non-Peptide δ- and κ-Opioid Receptor Agonists during Heart Reperfusion In Vivo.

A comparative analysis of the infarct-limiting activity of δ- and κ-opioid receptors (OR) agonists was carried out on a model of coronary occlusion (45 min) and reperfusion (120 min) in male Wistar rats. We used selective δ2-OR agonist deltorphin II (0.12 mg/kg), δ-OR agonists BW373U86 and p-Cl-Phe DPDPE (0.1 and 1 mg/kg), selective agonists of δ1-OR DPDPE (0.1 and 0.969 mg/kg), κ1-OR U-50,488 (0.1 and 1 mg/kg), κ2-OR GR-89696 (0.1 mg/kg), and κ-OR ICI-199,441 (0.1 mg/kg). All drugs were administered intravenously 5 min before reperfusion. Deltorphin II, BW373U86 (1 mg/kg), p-Cl-Phe DPDPE (1 mg/kg), U-50,488 (1 mg/kg), and ICI-199,441 had a cardioprotective effect. The most promising compounds for drug development are ICI-199,441 and deltorphin II.

Culprit Lesion Vessel Size and Risk of Reperfusion Injury in ST-Segment Elevation Myocardial Infarction: A Cardiac Magnetic Resonance Imaging Study.

BACKGROUND: Microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH) are well-established imaging biomarkers of failed myocardial tissue reperfusion in patients with ST-segment elevation-myocardial infarction treated with percutaneous coronary intervention. MVO and IMH are associated with an increased risk of adverse outcome independent of infarct size, but whether the size of the culprit lesion vessel plays a role in the occurrence and severity of reperfusion injury is currently unknown. This study aimed to evaluate the association between culprit lesion vessel size and the occurrence and severity of reperfusion injury as determined by cardiac magnetic resonance imaging. METHODS AND RESULTS: Patients (n=516) with first-time ST-segment-elevation myocardial infarction underwent evaluation with cardiac magnetic resonance at 4 (3-5) days after infarction. MVO was assessed with late gadolinium enhancement imaging and IMH with T2* mapping. Vessel dimensions were determined using catheter-based reference. Median culprit lesion vessel size was 3.1 (2.7-3.6) mm. MVO and IMH were found in 299 (58%) and 182 (35%) patients. Culprit lesion vessel size was associated with body surface area, diabetes, total ischemic time, postinterventional thrombolysis in myocardial infarction flow, and infarct size. There was no association between vessel size and MVO or IMH in univariable and multivariable analysis (P>0.05). These findings were consistent across patient subgroups with left anterior descending artery and non-left anterior descending artery infarctions and those with thrombolysis in myocardial infarction 3 flow post-percutaneous coronary intervention. CONCLUSIONS: Comprehensive characterization of myocardial tissue reperfusion injury by cardiac magnetic resonance revealed no association between culprit lesion vessel size and the occurrence of MVO and IMH in patients treated with primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction.

Quantitative visualization of myocardial ischemia-reperfusion-induced cardiac lesions via ferroptosis magnetic particle imaging.

Myocardial ischemia-reperfusion (MI/R) injury is a complication in vascular reperfusion therapy for MI, occurring in approximately 60% of patients. Ferroptosis is an important process in the development of MI/R cardiac lesions. Transferrin receptor 1 (TfR1), a marker of ferroptosis, corresponds to the changes in MI/R cardiac lesions and is expected to be a biomarker for detecting MI/R-induced ferroptosis. However, the noninvasive in vivo visualization of ferroptosis in MI/R is a big challenge. Thus, this study aimed to develop a novel multimodal imaging platform to identify markers of MI/R cardiac lesions in vivo through targeting TfR1. Methods: Magnetic particle imaging (MPI) modality for ferroptosis based on superparamagnetic cubic-iron oxide nanoparticles (SCIO NPs), named feMPI, has been developed. FeMPI used TfR1 as a typical biomarker. The feMPI probe (SCIO-ICG-CRT-CPPs NPs, CCI NPs) consists of SCIO NPs, TfR1-targeting peptides (CRT), cell-penetrating peptides (CPPs), and indocyanine green (ICG). The specificity and sensitivity of CCI NPs in the MI/R mouse model were evaluated by MPI, magnetic resonance imaging (MRI), and near-infrared (NIR) fluorescent imaging. Results: The intensity of the MPI signal correlates linearly with the percentage of infarct area in MI/R stained by TTC, enabling a quantitative assessment of the extent of cardiac lesions. Notably, these findings are consistent with the standard clinical biochemical indicators in MI/R within the first 24 h. FeMPI detects cardiac injury approximately 48 h prior to the current clinical imaging detection methods of MI/R. Conclusion: The feMPI strategy can be a powerful tool for studying the process of MI/R-induced ferroptosis in vivo, providing clues for molecular imaging and drug development of ferroptosis-related treatments.

Myocardial ischemia/reperfusion: Translational pathophysiology of ischemic heart disease.

Ischemic heart disease is the greatest health burden and most frequent cause of death worldwide. Myocardial ischemia/reperfusion is the pathophysiological substrate of ischemic heart disease. Improvements in prevention and treatment of ischemic heart disease have reduced mortality in developed countries over the last decades, but further progress is now stagnant, and morbidity and mortality from ischemic heart disease in developing countries are increasing. Significant problems remain to be resolved and require a better pathophysiological understanding. The present review attempts to briefly summarize the state of the art in myocardial ischemia/reperfusion research, with a view on both its coronary vascular and myocardial aspects, and to define the cutting edges where further mechanistic knowledge is needed to facilitate translation to clinical practice.

Evolution of REperfusion Strategies and impact on mortality in Old and Very OLD STEMI patients. The RESOVOLD-e-MUST study.

BACKGROUND: The use of myocardial reperfusion-mainly via angioplasty-has increased in our region to over 95%. We wondered whether old and very old patients have benefited from this development. METHODS: Setting: Greater Paris Area (Ile-de-France). DATA: Regional registry, prospective, including since 2003, data from 39 mobile intensive care units performing prehospital treatment of patients with ST segment elevation myocardial infarction (STEMI) (<24 h). PARAMETERS: Demographic, decision to perform reperfusion and outcome (in-hospital mortality). PRIMARY ENDPOINT: Reperfusion decision rate by decade over age 70. SECONDARY ENDPOINT: Outcome. RESULTS: We analysed the prehospital management of 27,294 patients. There were 21,311 (78%) men and 5,919 (22%) women with a median age of 61 (52-73 years). Among these patients, 8,138 (30%) were > 70 years, 3,784 (14%) > 80 years and 672 (2%) > 90 years.The reperfusion decision rate was 94%. It decreased significantly with age: 93, 90 and 76% in patients in their seventh, eighth and ninth decade, respectively. The reperfusion decision rate increased significantly over time. It increased in all age groups, especially the higher ones. Mortality was 6%. It increased significantly with age: 8, 16 and 25% in patients in their seventh, eighth and ninth decade, respectively. It significantly decreased over time in all age groups. The odds ratio of the impact of reperfusion decision on mortality reached 0.42 (0.26-0.68) in patients over 90 years. CONCLUSION: the increase in the reperfusion decision rate was the greatest in the oldest patients. It reduced mortality even in patients over 90 years of age.

Circ-MBOAT2 Regulates Angiogenesis via the miR-495/NOTCH1 Axis and Associates with Myocardial Perfusion in Patients with Coronary Chronic Total Occlusion.

Revascularization of coronary chronic total occlusion (CTO) still remains controversial. The factors that impact collateral circulation and myocardial perfusion are of interest. Circular RNA (circRNA) has been shown to regulate the process of angiogenesis. However, the effects of circ-membrane-bound O-acyltransferase domain containing 2 (circ-MBOAT2) on angiogenesis in patients with CTO were unclear. In this study, we evaluated circulating circRNAs and miRNAs in patients with CTO and stable coronary artery disease using high-throughput sequencing. Another cohort of patients were selected to verify the expressions of circ-MBOAT2 and miR-495. The role and mechanism of circ-MBOAT2 in the process of angiogenesis were explored through in vitro and vivo studies. Finally, we came back to a clinical perspective and investigated whether circ-MBOAT2 and miR-495 were associated with the improvement of myocardial perfusion evaluated by single-photon emission computed tomography (SPECT). We found that the expression of circ-MBOAT2 was significantly up-regulated while miR-495 was significantly down-regulated in patients with CTO. The expression of circ-MBOAT2 was negatively correlated with miR-495 in patients with CTO. In an in vitro study, we found that circ-MBOAT2 promoted tube formation and cell migration via the miR-495/NOTCH1 axis in endothelial cells. In an in vivo study, we showed that the inhibition of miR-495 caused the increase in collateral formation in mice after hindlimb ischemia. In a human study, we showed the expressions of circ-MBOAT2 and miR-495 were associated with myocardial perfusion improvement after revascularization of CTO. In conclusion, circ-MBOAT2 regulates angiogenesis via the miR-495/NOTCH1 axis and associates with myocardial perfusion in patients with CTO. Our findings suggest that circ-MBOAT2 and miR-495 may be potential therapeutic targets and prognostic factors for patients with CTO.

Delaying reperfusion plus left ventricular unloading reduces infarct size: Sub-analysis of DTU-STEMI pilot study.

INTRODUCTION: The STEMI-DTU pilot study tested the early safety and practical feasibility of left ventricular (LV) unloading with a trans-valvular pump before reperfusion. In the intent-to-treat cohort, no difference was observed for microvascular obstruction (MVO) or infarct size (IS) normalized to either the area at risk (AAR) at 3-5 days or total LV mass (TLVM) at 3-5 days We now report a per protocol analysis of the STEMI-DTU pilot study. METHODS: In STEMI-DTU STUDY 50 adult patients (25 in each arm) with anterior STEMI [sum of precordial ST-segment elevation (ΣSTE) ≥4 mm] requiring primary percutaneous coronary intervention (PCI) were enrolled. Only patients who met all inclusion and exclusion criteria were included in this analysis. Cardiac magnetic resonance (CMR) imaging 3-5 days after PCI quantified IS/AAR and IS/TLVM and MVO. Group differences were assessed using Student's t-tests and linear regression (SAS Version-9.4). RESULTS: Of the 50 patients enrolled, 2 died before CMR imaging. Of the remaining 48 patients those without CMR at 3-5 days (n = 8), without PCI of a culprit left anterior descending artery lesion (n = 2), with OHCA (n = 1) and with ΣSTE < 4 mm (n = 5) were removed from this analysis leaving 32/50 (64 %) patients meeting all inclusion and exclusion criteria (U-IR, n = 15; U-DR, n = 17) as per protocol. Despite longer symptom-to-balloon times in the U-DR arm (228 ± 80 vs 174 ± 59 min, p < 0.01), IS/AAR was significantly lower with 30 min of delay to reperfusion in the presence of active LV unloading (47 ± 16 % vs 60 ± 15 %, p = 0.02) and remained lower irrespective of the magnitude of precordial ΣSTE. MVO was not significantly different between groups (1.5 ± 2.8 % vs 3.5 ± 4.8 %, p = 0.15). Among patients who received LV unloading within 180 min of symptom onset, IS/AAR was significantly lower in the U-DR group. CONCLUSION: In this per-protocol analysis of the STEMI-DTU pilot study we observed that LV unloading for 30 min before reperfusion significantly reduced IS/AAR compared to LV unloading and immediate reperfusion, whereas in the ITT cohort no difference was observed between groups. This observation supports the design of the STEMI-DTU pivotal trial and suggests that strict adherence to the study protocol can significantly influence the outcome.

[e-MUST Registry - Evaluation of prehospital medical management of STEMI in Île-de-France]. / Registre e-MUST - Évaluation de la prise en charge médicale préhospitalière du SCA ST+ en Île-de-France.

The e-MUST registry has continuously and comprehensively documented ST-segment elevation myocardial infarctions (STEMIs) managed in the prehospital setting by the 39 Mobile Emergency and Resuscitation Services (SMUR) of the 8 Emergency Medical Assistance System (SAMU) and subsequently managed in the 36 interventional cardiology services in Île-de-France since 2000. This encompasses a population of over 12 million residents. To date, nearly 44,000 patients have been enrolled. The analysis of these findings reflects the real-world management of these patients and the evolution of their care. The results are shared annually with the investigators' teams and have led to around twenty publications. The latest acquired results have demonstrated, in a series of over 630 patients aged over 90, that nonagenarians particularly benefit from prehospital coronary reperfusion decisions, resulting in a nearly 60% reduction in mortality.

Long-Term Prognosis of Different Reperfusion Strategies for ST-Segment Elevation Myocardial Infarction in Chinese County-Level Hospitals: Insight from China Acute Myocardial Infarction Registry.

Objective: To evaluate the long-term prognosis of patients with ST-segment elevation myocardial infarction (STEMI) treated with different reperfusion strategies in Chinese county-level hospitals. Methods: A total of 2,514 patients with STEMI from 32 hospitals participated in the China Acute Myocardial Infarction registry between January 2013 and September 2014. The success of fibrinolysis was assessed according to indirect measures of vascular recanalization. The primary outcome was 2-year mortality. Results: Reperfusion therapy was used in 1,080 patients (42.9%): fibrinolysis ( n= 664, 61.5%) and primary percutaneous coronary intervention (PCI) ( n= 416, 38.5%). The most common reason for missing reperfusion therapy was a prehospital delay > 12 h (43%). Fibrinolysis [14.5%, hazard ratio ( HR): 0.59, 95% confidence interval ( CI) 0.44-0.80] and primary PCI (6.8%, HR= 0.32, 95% CI: 0.22-0.48) were associated with lower 2-year mortality than those with no reperfusion (28.5%). Among fibrinolysis-treated patients, 510 (76.8%) achieved successful clinical reperfusion; only 17.0% of those with failed fibrinolysis underwent rescue PCI. There was no difference in 2-year mortality between successful fibrinolysis and primary PCI (8.8% vs. 6.8%, HR = 1.53, 95% CI: 0.85-2.73). Failed fibrinolysis predicted a similar mortality (33.1%) to no reperfusion (33.1% vs. 28.5%, HR= 1.30, 95% CI: 0.93-1.81). Conclusion: In Chinese county-level hospitals, only approximately 2/5 of patients with STEMI underwent reperfusion therapy, largely due to prehospital delay. Approximately 30% of patients with failed fibrinolysis and no reperfusion therapy did not survive at 2 years. Quality improvement initiativesare warranted, especially in public health education and fast referral for mechanical revascularization in cases of failed fibrinolysis.

Dynamic Assessments of Coronary Flow Reserve after Myocardial Ischemia Reperfusion in Mice.

After cardiac ischemia, there is often insufficient myocardial perfusion, even if flow has been successfully and completely restored in an upstream artery. This phenomenon, known as the "no-reflow phenomenon," is attributed to coronary microvascular dysfunction and has been associated with poor clinical outcomes. In clinical practice, a reduction in coronary flow reserve (CFR) is frequently used as an indicator of coronary artery disease. CFR is defined as the ratio of the peak flow velocity induced by pharmacologic or metabolic factors to the resting flow velocity. This protocol focused on assessing the dynamic changes in CFR before and after ischemia-reperfusion (IR) using pulse wave Doppler measurements. In this study, normal mice exhibited the ability to increase the peak velocity of coronary blood flow up to two times higher than the resting values under isoflurane stimulation. However, after ischemia-reperfusion, the CFR at 1 h significantly decreased compared to the pre-operation baseline. Over time, the CFR showed gradual recovery, but it remained below the normal level. Despite the preservation of systolic function, early detection of microvascular dysfunction is crucial, and establishing a practical guide could aid doctors in this task, while also facilitating the study of cardiovascular disease progression over time.

Alterations of SIRT1/SIRT3 subcellular distribution in aging undermine cardiometabolic homeostasis during ischemia and reperfusion.

Age-related sensors Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) play an essential role in the protective response upon myocardial ischemia and/or reperfusion (I/R). However, the subcellular localization and co-regulatory network between cardiac SIRT1 and SIRT3 remain unknown, especially their effects on age-related metabolic regulation during acute ischemia and I/R. Here, we found that defects of cardiac SIRT1 or SIRT3 with aging result in an exacerbated cardiac physiological structural and functional deterioration after acute ischemic stress and failed recovery through reperfusion operation. In aged hearts, SIRT1 translocated into mitochondria and recruited more mitochondria SIRT3 to enhance their interaction during acute ischemia, acting as adaptive protection for the aging hearts from further mitochondria dysfunction. Subsequently, SIRT3-targeted proteomics revealed that SIRT1 plays a crucial role in maintaining mitochondrial integrity through SIRT3-mediated substrate metabolism during acute ischemic and I/R stress. Although the loss of SIRT1/SIRT3 led to a compromised PGC-1α/PPARα-mediated transcriptional control of fatty acid oxidation in response to acute ischemia and I/R, their crosstalk in mitochondria plays a more important role in the aging heart during acute ischemia. However, the increased mitochondria SIRT1-SIRT3 interaction promoted adaptive protection to aging-related fatty acid metabolic disorder via deacetylation of long-chain acyl CoA dehydrogenase (LCAD) during ischemic insults. Therefore, the dynamic network of SIRT1/SIRT3 acts as a mediator that regulates adaptive metabolic response to improve the tolerance of aged hearts to ischemic insults, which will facilitate investigation into the role of SIRT1/SIRT3 in age-related ischemic heart disease.

Biomarkers of Thrombotic Status Predict Spontaneous Reperfusion in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Spontaneous reperfusion, seen in ∼20% of patients with ST-segment elevation myocardial infarction (STEMI), manifests as normal epicardial flow in the infarct-related artery, with or without ST-segment resolution, before percutaneous coronary intervention (PCI). The drivers mediating this are unknown. OBJECTIVES: The authors sought to relate spontaneous reperfusion to the thrombotic profile. METHODS: In a prospective study, blood from STEMI patients (n = 801) was tested pre-PCI to assess in vitro, point-of-care, occlusion times (OT) and endogenous lysis times (LT). Spontaneous reperfusion was defined as infarct-related artery Thrombolysis In Myocardial Infarction flow grade 3 before PCI. Patients were followed for major cardiovascular events (death, myocardial infarction, or stroke). RESULTS: Spontaneous reperfusion was associated with a longer OT (435 seconds vs 366 seconds; P < 0.001) and a shorter LT (1,257 seconds vs 1,616 seconds; P < 0.001), lower troponin, and better left ventricular function. LT was superior to OT for predicting spontaneous reperfusion (area under the curve for LT: 0.707; 95% CI: 0.661-0.753; area under the curve for OT: 0.629; 95% CI: 0.581-0.677). Among patients with spontaneous reperfusion, those with complete, vs partial ST-segment resolution, had a longer OT (P = 0.002) and a shorter LT (P < 0.001). Spontaneous reperfusion was unrelated to clinical characteristics or pain-to-angiography times. Over 4 years, patients with spontaneous reperfusion experienced fewer major adverse cardiovascular events than those without (4.1% vs 10.6%; P = 0.013), especially in those with both spontaneous reperfusion and complete ST-segment resolution (1.5% vs 10.1%; P = 0.029). CONCLUSIONS: We demonstrate a novel hematological signature in STEMI patients with spontaneous reperfusion, namely, decreased platelet reactivity and faster endogenous fibrinolysis, relating to smaller infarcts and improved survival. This finding indicates a role for modulating thrombotic status early after STEMI onset, to facilitate spontaneous reperfusion and improve outcomes.

Cardiac ischemia and reperfusion in mice: a comprehensive hemodynamic, electrocardiographic and electrophysiological characterization.

Malignant ventricular arrhythmias (VA) after acute myocardial infarction remain a major threat. Aim of this study was to characterize the electrophysiological and autonomic sequelae of cardiac ischemia and reperfusion (I/R) in mice during the first week post incident. Left ventricular function was serially assessed using transthoracic echocardiography. VA were quantified by telemetric electrocardiogram (ECG) recordings and electrophysiological studies on the 2nd and 7th day after I/R. Cardiac autonomic function was evaluated by heart rate variability (HRV) and heart rate turbulence (HRT). Infarct size was quantified by planimetric measures. I/R caused significant myocardial scarring and diminished left ventricular ejection fraction. The ECG intervals QRS, QT, QTc, and JTc were prolonged in I/R mice. Both spontaneous VA scored higher and the inducibility of VA was raised in I/R mice. An analysis of HRV and HRT indicated a relative reduction in parasympathetic activity and disturbed baroreflex sensitivity up to 7 days after I/R. In summary, during the first week after I/R, the murine heart reflects essential features of the human heart after myocardial infarction, including a greater vulnerability for VA and a decreased parasympathetic tone accompanied by decelerated depolarization and repolarization parameters.