Effect of tocilizumab on endothelial and platelet-derived CXC-chemokines and their association with inflammation and myocardial injury in STEMI patients undergoing primary PCI.

BACKGROUND: Tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI) patients when administered before percutaneous coronary intervention (PCI). The mechanisms underlying ischemia-reperfusion injury remain unclear. In this sub-study, we investigated whether endothelial and platelet-derived CXC chemokines are involved, as they represent inflammatory mediators from two cell types relevant to myocardial infarction. Associations between these chemokines and neutrophils, C-reactive protein (CRP), troponin T (TnT), myocardial salvage index (MSI), microvascular obstruction (MVO), and infarct size. METHODS: This is a sub-study of the ASSAIL-MI trial, a double-blind clinical trial that randomized 199 STEMI patients to receive either 280 mg tocilizumab (n = 101) or placebo (n = 98) intravenously before PCI. Blood samples were collected prior to infusion, at day 1-2, 3-7, and at 3 and 6 months. Heparin was administered before baseline in 150 patients, while 49 received it after. We measured CXC-chemokines CXCL4, CXCL5, CXCL6, CXCL7, and CXCL12 using immunoassays. Cardiac MRI was performed in the first week and at 6 months. RESULTS: Tocilizumab did not significantly affect CXC-chemokines levels. Although some correlations were observed between chemokine levels and neutrophil counts and CRP, none of the CXC chemokines were associated with infarct size, MSI, MVO, or TnT levels. Notably, CXCL 12 levels increased in patients who received heparin before baseline, while other CXC-chemokines decreased significantly. CONCLUSION: This study suggests that the beneficial effects of tocilizumab in STEMI patients are not due to changes in circulating endothelial or platelet-derived CXC-chemokines, compared to placebo. However, heparin significantly influences the levels of these chemokines.

Cardioprotective effect of Perakine against myocardial ischemia-reperfusion injury of type-2 diabetic rat in Langendorff-Perfused Rat Hearts: Role of TLR4/NF-kB signalling pathway.

Myocardial ischemia-reperfusion (I/R) injury is a grave life-threatening situation, if not treated well in time. The development of natural remedies for myocardial I/R injury has witnessed dramatic growth in the last decade. Prompted by the above, in the present study, we have elucidated the pharmacological effect of Perakine (PER), an indole alkaloid in myocardial ischemia-reperfusion injury in type 2 diabetic rats. The model was established by inducing diabetes in experimental rats followed by the development of myocardial I/R injury model of isolated rat heart by the use of improved Langendorff retrograde perfusion technology. Results of the study suggest that PER significantly lowered the infarct size and infarct volume, and improvement in cardiac ability (LVSP, ±dP/dtmax, and heart rate). It also showed a significant lowering of cardiac biomarkers (CK, CK(MB), ALT, AST, and LDH) in a dose-dependent manner as compared to unprotected IR rats. The level of oxidative stress (MDA, SOD, and GSH) was also found lowered in IR rats together with a reduction in the production of pro-inflammatory cytokines (IL-1ß, IL-6, IL-17, and TNF-α). The anti-inflammatory acting of PER on IR rats is believed to be linked with the reduction of TNF-α, NF-κB, and TLR4 in both RT-qPCR and western blot analysis. Our research showed that Perakine could potentially alleviate cardiac ischemia-reperfusion injury in rats by blocking the TLR4/NF-κB signaling cascade.

Eosinopenia in patients with acute myocardial infarction- longitudinal imaging insights from the CAPRI study.

Eosinophils are recruited to the heart during acute myocardial infarction (MI) and are considered part of the inflammatory response associated with adverse clinical outcomes. We assessed the impact of eosinopenia on cardiac imaging biomarkers in patients presenting with ST-segment elevation MI. This is a post-hoc analysis of the Evaluating the effectiveness of intravenous Ciclosporin on reducing reperfusion injury in pAtients undergoing PRImary percutaneous coronary intervention (CAPRI) trial. Patients underwent cardiac MRI within 1 week and 12 weeks and low eosinophil was defined as less than 40 cells/ml. The study included 52 patients and 38% had low eosinophil. Ciclosporin administration was comparable between patients with low versus normal eosinophils. The ischaemia time was significantly longer in low eosinophil patients [262 (205-325) vs. 138 (102-195) minutes, P < 0.001]. At 12 weeks, patients with eosinopenia had larger infarct size [9.8% (5.7-18.4) vs. 7.4% (1.9-10.2), P = 0.045], larger left ventricle (LV) end systolic volume (89 ± 28 vs. 68 ± 23, P = 0.02), and lower LV ejection fraction (EF) (49 ± 9 vs. 58 ± 7, P < 0.001). After adjustments for significant predictors, including ischaemia time, low eosinophil count was an independent predictor of worse LVEF at 12 weeks [-5.78, 95% CI (-11.22 to -0.34), P = 0.038] but not infarct size [1.83, 95% CI (-2.77 to 6.43), P = 0.43]. Patients with low eosinophil count had larger infarct size and LV volumes and worse adverse remodeling compared to those with normal eosinophil count. At 12 weeks, eosinopenia was an independent predictor of worse LVEF but not infarct size.

Glycoprotein IIb/IIIa Inhibitors in Acute Myocardial Infarction and Angiographic Microvascular Obstruction: The REVERSE-FLOW Trial.

BACKGROUND AND AIMS: Glycoprotein (GP) IIb/IIIa inhibitors are recommended in acute myocardial infarction (AMI) for bailout treatment in case of angiographic microvascular obstruction (MVO), also termed no-reflow phenomenon, after percutaneous coronary intervention (PCI) with, however, lacking evidence (class IIa, level C). METHODS: The investigator-initiated, international, multicenter REVERSE-FLOW trial randomized 120 patients with AMI and Thrombolysis In Myocardial Infarction flow grade ≤2 after primary PCI to optimal medical therapy with or without GP IIb/IIIa inhibitor. The primary endpoint was infarct size (%LV) assessed by cardiac magnetic resonance (CMR). Secondary endpoints included CMR-derived MVO and 30-day adverse clinical events. The trial is registered with ClinicalTrials.gov: NCT02739711. RESULTS: The population was predominantly male (76.7%) with a median age of 66 years and ST-elevation myocardial infarction in 73.3% of patients. Clinical and angiographic characteristics were well balanced between the cohorts. Patients in the treatment group (n=62) received eptifibatide (n=41) or tirofiban (n=21). Infarct size assessed by CMR imaging was similar in both study groups (25.4% of left ventricular mass [LV] vs. 25.2%LV; p=0.386). However, the number of patients with evidence of CMR-derived MVO (74.5% vs. 92.2%; p=0.017) and the extent of MVO (2.1%LV vs. 3.4%LV; p=0.025) were significantly reduced in the GP IIb/IIIa inhibitor group compared to controls. Thirty-day outcome showed an increased bleeding risk after GP IIb/IIIa inhibitor administration restricted to non-life-threatening bleedings (22.6% vs. 6.9%; p=0.016) without differences in all-cause mortality (4.8% vs. 3.4%; p=0.703). CONCLUSIONS: Bailout GP IIb/IIIa inhibition in AMI patients with angiographic MVO failed to reduce the primary endpoint infarct size but decreased CMR-derived MVO and led to an increase in non-fatal bleeding events.

Colchicine Prevents Cardiac Rupture in Mice with Myocardial Infarction by Inhibiting P53-Dependent Apoptosis.

Cardiac rupture is a fatal complication following myocardial infarction (MI) and there are currently no effective pharmacological strategies for preventing this condition. In this study, we investigated the effect of colchicine on post-infarct cardiac rupture in mice and its underlying mechanisms.We induced MI in mice by permanently ligating the left anterior descending artery. Oral colchicine or vehicle was administered at a dose of 0.1 mg/kg/day from day 1 to day 7 after MI. Cultured neonatal cardiomyocytes and fibroblasts were exposed to normoxia or anoxia and treated with colchicine.Colchicine significantly improved the survival rate (colchicine, n = 46: 82.6% versus vehicle, n = 42: 61.9%, P < 0.05) at 1 week after MI. Histological analysis revealed colchicine significantly reduced the infarct size and the number of macrophages around the infarct area. Colchicine decreased apoptosis in the myocardium of the border zone and cultured cardiomyocytes and fibroblasts as assessed by TUNEL assay. Colchicine also attenuated the activation of p53 and decreased the expression of cleaved-caspase 3 and bax, as assessed by Western blotting.Colchicine prevents cardiac rupture via inhibition of apoptosis, which is attributable to the downregulation of p53 activity. Our findings suggest that colchicine may be a prospective preventive medicine for cardiac rupture, however, large clinical trials are required.

Relationship Between Infarct Artery, Myocardial Injury, and Outcomes After Primary Percutaneous Coronary Intervention in ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: The extent to which infarct artery impacts the extent of myocardial injury and outcomes in patients with ST-segment-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention is uncertain. METHODS AND RESULTS: We performed a pooled analysis using individual patient data from 7 randomized STEMI trials in which myocardial injury within 30 days after primary percutaneous coronary intervention was assessed in 1774 patients by cardiac magnetic resonance (n=1318) or technetium-99m sestamibi single-photon emission computed tomography (n=456). Clinical follow-up was performed at a median duration of 351 days (interquartile range, 184-368 days). Infarct size and outcomes were assessed in anterior (infarct vessel=left anterior descending) versus nonanterior (non-left anterior descending) STEMI. Median infarct size (percentage left ventricular myocardial mass) was larger in patients with anterior compared with nonanterior STEMI (19.7% [interquartile range, 9.4%-31.7%] versus 12.6% [interquartile range, 5.1%-20.5%]; P<0.001). Patients with anterior compared with nonanterior STEMI were at higher risk for 1-year all-cause mortality (6.2% versus 3.6%; adjusted hazard ratio [HR], 1.66 [95% CI, 1.02-2.69]; P=0.04) and heart failure hospitalization (4.4% versus 2.6%; adjusted HR, 1.96 [95% CI, 1.15-3.36]; P=0.01). Infarct size was a predictor of subsequent all-cause mortality or heart failure hospitalization in anterior STEMI (adjusted HR per 1% increase, 1.05 [95% CI, 1.03-1.07]; P<0.001), but not in nonanterior STEMI (adjusted HR, 1.02 [95% CI, 0.99-1.05]; P=0.19). The P value for this interaction was 0.04. CONCLUSIONS: Anterior STEMI was associated with substantially greater myonecrosis after primary percutaneous coronary intervention compared with nonanterior STEMI, contributing in large part to the worse prognosis in patients with anterior infarction.

Deep learning segmentation model for quantification of infarct size in pigs with myocardial ischemia/reperfusion.

Infarct size (IS) is the most robust end point for evaluating the success of preclinical studies on cardioprotection. The gold standard for IS quantification in ischemia/reperfusion (I/R) experiments is triphenyl tetrazolium chloride (TTC) staining, typically done manually. This study aimed to determine if automation through deep learning segmentation is a time-saving and valid alternative to standard IS quantification. High-resolution images from TTC-stained, macroscopic heart slices were retrospectively collected from pig experiments (n = 390) with I/R without/with cardioprotection to cover a wide IS range. Existing IS data from pig experiments, quantified using a standard method of manual and subsequent digital labeling of film-scan annotations, were used as reference. To automate the evaluation process with the aim to be more objective and save time, a deep learning pipeline was implemented; the collected images (n = 3869) were pre-processed by cropping and labeled (image annotations). To ensure their usability as training data for a deep learning segmentation model, IS was quantified from image annotations and compared to IS quantified using the existing film-scan annotations. A supervised deep learning segmentation model based on dynamic U-Net architecture was developed and trained. The evaluation of the trained model was performed by fivefold cross-validation (n = 220 experiments) and testing on an independent test set (n = 170 experiments). Performance metrics (Dice similarity coefficient [DSC], pixel accuracy [ACC], average precision [mAP]) were calculated. IS was then quantified from predictions and compared to IS quantified from image annotations (linear regression, Pearson's r; analysis of covariance; Bland-Altman plots). Performance metrics near 1 indicated a strong model performance on cross-validated data (DSC: 0.90, ACC: 0.98, mAP: 0.90) and on the test set data (DSC: 0.89, ACC: 0.98, mAP: 0.93). IS quantified from predictions correlated well with IS quantified from image annotations in all data sets (cross-validation: r = 0.98; test data set: r = 0.95) and analysis of covariance identified no significant differences. The model reduced the IS quantification time per experiment from approximately 90 min to 20 s. The model was further tested on a preliminary test set from experiments in isolated, saline-perfused rat hearts with regional I/R without/with cardioprotection (n = 27). There was also no significant difference in IS between image annotations and predictions, but the performance on the test set data from rat hearts was lower (DSC: 0.66, ACC: 0.91, mAP: 0.65). IS quantification using a deep learning segmentation model is a valid and time-efficient alternative to manual and subsequent digital labeling.

Clinical, electrocardiographic, echocardiographic, and angiographic predictors for the final infarct size assessed by cardiac magnetic resonance in acute STEMI patients after primary percutaneous coronary intervention.

BACKGROUND: Final infarct size (IS) after ST segment elevation myocardial infarction (STEMI) is a major predictor of mortality. Seeking early predictors for final IS can guide individualized therapeutic strategies for those recognized to be at higher risk. RESULTS: Eighty STEMI patients successfully treated with primary percutaneous coronary intervention (pPCI) underwent baseline (within 48 h) 2D, 3D echocardiography with speckle tracking and then underwent cardiac magnetic resonance (CMR) at 3 months to assess the final IS. After recruitment, 4 patients were excluded for uncontainable claustrophobia while 76 patients completed the final analysis. The mean ± standard deviation age was 54.1 ± 10.9 years, 84% were males, 25% had diabetes, 26% were hypertensives, 71% were current smokers, 82% had dyslipidemia, and 18% had a family history of premature coronary artery disease. By 3 months, CMR was performed to accurately evaluate the final IS. In univariate regression analysis, the admission heart rate, baseline and post-pPCI ST elevation, STEMI location (anterior vs. inferior), highest peri-procedural troponin, large thrombus burden, baseline thrombolysis in myocardial infarction flow grade, the final myocardial blush grade, the 2D and 3D left ventricular ejection fraction (LVEF), and the 2D and 3D global longitudinal strain (GLS) parameters were significant predictors for the final IS. In the multivariate regression analysis, four models were constructed and recognized the residual post-PCI ST segment elevation, the highest peri-procedural troponin, the 2D-LVEF, 3D-LVEF, and 2D-GLS as significant independent predictors for final IS. CONCLUSIONS: In STEMI patients who underwent successful pPCI, early predictors for the final IS are vital to guide therapeutic decisions. The residual post-pPCI ST elevation, the highest peri-procedural troponin, and the baseline 2D-LVEF, 3D-LVEF, and 2D-GLS can be excellent and timely tools to predict the final IS.

Sonothrombolysis Before and After Percutaneous Coronary Intervention Provides the Largest Myocardial Salvage in ST Segment Elevation Myocardial Infarction.

BACKGROUND: Sonothrombolysis is a therapeutic application of ultrasound with ultrasound contrast for patients with ST elevation myocardial infarction (STEMI). Recent trials demonstrated that sonothrombolysis, delivered before and after primary percutaneous coronary intervention (pPCI), increases infarct vessel patency, improves microvascular flow, reduces infarct size, and improves ejection fraction. However, it is unclear whether pre-pPCI sonothrombolysis is essential for therapeutic benefit. We designed a parallel 3-arm sham-controlled randomized controlled trial to address this. METHODS: Patients presenting with first STEMI undergoing pPCI within 6 hours of symptom onset were randomized 1:1:1 into 3 arms: sonothrombolysis pre-/post-pPCI (group 1), sham pre- sonothrombolysis post-pPCI (group 2), and sham pre-/post-pPCI (group 3). Our primary end point was infarct size (percentage of left ventricular mass) assessed by cardiac magnetic resonance imaging at day 4 ± 2. Secondary end points included myocardial salvage index (MSI) and echocardiographic parameters at day 4 ± 2 and 6 months. RESULTS: Our trial was ceased early due to the COVID pandemic. From 122 patients screened between September 2020 and June 2021, 51 patients (age 60, male 82%) were included postrandomization. Median sonothrombolysis took 5 minutes pre-pPCI and 15 minutes post-, without significant door-to-balloon delay. There was a trend toward reduction in median infarct size between group 1 (8% [interquartile range, 4,11]), group 2 (11% [7, 19]), or group 3 (15% [9, 22]). Similarly there was a trend toward improved MSI in group 1 (79% [64, 85]) compared to groups 2 (51% [45, 70]) and 3 (48% [37, 73]) No major adverse cardiac events occurred during hospitalization. CONCLUSIONS: Pre-pPCI sonothrombolysis may be key to improving MSI in STEMI. Multicenter trials and health economic analyses are required before clinical translation.

Evaluating Serum Copeptin as a Promising Biomarker for Predicting Acute Ischaemic Stroke Severity: A Hospital-Based Study on Strokes.

BACKGROUND: Stroke is the second cause of mortality and the foremost leading cause of disability globally. Many potential biomarkers have been described to contribute to prognosticating the severity in the acute phase of stroke as well as help with risk stratification. Copeptin, an inactive peptide that is produced in an equimolar ratio to arginine vasopressin and adequately mirrors an individual's stress response to acute illnesses like acute ischaemic stroke as evidenced by elevated or increasing levels is being explored in this study to determine its relationship with acute stroke severity and infarct size on admission. METHODS: This is a cross-sectional study of 80 neuroimaging-confirmed acute ischaemic patients who presented within seven days of symptom onset and 80 control subjects. The ischaemic stroke cases had stroke severity and infarct volume determined on admission by the National Institute of Health Stroke Scale (NIHSS) and neuroimaging (brain CT/MRI). A baseline serum copeptin level was measured in the study subjects. Spearman correlation and Kruskal Wallis test were used to determine the relationship between serum copeptin level with admission NIHSS and infarct size respectively. The receiver operating characteristic (ROC) curve was calculated to determine the sensitivity and specificity of copeptin to predict severity and outcome. RESULTS: The mean age of the study group was 61.3 ± 12.7 years with 55.0% males and 45.0% females. The serum level of copeptin was significantly higher in the stroke cases with a median of 28.6 pmol/L (interquartile range (IQR)- 15.4-31.6 pmol/L) versus 8.8 pmol/L (IQR- 3.2- 10.7 pmol/L) among the stroke-free controls (p= 0.001) at a statistically significant level. There was a weak correlation between copeptin and NIHSS calculated at admission to measure stroke severity (r- 0.02, p= 0.873). Patients with infarct sizes in the fourth quartile (infarct sizes greater than 18.78 cm3) had higher copeptin levels, though this was not statistically significant (H= 2.88; p= 0.410). Admission serum copeptin did not show a statistically significant prognostic value in predicting stroke severity and mortality in stroke patients who presented within seven days of symptom onset with an area under curve (AUC) of 0.51 (95% CI: 0.36-0.65; p= 0.982). CONCLUSION: In this study, copeptin was higher among the stroke cases compared with the stroke-free controls which suggests a significant prognostic value in risk stratification in the acute phase of stroke; however, this did not significantly correlate with stroke severity and thus warrants further study in this field to elucidate it's fascinating potential as a prognostic biomarker (especially in the acute period) as this may enable allocation of a better-focused therapy for stroke patients.

Science of left ventricular unloading.

The concept of left ventricular unloading has its foundation in heart physiology. In fact, the left ventricular mechanics and energetics represent the cornerstone of this approach. The novel sophisticated therapies for acute heart failure, particularly mechanical circulatory supports, strongly impact on the mechanical functioning and energy consuption of the heart, ultimately affecting left ventricle loading. Notably, extracorporeal circulatory life support which is implemented for life-threatening conditions, may even overload the left heart, requiring additional unloading strategies. As a consequence, the understanding of ventricular overload, and the associated potential unloading strategies, founds its utility in several aspects of day-by-day clinical practice. Emerging clinical and pre-clinical research on left ventricular unloading and its benefits in heart failure and recovery has been conducted, providing meaningful insights for therapeutical interventions. Here, we review the current knowledge on left ventricular unloading, from physiology and molecular biology to its application in heart failure and recovery.

Effect of Cangrelor on Infarct Size in ST-Segment-Elevation Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention: A Randomized Controlled Trial (The PITRI Trial).

BACKGROUND: The administration of intravenous cangrelor at reperfusion achieves faster onset of platelet P2Y12 inhibition than oral ticagrelor and has been shown to reduce myocardial infarction (MI) size in the preclinical setting. We hypothesized that the administration of cangrelor at reperfusion will reduce MI size and prevent microvascular obstruction in patients with ST-segment-elevation MI undergoing primary percutaneous coronary intervention. METHODS: This was a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial conducted between November 2017 to November 2021 in 6 cardiac centers in Singapore. Patients were randomized to receive either cangrelor or placebo initiated before the primary percutaneous coronary intervention procedure on top of oral ticagrelor. The key exclusion criteria included presenting <6 hours of symptom onset; previous MI and stroke or transient ischemic attack; on concomitant oral anticoagulants; and a contraindication for cardiovascular magnetic resonance. The primary efficacy end point was acute MI size by cardiovascular magnetic resonance within the first week expressed as percentage of the left ventricle mass (%LVmass). Microvascular obstruction was identified as areas of dark core of hypoenhancement within areas of late gadolinium enhancement. The primary safety end point was Bleeding Academic Research Consortium-defined major bleeding in the first 48 hours. Continuous variables were compared by Mann-Whitney U test (reported as median [first quartile-third quartile]), and categorical variables were compared by Fisher exact test. A 2-sided P<0.05 was considered statistically significant. RESULTS: Of 209 recruited patients, 164 patients (78%) completed the acute cardiovascular magnetic resonance scan. There were no significant differences in acute MI size (placebo, 14.9% [7.3-22.6] %LVmass versus cangrelor, 16.3 [9.9-24.4] %LVmass; P=0.40) or the incidence (placebo, 48% versus cangrelor, 47%; P=0.99) and extent of microvascular obstruction (placebo, 1.63 [0.60-4.65] %LVmass versus cangrelor, 1.18 [0.53-3.37] %LVmass; P=0.46) between placebo and cangrelor despite a 2-fold decrease in platelet reactivity with cangrelor. There were no Bleeding Academic Research Consortium-defined major bleeding events in either group in the first 48 hours. CONCLUSIONS: Cangrelor administered at the time of primary percutaneous coronary intervention did not reduce acute MI size or prevent microvascular obstruction in patients with ST-segment-elevation MI given oral ticagrelor despite a significant reduction of platelet reactivity during the percutaneous coronary intervention procedure. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03102723.

Significance of QRS scoring system in left ventricular function recovery after acute myocardial infarction.

AIMS: The Selvester scoring system has been derived from ECG parameters for estimating infarct size. However, there is still a lack of evidence for Selvester score as an alternative to cardiac magnetic resonance (CMR) myocardial injury makers for risk stratification and prediction of left ventricular function (LVF) recovery among patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: This multicentre observational study enrolled 328 STEMI patients (88.4% men, 57.3 ± 10.6 years of age) undergoing CMR examination 1 week post-reperfusion therapy. Patients with baseline left ventricular ejection fraction (LVEF) < 50% underwent a follow-up CMR 6 months later, categorized into baseline normal LVF (ejection fraction [EF] ≥ 50% at baseline, n = 155); recovered LVF (EF < 50% at baseline and ≥50% after 6 months, n = 69); and reduced LVF (EF < 50% at baseline and after 6 months, n = 104). The median follow-up was 4 (3-4) years for all patients, with 61 patients experiencing major adverse cardiovascular event (MACEs). Patients with reduced LVF had a higher risk of MACEs than those with baseline normal LVF (P = 0.01), while the recovered LVF group had no significant difference (P > 0.05). A Selvester score >10 doubled the risk of MACEs in patients with systolic dysfunction (1.91 [1.02 to 3.58], P = 0.04). Additionally, Selvester score, baseline LVEF, transmural infarction, and peak CK-MB were independent predictors of recovered LVF, with Selvester score providing incremental predictive value to peak CK-MB in predicting recovered LVF (∆AUC = 0.07, P < 0.05). CONCLUSIONS: The Selvester score improves risk stratification among STEMI patients beyond LVEF and provide independent and incremental information to clinical parameters in predicting recovered LVF.

Correlation of Non-Invasive Transthoracic Doppler Echocardiography with Invasive Doppler Wire-Derived Coronary Flow Reserve and Their Impact on Infarct Size in Patients with ST-Segment Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention.

Background: Coronary microvascular dysfunction is associated with adverse prognosis after ST-segment elevation myocardial infarction (STEMI). We aimed to compare the invasive, Doppler wire-based coronary flow reserve (CFR) with the non-invasive transthoracic Doppler echocardiography (TTDE)-derived CFR, and their ability to predict infarct size. Methods: We included 36 patients with invasive Doppler wire assessment on days 3-7 after STEMI treated with primary percutaneous coronary intervention (PCI), of which TTDE-derived CFR was measured in 47 vessels (29 patients) within 6 h of the invasive Doppler. Infarct size was assessed by cardiac magnetic resonance at a median of 8 months. Results: The correlation between invasive and non-invasive CFR was modest in the overall cohort (rho 0.400, p = 0.005). It improved when only measurements in the LAD artery were considered (rho 0.554, p = 0.002), with no significant correlation in the RCA artery (rho -0.190, p = 0.435). Both invasive (AUC 0.888) and non-invasive (AUC 0.868) CFR, measured in the recanalized culprit artery, showed a good ability to predict infarct sizes ≥18% of the left ventricular mass, with the optimal cut off values of 1.85 and 1.80, respectively. Conclusions: In patients with STEMI, TTDE- and Doppler wire-derived CFR exhibit significant correlation, when measured in the LAD artery, and both have a similarly strong association with the final infarct size.

Sodium-glucose cotransporter-2 inhibitors in individuals with ischemia reperfusion injury: A systematic review.

Background: The effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on ischemia reperfusion injury (IRI) is a novel concept and only limited number of animals studies have yet been investigated. We aimed to perform a systematic review of literature to explore the clinical studies which investigated the effects of SGLT-2 inhibitors on myocardial IRI setting.Methods: We searched MEDLINE, Embase, and Cochrane Library from inception until December 7th, 2023. ClinicalTrials.gov was also explored for ongoing studies. Two authors independently conducted the literature search, examined the studies, and evaluated the eligibility criteria. Any disagreements or uncertainties were resolved by the corresponding author. The search strategy followed the PICO process (Population, Intervention, Comparison, and Outcome) and Emtree was used to select relevant keywords.Results: Of 220 articles identified from the literature research, five articles were included in the study, of which three studies lately were retracted. The remaining studies included 1229 participants, with 209 receiving SGLT-2 inhibitors and 1090 not receiving them. All of the participants were diabetic patients admitted with acute myocardial infarction (AMI), undergoing percutaneous coronary intervention (PCI). The results demonstrated that the use of SGLT-2 inhibitors is associated with lower troponin levels, and higher rates of ST resolution. The results of the studies also showed smaller infarct sizes, lower inflammatory biomarkers and improved left ventricular function at discharge among SGLT-2 inhibitor users.Conclusion: In line with in vivo and ex vivo findings, the results of this systematic review supported benefits of SGLT-2 inhibitors in IRI through reducing infarct size and inflammatory biomarkers. However, further clinical trials are warranted to provide robust evidence.

"Expression of concern": publication bias for positive preclinical cardioprotection studies.

The present analysis reports on the robustness of preclinical cardioprotection studies with infarct size as endpoint which were published in Basic Research in Cardiology, Cardiovascular Research, and Circulation Research between January 2013 and December 2023. Only 26 out of 269 papers with technically robust analysis of infarct size by triphenyltetrazolium chloride staining, magnetic resonance imaging or single photon emission tomography applied a prospective power analysis. A retrospective power calculation revealed that only 75% of the reported data sets with statistically significant positive results from all these studies had a statistical power of ≥ 0.9, and an additional 9% had a statistical power ≥ 0.8. The remaining 16% of all significant positive data sets did not even reach the 0.8 threshold. Only 13% of all analyzed data sets were neutral. We conclude that neutral studies are underreported and there is indeed a significant lack of robustness in many of the published preclinical cardioprotection studies which may contribute to the difficulties of translating cardioprotection to patient benefit.

The enhanced reliability of higher national institute of health stroke scale thresholds over the conventional 6-point scale.

INTRODUCTION: It is still uncertain if higher thresholds on National Institute of Health Stroke Scale (NIHSS) are better predictors of large infarctions than the conventional 6-point cutoff. METHODS: We used 6-point and higher NIHSS thresholds including 8, 9, and 10-point to predict relative infarct areas, expressed as percentage of the affected hemisphere on axial brain computed tomography images, beginning at 5% with 5% increments each time until reaching the 40% cutoff for large infarctions, or achieving 100% sensitivity. Results were compared using area under the receiver operating characteristic curves (AUROC). RESULTS: We enrolled 151 patients of acute ischemic stroke (Mean age: 62.88 years ± 12.71; Female: 48.34%). 77 patients (50.99%) exhibited left hemisphere strokes, while 74 (49%) had right hemisphere involvement. Sensitivity values of the 6-point for infarcts measuring 5%, 10%, 20%, 30%, and 40% were 62%, 64%, 77%, 82%, and 100%, respectively. At 40% infarct-size, 8-point achieved comparable results (52%, 55%, 69%, 76%, 100%), closely aligning with the 9-point (50%, 53%, 69%, 76%, 100%). The10-point was slightly trailing behind in sensitivity at 40% infarct-core (96%). Moreover, higher thresholds exhibited improved false-positive rates (FPR). At 40% infarct size, the FPRs of 6, 8, 9, and 10 points were 39%, 27%, 27%, and 21% respectively. Higher thresholds had augmented AUROC values (0.86, 0.86, 0.89) as compared to the 6-point (0.80). Logistic regression identified 14-point as definitive cutoff for large infarctions. CONCLUSION: Higher thresholds can better differentiate small and medium infarcts as true-negatives and substantially reduce false-positive referrals for mechanical thrombectomy.

Infarct Size Reduction in an Anterior ST-Elevation Myocardial Infarction Following "Optimized" Supersaturated Oxygen Therapy.

This comprehensive case report documents the treatment of a 37-year-old female patient who presented with anterior ST-elevation myocardial infarction (STEMI). The patient underwent percutaneous coronary intervention (PCI), followed by an innovative therapy - optimized supersaturated oxygen therapy (SSO2). This therapy was chosen due to its potential to enhance myocardial salvage, particularly in severe MI cases like the patient. The report meticulously details the patient's clinical course, including the diagnostic procedures and the rationale behind opting for SSO2 therapy. It highlights the significant improvements observed post-therapy: enhanced left ventricular (LV) function and a remarkable reduction in the size of the LV apical aneurysm. These outcomes suggest a direct benefit of SSO2 in reducing myocardial damage. Finally, the report discusses the broader implications of these findings. It underscores the potential of optimized SSO2 therapy in clinical settings, particularly for patients with anterior MI. The case exemplifies how advanced therapeutic interventions like SSO2 can play a pivotal role in improving clinical outcomes post-MI, thereby advocating for its consideration in similar clinical scenarios.

Impact of Epicardial Adipose Tissue on Infarct Size and Left Ventricular Systolic Function in Patients with Anterior ST-Segment Elevation Myocardial Infarction.

We aimed to assess the correlation of cardiovascular magnetic resonance (CMR)-derived epicardial adipose tissue (EAT) with infarct size (IS) and residual systolic function in ST-segment elevation myocardial infarction (STEMI). We enrolled patients discharged for a first anterior reperfused STEMI submitted to undergo CMR. EAT, left ventricular (LV) ejection fraction (LVEF), and IS were quantified at the 1-week (n = 221) and at 6-month CMR (n = 167). At 1-week CMR, mean EAT was 31 ± 13 mL/m2. Patients with high EAT volume (n = 72) showed larger 1-week IS. After adjustment, EAT extent was independently related to 1-week IS. In patients with large IS at 1 week (>30% of LV mass, n = 88), those with high EAT showed more preserved 6-month LVEF. This association persisted after adjustment and in a 1:1 propensity score-matched patient subset. Overall, EAT decreased at 6 months. In patients with large IS, a greater reduction of EAT was associated with more preserved 6-month LVEF. In STEMI, a higher presence of EAT was associated with a larger IS. Nevertheless, in patients with large infarctions, high EAT and greater subsequent EAT reduction were linked to more preserved LVEF in the chronic phase. This dual and paradoxical effect of EAT fuels the need for further research in this field.

Myocardial infarct size is reduced by nitrite and nitrate administration: a systematic review and meta-analysis of animal studies.

Ischemic heart disease (IHD) is the leading cause of mortality worldwide and can be complicated by myocardial infarction (MI), leading to cardiac failure. Inorganic nitrite and nitrate, which release nitric oxide (NO), can protect the heart against myocardial injury. This animal systematic review and meta-analysis aims to assess whether the administration of nitrite/nitrate decreases myocardial infarct size. We systematically searched PubMed, Scopus, and Web of Science databases until October 2023; 15 eligible animal studies (35 study arms for in-vivo and 10 for in-vitro studies) published between 1989 and 2023 were included. In-vivo studies were conducted on rats, mice, cats, and dogs, and in-vitro studies on rats and mice with an overall exposure of 0.03 to 12713 mg/kg to nitrate/nitrite administrated before, after, or during ischemia mainly by intravenous single bolus or by oral over 270 days. All in-vitro studies used nitrite/nitrate before ischemia, with the concentration ranging between 0.34 to 201 µM. MI was induced by occlusion of the left anterior diagonal or left circumflex arteries in in-vitro studies and by isoproterenol in in-vivo studies. Infarct size was measured by direct staining of the sliced heart sections. In in-vivo studies, nitrite (overall effect size (ES)=-17.0 %, 95 % confidence interval (CI)=-21.3, -12.8, P<0.001) and nitrate (overall ES= -9.6 %, 95 % CI=-15.7, -3.4, P=0.002) reduced myocardial infarct size. In in-vitro studies, nitrite (overall ES=-15.8 %, 95 % CI=-25.5, -6.2, P=0.001) reduced the infarct size. Sensitivity analysis showed that the overall effect of nitrite on myocardial infarct size was unaffected by doses or health conditions in in-vivo and in-vitro studies. In conclusion, our meta-analysis showed that nitrite/nitrate administration can effectively reduce myocardial infarct size. However, these results should be approached with caution because of the limitations of animal studies and the existing high heterogeneity.