Left Ventricular Infarct Size Research Articles

Evaluation of Melatonin Therapy in Patients with Myocardial Ischemia-Reperfusion Injury: A Systematic Review and Meta-Analysis.

Objectives We conducted a meta-analysis to quantitatively evaluate the effect of melatonin therapy on patients with myocardial ischemia-reperfusion injury (MIRI) and explore the influencing factors. Background Although preclinical studies have shown that melatonin can alleviate MIRI, its protective effect on MIRI in patients remains controversial. Methods We searched PubMed, the Cochrane Library, and Embase. The primary outcome was cardiac function (left ventricular ejection fraction [LVEF], left ventricular end-diastolic volume [LVEDV], and left ventricular end-systolic volume [LVESV]) and myocardial infarct parameters (total left ventricular mass and infarct size). Results We included nine randomized controlled clinical trials with 631 subjects. Our results showed that melatonin had no significant effects on the primary outcome, but subgroup analyses indicated that when melatonin was administered by intravenous and intracoronary injection at the early stage of myocardial ischemia, LVEF was improved (<3.5 h; standardized mean difference [SMD]:0.50; 95% CI: 0.06 to 0.94; P = 0.03) and the infarct size was reduced (<2.5 h, SMD: −0.86; 95% CI: −1.51 to −0.22; P = 0.01), whereas when melatonin was injected at the late stage of myocardial ischemia (≥3.5 h or 2.5 h), the results were the opposite. Furthermore, melatonin intervention reduced the level of cardiac injury markers, inflammatory cytokines, oxidation factors, and increased the level of antioxidant factors (P < 0.001). Conclusions The results indicated that the cardioprotective function of melatonin for MIRI was influenced by the route and timing regimen of melatonin administration; the mechanism of which may be associated with the production of inflammatory cytokines, the balance of oxidation, and antioxidant factors.

Effect of Mitral Regurgitation on Left Ventricular Deformation in Myocardial Infarction Patients: Evaluation by Cardiac Magnetic Resonance Imaging.

Mitral regurgitation (MR) is a comorbidity of myocardial infarction (MI), which may promote the incidence of adverse cardiovascular clinical events. However, it is not yet completely understood how MR in MI patients is associated with impaired myocardial deformation. To determine the damaging myocardium effects of MR in MI patients in terms of the global peak strain (PS) and left ventricular (LV) function, and evaluate the independent risk factors impacting LV deformation after MI. Retrospective. One hundred eighty-six MI patients (17.7% female) and 84 normal control subjects (27.4% female). 3.0T; late gadolinium enhancement sequence, balanced steady-state free precession. LV function and LV global PS (global radial peak strain [GRPS]; global circumferential peak strain [GCPS]; and global longitudinal peak strain [GLPS]) were compared among normal controls, MI without MR (MR-) and MI with MR (MR+, mild, moderate, severe) patients. One-way analysis of variance (ANOVA) test, Mann-Whitney U test, Kruskal-Wallis test, and multiple linear regressions were used. A P value <0.05 indicated statistically significant difference (two-tailed). The MI (MR+) patients showed significantly lower LV global PS than both MI (MR-) and control groups in three directions (GRPS 16.66 ± 7.43%; GCPS -11.27 ± 4.27%; GLPS -7.75 ± 3.44%), and significantly higher LV end-systolic (128.85 [87.91, 188.01] mL) and end-diastolic volumes (210.29 [164.07, 264.00] mL) and significantly lower LV ejection fraction (38.23 ± 13.02%). Multiple regression analysis demonstrated that MR was independently associated with LV GCPS (β = -0.268) and GLPS (β = -0.320). LV infarct size was an independent indicator of LV GRPS (β = -0.215) and GCPS (β = -0.222). LV end-diastolic volume was an independent indicator of LV GRPS (β = -0.518), GCPS (β = -0.503), and GLPS (β = -0.331). MR may further exacerbate the reduction of LV global peak strains and function. The MR, infarct size, and LV end-diastolic volume can be used as independent association indicators for LV global PS in MI (MR+) patients. 4 Technical Efficacy Stage: 2 TOC Category: Chest.

Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS) - A phase II, randomized, double-blind, multi-center, placebo-controlled trial

Activation of inflammatory pathways during acute myocardial infarction contributes to infarct size and left ventricular (LV) remodeling. The present prospective randomized clinical trial was designed to test the efficacy and safety of broad-spectrum anti-inflammatory therapy with a mammalian target of rapamycin (mTOR) inhibitor to reduce infarct size. Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS, clinicaltrials.gov NCT01529554) is a phase II randomized, double-blind, multi-center, placebo-controlled trial on the effects of a 5-day course of oral everolimus on infarct size, LV remodeling, and inflammation in patients with acute ST-elevation myocardial infarction (STEMI). Within 5 days of successful primary percutaneous coronary intervention (pPCI), patients are randomly assigned to everolimus (first 3 days: 7.5 mg every day; days 4 and 5: 5.0 mg every day) or placebo, respectively. The primary efficacy outcome is the change from baseline (defined as 12 hours to 5 days after pPCI) to 30-day follow-up in myocardial infarct size as measured by cardiac magnetic resonance imaging (CMRI). Secondary endpoints comprise corresponding changes in cardiac and inflammatory biomarkers as well as microvascular obstruction and LV volumes assessed by CMRI. Clinical events, laboratory parameters, and blood cell counts are reported as safety endpoints at 30 days. The CLEVER-ACS trial tests the hypothesis whether mTOR inhibition using everolimus at the time of an acute STEMI affects LV infarct size following successful pPCI.

Cardiac Magnetic Resonance Imaging in Heart Failure

Cardiac magnetic resonance (CMR) is an important noninvasive imaging modality in the investigation of patients with heart failure that provides detailed characterization of myocardial tissue, and accurate assessment of left and right ventricular function, infarct size, the microvasculature, inducible ischemia and myocardial edema. The etiologies of ischemic and nonischemic cardiomyopathies can be gleaned from the localization, pattern and distribution of gadolinium enhancement, depending on the clinical information and context. In patients with severe left ventricular hypertrophy, CMR can help to distinguish the underlying disease, including amyloidosis, hypertrophic cardiomyopathy, Anderson-Fabry disease and sarcoidosis, particularly with the use of native T1 mapping. Importantly, the presence of late gadolinium has been shown to predict adverse outcomes. New imaging techniques including native T1 mapping, extracellular volume fraction, T2 mapping, and feature and speckle tracking for ventricular assessment further increase the power of CMR in determining and refining cardiovascular diagnoses. Cardiac magnetic resonance (CMR) is an important noninvasive imaging modality in the investigation of patients with heart failure that provides detailed characterization of myocardial tissue, and accurate assessment of left and right ventricular function, infarct size, the microvasculature, inducible ischemia and myocardial edema. The etiologies of ischemic and nonischemic cardiomyopathies can be gleaned from the localization, pattern and distribution of gadolinium enhancement, depending on the clinical information and context. In patients with severe left ventricular hypertrophy, CMR can help to distinguish the underlying disease, including amyloidosis, hypertrophic cardiomyopathy, Anderson-Fabry disease and sarcoidosis, particularly with the use of native T1 mapping. Importantly, the presence of late gadolinium has been shown to predict adverse outcomes. New imaging techniques including native T1 mapping, extracellular volume fraction, T2 mapping, and feature and speckle tracking for ventricular assessment further increase the power of CMR in determining and refining cardiovascular diagnoses.

Risk score for early risk prediction by cardiac magnetic resonance after acute myocardial infarction

BackgroundCardiac magnetic resonance (CMR) performed early after ST-segment elevation myocardial infarction (STEMI) can improve major adverse cardiac event (MACE) risk prediction. We aimed to create a simple clinical-CMR risk score for early MACE risk stratification in STEMI patients. MethodsWe performed a multicenter prospective registry of reperfused STEMI patients (n = 1118) in whom early (1-week) CMR-derived left ventricular ejection fraction (LVEF), infarct size and microvascular obstruction (MVO) were quantified. MACE was defined as a combined clinical endpoint of cardiovascular (CV) death, non-fatal myocardial infarction (NF-MI) or re-admission for acute decompensated heart failure (HF). ResultsDuring a median follow-up of 5.52 [2.63–7.44] years, 216 first MACE (58 CV deaths, 71 NF-MI and 87 HF) were registered. Mean age was 59.3 ± 12.3 years and most patients (82.8%) were male. Based on the four variables independently associated with MACE, we computed an 8-point risk score: time to reperfusion >4.15 h (1 point), GRACE risk score > 155 (3 points), CMR-LVEF <40% (3 points), and MVO >1.5 segments (1 point). This score permitted MACE risk stratification: MACE per 100 person-years was 1.96 in the low-risk category (0–2 points), 5.44 in the intermediate-risk category (3–5 points), and 19.7 in the high-risk category (6–8 points): p < 0.001 in multivariable Cox survival analysis. ConclusionsA novel risk score including clinical (time to reperfusion >4.15 h and GRACE risk score > 155) and CMR (LVEF <40% and MVO >1.5 segments) variables allows for simple and straightforward MACE risk stratification early after STEMI. External validation should confirm the applicability of the risk score.

Abstract 11063: Non-Ischemic Fibrosis on Cardiac Magnetic Resonance Impacts Adverse Left Ventricular Remodeling and Mortality Among Patients with Functional Mitral Regurgitation

Introduction: Functional mitral regurgitation (FMR) alters left ventricular (LV) remodeling, providing a nidus for non-ischemic fibrosis (NIF). Cardiac magnetic resonance (CMR) can measure FMR and LV tissue properties. Prevalence, remodeling manifestations, and prognostic implications of NIF in patients with FMR are unknown. Hypothesis: Among post-myocardial infarction (MI) patients with FMR, NIF associates with advanced LV remodeling and predicts adverse prognosis. Methods: The population comprised post-MI patients with FMR undergoing CMR. CMR exams were retrieved from a single-center registry, reviewed for MR etiology (degenerative excluded) and analyzed for FMR severity, LV structure/function, and late gadolinium enhancement (LGE) including ischemic pattern MI and NIF, which was defined via established criteria (mid-myocardial or epicardial LGE). Follow-up was performed for all-cause mortality. Results: 467 consecutive FMR patients (74% male, 63±16 years old) were studied, of whom 14% had NIF. Prevalence of NIF increased stepwise with FMR severity (12% mild, 16% moderate, 21% severe; p=0.33). Patients with NIF had higher LV end-diastolic (241±72ml vs 194±64ml) and end-systolic volumes (174±70ml vs 120±63ml), paralleled by lower EF (31±13% vs 41±15%) and stroke volumes (67±20ml vs 74±24ml); all p&lt;0.001. LV infarct size was similar between patients with and without NIF (13±8.6 vs 15±10, p=0.17). During follow-up (mean 3.0±2.5 years), overall mortality was 14% and was increased in patients with advanced (≥ moderate) FMR (HR 1.65 [CI 1.13-2.42], p=0.01) and NIF (HR 2.35 [CI 1.32-4.19], p=0.004: Figure). In multivariate analysis, NIF conferred over a 2-fold increase in risk for death (HR 2.15 [CI 1.20-3.85], p=0.01) independent of age and FMR severity. Conclusions: Among post-MI patients with FMR, NIF identifies an aggressive phenotype as evidenced by associations with adverse LV remodeling on CMR and increased mortality.

Abstract 6941: Cardiac Repair With Echocardiography-Guided Multiple Percutaneous Left Ventricular Intramyocardial Injection of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes After Myocardial Infarction

Objective: To investigate the cardiac repair potency with echocardiography-guided multiple percutaneous left ventricular intramyocardial injection of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) after myocardial infarction. Methods: The surgically induced myocardial infarcted mice were randomly divided into three groups (8 in each) and were injected with echocardiography-guided percutaneous left ventricular infarcted border zone of one shot hiPSC-CMs (single dose, 10ul of 3x10 5 cells), medium, or repeated delivery of hiPSC-CMs at post-MI week 1 and 2 (multiple dose). The sham group of animals underwent all surgical procedures necessary for MI induction except for the ligation step. 4 weeks after the MI, heart function was measured by the transthoracic echocardiography. The engraftment size was evaluated through the detection of human specific cardiac troponin T. Infarcted size and collagen volume were calculated by sirius-red and fast green staining. Angiogenesis was evaluated by the staining of isolectin B4. Cardiac remodeling was evaluated by the cardiomyocyte minimal fiber diameter in the infarcted border zone. Apoptosis was detected via tunel staining in cardiomyocyte from the infarcted border zone. Results: No death was detected with echocardiography-guided percutaneous left ventricular intramyocardial injection. The number of hiPSC-CMs was about 9-fold higher in multiple dose group at week 4 compaired to single dose group. The multiple dose transplantation was associated with significant improvement in left ventricular function, infarct size, angiogenesis, cardiac remodeling, and cardiomyocyte apoptosis. Conclusions: Echocardiography-guided multiple percutaneous left ventricular intramyocardial injection is a feasible, satisfactory, repeatable, relatively less invasive and effective delivery method for cell therapy and the delivery of hiPSC-CMs indicate a novel therapy for myocardial infarction.

Cardiac Repair With Echocardiography-Guided Multiple Percutaneous Left Ventricular Intramyocardial Injection of hiPSC-CMs After Myocardial Infarction.

Objective: We investigated the potency of cardiac repair based on echocardiography-guided multiple percutaneous left ventricular intramyocardial injection of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) after myocardial infarction (MI).Methods: Mice with surgically induced MI were randomly divided into three groups (n = 8 in each group) and subjected to echocardiography-guided percutaneous left ventricular infarcted border injection of hiPSC-CMs (single dose; 10 μl 3 × 105 cells) or repeated injections of hiPSC-CMs at post-MI weeks 1 and 2 (multiple doses). The sham group of animals underwent all surgical procedures necessary for MI induction except for ligation. Then 4 weeks after MI, heart function was measured with transthoracic echocardiography. Engraftment was evaluated through the detection of human-specific cardiac troponin T. Infarct size and collagen volume were calculated with Sirius Red/Fast Green staining. Angiogenesis was evaluated with isolectin B4 staining. Cardiac remodeling was evaluated from the cardiomyocyte minimal fiber diameter in the infarcted border zone. Apoptosis was detected via TdT-mediated dUTP Nick-End Labeling (TUNEL) staining in cardiomyocytes from the infarcted border zone.Results: No mice died after echocardiography-guided percutaneous left ventricular intramyocardial injection. hiPSC-CMs were about nine-fold higher in the multiple-dose group at week 4 compared to the single-dose group. Multiple-dose transplantation was associated with significant improvement in left ventricular function, infarct size, angiogenesis, cardiac remodeling, and cardiomyocyte apoptosis.Conclusion: Echocardiography-guided multiple percutaneous left ventricular intramyocardial injection is a feasible, satisfactory, repeatable, relatively less invasive, and effective method of delivering cell therapy. The delivery of hiPSC-CMs indicates a novel therapy for MI.

Intrapericardial Delivery of APA-Microcapsules as Promising Stem Cell Therapy Carriers in an Experimental Acute Myocardial Infarction Model.

The administration of cardiosphere-derived cells (CDCs) after acute myocardial infarction (AMI) is very promising. CDC encapsulation in alginate-poly-l-lysine-alginate (APA) could increase cell survival and adherence. The intrapericardial (IP) approach potentially achieves high concentrations of the therapeutic agent in the infarcted area. We aimed to evaluate IP therapy using a saline vehicle as a control (CON), a dose of 30 × 106 CDCs (CDCs) or APA microcapsules containing 30 × 106 CDCs (APA-CDCs) at 72 h in a porcine AMI model. Magnetic resonance imaging (MRI) was used to determine the left ventricular ejection fraction (LVEF), infarct size (IS), and indexed end diastolic and systolic volumes (EDVi; ESVi) pre- and 10 weeks post-injection. Programmed electrical stimulation (PES) was performed to test arrhythmia inducibility before euthanasia. Histopathological analysis was carried out afterwards. The IP infusion was successful in all animals. At 10 weeks, MRI revealed significantly higher LVEF in the APA-CDC group compared with CON. No significant differences were observed among groups in IS, EDVi, ESVi, PES and histopathological analyses. In conclusion, the IP injection of CDCs (microencapsulated or not) was feasible and safe 72 h post-AMI in the porcine model. Moreover, CDCs APA encapsulation could have a beneficial effect on cardiac function, reflected by a higher LVEF at 10 weeks.

The association between invasive microvascular function and CMR-derived microvascular injury indicators and left ventricular function and infarct size at 1-month after reperfused STEMI

Abstract Background The restoration of the coronary microcirculation in ST-segment elevation myocardial infarction (STEMI) patients remains hampered in up to 50% of the STEMI patients after successful primary percutaneous coronary intervention (PCI). The association between the coronary microvascular function and injury indicators and functional outcome remains debated. Purpose This study aims to investigate the relation between post-PCI invasive microvascular function and cardiovascular magnetic resonance (CMR)-derived microvascular injury indicators and left ventricular (LV) function and infarct size (IS) at 1-month after STEMI. Methods The study was performed in 110 STEMI patients who underwent angiography for primary PCI and at 1-month follow-up. Invasive assessment of coronary microcirculation physiology in the culprit artery was performed during both procedures and included coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR). Data were available for 101 patients. A ratio of &amp;gt;2 for CFR and a value of &amp;lt;25 U for IMR were considered normal. CMR was performed during the acute phase (2 to 7 days after PCI) and at 1-month and provided assessment of LV function, IS and non-invasive information of microvascular injury in 78 patients by microvascular obstruction (MVO) and intra-myocardial hemorrhage (IMH). Results Over 1-month, CFR, IMR, LV function, and IS all significantly improved (p≤0.001). In univariable linear regression analysis, the post-PCI normal index CFR and IMR (both p=0.04), MVO presence, MVO size, IMH presence, IMH size (all, p&amp;lt;0.001) were significantly associated with LV ejection fraction at 1-month. Additionally, the post-PCI index CFR (p=0.04), MVO presence, MVO size, IMH presence, IMH size (all, p&amp;lt;0.001) were all associated with 1-month IS. In a multivariable linear regression analysis model including invasive and non-invasive coronary microcirculation function and injury indicators, MVO presence was identified as the only independent marker related to both 1-month LV ejection fraction and IS (both p&amp;lt;0.001). Conclusion(s) In STEMI patients, CMR-derived coronary microcirculation injury indicators reveal a closer association with 1-month LV function and IS outcome than invasive microcirculatory measurements. MVO presence is independently associated with 1-month LV ejection fraction and IS. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The REDUCE-MVI study was funded by Astra Zeneca to MvL and NvR.

Uptake of [68Ga]-NODAGA-E[(cRGDyK)]2 is related to improvement in pump function in rats with chronic ischemic cardiomyopathy treated with cell therapy

Abstract Background An increasing number of patients living with chronic ischemic cardiomyopathy (ICM) are potential candidates for cell therapy, including adipose tissue-derived mesenchymal stromal cells (ASC). However, proper assessment of clinical effects in relation to cellular effector mechanisms, such as angiogenesis, is currently lacking. Purpose To investigate the prognostic value of assessing angiogenesis non-invasively using novel PET imaging in terms of functional outcome after cell therapy in a homologous animal model of ICM. Methods Myocardial infarction was induced by permanent ligation of the left anterior descending coronary artery. Four weeks after infarction, the rats were scanned with [18F]-FDG and echocardiography, and based on left ventricular ejection fraction (LVEF) and infarct size randomized to allogeneic ASC treatment (n=14) or saline (n=9). Animals were treated using echo-guided trans-thoracic intramyocardial injections. Follow-up echocardiography was performed four weeks after treatment. Angiogenesis was assessed non-invasively using the [68Ga]-NODAGA-E[(cRGDyK)]2 (RGD) PET-tracer before treatment and two weeks after the treatment (Figure). The output was RGD-uptake by maximum standardized uptake value (SUVmax). Results RGD-uptake in the infarct area significantly decreased in the saline group (p=0.04), while this decline was not significant in the ASC group (p=0.58). There was no effect on LVEF of the cell therapy in this study (p=0.70). When the rats were grouped by RGD-uptake post treatment, the high RGD-uptake group (n=8) improved LVEF compared to the rats with medium or low RGD-uptake (n=15, p=0.04) irrespective of the treatment. This could indicate that non-invasive detection of a high degree of myocardial angiogenesis measured using RGD is predictive of improvement in cardiac pump function in ICM. Conclusions Following injection of ASC or saline, a high RGD-uptake precluded improvement in pump function. This is the first evidence of how uptake of the novel RGD tracer relates to changes in pump function in ICM and the results could affect the design of future clinical trials using regenerative therapy for ICM patients. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Aase and Ejnar Danielsens FondDoctor Sofus Carl Emil Friis and wife Olga Doris Friis' Scholarship Study design, RGD-uptake, and results

Attenuated cardiac post-ischemic injury and endothelial dysfunction by stimulation of soluble guanylyl cyclase in red blood cells from patients with type 2 diabetes

Abstract Background Reduced bioavailability of nitric oxide (NO) contributes to ischemic heart disease in type 2 diabetes (T2D). Red blood cells (RBCs) are known to produce NO bioactivity and to contain a functional soluble guanylyl cyclase (sGC) that is activated by NO. Recent studies revealed that RBCs from patients with T2D exacerbates ischemia-reperfusion (I/R) injury and induces endothelial dysfunction via a mechanism that is dependent on reduced export of NO bioactivity from RBCs. It remains unknown whether stimulation of sGC in RBCs from patients with T2D protects against myocardial I/R injury and endothelial dysfunction. Purpose To test the hypothesis that stimulation of sGC in RBCs from T2D patients protects against myocardial I/R injury and improves endothelial function. Methods RBCs collected from T2D patients and healthy subjects were incubated with vehicle or the sGC stimulator CYR715 before being administered to isolated Langendorff-perfused rat hearts subjected to 25 min global ischemia and 60 min reperfusion. Left ventricular developed pressure (LVDP) and infarct size were determined. In addition, isolated rat aortic rings were incubated with RBCs subsequent determination of endothelium-dependent relaxation (EDR). Results Administration of RBCs from T2D patients impaired post-ischemic recovery of LVDP and induced endothelial dysfunction in comparison with RBCs from healthy subjects (P&amp;lt;0.001). Pre-incubation of RBCs from patients with T2D with CYR715 prior to administration to the isolated heart enhanced the recovery of LVDP (Fig.1A), reduced infarct size (Fig.1B), and attenuated endothelial dysfunction (Fig.1C). CYR715 did not induce cardioprotection in the absence of RBCs. The sGC inhibitor ODQ did not significantly affect cardiac recovery per se but totally abolished the protective effect of CYR715 (Fig.1A). Conclusions Stimulation of sGC in RBCs from patients with T2D protects against cardiac I/R injury and prevents development of endothelial dysfunction. Stimulation of the NO-sGC pathway in RBCs appears to be an attractive therapeutic strategy to prevent cardiovascular injury in T2D. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swedish Heart and Lung Foundation, the Swedish Research Council

Relationship between left ventricular global longitudinal strain, infarct size and left ventricular function in patients with acute myocardial infarction in a stem cell therapy study

Abstract Introduction It is critically important to determine the accuracy, and relationships between, non-invasive imaging modalities, such as two-dimensional echocardiography (TTE), gated single-photon emission computed tomography (SPECT) and cardiac magnetic resonance imaging (cMRI) in patients with recent acute myocardial infarction (AMI) because these are used as clinical trial endpoints. Modest improvements in the left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and infarct zone size (IS) have been reported in AMI stem cells therapy trials (SCT). Purpose The aim of the study was to evaluate left-ventricular global longitudinal strain (GLS) in patients with AMI enrolled to SCT and assess its relation with infarct zone, LVEF and LVEDV using multimodality imaging including TTE, cMRI and SPECT. Methods Twenty-eight patients (21 male, 7 female, mean age 60.0±8.7 years) with first AMI, 2–5 days after left anterior descending percutaneous coronary intervention (PCI) and IS ≥10% were enrolled. GLS was evaluated with two-dimensional speckle tracking echocardiography (aCMQ, Philips Epiq 7). Infarct zone was measured using SPECT (E.CAM, Siemens) and gadolinium-enhanced cMRI (Siemens Magnetom Sonata 1.5T). LVEF and LVEDV were assessed with TTE (Auto-ROI, Philips), SPECT (GSQUAN, Siemens) and cMRI (MASS Medis). Measurements were obtained independently by blinded analysts. Results Mean GLS was −11.0±2.5% and showed a positive correlation with infarct zone by SPECT and MRI, negative with TTE-LVEF and cMRI-LVEF (Figure 1) and borderline with SPECT-LVEF (r=−0.35, p=0.08). There was no correlation between GLS and TTE-LVEDV (r=−0.25, p=0.25); SPECT-LVEDV (r=−0.38, p=0.077) and MRI-LVEDV (r=−0.20, p=0.365). Patients in the third and fourth GLS quartile had a smaller IS measured by MRI and a trend toward a smaller infarct zone by SPECT (table 1). Patients in the GLS fourth quartile had higher TTE-LVEF and a trend toward higher cMRI-LVEF compared with other quartiles. LVEF measured with TTE and cMRI was higher compared with SPECT-LVEF (+2.6±6.8%, p=0.006 and +4.2±7.8%, p=0.030, respectively) with no difference between TTE-LVEF and MRI-LVEF (p=0.823) (Table 1). LVEDV evaluated by SPECT and MRI was higher compared with TTE-LVEDV (+48.3±24.9 ml, +47.7±29.5 ml, both p&amp;lt;0.001) with no difference between SPECT-LVEDV and MRI-LVEDV (p=0.984) Conclusions In patients with anterior wall AMI, 2–5 days after PCI, GLS showed a good correlation with infarct zone quantified by SPECT and MRI and with LVEF measured with TTE and cMRI. GLS might thus be a valuable tool in the evaluation of myocardial injury in SCT. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): STRATEGMED 265761 “CIRCULATE” National Centre for Research and Development/Poland/ZDS/00564 Jagiellonian University Medical College Table 1Figure 1

Citrate-Saline-Formulated mRNA Delivery into the Heart Muscle with an Electromechanical Mapping and Injection Catheter Does Not Lead to Therapeutic Effects in a Porcine Chronic Myocardial Ischemia Model

Based on recent success in using modified RNA in clinical applications, we tested the safety, feasibility, and efficacy of direct delivery of citrate-saline-formulated mRNA into an hibernating ischemic heart muscle using an electromechanical mapping and injection catheter system (NOGA/Myostar) in a porcine chronic myocardial ischemia model. Chronic ischemia was induced in domestic pigs (n = 24) using a bottleneck stent placed in the left anterior descending coronary artery. Low (1 mg) and high (7.5 mg) doses of citrate-saline-formulated vascular endothelial growth factor (VEGF)-A165 mRNA were administered in the study. LacZ mRNA and citrate-saline buffer were used as controls. Ten intramyocardial injections (200 μL each) of the mRNAs or citrate-saline buffer were given endovascularly into the hibernating ischemic myocardium using the NOGA catheter. Positron emission tomography 15O-radiowater imaging was performed 7 days after the induction of ischemia and 28 days after the mRNA delivery to measure quantitative myocardial blood perfusion. Coronary angiography, left ventricular function measurements, and clinical chemistry were obtained at each time point. Thirty-five days after the mRNA transfers, pigs were sacrificed, and infarct size and general histology were analyzed. LacZ mRNA pigs were sacrificed 24 h after the transduction. Citrate-saline-formulated mRNA delivery into the ischemic myocardium with endovascular injection catheter did not lead to meaningful transduction with the translation of VEGF-A165, nor therapeutic effects in the heart. VEGF-A165 mRNA showed no statistically significant improvements in left ventricular ejection fraction (LVEF), cardiac output, myocardial perfusion, infarct size, collateral growth, or capillary area in the study groups. However, there was a trend in the high-dose group toward an improved LVEF and cardiac output at rest. No significant adverse effects were observed. In conclusion, the NOGA/Myostar injection catheter system is ineffective in delivering citrate-saline-formulated mRNAs into the heart muscle with the doses and methods used in a porcine chronic myocardial ischemia model.

Hypoxic Stem Cell-Derived Extracellular Vesicles for Cardiac Repair in Preclinical Animal Models of Myocardial Infarction: A Meta-Analysis.

Given that the modification of stem cell-derived extracellular vesicles (EVs) can enhance their regenerative efficiency, an increasing number of studies pay attention to the therapeutic potential of hypoxic preconditioning of stem cell-derived EVs (Hypo-EVs) in cardiac repair. Our meta-analysis aims to evaluate the cardiac repair of Hypo-EVs in preclinical animal models of myocardial infarction (MI). We searched PubMed, EMBASE, and the Web of Science up to January 2021. The primary outcome was left ventricular ejection fraction (LVEF). The second outcomes were left ventricular fractional shortening (LVFS) and infarct size. Random-effects modeling was used to calculate pooled weighted mean differences (WMDs) and 95% confidence intervals (CIs). Nine studies satisfied the inclusion criteria. Compared with the model group, pooled analyses demonstrated that stem cell-derived EVs culturing in normal oxygen environment (Nor-EVs) can improve LVEF (WMD: 9.07, 95% CI: 6.76 to 11.38, I2 = 80.7%), LVFS (WMD: 3.03, 95% CI: 0.79 to 5.27, I2 = 86.3%), and reduce infarct size (WMD: -12.15, 95% CI: -19.12 to -5.18, I2 = 96.8%). Compared with Nor-EVs, Hypo-EVs can improve LVEF (WMD: 5.11, 95% CI: 1.63 to 8.60, I2 = 95%), LVFS (WMD: 6.54, 95% CI: 4.08 to 8.99, I2 = 90.6%), and reduce infarct size (WMD: -7.42, 95% CI: -12.97 to -1.87, I2 = 97.2%). These results suggest that Hypo-EVs could show more improvement than Nor-EVs therapy on cardiac repair in the preclinical MI animal model. However, future well-designed large animal studies might be necessary to clarify the methods and effects of Hypo-EVs therapy to help provide new ideas for future engineered EVs design.

Impact of residual thrombus burden on ventricular deformation after acute myocardial infarction: A sub-analysis from an intravascular optical coherence tomography study.

BackgroundCoronary residual thrombus before stenting in ST-segment elevation myocardial infarction (STEMI) has been linked to microvascular injury but its impact on ventricular deformation and cardiac dysfunction in longer term remains unclear.MethodsThis was a post-hoc sub-analysis from an optical coherence tomography registry. Residual thrombus before stenting was measured geometrically and maximal thrombus-to-lumen area ratio (MTR) was reported. Cardiovascular magnetic resonance (CMR) follow-ups were performed at 30 days post STEMI. The primary outcomes were CMR-derived parameters including left ventricular ejection fraction (LVEF), infarct size, microvascular obstruction (MVO), and left ventricular global strains in radial (GRS), circumferential (GCS), longitudinal (GLS) directions.FindingsFrom March 2017 to March 2019, forty-two patients with first-ever anterior STEMI were included. Average CMR follow-up time was 33 (IQR 30–37) days. In multivariable analysis, MTR was significantly associated with LVEF (per 10%, adjusted β = -1·96, 95%CI -3·66 to -0·26), MVO (per 10%, adjusted β = 0·07, 95%CI 0·01 to 0·13), GRS (per 10%, adjusted β = -1·26, 95%CI -2·28 to -0·23), and GCS (per 10%, adjusted β = 0·53, 95%CI 0·01 to 1·06). However, it was not related to GLS (per 10%, adjusted β = 0·29, 95%CI -0·85 to 1·43) or infarct size (per 10%, adjusted β = 0·07, 95%CI -0·40 to 0·55).InterpretationLarger residual thrombus burden was associated with worse GRS and GCS but not GLS after a first anterior myocardial infarction.FundingThis work was supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-1–009), National Natural Science Foundation of China (81,970,308, 81,930,044, and 81,620,108,015), Sanming Project of Medicine in Shenzhen (SZSM201911017), and Shenzhen Key Medical Discipline Construction Fund (No. SZXK001).

Prognostic implications of left ventricular torsion by feature-tracking cardiac magnetic resonance in patients with ST-elevation myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): the National Key Research and Development Program of China OnBehalf Renji Hospital Affiliated to Medical College of Shanghai Jiaotong University Background The prognostic implications of left ventricular (LV) torsion on the long-term prognosis of patients with acute ST-elevation myocardial infarction (STEMI) is not clear. Methods We analyzed Cardiac Magnetic Resonance (CMR) images and followed up 420 first STEMI patients from the EARLY Assessment of MYOcardial Tissue Characteristics by CMR in STEMI (EARLY-MYO-CMR) registry (NCT03768453). These patients received timely primary percutaneous coronary intervention (PCI) within 12h and CMR examination within 1 week (median,5 days; range, 2-7 days) after infarction. Besides, CMR images of 40 normal people were enrolled as the control group. LV torsion, torsion rate and other conventional CMR indexes were measured. Ultrasound cardiogram examinations were performed in the acute phase and 1 year post-STEMI to assess LV remodeling (≥ 20% increase in LV end-diastolic volume). Primary end point was composite major adverse cardiac and cerebrovascular events (MACCEs) including cardiovascular death, re-infarction, re-hospitalization for heart failure and stroke. Secondary end points were the formation of LV aneurysm/thrombus in hospital as well as LV remodeling at 1 year post-STEMI. Results During follow-up (median: 52 months, inter-quartile range: 29–78 months), 80 patients developed MACCEs. Compared with normal people, patients with STEMI had more decreased LV torsion (P &amp;lt; 0.001) and torsion rate (P = 0.033). Patients who experienced MACCEs had more impaired LV torsion (P &amp;lt; 0.001) and torsion rate (P &amp;lt; 0.001) than those who didn’t. LV torsion ≤ 0.876 deg/cm in the acute phase of STEMI was an independent predictive factor of MACCE (P = 0.001) and LV remodeling (P = 0.001). Patients with impaired LV torsion were more likely to experience MACCEs (P &amp;lt; 0.001). The impairment of LV torsion was also associated with the higher incidence of LV aneurysm (P &amp;lt; 0.001) and thrombus (P = 0.006). The addition of LV torsion to a risk model comprising LV ejection fraction (LVEF), infarct size (IS), and microvascular obstruction (MVO) led to a net reclassification improvement (continuous NRI 0.499 [95% CI, 0.261–0.737]; P &amp;lt; 0.001). Hypertension (P = 0.047), tobacco use (P = 0.005), worse TIMI flow post-PCI (P &amp;lt; 0.001), more extensive IS (P &amp;lt; 0.001) / MVO size (P = 0.002) were associated with the impairment of LV torsion. Conclusions Compared with normal people, patients with STEMI had more decreased LV torsion and torsion rate. LV torsion ≤ 0.876 deg/cm in the acute phase was an independent predictive factor of MACCE and LV remodeling. The addition of LV torsion to a risk model comprising LVEF, LV-IS and LV-MVO significantly improved risk stratification of patients with STEMI .

Combined protocol for remote ischemic conditioning as the method of cardioprotection in patients with acute ST-segment elevation myocardial infarction

Background. There is currently no commonly accepted strategy for limiting the reperfusion injury that occurs after revascularization in patients with myocardial infarction. This study aimed to investigate the efficacy of a promising cardioprotective method.Material and Methods. Patients with acute anterior ST-segment elevation myocardial infarction (STEMI) (n = 87) were included in an open-label prospective randomized controlled trial. Control group comprised patients with STEMI who underwent only primary percutaneous coronary intervention (PPCI) (n = 44). Patients of intervention group (n = 43) underwent PPCI and remote ischemic perconditioning combined with postconditioning (RIC). The efficacy of RIC was assessed based on cardiac magnetic resonance (CMR) imaging data.Results. The medians of left ventricular (LV) infarct size were significantly higher in patients of control group: 44.8 (33.6; 55.5) versus 52.7 (35.5; 73.9) mL (p = 0.039) at day 10 after STEMI and 34.0 (25.8; 39.8) mL versus 46.0 (32.8; 55.0) mL six months after STEMI in control and intervention groups, respectively (p = 0.004). The groups of patients did not differ in the sizes of area at risk relative to the total LV myocardial volume: 40 (35; 45) and 43 (34; 49)% in control and intervention groups, respectively (р = 0.232). The groups significantly differed in the ratios of infarct size to area at risk: 70.3 (65.1; 86.6)% in control group versus 63.5 (52.7; 72.0)% in intervention group (р = 0.014) as well as in the myocardial salvage indexes: 29.7 (13.5; 34.9)% in control group versus 36.5 (28.0; 47.3)% in intervention group (р = 0.014). The study showed the tendency to greater LV myocardial salvage in intervention group versus control group at six-months follow-up (р = 0.073). The groups significantly differed in the medians of microvascular obstruction volume: 1.9 (1.4; 2.9) mL in intervention group versus 2.5 (1.8; 8.1) mL in control group (p = 0.049) as well as in the proportions of microvascular obstruction in the LV myocardium: 0.94 (0.79; 1.37)% in intervention group versus 1.50 (0.89; 3.66)% in control group (р = 0.046).Conclusion. The RIC method combined with PPCI contributed to the limitation of infarct and microvascular obstruction sizes and was associated with an increase in the myocardial salvage index in STEMI patients.

Left ventricular function, strain, and infarct characteristics in patients with transient ST-segment elevation myocardial infarction compared to ST-segment and non-ST-segment elevation myocardial infarctions.

AimsThis study aims to explore cardiovascular magnetic resonance (CMR)-derived left ventricular (LV) function, strain, and infarct size characteristics in patients with transient ST-segment elevation myocardial infarction (TSTEMI) compared to patients with ST-segment and non-ST-segment elevation myocardial infarctions (STEMI and NSTEMI, respectively).Methods and resultsIn total, 407 patients were enrolled in this multicentre observational prospective cohort study. All patients underwent CMR examination 2–8 days after the index event. CMR cine imaging was performed for functional assessment and late gadolinium enhancement to determine infarct size and identify microvascular obstruction (MVO). TSTEMI patients demonstrated the highest LV ejection fraction and the most preserved global LV strain (longitudinal, circumferential, and radial) across the three groups (overall P ≤ 0.001). The CMR-defined infarction was less frequently observed in TSTEMI than in STEMI patients [77 (65%) vs. 124 (98%), P < 0.001] but was comparable with NSTEMI patients [77 (65%) vs. 66 (70%), P = 0.44]. A remarkably smaller infarct size was seen in TSTEMI compared to STEMI patients [1.4 g (0.0–3.9) vs. 13.5 g (5.3–26.8), P < 0.001], whereas infarct size was not significantly different from that in NSTEMI patients [1.4 g (0.0–3.9) vs. 2.1 g (0.0–8.6), P = 0.06]. Whilst the presence of MVO was less frequent in TSTEMI compared to STEMI patients [5 (4%) vs. 53 (31%), P < 0.001], no significant difference was seen compared to NSTEMI patients [5 (4%) vs. 5 (5%), P = 0.72].ConclusionTSTEMI yielded favourable cardiac LV function, strain, and infarct-related scar mass compared to STEMI and NSTEMI. LV function and infarct characteristics of TSTEMI tend to be more similar to NSTEMI than STEMI.

Global longitudinal strain improves risk assessment after ST-segment elevation myocardial infarction: a comparative prognostic evaluation of left ventricular functional parameters

AimWe aimed to investigate the comparative prognostic value of left ventricular ejection fraction (LVEF), mitral annular plane systolic excursion (MAPSE), fast manual long-axis strain (LAS) and global longitudinal strain (GLS) determined by cardiac magnetic resonance (CMR) in patients after ST-segment elevation myocardial infarction (STEMI).Methods and resultsThis observational cohort study included 445 acute STEMI patients treated with primary percutaneous coronary intervention (pPCI). Comprehensive CMR examinations were performed 3 [interquartile range (IQR): 2–4] days after pPCI for the determination of left ventricular (LV) functional parameters and infarct characteristics. Primary endpoint was the occurrence of major adverse cardiac events (MACE) defined as composite of death, re-infarction and congestive heart failure. During a follow-up of 16 [IQR: 12–49] months, 48 (11%) patients experienced a MACE. LVEF (p = 0.023), MAPSE (p < 0.001), LAS (p < 0.001) and GLS (p < 0.001) were significantly related to MACE. According to receiver operating characteristic analyses, only the area under the curve (AUC) of GLS was significantly higher compared to LVEF (0.69, 95% confidence interval (CI) 0.64–0.73; p < 0.001 vs. 0.60, 95% CI 0.55–0.65; p = 0.031. AUC difference: 0.09, p = 0.020). After multivariable analysis, GLS emerged as independent predictor of MACE even after adjustment for LV function, infarct size and microvascular obstruction (hazard ratio (HR): 1.13, 95% CI 1.01–1.27; p = 0.030), as well as angiographical (HR: 1.13, 95% CI 1.01–1.28; p = 0.037) and clinical parameters (HR: 1.16, 95% CI 1.05–1.29; p = 0.003).ConclusionGLS emerged as independent predictor of MACE after adjustment for parameters of LV function and myocardial damage as well as angiographical and clinical characteristics with superior prognostic validity compared to LVEF.Graphic abstract