ABSTRACT
Myocardial infarction (MI) is a serious acute cardiovascular syndrome that causes myocardial injury due to blood flow obstruction to a specific myocardial area. Under ischemic-reperfusion settings, a burst of reactive oxygen species is generated, leading to redox imbalance that could be attributed to several molecules, including myoglobin. Myoglobin is dynamic and exhibits various oxidation-reduction states that have been an early subject of attention in the food industry, specifically for meat consumers. However, rarely if ever have the myoglobin optical properties been used to measure the severity of MI. In the current study, we develop a novel imaging pipeline that integrates tissue clearing, confocal and light sheet fluorescence microscopy, combined with imaging analysis, and processing tools to investigate and characterize the oxidation-reduction states of myoglobin in the ischemic area of the cleared myocardium post-MI. Using spectral imaging, we have characterized the endogenous fluorescence of the myocardium and demonstrated that it is partly composed by fluorescence of myoglobin. Under ischemia-reperfusion experimental settings, we report that the infarcted myocardium spectral signature is similar to that of oxidized myoglobin signal that peaks 3 h post-reperfusion and decreases with cardioprotection. The infarct size assessed by oxidation-reduction imaging at 3 h post-reperfusion was correlated to the one estimated with late gadolinium enhancement MRI at 24 h post-reperfusion. In conclusion, this original work suggests that the redox state of myoglobin can be used as a promising imaging biomarker for characterizing and estimating the size of the MI during early phases of reperfusion.
Subject(s)
Myocardial Infarction , Myocardial Reperfusion Injury , Myocardium , Myoglobin , Oxidation-Reduction , Animals , Disease Models, Animal , Microscopy, Confocal , Microscopy, Fluorescence , Myocardial Infarction/metabolism , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/pathology , Myocardium/metabolism , Myocardium/pathology , Myoglobin/metabolismABSTRACT
BACKGROUND: Acoustically activatable perfluoropropane droplets (PD) can be formulated from commercially available microbubble preparations. Diagnostic transthoracic ultrasound frequencies have resulted in acoustic activation (AA) predominately within myocardial infarct zones (IZ). OBJECTIVE: We hypothesized that the AA area following acute coronary ischemia/reperfusion (I/R) would selectively enhance the developing scar zone, and target bioeffects specifically to this region. METHODS: We administered intravenous PD in 36 rats and 20 pigs at various stages of myocardial scar formation (30 minutes, 1 day, and 7 days post I/R) to determine what effect infarct age had on the AA within the IZ. This was correlated with histology, myeloperoxidase activity, and tissue nitrite activity. RESULTS: The degree of AA within the IZ in rats was not associated with collagen content, neutrophil infiltration, or infarct age. AA within 24 hours of I/R was associated with increased nitric oxide utilization selectively within the IZ (P < .05 compared with remote zone). The spatial extent of AA in pigs correlated with infarct size only when performed before sacrifice at 7 days (r = .74, P < .01). CONCLUSIONS: Acoustic activation of intravenous PD enhances the developing scar zone following I/R, and results in selective tissue nitric oxide utilization.
Subject(s)
Fluorocarbons , Myocardial Infarction , Animals , Fluorocarbons/pharmacokinetics , Swine , Rats , Myocardial Infarction/diagnostic imaging , Male , Contrast Media/pharmacokinetics , Nanoparticles , Rats, Sprague-Dawley , Myocardium/metabolism , Disease Models, Animal , Myocardial Reperfusion Injury/diagnostic imaging , Microbubbles , Female , Ultrasonography/methodsABSTRACT
PURPOSE: Myocardial ischemia-reperfusion (I/R) injury is associated with systemic oxidative stress, cardiac mitochondrial homeostasis, and cardiomyocyte apoptosis. Metformin has been recognized to attenuate cardiomyocyte apoptosis. However, the longitudinal effects and pathomechanism of metformin on the regulation of myocardial mitohormesis following I/R treatment remain unclear. This study aimed to investigate the longitudinal effects and mechanism of metformin in regulating cardiac mitochondrial homeostasis by serial imaging with the 18-kDa translocator protein (TSPO)-targeted positron emission tomography (PET) tracer 18F-FDPA. METHODS: Myocardial I/R injury was established in Sprague-Dawley rats, which were treated with or without metformin (150 mg/kg per day). Serial gated 18F-FDG and 18F-FDPA PET imaging were performed at 1, 4, and 8 weeks after surgery, followed by analysis of ventricular remodelling and cardiac mitochondrial homeostasis. The correlation between Hsp60 and 18F-FDPA uptake was analyzed. After PET imaging, the activity of antioxidant enzymes, immunostaining, and western blot analysis were performed to analyze the spatio-temporal effects and pathomechanism of metformin for cardiac protection after myocardial I/R injury. RESULTS: Oxidative stress and apoptosis increased 1 week after myocardial I/R injury (before significant progression of ventricular remodelling). TSPO expression was correlated with Hsp60 expression and was co-localized with inflammatory CD68+ macrophages in the infarct area, and TSPO uptake was associated with an upregulation of AMPK-p/AMPK and a downregulation of Bcl-2/Bax. However, these effects were reversed with metformin treatment. Eight weeks after myocardial I/R injury (representing the advanced stage of heart failure), 18F-FDPA uptake in myocardial cells in the distal non-infarct area increased without CD68+ expression, whereas the activity decreased with metformin treatment. CONCLUSION: Taken together, these results show that a prolonged metformin treatment has pleiotropic protective effects against myocardial I/R injury associated with a regional and temporal dynamic balance between mitochondrial homeostasis and cardiac outcome, which were assessed by TSPO-targeted imaging during cardiac remodelling.
Subject(s)
Metformin , Myocardial Reperfusion Injury , Rats , Animals , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/metabolism , Metformin/pharmacology , Metformin/therapeutic use , Rats, Sprague-Dawley , AMP-Activated Protein Kinases/metabolism , AMP-Activated Protein Kinases/pharmacology , Ventricular Remodeling , Myocytes, Cardiac/metabolism , Homeostasis , ApoptosisABSTRACT
OBJECTIVES: To evaluate myocardial viability in patients with myocardial ischemia reperfusion injury (MIRI) via dual-energy computed tomography myocardial blood pool imaging (DECT MBPI). METHODS: Between September 2017 and January 2019, we prospectively recruited 59 patients with acute myocardial infarction (AMI) who developed MIRI after revascularization during invasive coronary angiography (ICA). Then, they received DECT MBPI, SPECT, and PET sequentially within 1 week after the onset of MIRI. A total of 1003 myocardial segments of 59 patients were recruited for this study. The iodine reduction areas and delayed enhancement areas were calculated by cardiac iodine map with SPECT rest myocardial perfusion imaging (MPI) + PET myocardial metabolism imaging (MMI) as reference criteria. The paired sample t-test was used to measure the difference of the myocardial iodine value. Cohen's Kappa analysis was used to test the consistency among different observers. ROC analysis was used to calculate the myocardial viability of DECT MBPI. RESULTS: ROC showed the AUCs of DECT MBPI iodine value to identify a normal myocardium, an ischemic myocardium, and an infarcted myocardium were 0.957, 0.900, and 0.906 (p < 0.001). The sensitivity, specificity, and accuracy of DECT MBPI in identifying an ischemic myocardium were 87.6%, 89.3%, and 97.9% (p < 0.001). The sensitivity, specificity, and accuracy of DECT MBPI in identifying an infarcted myocardium were 88.9%, 92.2%, and 98.6% (p < 0.001). The cutoff value for DECT MBPI to differentiate between an ischemic and a normal myocardium was 0.84 mg I/mL. The cutoff value for DECT MBPI to differentiate between an infarct and a normal myocardium was 2.01 mg I/mL. CONCLUSION: DECT MBPI can be used to assess myocardial viability in patients with MIRI with high sensitivity and specificity. KEY POINTS: ⢠Dual-energy computed tomography myocardial blood pool imaging (DECT MBPI) can evaluate myocardial viability of myocardial ischemia-reperfusion injury (MIRI). ⢠DECT MBPI is a non-invasive and timesaving method for evaluation on myocardial ischemia-reperfusion injury in patients with acute myocardial infarction after coronary intervention.
Subject(s)
Iodine , Myocardial Infarction , Myocardial Ischemia , Myocardial Reperfusion Injury , Humans , Myocardial Reperfusion Injury/diagnostic imaging , Tomography, X-Ray Computed/methods , Myocardium , Myocardial Infarction/diagnostic imagingABSTRACT
PURPOSE: Magnetic susceptibility (Δχ) alterations have shown association with myocardial infarction (MI) iron deposition, yet there remains limited understanding of the relationship between relaxation rates and susceptibility or the effect of magnetic field strength. Hence, Δχ and R2∗ in MI were compared at 3T and 7T. METHODS: Subacute MI was induced by coronary artery ligation in male Yorkshire swine. 3D multiecho gradient echo imaging was performed at 1-week postinfarction at 3T and 7T. Quantitative susceptibility mapping images were reconstructed using a morphology-enabled dipole inversion. R2∗ maps and quantitative susceptibility mapping were generated to assess the relationship between R2∗ , Δχ, and field strength. Infarct histopathology was investigated. RESULTS: Magnetic susceptibility was not significantly different across field strengths (7T: 126.8 ± 41.7 ppb; 3T: 110.2 ± 21.0 ppb, P = NS), unlike R2∗ (7T: 247.0 ± 14.8 Hz; 3T: 106.1 ± 6.5 Hz, P < .001). Additionally, infarct Δχ and R2∗ were significantly higher than remote myocardium. Magnetic susceptibility at 7T versus 3T had a significant association (ß = 1.02, R2 = 0.82, P < .001), as did R2∗ (ß = 2.35, R2 = 0.98, P < .001). Infarct pathophysiology and iron deposition were detected through histology and compared with imaging findings. CONCLUSION: R2∗ showed dependence and Δχ showed independence of field strength. Histology validated the presence of iron and supported imaging findings.
Subject(s)
Magnetic Resonance Imaging , Myocardial Reperfusion Injury , Animals , Iron , Magnetic Phenomena , Magnetics , Male , Myocardial Reperfusion Injury/diagnostic imaging , SwineABSTRACT
The no-reflow phenomenon induced by ischemia-reperfusion (I/R) injury seriously limits the therapeutic value of coronary recanalization and leads to a poor prognosis. Previous studies have shown that luteolin (LUT) is a vasoprotective factor. However, whether LUT can be used to prevent the no-reflow phenomenon remains unknown. Positron emission tomography perfusion imaging, performed to detect the effects of LUT on the no-reflow phenomenon in vivo, revealed that LUT treatment was able to reduce the no-reflow area in rat I/R models. In vitro, LUT was shown to reduce the hypoxia-reoxygenation injury-induced endothelial permeability and apoptosis. The levels of malondialdehyde, reactive oxygen species and NADPH were also measured and the results indicated that LUT could inhibit the oxidative stress. Western blot analysis revealed that LUT protected endothelial cells from I/R injury by regulating the Wnt/ß-catenin pathway. Overall, we concluded that the use of LUT to minimize I/R induced microvascular damage is a feasible strategy to prevent the no-reflow phenomenon.
Subject(s)
Coronary Circulation/drug effects , Coronary Vessels/drug effects , Endothelial Cells/drug effects , Luteolin/pharmacology , Myocardial Reperfusion Injury/prevention & control , No-Reflow Phenomenon/prevention & control , Wnt Signaling Pathway/drug effects , Animals , Apoptosis/drug effects , Capillary Permeability/drug effects , Cells, Cultured , Coronary Vessels/diagnostic imaging , Coronary Vessels/metabolism , Coronary Vessels/physiopathology , Disease Models, Animal , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Myocardial Perfusion Imaging , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/physiopathology , No-Reflow Phenomenon/diagnostic imaging , No-Reflow Phenomenon/metabolism , No-Reflow Phenomenon/physiopathology , Oxidative Stress/drug effects , Positron-Emission Tomography , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND: The molecular mechanisms of protective effect of metformin (Met) on ischemic myocardium have not been fully understood. This study aims to evaluate the cardioprotective effect of metformin on myocardial ischemia-reperfusion injury (MIRI) in rat models at different time points using dynamic 18F-FDG micro-PET/CT imaging. METHODS: The I/R injury model in SD rats was established by ligation of left anterior descending coronary artery near the pulmonary arch root for 30 min. SD rats (n = 12) were randomly divided into 2 groups: Control group (n = 6) without any intervention and Met group (n = 6) with oral administration of metformin (50 mg/kg) twice a day. Gated 18F-FDG (40Mbq) micro-PET/CT imaging was performed for 10 min at different time points (day 1st, day 7th, day 14th and day 30th after operation). Volumes of interest were drawn to identify different myocardium regions (ischemia center, peri-ischemia area and remote area). Standardized uptake values (SUVs) (SUVmean and SUVmax) were analyzed to evaluate the FDG uptake activity, and then the center/remote ratio was calculated. In addition, the left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV) and LV ejection fraction (LVEF) were obtained. On the 30th day, all rats were scarified and myocardial ischemia was analyzed by HE staining and confirmed by pathology. RESULTS: In the Control group, the center/remote ratio showed no obvious change trend at each time point after reperfusion, while the LV EDV increased gradually over time, and they were significantly negatively correlated (r = - 0.507, p < 0.05). In the Met group, the center/remote ratio gradually increased with time, there was no significant correlation between center/remote ratio and LV EDV (r = - 0.078, p > 0.05). On the 30th day, the center/remote ratio of the Met group was significantly higher than that of the Control group (0.81 ± 0.06 vs. 0.65 ± 0.09, p < 0.05), while LV EDV in Met group was significantly lower than in Control group (358.21 ± 22.62 vs. 457.53 ± 29.91, p < 0.05). There was no significant difference of LVEF between Met group and Control group at different time points after reperfusion (p < 0.05). HE staining showed that the myocardial infarction and fibrosis in ischemic center area of the Control group was more serious than that of the Met group. CONCLUSIONS: Met could attenuate the severity of MIRI, delay and prevent the progress of LV remodeling. The cardioprotective progress could be dynamically assessed by 18F-FDG micro-PET/CT imaging.
Subject(s)
Metformin , Myocardial Reperfusion Injury , Animals , Fluorodeoxyglucose F18 , Metformin/pharmacology , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/prevention & control , Positron Emission Tomography Computed Tomography , Rats , Rats, Sprague-DawleyABSTRACT
Neuregulin-1 (NRG-1) is reported to be cardioprotective through the extracellular-regulated protein kinase (ERK) 1/2 pathway in myocardial ischaemia-reperfusion injury (MIRI). NOX4-induced ROS activated NLRP3 inflammasome and exacerbates MIRI. This study aims to investigate whether NRG-1 can suppress NOX4 by ERK1/2 and consequently inhibit the NLRP3/caspase-1 signal in MIRI. The myocardial infarct size (IS) was measured by TTC-Evans blue staining. Immunohistochemical staining, real-time quantitative PCR (RT-qPCR) and Western blotting were used for detection of the factors, such as NOX4, ERK1/2, NLRP3, caspase-1 and IL-1ß .The IS in the NRG-1 (3 µg/kg, intravenous) group was lower than that in the IR group. Immunohistochemical analysis revealed NRG-1 decreased 4HNE and NOX4. The RT-qPCR and Western blot analyses revealed that NRG-1 mitigated the IR-induced up-regulation of NOX4 and ROS production. Compared with the IR group, the NRG-1 group exhibited a higher level of P-ERK1/2 and a lower level of NLRP3. In the Langendorff model, PD98059 inhibited ERK1/2 and up-regulated the expression of NOX4, NLRP3, caspase-1 and IL-1ß, which exacerbated oxidative stress and inflammation. In conclusion, NRG-1 can reduce ROS production by inhibiting NOX4 through ERK1/2 and inhibit the NLRP3/caspase-1 pathway to attenuate myocardial oxidative damage and inflammation in MIRI.
Subject(s)
Caspase 1/metabolism , Myocardial Reperfusion Injury/etiology , Myocardial Reperfusion Injury/metabolism , NADPH Oxidase 4/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neuregulin-1/metabolism , Oxidative Stress , Animals , Biomarkers , Biopsy , Disease Models, Animal , Gene Expression , Immunohistochemistry , Male , Models, Biological , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/pathology , Myocardium/metabolism , Myocardium/pathology , Neuregulin-1/genetics , RatsABSTRACT
Despite advances in the diagnosis and treatment of ischemic heart disease (IHD), it remains the leading cause of death globally. Thus, there is a need to investigate the underlying pathophysiology and develop new therapies for the prevention and treatment of IHD. Murine models are widely used in IHD research because they are readily available, relatively inexpensive, and can be genetically modified to explore mechanistic questions. Ischemia-reperfusion (I/R)-induced myocardial infarction in mice is produced by the blockage followed by reperfusion of the left anterior descending branch (LAD) to imitate human IHD disease and its treatment. This I/R model can be widely used to investigate the potential reparative effect of putative treatments in the setting of reperfusion. However, the surgical technique is demanding and can produce an inconsistent amount of damage, which can make identification of treatment effects challenging. Therefore, determining which hearts have been significantly damaged by I/R is an important consideration in studies designed to either explore the mechanisms of disrupted function or test possible therapies. Noninvasive echocardiography (ECHO) is often used to determine structural and functional changes in the mouse heart following injury. In the present study, we determined that ECHO performed 3 days post I/R surgery could predict the permanent injury produced by the ischemic insult.NEW & NOTEWORTHY We believe our work is noteworthy due to its creation of standards for early evaluation of the level of myocardial injury in mouse models of ischemia-reperfusion. This improvement to study design could reduce the sample sizes used in evaluating therapeutics and lead to increased confidence in conclusions drawn regarding the therapeutic efficacy of treatments tested in these translational mouse models.
Subject(s)
Coronary Vessels/surgery , Echocardiography , Myocardial Infarction/diagnostic imaging , Myocardial Reperfusion Injury/diagnostic imaging , Myocardium/pathology , Animals , Coronary Circulation , Coronary Vessels/physiopathology , Disease Models, Animal , Female , Male , Mice, Inbred C57BL , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Predictive Value of Tests , Recovery of Function , Stroke Volume , Time Factors , Ventricular Function, LeftABSTRACT
AIMS: Remote ischemic conditioning (RIC) alleviates ischemia-reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection. METHODS AND RESULTS: We block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p < 0.05) at T3 following single- than double-cycle inflation (PBR:ΔT0-T3 = 0.249 ± 0.033 vs 0.126 ± 0.034 µm, p = 0.03 and PWV:0.4 ± 0.21 vs -1.02 ± 0.24 m/s, p = 0.03). Increased miR-150,-21,-208 (p < 0.05) and reduced MDA was observed after both protocols. Increased miR-144 was related to PWV reduction (r = 0.763, p < 0.001) after the first-cycle inflation in both protocols. After one year, single-cycle RIC was associated with LV end-systolic volume reduction (LVESV) > 15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC. CONCLUSION: RIC evokes "vascular conditioning" likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT03984123.
Subject(s)
Arteries/physiopathology , Ischemic Postconditioning , Myocardial Reperfusion Injury/prevention & control , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction/therapy , Upper Extremity/blood supply , Ventricular Function, Left , Ventricular Remodeling , Adult , Aged , Arteries/metabolism , Circulating MicroRNA/blood , Endothelial Cells/metabolism , Female , Glycocalyx/metabolism , Greece , Humans , Inflammation Mediators/metabolism , Ischemic Postconditioning/adverse effects , Male , MicroRNAs/blood , Middle Aged , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/physiopathology , Oxidative Stress , Percutaneous Coronary Intervention/adverse effects , Prospective Studies , Regional Blood Flow , ST Elevation Myocardial Infarction/diagnostic imaging , ST Elevation Myocardial Infarction/physiopathology , Time Factors , Treatment Outcome , Vascular StiffnessABSTRACT
Early diagnosis of myocardial ischaemia-reperfusion (MI/R) injury is important for protecting the myocardium and improving patient prognoses. Fortunately, the platelet membrane possesses the ability to target the region of MI/R injury. Therefore, we hypothesized that platelet membrane-coated particles (PMPs) could be used to detect early MI/R injury by ultrasound imaging. We designed PMPs with a porous polylactic-co-glycolic acid (PLGA) core coated with a platelet membrane shell. Red blood cell membrane-coated particles (RMPs) were fabricated as controls. Transmission electron microscopy (TEM) and fluorescence microscopy were applied to confirm the membrane coatings of the PMPs and RMPs. In vitro imaging of the PMPs and RMPs was verified. Moreover, binding experiments were designed to examine the targeting ability of the PMPs. Finally, we assessed the signal intensity of the adherent PMPs in the risk area and remote area by ultrasound imaging based on an MI/R rat model. The platelet membrane equipped the PMPs with an accurate targeting ability. Compared with RMPs, PMPs showed significantly more adhesion to human umbilical vein endothelial cells and collagen IV in vitro. Both PMPs and RMPs exhibited good enhancement ability in vitro and in vivo. Furthermore, the signal intensity of PMPs in the risk area was significantly higher than that in remote areas. These results were further validated by an immunofluorescence assay and ex vivo fluorescence imaging. In summary, ultrasound imaging with PMPs can detect early MI/R injury in a noninvasive manner.
Subject(s)
Biomimetic Materials/chemistry , Blood Platelets/metabolism , Cell Membrane/metabolism , Microbubbles , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/metabolism , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Animals , Blood Platelets/chemistry , Cell Adhesion , Cell Membrane/chemistry , Disease Models, Animal , Early Diagnosis , Erythrocytes/chemistry , Erythrocytes/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Male , Rats , Signal Transduction , Ultrasonography/methodsABSTRACT
Nesfatin-1 as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia-reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. These findings have shown that nesfatin-1 can exert cardioprotection against MI/R in a dose dependent manner by suppressing necroptosis via modulation of RIPK1-RIPK3-MLKL axis and RhoA/ROCK/RIP3 signaling pathway.
Subject(s)
Cardiotonic Agents/therapeutic use , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/pathology , Necroptosis , Nucleobindins/therapeutic use , Signal Transduction , rho-Associated Kinases/metabolism , rhoA GTP-Binding Protein/metabolism , Animals , Biomarkers/metabolism , Disease Models, Animal , Electrocardiography , Fibrosis , Glutathione/metabolism , Male , Malondialdehyde/metabolism , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/physiopathology , Myocardium/pathology , Necroptosis/drug effects , Nucleobindins/pharmacology , Protein Serine-Threonine Kinases/metabolism , Rats, Wistar , Reactive Oxygen Species/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Signal Transduction/drug effects , Superoxide Dismutase/metabolismABSTRACT
Early treatment with an oral ß-blocker is recommended in patients with a ST-segment-elevation myocardial infarction (STEMI). In this multicenter study, we evaluated the effects of a continuous administration of landiolol, an ultrashort-acting ß-blocker, before primary percutaneous coronary intervention (PCI) on myocardial salvage and its safety in STEMI patients. A total of 47 Japanese patients with anterior or lateral STEMI undergoing a primary PCI within 12 h of symptom onset were randomized to receive intravenous landiolol (started at 3 µg/min/kg dose and continued to a total of 50 mg; n=23) or not (control; n=24). Patients with Killip class III or more were excluded. The primary outcome was the myocardial salvage index on cardiac magnetic resonance imaging (MRI) performed 5-7 days after the PCI. Cardiac MRI was performed in 35 patients (74%). The myocardial salvage index in the landiolol group was significantly greater than that in the control group (44.4±14.6% vs. 31.7±18.9%, respectively; p=0.04). There were no significant differences in adverse events at 24 h between the landiolol and control groups. A continuous administration of landiolol before a primary PCI may increase the degree of myocardial salvage without additional hemodynamic adverse effects within the first 24 h after STEMI.
Subject(s)
Adrenergic beta-Antagonists/administration & dosage , Morpholines/administration & dosage , Myocardial Reperfusion Injury/prevention & control , ST Elevation Myocardial Infarction/drug therapy , Urea/analogs & derivatives , Administration, Intravenous , Aged , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/pathology , Percutaneous Coronary Intervention/methods , Prospective Studies , ST Elevation Myocardial Infarction/diagnostic imaging , Urea/administration & dosageABSTRACT
BACKGROUND: Despite successful restoration of epicardial vessel patency with primary percutaneous coronary intervention, coronary microvascular injury occurs in a large proportion of patients with ST-segment-elevation myocardial infarction, adversely affecting clinical and functional outcome. Ticagrelor has been reported to increase plasma adenosine levels, which might have a protective effect on the microcirculation. We investigated whether ticagrelor maintenance therapy after revascularized ST-segment-elevation myocardial infarction is associated with less coronary microvascular injury compared to prasugrel maintenance therapy. METHODS: A total of 110 patients with ST-segment-elevation myocardial infarction received a loading dose of ticagrelor and were randomized to maintenance therapy of ticagrelor (n=56) or prasugrel (n=54) after primary percutaneous coronary intervention. The primary outcome was coronary microvascular injury at 1 month, as determined with the index of microcirculatory resistance in the infarct-related artery. Cardiovascular magnetic resonance imaging was performed during the acute phase and at 1 month. RESULTS: The primary outcome of index of microcirculatory resistance was not superior in ticagrelor- or prasugrel-treated patients (ticagrelor, 21 [interquartile range, 15-39] U; prasugrel, 18 [interquartile range, 11-29] U; P=0.08). Recovery of microcirculatory resistance over time was not better in patients with ticagrelor versus prasugrel (ticagrelor, -13.9 U; prasugrel, -13.5 U; P=0.96). Intramyocardial hemorrhage was observed less frequently in patients receiving ticagrelor (23% versus 43%; P=0.04). At 1 month, no difference in infarct size was observed (ticagrelor, 7.6 [interquartile range, 3.7-14.4] g, prasugrel 9.9 [interquartile range, 5.7-16.6] g; P=0.17). The occurrence of microvascular obstruction was not different in patients on ticagrelor (28%) or prasugrel (41%; P=0.35). Plasma adenosine concentrations were not different during the index procedure and during maintenance therapy with ticagrelor or prasugrel. CONCLUSIONS: In patients with ST-segment-elevation myocardial infarction, ticagrelor maintenance therapy was not superior to prasugrel in preventing coronary microvascular injury in the infarct-related territory as assessed by the index of microcirculatory resistance, and this resulted in a comparable infarct size at 1 month. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02422888.
Subject(s)
Coronary Circulation , Microcirculation , Myocardial Reperfusion Injury/prevention & control , Percutaneous Coronary Intervention/adverse effects , Platelet Aggregation Inhibitors/administration & dosage , Prasugrel Hydrochloride/administration & dosage , ST Elevation Myocardial Infarction/therapy , Ticagrelor/administration & dosage , Aged , Female , Humans , Magnetic Resonance Imaging, Cine , Male , Middle Aged , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/etiology , Myocardial Reperfusion Injury/physiopathology , Netherlands , Platelet Aggregation Inhibitors/adverse effects , Prasugrel Hydrochloride/adverse effects , Prospective Studies , Risk Factors , ST Elevation Myocardial Infarction/diagnostic imaging , Spain , Ticagrelor/adverse effects , Time Factors , Treatment Outcome , Vascular ResistanceABSTRACT
Background After acute myocardial infarction (AMI), reperfusion injury is associated with microvascular lesions and myocardial edema. Purpose To evaluate the performance of apparent diffusion coefficient (ADC) quantification compared with T1 and T2 values in the detection of acute myocardial injury. Materials and Methods In this prospective study conducted from June 2016 to November 2018, participants without a history of heart failure or cardiomyopathy were enrolled after undergoing reperfusion for their first AMI. Quantitative T1 and T2 mapping were performed with a 1.5-T MRI scanner and compared with a fast free-breathing acquisition technique for ADC mapping (approximate duration, 3 minutes; five slices; spin-echo cardiac diffusion acquisition; b values, 0 and 200 sec/mm2; six diffusion-encoding directions; five repetitions). Quantitative ADC and unenhanced T1 and T2 values were compared in infarct, border, and remote regions by using Welch analysis of variance with Games-Howell post hoc test for pairwise comparisons. Results Thirty-four participants with AMI underwent MRI an average of 5 days ± 1.9 (standard deviation) after reperfusion. Mean ADC was markedly high in the infarcted regions (2.32 × 10-3 mm2/sec; 95% confidence interval [CI]: 2.28, 2.36) and moderately high in the border regions (1.91 ×10-3 mm2/sec; 95% CI: 1.89, 1.94; P < .001). In remote regions, mean ADC (1.62 ×10-3 mm2/sec; 95% CI: 1.59, 1.64) was comparable to that measured in vivo in healthy volunteers. Within the same regions of interest, although the measures showed similar trends in infarct and remote regions for T1 (mean, 1332 mec [95% CI: 1296, 1368] vs 1045 msec [95% CI: 1034, 1056]; P < .001) and T2 (72 msec [95% CI: 69, 75] vs 50 msec [95% CI: 49, 51]; P < .001), the magnitude of the differences among regions was greater when using ADC. Normalized signal differences between infarct and remote regions showed that diffusion-weighted MRI depicted edema 5.1 (P < .001) and 3.5 (P < .001) times greater than did T1 and T2 maps, respectively. Conclusion Multislice cardiac diffusion-weighted images could be acquired in those with acute myocardial injury. Quantitative apparent diffusion coefficient mapping showed greater differences among remote regions and lesions than did T1 or T2 mapping. © RSNA, 2020 See also the editorial by Lloyd and Farris in this issue.
Subject(s)
Edema/diagnostic imaging , Magnetic Resonance Angiography/methods , Myocardial Infarction/diagnostic imaging , Myocardial Reperfusion Injury/diagnostic imaging , Aged , Electrocardiography , Female , Humans , Male , Middle Aged , Prospective Studies , Sensitivity and SpecificityABSTRACT
Early metoprolol administration protects against myocardial ischemia-reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.
Subject(s)
Adrenergic beta-1 Receptor Antagonists/administration & dosage , Metoprolol/administration & dosage , Myocardial Reperfusion Injury/prevention & control , Myocardium/pathology , ST Elevation Myocardial Infarction/drug therapy , Administration, Intravenous , Animals , Cardiac Imaging Techniques , Disease Progression , Drug Evaluation, Preclinical , Magnetic Resonance Imaging , Male , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/pathology , ST Elevation Myocardial Infarction/diagnostic imaging , ST Elevation Myocardial Infarction/pathology , Swine , Time FactorsABSTRACT
An increased incidence of myocardial infarction (MI) has recently emerged as the cause of cardiovascular morbidity and mortality worldwide. In this study, cardiac function was investigated in a rat myocardial ischemia/reperfusion (I/R) model using echocardiography. Metformin administration significantly increased ejection fraction and fractional shortening values on Days 3 and 7 when MI occurred, indicating that metformin improved left ventricular systolic function. In the Sham + MET and MI + MET groups, the E' value was significantly different up to Day 3 but not at Day 7. This may mean that left ventricular diastolic function was effectively restored to some extent by Day 7 when metformin was administered. These results suggest that diastolic dysfunction, assessed by echocardiography, does not recover in the early phase of ischemic reperfusion injury in the rat myocardial I/R model. However, administering metformin resulted in recovery in the early phase of ischemic reperfusion injury in this model. Further gene expression profiling of left ventricle tissues revealed that the metformin-treated group had notably attenuated immune and inflammatory profiles. To sum up, a rat myocardial I/R injury model and ultrasound-based assessment of left ventricular systolic and diastolic function can be used in translational research and for the development of new heart failure-related drugs, in addition to evaluating the potential of metformin to improve left ventricular (LV) diastolic function.
Subject(s)
Echocardiography , Gene Expression Regulation/drug effects , Metformin/pharmacology , Myocardial Reperfusion Injury , Ventricular Dysfunction, Left , Animals , Disease Models, Animal , Gene Expression Profiling , Male , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/metabolism , Rats , Rats, Sprague-Dawley , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/metabolismABSTRACT
Adenosine is involved in classic preconditioning in most species and acts especially through adenosine A1 and A3 receptors. The aim of the present study was to evaluate whether remote ischemic preconditioning (rIPC) activates adenosine A1 receptors and improves mitochondrial function, thereby reducing myocardial infarct size. Isolated rat hearts were subjected to 30 min of global ischemia and 60 min of reperfusion [ischemia-reperfusion (I/R)]. In a second group, before isolation of the heart, a rIPC protocol (3 cycles of hindlimb I/R) was performed. Infarct size was measured with tetrazolium staining, and Akt/endothelial nitric oxide (NO) synthase (eNOS) expression/phosphorylation and mitochondrial function were evaluated after ischemia at 10 and 60 min of reperfusion. As expected, rIPC significantly decreased infarct size. This beneficial effect was abolished only when 8-cyclopentyl-1,3-dipropylxanthine (adenosine A1 receptor blocker) and NG-nitro-l-arginine methyl ester (NO synthesis inhibitor) were administered during the reperfusion phase. At the early reperfusion phase, rIPC induced significant Akt and eNOS phosphorylation, which was abolished by the perfusion with an adenosine A1 receptor blocker. I/R led to impaired mitochondrial function, which was attenuated by rIPC and mediated by adenosine A1 receptors. In conclusion, we demonstrated that rIPC limits myocardial infarct by activation of adenosine A1 receptors at early reperfusion in the isolated rat heart. Interestingly, rIPC appears to reduce myocardial infarct size by the Akt/eNOS pathway and improves mitochondrial function during myocardial reperfusion. NEW & NOTEWORTHY Adenosine is involved in classic preconditioning and acts especially through adenosine A1 and A3 receptors. However, its role in the mechanism of remote ischemic preconditioning is controversial. In this study, we demonstrated that remote ischemic preconditioning activates adenosine A1 receptors during early reperfusion, inducing Akt/endothelial nitric oxide synthase phosphorylation and improving mitochondrial function, thereby reducing myocardial infarct size.
Subject(s)
Ischemic Preconditioning, Myocardial , Mitochondria, Heart , Receptor, Adenosine A1 , Adenosine A1 Receptor Antagonists/therapeutic use , Adenosine Triphosphate/biosynthesis , Animals , Enzyme Inhibitors/therapeutic use , Male , Membrane Potential, Mitochondrial , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/diagnostic imaging , Myocardial Reperfusion Injury/physiopathology , Nitric Oxide Synthase Type III/antagonists & inhibitors , Nitric Oxide Synthase Type III/metabolism , Nitroarginine/therapeutic use , Oxygen Consumption , Rats , Rats, Sprague-Dawley , Xanthines/therapeutic useABSTRACT
ß-Adrenergic receptor (ß-AR) stimulation increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases ß-AR-stimulated myocyte apoptosis and myocardial fibrosis. Here, we hypothesized that exogenous UB modulates the inflammatory response, thereby playing a protective role in cardiac remodeling after ischemia-reperfusion (I/R) injury. C57BL/6 mice infused with vehicle or UB (1 µg·g-1·h-1) were subjected to myocardial I/R injury. Functional and biochemical parameters of the heart were examined 3 days post-I/R. Heart weight-to-body weight ratios were similarly increased in I/R and UB + I/R groups. The area at risk and infarct size were significantly lower in UB + I/R versus I/R groups. Measurement of heart function using echocardiography revealed that I/R decreases percent fractional shortening and percent ejection fraction. However, the decrease in fractional shortening and ejection fraction was significantly lower in the UB + I/R group. The UB + I/R group displayed a significant decrease in inflammatory infiltrates, neutrophils, and macrophages versus the I/R group. Neutrophil activity was significantly lower in the UB + I/R group. Analysis of the concentration of a panel of 23 cytokines/chemokines in the serum using a Bio-Plex assay revealed a significantly lower concentration of IL-12 subunit p40 in the UB + I/R versus I/R group. The concentration of monocyte chemotactic protein-1 was lower, whereas the concentration of macrophage inflammatory protein-1α was significantly higher, in the UB+I/R group versus the sham group. Expression of matrix metalloproteinase (MMP)-2 and activity of MMP-9 were higher in the UB + I/R group versus the I/R group. Levels of ubiquitinated proteins and tissue inhibitor of metalloproteinase 2 expression were increased to a similar extent in both I/R groups. Thus, exogenous UB plays a protective role in myocardial remodeling post-I/R with effects on cardiac function, area at risk/infarct size, the inflammatory response, levels of serum cytokines/chemokines, and MMP expression and activity. NEW & NOTEWORTHY Stimulation of ß-adrenergic receptors increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases ß-adrenergic receptor-stimulated myocyte apoptosis and myocardial fibrosis. Here, we provide evidence that exogenous UB decreases the inflammatory response and preserves heart function 3 days after myocardial ischemia-reperfusion injury. Further identification of the molecular events involved in the anti-inflammatory role of exogenous UB may provide therapeutic targets for patients with ischemic heart disease.
Subject(s)
Heart/physiopathology , Inflammation/drug therapy , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/physiopathology , Ubiquitin/therapeutic use , Animals , Body Weight , Chemokines/metabolism , Cytokines/metabolism , Heart/diagnostic imaging , Inflammation/etiology , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Myocardial Reperfusion Injury/diagnostic imaging , Neutrophil Infiltration/drug effects , Organ Size , Stroke Volume/drug effects , Ventricular Remodeling/drug effectsABSTRACT
BACKGROUND: Ex-vivo cardiovascular magnetic resonance (CMR) imaging has played an important role in the validation of in-vivo CMR characterization of pathological processes. However, comparison between in-vivo and ex-vivo imaging remains challenging due to shape changes occurring between the two states, which may be non-uniform across the diseased heart. A novel two-step process to facilitate registration between ex-vivo and in-vivo CMR was developed and evaluated in a porcine model of chronic myocardial infarction (MI). METHODS: Seven weeks after ischemia-reperfusion MI, 12 swine underwent in-vivo CMR imaging with late gadolinium enhancement followed by ex-vivo CMR 1 week later. Five animals comprised the control group, in which ex-vivo imaging was undertaken without any support in the LV cavity, 7 animals comprised the experimental group, in which a two-step registration optimization process was undertaken. The first step involved a heart specific flexible 3D printed scaffold generated from in-vivo CMR, which was used to maintain left ventricular (LV) shape during ex-vivo imaging. In the second step, a non-rigid co-registration algorithm was applied to align in-vivo and ex-vivo data. Tissue dimension changes between in-vivo and ex-vivo imaging were compared between the experimental and control group. In the experimental group, tissue compartment volumes and thickness were compared between in-vivo and ex-vivo data before and after non-rigid registration. The effectiveness of the alignment was assessed quantitatively using the DICE similarity coefficient. RESULTS: LV cavity volume changed more in the control group (ratio of cavity volume between ex-vivo and in-vivo imaging in control and experimental group 0.14 vs 0.56, p < 0.0001) and there was a significantly greater change in the short axis dimensions in the control group (ratio of short axis dimensions in control and experimental group 0.38 vs 0.79, p < 0.001). In the experimental group, prior to non-rigid co-registration the LV cavity contracted isotropically in the ex-vivo condition by less than 20% in each dimension. There was a significant proportional change in tissue thickness in the healthy myocardium (change = 29 ± 21%), but not in dense scar (change = - 2 ± 2%, p = 0.034). Following the non-rigid co-registration step of the process, the DICE similarity coefficients for the myocardium, LV cavity and scar were 0.93 (±0.02), 0.89 (±0.01) and 0.77 (±0.07) respectively and the myocardial tissue and LV cavity volumes had a ratio of 1.03 and 1.00 respectively. CONCLUSIONS: The pattern of the morphological changes seen between the in-vivo and the ex-vivo LV differs between scar and healthy myocardium. A 3D printed flexible scaffold based on the in-vivo shape of the LV cavity is an effective strategy to minimize morphological changes in the ex-vivo LV. The subsequent non-rigid registration step further improved the co-registration and local comparison between in-vivo and ex-vivo data.