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Secretome of apoptotic peripheral blood cells (APOSEC) attenuates microvascular obstruction in a porcine closed chest reperfused acute myocardial infarction model: role of platelet aggregation and vasodilation.

ABSTRACT: Although epicardial blood flow can be restored by an early intervention in most cases, a lack of adequate reperfusion at the microvascular level is often a limiting prognostic factor of acute myocardial infarction (AMI). Our group has recently found that paracrine factors secreted from apoptotic peripheral blood mononuclear cells (APOSEC) attenuate the extent of myocardial injury. The aim of this study was to determine the influence of APOSEC on microvascular obstruction (MVO) in a porcine AMI model. A single dose of APOSEC was intravenously injected in a closed chest reperfused infarction model. MVO was determined by magnetic resonance imaging and cardiac catheterization. Role of platelet function and vasodilation were monitored by means of ELISA, flow cytometry, aggregometry, western blot and myographic experiments in vitro and in vivo. Treatment of AMI with APOSEC resulted in a significant reduction of MVO. Platelet activation markers were reduced in plasma samples obtained during AMI, suggesting an anti-aggregatory capacity of APOSEC. This finding was confirmed by in vitro tests showing that activation and aggregation of both porcine and human platelets were significantly impaired by co-incubation with APOSEC, paralleled by vasodilator-stimulated phosphoprotein (VASP)-mediated inhibition of platelets. In addition, APOSEC evidenced a significant vasodilatory capacity on coronary arteries via p-eNOS and iNOS activation. Our data give first evidence that APOSEC reduces the extent of MVO during AMI, and suggest that modulation of platelet activation and vasodilation in the initial phase after myocardial infarction contributes to the improved long-term outcome in APOSEC treated animals.

SUBMITTER: Hoetzenecker K

PROVIDER: S-EPMC3442164 | biostudies-other | 2012 Sep

REPOSITORIES: biostudies-other

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Secretome of apoptotic peripheral blood cells (APOSEC) attenuates microvascular obstruction in a porcine closed chest reperfused acute myocardial infarction model: role of platelet aggregation and vasodilation.

Hoetzenecker K K Assinger A A Lichtenauer M M Lichtenauer M M Mildner M M Schweiger T T Starlinger P P Jakab A A Berényi E E Pavo N N Zimmermann M M Gabriel C C Plass C C Gyöngyösi M M Volf I I Ankersmit H J HJ

Basic research in cardiology 20120817 5

Although epicardial blood flow can be restored by an early intervention in most cases, a lack of adequate reperfusion at the microvascular level is often a limiting prognostic factor of acute myocardial infarction (AMI). Our group has recently found that paracrine factors secreted from apoptotic peripheral blood mononuclear cells (APOSEC) attenuate the extent of myocardial injury. The aim of this study was to determine the influence of APOSEC on microvascular obstruction (MVO) in a porcine AMI m ...[more]

PMID: 22899170

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Project description:Background Invasive measures of microvascular resistance in the culprit coronary artery have potential for risk stratification in acute ST-segment-elevation myocardial infarction. We aimed to investigate the pathological and prognostic significance of coronary thermodilution waveforms using a diagnostic guidewire. Methods and Results Coronary thermodilution was measured at the end of percutaneous coronary intervention, (PCI) and contrast-enhanced cardiac magnetic resonance imaging (MRI) was intended on day 2 and 6 months later to assess left ventricular (LV) function and pathology. All-cause death or first heart failure hospitalization was a pre-specified outcome (median follow-up duration 1469 days). Thermodilution recordings underwent core laboratory assessment. A total of 278 patients with acute ST-segment elevation myocardial infarction EMI (72% male, 59±11 years) had coronary thermodilution measurements classified as narrow unimodal (n=143 [51%]), wide unimodal (n=100 [36%]), or bimodal (n=35 [13%]). Microvascular obstruction and myocardial hemorrhage were associated with the thermodilution waveform pattern ( P=0.007 and 0.011, respectively), and both pathologies were more prevalent in patients with a bimodal morphology. On multivariate analysis with baseline characteristics, thermodilution waveform status was a multivariable associate of microvascular obstruction (odds ratio [95% confidence interval]=5.29 [1.73, 16.22];, P=0.004) and myocardial hemorrhage (3.45 [1.16, 10.26]; P=0.026), but the relationship was not significant when index of microvascular resistance (IMR) >40 or change in index of microvascular resistance (5 per unit) was included. However, a bimodal thermodilution waveform was independently associated with all-cause death and hospitalization for heart failure (odds ratio [95% confidence interval]=2.70 [1.10, 6.63]; P=0.031), independent of index of microvascular resistance>40, ST-segment resolution, and TIMI (Thrombolysis in Myocardial Infarction) Myocardial Perfusion Grade. Conclusions The thermodilution waveform in the culprit coronary artery is a biomarker of prognosis and may be useful for risk stratification immediately after reperfusion therapy.

Project description:BackgroundThe success of coronary reperfusion therapy in ST-segment-elevation myocardial infarction (MI) is commonly limited by failure to restore microvascular perfusion.Methods and resultsWe performed a prospective cohort study in patients with reperfused ST-segment-elevation MI who underwent cardiac magnetic resonance 2 days (n=286) and 6 months (n=228) post MI. A serial imaging time-course study was also performed (n=30 participants; 4 cardiac magnetic resonance scans): 4 to 12 hours, 2 days, 10 days, and 7 months post reperfusion. Myocardial hemorrhage was taken to represent a hypointense infarct core with a T2* value of <20 ms. Microvascular obstruction was assessed with late gadolinium enhancement. Adverse remodeling was defined as an increase in left ventricular end-diastolic volume ≥20% at 6 months. Cardiovascular death or heart failure events post discharge were assessed during follow-up. Two hundred forty-five patients had evaluable T2* data (mean±age, 58 [11] years; 76% men). Myocardial hemorrhage 2 days post MI was associated with clinical characteristics indicative of MI severity and inflammation. Myocardial hemorrhage was a multivariable associate of adverse remodeling (odds ratio [95% confidence interval]: 2.64 [1.07-6.49]; P=0.035). Ten (4%) patients had a cardiovascular cause of death or experienced a heart failure event post discharge, and myocardial hemorrhage, but not microvascular obstruction, was associated with this composite adverse outcome (hazard ratio, 5.89; 95% confidence interval, 1.25-27.74; P=0.025), including after adjustment for baseline left ventricular end-diastolic volume. In the serial imaging time-course study, myocardial hemorrhage occurred in 7 (23%), 13 (43%), 11 (33%), and 4 (13%) patients 4 to 12 hours, 2 days, 10 days, and 7 months post reperfusion. The amount of hemorrhage (median [interquartile range], 7.0 [4.9-7.5]; % left ventricular mass) peaked on day 2 (P<0.001), whereas microvascular obstruction decreased with time post reperfusion.ConclusionsMyocardial hemorrhage and microvascular obstruction follow distinct time courses post ST-segment-elevation MI. Myocardial hemorrhage was more closely associated with adverse outcomes than microvascular obstruction.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850.

Project description:We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, n = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) (n = 9), or AMI-PostC (n = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs.

Project description:Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S in contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51±2 years; blood pressure, 116±3/76±3 mm Hg) and 14 HTN adults (57±2 years; blood pressure 140±3/89±2 mm Hg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10-6-10-1 mol/L) and sodium sulfide (10-5-101 mol/L) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (all P<0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN adults (P=0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31±0.13 versus ACh+aminooxyacetic acid, 1.07±0.09 flux/mm Hg; P=0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16±0.10 versus ACh+aminooxyacetic acid, 1.37±0.11 flux/mm Hg; P=0.47). Sodium sulfide-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension.

Project description:BackgroundIn the care of patients with congenital heart disease, percutaneous interventional treatments have supplanted many surgical approaches for simple lesions, such as atrial septal defect. By contrast, complex congenital heart defects continue to require open-heart surgery. In single-ventricle patients, a staged approach is employed, which requires multiple open-heart surgeries and significant attendant morbidity and mortality. A nonsurgical transcatheter alternative would be attractive.ObjectivesThe authors sought to show the feasibility of catheter-only, closed-chest, large-vessel anastomosis (superior vena cava and pulmonary artery [PA] or bidirectional Glenn operation equivalent) in a patient.MethodsIn preclinical testing over a decade, the authors developed the techniques and technology needed for nonsurgical crossing from a donor (superior vena cava) to a recipient (PA) vessel and endovascular stent-based anastomosis of those blood vessels. The authors undertook this transcatheter approach for an adult with untreated congenital heart disease with severe cyanosis and significant surgical risk. They rehearsed the procedure step by step using contrast-enhanced cardiac computed tomography and a patient-specific 3-dimensional printed heart model.ResultsThe authors describe a first-in-human, fully percutaneous superior cavopulmonary anastomosis (bidirectional Glenn operation equivalent). The patient, a 35-year-old woman, was homebound due to dyspnea and worsening cyanosis. She was diagnosed with functional single ventricle and very limited pulmonary blood flow. The heart team believed surgical palliation conferred high operative risk due to the patient's complete condition. With the percutaneous procedure, the patient recovered uneventfully and remained improved clinically after 6 months.ConclusionsThis procedure may provide a viable alternative to one of the foundational open-heart surgeries currently performed to treat single-ventricle congenital heart disease.

Project description:Rationale: Microembolization during PCI for acute myocardial infarction can cause microvascular obstruction (MVO). MVO severely limits the success of reperfusion therapies, is associated with additional myonecrosis, and is linked to worse prognosis, including death. We have shown, both in in vitro and in vivo models, that ultrasound (US) and microbubble (MB) therapy (termed "sonoreperfusion" or "SRP") is a theranostic approach that relieves MVO and restores perfusion, but the underlying mechanisms remain to be established. Objective: In this study, we investigated the role of nitric oxide (NO) during SRP. Methods and results: We first demonstrated in plated cells that US-stimulated MB oscillations induced a 6-fold increase in endothelial nitric oxide synthase (eNOS) phosphorylation in vitro. We then monitored the kinetics of intramuscular NO and perfusion flow rate responses following 2-min of SRP therapy in the rat hindlimb muscle, with and without blockade of eNOS with LNAME. Following SRP, we found that starting at 6 minutes, intramuscular NO increased significantly over 30 min and was higher than baseline after 13 min. Concomitant contrast enhanced burst reperfusion imaging confirmed that there was a marked increase in perfusion flow rate at 6 and 10 min post SRP compared to baseline (>2.5 fold). The increases in intramuscular NO and perfusion rate were blunted with LNAME. Finally, we tested the hypothesis that NO plays a role in SRP by assessing reperfusion efficacy in a previously described rat hindlimb model of MVO during blockade of eNOS. After US treatment 1, microvascular blood volume was restored to baseline in the MB+US group, but remained low in the LNAME group. Perfusion rates increased in the MB+US group after US treatment 2 but not in the MB+US+LNAME group. Conclusions: These data strongly support that MB oscillations can activate the eNOS pathway leading to increased blood perfusion and that NO plays a significant role in SRP efficacy.

Dataset Information

Secretome of apoptotic peripheral blood cells (APOSEC) attenuates microvascular obstruction in a porcine closed chest reperfused acute myocardial infarction model: role of platelet aggregation and vasodilation.

Publications

Secretome of apoptotic peripheral blood cells (APOSEC) attenuates microvascular obstruction in a porcine closed chest reperfused acute myocardial infarction model: role of platelet aggregation and vasodilation.

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