Canine Model Of Myocardial Infarction Research Articles

Myocardial glucose suppression may interfere with the detection of inflammatory cells with FDG-PET as suggested in a canine model of myocardial infarction

BackgroundAfter myocardial infarction, fibrosis and an ongoing dysregulated inflammatory response have been shown to lead to adverse cardiac remodeling. FDG PET is an imaging modality sensitive to inflammation as long as suppression protocols are observed while gadolinium enhanced MRI can be used to determine extracellular volume (ECV), a measure of fibrosis. In patients, glucose suppression is achieved variously through a high fat diet, fasting and injection of heparin. To emulate this process in canines, a heparin injection and lipid infusion are used, leading to similar fatty acids in the blood. The aim of this study was to examine the effect of glucose suppression on the uptake of FDG in the infarcted myocardial tissue and also on the determination of ECV in both the infarcted tissue and in the myocardium remote to the zone of infarction during a long constant infusion of FDG and Gd-DTPA.ResultsExtracellular volume was affected neither by suppression nor the length of the constant infusion in remote and infarcted tissue. Metabolic rate of glucose in infarcted tissue decreased during and after suppression of glucose uptake by lipid infusion and heparin injection. An increase in fibrosis and inflammatory cells was found in the center of the infarct as compared to remote tissue.ConclusionThe decrease in the metabolic rate of glucose in the infarcted tissue suggests that inflammatory cells may be affected by glucose suppression through heparin injection and lipid infusion.

Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model.

The stellate ganglia play an important role in cardiac remodeling after myocardial infarction (MI). This study aimed to investigate whether adiponectin (APN), an adipokine mainly secreted by adipose tissue, could modulate the left stellate ganglion (LSG) and exert cardioprotective effects through the sympathetic nervous system (SNS) in a canine model of MI. APN microinjection and APN overexpression with recombinant adeno-associated virus vector in the LSG were performed in acute and chronic MI models, respectively. The results showed that acute APN microinjection decreased LSG function and neural activity, and suppressed ischemia-induced ventricular arrhythmia. Chronic MI led to a decrease in the effective refractory period and action potential duration at 90% and deterioration in echocardiography performance, all of which was blunted by APN overexpression. Moreover, APN gene transfer resulted in favorable heart rate variability alteration, and decreased cardiac SNS activity, serum noradrenaline and neuropeptide Y, which were augmented after MI. APN overexpression also decreased the expression of nerve growth factor and growth associated protein 43 in the LSG and peri-infarct myocardium, respectively. Furthermore, RNA sequencing of LSG indicated that 4-week MI up-regulated the mRNA levels of macrophage/microglia activation marker Iba1, chemokine ligands (CXCL10, CCL20), chemokine receptor CCR5andpro-inflammatory cytokine IL6, and downregulated IL1RN and IL10 mRNA, which were reversed by APN overexpression. Our results reveal that APN inhibits cardiac sympathetic remodeling and mitigates cardiac remodeling after MI. APN-mediated gene therapy may provide a potential therapeutic strategy for the treatment of MI.

Tracking the progress of inflammation with PET/MRI in a canine model of myocardial infarction

BackgroundFollowing myocardial infarction, tissue undergoes pathophysiological changes involving inflammation and scar tissue formation. However, little is known about the pathophysiology and prognostic significance of any corresponding changes in remote myocardium. The aim of this study was to investigate the potential application of a combined constant infusion of 18F-FDG and Gd-DTPA to quantitate inflammation and extracellular volume (ECV) from 3 to 40 days after myocardial infarction. MethodsEight canine subjects were imaged at multiple time points following induction of an MI with a 60-minute concurrent constant infusion of Gd-DTPA and 18F-FDG using a hybrid PET/MRI scanner. ResultsThere was a significant increase in ECV in remote myocardium on day 14 post-MI (P = .034) and day 21 (P = .021) compared to the baseline. ECV was significantly elevated in the infarcted myocardium compared to remote myocardium at all time points post-MI (days 3, 7, 14, 21, and 40) (P < .001) while glucose uptake was also increased within the infarct on days 3, 7, 14, and 21 but not 40. ConclusionsThe significant increase in ECV in remote tissue may be due to an ongoing inflammatory process in the early weeks post-infarct.

Regional Left Ventricular Myocardial Injury and Function Characterisation by Cardiac Magnetic Resonance Imaging in a Sheep Model of Myocardial Infarction

Left ventricular (LV) remodelling following a myocardial infarction(MI) elicits different responses in infarct and remote LV, with prior studies reporting increased contractility in the latter. We explored the relationship between myocardial injury and its functional consequences using a combination of 3D late gadolinium enhancement (LGE), feature tracking (FT) cardiac magnetic resonance (CMR) and autopsy findings in a sheep model of MI. MI was induced in sheep (n=11) by coronary artery ligation under general anaesthesia. Baseline (pre-MI) and follow-up (15d post-MI) CMR exams were performed for cine imaging. LGE imaging was performed using a 3D inversion recovery fast low angle shot (IR-FLASH) sequence in the follow-up examination. MI size was confirmed at post-mortem. Regions of MI identified by imaging were compared with post-mortem findings using AHA LV segmentation. The sensitivity and specificity of the LGE imaging was calculated and compared to post-mortem using McNemar’s test. FT was applied to the cine imaging to quantify regional circumferential strain (CS). The percentage change in regional CS was calculated for each segment (Data: mean±SD; *p<0.05). LGE detected MI with a sensitivity of 90.6% and specificity of 96.4% (p=0.7). LV ejection fraction (EF) was 55.7±5.6% post-MI. Percentage changes in regional CS were -34.3±13.8% and -17.4±30.7% in AHA segments 13 and 16, respectively, while other segments exhibited increased CS (range=+0.1% to +28.7%). Our novel application of 3D IR-FLASH and FT provided comprehensive visualisation of LV injury and function in the setting of MI. Our data reproduces prior descriptions of compensatory increases in myocardial contractility in remote regions in STEMI patients with ≥50% EF [[1]Leung S.W. Ratajczak T.M. Abo-Aly M. Shokri E. Abdel-Latif A. Wenk J.F. Regional end-systolic circumferential strain demonstrates compensatory segmental contractile function in patients with ST-segment elevation myocardial infarction.J Biomech. 2021; 129 (110794)Crossref PubMed Scopus (1) Google Scholar] and a canine model of MI [[2]Lew W.Y. Chen Z.Y. Guth B. Covell J.W. Mechanisms of augmented segment shortening in nonischemic areas during acute ischemia of the canine left ventricle.Circ Res. 1985; 56: 351-358Crossref PubMed Scopus (112) Google Scholar].

Transthoracic ultrasound-guided percutaneous intramyocardial injection combined with ultrasound-targeted microbubble destruction-mediated angiogenin 1 gene therapy in canine myocardial infarction model.

Intravenous (IV) ultrasound-targeted microbubble destruction (UTMD) has made distinct but limited progress in gene transfected therapy. Intramyocardial (IM) injection also has some effect. In this study, IM injection could be performed under the guidance of transthoracic ultrasound without thoracotomy. We aimed to evaluate the effect of combination transthoracic ultrasound-guided percutaneous IM injection and UTMD for mediating the angiogenin 1 (Ang1) gene therapy in myocardial infarction (MI) canines. Forty-two canines were divided into four groups: IM-UTMD group (intramyocardial injection of the negative control plasmid with UTMD as the sham group); IM-Ang1 group (intramyocardial injection of the Ang1 plasmid without UTMD); IM-Ang1-UTMD group (intramyocardial injection of the Ang1 plasmid with UTMD); and IV-Ang1-UTMD group (intravenous injection of the Ang1 plasmid with UTMD). The FITC green fluorescence and Ang1 protein in myocardial tissue were used for the distribution of Ang1 gene. Left ventricular dimension and systolic function were observed by echocardiography. The Masson's and Sirius Red's staining were used for evaluating the collagen fiber. The immunohistochemistry for CD31 and alpha-smooth muscle actin (α-SMA) were as the indicators of microvasculature. Myocardial contrast echocardiography was used to reflect the microvascular perfusion. More FITC-labeled plasmid was observed in the three IM injection groups than in the IV-Ang1-UTMD group, and the Ang1 protein expression was higher in the IM-Ang1-UTMD group. One month later, no significant differences in survival rate and complications were observed among all four groups. Although there were no differences in the left ventricular end-diastolic diameter among the 4 groups, the left ventricular end-systolic diameter was lower in the IM-Ang1-UTMD group than in the other groups. Then, the left ventricular ejection fraction was increased in the IM-Ang1-UTMD group, with lower collagen fiber percentage, higher blood vessel density and myocardial reperfusion intensity than those in the other groups (P<0.05). Transthoracic ultrasound-guided percutaneous IM injection combined with UTMD is a safe and effective method for mediating Ang1 plasmid therapy in MI canines.

Combined use of external therapeutic ultrasound and tirofiban has synergistic therapeutic effects on no-reflow after myocardial reperfusion.

This study aimed to evaluate the effects of the combined use of external therapeutic ultrasound (ETUS) and the specific glycoprotein IIb/IIIa inhibitor tirofiban on myocardial no-reflow in a canine model of acute myocardial infarction after reperfusion. The canine myocardial no-reflow model was established by a 3-hour occlusion of the left anterior desecending coronary artery followed by a 2-hour reperfusion. Twenty-four canines were divided into four groups (6/group): (1) control, (2) tirofiban alone, (3) ETUS combined with tirofiban (ETUS+tirofiban), and (4) ETUS alone. The area of no-reflow in each of the three treatment groups was significantly decreased, compared with the control group, with the ETUS+tirofiban group having the smallest area. Also, the ETUS+tirofiban group had the highest recanalized rate of microvessels in the no-reflow area and fewer impaired cellular organelles. The recovery rates of the endocardial and middle circumferential strain as well as longitudinal strain in the ETUS+tirofiban group were significantly greater than those of the tirofiban group. Moreover, the expression of hypoxia-inducible factor-1α (HIF-1α) was significantly increased in the ETUS+tirofiban group, compared with the other groups. The combined use of ETUS and tirofiban offers synergistic benefits for the treatment of myocardial no-reflow.

Targeted ablation of cardiac sympathetic neurons improves ventricular electrical remodelling in a canine model of chronic myocardial infarction.

The purpose of this study was to evaluate the cardiac electrophysiologic effects of targeted ablation of cardiac sympathetic neurons (TACSN) in a canine model of chronic myocardial infarction (MI). Thirty-eight anaesthetized dogs were randomly assigned into the sham-operated, MI, and MI-TACSN groups, respectively. Myocardial infarction-targeted ablation of cardiac sympathetic neuron was induced by injecting cholera toxin B subunit-saporin compound in the left stellate ganglion (LSG). Five weeks after surgery, the cardiac function, heart rate variability (HRV), ventricular electrophysiological parameters, LSG function and neural activity, serum norepinephrine (NE), nerve growth factor (NGF), and brain natriuretic peptide (BNP) levels were measured. Cardiac sympathetic innervation was determined with immunofluorescence staining of growth associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Compared with MI group, TACSN significantly improved HRV, attenuated LSG function and activity, prolonged corrected QT interval, decreased Tpeak-Tend interval, prolonged ventricular effective refractory period (ERP), and action potential duration (APD), decreased the slopes of APD restitution curves, suppressed the APD alternans, increased ventricular fibrillation threshold, and reduced serum NE, NGF, and BNP levels. Moreover, the densities of GAP43 and TH-positive nerve fibres in the infarcted border zone in the MI-TACSN group were lower than those in the MI group. Targeted ablation of cardiac sympathetic neuron attenuates sympathetic remodelling and improves ventricular electrical remodelling in the chronic phase of MI. These data suggest that TACSN may be a novel approach to treating ventricular arrhythmias.

Effect of renal sympathetic denervation on ventricular and neural remodeling.

BackgroundThis study assessed the therapeutic effects of renal sympathetic denervation (RDN) on post-myocardial infarction (MI) ventricular remodeling and sympathetic neural remodeling in dogs. The possible mechanisms and optimal time for treatment are discussed.MethodsWe randomly assigned 30 dogs to five groups: RDN 1 week before MI (RDN1w + MI; n = 6), RDN 1 week after MI (MI1w + RDN; n = 6), RDN 2 weeks after MI (MI2w + RDN; n = 6), control (N; n = 6), and MI (n = 6). A canine model of myocardial infarction was established by interventional occlusion with a gelatin sponge via the femoral artery. Brain natriuretic peptide (BNP) and endothelin-1 (ET-1) levels were measured and echocardiography was performed to assess cardiac function and heart size. All dogs were killed at the end of the experiment and samples of cardiac and renal arteries were obtained. The expression of matrix metalloproteinase (MMP)-2 and MMP-9 in cardiac and of tyrosine hydroxylase (TH) in renal arteries was assessed by immunohistochemistry. Sympathetic innervations in the infarction border zone were investigated via Western blotting and real-time PCR.ResultsLeft ventricular function in the MI group decreased significantly, while plasma BNP and ET-1 levels as well as MMP-2 and MMP-9 expression increased. Compared with the MI group, the RD groups showed significantly reduced MMP‑2, MMP‑9, TH, and growth-associated protein (GAP) 43 expression in the RDN1w + MI, MI1w + RDN, and MI2w + RDN groups was significantly improved. Additionally, the expression of TH in renal arteries decreased after RDN.ConclusionRDN has preventive and therapeutic effects on post-MI ventricular remodeling and sympathetic neural remodeling. The mechanism of RDN is likely mediated through restraint of renal sympathetic nerve activity.

A non-contrast CMR index for assessing myocardial fibrosis

PurposeSafe, sensitive, and non-invasive imaging methods to assess the presence, extent, and turnover of myocardial fibrosis are needed for early stratification of risk in patients who might develop heart failure after myocardial infarction. We describe a non-contrast cardiac magnetic resonance (CMR) approach for sensitive detection of myocardial fibrosis using a canine model of myocardial infarction and reperfusion. MethodsSeven dogs had coronary thrombotic occlusion of the left anterior descending coronary arteries followed by fibrinolytic reperfusion. CMR studies were performed at 7days after reperfusion. A CMR spin-locking T1ρ mapping sequence was used to acquire T1ρ dispersion data with spin-lock frequencies of 0 and 511Hz. A fibrosis index map was derived on a pixel-by-pixel basis. CMR native T1 mapping, first-pass myocardial perfusion imaging, and post-contrast late gadolinium enhancement imaging were also performed for assessing myocardial ischemia and fibrosis. Hearts were dissected after CMR for histopathological staining and two myocardial tissue segments from the septal regions of adjacent left ventricular slices were qualitatively assessed to grade the extent of myocardial fibrosis. ResultsHistopathology of 14 myocardial tissue segments from septal regions was graded as grade 1 (fibrosis area, <20% of a low power field, n=9), grade 2 (fibrosis area, 20–50% of field, n=4), or grade 3 (fibrosis area, >50% of field, n=1). A dramatic difference in fibrosis index (183%, P<0.001) was observed by CMR from grade 1 to 2, whereas differences were much smaller for T1ρ (9%, P=0.14), native T1 (5.5%, P=0.12), and perfusion (−21%, P=0.05). ConclusionA non-contrast CMR index based on T1ρ dispersion contrast was shown in preliminary studies to detect and correlate with the extent of myocardial fibrosis identified histopathologically. A non-contrast approach may have important implications for managing cardiac patients with heart failure, particularly in the presence of impaired renal function.

Automatic high-resolution infarct detection using volumetric multiphase dual-energy CT

ObjectivesLate contrast enhancement CT (LCE-CT) visualizes the presence of myocardial infarcts. Differentiation of the contrast-enhanced infarct from blood pool is challenging. We developed a novel method using data from first pass CT angiography (CTA) imaging to enable automatic infarct detection. Materials and methodsA canine model of myocardial infarction was produced in 11 animals. Two months later, first pass CTA (90 kVp) and LCE-CT (dual energy 90 kVp/150 kVp tin filtered) were performed. Late gadolinium enhancement MRI was used as reference standard. The CTA and LCE-CT were co-registered using a fully automatic non-rigid method based on curved B-splines. The method allowed for limited elastic deformation and the considerable differences in attenuation between first-pass and delayed image. The blood pool was easily identified on the CTA image by high attenuation. Because CTA and LCE-CT were registered, the blood pool segmentation can be directly transferred to the LCE-CT – thereby solving the key problem of infarct/blood pool differentiation. The remaining segmentation of infarcted vs. noninfarcted myocardium was performed using a threshold. Automatic and MRI-guided expert segmentations of LCE-CT infarcts were compared to each other on volume and area basis (intraclass correlation coefficient, ICC) and on voxel basis (dice similarity coefficient, DSC between automatic and expert CT segmentation). CT infarct volumes were compared with the reference standard MRI. ResultsThe infarcts were mainly subendocardial (81%) and relatively small (median MRI infarct mass 7.4 g). The automatic segmentation showed excellent agreement with expert segmentation on volume and area measurements (ICC = 0.96 and 0.87, respectively). DSC showed moderately good agreement (DSC = 0.47). Compared to MRI there was modest agreement (ICC = 0.62) and excellent correlation (R = 0.9). Manual interaction was less than 1 min per exam. ConclusionWe propose an automatic method for infarct segmentation on LCE-CT using multiphase CT information, which showed excellent agreement with expert readers and favorable correlation with MRI.

Optimized energy of spectral CT for infarct imaging: Experimental validation with human validation

ObjectivesLate contrast enhancement visualizes myocardial infarction, but the contrast to noise ratio (CNR) is low using conventional CT. The aim of this study was to determine if spectral CT can improve imaging of myocardial infarction. Materials and MethodsA canine model of myocardial infarction was produced in 8 animals (90-min occlusion, reperfusion). Later, imaging was performed after contrast injection using CT at 90 kVp/150 kVpSn. The following reconstructions were evaluated: Single energy 90 kVp, mixed, iodine map, multiple monoenergetic conventional and monoenergetic noise optimized reconstructions. Regions of interest were measured in infarct and remote regions to calculate contrast to noise ratio (CNR) and Bhattacharya distance (a metric of the differentiation between regions). Blinded assessment of image quality was performed. The same reconstruction methods were applied to CT scans of four patients with known infarcts. ResultsFor animal studies, the highest CNR for infarct vs. myocardium was achieved in the lowest keV (40 keV) VMo images (CNR 4.42, IQR 3.64–5.53), which was superior to 90 kVp, mixed and iodine map (p = 0.008, p = 0.002, p < 0.001, respectively). Compared to 90 kVp and iodine map, the 40 keV VMo reconstructions showed significantly higher histogram separation (p = 0.042 and p < 0.0001, respectively). The VMo reconstructions showed the highest rate of excellent quality scores.A similar pattern was seen in human studies, with CNRs for infarct maximized at the lowest keV optimized reconstruction (CNR 4.44, IQR 2.86–5.94). ConclusionsDual energy in conjunction with noise-optimized monoenergetic post-processing improves CNR of myocardial infarct delineation by approximately 20–25%.

Enhancement of Angiogenesis by Ultrasound-Targeted Microbubble Destruction Combined with Nuclear Localization Signaling Peptides in Canine Myocardial Infarction.

Objective This study aimed to develop a gene delivery system using ultrasound-targeted microbubbles destruction (UTMD) combined with nuclear localization signal (NLS) and investigate its efficacy and safety for therapeutic angiogenesis in canine myocardial infarction (MI) model. Methods Fifty MI dogs were randomly divided into 5 groups and transfected with Ang-1 gene plasmid: (i) group A: only injection of microbubbles and Ang-1 plasmid; (ii) group B: only UTMD mediated gene transfection; (iii) group C: UTMD combined with classical NLS mediated gene transfection; (iv) group D: UTMD combined with mutational NLS mediated transfection; and (v) group E: UTMD combined with classical NLS in the presence of a nucleus transport blocker. The mRNA and protein expression of Ang-1 gene, microvessel density (MVD) cardiac troponin I (cTnI), and cardiac function were determined after transfection. Results The expression of mRNA and protein of Ang-1 gene in group C was significantly higher than that of the other groups (all P < 0.01). The MVD of group C was 10.2-fold of group A and 8.1-fold of group E (P < 0.01). The cardiac function in group C was significant improvement without cTnI rising. Conclusions The gene delivery system composed of UTMD and NLS is efficient and safe.

Effect of salvianolic acid A on anesthetized canine experimental myocardial infarction

Salvianolic acid A (SAA), one of the major active water-soluble salvianolic acids of traditional Chinese medicine Salvia miltiorrhiza Bunge, has been reported to be effective on anti-myocardial ischemia, anti-oxidation and anti-thrombus. This study aimed to investigate appropriate administration route on dogs with acute myocardial ischemia(AMI). Twenty-four dogs were randomized into four groups (n=6), model, oral administration of SAA (8 mg•kg⁻¹), intravenous administration of SAA (4 mg•kg⁻¹), intravenous administration of Herbesser(0.5 mg•kg⁻¹) as positive drug group. AMI model was established by ligating left anterior descending coronary arteries(LAD) of dogs. Changes of ST segment were determined by epicardial electrocardiogram(ECG), coronary blood flow (CBF) and myocardial oxygen consumption were measured by ultrasonic Doppler flow meter, serum creatine kinase (CK) and lactate dehydrogenase (LDH) were observed by fully automatic biochemical analyser. Myocardial infarct size was assessed by nitro blue tetrazolium (NBT) staining. Both oral and intravenous administration of SAA reduced the myocardial infarct area/left ventricle area significantly [(16.73±6.52)% and (13.19±2.38)%, compared with (24.35±4.89)% in model group, P<0.01). Oral administration of SAA improved the ECG performance of Σ-ST from 30-190 min after ischemia (P<0.05-0.01), while intravenous SAA had a rapid onset (10-190 min after ischemia, P<0.05-0.01). Compared with model group, oral and intravenous SAA both decreased serum CK and LDH significantly (P<0.05-0.01), while the difference of intravenous administration is more significant. SAA protects myocardium in canine experimental myocardial infarction models. Intravenous administration of SAA alleviates myocardial infarction with greater significance than oral route.

Relationship between new-onset atrial fibrillation and sympathetic neural remodeling in a canine acute myocardial infarction model

To establish the canine model of new-onset atrial fibrillation (AF) after acute myocardial infarction (AMI), and explore the relationship between new-onset AF and sympathetic neural remodeling in this model. Twenty four adult mongrel dogs were randomly divided into 4 groups by applying random number table. Group A (n=6): ligate the left circumflex artery (LCX). Group B (n=6): ligate the LCX and right atrial anterior artery and right atrial middle artery. Group C (n=6): ligate left anterior descending artery.Group D (n=6): sham operation.Sequential electrophysiology study was performed in all dogs to determine the AF induction rate, AF duration, effective refractory period (ERP), the density of tyrosine hydroxylase (TH) and norepinephrine transporter (NET) before AMI or sham operation, and at 30 min, 2 hours and 4 hours after AMI or sham operation. (1) The highest AF induction rate of right atrium and left auricle was 96.7%(58/60) and 95.0%(57/60) in group B, 81.7%(49/60) and 38.3%(23/60) in group A, 28.3%(17/60) and 35.0%(21/60) in group C, 20.0%(12/60) and 33.3%(20/60) in group D. (2) At 4 hours after AMI, AF duration was significantly prolonged in group B(193.50±54.67) s, compared with group A(53.83±9.37) s, group C(45.00±19.50) s, and group D(16.67±4.50) s (all P<0.05). (3) In group B, the ERP of AF was prolonged at 30 minutes after AMI and shortened at 2 hours and 4 hours after AMI compared with baseline level(all P<0.05). (4) The TH density of left atrium ((3 485±694) µm2/mm2) and left auricle((2 645±454) µm2/mm2) in group A and the TH density of left atrium ((7 873±1159) µm2/mm2) and left auricle((3 070±605) µm2/mm2) in group B were significantly higher than those in group C ((1 474±475) µm2/mm2, (1 177±277) µm2/mm2) and group D ((678±206) µm2/mm2, (489±125) µm2/mm2) (all P<0.05), and the TH density of right atrium and right auricle in group B were higher than group A (all P<0.05). The NET density of left atrium((476±75) µm2/mm2) and left auricle ((414±52) µm2/mm2) in group A and the NET density of left atrium((527±81) µm2/mm2) and left auricle((429±85) µm2/mm2) in group B were lower than that in group C ((1 044±105) µm2/mm2, (867±67) µm2/mm2) and group D ((1 438±60) µm2/mm2, (1 027±119) µm2/mm2) (all P<0.05). Ligating the LCX, right atrial anterior artery and right atrial middle artery at the same time can significantly increase the success rate in establishing the canine model of new-onset atrial fibrillation after acute myocardial infarction and can also increase the AF duration.Cardiac sympathetic remodeling after acute myocardial infarction is associated with induction and duration of AF.

Assessment of Retrograde Coronary Venous Infusion of Mesenchymal Stem Cells Combined with Basic Fibroblast Growth Factor in Canine Myocardial Infarction Using Strain Values Derived from Speckle-Tracking Echocardiography

Speckle-tracking echocardiography was used to assess retrograde coronary venous infusion of mesenchymal stem cells (MSCs) combined with basic fibroblast growth factor (bFGF) in a canine model of acute myocardial infarction (AMI). AMI was induced by ligation of the left anterior descending coronary artery. Coronary venous retroperfusion was performed at 1 wk after AMI. Twenty-eight animals were randomized into four groups: saline, bFGF+saline, saline+MSCs and bFGF+MSCs. Echocardiography was performed before AMI, at 7 d post-AMI and 40 d after retroperfusion. Apoptotic cardiomyocytes in the border zone of the ischemic region were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling. Vascular endothelial growth factor and factor VIII concentrations were measured by western blotting. The left ventricular end-systolic volume increased significantly, whereas the left ventricular ejection fraction and global and segmental strain values decreased significantly after AMI. After retroperfusion, the strain values of the infarct zone, but not conventional echocardiographic parameters, were significantly different between control and bFGF+MSC groups. Cardiomyocyte apoptosis decreased, whereas vascular endothelial growth factor and factor VIII concentrations were higher in the bFGF+MSC, bFGF and MSC groups. Cardiomyocyte apoptosis was well correlated with the strain values. Although retrograde coronary venous infusion of bFGF and MSCs promoted neo-vascularization of the infarcted myocardium and inhibited apoptosis, there was only a slight strain improvement without a substantial increase in global cardiac functions.

Adenovirus-mediated expression of human sodium-iodide symporter gene permits in vivo tracking of adipose tissue-derived stem cells in a canine myocardial infarction model

IntroductionIn vivo tracking of the transplanted stem cells is important in pre-clinical research of stem cell therapy for myocardial infarction. We examined the feasibility of adenovirus-mediated sodium iodide symporter (NIS) gene to cell tracking imaging of transplanted stem cells in a canine infarcted myocardium by clinical single photon emission computed tomography (SPECT). MethodsBeagle dogs were injected intramyocardially with NIS-expressing adenovirus-transfected canine stem cells (Ad-hNIS-canine ADSCs) a week after myocardial infarction (MI) development. 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) and 99mTc-pertechnetate (99mTcO4−) SPECT imaging were performed for assessment of infarcted myocardium and viable stem cell tracking. Transthoracic echocardiography was performed to monitor any functional cardiac changes. ResultsLeft ventricular ejection fraction (LVEF) was decreased after LAD ligation. There was no significant difference in EF between the groups with the stem cell or saline injection. 125I uptake was higher in Ad-hNIS-canine ADSCs than in non-transfected ADSCs. Cell proliferation and differentiation were not affected by hNIS-carrying adenovirus transfection. 99mTc-MIBI myocardial SPECT imaging showed decreased radiotracer uptake in the infarcted apex and mid-anterolateral regions. Ad-hNIS-canine ADSCs were identified as a region of focally increased 99mTcO4− uptake at the lateral wall and around the apex of the left ventricle, peaked at 2 days and was observed until day 9. ConclusionsCombination of adenovirus-mediated NIS gene transfection and clinical nuclear imaging modalities enables to trace the fate of transplanted stem cells in infarcted myocardium for translational in vivo cell tracking study for prolonged duration.

Imaging of post-infarction myocardial inflammation with hybrid FDG PET/MR: feasibilty and preliminary findings in a canine model

Background An understanding of inflammation following myocardial infarction may be of importance in the development of novel therapeutics to limit the development of heart failure following myocardial injury. However, the quantification of inflammation in this setting continues to be challenging. Hybrid FDG PET/MR may offer a non-invasive in vivo solution through intrinsic registration of these complementary modalities. This study sought to validate its use in a canine model of myocardial infarction (MI).

Abstract 14877: Native T1-based Cardiovascular Magnetic Resonance for Characterizing Chronic Myocardial Infarctions: Proof-of-Concept Study in Canines

Introduction: Gadolinium infusion required for Late Gadolinium Enhancement (LGE) Cardiovascular Magnetic Resonance (CMR) imaging is contraindicated in nearly 20% of myocardial infarction (MI) patients due to chronic end-stage kidney disease. Hypothesis: Using a canine model of MI, we investigated whether native T1 mapping at 3T could be an alternative to LGE CMR for characterizing chronic MIs (CMIs). Methods: Canines (n=29) were subjected to ischemia-reperfusion injury. Native T1 maps, native T2 maps and LGE images were acquired at 7 days (acute, AMI) and 4 months (CMI) post-MI at 1.5T and 3T. Infarct location, size and transmurality, measured using Mean + 5 Standard Deviations criterion, were compared between T1 maps and LGE images. Native T2 maps were used to examine the resolution of edema between AMI and CMI. Following the CMR studies, animals were euthanized and ex-vivo histology was performed. Results: T1 maps and LGE images were not different for measuring infarct size (p=0.61) and transmurality (p=0.81) in CMI at 3T. In AMI at 3T, T1 maps overestimated both infarct size (p=0.007) and transmurality (p=0.007) relative to LGE images. At 1.5T, T1 maps underestimated both infarct size and transmurality relative to LGE images in both AMI and CMI (p&lt;0.001 for all cases). Relative to the remote territories, T1 of the infarcted myocardium was elevated in AMI (3T: p&lt;0.001; 1.5T: p&lt;0.001) and CMI (3T: p&lt;0.001; 1.5T: p=0.037). T2 of the infarcted myocardium was elevated in AMI (p&lt;0.001 at both 3T and 1.5T), but not in CMI (3T: p=0.19, 1.5T: p=0.55) indicating that myocardial edema resolved by 4 months post-MI. Masson’s trichrome staining showed extensive replacement fibrosis within CMIs. Sensitivity and specificity of T1 maps to detect CMI were 95% and 97% respectively at 3T, and 58% and 78% respectively at 1.5T. Conclusions: Native T1 mapping at 3T can characterize CMIs with high diagnostic accuracy. T1 elongations in CMI appear to arise predominantly from replacement fibrosis.

Determination of Location, Size, and Transmurality of Chronic Myocardial Infarction Without Exogenous Contrast Media by Using Cardiac Magnetic Resonance Imaging at 3 T

Late-gadolinium-enhanced (LGE) cardiac MRI (CMR) is a powerful method for characterizing myocardial infarction (MI), but the requisite gadolinium infusion is estimated to be contraindicated in ≈20% of patients with MI because of end-stage chronic kidney disease. The purpose of this study is to investigate whether T1 CMR obtained without contrast agents at 3 T could be an alternative to LGE CMR for characterizing chronic MIs using a canine model of MI. Canines (n=29) underwent CMR at 7 days (acute MI [AMI]) and 4 months (chronic MI [CMI]) after MI. Infarct location, size, and transmurality measured by using native T1 maps and LGE images at 1.5 T and 3 T were compared. Resolution of edema between AMI and CMI was examined with T2 maps. T1 maps overestimated infarct size and transmurality relative to LGE images in AMI (P=0.016 and P=0.007, respectively), which was not observed in CMI (P=0.49 and P=0.81, respectively) at 3 T. T1 maps underestimated infarct size and transmurality relative to LGE images in AMI and CMI (P<0.001) at 1.5 T. Relative to the remote territories, T1 of the infarcted myocardium was increased in CMI and AMI (P<0.05), and T2 of the infarcted myocardium was increased in AMI (P<0.001) but not in CMI (P>0.20) at both field strengths. Histology showed extensive replacement fibrosis within the CMI territories. CMI detection sensitivity and specificity of T1 CMR at 3 T were 95% and 97%, respectively. Native T1 maps at 3 T can determine the location, size, and transmurality of CMI with high diagnostic accuracy. Patient studies are necessary for clinical translation.

Severity of blood flow reduction associated with detectable T2 enhancement in the area at risk of a reperfused canine model of acute myocardial infarction

Background T2-weighted enhancement depicts the myocardial area at risk (AAR) associated with coronary occlusion. However, the severity of blood flow abnormality required to cause a detectable elevation in myocardial T2 is unknown. The aim of this study was to use microspheres to determine the severity of reduction in myocardial blood flow that results in visually detectable T2 weighted enhancement. Methods Surface coil intensity corrected T2 prepared SSFP at 1.5T was performed after 2 hours of coronary occlusion followed by 4 hours of reperfusion in a canine model. Myocardial blood flow during ischemia was determined by administering microspheres. A mid-ventricular short axis slice of the heart was divided into 16 transmural sectors for microsphere analysis. MR images were matched to the pathological slices at the sector level using papillary muscles and RV insertion as landmarks. ROIs delineated T2-enhanced and remote regions of the MR images and measurements were compared with microsphere blood flows. Results were reported as median (interquartile range [IQ]) and compared using the signed Wilcoxon rank test. Each T2-prepared sector was classified as bright (AAR) or normal (remote) by 2 independent readers and compared with absolute microsphere blood