Creation Of Myocardial Infarction Research Articles

PO-02-178 ABLATION TISSUE HISTOLOGY AND CORRELATION WITH MAGNETIC RESONANCE IMAGING WITH A DIAMOND-BASED, TEMPERATURE-CONTROLLED RADIOFREQUENCY ABLATION

A new catheter has been developed which uses diamonds embedded in the catheter tip to enable temperature-guided ablation. The degree to which subsequent Magnetic Resonance (MR) findings correlate with actual tissue pathology has never been assessed. To evaluate the correlation between MR imaging and lesions assessed by Gross pathology. 20 canines underwent evaluation, after ablation. 4 were studied acutely 4-6 hours after ablation, 8 animals were studied at a time of chronic assessment 4 weeks later, and 8 were studied at a time of chronic assessment 4 weeks later myocardial infarction creation. MR lesions were followed by intravenous gadolinium and 8-10% triphenyl tetrazolium chloride administration. Ex-vivo delayed contrast enhancement MR imaging on a 3 Tesla scanner (Signa HDxt, GE Healthcare) was performed followed by pathology examination after fixation in 10% formalin solution. Total of 111 lesions were created in LV and RV tissue. In the acute animals 30 deliveries were made to a temperature set-point of 50 or 60°C. The target temperatures were set at 60°C with 32 deliveries to healthy myocardium, and 8 to post-infarcted myocardium. Lesion size and characteristic are shown in table 1. The correlation between the actual lesion size and the MR contoured size is shown in Fig 1. In all animals taken together, MR proved to be an exceptional means of determining actual lesion size. While tissue histology, seen in the table, is more useful and accurate. Overall, the correlation R2 value is 0.72±0.11 (p<0.0001) in all groups. In individual groups, the correlation was 0.94±0.54 (p<0.0001) for acute, 0.48±0.13 (p<0.0001) for chronic healthy, and 0.97± 0.35 (p=0.0006) in infarcted tissue. Even with infarctions, the MR correlation remained consistent but lesions were smaller in infarcted myocardium. These data showed the characteristics of lesion size of correlation to energy delivered. MR with gadolinium is a very useful means of identifying actual lesion size in situ. This correlates well with actual tissue findings and disclose that heat penetration in infarcted tissue is less robust as seen with other catheter systems.

Vagus Nerve Stimulation in Early Stage of Acute Myocardial Infarction Prevent Ventricular Arrhythmias and Cardiac Remodeling.

Aims: To evaluate whether low level left vagus nerve stimulation (LLVNS) in early stage of myocardial infarction (MI) could effectively prevent ventricular arrhythmias (VAs) and protect cardiac function, and explore the underlying mechanisms.Methods and Results: After undergoing implantable cardioverter defibrillators (ICD) and left cervical vagal stimulators implantation and MI creation, 16 dogs were randomly divided into three groups: the MI (n = 6), MI+LLVNS (n = 5), and sham operation (n = 5) groups. LLVNS was performed for 3 weeks. VAs, the left ventricular function, the density of the nerve fibers in the infarction area and gene expression profiles were analyzed. Compared with the MI group, dogs in the MI+LLVNS group had a lower VAs incidence (p < 0.05) and better left ventricular function. LLVNS significantly inhibited excessive sympathetic nerve sprouting with the evidences of decreased density of TH, GAP43 and NF positive nerves (p < 0.05). The gene expression profiling found a total of 206 genes differentially expressed between MI+LLVNS and MI dogs, mainly involved in cardiac tissue remodeling, cardiac neural remodeling, immune response and apoptosis. These genes, including 55 up-regulated genes and 151 down-regulated genes, showed more protective expressions under LLVNS.Conclusions: This study suggests that LLVNS was delivered without altering heart rate, contributing to reduced incidences of VAs and improved left ventricular function. The potential mechanisms included suppressing cardiac neuronal sprouting, inhibiting excessive sympathetic nerve sprouting and subduing pro-inflammatory responses by regulating gene expressions from a canine experimental study.

A Robust Percutaneous Myocardial Infarction Model in Pigs and Its Effect on Left Ventricular Function.

In this study, we created a reproducible myocardial infarction (MI) model in pigs characterized by a low mortality rate and significant changes in left ventricular function. After administering an arrhythmia prevention regimen, we created a 90-min balloon-induced percutaneous MI in 42 pigs below the first diagonal branch (D1) of the left anterior descending artery. Echocardiograms were performed before and 14 days after MI induction. Pigs with a > 30% decrease in left ventricular ejection fraction (LVEF) underwent electrophysiological mapping by the NOGA system. Our mortality rate was 4.8%. The incidence of ventricular fibrillation (VF) was 28.6%; all VF events were successfully resuscitated. At day 14, echocardiography and NOGA mapping confirmed transmural scar. LVEF decreased 41% from baseline. Radial and circumferential strain significantly decreased in the LAD distal to D1, and the LV showed dyssynchrony. An anti-arrhythmia regimen decreased mortality significantly, and our model induced dramatic functional changes. The basic procedures of the model included an arrhythmia prevention protocol and myocardial infarction creation, which effectively decreased mortality and provided a robust change in left ventricular (LV) function after 14 days.

LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model

Background LCZ696 (valsartan/sacubitril) therapy significantly reduced mortality in patients with heart failure (HF). Although a clinical trial (PARADISE-MI Trial) has been ongoing to examine the effects of LCZ696 in myocardial infarction (MI) patients, the effects of LCZ696 on remodeling of cardiac electrophysiology in animal models remain largely unclear. Methods We performed coronary artery ligation to create MI in Sprague-Dawley rats. Echocardiography was performed one week after MI to confirm the development of HF with left ventricular ejection fraction ≤ 40%. MI rats were randomly assigned to receive medical therapy for 4 weeks: LCZ696, enalapril, or vehicle. The sham-operation rats received sham operation without MI creation. In vivo electrophysiological exams were performed under general anesthesia. Western blot analyses were conducted to quantify ion channel proteins. Results The HF-vehicle group did not show significant changes in LVEF. Both enalapril and LCZ696 therapy significantly improved LVEF. The HF-vehicle group had higher ventricular arrhythmia (VA) inducibility than the sham group. As compared with the HF-vehicle group, LCZ696 therapy significantly reduced VA inducibility, but enalapril therapy did not. Western blot analyses showed significant downregulation of NaV1.5, ERG, KCNE1, and KCNE2 channel proteins in the HF vehicle group compared with the sham group. LCZ696 therapy upregulated protein expression of ERG, KCNE1, and KCNE2. Conclusion As compared with enalapril therapy, LCZ696 therapy led to improvement of LVEF, reduced VA inducibility, and upregulated expression of K+ channel proteins.

Pretreatment with an angiotensin II receptor blocker abolished ameliorating actions of adipose-derived stem cell sheets on cardiac dysfunction and remodeling after myocardial infarction.

IntroductionCell sheets using myoblasts have been developed for the treatment of heart failure after myocardial infarction (MI) bridging to heart transplantation. Stem cells are supposed to be better than myoblasts as a source of cells, since they possess a potential to proliferate and differentiate into cardiomyocytes, and also have capacity to secrete angiogenic factors. Adipose-derived stem cells (ASCs) obtained from fat tissues are expected to be a new cell source for ASC sheet therapies. Administration of angiotensin II receptor blockers (ARBs) is a standard therapy for heart failure after MI. However, it is not known whether ARBs affect the cell sheet therapy. This study aimed to examine ameliorating effects of ASC sheets on heart failure and remodeling after MI, and how pretreatment with ARBs prior to the creation of MI and ASC sheet transplantation modifies the effects of ASC sheets.MethodsASCs were isolated from fat tissues of wild-type rats, and ASC sheets were engineered on temperature-responsive dishes. In in vitro studies using cultured cells, mRNA levels of vascular endothelial growth factor (VEGF) in ASCs were determined by RT-PCR in the presence of angiotensin II and/or an ARB, irbesartan, under normoxia and hypoxia; mRNA and protein levels of angiotensin II receptor type 1a (AT1aR), type 1b (AT1bR) and type 2 (AT2R) were also determined by RT-PCR and western blotting. In in vivo studies using a rat MI model, effects of transplanted ASC sheets and/or irbesartan on cardiac functions and remodeling after MI were evaluated by echocardiography, histological analysis and molecular biological techniques.ResultsIn the in vitro studies, ASCs expressed higher levels of VEGF mRNA under hypoxia. They also expressed mRNA and protein of AT1aR but not AT1bR or AT2R. Under normoxia, angiotensin II increased the level of VEGF mRNA in ASCs, which was abolished by irbesartan. Under hypoxia, irbesartan reduced the level of VEGF mRNA in ASCs regardless of whether angiotensin II was present or not. In the in vivo studies, ASC sheets improved cardiac functions after MI, leading to decreased interstitial fibrosis and increased capillary density in border zones. These effects of ASC sheets were abolished by oral administration of irbesartan before MI and their transplantation.ConclusionsASC sheets ameliorated cardiac dysfunctions and remodeling after MI via increasing VEGF expression, which was abolished by pretreatment with irbesartan before the creation of MI and transplantation.

Effect of exercise training intensity on mitochondrial dynamics and mitophagy in post myocardial infarction rats

Myocardial infarction (MI) is the most common type of heart disease. According to recent studies, mitochondrial dysfunction has been suggested as a central player in cardiac disease and evidences point out the association of mitochondrial morphology with development of heart diseases. Exercise training plays a protective role against cardiovascular disease. However, the role of exercise training on proteins involved in mitochondrial dynamics and mitophagy system are not well understood. Therefore, the aim of the present study was to investigate these on cardiac mitochondrial dynamic and mitophagy proteins in rats with myocardial infarction. The present study was post-test design experiment with the control group. after MI with ligation of the left anterior descending coronary artery (LAD) and ensuring the creation of MI by echocardiography, male rats were subjected to high intensity interval training (HIIT), moderate (MIIT), low (LIIT), sedentary myocardial infarction (SED-MI) and healthy control groups. After six weeks exercise, the levels of MFN2, DRP1, Parkin, P62 and PGC-1α proteins were measured by ELISA method. Data analysis showed that proteins levels of MFN2, PGC-1α, Parkin and P62 decreased significantly in SED-MI group compared to healthy control while DRP1 protein levels increased significantly (P≤0.05). Also, MFN2 and PGC-1α proteins increased in MIIT group compared with SED-MI group and DRP1 protein levels were significantly decreased (P≤0.05). Moderate-intensity interval training (MIIT) resulted to improve mitochondrial fusion and fusion proteins in rats with myocardial infarction. While high and low intensity interval training (HIIT, LIIT), despite increasing MFN2 and PGC-1α and reducing DRP1, failed to improve fusion and mitochondrial fission

Abstract 19747: The Effect of Internal vs. External Shocks on Myocardial Injury in an Animal Model of Myocardial Infarction

Introduction: ICD use early after myocardial infarction (MI) has not proven advantageous, possibly in part due to myocardial injury associated with intracardiac defibrillation shocks. Previous studies have reported myocardial injury with internal defibrillation, but external defibrillation from the wearable cardioverter defibrillator (WCD) has not been investigated. The goal of this study was to determine the acute damage to the heart caused by external defibrillation from the WCD as compared to an ICD in an animal model of myocardial infarction (MI) using typical energy levels and times to shock. Methods: Two weeks after MI creation, 20 pigs were anesthetized and induced into VF through direct current applied to the right ventricular endocardium via an implanted transvenous lead. Control animals received 20-J internal shocks from the dual-coil defibrillator lead after 30 seconds of VF, while experimental animals received 150-J external shocks from a WCD after 45 seconds of VF. Each animal received a total of five consecutive internal or external shocks. Blood samples were collected at baseline (prior to first shock), immediately after the last shock, and at 4- and 24-hours post-shocks to determine myocardial biomarkers. Animals that did not survive 24 hours, control animals that had to be rescue-defibrillated externally, or those requiring &gt;5 shocks were excluded from analysis (n=6, 3 per arm). Differences were determined using t-tests. Results: Troponin I (cTnI), a specific marker of myocardial damage, was elevated above baseline in both the ICD (n = 7) and WCD (n = 7) groups at the 4 hr and 24 hr post-shock time points (Figure). However, the cTnI at 4 hr and 24 hr was significantly higher in the ICD control group as compared to the WCD (p &lt; 0.05). Conclusions: In an animal model of myocardial injury, cardiac-specific cTnI increases are significantly greater following internal 20-J shocks than external 150-J shocks, indicating less myocardial damage with external shocks.

ENOS Overexpressing Bone Marrow Cells are Safe and Effective in a Porcine Model of Myocardial Regeneration Following Acute Myocardial Infarction

Cell therapy has been shown to be effective in improving LV function postmyocardial infarction (MI). We hypothesized that eNOS-transfected bone marrow cells (BMCs) are safe in a swine model of myocardial infarction (MI). We also hypothesized that endothelial nitric oxide synthase (eNOS) transfection would enhance cell function, as assessed by myocardial functional recovery post-MI. Fifteen female Yorkshire pigs underwent bone marrow aspiration and creation of MI. Bone marrow cells were cultured for 7days, and each pig received either autologous BMCs transiently transfected with eNOS plasmid (eNOS-BMC, n=5), nontransfected BMCs (nt-BMC, n=4), or phosphate-buffered saline (PBS) control (n=6). Cardiac MRI was performed at baseline (1week post-MI) and 6weeks post-MI. There was no difference in safety outcomes between groups. Absolute left ventricular ejection fraction (LVEF) at 6weeks showed a trend toward improvement in both cell therapy groups compared with baseline but worsened in the PBS control group. The absolute improvement in LVEF was significantly greater in both cell therapy groups compared with PBS control. Infarct mass was significantly lower in the eNOS-BMC group between baseline and 6weeks, but the absolute change in infarct mass was not different between groups. Finally, there was a trend toward reduced LV mass in the eNOS-BMC group. Bone marrow cell delivery, with and without eNOS overexpression, is safe and leads to improvement in LVEF when administered in the coronary circulation 7days following acute MI in swine. Transfection of healthy BMCs with eNOS resulted in some improvement in left ventricular remodeling. Further study is warranted in a preclinical model that approximates the impact of cardiovascular risk factors on BMC function.

New Angiotensin II Type 1 Receptor Blocker, Azilsartan, Attenuates Cardiac Remodeling after Myocardial Infarction

After an acute myocardial infarction (MI), neurohumoral systems including renin-angiotensin-aldosterone system (RAAS) are activated which in turn aggravate cardiac remodeling. Angiotensin receptor blockers (ARBs) are useful drugs for suppression of RAAS. The purpose of this study was to evaluate a new ARB, azilsartan, for suppressing cardiac remodeling and progression to heart failure after MI. We created MI by left anterior descending coronary artery ligation in male mice, and these mice were orally administered saline (0.2 mL) in the control group (Group C), 0.1 mg/kg/d of azilsartan in the low dose group (Group L), and 1.0 mg/kg/d in the high dose group (Group H) everyday. Blood pressure was decreased in Group H, but not in Group L, compared to Group C. At 2 weeks after MI creation, infarct size and fibrotic change at the site remote to the myocardial infarcted area were attenuated in Group L and Group H compared to Group C. Echocardiography revealed that cardiac remodeling was suppressed in Group L and Group H compared to Group C. Increases of mRNA expression levels related to fibrotic change were attenuated in Group L and Group H compared to Group C. The new ARB, azilsartan, had a cardiac remodeling suppression effect after MI, and this effect was observed without blood pressure lowering.

Activation of Natural Killer T Cells Ameliorates Postinfarct Cardiac Remodeling and Failure in Mice

Chronic inflammation in the myocardium is involved in the development of left ventricular (LV) remodeling and failure after myocardial infarction (MI). Invariant natural killer T (iNKT) cells have been shown to produce inflammatory cytokines and orchestrate tissue inflammation. However, no previous studies have determined the pathophysiological role of iNKT cells in post-MI LV remodeling. The purpose of this study was to examine whether the activation of iNKT cells might affect the development of LV remodeling and failure. After creation of MI, mice received the injection of either α-galactosylceramide (αGC; n=27), the activator of iNKT cells, or phosphate-buffered saline (n=31) 1 and 4 days after surgery, and were followed during 28 days. Survival rate was significantly higher in MI+αGC than MI+PBS (59% versus 32%, P<0.05). LV cavity dilatation and dysfunction were significantly attenuated in MI+αGC, despite comparable infarct size, accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis. The infiltration of iNKT cells were increased during early phase in noninfarcted LV from MI and αGC further enhanced them. It also enhanced LV interleukin (IL)-10 gene expression at 7 days, which persisted until 28 days. AntienIL-10 receptor antibody abrogated these protective effects of αGC on MI remodeling. The administration of αGC into iNKT cell-deficient Jα18(-/-) mice had no such effects, suggesting that αGC was a specific activator of iNKT cells. iNKT cells play a protective role against post-MI LV remodeling and failure through the enhanced expression of cardioprotective cytokines such as IL-10.

Assessing left ventricular systolic dysfunction after myocardial infarction: are ejection fraction and dP/dtmax complementary or redundant?

Among the various cardiac contractility parameters, left ventricular (LV) ejection fraction (EF) and maximum dP/dt (dP/dt(max)) are the simplest and most used. However, these parameters are often reported together, and it is not clear if they are complementary or redundant. We sought to compare the discriminative value of EF and dP/dt(max) in assessing systolic dysfunction after myocardial infarction (MI) in swine. A total of 220 measurements were obtained. All measurements included LV volumes and EF analysis by left ventriculography, invasive ventricular pressure tracings, and echocardiography. Baseline measurements were performed in 132 pigs, and 88 measurements were obtained at different time points after MI creation. Receiver operator characteristic (ROC) curves to distinguish the presence or absence of an MI revealed a good predictive value for EF [area under the curve (AUC): 0.998] but not by dP/dt(max) (AUC: 0.69, P < 0.001 vs. EF). Dividing dP/dt(max) by LV end-diastolic pressure and heart rate (HR) significantly increased the AUC to 0.87 (P < 0.001 vs. dP/dt(max) and P < 0.001 vs. EF). In naïve pigs, the coefficient of variation of dP/dt(max) was twice than that of EF (22.5% vs. 9.5%, respectively). Furthermore, in n = 19 pigs, dP/dt(max) increased after MI. However, echocardiographic strain analysis of 23 pigs with EF ranging only from 36% to 40% after MI revealed significant correlations between dP/dt(max) and strain parameters in the noninfarcted area (circumferential strain: r = 0.42, P = 0.05; radial strain: r = 0.71, P < 0.001). In conclusion, EF is a more accurate measure of systolic dysfunction than dP/dt(max) in a swine model of MI. Despite the variability of dP/dt(max) both in naïve pigs and after MI, it may sensitively reflect the small changes of myocardial contractility.

Syndecan-4 Prevents Cardiac Rupture and Dysfunction After Myocardial Infarction

Syndecan-4 (Syn4), a cell-surface heparan sulfate proteoglycan, has been detected in the infarct region after myocardial infarction (MI), but its functional significance has not been elucidated. We examined whether and how Syn4 regulates the cardiac healing process after MI. Although the heart in Syn4-deficient (Syn4(-/-)) mice was morphologically and functionally normal, Syn4(-/-) mice exhibited impaired heart function and increased mortality rate as a result of cardiac ruptures after MI. Cardiac ruptures in Syn4(-/-) mice were associated with reduced inflammatory reaction and impaired granulation tissue formation during the early phase of MI, as evidenced by reduced numbers of leukocytes, fibroblasts, myofibroblasts, macrophages, and capillary vessels, along with reduced extracellular matrix protein deposition in the infarct region after MI. Transforming growth factor-β1-dependent cell signaling was preserved, whereas cell migration, fibronectin-induced cell signaling, and differentiation into myofibroblasts were defective in Syn4(-/-) cardiac fibroblasts. We also found that Syn4 was involved in basic fibroblast growth factor-dependent endothelial cell signaling, cell proliferation, and tube formation. Finally, overexpression of the shed form of Syn4 before MI creation led to an increase in mortality due to cardiac rupture via its action as a dominant-negative inhibitor of endogenous Syn4 signaling, which suggested a protective role of Syn4 signaling in MI. These results suggest that Syn4 plays an important role in the inflammatory response and granulation tissue formation, thereby preventing cardiac rupture and dysfunction after MI.

Inhibition of Secretory Phospholipase A2 Activity Attenuates Acute Cardiogenic Pulmonary Edema Induced by Isoproterenol Infusion in Mice After Myocardial Infarction

Several types of secretory phospholipase A2 (sPLA2) are expressed in lung tissue, yielding various eicosanoids that might cause pulmonary edema. This study examined whether inhibition of sPLA2 activity attenuates acute cardiogenic pulmonary edema in mice. Acute cardiogenic pulmonary edema was induced in C57BL/6J male mice by an increase in heart rate with continuous intravenous infusion of isoproterenol (ISP) (10 mg/kg/h) at 2 weeks after the creation of myocardial infarction by left coronary artery ligation. Just before ISP infusion, a single intraperitoneal injection of 100 mg/kg LY374388, a prodrug of LY329722 that inhibits sPLA2 activity, or vehicle was administered. The ISP infusion after myocardial infarction induced interstitial and alveolar edema on lung histology. Furthermore, it increased the lung-to-body weight ratio, pulmonary vascular permeability evaluated by the Evans blue extravasation method, lung activity of sPLA2, and lung content of thromboxane A2 and leukotriene B4. These changes were significantly attenuated by LY374388 treatment. In Kaplan-Meier analysis, the survival rate during the ISP infusion after myocardial infarction was significantly higher in LY374388- than in vehicle-treated mice. Similar results were obtained with another inhibitor of sPLA2 activity, para-bromophenacyl bromide. In conclusion, inhibition of sPLA2 activity suppressed acute cardiogenic pulmonary edema.

Assessment of left ventricular time-related deformations in post-infarction rats by ultrasound speckle tracking imaging

Objective To evaluate left ventricular (LV) remodeling and function after acute myocardial infarction (MI) in rats using speckle tracking imaging (STI). Methods The left anterior descending coronary was ligated to induce MI in twenty normal rats. One day after creation of MI, fifty survivals based on the diagnostic criteria of MI were divided into 4 groups as follows:pre-infarction, 1 day,4weeks,and 8 weeks after MI. Echocardiography was performed to evaluate the changes of left ventricularfunction in rats. M-mode and two-dimensional cross-sectional echocardiography data were acquired at the papillary muscle level and digitally stored for further analysis. Circumferential strain rate(SRcir) and radial strain rate(SRrad) indexes were measured by STI software for each animal. Results One day after MI,indexes of SRcir and SRrad in anterior and lateral segments were significantly decreased (P ＜0.01, for both). Four weeks after MI,compared with baseline,SRrad and SRcir were decreased in all segments ( P ＜0.01). Eight weeks after MI, however, SRrad and SRcir showed no significant difference compared with 4weeks group. Conclusions STI can correctly identify LV dysfunction in rats and can be used for serial assessment of cardiac remodeling in rats models. Key words: Echocardiography; Myocardial infarction; Ventricular function, left ; Rats; Speckle tracking imaging

Alteration of Parasympathetic/Sympathetic Ratio in the Infarcted Myocardium After Schwann Cell Transplantation Modified Electrophysiological Function of Heart

Neural remodeling after myocardial infarction (MI) may cause fatal ventricular arrhythmia. Schwann cells (SCs), which are important for neurogenesis, are dramatically reduced after MI. We investigated the feasibility of modifying nervous system regeneration after MI and the efficacy by which it may prevent ventricular arrhythmia following SC transplantation. Immediately after creation of MI, syngenic Lewis rats were randomized into cell transplantation (n=80) and control groups (n=72). SCs were isolated from sciatic nerves, and 5×10(6) cells were intramyocardially injected into the infarct region. Expression levels of myocardial nerve growth factor, vascular endothelial growth factor, growth-associated protein 43, connexin 43, and laminin in the SC group were significantly higher than control at 7 and 14 days after cell transplantation. Immunohistochemical staining illustrated increases in sympathetic and parasympathetic nerves in both groups. However, SC transplantation significantly increased the parasympathetic/sympathetic ratio at 14 days after cell injection. Dynamic electrocardiography and programmed electric stimulation were also performed. The SCs significantly decreased the low-/high-frequency ratio and arrhythmia score of programmed electric stimulation-induced ventricular arrhythmia at 2 weeks after cell injection. However, SCs did not restore heart function. Transplanted SCs in the infarcted myocardium secrete multiple biological molecules, which alter the ratio of parasympathetic/sympathetic nerve density to normalize irritable myocardium. SC transplantation might be a novel cell-based antiarrhythmic therapy following MI.

Abstract 2617: Inhibition of Secretory Phospholipase A 2 Activity Attenuates Acute Cardiogenic Pulmonary Congestion Induced by Isoproterenol Infusion in Mice with Post-Myocardial Infarction

Several types of secretory phospholipase A 2 (sPLA 2 ) are expressed in airway epithelial cells and alveolar inflammatory cells, yielding various eicosanoids that might cause pulmonary edema. This study examined whether inhibition of sPLA 2 activity attenuates acute cardiogenic pulmonary congestion in mice. Acute cardiogenic pulmonary congestion in 10-week-old male C57BL/6J mice was induced by continuous intravenous infusion of isoproterenol (ISP) (10 mg/kg/hr) at 2 weeks after the creation of myocardial infarction by left coronary artery ligation. Just before ISP infusion, a single intraperitoneal injection of 100 mg/kg of LY374388 (LY), a prodrug of LY329722 that is a specific inhibitor of activity of all sPLA 2 , or vehicle was administered. Arterial systolic pressure, heart rate, and LV end-diastolic pressure were comparably increased after ISP in both LY-mice and vehicle-mice. Also, lung expression levels of mRNA and protein of group V and X sPLA 2 were comparably increased from baseline by 3 ~ 5-fold in both groups of mice. sPLA 2 activity in lung tissue after ISP was increased from baseline by 5-fold in vehicle-mice, while the activity was not detected in LY-mice. In isolated neutrophils, incubation with LY329722 inhibited the respiratory burst and migration in response to fMLP or C5a by 40~50%. LY significantly reduced the lung-to-body weight ratio after ISP (71% of vehicle-mice) and attenuated alveolar neutrophil accumulation based on the lung histology (56% of vehicle-mice). Using the Evans Blue extravasation method, pulmonary vascular permeability was suppressed in LY-mice (Evans Blue content in lung; 66% of vehicle-mice). The lung content of thromboxane A 2 and leukotriene B 4 was increased in both groups, but was lower in LY-mice (71% and 64% of vehicle-mice, respectively). In Kaplan-Meyer analysis, the survival rate during the 12hr ISP infusion was higher in LY-mice than vehicle-mice (p &lt; 0.01, n = 15 mice per group). Similar results were obtained with another inhibitor of sPLA 2 activity, para -bromophenacyl bromide. Inhibition of sPLA 2 activity suppressed acute cardiogenic pulmonary edema, and sPLA 2 inhibition may have therapeutic value in acute cardiogenic pulmonary congestion.

Respiratory Motion and Cardiac Arrhythmia Effects on Diagnostic Accuracy of Myocardial Delayed-enhanced MR Imaging in Canines

To prospectively compare in canines the diagnostic accuracy for myocardial infarction (MI) of standard delayed-enhancement (DE) magnetic resonance (MR) imaging versus that of subsecond DE MR imaging with and without breath holding and/or cardiac arrhythmia, with histologic findings or absence of surgical creation of MI as the reference standard. This study was approved by the Institutional Animal Care and Use Committee; 21 canines were imaged with one standard and two subsecond DE MR techniques in four conditions: condition 1, breath holding and steady gating; 2, non-breath holding and steady gating; 3, breath holding and irregular heart rhythm; and 4, non-breath holding and irregular heart rhythm. Images were randomized and scored for diagnostic accuracy, image quality, and observer confidence. Sensitivity, specificity, and diagnostic accuracy for MI detection were calculated for each technique and clinical condition separately. The chi(2), paired t, and McNemar tests were used for comparisons. Fifteen dogs had MIs. Among conditions 2-4, differences were not significant (P > .05); data were pooled and referred to as group B. Condition 1 was group A. Accuracy, image quality, and observer confidence, respectively, for standard DE MR imaging were 96%, 3.7 +/- 0.8, and 2.7 +/- 0.6 in group A but only 74%, 2.4 +/- 0.8, and 1.8 +/- 0.7 in group B (P < or = .004 for each). Corresponding scores for subsecond techniques were unaffected by respiratory motion and/or arrhythmia. Subsecond techniques had higher accuracy (82% and 86% vs 74%), better image quality (3.9 +/- 0.7 and 3.2 +/- 0.8 vs 2.4 +/- 0.8), and greater confidence (2.4 +/- 0.7 and 2.1 +/- 0.7 vs 1.8 +/- 0.7) (P < or = .0002 for each) than standard DE MR imaging. In group A, standard performed better than subsecond DE MR imaging. Standard DE MR imaging is appropriate for MI detection with breath holding and regular heart rhythm, while subsecond techniques are appropriate with an irregular heart rhythm and when breath holding is not possible.

Ischemic ventricular arrhythmias during heart failure: A canine model to replicate clinical events

Development of experimental animal models has played an invaluable role in understanding the mechanisms of ventricular arrhythmias. The purpose of this study was to evaluate a new canine model of myocardial infarction (MI), heart failure, and ischemic ventricular arrhythmias in an attempt to replicate clinical conditions. Thirty-six mongrel dogs underwent placement of a permanent ventricular pacemaker and induction of an anterior MI by percutaneous transcatheter embolization of polyvinyl foam particles into the left anterior descending coronary artery (just distal to the first septal branch). After a 2-week recovery period, heart failure was induced by continuous rapid ventricular pacing at 200 to 240 ppm for 3 weeks. Transient (4-minute) myocardial ischemia was induced via balloon occlusion of the proximal left circumflex coronary artery. Echocardiographic and electrophysiologic testing was performed before MI creation and repeated prior to acute ischemia induction. Seven dogs (19%) died within several hours of MI creation. All surviving dogs developed severe left ventricular systolic dysfunction. Significant increases in the intraatrial and intraventricular conduction intervals were observed following MI creation and heart failure induction compared with baseline values, as evidenced by increases in the duration of the P wave and QRS complex. Significant increases in corrected QT interval and ventricular refractoriness were observed. Acute transient ischemia induced sustained ventricular tachycardia or ventricular fibrillation in 21 of 29 dogs (72%). This canine model can serve as a useful tool for studying ventricular arrhythmias during the interactions of healed infarction, heart failure, increased sympathetic tone, and myocardial ischemia.

Effect of left ventricular systolic pressure increase on ventricular arrhythmogenicity in old canine myocardial infarction.

The aim was to examine the effect of an increase in left ventricular systolic pressure (LVSP) on ventricular arrhythmogenicity in old canine myocardial infarction. Fourteen mongrel dogs of either sex weighing 11 to 15 kg were used. Studies were performed 28 d after creation of myocardial infarction by ligation of the anterior descending coronary artery. Electrical induction of ventricular arrhythmia and determinations of effective refractory period (ERP) and local intraventricular conduction delay (LIVCD) were performed using the extrastimulus technique with a cycle length of 300 ms in the normal and infarcted zones of the left ventricle. Heterogeneity of ERP (delta ERP) was determined as a difference between the longest and shortest ERP values in each site. LVSP was raised by constriction of the ascending aorta in a stepwise fashion (control, level A, level B). Incidence of electrically induced ventricular arrhythmia was increased from 28.6% at control level of LVSP [130.7(SEM 7.3) mm Hg] to 42.9% at level A [190.9(6.0) mm Hg] and to 64.3% (p < 0.05) at level B [243.3(4.0) mm Hg]. delta ERP and LIVCD were greater in the infarct zone than in the normal zone at each level of LVSP (p < 0.001). delta ERP in the infarct zone increased from 18.9(4.3) ms at control level of LVSP to 20.7(6.8) ms at level A, and to 27.1(8.1) ms at level B (p < 0.001). LIVCD in the infarct zone also increased from 22.9(6.2) ms at control level of LVSP to 26.8(4.9) ms at level A (p < 0.001), and to 36.1(6.0) ms at level B (p < 0.001). delta ERP and LIVCD in the normal zone were only slightly raised by increasing the LVSP. delta ERP and LIVCD in the infarct zone were closely correlated with incidence of electrically induced ventricular arrhythmia. Increasing the LVSP enhances ventricular arrhythmogenicity and pre-existing electrophysiologic abnormalities of the heart in the presence of old myocardial infarction. Thus a rise in LVSP from any cause in the old myocardial infarction can be a trigger of life threatening ventricular arrhythmias.