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At-risk but viable myocardium in a large animal model of non ST-segment elevation acute coronary syndrome: cardiovascular magnetic resonance with ex vivo validation.

Chang H, Tran T, Billman GE, Julian MW, Hamlin RL, Simonetti OP, Ambrosio G, Baker PB, Shao G, Crouser ED, Raman SV - J Cardiovasc Magn Reson (2013)

Bottom Line: A large animal NSTE-ACS model with mild TnI elevation and without ST elevation, similar to the human syndrome, demonstrates signs of acute myocardial injury by T2-CMR without significant irreversible damage.Reduced tissue respiration and associated adaptations of critical metabolic pathways correspond to increased myocardial injury by serum biomarkers in this model.T2-CMR as a biomarker of at-risk but salvageable myocardium warrants further consideration in preclinical and clinical studies of NSTE-ACS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dorothy M, Davis Heart and Lung Research Institute, The Ohio State University, 473 W 12th Ave, Suite 200, Columbus, OH 43210, USA. raman.1@osu.edu.

ABSTRACT

Background: Patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) have varying degrees of salvageable myocardium at risk of irreversible injury. We hypothesized that a novel model of NSTE-ACS produces acute myocardial injury, measured by increased T2 cardiovascular magnetic resonance (CMR), without significant necrosis by late gadolinium enhancement (LGE).

Methods: In a canine model, partial coronary stenosis was created and electrodes placed on the epicardium. Myocardial T2, an indicator of at-risk myocardium, was measured pre- and post-tachycardic pacing.

Results: Serum troponin-I (TnI) was not detectable in unoperated sham animals but averaged 1.97 ± 0.72 ng/mL in model animals. Coronary stenosis and pacing produced significantly higher T2 in the affected vs. the remote myocardium (53.2 ± 4.9 vs. 43.6 ± 2.8 ms, p < 0.01) with no evident injury by LGE. Microscopy revealed no significant irreversible cellular injury. Relative respiration rate (RRR) of affected vs. remote myocardial tissue was significantly lower in model vs. sham animals (0.72 ± 0.07 vs. 1.04 ± 0.07, p < 0.001). Lower RRR corresponded to higher final TnI levels (R(2) = 0.83, p = 0.004) and changes in CaMKIID and mitochondrial gene expression.

Conclusions: A large animal NSTE-ACS model with mild TnI elevation and without ST elevation, similar to the human syndrome, demonstrates signs of acute myocardial injury by T2-CMR without significant irreversible damage. Reduced tissue respiration and associated adaptations of critical metabolic pathways correspond to increased myocardial injury by serum biomarkers in this model. T2-CMR as a biomarker of at-risk but salvageable myocardium warrants further consideration in preclinical and clinical studies of NSTE-ACS.

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Experiment procedure timeline. The diagram provides an overview of experimental procedures for the NSTE-ACS model. Sham animals underwent neither stenosis creation nor pacing, and 2 control animals had no thoracotomy.
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Figure 1: Experiment procedure timeline. The diagram provides an overview of experimental procedures for the NSTE-ACS model. Sham animals underwent neither stenosis creation nor pacing, and 2 control animals had no thoracotomy.

Mentions: An overview of the study protocol is shown in Figure 1. All the animal procedures were approved by The Ohio State University Institutional Animal Care and Use Committee and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. Thirteen heartworm-free, random-source, mixed-breed dogs (aged 1-3 years, weight 11.4-15.9 kg) were anesthetized using ketamine (5-8 mg/kg, IM) and inhaled isoflurane (1-2% in 95% O2) and remained anesthetized throughout all experimental procedures. In 2 randomized dogs, no surgical operations were performed (unoperated shams). ECG was monitored via surface electrodes. After left thoracotomy in the remaining 11 dogs, a catheter was placed in the left atrial appendage for microsphere injection. In a random selection of 4 dogs, no further operations were performed prior to closing of the chest wall (shams). In the 7 model dogs, an 18-gauge needle was laid flat on the left circumflex coronary artery (LCx) then removed once a suture was secured around the artery and needle, leaving a lumen constricted to the nominal outer diameter of the needle (~1.27 mm). Copper pacing wires were then threaded through the epicardium of the right ventricle and connected to an external electrical stimulator for later myocardial pacing. Standard chest wall closing procedures and post-operative anesthesia and analgesia protocols were then followed [10].


At-risk but viable myocardium in a large animal model of non ST-segment elevation acute coronary syndrome: cardiovascular magnetic resonance with ex vivo validation.

Chang H, Tran T, Billman GE, Julian MW, Hamlin RL, Simonetti OP, Ambrosio G, Baker PB, Shao G, Crouser ED, Raman SV - J Cardiovasc Magn Reson (2013)

Experiment procedure timeline. The diagram provides an overview of experimental procedures for the NSTE-ACS model. Sham animals underwent neither stenosis creation nor pacing, and 2 control animals had no thoracotomy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852225&req=5

Figure 1: Experiment procedure timeline. The diagram provides an overview of experimental procedures for the NSTE-ACS model. Sham animals underwent neither stenosis creation nor pacing, and 2 control animals had no thoracotomy.
Mentions: An overview of the study protocol is shown in Figure 1. All the animal procedures were approved by The Ohio State University Institutional Animal Care and Use Committee and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. Thirteen heartworm-free, random-source, mixed-breed dogs (aged 1-3 years, weight 11.4-15.9 kg) were anesthetized using ketamine (5-8 mg/kg, IM) and inhaled isoflurane (1-2% in 95% O2) and remained anesthetized throughout all experimental procedures. In 2 randomized dogs, no surgical operations were performed (unoperated shams). ECG was monitored via surface electrodes. After left thoracotomy in the remaining 11 dogs, a catheter was placed in the left atrial appendage for microsphere injection. In a random selection of 4 dogs, no further operations were performed prior to closing of the chest wall (shams). In the 7 model dogs, an 18-gauge needle was laid flat on the left circumflex coronary artery (LCx) then removed once a suture was secured around the artery and needle, leaving a lumen constricted to the nominal outer diameter of the needle (~1.27 mm). Copper pacing wires were then threaded through the epicardium of the right ventricle and connected to an external electrical stimulator for later myocardial pacing. Standard chest wall closing procedures and post-operative anesthesia and analgesia protocols were then followed [10].

Bottom Line: A large animal NSTE-ACS model with mild TnI elevation and without ST elevation, similar to the human syndrome, demonstrates signs of acute myocardial injury by T2-CMR without significant irreversible damage.Reduced tissue respiration and associated adaptations of critical metabolic pathways correspond to increased myocardial injury by serum biomarkers in this model.T2-CMR as a biomarker of at-risk but salvageable myocardium warrants further consideration in preclinical and clinical studies of NSTE-ACS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dorothy M, Davis Heart and Lung Research Institute, The Ohio State University, 473 W 12th Ave, Suite 200, Columbus, OH 43210, USA. raman.1@osu.edu.

ABSTRACT

Background: Patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) have varying degrees of salvageable myocardium at risk of irreversible injury. We hypothesized that a novel model of NSTE-ACS produces acute myocardial injury, measured by increased T2 cardiovascular magnetic resonance (CMR), without significant necrosis by late gadolinium enhancement (LGE).

Methods: In a canine model, partial coronary stenosis was created and electrodes placed on the epicardium. Myocardial T2, an indicator of at-risk myocardium, was measured pre- and post-tachycardic pacing.

Results: Serum troponin-I (TnI) was not detectable in unoperated sham animals but averaged 1.97 ± 0.72 ng/mL in model animals. Coronary stenosis and pacing produced significantly higher T2 in the affected vs. the remote myocardium (53.2 ± 4.9 vs. 43.6 ± 2.8 ms, p < 0.01) with no evident injury by LGE. Microscopy revealed no significant irreversible cellular injury. Relative respiration rate (RRR) of affected vs. remote myocardial tissue was significantly lower in model vs. sham animals (0.72 ± 0.07 vs. 1.04 ± 0.07, p < 0.001). Lower RRR corresponded to higher final TnI levels (R(2) = 0.83, p = 0.004) and changes in CaMKIID and mitochondrial gene expression.

Conclusions: A large animal NSTE-ACS model with mild TnI elevation and without ST elevation, similar to the human syndrome, demonstrates signs of acute myocardial injury by T2-CMR without significant irreversible damage. Reduced tissue respiration and associated adaptations of critical metabolic pathways correspond to increased myocardial injury by serum biomarkers in this model. T2-CMR as a biomarker of at-risk but salvageable myocardium warrants further consideration in preclinical and clinical studies of NSTE-ACS.

Show MeSH
Related in: MedlinePlus