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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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Troponin I and ECG. A) Blood was drawn for troponin-I (TnI) measurement at three time points: baseline/pre-surgery (Time 0), post-stenosis and post-pacing in model dogs or at the end of CMR examination in sham dogs (Time 1, approximately 2 hours after surgery), and just before euthanasia (Time 2, approximately 3 hours after surgery). While thoracotomy and instrumentation produced minimal TnI elevation in operated sham animals, TnI was significantly higher (though only mildly elevated) in the NSTE-ACS model. B) Representative ECG tracings at baseline and after ischemia (stenosis and pacing) demonstrated premature ventricular contractions but no ST elevation with ischemic conditions in the NSTE-ACS model.
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Figure 2: Troponin I and ECG. A) Blood was drawn for troponin-I (TnI) measurement at three time points: baseline/pre-surgery (Time 0), post-stenosis and post-pacing in model dogs or at the end of CMR examination in sham dogs (Time 1, approximately 2 hours after surgery), and just before euthanasia (Time 2, approximately 3 hours after surgery). While thoracotomy and instrumentation produced minimal TnI elevation in operated sham animals, TnI was significantly higher (though only mildly elevated) in the NSTE-ACS model. B) Representative ECG tracings at baseline and after ischemia (stenosis and pacing) demonstrated premature ventricular contractions but no ST elevation with ischemic conditions in the NSTE-ACS model.

Mentions: Of the seven dogs in the NSTE-ACS model group, five survived the entire experiment. Two expired due to ventricular fibrillation – one during the initial surgery and the other during pacing. No pre-euthanasia deaths occurred in the sham group. No coronary artery anomalies were identified with the left circumflex artery observed to supply the lateral LV wall in all operated animals. TnI was undetectable on serial measurement in the serum of the 2 unoperated control animals, while thoracotomy and cardiac instrumentation presumably produced the borderline TnI elevation (0.44 ± 0.48 ng/mL at final measurement) in operated sham animals. The NSTE-ACS model resulted in final TnI levels of 1.97 ± 0.72 ng/mL, which was significantly higher than the operated sham animals (p = 0.02) and the averaged final TnI levels across all sham animals (0.27 ± 0.41 ng/mL, p < 0.01) (Figure 2A); no significant ST segment elevation was observed in the NSTE-ACS model animals throughout any of the experiments (Figure 2B). Two-way ANOVA showed significant contributions to TnI changes due to time (p < 0.001), animal group (p < 0.001), and time-group interaction (p < 0.001).


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)

Troponin I and ECG. A) Blood was drawn for troponin-I (TnI) measurement at three time points: baseline/pre-surgery (Time 0), post-stenosis and post-pacing in model dogs or at the end of CMR examination in sham dogs (Time 1, approximately 2 hours after surgery), and just before euthanasia (Time 2, approximately 3 hours after surgery). While thoracotomy and instrumentation produced minimal TnI elevation in operated sham animals, TnI was significantly higher (though only mildly elevated) in the NSTE-ACS model. B) Representative ECG tracings at baseline and after ischemia (stenosis and pacing) demonstrated premature ventricular contractions but no ST elevation with ischemic conditions in the NSTE-ACS model.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Troponin I and ECG. A) Blood was drawn for troponin-I (TnI) measurement at three time points: baseline/pre-surgery (Time 0), post-stenosis and post-pacing in model dogs or at the end of CMR examination in sham dogs (Time 1, approximately 2 hours after surgery), and just before euthanasia (Time 2, approximately 3 hours after surgery). While thoracotomy and instrumentation produced minimal TnI elevation in operated sham animals, TnI was significantly higher (though only mildly elevated) in the NSTE-ACS model. B) Representative ECG tracings at baseline and after ischemia (stenosis and pacing) demonstrated premature ventricular contractions but no ST elevation with ischemic conditions in the NSTE-ACS model.
Mentions: Of the seven dogs in the NSTE-ACS model group, five survived the entire experiment. Two expired due to ventricular fibrillation – one during the initial surgery and the other during pacing. No pre-euthanasia deaths occurred in the sham group. No coronary artery anomalies were identified with the left circumflex artery observed to supply the lateral LV wall in all operated animals. TnI was undetectable on serial measurement in the serum of the 2 unoperated control animals, while thoracotomy and cardiac instrumentation presumably produced the borderline TnI elevation (0.44 ± 0.48 ng/mL at final measurement) in operated sham animals. The NSTE-ACS model resulted in final TnI levels of 1.97 ± 0.72 ng/mL, which was significantly higher than the operated sham animals (p = 0.02) and the averaged final TnI levels across all sham animals (0.27 ± 0.41 ng/mL, p < 0.01) (Figure 2A); no significant ST segment elevation was observed in the NSTE-ACS model animals throughout any of the experiments (Figure 2B). Two-way ANOVA showed significant contributions to TnI changes due to time (p < 0.001), animal group (p < 0.001), and time-group interaction (p < 0.001).

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