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1.  Repeated epinephrine doses during prolonged cardiopulmonary resuscitation have limited effects on myocardial blood flow: a randomized porcine study 
Background
In current guidelines, prolonged cardiopulmonary resuscitation (CPR) mandates administration of repeated intravenous epinephrine (EPI) doses. This porcine study simulating a prolonged CPR-situation in the coronary catheterisation laboratory, explores the effect of EPI-administrations on coronary perfusion pressure (CPP), continuous coronary artery flow average peak velocity (APV) and amplitude spectrum area (AMSA).
Methods
Thirty-six pigs were randomized 1:1:1 to EPI 0.02 mg/kg/dose, EPI 0.03 mg/kg/dose or saline (control) in an experimental cardiac arrest (CA) model. During 15 minutes of mechanical chest compressions, four EPI/saline-injections were administered, and the effect on CPP, APV and AMSA were recorded. Comparisons were performed between the control and the two EPI-groups and a combination of the two EPI-groups, EPI-all.
Result
Compared to the control group, maximum peak of CPP (Pmax) after injection 1 and 2 was significantly increased in the EPI-all group (p = 0.022, p = 0.016), in EPI 0.02-group after injection 2 and 3 (p = 0.023, p = 0.027) and in EPI 0.03-group after injection 1 (p = 0.013). At Pmax, APV increased only after first injection in both the EPI-all and the EPI 0.03-group compared with the control group (p = 0.011, p = 0.018). There was no statistical difference of AMSA at any Pmax. Seven out of 12 animals (58%) in each EPI-group versus 10 out of 12 (83%) achieved spontaneous circulation after CA.
Conclusion
In an experimental CA-CPR pig model repeated doses of intravenous EPI results in a significant increase in APV only after the first injection despite increments in CPP also during the following 2 injections indicating inappropriate changes in coronary vascular resistance during subsequent EPI administration.
doi:10.1186/1471-2261-14-199
PMCID: PMC4289585  PMID: 25528598
Cardiac arrest; Mechanical chest compressions; Epinephrine
2.  A pharmacodynamic comparison of 5 anti-platelet protocols in patients with ST-elevation myocardial infarction undergoing primary PCI 
Background
Despite advances in anti-platelet treatments, there still exists an early increase in both ischemic as well as bleeding events following primary PCI in patients with ST-elevation myocardial infarction (STEMI). Platelet inhibition data of different anti-platelet treatments in the acute phase of a myocardial infarction might offer some insight into these problems. The aim of this study was to evaluate the pharmacodynamic profile of 5 different anti-platelet treatments in the acute phase of STEMI in patients undergoing primary PCI.
Methods
A total of 223 STEMI patients undergoing primary PCI were prospectively included. Patients received either pre-hospital clopidogrel only, pre-hospital clopidogrel followed by prasugrel switch in the cath lab, prasugrel treatment only, pre-hospital clopidogrel followed by ticagrelor switch in the cath lab or pre-hospital ticagrelor only. Platelet reactivity was measured serially using vasodilator-stimulated phosphoprotein (VASP).
Results
Patients receiving pre-hospital clopidogrel followed by prasugrel switch showed similar platelet inhibition data as patients receiving prasugrel only, with more than 90% being good responders the day after PCI. Average time from prasugrel administration to a VASP value of <50% was 1.5 hours. In patients receiving pre-hospital ticagrelor, 50% were good responders at completion of PCI and average time to a VASP-value of <50% was 2.3 hours. Only 32% of patients receiving clopidogrel only were responders the day after PCI.
Conclusions
Switching from an upstream bolus dose of clopidogrel to prasugrel at the time of PCI, appeared as a safe and feasible option with no tendency for overshoot or attenuation of platelet inhibition. Pre-hospital administration of ticagrelor was associated with a 50% good responder rate at completion of PCI.
doi:10.1186/1471-2261-14-189
PMCID: PMC4274705  PMID: 25516485
Prasugrel; Ticagrelor; Clopidogrel; Upstream; STEMI
3.  Regional wall function before and after acute myocardial infarction; an experimental study in pigs 
Background
Left ventricular function is altered during and after AMI. Regional function can be determined by cardiac magnetic resonance (CMR) wall thickening, and velocity encoded (VE) strain analysis. The aims of this study were to investigate how regional myocardial wall function, assessed by CMR VE-strain and regional wall thickening, changes after acute myocardial infarction, and to determine if we could differentiate between ischemic, adjacent and remote segments of the left ventricle.
Methods
Ten pigs underwent baseline CMR study for assessment of wall thickening and VE-strain. Ischemia was then induced for 40-minutes by intracoronary balloon inflation in the left anterior descending coronary artery. During occlusion, 99mTc tetrofosmin was administered intravenously and myocardial perfusion SPECT (MPS) was performed for determination of the ischemic area, followed by a second CMR study. Based on ischemia seen on MPS, the 17 AHA segments of the left ventricle was divided into 3 different categories (ischemic, adjacent and remote). Regional wall function measured by wall thickening and VE-strain analysis was determined before and after ischemia.
Results
Mean wall thickening decreased significantly in the ischemic (from 2.7 mm to 0.65 mm, p < 0.001) and adjacent segments (from 2.4 to 1.5 mm p < 0.001). In remote segments, wall thickening increased significantly (from 2.4 mm to 2.8 mm, p < 0.01). In ischemic and adjacent segments, both radial and longitudinal strain was significantly decreased after ischemia (p < 0.001). In remote segments there was a significant increase in radial strain (p = 0.002) while there was no difference in longitudinal strain (p = 0.69). ROC analysis was performed to determine thresholds distinguishing between the different regions. Sensitivity for determining ischemic segments ranged from 70-80%, and specificity from 72%-77%. There was a 9% increase in left ventricular mass after ischemia.
Conclusion
Differentiation thresholds for wall thickening and VE-strain could be established to distinguish between ischemic, adjacent and remote segments but will, have limited applicability due to low sensitivity and specificity. There is a slight increase in radial strain in remote segments after ischemia. Edema was present mainly in the ischemic region but also in the combined adjacent and remote segments.
doi:10.1186/1471-2261-14-118
PMCID: PMC4169797  PMID: 25218585
4.  Infarct quantification using 3D inversion recovery and 2D phase sensitive inversion recovery; validation in patients and ex vivo 
Background
Cardiovascular-MR (CMR) is the gold standard for quantifying myocardial infarction using late gadolinium enhancement (LGE) technique. Both 2D- and 3D-LGE-sequences are used in clinical practise and in clinical and experimental studies for infarct quantification. Therefore the aim of this study was to investigate if image acquisitions with 2D- and 3D-LGE show the same infarct size in patients and ex vivo.
Methods
Twenty-six patients with previous myocardial infarction who underwent a CMR scan were included. Images were acquired 10-20 minutes after an injection of 0.2 mmol/kg gadolinium-based contrast agent. Two LGE-sequences, 3D-inversion recovery (IR) and 2D-phase-sensitive (PS) IR, were used in all patients to quantify infarction size. Furthermore, six pigs with reperfused infarction in the left anterior descending artery (40 minutes occlusion and 4 hours of reperfusion) were scanned with 2D- and 3D-LGE ex vivo. A high resolution T1-sequence was used as reference for the infarct quantification ex vivo. Spearman’s rank-order correlation, Wilcoxon matched pairs test and bias according to Bland-Altman was used for comparison of infarct size with different LGE-sequences.
Results
There was no significant difference between the 2D- and 3D-LGE sequence in left ventricular mass (LVM) (2D: 115 ± 25 g; 3D: 117 ± 24 g: p = 0.35). Infarct size in vivo using 2D- and 3D-LGE showed high correlation and low bias for both LGE-sequences both in absolute volume of infarct (r = 0.97, bias 0.47 ± 2.1 ml) and infarct size as part of LVM (r = 0.94, bias 0.16 ± 2.0%). The 2D- and 3D-LGE-sequences ex vivo correlated well (r = 0.93, bias 0.67 ± 2.4%) for infarct size as part of the LVM. The IR LGE-sequences overestimated infarct size as part of the LVM ex vivo compared to the high resolution T1-sequence (bias 6.7 ± 3.0%, 7.3 ± 2.7% for 2D-PSIR and 3D-IR respectively, p < 0.05 for both).
Conclusions
Infarct quantification with 2D- and 3D-LGE gives similar results in vivo with a very low bias. IR LGE-sequences optimized for in vivo use yield an overestimation of infarct size when used ex vivo.
doi:10.1186/1471-2261-13-110
PMCID: PMC4029523  PMID: 24308673
5.  The combination of high sensitivity troponin T and copeptin facilitates early rule-out of ACS: a prospective observational study 
Background
The combination of the new high sensitivity troponin T (hsTnT) assays and copeptin, a biomarker of endogenous stress, has been suggested to have the potential of early rule-out of acute coronary syndrome (ACS). The aim of this study was to examine the ability of this combination to rule out ACS in patients presenting with chest pain and to compare the diagnostic performance to hsTnT alone.
Method
In this prospective observational study, patients with chest pain admitted for observation were consecutively included. Patients presenting with ST elevation were excluded. Copeptin and hsTnT were analyzed at admission and hsTnT was thereafter determined approximately every 3rd hour as long as clinically indicated. The follow-up period was 60 days. A combined primary endpoint of ACS, non-elective percutanous coronary intervention, non-elective coronary artery bypass surgery and death of all causes was used.
Results
478 patients were included. 107 (22%) patients were diagnosed with ACS during hospital stay. 70 (14%) had non-ST-segment elevation myocardial infarction (NSTEMI) and 37 (8%) had unstable angina pectoris (UAP).
The combination of hsTnT >14 ng/L or copeptin ≥14 pmol/L at admission identified ACS with a higher sensitivity than hsTnT alone: 0.83 (95% confidence interval (CI): 0.74-0.89) versus 0.69 (95% CI: 0.59-0.77), p <0.001. Negative predictive values (NPV) 91% (95% CI: 86-94) versus 89% (95% CI: 84-92). A repeated hsTnT analyzed 3-4 hours after admission resulted in a sensitivity of: 0.77 (95% CI: 0.65-0.86), p =0.031 for comparison with the combination analyzed at admission.
Conclusions
In patients presenting with chest pain admitted for observation, the combination of hsTnT and copeptin analyzed at admission had a significantly higher sensitivity to diagnose ACS than hsTnT alone. We report a sensitivity of 83% and a NPV of 91% for the combination of hsTnT and copeptin and we conclude that biomarkers alone are not sufficient to rule out ACS. However, the combination of hsTnT and copeptin seems to have a significantly higher sensitivity to identify ACS than a repeated hsTnT test, and thus enables an earlier risk stratification of chest pain patients. This can be time-saving and beneficial for the individual patient by contributing to early decisions on treatment, need of further assessment and level of care.
doi:10.1186/1471-2261-13-42
PMCID: PMC3698067  PMID: 23777442
Copeptin; High sensitivity troponin; Acute coronary syndrome; Emergency department
6.  Circulating cardio-enriched microRNAs are associated with long-term prognosis following myocardial infarction 
Background
Increased levels of cardio-enriched microRNAs (miRNAs) have been described in patients with myocardial infarction (MI). We wanted to evaluate the diagnostic and prognostic potential of cardio-enriched miRNAs in patients presenting with a suspected acute coronary syndrome (ACS).
Methods
Cardio-enriched miRNAs (miR-1, miR-208b and miR-499-5p) were measured using real time PCR in plasma samples from 424 patients with suspected ACS treated in a coronary care unit. miRNAs were assessed for discrimination of a clinical diagnosis of myocardial infarction and for association with 30-day mortality and diagnosis of heart failure. Correlation with left ventricular systolic dysfunction as measured by the ejection fraction (LVEF) was also assessed. To confirm myocardial origin miRNA was measured during coronary artery bypass surgery.
Results
miRNAs were higher in MI patients and correlated with LVEF (p < 0.001). Discrimination of MI was accurate for miR-208b (AUC = 0.82) and miR-499-5p (AUC = 0.79) but considerable lower than for Troponin T (AUC = 0.95). Increased miRNA levels were strongly associated with increased risk of mortality or heart failure within 30 days for miR-208b (OR 1.79, 95% CI = 1.38-2.23, p = 1 × 10-5) and miR-499-5p (OR 1.70, 95% CI = 1.31-2.20, p = 5 × 10-5) but the association was lost when adjusting for Troponin T. During surgery miR-208b and miR-499-5p was released in the coronary sinus after cardioplegia-reperfusion to markedly higher levels than in a peripheral vein.
Conclusions
Our findings confirm increased levels of cardio-enriched miRNAs in the blood of MI patients and establish association of increased miRNA levels with reduced systolic function after MI and risk of death or heart failure.
doi:10.1186/1471-2261-13-12
PMCID: PMC3598930  PMID: 23448306
MiRNA; Myocardial infarction; Acute coronary syndrome; Biomarker; Prognosis
7.  Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model 
Background
Polymorphonuclear neutrophils, stimulated by the activated complement factor C5a, have been implicated in cardiac ischemia/reperfusion injury. ADC-1004 is a competitive C5a receptor antagonist that has been shown to inhibit complement related neutrophil activation. ADC-1004 shields the neutrophils from C5a activation before they enter the reperfused area, which could be a mechanistic advantage compared to previous C5a directed reperfusion therapies. We investigated if treatment with ADC-1004, according to a clinically applicable protocol, would reduce infarct size and microvascular obstruction in a large animal myocardial infarct model.
Methods
In anesthetized pigs (42-53 kg), a percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 minutes, followed by 4 hours of reperfusion. Twenty minutes after balloon inflation the pigs were randomized to an intravenous bolus administration of ADC-1004 (175 mg, n = 8) or saline (9 mg/ml, n = 8). Area at risk (AAR) was evaluated by ex vivo SPECT. Infarct size and microvascular obstruction were evaluated by ex vivo MRI. The observers were blinded to the treatment at randomization and analysis.
Results
ADC-1004 treatment reduced infarct size by 21% (ADC-1004: 58.3 ± 3.4 vs control: 74.1 ± 2.9%AAR, p = 0.007). Microvascular obstruction was similar between the groups (ADC-1004: 2.2 ± 1.2 vs control: 5.3 ± 2.5%AAR, p = 0.23). The mean plasma concentration of ADC-1004 was 83 ± 8 nM at sacrifice. There were no significant differences between the groups with respect to heart rate, mean arterial pressure, cardiac output and blood-gas data.
Conclusions
ADC-1004 treatment reduces myocardial ischemia-reperfusion injury and represents a novel treatment strategy of myocardial infarct with potential clinical applicability.
doi:10.1186/1471-2261-10-45
PMCID: PMC2955599  PMID: 20875134
8.  Apyrase treatment of myocardial infarction according to a clinically applicable protocol fails to reduce myocardial injury in a porcine model 
Background
Ectonucleotidase dependent adenosine generation has been implicated in preconditioning related cardioprotection against ischemia-reperfusion injury, and treatment with a soluble ectonucleotidase has been shown to reduce myocardial infarct size (IS) when applied prior to induction of ischemia. However, ectonucleotidase treatment according to a clinically applicable protocol, with administration only after induction of ischemia, has not previously been evaluated. We therefore investigated if treatment with the ectonucleotidase apyrase, according to a clinically applicable protocol, would reduce IS and microvascular obstruction (MO) in a large animal model.
Methods
A percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 min, in 16 anesthetized pigs (40-50 kg). The pigs were randomized to 40 min of 1 ml/min intracoronary infusion of apyrase (10 U/ml, n = 8) or saline (0.9 mg/ml, n = 8), twenty minutes after balloon inflation. Area at risk (AAR) was evaluated by ex vivo SPECT. IS and MO were evaluated by ex vivo MRI.
Results
No differences were observed between the apyrase group and saline group with respect to IS/AAR (75.7 ± 4.2% vs 69.4 ± 5.0%, p = NS) or MO (10.7 ± 4.8% vs 11.4 ± 4.8%, p = NS), but apyrase prolonged the post-ischemic reactive hyperemia.
Conclusion
Apyrase treatment according to a clinically applicable protocol, with administration of apyrase after induction of ischemia, does not reduce myocardial infarct size or microvascular obstruction.
doi:10.1186/1471-2261-10-1
PMCID: PMC2820435  PMID: 20047685
9.  Rapid short-duration hypothermia with cold saline and endovascular cooling before reperfusion reduces microvascular obstruction and myocardial infarct size 
Background
The aim of this study was to evaluate the combination of a rapid intravenous infusion of cold saline and endovascular hypothermia in a closed chest pig infarct model.
Methods
Pigs were randomized to pre-reperfusion hypothermia (n = 7), post-reperfusion hypothermia (n = 7) or normothermia (n = 5). A percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 min. Hypothermia was started after 25 min of ischemia or immediately after reperfusion by infusion of 1000 ml of 4°C saline and endovascular hypothermia. Area at risk was evaluated by in vivo SPECT. Infarct size was evaluated by ex vivo MRI.
Results
Pre-reperfusion hypothermia reduced infarct size/area at risk by 43% (46 ± 8%) compared to post-reperfusion hypothermia (80 ± 6%, p < 0.05) and by 39% compared to normothermia (75 ± 5%, p < 0.05). Pre-reperfusion hypothermia infarctions were patchier in appearance with scattered islands of viable myocardium. Pre-reperfusion hypothermia abolished (0%, p < 0.001), and post-reperfusion hypothermia significantly reduced microvascular obstruction (10.3 ± 5%; p < 0.05), compared to normothermia: (30.2 ± 5%).
Conclusion
Rapid hypothermia with cold saline and endovascular cooling before reperfusion reduces myocardial infarct size and microvascular obstruction. A novel finding is that hypothermia at the onset of reperfusion reduces microvascular obstruction without reducing myocardial infarct size. Intravenous administration of cold saline combined with endovascular hypothermia provides a method for a rapid induction of hypothermia suggesting a potential clinical application.
doi:10.1186/1471-2261-8-7
PMCID: PMC2323360  PMID: 18402663
10.  Mild hypothermia reduces cardiac post-ischemic reactive hyperemia 
Background
In experimentally induced myocardial infarction, mild hypothermia (33–35°C) is beneficial if applied prior to ischemia or reperfusion. Hypothermia, when applied after reperfusion seems to confer little or no benefit. The mechanism by which hypothermia exerts its cell-protective effect during cardiac ischemia remains unclear. It has been hypothesized that hypothermia reduces the reperfusion damage; the additional damage incurred upon the myocardium during reperfusion. Reperfusion results in a massive increase in blood flow, reactive hyperemia, which may contribute to reperfusion damage. We postulated that hypothermia could attenuate the post-ischemic reactive hyperemia.
Methods
Sixteen 25–30 kg pigs, in a closed chest model, were anesthetized and temperature was established in all pigs at 37°C using an intravascular cooling catheter. The 16 pigs were then randomized to hypothermia (34°C) or control (37°C). The left main coronary artery was then catheterized with a PCI guiding catheter. A Doppler flow wire was placed in the mid part of the LAD and a PCI balloon was then positioned proximal to the Doppler wire but distal to the first diagonal branch. The LAD was then occluded for ten minutes in all pigs. Coronary blood flow was measured before, during and after ischemia/reperfusion.
Results
The peak flow seen during post-ischemic reactive hyperemia (during the first minutes of reperfusion) was significantly reduced by 43 % (p < 0.01) in hypothermic pigs compared to controls.
Conclusion
Mild hypothermia significantly reduces post-ischemic hyperemia in a closed chest pig model. The reduction of reactive hyperemia during reperfusion may have an impact on cardiac reperfusion injury.
doi:10.1186/1471-2261-7-5
PMCID: PMC1808476  PMID: 17324251

Results 1-10 (10)