Vegard Tuseth

Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results

AIM The MITOCARE study evaluated the efficacy and safety of TRO40303 for the reduction of reperfusion injury in patients undergoing revascularization for ST-elevation myocardial infarction (STEMI). METHODS Patients presenting with STEMI within 6 h of the onset of pain randomly received TRO40303 (n = 83) or placebo (n = 80) via i.v. bolus injection prior to balloon inflation during primary percutaneous coronary intervention in a double-blind manner. The primary endpoint was infarct size expressed as area under the curve (AUC) for creatine kinase (CK) and for troponin I (TnI) over 3 days. Secondary endpoints included measures of infarct size using cardiac magnetic resonance (CMR) and safety outcomes. RESULTS The median pain-to-balloon time was 180 min for both groups, and the median (mean) door-to-balloon time was 60 (38) min for all sites. Infarct size, as measured by CK and TnI AUCs at 3 days, was not significantly different between treatment groups. There were no significant differences in the CMR-assessed myocardial salvage index (1-infarct size/myocardium at risk) (mean 52 vs. 58% with placebo, P = 0.1000), mean CMR-assessed infarct size (21.9 g vs. 20.0 g, or 17 vs. 15% of LV-mass) or left ventricular ejection fraction (LVEF) (46 vs. 48%), or in the mean 30-day echocardiographic LVEF (51.5 vs. 52.2%) between TRO40303 and placebo. A greater number of adjudicated safety events occurred in the TRO40303 group for unexplained reasons. CONCLUSION This study in STEMI patients treated with contemporary mechanical revascularization principles did not show any effect of TRO40303 in limiting reperfusion injury of the ischaemic myocardium.

Rationale and Design of the 'MITOCARE' Study: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of TRO40303 for the Reduction of Reperfusion Injury in Patients Undergoing Percutaneous Coronary Intervention for Acute Myocardial Infarction

Treatment of acute ST-elevation myocardial infarction (STEMI) by reperfusion using percutaneous coronary intervention (PCI) or thrombolysis has provided clinical benefits; however, it also induces considerable cell death. This process is called reperfusion injury. The continuing high rates of mortality and heart failure after acute myocardial infarction (AMI) emphasize the need for improved strategies to limit reperfusion injury and improve clinical outcomes. The objective of this study is to assess safety and efficacy of TRO40303 in limiting reperfusion injury in patients treated for STEMI. TRO40303 targets the mitochondrial permeability transition pore, a promising target for the prevention of reperfusion injury. This multicenter, double-blind study will randomize patients with STEMI to TRO40303 or placebo administered just before balloon inflation or thromboaspiration during PCI. The primary outcome measure will be reduction in infarct size (assessed as plasma creatine kinase and troponin I area under the curve over 3 days). The main secondary endpoint will be infarct size normalized to the myocardium at risk (expressed by the myocardial salvage index assessed by cardiac magnetic resonance). The study is being financed under an EU-FP7 grant and conducted under the auspices of the MITOCARE research consortium, which includes experts from clinical and basic research centers, as well as commercial enterprises, throughout Europe. Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present paper describes the rationale, design and the methods of the trial.Treatment of acute ST-elevation myocardial infarction (STEMI) by reperfusion using percutaneous coronary intervention (PCI) or thrombolysis has provided clinical benefits; however, it also induces considerable cell death. This process is called reperfusion injury. The continuing high rates of mortality and heart failure after acute myocardial infarction (AMI) emphasize the need for improved strategies to limit reperfusion injury and improve clinical outcomes. The objective of this study is to assess safety and efficacy of TRO40303 in limiting reperfusion injury in patients treated for STEMI. TRO40303 targets the mitochondrial permeability transition pore, a promising target for the prevention of reperfusion injury. This multicenter, double-blind study will randomize patients with STEMI to TRO40303 or placebo administered just before balloon inflation or thromboaspiration during PCI. The primary outcome measure will be reduction in infarct size (assessed as plasma creatine kinase and troponin I area under the curve over 3 days). The main secondary endpoint will be infarct size normalized to the myocardium at risk (expressed by the myocardial salvage index assessed by cardiac magnetic resonance). The study is being financed under an EU-FP7 grant and conducted under the auspices of the MITOCARE research consortium, which includes experts from clinical and basic research centers, as well as commercial enterprises, throughout Europe. Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present paper describes the rationale, design and the methods of the trial. Copyright (c) 2012 S. Karger AG, Basel (Less)

Percutaneous left ventricular assist device can prevent acute cerebral ischaemia during ventricular fibrillation

AIMS A percutaneous left ventricular assist device has been shown to be able to perfuse cardiac and cerebral tissues during cardiac arrest and may be a useful supplement to current methods in resuscitation. We wished to assess device-assisted circulation during cardiac arrest with microspheres injections and continuous end-tidal CO(2) monitoring, and used cerebral microdialysis to detect ischaemia in the brain. METHODS 12 anaesthetised pigs had microdialysis and pressure catheters implanted via craniotomy. The percutaneous assist device was deployed transfemorally. Ventricular fibrillation was induced by angioplasty-balloon occlusion of the left coronary artery. Cerebral microdialysis samples representing 0-20 and 20-40 min of cardiac arrest with assisted circulation were analysed for markers of cerebral injury (glucose, pyruvate, lactate, and glycerol). RESULTS Microdialysis showed no ischaemic changes after 20 min of cardiac arrest (P=NS to Baseline for glucose, glycerol, lactate, pyruvate and lactate/pyruvate ratio) in subjects with maintained end-tidal CO(2) values above 1.3 kPa (10 mmHg). After 40 min only lactate showed a significant change compared to Baseline (P<0.05). Microspheres flow to the brain was 57% and myocardial flow was 72% compared to Baseline after 15 min (P<0.05). After 45 min flow declined to 22% and 40% of Baseline, respectively (P=NS vs. 15 min). CONCLUSIONS A percutaneous left ventricular assist device may prevent ischaemic cerebral injury during cardiac arrest for a limited time. Cerebral injury and tissue perfusion were indicated by end-tidal CO(2).

Percutaneous left ventricular assist in ischemic cardiac arrest.

Background: Ischemic cardiac arrest represents a challenge for optimal emergency revascularization therapy. A percutaneous left ventricular assist device (LVAD) may be beneficial. Objective: To determine the effect of a percutaneous LVAD during cardiac arrest without chest compressions and to assess the effect of fluid loading. Design: Totally, 16 pigs randomized to either conventional or intensive fluid with LVAD support during ventricular fibrillation (VF). Setting: Acute experimental trial with pigs under general anesthesia. Subjects: Farm pigs of both sexes. Interventions: After randomization for fluid infusion, VF was induced by balloon occlusion of the proximal left anterior descending artery. LVAD and fluid were started after VF had been induced. Measurements: Brain, kidney, myocardial tissue perfusion, and cardiac index were measured with the microsphere injection technique at baseline, 3, and 15 minutes. Additional hemodynamic monitoring continued until 30 minutes. Main results: At 15 minutes, vital organ perfusion was maintained without significant differences between the two groups. Mean cardiac index at 3 minutes of VF was 1.2 L·min−1·m2 (29% of baseline, p < 0.05). Mean perfusion at 3 minutes was 65% in the brain and 74% in the myocardium compared with baseline (p < 0.05), then remained unchanged during the initial 15 minutes. At 30 minutes, LVAD function was sustained in 11 of 16 animals (8 of 8 intensified fluid vs. 3 of 8 conventional fluid) and was associated with intensified fluid loading (p < 0.001). Conclusions: During VF, a percutaneous LVAD may sustain vital organ perfusion. A potential clinical role of the device during cardiac arrest has yet to be established.

Randomised comparison of percutaneous left ventricular assist device with open-chest cardiac massage and with surgical assist device during ischaemic cardiac arrest.

AIMS A percutaneous left ventricular assist device can maintain blood flow to vital organs during ventricular fibrillation and may improve outcomes in ischaemic cardiac arrest. We compared haemodynamic and clinical effects of a percutaneous left ventricular assist device with a larger device deployed via endovascular prosthesis and with open-chest cardiac massage during ischaemic cardiac arrest. METHODS Eighteen swine were randomised into three groups. After thoracotomy, coronary ischaemia and ventricular fibrillation was induced. Cardiac output was measured with transit-time flowmetry. Tissue perfusion was measured with microspheres. Defibrillation was performed after 20 min. RESULTS Cardiac output with cardiac massage was 1129 mL min⁻¹ vs. 1169 mL min⁻¹ with the percutaneous- and 570 mL min⁻¹ with the surgical device (P < 0.05 surgical vs. others). End-tidal CO₂ was 3.3 kPa with cardiac massage vs. 3.2 kPa with the percutaneous- and 2.3 kPa with the surgical device (P < 0.05 surgical vs. others). Subepicardial perfusion was 0.33 mL min⁻¹ g⁻¹ with cardiac massage vs. 0.62 mL min⁻¹ g⁻¹ with both devices (P < 0.05 devices vs. massage), cerebral perfusion was comparable between groups (all reported values after 3 min cardiac arrest, all P<0.05 vs. baseline, all P = NS for 3 min vs. 15 min). Return of spontaneous circulation was achieved in 5/6 subjects with cardiac massage vs. 6/6 with the percutaneous- and 4/6 with the surgical device (P = NS). CONCLUSION The percutaneous device improved myocardial perfusion, maintained cerebral perfusion and systemic circulation with similar rates of successful defibrillation vs. cardiac massage. Increased delivery was not obtained with the surgical device during cardiac arrest.

Treatment of cardiogenic shock with left ventricular assist device combined with cardiac resynchronization therapy: A case report

Cardiogenic shock has a poor prognosis with established treatment strategies. We report a 62 years old man with heart failure exacerbating into refractory cardiogenic shock successfully treated with the combination of a percutaneous left ventricular assist device (LVAD) and subacute cardiac resynchronization therapy (CRT) implantable cardioverter-defibrillator device (CRT-D).

Percutaneous Catheter-based Intracoronary Infusion of Insulin - A Dose Finding Study in the Porcine Model

Insulin given at immediate reperfusion reduces myocardial infarct size in the in vitro and the ex vivo rat heart. In vivo, insulin may cause hypoglycaemia, hypokalaemia and elevation of catecholamines, potentially harmful during an acute myocardial infarction. The purpose of this study was to evaluate tolerance and safety of intracoronary insulin infusions in a porcine model applying percutaneous intervention techniques.

Administration of the Mitochondrial Permeability Transition Pore Inhibitor, TRO40303, prior to Primary Percutaneous Coronary Intervention, Does Not Affect the Levels of Pro-Inflammatory Cytokines or Acute-Phase Proteins

Objectives: In the MITOCARE study, reperfusion injury was not prevented after administration of the mitochondrial permeability transition pore (mPTP) opening inhibitor, TRO40303, in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). The effects of TRO40303 on pro-inflammatory cytokines and acute-phase proteins were assessed. Methods: STEMI patients (n = 163, mean age 62 years) with chest pain within 6 h before admission for pPCI were randomized to intravenous bolus of TRO40303 (n = 83) or placebo (n = 80) prior to reperfusion. We tested whether the groups differed in levels of IL-1β, IL-6, IL-10, TNF, and high-sensitive C-reactive protein at various time points (0, 12, and 72 h) after PCI. Further, potential differences between groups in the change of biomarker levels between 0 and 72 h, 0 and 12 h, and 12 and 72 h were tested. Results: There were no statistically significant differences between the two groups, neither in levels of pro-inflammatory cytokines nor in levels of acute-phase proteins, and there were no statistically significant differences in the change of biomarker levels between the groups considering the time intervals from 0 to 72 h, from 0 to 12 h, and from 12 to 72 h. Conclusion: The administration of the mPTP, TRO40303, prior to reperfusion does not alter the pharmacokinetics of pro-inflammatory cytokines or acute-phase proteins during the first 72 h after PCI.

Left Versus Biventricular Assist Devices in Cardiac Arrest

Maintaining adequate organ perfusion during cardiac arrest remains a challenge, and various assist techniques have been evaluated. We assessed whether a right ventricular impeller assist device (RVAD) in adjunct to a left ventricular impeller assist device (LVAD) is beneficial. Twenty anesthetized pigs were randomized to maximized circulatory support by percutaneously implanted left- or biventricular assist device(s) during 30 minutes of electrically induced ventricular fibrillation followed by three attempts of cardioversion. Continuous hemodynamic variables were recorded. Cardiac output and myocardial, cerebral, renal, and ileum mucosa tissue perfusion were measured with fluorescent microspheres, and repeated blood gas analyses were obtained. With biventricular support, an increased LVAD output was found compared with left ventricular (LV) support; 3.2 ± 0.2 (SEM) vs. 2.0 ± 0. 2 L/minute just after start of ventricular fibrillation, 3.2 ± 0.1 vs. 2.0 ± 0.1 L/minute after 15 minutes, and 3.0 ± 0.1 vs. 2.1 ± 0.1 L/minute after 30 minutes of cardiac arrest (pg < 0.001). Biventricular support also increased aortic and LV pressure, in addition to end-tidal CO2. Tissue blood flow rates were increased for most organs with biventricular support. Blood gas analyses showed improved oxygenation and lower s-lactate values. However, myocardial perfusion was degraded with biventricular support and return of spontaneous circulation less frequent (5/10 vs. 10/10; p = 0.033). Biventricular support was associated with high intraventricular pressure and decreased myocardial perfusion pressure, correlating significantly with flow rates in the LV wall. A transmural flow gradient was observed for both support modes, with better maintained subepicardial than midmyocardial and subendocardial perfusion.

Infusion of TRO40303 in patients with ST-elevation myocardial infarction prior to primary percutaneous coronary intervention did not alter levels of inflammatory biomarkers in the MITOCARE study

Successful reperfusion is associated with lower levels of markers of myocardial damage and dysfunction in ST-elevation but not in non-ST-elevation myocardial infarction : insights from the PLATO trialBackground: Carbohydrate antigen 125 (CA125) is a mucin produced by serosal cells in response to mechanical and inflammatory stimuli. CA125 has emerged as prognostic biomarker in heart failure (HF) and correlates with markers of fluid overload, echocardiographic parameters and prognosis in HF patients. In patients with acute coronary syndrome (ACS), elevated CA125 is correlated with a higher risk of in-hospital HF. The relationship between CA125 and long-term prognosis in ACS patients has not previously been assessed. Purpose: The purpose of our study was to investigate if CA125 measured at the time of an acute coronary event is related to cardiac remodeling during the first year of follow-up and long-term risk for HF and death Methods: We measured CA125 in plasma within 24 hours of the acute event in 523 patients with acute myocardial infarction or unstable angina admitted to the Coronary Care Unit. Routine echocardiograms were performed in all participants. The primary outcomes were hospitalization with a diagnosis of heart failure or death during follow-up, identified through data from the Swedish Hospital Discharge Register and the Swedish Cause of Death Register. In a subgroup of 109 patients aged 75 years or above we assessed the relationships between baseline CA125 and echocardiographical parameters of cardiac structure and function at 1 year after the index ACS. Results: The median follow-up period was 27.3 months for incident HF and 39.5 months for mortality. In Cox proportional hazards models we found an adjusted hazard ratio of 1.51 (95% CI 1.08-2.12; p (Less)