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Background Early reperfusion in the setting of an ST ‐elevation myocardial infarction ( STEMI ) is of utmost importance. However, the effects of early versus late reperfusion in this patient group undergoing primary percutaneous coronary intervention (PCI) have so far been inconsistent in previous studies. The purpose of this study was to evaluate in a nationwide cohort the effects of delay from first medical contact to PCI (first medical contact [FMC] ‐to‐ PCI ) and secondarily delay from symptom‐to‐ PCI on clinical outcomes. Methods and Results Using the national Swedish Coronary Angiography and Angioplasty Register (SCAAR) registry, STEMI patients undergoing primary PCI between the years 2003 and 2008 were screened for. A total of 13 790 patients were included in the FMC ‐to‐ PCI analysis and 11 489 patients were included in the symptom‐to‐ PCI analyses. Unadjusted as well as multivariable analyses showed an overall significant association between increasing FMC ‐to‐ PCI delay and 1‐year mortality. A statistically significant increase in mortality was noted at FMC ‐to‐ PCI delays exceeding 1 hour in an incremental fashion. FMC ‐to‐ PCI delays in excess of 1 hour were also significantly associated with an increase in severe left ventricular dysfunction at discharge. An overall significant association between increasing symptom‐to‐ PCI delays and 1‐year mortality was noted. However, when stratified into time delay cohorts, no symptom‐to‐ PCI delay except for the highest time delay showed a statistically significant association with increased mortality. Conclusions Delays in FMC ‐to‐ PCI were strongly associated with increased mortality already at delays of more than 1 hour, possibly through an increase in severe heart failure. A goal of FMC ‐to‐ PCI of less than 1 hour might save patient lives.

Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently.Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

In experimentally induced myocardial ischemia, mild hypothermia (33-35 degrees C) has a robust cardioprotective effect. Tissue plasminogen activator (t-PA) is a profibrinolytic enzyme that is released from the vascular endothelial cells in response to ischemia and other injurious stimuli. t-PA has also been found to have proinflammatory properties that could contribute to reperfusion injury. We postulated that hypothermia could attenuate t-PA release in the setting of myocardial ischemia. Sixteen 25-30 kg pigs were anesthetized and a temperature of 37 degrees C was established using an intravascular cooling/warming catheter. The pigs were then randomized to hypothermia (34 degrees C) or control (37 degrees C). A doppler flow wire was placed distal to a percutaneous coronary intervention balloon positioned immediately distal to the first diagonal branch of the left anterior descending artery (LAD). The LAD was then occluded for 10 min in all pigs. Coronary blood flow and t-PA was measured before, during and after ischemia/reperfusion. t-PA was measured in peripheral arterial blood and locally in the venous blood from the coronary sinus. Net t-PA release over the coronary bed was calculated by subtraction of arterial values from coronary sinus values. An estimate of differences in total t-PA release was calculated by multiplying net t-PA release with the relative increase in flow compared to baseline, measured in relative units consisting of ((ng/ml - ng/ml) x (cm/s/cm/s)). There was no observed difference in t-PA levels in peripheral arterial samples. As shown previously, net t-PA release increased during reperfusion. Hypothermia significantly inhibited the increase in t-PA release during reperfusion (peak value 9.44 +/- 4.34 ng/ml vs. 0.79 +/- 0.45 ng/ml, P = 0.02). The effect was even more prominent when an estimation of total t-PA release was performed with mean peak value in the control group 26-fold higher than in the hypothermia group (69.74 +/- 33.86 units vs. 2.62 +/- 1.10 units, P = 0.01). Mild hypothermia markedly reduces ischemia related coronary tissue plasminogen activator release. The reduction of t-PA release may contribute to the cardioprotective effect of hypothermia.

INTRODUCTION: Cardiogenic shock is the main cause of death in patients hospitalized due to an acute myocardial infarction. Mild hypothermia reduces metabolism and could offer protective effects for this condition. The aim of our study was to investigate if mild therapeutic hypothermia would improve outcome and hemodynamic parameters in an ischemic cardiogenic shock pig model. METHODS: Twenty-five pigs (40-50kg) were anesthetized and a normothermic temperature of 38 degrees C was established utilising an endovascular cooling catheter in a closed-chest model. A Swan-Ganz catheter was placed in the pulmonary artery. Hemodynamic parameters were continuously monitored and blood gases were sampled every 30min. Ischemia was induced by inflation of a PCI balloon in proximal LAD for 40min. Sixteen pigs that have fulfilled predefined shock criteria were randomized to hypothermia (n=8), or normothermia (n=8). Hypothermia (33 degrees C) was induced after onset of reperfusion by using an endovascular temperature modulating catheter and was maintained until termination of the experiment. RESULTS: The pigs in the hypothermia group were cooled to

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.

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.

Background T1-weighted contrast enhanced CMR images of explanted hearts in experimental studies provide a high resolution reference standard for quantification of myocardial infarction. Manual delineation is considered the reference standard, however it is time consuming and observer dependent. Especially since a data set may consist of more than 150 images with a resolution of typically 0.5×0.5×0.5 mm. Previous studies have used an algorithm for infarct quantification based on a fix number of 8 standard deviations (SD) from remote with manual corrections if necessary [1]. This algorithm may fail if images have different contrast to noise ratio, and is time consuming as the user needs to draw regions of interest in each slice. Therefore, the aim of this study was to provide a fully automated segmentation algorithm for quantification of myocardial infarction in T1-weighted contrast enhanced high resolution ex-vivo images.

Cardiogenic shock is a state of inadequate systemic tissue perfusion, despite adequate left ventricular filling pressure. It is caused by extensive myocardial damage and appears to be aggravated by a systemic inflammatory response [1-4]. The result is hypotension with metabolic acidosis and often a fatal outcome. The condition affects approximately 5% of the patients with myocardial infarction, and carries a dismal prognosis if it prevails after reperfusion. Therapeutic hypothermia has several properties of potential benefit in cardiogenic shock: Experiments with isolated myofibrils, papillary muscles and cross-circulated hearts have demonstrated that mild hypothermia increases myocardial contractility [5-7]. In the in vivo heart, mild hypothermia has been found to increase stroke volume and cardiac output [6,8]. The increase in contractility is considered to be mediated by an increased myofilament sensitivity to existing Ca2+, without a corresponding increase in myocardial oxygen consumption [9]. Moreover, hypothermia reduces the metabolic rate with 5 to 7%/°C [10,11], thereby reducing the demand on the circulation from the peripheral tissues. In an experimental setting, it also has the ability to reduce infarct size if applied prior to reperfusion [12,13]. In dog-based and porcine-based models of cardiogenic shock secondary to ischemia, therapeutic hypothermia has improved hemodynamic and metabolic parameters, and reduced mortality [14,15]. No randomized controlled trials of therapeutic hypothermia in cardiogenic shock in humans exist, but case series indicate that the effects observed in animal experiments can be reproduced [16-19]. In conclusion, therapeutic hypothermia is a promising treatment option for patients in cardiogenic shock that warrants further investigation.

Background In the situation of an acute coronary occlusion, the myocardium supplied by the affected artery becomes ischemic. This part of the myocardium is at risk of developing infarction unless reperfusion occurs, and is therefore referred to as the myocardium at risk (MaR). Myocardium at risk and infarct size can be used to calculate myocardial salvage when evaluating efficacy of interventional or cardioprotective therapies. Cardiovascular magnetic resonance (CMR) has been shown to enable quantification of MaR using T2-weighted CMR and has been validated for use in patients. There are few studies validating T2-weighted CMR for ex vivo quantification of MaR in experimental studies, especially with presence of a gadolinium-based contrast agent needed for assessment of infarct size. The purpose of this study was to test if the clinically validated T2-weighted short tau inversion recovery (T2-STIR) imaging sequence can be used to assess MaR with gadolinium present in an experimental ex vivo setting. Methods Acute ischemia was induced in 26 pigs for 40 minutes followed by 4 hours of reperfusion using a closed-chest, catheter-based experimental model. After explantation and preparation of the heart, T2-STIR CMR images were acquired for quantification of MaR. As reference standard for MaR, ex vivo myocardial perfusion SPECT was used. For assessment of infarct size, high resolution T1-weighted CMR images were acquired. Results A strong correlation between MaR by T2-STIR CMR imaging and myocardial perfusion SPECT was found (r2=0.81, p

Aims Cardiovascular magnetic resonance (CMR) imaging can measure the myocardial area at risk (AAR), but the technique has received criticism for inadequate validation. CMR commonly depicts an AAR that is wider than the infarct, which in turn would require a lateral perfusion gradient within the AAR. We investigated the presence of a lateral perfusion gradient within the AAR and validated CMR measures of AAR against three independent reference standards of high quality. Methods and results Computed tomography (CT) perfusion imaging, microsphere blood flow analysis, T1-weighted 3T CMR and fluorescent microparticle pathology were used to investigate the AAR in a canine model ( n = 10) of ischaemia and reperfusion. AAR size by CMR correlated well with CT ( R 2 = 0.80), microsphere blood flow ( R 2 = 0.80), and pathology ( R 2 = 0.74) with good limits of agreement [−0.79 ± 4.02% of the left ventricular mass (LVM) vs. CT; −1.49 ± 4.04% LVM vs. blood flow and −1.01 ± 4.18% LVM vs. pathology]. The lateral portion of the AAR had higher perfusion than the core of the AAR by CT perfusion imaging (40.7 ± 11.8 vs. 25.2 ± 17.7 Hounsfield units, P = 0.0008) and microsphere blood flow (0.11 ± 0.04 vs. 0.05 ± 0.02 mL/g/min, lateral vs. core, P = 0.001). The transmural extent of MI was lower in the lateral portion of the AAR than the core (28.2 ± 10.2 vs. 17.4 ± 8.4% of the wall, P = 0.001). Conclusion T1-weighted CMR accurately quantifies size of the AAR with excellent agreement compared with three independent reference standards. A lateral perfusion gradient results in lower transmural extent of infarction at the edges of the AAR compared with the core.