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AIMSCardiovascular magnetic resonance (CMR) can accurately measure left ventricular (LV) mass, which is associated with morbidity and mortality. Several measures related to LV wall thickness exist, with uncertain relative prognostic strength. We hypothesized that prognosis can be used to select an optimal measure of wall thickness for characterizing LV hypertrophy.METHODS AND RESULTSSubjects having undergone CMR were studied (cardiac patients, n=2543; healthy volunteers, n=100). A new measure, global wall thickness (GT, GTI if indexed to body surface area), and related measures, including mass/volume and mass/volume2/3, were calculated. GT was accurately calculated from LV mass and LV end-diastolic volume. Among patients with follow-up (n=1575, median follow-up 5.4 years), the most predictive measure of death or hospitalization for heart failure was LV mass index (LVMI) (hazard ratio (HR)[95% confidence interval] 1.16[1.12–1.20], pCONCLUSIONSLV mass is highly prognostic when mass is elevated (advanced disease), but global wall thickness is easily and accurately calculated, and adds value and discrimination amongst those with normal mass (early disease). The combination of these two measures can be used to characterize hypertrophy.

The objective of this study was to investigate the correlation between local myocardial function estimates from CT and myocardial strain from tagged MRI in the same heart. Accurate detection of regional myocardial dysfunction can be an important finding in the diagnosis of functionally significant coronary artery disease. Tagged MRI is currently a reference standard for noninvasive regional myocardial function analysis; however, it has practical drawbacks. We have developed a CT imaging protocol and automated image analysis algorithm for estimating regional cardiac function from a few heartbeats. This method tracks the motion of the left ventricular (LV) endocardial surface to produce local function maps: we call the method Stretch Quantification of Endocardial Engraved Zones (SQUEEZ). Myocardial infarction was created by ligation of the left anterior descending coronary artery for 2 h followed by reperfusion in canine models. Tagged and cine MRI scans were performed during the reperfusion phase and first-pass contrast enhanced CT scans were acquired. The average delay between the CT and MRI scans was

Objectives This study aimed to investigate whether an overestimation of infarct size on cardiac magnetic resonance (CMR) versus triphenyltetrazolium chloride (TTC) exists acutely and whether it remains after 7 days in an experimental pig model and to elucidate possible mechanisms. Background Overestimation of infarct size (IS) on late gadolinium enhancement CMR early after acute myocardial infarction has been debated. Methods Pigs were subjected to 40 min of left anterior descending artery occlusion and 6 h (n = 9) or 7 days (n = 9) reperfusion. IS by in vivo and ex vivo CMR was compared with TTC staining. Extracellular volume (ECV) was obtained from biopsies using technetium 99m diethylenetriamine pentaacetic acid (99mTc-DTPA) and light microscopy. TTC slices were rescanned on CMR enabling slice-by-slice comparison. Results IS did not differ between in vivo and ex vivo CMR (p = 0.77). IS was overestimated by 27.3% with ex vivo CMR compared with TTC (p = 0.008) acutely with no significant difference at 7 days (p = 0.39). Slice-by-slice comparison showed similar results. A significant decrease in ECV was seen in biopsies of myocardium at risk (MaR) close to the infarct (sometimes referred to as the peri-infarction zone) over 7 days (48.3 ± 4.4% vs. 29.2 ± 2.4%; p = 0.0025). The ECV differed between biopsies of MaR close to the infarct and the rest of the salvaged MaR acutely (48.3 ± 4.4% vs. 32.4 ± 3.2%; p = 0.013) but not at 7 days (29.2 ± 2.4% vs 25.7 ± 1.4%; p = 0.23). Conclusions CMR overestimates IS compared with TTC acutely but not at 7 days. This difference may be explained by higher ECV in MaR closest to the infarct acutely that decreases during 7 days to the same level as the rest of the salvaged MaR. The increased ECV in the MaR closest to the infarct day 1 could be due to severe edema or an admixture of infarcted and salvaged myocardium (partial volume) or both. Nonetheless, this could not be reproduced at 7 days. These results have implications for timing of magnetic resonance infarct imaging early after acute myocardial infarction.

We thank Guaricci et al for their interest in our study1 to find a late gadolinium enhancement (LGE) cardiovascular magnetic resonance characteristic as a predictor of implantable cardioverter defibrillator therapy. Below, we have addressed the concerns raised about certain technical aspects of the study. Guaricci et al state that acquisition of LGE using different schemes (2-dimensional [2D] and 3D acquisition) in the current study1 should be considered a limitation. In this context, Guaricci et al discuss the result from a previous validation study2 from our group, and refer to the use of 8 SD from remote myocardium for infarct quantification as a problem. This previous validation study from 20132 included 2D phase sensitive inversion recovery (PSIR) and 3D-IR in patients with …

Introduction Treatment with warfarin in combination with clopidogrel has been shown to reduce the incidence of major bleeding as compared to triple antithrombotic therapy (TT; warfarin, clopidogrel and aspirin). However, there are uncertainties regarding the risk for thrombosis since poor-responsiveness to clopidogrel is common. Ticagrelor is a more potent platelet inhibitor, but data supporting concurrent use of ticagrelor and warfarin (dual antithrombotic therapy, DT) is limited. This study therefore sought to evaluate the risk of bleeding and thrombosis associated with DT after an acute coronary syndrome (ACS). Materials and methods We identified all ACS patients on DT upon discharge from Helsingborg Hospital and Skane University Hospital in Malmo and Lund, Sweden, during 2013. Patients on DT were compared with historical controls discharged with TT. Major bleeding was defined in accordance with the HAS-BLED derivation study. Patients were retrospectively followed for three months. Results In total, 107 DT patients were identified and compared with 159 controls on TT. Mean HAS-BLED bleeding risk score and duration of treatment were similar between the groups (HAS-BLED 2.2 +/− 0.8 vs 2.2 +/− 1.0 units, p = NS; duration 2.7 +/− 0.8 vs 2.5 +/− 0.9 months, p = NS; DT vs TT). The incidence of spontaneous major bleeding was similar between the groups, as was a composite of all thrombotic events, i.e. peripheral embolism, stroke/TIA and acute coronary syndrome (bleeding 8/106 (7.5%) vs 11/157 (7.0%), p = NS; thrombosis 5/106 (4.7%) vs 5/157 (3.2%), p = NS; DT vs TT). Conclusions Rates of thrombotic and bleeding events were similar in patients with TT and patients with ticagrelor and warfarin.

Background— Late gadolinium enhancement (LGE) border zone on cardiac magnetic resonance imaging has been proposed as an independent predictor of ventricular arrhythmias. The purpose was to determine whether size and heterogeneity of LGE predict appropriate implantable cardioverter defibrillator (ICD) therapy in ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM) patients and to evaluate 4 LGE border-zone algorithms. Methods and Results— ICM and NICM patients who underwent LGE cardiac magnetic resonance imaging prior to ICD implantation were retrospectively included. Two semiautomatic algorithms, expectation maximization, weighted intensity, a priori information and a weighted border zone algorithm, were compared with a modified full-width half-maximum and a 2-3SD threshold-based algorithm (2-3SD). Hazard ratios were calculated per 1% increase in LGE. A total of 74 ICM and 34 NICM were followed for 63 months (1–140) and 52 months (0–133), respectively. ICM patients had 27 appropriate ICD events, and NICM patients had 7 ICD events. In ICM patients with primary prophylactic ICD, LGE border zone predicted ICD therapy in univariable and multivariable analysis measured by the expectation maximization, weighted intensity, a priori information, weighted border zone, and modified full-width half-maximum algorithms (hazard ratios 1.23, 1.22, and 1.05, respectively; P P Conclusions— Appropriate ICD therapy can be predicted in ICM patients with primary prevention ICD by quantifying the LGE border zone. In NICM patients, total LGE but not LGE border zone had predictive value for ICD therapy. However, the algorithms used affects the predictive value of these measures.

Background: Myocardial scar burden quantification is an emerging clinical parameter for risk stratification of sudden cardiac death and prediction of ventricular arrhythmias in patients with left ventricular dysfunction. We investigated the relationships among semiautomated Selvester score burden and late gadolinium enhancement-cardiovascular magnetic resonance (LGE-CMR) assessed scar burden and clinical outcome in patients with underlying heart failure, left bundle branch block (LBBB) and implantable cardioverter-defibrillator (ICD) treatment. Methods: Selvester QRS scoring was performed on all subjects with ischemic and nonischemic dilated cardiomyopathy at Skane University Hospital Lund (2002-2013) who had undergone LGE-CMR and 12-lead ECG with strict LBBB pre-ICD implantation. Results: Sixty patients were included; 57% nonischemic dilated cardiomyopathy and 43% ischemic cardiomyopathy with mean left ventricular ejection fraction of 27.6% ± 11.7. All patients had scar by Selvester scoring. Sixty-two percent had scar by LGE-CMR (n = 37). The Spearman correlation coefficient for LGE-CMR and Selvester score derived scar was r = .35 (p = .007). In scar negative LGE-CMR, there was evidence of scar by Selvester scoring in all patients (range 3%-33%, median 15%). Fourteen patients (23%) had an event during the follow-up period; 11 (18%) deaths and six adequate therapies (10%). There was a moderate trend indicating that presence of scar increased the risk of clinical endpoints in the LGE-CMR analysis (p = .045). Conclusion: There is a modest correlation between LGE-CMR and Selvester scoring verified myocardial scar. CMR based scar burden is correlated to clinical outcome, but Selvester scoring is not. The Selvester scoring algorithm needs to be further refined in order to be clinically relevant and reliable for detailed scar evaluation in patients with LBBB. (Less)

Aims: The aim of this study was to evaluate the prevalence of triple antithrombotic therapy (TT) (warfarin, aspirin and clopidogrel) in patients following an acute coronary syndrome (ACS), the bleeding risk compared to double antiplatelet therapy (DAPT) (aspirin and clopidogrel) and evaluate the accuracy of the HAS-BLED risk score in predicting serious bleeding events in TT patients. Methods and results: We retrospectively identified all ACS patients on TT upon discharge from the Coronary Care Unit at Skane University Hospital between 2005 and 2010. TT patients were compared to age- and sex-matched control patients discharged with DAPT. Major bleeding was defined in accordance with the HAS-BLED derivation study. A total of 2,423 patients were screened, of whom 159 (6.6%) were on TT. The mean age was 67.2 (±0.9) years. The most common indication for TT was atrial fibrillation (n=63, 39.6%) followed by apical akinesia (n=60, 37.8%), and the mean duration of TT was 3.7 (±0.3) months. Upon termination of TT, warfarin was discontinued in 82 (52.2%) patients and clopidogrel in 57 (36.3%) patients. The cumulative incidence of spontaneous bleeding events was significantly higher with TT compared to DAPT at one year (10.2% vs. 3.2%; p=0.01). The HAS-BLED score significantly predicted spontaneous bleeding events in TT patients (area under the receiver operating characteristic [ROC] curve 0.67; 95% CI=0.54-0.79; p=0.048). Conclusions: TT was relatively common following acute coronary syndrome and was associated with a threefold increase in major bleeding compared to DAPT at one year. The HAS-BLED risk score predicted bleeding events with moderate accuracy. (Less)

Tissue-specific circulating micro-RNAs (miRNAs) are released into the blood after organ injury. In an ischemic porcine cardiogenic shock model, we investigated the release pattern of cardiac-specific miR-208b and liver-specific miR-122 and assessed the effect of therapeutic hypothermia on their respective plasma levels. Pigs were anesthetized, and cardiogenic shock was induced by inflation of a percutaneous coronary intervention balloon in the proximal left anterior descending artery for 40 min followed by reperfusion. After fulfillment of the predefined shock criteria, the pigs were randomized to hypothermia (33°C, n = 6) or normothermia (38°C, n = 6). Circulating miRNAs were extracted from plasma and measured with quantitative real-time polymerase chain reaction (PCR). Tissue specificity was assessed by miRNA extraction from porcine tissues followed by quantitative real-time PCR. In vitro, the release of miR-122 from a cultured hepatocyte cell line exposed to either hypoxia or acidosis was assessed by real-time PCR. miR-122 was found to be highly liver specific, whereas miR-208b was expressed exclusively in the heart. In the control group, ischemic cardiogenic shock induced a 460,000-fold and a 63,000-fold increase in plasma levels of miR-122 (P0.05) and miR-208b (P0.05), respectively. Therapeutic hypothermia significantly diminished the increase in miR-122 compared with the normothermic group (P0.005). In our model, hypothermia was initiated after coronary reperfusion and did not affect either myocardial damage as previously assessed by magnetic resonance imaging or the plasma level of miR-208b. Our results indicate that liver-specific miR-122 is released into the circulation in the setting of cardiogenic shock and that therapeutic hypothermia significantly reduces the levels of miR-122.

Background: Myocardial perfusion single-photon emission computed tomography (MPS) can be used to assess myocardium at risk in occlusive coronary ischaemia. The aim was to develop a method to quantify myocardium at risk as perfusion defect size on ex vivo MPS using co-registration and fusion with ex vivo magnetic resonance imaging (MRI). Methods: Pigs (n = 19) were injected 99mTc-tetrofosmin prior to concluding 40 min of coronary artery occlusion, followed by reperfusion and MRI contrast injection. The excised heart was imaged with T1-weighted MRI and MPS, and images were co-registered using freely available software (Segment v1.8, http://segment.heiberg.se). The left ventricle was semi-automatically delineated in MRI and copied to MPS. The threshold for a MPS perfusion defect was defined as the mean counts in the MPS image at the MRI-determined border between remote myocardium and air. The threshold was measured using count maxima set to the 100th-95th percentile of counts within the myocardium. The count maximum that gave the lowest threshold variability (SD) was considered the most robust. Results: A count maximum using the 100th percentile yielded a threshold of (mean ± SD) 55 ± 6·2%. This method showed the lowest SD compared to 99th-95th percentile count maxima (6·6-7·2%). Conclusions: We describe a method for objective quantification of myocardium at risk as perfusion defect size on MPS using knowledge of the anatomy of the myocardium from co-registered MRI. This enables simultaneous quantification of myocardium at risk by MPS and infarct size by MRI for the evaluation of treatments for myocardial infarction. (Less)

BACKGROUND Certain types of the early repolarization phenomenon, previously considered to be benign, have been reported to be associated with ventricular fibrillation (VF), both in populationbased studies and in the myocardial infarction (MI) settings. OBJECTIVE To analyze whether QRS widening and appearance of a J-wave pattern in experimental MI settings is predictive of VF. METHODS MI was induced in 32 pigs by 40-minute inflation of an angioplasty balloon in the left descending artery, and electrocardiogram was continuously recorded. Multilead QRS boundaries were computed, and QRS duration was calculated on a beat-to-beat basis during the occlusion period for each pig. An association between QRS widening and subsequent VF was studied using receiver operating characteristic curve analysis. Electrocardiograms at maximum QRS duration were reviewed for the presence of a J-wave pattern. RESULTS Sixteen animals had VF episodes during the occlusion period. Two peaks of QRS wideningwerefound inall animals:the first peak immediately on left descending artery occlusion and the second peak 19.1 4.0 minutes later. The magnitude of changes in the QRS width over time had significant interindividual differences. A QRS widening ofZ28 ms during a 3-minutetime window was observed in 14 animals and predicted impending VF (selectivity 80%, specificity 73%, positive predictive value 57%, and negative predictive value 89%; P ¼ .008). In 10 of 14 (71%) pigs, a J-wave pattern appeared at maximal QRS duration. The appearance of a J-wave pattern predicted VF with selectivity 80%, specificity 68%, positive predictive value 53%, and negative predictive value 88% (P ¼ .02). CONCLUSION Transient QRS widening, commonly associated with a J-wave pattern, appears to predict impending VF in acute ischemia settings and motivates further clinical studies for monitoring immediate risk of VF in MI.

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.

Background Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) is considered the gold standard for quantification of myocardial infarction in vivo. Myocardium with increased fractional distribution volume (fDV) due to acute necrosis or chronic scar exhibit hyperenhancement relative to viable myocardium when using a gadoliniumbased extracellular contrast agent. Previous studies have

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.).

Background T-wave alternans (TWA) is associated with prognosis after myocardial infarction (MI), however its link to the extent of ischemic injury has not been clarified. We analyzed the course of TWA and its relation to myocardial damage in experimental myocardial infarction. Methods In 21 pigs, infarction was induced by 40-minute long balloon inflation in LAD under continuous 12-lead ECG monitoring. TWA was assessed in a 32-beat sliding window, using periodic component analysis and the Laplacian Likelihood Ratio method. Myocardium at risk (MaR) and infarct size (IS) were evaluated by SPECT and magnetic resonance imaging respectively. Results TWA appeared at 7.2 ± 4.5 minutes of occlusion, reached its maximum at 12.7 ± 6.3 and lasted until 26.5 ± 9.2 minutes. The maximal level of TWA was associated with both MaR (r = 0.499, p = 0.035) and IS (r = 0.65, p = 0.004). Conclusion TWA magnitude is associated with both MaR and IS in experiment, which encourages further studies in clinical settings.

Aims Determination of the myocardium at risk (MaR) and final infarct size by cardiac magnetic resonance imaging (CMR) enables calculation of salvaged myocardium in acute infarction. T2-weighted imaging is performed prior to the administration of gadolinium, since gadolinium affects T2 tissue properties. This is, however, difficult in an ex vivo model since gadolinium must be administered for determination of infarct size by CMR. We aimed to test the ability of ex vivo T2-weighted imaging to assess MaR using myocardial perfusion single photon emission computed tomography (SPECT) as reference and to investigate whether MaR could be assessed by ex vivo T2-weighted imaging after injection of gadolinium. Materials and methods In 18 domestic pigs, the left anterior descending artery was occluded for either 30 or 40 min, followed by 4 h of reperfusion. After explantation of the hearts, myocardial perfusion SPECT and T2-weighted imaging were performed for determination of MaR, either with or without gadolinium. Infarct size was determined by T1-weighted imaging and by triphenyl tetrazolium chloride (TTC) staining. Results T2-weighted imaging agreed with myocardial perfusion SPECT, both with and without gadolinium ( r 2= 0.70, P < 0.01) with a bias of 2.6 ± 5.1% ( P = 0.04). Infarct size was 15.4 ± 5.3 and 22.1 ± 5.6% with TTC and T1-weighted imaging, respectively ( P = 0.008) in nine pigs who had both infarct measures. Conclusion T2-weighted CMR imaging can be used to determine MaR in an ex vivo experimental model, both with and without the presence of gadolinium. Thus, CMR alone can be used to assess myocardial salvage in experimental studies.

Myocardial perfusion single-photon emission computed tomography (MPS) can be used to assess myocardium at risk in occlusive coronary ischaemia. The aim was to develop a method to quantify myocardium at risk as perfusion defect size on ex vivo MPS using co-registration and fusion with ex vivo magnetic resonance imaging (MRI).Pigs (n = 19) were injected 99mTc-tetrofosmin prior to concluding 40 min of coronary artery occlusion, followed by reperfusion and MRI contrast injection. The excised heart was imaged with T1-weighted MRI and MPS, and images were co-registered using freely available software (Segment v1.8, http://segment.heiberg.se). The left ventricle was semi-automatically delineated in MRI and copied to MPS. The threshold for a MPS perfusion defect was defined as the mean counts in the MPS image at the MRI-determined border between remote myocardium and air. The threshold was measured using count maxima set to the 100th-95th percentile of counts within the myocardium. The count maximum that gave the lowest threshold variability (SD) was considered the most robust.A count maximum using the 100th percentile yielded a threshold of (mean ± SD) 55 ± 6·2%. This method showed the lowest SD compared to 99th-95th percentile count maxima (6·6-7·2%).We describe a method for objective quantification of myocardium at risk as perfusion defect size on MPS using knowledge of the anatomy of the myocardium from co-registered MRI. This enables simultaneous quantification of myocardium at risk by MPS and infarct size by MRI for the evaluation of treatments for myocardial infarction.

Therapeutic hypothermia has been found to improve hemodynamic and metabolic parameters in cardiogenic shock. Tissue plasminogen activator (t-PA) is a pro-thrombolytic enzyme, which also possesses pro-inflammatory properties. Interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) are pro-inflammatory cytokines; interleukin 10 (IL-10) and transforming growth factor beta 1 (TGF-β1) are anti-inflammatory cytokines. The aim of this experiment was to investigate the mechanism behind the protective effect of therapeutic hypothermia in cardiogenic shock. This was done by studying the effect of hypothermia on basal t-PA levels, peripheral t-PA release, and on the inflammatory response. Cardiogenic shock was induced by inflation of an angioplasty balloon in the proximal left anterior descending artery for 40 min in 16 pigs, followed by 110 min of reperfusion. The animals were randomized to hypothermia (33°C, n = 8), or normothermia (n = 8) at reperfusion. Hemodynamic parameters were continuously monitored. Plasma was sampled every 30 min for analysis of blood-gases and t-PA, and for analysis of inflammatory markers at baseline and at the end of the experiment. t-PA, IL-6 and TGF-β1 increased during cardiogenic shock. Apart from favourably affecting hemodynamic and metabolic variables, hypothermia was found to reduce basal arterial and venous t-PA levels, and to inhibit the release of t-PA from the peripheral vascular bed. Hypothermia did not alter the inflammatory response. In conclusion, mild hypothermia improves hemodynamic and metabolic parameters in cardiogenic shock. This is associated with a reduction in basal t-PA levels and t-PA release from the peripheral vascular bed, but not with an altered inflammatory response.

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.

Background— Experimental studies have shown that induction of hypothermia before reperfusion of acute coronary occlusion reduces infarct size. Previous clinical studies, however, have not been able to show this effect, which is believed to be mainly because therapeutic temperature was not reached before reperfusion in the majority of the patients. We aimed to evaluate the safety and feasibility of rapidly induced hypothermia by infusion of cold saline and endovascular cooling catheter before reperfusion in patients with acute myocardial infarction. Methods and Results— Twenty patients with acute myocardial infarction scheduled to undergo primary percutaneous coronary intervention were enrolled in this prospective, randomized study. After 4±2 days, myocardium at risk and infarct size were assessed by cardiac magnetic resonance using T2-weighted imaging and late gadolinium enhancement imaging, respectively. A core body temperature of P =0.12). Despite similar duration of ischemia (174±51 minutes versus 174±62 minutes, hypothermia versus control, P =1.00), infarct size normalized to myocardium at risk was reduced by 38% in the hypothermia group compared with the control group (29.8±12.6% versus 48.0±21.6%, P =0.041). This was supported by a significant decrease in both peak and cumulative release of Troponin T in the hypothermia group ( P =0.01 and P =0.03, respectively). Conclusions— The protocol demonstrates the ability to reach a core body temperature of Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00417638.

Exacerbation of ST elevation associated with reperfusion has been reported in patients with myocardial infarction. However, the cause of the "reperfusion peak" and relation of its magnitude to the size of myocardial damage has not been explored. The aim of our study was to assess the correlation between the ST-dynamics during reperfusion, the myocardium at risk (MaR), and the infarct size (IS).Infarction was induced in 15 pigs by a 40-minute-long balloon inflation in the left anterior descending coronary artery. Tetrofosmin Tc 99m was given intravenously after 20 minutes of occlusion, and ex vivo single photon emission computed tomography was performed to assess MaR. Maximal ST elevation in a single lead and maximal sum of ST deviations in 12 leads were measured before, during, and after occlusion from continuous 12-lead electrocardiographic monitoring. A gadolinium-based contrast agent was given intravenously 30 minutes before explantation of the heart. Final IS was estimated using ex vivo cardiac magnetic resonance imaging.All pigs developed an anteroseptal infarct with MaR = 42% ± 9% and IS = 26% ± 7% of left ventricle. In all pigs, reperfusion was accompanied by transitory exacerbation of ST elevation that measured 1300 ± 500 μV as maximum in a single lead compared with 570 ± 220 μV at the end of occlusion (P.001). The transitory exacerbation of ST elevation exceeded the maximal ST elevation during occlusion (920 ± 420 μV, P.05). The ST elevation resolved by the end of the reperfusion period (90 ± 30 μV, P.001). Exacerbation of ST elevation after reperfusion correlated with the final IS (r = 0.64, P = .025 for maximal ST elevation in a single lead and r = 0.80, P = .002 for sum of ST deviations) but not with MaR (r = 0.43, P = .17 for maximal ST elevation in a single lead and r = 0.49, P = .11 for sum of ST deviations). The maximal ST elevation in a single lead and the sum of ST deviations during occlusion did not correlate with either MaR or final IS.In the experiment, exacerbation of ST elevation is common during restoration of blood flow in the occluded coronary artery. The magnitude of the exacerbation of ST elevation after reperfusion in experimentally induced myocardial infarction in pigs is associated with infarct size but not with MaR.

Two previous clinical trials investigating hypothermia as an adjunct therapy for myocardial infarction have failed. Recently a pilot study has demonstrated a significant reduction in infarct size. The aims of this study were to elucidate the effects of hypothermia on reperfusion injury and to investigate the optimal hypothermia protocol for a future clinical trial. Pigs (40–50 kg) were anesthetized and a normal pig temperature of 38°C was established utilizing an endovascular temperature modulating catheter. The pigs were randomized to a combination hypothermia group (1,000 ml of 4°C saline solution and endovascular cooling, n = 8), or to normothermic controls (n = 8). A PCI balloon was then inflated in the LAD for 40 min (control) or 45 min with hypothermia induced during the last 5 min. Furthermore, hypothermia induced by cold saline alone (n = 8), and prolonged combination hypothermia during reperfusion (n = 7) were also examined. Infarct size and area at risk were determined ex vivo after 4 h of reperfusion using gadolinium-enhanced MRI and Tc-99-tetrofosmin SPECT, respectively. All pigs in the combination hypothermia group were cooled to

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 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.

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.