Prognostic utility and characterization of left ventricular hypertrophy using global thickness.

Cardiovascular magnetic resonance (CMR) can accurately measure left ventricular (LV) mass, and several measures related to LV wall thickness exist. We hypothesized that prognosis can be used to select an optimal measure of wall thickness for characterizing LV hypertrophy. Subjects 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) was accurately calculated from LV mass and 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], p < 0.001), followed by GTI (HR 1.14[1.09-1.19], p < 0.001). Among patients with normal findings (n = 326, median follow-up 5.8 years), the most predictive measure was GT (HR 1.62[1.35-1.94], p < 0.001). GT and LVMI could characterize patients as having a normal LV mass and wall thickness, concentric remodeling, concentric hypertrophy, or eccentric hypertrophy, and the three abnormal groups had worse prognosis than the normal group (p < 0.05 for all). LV mass is highly prognostic when mass is elevated, but GT is easily and accurately calculated, and adds value and discrimination amongst those with normal LV mass (early disease).

Progressive increase of the Tpeak-Tend interval is associated with ischaemia-induced ventricular fibrillation in a porcine myocardial infarction model.

Aims: Repolarization indices of ECG have been widely assessed as predictors of ventricular arrhythmias. However, little is known of the dynamic changes of these parameters during continuous monitoring in acute ischaemic episodes. The objective of the study was to evaluate repolarization-related predictors of ventricular fibrillation (VF) during progression of experimental myocardial infarction. Methods and results: Myocardial infarction was induced in 27 pigs by 40-min balloon inflation in the left anterior descending coronary artery, and 12-lead ECG was continuously recorded. Rate-corrected durations of the total Tpeak-Tend intervals measured from the earliest T-wave peak to the latest T-wave end in any lead were determined at baseline and at minute 1, 2, 5, and then every 5th minute of occlusion. There were 7 early (1-3 min) and 10 delayed (15-30 min) VFs in 16 pigs. Baseline Tpeak-Tend did not differ between animals with and without VF. Tpeak-Tend interval rapidly increased immediately after balloon inflation and was greater in VF-susceptible animals at 2-15 min compared with the animals that never developed VF (P < 0.05). Tpeak-Tend was tested as a predictor of delayed VFs. Median Tpeak-Tend at 10th min of occlusion was higher in delayed VF group (n = 10) than in animals without VF (n = 11): 138 [IQR 121-148] ms vs. 111 [IQR 106-127] ms, P = 0.02. Tpeak-Tend ≥123 ms (10th min) predicted delayed VF episodes with HR = 4.5 95% CI 1.1-17.8, P = 0.031. Conclusion: Tpeak-Tend prolongation during ischaemia progression predicts VF in the experimental porcine myocardial infarction model and warrants further testing in clinical settings of acute coronary syndromes.

Cardiovascular Magnetic Resonance to Predict Appropriate Implantable Cardioverter Defibrillator Therapy in Ischemic and Nonischemic Cardiomyopathy Patients Using Late Gadolinium Enhancement Border Zone: Comparison of Four Analysis Methods.

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<0.05; negative predictive value 92%). For NICM, total LGE by all 4 methods was the strongest predictor (hazard ratios, 1.03-1.04; P<0.05), though the number of events was small. 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.

Evaluation of the ECG based Selvester scoring method to estimate myocardial scar burden and predict clinical outcome in patients with left bundle branch block, with comparison to late gadolinium enhancement CMR imaging.

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 Skåne 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.

Correlation of CT-based regional cardiac function (SQUEEZ) with myocardial strain calculated from tagged MRI: an experimental study.

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 <1 h. Circumferential myocardial strain (Ecc) was calculated from the tagged MRI data. The agreement between peak systolic Ecc and SQUEEZ was investigated in 162 segments in the 9 hearts. Linear regression and Bland-Altman analysis was used to assess the correlation between the two metrics of local LV function. The results show good agreement between SQUEEZ and Ecc: (r = 0.71, slope = 0.78, p < 0.001). Furthermore, Bland-Altman showed a small bias of -0.02 with 95 % confidence interval of 0.1, and standard deviation of 0.05 representing ~6.5 % of the dynamic range of LV function. The good agreement between the estimates of local myocardial function obtained from CT SQUEEZ and tagged MRI provides encouragement to investigate the use of SQUEEZ for measuring regional cardiac function at a low clinical dose in humans.

Contrast-Enhanced CMR Overestimates Early Myocardial Infarct Size: Mechanistic Insights Using ECV Measurements on Day 1 and Day 7.

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.

Temporal and spatial characteristics of the area at risk investigated using computed tomography and T1-weighted magnetic resonance imaging.

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.

Concomitant use of warfarin and ticagrelor as an alternative to triple antithrombotic therapy after an acute coronary syndrome.

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 Skåne University Hospital in Malmö 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+/-0.9months, 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.

Transient and rapid QRS-widening associated with a J-wave pattern predicts impending ventricular fibrillation in experimental myocardial infarction.

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 population-based 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 widening were found in all 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 of ≥28 ms during a 3-minute time window was observed in 14 animals and predicted impending VF (selectivity 80%, specificity 73%, positive predictive value 57%, and negative predictive value 89%; P = .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 = .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.

Delay from first medical contact to primary PCI and all-cause mortality: a nationwide study of patients with ST-elevation myocardial infarction.

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.

T wave alternans in experimental myocardial infarction: time course and predictive value for the assessment of myocardial damage.

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±4.5minutes of occlusion, reached its maximum at 12.7±6.3 and lasted until 26.5±9.2minutes. 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.

Genetic associations with valvular calcification and aortic stenosis.

BACKGROUND: Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS: 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. RESULTS: 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 (P<0.05 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. CONCLUSIONS: 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.).

Myocardium at risk can be determined by ex vivo T2-weighted magnetic resonance imaging even in the presence of gadolinium: comparison to myocardial perfusion single photon emission computed tomography.

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.

Triple antithrombotic therapy following an acute coronary syndrome: prevalence, outcomes and prognostic utility of the HAS-BLED score.

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.

Quantification of myocardium at risk in myocardial perfusion SPECT by co-registration and fusion with delayed contrast-enhanced magnetic resonance imaging--an experimental ex vivo study.

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.

Plasma levels of liver-specific miR-122 is massively increased in a porcine cardiogenic shock model and attenuated by hypothermia.

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 (P < 0.05) and miR-208b (P < 0.05), respectively. Therapeutic hypothermia significantly diminished the increase in miR-122 compared with the normothermic group (P < 0.005). 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.

Optimal timing of hypothermia in relation to myocardial reperfusion.

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 <35°C within 5 min. Combination hypothermia reduced IS/AAR by 18% compared with normothermic controls despite 5 min longer ischemic time (61 ± 5 vs. 74 ± 4%, p = 0.03). Cold saline did not reduce IS/AAR. Prolonging hypothermia treatment after onset of reperfusion by an additional 45 min over that used in a previous paper did not confer any additional benefit. The cardioprotective effects of hypothermia treatment are due to an attenuation of myocardial injury during both ischemia and reperfusion. The results suggest that a hypothermia protocol using a cold saline infusion and endovascular cooling enables hypothermia to be induced in a clinical setting without delaying reperfusion therapy.