| 1. |
- Engblom, Henrik, et al.
(författare)
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A new automatic algorithm for quantification of myocardial infarction imaged by late gadolinium enhancement cardiovascular magnetic resonance : Experimental validation and comparison to expert delineations in multi-center, multi-vendor patient data
- 2016
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Ingår i: Journal of Cardiovascular Magnetic Resonance. - : Springer Science and Business Media LLC. - 1097-6647 .- 1532-429X. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) using magnitude inversion recovery (IR) or phase sensitive inversion recovery (PSIR) has become clinical standard for assessment of myocardial infarction (MI). However, there is no clinical standard for quantification of MI even though multiple methods have been proposed. Simple thresholds have yielded varying results and advanced algorithms have only been validated in single center studies. Therefore, the aim of this study was to develop an automatic algorithm for MI quantification in IR and PSIR LGE images and to validate the new algorithm experimentally and compare it to expert delineations in multi-center, multi-vendor patient data. Methods: The new automatic algorithm, EWA (Expectation Maximization, weighted intensity, a priori information), was implemented using an intensity threshold by Expectation Maximization (EM) and a weighted summation to account for partial volume effects. The EWA algorithm was validated in-vivo against triphenyltetrazolium-chloride (TTC) staining (n = 7 pigs with paired IR and PSIR images) and against ex-vivo high resolution T1-weighted images (n = 23 IR and n = 13 PSIR images). The EWA algorithm was also compared to expert delineation in 124 patients from multi-center, multi-vendor clinical trials 2-6 days following first time ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) (n = 124 IR and n = 49 PSIR images). Results: Infarct size by the EWA algorithm in vivo in pigs showed a bias to ex-vivo TTC of -1 ± 4%LVM (R = 0.84) in IR and -2 ± 3%LVM (R = 0.92) in PSIR images and a bias to ex-vivo T1-weighted images of 0 ± 4%LVM (R = 0.94) in IR and 0 ± 5%LVM (R = 0.79) in PSIR images. In multi-center patient studies, infarct size by the EWA algorithm showed a bias to expert delineation of -2 ± 6 %LVM (R = 0.81) in IR images (n = 124) and 0 ± 5%LVM (R = 0.89) in PSIR images (n = 49). Conclusions: The EWA algorithm was validated experimentally and in patient data with a low bias in both IR and PSIR LGE images. Thus, the use of EM and a weighted intensity as in the EWA algorithm, may serve as a clinical standard for the quantification of myocardial infarction in LGE CMR images. Clinical trial registration: CHILL-MI: NCT01379261. MITOCARE: NCT01374321.
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| 2. |
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| 3. |
- Erlinge, David, et al.
(författare)
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Rapid Endovascular Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction The CHILL-MI Trial : A Randomized Controlled Study of the Use of Central Venous Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction
- 2014
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 63:18, s. 1857-1865
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The aim of this study was to confirm the cardioprotective effects of hypothermia using a combination of cold saline and endovascular cooling. Background Hypothermia has been reported to reduce infarct size (IS) in patients with ST-segment elevation myocardial infarctions. Methods In a multicenter study, 120 patients with ST-segment elevation myocardial infarctions (<6 h) scheduled to undergo percutaneous coronary intervention were randomized to hypothermia induced by the rapid infusion of 600 to 2,000 ml cold saline and endovascular cooling or standard of care. Hypothermia was initiated before percutaneous coronary intervention and continued for 1 h after reperfusion. The primary end point was IS as a percent of myocardium at risk (MaR), assessed by cardiac magnetic resonance imaging at 4 +/- 2 days. Results Mean times from symptom onset to randomization were 129 +/- 56 min in patients receiving hypothermia and 132 +/- 64 min in controls. Patients randomized to hypothermia achieved a core body temperature of 34.7 degrees C before reperfusion, with a 9-min longer door-to-balloon time. Median IS/MaR was not significantly reduced (hypothermia: 40.5% [interquartile range: 29.3% to 57.8%; control: 46.6% [interquartile range: 37.8% to 63.4%]; relative reduction 13%; p = 0.15). The incidence of heart failure was lower with hypothermia at 45 +/- 15 days (3% vs. 14%, p < 0.05), with no mortality. Exploratory analysis of early anterior infarctions (0 to 4 h) found a reduction in IS/MaR of 33% (p < 0.05) and an absolute reduction of IS/left ventricular volume of 6.2% (p = 0.15). Conclusions Hypothermia induced by cold saline and endovascular cooling was feasible and safe, and it rapidly reduced core temperature with minor reperfusion delay. The primary end point of IS/MaR was not significantly reduced. Lower incidence of heart failure and a possible effect in patients with early anterior ST-segment elevation myocardial infarctions need confirmation. (Efficacy of Endovascular Catheter Cooling Combined With Cold Saline for the Treatment of Acute Myocardial Infarction [CHILL-MI]; NCT01379261)
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| 4. |
- Erlinge, David, et al.
(författare)
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Therapeutic Hypothermia for the Treatment of Acute Myocardial Infarction-Combined Analysis of the RAPID MI-ICE and the CHILL-MI Trials
- 2015
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Ingår i: Therapeutic Hypothermia and Temperature Management. - : Mary Ann Liebert Inc. - 2153-7658 .- 2153-7933. ; 5:2, s. 77-84
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Tidskriftsartikel (refereegranskat)abstract
- In the randomized rapid intravascular cooling in myocardial infarction as adjunctive to percutaneous coronary intervention (RAPID MI-ICE) and rapid endovascular catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction CHILL-MI studies, hypothermia was rapidly induced in conscious patients with ST-elevation myocardial infarction (STEMI) by a combination of cold saline and endovascular cooling. Twenty patients in RAPID MI-ICE and 120 in CHILL-MI with large STEMIs, scheduled for primary percutaneous coronary intervention (PCI) within <6 hours after symptom onset were randomized to hypothermia induced by rapid infusion of 600-2000mL cold saline combined with endovascular cooling or standard of care. Hypothermia was initiated before PCI and continued for 1-3 hours after reperfusion aiming at a target temperature of 33 degrees C. The primary endpoint was myocardial infarct size (IS) as a percentage of myocardium at risk (IS/MaR) assessed by cardiac magnetic resonance imaging at 4 +/- 2 days. Patients randomized to hypothermia treatment achieved a mean core body temperature of 34.7 degrees C before reperfusion. Although significance was not achieved in CHILL-MI, in the pooled analysis IS/MaR was reduced in the hypothermia group, relative reduction (RR) 15% (40.5, 28.0-57.6 vs. 46.6, 36.8-63.8, p=0.046, median, interquartile range [IQR]). IS/MaR was predominantly reduced in early anterior STEMI (0-4h) in the hypothermia group, RR=31% (40.5, 28.8-51.9 vs. 59.0, 45.0-67.8, p=0.01, median, IQR). There was no mortality in either group. The incidence of heart failure was reduced in the hypothermia group (2 vs. 11, p=0.009). Patients with large MaR (>30% of the left ventricle) exhibited significantly reduced IS/MaR in the hypothermia group (40.5, 27.0-57.6 vs. 55.1, 41.1-64.4, median, IQR; hypothermia n=42 vs. control n=37, p=0.03), while patients with MaR<30% did not show effect of hypothermia (35.8, 28.3-57.5 vs. 38.4, 27.4-59.7, median, IQR; hypothermia n=15 vs. control n=19, p=0.50). The prespecified pooled analysis of RAPID MI-ICE and CHILL-MI indicates a reduction of myocardial IS and reduction in heart failure by 1-3 hours with endovascular cooling in association with primary PCI of acute STEMI predominantly in patients with large area of myocardium at risk. (ClinicalTrials.gov id NCT00417638 and NCT01379261).
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| 5. |
- Gidlöf, Olof, et al.
(författare)
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Inhibition of the long non-coding RNA NEAT1 protects cardiomyocytes from hypoxia in vitro via decreased pri-miRNA processing
- 2020
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Ingår i: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- While restoration of coronary blood flow to the ischemic heart is the most effective strategy for reducing infarct size, reperfusion injury represents a significant limiting factor on clinical outcomes in myocardial infarction patients. Ischemic preconditioning (IPC) has been shown to inhibit reperfusion injury and represents an attractive model for studying cardioprotective signal transduction pathways. Long non-coding RNAs (lncRNAs) are a structurally and functionally heterogenous class of RNA transcripts with unknown roles in IPC-induced cardioprotection. Through microarray-based expression profiling of 31,423 lncRNAs in cardiac tissue from IPC mice, we identified the nuclear transcript Neat1 to be rapidly and robustly decreased in response to IPC. siRNA-mediated knock down of Neat1 reduced apoptosis and necrosis in murine cardiomyocytes (CM) and human iPS-derived CMs in response to prolonged hypoxia and hypoxia-reoxygenation, assessed with Annexin V/propidium iodide-staining, a Caspase 3/7 activity assay, LDH release, and western blot for cleaved Caspase 3. Mechanistically, Neat1 was shown to regulate processing of pro-apoptotic microRNA-22 (miR-22) in murine and human CM nuclei using a luciferase reporter assay. Hypoxia-induced downregulation of Neat1 was shown to result in accumulation of unprocessed pri-miRNA and decreased availability of biologically active miRNA, including miR-22. Addition of exogenous synthetic miR-22 reversed the protective effect of Neat1 knock down in human iPS-CM. In conclusion, we have identified the nuclear lncRNA Neat1 as part of a conserved oxygen-sensitive feedback mechanism by regulation of miRNA processing and a potential target in cardioprotection.
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| 6. |
- Gidlöf, Olof, et al.
(författare)
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Ischemic Preconditioning Confers Epigenetic Repression of Mtor and Induction of Autophagy Through G9a-Dependent H3K9 Dimethylation
- 2016
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Ischemic preconditioning (IPC) protects the heart from prolonged ischemic insult and reperfusion injury through a poorly understood mechanism. Post-translational modifications of histone residues can confer rapid and drastic switches in gene expression in response to various stimuli, including ischemia. The aim of this study was to investigate the effect of histone methylation in the response to cardiac ischemic preconditioning.METHODS AND RESULTS: We used cardiac biopsies from mice subjected to IPC to quantify global levels of 3 of the most well-studied histone methylation marks (H3K9me2, H3K27me3, and H3K4me3) with Western blot and found that H3K9me2 levels were significantly increased in the area at risk compared to remote myocardium. In order to assess which genes were affected by the increase in H3K9me2 levels, we performed ChIP-Seq and transcriptome profiling using microarray. Two hundred thirty-seven genes were both transcriptionally repressed and enriched in H3K9me2 in the area at risk of IPC mice. Of these, Mtor (Mechanistic target of rapamycin) was chosen for mechanistic studies. Knockdown of the major H3K9 methyltransferase G9a resulted in a significant decrease in H3K9me2 levels across Mtor, increased Mtor expression, as well as decreased autophagic activity in response to rapamycin and serum starvation.CONCLUSIONS: IPC confers an increase of H3K9me2 levels throughout the Mtor gene-a master regulator of cellular metabolism and a key player in the cardioprotective effect of IPC-leading to transcriptional repression via the methyltransferase G9a. The results of this study indicate that G9a has an important role in regulating cardiac autophagy and the cardioprotective effect of IPC.
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| 7. |
- Mohammad, Moman A., et al.
(författare)
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Predictive Value of High-Sensitivity Troponin T for Systolic Dysfunction and Infarct Size (Six Months) After ST-Elevation Myocardial Infarction
- 2018
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Ingår i: American Journal of Cardiology. - : EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC. - 0002-9149 .- 1879-1913. ; 122:5, s. 735-743
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Tidskriftsartikel (refereegranskat)abstract
- The association of markers of myocardial injury and dysfunction with infarct size (IS) and ejection fraction (EF) are well documented. However, limited data are available on the newer high-sensitivity troponin assays and comparison with morphologic and functional assessment with cardiac magnetic resonance imaging. We aimed to examine the associations of high-sensitivity cardiac Troponin-T (hs-cTnT), creatine kinase MB iso-enzyme (CKMB), and N-terminal pro B-type Natriuretic Peptide (NT-proBNP) to IS and EF at 6 months. Blood samples from 119 ST-segment elevation myocardial infarction patients from the Rapid Endovascular Catheter Core Cooling Combined With Cold Saline solution as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction trial were collected at baseline, 6, 24, and 48 hours after admission. Cardiac magnetic resonance was performed at 4 +/- 2 days and 6 months. The association of biomarker levels to IS and EF was tested with Pearson's correlation coefficients and linear regression models with bootstrap resampling. The correlation coefficient of biomarker to IS was (CKMB: r = 0.71); (NT-proBNP: r = 0.55); (hs-cTnT: r = 0.80); and for EF (CKMB: r = 0.57); (NT-proBNP: r = 0.48); and (peak hs-cTnT: r = 0.68). IS and EF at 4 +/- 2 days had the strongest correlations with IS and EF at 6 months respectively (IS: r = 0.84) and (EF: r = 0.74). Receiver operating characteristic of peak hs-cTnT for predicting EF <= 40% at 6 months was 0.87 compared with 0.75 for early IS. Early EF was a negative predictor of late EF <40%, 1-area under curve = 0.93. In conclusion, high-sensitivity Troponin T is a rapid, cheap, generally available tool for accurate prediction of systolic dysfunction in patients 6 months after first-time ST-segment elevation myocardial infarction.
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| 8. |
- Mohammad, Moman A, et al.
(författare)
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Proteomics in Hypothermia as Adjunctive Therapy in Patients with ST-Segment Elevation Myocardial Infarction : A CHILL-MI Substudy
- 2017
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Ingår i: Therapeutic hypothermia and temperature management. - : Mary Ann Liebert Inc. - 2153-7933 .- 2153-7658. ; 7:3, s. 152-161
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular and inflammatory biomarkers in therapeutic hypothermia have been studied in cardiac arrest, but data on patients with ST-segment elevation myocardial infarction (STEMI) treated with therapeutic hypothermia are currently unavailable. A multiplex proximity extension assay allowed us to measure 157 cardiovascular disease (CVD) and inflammatory disease-related biomarkers in patients from the international, multicenter, and randomized trial; CHILL-myocardial infarction (MI) and to explore the associations of cardiovascular and inflammatory biomarkers. Blood samples were obtained from 119 patients with STEMI, randomized to hypothermia as adjunctive therapy to percutaneous coronary intervention (PCI) or standard care with PCI only. Blood samples were obtained at baseline (0 hour), 6, 24, and 96 hours post PCI, and stored at -80°C until they were analyzed by PROSEEK Multiplex CVD and PROSEEK Multiplex INF (Olink Bioscience, Uppsala, Sweden). Peak values from 6, 24, and 96 hours postrandomization were compared between treatment groups. One hundred fifty-seven cardiovascular and inflammatory biomarkers were evaluated. Peak values of four biomarkers (BDNF, DNER, CCL20, MMP3) were reduced in the hypothermia group as compared with the control group. In addition, seven markers were slightly elevated in the hypothermia group (OPG, FGF21, FS, IL12B, PRL, TIM, IL6). In a prespecified subgroup analysis of anterior infarctions, two additional markers were reduced (PTX3 and SELE). In this explorative proteomic study from the randomized trial CHILL-MI, four biomarkers were identified as having reduced peak plasma values in patients with STEMI treated with therapeutic hypothermia as adjunctive therapy to PCI as compared with patients treated with standard care of PCI. In addition, seven biomarkers were elevated in the group treated with hypothermia therapy. The effect of hypothermia on biomarker peak values was modest, possibly due to a low reduction in mean body temperature. Whether a faster and deeper cooling results in more pronounced effects is yet to be established.
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| 9. |
- Mohammad, Moman A., et al.
(författare)
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Using proximity extension proteomics assay to identify biomarkers associated with infarct size and ejection fraction after ST-elevation myocardial infarction
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Plasma concentrations of many cardiovascular and inflammatory proteins are altered after ST-elevation myocardial infarction (STEMI) and may provide prognostic information. We conducted a large-scale proteomic analysis in patients with STEMI, correlating protein levels to infarct size and left ventricular ejection fraction (LVEF) determined with cardiac magnetic resonance imaging. We analysed 131 cardiovascular and inflammatory proteins using a multiplex proximity extension assay and blood samples obtained at baseline, 6, 24, and 96 h from the randomised clinical trial CHILL-MI. Cardiac magnetic resonance imaging data at 4 ± 2 days and 6 months were available as per trial protocol. Using a linear regression model with bootstrap resampling and false discovery rate adjustment we identified five proteins (ST2, interleukin-6, pentraxin-3, interleukin-10, renin, and myoglobin) with elevated values corresponding to larger infarct size or worse LVEF and four proteins (TNF-related apoptosis-inducing ligand, TNF-related activation induced cytokine, interleukin-16, and cystatin B) with values inversely related to LVEF and infarct size, concluding that among 131 circulating inflammatory and cardiovascular proteins in the acute and sub-acute phase of STEMI, nine showed a relationship with infarct size and LVEF post-STEMI, with IL-6 and ST2 exhibiting the strongest association.
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| 10. |
- Noc, Marko, et al.
(författare)
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A multicentre, prospective, randomised controlled trial to assess the safety and effectiveness of cooling as an adjunctive therapy to percutaneous intervention in patients with acute myocardial infarction : The COOL AMI EU Pivotal Trial
- 2021
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Ingår i: EuroIntervention. - 1774-024X. ; 17:6, s. 466-473
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite primary PCI (PPCI), ST-elevation myocardial infarction (STEMI) can still result in large infarct size (IS). New technology with rapid intravascular cooling showed positive signals for reduction in IS in anterior STEMI. Aims: We investigated the effectiveness and safety of rapid systemic intravascular hypothermia as an adjunct to PPCI in conscious patients, with anterior STEMI, without cardiac arrest. Methods: Hypothermia was induced using the ZOLL® Proteus™ intravascular cooling system. After randomisation of 111 patients, 58 to hypothermia and 53 to control groups, the study was prematurely discontinued by the sponsor due to inconsistent patient logistics between the groups resulting in significantly longer total ischaemic delay in the hypothermia group (232 vs 188 minutes; p<0.001). Results: There were no differences in angiographic features and PPCI result between the groups. Intravascular temperature at wire crossing was 33.3+0.9°C. Infarct size/left ventricular (IS/LV) mass by cardiac magnetic resonance (CMR) at day 4-6 was 21.3% in the hypothermia group and 20.0% in the control group (p=0.540). Major adverse cardiac events at 30 days increased non-significantly in the hypothermia group (8.6% vs 1.9%; p=0.117) while cardiogenic shock (10.3% vs 0%; p=0.028) and paroxysmal atrial fibrillation (43.1% vs 3.8%; p<0.001) were significantly more frequent in the hypothermia group. Conclusions: The ZOLL Proteus intravascular cooling system reduced temperature to 33.3°C before PPCI in patients with anterior STEMI. Due to inconsistent patient logistics between the groups, this hypothermia protocol resulted in a longer ischaemic delay, did not reduce IS/LV mass and was associated with increased adverse events.
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