429 results on '"Hausenloy, DJ"'
Search Results
152. Remote Ischemic Conditioning in Emergency Medicine-Clinical Frontiers and Research Opportunities.
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Ho AFW, Chong J, Ong MEH, and Hausenloy DJ
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- Humans, Emergency Medicine, Extremities blood supply, Ischemic Preconditioning, Reperfusion Injury prevention & control
- Abstract
Time-critical acute ischemic conditions such as ST-elevation myocardial infarction and acute ischemic stroke are staples in Emergency Medicine practice. While timely reperfusion therapy is a priority, the resultant acute ischemia/reperfusion injury contributes to significant mortality and morbidity. Among therapeutics targeting ischemia/reperfusion injury (IRI), remote ischemic conditioning (RIC) has emerged as the most promising.RIC, which consists of repetitive inflation and deflation of a pneumatic cuff on a limb, was first demonstrated to have protective effect on IRI through various neural and humoral mechanisms. Its attractiveness stems from its simplicity, low-cost, safety, and efficacy, while at the same time it does not impede reperfusion treatment. There is now good evidence for RIC as an effective adjunct to reperfusion in ST-elevation myocardial infarction patients for improving clinical outcomes. For other applications such as acute ischemic stroke, subarachnoid hemorrhage, traumatic brain injury, cardiac arrest, and spinal injury, there is varying level of evidence.This review aims to describe the RIC phenomenon, briefly recount its historical development, and appraise the experimental and clinical evidence for RIC in selected emergency conditions. Finally, it describes the practical issues with RIC clinical application and research in Emergency Medicine.
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- 2020
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153. Nanoparticle delivery of cardioprotective therapies.
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Mendez-Fernandez A, Cabrera-Fuentes HA, Velmurugan B, Irei J, Boisvert WA, Lu S, and Hausenloy DJ
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Acute myocardial infarction (AMI), and the heart failure (HF) that often follows, are leading causes of death and disability worldwide. Crucially, there are currently no effective treatments, other than myocardial reperfusion, for reducing myocardial infarct (MI) size and preventing HF following AMI. Thus, there is an unmet need to discover novel cardioprotective therapies to reduce MI size, and prevent HF in AMI patients. Although a large number of therapies have been shown to reduce MI size in experimental studies, the majority have failed to benefit AMI patients. Failure to deliver cardioprotective therapy to the ischemic heart in sufficient concentrations following AMI is a major factor for the lack of success observed in previous clinical cardioprotection studies. Therefore, new strategies are needed to improve the delivery of cardioprotective therapies to the ischemic heart following AMI. In this regard, nanoparticles have emerged as drug delivery systems for improving the bioavailability, delivery, and release of cardioprotective therapies, and should result in improved efficacy in terms of reducing MI size and preventing HF. In this article, we provide a review of currently available nanoparticles, some of which have been FDA-approved, in terms of their use as drug delivery systems in cardiovascular disease and cardioprotection., Competing Interests: Conflicts of interest statement The authors declare that they have no conflicts of interest.
- Published
- 2020
154. Feasibility to Perform T 2 * Mapping Postcontrast Administration in Reperfused STEMI Patients for the Detection of Intramyocardial Hemorrhage.
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Bulluck H, Chowdhury N, Lim MX, Allen JC, Bryant JA, Chan MY, Chan MHH, Chin CWL, Ho HH, Lim ST, Tan RS, Tan JW, Wong PE, Yeo KK, Cook SA, and Hausenloy DJ
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- Feasibility Studies, Hemorrhage diagnostic imaging, Humans, Magnetic Resonance Imaging, Myocardial Reperfusion, ST Elevation Myocardial Infarction diagnostic imaging
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- 2020
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155. Periprocedural Cardiac Troponin and Mortality in Stable Patients Undergoing PCI: More Data Needed.
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Bulluck H, Paradies V, Zeitouni M, Silvain J, and Hausenloy DJ
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- Biomarkers, Humans, Myocardium, Treatment Outcome, Troponin, Percutaneous Coronary Intervention
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- 2020
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156. The Fourth European-South African Cardiovascular Research Workshop.
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Lecour S, Hausenloy DJ, and Madonna R
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- 2020
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157. Why did remote ischaemic conditioning not improve clinical outcomes in acute myocardial infarction in the CONDI-2/ERIC-PPCI trial?
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Hausenloy DJ and Bøtker HE
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- Animals, Europe, Humans, Ischemic Preconditioning adverse effects, Ischemic Preconditioning mortality, Multicenter Studies as Topic, Myocardial Infarction diagnosis, Myocardial Infarction mortality, Myocardial Infarction physiopathology, Randomized Controlled Trials as Topic, Recovery of Function, Regional Blood Flow, Risk Factors, Treatment Outcome, Ischemic Preconditioning methods, Myocardial Infarction therapy, Percutaneous Coronary Intervention adverse effects, Percutaneous Coronary Intervention mortality, Upper Extremity blood supply, Ventricular Function, Left
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- 2019
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158. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.
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Hausenloy DJ, Kharbanda RK, Møller UK, Ramlall M, Aarøe J, Butler R, Bulluck H, Clayton T, Dana A, Dodd M, Engstrom T, Evans R, Lassen JF, Christensen EF, Garcia-Ruiz JM, Gorog DA, Hjort J, Houghton RF, Ibanez B, Knight R, Lippert FK, Lønborg JT, Maeng M, Milasinovic D, More R, Nicholas JM, Jensen LO, Perkins A, Radovanovic N, Rakhit RD, Ravkilde J, Ryding AD, Schmidt MR, Riddervold IS, Sørensen HT, Stankovic G, Varma M, Webb I, Terkelsen CJ, Greenwood JP, Yellon DM, and Bøtker HE
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- Aged, Combined Modality Therapy, Death, Sudden, Cardiac prevention & control, Female, Heart Failure etiology, Hospitalization, Humans, Intention to Treat Analysis, Male, Middle Aged, Myocardial Infarction complications, Myocardial Infarction surgery, Prospective Studies, Single-Blind Method, Treatment Outcome, United Kingdom, Ischemic Preconditioning, Myocardial methods, Myocardial Infarction therapy, Percutaneous Coronary Intervention
- Abstract
Background: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months., Methods: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed., Findings: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed., Interpretation: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI., Funding: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2019
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159. Is there a role for remote ischemic conditioning in preventing 5-fluorouracil-induced coronary vasospasm?
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Chong J, Ho AF, Yap J, Bulluck H, and Hausenloy DJ
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Cardiac ischemia associated with chemotherapy has been linked to several anti-neoplastic agents and is multifactorial in etiology. Coronary artery vasospasm is one of the most commonly reported effects of cancer therapy that can lead to myocardial ischemia or infarction. The chemotherapy agent 5-fluorouracil (5-FU) or its oral pro-drug capecitabine can result in coronary vascular endothelial dysfunction causing coronary artery spasm, and possibly coronary thrombosis. These drugs have also been shown to be associated with myocardial infarction, malignant ventricular arrhythmias, heart failure, cardiogenic shock, and sudden death. The proposed mechanisms underlying cardiotoxicity induced by 5-FU are vascular endothelial damage followed by thrombus formation, ischemia secondary to coronary artery vasospasm, direct toxicity on myocardium, and thrombogenicity. There remains a pressing need to discover novel and effective therapies that can prevent or ameliorate 5-FU associated cardiotoxicity. To this point, promising overlap has been observed between proposed remote ischemic conditioning (RIC) cardioprotective mechanisms and 5FU-associated cardiotoxic cellular pathways. RIC, in which transient episodes of limb ischemia and reperfusion (induced by inflations and deflations of a pneumatic cuff placed on the upper arm or thigh), confer both cardioprotective and vasculoprotective effects, and may therefore prevent 5-FU coronary artery spasm/cardiotoxicity. In this review, we will be discussing the following potentially therapeutic aspects of RIC in ameliorating 5-FU associated cardiotoxicity: sequential phases of 5-FU cardiotoxicity as possible targets for dual windows of cardioprotection characteristic of RIC; protective effects of RIC on endothelial function and microvasculature in relation to 5-FU induced endothelial dysfunction/microvascular dysfunction; reduction in platelet activation by RIC in the context of 5-FU induced thrombogenicity; and the utility of improvement in mitochondrial function conferred by RIC in 5-FU induced cellular toxicity secondary to mitochondrial dysfunction., Competing Interests: Conflict of interests None.
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- 2019
160. New insights provided by myofibril mechanics in inherited cardiomyopathies.
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Lin YH, Yap J, Ramachandra CJA, and Hausenloy DJ
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Cardiomyopathies represent a heterogeneous group of cardiac disorders that perturb cardiac contraction and/or relaxation, and can result in arrhythmias, heart failure, and sudden cardiac death. Based on morphological and functional differences, cardiomyopathies have been classified into hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM). It has been well documented that mutations in genes encoding sarcomeric proteins are associated with the onset of inherited cardiomyopathies. However, correlating patient genotype to the clinical phenotype has been challenging because of the complex genetic backgrounds, environmental influences, and lifestyles of individuals. Thus, "scaling down" the focus to the basic contractile unit of heart muscle using isolated single myofibril function techniques is of great importance and may be used to understand the molecular basis of disease-causing sarcomeric mutations. Single myofibril bundles harvested from diseased human or experimental animal hearts, as well as cultured adult cardiomyocytes or human cardiomyocytes derived from induced pluripotent stem cells, can be used, thereby providing an ideal multi-level, cross-species platform to dissect sarcomeric function in cardiomyopathies. Here, we will review the myofibril function technique, and discuss alterations in myofibril mechanics, which are known to occur in sarcomeric genetic mutations linked to inherited HCM, DCM, and RCM, and describe the therapeutic potential for future target identification., Competing Interests: Confilct of interests: None
- Published
- 2019
161. Manipulating energy migration within single lanthanide activator for switchable upconversion emissions towards bidirectional photoactivation.
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Mei Q, Bansal A, Jayakumar MKG, Zhang Z, Zhang J, Huang H, Yu D, Ramachandra CJA, Hausenloy DJ, Soong TW, and Zhang Y
- Abstract
Reliance on low tissue penetrating UV or visible light limits clinical applicability of phototherapy, necessitating use of deep tissue penetrating near-infrared (NIR) to visible light transducers like upconversion nanoparticles (UCNPs). While typical UCNPs produce multiple simultaneous emissions for unidirectional control of biological processes, programmable control requires orthogonal non-overlapping light emissions. These can be obtained through doping nanocrystals with multiple activator ions. However, this requires tedious synthesis and produces complicated multi-shell nanoparticles with a lack of control over emission profiles due to activator crosstalk. Herein, we explore cross-relaxation (CR), a non-radiative recombination pathway typically perceived as deleterious, to manipulate energy migration within the same lanthanide activator ion (Er
3+ ) towards orthogonal red and green emissions, simply by adjusting excitation wavelength from 980 to 808 nm. These UCNPs allow programmable activation of two synergistic light-gated ion channels VChR1 and Jaws in the same cell to manipulate membrane polarization, demonstrated here for cardiac pacing.- Published
- 2019
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162. ST-segment elevation myocardial infarction with non-chest pain presentation at the Emergency Department: Insights from the Singapore Myocardial Infarction Registry.
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Pong JZ, Ho AFW, Tan TXZ, Zheng H, Pek PP, Sia CH, Hausenloy DJ, and Ong MEH
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- Adult, Aged, Aged, 80 and over, Chi-Square Distribution, Diagnosis, Differential, Emergency Service, Hospital organization & administration, Emergency Service, Hospital statistics & numerical data, Female, Humans, Logistic Models, Male, Middle Aged, Retrospective Studies, ST Elevation Myocardial Infarction epidemiology, ST Elevation Myocardial Infarction physiopathology, Singapore epidemiology, Statistics, Nonparametric, Registries statistics & numerical data, ST Elevation Myocardial Infarction diagnosis
- Abstract
ST-segment elevation myocardial infarction (STEMI) often presents acutely at the Emergency Department (ED). Although chest pain is a classical symptom, a significant proportion of patients do not present with chest pain. The impact of a non-chest pain (NCP) presentation on ED processes-of-care and outcomes is not fully understood. We utilised a national registry to characterise predictors, processes-of-care, and outcomes of NCP STEMI presentations. Retrospective data for all STEMI cases occurring between 2010 and 2012 were analysed from the Singapore Myocardial Infarction Registry. Cases of inpatient onset, inter-facility transfers, and out-of-hospital cardiac arrests were excluded. Univariable analysis of demographic, clinical, processes-of-care, and outcome variables was conducted. Multivariable logistic regression ascertained independent predictors of a NCP presentation and 28-day mortality. Of 4667 STEMI cases, 12.9% presented without chest pain. Patients with NCP presentation were older (median, years = 74 vs. 58; p < 0.001), more likely to be female (39.1% vs. 15.7%; p < 0.001), of the Chinese race (72.5% vs. 62.7%; p < 0.001), and with diabetes (48.6% vs. 36.7%; p < 0.001). These patients were more likely to present with syncope (6.0% vs. 1.9%; p < 0.001) or epigastric pain (10.6% vs. 4.9%; p < 0.001). Patients with NCP presentation were less likely to receive percutaneous coronary intervention (27.0% vs. 75.6%; p < 0.001), had longer door-to-balloon time (median, minutes = 83 vs. 63; p < 0.001), and experienced greater mortality at 28 days (31.2% vs. 4.5%; p < 0.001). On multivariable logistic regression, independent predictors of a NCP presentation included age (adjusted odds ratio [aOR] = 1.05, 95% confidence interval [CI] 1.04-1.07), diabetes (aOR = 1.76, 95% CI 1.40-2.19), BMI (aOR = 0.93, 95% CI 0.91-0.96), and dyslipidemia (aOR = 0.73, 95% CI 0.58-0.91). Absence of chest pain was an independent predictor for 28-day mortality (aOR = 3.46, 95% CI 2.64-4.52). Patients who presented with a NCP STEMI had a distinct clinical profile and experienced poorer outcomes. Routine triage ECG could be considered for patients with high-risk factors and non-classical symptoms.
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- 2019
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163. Targeting Mitochondrial Fission Using Mdivi-1 in A Clinically Relevant Large Animal Model of Acute Myocardial Infarction: A Pilot Study.
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Ong SB, Kwek XY, Katwadi K, Hernandez-Resendiz S, Crespo-Avilan GE, Ismail NI, Lin YH, Yap EP, Lim SY, Ja KPMM, Ramachandra CJA, Tee N, Toh JJ, Shim W, Wong P, Cabrera-Fuentes HA, and Hausenloy DJ
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- Animals, Disease Models, Animal, Echocardiography, Female, Mitochondrial Dynamics drug effects, Myocardial Infarction drug therapy, Myocardial Infarction metabolism, Pilot Projects, Swine, Ventricular Function, Left drug effects, Myocardial Reperfusion Injury drug therapy, Myocardial Reperfusion Injury metabolism, Quinazolinones therapeutic use
- Abstract
Background : New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined. Methods : Adult pigs (30-40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology. Results : A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 ± 8.6 vs. mdivi-1 50.5 ± 11.4; p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 ± 0.4 vs. mdivi-1 59.6 ± 0.6; p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups. Conclusion : Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings.
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- 2019
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164. Chronic remote ischemic conditioning for cardiovascular protection.
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Chong J, Bulluck H, Fw Ho A, Boisvert WA, and Hausenloy DJ
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New treatments are needed to prevent adverse left ventricular remodelling following acute myocardial infarction (AMI), in order to prevent heart failure and improve clinical outcomes following AMI. Remote ischemic conditioning (RIC) using transient limb ischemia and reperfusion has been reported to reduce myocardial infarct (MI) size in AMI patients treated by primary percutaneous coronary intervention, and whether it can improve clinical outcomes is currently being investigated. Interestingly, repeated daily episode of limb RIC (termed 'chronic remote ischemic conditioning', or CRIC) has been shown in experimental and clinical studies to confer beneficial effects on post-AMI cardiac remodelling and chronic heart failure. In addition, the beneficial effects of CRIC extend to vascular function, peripheral arterial disease and stroke. In this review article, we focus on the therapeutic potential of CRIC as a strategy for cardiovascular protection and for improving clinical outcomes in patients with cardiovascular disease.
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- 2019
165. Cardiac MRI Endpoints in Myocardial Infarction Experimental and Clinical Trials: JACC Scientific Expert Panel.
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Ibanez B, Aletras AH, Arai AE, Arheden H, Bax J, Berry C, Bucciarelli-Ducci C, Croisille P, Dall'Armellina E, Dharmakumar R, Eitel I, Fernández-Jiménez R, Friedrich MG, García-Dorado D, Hausenloy DJ, Kim RJ, Kozerke S, Kramer CM, Salerno M, Sánchez-González J, Sanz J, and Fuster V
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- Biomedical Research, Clinical Trials as Topic, Humans, Postoperative Period, Cardiac Imaging Techniques, Heart diagnostic imaging, Magnetic Resonance Imaging methods, Myocardial Infarction surgery, Myocardial Reperfusion
- Abstract
After a reperfused myocardial infarction (MI), dynamic tissue changes occur (edema, inflammation, microvascular obstruction, hemorrhage, cardiomyocyte necrosis, and ultimately replacement by fibrosis). The extension and magnitude of these changes contribute to long-term prognosis after MI. Cardiac magnetic resonance (CMR) is the gold-standard technique for noninvasive myocardial tissue characterization. CMR is also the preferred methodology for the identification of potential benefits associated with new cardioprotective strategies both in experimental and clinical trials. However, there is a wide heterogeneity in CMR methodologies used in experimental and clinical trials, including time of post-MI scan, acquisition protocols, and, more importantly, selection of endpoints. There is a need for standardization of these methodologies to improve the translation into a real clinical benefit. The main objective of this scientific expert panel consensus document is to provide recommendations for CMR endpoint selection in experimental and clinical trials based on pathophysiology and its association with hard outcomes., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2019
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166. Independent Predictors of Cardiac Mortality and Hospitalization for Heart Failure in a Multi-Ethnic Asian ST-segment Elevation Myocardial Infarction Population Treated by Primary Percutaneous Coronary Intervention.
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Bulluck H, Zheng H, Chan MY, Foin N, Foo DC, Lee CW, Lim ST, Sahlen A, Tan HC, Tan JW, Tong KL, Wong AS, Wong PE, Yeo KK, Foo LL, Chua TS, Koh TH, and Hausenloy DJ
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- Aged, Cohort Studies, Electrocardiography, Female, Heart Failure mortality, Heart Failure surgery, Hospitalization, Humans, Male, Middle Aged, Myocardial Infarction mortality, Myocardial Infarction surgery, Prognosis, Risk Factors, Singapore, Survival Analysis, Treatment Outcome, Age Factors, Asian People, Heart Failure diagnosis, Myocardial Infarction diagnosis, Percutaneous Coronary Intervention
- Abstract
We aimed to identify independent predictors of cardiac mortality and hospitalization for heart failure (HHF) from a real-world, multi-ethnic Asian registry [the Singapore Myocardial Infarction Registry] of ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention. 11,546 eligible STEMI patients between 2008 and 2015 were identified. In-hospital, 30-day and 1-year cardiac mortality and 1-year HHF rates were 6.4%, 6.8%, 8.3% and 5.2%, respectively. From the derivation cohort (70% of patients), age, Killip class and cardiac arrest, creatinine, hemoglobin and troponin on admission and left ventricular ejection fraction (LVEF) during hospitalization were predictors of in-hospital, 30-day and 1-year cardiac mortality. Previous ischemic heart disease (IHD) was a predictor of in-hospital and 30-day cardiac mortality only, whereas diabetes was a predictor of 1-year cardiac mortality only. Age, previous IHD and diabetes, Killip class, creatinine, hemoglobin and troponin on admission, symptom-to-balloon-time and LVEF were predictors of 1-year HHF. The c-statistics were 0.921, 0.901, 0.881, 0.869, respectively. Applying these models to the validation cohort (30% of patients) showed good fit and discrimination (c-statistic 0.922, 0.913, 0.903 and 0.855 respectively; misclassification rate 14.0%, 14.7%, 16.2% and 24.0% respectively). These predictors could be incorporated into specific risk scores to stratify reperfused STEMI patients by their risk level for targeted intervention.
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- 2019
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167. Optimized Treatment of ST-Elevation Myocardial Infarction.
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Niccoli G, Montone RA, Ibanez B, Thiele H, Crea F, Heusch G, Bulluck H, Hausenloy DJ, Berry C, Stiermaier T, Camici PG, and Eitel I
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- Adrenergic beta-Antagonists therapeutic use, Animals, Fibrinolytic Agents therapeutic use, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, ST Elevation Myocardial Infarction metabolism, ST Elevation Myocardial Infarction physiopathology, Coronary Circulation, Microcirculation, ST Elevation Myocardial Infarction drug therapy
- Abstract
Primary percutaneous coronary intervention is nowadays the preferred reperfusion strategy for patients with acute ST-segment-elevation myocardial infarction, aiming at restoring epicardial infarct-related artery patency and achieving microvascular reperfusion as early as possible, thus limiting the extent of irreversibly injured myocardium. Yet, in a sizeable proportion of patients, primary percutaneous coronary intervention does not achieve effective myocardial reperfusion due to the occurrence of coronary microvascular obstruction (MVO). The amount of infarcted myocardium, the so-called infarct size, has long been known to be an independent predictor for major adverse cardiovascular events and adverse left ventricular remodeling after myocardial infarction. Previous cardioprotection studies were mainly aimed at protecting cardiomyocytes and reducing infarct size. However, several clinical and preclinical studies have reported that the presence and extent of MVO represent another important independent predictor of adverse left ventricular remodeling, and recent evidences support the notion that MVO may be more predictive of major adverse cardiovascular events than infarct size itself. Although timely and complete reperfusion is the most effective way of limiting myocardial injury and subsequent ventricular remodeling, the translation of effective therapeutic strategies into improved clinical outcomes has been largely disappointing. Of importance, despite the presence of a large number of studies focused on infarct size, only few cardioprotection studies addressed MVO as a therapeutic target. In this review, we provide a detailed summary of MVO including underlying causes, diagnostic techniques, and current therapeutic approaches. Furthermore, we discuss the hypothesis that simultaneously addressing infarct size and MVO may help to translate cardioprotective strategies into improved clinical outcome following ST-segment-elevation myocardial infarction.
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- 2019
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168. Interrogation of the infarcted and salvaged myocardium using multi-parametric mapping cardiovascular magnetic resonance in reperfused ST-segment elevation myocardial infarction patients.
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Hausenloy DJ, Lim MX, Chan MHH, Paradies V, Francis R, Kotecha T, Knight DS, Fontana M, Kellman P, Moon JC, and Bulluck H
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- Aged, Cohort Studies, Female, Humans, Male, Middle Aged, ST Elevation Myocardial Infarction pathology, ST Elevation Myocardial Infarction physiopathology, Magnetic Resonance Imaging, Cine methods, ST Elevation Myocardial Infarction diagnostic imaging
- Abstract
We used multi-parametric cardiovascular magnetic resonance (CMR) mapping to interrogate the myocardium following ST-segment elevation myocardial infarction (STEMI). Forty-eight STEMI patients underwent CMR at 4 ± 2 days. One matching short-axis slice of native T1 map, T2 map, late gadolinium enhancement (LGE), and automated extracellular volume fraction (ECV) maps per patient were analyzed. Manual regions-of-interest were drawn within the infarcted, the salvaged and the remote myocardium. A subgroup analysis was performed in those without MVO and with ≤75% transmural extent of infarct. For the whole cohort, T1, T2 and ECV in both the infarcted and the salvaged myocardium were significantly higher than in the remote myocardium. T1 and T2 could not differentiate between the salvaged and the infarcted myocardium, but ECV was significantly higher in the latter. In the subgroup analysis of 15 patients, similar findings were observed for T1 and T2. However, there was only a trend towards ECV
salvage being higher than ECVremote . In the clinical setting, current native T1 and T2 methods with the specific voxel sizes at 1.5 T could not differentiate between the infarcted and salvaged myocardium, whereas ECV could differentiate between the two. ECV was also higher in the salvaged myocardium when compared to the remote myocardium.- Published
- 2019
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169. Magnetic Resonance Perfusion or Fractional Flow Reserve in Coronary Disease.
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Nagel E, Greenwood JP, McCann GP, Bettencourt N, Shah AM, Hussain ST, Perera D, Plein S, Bucciarelli-Ducci C, Paul M, Westwood MA, Marber M, Richter WS, Puntmann VO, Schwenke C, Schulz-Menger J, Das R, Wong J, Hausenloy DJ, Steen H, and Berry C
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- Adult, Aged, Angina, Stable complications, Angina, Stable diagnostic imaging, Angina, Stable physiopathology, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease physiopathology, Female, Humans, Male, Middle Aged, Risk Factors, Angina, Stable diagnosis, Coronary Angiography, Fractional Flow Reserve, Myocardial, Magnetic Resonance Angiography
- Abstract
Background: In patients with stable angina, two strategies are often used to guide revascularization: one involves myocardial-perfusion cardiovascular magnetic resonance imaging (MRI), and the other involves invasive angiography and measurement of fractional flow reserve (FFR). Whether a cardiovascular MRI-based strategy is noninferior to an FFR-based strategy with respect to major adverse cardiac events has not been established., Methods: We performed an unblinded, multicenter, clinical-effectiveness trial by randomly assigning 918 patients with typical angina and either two or more cardiovascular risk factors or a positive exercise treadmill test to a cardiovascular MRI-based strategy or an FFR-based strategy. Revascularization was recommended for patients in the cardiovascular-MRI group with ischemia in at least 6% of the myocardium or in the FFR group with an FFR of 0.8 or less. The composite primary outcome was death, nonfatal myocardial infarction, or target-vessel revascularization within 1 year. The noninferiority margin was a risk difference of 6 percentage points., Results: A total of 184 of 454 patients (40.5%) in the cardiovascular-MRI group and 213 of 464 patients (45.9%) in the FFR group met criteria to recommend revascularization (P = 0.11). Fewer patients in the cardiovascular-MRI group than in the FFR group underwent index revascularization (162 [35.7%] vs. 209 [45.0%], P = 0.005). The primary outcome occurred in 15 of 421 patients (3.6%) in the cardiovascular-MRI group and 16 of 430 patients (3.7%) in the FFR group (risk difference, -0.2 percentage points; 95% confidence interval, -2.7 to 2.4), findings that met the noninferiority threshold. The percentage of patients free from angina at 12 months did not differ significantly between the two groups (49.2% in the cardiovascular-MRI group and 43.8% in the FFR group, P = 0.21)., Conclusions: Among patients with stable angina and risk factors for coronary artery disease, myocardial-perfusion cardiovascular MRI was associated with a lower incidence of coronary revascularization than FFR and was noninferior to FFR with respect to major adverse cardiac events. (Funded by the Guy's and St. Thomas' Biomedical Research Centre of the National Institute for Health Research and others; MR-INFORM ClinicalTrials.gov number, NCT01236807.)., (Copyright © 2019 Massachusetts Medical Society.)
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- 2019
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170. Sex Differences in 1-Year Rehospitalization for Heart Failure and Myocardial Infarction After Primary Percutaneous Coronary Intervention.
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Zheng H, Foo LL, Tan HC, Richards AM, Chan SP, Lee CH, Low AFH, Hausenloy DJ, Tan JWC, Sahlen AO, Ho HH, Chai SC, Tong KL, Tan DSY, Yeo KK, Chua TSJ, Lam CSP, and Chan MY
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- Aged, Drug-Eluting Stents, Female, Heart Failure therapy, Humans, Male, Middle Aged, Platelet Aggregation Inhibitors therapeutic use, Proportional Hazards Models, Retrospective Studies, Sex Factors, Time Factors, Time-to-Treatment, Treatment Outcome, Heart Failure epidemiology, Myocardial Infarction epidemiology, Myocardial Infarction therapy, Patient Readmission statistics & numerical data, Percutaneous Coronary Intervention
- Abstract
It is unclear whether universal access to primary percutaneous coronary intervention (pPCI) may reduce sex differences in 1-year rehospitalization for heart failure (HF) and myocardial infarction (MI) after ST-elevation myocardial infarction (STEMI). We studied 7,597 consecutive STEMI patients (13.8% women, n = 1,045) who underwent pPCI from January 2007 to December 2013. Cox regression models adjusted for competing risk from death were used to assess sex differences in rehospitalization for HF and MI within 1 year from discharge. Compared with men, women were older (median age 67.6 vs 56.0 years, p < 0.001) with higher prevalence of co-morbidities and multivessel disease. Women had longer median door-to-balloon time (76 vs 66 minutes, p < 0.001) and were less likely to receive drug-eluting stents (19.5% vs 24.1%, p = 0.001). Of the medications prescribed at discharge, fewer women received aspirin (95.8% vs 97.6%, p = 0.002) and P2Y
12 antagonists (97.6% vs 98.5%, p = 0.039), but there were no significant sex differences in other discharge medications. After adjusting for differences in baseline characteristics and treatment, sex differences in risk of rehospitalization for HF attenuated (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.79 to 1.40), but persisted for MI (HR 1.68, 95% CI 1.22 to 2.33), with greater disparity in patients aged ≥60 years (HR 1.83, 95% CI 1.18 to 2.85) than those aged <60 years (HR 1.45, 95% CI 0.84 to 2.50). In conclusion, in a setting of universal access to pPCI, the adjusted risk of 1-year rehospitalization for HF was similar in both sexes, but women had significantly higher adjusted risk of 1-year rehospitalization for MI, especially older women., (Copyright © 2019. Published by Elsevier Inc.)- Published
- 2019
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171. Shining the spotlight on cardioprotection: beyond the cardiomyocyte.
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Davidson SM, Andreadou I, Garcia-Dorado D, and Hausenloy DJ
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- Animals, Cardiovascular Agents adverse effects, Extracellular Vesicles metabolism, Humans, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury physiopathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Paracrine Communication, Platelet Activation drug effects, Signal Transduction, Treatment Outcome, Cardiovascular Agents therapeutic use, Extracellular Vesicles transplantation, Ischemic Preconditioning adverse effects, Myocardial Infarction therapy, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac drug effects, Ventricular Function, Left drug effects, Ventricular Remodeling drug effects
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- 2019
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172. The coronary circulation in acute myocardial ischaemia/reperfusion injury: a target for cardioprotection.
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Hausenloy DJ, Chilian W, Crea F, Davidson SM, Ferdinandy P, Garcia-Dorado D, van Royen N, Schulz R, and Heusch G
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- Animals, Cardiovascular Agents adverse effects, Collateral Circulation drug effects, Humans, Ischemic Preconditioning, Myocardial, Microcirculation drug effects, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury physiopathology, Myocardium metabolism, Neovascularization, Physiologic drug effects, No-Reflow Phenomenon metabolism, No-Reflow Phenomenon pathology, No-Reflow Phenomenon physiopathology, Treatment Outcome, Cardiovascular Agents therapeutic use, Coronary Circulation drug effects, Ischemic Postconditioning, Ischemic Preconditioning adverse effects, Myocardial Infarction therapy, Myocardial Reperfusion Injury prevention & control, Myocardium pathology, No-Reflow Phenomenon prevention & control
- Abstract
The coronary circulation is both culprit and victim of acute myocardial infarction. The rupture of an epicardial atherosclerotic plaque with superimposed thrombosis causes coronary occlusion, and this occlusion must be removed to induce reperfusion. However, ischaemia and reperfusion cause damage not only in cardiomyocytes but also in the coronary circulation, including microembolization of debris and release of soluble factors from the culprit lesion, impairment of endothelial integrity with subsequently increased permeability and oedema formation, platelet activation and leucocyte adherence, erythrocyte stasis, a shift from vasodilation to vasoconstriction, and ultimately structural damage to the capillaries with eventual no-reflow, microvascular obstruction (MVO), and intramyocardial haemorrhage (IMH). Therefore, the coronary circulation is a valid target for cardioprotection, beyond protection of the cardiomyocyte. Virtually all of the above deleterious endpoints have been demonstrated to be favourably influenced by one or the other mechanical or pharmacological cardioprotective intervention. However, no-reflow is still a serious complication of reperfused myocardial infarction and carries, independently from infarct size, an unfavourable prognosis. MVO and IMH can be diagnosed by modern imaging technologies, but still await an effective therapy. The current review provides an overview of strategies to protect the coronary circulation from acute myocardial ischaemia/reperfusion injury. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)
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- 2019
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173. Cardiac innervation in acute myocardial ischaemia/reperfusion injury and cardioprotection.
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Hausenloy DJ, Bøtker HE, Ferdinandy P, Heusch G, Ng GA, Redington A, and Garcia-Dorado D
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- Animals, Heart Failure metabolism, Heart Failure pathology, Heart Failure physiopathology, Humans, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury physiopathology, Treatment Outcome, Heart innervation, Heart Failure prevention & control, Ischemic Preconditioning, Myocardial adverse effects, Myocardial Infarction therapy, Myocardial Reperfusion Injury prevention & control, Vagus Nerve Stimulation adverse effects
- Abstract
Acute myocardial infarction (AMI) and the heart failure (HF) that often complicates this condition, are among the leading causes of death and disability worldwide. To reduce myocardial infarct (MI) size and prevent heart failure, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). In this regard, targeting cardiac innervation may provide a novel therapeutic strategy for cardioprotection. A number of cardiac neural pathways mediate the beneficial effects of cardioprotective strategies such as ischaemic preconditioning and remote ischaemic conditioning, and nerve stimulation may therefore provide a novel therapeutic strategy for cardioprotection. In this article, we provide an overview of cardiac innervation and its impact on acute myocardial IRI, the role of extrinsic and intrinsic cardiac neural pathways in cardioprotection, and highlight peripheral and central nerve stimulation as a cardioprotective strategy with therapeutic potential for reducing MI size and preventing HF following AMI. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
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- 2019
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174. Immune cells as targets for cardioprotection: new players and novel therapeutic opportunities.
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Andreadou I, Cabrera-Fuentes HA, Devaux Y, Frangogiannis NG, Frantz S, Guzik T, Liehn EA, Gomes CPC, Schulz R, and Hausenloy DJ
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- Animals, Anti-Inflammatory Agents adverse effects, Cardiovascular Agents adverse effects, Dendritic Cells drug effects, Dendritic Cells immunology, Dendritic Cells metabolism, Fibroblasts drug effects, Fibroblasts immunology, Fibroblasts metabolism, Heart Failure immunology, Heart Failure metabolism, Heart Failure pathology, Humans, Inflammation Mediators immunology, Inflammation Mediators metabolism, Lymphocytes drug effects, Lymphocytes immunology, Lymphocytes metabolism, Mast Cells drug effects, Mast Cells immunology, Mast Cells metabolism, Monocytes drug effects, Monocytes immunology, Monocytes metabolism, Myocardial Infarction immunology, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Reperfusion Injury immunology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardium metabolism, Myocardium pathology, Neutrophils drug effects, Neutrophils immunology, Neutrophils metabolism, Signal Transduction, Ventricular Function, Left drug effects, Ventricular Remodeling drug effects, Anti-Inflammatory Agents therapeutic use, Cardiovascular Agents therapeutic use, Heart Failure prevention & control, Myocardial Infarction therapy, Myocardial Reperfusion Injury prevention & control, Myocardium immunology
- Abstract
New therapies are required to reduce myocardial infarct (MI) size and prevent the onset of heart failure in patients presenting with acute myocardial infarction (AMI), one of the leading causes of death and disability globally. In this regard, the immune cell response to AMI, which comprises an initial pro-inflammatory reaction followed by an anti-inflammatory phase, contributes to final MI size and post-AMI remodelling [changes in left ventricular (LV) size and function]. The transition between these two phases is critical in this regard, with a persistent and severe pro-inflammatory reaction leading to adverse LV remodelling and increased propensity for developing heart failure. In this review article, we provide an overview of the immune cells involved in orchestrating the complex and dynamic inflammatory response to AMI-these include neutrophils, monocytes/macrophages, and emerging players such as dendritic cells, lymphocytes, pericardial lymphoid cells, endothelial cells, and cardiac fibroblasts. We discuss potential reasons for past failures of anti-inflammatory cardioprotective therapies, and highlight new treatment targets for modulating the immune cell response to AMI, as a potential therapeutic strategy to improve clinical outcomes in AMI patients. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
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- 2019
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175. Role of Macrophages in Cardioprotection.
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Yap J, Cabrera-Fuentes HA, Irei J, Hausenloy DJ, and Boisvert WA
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- Animals, Cardiovascular Diseases pathology, Cardiovascular Diseases physiopathology, Cardiovascular Diseases therapy, Heart physiopathology, Humans, Macrophages pathology, Myocardial Infarction immunology, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardial Infarction therapy, Myocardium cytology, Myocardium pathology, Protective Factors, Ventricular Remodeling, Cardiovascular Diseases immunology, Immunity, Innate, Macrophages immunology, Myocardium immunology
- Abstract
Cardiovascular diseases are the leading cause of mortality worldwide. It is widely known that non-resolving inflammation results in atherosclerotic conditions, which are responsible for a host of downstream pathologies including thrombosis, myocardial infarction (MI), and neurovascular events. Macrophages, as part of the innate immune response, are among the most important cell types in every stage of atherosclerosis. In this review we discuss the principles governing macrophage function in the healthy and infarcted heart. More specifically, how cardiac macrophages participate in myocardial infarction as well as cardiac repair and remodeling. The intricate balance between phenotypically heterogeneous populations of macrophages in the heart have profound and highly orchestrated effects during different phases of myocardial infarction. In the early "inflammatory" stage of MI, resident cardiac macrophages are replaced by classically activated macrophages derived from the bone marrow and spleen. And while the macrophage population shifts towards an alternatively activated phenotype, the inflammatory response subsides giving way to the "reparative/proliferative" phase. Lastly, we describe the therapeutic potential of cardiac macrophages in the context of cell-mediated cardio-protection. Promising results demonstrate innovative concepts; one employing a subset of yolk sac-derived, cardiac macrophages that have complete restorative capacity in the injured myocardium of neonatal mice, and in another example, post-conditioning of cardiac macrophages with cardiosphere-derived cells significantly improved patient's post-MI diagnoses.
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- 2019
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176. Mineralocorticoid receptor antagonist pre-treatment and early post-treatment to minimize reperfusion injury after ST-elevation myocardial infarction: The MINIMIZE STEMI trial.
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Bulluck H, Fröhlich GM, Nicholas JM, Mohdnazri S, Gamma R, Davies J, Sirker A, Mathur A, Blackman D, Garg P, Moon JC, Greenwood JP, and Hausenloy DJ
- Subjects
- Aged, Cardiac Imaging Techniques, Double-Blind Method, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Pilot Projects, Proof of Concept Study, ST Elevation Myocardial Infarction diagnostic imaging, ST Elevation Myocardial Infarction physiopathology, Ventricular Remodeling drug effects, Ventricular Remodeling physiology, Canrenoic Acid therapeutic use, Mineralocorticoid Receptor Antagonists therapeutic use, Myocardial Reperfusion Injury prevention & control, Percutaneous Coronary Intervention, ST Elevation Myocardial Infarction drug therapy, ST Elevation Myocardial Infarction surgery, Spironolactone therapeutic use
- Abstract
Background: Mineralocorticoid receptor antagonist (MRA) therapy has been shown to prevent adverse left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients with heart failure. Whether initiating MRA therapy prior to primary percutaneous coronary intervention (PPCI) accrues additional benefit of reducing myocardial infarct size and preventing adverse LV remodeling is not known. We aimed to investigate whether MRA therapy initiated prior to reperfusion reduces myocardial infarct (MI) size and prevents adverse LV remodeling in STEMI patients., Methods: STEMI patients presenting within 12 hours and with a proximal coronary artery occlusion with Thrombolysis In Myocardial Infarction flow grade 0 were consented and randomized to either an intravenous bolus of potassium canrenoate, followed by oral spironolactone for 3 months or matching placebo. The primary endpoint was MI size by cardiovascular magnetic resonance at 3 months., Results: Sixty-seven patients completed the study. There was no significant difference in the final MI size at 3 months between the 2 groups (placebo: 17 ± 11%, MRA: 16 ± 10%, P = .574). There was also no difference in acute MI size (26 ± 16% versus 23 ± 14%, P = .425) or myocardial salvage (26 ± 12% versus 24 ± 8%, P = .456). At follow-up, there was a trend towards an improvement in LVEF (placebo: 49 ± 8%, MRA: 54 ± 11%, P = .053), and the MRA group had significantly greater percentage decrease in LVEDV (mean difference: -12.2 (95% CI -20.3 to -4.4)%, P = .003) and LVESV (mean difference: -18.2 (95% CI -30.1 to -6.3)%, P = .003)., Conclusion: This pilot study showed no benefit of MRA therapy in reducing MI size in STEMI patients when initiated prior to reperfusion, but there was an improvement in LV remodeling at 3 months. Adequately powered studies are warranted to confirm these findings., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2019
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177. Effect of Ischemic Preconditioning and Postconditioning on Exosome-Rich Fraction microRNA Levels, in Relation with Electrophysiological Parameters and Ventricular Arrhythmia in Experimental Closed-Chest Reperfused Myocardial Infarction.
- Author
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Spannbauer A, Traxler D, Lukovic D, Zlabinger K, Winkler J, Gugerell A, Ferdinandy P, Hausenloy DJ, Pavo N, Emmert MY, Hoerstrup SP, Jakab A, Gyöngyösi M, and Riesenhuber M
- Subjects
- Animals, Female, Heart Ventricles metabolism, MicroRNAs genetics, Myocardial Infarction complications, Myocardial Infarction therapy, Swine, Ventricular Fibrillation etiology, Ventricular Fibrillation therapy, Ventricular Function, Exosomes metabolism, Ischemic Postconditioning, Ischemic Preconditioning, Myocardial, MicroRNAs metabolism, Myocardial Infarction metabolism, Ventricular Fibrillation metabolism
- Abstract
We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, n = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) ( n = 9), or AMI-PostC ( n = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs.
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- 2019
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178. Translating Cardioprotection for Patient Benefit: The EU-CARDIOPROTECTION COST Action.
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Hausenloy DJ and Heusch G
- Subjects
- European Union, Heart Failure etiology, Humans, Myocardial Infarction diagnosis, Myocardial Infarction therapy, Research Design, Risk Assessment, Cardiotonic Agents administration & dosage, Health Workforce organization & administration, Heart Failure prevention & control, Myocardial Infarction complications, Patient Safety
- Published
- 2019
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179. Time-Stratified Case Crossover Study of the Association of Outdoor Ambient Air Pollution With the Risk of Acute Myocardial Infarction in the Context of Seasonal Exposure to the Southeast Asian Haze Problem.
- Author
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Ho AFW, Zheng H, Earnest A, Cheong KH, Pek PP, Seok JY, Liu N, Kwan YH, Tan JWC, Wong TH, Hausenloy DJ, Foo LL, Tan BYQ, and Ong MEH
- Subjects
- Aged, Cross-Over Studies, Female, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Myocardial Infarction etiology, Retrospective Studies, Seasons, Singapore epidemiology, Time and Motion Studies, Air Pollution adverse effects, Myocardial Infarction epidemiology, Particulate Matter adverse effects, Registries, Risk Assessment methods
- Abstract
Background Prior studies have demonstrated the association of air pollution with cardiovascular deaths. Singapore experiences seasonal transboundary haze. We investigated the association between air pollution and acute myocardial infarction ( AMI ) incidence in Singapore. Methods and Results We performed a time-stratified case-crossover study on all AMI cases in the Singapore Myocardial Infarction Registry (2010-2015). Exposure on days where AMI occurred (case days) were compared with the exposure on days where AMI did not occur (control days). Control days were chosen on the same day of the week earlier and later in the same month and year. We fitted conditional Poisson regression models to daily AMI incidence to include confounders such as ambient temperature, rainfall, wind-speed, and Pollutant Standards Index. We assessed relationships between AMI incidence and Pollutant Standards Index in the entire cohort and subgroups of individual-level characteristics. There were 53 948 cases. Each 30-unit increase in Pollutant Standards Index was association with AMI incidence (incidence risk ratio [ IRR ] 1.04, 95% CI 1.03-1.06). In the subgroup of ST -segment-elevation myocardial infarction the IRR was 1.00, 95% CI 0.98 to 1.03, while for non-ST-segment-elevation myocardial infarction, the IRR was 1.08, 95% CI 1.05 to 1.10. Subgroup analyses showed generally significant. Moderate/unhealthy Pollutant Standards Index showed association with AMI occurrence with IRR 1.08, 95% CI 1.05 to 1.11 and IRR 1.09, 95% CI 1.01 to 1.18, respectively. Excess risk remained elevated through the day of exposure and for >2 years after. Conclusions We found an effect of short-term air pollution on AMI incidence, especially non-ST-segment-elevation myocardial infarction and inpatient AMI . These findings have public health implications for primary prevention and emergency health services during haze.
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- 2019
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180. FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice.
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Yakala GK, Cabrera-Fuentes HA, Crespo-Avilan GE, Rattanasopa C, Burlacu A, George BL, Anand K, Mayan DC, Corlianò M, Hernández-Reséndiz S, Wu Z, Schwerk AMK, Tan ALJ, Trigueros-Motos L, Chèvre R, Chua T, Kleemann R, Liehn EA, Hausenloy DJ, Ghosh S, and Singaraja RR
- Subjects
- Animals, Aorta enzymology, Atherosclerosis genetics, Atherosclerosis pathology, Carotid Artery, Common, Disease Progression, Drug Evaluation, Preclinical, Enzyme Induction drug effects, Furin genetics, Furin physiology, Gene Expression Regulation drug effects, Macrophages physiology, Male, Matrix Metalloproteinase 2 analysis, Mice, Mice, Inbred C57BL, Monocytes physiology, Plaque, Atherosclerotic pathology, Receptors, LDL deficiency, Tunica Intima drug effects, Tunica Intima pathology, Vascular Remodeling, alpha 1-Antitrypsin pharmacology, Atherosclerosis prevention & control, Furin antagonists & inhibitors, Plaque, Atherosclerotic drug therapy, alpha 1-Antitrypsin therapeutic use
- Abstract
Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery disease-associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis. Approach and Results- In vitro, FURIN inhibitor treatment resulted in reduced monocyte migration and reduced macrophage and vascular endothelial cell inflammatory and cytokine gene expression. In vivo, administration of an irreversible inhibitor of FURIN, α-1-PDX (α1-antitrypsin Portland), to hyperlipidemic Ldlr
-/- mice resulted in lower atherosclerotic lesion area and a specific reduction in severe lesions. Significantly lower lesional macrophage and collagen area, as well as systemic inflammatory markers, were observed. MMP2 (matrix metallopeptidase 2), an effector of endothelial function and atherosclerotic lesion progression, and a FURIN substrate was significantly reduced in the aorta of inhibitor-treated mice. To determine FURIN's role in vascular endothelial function, we administered α-1-PDX to Apoe-/- mice harboring a wire injury in the common carotid artery. We observed significantly decreased carotid intimal thickness and lower plaque cellularity, smooth muscle cell, macrophage, and inflammatory marker content, suggesting protection against vascular remodeling. Overexpression of FURIN in this model resulted in a significant 67% increase in intimal plaque thickness, confirming that FURIN levels directly correlate with atherosclerosis. Conclusions- We show that systemic inhibition of FURIN in mice decreases vascular remodeling and atherosclerosis. FURIN-mediated modulation of MMP2 activity may contribute to the atheroprotection observed in these mice.- Published
- 2019
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181. Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: a novel mechanism for an old drug.
- Author
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Bibli SI, Papapetropoulos A, Iliodromitis EK, Daiber A, Randriamboavonjy V, Steven S, Brouckaert P, Chatzianastasiou A, Kypreos KE, Hausenloy DJ, Fleming I, and Andreadou I
- Subjects
- Adult, Aged, Animals, Cyclophilins genetics, Cyclophilins metabolism, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, ApoE, Middle Aged, Myocardial Infarction enzymology, Myocardial Infarction pathology, Myocardial Reperfusion Injury enzymology, Myocardial Reperfusion Injury pathology, Myocytes, Cardiac enzymology, Myocytes, Cardiac pathology, Necrosis, Nitric Oxide Synthase Type III genetics, Nitric Oxide Synthase Type III metabolism, Nitrosation, Signal Transduction, Cyclophilins antagonists & inhibitors, Enzyme Inhibitors pharmacology, Myocardial Infarction prevention & control, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac drug effects, Nitric Oxide Donors pharmacology, Nitroglycerin pharmacology
- Abstract
Aims: Nitroglycerine (NTG) given prior to an ischaemic insult exerts cardioprotective effects. However, whether administration of an acute low dose of NTG in a clinically relevant manner following an ischaemic episode limits infarct size, has not yet been explored., Methods and Results: Adult mice were subjected to acute myocardial infarction in vivo and then treated with vehicle or low-dose NTG prior to reperfusion. This treatment regimen minimized myocardial infarct size without affecting haemodynamic parameters but the protective effect was absent in mice rendered tolerant to the drug. Mechanistically, NTG was shown to nitrosate and inhibit cyclophilin D (CypD), and NTG administration failed to limit infarct size in CypD knockout mice. Additional experiments revealed lack of the NTG protective effect following genetic (knockout mice) or pharmacological inhibition (L-NAME treatment) of the endothelial nitric oxide synthase (eNOS). The protective effect of NTG was attributed to preservation of the eNOS dimer. Moreover, NTG retained its cardioprotective effects in a model of endothelial dysfunction (ApoE knockout) by preserving CypD nitrosation. Human ischaemic heart biopsies revealed reduced eNOS activity and exhibited reduced CypD nitrosation., Conclusion: Low-dose NTG given prior to reperfusion reduces myocardial infarct size by preserving eNOS function, and the subsequent eNOS-dependent S-nitrosation of CypD, inhibiting cardiomyocyte necrosis. This novel pharmacological action of NTG warrants confirmation in clinical studies, although our data in human biopsies provide promising preliminary results., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)
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- 2019
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182. ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure.
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Madonna R, Van Laake LW, Botker HE, Davidson SM, De Caterina R, Engel FB, Eschenhagen T, Fernandez-Aviles F, Hausenloy DJ, Hulot JS, Lecour S, Leor J, Menasché P, Pesce M, Perrino C, Prunier F, Van Linthout S, Ytrehus K, Zimmermann WH, Ferdinandy P, and Sluijter JPG
- Subjects
- Consensus, Heart Failure pathology, Heart Failure physiopathology, Humans, Myocardial Ischemia pathology, Myocardial Ischemia physiopathology, Recovery of Function, Stem Cell Transplantation adverse effects, Treatment Outcome, Biomedical Research standards, Cardiology standards, Heart Failure surgery, Myocardial Ischemia surgery, Myocardium pathology, Regeneration, Stem Cell Transplantation standards, Tissue Engineering standards
- Abstract
Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
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- 2019
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183. The Role of O-GlcNAcylation for Protection against Ischemia-Reperfusion Injury.
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Jensen RV, Andreadou I, Hausenloy DJ, and Bøtker HE
- Subjects
- Animals, Cardiotonic Agents pharmacology, Cardiotonic Agents therapeutic use, Comorbidity, Humans, Metabolic Networks and Pathways, Mitochondrial Membrane Transport Proteins metabolism, Mitochondrial Permeability Transition Pore, Myocardial Reperfusion Injury etiology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury prevention & control, Protein Processing, Post-Translational, Reactive Oxygen Species metabolism, Reperfusion Injury etiology, Reperfusion Injury pathology, Reperfusion Injury prevention & control, Acetylglucosamine metabolism, Oxidative Stress drug effects, Reperfusion Injury metabolism
- Abstract
Ischemia reperfusion injury (IR injury) associated with ischemic heart disease contributes significantly to morbidity and mortality. O-linked β-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that plays an important role in numerous biological processes, both in normal cell functions and disease. O-GlcNAc increases in response to stress. This increase mediates stress tolerance and cell survival, and is protective. Increasing O-GlcNAc is protective against IR injury. Experimental cellular and animal models, and also human studies, have demonstrated that protection against IR injury by ischemic preconditioning, and the more clinically applicable remote ischemic preconditioning, is associated with increases in O-GlcNAc levels. In this review we discuss how the principal mechanisms underlying tissue protection against IR injury and the associated immediate elevation of O-GlcNAc may involve attenuation of calcium overload, attenuation of mitochondrial permeability transition pore opening, reduction of endoplasmic reticulum stress, modification of inflammatory and heat shock responses, and interference with established cardioprotective pathways. O-GlcNAcylation seems to be an inherent adaptive cytoprotective response to IR injury that is activated by mechanical conditioning strategies.
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- 2019
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184. Air pollution in relation to very short-term risk of ST-segment elevation myocardial infarction: Case-crossover analysis of SWEDEHEART.
- Author
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Sahlén A, Ljungman P, Erlinge D, Chan MY, Yap J, Hausenloy DJ, Yeo KK, and Jernberg T
- Subjects
- Adult, Cross-Over Studies, Female, Humans, Incidence, Male, Risk Factors, ST Elevation Myocardial Infarction epidemiology, Seasons, Sweden epidemiology, Time Factors, Air Pollutants adverse effects, Electrocardiography, ST Elevation Myocardial Infarction etiology
- Abstract
Objective: Studies have related air pollution to myocardial infarction (MI) events over days or weeks, with few data on very short-term risks. We studied risk of ST-segment elevation MI (STEMI) within hours of exposure to air pollution while adjusting for weather., Methods: We performed a case-crossover study of STEMI cases in Stockholm, Sweden (Jan 2000-June 2014) based on SWEDEHEART. Exposures during hazard periods up to 24 h prior to admission were compared to bidirectionally sampled control periods. Risks attributable to sulphur dioxide (SO
2 ), nitrogen dioxide (NO2 ), ozone and particulate pollutants (PM2.5 , PM10 ) were studied in conditional logistic regression models for interquartile range increments., Results: Risk of STEMI (n = 14,601) was associated with NO2 (strongest at 15-h lag) and with PM2.5 (strongest at 20-h lag), in single-pollutant models adjusting for air temperature and humidity (NO2 : odds ratio (OR; 95% confidence interval) 1.065 (1.031-1.101); PM2.5 : 1.026 (1.001-1.054)). After adjusting models for atmospheric pressure (significantly associated with STEMI risk at 14-24-h lags), NO2 remained highly statistically significant (1.057 (1.022-1.094)) but not PM2.5 (1.024 (0.997-1.052)). No associations were seen for SO2 , ozone or PM10 ., Conclusion: Risk of STEMI rises within hours of exposure to air pollutants, with strongest impact of NO2 . These findings are complementary to earlier reports which have not acknowledged widely the importance of very short-term fluctuations in air pollution., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2019
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185. Sevoflurane, Propofol and Carvedilol Block Myocardial Protection by Limb Remote Ischemic Preconditioning.
- Author
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Cho YJ, Nam K, Kim TK, Choi SW, Kim SJ, Hausenloy DJ, and Jeon Y
- Subjects
- Adult, Aged, Animals, Cardiac Surgical Procedures, Carvedilol administration & dosage, Case-Control Studies, Cross-Over Studies, Disease Models, Animal, Female, Humans, Male, Middle Aged, Propofol administration & dosage, Random Allocation, Rats, Rats, Sprague-Dawley, Sevoflurane administration & dosage, Carvedilol adverse effects, Extremities blood supply, Ischemic Preconditioning methods, Myocardial Infarction prevention & control, Propofol adverse effects, Sevoflurane adverse effects
- Abstract
The effects of remote ischemic preconditioning (RIPC) in cardiac surgery have been inconsistent. We investigated whether anesthesia or beta-blockers interfere with RIPC cardioprotection. Fifty patients undergoing cardiac surgery were randomized to receive limb RIPC (four cycles of 5-min of upper arm cuff inflation/deflation) in the awake state (no-anesthesia; n = 17), or under sevoflurane ( n = 17) or propofol ( n = 16) anesthesia. In a separate crossover study, 11 healthy volunteers received either carvedilol or no medication prior to RIPC. Plasma dialysates were obtained and perfused through an isolated male Sprague⁻Dawley rat heart subjected to 30-min ischemia/60-min reperfusion, following which myocardial infarct (MI) size was determined. In the cardiac surgery study, pre-RIPC MI sizes were similar among the groups (39.7 ± 4.5% no-anesthesia, 38.9 ± 5.3% sevoflurane, and 38.6 ± 3.6% propofol). However, post-RIPC MI size was reduced in the no-anesthesia group (27.5 ± 8.0%; p < 0.001), but not in the anesthesia groups (35.7 ± 6.9% sevoflurane and 35.8 ± 5.8% propofol). In the healthy volunteer study, there was a reduction in MI size with RIPC in the no-carvedilol group (41.7 ± 4.3% to 30.6 ± 8.5%; p < 0.0001), but not in the carvedilol group (41.0 ± 4.0% to 39.6 ± 5.6%; p = 0.452). We found that the cardioprotective effects of limb RIPC were abolished under propofol or sevoflurane anesthesia and in the presence of carvedilol therapy.
- Published
- 2019
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186. Multitarget Strategies to Reduce Myocardial Ischemia/Reperfusion Injury: JACC Review Topic of the Week.
- Author
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Davidson SM, Ferdinandy P, Andreadou I, Bøtker HE, Heusch G, Ibáñez B, Ovize M, Schulz R, Yellon DM, Hausenloy DJ, and Garcia-Dorado D
- Subjects
- Humans, Myocardial Reperfusion Injury etiology, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury prevention & control
- Abstract
Many treatments have been identified that confer robust cardioprotection in experimental animal models of acute ischemia and reperfusion injury. However, translation of these cardioprotective therapies into the clinical setting of acute myocardial infarction (AMI) for patient benefit has been disappointing. One important reason might be that AMI is multifactorial, causing cardiomyocyte death via multiple mechanisms, as well as affecting other cell types, including platelets, fibroblasts, endothelial and smooth muscle cells, and immune cells. Many cardioprotective strategies act through common end-effectors and may be suboptimal in patients with comorbidities. In this regard, emerging data suggest that optimal cardioprotection may require the combination of additive or synergistic multitarget therapies. This review will present an overview of the state of cardioprotection today and provide a roadmap for how we might progress towards successful clinical use of cardioprotective therapies following AMI, focusing on the rational combination of judiciously selected, multitarget therapies. This paper emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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187. INDUCED PLURIPOTENT STEM CELLS FOR MODELLING ENERGETIC ALTERATIONS IN HYPERTROPHIC CARDIOMYOPATHY.
- Author
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Ramachandra CJA, Mai Ja KPM, Lin YH, Shim W, Boisvert WA, and Hausenloy DJ
- Abstract
Hypertrophic cardiomyopathy (HCM) is one of the most commonly inherited cardiac disorders that manifests with increased ventricular wall thickening, cardiomyocyte hypertrophy, disarrayed myofibers and interstitial fibrosis. The major pathophysiological features include, diastolic dysfunction, obstruction of the left ventricular outflow tract and cardiac arrhythmias. Mutations in genes that encode mostly for sarcomeric proteins have been associated with HCM but, despite the abundant research conducted to decipher the molecular mechanisms underlying the disease, it remains unclear as to how a primary defect in the sarcomere could lead to secondary phenotypes such as cellular hypertrophy. Mounting evidence suggests energy deficiency could be an important contributor of disease pathogenesis as well. Various animal models of HCM have been generated for gaining deeper insight into disease pathogenesis, however species variation between animals and humans, as well as the limited availability of human myocardial samples, has encouraged researchers to seek alternative 'humanized' models. Using induced pluripotent stem cells (iPSCs), human cardiomyocytes (CMs) have been generated from patients with HCM for investigating disease mechanisms. While these HCM-iPSC models demonstrate most of the phenotypic traits, it is important to ascertain if they recapitulate all pathophysiological features, especially that of energy deficiency. In this review we discuss the currently established HCM-iPSC models with emphasis on altered energetics.
- Published
- 2019
188. Platelet inhibition to target reperfusion injury trial: Rationale and study design.
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Bulluck H, Chan MHH, Bryant JA, Chai P, Chawla A, Chua TS, Chung YC, Fei G, Ho HH, Ho AFW, Hoe AJ, Imran SS, Lee CH, Lim SH, Liew BW, Yun PLZ, Hock MOE, Paradies V, Roe MT, Teo L, Wong AS, Wong E, Wong PE, Watson T, Chan MY, Tan JW, and Hausenloy DJ
- Subjects
- Adenosine Monophosphate administration & dosage, Adult, Aged, Aged, 80 and over, Double-Blind Method, Female, Follow-Up Studies, Humans, Infusions, Intravenous, Magnetic Resonance Imaging, Cine, Male, Middle Aged, Myocardial Reperfusion Injury diagnosis, Myocardial Reperfusion Injury physiopathology, Myocardium pathology, Platelet Aggregation Inhibitors administration & dosage, ST Elevation Myocardial Infarction diagnosis, ST Elevation Myocardial Infarction physiopathology, Treatment Outcome, Young Adult, Adenosine Monophosphate analogs & derivatives, Coronary Circulation physiology, Myocardial Reperfusion methods, Myocardial Reperfusion Injury prevention & control, Percutaneous Coronary Intervention methods, ST Elevation Myocardial Infarction therapy, Ventricular Remodeling physiology
- Abstract
Background: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI), current oral P2Y12 platelet inhibitors do not provide maximal platelet inhibition at the time of reperfusion. Furthermore, administration of cangrelor prior to reperfusion has been shown in pre-clinical studies to reduce myocardial infarct (MI) size. Therefore, we hypothesize that cangrelor administered prior to reperfusion in STEMI patients will reduce the incidence of microvascular obstruction (MVO) and limit MI size in STEMI patients treated with PPCI., Methods: The platelet inhibition to target reperfusion injury (PITRI) trial, is a phase 2A, multi-center, double-blinded, randomized controlled trial, in which 210 STEMI patients will be randomized to receive either an intravenous (IV) bolus of cangrelor (30 μg/kg) followed by a 120-minute infusion (4 μg/kg/min) or matching saline placebo, initiated prior to reperfusion (NCT03102723)., Results: The study started in October 2017 and the anticipated end date would be July 2020. The primary end-point will be MI size quantified by cardiovascular magnetic resonance (CMR) on day 3 post-PPCI. Secondary endpoints will include markers of reperfusion, incidence of MVO, MI size, and adverse left ventricular remodeling at 6 months, and major adverse cardiac and cerebrovascular events., Summary: The aim of the PITRI trial is to assess whether cangrelor administered prior to reperfusion would reduce acute MI size and MVO, as assessed by CMR., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2019
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189. Fatty acid metabolism driven mitochondrial bioenergetics promotes advanced developmental phenotypes in human induced pluripotent stem cell derived cardiomyocytes.
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Ramachandra CJA, Mehta A, Wong P, Ja KPMM, Fritsche-Danielson R, Bhat RV, Hausenloy DJ, Kovalik JP, and Shim W
- Subjects
- Cells, Cultured, Humans, Induced Pluripotent Stem Cells ultrastructure, Mitochondria ultrastructure, Myocytes, Cardiac ultrastructure, Phenotype, Energy Metabolism physiology, Fatty Acids metabolism, Induced Pluripotent Stem Cells metabolism, Lipid Metabolism physiology, Mitochondria metabolism, Myocytes, Cardiac metabolism
- Abstract
Background: Preferential utilization of fatty acids for ATP production represents an advanced metabolic phenotype in developing cardiomyocytes. We investigated whether this phenotype could be attained in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) and assessed its influence on mitochondrial morphology, bioenergetics, respiratory capacity and ultra-structural architecture., Methods and Results: Whole-cell proteome analysis of day 14 and day 30-CMs maintained in glucose media revealed a positive influence of extended culture on mitochondria-related processes that primed the day 30-CMs for fatty acid metabolism. Supplementing the day 30-CMs with palmitate/oleate (fatty acids) significantly enhanced mitochondrial remodeling, oxygen consumption rates and ATP production. Metabolomic analysis upon fatty acid supplementation revealed a β-oxidation fueled ATP elevation that coincided with presence of junctional complexes, intercalated discs, t-tubule-like structures and adult isoform of cardiac troponin T. In contrast, glucose-maintained day 30-CMs continued to harbor underdeveloped ultra-structural architecture and more subdued bioenergetics, constrained by suboptimal mitochondria development., Conclusion: The advanced metabolic phenotype of preferential fatty acid utilization was attained in hiPSC-CMs, whereby fatty acid driven β-oxidation sustained cardiac bioenergetics and respiratory capacity resulting in ultra-structural and functional characteristics similar to those of developmentally advanced cardiomyocytes. Better understanding of mitochondrial bioenergetics and ultra-structural adaptation associated with fatty acid metabolism has important implications in the study of cardiac physiology that are associated with late-onset mitochondrial and metabolic adaptations., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
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190. Hybrid PET/CT and PET/MRI imaging of vulnerable coronary plaque and myocardial scar tissue in acute myocardial infarction.
- Author
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Marchesseau S, Seneviratna A, Sjöholm AT, Qin DL, Ho JXM, Hausenloy DJ, Townsend DW, Richards AM, Totman JJ, and Chan MYY
- Subjects
- Adult, Female, Fluorine Radioisotopes, Humans, Male, Middle Aged, Sodium Fluoride, Cicatrix diagnostic imaging, Coronary Artery Disease diagnostic imaging, Magnetic Resonance Imaging methods, Multimodal Imaging methods, Myocardial Infarction diagnostic imaging, Plaque, Atherosclerotic diagnostic imaging, Positron Emission Tomography Computed Tomography methods, Positron-Emission Tomography methods
- Abstract
Background: Following an acute coronary syndrome, combined CT and PET with
18 F-NaF can identify coronary atherosclerotic plaques that have ruptured or eroded. However, the processes behind18 F-NaF uptake in vulnerable plaques remain unclear., Methods and Results: Ten patients with STEMI were scanned after18 F-NaF injection, for 75 minutes in a Siemens PET/MR scanner using delayed enhancement (LGE). They were then scanned in a Siemens PET/CT scanner for 10 minutes. Tissue-to-background ratio (TBR) was compared between the culprit lesion in the IRA and remote non-culprit lesions in an effort to independently validate prior studies. Additionally, we performed a proof-of-principle study comparing TBR in scar tissue and remote myocardium using LGE images and PET/MR or PET/CT data. From the 33 coronary lesions detected on PET/CT, TBRs for culprit lesions were higher than for non-culprit lesions (TBR = 2.11 ± 0.45 vs 1.46 ± 0.48; P < 0.001). Interestingly, the TBR measured on the PET/CT was higher for infarcted myocardium than for remote myocardium (TBR = 0.81 ± 0.10 vs 0.71 ± 0.05; P = 0.003). These results were confirmed using the PET/MR data (TBR = 0.81 ± 0.10 for scar, TBR = 0.71 ± 0.06 for healthy myocardium, P = 0.03)., Conclusions: We confirmed the potential of18 F-NaF PET/CT imaging to detect vulnerable coronary lesions. Moreover, we demonstrated proof-of-principle that18 F-NaF concurrently detects myocardial scar tissue.- Published
- 2018
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191. Incidence and predictors of left ventricular thrombus by cardiovascular magnetic resonance in acute ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention: a meta-analysis.
- Author
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Bulluck H, Chan MHH, Paradies V, Yellon RL, Ho HH, Chan MY, Chin CWL, Tan JW, and Hausenloy DJ
- Subjects
- Adult, Aged, Drug Therapy, Combination, Female, Heart Diseases epidemiology, Heart Diseases physiopathology, Hemorrhage chemically induced, Hemorrhage epidemiology, Humans, Incidence, Male, Middle Aged, Platelet Aggregation Inhibitors administration & dosage, Platelet Aggregation Inhibitors adverse effects, Predictive Value of Tests, Risk Factors, ST Elevation Myocardial Infarction diagnostic imaging, ST Elevation Myocardial Infarction epidemiology, ST Elevation Myocardial Infarction physiopathology, Thrombosis epidemiology, Thrombosis physiopathology, Time Factors, Treatment Outcome, Ventricular Function, Left, Heart Diseases diagnostic imaging, Magnetic Resonance Imaging, Percutaneous Coronary Intervention adverse effects, ST Elevation Myocardial Infarction surgery, Thrombosis diagnostic imaging
- Abstract
Introduction: The incidence of left ventricular (LV) thrombus formation in ST-segment elevation myocardial infarction (STEMI) patients in the current era of primary percutaneous coronary intervention (PCI) is not well established. We performed a meta-analysis to assess the actual incidence and predictors of LV thrombus by cardiovascular magnetic resonance (CMR) in STEMI treated by primary PCI., Methods: We searched MEDLINE and EMBASE databases up to February 2018. We included all studies published as a full-text article, reporting the incidence of LV thrombus by CMR within 1 month following acute STEMI in patients treated by primary PCI. A binary random-effects model was used to estimate the pooled incidence of LV thrombus. The diagnostic performance of transthoracic echocardiography (TTE) as compared with CMR was pooled to obtain the sensitivity and specificity of TTE with CMR as the gold standard. Embolic and bleeding complications of LV thrombus were also evaluated., Results: Ten studies were included in the meta-analysis. The incidence of LV thrombus by CMR in all-comer STEMI patients (n = 2072) was 6.3% with 96% of LV thrombus occurring in those with anterior STEMI (12.2% incidence). When only anterior STEMI with LVEF< 50% were considered (n = 447), the incidence of LV thrombus was 19.2%. Compared with CMR, the sensitivity of TTE to detect LV thrombus was 29% with a specificity of 98%. The sensitivity of TTE increased to 70% in those with anterior STEMI and reduced LVEF. LV thrombus resolved in 88% of cases by 3 to 6 months. After 1-2 years follow-up, the embolic complication rate was similar at 1.5% (P = 0.25) but the bleeding complication rate was significantly higher (8.8% versus 0.5%, P < 0.001) in the LV thrombus group on triple therapy when compared to the no LV thrombus group on dual antiplatelet therapy., Conclusion: In the primary PCI era, CMR detection of an LV thrombus post-STEMI remains high with incidence of nearly 20% in anterior STEMI with depressed LVEF. Patients with LV thrombus treated by triple therapy had similar embolic complications but higher bleeding complications than those with no LV thrombus treated with dual antiplatelet therapy. A 3 month follow-up CMR scan to guide anticoagulation duration might help mitigate bleeding risk.
- Published
- 2018
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192. Coronary Microvascular Injury in Reperfused Acute Myocardial Infarction: A View From an Integrative Perspective.
- Author
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Sezer M, van Royen N, Umman B, Bugra Z, Bulluck H, Hausenloy DJ, and Umman S
- Subjects
- Cardiomyopathies etiology, Coronary Occlusion etiology, Hemorrhage etiology, Humans, Coronary Disease etiology, Microvessels, Myocardial Infarction surgery, Myocardial Reperfusion adverse effects, Myocardial Reperfusion Injury etiology
- Published
- 2018
- Full Text
- View/download PDF
193. Optimizing the Detection of Left Ventricular Thrombus Following Acute Myocardial Infarction in the Current Era.
- Author
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Bulluck H, Vincent M, and Hausenloy DJ
- Subjects
- Humans, Myocardial Infarction, Thrombosis
- Published
- 2018
- Full Text
- View/download PDF
194. Importance of Sex-Specific Regression Models to Estimate Synthetic Hematocrit and Extracellular Volume Fraction.
- Author
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Lim EH, Le TT, Bryant J, Chung YC, Su B, Gan J, Hausenloy DJ, Cook SA, and Chin CWL
- Subjects
- Age Factors, Aged, Female, Humans, Hypertension complications, Hypertrophy, Left Ventricular blood, Hypertrophy, Left Ventricular etiology, Male, Middle Aged, Predictive Value of Tests, Sex Factors, Hematocrit, Hypertrophy, Left Ventricular diagnostic imaging, Magnetic Resonance Imaging, Models, Biological
- Published
- 2018
- Full Text
- View/download PDF
195. Modulating NAD + metabolism to prevent acute kidney injury.
- Author
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Bulluck H and Hausenloy DJ
- Subjects
- Humans, Kidney, Acute Kidney Injury, NAD
- Published
- 2018
- Full Text
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196. Remote ischemic conditioning in ST-segment elevation myocardial infarction - an update.
- Author
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Chong J, Bulluck H, Yap EP, Ho AF, Boisvert WA, and Hausenloy DJ
- Abstract
Acute myocardial infarction (AMI) and the heart failure (HF) that often results are among the leading causes of death and disability in the world. As such, novel strategies are required to protect the heart against the detrimental effects of acute ischemia/reperfusion injury (IRI), in order to reduce myocardial infarct (MI) size and prevent the onset of HF. The endogenous cardioprotective strategy of remote ischemic conditioning (RIC), in which cycles of brief ischemia and reperfusion are applied to a tissue or organ away from the heart, has been reported in experimental studies to reduce MI size in animal models of acute IRI. In the clinical setting, RIC can be induced by simply inflating and deflating a cuff placed on the upper arm or thigh to induce brief cycles of ischemia and reperfusion, a strategy which has been shown to reduce MI size in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). The results of the ongoing CONDI2/ERIC-PPCI trial are eagerly awaited, and will provide definitive answers with regards to the cardioprotective effect and clinical outcome benefits of RIC in STEMI.
- Published
- 2018
197. MiD49 and MiD51: New mediators of mitochondrial fission and novel targets for cardioprotection.
- Author
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Samangouei P, Crespo-Avilan GE, Cabrera-Fuentes H, Hernández-Reséndiz S, Ismail NI, Katwadi KB, Boisvert WA, and Hausenloy DJ
- Abstract
Acute myocardial infarction (AMI) and the heart failure (HF) that often follows are among the leading causes of death and disability worldwide. As such novel therapies are needed to reduce myocardial infarct (MI) size, and preserve left ventricular (LV) systolic function in order to reduce the propensity for HF following AMI. Mitochondria are dynamic organelles that can undergo morphological changes by two opposing processes, mitochondrial fusion and fission. Changes in mitochondrial morphology and turnover are a vital part of maintaining mitochondrial health, DNA stability, energy production, calcium homeostasis, cellular division, and differentiation, and disturbances in the balance of fusion and fission can predispose to mitochondrial dysfunction and cell death. Changes in mitochondrial morphology are governed by mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1) and mitochondrial fission proteins (Drp1, hFis1, and Mff). Recent experimental data suggest that mitochondria undergo fission during acute ischemia/reperfusion injury (IRI), generating fragmented dysfunctional mitochondrial and predisposing to cell death. We and others have shown that genetic and pharmacological inhibition of the mitochondrial fission protein Drp1 can protect cardiomyocytes from acute IRI and reduce MI size. Novel components of the mitochondrial fission machinery, mitochondrial dynamics proteins of 49 kDa (MiD49) and mitochondrial dynamics proteins of 51 kDa (MiD51), have been recently described, which have been shown to mediating mitochondrial fission by targeting Drp1 to the mitochondrial surface. In this review article, we provide an overview of MiD49 and MiD51, and highlight their potential as novel therapeutic targets for treating cardiovascular diseases such as AMI, anthracycline cardiomyopathy, and pulmonary arterial hypertension., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest.
- Published
- 2018
198. Impact of Cardioprotective Therapies on the Edema-Based Area at Risk by CMR in Reperfused STEMI.
- Author
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Bulluck H, Chan MHH, Paradies V, Bryant JA, Hernández-Reséndiz S, Cabrera-Fuentes HA, Watson TJ, Chan MY, Tan JW, and Hausenloy DJ
- Subjects
- Cardiac Imaging Techniques, Edema, Cardiac diagnostic imaging, Humans, Magnetic Resonance Imaging, Randomized Controlled Trials as Topic, ST Elevation Myocardial Infarction therapy, ST Elevation Myocardial Infarction diagnostic imaging
- Published
- 2018
- Full Text
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199. An automated workflow for segmenting single adult cardiac cells from large-volume serial block-face scanning electron microscopy data.
- Author
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Hussain A, Ghosh S, Kalkhoran SB, Hausenloy DJ, Hanssen E, and Rajagopal V
- Subjects
- Adult, Humans, Image Processing, Computer-Assisted methods, Microscopy, Electron, Scanning methods, Myocytes, Cardiac ultrastructure, Single-Cell Analysis methods
- Abstract
This paper presents a new algorithm to automatically segment the myofibrils, mitochondria and nuclei within single adult cardiac cells that are part of a large serial-block-face scanning electron microscopy (SBF-SEM) dataset. The algorithm only requires a set of manually drawn contours that roughly demarcate the cell boundary at routine slice intervals (every 50th, for example). The algorithm correctly classified pixels within the single cell with 97% accuracy when compared to manual segmentations. One entire cell and the partial volumes of two cells were segmented. Analysis of segmentations within these cells showed that myofibrils and mitochondria occupied 47.5% and 51.6% on average respectively, while the nuclei occupy 0.7% of the cell for which the entire volume was captured in the SBF-SEM dataset. Mitochondria clustering increased at the periphery of the nucleus region and branching points of the cardiac cell. The segmentations also showed high area fraction of mitochondria (up to 70% of the 2D image slice) in the sub-sarcolemmal region, whilst it was closer to 50% in the intermyofibrillar space. We finally demonstrate that our segmentations can be turned into 3D finite element meshes for cardiac cell computational physiology studies. We offer our large dataset and MATLAB implementation of the algorithm for research use at www.github.com/CellSMB/sbfsem-cardiac-cell-segmenter/. We anticipate that this timely tool will be of use to cardiac computational and experimental physiologists alike who study cardiac ultrastructure and its role in heart function., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
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200. Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities.
- Author
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Ong SB, Hernández-Reséndiz S, Crespo-Avilan GE, Mukhametshina RT, Kwek XY, Cabrera-Fuentes HA, and Hausenloy DJ
- Subjects
- Animals, Anti-Inflammatory Agents administration & dosage, Disease Models, Animal, Heart Failure immunology, Humans, Inflammation, Myocardial Infarction immunology, Ventricular Remodeling immunology, Anti-Inflammatory Agents therapeutic use, Heart Failure prevention & control, Inflammation Mediators metabolism, Myocardial Infarction drug therapy, Ventricular Remodeling drug effects
- Abstract
Acute myocardial infarction (AMI) and the heart failure that often follows, are major causes of death and disability worldwide. As such, new therapies are required to limit myocardial infarct (MI) size, prevent adverse left ventricular (LV) remodeling, and reduce the onset of heart failure following AMI. The inflammatory response to AMI, plays a critical role in determining MI size, and a persistent pro-inflammatory reaction can contribute to adverse post-MI LV remodeling, making inflammation an important therapeutic target for improving outcomes following AMI. In this article, we provide an overview of the multiple players (and their dynamic roles) involved in the complex inflammatory response to AMI and subsequent LV remodeling, and highlight future opportunities for targeting inflammation as a therapeutic strategy for limiting MI size, preventing adverse LV remodeling, and reducing heart failure in AMI patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
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