Mechanistic Insights to A Translatable Therapy for Acute Reperfused Hemorrhagic Myocardial Infarctions
急性再灌注出血性心肌梗塞可转化疗法的机制见解
基本信息
- 批准号:10630055
- 负责人:
- 金额:$ 74.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-05 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcuteAcute myocardial infarctionAddressAdverse effectsAnimal ModelAutophagocytosisBiologicalBlood VesselsBlood flowCardiacCardiac MyocytesCardiovascular systemCaringCenters for Disease Control and Prevention (U.S.)Cessation of lifeChelation TherapyChronicChronic PhaseCicatrixClinicalCommunitiesCongestive Heart FailureCoronary arteryDataDepositionEpidemicEventExtravasationFDA approvedFoundationsHealth Care CostsHeartHeart DiseasesHemeHeme IronHemorrhageImageImpairmentInfarctionInflammasomeInflammatoryInjuryIronIron Chelating AgentsIron ChelationLeft Ventricular RemodelingLinkLocationMacrophageMediatingMitochondriaMuscle CellsMyocardial InfarctionMyocardial ReperfusionObstructionOrganOxidative StressPathway interactionsPatientsPersonsPharmacologic SubstancePhasePhenotypeReperfusion InjuryReperfusion TherapyReportingResearchResolutionRiskSiteTestingTherapeutic InterventionTimeTissuesTranslationsadverse outcomecatalystclinically relevantcytokineextracellularfluoroformheart damageheme aimprovedinsightiron chelation therapymyocardial infarct sizingmyocardial injuryoptimal treatmentsoxidationrecruittargeted treatmenttherapeutic development
项目摘要
PROJECT SUMMARY
Chronic heart failure culminating in major adverse cardiovascular events (MACE) has become epidemic in
patients with prior myocardial infarction (MI). According to the Centers for Disease Control, >300,000 deaths
per year are attributable to chronic heart failure in the US. A long-established predictor of chronic heart failure
is infarct size. However, late microvascular obstruction, a condition where microvascular blood flow in the MI
territory is lost despite reperfusion of the epicardial coronary artery, has emerged as another independent
predictor of chronic heart failure. Notably, late microvascular obstruction is often associated with
intramyocardial hemorrhage and that hemorrhagic MIs (hMI) are the most prone to MACE. Accordingly,
therapeutic intervention for hMI patients will substantially curb MACE: establishing the causes, mechanisms
and timing of events linking hMI to MACE risk is key. Several important observations relevant to hMIs in the
acute and chronic phases of MI have been reported, but an overarching mechanism of how hemorrhage drives
adverse outcomes throughout post-infarction period is not known. Key studies have shown that in reperfused
acute MIs (a) large MIs often have hemorrhage; (b) reperfusion itself can cause marked oxidative stress within
the MI zone; and (c) that iron is a critical catalyst contributing to the oxidative stress that drives cardiomyocyte
death. However, it is not known whether hemorrhage, which is rich in iron, exacerbates reperfusion injury and
causes infarct expansion. In the chronic phase of MI, studies have shown that timely resolution of
proinflammatory cytokines is critical, which can otherwise impair scar formation and accelerate adverse
remodeling. But why some MIs have prolonged proinflammatory burden and continue to adversely remodel is
not known. Importantly, current therapies are not beneficial for hMI patients and previously studied therapies
have not targeted iron from hemorrhage. We hypothesize that the evolving changes of hemorrhage within the
infarct zone precipitates (a) a heme-iron mediated death (ferroptosis) of surviving cardiomyocytes in the acute
phase of MI; (b) the formation of ferric-iron crystals within macrophages that attempt to remove them polarize
them to a proinflammatory state in chronic phase of MI; and (c) a therapy that accounts for the temporal
changes in hemorrhage can rescue the hearts from infarct expansion and rapid adverse LV remodeling. To
investigate these hypotheses, Aim 1 will establish the mechanistic framework by which hemorrhage promotes
time-dependent damage to the heart in the post MI period; Aim 2 will determine the time-dependent changes
that alter the features of iron within hemorrhage to tune the development of therapeutic strategies; and Aim 3
will determine optimal iron chelation strategies to reduce the adverse effects of hemorrhage following
reperfusion. To address these Aims, this proposal brings together an interdisciplinary team to derive an
overarching framework of how hemorrhage promotes adverse outcomes, which is then used to test therapies
against hMI. Hence, this proposal is a major step toward curbing the chronic heart failure epidemic in the US.
项目总结
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Reperfused hemorrhagic myocardial infarction in rats.
在大鼠中再生出血性心肌梗塞。
- DOI:10.1371/journal.pone.0243207
- 发表时间:2020
- 期刊:
- 影响因子:3.7
- 作者:Nair AR;Johnson EA;Yang HJ;Cokic I;Francis J;Dharmakumar R
- 通讯作者:Dharmakumar R
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Rohan Dharmakumar其他文献
Rohan Dharmakumar的其他文献
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{{ truncateString('Rohan Dharmakumar', 18)}}的其他基金
Mechanistic Insights to A Translatable Therapy for Acute Reperfused Hemorrhagic Myocardial Infarctions
急性再灌注出血性心肌梗塞可转化疗法的机制见解
- 批准号:
10359807 - 财政年份:2020
- 资助金额:
$ 74.99万 - 项目类别:
Accurate, Needle-Free, MRI-based Detection of Ischemic Heart Disease without Contrast Agents
无需造影剂即可通过 MRI 进行准确、无针、基于 MRI 的缺血性心脏病检测
- 批准号:
10686342 - 财政年份:2020
- 资助金额:
$ 74.99万 - 项目类别:
Accurate, Needle-Free, MRI-based Detection of Ischemic Heart Disease without Contrast Agents
无需造影剂即可通过 MRI 进行准确、无针、基于 MRI 的缺血性心脏病检测
- 批准号:
9981378 - 财政年份:2020
- 资助金额:
$ 74.99万 - 项目类别:
Mechanistic Insights to A Translatable Therapy for Acute Reperfused Hemorrhagic Myocardial Infarctions
急性再灌注出血性心肌梗塞可转化疗法的机制见解
- 批准号:
9887771 - 财政年份:2020
- 资助金额:
$ 74.99万 - 项目类别:
Accurate, Needle-Free, MRI-based Detection of Ischemic Heart Disease without Contrast Agents
无需造影剂即可通过 MRI 进行准确、无针、基于 MRI 的缺血性心脏病检测
- 批准号:
10201743 - 财政年份:2020
- 资助金额:
$ 74.99万 - 项目类别:
Accurate, Needle-Free, MRI-based Detection of Ischemic Heart Disease without Contrast Agents
无需造影剂即可通过 MRI 进行准确、无针、基于 MRI 的缺血性心脏病检测
- 批准号:
10655692 - 财政年份:2020
- 资助金额:
$ 74.99万 - 项目类别:
Developing a MRI-guided Disease-Modifying Therapy for Post Infarction Chronic Heart Failure
开发 MRI 引导的梗死后慢性心力衰竭疾病缓解疗法
- 批准号:
9981537 - 财政年份:2017
- 资助金额:
$ 74.99万 - 项目类别:
Developing a MRI-guided Disease-Modifying Therapy for Post Infarction Chronic Heart Failure
开发 MRI 引导的梗死后慢性心力衰竭疾病缓解疗法
- 批准号:
9756228 - 财政年份:2017
- 资助金额:
$ 74.99万 - 项目类别:
4D SSFP MRI for Detecting Functionally Important Coronary Artery Stenosis at Rest
4D SSFP MRI 用于检测静息时具有重要功能的冠状动脉狭窄
- 批准号:
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4D SSFP MRI for Detecting Functionally Important Coronary Artery Stenosis at Rest
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