Mechanisms Underlying Takotsubo Syndrome
Takotsubo 综合征的潜在机制
基本信息
- 批准号:10522633
- 负责人:
- 金额:$ 58.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AbateAgreementApex of the HeartApicalAreaBlood flowCardiacCardiac MyocytesCell DeathClinicalComplexContrast EchocardiographyCoronaryCoronary OcclusionsDevelopmentDown-RegulationDrug usageEchocardiographyEventGene ExpressionGlucoseHeartHibernationHypoxiaImageImpairmentInjuryIschemiaLaboratoriesLeftLeft ventricular structureMass Spectrum AnalysisMeasurementMedicalMetabolicMetabolic PathwayMetabolic dysfunctionMetabolismMicrocirculationMindMitochondriaModelingMolecularMyocardialMyocardial HibernationMyocardial IschemiaMyocardial dysfunctionNecrosisOhioOxygen ConsumptionPatientsPhenotypePhosphorylationPlayProcessRNAReactionRecoveryRegulationResearchReverse Transcriptase Polymerase Chain ReactionRoleScientistSmooth MuscleStressStress cardiomyopathySyndromeTestingThinkingTimeTissuesTransgenic ModelTranslationsUniversitiesVasoconstrictor AgentsVasodilationVasodilator AgentsVentricularWestern Blottingacute coronary syndromearteriolebasecontrast enhanced computed tomographyfatty acid metabolismheart functionheart metabolismhemodynamicsimprovedinterdisciplinary approachmortalitymouse modelmultiphoton imagingnecrotic tissuepreventprogramsprotein expressionregional differencerestorationtranscriptome sequencingtwo-photon
项目摘要
Our proposal tests the overarching hypothesis that regional differences in coronary regulation cause micro-
areas of ischemia in the apex of the heart and induce Takotsubo Syndrome. We posit that the level of
ischemia in the ballooning area is not sufficient to produce cell death, but enough of a decrease to invoke an
adaptive program of “myocardial hibernation,” confined to area of ballooning, where the decrease in flow leads
to a decrease in cardiac function. The consequence of apical hibernation is a restoration of the match
between myocardial blood flow and function as the reduced apical function matches the lower myocardial
blood flow, resolving the ischemia. The “benefit” of this hibernation is to prevent irreversible injury, i.e.,
necrosis. To determine if these hypotheses are correct, we have incorporated a multidisciplinary approach that
will not only provide a comprehensive mechanistic analysis of TTS (Aim 1), but will also determine if increasing
blood flow in the apex of the heart exerts a salubrious effect in TTS (Aim 2). Within this context, we propose
two aims: Specific Aim 1. To determine if Takotsubo Syndrome is caused by impaired flow regulation in the
apical regions of the heart leading to micro-areas of myocardial ischemia and a down-regulation of function.
Furthermore, we will determine if the ischemia is abated when function downregulates to match the reduced
flow. This aim will be tested by the following hypotheses: Hypothesis 1. Vasoactive reactions to vasodilators
and vasoconstrictors are different in coronary arterioles from the apex and base of the heart. Hypothesis 2.
During the initial development of TTS, the apex of the heart is ischemic. Hypothesis 3. During the stage of
TTS characterized by apical ballooning, the downregulation of both cardiac function and myocardial blood flow
in the apex eliminates myocardial ischemia and produces apical hibernation. The second specific aim
proposes to determine if improving myocardial blood flow (MBF) will induce recovery of metabolic and
molecular changes induced during Takotsubo Syndrome. This will be tested in the following hypothesis using
two independent mechanisms to increase blood flow: Hypothesis 4. Increasing MBF in the area of ballooning
prevents or restores cardiac, coronary, and metabolic dysfunction. This application builds upon the expertise
and technological capability of research teams at Northeast Ohio Medical University and Cornell University to
decipher mechanisms underlying Takotsubo Syndrome, and to determine whether coronary vasodilation
rescues the abnormalities associated with this syndrome. A comprehensive, interdisciplinary approach is
imbedded in the experimental plan to include measurements of myocardial blood flow (echocardiography)
tissue metabolism and (mass spectrometry), gene expression (RNA seq, RT-PCR), protein expression and
phosphorylation (Western blotting) and cardiac myocyte hypoxia using cardiac myocyte specific hypoxia fate-
mapping.
我们的建议验证了冠状动脉调节的区域差异导致微动脉粥样硬化的总体假设
项目成果
期刊论文数量(0)
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会议论文数量(0)
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WILLIAM M CHILIAN其他文献
WILLIAM M CHILIAN的其他文献
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{{ truncateString('WILLIAM M CHILIAN', 18)}}的其他基金
The critical role of the coronary microcirculation in heart failure
冠状动脉微循环在心力衰竭中的关键作用
- 批准号:
9383841 - 财政年份:2017
- 资助金额:
$ 58.94万 - 项目类别:
What mechanisms underlie coronary collateral growth?
冠状动脉侧枝生长的机制是什么?
- 批准号:
9220295 - 财政年份:2016
- 资助金额:
$ 58.94万 - 项目类别:
Reactive Oxygen Species in Coronary Collateral Growth
冠状动脉侧枝生长中的活性氧
- 批准号:
8267619 - 财政年份:2009
- 资助金额:
$ 58.94万 - 项目类别:
Reactive Oxygen Species in Coronary Collateral Growth
冠状动脉侧枝生长中的活性氧
- 批准号:
7898715 - 财政年份:2009
- 资助金额:
$ 58.94万 - 项目类别:
Reactive Oxygen Species in Coronary Collateral Growth
冠状动脉侧枝生长中的活性氧
- 批准号:
8471748 - 财政年份:2009
- 资助金额:
$ 58.94万 - 项目类别:
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