Dynamic Single Cell Imaging of Coronary Microvascular Dysfunction in the Failing Heart

心力衰竭冠状动脉微血管功能障碍的动态单细胞成像

• 批准号: 10523513
• 负责人: Aaron D Aguirre
• 金额: $ 41.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523513
• 关键词: Acute myocardial infarction; Adenosine; Affect; Animal Model; Arteries; Atherosclerosis; Blood Vessels; Blood capillaries; Blood flow; Brain; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Clinical; Clinical Treatment; Complex; Computer Models; Coronary; Coronary Arteriosclerosis; Coronary Vessels; Coronary artery; Coronary heart disease; Diagnosis; Diameter; Epidemic; Erythrocytes; Exercise; Exhibits; Fibrosis; Flow Cytometry; Four-dimensional; Functional disorder; Future; Heart; Heart Diseases; Heart Injuries; Heart failure; Heterogeneity; Histologic; Hyperemia; Hypertrophy; Image; Image Cytometry; In Vitro; Individual; Inflammation; Inflammatory Response; Link; Maps; Measures; Membrane Potentials; Metabolic; Metabolism; Methods; Microcirculation; Microscopy; Microvascular Dysfunction; Modeling; Molecular; Morphologic artifacts; Motion; Mus; Muscle Cells; Myocardial; Myocardial Ischemia; NADH; Neurosciences; Optics; Organ; Pathologic; Pathology; Patients; Pattern; Pericytes; Physiological; Physiology; Property; Protocols documentation; Regulation; Reporter; Resistance; Resolution; Role; Science; Stress; Techniques; Testing; Therapeutic; Time; Transgenic Mice; Tumor Biology; Veins; Work; aging population; aorta constriction; automated image analysis; cellular imaging; clinical diagnosis; empowerment; experimental study; heart imaging; hemodynamics; high resolution imaging; imaging modality; improved; in vivo; innovation; insight; intravital imaging; intravital microscopy; mouse model; novel strategies; novel therapeutics; optogenetics; pharmacologic; physiologic model; pressure; quantitative imaging; response; therapeutic development; tool; two photon microscopy

Despite decades of advances in clinical diagnosis and treatment of heart disease, there is a rising epidemic of heart failure in an aging population worldwide. Historically, much focus has been on atherosclerosis, acute myocardial infarction, and treatment of large vessel coronary disease. However, relatively little is known at a mechanistic level about the vast network of small arteries, capillaries and veins in the heart beyond the large coronary arteries, the coronary microcirculation, and increasing evidence links dysfunction of the microcirculation to various forms of heart disease including heart failure. In vitro experiments, histologic analysis, and computational modeling have provided insight about how the coronary microcirculation is regulated and remodels in the failing heart, but prior studies have been unable to directly evaluate the complex microcirculatory physiology of the heart at the cellular level in vivo. Intravital optical microscopy is being used in the neurosciences and tumor biology to decipher dynamic vascular physiology in vivo, but these techniques have not been applicable in the heart due to severe imaging limitations imposed by contractile motion. We have recently pioneered intravital imaging methods to perform motion-artifact free, cellular resolution microscopy in the beating heart. Building on this work, this proposal seeks to investigate mechanisms of coronary microvascular dysfunction by utilizing intravital microscopy to quantitatively map flow in the coronary microcirculation down to the capillary level in animal models of heart disease. Studies will be performed in mice comparing microcirculatory function in healthy controls, in a model of physiologic hypertrophy due to exercise, and in a model of pressure overload leading to pathologic hypertrophy and heart failure. In addition, the specific role of microvascular pericytes will be investigated as a master regulator of capillary blood flow. Intravital confocal and two-photon microscopy, multiplexed fluorescent reporters, and cell-specific optogenetics approaches will be used to record and manipulate microvascular flow, and to correlate abnormal flow patterns with cardiomyocyte metabolism, inflammatory response, and fibrosis. This work will lead to new understanding of microcirculatory pathophysiology in the failing heart at the single cell level and promising new insights for clinical therapeutics.

尽管几十年来在心脏病的临床诊断和治疗方面取得了进展，但心脏病的流行仍在上升

项目成果

Intravital Microscopy in Atherosclerosis Research.

• DOI: 10.1007/978-1-0716-1924-7_40
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)

The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by Nrf2-activated macrophages.

• DOI: 10.1126/sciimmunol.aaz1974
• 发表时间: 2020-09-25
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Calcagno DM;Ng RP Jr;Toomu A;Zhang C;Huang K;Aguirre AD;Weissleder R;Daniels LB;Fu Z;King KR
• 通讯作者: King KR

Optical Coherence Tomography of Plaque Vulnerability and Rupture: JACC Focus Seminar Part 1/3.

• DOI: 10.1016/j.jacc.2021.06.050
• 发表时间: 2021-09-21
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 影响因子: 24
• 作者: Aguirre, Aaron D.;Arbab-Zadeh, Armin;Soeda, Tsunenari;Fuster, Valentin;Jang, Ik-Kyung
• 通讯作者: Jang, Ik-Kyung