Mechanisms Underlying the Progression of Arterial Stiffness in Hypertension

高血压动脉僵硬进展的机制

基本信息

批准号：
8588345
负责人：
Carlos Alberto Figueroa
金额：
$ 38.61万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8588345
关键词：
Abdomen Affect Aging Ally Animals Aorta Arteries Attenuated Biochemical Biological Biomechanics Blood Vessels Brain Cardiovascular Diseases Cardiovascular Physiology Cause of Death Central Artery Chemicals Clinical Clinical Treatment Clinical assessments Collagen Collagen Fiber Complex Coupled Data Deposition Development Dilatation - action Disease Disease susceptibility Dissection Distal Doxycycline Early Diagnosis Elastic Fiber Elastin End stage renal failure Endothelium Equation Exhibits FBN1 Fatigue Fibrillar Collagen Functional disorder Gene Mutation Genetic Geometry Growth Heart Human Hypertension Individual Intervention Kidney Knockout Mice Liquid substance Longitudinal Studies Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measurable Measures Mechanics Methods Metric Microfibrils Modeling Molecular Motion Mus Muscle Muscle Tonus Myocardial Infarction NG-Nitroarginine Methyl Ester Nitric Oxide Organ Pathology Peptide Hydrolases Physiologic pulse Play Property Protein-Lysine 6-Oxidase Pulse Pressure Resistance Risk Assessment Risk Factors Role Rupture Smooth Muscle Solid Spatial Distribution Stretching Stroke Structure Study models System Testing Thick Time Validation Work arterial stiffness base cardiovascular risk factor computerized tools crosslink disability early onset effective intervention endothelial dysfunction fibulin genome wide association study hemodynamics improved indexing inhibitor/antagonist insight middle age mouse model novel pressure prevent public health relevance simulation tool treatment planning

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease remains the leading cause of death and disability in the USA and stiffening of central arteries is now an unquestioned independent risk factor for many such diseases, including heart attack, stroke, and end-stage renal disease. The six primary determinants of the structural stiffness of arteries are elastic fiber integrity, collagen organization, smooth muscle tone, wall thickness, axial pre-stretch, and perivascular support, each of which has a molecular and cellular basis and affects system-level hemodynamics. Easily measured clinical metrics, such as pulse wave velocity, can and must play an increasingly greater role in cardiovascular risk assessment, but we must understand much better the mechanical and biological basis for changes in such metrics. For example, the relation between pulse wave velocity and arterial stiffness is often justified based on the Moens-Korteweg equation, which ignores almost all of the key determinants of wall stiffness. Our approach is unique because we will be the first to combine genetically modified mouse models and pharmacological interventions to delineate directly the effects on the material stiffness of the wall due to the integrity of elastic fibers, organization of collagen fibers, and contractility of smooth muscle. Moreover, this information will be incorporated within a novel computational tool that will allow effects of axial prestretch, perivascular support, and most importantly spatially and temporally progressive changes in large artery wall composition on hemodynamic metrics to be rigorously assessed for the first time. In particular, we suggest that large artery stiffening likely progresses from proximal to distal large arteries and identification of the early onset of such changes (e.g., prior to marked changes in pulse wave velocity) may allow earlier diagnosis and thus more effective intervention, prior to the propagation of detrimental effects of large artery stiffening to distal muscular arteries and eventually the microvessels, changes to which may be more difficult to reverse pharmacologically. Hence, we seek to deepen our fundamental understanding of the basis of arterial stiffening and to enable better clinical assessments and treatment planning based on readily available data. Specifically, we hypothesize that central arteries stiffen due, in large part, to a cyclic-strain induced damage to or degradation of elastic fibers that likely progresses over time from proximal to distal arteries because of initial spatial distributions of elastin and associated wall strains. To test this hypothesis, we will quantify and compare for the first time progressive changes in wall mechanics, composition, and hemodynamics in 3 basic mouse models (wild-type, fibrillin-1 deficient, and fibulin-5 null), each subjected to 3 pharmacological inter- ventions (L-NAME, doxycycline, and BAPN). That is, we will use genetically modified mouse models of graded decreases in elastic fiber integrity, not initially diminished elastin, for this will allow progressive changes to be quantified independent of possible compensatory adaptations that occur during development in elastin deficient mice. We expect loss of nitric oxide (L-NAME group) to highlight a role of smooth muscle tone and exacerbate the progression of wall stiffening, diminished proteinase activity (doxycycline) to separate roles of mechanical damage and chemical degradation of elastin while attenuating wall stiffening, and inhibiting collagen cross-linking (BAPN) to separate the coupled effects of elastin on the stiffness of extant collagen from the role of new collagen deposition. The experimental data will be used to construct, verify, and validate a novel fluid-solid-interaction model that can reveal precisely the effects of individual determinants of wall stiffening on system-level hemodynamics. Once accomplished for the mouse, parametric studies will be performed on 3 prototypical models of hemodynamics in humans (young, middle-aged, and old) to reveal, for the first time, the effects of progressive wall stiffening on clinical metrics of hemodynamics such as pulse wave velocity, pulse pressure, and pulse pressure waveform. We submit that modeling studies alone can delineate effects of spatially and temporally progressive increases in arterial stiffening on system-level hemodynamics, with the potential to identify improved indicators of early stiffening that may allow an earlier clinical intervention that can prevent the longer-term irreversible changes to the microstructure that otherwise inevitably occur.