Ventricular-vascular coupling in the elderly: lifecourse determinants, trajectories and prognostic significance

老年人的心室-血管耦合：生命历程的决定因素、轨迹和预后意义

• 批准号: 10202703
• 负责人: Susan Cheng
• 金额: $ 78.17万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202703
• 关键词: Activities of Daily Living; Adult; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Aorta; Arteries; Blood Vessels; Blood capillaries; Brain; Brain Injuries; Cardiac; Cardiac Output; Cardiovascular system; Carotid Arteries; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Coupled; Coupling; Data Collection; Dementia; Deposition; Development; Diastole; EFRAC; Echocardiography; Elderly; Endothelium; Evolution; Frequencies; Functional disorder; Funding; Generations; Heart; Heart Abnormalities; Heart Atrium; Heart Diseases; Heart failure; Homeostasis; Hypertension; Hypertrophy; Impaired cognition; Impairment; Left; Left Atrial Function; Left Ventricular Remodeling; Left atrial structure; Left ventricular structure; Lung; Lung diseases; Lymphatic; Magnetic Resonance Imaging; Measures; Mechanics; Mediating; Memory; Memory impairment; Microcirculation; Minority; Modification; Organ; Orthostasis; Participant; Pathogenesis; Penetration; Positron-Emission Tomography; Pulmonary Hypertension; Pulmonary artery structure; Pulsatile Flow; Pulse Pressure; Pump; Research; Resistance; Rest; Right Ventricular Function; Right ventricular structure; Risk; Sex Differences; Side; Stretching; Stroke; Structure; Suction; Syndrome; Systole; Systolic Pressure; Testing; Tissues; Ultrasonography; Vascular Cognitive Impairment; Ventricular; Woman; Women' s Health; age related; aging brain; arterial stiffness; arterial tonometry; base; brain parenchyma; cerebral microvasculature; cerebrovascular; cognitive function; cohort; comparative; electric impedance; follow-up; glymphatic system; hemodynamics; middle age; multidisciplinary; neurovascular coupling; offspring; premature; preservation; pressure; prevent; prognostic significance; prospective; proteostasis; response; sex; stressor; tau Proteins; tonometry; transmission process; vascular cognitive impairment and dementia

Abstract Aortic stiffness increases markedly with age and is associated with hypertension, heart failure and accelerated brain aging. Abnormal hemodynamic coupling between left ventricle (LV) and aorta contributes to pathogenesis of target organ damage. However, the LV is also mechanically coupled to and stretches the proximal aorta during systole. The force associated with stretch of the `aortic spring' is considerable, comparable to the force required for LV pressure generation. `Mechanical coupling' loads the LV but also stores energy in the aortic spring, which contributes to the recoil of the base of the heart during diastole, producing the suction that facilitates early diastolic filling. Aortic stiffening disrupts this mechanical coupling and imposes an asymmetric load on the LV long axis that impairs global longitudinal strain (GLS) and early diastolic filling. Impaired mechanical coupling contributes to left atrial (LA) enlargement and dysfunction, which increases pulmonary artery (PA) pressure and stiffness, leading to abnormal right ventricular (RV)-PA hemodynamic coupling, and an age-related increase in PA systolic pressure. An associated increase in PA pulse pressure could contribute to remodeling of resistance vessels in the lung, leading to combined pre- and post-capillary pulmonary hypertension. The resulting combination of right and left heart abnormalities limits cardiac output and contributes to the syndrome of heart failure with preserved LV ejection fraction (HFpEF). In young, healthy adults, the low impedance of a compliant aorta interfaces with normally stiff conduit arteries, creating impedance mismatch and wave reflection that limits the transmission of excessive pulsatile energy into the microcirculation, resulting in optimal `hemodynamic coupling' between the left heart and target organs, such as the brain. Aortic stiffening increases aortic impedance, reduces impedance mismatch, and results in an increased transmission of harmful pulsatile energy into the microcirculation, resulting in microvascular damage, accumulation of amyloid fibrils in brain parenchyma, premature brain aging and cognitive impairment. We will use tonometry and echocardiography in the elderly Framingham Offspring cohort to test the hypothesis that aortic stiffness impairs mechanical coupling between the aorta and LV, reduces LV GLS and impairs LV diastolic function and LA function. We will assess RV structure and function and RV-PA coupling with echocardiography to test the hypothesis that an increase in LA pressure increases PA pressure, stiffness and impedance, impairs RV-PA coupling and contributes to the age-related increase in pulmonary artery systolic pressure. Finally, we will assess carotid input impedance and aorta-carotid coupling to test the hypothesis that a disproportionate increase in aortic as compared to common carotid and cerebrovascular input impedances reduces the impedance gradient and increases penetration of pulsatile flow into the cerebral circulation, resulting in microvascular tissue damage, accumulation of amyloid and impaired cognitive function.

摘要 随着年龄的增长，主动脉僵硬显著增加，并与高血压、心力衰竭和加速有关。 大脑老化。左心室(LV)和主动脉之间的血流动力学耦合异常有助于 靶器官损害的发病机制。然而，LV也机械地耦合到并拉伸 收缩时的近端大动脉。与伸展“主动脉弹簧”相关的力是相当大的， 与LV压力产生所需的力相当。‘机械联轴器’不仅装载LV，而且 在主动脉弹簧中储存能量，这有助于在舒张期心脏底部的回缩， 产生有利于早期舒张期充盈的吸力。主动脉硬化破坏了这种机械连接。 并在LV长轴上施加不对称载荷，从而损害全局纵向应变(GLS)和早期 舒张期充盈。机械耦合受损可导致左房增大和功能障碍。 肺动脉(PA)压力和僵硬增加，导致右室(RV)-PA异常 血流动力学耦合，以及与年龄相关的PA收缩压升高。PA的相关增加 脉压可促进肺中阻力血管的重塑，导致前和后两者的合并 毛细血管后肺动脉高压。由此产生的右心和左心异常限制的组合 心输出量并导致左心室射血分数保留的心力衰竭综合征(HFpEF)。在……里面 年轻、健康的成年人，顺从的主动脉的低阻抗与通常僵硬的导管动脉相接， 造成阻抗失配和波反射，限制了过多脉动能量的传输 进入微循环，在左心和靶器官之间产生最佳的“血流动力学耦合”， 比如大脑。主动脉硬化增加了主动脉阻抗，减少了阻抗失配，并导致 有害的脉动能量进入微循环的增加，导致微血管 损伤，脑实质中淀粉样纤维的堆积，大脑过早衰老和认知障碍。 我们将使用眼压测量和超声心动图在老年Framingham后代队列中测试 假设主动脉僵硬损害了主动脉和左心室之间的机械耦合，降低了左心室GLS和 损害左室舒张功能和左房功能。我们将评估RV的结构和功能以及RV-PA偶联 用超声心动图来验证这样的假设，即左房压力的增加会增加右房的压力，僵硬 和阻抗，损害RV-PA偶联，并有助于年龄相关性的肺动脉增加 收缩压。最后，我们将评估颈动脉输入阻抗和主动脉-颈动脉耦合以测试 假设与颈总动脉和脑血管相比，主动脉不成比例的增加 输入阻抗降低了阻抗梯度，增加了脉动血流进入大脑的渗透率 循环，导致微血管组织损伤，淀粉样蛋白积聚和认知功能受损。