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

摘要 主动脉僵硬度随着年龄的增长而明显增加，并与高血压、心力衰竭和加速性高血压有关。 大脑老化左心室（LV）和主动脉之间的异常血流动力学耦合有助于 靶器官损伤的发病机制。然而，LV也机械地耦合到并拉伸 收缩期的近端主动脉。与“主动脉弹簧”的拉伸相关的力是相当大的， 与LV压力产生所需的力相当。“机械耦合”加载LV，但也 在主动脉弹簧中储存能量，这有助于心脏底部在舒张期间的反冲， 产生有助于舒张早期充盈的吸力。主动脉硬化破坏了这种机械耦合 并在LV长轴上施加不对称负荷，损害整体纵向应变（GLS）， 舒张期充盈受损的机械耦合导致左心房（LA）扩大和功能障碍， 增加肺动脉（PA）压力和僵硬度，导致右心室（RV）-PA异常 血流动力学耦合，以及年龄相关的PA收缩压增加。PA的相关增加 脉压可能有助于肺内阻力血管的重塑，导致合并的前和 毛细血管后肺动脉高压由此产生的左、右心脏畸形的组合限制了 心输出量，并导致左心室射血分数正常的心力衰竭综合征（HFpEF）。在 年轻、健康的成年人，顺应性主动脉的低阻抗与正常僵硬的导管动脉交界， 从而产生阻抗失配和波反射， 进入微循环，导致左心和目标器官之间的最佳“血液动力学耦合”， 比如大脑。主动脉硬化增加主动脉阻抗，减少阻抗失配，并导致 有害脉动能量向微循环的传输增加，导致微血管 损伤、脑实质中淀粉样纤维的积累、过早的脑老化和认知障碍。 我们将在老年Frachial Offspring队列中使用眼压测量和超声心动图来测试 假设主动脉僵硬损害主动脉和LV之间的机械耦合，减少LV GLS， 损害LV舒张功能和LA功能。我们将评估RV结构和功能以及RV-PA偶联 用超声心动图检验左心房压力增加会增加右心房压力、僵硬度 和阻抗，损害RV-PA耦合，并有助于肺动脉年龄相关性增加 收缩压最后，我们将评估颈动脉输入阻抗和颈动脉-颈动脉耦合，以测试 假设主动脉与颈总动脉和脑血管相比不成比例增加 输入阻抗降低了阻抗梯度，并增加了脉动流对大脑的渗透 血液循环，导致微血管组织损伤，淀粉样蛋白积累和认知功能受损。

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.