Endothelial Function in Mechanical Circulatory Support

Summary

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Description

The advances in LVAD engineering and design, tailored towards defined physiological goals, have resulted in the creation of much smaller CF pumps that possess technical superiority, pump durability, and ease of implantation compared to the older and larger PF pumps. The addition of artificial pulsat...

The advances in LVAD engineering and design, tailored towards defined physiological goals, have resulted in the creation of much smaller CF pumps that possess technical superiority, pump durability, and ease of implantation compared to the older and larger PF pumps. The addition of artificial pulsatility to the next generation centrifugal CF LVADs, has decreased the incidence of device related adverse events. However, given the recent nature of these advances, the physiologic impact has yet to be fully elucidated. LVADs in general have demonstrated good outcomes and are rapidly gaining traction towards becoming standard therapy for refractory end stage HF. The investigators are in a position to study this new technology and the impact of the resultant altered physiologic state. Our interest lies in the impact of continuous flow hemodynamics on endothelial function and the cardiac and end-organ responses to this novel therapy. Basal homeostatic properties of healthy endothelium are in part based on the effects of hemodynamic forces such as hydrostatic pressure, cyclic stretch, and fluid shear stress, which occur as a consequence of blood pressure and pulsatile blood flow in the vasculature. Under ambient conditions, these forces are generally atheroprotective and increase the expression of nitric oxide synthase (eNOS) to generate nitric oxide (NO), decrease reactive oxidative species (ROS) and oxidative stress, decrease expression of proinflammatory adhesion molecules, and maintain an antithrombotic surface. Increases in shear stress stimulate compensatory expansion of the vessels and thereby return shear forces to basal levels. Likewise, a decrease in shear stress can narrow the lumen of the vessel in an endothelium-dependent manner. In essence, the vessel remodels itself in response to long-term changes in flow, such that the luminal diameter is reshaped to maintain a constant predetermined level of shear stress. The capacity of the endothelium to sense shear stress is therefore an important determinant of luminal diameter and overall vessel structure. Failure to adapt to pathophysiological stimuli may lead to maladaptive responses that result in seemingly permanent alterations in endothelial phenotype and promote endothelial dysfunction. This phenomenon plays an integral role in several cardiovascular disease processes. Endothelial dysfunction (of both microvascular and conduit arteries) is a component of chronic heart failure and correlates with severity of disease. Improvement in cardiac function, whether via medical therapy or cardiac output augmentation, can improve endothelial function and benefit patients through better peripheral vascular reactivity. However, much of the improvement in endothelial function is thought to be related to the pulsatile laminar flow that occurs in majority of vascular beds. With the increasing use of CF pumps, it has become clear that the lack of pulsatility adversely affects the endothelium by decreasing vessel wall shear stress; reducing cyclic stretch that affects vascular cell proliferation; disrupting endothelium-dependent vasodilation; activating extrinsic pathway of thrombosis; and heightening vascular inflammation. The reintroduction of pulsatility through flow modulation control strategies could help mitigate these device specific issues and help promote endothelial recovery. Our knowledge of the impact of these specific advances in LVAD therapy is however limited by the relative youth of the field. Thus, the goal of this research project is to study human LVAD patients to determine the impact of artificial pulsatility in CF physiology on microvascular and endothelial function and its association with cardiac and peripheral organ function.

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