Functional Optimization of Cardiac Resynchronization Therapy in Heart Failure

描述（由申请人提供）：双心室起搏的心脏再同步化治疗（CRT）已经成为晚期心力衰竭（HF）患者的重要治疗进展。据估计，2007年北美共植入了150万台CRT设备，初始成本约为30亿至30亿美元，植入后的成本要高得多。然而，近30%的受试者被认为无反应或反应差。虽然这可能是由于患者选择的问题，但这也可能表明CRT装置的房室（AV）和室间（V-V）间隔的优化问题。目前CRT的选择标准仅限于LVEF <35%， QRS持续时间bb0 - 120ms，尽管优化了药物治疗，但仍有难治性NYHA III-IV级症状。然而，很明显，需要更多的个性化和基于生理的方法来提高反应率。低水平的体力活动通过增加代谢需求、改变全身静脉回流、对心脏负荷前后和心力衰竭的影响来挑战（压力）心脏，可能会增强心室的相互依赖性。肺与心脏串联在一起，共享一个共同的表面积，并且在血液动力学和神经力学上紧密相连，因此呼吸模式和气体交换的测量，特别是在轻度心脏负荷期间，提供了综合心肺功能的动态窗口。这一建议的前提是，低水平、无创心肺运动为确定哪些HF患者最有可能从CRT中获益以及个性化和优化CRT间隔设置提供了一种新的方法。这将通过两个具体目标来解决。目的1将测试和完善一种算法，该算法基于低强度运动期间获得的呼吸模式、气体交换和心率的非侵入性测量，预测HF患者对CRT设备治疗的反应性。Aim 2将测试基于无创心肺气体交换措施的类似算法的能力，以优化接受CRT装置治疗的HF患者相对于设置CRT间隔的标准方法的房室同步和心室激活。这种方法填补了这一不断发展的领域的重要需求，具有降低成本和个性化治疗方法的潜力。本提案旨在获得初步的探索性数据，以测试技术，并进一步开发气体交换算法/模型，以优化CRT的临床实践。

DESCRIPTION (provided by applicant): Cardiac resynchronization therapy (CRT) by bi-ventricular pacing has been an important treatment advance for patients with advanced heart failure (HF). It is estimated that there were >150,000 CRT devices implanted in North America in 2007 at an initial cost of ~1-3 billion dollars, with much higher post implantation costs. However, nearly 30% of subjects are considered non or poor responders. While this may be due to problems with patient selection, this may also suggest problems of optimization of atrioventricular (AV) and interventricular (V-V) intervals of the CRT devices. Current selection criteria for CRT are limited to LVEF <35%, QRS duration >120 ms, and refractory NYHA class III-IV symptoms despite optimized pharmacotherapy. However, it is clear that more individualized and physiologically based approaches are needed to improve response rates. Low level physical activity challenges (stresses) the heart through increased metabolic demands, altered systemic venous return, influences on cardiac pre and after load and in HF may enhance ventricular interdependence. The lungs lie in series with the heart, share a common surface area and are intimately linked hemodynamically as well as neuro-mechanically and thus measures of breathing pattern and gas exchange particularly during a mild cardiac load provide a dynamic window of integrated cardiopulmonary function. It is the premise of this proposal that low level, non-invasive cardiopulmonary exercise provides a novel approach for determining which HF patients may be most likely to benefit from CRT and individualizing and optimizing CRT interval settings. This will be addressed in two specific aims. Aim 1 will test and refine an algorithm based on non-invasive measures of breathing pattern, gas exchange and heart rate, obtained during low intensity exercise that predicts HF patient responsiveness to CRT device therapy. Aim 2 will test the ability of a similar algorithm, based on non-invasive cardiopulmonary gas exchange measures, to optimize atrial- ventricular synchrony and ventricular activation in HF patients receiving CRT device therapy relative to standard approaches for setting CRT intervals. This approach fills a significant need in this growing field, has the potential to reduce cost and individualize the approach to treatment. This proposal is designed to obtain initial exploratory data in order to test the techniques and further develop gas exchange algorithms/models to optimize the clinical practice of CRT. PUBLIC HEALTH RELEVANCE: The long term goal of our research program has been to understand the functional relationships between the cardiovascular and pulmonary systems, particularly as it relates to the heart failure population. This R21 application takes advantage of important cardio-pulmonary relationships and focuses on a novel approach to using non invasive pulmonary gas exchange measures obtained during slow treadmill walking to optimize atrioventricular (AV) and interventricular (V-V) intervals of cardiac resynchronization therapy (CRT) devices. This is important as CRT has become an important adjunct to medical therapy in the heart failure population, however, 25-30% of patients implanted have a poor or refractory response. This may be due to patient selection or current methods of setting device intervals. The premise of this proposal is that an algorithm of non invasive pulmonary gas exchange measures will not only help guide which patients would respond most positively to treatment, but will help to improve the response. This approach has the potential to improve patient health, simplify device optimization procedures, support an individualized approach to medicine and substantially impact CRT costs.