Functional Optimization of Cardiac Resynchronization Therapy in Heart Failure

描述(申请人提供)：双室起搏心脏再同步治疗(CRT)已成为晚期心力衰竭(HF)患者的重要治疗进展。据估计，2007年北美共植入了15万台CRT设备，初始成本约为10-30亿美元，植入后的成本要高得多。然而，近30%的受试者被认为是无反应或反应差的。虽然这可能是由于患者选择的问题，但这也可能表明CRT设备的房室(AV)和室间(V-V)间期的优化问题。目前CRT的选择标准仅限于LVEF&lt；35%，QRS持续时间&gt；120ms，以及难治性NYHA III-IV级症状，尽管优化了药物治疗。然而，很明显，需要更个性化和基于生理的方法来提高应答率。低水平的体力活动通过增加代谢需求、改变全身静脉回流、对心脏前后负荷的影响以及在心衰时对心脏的影响来挑战(应激)心脏，可能会增强心脏的相互依赖性。肺与心脏串联在一起，共享一个共同的表面积，并在血液动力学和神经机械上紧密相连，因此呼吸模式和气体交换的测量，特别是在轻微的心脏负荷期间，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、无创的心肺运动为确定哪些心衰患者最有可能受益于CRT以及个性化和优化CRT间期设置提供了一种新的方法。这将在两个具体目标中得到解决。目标1将测试和改进一种算法，该算法基于在低强度运动中获得的呼吸模式、气体交换和心率的非侵入性测量，预测心力衰竭患者对CRT设备治疗的反应。目的2将测试基于非侵入性心肺气体交换措施的类似算法相对于设置CRT间期的标准方法来优化接受CRT设备治疗的心衰患者的房室同步性和心室激活的能力。这种方法满足了这一不断增长的领域的重大需求，具有降低成本和个性化治疗方法的潜力。这项建议旨在获得初步的探索性数据，以便测试这些技术，并进一步开发气体交换算法/模型，以优化CRT的临床实践。 公共卫生相关性：我们研究计划的长期目标一直是了解心血管和肺系统之间的功能关系，特别是当它与心力衰竭人群有关时。这项R21应用利用了重要的心肺关系，并专注于一种新的方法，利用慢速跑步机行走时获得的非侵入性肺气体交换措施来优化心脏再同步治疗(CRT)设备的房室(AV)和室间(V-V)间期。这一点很重要，因为CRT已经成为心力衰竭人群药物治疗的重要辅助手段，然而，25%-30%的植入患者的反应较差或难治。这可能是由于患者选择或当前设置设备间隔的方法所致。这一建议的前提是，无创肺气体交换措施的算法不仅有助于指导哪些患者对治疗反应最积极，而且有助于提高反应。这种方法有可能改善患者的健康，简化设备优化程序，支持个性化的药物治疗方法，并显著影响CRT成本。

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.