Cardiovascular reserve capacity in survivors of hematopoietic cell transplantation

摘要 目前，美国有20万名造血细胞移植(HCT)幸存者，这个数字 到2030年将超过50万。尽管总体存活率有所改善，但长期存活的HCT患者仍处于高位 心血管疾病(CVD)等慢性健康并发症风险。心血管并发症， 例如心肌梗死和心肌病/心力衰竭，不仅在HCT幸存者中更为常见， 但它们比一般人群发生得更早；从本质上说，Hct与加速 心血管老化。然而，正如最近的NIH HCT后效共识会议所强调的那样， 这个问题背后的生物学机制仍不清楚。我们的总体假设是 在HCT加速之前、期间或之后持续的顺序器官系统和代谢损害 心血管生理储备(心血管储备能力)耗尽，易早发 心血管疾病。为了验证这一假设，我们将测量一组HCT幸存者的心血管储备能力 随着时间的推移。根据心肺运动试验得出的最大耗氧量(VO2峰值)是最好的 心血管储备能力的标准衡量标准，因为它代表了 哪些多器官系统提供和使用氧气用于ATP的重新合成。采用纵向研究设计， 我们将在基线(HCT前)、HCT后6个月、一年和两年评估VO2峰值，使我们能够 确定其随时间变化的轨迹。我们还将确定VO2峰值对自我报告的身体状况的影响 并确定HCT后VO2峰值加速下降的高危人群(目标1)。重要的是 我们将使用新的诊断策略来确定VO2峰值及其损害的有机特定决定因素 在Hct之后(目标2)。到我们的研究结束时，我们将有：1)建立患者的初始VO2峰值 HCT，并表征其HCT后随时间的轨迹，确定患者在以下情况下下降的风险最高 HCT；2)使用临床上容易应用的策略，为亚临床心血管疾病的筛查提供了信息 环境；以及3)确定了器官特异性损伤单独和联合使用的机制， 可能是HCT后VO2峰异常的原因。这项建议建立在我们之前成功的研究和 将解决关于HCT幸存者心血管并发症的重要知识空白。信息 从这项提案中获得的信息将支持循证干预措施的发展，以降低 HCT后CVD。不断增长的长期血细胞移植幸存者人口使预防工作取得了进展 战略势在必行，以确保这些幸存者在完成HCT后过上健康长寿的生活。

Abstract There are currently 200,000 hematopoietic cell transplantation (HCT) survivors in the U.S today, a number that will exceed 500,000 by 2030. Despite improvements in overall survival, long-term HCT survivors remain at high risk for chronic health complications such as cardiovascular disease (CVD). Cardiovascular complications, such as myocardial infarction and cardiomyopathy/heart failure, are not only more common in HCT survivors, but they occur earlier than in the general population; in essence, HCT is associated with accelerated cardiovascular aging. However, as highlighted by the recent NIH HCT Late Effects Consensus Conference, the biological mechanisms underlying this problem remain unknown. Our overall hypothesis is that multiple sequential organ system and metabolic impairments sustained prior to, during, or after HCT accelerates depletion of cardiovascular physiologic reserves (cardiovascular reserve capacity), predisposing to early onset CVD. To test this hypothesis, we will measure cardiovascular reserve capacity in a group of HCT survivors over time. Peak oxygen consumption (VO2peak), as derived from cardiopulmonary exercise testing, is the gold standard measure of cardiovascular reserve capacity, because it represents the integrative efficiency with which multiple organ systems deliver and use oxygen for ATP resynthesis. Using a longitudinal study design, we will evaluate VO2peak at baseline (prior to HCT), 6 months, one year and two years post-HCT, allowing us to determine its trajectory over time. We will also determine the impact VO2peak on self-reported physical functioning, and identify populations at high risk for accelerated VO2peak decline after HCT (Aim 1). Importantly, we will use novel diagnostic strategies to define the organic-specific determinants of VO2peak and its impairment after HCT (Aim 2). By the end of our study, we will have: 1) established initial VO2peak in patients undergoing HCT and characterized its post-HCT trajectory over time, identifying patients at highest risk for decline after HCT; 2) informed the screening for subclinical CVD, using strategies that are readily applicable in the clinical setting; and 3) identified mechanisms by which organ-specific impairments, alone and in combination, contribute to abnormalities in VO2peak after HCT. This proposal builds on our previous successful research and will address important knowledge gaps about cardiovascular complications in HCT survivors. Information obtained from this proposal will support development of evidence-based interventions to decrease the risk of CVD after HCT. The growing population of long-term HCT survivors makes development of prevention strategies imperative, to ensure that these survivors live long and healthy lives well after completion of HCT.