Cardiovascular reserve capacity in survivors of hematopoietic cell transplantation

摘要 目前在美国有200，000名造血细胞移植（HCT）幸存者， 到2030年将超过50万。尽管总生存率有所改善，但长期HCT存活者仍处于高水平。 慢性健康并发症的风险，如心血管疾病（CVD）。心血管并发症， 例如心肌梗塞和心肌病/心力衰竭，不仅在HCT幸存者中更常见， 但它们比一般人群更早发生;本质上，HCT与加速的 心血管老化然而，正如最近的NIH HCT迟效共识会议所强调的那样， 这个问题的生物学机制仍然未知。我们的总体假设是， 在HCT加速之前、期间或之后持续的连续器官系统和代谢损伤 心血管生理储备（心血管储备能力）耗竭，易早发 CVD。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 随着时间最大耗氧量（VO 2 peak），来自心肺运动测试，是黄金 心血管储备能力的标准衡量标准，因为它代表了与 多个器官系统输送并使用氧气进行ATP再合成。采用纵向研究设计， 我们将在基线（HCT前）、HCT后6个月、1年和2年评估VO 2峰值，使我们能够 确定其随时间的轨迹我们还将确定VO 2峰值对自我报告的身体状况的影响。 功能，并确定HCT后VO 2峰值加速下降的高风险人群（目标1）。重要的是， 我们将使用新的诊断策略来确定VO 2峰值及其损伤的器官特异性决定因素 HCT后（目标2）。在我们的研究结束时，我们将：1）在接受治疗的患者中建立初始VO 2峰值， HCT并表征其随时间推移的HCT后轨迹，确定HCT后下降风险最高的患者。 HCT; 2）告知亚临床CVD的筛查，使用易于应用于临床的策略， 设置;和3）确定的机制，通过该机制，器官特异性损伤，单独和组合， 导致HCT后VO 2峰值异常。这项建议建立在我们以前成功的研究基础上， 将解决HCT幸存者心血管并发症的重要知识差距。信息 从该提案中获得的信息将支持制定基于证据的干预措施，以降低 HCT后CVD。长期HCT存活者的不断增长使得预防的发展 因此，我们必须采取必要的战略，以确保这些幸存者在完成HCT后能够健康长寿。

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.