Mechanisms of Phenotypic Variance in Cardiovascular Responses to Exercise

当人们进行有氧运动等身体活动时，心血管系统会将氧气输送与肌肉的氧气需求相匹配。这是可持续能源生产的基石，最终决定了我们的表现和容忍运动的能力。肌肉接受的血液量取决于心脏的血液输出量和活动肌肉中血管扩张的程度。我最近的工作已经证明了血管和心脏对运动的反应存在着深刻的个体间表型差异。这种表型变异性会影响运动表现，因为氧气输送与肌肉氧气需求的匹配程度不同，但表型变异性往往被传统的组水平平均数据实验设计所掩盖。我的研究计划利用了一种新的实验方法，专注于独特的表型反应，以探索个人如何在运动过程中将氧气输送与氧气需求相匹配。我的研究计划的长期目标是确定和了解个体间表型心血管反应如何影响体力消耗期间氧气输送与氧气需求相匹配的能力。在目前的建议中，我试图：1）确定红细胞去饱和对运动期间血管扩张的个体间差异的贡献; 2）确定左心室结构和功能对运动期间心脏输出的个体间差异的贡献程度;以及3）探索统计模型的应用，以识别预测个体对运动的急性心血管反应的潜在独特表型特征。对于研究界来说，这项研究计划将首次尝试识别和揭示解释血管和心脏如何对运动做出反应的个体间表型变异性的机制，并将促进我们对如何以及为什么个体化策略和结果存在的理解当检查急性反应和慢性适应运动时。这些信息可能代表了理解心血管控制、个体运动能力和对运动训练的反应性以及对劳力不耐受的脆弱性的关键缺失环节。这一基本机制研究的结果可以用来确定个性化的氧气输送途径，这不仅可以在人类表现和运动训练中有巨大的应用，而且可以为有针对性的、个性化的或“精确”干预的策略提供信息，类似于个性化医疗的新兴领域。一个关键的结果将是提高运动耐受性，这是一个已知的限制性能和康复谱。拟议的研究将提供开始利用这些信息改善加拿大人生活所需的基础知识。

When people perform physical activity like aerobic exercise, the cardiovascular system matches oxygen delivery to the muscle's oxygen demand. This is the corner stone of sustainable energy production and in the end, governs our capacity to perform and tolerate exercise. The amount of blood the muscle receives depends on the output of blood from the heart and the degree of blood vessel dilation in the active muscle. My recent work has demonstrated profound inter-individual phenotypic differences in how the blood vessels and heart respond to exercise. This phenotypic variability impacts exercise performance due to differences in how well oxygen delivery is matched to the muscle's oxygen demand, yet phenotypic variability is often masked by traditional experimental design of group-level mean data. My research program utilizes a novel experimental approach focusing on unique phenotypic responses in order to explore how well individuals match oxygen delivery to oxygen demand during exercise. The long-term objective of my research program is to identify and understand how inter-individual phenotypic cardiovascular responses impact the ability to match oxygen delivery to oxygen demand during physical exertion. In the present proposal, I am seeking to: 1) Determine the contribution of red blood cell desaturation to inter-individual differences in how our blood vessels dilate during exercise; 2) Determine the extent to which left ventricular structure and function contribute to inter-individual differences in output from the heart during exercise; and 3) Explore the application of statistical models to identify potential unique phenotypic signatures that predict an individual's acute cardiovascular response to exercise. For the research community, this research program will, for the first time, attempt to identify and unmask the mechanisms explaining inter-individual phenotypic variability in how the blood vessels and heart respond to exercise and will advance our understanding about how and why individualized strategies and outcomes exist when examining acute responses and chronic adaptations to exercise. This information may represent a critical missing link in understanding cardiovascular control, the individual capacity for exercise performance and the responsiveness to exercise training, and the vulnerability to exertional intolerance. The findings from this basic mechanistic research may be leveraged to identify personalized oxygen delivery pathways, which can have a tremendous application in not only human performance and exercise training, but can inform strategies of targeted, personalized or `precision' interventions, similar to the emerging field of personalized medicine. A key outcome would be to improve exertional tolerance, a known limitation across performance and rehabilitation spectrums. The proposed research will provide the foundational knowledge required to begin utilizing this information to improve the lives of Canadians.