In vivo Studies of Creatine Kinase Kinetics by 31P Magnetization Transfer MRS

描述(申请人提供)：心血管疾病是美国的主要死亡原因，尽管在预防、检测和治疗方面有所改进。虽然心力衰竭的原因是多因素的，但越来越多的证据表明，心肌能量供需不匹配导致左心功能不全的发展。心脏使用三磷酸腺苷(ATP)形式的化学能量来支持收缩和舒张期功能。肌酸激酶(CK)系统作为心脏的主要ATP储备，为心脏的收缩功能瞬间提供ATP。CK系统的变化在人类和动物心肌的心力衰竭中都可以看到，这表明ATP向能量消耗系统的输送受损。因此，发展新的非侵入性定量方法用于能量代谢的系列研究对于加深我们对心力衰竭的发生发展的理解是合乎逻辑的。 磁化转移磷-31磁共振波谱(MRS)是一种理想的 测量活体组织中高能磷酸盐代谢的动力学，并已用于 在离体心准备和开胸动物实验中。体内CK通量的检测方法 由于这项技术的敏感性和复杂性，心脏测量一直滞后。 主要问题是检查时间长和骨骼的信号污染 胸壁的肌肉，呼吸运动会进一步加剧这种情况。一种新的测量方法 在体内CK通量，克服了检测时间长的问题。再加上 一种利用非均匀信息消除胸肌信号污染的新方法 磁场梯度表面破坏将导致临床上有用的磁共振成像技术的定量 在活体心肌CK流量，从而提供准确的评估能量代谢产物在 心。 最初的技术开发将集中在小动物实验上，结果将是 对比开胸实验，评价该技术的准确性。人血清白蛋白在体内的敏感性 这项技术将使用糖尿病大鼠心脏模型建立，在该模型中，CK流量预计将在 射程很大。这将与CK同工酶的生化测定结果相关联。这个 研究项目将以临床应用技术的开发和可行性测试结束 研究。 公共卫生相关性(由申请者提供)：肥胖、糖尿病和相关并发症，特别是心血管疾病，对个人和整个美国经济都是一个巨大的负担。开发新的和改进的技术来了解体内新陈代谢和产生新的知识将对了解、诊断、治疗和管理这些并发症至关重要。拟议的项目旨在开发新的方法来测量和了解心血管疾病中的能量紊乱，所开发的技术将对推进基础研究和医疗保健至关重要。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death in the U.S. despite improvements in prevention, detection, and treatment. Although the cause of heart failure is multi-factorial, there is increasing evidence that a mismatch in myocardial energy supply and demand contributes to the development of left ventricular dysfunction. Heart uses chemical energy in the form of adenosine triphosphate (ATP) to support systolic and diastolic function. The creatine kinase (CK) system acts as the primary ATP reserve for the heart and instantaneously supplies ATP for its contractile function. Changes in the CK system are seen in heart failure in both the human and animal myocardium indicative of impaired delivery of ATP to energy consuming systems. Therefore it is logical to hypothesize that the development of new noninvasive quantitative methods for serial studies of energy metabolism would be especially valuable for enhancing our understanding of the development and progression of heart failure. Magnetization transfer phosphorous-31 magnetic resonance spectroscopy (MRS) is an ideal tool to measure the kinetics of high energy phosphate metabolism in living tissue, and has been used for such in isolated heart preparations and open chest animal experiments. Methods for in vivo CK flux measurements in hearts have been lagging because of the sensitivity and complexity of the technique. The major problems arise from long examination time and signal contamination from the skeletal muscles in chest wall, which is further exacerbated by respiratory motion. A new approach to measure in vivo CK flux, overcoming the issues of lengthy examination time will be developed. Coupled with novel approach to eliminate signal contamination from the chest muscles using inhomogeneous magnetic field gradient surface spoiling will lead to clinically useful MRS technique to quantify myocardial CK flux in vivo and, thus provide accurate evaluation of energy metabolite turnover in the heart. The initial technique development will focus on small animal experiments and the results will be compared to open chest experiments to evaluate the accuracy of the technique. In vivo sensitivity of the technique will be established using a diabetic rat heart model where CK flux is expected to vary over a large range. Correlations will be obtained with the biochemical measurements of CK isoenzyme. The research project will conclude with the development and feasibility testing of the technique for clinical research. PUBLIC HEALTH RELEVANCE (provided by applicant): Obesity, diabetes and related complications especially cardiovascular disease are a huge burden on individuals in particular and US economy in general. Development of new and improved techniques to understand in vivo metabolism and generate new knowledge will be of paramount importance to understand, diagnose, treat and manage these complications. The proposed project aims to develop new methodology to measure and understand energy disorders in cardiovascular disease and the techniques developed will be critically useful to advance basic research and medical care.