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

描述（由申请人提供）：尽管在预防、检测和治疗方面有所改进，心血管疾病仍是美国的主要死亡原因。虽然心力衰竭的原因是多因素的，但越来越多的证据表明，心肌能量供应和需求的不匹配有助于左心室功能障碍的发展。心脏使用三磷酸腺苷（ATP）形式的化学能来支持收缩和舒张功能。肌酸激酶（CK）系统作为心脏的主要ATP储备，并立即为其收缩功能提供ATP。在人类和动物心肌的心力衰竭中都可以看到CK系统的变化，这表明ATP向能量消耗系统的输送受损。因此，我们可以合理地假设，开发新的无创定量方法来进行能量代谢的系列研究，对于增强我们对心力衰竭的发展和进展的理解尤其有价值。

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.