Purpose To use manganese-enhanced MRI (MEMRI) to detect changes in calcium

Purpose To use manganese-enhanced MRI (MEMRI) to detect changes in calcium handling associated with cardiac hypertrophy in a mouse model and to determine whether the impact of creatine kinase ablation is detectable using this method. was administered and the producing switch in R1 (=1/T1) was calculated. Two anatomical regions-of-interest (ROIs) were considered: the left-ventricular free wall (LVFW) and the septum and one ROI in a Mn-containing standard placed next to the mouse. Results We found statistically significant (p < 0.05) decreases in the uptake of Mn in both the LVFW and septum following induction of cardiac hypertrophy. No statistically significant decreases were detected in the standard and no statistically significant differences were found among the sham mice. Conclusion Using a murine model we successfully demonstrated that changes in manganese uptake due to cardiac hypertrophy are detectable using the functional contrast agent and calcium mimetic manganese. Our measurements showed a decrease in the relaxivity (R1) of the myocardium following cardiac hypertrophy compared to normal control mice. experimentation or clinical use. For HCM in particular there are a wide variety of mutations that lead to the hypertrophic phenotype (17) and it has been suggested that these mutations result in increased calcium sensitivity which then causes hypertrophy (13 15 This suggestion is based on evidence demonstrating increased calcium sensitivity in a number of studies of various sarcomere mutations as measured by the log of the calcium ion concentration needed to give 50% of maximal activation (ΔpCa50). It is not presently known whether the degree of calcium perturbation has any prognostic Faldaprevir value in predicting overall phenotype or in stratifying risk for heart failure arrhythmia or sudden cardiac death. Although advanced morphological changes due to hypertrophy can be Faldaprevir very easily detected using MRI and echocardiography early detection requires sensitivity to cellular changes in gene expression and calcium homeostasis which precede morphological changes. Regrettably these early cellular changes are undetectable using standard imaging techniques but can be exploited using new functional imaging techniques such as manganese-enhanced MRI (MEMRI) (18-22). In addition to force generation ion homeostasis requires significant energy expenditure by the cardiac myocyte due to regulating calcium at concentrations ranging from micro to millimolar levels across the cell and within a single heartbeat. In order to maintain the large calcium gradient across the sarcoplasmic reticulum (SR) membrane in the cardiac myocyte the SR Ca2+-ATPase requires 85-90% of ΔG from ATP (23) and requires sufficient myocardial metabolism. Myocardial energetics play a central role in maintaining normal cardiac function and when unable to maintain the PCr to ATP ratio needed to sustain Ca2+ homeostasis in excitation-contraction Faldaprevir coupling (E-C coupling) (24-28) heart failure results. Creatine kinase in an enzyme abundant in striated muscle which catalyzes the equilibrium reaction between adenosine triphosphate (ATP) and creatine (Cr) to ADP and phosphocreatine (PCr). Previous investigations on left- ventricular hypertrophy (LVH) and heart failure with CK-deficient mice have shown mixed results. Studies in which aortic banding was used to induce cardiac LVH have found that C57BL/6 mice do not have significant alterations in CK activity or total myocardial creatine concentrations (26). In contrast CK-Mito?/? and CK-M/Mito?/? mice on a C57BL/6-129/SV background have shown significant increases at baseline in Rabbit Polyclonal to CLEC6A. left ventricular mass and end-diastolic wall Faldaprevir thickness (29). It is possible that CK-deficiency causes alterations of the calcium handling proteins and the calcium transients could explain these cardiac complications. It has been recently shown that ablations or mutations of proteins of the sarcoplasmic reticulum (SR) can alter Ca2+ handling and ultimately cardiac hypertrophy in the murine heart (30-32). Manganese-enhanced MRI (MEMRI) uses the contrast agent and functional calcium analog manganese (Mn). Mn has an ionic radius similar to that of calcium and is handled similarly in many biological systems (33). Divalent manganese ions (Mn2+) can enter cells through voltage-gated calcium channels (33) and are known to do so by this mechanism. Like Ca2+ Mn2+ can become sequestered in mitochondria and secretory granules (34) and has been used as a tool to better understand Ca2+ pathways. Mn is also an excellent NMR.