This work shows that MR systems with a vertical bore design can be used to accurately measure cardiac function in both normal and chronically failing mouse hearts within one hour. The increased signal-to-noise ratio (SNR) due to the higher field strength could be exploited to obtain higher temporal and spatial resolution compared to previous studies that were performed on horizontal systems with lower field strengths.

Background-The neuronal isoform of nitric oxide synthase (nNOS) has been implicated in the regulation of basal and ␤-adrenergic inotropy in normal and chronically infarcted hearts. Furthermore, myocardial nNOS expression and activity increase in failing hearts, raising the possibility that nNOS may influence left ventricular (LV) remodeling progression and functional deterioration after myocardial infarction (MI) Methods and Results-We compared LV remodeling at 1, 4, and 8 weeks after MI in nNOS-knockout mice (nNOS -/-) and their wild-type (WT) littermates matched for infarct size by using a highly accurate 3-dimensional echocardiographic technique. Basal LV hemodynamics and the inotropic response to dobutamine infusion (4 and 16 ng · g Ϫ1 · min Ϫ1 ) were also evaluated 8 weeks after MI. Sham-operated nNOS -/-mice showed enhanced basal LV contractility (PϽ0.03 versus WT, as evaluated by preload-recruitable stroke work) but an attenuated inotropic response to dobutamine infusion (PϽ0.01 versus WT). Both basal and ␤-adrenergic LV relaxations were significantly impaired in nNOS -/-mice. Survival after MI did not differ between groups. However, nNOS -/-mice developed a faster and more severe LV dilation compared with WT mice (PϽ0.05 for both end-systolic and end-diastolic volume indices). WT mice maintained a positive inotropic response to dobutamine 8 weeks after MI. In contrast, infarcted nNOS -/-mice responded to dobutamine with a dramatic fall in LV contractility (PϽ0.01 for preload-recruitable stroke work). Conclusions-nNOS plays a crucial role in preventing adverse LV remodeling and maintaining myocardial ␤-adrenergic reserve after MI. Taken together, our findings suggest that upregulation of myocardial nNOS in infarcted hearts may be an important adaptive mechanism. (Circulation. 2005;112:3729-3737.)

Background-Insufficient techniques exist for rapid and reliable phenotype characterization of genetically manipulated mouse models of cardiac dysfunction. We developed a new, robust, 3-dimensional echocardiography (3D-echo) technique and hypothesized that this 3D-echo technique is as accurate as magnetic resonance imaging (MRI) and histology for assessment of left ventricular (LV) volume, ejection fraction, mass, and infarct size in normal and chronically infarcted mice. Methods and Results-Using a high-frequency, 7/15-MHz, linear-array ultrasound transducer, we acquired ECG and respiratory-gated, 500-m consecutive short-axis slices of the murine heart within 4 minutes. The short-axis movies were reassembled off-line in a 3D matrix by using the measured platform locations to position each slice in 3D. Epicardial and endocardial heart contours were manually traced, and a B-spline surface was fitted to the delineated image curves to reconstruct the heart volumes.

Background-Heart failure is associated with deranged cardiac energy metabolism, including reductions of creatine and phosphocreatine. Interventions that increase myocardial high-energy phosphate stores have been proposed as a strategy for treatment of heart failure. Previously, it has not been possible to increase myocardial creatine and phosphocreatine concentrations to supranormal levels because they are subject to tight regulation by the sarcolemmal creatine transporter (CrT). Methods and Results-We therefore created 2 transgenic mouse lines overexpressing the myocardial creatine transporter (CrT-OE). Compared with wild-type (WT) littermate controls, total creatine (by high-performance liquid chromatography) was increased in CrT-OE hearts (66Ϯ6 nmol/mg protein in WT versus 133Ϯ52 nmol/mg protein in CrT-OE). Phosphocreatine levels (by 31 P magnetic resonance spectroscopy) were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed left ventricular (LV) dilatation (LV end-diastolic volume: 21.5Ϯ4.3 L in WT versus 33.1Ϯ9.6 L in CrT-OE; Pϭ0.002), substantial LV dysfunction (ejection fraction: 64Ϯ9% in WT versus 49Ϯ13% in CrT-OE; range, 22% to 70%; Pϭ0.003), and LV hypertrophy (by 3-dimensional echocardiography and magnetic resonance imaging). Myocardial creatine content correlated closely with LV end-diastolic volume (rϭ0.51, Pϭ0.02), ejection fraction (rϭϪ0.74, Pϭ0.0002), LV weight (rϭ0.59, Pϭ0.006), LV end-diastolic pressure (rϭ0.52, Pϭ0.02), and dP/dt max (rϭϪ0.69, Pϭ0.0008). Despite increased creatine and phosphocreatine levels, CrT-OE hearts showed energetic impairment, with increased free ADP concentrations and reduced free-energy change levels. Conclusions-Overexpression of the CrT leads to supranormal levels of myocardial creatine and phosphocreatine, but the heart is incapable of keeping the augmented creatine pool adequately phosphorylated, resulting in increased free ADP levels, LV hypertrophy, and dysfunction. Our data demonstrate that a disturbance of the CrT-mediated tight regulation of cardiac energy metabolism has deleterious functional consequences. These findings caution against the uncritical use of creatine as a therapeutic agent in heart disease. (Circulation. 2005;112:3131-3139.)