Myocardial infarct size measurement in the mouse chronic infarction model: comparison of area-and length-based approaches. J Appl Physiol 102: 2104 -2111, 2007. First published March 8, 2007; doi:10.1152/japplphysiol.00033.2007.-Efficacy of potential treatments for myocardial infarction (MI) is commonly assessed by histological measurement of infarct size in rodent models. In experiments involving an acute MI setting, measurement of the infarcted area in tissue sections of the left ventricle is a standard approach to determine infarct size. This approach has also been used in the chronic infarct setting to measure infarct area several weeks post-MI. We tested the hypothesis that, because wall thinning is known to occur in the chronic setting, the area measurement approach would be less appropriate. We compared infarct measurements in tissue sections based on 1) infarct area, 2) epicardial and endocardial infarct arc lengths, and 3) midline infarct arc length. Infarct sizes from all three measurement approaches correlated significantly with left ventricular ejection fraction and wall motion abnormality. However, the infarct size values derived from the area measurement approach were significantly smaller than those from the other two measurement approaches, and the range of values obtained was compressed 0.4-fold. The midline method allowed detection of the expected size differences between infarcts of variable severity resulting from proximal vs. distal ligation of the coronary artery. Segmental infarct size was correlated with segmental wall motion abnormality. We conclude that both area-and length-based measurements can be used to determine relative infarct size over a wide range of severity, although the area-based measurements are substantially more compressed due to wall thinning, and that the estimation of infarct midlines is a simple, reliable approach to infarct size assessment. cardiac remodeling; area-based measurement; length-based measurement; histology RODENT MODELS OF MYOCARDIAL infarction (MI) have been frequently used to elucidate the pathophysiological and molecular mechanisms of cardiac remodeling after the onset of MI (5,7,18,19,23,24). In recent years, the delivery of potentially therapeutic genes and the implantation of stem cells have attracted much interest and have been evaluated with the use of rat or mouse MI models (2,4,9,12,14,21,22). In many published studies exploring these potential therapies, success has commonly been evaluated by determination of infarct size, as well as by functional and other histological parameters. In experiments involving an acute MI setting, infarct size is typically based on histological measurement of the area of the infarcted region in tissue sections of the left ventricle (LV) (13,16,20,26). In contrast, histological measurement of the arc length of the infarct scar has been commonly used in a chronic MI setting (8,14,18,19). Although it is well known that there is progressive thinning of the infarcted wall with reduction in the volume of the infarcted...

We compared therapeutic benefits of intramyocardial injection of unfractionated bone marrow cells (BMCs) versus BMC extract as treatments for myocardial infarction (MI), using closed-chest ultrasound-guided injection at a clinically relevant time post-MI. MI was induced in mice and the animals treated at day 3 with either: (i) BMCs from green fluorescent protein (GFP)-expressing mice (n = 14), (ii) BMC extract (n = 14), or (iii) saline control (n = 14). Six animals per group were used for histology at day 6 and the rest followed to day 28 for functional analysis. Ejection fraction was similarly improved in the BMC and extract groups versus control (40.6 +/- 3.4 and 39.1 +/- 2.9% versus 33.2 +/- 5.0%, P < 0.05) with smaller scar sizes. At day 6 but not day 28, both therapies led to significantly higher capillary area and number of arterioles versus control. At day 6, BMCs increased the number of cycling cardiomyocytes (CMs) versus control whereas extract therapy resulted in significant reduction in the number of apoptotic CMs at the border zone (BZ) versus control. Intracellular components within BMCs can enhance vascularity, reduce infarct size, improve cardiac function, and influence CM apoptosis and cycling early after therapy following MI. Intact cells are not necessary and death of implanted cells may be a major component of the benefit.

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Delivery of bone marrow cells (BMCs) to the heart has substantially improved cardiac function in most rodent models of myocardial infarction (MI), but clinical trials of BMC therapy have led to only modest improvements. Rodent models typically involve intra-myocardial injection of BMCs from distinct donor individuals that are healthy, unlike autologous BMCs used for clinical trials that are from post-MI individuals. Using BMCs from post-MI donor mice, we discovered that recent MI impaired BMC therapeutic efficacy. MI led to myocardial inflammation and an increased inflammatory state in the bone marrow, changing the BMC composition and reducing their efficacy. Injection of a general anti-inflammatory drug or a specific interleukin-1 inhibitor to post-MI donor mice prevented this impairment. Our findings offer an explanation of why human trials have not matched the success of rodent experiments, and suggest potential strategies to improve the success of clinical autologous BMC therapy.

. Validation of the wall motion score and myocardial performance indexes as novel techniques to assess cardiac function in mice after myocardial infarction. Am J Physiol Heart Circ Physiol 292: H1187-H1192, 2007. First published October 20, 2006; doi:10.1152/ajpheart.00895.2006.-The aim of this study was to determine the feasibility and accuracy of wall motion score index (WMSI) and myocardial performance index (MPI) for measuring regional and global left ventricular (LV) function with use of high-resolution echocardiography after myocardial infarction (MI) in mice. In 48 mice, myocardial infarction was induced by ligation in the middle of the left anterior descending coronary artery. Echocardiography was performed under anesthesia at baseline and 1 mo after MI. WMSI was analyzed by a 16-segment model on short-axis views, and wall motion was scored as 1 for normal, 2 for hypokinetic, 3 for akinetic, 4 for dyskinetic, and 5 for aneurysmal. WMSI was calculated as the sum of scores divided by the total number of segments. MPI was calculated on the basis of isovolumetric contraction time (IVCT), isovolumetric relaxation time (IVRT), and ejection time (ET): MPI ϭ (IVCT ϩ IVRT)/ET. We measured LV ejection fraction (LVEF), end-systolic and end-diastolic volumes (ESV and EDV), fractional shortening (FS), and infarct size (IS). LVEF at 4 wk after MI was reduced at 32.8 Ϯ 9.0%. Linear correlation analyses showed that WMSI (1.6 Ϯ 0.3) correlated with LVEF (r ϭ Ϫ0.84, P Ͻ 0.0005), FS (r ϭ Ϫ0.43, P ϭ 0.003), and IS (34.3 Ϯ 15.3%, r ϭ 0.86, P Ͻ 0.0005). MPI (0.67 Ϯ 0.09) correlated with LVEF (r ϭ Ϫ0.67, P Ͻ 0.0005) and IS (r ϭ 0.72, P Ͻ 0.0005). MPI also correlated with mitral inflow velocity (r ϭ Ϫ0.68, P Ͻ 0.0005) and deceleration time (r ϭ Ϫ0.42, P ϭ 0.003). Stepwise regression analysis revealed that WMSI was independently associated with IS. IS, FS, mitral inflow velocity, and deceleration time were independent determinants of MPI. In conclusion, echocardiographic assessments of WMSI and MPI in mice are feasible and correlate strongly with two-dimensional measurement of LV function and IS. These novel parameters provide additional noninvasive assessment of regional and global LV function in mice after MI. experimental myocardial infarction; echocardiography; infarct size EXPERIMENTAL MODELS of myocardial infarction (MI) in mice are increasingly important for testing novel therapies for tissue repair, such as gene transfer and stem cell delivery, because of the availability of genetically marked and functionally transgenic strains commonly used in the study of the cardiovascular system. Researchers have applied echocardiographic assessment of global left ventricular (LV) ejection fraction (LVEF), fractional shortening (FS), LV dimensions, and mass to assess the process of remodeling after surgically induced infarction in murine models (1,8,14). Although the wall motion score index (WMSI) (16, 17), based on a 16-segment model, and the myocardial performance index (MPI) (6, 22) have been validated in humans after MI, these i...

Co-injection of MLCVEGF and MSCs in ischemic hearts can result in better cardiac function and MSC survival, compared to their individual injections, as a result of the additive effects of each therapy.

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