Rationale High-sensitivity in vivo phenotyping of cardiac function is essential for evaluating genes of interest and novel therapies in small animal models of cardiovascular disease. Transthoracic echocardiography is the principal method currently used for assessing cardiac structure and function; however, standard echocardiographic techniques are relatively insensitive to early or subtle changes in cardiac performance, particularly in mice. Objective To develop and validate an echocardiographic strain imaging methodology for sensitive and rapid cardiac phenotyping in small animal models. Methods and Results Herein, we describe a modified echocardiographic technique that utilizes speckle-tracking based strain analysis for the non-invasive evaluation of cardiac performance in adult mice. This method is found to be rapid, reproducible, and highly sensitive in assessing both regional and global left ventricular (LV) function. Compared to conventional echocardiographic measures of LV structure and function, peak longitudinal strain and strain rate were able to detect changes in adult mouse hearts at an earlier time point following myocardial infarction (post-MI) and predicted the later development of adverse LV remodeling. Moreover, speckle-tracking based strain analysis was able to clearly identify subtle improvement in LV function that occurred early in response to standard post-MI cardiac therapy. Conclusions Our results highlight the utility of speckle-tracking based strain imaging for detecting discrete functional alterations in mouse models of cardiovascular disease in an efficient and comprehensive manner. Echocardiography speckle-tracking based strain analysis represents a method for relatively high-throughput and sensitive cardiac phenotyping, particularly in evaluating emerging cardiac agents and therapies in mice.

Photoacoustic (PA) imaging for biomedical applications has been under development for many years. Based on the many advances over the past decade, a new photoacoustic imaging system has been integrated into a micro-ultrasound platform for co-registered PA-ultrasound (US) imaging. The design and implementation of the new scanner is described and its performance quantified. Beamforming techniques and signal processing are described, in conjunction with in vivo PA images of normal subcutaneous mouse tissue and selected tumor models. In particular, the use of the system to estimate the spatial distribution of oxygen saturation (sO2) in blood and co-registered with B-mode images of the surrounding anatomy are investigated. The system was validated in vivo against a complementary technique for measuring partial pressure of oxygen in blood (pO2). The pO2 estimates were converted to sO2 values based on a standard dissociation curve found in the literature. Preliminary studies of oxygenation effects were performed in a mouse model of breast cancer (MDA-MB-231) in which control mice were compared with mice treated with a targeted antiangiogenic agent over a 3 d period. Treated mice exhibited a >90% decrease in blood volume, an 85% reduction in blood wash-in rate, and a 60% decrease in relative tissue oxygenation.

Systolic and diastolic dysfunction of the left ventricle (LV) is a hallmark of most cardiac diseases. In vivo assessment of heart function in animal models, particularly mice, is essential to refining our understanding of cardiovascular disease processes. Ultrasound echocardiography has emerged as a powerful, noninvasive tool to serially monitor cardiac performance and map the progression of heart dysfunction in murine injury models. This review covers current applications of small animal echocardiography, as well as emerging technologies that improve evaluation of LV function. In particular, we describe speckle-tracking imaging-based regional LV analysis, a recent advancement in murine echocardiography with proven clinical utility. This sensitive measure enables an early detection of subtle myocardial defects before global dysfunction in genetically engineered and rodent surgical injury models. Novel visualization technologies that allow in-depth phenotypic assessment of small animal models, including perfusion imaging and fetal echocardiography, are also discussed. As imaging capabilities continue to improve, murine echocardiography will remain a critical component of the investigator's armamentarium in translating animal data to enhanced clinical treatment of cardiovascular diseases. murine echocardiography; systolic and diastolic function; speckle-tracking imaging; strain analysis; heart failure THIS ARTICLE is part of a collection on Assessing Cardiovascular Function in Mice: New Developments and Methods. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.Rodents are invaluable models for cardiovascular research, in part because of the extensive knowledge of their genome, homogeneity of study population, reproducible pathological phenotypes, and relative ease of creating genetically modified models. Surgical techniques that induce myocardial overload, infarction, and dysfunction in mice and rats have enabled a reliable identification and assessment of key physiological, molecular, and biochemical mechanisms of cardiovascular diseases (43). With the use of noninvasive imaging tools such as ultrasound echocardiography, cardiovascular evaluation of rodents has further led to the translational development of new diagnostic techniques and therapeutic strategies to predict and prevent cardiovascular disease complications in humans (82).Echocardiography remains a gold standard for a reliable assessment of cardiovascular structure and function in humans (19). The technology's allure lies primarily in its portability, relative affordability, widespread availability, noninvasive nature, and rapid real-time imaging capabilities. With advancements in clinical echocardiography, the technicalities and conceptual framework of the methodology and equipment have been extended from humans to small animals. Ultrasound imaging greatly facilitates the evaluation of cardiac function in transgenic animals, as well as surgically induced ...

Abstract-The injured mammalian heart is particularly susceptible to tissue deterioration, scarring, and loss of contractile function in response to trauma or sustained disease. We tested the ability of a locally acting insulin-like growth factor-1 isoform (mIGF-1) to recover heart functionality, expressing the transgene in the mouse myocardium to exclude endocrine effects on other tissues. supplemental mIGF-1 expression did not perturb normal cardiac growth and physiology. Restoration of cardiac function in post-infarct mIGF-1 transgenic mice was facilitated by modulation of the inflammatory response and increased antiapoptotic signaling. mIGF-1 ventricular tissue exhibited increased proliferative activity several weeks after injury. The canonical signaling pathway involving Akt, mTOR, and p70S6 kinase was not induced in mIGF-1 hearts, which instead activated alternate PDK1 and SGK1 signaling intermediates. The robust response achieved with the mIGF-1 isoform provides a mechanistic basis for clinically feasible therapeutic strategies for improving the outcome of heart disease. (Circ Res. 2007;100:1732-1740.)Key Words: cardiac muscle Ⅲ insulin-like growth factor-1 Ⅲ regeneration Ⅲ wound healing T he insulin/insulin-like growth factor signaling pathway arose early in the evolution and is highly conserved among invertebrates and vertebrates. 1 Mammalian IGF-1 acts predominately as a growth, survival, and differentiation factor. The pleiotropic functions of IGF-1 are reflected in the complicated structure and regulation of Igf-1 gene. 2 The products include variable amino-terminal signal peptides and different carboxy-terminal E peptides, the precise function of which is still unclear. Injury of mammalian tissues induces transient production of locally acting IGF-1 isoforms that control growth, survival, and differentiation. 3 By contrast, high levels of circulating IGF-1, produced by the liver, has been implicated in the restriction of lifespan 1 and predisposition to neoplasia. 4 When expressed as transgenes, different IGF-1 isoforms have contrasting effects on the mouse heart. Transgenic mice generated with a minor human IGF-1 cDNA under the control of the rat ␣-myosin heavy chain (␣-MHC) promoter showed no striking differences in size and cell volume when compared with control mice, but harbored an increased number of cardiomyocytes, coupling IGF-1 overexpression with myocyte proliferation. 5 The hearts of these animals responded to coronary ligation with attenuated diastolic wall stress, cardiac weight, ventricular dilatation, and hypertrophy, attributable mainly to a prevention of cardiac cell death. 6 In another report, cardiac expression of a modified human IGF-1 cDNA produced no hyperplasia but instead induced physiologic, then pathologic, cardiac hypertrophy in transgenic mice. 7 Here, we have used the mIGF-1 isoform, comprising a Class 1 signal peptide and a C-terminal Ea extension peptide. 8 This isoform is expressed at high levels in neonatal tissues and in the adult liver, but decreases during aging ...