Detection of myocardial dysfunction during cancer chemotherapy with tissue Doppler imaging: a canary in the coal mine?

For technical and economic considerations, mouse models are increasingly used to identify the mechanisms underlying cardiovascular development, function, and disease. The phenotypic characterization of the small and rapidly beating mouse heart in vivo has required miniaturization and refinement of techniques that are used to study the cardiovascular system in larger animals; of these, echocardiography isarguablytheforemostmethodforimagingthecardiovascularsystem in small animals because it is noninvasive, versatile, widely available, inexpensive,andwellsuitedforserialstudiesoverawiderangeofages. Two-dimensionally directed M-mode echocardiography has been usedtophenotypethecardiovascularsysteminahostofgeneticmouse models by many laboratories over the past decade. 1 Broadband transducers operating at 12 to 15 MHz enhance spatial, contrast, temporal resolution,andnearfielddefinition,andaccuratelyandreliablymeasure left ventricular (LV)dimensions, function, and mass 2 ; assessment of the vascular system and fetal echocardiography justifies ultrasound biomicroscopy operating atfrequencies of30 to50 MHz. Incontrastwith ultrasound biomicroscopy, tissue Doppler imaging (TDI), color M-mode, and strain rate and velocity-vector imaging have been used to analyze cardiovascular function in a relatively load-independent manner in mice using conventional ultrasound platforms. It is worth reiterating that the major advantages of these echocardiographic approaches include theability to assess age-ordisease-related cardiovascular changes serially over time and to determine the effects of genetic, surgical, and pharmacologic interventions in the intact animal. However,thereareseveralimportantlimitationstotheuseofechocardiography in mice. First, although parasternal long- and short-axes are readily obtained, the vertical orientation of the mouse heart precludes the acquisition of reproducible apical views; thus, ejection fraction determinations (obtained from apical views in humans) are suboptimal, an ideal insonation angle for spectral, TDI, and longitudinal strain analyses is often impractical, and visualization of the right ventricle is usually incomplete. Second, the accuracy, reproducibility, anddiagnosticdiscriminationofanechocardiographicparametermay not be similar among laboratories, particularly when a ‘‘new’’ technique has been investigated by only a few groups. For example, although measurements of myocardial velocities and strain rate using TDI have been shown to be sensitive parameters of LV systolic function, 3,4 their reproducibility among experienced laboratories is as high as approximately 15%, and the temporal and spatial resolution requirements for TDI and speckle tracking (owing to the rapid heart rate and thin walls of the mouse heart) are not completely resolved. 5 Third, the effects of anesthesia, mechanical ventilation, and surgical instrumentation may each independently and variably influence the specific physiologic parameter under study, rendering difficult interpretation and extrapolation. Conversely, interpretation of conscious studies not conducive to telemetric monitoring should allow for the effects of restraint and in some instances, recovery from anesthesia. In addition, the rapid heart rates in the conscious mouse generally precludeacompleteassessmentofdiastolicfunctionbecauseoffusion of the diastolic transmitral E- and A-velocity waveforms. Fourth, the particular strain of mouse may significantly and selectively affect parameters of cardiovascular performance 6 ; in this regard, potential strain differences may not simulate the widely variable susceptibility to anthracycline-induced cardiotoxicity seen in patients. 7 An example of the utility of echocardiography in the mouse is reportedinastudybyJassaletal 8 inthismonth’sJournaloftheAmerican Society of Echocardiography. These authors studied the cardiotoxic effectsoftheanthracyclinedoxorubicin,thelesscardiotoxicnon-pegylated liposomal encapsulated doxorubicin (Myocet, Elan Pharmaceuticals, Princeton, NJ), and their combination with the monoclonal antibody against the HER-2 protein, trastuzumab (Herceptin, Genentech, South San Francisco, CA) using TDI (posterior wall endocardial systolicvelocityandradialstrainrate)andM-modeejectionfractionin C57Bl/6 mice. The authors reasoned that the less load-sensitive TDIderived indices would detect subtle cardiotoxicity before the more commonly used parameter, ejection fraction, and could distinguish the relative toxicity of the different regimens. The rationale for this hypothesisisbasedinpartonapreviousstudyinmice,inwhichendocardial tissue velocity and strain rate from the posterior LV wall on shortaxis views of the LV were obtained with lowinterpretative variability. 4 These relatively load-independent indices of LV contraction were linearly and significantly related to LV dP/dtmax, and decreases were detected earlier than LV shortening fraction in a model of endotoxin-induced LV dysfunction.