Dobutamine-stress magnetic resonance microimaging in mice : acute changes of cardiac geometry and function in normal and failing murine hearts.

The aim of this study was to assess the capability of MRI to characterize systolic and diastolic function in normal and chronically failing mouse hearts in vivo at rest and during inotropic stimulation. Applying an ECG-gated FLASH-cine sequence, MRI at 7 T was performed at rest and after administration of 1.5 microgram/g IP dobutamine. There was a significant increase of heart rate, cardiac output, and ejection fraction and significant decrease of end-diastolic and end-systolic left ventricular (LV) volumes (P<0.01 each) in normal mice during inotropic stimulation. In mice with heart failure due to chronic myocardial infarction (MI), MRI at rest revealed gross LV dilatation. There was a significant decrease of LV ejection fraction in infarcted mice (29%) versus sham mice (58%). Mice with MI showed a significantly reduced maximum LV ejection rate (P<0.001) and LV filling rate (P<0.01) and no increase of LV dynamics during dobutamine action, indicating loss of contractile and relaxation reserve. In 4-month-old transgenic mice with cardiospecific overexpression of the beta(1)-adrenergic receptor, which at this early stage do not show abnormalities of resting cardiac function, LV filling rate failed to increase after dobutamine stress (transgenic, 0.19+/-0.03 microL/ms; wild type, 0.36+/-0.01 microL/ms; P<0.01). Thus, MRI unmasked diastolic dysfunction during dobutamine stress. Dobutamine-stress MRI allows noninvasive assessment of systolic and diastolic components of heart failure. This study shows that MRI can demonstrate loss of inotropic and lusitropic response in mice with MI and can unmask diastolic dysfunction as an early sign of cardiac dysfunction in a transgenic mouse model of heart failure.

Na(+)/H(+) exchange inhibition with HOE642 improves postischemic recovery due to attenuation of Ca(2+) overload and prolonged acidosis on reperfusion.

BACKGROUND: Na(+)/H(+) exchange inhibition with HOE642 (cariporide) improves postischemic recovery of cardiac function, but the mechanisms of action remain speculative. Because Na(+)/H(+) exchange is activated on reperfusion, it was hypothesized that its inhibition delays realkalinization and decreases intracellular Na(+) and, via Na(+)/Ca(2+) exchange, Ca(2+) overload. Attenuated Ca(2+) overload and prolonged acidosis are known to be cardioprotective. METHODS AND RESULTS: Left ventricular developed and end-diastolic pressures were measured in isolated buffer-perfused rat hearts subjected to 30 minutes of no-flow ischemia and 30 minutes of reperfusion (37 degrees C) with or without 1 micromol/L HOE642 added to the perfusate 15 minutes before ischemia. Intracellular Ca(2+) concentration ([Ca(2+)](i)) and pH(i) were measured with aequorin (n=10 per group) and (31)P NMR spectroscopy (n=6 per group), respectively. HOE642 did not affect preischemic mechanical function, [Ca(2+)](i), or pH(i). Mechanical recovery after 30 minutes of reperfusion was substantially improved with HOE642: left ventricular developed pressure (in percent of preischemic values) was 92+/-3 versus 49+/-7 and left ventricular end-diastolic pressure was 16+/-3 versus 46+/-5 mm Hg (P<0.05 for HOE642-treated versus untreated hearts). End-ischemic [Ca(2+)](i) was significantly lower in HOE642-treated than in untreated hearts (1.04+/-0.06 versus 1.84+/-0. 02 micromol/L, P<0.05). Maximal intracellular Ca(2+) overload during the first 60 seconds of reperfusion was attenuated with HOE642 compared with untreated hearts: 2.0+/-0.3 versus 3.2+/-0.3 micromol/L (P<0.05). pH(i) was not different at end ischemia ( approximately 5.9+/-0.05). Realkalinization was similar in the first 90 seconds of reperfusion and significantly delayed in the next 3 minutes (eg, 6.8+/-0.07 in HOE642-treated hearts compared with 7. 2+/-0.07 in untreated hearts; P<0.05). CONCLUSIONS: HOE642 improves postischemic recovery by reducing Ca(2+) overload during ischemia and early reperfusion and by prolonging postischemic acidosis.