Ming Wu

Remodeling of T-Tubules and Reduced Synchrony of Ca2+ Release in Myocytes From Chronically Ischemic Myocardium

In ventricular cardiac myocytes, T-tubule density is an important determinant of the synchrony of sarcoplasmic reticulum (SR) Ca2+ release and could be involved in the reduced SR Ca2+ release in ischemic cardiomyopathy. We therefore investigated T-tubule density and properties of SR Ca2+ release in pigs, 6 weeks after inducing severe stenosis of the circumflex coronary artery (91±3%, N=13) with myocardial infarction (8.8±2.0% of total left ventricular mass). Severe dysfunction in the infarct and adjacent myocardium was documented by magnetic resonance and Doppler myocardial velocity imaging. Myocytes isolated from the adjacent myocardium were compared with myocytes from the same region in weight-matched control pigs. T-tubule density quantified from the di-8-ANEPPS (di-8-butyl-amino-naphthyl-ethylene-pyridinium-propyl-sulfonate) sarcolemmal staining was decreased by 27±7% (P<0.05). Synchrony of SR Ca2+ release (confocal line scan images during whole-cell voltage clamp) was reduced in myocardium myocytes. Delayed release (ie, half-maximal [Ca2+]i occurring later than 20 ms) occurred at 35.5±6.4% of the scan line in myocardial infarction versus 22.7±2.5% in control pigs (P<0.05), prolonging the time to peak of the line-averaged [Ca2+]i transient (121±9 versus 102±5 ms in control pigs, P<0.05). Delayed release colocalized with regions of T-tubule rarefaction and could not be suppressed by activation of protein kinase A. The whole-cell averaged [Ca2+]i transient amplitude was reduced, whereas L-type Ca2+ current density was unchanged and SR content was increased, indicating a reduction in the gain of Ca2+-induced Ca2+ release. In conclusion, reduced T-tubule density during ischemic remodeling is associated with reduced synchrony of Ca2+ release and reduced efficiency of coupling Ca2+ influx to Ca2+ release.

Non-invasive characterization of the area-at-risk using magnetic resonance imaging in chronic ischaemia

AIMSnwe investigated the performance of quantitative stress perfusion magnetic resonance imaging (MRI) as a basis for identifying and characterizing the area-at-risk subtending a chronic coronary artery (CA) stenosis.nnnMETHODS AND RESULTSnpigs underwent a percutaneous copper-coated stent implantation in the circumflex CA (n = 11) or a sham operation (n = 5). After 6 weeks, angiography and MRI were performed including cine (rest, low- and high-dose dobutamine stress), dual-bolus first-pass perfusion (rest and adenosine stress), and contrast-enhanced imaging to quantify myocardial infarction (MI). Myocardial blood flow (MBF) was quantified based on Fermi-model deconvolution and compared with microsphere measurements. On the basis of Evans blue staining, MBF thresholds to define the area-at-risk were determined by receiver-operating characteristic (ROC) analysis. CA stenosis was 94 ± 7% and infarct size (IS) 7.3 ± 3.1% of left ventricular mass. Segmental thresholds of hyperaemic MBF yielded the best performance for detecting area-at-risk. There was a good correlation between MRI and microsphere perfusion (r(2) = 0.84, P < .0001). The area-at-risk presented a mixed substrate of non-infarcted (non-MI), <50% infarcted (MI+), and >50% infarcted (MI++) segments. MBF was reduced in at-risk vs. remote segments at rest (non-MI, 0.50 ± 0.21; MI+, 0.47 ± 0.14; MI++, 0.42 ± 0.14; remote, 0.84 ± 0.25 mL/min/g) and during stress (non-MI, 0.69 ± 0.09; MI+, 0.66 ± 0.14; MI++, 0.51 ± 0.11; remote, 1.70 ± 0.36 mL/min/g). Segmental wall thickening showed different responses to stress (remote, progressive increase during incremental stress; non-MI, increase at low-dose and discontinued at high-dose; MI+, initial increase and decrease at high-dose; MI++, progressive decrease).nnnCONCLUSIONnquantitative hyperaemic perfusion MRI accurately defines segments in the area-at-risk in chronic ischaemia, which present with different functional response to stress related to segmental IS.

Closed-chest animal model of chronic coronary artery stenosis. Assessment with magnetic resonance imaging

To evaluate the consequences of chronic non-occlusive coronary artery (CA) stenosis on myocardial function, perfusion and viability, we developed a closed-chest, closed-pericardium pig model, using magnetic resonance imaging (MRI) as quantitative imaging tool. Pigs underwent a percutaneous copper-coated stent implantation in the left circumflex CA (nxa0=xa019) or sham operation (nxa0=xa05). To evaluate the occurrence of myocardial infarction, cardiac troponin I (cTnI) levels were repetitively measured. At week 6, CA stenosis severity was quantified with angiography and cine, first-pass and contrast-enhanced MRI were performed to evaluate cardiac function, perfusion and viability. In the stenting group, cTnI values significantly increased at day 3 and day 5 (Pxa0=xa00.01), and normalized at day 12. At angiography, 13/19 stented pigs had a stenosisxa0>75%. Mean degree of CA stenosis was 91xa0±xa04%, range 83–98%. At contrast-enhanced MRI, mean infarct size was 7xa0±xa06%, range 0.7–18.4%. Five of the 6 pigs with stenosisxa0<75% had no infarction. Stented pigs showed significantly higher Left-ventricular volumes and normalized mass (Pxa0<xa00.05), and lower ejection fraction (Pxa0=xa00.03) than the sham pigs. Both wall thickening and myocardial perfusion were significantly lower in animals with at least one segmentxa0>50% infarct (23xa0±xa08%; 0.05xa0±xa00.01xa0a.u./s) and animals with onlyxa0<50% infarct segments (29%xa0±xa012%; 0.07xa0±xa00.02xa0a.u./s), than sham pigs (52xa0±xa06%; 0.10xa0±xa00.03xa0a.u./s) (Pxa0<xa00.001; Pxa0<xa00.05). This minimally-invasive animal model of chronic, non-occlusive CA stenosis, presenting a mixture of perfusion and functional impairment and a variable degree of myocardial necrosis, can be used as substitute to study chronic myocardial hypoperfusion.

Choice of coordinate system for left ventricular FE-mesh generation

Given the ellipsoid shape of the left ventricle (LV), prolate spheroidal coordinates are often adopted to construct a finite element (FE) -mesh of the left ventricle. However, a Cartesian reference frame is needed to define these coordinates. The aim of this study was therefore to examine whether the fitting of a FE-mesh to the LV-surfaces is influenced by the choice of cardiac cycle phase used to define the frame of reference. In 6 MRI datasets of pig hearts the LV borders were manually segmented at end-diastole (ED) and at end-systole (ES). Based on these segmentations, 3 reference systems were defined using the ED contours (EDRF), the ES contours (EDRF) and the average of the two (AVRF). In each reference system, FE-meshes of the LV-surfaces were fitted to the segmentation data of both the ES- and ED-phase. The root mean square Euclidean distance (RMSE) between the data points and their radial projections was assessed as a measure of the goodness of fit. The RMSE over the entire fitted surface was < 1 mm in all cases. The average RMSE between corresponding points on the meshes in the different reference frames was 0.06 mm. Comparison of the RMSE showed no significant difference between the three choices of reference frames. Based on these results, no preferred reference frame was found and the resulting meshes are independent of the frame chosen.

Different Approaches to the Choice of Coordinate System for Left-ventricular FE-mesh generation

The modern in-vivo evaluation of cardiac patho-physiology requires the integration of different data on cardiac function, tissue characterization, perfusion etc. and aims at the extraction of relevant physiological parameters that combine these data. For these purposes, the use of finite element (FE) models is becoming an increasingly important part of cardiac analysis [1].© 2008 ASME