Published online before print December 13, 2007, doi: 10.1161/CIRCRESAHA.107.160085
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© 2008 American Heart Association, Inc.
Cellular Biology |
Remodeling of T-Tubules and Reduced Synchrony of Ca2+ Release in Myocytes From Chronically Ischemic Myocardium
From the Division of Experimental Cardiology (F.R.H., V.B., L.B., E.D., K.S.), Division of Cardiac Imaging (M.W., P.C., F.R., J.D’h.), Division of Radiology (S.D., J.B.), Department of Electrical Engineering (F.M.), University Hospital Gasthuisberg and University of Leuven, Belgium; and Medical Biophysics (F.v.W.), Institute for Physiology and Pathophysiology, University of Heidelberg, Germany. F.R.H. is currently at the Division of Cardiology, Medical University of Graz, Austria.
Correspondence to Karin R. Sipido, MD, PhD, Laboratory of Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th Floor, Herestraat 49, B-3000 Leuven, Belgium. E-mail Karin.Sipido{at}med.kuleuven.ac.be
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Abstract |
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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.
Key Words: myocardial infarction • contractility • myocytes • calcium
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Introduction |
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Although new therapeutic approaches have decreased the mortality associated with myocardial infarction (MI) over the past decades,1 many patients nevertheless sustain a regional loss of myocardial contractile tissue following an ischemic event. The resulting increased hemodynamic burden on the left ventricle leads to structural and functional changes in the remaining viable myocardium, which further reduces ventricular performance, a process referred to as myocardial remodeling.2 Sustained regional chronic and/or intermittent ischemia further contributes to this process, and the resulting ischemic cardiomyopathy is currently among the major causes of heart failure.3
Contractile dysfunction of the ventricle is partly related to the abnormal loading in vivo4 and partly to the intrinsic properties of the cardiomyocytes. Myocytes isolated from patients with ischemic cardiomyopathy at the time of heart transplantation have a reduced contractile function resulting from abnormal Ca2+ handling.5–7 Animal models have examined the mechanisms of cellular dysfunction in ischemic cardiomyopathy in more detail. Myocytes from the infarct border zone have a reduced contraction and slowed and reduced [Ca2+]i transients.8–11 The mechanisms leading to this impaired Ca2+ handling are not completely understood. Decreased intracellular Ca2+ release may be the result of a reduced sarcoplasmic reticulum (SR) Ca2+ content caused by decreased SR Ca2+ pump activity, as has been observed in some8,11,12 but not all10,13 models of postinfarct remodeling. Increased Na/Ca exchange (NCX) activity and abnormal expression and phosphorylation of the ryanodine receptor (RyR) have also been reported.10,14,15
Even in the presence of a normal SR Ca2+ content, defective coupling between Ca2+ influx and activation of RyR could lead to reduced Ca2+ release.16 Dyssynchronous opening of RyRs and decreased [Ca2+]i transients were observed in a rabbit model of postinfarct remodeling,17 and, in this model, a reduction of the L-type Ca2+ current (ICaL) was seen; such a reduced ICaL has been reported in other18,19 but not all models of MI.20
Efficient coupling of Ca2+ influx through sarcolemmal Ca2+ channels (dihydropyridine receptors) and activation of RyRs in the SR is related to the structural organization in couplons, which, in ventricular cardiomyocytes, are found to a large extent along the T-tubules.21 Experimentally reducing T-tubule density indeed leads to dyssynchronous intracellular Ca2+ release and reduced [Ca2+]i transients.22–24 A loss of T-tubules could be part of the postinfarction remodeling process. In end-stage human heart failure, histological examination showed dilation of T-tubules25,26 with an increase25 or decrease26 in the density of T-tubules in tissue sections. Studies on intact living human ventricular myocytes have not yet been conclusive as to whether T-tubule density is altered,24,27,28 but the contribution of alterations in T-tubules to remodeling is supported by observations in animal models of heart failure.29–31
In this study, we investigated potential changes in T-tubule density and their impact on intracellular Ca2+ release in a pig model of severe chronic coronary stenosis with regional myocardial dysfunction and limited infarction without heart failure.
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Materials and Methods |
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An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org.
Animal Model
A detailed description is provided in the online data supplement. Briefly, a copper-coated stent was inserted into the proximal circumflex artery of young domestic pigs (20 to 25 kg) to induce intima proliferation and severe nonthrombotic coronary stenosis, quantified during coronary angiography. Global and regional left ventricular (LV) function were evaluated at baseline and at 3 and 6 weeks after stent implantation using color Doppler myocardial velocity imaging at baseline and during dobutamine stress. In a number of animals, MRI was used to assess global and regional LV function4 and to quantify MI as a fraction of total LV mass. The stent implantation induces a severe but slightly variable stenosis and degree of LV dysfunction. In the present study, we used only animals with documented small transmural infarctions; their functional characteristics are shown under Results.
At the time of euthanasia (47±1 days after stent implantation), pigs with MI (N=13) weighed 51±2 kg; matched healthy pigs were used as controls (CTRL) (N=15; weight, 55±4 kg).
Isolation of Cardiac Myocytes
The procedure for isolating myocytes was as described previously.32 After enzymatic digestion of the tissue wedge perfused by the stenotic artery, the infarct area and 5 to 10 mm around the infarct core were discarded; midmyocardial cells from the remaining digested tissue were used. Myocytes isolated from the midmyocardial layer of the posterior wall of the weight-matched healthy pigs served as controls.
Subcellular [Ca2+]i Measurements and T-Tubule Quantification
The setup for confocal imaging was as described previously, and image acquisition and analysis is detailed in the online data supplement. [Ca2+]i transients were recorded during steady-state stimulation at 1 Hz, with depolarizing steps from –70 to 0 mV for 150 ms along a line through the center parallel to the long axis of the cell as described previously24,33; temporal resolution was 1.54 ms per line, and pixel size (x, y) was 0.2 to 0.4 µm. For T-tubule density (di-8-ANEPPS [di-8-butyl-amino-naphthyl-ethylene-pyridinium-propyl-sulfonate] staining) 8 to 10 sequential xy images centered around the equatorial plane of the cell were recorded from each cell, with a spacing of 1 µm in the z-direction and a pixel width of 0.11 to 0.20 µm.
Global [Ca2+]i and Membrane Current Measurements
The setup for epifluorescence recording, protocols, and solutions are described in the online data supplement.
Immunofluorescence Imaging and Western Blot
The procedures are described in the online data supplement. For protein expression, we used transmural needle biopsies from the ischemic area taken in situ at the time of euthanasia. Control tissue was obtained from the same area in hearts of CTRL pigs.
Image Analysis
Algorithms to analyze the spatial and temporal characteristics of the [Ca2+]i transients were custom-made (IDL 6.1, Research Systems International, Paris, France); the approaches are detailed in the online data supplement. All temporal data refer to the onset of the whole-line averaged [Ca2+]i transient. F50 was defined as the half-maximum of the normalized overall peak [Ca2+]i-dependent fluorescence and served as a threshold to discriminate local Ca2+ release as described previously.33 To evaluate T-tubules, the images were deconvolved and automatically thresholded; the sarcolemmal surface membrane was excluded from analysis in all images (more details are available in online data supplement). T-tubule density is expressed as the fraction of positive pixels of all pixels within the sarcolemmal boundaries; data are per cell and subsequently pooled per animal.
Statistics
Data are shown as means±SEM and were compared using Student’s t test or 2-way ANOVA; Fisher’s least-significant difference test was performed when significant overall effects were detected. P<0.05 was considered significant.
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Results |
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Global and Regional LV Function In Vivo
The degree of circumflex arterial stenosis was 91±3% of the vessel lumen. At 6 weeks, LV ejection fraction at rest, as determined from MRI, was slightly but significantly decreased in MI versus CTRL (Figure 1A); the LV end-diastolic volume was not increased (116±10 mL in MI versus 106±10 mL in CTRL, P=0.1). Infarction, as determined from the delayed enhancement images (Figure 1B), comprised 8.8±2.0% of the total LV mass; this corresponds to
50% of the area at risk. MRI confirmed the regional dysfunction in the segments with delayed enhancement as well as in the adjacent segments within the area subtended by the stenotic artery (Figure 1B).
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P<0.05 vs preimplant, *P<0.05 vs CTRL, #P<0.05 vs rest.Myocardial velocity imaging during follow-up showed the regional dysfunction present at 3 weeks as a severely reduced systolic strain rate (Figure 1C). At 6 weeks, there was no inotropic response to dobutamine (Figure 1D), consistent with the presence of transmural MI.34
(Ultra)structural Remodeling of Myocytes
Cardiomyocytes from the MI adjacent area were hypertrophied, as indicated by a significant increase in cell length: 186±6 µm in MI (Nanimals=9, ncells=254) versus 147±6 µm in CTRL (Nanimals=6, ncells=180, P<0.05). Cell width and cell depth tended to be increased as well (29±2 versus 28±1 µm in CTRL, P=0.2; 22±1 versus 18±1 µm in CTRL, P=0.07). The calculated increase of cell volume assuming a brick-like shape for MI was 51%. This contrasts with the increase of total, ie, external and T-tubular, membrane area measured from the cell capacitance of 30% from 91±5 pF (CTRL: Nanimals=9, ncells=65) to 118±8 pF (MI: Nanimals=5, ncells=43, P<0.05).
T-tubule density expressed as the fraction of positive pixels of all pixels within the sarcolemmal boundaries was significantly reduced in MI (Figure 2). Expressed as a fraction of the external sarcolemmal boundary, the values were also close to significance (0.77±0.05 versus 0.92±0.06 µm–1 in CTRL, P=0.057). In contrast, the intracellular distribution of RyR appeared homogeneous and similar in CTRL and MI (Figure 2C). This was quantified by measuring RyR signal density, which was similar in cells from CTRL (Nanimals=3, ncells=17) and MI (Nanimals=5, ncells=17; Figure 2D). We also examined the variability in either RyR or T-tubule signal in individual 5x5 µm boxed areas of a cell (detailed in the online data supplement), as regional loss would result in a higher variability. Here, again, there was a significant difference between MI and CTRL for T-Tubules but not for RyR (Figure 2E).
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Reduced Synchrony of Ca2+ Release
During confocal line scan imaging of the [Ca2+]i transient, myocytes from MI had numerous areas with delayed Ca2+ release, persistently present during consecutive pulses, as evident in the [Ca2+]i transient averaged over 10 beats (Figure 3A). The absence of beat-to-beat variability is further illustrated in Figure 3B, showing the line at 17 ms during sequential beats and the small extent of variability in this line. In myocytes in which the sarcolemma was stained with wheat germ agglutinin (WGA)-Alexa594, a first line scan using the 543 nm excitation showed T-tubules as continuous lines of constant intensity (Figure 3C, left); during the subsequent line scan using the 488 nm excitation of fluo-3, the regions of delayed Ca2+ release could be related to areas of T-tubule rarefaction (Figure 3C, right). Figure 3D shows another cell with the 2D WGA-Alexa594 image and the area from which the recording was made.
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We hypothesized that these regions of delayed Ca2+ release lead to a slowed upstroke of the [Ca2+]i transient in MI. This was quantified by measuring for each consecutive line scan the fraction of the line that had a fluorescence larger than 50% of the maximal (F>F50).33 As shown in Figure 4A, in MI cells, this proceeded more slowly than in CTRL, and, at 20 ms, Ca2+ release remained below F50 along 36.7±5.7% of the line in MI versus only 22.7±2.5% of the line in CTRL (P<0.05). Likewise, the time to peak of the [Ca2+]i transient, spatially averaged over the entire line, was longer in MI (122±8 ms, Nanimals=8, ncells=35 versus 102±5 ms, Nanimals=13, ncells=41 in CTRL, P<0.05).
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Increased inhomogeneity in Ca2+ release in MI cells was attributable to a larger number (Figure 4B), as well as a larger size (Figure 4C), of the regions of delayed Ca2+ release.
We further examined the properties of Ca2+ release within both early and delayed regions. Time to local peak [Ca2+]i in regions of early Ca2+ release was not different in MI versus CTRL (66±9 versus 74±8 ms, ncells=17 and 14), and amplitude was also not different (F/F0 3.2±0.2 versus 3.4±0.3). In areas of delayed release, the Ca2+ release was shown previously to propagate in a wave-like manner because of Ca2+-induced Ca2+ release.24 In the current study, this process was quantified as the rate of filling (decrease in width as a function of time) for regions of delayed Ca2+ release with a width of >5 µm (n=35 in MI and n=20 in CTRL), as illustrated in Figure 5A. No difference in rate of filling was found between MI and CTRL (Figure 5B).
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We also examined whether cAMP-mediated positive inotropic stimulation could synchronize Ca2+ release in early and delayed Ca2+ release sites. As demonstrated in Figure 6A and 6B, the amplitude of Ca2+ release was greatly increased in the presence of forskolin (top); the extent and distribution of delayed Ca2+ release sites however appeared unchanged (bottom). Quantitative analysis of local [Ca2+]i transients (ncells=9) confirmed that the fraction of delayed release areas was unchanged (41±7 versus 33±6% at baseline). Time to peak [Ca2+]i in regions defined as delayed before the addition of forskolin remained significantly longer than in early regions also in the presence of the drug. The response to forskolin was not different in MI from CTRL (Figure 6C).
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Reduced Overall Gain of SR Ca2+ Release in MI
In a subset of animals (N=4 for MI, N=5 for CTRL), the whole-cell averaged [Ca2+]i transients were studied in a epifluorescence setup. Peak [Ca2+]i during steps from –70 to +10 mV, as used in the confocal analysis, was lower in MI (ncells=12) versus CTRL (n=15, P<0.05; Figure 7A), and the time to peak [Ca2+]i was prolonged (Figure 7B). The density of the L-type Ca2+ current was not significantly different (Figure 7C).
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Because the [Ca2+]i transients were of lower amplitude despite unchanged Ca2+ current, a reduction of SR content was expected, and this was tested using caffeine to release all SR Ca2+; Figure 8A shows the averaged signals of [Ca2+]i and inward NCX current for all MI (ncells=12) and CTRL myocytes (ncells=15). The integral of the inward NCX current (
INCX) during caffeine application (Figure 8B) was unexpectedly increased in MI versus CTRL, suggesting an increased Ca2+ content of the SR. In contrast, the caffeine-induced peak [Ca2+]i was reduced in MI (Figure 8C). These latter observations may rather reflect altered kinetics of Ca2+ release from the SR in response to caffeine in MI cells, as time to peak (Figure 8D) of the caffeine-induced [Ca2+]i transient was significantly increased in MI versus CTRL. The rate of decay was also significantly increased (Figure 8E), reflecting a reduced rate of Ca2+ removal by the NCX. Yet global protein expression of the NCX was unaltered (Figure 8F).
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We analyzed the properties of spontaneous release events or sparks, observed in a 15-second period following stimulation at 1 Hz (for MI: Nanimals=7, ncells=36, 2472 sparks; for CTRL: Nanimals=12, ncells=44, 2280 sparks). In MI animals, 100% of cells had spontaneous release events versus 74% in CTRL (P<0.05), but analysis of mean frequency was not statistically different (1.69±0.35 versus 1.27±0.23 sparks/sec per 100 µm in CTRL). Amplitude and duration were also not statistically different (F/F0, 1.76±0.05 versus 1.70±0.06 in CTRL; full duration at half-magnitude, 39±2 versus 36±2 ms in CTRL).
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Discussion |
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In Vivo Function and Remodeling With Chronic Coronary Stenosis
The most commonly used models for cellular remodeling after MI rely on smaller animals with ligation of a coronary artery, usually the left anterior descending. In these animals, MI typically is large, leading to heart failure (eg, in the rat35 and rabbit36). In the current animal model, we have a limited infarction within a larger area of chronic underperfusion; at 6 weeks, the impact on global function is present but limited. Therefore, this model allows us to study the changes with chronic ischemia in the area adjacent to the infarct, before the onset of heart failure. One can then question whether this is essentially different from the condition we have studied previously, namely hibernation, where there is no or only very limited subendocardial necrosis. We think, at present, these data should not be mixed. The regional contractile function in the hibernating myocardium is less affected because the loss of contractile cells is small. This implies that mechanical loading on the remaining myocytes is less than in the presence of MI, which could lead to different stimuli for remodeling.
We currently have a limited number of data to sustain that there is a difference in cellular remodeling in cardiomyocytes from hibernating myocardium as compared with cells from the area adjacent to the infarct. At the whole-cell level, the overall [Ca2+]i transients are more affected in the present dataset than in our earlier group of hibernation,32 although the Ca2+ current in the present study was less affected. There are also a number of similarities because SR Ca2+ content was similarly preserved. We currently have no data on subcellular synchrony of release in hibernating myocardium, but preliminary data also have shown a reduction in T-tubule density. Cellular hypertrophy is present in both groups.
Remodeling of T-Tubules
Ventricular myocytes develop T-tubules after birth,37 whereas atrial myocytes or Purkinje cells do not.38–40 The density of the T-tubule system is variable between species, and T-tubules disappear during culture of adult cardiac myocytes.23,24,33 These observations indicate that the T-tubule system is under active regulation and that it could change with disease. Yet the observations of remodeling with disease are limited.29–31 The present data document a lower density of T-tubules during ischemic remodeling before the development of heart failure.
This does not necessarily represent a net loss. Indeed, the myocytes were clearly hypertrophied, and the lower density of T-tubules could represent a differential growth and organization of this organelle in relation to the addition of sarcomeres. A striking finding was also that the distribution of RyR was unchanged. The data thus support the idea that T-tubules have a degree of plasticity and can undergo remodeling independent of the organization of the SR.
Song et al31 observed reorganization of T-tubules in spontaneously hypertensive rats, with a decrease in the transverse tubules in favor of an increase in the longitudinal tubules; the authors did not report a decrease in overall density. Similar observations were made in the mouse.30 This could be related to the different stimulus for remodeling but also to differences in small versus large animals. The rat, like the mouse, has a very dense network, possibly related to high heart rates, whereas pigs have a lower density, more like humans.24,33 In the latter system, reorganization may be more likely to result in true loss of T-tubules in certain areas.
Reduced Synchrony of Ca2+ Release
Litwin et al were the first to describe dyssynchronous Ca2+ release in myocytes from failing rabbit hearts after MI.17 In their study, Ca2+ release had a beat-to-beat regional variation, and release events were observed to occur late during depolarization. This dyssynchrony was linked to a reduced ICaL and the presence of functional couplons with decreased triggering; it could be rescued at least partially by protein kinase A–dependent phosphorylation and increased activity of ICaL. In a model of right ventricular failure, a reduction in ICa associated with changes in early repolarization also resulted in a regional beat-by-beat variation in intracellular Ca2+ release.41 The current study points to a different mechanism underlying reduced synchrony of Ca2+ release. First, we studied Ca2+ release during square voltage-clamp pulses, eliminating the influence of potential changes in early repolarization. Second, we focused on regions where Ca2+ release was persistently delayed in sequential [Ca2+]i transients, independent of beat-to-beat variability. We could not "rescue" the delayed release by increasing cAMP. In contrast, we could link the delayed release sites to areas of low T-tubule density. These data are consistent with a structural alteration. Recent computational analysis supports the importance of small changes in the structures relating dihydropyridine receptor and RyR.42
We also considered the possibility of a reduction in couplon size, which would result in a longer latency and reduced probability of release at spark sites.43 This additional analysis is presented in the online data supplement. The data suggest that, in addition to the larger number of delayed release sites, increased dyssynchrony at presumed spark sites is present. This could result from a smaller couplon size. Additional experiments are needed to evaluate the contribution of these changes to the overall reduced synchrony.
Coupling Efficiency Between Dihydropyridine Receptor and RyR and the Role of T-Tubules
The consequences of reduced synchrony are a global slowing of the rate of rise of [Ca2+]i, as also observed in the spatially averaged whole-cell [Ca2+]i transients. In such recordings, the longer time to peak, in particular together with the reduced amplitude of the [Ca2+]i transient, indicates that, overall, the SR Ca2+ release is reduced, despite preserved global Ca2+ influx and SR Ca2+ content. This can be interpreted as a reduced efficiency of coupling, as was initially proposed in the rat with hypertension-induced heart failure.44
Reduced coupling efficiency in MI may be the result of a smaller fraction of existing RyRs that are activated, because of a lack of T-tubules and possibly because of a reduction in couplon size. The distribution of RyRs was preserved, and the propagation of Ca2+ release within the delayed areas was the same for MI and CTRL, as were the properties of sparks, suggesting that the intrinsic properties of the RyR were not altered.
The presence of RyRs that are not coupled to the dihydropyridine receptor has analogies with experimentally reducing the probability of activating the RyR, eg, with low doses of caffeine or by reducing the activation of Ca2+ channels.45,46 Under those conditions, the SR can (locally) become overloaded, and this can give rise to even more pronounced heterogeneity in release under the form of alternans. This was currently not observed, but the larger SR content could be the result of reduced RyR activation.
The slower decay of the caffeine transient points toward a reduced efficiency in Ca2+ removal. This was also noticed in studies with acute detubulation22 and during cell culture.24 The reduced rate of rise of [Ca2+]i with caffeine application in MI myocytes might be related to reduced T-tubule density, because we likewise noted a significant increase in time to peak of 50%, with a 60% reduction of T-tubule density in cultured myocytes (data from Louch et al24). Alternatively, this may indicate additional changes in RyR properties, with a reduced response to caffeine.
Conclusions
In myocytes from the area adjacent to MI, decreased T-tubule density is associated with reduced global coupling efficiency, reduced synchrony of Ca2+ release, and slowed and reduced cellular [Ca2+]i transients. This occurs in the absence of changes in distribution of the RyR and indicates that plasticity of T-tubules is an independent factor in the remodeling process.
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Acknowledgments |
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We thank Patricia Holemans and Pascal Hamaekers for technical assistance and Niall Macquaide (Glasgow University, UK) for the MacSpark analysis program.
Sources of Funding
This study was supported by grants to K.R.S. from the Fund for Scientific Research–Flanders (G.0384.07), the European Union (LSHM-CT-2005-018833, EUGeneHeart), and Belgian Science Program IAP6/31.
Disclosures
None.
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Footnotes |
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Original received March 30, 2006; resubmission received July 19, 2007; revised resubmission received November 1, 2007; accepted November 29, 2007.
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References |
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