|
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
|
|
|
|||||||||
|
|||||||||||
|
J Am Coll Cardiol, 1999; 34:594-602 © 1999 by the American College of Cardiology Foundation |
a Division of Cardiology, Veterans Affairs Medical Center and the University of Minnesota Medical School, Minneapolis, Minnesota, USA
Manuscript received October 28, 1998; revised manuscript received February 28, 1999, accepted April 26, 1999.
Reprint requests and correspondence: Dr. Inder S. Anand, Professor of Medicine, University of Minnesota Medical School, Veterans Affairs Medical Center IIIC, 1 Veterans Drive, Minneapolis, Minnesota 55417
anand001{at}maroon.tc.umn.edu
 |
Abstract |
|---|
 Top Abstract MethodsResultsDiscussionConclusion and significanceReferences |
|---|
This study evaluated contractile function in cardiomyocytes isolated from hearts with global left ventricular dysfunction following ischemia-reperfusion.
BACKGROUND
Ischemia followed by reperfusion is associated with transient contractile dysfunction, termed "stunning." It is not clear whether this phenomenon is primarily due to intrinsic cardiomyocyte contractile dysfunction.
METHODS
Global contractile dysfunction was induced in isolated perfused rat hearts (n = 8) using a model of transient global ischemia (20 min) followed by reperfusion (20 min). Hearts perfused uninterrupted for 40 min were used as controls (n = 8). Cardiomyocytes were isolated using enzymatic digestion and were studied under varying degrees of inotropy (using increasing extracellular calcium [Ca2+]o) and loading conditions (varying extracellular perfusate viscosity). Mechanical function was studied with video edge detection and intracellular calcium ([Ca2+]i) kinetics using fura-2 AM.
RESULTS
Global ischemia-reperfusion increased left ventricle (LV) end diastolic pressure (450% vs. 33%, p < 0.01) and reduced LV developed pressure (9% vs. 33%, p < 0.01), LV positive (3% vs. 26%, p < 0.01) and negative (5% vs. 33%, p < 0.01) dP/dt. However, cells isolated from these hearts did not manifest contractile dysfunction. In fact, cell shortening (p < 0.0001) and peak rate of cell shortening (p < 0.05) and increase in [Ca2+]i with each contraction (p < 0.024) were higher in these cells during stimulation with [Ca2+]o of 1 to 10 mmol/liter. The EC50 values for calcium dose response and the slope of the relation between change in [Ca2+]i and change in cell length were no different between the groups. Cell loading (with increasing superfusate viscosity from 1 cp to 300 cp) also did not reveal any abnormalities in cells from the hearts subjected to ischemia-reperfusion.
CONCLUSIONS
Cardiomyocytes isolated from hearts with ischemia-reperfusion-induced LV dysfunction or "stunning" have normal contractile function and normal [Ca2+]i transients, when studied both in the unloaded and loaded state. Our data suggest that nonmyocyte factors such as abnormalities in extracellular matrix or abnormal myocyte-interstitial tissue coupling may be important for the genesis of cardiac contractile failure in the stunned heart.
| ||||||||||||||||
contractile failure in the stunned heart. Although these findings suggest that stunning may be due to intrinsic cardiomyocyte dysfunction, other data indicate that changes in the interstitium may contribute to ventricular dysfunction following single (18,19) or repeated episodes of ischemia and reperfusion (20).
Studies in myocytes isolated from the stunned heart may help to resolve whether the primary defect in stunning lies in the muscle itself. However, there are no reports that have systematically investigated the contractile behavior of cells isolated from the stunned heart. Cardiomyocytes, isolated from a number of models of heart failure, show contractile abnormalities (21,22). These abnormalities are thought to contribute to global ventricular dysfunction. However, we and other investigators have shown that severe global contractile dysfunction can coexist with apparently normal isolated cardiomyocyte function (23–25). We therefore evaluated the mechanical function (contraction and relaxation) and intracellular calcium ([Ca2+]i) transients in cardiomyocytes isolated from rat hearts subjected to ischemia and reperfusion to determine whether contractile dysfunction occurs at the cellular level.
|
Methods |
|---|
|
TopAbstractMethodsResultsDiscussionConclusion and significanceReferences |
|---|
Isolated perfused heart studies. Animals were anesthetized with 50 mg/kg pentobarbital IP and were given 1,000 IU/kg of heparin. The hearts were rapidly excised, arrested in ice-cold modified Krebs-Henseleit (KH) buffer, and suspended as a Langendorff preparation. Retrograde perfusion was started with KH buffer [containing (in mmol/liter) NaCl 117; KCl 5.6; CaCl2·2H2O 1.8; NaHCO3 20; KH2PO4 1.2; MgCl2·6H2O 1.2; glucose 12.1 gassed with 95% O2 and 5% CO2, pH 7.4 at 37°C] at 10 ml/g/min. A highly compliant fluid-filled latex balloon connected to a pressure transducer (Statham P23Db, Spectramed Oxnard, California) was inserted into the left ventricle (LV) for measuring ventricular pressures. Aortic perfusion pressure was measured using a pressure transducer connected to a side arm just above the aortic cannula. Temperature of the heart was measured using a fine temperature probe inserted into the left ventricular muscle. The heart temperature was maintained at 37°C throughout the experiment. All data were acquired on a data acquisition system (MacLab, AD Instruments, New South Wales, Australia) and were also continuously recorded on a paper chart recorder.
Protocol for global ischemia-reperfusion. The protocol for ischemia reperfusion was similar to that reported previously (5,7). After excising the atria, the atrioventricular (AV) node was crushed and the heart was paced at 4 Hz using a Grass Stimulator (Grass Instruments, Quincy, Massachusetts). The left ventricular balloon was inflated and the volume adjusted to maintain the left ventricular end diastolic pressure (LVEDP) at 10 mm Hg. Hearts were paced for 10 min before obtaining baseline measurements. These included left ventricular systolic pressure (LVSP), left ventricular developed pressure (LVDP = LVSP – LVEDP), positive and negative peak rate of change in LV pressures (+ve and –ve dP/dt) and the aortic perfusion pressure. Hearts were then randomly assigned either to the ischemia reperfusion protocol (called the "stunning" protocol hereafter; n = 8, 20 min ischemia followed by 20 min reperfusion) or to the control group (n = 8, 40 min of uninterrupted perfusion). A third group, called the "normal, nonperfused" group (n = 8, no ischemia, no prolonged buffer perfusion), was used to see if prolonged perfusion (as in the control group) itself affected isolated cardiomyocyte function. Hearts in this normal group were directly subjected to enzymatic digestion for isolating cardiomyocytes, without any prolonged buffer perfusion. Ischemia was induced by complete cessation of flow. Pacing was stopped at onset of ischemia and reinstituted 3 min after onset of reperfusion. Hearts were kept moist and maintained at a constant temperature of 37°C using a chamber filled with iso-osmotic buffer. All pressures were continuously monitored during the course of the experiment.
Isolated cardiomyocyte studies.
Isolation of rat cardiac myocytes
Cardiomyocytes were isolated using our previously described protocol (23). Briefly, the coronary arteries were perfused for 5 min with the prewarmed (37°C) HEPES buffer ([in mmol/liter]: NaCl 120; KCl 5.4; MgSO4 5; pyruvate 5; glucose 20; taurine 20; and HEPES 10; 1 mmol/liter calcium, pH 7.4), rapidly switched to nominally calcium free (10 to 12 mmol/liter calcium) HEPES solution for 7 min and then changed to the enzyme solution (1 mg/ml type II collagenase [Worthington Biochemicals, Freehold, New Jersey], 0.8 mg/ml hyaluronidase [Sigma Chemical, St. Louis, Missouri], and 30 µmol/liter of calcium in the HEPES buffer) for 20 min (26). The heart was removed and dissected in fresh enzyme solution to remove residual atrial and right ventricular tissue. The LV tissue was cut into 1-mm3 pieces, and agitated in a temperature-controlled water bath for 10 min. Cells were collected by filtering the solution through a nylon mesh and suspended in 200 µmol/liter calcium HEPES buffer. Cardiac myocytes were loaded with fura by incubating 1 ml of myocyte suspension with fura-2 AM (0.5 µmol/liter) for 20 min at 37°C. This protocol has been shown to minimize compartmentalization of fura or generate calcium-insensitive/incompletely de-esterified forms of fura-2 (27,28). We have found excellent and uniform loading with these concentrations without affecting myocyte viability.
Isolated myocyte function studies
Simultaneous mechanical function and intracellular calcium data were continuously obtained during contraction and relaxation for each cell using our previously described method (23). This allowed us to relate mechanical events to simultaneous changes in intracellular calcium kinetics in our study.
Myocyte mechanical function studies
Myocytes were studied in a custom-designed perspex chamber. The equipment consisted of an inverted-phase contrast microscope (Olympus IMT-2, Leeds Precision Instruments, Minneapolis, Minnesota) coupled with a noninterlacing high-speed CCTV video camera (Javelin, Los Angeles, California). Video images of the myocyte were passed through a video edge detector (VED 103, Crescent Electronics, Sandy, Utah) and displayed on a video monitor. Myocyte edges were continuously tracked during contraction and relaxation, displayed as a voltage signal proportional to the changes in myocyte length, and sent to a dedicated on-line analysis package (IonOptix, Milton, Massachusetts) on a Pentium PC for analyses of various contraction and relaxation parameters.
Intracellular calcium studies
Intracellular calcium transients were measured using the fluorescent indicator fura-2 AM. Measurement of intracellular calcium was done using the Interpolated Numerator Strategy as previously described (23,27,28).
Study protocol
Myocyte function was assessed using two separate protocols. In the first protocol, cells were studied in the unloaded state. The second protocol evaluated myocyte mechanical function in the presence of external loading.
Criteria for selecting cells for the study. Cells were selected for study using previously defined criteria (26). Cells were studied if they had sharp outlines, clearly visible striations and were without blebs. They did not show spontaneous contractile activity while suspended in HEPES buffer containing 1 mmol/liter extracellular calcium. Selection bias was further limited by consecutively studying all eligible cells in the randomly chosen field, irrespective of size or shape.
Protocol for studying unloaded cells
Fura-2 AM loaded myocytes were allowed to adhere to the base of a perspex perfusion chamber. Study drugs were made in the HEPES buffer with 1 mmol/liter calcium, which was prewarmed, oxygenated, and perfused into the chamber at 1 ml/min. The cells were superfused with 1 mmol/liter calcium HEPES buffer at 32°C and paced at 0.5 Hz for 10 min before basal recordings were made. The HEPES buffer with increasing extracellular calcium ([Ca2+]o) was (up to 10 mmol/liter in steps of 2 mmol/liter) superfused for 3 min at each dose to obtain a calcium dose response curve. All myocyte studies were completed within 3 to 4 h of isolation.
Protocol for studying loaded cells
Because load is an important determinant of cellular function, we used a protocol of cellular loading using increasing concentrations of methylcellulose in the cell suspension media as described by Kent et al. (29). Media viscosity was measured using a falling-ball viscometer. Cells were suspended in media of increasing viscosity (1 cp to 300 cp) and the contraction and relaxation parameters were studied under resting conditions and during peak inotropic stimulation using increasing extracellular calcium. Because the behavior of fura-2 in this setup is unclear, only mechanical function measurements were made in these cells.
Parameters measured for inotropic and lusitropic function
Contractile function in the cells was measured using the following parameters: peak % cell shortening (normalized to resting cell length), peak (+ve dL/dt) and mean rate of cell shortening, and time to peak shortening. Cellular relaxation indexes included peak (–ve dL/dt) and mean rate of cell relengthening, and time to 70% relengthening. Similar indexes were used to analyze the intracellular calcium transients.
Statistics. Single between-group comparisons of continuous, normally distributed data were done using an unpaired t test. Comparisons of dose-response curves between the two groups were done with a two-way ANOVA for repeated measures using the multivariate analysis of variance (MANOVA) module of a commercially available package (Statistica, Statsoft, Tulsa, Oklahoma). Comparison of slopes of the relation between calcium and cell shortening in the two groups was done using linear regression. All data are expressed as mean ± SE. A p < 0.05 was considered significant.
|
Results |
|---|
|
TopAbstractMethodsResultsDiscussionConclusion and significanceReferences |
|---|
|
|
|
Similarly, when the cell shortening was added over all doses, cells from the hearts subjected to ischemia-reperfusion had greater shortening compared with controls (ANOVA group effect, p < 0.0001). The cardiomyocyte dose-response curve revealed a plateau in cell shortening after 6 mmol/liter [Ca2+]o in both groups. There was no difference in the EC50 for calcium dose response between myocytes from the control and hearts subjected to ischemia-reperfusion (LogEC50 1.6 ± 0.14 in stunned hearts, 95% CI 1.13 to 2.01 vs. 2.3 ± 0.27 in controls, 95% CI 1.5 to 3.2).
Other mechanical indexes. The basal (1 mmol/liter [Ca2+]o) peak positive and peak negative dL/dt were similar in both groups of cells (Table 2). However, cells from the hearts subjected to ischemia-reperfusion had a higher positive dL/dt (with max [Ca2+]o: 284 ± 18 µm/s vs. 187 ± 13 µm/s, p = 0.001), negative dL/dt [with max [Ca2+]o: 222 ± 21 µm/s vs. 130 ± 11 µm/s, p = 0.002] and mean velocity of shortening (with max [Ca2+]o: 104 ± 5.7 µm/s vs. 76 ± 4.6 µm/s, p = 0.005). The time to peak shortening and time for 70% relaxation were not significantly different between the two groups.
Myocyte intracellular calcium. These data are presented in Figure 2 and Table 2. Resting diastolic [Ca2+]i was similar in both groups of cells (81 ± 4 nmol/liter vs. 85 ± 2 nmol/liter at 1 mmol/liter [Ca2+]o) and increased with increasing [Ca2+]o, to a similar extent in both groups (133 ± 8 nmol/liter vs. 134 ± 25 nmol/liter at the highest dose of [Ca2+]o, p = 0.15). Increasing [Ca2+]o caused a dose-dependent increase in the amplitude of the [Ca2+]i transient seen with each contraction; however, the increase was higher in cells from hearts subjected to ischemia-reperfusion (Fig. 2) when analyzed over the dose-response curve (the interaction factor p = 0.024) or when averaged over all the calcium doses (Group factor, p = 0.002). Likewise, the peak rate of rise of calcium (peak positive dCa2+/dt, p = 0.005) and peak rate of decline of Ca2+ transients (peak negative dCa2+/dt, p = 0.006) were higher in the cells from hearts subjected to ischemia-reperfusion, whereas time to peak (p = 0.67) and time to 70% decline (p = 0.99) of calcium transients were not significantly different when analyzed over the whole range of [Ca2+]o.
|
|
|
|
Discussion |
|---|
|
TopAbstractMethodsResultsDiscussionConclusion and significanceReferences |
|---|
Studies in isolated cardiomyocytes have several advantages; the confounding effects of perfusion limitation, substrate deficiency, autonomic influences and the restraining effects of the interstitium are avoided. Thus, any difference in cell shortening in unloaded cardiomyocytes would represent differences in "intrinsic cellular" contractile properties. Our studies suggest that global contractile dysfunction seen in the "stunned" heart cannot be entirely explained on the basis of "intrinsic" contractile dysfunction in cardiomyocytes.
There is little published data on the mechanical behavior of cells isolated from the stunned heart. One study, partly addressing this issue, was conducted by Lew et al. (12), who found reduced cell shortening in cells from rabbits with regional ischemia. However, they did not find any abnormalities in peak rates of shortening or relengthening in cells from the stunned hearts. These data suggest that cellular abnormalities do not fully explain myocardial stunning. The Lew et al. (12) study was also limited by the fact that they investigated only a few cells, evaluated one single dose of extracellular calcium, and did not obtain a dose-response curve or maximal cellular effects of extracellular calcium. Moreover, they induced stunning in vivo, in a rabbit subjected to general anesthesia, and their cell-isolation procedure lasted four times longer than did ours. These factors may explain some of the differences between their findings and ours.
Another preliminary study found that 30 min of ischemia followed by 30 min of reperfusion in a canine model was associated with a paradoxical increase in isolated cell shortening at a time when both global and regional functions were depressed (31). Although that report did not clarify the number of cells studied, the findings are consistent with the results in our study.
Is stunning a cellular or extracellular phenomenon?. The mechanisms responsible for stunning are unclear. Increased oxygen free radicals have been implicated as an important factor in the genesis of stunning (30). However, the exact site (cellular or extracellular) at which these and other mediators of stunning act to produce myocardial contractile failure is controversial. Evidence from isolated muscle preparations seems to suggest that a calcium overload causes activation of intracellular proteolytic enzymes, which in turn affect the myofilament regulatory proteins (4,5,32). Moreover, a number of intracellular abnormalities in the excitation contraction coupling pathway have been described (1–3,30), suggesting that stunning occurs at the cardiomyocyte level.
However, other data seem to suggest that changes in myocardial interstitium may also contribute to contractile dysfunction in stunning (18,19,33). Zhao et al. (19) showed that ischemia-reperfusion can result in degradation of interstitial collagen, which could contribute to ventricular dysfunction in stunning. Charney et al. (18) found that ischemia-reperfusion is followed by a significant reduction in collagen content and activation of endogenous collagenase in the stunned myocardium. Others, however, found that repeated episodes of ischemia and reperfusion are needed for these changes to develop (20). Studies by Yoshida et al. (16) showed that stunning is associated with a rapid degradation of cardiac structural proteins; such an effect could impair cell-to-cell coupling and probably reduce force transmission. Thus, the relative contributions of myocellular versus extracellular dysfunction in stunning is far from resolved. Our data do not support a primary role for intrinsic cardiomyocyte dysfunction in stunning.
Myofilament calcium responsiveness and stunning. Two major abnormalities in calcium and myofilament interaction have been postulated to account for stunning (2), namely (a) reduced maximal calcium activated force development and (b) reduced calcium sensitivity (shortening response per unit change in intracellular calcium). Much of this data is controversial. Reduced maximal calcium activated force generation has been demonstrated in both isolated (5,7,8) and in situ preparations (6). However, others could not confirm this in whole heart canine (15,34) and porcine preparations (35), in skinned trabeculae (9,11) or in loaded myocyte-sized preparations from the stunned heart (9,10). Methods for measuring force generation at the single-cell level are imperfect as yet (36), and there is therefore no such data in isolated single cardiomyocytes. However, we found that maximal cell shortening, an approximate surrogate of maximal force generation (37), was unimpaired in cells from the stunned heart.
Abnormal myofilament calcium sensitivity has been demonstrated in the whole heart (7), in isolated muscle preparations (5) and in isolated skinned fibers (9); also, improving calcium sensitivity is known to benefit the stunned heart (38). However, other investigators have not been able to confirm this in a number of different experimental preparations (6,8,10,11,35). In our studies, when peak change in intracellular calcium was plotted against peak cell shortening, the slopes of the lines were similar in the stunned and normal hearts (Fig. 3). These data argue against altered "intrinsic" myofilament calcium sensitivity in the development of ventricular stunning.
Mechanical transient kinetics in the stunned heart. Maximum velocity of shortening of unloaded muscles is thought to reflect cross-bridge cycling rate (5,10) and has been used as an index of contractility. Maximum velocity of shortening was reduced in unloaded myocyte-sized preparations from the stunned heart in one study (10) and was postulated to contribute to contractile dysfunction. However, other studies did not find reduced time to peak shortening in muscle preparations (5). Some have found even an increase in peak rate of cell shortening in cardiomyocytes isolated from the stunned heart (12), which is similar to our findings.
Diastolic function is thought to be altered in the stunned heart (39,40). However, relaxation is paradoxically enhanced in trabeculae (5) and cells (12) from the stunned heart. We, too, found that the peak rate of cell relengthening and peak rate of change in intracellular calcium during cell relaxation were higher in the stunned cells. Thus, cells isolated from the stunned heart and manifesting severe diastolic dysfunction do not exhibit major relaxation abnormalities when studied in the unloaded state. Moreover, the lack of abnormalities in cell relaxation seen in our studies is consistent with unimpaired rate of calcium uptake by the sarcoplasmic reticulum (5,41,42).
Intracellular calcium kinetics. Although intracellular calcium is known to increase during ischemia and early reperfusion, most studies show a rapid return to normal (42). Peak [Ca2+]i is not reduced in the stunned heart (41,43) and was even found to be increased in one study (7). This is consistent with the absence of major changes in [Ca2+]i in stunned cells in our studies. Studies by Gao et al. (5) suggest that trabeculae from the stunned heart are unable to handle calcium homeostasis in the presence of increased [Ca2+]o. When exposed to increasing [Ca2+]o, the diastolic calcium rose only in the muscle trabeculae isolated from the stunned hearts. We found that even at a higher extracellular calcium (than that in previous reports), the increase in resting diastolic intracellular calcium was similar to that seen in cells from the normal heart. The reason for this difference is unclear.
Can normal cardiomyocyte function coexist with abnormal whole heart function?. It might appear counterintuitive that cells isolated from the stunned heart contract normally. There is, however, evidence that dysfunction in the whole heart can coexist with normal isolated cardiomyocyte function in some models of congestive heart failure (CHF). We have recently shown that cardiomyocytes isolated from rats with severe LV remodeling and global LV dysfunction had normal contractile function in the unloaded state (23). We hypothesized that changes in the interstitium or in the structural proteins could impair force transmission and explain global LV dysfunction, despite normal cardiomyocyte contractility. A similar situation may exist in the stunned heart. Todaka et al. (33) showed that degrading cardiac interstitial collagen with 5,5-dithio-z-nitrobenzoic acid (DTNB) caused significant systolic and diastolic abnormalities, similar to that seen in the stunned heart. However, cardiomyocytes treated with DTNB contracted normally. A number of other changes occur during stunning and could contribute to contractile dysfunction in the heart independent of any changes in "intrinsic" cardiomyocyte function. Yoshida et al. (16) showed a significant degradation of calspectrin, a structural protein, located predominantly at the intercalated disks. This could impair cell-to-cell electromechanical coupling and might manifest as whole-heart dysfunction even in the presence of normal cardiomyocyte function.
Study limitations. It has been argued that this model of global ischemia-reperfusion in the rat heart (in vitro) may not represent true stunning (30). Some believe that this might be better termed "postischemic ventricular dysfunction." Although this is an area of ongoing debate, a number of studies have used this model as representing a stunned heart (4,5,7,8,11). Studies in isolated cardiomyocytes have several advantages, but they should be interpreted in light of several methodological limitations. In general, isolated preparations are unphysiologic and lack the compensatory mechanisms associated with adequate blood flow and circulating catecholamines. Therefore, it is not clear to what extent these results directly reflect the in vivo situation. Methods of loading the cell are presently imperfect (36); we used graded viscous loading (23,29), but it is unclear how this relates to the load seen by cardiomyocytes in vivo.
Although cells were studied within 3 to 4 h of isolation, it is possible that intracellular changes associated with stunning might have recovered in this period. This, however, seems unlikely because contractile dysfunction persists for a much longer period in stunned hearts (12) and in isolated muscle preparations (5). The isolation process itself may kill the more severely affected cells and bias the results toward normally functioning cells. We believe that this is less likely given the similar yield of viable myocytes (72 ± 5% and 74 ± 6% in stunned and control groups, respectively, p = NS) in both the groups in our study.
Finally, there could be a selection bias while choosing cells for study. We used previously defined and validated criteria for selecting cells for study (23,26,44), which would limit selection bias. Second, the mean length (112 ± 1.6 vs. 114 ± 2 µm) and width (22 ± 0.4 vs. 22 ± 0.6 µm) of cells studied were similar, suggesting that similar distributions of cells were studied in both groups. Third, a large number of cells were examined (203 cells from the stunned heart and 180 from control hearts), much more than most of the published reports that have evaluated isolated cardiomyocyte function (12,23,44–49), making the results more representative.
|
Conclusion and significance |
|---|
|
TopAbstractMethodsResultsDiscussionConclusion and significanceReferences |
|---|
|
References |
|---|
|
TopAbstractMethodsResultsDiscussionConclusion and significanceReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  T Bragadeesh, A R Jayaweera, M Pascotto, A Micari, D E Le, C M Kramer, F H Epstein, and S Kaul Post-ischaemic myocardial dysfunction (stunning) results from myofibrillar oedema Heart, February 1, 2008; 94(2): 166 - 171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Deschamps, J. Zavadzkas, R. L. Murphy, C. N. Koval, J. E. McLean, L. Jeffords, S. M. Saunders, N. J. Sheats, R. E. Stroud, and F. G. Spinale Interruption of endothelin signaling modifies membrane type 1 matrix metalloproteinase activity during ischemia and reperfusion Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H875 - H883. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. R. Heyndrickx Early reperfusion phenomena. Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2006; 10(3): 236 - 241. [Abstract] [PDF]
|
|
|
|
|
|
H. K. Saini, V. Elimban, and N. S. Dhalla Attenuation of extracellular ATP response in cardiomyocytes isolated from hearts subjected to ischemia-reperfusion Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H614 - H623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. K. Saini and N. S. Dhalla Defective calcium handling in cardiomyocytes isolated from hearts subjected to ischemia-reperfusion Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2260 - H2270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. B. C. Dang, J. M. Guccione, J. M. Mishell, P. Zhang, A. W. Wallace, R. C. Gorman, J. H. Gorman III, and M. B. Ratcliffe Akinetic myocardial infarcts must contain contracting myocytes: finite-element model study Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1844 - H1850. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Baicu, J. D. Stroud, V. A. Livesay, E. Hapke, J. Holder, F. G. Spinale, and M. R. Zile Changes in extracellular collagen matrix alter myocardial systolic performance Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H122 - H132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M. Vizgirda, G. M. Wahler, K. L. Sondgeroth, M. T. Ziolo, and D. W. Schwertz Mechanisms of sex differences in rat cardiac myocyte response to beta -adrenergic stimulation Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H256 - H263. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
