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(Circulation. 1997;96:3974-3984.)
© 1997 American Heart Association, Inc.

Articles

Isolated Myocyte Contractile Function Is Normal in Postinfarct Remodeled Rat Heart With Systolic Dysfunction

Inder S. Anand, MD, DPhil (Oxon), FRCP; Daosheng Liu, MD; Sumeet S. Chugh, MD; Arun J.C. Prahash, MD; Sudhir Gupta, PhD; Rohan John, MD; F. Popescu, BSc; ; Y. Chandrashekhar, MD, DM

From the Department of Cardiology, University of Minnesota School of Medicine, VA Medical Center (Minneapolis).

Correspondence to Inder S. Anand, MD, DPhil (Oxon), FRCP, Professor of Medicine, Department of Cardiology, VA Medical Center 111C, Minneapolis, MN 55417. E-mail anand001{at}maroon.tc.umn.edu

	Abstract

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Background Postinfarction ventricular remodeling is associated with lengthening and contractile dysfunction of the remote noninfarcted myocardium. Mechanisms underlying this phenomenon remain unclear.

Methods and Results We studied serial changes in global left ventricular (LV) structure and function in infarcted (1, 2, 4, and 6 weeks after myocardial infarction) and sham-operated rat hearts and correlated them with structural and functional changes in myocytes isolated from the remote LV myocardium in the same hearts. Rats with myocardial infarction developed significant remodeling. The heart weight–to–body weight ratios were increased. LV volumes at filling pressure of 10 mm Hg were higher (305±28 versus 215±12 µL, P<.01). This was accompanied by global LV dysfunction (in vivo LV end-diastolic pressure, 4±1 versus 23±1.6 mm Hg; Langendorff LV developed pressure, 105±4 versus 62±9 mm Hg, P<.001 for both). Myocytes isolated from these hearts showed significant structural remodeling (LV myocytes, 24% longer and 15% wider; right ventricular myocytes, 38% longer and 31% wider, all P<.05). LV myocyte length correlated with changes in LV volume (r=.79) and function (LV developed pressure, r=-.81). However, LV myocytes from the same hearts showed normal contractile function and intracellular Ca²⁺ transients at baseline and during inotropic stimulation with increasing extracellular Ca²⁺ (1 to 6 mmol/L). The shortening-frequency relationship was also similar in myocytes from sham and myocardial infarction rats.

Conclusions Postinfarct LV remodeling occurs predominantly by myocyte lengthening rather than by myocyte slippage. However, contractile function of the unloaded myocytes from the remote noninfarcted LV myocardium of the remodeled heart is normal. Therefore, myocyte contractile abnormalities may not contribute to global dysfunction of the remodeled heart. Reduced myocyte mass and nonmyocyte factors like increased wall stress, altered LV geometry, and changes in the myocardial interstitium may be more important in the genesis of postinfarct LV dysfunction in this model.

Key Words: myocardial infarction • remodeling heart failure • contractility • myocytes

	Introduction

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The development of CHF is one of the most significant events in the natural history of patients with MI and is an important predictor of adverse prognosis.^1,2 Unfortunately, although the incidence of MI is decreasing in the developed world, the prevalence of CHF continues to increase.³ The occurrence of CHF soon after a very large MI or after repeated infarctions, which cumulatively result in severe loss of left ventricular muscle, is to be expected. However, in a larger group of patients, the LV undergoes a series of morphologic changes characterized by progressive increase in LV mass and volume and decrease in global LV systolic performance.^2,4 These changes, termed ventricular remodeling, culminate in CHF despite the fact that the initiating MI itself did not compromise LV performance. Although ACE inhibitor therapy has been shown to attenuate post-MI remodeling,^5–7 CHF remains a significant clinical problem. A major obstacle to more effective prevention of post-MI CHF is the lack of clear understanding of its pathogenesis; such an understanding might lead to more effective therapeutic approaches.

The global systolic LV dysfunction seen during post-MI remodeling is associated with lengthening and progressive contractile dysfunction of myocardial segments remote from the infarcted myocardium.^4,8–10 The mechanisms responsible for global LV dysfunction and contractile dysfunction of the remote noninfarcted myocardium are not fully understood. A number of changes are observed in the post-MI hearts that could explain global LV dysfunction, including alterations in LV geometry,⁴ changes in interstitial collagen¹¹ and other structural proteins,¹² and myocyte loss from apoptosis.^13,14 LV dysfunction may also be explained by a decrease in ß-adrenergic receptor density and second-messenger pathways.^15,16 In addition, various intrinsic biochemical^17,18 and bioenergetic^19,20 abnormalities have been described in the surviving myocardial cells. If the latter have functional importance, the contractile properties of the myocytes should be impaired. Whether myocytes isolated from areas remote from the infarct zone manifest contractile dysfunction remains controversial and has not been addressed comprehensively.^21–25

We hypothesized that because LV enlargement during remodeling results largely from an increase in the length of the remote noninfarcted contractile segment of the myocardium,⁴ the extent of LV dilatation and dysfunction would be proportional to the degree of myocyte structural changes in noninfarcted myocardium. We also hypothesized that because myocytes in the remote noninfarcted myocardium are exposed to chronic increase in wall stress,^20,26 they are likely to show intrinsic contractile abnormalities. The purpose of this study was, therefore, to test these hypotheses by determining (1) the extent to which structural changes in the myocytes isolated from remote noninfarcted myocardium can explain LV dilatation and global LV dysfunction and (2) whether defects in the contractile function and intracellular Ca²⁺ transient kinetics of isolated myocytes contribute to the global LV systolic dysfunction seen in the remodeled heart. The well established rat infarct model of heart failure was used in this study. Experiments were designed to study LV remodeling and LV systolic function and isolated myocyte structure and function in the same hearts of MI and sham-operated rats.

	Methods

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Model
Male Sprague-Dawley rats weighing 250 to 300 g were used. Coronary artery ligation to produce MI was performed as described by Pfeffer et al.² In sham-operated rats, a suture was passed around the coronary artery but not tied. Rats (n=46) surviving the procedure were studied at 1 week (10 rats, 6 MI and 4 sham), 2 weeks (10 rats, 6 MI and 4 sham), 4 weeks (11 rats, 7 MI and 4 sham), and 6 weeks (15 rats, 10 MI and 5 sham) after surgery. Hemodynamic measurements were made in all animals. Isolated heart function was studied in 25 animals (16 MI rats; 3 rats each at 1, 2, and 4 weeks and 7 rats at 6 weeks post-MI; and 9 sham rats). Myocytes were isolated from all animals for morphometric and functional studies; thus, we were able to correlate the indices of global LV function with myocyte morphology and function in the same heart. A separate group of sham-operated (n=8) and MI rats (n=6) were also studied 6 weeks after surgery to compare the effects of temperature (30°C versus 37°C) and frequency of stimulation (0.2, 0.3, 0.5, 1, and 2 Hz) on myocyte function. The study was approved by our institutional review board.

Hemodynamics in the Intact Rat
Under ether anesthesia, rats were intubated and connected to a Harvard rodent respirator (model 683 Harvard Apparatus). The right carotid artery was cannulated by a saline-filled PE 50 catheter connected to a pressure transducer (Statham P23Db, Spectramed). Data were acquired with acquisition software (Chart v3.5, Maclab, AD Instruments). After recording of aortic pressure, the catheter was advanced to record LVEDP and LVSP.

Isolated, Perfused Rat Heart Studies
After hemodynamic studies, rats were heparinized (1000 U IP) and hearts were excised, rapidly immersed in ice-cold buffer, and weighed. Retrograde aortic perfusion was then initiated with modified Krebs-Henseleit buffer containing (in mmol/L) NaCl 117, KCl 5.6, CaCl₂.2H₂O 1.8, NaHCO₃ 20, KH₂PO₄ 1.2, MgCl₂.6H₂O 1.2, and glucose 12.1, pH 7.4, gassed with 95% O₂/5% CO₂ in a Langendorff setup (flow, 10 mL · g^-1 · min^-1 at 37°C). Both atria were excised, and the RV and LV vented. A highly compliant, fluid-filled latex balloon connected to a pressure transducer was inserted into the LV. Baseline LVDP (=LVSP-LVEDP) was recorded at an LVEDP of 10 mm Hg, while hearts were paced at 4 Hz. LVDP was taken as an index of global LV function.

Passive Diastolic P-V Relationship of the Heart
Hearts were then arrested in diastole using cold (4°C) cardioplegia and a set of three P-V curves recorded. Balloon volume was increased in increments of 5 µL using a microsyringe while recording the intraventricular pressures over the range of 7.5 to +30 mm Hg. The balloon compliance was much greater than that of the LV under study. The absolute LV volume at any diastolic pressure was calculated as the sum of the volume injected and the predetermined volume of the collapsed balloon. LVV₁₀ was computed as an index of LV remodeling.

Measurement of Myocyte Morphology, Contractile Function, and Intracellular Ca²⁺
Myocyte Isolation Procedure
After study of the P-V relationships, hearts were reperfused for 5 minutes with oxygenated HEPES buffer, and myocytes were enzymatically isolated as described previously.^27,28 Hearts were removed when they were digested, and the RV free wall was separated from LV and septum. In the MI rats, the infarct area and a 2-mm rim of the adjoining normal appearing myocardium was removed and discarded. Myocytes from RV and LV of sham-operated rats and from RV and LV remote from the infarct in the MI rats were isolated separately. Cells were suspended in 200 µM Ca²⁺ HEPES buffer and divided into aliquots for functional and morphometric studies. Function studies were done in LV myocytes only. Aliquots of cells for morphometric analysis were fixed in 1.5% glutaraldehyde.

Measurement of Myocyte Morphology
The length and width of 100 randomly chosen myocytes from each heart were determined by phase contrast microscopy. Myocyte length was defined as the longest dimension parallel to the long axis of the cell, and the width was defined as the widest dimension perpendicular to the long axis. A total of 1500 RV and LV myocytes from sham-operated and 2100 RV and 2800 LV myocytes from MI hearts were measured. In addition, length and width were recorded separately on myocytes whose contractile function was studied.

Measurement of Myocyte Contractile Response and Intracellular Ca²⁺
Simultaneous myocyte contractile and intracellular Ca²⁺ transient measurements were made using a high-speed (240-Hz) CCD camera (model TM640, Pulnix) and a video edge detector (model VED 103, Crescent Electronics)²⁹ coupled to a dual-excitation fluorescence system (IonOptix Corp). Excitation light alternating between wavelengths 360 and 380 nm was directed to the myocytes, and the ratiometric strategy called Interpolated Numerator was used for Ca²⁺ quantification.³⁰ In vivo calibration was done according to Cheung et al.³⁰

Study Protocol
FURA-2 AM–loaded LV myocytes were studied in a specially designed perfusion chamber perfused at 2 mL/min with HEPES buffer at 30°C or 37°C. Myocytes were stimulated by a bipolar field stimulator. Two protocols were used.

Dose-Response Relationship to Extracellular Ca²⁺
In the first protocol, a Ca²⁺ dose-response relationship (1, 2, 4, and 6 mmol/L Ca²⁺) was obtained for myocytes at 30°C and 0.5 Hz.

Myocyte Shortening-Frequency Relationship at 30°C and 37°C
The second protocol was done to compare the effect of temperature (30°C and 37°C) and stimulation frequency (0.2, 0.3, 0.5, 1, and 2 Hz). Each myocyte was tested at both temperatures and at all five frequencies.

Statistical Analysis
All data are presented as mean±SEM. Amplitude of myocyte shortening is expressed as percent of resting myocyte length, mean velocity of shortening is the average rate of change myocyte length (µm/s), and positive and negative dL/dt are the peak rates of change in myocyte length (µm/s). Time to 70% relengthening is expressed in ms. The Ca²⁺ transient parameters that were analyzed include amplitude of 360/380 nm ratio, mean velocity of rise in 360/380 nm ratio, peak rate of change in 360/380 nm ratio (positive and negative d[Ca]ratio/dt), and time to 70% reduction in peak ratio. Myocyte contractile data were analyzed with a repeated-measures ANOVA where applicable. For shortening-frequency study, a two-way (temperature and stimulation frequency) repeated-measures ANOVA was used. A value of P<.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The body weight, heart weight, and heart weight–to–body weight ratios of the MI and sham-operated rats are shown in Table 1. Both groups of animals gained weight with age. The increase in weight was, however, greater in the sham-operated than in the MI rats (P<.005). The hearts from sham-operated rats showed a small increase in weight over the 6-week period, but the weight of hearts from MI rats, as a group, was significantly greater (P<.001). The heart weight–to–body weight ratio was also significantly greater in the MI group (P<.001).

View this table: [in this window] [in a new window]   Table 1. Body Weight, Heart Weight, and Hemodynamics in Sham-Operated and MI Rats

In Vivo Hemodynamics
Hemodynamic data are displayed in Table 1. The heart rates of sham-operated and MI rats were similar at all time points. In MI rats as a group, the systolic, diastolic, and mean arterial blood pressures and LVSP were lower and LVEDP was higher than in sham-operated rats (P<.001 in each case) and remained so throughout the study.

LV Function in Isolated, Perfused Hearts
Isovolumic LVDP was compared in 10 sham-operated and 16 MI rats under similar LVEDP (10 mm Hg) and aortic perfusion pressure (70 to 80 mm Hg). LVDP was similar in the 1-, 2-, 4-, and 6-week sham-operated hearts. Hence, data for all rats in the sham-operated group were combined. Compared with these, MI rats as a group had depressed LV systolic function (LVDP, 105±4 versus 62±9 mm Hg, P<.001). Although rats with longer duration of MI tended to have lower LVDP, the numbers were too small for statistical comparison.

LV Developed P-V Relationships
The LV diastolic P-V relationship was shifted to the right in the MI rats compared with sham-operated rats (Fig 1). LVV₁₀ was significantly higher in the MI than the sham-operated hearts (305±28 versus 215±12 µL, P<.01). Again, there was a trend for rats with longer duration of MI to have larger ventricular volumes.

View larger version (15K): [in this window] [in a new window]   Figure 1. Diastolic P-V relationship in sham and remodeled MI hearts. MI hearts show a rightward shift in the P-V relationship, a characteristic feature of the remodeled heart.

Morphology of Isolated Cardiac Myocytes
Regional differences in myocyte length and width for the sham-operated and MI rats are summarized in Table 2. LV myocytes were both longer and wider than RV myocytes in sham-operated rats (P<.01) There was a small but insignificant trend toward an increase in the length but not the width of LV myocytes in sham-operated rats, as animals grew, over the 6-week period. Length and width of RV myocytes in the sham-operated group did not change during the study period. The most impressive change was the time-dependent increase in the length of LV and RV myocytes in the MI group (P<.001). A small increase in the width of LV myocytes from MI rats was also seen (P<.05) over this period. At 6 weeks, the LV myocytes from MI rats were 22% longer (138 versus 113 µm, P<.001) and 14% wider (23 versus 20 µm, P<.001) than myocytes from the sham-operated hearts. The length and width of RV myocytes were also larger in the MI rats when averaged over at all time points (P<.01). At 6 weeks, RV myocytes from MI rats were 38% longer (131 versus 95 µm) and 31% wider (22 versus 17 µm) than those from their sham counterparts. Length-to-width ratios of RV and LV myocytes as a group were significantly greater in the MI than in sham-operated rats (P<.05).

View this table: [in this window] [in a new window]   Table 2. Myocyte Morphology in Sham-Operated and MI Rats

The length and width of LV myocytes were also measured on those cells selected for functional study. The mean length of the 68 myocytes from sham-operated rats (131±3 µm) was not significantly different from myocytes of 1- or 2-week post-MI rats. Myocytes from the 4- and 6-week MI rats were, however, longer than their sham counterparts (Tables 3 and 4). Therefore, myocytes chosen for the contractile function study were more severely remodeled than the average dimensions of myocytes selected for morphological analysis.

View this table: [in this window] [in a new window]   Table 3. Myocyte Contractile Function in Sham-Operated and MI Rats

View this table: [in this window] [in a new window]   Table 4. Myocyte Intracellular Ca2+ Transient Analysis in Sham-Operated and MI Rats

Contractile and Intracellular Ca²⁺ Responses of Isolated Myocytes
The contractile function and intracellular Ca²⁺ transient kinetics of 68 LV myocytes from 17 sham-operated rats were compared with 83 LV myocytes from 29 rats with MI.

Contractile Responses
Extracellular Ca²⁺ [Ca²⁺]_o (1, 2, 4, and 6 mmol/L) caused a dose-dependent increase in percent shortening, velocity of shortening, peak positive dL/dt, peak negative dL/dt, and a decrease in time to 70% relengthening of myocytes from sham-operated rats. No differences in these contractile parameters were seen in myocytes isolated from sham-operated rats over the 6 weeks. Therefore, data for all weeks were combined for sham-operated rats (Table 3 and Fig 2). Myocytes from MI rats also showed similar dose-dependent responses to [Ca²⁺]_o. There were no differences in the dose response relationship of any of the contractile parameters between myocytes from MI rats at 1, 2, 4, and 6 weeks post-MI and those from sham-operated rats (ANOVA interaction term). However, when contractile responses were averaged over all four [Ca²⁺]_o doses in each group, myocytes from MI rats were found to show higher responses in some contractile parameters compared with myocytes from sham-operated rats. These are summarized in Table 3 and Fig 2.

View larger version (27K): [in this window] [in a new window]   Figure 2. Ca2+ dose response for some contractile parameters. There were no significant differences between sham and MI myocytes (interaction term) in any parameters. Taken as a group (averaged over the four Ca2+ doses), however, a small increase in myocyte shortening and positive dL/dt was seen in 2- and 6-week MI rats. Myocytes from 1-, 2-, 4-, and 6-week MI rats (each as a group) had a slightly higher velocity of shortening than sham myocytes. The negative dL/dt of 6-week MI rats was also higher than that of sham rats. P values are for the group factor.

Intracellular Ca²⁺ Responses
Intracellular Ca²⁺ during each contraction cycle was expressed as FURA 2-360/380 nm fluorescence ratio. Like the contractile response, increase in [Ca²⁺]_o caused a dose-dependent increase in the 360/380 ratio nm amplitude, velocity of rise in 360/380 nm ratio, peak positive d[Ca]ratio/dt, peak negative d[Ca]ratio/dt, and a decrease in the time to 70% fall in 360/380 nm ratio amplitude (Table 4 and Fig 3). Because intracellular Ca²⁺ transient parameters in myocytes from different weeks of sham-operated rats were similar, data from all sham myocytes was combined. Myocytes from all MI rats also demonstrated similar dose-dependent changes in Ca²⁺ transient parameters and were not significantly different from those seen in myocytes from sham-operated rats. However, when responses were averaged over all four [Ca²⁺]_o doses, differences in some parameters were seen in myocytes from MI compared with sham-operated rats (Table 4 and Fig 3).

View larger version (29K): [in this window] [in a new window]   Figure 3. Ca2+ dose-response curves for some intracellular Ca2+ (360/380 nm ratio) parameters. There was no significant difference any parameters between sham and MI rats (interaction term). However, as a group (averaged over four Ca2+ doses), a small increase in peak intracellular Ca2+ ([Ca2+]i) and peak rate of rise in[Ca2+]i was seen in 2- and 6-week MI rats. The peak rate of fall in [Ca2+]i was higher in 1-, 2-, and 6-week but lower in 4-week MI myocytes compared with sham. The velocity of rise in [Ca2+]i was lower in 4-week MI compared with other rats. P values are for group factor.

The slopes relating peak 360/380 nm ratio and peak myocyte shortening (Fig 4) for the four [Ca²⁺]_o doses were not different in myocytes from sham-operated and MI rats.

View larger version (16K): [in this window] [in a new window]   Figure 4. Relationship of peak intracellular Ca2+ 360/380 ratio and myocyte shortening for four [Ca2+]o doses. Myocyte Ca2+ sensitivity was unchanged in MI compared with sham rats.

Effect of Stimulation Frequency and Temperature on Myocyte Function
The effects of temperature (30°C and 37°C) and stimulation frequency (0.2, 0.3, 0.5, 1, and 2 Hz) were studied in 60 myocytes from 6 MI rats and 57 myocytes from 8 sham-operated rats at 4 mmol/L Ca²⁺. MI rat hearts from this group also had depressed global LV function (Langendorff: LVDP, 69±12.9 versus 112±7.5 mm Hg, P<001) and were significantly larger (LVV₁₀, 312±25 versus 187±31.4 µL, P=.015). MI myocytes studied were longer than those from the sham hearts (126±3 versus 107±1 µm, P<.001). A negative myocyte percent shortening-frequency relationship was seen in both sham and MI groups at either temperature (Fig 5, P<.001, repeated-measures ANOVA). Sham myocytes showed a slightly greater percent shortening at 37°C compared with 30°C (P<.001, two-factor repeated-measures ANOVA). Although a similar trend was seen in MI myocytes, the differences were not statistically significant. MI myocytes at either temperature tended to have a greater percent shortening (not statistically significant) at all frequencies compared with myocytes from sham-operated rats.

View larger version (16K): [in this window] [in a new window]   Figure 5. Effect of temperature on myocyte shortening-frequency relationship. Both groups show a negative shortening-frequency relationship (P<.001). Higher temperature caused a significant increase in myocyte shortening in the sham but not MI cells. There was no significant difference in shortening-frequency response between MI and sham myocytes at either temperature.

Correlation Between Structural Remodeling and Contractile Function
An important objective of this study was to relate global LV and cellular structural alterations with functional changes in the remodeled heart. Data on LV volume and global function and on myocyte structure and function were available from the same heart in 25 rats. LVDP could not be obtained for two 1-week MI rats because of technical difficulties. Good correlations were seen between LVV₁₀ (an index of global LV remodeling) and mean myocyte length (r=.78, P<.001), between LVV₁₀ and LVDP (r=-.81, P<.001), and between LVDP and myocyte length (r=-.8, P<.001, Fig 6). However, no correlation was found between peak myocyte shortening at 6 mmol/L Ca²⁺ and LVDP of the hearts from which the myocytes were obtained (r=.13, Fig 7), suggesting that global depression of LV systolic function in the rat infarct hearts may not be due to depression of contractile function of the unloaded LV myocytes obtained from the remote myocardium. There also was no correlation between myocyte length or width (measured during measurement of contractile responses) of sham or MI hearts and peak myocyte shortening at 6 mmol/L Ca²⁺ (r=.04, Fig 8, only length data shown), suggesting that structural myocyte remodeling was not associated with contractile dysfunction in the isolated myocytes.

View larger version (19K): [in this window] [in a new window]   Figure 6. Scatterplot showing good correlation between (A) LVV10 and mean length of myocytes obtained from the same heart (r=.79), (B) LVDP and mean myocyte length (r=-.81), and (C) LVDP and LVV10 (r=-.80).

View larger version (15K): [in this window] [in a new window]   Figure 7. Scatterplot of LVDP and contractile function of myocytes isolated from the same heart. There was no relation between isolated myocyte function and LV systolic function.

View larger version (18K): [in this window] [in a new window]   Figure 8. Scatterplot of myocyte length and peak myocyte shortening (6 mmol/L [Ca2+]o). There was no relation between myocyte length (an index of cellular remodeling) and contractile function.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this study, we used the rat infarct model to study in vivo LVSP, diastolic LV pressure, ex vivo diastolic P-V relationship, and LV systolic function in remodeled and sham-operated age-matched hearts. These findings were then related to changes in myocyte morphology and contractile function. The main findings were that in remodeled hearts, (1) the severity of changes in overall LV geometry highly correlated with changes in myocyte length and (2) by a number of criteria, myocyte systolic contractile performance and intracellular Ca²⁺ dynamics were not different from those obtained from sham-operated hearts.

Abnormalities of LV Performance and Geometry in Relation to Myocyte Morphology
Serial studies confirmed the presence of significant remodeling in post-MI hearts. Heart weights were greater in the MI rats and tended to increase with post-MI duration. Direct measurement further confirmed that the LV volumes of MI hearts were, on average, 42% larger than those of sham-operated hearts. Hearts with a longer duration of MI also tended to have larger volumes. The P-V relationship was shifted to the right in the MI rats, suggesting a significant increase in LV volume, a characteristic feature of the remodeled heart. The magnitude of these changes are similar to that described in the literature.^31,32 Remodeling was also seen at the level of the myocyte in both ventricles. Cells were longer in both LV and RV, but the width of LV myocytes was less affected. This suggests that there may be a disproportionate addition of sarcomeres in series rather than parallel in remodeling LV myocytes. Hemodynamic and isolated heart function studies confirmed the presence of LV systolic dysfunction and increased LV filling pressures previously reported in this model.^33,34 These results establish that the post-MI hearts included in our study had significant ventricular remodeling and global contractile dysfunction.

One of the major strengths of this study was our ability to obtain both whole-heart and isolated myocyte data from the same animals. This allowed us to accurately relate changes in global LV volume and function to changes in myocyte structure and function. We believe that this is the first study to follow this approach. The increase in length of remodeled myocytes correlated directly with the increase in volume of the remodeled LV and inversely with global LV function (Fig 6A and 6B). Global LV systolic function was significantly depressed in the MI hearts, but we could not demonstrate any contractile abnormalities in unloaded myocytes isolated from their remote myocardium (see discussion below); therefore, the global LV systolic dysfunction seen in these remodeled rat hearts can occur in absence of contractile dysfunction of isolated myocytes. Thus, although it is possible that myocytes could develop contractile dysfunction at a later stage in the natural history of CHF, our data suggest they contract normally for up to 6 weeks after an MI, at a stage by which marked LV structural remodeling and global LV contractile dysfunction had already appeared. Although we did not measure regional contractile function in the remote noninfarcted myocardial segments in the post-MI rats, there is considerable evidence that contraction in these segments may be abnormal in the rat infarct⁸ and other models.^9,10 Abnormalities of fractional shortening in the remote myocardium are present as early as 1 week after MI.⁸ Contractile function of papillary muscle isolated from the noninfarcted regions of remodeled rat hearts are also abnormal 3 to 24 weeks after MI.^35–37 Therefore, the time points we chose to study myocyte function were those at which global LV dysfunction would be expected to be accompanied by regional and papillary muscle dysfunction in the remote myocardium.

Myocyte Structural Changes
Our study was also notable for the large number of myocytes from RV (3600) and LV (4300) that were used for morphologic analysis. There was an increase in length and width of the myocytes from MI hearts. However, increase in length (24%) contributed more to the LV myocyte remodeling than the increase in width (15%) (Table 2). The RV myocytes appeared to be more hypertrophied and showed a greater increase in length (38%) and width (31%) than the LV myocytes. These differences in hypertrophic response may be due to different loading conditions of the two ventricles: a predominant volume overload on the LV and pressure overload on the RV.³³ Although the myocyte morphological changes seen in this study are generally similar to those described in the literature,^21,33 an exact comparison would be difficult due to differences in methodology.

The morphological changes in the myocyte correlated well with the degree of global LV remodeling (Fig 6A). These findings suggest that post-MI remodeling in the heart occurs predominantly by myocyte lengthening³⁸ rather than by myocyte slippage.³⁹ Furthermore, myocyte remodeling correlated well with global LV dysfunction (Fig 6B); however, myocyte structural remodeling seemed unrelated to unloaded myocyte contractile function (Fig 8).

Contractile Function of Normal and Remodeled Myocytes
We are unaware of any study in which whole-heart and isolated myocyte contractile function have been serially compared in the same animals. However, at least five previous studies have reported conflicting results on myocyte contractile function in the rat MI model. Contractile function was abnormal^21–23 in three and normal^24,25 in two. Capasso and Anversa²¹ showed that myocytes from rat hearts 1 week after MI had lower peak and velocity of shortening than those from sham-operated rats. A subsequent study, from the same group, reported similar findings in rats studied at different time periods (6 hours, 2 to 3 days, 1 week, and 1 month after MI).²³ Cheung et al²² studied rats 3 weeks after MI; although no significant change in myocyte contractility was seen in the basal state ([Ca]_o=1.1 mmol/L, 37°C, 0.2 Hz), at higher extracellular Ca²⁺ (4.9 mmol/L), myocytes from infarcted hearts demonstrated a decrease in percent shortening. It is not clear whether myocytes, in any of the above mentioned studies, were isolated from myocardium adjacent to or remote from the infarct zone. This appears to be important because Melillo et al²⁴ found that myocytes from segments adjacent to the infarcted area show contractile dysfunction, whereas those from the remote myocardium, although hypertrophied, do not. Lefroy et al²⁵ also could not find any differences in the contractile response of myocytes isolated from segments remote from infarct area in sham and 1-week-MI rats. Our findings of normal myocyte contractile function are therefore comparable with those studies in which myocytes were extracted from the remote myocardium.^24,25

Intracellular Ca²⁺ Dynamics
A number of defects in intracellular Ca²⁺ dynamics have been shown to occur in different models of CHF.⁴⁰ We found no major abnormalities in resting or peak intracellular Ca²⁺ in myocytes from MI rats. Likewise, the relation between peak myocyte contraction and peak intracellular Ca²⁺ was no different (over the range of Ca²⁺ concentrations studied) in the sham and MI myocytes (Fig 4). This finding suggests that abnormalities of myofilament Ca²⁺ sensitivity are not present and cannot account for the contractile dysfunction observed in myocardium obtained from remodeled hearts. There are only a few reports in the literature in which Ca²⁺ handling in myocytes from the rat infarct model has been examined.^22,23,41 Cheung et al²² found peak intracellular Ca²⁺ to be normal under basal conditions ([Ca]_o=1.1 mmol/L, 37°C, 0.2 Hz) but reduced at higher (4.9 mmol/L) extracellular Ca²⁺ . It is to be noted that in this study, intracellular Ca²⁺ was measured in cultured myocytes. A subsequent study in freshly isolated myocytes ([Ca]_o=1.8 mmol/L, 37°C, 0.5 to 5.0 Hz) showed a decrease in systolic and an increase in diastolic Ca²⁺ in MI compared with sham rats.⁴¹ Li et al²³ found reduced peak intracellular Ca²⁺ in myocytes from rats at different intervals after MI (6 hours to 1 month).

Can Global LV Dysfunction Exist With Normal Myocyte Function?
Although there are data suggesting that myocyte function may be abnormal in the rat infarct^21–23 and other models of LV dysfunction^42–44 and hypertrophy,⁴¹ there also is evidence that myocyte function is normal in the failing heart. Apart from the rat myocyte studies cited above,^24,25 Harding et al⁴⁵ found that myocytes from failing human hearts also have normal contractile responses to extracellular Ca²⁺. More recently, these authors confirmed that although myocytes from explanted human hearts had normal function under basal conditions (0.2 Hz), at a higher stimulation frequencies, myocyte contractile dysfunction becomes apparent.⁴⁴ We found, however, that even at higher frequencies of stimulation, the responses of the sham and MI myocytes were not different. The two groups of myocytes showed similar negative shortening-frequency relationship. Unlike cardiac muscle preparations from other mammalian species,⁴⁶ the rat heart demonstrates a negative force-frequency relationship. However, there has been no systematic study of this relationship in myocytes from rats with heart failure.

Some studies on papillary muscles and trabeculae are also consistent with the possibility that global LV dysfunction need not be accompanied by dysfunction at the isolated muscle level, especially in human end-stage heart failure.^47–49 Contractile abnormalities at the isolated muscle level may be dependent on the duration of CHF. Bing et al³⁷ showed no reduction in papillary muscle peak shortening at 3 weeks after MI, at a time when the remote noninfarct myocardial function has been shown to be depressed.⁸ However, animals studied for a longer duration did reveal an onset of papillary muscle dysfunction.³⁵

The present data therefore indicate that abnormal contractile performance and Ca²⁺ dynamics of isolated myocyte are not necessarily the basis of the global contractile dysfunction present in the remodeled LV. There could be a number of possible explanations for the disparity between in situ and isolated myocyte contractile function in remodeled myocardium. The simplest explanation is that less myocardium is available to develop pressure in the infarcted heart. Although this factor is responsible for early LV dysfunction, it cannot explain the progressive decrease in LV systolic function seen during LV remodeling. However, myocyte loss from apoptosis^13,14 could contribute to this mechanism. Abnormal wall stress imposed on the myocytes in situ could also be a major cause of global LV dysfunction in the presence of normal myocyte function because of unfavorable load velocity-shortening relationship.^50,51 Although we did not measure wall stress, it is very likely to be increased in our remodeled hearts given the increase in LV volume. Another possibility is that abnormal myocyte tethering by the altered interstitial collagen could lead to abnormal systolic loading or restrained shortening. Abnormalities have been reported in the cytoskeletal and extracellular matrix proteins.^12,52 Some of these abnormalities might result in excessive or decreased tethering of myocytes. Either abnormality could impair contractile performance by restraining shortening (in the "overtethered" state) or by reducing force transmission and the cell-to-cell mechanical coupling (in the "undertethered" state). These possibilities could explain the decrease in myocardial contractile performance in presence of normal myocyte function.⁵³

Study Limitations
Our study has several limitations. Isolated heart function was studied at a fixed LVEDP of 10 mm Hg. This is high for sham but low for MI rats. It is unlikely, however, that testing of isolated heart function at different LVEDP would have altered our conclusions because the Frank-Starling relationship of the infarcted rat heart is flat.³⁴ Another concern is that the myocytes selected are only a fraction of the heart and may not be representative of the majority. It is also unclear whether the myocyte isolation procedure and the preceding manipulation of the heart influenced their function. Nor is it clear whether the procedure affects myocytes from MI and sham hearts differently. In normal hearts, however, isolated myocyte and papillary muscle functions are similar.⁵⁴ Perhaps the most important limitation is that myocytes were tested in unloaded state. Load is an important determinant of muscle function, and myocyte shortening might be reduced under different loading conditions. Methods to load cells are imperfect,^55,56 and until better methods to study loaded cells become available, this will remain a limitation. Despite these limitations, studies on isolated myocytes have several advantages. They are not influenced by confounders such as load, circulating neurohormones, and interstitial constraints, all of which are abnormal in heart failure. Moreover, limitations imposed by substrate deficiency can be easily overcome. Hence, comparisons between normal and abnormal cells can be made under similar conditions.

Conclusions
These data confirm our hypothesis that post-MI remodeling in the heart occurs predominantly through myocyte lengthening rather than myocyte slippage. However, the contractile function and intracellular Ca²⁺ kinetics of remodeled myocytes remain normal under basal conditions, during increased frequency of stimulation, and during inotropic stimulation with Ca²⁺ for up to 6 weeks after MI. Therefore, abnormal myocyte contractile function is not a prerequisite for global LV contractile dysfunction to occur in the post-MI remodeled heart. Factors such as increased wall stress due to altered LV geometry, interstitial tissue abnormalities, and myocyte loss due to apoptosis may be more important contributors to the progression of remodeling and the genesis of LV dysfunction after MI.

	Selected Abbreviations and Acronyms

 

CHF = congestive heart failure LV = left ventricular, ventricle LVEDP = left ventricular end-diastolic pressure LVSP = left ventricular systolic pressure LVV10 = left ventricular volume at 10 mm Hg MI = myocardial infarction P-V = pressure-volume RV = right ventricular, ventricle

	Footnotes

 
Presented in part at the 69th Scientific Sessions of the American Heart Association, November 10 through 13, 1996, New Orleans, La.

Received July 3, 1997; revision received August 22, 1997; accepted August 29, 1997.

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