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(Circulation Research. 1997;81:1083-1093.)
© 1997 American Heart Association, Inc.

Articles

Enhanced Na⁺-Ca²⁺ Exchange in the Infarcted Heart

Implications for Excitation-Contraction Coupling

Sheldon E. Litwin, , John H. B. Bridge

From the Division of Cardiology, Salt Lake City Veterans Affairs Medical Center (S.E.L.), the Nora Eccles Harrison Cardiovascular Research and Training Institute (S.E.L., J.H.B.B.), and the University of Utah (S.E.L., J.H.B.B.), Salt Lake City.

Correspondence to Sheldon E. Litwin, MD, Cardiovascular Division, Veterans Affairs Medical Center, 500 Foothill Blvd, Salt Lake City, UT 84148. E-mail SLitwin{at}msscc.med.utah.edu

	Abstract

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Abstract Cellular Ca²⁺ regulation is abnormal in diseased hearts. We designed this study to assess the role of the Na⁺-Ca²⁺ exchanger in excitation-contraction coupling in surviving myocardium of the infarcted heart. We measured cellular contractions and whole-cell currents in single left ventricular myocytes isolated from the hearts of rabbits with healed myocardial infarction (MI). Eight weeks after MI, rabbits had left ventricular dysfunction without overt heart failure. Myocytes isolated from regions adjacent to the infarcted zone were significantly longer than cells from control hearts. At low stimulation rates (0.5 Hz), the amplitude of field-stimulated contractions was increased (11.6±0.5% versus 10.2±0.6% resting cell length), whereas the time to peak shortening and action potential duration were prolonged in the MI cells. When stimulation frequency was increased to 2.0 Hz, cellular shortening did not change or decreased in myocytes from infarcted hearts, whereas control cells had a positive shortening-interval relationship. Cells from infarcted hearts had a significantly decreased (31%) L-type Ca²⁺ current (I_Ca) density but no change in the current-voltage relationship or the kinetics of I_Ca inactivation. Maximal Na⁺-Ca²⁺ exchange current density was significantly increased (32%) in the cells from infarcted hearts. Sarcoplasmic reticulum (SR) Ca²⁺ content during a stable train of contractions, as estimated from caffeine-induced inward currents, was slightly increased (P=NS) in the MI myocytes. To determine whether Na⁺-Ca²⁺ exchange influenced SR Ca²⁺ content, cells were clamped at potentials between -70 and +90 mV for 400 ms. The amplitude of the contraction during a subsequent clamp step to +10 mV was then measured as an index of SR loading that occurred during the preceding clamp step. Steps to positive potentials produced greater augmentation of the subsequent contraction in MI than in control myocytes. In myocytes from the infarcted heart, increased activity of the Na⁺-Ca²⁺ exchanger may promote Ca²⁺ entry or decrease Ca²⁺ extrusion. This relative augmentation of inward Ca²⁺ flux by the exchanger may enhance SR Ca²⁺ loading and thus support contractility that would otherwise be impaired as a result of decreased Ca²⁺ current. However, Ca²⁺ influx by the exchanger may contribute to the prolongation of contractions in myocytes from infarcted hearts.

Key Words: myocardial infarction • Ca²⁺ • ion channel • Na⁺-Ca²⁺ exchange • heart failure

	Introduction

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The development of heart failure after MI is a gradual process resulting from geometric and biochemical changes in both the infarcted and noninfarcted portions of the heart.¹ Surviving myocytes, particularly those adjacent to the zone of infarcted tissue, elongate in response to hemodynamic stresses and/or neurohumoral influences.^2,3 Although this hypertrophic response may partially compensate for the loss of contractile tissue in the infarcted zone, there is mounting evidence that abnormalities of excitation-contraction coupling develop in the surviving myocytes of the infarcted heart. For example, several groups have observed prolongation of intracellular Ca²⁺ transients and contractions in papillary muscles or isolated cells from noninfarcted regions of the rat heart.^4,5

A number of systems involved in cellular Ca²⁺ homeostasis have been considered as potential causes of the prolongation of the intracellular Ca²⁺ transients in myocytes from diseased hearts. Some investigators have focused on the significance of changes in SR function. In this regard, decreased expression of the SR Ca²⁺-ATPase (mRNA and protein) has been reported in several forms of cardiac overload.^6,7 Although these changes are clearly important, they may not explain all of the functional abnormalities found in cells from hypertrophied or failing hearts. If impaired sequestration of Ca²⁺ by the SR were the only abnormality, then SR Ca²⁺ content should be depleted during repetitive stimulation, since the SR Ca²⁺-ATPase and the sarcolemmal Na⁺-Ca²⁺ exchanger compete for Ca²⁺ removal from the cytoplasm.⁸ Significantly decreased cellular contractions or Ca²⁺ transients should, therefore, be consistently observed in failing or nonfailing hypertrophied myocardium. Contrary to this prediction, many investigators have found only modest reductions or no differences in the amplitude of contractions or Ca²⁺ transients in tissue or cells from diseased hearts.^5,9–12 Hence, other Ca²⁺ regulatory systems that may contribute to the observed changes in Ca²⁺ transients of dysfunctional hearts have been examined.

Several groups have reported that the sarcolemmal Na⁺-Ca²⁺ exchanger is upregulated in myocardium from humans and experimental animals with myocardial hypertrophy or heart failure.^13–16 Based on these findings, it has been hypothesized that increased Ca²⁺ extrusion by the Na⁺-Ca²⁺ exchanger is an adaptive mechanism that may "compensate" for decreased Ca²⁺ uptake by the SR and may help to maintain normal diastolic Ca²⁺ levels.¹⁵ There is some evidence to support this view¹¹; however, the Na⁺-Ca²⁺ exchanger can transport Ca²⁺ in either direction and, hence, could promote Ca²⁺ entry as well as Ca²⁺ extrusion.¹⁷ There are many factors that affect Na⁺-Ca²⁺ exchange activity, including membrane potential and the transsarcolemmal Na⁺ and Ca²⁺ gradients. Since we have very limited information regarding these variables in pathological states, it is difficult to predict the function of the exchanger in diseased hearts. Therefore, we measured contractility, sarcolemmal Ca²⁺ transport, and SR Ca²⁺ content in surviving myocytes from infarcted hearts. We found evidence suggesting that Ca²⁺ influx by the Na⁺-Ca²⁺ exchanger might support contractility that would otherwise be impaired as a result of reduced Ca²⁺ current; however, Ca²⁺ entry by the exchanger may prolong cellular contractions or delay the onset of relaxation.

	Materials and Methods

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Male New Zealand White rabbits weighing 2.0 to 3.0 kg were used for all experiments. Animals were cared for according to the guidelines of the American Physiological Society. The studies were approved by the institutional animal care committee.

Production of MI
MIs were induced using a modification of a published protocol.¹⁸ Briefly, rabbits were injected with acepromazine (16 mg/kg) and xylazine (3 mg/kg) intramuscularly. Approximately 10 to 15 minutes later, they were anesthetized with 2% isoflurane delivered by face mask. They were orotracheally intubated and ventilated at 40 breaths/min with 1% isoflurane supplemented with oxygen (2 L/min). A thoracotomy was made in the left fourth intercostal space. The large branch of the circumflex artery that runs on the lateral aspect of the heart was identified and ligated 1 to 2 mm below the atrioventricular groove using 6–0 silk suture. Lidocaine HCl (1 mg/kg IV) was administered at the time of coronary occlusion, and a second dose (0.5 mg/kg) was given 10 minutes later. Transthoracic defibrillation with 10 to 50 J of energy delivered via pediatric paddles was used if required (20% of infarcted rabbits). Procaine penicillin G (300 000 U) was administered intramuscularly just before the operation.

In 10% to 20% of the rabbits undergoing surgery, the artery was very small or could not be visualized. These rabbits sustained minimal or no infarctions. In a subgroup of animals, the chest was opened, but the coronary artery was intentionally not ligated (sham surgery). To minimize the number of survival surgeries, we compared characteristics (cell size, action potentials, Ca²⁺ current density, and current-voltage relationships) of cells from rabbits with minimal or no infarcts and from sham-operated animals with cells from unoperated rabbits. Since we did not see significant differences (data not shown), we included animals from all three groups (minimal infarct, sham surgery, and unoperated) as controls. It seems unlikely that residual effects of the surgical procedure would still be present 8 weeks after surgery.

Myocyte Isolation
Rabbits were killed 8±0.7 weeks after MI. This duration of time was chosen because scar healing is complete and compensatory processes are likely to be activated, but direct effects of the surgical procedure were anticipated to be largely dissipated. Left ventricular myocytes from the peri-infarct border zone were isolated by using a variation of standard methods. We chose to use only cells from this specified region to reduce variability in data due to regional differences in the infarcted ventricle. In addition, we anticipated that the differences in cellular physiology would be greatest in this region, since previous investigators have shown that the infarct border zone has more contractile dysfunction and a greater amount of myocyte hypertrophy.^2,19 Rabbits were euthanized with Beuthanasia (Schering-Plow Animal Health) administered through an ear vein. The heart was quickly excised and then retrogradely perfused via the aorta (50 mm Hg pressure) with a Ca²⁺-free HEPES-buffered saline solution that was bubbled with 100% O₂. After 5 minutes, the solution was changed to one containing 0.08% collagenase and 0.02% protease, and perfusion was continued for an additional 15 to 25 minutes. When the heart was soft, the right ventricle and atria were removed. The scar tissue was carefully cut away from the rest of the left ventricle. A rim of 2 to 3 mm of surviving myocardium was left intact. The rim of surviving tissue was then dissected from the scar, and this tissue was minced. In some rabbits, cells from the remote portion of the infarcted left ventricle were also studied. The minced tissue was gently shaken in a low-Ca²⁺ saline solution free of digestive enzymes and strained, and the dissociated myocytes were allowed to settle in a storage solution containing 1.0 mmol/L Ca²⁺. In a subgroup of rabbits, the atria, right ventricle, left ventricle, and the scar were weighed after perfusion with collagenase, but before mincing. Large numbers of Ca²⁺-tolerant rod-shaped cells with clear striations were consistently obtained in both control and infarcted hearts.

Hemodynamic Measurements
In a subgroup of animals, intracardiac pressures were measured before they were killed. Ketamine (50 mg/kg IM) and xylazine (5 mg/kg IM) were administered. The right carotid artery was isolated, and a 2F micromanometer-tipped catheter (Millar Instruments) was inserted and passed retrogradely into the left ventricle.

General Features of All Studies
Studies were performed within 8 hours after cell dissociation. The cells were affixed with natural mouse laminin (Collaborative Biomedical Products) to a glass coverslip, which formed the bottom of a bath. The bath was continuously perfused with a HEPES-buffered modified Tyrode's solution (mmol/L: NaCl 138, MgCl₂ 1.0, KCl 4.4, dextrose 11.0, CaCl₂ 2.7, and HEPES 24.0, pH adjusted to 7.4 with NaOH) maintained at 30°C. Cells were viewed with an inverted phase-contrast microscope (Nikon or Olympus). Cell motion was monitored with a video edge-detection system (Crescent Electronics). Solutions superfusing cells were rapidly changed using a modification of a previously described solution switcher.²⁰ The modified switching device directs the solutions through two square glass tubes (200 µm) separated by a 70-µm glass septum. The bulk solution over the cell may be changed in 7 ms using this device.²⁰ Command voltage pulses were generated by pClamp software, which controlled an Axopatch 200A or an Axoclamp 2B voltage-clamp circuit (Axon Instruments Inc). Pipettes were fashioned from 7052 borosilicate glass (1.2-mm inner diameter, 1.65-mm outer diameter) using a horizontal micropipette puller (P97, Sutter Instruments Co). When the pipettes were filled with solution, tip resistance was typically 1 to 2 M. Stray capacitance was compensated as fully as possible. Current or membrane potential and cell motion were digitized at 1 to 2 kHz with an analogue-to-digital converter (TL-1 or Digidata 1200, Axon Instruments) and stored on a personal computer for later analysis using pClamp software (Axon Instruments).

In all studies, quiescent rod-shaped myocytes with clear striations and lack of granulation were selected. In voltage-clamp experiments, very long, thin, or irregularly shaped cells were avoided, since voltage control may be suboptimal. In experiments in which cell shortening was measured, myocytes with more square ends were preferentially selected, since tracking cell motion is more reliable. In all cases, an effort was made to avoid the use of cell size as a selection criteria.

Measurements of Cell Size
Cell size (length and width) was measured in randomly selected cells from control and infarcted hearts. To avoid bias, 50 to 100 cells from each heart (4 or 5 in each group) were measured by randomly moving the microscope stage (x20 objective) and measuring all the quiescent rod-shaped cells in each field. In two hearts, cells remote from the region of infarction were also measured.

Field Stimulation Studies
Cellular contractions were recorded at pacing intervals of 0.5, 1.0, and 2.0 Hz during field stimulation. The advantage of this approach is that the intracellular milieu (ion concentrations, pH, etc) is unperturbed. Constant current pulses of 5-ms duration (10% above threshold) were delivered by a pair of parallel platinum wires positioned near the cell. Cells were stimulated to contract at 0.5 Hz for at least 2 minutes to achieve stable SR Ca²⁺ loading. Steady-state contractions were recorded 30 s after each change in stimulation frequency. Maximal amplitude of shortening (percent resting cell length), peak rate of shortening, time to peak shortening, and peak rate of cellular relengthening were determined for contractions at each stimulation frequency. In every cell, measurements were made on four or five contractions at each stimulation frequency.

Measurement of Action Potentials
Action potentials were measured using a discontinuous voltage-clamp circuit in bridge mode (Axoclamp 2B, Axon Instruments Inc). For these experiments, the pipette solution contained (mmol/L) KCl 113, dextrose 5.5, K₂ATP 5.0, HEPES 10, EGTA 0.02, MgCl 0.5, and NaCl 10, with pH adjusted to 7.1 using KOH. Five-ms current injections were adjusted to a level 10% above threshold. Cells were stimulated at 0.5 Hz for at least 2 minutes before making recordings. Action potentials were measured at stimulation frequencies of 0.5, 1.0, 2.0, and 3.0 Hz. Resting membrane potential, peak and plateau potentials, and APD₉₀ were measured on at least three action potentials at each frequency.

Measurement of Ca²⁺ Current Density and Inactivation Kinetics
For measurements of I_Ca density and inactivation, the pipette filling solution contained (mmol/L) CsCl 130, dextrose 5.5, K₂ATP 5.0, EGTA 14, MgCl 0.5, CaCl₂ 3.92, HEPES 10, and tetraethylammonium chloride 10, with pH adjusted to 7.1 using KOH. Free Ca²⁺ concentration in the pipette solution was calculated to be 0.1 µmol/L. Cells were held at a potential of -80 mV. A 75-ms prepulse to -40 mV was applied to inactivate Na⁺ current. Voltage-clamp steps (400 ms) to test potentials between -40 and +60 mV were then applied at 5-s intervals. Cells were held at -80 mV between episodes to minimize rundown of Ca²⁺ current. To calculate current density, membrane capacitance was measured at the beginning of each study. This was performed by recording capacitative transients induced by a 15-ms hyperpolarizing voltage-clamp step (5 mV). The area under the capacitative transient was integrated and divided by the voltage difference. Peak Ca²⁺ current was taken as the difference of the peak current and the current 350 ms after the start of the voltage-clamp pulse. Each current was then expressed relative to membrane capacitance (pA/pF).

Steady-state inactivation of Ca²⁺ current was determined using a double-pulse protocol.²¹ Cells were held at -40 mV to inactivate Na⁺ current. Voltage-clamp pulses to potentials between -50 and +40 mV were applied for 400 ms. These prepulses were of sufficient duration to induce maximal inactivation. The cell was then briefly clamped back to -40 mV (10 ms), followed by a 300-ms clamp step to +10 mV. The amplitude of the Ca²⁺ current during each test pulse (I_Ca) to +10 mV was normalized to the maximum current (I_Camax) and plotted against the voltage of the preceding clamp step. The normalized current-voltage relationship (I_Ca/I_Camax) was fitted to a Boltzmann function: I_Ca/I_Camax=1/[1+exp(V_1/2-V_t)/k], where V_t is the test pulse. The half-point (V_1/2) and slope factor (k) were determined from this fit.

The time course of Ca²⁺ current inactivation, I_Ca(t), was assessed by fitting the declining phase of individual current records to an exponential relationship, I_Ca(t)=A₀+A₁e^(-t/), with a Chebyshev noniterative fitting technique (pClamp, Axon Instruments).

I_NaCa Density
Maximal I_NaCa density was recorded using previously described methods.²² First, cells were patch-clamped with a pipette containing (mmol/L) CsCl 85, dextrose 5.5, MgATP 3.0, EGTA 14, MgCl 0.5, CaCl₂ 3.92, HEPES 10, and NaCl 15, with pH adjusted to 7.1 using CsOH (total Cs, 130 mmol/L). Free Ca²⁺ concentration in the pipette solution was calculated to be 0.1 µmol/L. After the membrane was ruptured, the cell was superfused with a solution similar to the normal Tyrode's solution, except that no K⁺ was added. Extracellular K⁺ was eliminated to inhibit the Na⁺ pump and thus allow more rapid accumulation of intracellular Na⁺. In addition, this approach should also eliminate overlapping currents due to activation of the Na⁺ pump during changes in sarcolemmal Na⁺ gradients. In some experiments, 3 mmol/L ouabain was also added to the superfusing solution. Results were comparable whether ouabain was present or not, suggesting that the Na⁺ pump was effectively inhibited by elimination of extracellular K⁺ (data not shown). The cell was held at -40 mV, and the superfusing solution was rapidly changed to a solution in which LiCl was substituted for NaCl. Exposure to zero extracellular Na⁺ was continued for 3 s. The sudden decrease in extracellular Na⁺ caused rapid extrusion of Na⁺ by the Na⁺-Ca²⁺ exchanger. This produced an outward current. After patch rupture, intracellular Na⁺ concentration gradually increased (as a result of dialysis of the cell by the pipette filling solution), and the amplitude of the outward current increased. Rapid solution switches were performed every 2 to 3 minutes until current amplitude reached steady state. Cells were held at -80 mV between rapid solution switches. I_NaCa amplitude reached a plateau 2 to 15 minutes after rupture of the patch. The largest value of the exchange current (difference between holding current and the maximal outward current) was recorded for each cell and expressed relative to membrane capacitance.

In these experiments, intracellular Ca²⁺ concentration was buffered to 0.1 µmol/L. Therefore, I_NaCa are probably not truly maximal, since Ca²⁺ binding to the regulatory site on the exchanger may enhance exchanger activity up to Ca²⁺ concentrations of 1 µmol/L. However, the measurements should provide physiologically relevant data, since they are obtained near normal diastolic Ca²⁺ levels.

Voltage Dependence of Cellular Contractions
The voltage-dependence of cellular shortening rate was determined by applying 400-ms voltage-clamp steps from a holding potential of -40 mV to potentials between -30 and +60 mV. The pipette solution contained (mmol/L) CsCl 130, dextrose 5.5, K₂ATP 5.0, EGTA 0.02, MgCl 0.5, HEPES 10, and NaCl 10, with pH adjusted to 7.1 using KOH. This solution was used to minimize outward K⁺ currents but included enough K⁺ in the pipette solution to support normal SR Ca²⁺ release. Stable SR Ca²⁺ loading was maintained by a series of five conditioning pulses (400-ms pulses at 3-s intervals) to +10 mV between each test pulse. Peak Ca²⁺ current was taken as the difference between the maximal inward current and the current measured near the end of the 400-ms voltage-clamp step. The peak rate of cellular shortening was analyzed as described above.

Measurements of SR Ca²⁺ Content
SR Ca²⁺ content was estimated by applying a train of six conditioning pulses (400-ms clamp steps at 2-s intervals) from -40 to +10 mV to establish uniform SR loading conditions. The cell was then rapidly superfused with normal Tyrode's solution containing 20 mmol/L caffeine. The caffeine was applied for 5 s. The application of caffeine induced a large contraction accompanied by an inward current. The inward current induced by caffeine has previously been shown to be caused by Na⁺-Ca²⁺ exchange, which extrudes the Ca²⁺ released from the SR.²³ Integration of the inward current gives an estimate of the total amount of Ca²⁺ released from the SR.²³ Since cell size differs between control and infarcted hearts, we expressed the caffeine current integral relative to cell capacitance. Currents were integrated for 5 s. Longer applications of caffeine (10 s) were associated with a small inward current that did not decay and a tonic component of contraction that did not relax until the caffeine was removed. This tonic component of the contraction may be due to increased myofilament sensitivity to Ca²⁺ induced by caffeine.

Influence of Na⁺-Ca²⁺ Exchange on SR Ca²⁺ Content
To determine the effect of Na⁺-Ca²⁺ exchange on SR Ca²⁺ content, we held cells at -40 mV and applied five conditioning pulses to +10 mV (300-ms pulses applied every 3 s) to achieve steady-state SR content. We then applied a 400-ms voltage-clamp step to a potential between -70 and +90 mV ("loading pulses"). Three seconds later, another clamp step to +10 mV was applied ("test pulse"). We assumed that the cellular contraction during the test pulse would reflect any changes in SR content that occurred during the loading pulse. Since I_Ca has a bell-shaped relationship with voltage and Na⁺-Ca²⁺ exchange has an exponential current-voltage relationship, pulses to positive potentials should produce a small I_Ca and a relatively larger I_NaCa. Thus, after loading pulses to positive potentials, changes in SR content should predominantly reflect the effects of reverse Na⁺-Ca²⁺ exchange. Therefore, we expected that steps to positive potentials (loading pulse) might cause more augmentation of the subsequent contraction (test pulse) in the MI than the control myocytes.

The peak rate of cell shortening during the test pulse was used as an index of changes in SR Ca²⁺ content induced by the prior loading pulse. The peak cellular shortening rate of each contraction was expressed relative to that of the first postloading contraction for the same cell. In these experiments, the pipette solution contained (mmol/L) CsCl 130, dextrose 5.5, K₂ATP 5.0, EGTA 0.02, MgCl 0.5, HEPES 10, and NaCl 10, with pH adjusted to 7.1 using KOH. Cells were held at -80 mV between each episode to minimize rundown of Ca²⁺ current. To determine if augmentation of contractions was due to changes in SR content, the protocol was performed in cells (n=3) that were pretreated with ryanodine (1 µmol/L) and thapsigargin (1 µmol/L). This treatment abolished the augmentation seen with loading pulses to positive potentials.

Statistics
All data are shown as mean±SEM. Comparisons of cellular contractions, action potentials, or whole-cell currents in cells from control and infarcted hearts were performed using a two-tailed unpaired Student's t test. A value of P<05 was considered to be significant.

	Results

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Data from a total of 991 (control, 441; MI, 550) cells isolated from 59 (control, 28; MI, 31) rabbits were included in this report. Two rabbits that survived the initial surgery died before the anticipated study date. At autopsy, both of these rabbits had large pleural effusions and ascites. There was no gross evidence of fluid retention in any of the other rabbits. Hearts from the infarcted rabbits showed transmural scarring of the posterolateral wall and apex (Fig 1). Infarct size was variable, with the largest infarctions involving 25% of the left ventricle. During the early portions of this study, infarct size was estimated as minimal, small, moderate, or large on the basis of visual assessment. To better characterize this animal model and to aid in comparison of our findings with those seen in other animal models of left ventricular dysfunction, we measured chamber weights and intracardiac pressures in all rabbits during the later portions of the study. These data are shown in the Table. Since infarct sizes could not be measured histologically in hearts perfused with collagenase, we stratified them into small, moderate, and large infarcts on the basis of scar weight (small, <1.0 g; moderate, 1.0 to 2.0 g; and large, >2.0 g). Small, moderate, and large infarctions corresponded to >10%, 10% to 20%, and >20% of total left ventricular mass, respectively. Measurements of infarct size based on weight probably underestimate the true percentage of the left ventricle that is infarcted, because the viable portions of the heart become quite edematous after collagenase perfusion, whereas the scar does not. During the portion of the study when we routinely measured scar weights, 7 rabbits had small infarcts, 7 rabbits had moderate infarcts, and 20 rabbits had large infarcts (on the basis of the above criteria). Data from hearts with moderate and large infarcts were included in the MI group of the present study. Cell length and width were measured in randomly selected cells from control and infarcted hearts. Cells from the infarct border zone (n=300) were significantly increased in length, with a minimal increase in width (P=NS) compared with those from control cells (n=300, Fig 2B).

View larger version (133K): [in this window] [in a new window]   Figure 1. Example of an infarcted rabbit heart 4 weeks after surgery. The heart was sliced into four sections transversely from apex to base. Transmural scar (thin and light colored) is circumferential at the apex (upper right) and occupies progressively smaller amounts of the total left ventricular circumference in more basal sections (counterclockwise). Surviving myocardium is darker and thicker. Scale at bottom shows 1-mm increments.

View this table: [in this window] [in a new window]   Table 1. Chamber Weights and Hemodynamics in a Subgroup of Control Rabbits and Rabbits With Healed MIs

View larger version (43K): [in this window] [in a new window]   Figure 2. A, Representative examples of myocytes from a control and an infarcted (MI) heart. Bar=100 µm. B, Distribution of cell sizes in randomly selected single myocytes from the surviving border zone (n=300) of MI hearts or from control hearts (n=300). Cell length was 120.0±3.1 vs 146.9±1.3 µm in control and MI hearts, respectively (P<.05). Cell width was 28.0±0.7 vs 29.9±0.4 µm in control and MI hearts, respectively (P=NS).

To investigate cellular mechanical function under relatively physiological intracellular conditions, we measured changes in cell length during field stimulation (control, n=28; MI, n=39; Fig 3). With this approach, cytoplasmic ion concentrations (eg, Na⁺) are determined largely by the actions of cellular ion pumps or transporters. At 0.5- and 1.0-Hz stimulation frequencies, contractions were larger in cells from the infarcted hearts (Fig 3B). However, the time to peak shortening was consistently prolonged in the MI cells (Fig 3D). The shortening-interval relationship was shifted upward at slower stimulation rates but showed more of a decline at 2.0 Hz in the myocytes from infarcted hearts compared with control myocytes. These findings were similar whether contractile amplitude or rate of shortening was measured (Fig 3B and 3C).Cellular relengthening rate also failed to increase at the 2.0-Hz stimulation rate in the MI cells (Fig 3E). The time to 50% cellular relengthening was significantly prolonged in the post-MI myocytes at all stimulation frequencies. However, the degree of prolongation was less pronounced at 2.0 Hz.

View larger version (21K): [in this window] [in a new window]   Figure 3. A, Examples of unloaded contractions in representative myocytes from control and infarcted (MI) hearts. Contractions were recorded during field stimulation at a frequency of 1.0 Hz. Compared with the normal cell, the contraction of the cell from the MI heart was increased in total amplitude, but the time to peak shortening was prolonged. In this example, the peak shortening rates were similar; however, the onset of relaxation was delayed, and the maximal relengthening rate was lower in the MI cell. B, Shortening-interval relationship in myocytes from control and MI hearts. Cell shortening is shown as percent change from resting cell length. Cell shortening declined more at a stimulation frequency of 2.0 Hz in cells from MI hearts. C, Peak rate of cell shortening vs stimulation frequency. Contractility does not increase at faster stimulation rates in the MI myocytes, whereas it does in the control cells. D, Time to peak shortening vs stimulation frequency. The duration of contraction was prolonged at all stimulation frequencies in MI myocytes. The reductions in time to peak shortening at faster pacing rates were similar in both cell types. E, Relaxation-interval relationships. Peak relengthening rate was comparable at 0.5 and 1.0 Hz in myocytes from control and MI hearts. At a stimulation frequency of 2.0 Hz, the relaxation rate was slower in the cells from the MI hearts. Data are mean±SEM (control, n=28; MI, n=39). *P<.05 vs control.

We also recorded action potentials in control (n=28) and MI (n=17) myocytes at different stimulation frequencies (Fig 4). Resting membrane potential was slightly, but consistently, more negative (P<.05) in the MI myocytes (Fig 4C). The peaks of the action potentials were not different at any of the stimulation frequencies (Fig 4B). The action potential overshoots (peak minus plateau potential) were similar at 0.5, 1.0, and 2.0 Hz but modestly increased at 3.0 Hz in the MI myocytes (Fig 4D). APD₉₀ was significantly prolonged in cells from infarcted hearts (Fig 4E). APD₉₀ shortened as stimulation frequency was increased in both cell types. However, it decreased more in the MI myocytes, so that APD₉₀ was not different in the control and MI myocytes at the 3.0-Hz stimulation rate.

View larger version (23K): [in this window] [in a new window]   Figure 4. A, Examples of action potentials measured at 1.0-Hz stimulation frequency in representative myocytes from control and infarcted (MI) hearts are shown. B, The peak of the action potentials did not differ in control (n=28) and MI (n=17) myocytes. C, Resting membrane potential was slightly, but consistently, more negative in the MI myocytes (*P<.05 vs control). D, The overshoot (peak minus plateau potentials) was similar at lower stimulation frequencies but slightly increased in the MI myocytes at a stimulation frequency of 3.0 Hz. E, APD90 was markedly prolonged at slower stimulation frequencies in the MI myocytes. At faster rates of stimulation, the action potential duration shortened such that APD90 was not different in control and MI cells at 3.0 Hz.

Transsarcolemmal Ca²⁺ influx is a major determinant of contractile function in cardiac myocytes. Therefore, we measured I_Ca in cells from infarcted hearts (n=32) and cells from control hearts (n=34). We found that there was a significant decrease in peak I_Ca density in the cells from infarcted hearts (Fig 5B). However, there was no change in the current-voltage relationship (Fig 5B). Voltage-dependent and steady-state inactivation kinetics of I_Ca were similar in cells from infarcted and control hearts (Fig 5C and 5D).

View larger version (21K): [in this window] [in a new window]   Figure 5. A, Family of ICa recorded during 300-ms voltage-clamp steps from a holding potential of -40 mV in representative myocytes from a control heart and an infarcted (MI) heart. B, Current-voltage relationships for the peak Ca2+ current in single left ventricular myocytes from control and MI hearts (control, n=34; MI, n=32). Ca2+ current density was significantly decreased in the cells from the MI hearts. *P<.05 vs control. C, Steady-state inactivation of ICa. Cells were held at -40 mV and prepulsed to potentials between -50 and +40 mV for 400 ms (see "Materials and Methods"). After brief repolarization to -40 mV, cells were clamped to +10 mV. Ca2+ current amplitude during steps to +10 mV is plotted vs potential of prepulse. Smooth curves are least-squares Boltzmann fits. The half-point (V1/2) and slope factor (k) for these curves were -20.6 mV and 4.97 and -18.6 mV and 5.17 for control and MI cells, respectively (control, n=10; MI, n=9; P=NS). D, Time course of ICa inactivation determined by fitting the decay phase of Ca2+ currents with a single exponential function (control, n=10; MI, n=9). The time constants for ICa inactivation (tau) were not different in the two cell types. All data are mean±SEM.

We next measured I_NaCa density in myocytes from infarcted (n=13) and control (n=10) hearts. Exchange currents were activated by rapidly reducing extracellular Na⁺ concentration in voltage-clamped cells (see "Materials and Methods"). These currents generally increased in amplitude with time after patch rupture (Fig 6A). Current amplitude reached a plateau 2 to 15 minutes after rupture of the membrane. Maximal I_NaCa density (measured after steady state was achieved) was increased by 32% in the infarcted hearts (Fig 6B).

View larger version (16K): [in this window] [in a new window]   Figure 6. INaCa in single myocytes from control and infarcted (MI) hearts. A, Example of time-dependent increase in current amplitude after patch rupture in a representative cell from an MI heart (capacitance, 249 pF). The increase in current amplitude over time probably reflects accumulation of intracellular Na+ due to dialysis from the contents of the pipette. Currents were induced by an abrupt change to a Na+-deficient superfusing solution (see "Materials and Methods"). In this example, currents were recorded 1, 5, and 10 minutes after rupture of the patch. Current amplitude did not increase further after 10 minutes. B, Peak INaCa density in myocytes from control and MI hearts (recorded at the time after patch rupture when current amplitude reached a plateau). Current density was obtained by dividing current amplitude by membrane capacitance. In this series of experiments, membrane capacitance was 142±8 and 220±11 pF in control and MI myocytes, respectively. Data are mean±SEM (control, n=10; MI, n=13). *P<.05 vs control.

To determine the functional significance of the increased activity of the exchanger in the infarcted hearts, we performed several experiments. First, we tested the hypothesis that Ca²⁺ entry by Na⁺-Ca²⁺ exchange might affect the voltage dependence of contractions in myocytes from the infarcted heart. We found an increased peak cellular shortening rate during square voltage-clamp steps in the MI cells; however, there was no difference in the voltage dependence of peak shortening rate (Fig 7). This finding suggests that any component of SR Ca²⁺ release triggered by reverse Na⁺-Ca²⁺ exchange is comparable in the control and MI myocytes.

View larger version (22K): [in this window] [in a new window]   Figure 7. Shortening-voltage and Ca2+ current-voltage relationships in single myocytes from control (n=12) and infarcted (MI) hearts (n=19). The peak rate of cellular shortening was measured during voltage-clamp steps to potentials between -30 and +60 mV from a holding potential of -40 mV. A train of five conditioning pulses to +10 mV was applied at 3-s intervals between the steps to each test potential in order to achieve steady-state SR Ca2+ loading. In these experiments, the pipette contained 10 mmol/L Na+ (see "Materials and Methods") Contractions and Ca2+ currents were normalized to those obtained at +10 mV in each individual cell. There was no difference in the voltage dependence of the current or peak shortening rate in the two groups of cells. These data imply a similar small contribution of reverse Na+-Ca2+ exchange to the early portion of the contraction in control and MI myocytes.

Next, we examined SR Ca²⁺ content and the ability of Na⁺-Ca²⁺ exchange to modulate SR Ca²⁺ content. SR Ca²⁺ content was estimated by integrating the inward current induced by rapid application of caffeine.²³ We found that releasable SR Ca²⁺ stores (normalized to membrane capacitance) during a stable train of conditioning pulses were slightly increased (11%, P=NS) in myocytes from the infarcted hearts (Fig 8). We then tested the hypothesis that enhanced reverse Na⁺-Ca²⁺ exchange might augment SR Ca²⁺ content to a greater extent in MI than control myocytes. This was determined by applying conditioning pulses to various potentials and then measuring the rate of cellular shortening during a standard voltage-clamp step from -40 to +10 mV applied 3 s later (see "Materials and Methods"). We found that voltage-clamp steps to positive potentials (>+30 mV) produced significantly greater augmentation of the subsequent cellular contraction in the myocytes from the infarcted hearts than in those from control hearts (Fig 9). No augmentation of the contraction after clamp steps to positive potentials was seen in cells pretreated with ryanodine and thapsigargin (Fig 9B). Thus, the augmentation must be due to changes in SR Ca²⁺ content. These data imply that reverse Na⁺-Ca²⁺ exchange is more effective in producing Ca²⁺ influx in the cells from the infarcted hearts than in control cells. Moreover, this Ca²⁺ influx may help to load SR stores.

View larger version (19K): [in this window] [in a new window]   Figure 8. SR Ca2+ content in myocytes from control and infarcted (MI) hearts. A, Example is shown of contractions and currents in an MI myoycte (capacitance, 173 pF) during the sixth voltage-clamp step of a conditioning train and during rapid application of 20 mmol/L caffeine 3 s later. The decaying inward current during caffeine application is due to Ca2+ being extruded by the Na+-Ca2+ exchanger (see "Materials and Methods"). B, There was minimal inward current or contraction when caffeine was applied to a cell with SR function disabled by pretreatment with ryanodine (5 µmol/L) and thapsigargin (5 µmol/L. C, Average data are shown for SR Ca2+ content (current integral/membrane capacitance) in cells from control (n=15) and MI (n=17) hearts. In these experiments, membrane capacitance was 183±5 and 171±8 pF (mean±SEM) in myocytes from control and MI hearts, respectively. SR content indexed to membrane capacitance tended to be increased in the MI cells (P=NS).

View larger version (24K): [in this window] [in a new window]   Figure 9. Evidence that Na+-Ca2+ exchange is more effective in loading the SR in cells from infarcted (MI) hearts compared with control hearts. A, Example of the experimental protocol in a cell from an MI heart (for details, see "Materials and Methods"). The last voltage-clamp step in a train of five conditioning pulses from -40 to +10 mV is shown. This is followed by a "loading pulse" produced by clamping from -40 mV to various potentials between -70 and +90 mV for 400 ms. We assumed that any changes in SR Ca2+ content induced by the loading pulse would be reflected in the rate and amplitude of the subsequent contraction. The amplitude of the contraction during the test pulse (+10 mV), which was applied 3 s after the loading pulse, was used as evidence of the effect of Na+-Ca2+ exchange on SR Ca2+ content. In this example, there is clear augmentation of the subsequent contractions as the potential of the loading pulse became more positive. B, Evidence that the augmentation of the contraction following the loading pulse was due to changes in SR Ca2+ content. In this example, the cell was pretreated for 1 hour with ryanodine and thapsigargin to inhibit SR function. The cell was then subjected to the same protocol shown in panel A. With the SR disabled, the cell still contracts during voltage-clamp depolarizations. However, the magnitude of the loading pulse has no effect on the subsequent contractions. C, Average data for cells from control (n=10) and MI (n=20) hearts. The normalized peak rate of cellular shortening (relative to the first contraction in the series, ie, the contraction following the loading pulse to -70 mV) was plotted as a function of the membrane potential during the preceding loading pulse. Depolarization to positive potentials produced greater augmentation of contractility in the cells from MI compared with control hearts. *P<.05. These data suggest that Ca2+ entry by the Na+-Ca2+ exchanger is more effective in loading the SR in cells from MI hearts than in cells from control hearts.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Our goal was to begin defining the role of the sarcolemmal Na⁺-Ca²⁺ exchanger in excitation-contraction coupling in surviving myocytes of the infarcted heart. Although infarctions involved as much as 25% of the left ventricle, animals had relatively compensated left ventricular dysfunction at the time of study. Myocytes from the infarct border zone in the rabbit were significantly elongated, with little increase in cell width. These myocytes had contractions of normal or increased amplitude but prolonged duration. Peak Ca²⁺ current density was significantly decreased, whereas Na⁺-Ca²⁺ exchange density was increased. SR Ca²⁺ content after a standard train of conditioning pulses was slightly increased, and voltage-clamp steps to positive potentials produced greater augmentation of a subsequent contraction in the myocytes from infarcted hearts compared with control hearts. These data provide evidence that in surviving myocytes from chronically infarcted hearts, Ca²⁺ influx by the Na⁺-Ca²⁺ exchanger may support contractility that would otherwise be reduced.

I_Ca in Myocytes From the Infarcted Heart
We found a significant reduction in peak I_Ca density in myocytes from infarcted hearts without significant changes in the current-voltage relationship or inactivation kinetics. These data suggest that the number of Ca²⁺ channels is reduced relative to cell surface area. Reductions in dihydropyridine receptor density or I_Ca density have been observed in myocardium from patients with heart failure and in several experimental animal models.^14,24–27 However, it should be recognized that not all forms of left ventricular hypertrophy or failure show decreased I_Ca density.^9,28,29 Furthermore, there may be complex changes in Ca²⁺ channel expression during the progression of disease in some models.³⁰ Hence, findings in one experimental model may not be generalizable to all forms of left ventricular dysfunction. I_Ca is commonly thought to serve as the primary trigger for SR Ca²⁺ release.^31,32 As such, the size of the Ca²⁺ current generally has a very significant effect on the amplitude and rate of cellular contraction. If Ca²⁺ entry via L-type Ca²⁺ channels is reduced in our model, why is cellular contractility not more impaired? A likely explanation is that there is another source of cellular Ca²⁺ influx.

Na⁺-Ca²⁺ Exchanger in Myocytes From the Infarcted Heart
Several investigators have found evidence of increased expression of the Na⁺-Ca²⁺ exchanger (mRNA and/or protein) in tissue from failing or hypertrophied hearts.^13–16 It has been hypothesized that increased activity of the Na⁺-Ca²⁺ exchanger may "compensate" for impairment of SR function by enhancing the ability of the cells to restore diastolic Ca²⁺ to normal levels.¹⁵ This view may be incomplete, since the exchanger can transport Ca²⁺ into or remove Ca²⁺ from the cell. Although the Na⁺-Ca²⁺ exchanger clearly is a critical mechanism for cellular Ca²⁺ extrusion, the Ca²⁺ influx mode may be more important than previously appreciated. For example, recent work suggests that Ca²⁺ entering a cell via the exchanger may contribute to the trigger for SR Ca²⁺ release.^33–35 It has also been proposed that SR Ca²⁺ loading may be mediated through Na⁺-Ca²⁺ exchange.³⁶

Our finding that contractions were of normal or increased amplitude in myocytes from infarcted hearts despite a decrease in peak I_Ca density suggests that there might be another source of Ca²⁺ influx in these cells. Since there is an increase in I_NaCa density, this might be an alternative mechanism of Ca²⁺ entry. Cellular Ca²⁺ entry by the reverse mode of Na⁺-Ca²⁺ exchange could enhance contractility by triggering release of Ca²⁺ from the SR, enhancing SR Ca²⁺ content, or directly activating the myofilaments. We tested each of these hypotheses. If Ca²⁺ entry by reverse exchange had a greater role in triggering SR Ca²⁺ release in cells from infarcted hearts, we would have expected to see a rightward and upward shift in the relationship between cellular contraction and membrane potential. However, we did not observe a change in the voltage dependence of contraction in the MI myocytes (Fig 7). This observation is similar to one previously reported in a model of pressure-overload left ventricular hypertrophy.²⁷ Therefore, it seems unlikely that Ca²⁺ influx by the Na⁺-Ca²⁺ exchanger has a greater role in inducing SR Ca²⁺ release in MI than in control myocytes. The shape of the shortening-voltage relationships suggests that under the conditions of these experiments, triggering of SR Ca²⁺ release by reverse Na⁺-Ca²⁺ exchange is relatively small in both control and post-MI myocytes. In contrast, we found evidence that SR Ca²⁺ content tended to be enhanced in the MI cells and that this may be mediated by Na⁺-Ca²⁺ exchange. Since the fractional release of Ca²⁺ tends to increase with SR Ca²⁺ content, a relatively normal SR release might occur despite a smaller trigger for SR release (ie, decreased Ca²⁺ current amplitude) in the post-MI myocytes.³⁷ Together, these data suggest that any additional Na⁺-Ca²⁺ exchangers that may be present in the remodeled myocytes of the infarcted heart may not be directly apposed to the Ca²⁺ release channels of the SR. Direct activation of the myofilaments by Ca²⁺ entering via the exchanger could also contribute to the normal or enhanced contractility in the MI myocytes despite a reduced stimulus for Ca²⁺-induced Ca²⁺ release from the SR (decreased I_Ca). Direct myofilament activation by reversed Na⁺-Ca²⁺ exchange could partially explain why the time to peak shortening was significantly prolonged.

During the cardiac action potential, there are likely to be extremely complex interactions between I_Ca and I_NaCa. Both of these currents will simultaneously affect membrane potential and intracellular Ca²⁺ concentration. In turn, these variables will affect the electrochemical forces that drive the ionic currents. The situation is further complicated by the fact that Ca²⁺ channels exhibit Ca²⁺-dependent inactivation, whereas the Na⁺-Ca²⁺ exchanger has a regulatory site that tends to stimulate the exchanger when Ca²⁺ is bound.¹⁷ Thus, the size and shape of the two currents during an action potential are very difficult to predict.

Although the amplitude or peak rate of cellular contraction was normal or enhanced in the MI myocytes, the contractions were prolonged. The main prolongation seemed to be in the time to peak shortening, whereas the rates of cellular shortening and relengthening were relatively preserved (at least at slower stimulation frequencies). This finding suggests that there might be continued transsarcolemmal Ca²⁺ influx, prolonged SR Ca²⁺ release, or a delay in the Ca²⁺ reuptake (SR) or extrusion (Na⁺-Ca²⁺ exchange) processes. We hypothesize that continued Ca²⁺ entry via the Na⁺-Ca²⁺ exchanger during the prolonged plateau of the action potential in the MI cells might explain the prolongation of the mechanical contraction. Additional Ca²⁺ influx might also occur through L-type Ca²⁺ channels during the prolonged plateau of the action potential. Since the peak I_Ca density appears to be reduced, prolongation of the action potential may be an important mechanism for increasing Ca²⁺ influx by either mechanism. Furthermore, shortening of the action potential at more rapid stimulation frequencies might partially explain the flat slope of the shortening-interval relationship at higher stimulation rates in the MI myocytes.

Overall, our data support the notion that the Na⁺-Ca²⁺ exchanger may have a more important role in beat-to-beat regulation of excitation-contraction coupling in surviving myocytes from the infarcted left ventricle than in normal myocytes. We have focused on the potential importance of Ca²⁺ influx by the exchanger. However, enhanced Ca²⁺ efflux by Na⁺-Ca²⁺ exchange probably assumes greater significance as well. Because of these changes, the Na⁺-Ca²⁺ exchanger could represent an important new target for therapeutic interventions in the damaged heart.

	Selected Abbreviations and Acronyms

 

APD90 = action potential duration at 90% repolarization ICa = L-type Ca2+ current(s) INaCa = Na+-Ca2+ exchange current(s) MI = myocardial infarction SR = sarcoplasmic reticulum

	Acknowledgments

 
This study was supported by grants from the Department of Veterans Affairs, the National Heart, Lung, and Blood Institute (HL-42357), and the University of Utah. Dr Litwin was the recipient of a Clinician Scientist Award from the American Heart Association. The authors wish to acknowledge the excellent technical assistance provided by Phyllis Roberge and Gary Webster.

Received April 23, 1997; accepted September 5, 1997.

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