Ann Thorac Surg 2003;76:2054-2061
© 2003 The Society of Thoracic Surgeons
Original article: cardiovascular
Modulation of calcium transport improves myocardial contractility and enzyme profiles after prolonged ischemia-reperfusion
William M. Yarbrough, MDa,
Rupak Mukherjee, PhDa,
G. Patricia Escobar, DVMa,
Jennifer W. Hendricka,
Jeffrey A. Samplea,
Kathryn B. Dowdya,
Julie E. McLeana,
Joseph T. Mingoiaa,
Fred A. Crawford, Jr, MDa,
Francis G. Spinale, MD, PhDa*
a Division of Cardiothoracic Surgery, Medical University of South Carolina, and the Ralph H. Johnson Veteran's Association Medical Center, Charleston, South Carolina, USA
Accepted for publication June 5, 2003.
* Address reprint requests to Dr Spinale, Cardiothoracic Research, Strom Thurmond Research Building, 770 MUSC Complex, Suite 625, Medical University of South Carolina, Charleston, SC 29425, USA
e-mail: wilburnm{at}musc.edu
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Abstract
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BACKGROUND: Ischemia-reperfusion (IR) injury causes myocardial dysfunction in part through intracellular calcium overload. A recently described pharmacologic compound, MCC-135 (5-methyl-2-[1-piperazinyl] benzenesulfonic acid monohydrate, Mitsubishi Pharma Corporation), alters intracellular calcium levels. This project tested the hypothesis that MCC-135 would influence regional myocardial contractility when administered at reperfusion and after a prolonged period of ischemia.
METHODS: A circumflex snare and sonomicrometry crystals within remote and area-at-risk regions were placed in pigs (n = 18, 32 kg). Coronary occlusion was instituted for 120 minutes followed by 180 minutes of reperfusion. At 105 minutes of ischemia pigs were randomly assigned to IR only (n = 11) or MCC-135 (IR-MCC [300 µg · kg-1 · h-1, n = 7]) administered intravenously. Regional myocardial contractility was determined by calculation of the regional end-systolic pressure-dimension relation (RESPDR [mm Hg/cm]). Myocardial injury was determined by measurement of plasma levels of myocyte-specific enzymes.
RESULTS: At 90 minutes ischemia, mean troponin-I was 35 ± 8 ng/mL with no significant difference between groups. At 180 minutes reperfusion, heart rate was increased by 18% ± 5% in the IR only group (p < 0.05) and was reduced by 11% ± 4% with IR-MCC (p < 0.05). At 90 minutes ischemia RESPDR was reduced from baseline by 51% ± 6% (p < 0.05). By 30 minutes reperfusion, reductions in RESPDR were attenuated with IR-MCC compared with IR only values. The CK-MB levels were increased at 180 minutes reperfusion in the IR only group (52 ± 9 ng/mL) compared with baseline (6 ± 1 ng/mL, p < 0.05) but were attenuated with IR-MCC (24 ± 4 ng/mL, p < 0.05) compared with IR only values.
CONCLUSIONS: Despite similar degrees of injury at 90 minutes ischemia MCC-135 improved regional contractility and reduced the egress of CK-MB. Moreover MCC-135 was associated with decreased heart rate, a determinant of myocardial oxygen demand. Pharmacologic modulation of calcium transport ameliorates myocardial dysfunction in the acute IR period.
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Introduction
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Reestablishment of coronary blood flow to ischemic myocardium forms the underpinning of therapeutic modalities targeted at myocardial ischemia and infarction [1, 2]. However a transient exacerbation of regional myocardial contractile function can occur after restoration of coronary blood flow [3, 4]. This deleterious phenomenon, termed ischemia-reperfusion (IR) injury, has been observed in clinical investigations [5–7] and has been reproduced in animal models of IR and isolated myocyte systems [8–12]. While the causes of IR-induced contractile dysfunction are multifactorial [13] it is likely that perturbations in calcium transport play a prominent role. For example increased intracellular calcium levels have been observed in isolated myocyte preparations simulating IR and were associated with diminished contractile function [14–15]. Moreover pharmacologic strategies designed to modulate calcium reuptake into the sarcoplasmic reticulum or efflux across the sarcolemma favorably affected contractile function after IR [16]. A recently described pharmacologic compound, MCC-135 (5-methyl-2-[1-piperazinyl] benzenesulfonic acid monohydrate, Mitsubishi Pharma Corporation), has been demonstrated to modify calcium transport processes [17–19]. While the precise mechanisms of action of this compound remain to be defined, past in vitro studies have demonstrated that MCC-135 prevents myocyte calcium overload through inhibition of the sodium-calcium exchanger, enhances calcium reuptake into the sarcoplasmic reticulum, and accelerates relaxation of left ventricular myocytes [17–19]. However whether and to what degree MCC-135 attenuates the degree of IR-mediated contractile dysfunction in an in vivo model that mimics the clinical scenario of myocardial IR has not been examined. Accordingly, the goal of the present study was to examine the effects of MCC-135 upon regional myocardial contractile function and indices of myocardial injury in an acute porcine model of prolonged myocardial ischemia followed by reperfusion.
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Material and methods
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Study rationale and overview
The present study employed an acute porcine model in which the effects of MCC-135 upon regional left ventricular (LV) contractility and markers of myocardial injury were assessed after prolonged regional myocardial IR. Pigs were used as an animal model because they exhibit coronary artery anatomy and cardiac physiology similar to that of humans [20]. Importantly, these anatomic features facilitated creation of consistent and fixed myocardial defects. The chemical structure and formulation of MCC-135 has been described previously [18]; it was administered intravenously (IV) just before myocardial reperfusion and was continued for the remainder of the protocol. All animals were treated and cared for in accordance with the National Institute of Health "Guide for the Care and Use of Laboratory Animals" (National Research Council, Washington, DC, 1996).
Experimental design
Acute instrumentation
Yorkshire pigs (n = 18, 32 kg) were sedated with valium (200 mg, orally) and anesthetized with sufentanyl (2 µg/kg IV; Baxter Healthcare, Deerfield, IL) and etomidate (0.3 mg/kg IV; Bedford Laboratories, Bedford, OH). After endotracheal intubation, mechanical ventilation was initiated and a stable anesthetic plane was achieved using morphine sulfate (3 mg · kg-1 · h-1 IV; Elkins-Sinn, Cherry Hill, NJ) and isoflurane (1%, 1.5 L/min O2). Maintenance intravenous fluids (150 mL/h, lactated ringers) and lidocaine HCl (1 mg/h IV; Elkins-Sinn) were administered throughout the protocol. An aortic (8F) line was placed into the right carotid artery in order to continuously monitor systemic pressures and facilitate plasma collection. A multilumened thermodilution catheter (7.5F; Baxter Healthcare, Irvine, CA) was positioned in the pulmonary artery through the left external jugular vein. A median sternotomy was performed and a vessel loop was placed around the inferior vena cava in order to perform transient caval occlusions. A precalibrated microtipped transducer (7.5F, Millar Instruments, Houston, TX) was advanced into the left ventricle (LV) through a small apical stab wound (Fig 1).
Two pairs of piezoelectric crystals (2 mm; Sonometrics, Ontario) were positioned against the LV endocardial surface in order to measure segmental wall motion. One crystal pair was placed between the first and second diagonal branches of the left anterior descending coronary artery (remote region). The second crystal pair was placed between the third and fourth obtuse marginal branches of the circumflex coronary artery (area-at-risk region) so that they were positioned across the LV chamber relative to the first crystal pair (Fig 1). Finally a loose snare was placed around the circumflex coronary artery just distal to the first obtuse marginal branch. Pressure waveforms and crystal signals were digitized on computer for subsequent analysis at a sampling frequency of 100 Hz (Sonolab, Sonometrics).
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Fig 1. (A) A schematic of the pig heart after instrumentation. Snares were placed around the inferior vena cava and proximal circumflex coronary artery. Sonomicrometry crystals (cry) were positioned adjacent to the endocardial surface of the left ventricular (LV) free wall within the anterior surface (remote region) perfused by the left anterior descending artery and posterolateral surface (area-at-risk, shaded) perfused by the circumflex coronary artery. (B) A schematic depicting the instrumented LV as observed from a view perpendicular to the LV long axis. Sonomicrometry crystal heads are apparent along the endocardial surface of the LV. Regional shortening was determined between the remote and area-at-risk myocardial regions using end-diastolic and end-systolic crystal "chord" lengths obtained between these regions. These interregional distances approximated the diameter of the LV. (CIRC = circumflex; LAD = left anterior descending; OM = obtuse marginal; RV = right ventricle.)
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Baseline measurements
Hemodynamic variables were assessed and LV function was determined by utilizing transient caval occlusion and sonomicrometry. Specifically, the distance between the crystals placed within each region was recorded at end-systole and diastole in order to compute segmental shortening. These measurements were used to generate end-systolic pressure-segment distance (dimension) relationships. Distances between the remote and area-at-risk regions were determined at end-systole and diastole as well. Plasma (15 mL) samples were obtained and heparin sodium (150 U/kg IV; Pharmacia and Upjohn, Kalamazoo, MI) and lidocaine HCl (100 mg IV) boluses were administered. These measurements were repeated at 30 minute intervals throughout the remainder of the protocol. Data were collected for 15 seconds at each designated time-point and was averaged.
Myocardial ischemia
The coronary snare was tightened. Regional myocardial ischemia was confirmed by paradoxical LV wall motion, tissue blanching within the area-at-risk, electrocardiographic changes, and deteriorations in regional function as evidenced by gross changes in sonomicrometry crystal traces. Episodes of ventricular tachycardia and fibrillation were terminated with additional boluses of lidocaine HCl (50 mg, IV) and internal defibrillation, respectively.
Randomization
The pigs were randomly assigned to IR only (n = 11, normal saline, 60 mL/h IV) or MCC-135 (n = 7, IR-MCC, 300 µg · kg-1 · h-1 IV) groups at 105 minutes of ischemia by a masked and independent veterinarian. The sample size used and power curve calculation resulted in a computed power that exceeded 0.80 for indices of LV systolic function. Pharmacokinetic studies in pigs utilizing MCC-135 demonstrated that a continuous intravenous infusion 300 µg · kg-1 · h-1 achieved steady-state plasma levels of approximately 1 to 2 µm. This concentration was similar to that employed in prior in vitro studies in which beneficial effects of MCC-135 on papillary muscle relaxation were observed [17].
Myocardial reperfusion
After 120 minutes of ischemia the coronary snare was removed and the pigs were reperfused for 180 minutes. A previous internal study of porcine IR utilized microsphere injections to demonstrate immediate and complete reperfusion of the area-at-risk.
Plasma profiles
Plasma troponin-I, total creatine-kinase, and creatine kinase-MB levels were assessed using the AxSYM automated microparticle enzyme immunoassay analyzer (Abbott Laboratories, Abbott Park, IL).
Data analysis
Temporal changes in hemodynamic, functional, and plasma enzyme values between the IR only and IR-MCC groups were analyzed using a two-way analysis of variance (ANOVA) followed by mean separation using pair-wise Bonferroni corrections. Values are presented as the mean and standard error of the mean and p values of less than 0.05 were considered statistically significant.
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Results
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During the ischemic interval and before randomization, internal defibrillation for ventricular fibrillation was required in 2 pigs in the IR only group and no pigs in the MCC-135 group. This difference did not translate into statistical significance (Pearson corrected chi-square analysis, p = 0.23). There were no episodes of ventricular fibrillation during the reperfusion interval in either IR group.
Steady-state hemodynamics
Steady-state hemodynamic measurements are summarized in Table 1. Since the pigs were treated in identical fashion for the first 105 minutes of ischemia and analysis of variance revealed no difference between groups before randomization, the measurements obtained from these initial time-points were pooled. At 180 minutes of reperfusion, heart rate was increased and mean arterial pressure was decreased in the IR only group compared with baseline values. Compared with IR only, values cardiac output and mean aortic pressure were decreased in the IR-MCC group. When presented as a change from 90 minutes of ischemia, heart rate was not significantly changed in the IR-MCC group and was less than IR only values (Fig 2).
In contrast, mean aortic pressure decreased from 90 minutes ischemic and IR only values in the IR-MCC group (Fig 2). Infusion of MCC-135 was associated with a significant decrease in LV stroke volume during the reperfusion interval compared with IR only values. Isovolumic LV relaxation, defined as 50% relaxation (Tau, ms) [21], was prolonged with ischemia and increased further at reperfusion (Table 1). However, infusion of MCC-135 prevented the prolongation of Tau during the reperfusion interval.
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Fig 2. Heart rate (A) and mean aortic pressure (B) presented as changes from 90 minutes ischemic values. By 60 minutes of reperfusion heart rate was increased and mean aortic pressure was decreased in the ischemia-reperfusion (IR) only group compared with 90 minutes ischemic values. Heart rate did not change from 90 minutes ischemic values in the IR-MCC group but was decreased compared with IR only values. By 60 minutes of reperfusion mean aortic pressure was decreased in the IR-MCC group compared with 90 minutes ischemic and IR only values. +p < 0.05 versus 90 minutes ischemia; *p < 0.05 versus IR only; circles = IR only; triangles = IR-MCC.
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Intraregional contractile function
By 30 minutes of ischemia the regional end-systolic pressure-dimension relation (RESPDR) was decreased from baseline values within the area-at-risk region in both IR groups (Fig 3).
However, within 15 minutes of MCC-135 infusion (120 minutes ischemia) the RESPDR was higher in the IR-MCC group compared with IR only values, and remained increased throughout the reperfusion interval. There were no significant changes in the RESPDR within the remote region in either IR group.
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Fig 3. Change from baseline in the regional end-systolic pressure-dimension relation (RESPDR) within the area-at-risk. By 30 minutes of ischemia the RESPDR was decreased from baseline in both ischemia-reperfusion (IR) groups. Within 15 minutes of MCC-135 infusion (120 minutes ischemia) the RESPDR was increased in the IR-MCC group compared with IR only values. #p < 0.05 versus baseline; +p < 0.05 versus ischemia; *p < 0.05 versus IR only; circles = IR only; triangles = IR-MCC.
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Interregional contractile function
Interregional shortening was determined between the remote and area-at-risk regions (Fig 4).
Interregional shortening was reduced at 90 minutes of ischemia in both IR groups compared with baseline values. However, by 120 minutes of ischemia and throughout the reperfusion interval interregional shortening was greater in the IR-MCC group compared with IR only values.
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Fig 4. Inter-regional shortening presented as a change from baseline values. Shortening was reduced at 90 minutes of ischemia in both ischemia-reperfusion (IR) groups. By 120 minutes of ischemia and throughout reperfusion inter-regional shortening was increased in the IR-MCC group compared with IR only. #p < 0.05 versus baseline; +p < 0.05 versus ischemia; *p < 0.05 versus IR only; open bars = IR only; shaded bars = IR-MCC.
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Plasma profiles
The plasma levels of total creatine kinase and the myocyte-specific enzymes, troponin-I, and creatine kinase-MB (CK-MB) were serially measured during the IR protocol (Fig 5).
In the IR only group robust increases in the plasma levels of total creatine kinase and CK-MB were observed immediately after coronary snare release. However the plasma levels of both of these enzymes were decreased during the reperfusion interval in the IR-MCC group compared with IR only values. Troponin-I values similarly increased in both IR groups during the reperfusion interval compared with baseline values.
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Fig 5. Plasma levels of total creatine kinase (A), creatine kinase-MB (CK-MB) (B), and troponin-I (C) during ischemia-reperfusion (IR). Before reperfusion total creatine kinase was significantly reduced in the IR-MCC group compared with IR only values. Marked increases in plasma values of total creatine kinase and CK-MB were apparent after snare removal in the IR only group. The IR-MCC was associated with significantly decreased CK-MB egress compared with IR only values thus contributing to the significant reduction in total creatine kinase levels immediately before reperfusion in this group. Troponin-I values similarly increased in both IR groups during the reperfusion interval compared with baseline values. #p < 0.05 versus baseline; +p < 0.05 versus ischemia; *p < 0.05 versus IR only; circles = IR only; triangles = IR-MCC.
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Comment
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Myocardial contractile dysfunction, secondary to IR injury, is a common clinical occurrence particularly in settings in which percutaneous coronary interventions and cardiopulmonary bypass procedures are required [3–7]. While there are innumerable potential contributory factors to this phenomenon [13], it is likely that defects in myocyte intracellular calcium handling play a prominent role. Past studies utilizing short periods of myocardial IR and pharmacologic blockade of the sodium-hydrogen transporter suggests that modulation of intracellular calcium levels may contribute to alterations in myocardial contractile function [8–10]. The present study employed a unique compound, MCC-135, known to inhibit myocyte calcium overload [17, 19] and enhance calcium reuptake into the sarcoplasmic reticulum [18] in a setting of prolonged myocardial IR. Moreover, MCC-135 was administered just before reperfusion in order to mimic the more common clinical scenario of myocardial IR.
The unique findings of the present investigation were threefold. First, when instituted at reperfusion MCC-135 was associated with significant and sustained improvements in regional contractile function after a prolonged period of myocardial ischemia. Second, despite equivalent degrees of cardiac troponin-I release MCC-135 was associated with marked reductions in the egress of creatine kinase-MB during the reperfusion interval. Third, MCC-135 appeared to confer a favorable chronotropic (decreased heart rate) and lusitropic (active relaxation) effect throughout the acute reperfusion period. Taken together these results suggest that infusion of MCC-135 at the time of reperfusion may favorably modify myocardial contractility and energetics after a prolonged period of regional ischemia.
Regional contractility after IR: effects of MCC-135
Past experimental studies suggest that modifying determinants of calcium transport might favorably affect the degree of IR injury [8–11]. However, the majority of these past studies deployed pharmacologic intervention before or shortly after the onset of brief ischemic intervals. Thus translation of these preclinical investigations to the clinical context of IR may be problematic. Accordingly, the present study utilized a prolonged period of coronary artery occlusion and administered MCC-135 just before myocardial reperfusion. This strategy more closely approximated the clinical context of IR and resulted in significant reductions in regional and global LV function. Consistent with the myocardial IR phenomenon, resumption of coronary blood flow in this acute porcine model resulted in further deteriorations in regional contractile function. In contrast, institution of MCC-135 at the time of reperfusion abolished the further decline in contractility as evidenced by improvements in regional and interregional contractile function. However, it must be recognized that the increased regional contractility observed with MCC-135 was not translated into improved global pump function as assessed by cardiac output. Potential mechanisms responsible for this effect are multifactorial and may include both intracellular and extracellular factors. For instance, MCC-135 infusion was associated with a fall in heart rate during the reperfusion interval. A previous in vitro investigation demonstrated that spontaneous beating of sinoatrial nodal cells could be abolished by acute pharmacologic blockade of the reversible sodium/calcium exchanger [22]. Thus while remaining speculative, administration of MCC-135 may have affected sinoatrial nodal cell automaticity in a similar fashion, thus accounting for the reduction in heart rate observed during reperfusion.
Administration of MCC-135 was associated with decreased cardiac output and increased mean aortic pressure compared with IR only values immediately after reperfusion. These results suggest that MCC-135 may have altered systemic vascular resistance. Moreover preliminary data suggest that MCC-135 alters intracellular calcium [17]. This effect may have influenced rudimentary contractile proteins within the vascular compartment and altered resistance properties accordingly. The decreased stroke volume associated with administration of MCC-135 may have contributed to the subsequent reductions in pulse and mean aortic pressures during the latter stages of reperfusion. Finally, IR has been demonstrated to activate proteolytic enzymes within the myocardial interstitium that degrade critical components the extracellular matrix [23]. Degradation of the myocardial extracellular matrix may explain the failure of the increased regional LV contractility observed with MCC-135 infusion to be translated into an overall improvement in LV ejection. Failure of MCC-135 to modify contractile performance within the remote region was not unexpected. In fact, a past in vitro study examining the effects of MCC-135 on contractile and relaxation properties of normal LV fiber preparations similarly demonstrated lack of effect [18].
Myocardial injury after IR: effects of MCC-135
Past studies of myocardial IR suggest that pharmacologic manipulation of calcium transport mechanisms might attenuate myocardial injury as assessed by postmortem histochemical staining [8–11]. For example, Klein and coworkers [8] subjected pigs to regional myocardial ischemia and demonstrated that simultaneous blockade of the sodium/hydrogen exchanger reduced infarct size by 45% as assessed by myocardial staining. The present study was unique from past investigations in two important respects. First, pharmacologic manipulation was instituted just before myocardial reperfusion. Second, an alternative method was employed to evaluate the effects of prolonged IR and MCC-135 administration upon myocardial injury. Specifically, the degree of myocardial injury post-IR was evaluated by temporally profiling the plasma levels of myocyte-specific enzymes. Administration of MCC-135 at the time of reperfusion appeared to have differential effects upon myocyte-specific enzyme release. For example, MCC-135 reduced the egress of creatine kinase-MB from the myocytes. In contrast, the plasma levels of cardiac troponin-I were equivalent. These results suggest that similar degrees of myocyte death occurred within the area-at-risk during IR but that MCC-135 reduced CK-MB release in the bordering viable myocardium. However, as both CK-MB and troponin-I are markers for myocyte, necrosis, additional investigations examining the effects of MCC-135 on enzyme release in similar settings are warranted. Because the area-at-risk was devoid of significant collateral vessels [Weaver], an extensive amount of tissue loss was inflicted by the ischemic interval as evidenced by the marked elevations in plasma troponin-I values after reperfusion. Although this elevation suggests that necrosis represented the dominant pattern of cell death, an assessment of myocardial apoptosis was not performed.
Potential mechanisms for improved regional contractility after IR
While still the focus of ongoing investigations, the mechanism through which MCC-135 operates at the level of the myocyte probably involves modulation of calcium homeostatic processes [17, 18]. In a recent study performed by Satoh and associates [18] that utilized papillary muscle preparations obtained from diabetic rats, MCC-135 decreased the time required for active relaxation (positive lusitropic effect). Importantly, the authors suggested that these effects were achieved without modification of cAMP levels within the LV myocardium. Moreover, MCC-135 has been associated with enhanced calcium reuptake into the sarcoplasmic reticulum and inhibition of myocyte calcium overload [18, 19]. Consistent with these past in vitro effects, the present study demonstrated that administration of MCC-135 at the time of reperfusion improved indices of LV relaxation (Tau). Thus MCC-135 may serve as an alternative to phosphodiesterase inhibitors as a means by which to modify LV dysfunction with lusitropic abnormalities. Left ventricular active relaxation is an energy-dependent process that necessitates high rates of calcium sequestration into the sarcoplasmic reticulum through the activity of calcium-ATPases localized to the sarcoplasmic reticulum membrane [24]. In the present study, utilization of MCC-135 was associated with significant attenuations in creatine kinase-MB egress from the myocytes during the reperfusion interval. Therefore, MCC-135 may have increased myocyte creatine-kinase MB levels during reperfusion that may have provided beneficial effects upon high-energy phosphate stores. Although additional studies are necessary, the present investigation demonstrated that MCC-135 infusion increased regional LV contractility and provided a beneficial lusitropic effect during the critical reperfusion interval.
Study limitations and clinical implications
The present study employed MCC-135 in an acute model of myocardial IR. Therefore, whether and to what degree MCC-135 influences regional LV contractility beyond the acute reperfusion period remains to be determined. Moreover, future studies are necessary in order to examine the effects of MCC-135 upon myocyte viability within the border-zone and upon hemodynamic indicators in healthy subjects. Of greatest importance is a requirement to elucidate the precise mechanism of action of this novel compound in vivo. Nevertheless, the present study demonstrated that MCC-135 administration at the time of reperfusion attenuated LV contractile dysfunction after a prolonged period of regional ischemia. Moreover, MCC-135 was associated with beneficial chronotropic and lusitropic effects and protection against myocardial creatine-kinase MB egress. These effects may have improved energetics and decreased myocardial oxygen consumption during the critical reperfusion period. Thus strategies that modulate calcium homeostasis such as MCC-135 may hold significant therapeutic potential in the setting of IR.
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Acknowledgments
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This study was supported by the National Heart, Lung, and Blood Institute Grants HL-45024, HL-97012, a Career Development Award from the Ralph H. Johnson Veterans' Association Medical Center, the National Institutes of Health Postdoctoral Training Grant HL-07260, and a Basic Science Research Grant provided by Mitsubishi Pharma Corporation. The authors acknowledge Robert E. Stroud, Marlina Multani, Anne M. Deschamps, and Jennifer R. Holder for assisting with this project.
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Abstract
Introduction
