doi: 10.1161/hc3901.095766
(Circulation. 2001;104:1657.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Electrical Remodeling in Pressure-Overload Cardiac Hypertrophy
Role of Calcineurin
Departments of Internal Medicine (Z.W., W.K., J.A.H.), Pharmacology (J.A.H.), and Surgery (M.K.), and the Interdisciplinary Graduate Program in Molecular Biology (K.E.R., J.A.H.), University of Iowa College of Medicine, and the Department of Veterans Affairs (J.A.H.), Iowa City, Iowa.
Correspondence to Joseph A. Hill, MD, PhD, Cardiovascular Division, University of Iowa College of Medicine, E318GH, UIHC, 200 Hawkins Dr, Iowa City, IA 52242-1081. E-mail joseph-hill{at}uiowa.edu
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Abstract |
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Background— Myocyte hypertrophy accompanies many forms of heart disease, but its contribution to electrical remodeling is unknown.
Methods and Results— We studied mouse hearts subjected to pressure overload by surgical thoracic aortic banding. In unbanded control hearts, action potential duration (APD) was significantly longer in subendocardial myocytes compared with subepicardial myocytes. Hypertrophy-associated APD prolongation was significantly greater in subendocardial myocytes compared with subepicardial myocytes, indicating stress-induced amplification of repolarization dispersion. To investigate the underlying basis, we performed voltage-clamp recordings on dissociated myocytes. Under control unoperated conditions, subendocardial myocytes exhibited significantly less transient outward current (Ito) than did subepicardial cells. Hypertrophy was not associated with significant changes in Ito, sustained current, or inward rectifier current densities, but peak L-type Ca2+ current density (ICa,L) increased 26% (P<0.05). Recovery from ICa,L inactivation was accelerated in hypertrophied myocytes. Inhibition of calcineurin with cyclosporin A prevented increases in heart mass and myocyte size but was associated with an intermediate APD. The hypertrophy-associated increase in ICa,L and the accelerated recovery from inactivation were blocked by cyclosporin A.
Conclusions— These data reveal regional variation in the electrophysiological response within the left ventricle by way of a mechanism involving upregulated Ca2+ current and calcineurin. Furthermore, these results reveal partial uncoupling of electrophysiological and structural remodeling in hypertrophy.
Key Words: calcium • electrophysiology • action potentials • arrhythmia • hypertrophy
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Introduction |
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Faced with stressful stimuli, cardiac myocytes mount a growth response that culminates in hypertrophy. Cardiac hypertrophy is associated with a significantly increased risk of cardiovascular morbidity and mortality, much of which stems from electrical remodeling and arrhythmogenesis.1,2 In the left ventricle (LV), electrical remodeling is usually manifested as action potential prolongation, which predisposes to early and late afterdepolarizations3 and underlies the propensity to arrhythmia, syncope, and sudden death.
Considerable progress has been reported recently in elucidating the molecular pathogenesis of hypertrophy (as reviewed recently in Olson and Williams4, and Molkentin5), but our understanding of the mechanisms of electrical remodeling in hypertrophy is limited. Development of new antiarrhythmic therapies will require identification of disease-specific mechanistic pathways leading to action potential prolongation.
In humans, electrophysiological heterogeneity within the ventricular wall underlies a number of physiological (upright T wave on the surface ECG) and pathological (torsades de pointes, J wave of Osborne, U waves) processes.6,7 In many species, this dispersion of repolarization stems from the relatively brief action potential duration (APD) of subepicardial myocytes, which manifest a high-density transient-outward current (Ito).7–9 Although genetic models in mice have been instrumental in dissecting the electrical anatomy of the ventricular action potential,10–12 it is not known whether transmural electrical heterogeneity exists in the mouse. Furthermore, it is not known whether hypertrophy alone, a process associated with a markedly increased risk of sudden death, is associated with heightened spatial heterogeneity of electrical remodeling.
In this study, we investigated the electrophysiological phenotype of myocardial hypertrophy in a model with no LV dysfunction.13 We addressed 3 questions: (1) Is hypertrophy associated with electrical remodeling, and if so, what is the underlying electrophysiological basis? (2) Does hypertrophic transformation amplify the regional variation of recovery of electrical excitability in the LV? (3) What is the role of a recently described calcineurin transcriptional pathway?
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Methods |
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Pressure-Overload Hypertrophy Model
Male mice (C57BL6, 6 to 8 weeks old) were subjected to pressure overload by thoracic aortic banding (TAB).13 Some mice were subjected to a sham operation in which the aortic arch was visualized but not banded. Perioperative (24-hour) mortality was <10%. On the morning of postoperative day 1, TAB or sham-operated mice were randomized to receive either cyclosporin A (CsA) 25 mg/kg or vehicle (Veh) subcutaneously twice daily.
Myocyte Isolation
LV cardiomyocytes were isolated by using a protocol slightly modified from that of Xu et al.14 In brief, after retrograde perfusion with Ca2+-free buffer followed by collagenase solution, the apex was removed and the LV midwall was divided into subendocardial- and subepicardial-enriched fractions. After trituration, cells were plated and studied within 6 to 8 hours.
Electrophysiological Recordings
Myocytes were superfused at 1 to 2 mL/min (21°C to 23°C) with Tyrode’s solution containing (in mmol/L) 137 NaCl, 5.4 KCl, 1.0 MgCl2, 1.0 CaCl2, 10.0 dextrose, and 10.0 HEPES (pH 7.4). Calcium-tolerant quiescent myocytes with a typical rod-shaped appearance and clear cross striations were chosen for experimentation. Borosilicate glass capillaries (7052 glass, 1.65-mm OD, A-M Systems) were prepared with tip resistances of 1.5 to 3.0 M
when filled with a solution containing (in mmol/L) 137.0 KCl, 1.0 MgCl2, 0.5 CaCl2, 10.0 HEPES, 5.0 EGTA, 5.0 Mg2-ATP, 5.0 sodium creatine phosphate, and 0.5 GTP-Tris (pH 7.2). Tip potentials were compensated before the pipette touched the cell. After whole-cell voltage clamp with a gigaohm seal was obtained, whole-cell membrane capacitance was calculated as the time integral of the capacitative response to a 10-mV hyperpolarizing step. Cells with significant leak current (
100 pA) were rejected (
20%). When whole-cell currents (depolarized every 15 seconds) were measured, series resistance and membrane capacitance were compensated electronically 85%.
To record depolarization-activated K+ currents, the L-type Ca2+ current (ICa,L) was inhibited with 2 mmol/L CoCl2. This agent was chosen because other blockers have nonspecific actions on the Na+ current (Cd2+) or Ito (dihydropyridines). A holding potential of -50 mV was used to inactivate rapid Na+ currents.15 To record Ito and Isus, 350-ms depolarizing pulses (-40 to +60 mV) from a holding potential of -50 mV were applied. Isus was defined as the current remaining at the end of the pulse. Ito was defined as the difference between peak current (Ipeak) and Isus. To measure ICa,L, cells were continuously superfused with a solution containing (in mmol/L)16 2.0 CaCl2, 1.0 MgCl2, 135.0 tetraethylammonium chloride, 5.0 4-aminopyridine, 10.0 glucose, and 10.0 HEPES (pH 7.3). The pipette-filling solution contained (in mmol/L) 100.0 cesium aspartate, 20.0 CsCl, 1.0 MgCl2, 2.0 Mg2-ATP, 0.5 GTP, 5.0 EGTA, and 5.0 HEPES (pH 7.3).
Statistical Methods
Averaged data are reported as mean±SEM. Sample sizes are listed as n=x/y to denote x cells from y mice. Statistical significance was analyzed with a Student’s unpaired t test or 1-way ANOVA followed by Bonferroni’s method for post hoc pairwise multiple comparisons. Quality of exponential fits was analyzed with a 
2 test statistic.
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Results |
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Recent studies have revealed heterogeneity in the electrophysiological architecture of the mammalian heart in physiological and pathological conditions.6 In large mammals, the transient outward current (Ito) is more prominent in subepicardial myocytes than in other cells.7,8 To investigate this in mice, short-axis slices of LV were microdissected into subepicardial- and subendocardial-enriched fractions. Current-clamp action potentials recorded in subepicardial (Figure 1A) and subendocardial (Figure 1C) myocytes from unoperated control mice were similar in morphology, displaying relatively little phase 2 plateau. APD in subendocardial myocytes was statistically significantly greater than that recorded in subepicardial cells (Table 1).
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To investigate the basis for the differences in APD, whole-cell depolarization-activated K+ currents were recorded under conditions in which inward Na+ and Ca2+ currents were inhibited (Table 1). In the majority of myocytes (16/22 cells from 10 mice, 73%) isolated from the subepicardial fraction of unoperated control LV, voltage-clamp recordings revealed a large Ito (Figure 1B). In contrast, the majority of cells (15/23 cells from 11 mice, 65%) isolated from the subendocardial fraction did not reveal substantial Ito (Figure 1D). In contrast, Isus densities were similar in these 2 cell fractions.
Role of Calcineurin in Spatial Dispersion of Hypertrophic Electrical Remodeling
To determine whether hypertrophic electrical remodeling is heterogeneous within the mouse LV, mice were subjected to surgical aortic banding for 3 weeks. Heart weight normalized to body weight increased 59% (P<0.05) in TAB+Veh-treated hearts compared with controls (Sham+Veh; Table 2). Isolated ventricular myocytes were enlarged significantly in TAB+Veh hearts compared with Sham+Veh hearts assayed in terms of whole-cell membrane capacitance (increase of 33%, P<0.01) and 2-dimensional cell surface area (increase of 52%, P<0.01; Table 2). Within each treatment group, cell capacitances and 2-dimensional cell surface areas were similar in subendocardial and subepicardial myocytes (Table 2).
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We have shown previously that calcineurin inhibition with CsA blocks the increases in heart mass and myocyte size associated with pressure overload in this model.13 Because it is not known whether the electrophysiological and structural phenotypes of hypertrophy are causally linked, we examined whether they could be dissociated by calcineurin inhibition. To control for the influence of hypertrophic growth on electrophysiological remodeling, mice were randomized on the morning after TAB or sham operation to receive either CsA (25 mg/kg SC BID) or vehicle. In hearts exposed to CsA (TAB+CsA or Sham+CsA), heart mass, myocyte surface area, and myocyte capacitance were not significantly different from baseline (Table 2), thereby confirming the efficacy of hypertrophy abrogation. Calcineurin phosphatase activity in the sham-operated LV was 349±18 pmol · mg-1 · min-1 (n=8), which was not statistically significantly different from TAB (260±40 pmol · mg-1 · min-1, n=7, P=NS). In the presence of CsA, however, calcineurin activity (49±7 pmol · mg-1 · min-1, n=7) was significantly diminished compared with sham-operated (P<0.01) or TAB (P<0.01) conditions.
Current-clamp action potentials revealed significant differences in the electrophysiological response to pressure overload in cells derived from 2 regions of the LV wall (Table 1). Action potentials recorded in hypertrophied (TAB+Veh) subepicardial myocytes (Figure 2A) were prolonged 23% (P<0.05). Significantly greater effects were observed in subendocardial myocytes, in which a phase 2 shoulder began to appear (Figure 2B), and the APD increased 60% (P<0.01) at 3 weeks (Figure 2C). Comparison of subepicardial and subendocardial responses to hemodynamic stress (Figure 2D) revealed a strikingly greater degree of action potential prolongation (measured as APD90 or APD50) in subendocardial cells (P<0.01). Current- and voltage-clamp recordings in sham-operated mice were similar to those of unoperated controls.
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Calcineurin inhibition completely blocked the increases in cell size associated with TAB (Table 2). Despite elimination of the structural changes of hypertrophy, APD prolongation was blunted though not normalized by calcineurin inhibition (Figure 2, Table 1), suggesting that the structural and electrophysiological components of remodeling in hypertrophy are partially dissociable.
Repolarizing K+ Currents
Ito is a major determinant of repolarization in murine ventricular myocytes and is frequently implicated in the electrical remodeling of heart failure.17 We studied the effects of TAB+Veh and TAB+CsA on Ito and on the current that persists at 300 ms (Isus). At baseline, Ito was relatively large in myocytes isolated from the subepicardial aspect of the LV (Figure 3A). With hypertrophy, Ito and Isus did not change significantly (Figure 3B, Table 1), and the proportion of subendocardial cells exhibiting substantial Ito (32/43 cells from 16 mice, 74%) was unchanged. Inhibition of hypertrophy with calcineurin blockade (TAB+CsA) was associated with similar Ito and Isus waveforms (Figure 3C) and densities (Figures 3E and 3F), as was exposure to CsA alone (Figures 3D through 3F, Table 1). Calcineurin inhibition (TAB+CsA) did not alter the proportion of subepicardial myocytes exhibiting Ito (17/27 cells from 10 mice, 63%). Ito and Isus densities were similar under conditions of TAB+CsA and Sham+CsA (Figures 3E through 3F, Table 1).
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In contrast with subepicardial cells, LV myocytes isolated from the subendocardial fraction exhibited relatively little Ito at baseline (see online Figure IA at www.circulationaha.org). Similar to subepicardial cells, hypertrophy (TAB+Veh) had no effect on Ito or Isus waveforms (online Figure IB) and densities (online Figures IE through IF, Table 1). The proportion of cells exhibiting substantial Ito was not altered by hypertrophy (TAB+Veh, 12/36 cells from 13 mice, 33%) or by exposure to CsA (TAB+CsA, 10/22 cells from 9 mice, 45%). Ito and Isus densities were similar under conditions of TAB+CsA and Sham+CsA (online Figures IE and IF, Table 1).
Inward rectifier current (IK1) densities and kinetics did not differ between subepicardial and subendocardial cells. IK1 recorded from hypertrophied myocytes (TAB+Veh) was similar to baseline (control and sham operated) and after exposure to CsA (TAB+CsA, Sham+CsA; negative data not shown).
Hypertrophic Upregulation of Inward Ca2+ Current
Because intracellular Ca2+ is increasingly viewed as a central point of regulation in the pathogenesis of hypertrophy18 and disease-related electrical remodeling,19,20 we measured the L-type Ca2+ current (ICa,L) in the presence (TAB+Veh) and absence (Sham+Veh, TAB+CsA, Sham+CsA) of hypertrophy. No differences in ICa,L amplitude or kinetics were observed between subendocardial (Figure 4A) and subepicardial (online Figure II) cell fractions. The amplitude of ICa,L in hypertrophied myocytes (TAB+Veh), however, was larger than in sham-operated controls (Figure 4B). Normalization to cell size (capacitance) revealed that peak ICa,L density increased 26% (P<0.05) in TAB+Veh myocytes (14±1 pA/pF) compared with Sham+Veh cells (11.1±0.4 pA/pF). ICa,L density was increased in TAB+Veh cells at all potentials ranging from -20 to +50 mV (Figure 4F).
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, n=22/6), TAB+Veh (•, n=18/6), TAB+CsA (
, n=15/5), and Sham+CsA (
, n=15/5) LV.
Peak ICa,L and current-voltage relations in cells exposed to TAB+CsA (Figure 4C) were not significantly different from sham-operated controls. The peak ICa,L density measured in Sham+CsA cells was slightly less than that measured in Sham+Veh myocytes (9.3±0.9 pA/pF, P<0.05).
To determine whether changes in channel availability underlie the differences in peak ICa,L, we examined the voltage dependence of activation and inactivation (Figures 5A through 5C). This analysis revealed no significant differences in steady-state voltage-dependent activation or inactivation of ICa,L among any of the 4 treatment groups (Figure 5C). Because intracellular Ca2+, acting through calmodulin,21 modulates the kinetics of L-type Ca2+ channel inactivation, we examined the time dependence of recovery from steady-state ICa,L inactivation by using a paired-pulse protocol (Figure 5D). The time constants of recovery from inactivation for TAB+Veh and Sham+Veh cells were 65±7 ms (2=0.0055) and 168±11 ms (2=0.0067), respectively (P<0.05), revealing a significant acceleration of recovery from inactivation in hypertrophied myocytes. The faster recovery from ICa,L inactivation was absent in nonhypertrophied banded hearts (TAB+CsA, Figure 5F). The time constants of recovery from steady-state inactivation in TAB+CsA (149±14 ms, 2=0.00033) and Sham+CsA (130±13 ms, 2=0.00031) cells were not significantly different from sham-operated controls.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In recent years, electrophysiological remodeling has emerged as an important pathophysiological mechanism in many types of cardiac pathology. Because clinical heart disease often involves both hypertrophic and failure cellular phenotypes, we sought to elucidate the contribution of hypertrophy in isolation. Working with a model of pressure overload that induces cardiac hypertrophy without LV dysfunction, we evaluated action potential characteristics across the LV and studied the major currents involved in repolarization. We identified differences within the LV in cellular APD that are amplified by hemodynamic stress, and we addressed the role of a recently described calcineurin signaling pathway.
Accumulating evidence points to disorders of ventricular refractoriness underlying ventricular tachyarrhythmias.3 Data from clinical electrophysiological studies, surface electrocardiography, and animal models all point to dispersion of ventricular refractoriness as a major predisposing factor in the development of reentrant ventricular arrhythmias.22,23 At a basic level, it is becoming increasingly apparent that the electrophysiological characteristics of ventricular tissue are heterogeneous across the ventricular wall,9,24,25 including murine ventricle,14,26 and that these regional differences are altered in hypertrophy.27,28 It will be important in the future to determine why myocytes from different regions of the LV wall (1 mm thick in mouse heart) display markedly different electrophysiological phenotypes.
The cellular and molecular phenotype of hypertrophy is modulated by the degree of hypertrophy and the primary lesion that induces hypertrophy.29 In the TAB hypertrophy model, outward K+ currents (Ito, IK1) do not change, whereas the inward current (ICa,L) increases, thus inducing greater APD prolongation in subendocardial myocytes, given their relative lack of repolarizing Ito. Other models of moderate hypertrophy also manifest increased ICa,L.19,30 These findings contrast with numerous models of heart failure in which outward K+ currents, especially Ito, are decreased.19,30–32 Differences in mechanisms underlying action potential prolongation in hypertrophy and heart failure may have significant implications in devising therapeutic approaches to treating arrhythmias in these diseases.
TAB in mice induces 50% cardiac hypertrophy at 3 to 5 weeks, and this process is blocked by calcineurin inhibition (see Table 2 and Hill et al13). We have exploited calcineurin inhibition with CsA to control for the structural changes of hypertrophic growth. Calcineurin blockade eliminated the increases in heart mass and myocyte size associated with pressure overload and attenuated the APD prolongation of hypertrophy in both subepicardial and subendocardial myocytes. Similarly, calcineurin blockade prevented the upregulation of ICa,L and prevented the accelerated recovery from ICa,L inactivation seen with hypertrophy. At present, we do not know whether the CsA-mediated changes in ICa,L are secondary to the abrogated structural changes of hypertrophy, vice versa, or are separate phenomena. Because the action potential prolongation did not normalize completely with CsA, electrogenic transport processes in addition to ICa,L must be involved. Nevertheless, it is possible that the modulatory effects of CsA on hypertrophy are mediated via the L-type channel; a model could be proposed wherein CsA decreases ICa,L, which diminishes intracellular Ca2+, a central point in several hypertrophic signaling pathways.18,33
Calcineurin was inhibited with CsA at a dose that produced CsA trough levels of 2.6±0.2 µg/mL,13 which inhibited 90% of total calcineurin phosphatase activity in the heart. Our assay of calcineurin activity relies on myocyte disruption with provision of exogenous Ca2+ and calmodulin, thereby activating total myocyte stores of calcineurin. Although documenting the efficacy of calcineurin inhibition by CsA, this assay does not distinguish between activated and inactive calcineurin within the cell.
The central role of intracellular calcium signaling in hypertrophy is established. In the heart, a small amount of Ca2+ entering through L-type channels triggers the release of much larger amounts of Ca2+ from intracellular stores. Thus, modest changes in Ca2+ influx are amplified within the cell. We predict that hypertrophy-associated ICa,L upregulation may generate positive feedback in the hypertrophic cascade. CsA-sensitive changes in ICa,L inactivation kinetics are suggestive of calcineurin-mediated regulation of the Ca2+ channel complex, as has been reported for a number of proteins involved in Ca2+ homeostasis, including the 1,4,5-triphosphate and ryanodine receptors, and the neuronal and cardiac34 Na+-Ca2+ exchangers (reviewed in Carafoli et al35).
Cardiac hypertrophy has been viewed as a pathological milestone in disease progression leading to heart failure, a syndrome in which compensatory responses such as vasoconstriction, neurohumoral recruitment, and cytokine activation are maladaptive in the long term. To this list, we must add ICa,L upregulation and action potential prolongation.19,32 Although an increased influx of Ca2+ may prove beneficial by maximizing inotropic potential in the short run, the resulting action potential prolongation heightens dispersion of refractoriness and predisposes to afterdepolarizations and triggered automaticity, reentry, and arrhythmogenesis.
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Acknowledgments |
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This work was supported by grants from the Donald W. Reynolds Cardiovascular Clinical Research Center, American Heart Association–Heartland Affiliate, Department of Veterans Affairs, National Institutes of Health grant HL-03908, and the Roy J. Carver Charitable Trust. We sincerely thank Drs Donald Heistad, Michael Welsh, and Kevin Campbell for helpful advice and support.
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Footnotes |
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Figures I and II can be found Online at http://www.circulationaha.org
Received February 12, 2001; revision received June 21, 2001; accepted June 22, 2001.
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J. Li, M. McLerie, and A. N. Lopatin Transgenic upregulation of IK1 in the mouse heart leads to multiple abnormalities of cardiac excitability Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2790 - H2802. [Abstract] [Full Text] [PDF]
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D. Lebeche, R. Kaprielian, F. del Monte, G. Tomaselli, J. K. Gwathmey, A. Schwartz, and R. J. Hajjar In Vivo Cardiac Gene Transfer of Kv4.3 Abrogates the Hypertrophic Response in Rats After Aortic Stenosis Circulation, November 30, 2004; 110(22): 3435 - 3443. [Abstract] [Full Text] [PDF]
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S. G. Birnbaum, A. W. Varga, L.-L. Yuan, A. E. Anderson, J. D. Sweatt, and L. A. Schrader Structure and Function of Kv4-Family Transient Potassium Channels Physiol Rev, July 1, 2004; 84(3): 803 - 833. [Abstract] [Full Text] [PDF]
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M. Schoenmakers, C. Ramakers, J. M. van Opstal, J. D.M. Leunissen, C. Londono, and M. A. Vos Asynchronous development of electrical remodeling and cardiac hypertrophy in the complete AV block dog Cardiovasc Res, August 1, 2003; 59(2): 351 - 359. [Abstract] [Full Text] [PDF]
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H. K. Reddy, S. Wasson, S. K.G. Koshy, and R. Komatireddy Structural correlates of electrical remodeling in ventricular hypertrophy Cardiovasc Res, June 1, 2003; 58(3): 495 - 497. [Full Text] [PDF]
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R. Wolk Calcineurin, myocardial hypertrophy, and electrical remodeling Cardiovasc Res, February 1, 2003; 57(2): 289 - 293. [Full Text] [PDF]
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M. C. Sanguinetti Reduced Transient Outward K+ Current and Cardiac Hypertrophy: Causal Relationship or Epiphenomenon? Circ. Res., March 22, 2002; 90(5): 497 - 499. [Full Text] [PDF]
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O. F. Bueno, B. J. Wilkins, K. M. Tymitz, B. J. Glascock, T. F. Kimball, J. N. Lorenz, and J. D. Molkentin Impaired cardiac hypertrophic response in Calcineurin Abeta -deficient mice PNAS, April 2, 2002; 99(7): 4586 - 4591. [Abstract] [Full Text] [PDF]
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