A more recent version of this article appeared on June 8, 2001

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(Circulation Research. 2001;0:hh1101.091193.)
© 2001 American Heart Association, Inc.

Article

Arrhythmogenesis and Contractile Dysfunction in Heart Failure

Roles of Sodium-Calcium Exchange, Inward Rectifier Potassium Current, and Residual ß-Adrenergic Responsiveness

Steven M. Pogwizd¹, Klaus Schlotthauer¹, Li Li, Weilong Yuan Donald M. Bers

From the Department of Medicine (S.M.P.), University of Illinois, Chicago, Ill, and Department of Physiology and Cardiovascular Institute (K.S., L.L., W.Y., D.M.B.), Loyola University Chicago.

Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Chicago, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}luc.edu

Abstract

Abstract— Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these same aspects of human HF, we demonstrate that a 2-fold functional upregulation of Na⁺-Ca²⁺ exchange (NaCaX) unloads sarcoplasmic reticulum (SR) Ca²⁺ stores, reducing Ca²⁺ transients and contractile function. Whereas ß-adrenergic receptors (ß-ARs) are progressively downregulated in HF, residual ß-AR responsiveness at this critical HF stage allows SR Ca²⁺ load to increase, causing spontaneous SR Ca²⁺ release and transient inward current carried by NaCaX. A given Ca²⁺ release produces greater arrhythmogenic inward current in HF (as a result of NaCaX upregulation), and 50% less Ca²⁺ release is required to trigger an action potential in HF. The inward rectifier potassium current (I_K1) is reduced by 49% in HF, and this allows greater depolarization for a given NaCaX current. Partially blocking I_K1 in control cells with barium mimics the greater depolarization for a given current injection seen in HF. Thus, we present data to support a novel paradigm in which changes in NaCaX and I_K1, and residual ß-AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.

Key Words: heart failure • excitation-contraction coupling • Na⁺-Ca²⁺ exchange • Ca²⁺ transport • K⁺ currents

Heart failure (HF), which affects more than two million Americans, is associated with high mortality as a result of contractile dysfunction (pump failure) or sudden death caused by ventricular arrhythmias.¹ The genesis of HF syndromes is complex and multifactorial, but altered cellular Ca²⁺ regulation may be a final common pathway in both pump failure and arrhythmogenesis.^{2 3 4 5}

Decreased Ca²⁺ transients in HF reduce myofilament activation and depress contractility.² Although it is unknown why Ca²⁺ transients are depressed, it is likely due to a decrease in sarcoplasmic reticulum (SR) Ca²⁺ release or Ca²⁺ influx via Ca²⁺ current (I_Ca). Many, although not all, HF studies show that I_Ca is unchanged.^{3 4 6} Decreased SR Ca²⁺ release could reflect either reduced SR Ca²⁺ release channel sensitivity to I_Ca⁴ or reduced SR Ca²⁺ content. Reduced SR Ca²⁺ load can be caused by decreased SR Ca²⁺-ATPase (SERCA) and/or increased Na⁺-Ca²⁺ exchange (NaCaX), because these transporters compete for [Ca²⁺]_i during relaxation and diastole.⁷ Moreover in HF, data indicate lower SERCA expression^{8 9} and increased NaCaX expression,^{6 10 11} but direct assessment of SR Ca²⁺ content in HF is limited. It is also unclear what role altered NaCaX plays with respect to contractile dysfunction in HF. These issues are addressed here.

Electrical reentry contributes to ventricular tachycardia (VT) in many pathophysiological states, but 3-dimensional mapping studies show that most fatal arrhythmias in HF initiate by a nonreentrant mechanism^{12 13 14 15} such as delayed afterdepolarizations (DADs) and early afterdepolarizations.^{16 17} This is true for 100% of VTs in human nonischemic cardiomyopathy (and 50% in ischemic cardiomyopathy).^{18 19} At normal action potential (AP) duration and heart rates, DADs may predominate over early afterdepolarizations. DADs, which are enhanced by ß-adrenergic receptor (ß-AR) stimulation,¹⁶ occur after AP repolarization and are initiated by spontaneous SR Ca²⁺ release. This leads to activation of a Ca²⁺-activated transient inward current (I_ti), which has been proposed to be carried by any of the following different Ca²⁺-activated currents: (1) NaCaX current (I_Na-Ca), (2) Ca²⁺-activated chloride current (I_Cl(Ca)), or (3) a non-selective cationic current (I_NS(Ca)).^{16 20 21 22} The inward rectifying K current I_K1 is crucial in stabilizing the resting membrane potential (E_m). Although I_K1 is reduced in human HF,²³ it is unclear, especially from a quantitative standpoint, how this may destabilize resting E_m and ultimately contribute to the genesis of DADs, triggered APs, and arrhythmogenesis in HF.

The goal of this study was to define molecular mechanisms underlying both arrhythmogenesis and contractile dysfunction in HF. Studies were performed in an arrhythmogenic rabbit HF model of combined aortic insufficiency and constriction. This rabbit HF model resembles human nonischemic HF in exhibiting marked left ventricular (LV) dilation and hypertrophy, severely reduced systolic function, moderately decreased ß-AR density, and nonreentrant ventricular arrhythmias.^{6 13 15 24 25} We previously found an increase in heart weight/body weight (by 80%), average myocyte size (89%), and LV end-diastolic diameter (41%).⁶ LV fractional shortening is reduced by 36%, and isolated ventricular myocyte shortening is reduced by 30%. Greater than 10% of the HF rabbits die from sudden cardiac death, and during 24-hour Holter monitoring 90% of these animals show runs of nonsustained VT.⁶ Three-dimensional mapping showed that these arrhythmias all initiate by a nonreentrant mechanism.¹³ Thus, this arrhythmogenic rabbit HF model exhibits the contractile and electrophysiological alterations seen in human HF at the critical stage at which arrhythmogenesis and contractile dysfunction are manifest. This provides a unique opportunity for assessment of the underlying molecular mechanisms.

Here we demonstrate that I_Na/Ca is the current producing DADs in HF and that upregulated NaCaX, reduced I_K1, and residual ß-AR responsiveness work together to greatly increase arrhythmogenesis in HF. We also show that NaCaX plays a central role in mediating both arrhythmogenesis and contractile dysfunction in HF (by lowering SR Ca²⁺ load).

Materials and Methods

Rabbit HF Model and Myocyte Isolation
In New Zealand White rabbits (3.5 kg), HF was induced by aortic insufficiency and 2 to 4 weeks later by thoracic aortic constriction (both induced during ketamine/pentobarbital anesthesia) as previously described.⁶ Progression was assessed by 2-dimensional echocardiography.⁶ Rabbits were studied 9.5±2.0 months after aortic constriction, when the LV end-systolic dimension exceeded 1.20 cm.⁶ At this stage, intravenous infusion of isoproterenol (1 µg/kg per minute) for 3 minutes was performed in conscious control and HF rabbits with monitoring of the surface ECG. Protocols were approved by the University of Illinois at Chicago Animal Studies Committee. Rabbit LV myocytes were isolated as described,⁶ with back flow across the incompetent aortic valve in HF rabbits blocked by a balloon-tipped catheter inflated in the LV outflow tract.

Contraction [Ca²⁺]_i and Patch Clamp
Myocyte shortening was measured by video edge detection and [Ca²⁺]_i was measured by indo-1 and fluo-3 epifluorescence.^{26 27} The normal Tyrode’s (NT) solution contained (in mmol/L) NaCl 140, KCl 4, MgCl₂ 1, CaCl₂ 2, glucose 10, and HEPES 5 (pH 7.4). Myocytes were studied at 23°C or 37°C.

Some myocytes were field-stimulated in NT (Figure 1B). Perforated patch voltage clamp was done in experiments illustrated in Figures 1C through 1F, 2B, 3A, 3B, and 3D with pipettes containing (in mmol/L) cesium methanesulfonate 70, CsCl 55, NaCl 8, MgCl₂ 1, HEPES 10, and EGTA 0.1 (pH 7.3), as well as 200 µg/mL amphotericin B, at 23°C. For potassium currents (Figures 5B, 5C, and 6B [left]), ruptured patch voltage clamp was used, and pipettes (resistance=0.8 to 2 M) contained (in mmol/L) potassium glutamate 120, KCl 15, MgCl₂ 2, potassium HEPES 10, K₅-EGTA 5, and Mg-ATP 2 (pH 7.2) at 23°C (Figures 5B and 5C) or 37°C (Figure 6B). For current clamp (Figures 4, 5A, 6A, and 6B, right) and voltage clamp in Figure 3C, sharper pipettes (5 to 20 M) contained (in mmol/L) potassium aspartate 120, KCl 8, NaCl 7, HEPES 10, MgCl₂ 1, Mg-ATP 5, Li-GTP 0.3, and K₅–indo-1 0.05 (pH 7.2) at 37°C, and cells were preloaded with indo-1–acetoxymethyl ester.²² I_Na/Ca integral (in C/F) was multiplied by 71.8 µmolxF/(CxL cytosol),²⁸ yielding SR Ca²⁺ load in µmol/L cytosol. Cells were either voltage clamped in NT (Figure 3C), voltage clamped in NT with 6 mmol/L cesium replacing potassium (Figures 1C through 1F, 2B, 2C, 3A, 3B, and 3D), voltage clamped in NT plus 0.3 mmol/L cadmium (Figures 5B and 5C), or current clamped in NT (Figures 2A, 4, 5A, 6A, and 6B [right]). Membrane capacitance was measured from responses to 5-mV hyperpolarizing and depolarizing pulses.²⁹

View larger version (41K): [in this window] [in a new window]   Figure 1. Aortic insufficiency/constriction rabbit HF model. A, Cross sections of control and HF hearts and Holter recording of nonsustained VT seen in 90% of HF vs 0% of control rabbits.6 B, Spontaneous aftercontractions and [Ca2+]i observed in HF myocytes after 1.2-Hz stimulation (37°C), only in the presence of isoproterenol. C, Isoproterenol (1 µmol/L) increased both ICa and [Ca2+]i in voltage-clamped control and HF myocytes (23°C). D, ICa was not altered in HF, but [Ca2+]i was lower (significantly at 0 mV, but not all Em; n=21 HF and 10 control). E, Mean effects of 1 µmol/L isoproterenol on ICa and [Ca2+]i (n=11 HF and 4 control). *P<0.05. F, ICa inactivation (fast and slow components) and percentage of inactivation occurring with fast in HF and control myocytes (n=12 HF and 11 control). Iso indicates isoproterenol; Ctl, control.

View larger version (28K): [in this window] [in a new window]   Figure 5. cDAD [Ca2+]i dependence and potassium currents. A, [Ca2+]i dependence of cDADs as in Figure 4A, fit to Em=0.4exp(kx[Ca2+]i). Small symbols and thin curves are for 6 representative cells (3 HF and 3 control, subthreshold events only). Subthreshold Em doubles for [Ca2+]i of 59±5 nmol/L in HF vs 105±9 nmol/L in control (n=14 HF and 16 control, P<0.05). Threshold [Ca2+]i for an AP is reduced 46% in HF (). B, Ito during 300-ms steps from Em=-60 to -20–+80 mV. Peak currents are shown, but results are similar for the inactivating- or 4-aminopyridine–sensitive component (3 mmol/L, n=6 HF and 6 control). C, IK1 during 500-ms steps from Em=-30 to -120–+40 mV was blockable by 1 mmol/L barium (n=6 HF and 6 control). Ito and IK1 were measured in NT with 0.3 mmol/L CdCl2 at 23°C (*P<0.05).

View larger version (36K): [in this window] [in a new window]   Figure 6. Pseudo-Iti–induced depolarization. A, Ca2+-independent current injection (pseudo-Iti; time course in inset) causes depolarizations fit to an exponential; Em=exp(kItidt). Small symbols are for 6 representative cells (3 HF and 3 control, subthreshold events only). Em doubles for 27% less charge in HF than in control (0.33±0.02 vs 0.45±0.06 C/F, n=16 HF and 14 control; P<0.05). Threshold charge was reduced 25% in HF vs control (, P<0.05). B, Barium blocks IK1 in control cells (IC50 5 µmol/L, left) and in a representative cell (right) shifts Em vs pseudo-Iti as in HF.

View larger version (43K): [in this window] [in a new window]   Figure 4. cDADs. A, Last steady-state (SS) AP and twitch [Ca2+]i (1 to 4 Hz), and caffeine-induced SR Ca2+ release. B, Frequency dependence of AP duration at 95% repolarization (APD95) and twitch [Ca2+]i (n=8 HF and 11 control). C, Blocking NaCaX in Na-free, Ca2+-free solution (0Na/0Ca; with lithium replacing sodium, n=12) abolished cDADs despite similar [Ca2+]i, whereas blocking ICl(Ca) with 50 µmol/L niflumate did not prevent cDADs (mean Em, n=10). *P<0.01.

View larger version (28K): [in this window] [in a new window]   Figure 3. SR Ca2+ load, spontaneous SR Ca2+ release, Iti, and INa/Ca. A, Varying SR Ca2+ load in voltage-clamped myocytes by the indicated protocol (23°C). Longer times at +50 mV drive more Ca2+ in via INa/Ca, and higher SR Ca2+ load (inset). On repolarization (Em=-80 mV), resting cell length (RCL), [Ca2+]i, and Itis were recorded. Rapid application of caffeine (10 mmol/L) released remaining SR Ca2+. Summing Iti and INa/Ca integrals indicates SR Ca2+ content before Iti. Aggressive Ca2+ loading conditions were required to induce Itis (1 to 10 µmol/L isoproterenol and/or [Ca2+]=4 mmol/L). B, Threshold SR Ca2+ load for Iti occurrence (average of 4 lowest loads that gave an Iti and 4 highest that did not) were not different in HF and control (n=93 HF and 100 control). C, Caffeine-activated [Ca2+]i-induced current was abolished by blockade of INa/Ca (37°C). D, Peak and integrated Iti from experiments as in panel A (n=34 HF and 56 control). *P<0.05.

View larger version (34K): [in this window] [in a new window]   Figure 2. SR Ca2+ load is reduced and NaCaX is upregulated in HF. A, Steady-state twitch [Ca2+]i during AP recording (1 Hz, 37°C) with caffeine-induced [Ca2+]i to assess SR Ca2+ load (n=17 HF and 18 control; *P=0.00036 for twitch and 0.0027 for caffeine). B, INa/Ca evoked by caffeine (Caff) application reveals a greater INa/Ca for a given [Ca2+]i transient in HF vs control (n=10 HF and 7 control). Slopes are from linear regressions. *P<0.05. C, Cytosolic Ca2+ buffering was not different for HF vs control myocytes (n=10 HF and 7 control), for which buffer power is taken as the slope of the [Ca2+]Tot/[Ca2+]i relationship.

SR Ca²⁺ load was varied before caffeine application by changing AP frequency, pulse number, or rest interval. For testing I_ti effects on E_m, we applied a synthetic current waveform chosen to match I_tis measured in rabbit myocytes.²² This injected pseudo-I_ti was varied in amplitude. Data are mean±SE, and statistical significance was based on P<0.05 (Student t test, ANOVA, and ²).

An expanded Materials and Methods section can be found in the online data supplement available at http://www.circresaha.org.

Results

Figure 1A shows cardiac enlargement and spontaneous nonsustained VT that are typical of HF rabbits used in the present study. Isolated LV myocytes from HF rabbit (Figure 1B) also show spontaneous closely coupled aftercontractions and Ca²⁺ transients after 1-Hz stimulation at 37°C, seen only after isoproterenol 1 µmol/L (blockable by 1 µmol/L propranolol). All HF myocytes (7 of 7 from 5 hearts) exhibited such aftercontractions, versus a minority of control myocytes with this protocol (2 of 7 from 3 hearts; P<0.01). Thus, HF rabbit myocytes exhibit enhanced susceptibility to aftercontractions. As discussed elsewhere, control myocytes have safety factors that limit the ability of a spontaneous SR Ca²⁺ release to trigger an AP.²²

Ca²⁺ Transients, I_Ca, and ß-Adrenergic Stimulation
In voltage-clamped HF myocytes, Ca²⁺ transients ([Ca²⁺]_i) were smaller than control, but peak I_Ca was unaltered (Figures 1C and 1D). This agrees with previous I_Ca data in which Ca²⁺ transients were prevented.⁶ If the coupling between the L-type Ca²⁺ channel and SR Ca²⁺ release channel were altered in HF, SR Ca²⁺ release would cause less Ca²⁺-dependent I_Ca inactivation in HF.⁴ However, we found no HF-associated change in time constants of I_Ca inactivation (_fast or _slow) or fraction of inactivation in the fast phase (Figure 1F). Ca²⁺ transients and I_Ca were increased by exposure to isoproterenol in both control and HF myocytes (Figures 1C and 1E). Whereas the ß-AR stimulation of I_Ca in HF was significantly less than in control, the [Ca²⁺]_i response was comparable (65% in HF versus 78% in control). Thus, HF cells exhibit clear residual ß-AR responsiveness, consistent with the progressive but incomplete ß-AR downregulation seen both in human HF^{30 31} and in this rabbit HF model.²⁵

Contractile Dysfunction, Reduced SR Ca²⁺, and Enhanced NaCaX
Steady-state twitch Ca²⁺ transients and contractions in nondialyzed and non-voltage–clamped HF myocytes at 37°C (1 Hz) were reduced by 40%. This was paralleled by a 40% decrease in SR Ca²⁺ content (Figure 2A), as assessed by caffeine-induced Ca²⁺ transients.²⁶ This lower SR Ca²⁺ load is sufficient to explain the reduced twitches and [Ca²⁺]_i in HF. At constant I_Ca, the ratio of [Ca²⁺]_i for twitch:caffeine is a useful index of fractional SR Ca²⁺ release and excitation-contraction coupling. This ratio was unchanged in the HF rabbit, in contrast to previous results in failing rat heart.⁴ There was also no reason to infer altered myofilament Ca²⁺ sensitivity, because changes in [Ca²⁺]_i paralleled those of contraction. To completely rule out changes in myofilament Ca²⁺ sensitivity or ryanodine receptor responsiveness, more detailed study is required.

Although reduced SR Ca²⁺ content is the simplest interpretation of the lower Ca²⁺ transients induced by APs and caffeine, increased cytosolic Ca²⁺ buffering could also be involved. Figures 2B and 2C show cytosolic Ca²⁺ buffering measured by the method of Trafford et al.³² Rapid caffeine-induced Ca²⁺ release activates Ca²⁺ extrusion via I_Na/Ca (Figure 2B, top). The amount of total Ca²⁺ ([Ca²⁺]_Tot) removed is given by the I_Na/Ca integral, and that Ca²⁺ removal causes [Ca²⁺]_i to change (Figure 2C, left). The Ca²⁺ buffering slope ([Ca²⁺]_Tot/[Ca²⁺]_i) for physiological [Ca²⁺]_i is unaltered in HF. Nevertheless, instantaneous inward I_Na/Ca for any given [Ca²⁺]_i was much larger in HF (Figure 2B, bottom), indicating that I_Na/Ca is functionally upregulated during dynamic Ca²⁺ transients (confirming our data showing 2-fold increases in NaCaX mRNA, protein, and I_Na/Ca, where [Ca²⁺]_i was clamped).⁶ The enhanced inward I_Na/Ca means that NaCaX must compete better with SERCA during twitch relaxation and diastole and thereby directly explains the reduced SR Ca²⁺ and contractile dysfunction in HF (even if SERCA was relatively unchanged; see Discussion).

SR Ca²⁺ Load, Spontaneous SR Ca²⁺ Release, and Arrhythmogenesis
How might these Ca²⁺ alterations be involved in arrhythmogenesis? Indeed, if SR Ca²⁺ load is reduced, one may expect less spontaneous SR Ca²⁺ release and triggered APs in HF. One resolution to this paradox might be that in HF a lower-threshold SR Ca²⁺ load causes spontaneous SR Ca²⁺ release and I_ti. We measured this threshold in voltage-clamped myocytes (Figures 3A and 3B) by driving increasing amounts of Ca²⁺ into the cell and SR by varying the duration of a loading pulse at +50 mV and also by increasing [Ca²⁺]_o to 4 mmol/L and adding 1 to 10 µmol/L isoproterenol. On repolarization to -80 mV, we monitored appearance of aftercontractions, [Ca²⁺]_i and I_tis. Finally, caffeine was applied to release all SR Ca²⁺. These Ca²⁺-activated inward currents in HF were carried entirely by I_Na/Ca, because they were abolished by blocking NaCaX (Figure 3C) as in control.²⁹ Thus, I_Cl(Ca) and I_NS(Ca) do not contribute significantly to I_tis, and our preliminary data suggest that this is also true in human HF ventricular myocytes at 37°C (S.M.P., K.S., D.M.B., unpublished data, 2000). As such, the I_Na/Ca (including I_tis) in Figure 3A can be integrated to evaluate the SR Ca²⁺ load that was present at the moment the first spontaneous I_ti occurred. Although I_tis in Figures 3A and 3B were seen only with isoproterenol, for a given depolarizing pulse, I_tis were more readily induced in HF than control (8 of 10 versus 3 of 9; P<0.05; for 10 µmol/L isoproterenol, [Ca²⁺]_o=2 mmol/L). We attribute this to the upregulated NaCaX and greater Ca²⁺ influx while holding at +50 mV. However, the crucial result is that the threshold SR Ca²⁺ load for I_ti induction was unchanged in HF (Figure 3B).

A typical I_ti removes 15 to 20 µmol Ca²⁺/L cytosol from the cell (and SR). Thus, in cells in which SR Ca²⁺ was driven to the highest levels (as in Figure 3A), two or more I_tis were reproducibly observed and the second I_ti brought the SR Ca²⁺ load below threshold. At more modest SR Ca²⁺ load (eg, 115 µmol/L cytosol), a single I_ti was sufficient to bring SR Ca²⁺ load below threshold.

If SR Ca²⁺ load is low in HF myocyte and threshold SR Ca²⁺ load for triggering an I_ti is unaltered, how does it increase to produce I_tis? This paradox can be explained by sympathetic bursts, which stimulate the SERCA,³³ raising SR Ca²⁺ load above threshold. This is supported by our findings above that ß-AR activation significantly enhanced aftercontractions (in 100% of HF cells) and I_tis (in 80% of HF cells) by increasing SR Ca²⁺ (Figures 1B, 3A, and 3B) and also induced ventricular arrhythmias including nonsustained VT in 3 of 3 intact HF rabbits (versus 0 of 3 controls). This may also explain why sudden arrhythmic deaths are more common before end-stage HF, ie, before ß-AR responsiveness is largely lost.^{31 34} Thus, some residual ß-AR responsiveness may be critical in enabling the spontaneous SR Ca²⁺ releases that trigger arrhythmias.

[Ca²⁺]_i Required to Trigger an AP
If the threshold SR Ca²⁺ for release is unchanged, perhaps the increased propensity for triggered arrhythmias in HF reflects the way the cell responds to a given SR Ca²⁺ release. Indeed, in HF peak I_Na/Ca during spontaneous I_tis was larger, even for a comparable amount of net charge moved (integrated I_ti, Figure 3D). This higher peak I_ti agrees with greater inward I_Na/Ca versus [Ca²⁺]_i during caffeine-induced contractions (Figure 2B). This is expected to cause greater depolarization (E_m) in HF for a given [Ca²⁺]_i, bringing E_m closer to threshold to fire an AP.

We tested this quantitatively by measuring E_m in current-clamped myocytes and applying caffeine to produce controlled [Ca²⁺]_i. Figures 4A and 4B show APs, twitch [Ca²⁺]_i and subsequent caffeine-induced Ca²⁺ transients, and the associated caffeine-induced afterdepolarizations (or cDADs).²² In HF, the AP duration was 19% longer and the increase in twitch [Ca²⁺]_i with frequency was blunted (as in human HF).² At low frequency and SR Ca²⁺ load, cDADs are subthreshold. As SR Ca²⁺ increases with frequency, we can measure a threshold for AP induction with respect to [Ca²⁺]_i and E_m (Figure 4A). As for I_ti, three different Ca²⁺-activated currents have been suggested to play a role in DADs (I_Na/Ca, I_Cl(Ca), and I_NS(Ca)). Figure 4C shows that cDADs in HF cells are virtually abolished when I_Na/Ca is blocked by removing extracellular Na⁺ and Ca²⁺ (which should still allow both I_Cl(Ca) and I_NS(Ca)). Note also that [Ca²⁺]_i decline is drastically slowed by blocking NaCaX, which is the main means of Ca²⁺ removal in the presence of caffeine.^{22 29} Blocking I_Cl(Ca) with niflumate hardly affected cDADs, which confirms that DADs are driven almost exclusively by I_Na/Ca. The same approach can be used to induce cDADs and APs in human HF ventricular myocytes (S.M.P., K.S., D.M.B., unpublished observations, 2000).

Figure 5A shows quantitatively that in HF versus control, a given [Ca²⁺]_i produces greater depolarization (E_m doubles for each 59 versus 105 nmol/L [Ca²⁺]_i) for subthreshold cDADs (curves and small points). In HF, the mean [Ca²⁺]_i threshold for a triggered AP is also reduced by nearly 50% (280 versus 515 nmol/L, large squares). Although the stimulation frequencies at which caffeine triggered APs were comparable for HF and controls (1.5 to 2 Hz), this may merely reflect a lower-baseline SR Ca²⁺ load in HF coincidentally offset by the decreased level of [Ca²⁺]_i necessary to trigger an AP. The crucial result is that lower [Ca²⁺]_i is required for a cDAD to trigger an AP in HF (as expected from the increased I_Na/Ca). However, E_m might also respond differently to a given I_Na/Ca in HF (eg, as a result of other currents).

Altered Potassium Currents: Ca²⁺- Independent Changes
Figures 5B and 5C show that in HF rabbits, transient outward and inward rectifier potassium currents (I_to and I_K1) were reduced significantly (by 34% and 49%, respectively), as has been reported in human HF.²³ Notably, the 49% reduction in I_K1 was observed at all E_m values and would tend to destabilize the resting E_m (Figure 5C, inset). Thus, a given I_ti might produce greater depolarization in the face of reduced I_K1.

Figure 6A tests this expectation quantitatively using current injections of varying amplitude, with time courses that simulate real I_tis (but without changing [Ca²⁺]_i or Ca²⁺-activated currents). Increasing the amplitude of these pseudo-I_tis results in larger depolarization,²² and with sufficient injected charge (ie, threshold charge) an AP is triggered. In HF, any given pseudo-I_ti produces greater depolarization (small points and curves in Figure 6A). More importantly, the threshold current integral (or charge) to trigger an AP is 25% smaller in HF (large squares; P<0.05).

To test whether the reduction in I_K1 in HF would be quantitatively sufficient to explain the Ca²⁺-independent shifts seen in Figure 6A, we partially blocked I_K1 in control cells (Figure 6B) to see whether that could mimic the shift seen in HF. Barium blocked I_K1 with an IC₅₀ of 5 to 15 µmol/L (depending slightly on E_m). Subthreshold pseudo-I_tis in a representative control cell are shown in the absence and presence of 3 µmol/L barium. Barium shifted the relation just as seen in HF. Mean barium effects were to shift doubling charge from 0.45±0.06 to 0.21±0.03 C/F at 3 µmol/L barium and to 0.157±0.013 C/F at 5 µmol/L barium (n=14, 4, and 4, P<0.05). Therefore, the 49% I_K1 reduction in HF is sufficient to completely and quantitatively explain the greater depolarization for a given current injection in HF (Figure 6A).

Discussion

We conclude (Figure 7) that three major factors conspire to greatly enhance the propensity for arrhythmogenesis in HF: (1) increased NaCaX (providing more arrhythmogenic I_ti for any given SR Ca²⁺ release), (2) reduced I_K1 (allowing greater depolarization for any given I_ti), and (3) residual ß-AR responsiveness (required to raise the low SR Ca²⁺ load in HF to the point at which more spontaneous SR Ca²⁺ release occurs).

View larger version (32K): [in this window] [in a new window]   Figure 7. Roles of NaCaX, IK1, and ß-AR in contractile dysfunction and arrhythmogenesis in HF.

The current(s) responsible for DADs has been controversial, but we have shown that I_Na/Ca is the current that underlies I_ti and DAD in myocytes from HF rabbits at 37°C (similar to I_ti data at 20°C in human HF).³⁵ Although other Ca²⁺-activated currents may occur, particularly in other species or cell types in the heart, they do not contribute quantitatively to I_ti or DADs under physiological conditions in ventricular myocytes from rabbits (and likely, humans) with HF. Moreover, the 2-fold upregulation of NaCaX in rabbit and human HF indicates that larger I_tis and DADs would be expected for a given [Ca²⁺]_i (and we have demonstrated this quantitatively for I_tis and cDADs).

I_K1 was decreased by 49% in HF rabbit myocytes (similar to human HF²³ ). No quantitative functional link has previously been developed for I_K1 in arrhythmogenesis in HF. We show that the reduction of I_K1 is quantitatively sufficient to explain the greater depolarization seen for a given inward current (Ca²⁺-independent pseudo-I_ti) in HF. Thus, reduced I_K1 in HF is of paramount importance in lowering the threshold for an I_ti-triggered AP. Although I_Na/Ca is almost entirely responsible for I_tis (in control and HF), reduced I_K1 in HF allows that I_Na/Ca to produce greater depolarization. Based on the HF shifts in Figures 5A and 6A and computer models (J.L. Puglisi and D.M. Bers, unpublished observations, 2000), the increased I_Na/Ca and reduced I_K1 contribute about equally to the altered [Ca²⁺]_i threshold and propensity for triggered arrhythmias.

The role of SR Ca²⁺ load in arrhythmogenesis has been unclear, especially because of the paradoxical lower SR Ca²⁺ load in HF versus high SR Ca²⁺ required to cause spontaneous SR Ca²⁺ release. Here we resolve this paradox by demonstrating directly that HF cells can be readily driven to high SR Ca²⁺ load and spontaneous SR Ca²⁺ release (which causes arrhythmias initiated by DADs). This is where residual ß-AR responsiveness in our paradigm is critical. Indeed, we found that 100% of HF cells exhibit spontaneous SR Ca²⁺ release and aftercontractions after isoproterenol (although an IC₅₀ for isoproterenol was not determined). Moreover, in very-late-stage human HF, there are fewer sudden arrhythmic deaths, and this corresponds to the time when there is more complete loss of ß-AR responsiveness.^{31 34} At this stage as pump failure continues, arrhythmias may be less likely because the SR Ca²⁺ load never gets high enough for spontaneous SR Ca²⁺ release (although elevated NaCaX and reduced I_K1 may persist).

The higher NaCaX in HF also contributes to contractile dysfunction by competing with the SERCA and unloading the SR. In this rabbit HF model, we had not detected alteration in SERCA on Northern or Western blots, but function in HF myocytes appeared to be decreased by up to 24%.⁶ This minimal SERCA alteration (compared with some HF models) illustrates that the large increase in NaCaX alone may be sufficient to unload the SR and hence cause contractile dysfunction. Of course, any reduction in SERCA versus NaCaX would further shift this balance and lower the SR Ca²⁺ load more severely. This demonstrates a novel dual role for elevated NaCaX as a central causative factor in both arrhythmogenesis and contractile dysfunction. This also relates to human HF, in which Hasenfuss et al¹¹ found that 44% of failing human hearts (their group I, with preserved diastolic function) had 2-fold increase in NaCaX protein expression and 25% decrease in SERCA, which is very similar to our HF rabbits. Additional reduction of SERCA seen in HF patients with diastolic dysfunction slows twitch relaxation and further decreases SR Ca²⁺ load and systolic function.¹¹ Although increased NaCaX expression in HF could enhance Ca²⁺ entry (via outward I_Na/Ca),^{36 37} this seems likely only for very prolonged APs in HF. This effect was not seen here.

This work and novel paradigm (Figure 7) raise the issue of molecular targets for therapeutics in HF. Inhibiting NaCaX might improve contractile function and acutely limit arrhythmias but is dangerous because of the crucial role of NaCaX in removing the Ca²⁺, which enters at each beat via I_Ca. Partially blocking NaCaX could worsen cellular Ca²⁺ overload, ultimately causing spontaneous SR Ca²⁺ release and arrhythmia (as seen with Na/K-ATPase inhibition in digitalis toxicity). Such spontaneous SR Ca²⁺ release can seriously exacerbate contractile dysfunction by desynchronizing contractions in cells, which are in series with each other,⁷ even if arrhythmogenic I_Na/Ca was less. Increasing SERCA (eg, by gene transfer or phospholamban inhibition)^{38 39} would help the SERCA compete better with NaCaX to maintain more normal SR Ca²⁺ load and improve contractile function, but it may increase the propensity for Ca²⁺ overload and DADs. SR Ca²⁺-pump stimulation could be the reason why phosphodiesterase inhibitory inotropes (which increase cAMP) are proarrhythmic and increase mortality.⁴⁰ Blocking ß-ARs could prevent spontaneous SR Ca²⁺ release by reducing the increment in SR Ca²⁺ load (induced by adrenergic surges). This would account for the effectiveness of ß-AR blockers in reducing sudden death in HF.⁴¹ Enhancing I_K1 to stabilize resting E_m could also be beneficial but could also reduce excitability, propagation rate, and AP duration. Overall, a balance must be sought to enhance SERCA function without increasing arrhythmogenesis.

HF and its etiologies are extremely complex, but altered myocyte Ca²⁺ regulation and ion channels appear to be crucial in the final common pathways of sudden death and pump failure. The data here support a novel paradigm of three key factors (increased NaCaX, reduced I_K1, and residual ß-adrenergic responsiveness) that conspire to greatly increase arrhythmogenesis in HF. The increased NaCaX is unique in contributing to both contractile dysfunction (reducing SR Ca²⁺ load) and arrhythmogenesis. This novel paradigm provides both a framework and a challenge for further understanding and therapeutic development.

Acknowledgments

Financial support was provided by NIH Grants HL-46929 (to S.M.P.) and HL-30077 and HL-64724 (to D.M.B.). We appreciate the technical contributions of S. Scaglione and L. Leach.

Footnotes

Original received January 29, 2001; revision received April 6, 2001; accepted April 9, 2001.

¹ Both authors contributed equally to this study.

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