Cellular Basis of Triggered Arrhythmias in Heart Failure (2023)

Table of Contents
Trends in Cardiovascular Medicine Abstract Section snippets Electrophysiologic Alterations in HF Nonreentrant Initiation of VT Nature of Nonreentrant Mechanism in HF Altered Myocyte Ca Handling in HF Preserved β-AR Responsiveness NCX Current Underlies Iti and DADs Enhanced NCX and Decreased IK1 Increase DADs in HF New Paradigm for Arrhythmogenesis in HF and Implications NCX Is a Difficult Therapeutic Target β-AR Blockade Reduces Sudden Death in HF IK1 and SR Ca Transport as Potential Therapeutic Targets References (45) Lancet J Am Coll Cardiol Cell J Mol Cell Cardiol Am Heart J Transmural electrophysiological heterogeneities underlying arrhythmogenesis in heart failure Circ Res Response of failing canine and human heart cells to beta-2 adrenergic stimulation Circulation Myocardial electrical propagation in patients with idiopathic dilated cardiomyopathy J Clin Invest Upregulated Na/Ca exchange is involved in both contractile dysfunction and arrhythmogenesis in heart failure Basic Res Cardiol Sarcoplasmic reticulum Ca2+ and heart failure. Roles of diastolic leak and Ca2+ transport Circ Res Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts N Engl J Med Type I phosphatase, a negative regulator of cardiac function Mol Cell Biol Intracellular Na+ concentration is elevated in heart failure, but Na/K pump function is unchanged Circulation Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility J Clin Invest Cellular electrophysiologic abnormalities of diseased human ventricular myocardium Am J Cardiol Heart failure after myocardial infarction: altered excitation-contraction coupling Circulation Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+-ATPase in failing and nonfailing myocardium Circ Res Decreased sarcoplasmic reticulum calcium content is responsible for defective excitation-contraction coupling in canine heart failure Circulation Restoration of Ca handling by Na/Ca exchange blockade in canine pacing-induced heart failure [abst] Circulation Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current Circ Res Activation of beta-2 adrenergic receptors hastens relaxation and mediates phosphorylation of phospholamban, troponin I, and C-protein in ventricular myocardium from patients with terminal heart failure Circulation Characterization of a [Ca2+]i-dependent current in human atrial and ventricular cardiomyocytes in the absence of Na+ and K+ Cardiovasc Res Cited by (281) Recommended articles (6) Videos
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Trends in Cardiovascular Medicine

Volume 14, Issue 2,

February 2004

, Pages 61-66

Abstract

Ventricular tachycardia in nonischemic heart failure (HF) initiates by a nonreentrant mechanism that appears to be due to triggered activity primarily from delayed afterdepolarizations that arise from altered cellular Ca handling and ionic currents. In HF, factors that conspire to enhance triggered arrhythmias include upregulated Na/Ca exchange, preserved β-adrenergic responsiveness, and decreased IK1. Overall, the further delineation of key factors that underlie triggered arrhythmias in HF will provide the basis for new therapeutic strategies directed toward novel targets that can reduce the high incidence of sudden death in patients with HF.

Section snippets

Electrophysiologic Alterations in HF

In animal models of ventricular hypertrophy and HF, action potential duration (APD) is prolonged, and resting membrane potential (Em) and action potential (AP) rate of rise (phase 0 Vmax) are often reduced (see Vermeulen 1998). Myocytes from patients with end-stage HF also exhibit prolonged APDs, which may be due to decreased outward K currents such as Ito or IK1 (Vermeulen 1998). Slow conduction and heterogeneous repolarization, which has been demonstrated in experimental models of nonischemic

Nonreentrant Initiation of VT

Delineating reentrant versus nonreentrant (or triggered) mechanisms of VT in HF requires a mechanistic arrhythmia assessment in vivo, and an animal model of HF that is arrhythmogenic. Pogwizd (1995) used computerized three-dimensional (3-D) cardiac mapping to record bipolar electrograms from several hundred intramural sites throughout the hearts in an arrhythmogenic rabbit HF model (combined pressure and volume overload, Figure 1A). These HF rabbits exhibit moderate to severe LV dysfunction,

Nature of Nonreentrant Mechanism in HF

The nonreentrant mechanism in HF likely involves triggered activity from either DADs or EADs (Figure 1B). DADs occur at high intracellular Ca load and are due to spontaneous sarcoplasmic reticulum (SR) Ca release and activation of a transient inward current (Iti) that is mediated by either Na/Ca exchange (NCX), a nonspecific cationic current (INS), or a Ca-activated chloride current (ICl (Ca)) although NCX is favored Pogwizd et al., 2001, Wit & Rosen, 1992. DADs tend to occur with rapid

Altered Myocyte Ca Handling in HF

Myocyte Ca transients (and contractions) are depressed in HF (Figure 2), and this is associated with comparable reductions in SR Ca content in human HF and in rabbit and canine HF models Hobai & O'Rourke, 2001, Piacentino et al., 2003, Pogwizd et al., 2001. ICa density is typically unchanged, and these studies all suggest that there is no intrinsic alteration of the excitation-contraction coupling (ECC) mechanism itself (i.e., fractional release is not depressed), although Gómez et al. (2001)

Preserved β-AR Responsiveness

If SR Ca load is reduced in HF, how might DADs and triggered APs arise? One possibility is that a lower threshold SR Ca load might cause spontaneous SR Ca release. We measured this threshold directly in voltage-clamped rabbit HF cells using protocols to drive increasing amounts of Ca into the cell, and measuring the occurrence of aftercontractions and Iti (at measured SR Ca loads). The threshold SR Ca load for triggering Iti was unchanged in HF (Pogwizd et al. 2001). Therefore, if SR Ca load is

NCX Current Underlies Iti and DADs

In myocytes from both rabbit and human HF, we used rapid application of caffeine to produce controlled SR Ca releases and Ca-dependent afterdepolarizations (or cDADs) and Iti (Figure 3A) (Bers et al., 2002, Pogwizd et al., 2001; see also Köster et al. 1999). These cDADs and Itis were almost 100% blocked when NCX was prevented (but when both INS and ICl(Ca) should be functional). Blocking ICl(Ca) with niflumic acid had little effect on either cDADs or Iti. These results demonstrate that

(Video) Mechanisms of cardiac arrhythmias | Tachyarrhythmias | Cardiovascular Pathophysiology

Enhanced NCX and Decreased IK1 Increase DADs in HF

Once a spontaneous SR Ca release event occurs in HF, we would expect a larger Iti (where functional NCX expression is elevated) and a consequently larger DAD. We analyzed this hypothesis quantitatively, using controlled SR Ca releases of different amplitudes (cDADs as above at different SR Ca loads) in voltage-clamped rabbit myocytes. Indeed in HF, a given Δ[Ca]i produced a greater depolarization (vs. control). Moreover, the mean Δ[Ca]i threshold for a triggered AP was decreased by ~50% in HF

New Paradigm for Arrhythmogenesis in HF and Implications

The above data support a novel paradigm in which changes in NCX, IK1, and retained β-adrenergic responsiveness combine to greatly enhance the propensity for triggered arrhythmias in HF (Figure 4). An important implication of this paradigm is the enhanced safety margin evident in control cardiac myocytes. Thus, in control hearts, even when a spontaneous SR Ca release occurs, there is low enough NCX to limit the Iti amplitude and enough IK1 to keep that Iti from depolarizing the cell to the

NCX Is a Difficult Therapeutic Target

Although upregulated NCX plays a dual role in contributing to contractile dysfunction and arrhythmogenesis (by mediating enhanced Iti), it represents a difficult therapeutic target. Inhibiting NCX would limit Ca efflux and enhance SR Ca load (as with glycoside inotropy) and reduce Iti. However, this could also impair relaxation, cause diastolic Ca overload, and increase DAD incidence. On the positive side, Hobai and O'Rourke (2002) showed that modest (~30%) NCX inhibition with intracellular

β-AR Blockade Reduces Sudden Death in HF

The β-AR is already recognized as a therapeutic target in HF, and there are data from several clinical trials showing reduction in SCD (sudden cardiac death) in HF with β-AR blockade (e.g., MERIT-HF Study Group 1999; Poole-Wilson et al. 2003). It should also help in limiting the occasional and potentially regional SR Ca overload that is arrhythmogenic in our paradigm. Whether the arrhythmogenic effects of β-adrenergic stimulation are due to β1- and/or β2-ARs remains to be determined.

IK1 and SR Ca Transport as Potential Therapeutic Targets

Until recently, little attention has been given to modulating IK1. Gene transfer to enhance IK1 may stabilize the resting Em, but it may also reduce APD and consequently reduce Ca entry, SR Ca load, and contractile function (Nuss et al. 1996). However, recent approaches by Ennis et al. (2002), with combined Kir2.1 (which encodes IK1) plus SERCA1 (the skeletal muscle form of SR Ca ATPase), showed important proof of principle that this combined approach could be contractile function neutral.

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      A new N4103K/+ knock-in (KI) mice model was generated.

      Sustained ventricular tachycardia was frequently observed after infusion of caffeine plus epinephrine in KI mice. Endogenous CaM bound to RyR2 decreased even at baseline in isolated KI cardiomyocytes. Ca2+ spark frequency (CaSpF) was much higher in KI cells than in wild-type cells. Addition of GSH-CaM (higher affinity CaM to RyR2) significantly decreased CaSpF. In response to isoproterenol, spontaneous Ca2+ transient (SCaT) was frequently observed in intact KI cells. Incorporation of GSH-CaM into intact KI cells using a protein delivery kit decreased SCaT significantly. An assay using a quartz crystal microbalance technique revealed that mutated CaMLD peptide showed higher binding affinity to CaM binding domain (CaMBD) peptide.

      In the N4103K mutant, CaM binding affinity to RyR2 was significantly reduced regardless of beta-adrenergic stimulation. We found that this was caused by an abnormally tight interaction between CaMBD and mutated CaM-like domain (N4103K-CaMBD). Thus, CaMBD–CaMLD interaction may be a novel therapeutic target for treatment of lethal arrhythmia.

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