Calcium Signaling and Cardiac Arrhythmias
Abstract
There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function—in particular, excitation–contraction coupling and normal electric rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2+-handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.
The bivalent cation calcium (Ca2+) represents one of the most ubiquitous signal transduction molecules known.1 It mediates a diverse array of biological functions including muscle contraction, cellular exocytosis, neuronal activity, and triggering of programmed cell death. Since the first observation by Ringer in 1883 that Ca2+ was required for cardiac contraction, the role of Ca2+ as a signaling ion in the heart has become increasingly appreciated.2 In addition, it has become clear that abnormalities of Ca2+ homeostasis can play a key role in the pathogenesis of common cardiovascular disorders, including cardiac arrhythmias. Human genetic studies of patients with inherited arrhythmia syndromes have uncovered inherited mutations in various Ca2+ channels and Ca2+ transporters, directly implicating dysfunction of these proteins in the disease mechanisms. Moreover, acquired modifications of various Ca2+-handling proteins have been associated with cardiac arrhythmias, including atrial fibrillation (AF) and ventricular arrhythmias in failing hearts. In this review, we provide a comprehensive overview of the potential contributions of Ca2+ in arrhythmia mechanisms and highlight various gaps in knowledge and controversies in the field.
Overview of Excitation–Contraction Coupling in the Heart
Regular contraction of the heart requires the conversion of electric activation (excitation) into mechanical force (contraction). This process, known as excitation–contraction (EC) coupling, requires coordinated movement of Ca2+ ions at the cardiomyocyte level (Figure 1A). Each action potential (AP), triggered by influx of sodium (Na+) through the voltage-gated sodium channel (Nav1.5), thereby generating the INa current, induces Ca2+ influx through voltage-activated L-type Ca2+ channels (LTCCs, Cav1.2), creating the ICa,L current. This Ca2+ triggers a much larger Ca2+ release from the sarcoplasmic reticulum (SR), the principal intracellular Ca2+ storage organelle.3 SR Ca2+ release is mediated by specialized Ca2+-release channels known as ryanodine receptor type-2 (RyR2).4 This process of Ca2+-sensitive RyR2-mediated SR release is known as Ca2+-induced Ca2+-release (CICR). The cytosolic Ca2+ binds to and activates cardiac troponin C (TnC), the Ca2+-sensing protein of the contractile apparatus and initiates myofilament contraction. During diastole, cardiac muscle relaxation occurs when Ca2+ is removed from the cytosol either by sequestration into the SR by the SR Ca2+-ATPase type-2a (SERCA2a) or out into the extracellular space by the Na+/Ca2+-exchanger type-1 (NCX). In addition, there is a minor contribution by the PMCA (plasmalemmal Ca2+-ATPase). Na+/Ca2+-exchanger type-1 is electrogenic, as it imports 3 Na+ ions into the cell for each extruded Ca2+ ion, thereby creating a depolarizing transient inward current (INCX). The rapid release of Ca2+ from the SR into the cytosol, followed by rapid reuptake into the SR or extrusion from the cell, creates a Ca2+ wave that runs through the cardiomyocyte, and is known as the Ca2+ transient. The amount of Ca2+ released from the SR via RyR2 largely determines the Ca2+-transient amplitude, which correlates with the strength of systolic contraction.
Figure 1. Role of calcium-handling in excitation–contraction (EC) coupling. A, Schematic overview of key Ca2+-handling proteins involved in EC coupling. B, Schematic diagram of Ca2+ release unit and major components of the JMC (junctional membrane complex). The transverse tubule (TT) and sarcoplasmic reticulum (SR) membranes approximate to form the dyad. BIN1 indicates bridging integrator 1; Cav1.2, L-type Ca2+ channel; CAV3, caveolin-3; JPH2, juncophilin-2; NCX1, Na+/Ca2+ exchanger type-1; PM, plasma membrane; PMCA, plasmalemmal Ca2+-ATPase; RyR2, ryanodine receptor type-2; and SERCA2a, sarco/endoplasmic reticulum ATPase type-2a.*
EC coupling occurs within specialized subcellular structures called junctional membrane complexes (JMCs), where LTCCs on transverse T-tubules—plasmalemmal invaginations that reach deep into myocytes—are positioned in close proximity of the RyR2 channels on the SR membranes (Figure 1B).5 The movement of Ca2+ within these dyadic cleft domains is, in part, regulated by JPH2 (junctophilin-2), a protein that provides a structural bridge between the plasmalemma and SR ensuring appropriate proximity between the LTCC and RyR2 channels.6,7 JPH2 is also necessary for BIN1 (bridging integrator 1) recruitment to develop the T-tubule forming the dyad. There are important differences in the organization of the JMC between atrial and ventricular cardiomyocytes.8 In ventricular myocytes, almost all Ca2+ release events (ie, sparks and transients/waves) are activated directly by LTCC on T tubules, which leads to synchronized SR Ca2+ release and a rapid upstroke of the Ca2+ transient. In atrial cardiomyocytes, in which T tubules are relatively underdeveloped, the Ca2+ transient begins with LTCC-triggered local SR Ca2+-release events at the cell periphery that propagate slowly as Ca2+ waves toward the cell center.9,10 In addition, atrial cardiomyocytes possess larger and more heterogeneous axial tubules and much more Ca2+-buffering mitochondria than ventricular cardiomyocytes.11,12 Finally, another class of Ca2+ release channels known as inositol 1,4,5-trisphosphate type 2 receptors may also contribute to CICR.13
Regulation of Intracellular Calcium Handling
The activity of Ca2+ channels and exchangers involved in EC coupling is regulated by several mechanisms and signaling pathways in response to changing demands for cardiac output. For example, the fight-or-flight response activates the sympathetic portion of the autonomous nervous system with downstream effects on Ca2+ signaling (recently reviewed).14 Activation of the β-adrenoceptor (βAR) causes a rise in the intracellular concentration of the second messenger cAMP. Downstream effectors of cAMP include cAMP-dependent protein kinase A (PKA), which in turn can phosphorylate Ca2+ transporters including LTCC, RyR2, and SERCA2a regulatory proteins like phospholamban and sarcolipin. In addition, the Ca2+/calmodulin-dependent protein kinase II (CaMKII) can modulate Ca2+ homeostasis in response to changes in heart rate, cellular oxidation levels, and persistent βAR stimulation.4,15
Each of the Ca2+ channels and transporters consists of pore-forming proteins and various accessory subunits that modulate the amount of Ca2+ that is moved through the pore. These channels and exchangers have been extensively reviewed elsewhere.16,17 Perhaps one of the most well-studied multiprotein complexes is the RyR2 macromolecular complex. A diverse array of RyR2-interacting proteins directly regulate RyR2 channel activity by binding to the pore subunit (ie, FKBP12.6 [FK506-binding protein-12.6], CaM [calmodulin], CASQ2 [calsequestrin-2], JCTN [junctin], TRDN [triadin], βII-spectrin; Figure 2).18,19 CASQ2 binds to RyR2 via both JCTN and TRDN. RyR2 is strongly regulated by luminal (within the SR) Ca2+ levels, either by direct Ca2+ binding to RyR2 or by luminal Ca2+ interacting with CASQ2, JCTN, and TRDN.20 Other proteins in the RyR2 macromolecular complex regulate the level of RyR2 post-translational modification. Examples include the protein kinases PKA, CaMKII, and newly discovered SPEG (striated preferentially expressed protein kinase), and protein phosphatase type-1 and type-2A (PP1 and PP2A, respectively) that regulate the actual level of RyR2 phosphorylation.21–24 The RyR2 channel is also regulated by S-nitrosylation and oxidation.25
Figure 2. Ryanodine receptor type-2 (RyR2) macromolecular complex. Cartoon representing RyR2 pore-forming subunits with accessory proteins that bind to and/or modulate channel function. CaM indicates calmodulin; CaMKII, Ca2+/calmodulin-dependent protein kinase II; CASQ2, calsequestrin-2; FKBP12.6, FK506-binding protein-12.6; JCTN, junctin; JPH2, juncophilin-2; PKA, protein kinase A; PM, plasma membrane; PP, protein phosphatase; SR, sarcoplasmic reticulum; TECRL, trans-2,3-enoyl-CoA reductase-like protein; and TRDN; triadin.
The LTCC, responsible for voltage-dependent Ca2+ entry into the cells, consists of a macromolecular protein complex comprised of a pore-forming Cav1.2 (α subunit) and various auxillary subunits (α2, β, δ, and γ) that modulate channel function (Figure 3). Similar to RyR2, the LTCC is regulated by protein kinases such as CaMKII and PKA as well as protein phosphatase type 1, phosphatase type 2A, and calcineurin (also known as protein phosphatase type 2B), which can modulate channel gating. In addition, regulatory subunits, like CaM, are embedded within the channel complex.26 LTCC are localized to rafts of other sarcolemmal ion channels and membrane-limited proteins.27,28 A critical mediator of this membrane clustering is CAV3 (caveolin 3) that binds and interacts with the N-terminal part of JPH2.29
Figure 3. L-type Ca2+ channel (LTCC) macromolecular complex. Cartoon representing Cav1.2 pore-forming α subunit with accessory α2, β, γ, δ subunits. CaMKII indicates Ca2+/calmodulin-dependent protein kinase II; CAV3, caveolin-3; ICa,L, L-type Ca2+ current; JPH2, juncophilin-2; PKA, protein kinase A; PM, plasma membrane; PP, protein phosphatase; and SR, sarcoplasmic reticulum.
Finally, SERCA2a is a macromolecular complex required for Ca2+-reuptake into the SR (Figure 4). It is allosterically regulated by phosphorylation-mediated conformational shifts of its regulatory subunit phospholamban that can be phosphorylated by PKA and CaMKII.30,31 These post-translational modifications can relieve the phospholamban -mediated inhibition of SERCA2a, allowing for rapid Ca2+-reuptake. HRC (histidine-rich Ca2+-binding protein) has been shown to bind the SR luminal side of SERCA2a and to interact with TRDN, potentially coordinating Ca2+-reuptake with SR Ca2+-release along with S100A1.32,33 Moreover, CALR (calreticulin) may play a role in the inactivation and degradation of SERCA2a under oxidative stress.34
Figure 4. SR Ca2+-ATPase type-2a (SERCA2a) macromolecular complex. Cartoon representing SERCA2a complex required for reuptake of Ca2+ from the cytosol to the SR. CALR indicates calreticulin; CaMKII, Ca2+/calmodulin-dependent protein kinase II; HRC, histidine-rich Ca2+ binding protein; PKA, protein kinase A; PP, protein phosphatase; ROS, reactive oxygen species; RyR2, ryanodine receptor type-2; SERCA2a, sarco/endoplasmic reticulum ATPase type-2a; SR, sarcoplasmic reticulum; and TRDN, triadin.
Fundamental Arrhythmia Mechanisms
The mechanisms responsible for cardiac arrhythmias are generally divided into 2 major categories: enhanced or abnormal impulse generation (ie, focal activity) and conduction disturbances (ie, reentry).35,36 Focal activity includes enhanced automaticity and triggered activity. Automaticity causes spontaneous generation of APs that do not require induction by previous beats. Healthy myocardium is not normally automatic, but disease conditions (ie, heart failure [HF]) can lead to resting membrane potential depolarization to more positive values causing abnormal automaticity. The most common causes of focal arrhythmias are early afterdepolarizations (EADs) that precede full repolarization (typically corresponding to phase 2 and phase 3 repolarization of the human AP) and delayed afterdepolarizations (DADs) that occur after full repolarization.
EADs cause focal firing by depolarizing surrounding tissue to excitation threshold EADs and are most characteristic of Purkinje-fiber tissue and ventricular tachyarrhythmias associated with HF and long QT syndrome (LQTS; Figure 5A). EADs are usually, but not exclusively, associated with excessive AP prolongation (ie, by increased inward ICa,L37 and late Na+-current INa,L or INCX38,39 or by reduced K+-currents [IK]), allowing ICa,L to recover from inactivation and depolarize the cardiomyocyte by allowing Ca2+ to enter.40 CaMKII-dependent ICa,L phosphorylation slows inactivation and accelerates recovery from inactivation, further enhancing the likelihood of EADs.37 At membrane potentials negative to the threshold of ICa,L activation, spontaneous SR Ca2+ release–activated NCX favors the nonequilibrium reactivation of INa, driving phase 3 EADs induction.41,42 Finally, EADs have also been associated with AP duration (APD) shortening, occurring late in phase 3 of the AP.43 If the intracellular Ca2+ concentration is still high (ie, because of a large Ca2+ transient) when the membrane potential is negative to the equilibrium potential for NCX, INCX can be activated leading to membrane depolarization. This type of EADs typically occurs after termination of ventricular tachycardia (VT), ventricular fibrillation (VF), and AF. Overall, in regions where EADs reach the threshold to propagate, they generate triggers that initiate reentry.
Figure 5. Key electrophysiological mechanisms leading to cardiac arrhythmias. Ectopic (triggered) activity is primarily caused by (A) early afterdepolarizations (EADs) that occur mainly during bradycardia or after a pause, and (B) delayed after depolarizations (DADs) that occur usually during tachycardia. Reentry requires a vulnerable substrate, which can be caused by (C) action potential shortening or (D) dispersion of refractoriness. ICa,L indicates L-type Ca2+ current; IK,Ca, Ca2+ dependent K+ current; INa,L, late Na+ current; and INCX, Na+/Ca2+ exchanger current.
DADs typically occur during diastole and conditions of elevated cellular Ca2+-loading (Figure 5B). They are caused by spontaneous rises in cytoplasmic Ca2+-concentration, which activate NCX, generating forward mode INCX, although other Ca2+-sensitive currents (nonselective cationic currents and chloride currents) might also contribute to DAD formation.44 The amplitude of the DAD depends on the size of the resting K+ conductance, mainly determined by the inward-rectifier K+-current IK1, relative to INCX amplitude. When IK1 is low, the same INCX will produce a larger DAD and vice versa.45 When DADs reach excitation threshold, INa is activated and spontaneous APs can arise. DAD-mediated triggered activity contributes to arrhythmogenesis associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), HF, and AF.
Reentry can occur around a fixed anatomic obstacle or in a substrate in which functional properties permit initiation and maintenance of reentrant circuits.46 The likelihood of reentry formation is determined by the tissue properties of conduction and refractoriness, with abnormal conduction (slowing and local block) and refractoriness (abbreviated or prolonged) making reentry more likely (Figure 5C and 5D). Refractory period depends on APD, whereas conduction velocity largely depends on INa, expression and localization of gap-junction proteins, and composition of extracellular matrix (ie, fibrosis). When the refractory period decreases (like in AF), the circuits are smaller and more numerous, simultaneous termination of all circuits is unlikely and the arrhythmia is sustained. When the refractory period is prolonged (like in HF), the heterogeneity (dispersion) of refractoriness is increased and the occurrence of reentry promoting conduction block is more likely. The reentry-promoting substrate can be caused by disease-related cardiac remodeling or predisposing genetic factors, but can also be produced by altered restitution dynamics and subcellular Ca2+-alternans (SR Ca2+ load and release alternans).47 Altered Ca2+ signaling can contribute to the formation of a reentry substrate by 2 mechanisms: promoting dispersion of excitability, and promoting dispersion of refractoriness.35 For example, DADs that do not reach the threshold to trigger an AP can cause resting membrane potential depolarization, increasing Na+-channel inactivation and promoting dispersion of excitability. The latter might lead to regional conduction block of impulses arising from regions with suprathreshold DADs, thereby promoting reentry initiation. EADs that remain below the threshold to propagate may increase dispersion of refractoriness, also creating a reentry substrate. The rapid rates during DAD-induced triggered activity can promote Ca2+ transient alternans, which can cause spatially discordant APD alternans, thereby enhancing the dispersion of refractoriness and the likelihood of reentry.48 Thus depending on the cellular and tissue context, EADs, DADs, and Ca2+ alternans can provide the trigger and may contribute to the formation of the reentry-promoting substrate. A deep understanding of the detailed molecular mechanisms by which abnormal Ca2+-signaling increases the susceptibility to cardiac arrhythmias is key for the development of novel therapeutic options for prevention and treatment of cardiac arrhythmias.
Arrhythmias Caused By Heritable Defects in Calcium-Handling Genes
The discovery of the first inherited mutations in genes encoding Ca2+-regulatory proteins has provided the best evidence to date that defects in intracellular Ca2+-handling can directly cause different cardiac arrhythmias (Figure 6). In the following section, we will review several inherited arrhythmia syndromes that are often caused by mutations in genes encoding Ca2+ channels, transporters, or related proteins.49
Figure 6. Diagram showing which genes have been linked to genetic arrhythmia disorders. Yellow fill indicates gene that encodes a Ca2+-sensitive or Ca2+-handling protein. CPVT indicates catecholaminergic polymorphic ventricular tachycardia; and IVF, idiopathic ventricular fibrillation.
Catecholaminergic Polymorphic Ventricular Tachycardia
The inherited arrhythmia disorder CPVT is one of the most-deadly arrhythmias known, and it classically manifests with βAR-induced syncope or sudden cardiac death (SCD).50,51 CPVT was first described in 1978 as a distinct syndrome associated with syncope and arrhythmia in the setting of a structurally normal heart. This condition can present with premature ventricular contractions at rest, or with exercise, and this ventricular ectopy can degenerate into bidirectional VT or VF. The majority of CPVT cases present in childhood and have normal cardiac repolarization on ECG measurement of the QT interval.52 The estimated prevalence of CPVT is around 1:5000 to 1:10 000 depending on the population studied.53
RYR2-Encoded Ryanodine Receptor Type-2 (CPVT-1)
In the first major case series of children described to have CPVT, the authors noted the presence of bidirectional VT as an arrhythmia previously associated with digitalis toxicity.52 This led to the hypothesis that the cause of CPVT may be because of DADs induced by increased SR Ca2+ load exacerbated by catecholamines.54 A genetic locus associated with CPVT was first mapped to 1q42-43 of the genome in a large study of 2 unrelated families with a heritable, autosomal-dominant syndrome manifesting as stress-induced polymorphic VT, syncope, and SCD with structurally normal hearts.55 Two years later, inherited mutations in the RYR2 gene were identified as the most common genetic subtype of CPVT (CPVT-1; Table 1).56,57
| Type | MIM* | Gene | Protein | Genetic Locus | Frequency | Inheritance |
|---|---|---|---|---|---|---|
| CPVT 1 | 604772 | RYR2 | Ryanodine receptor 2 | 1q42.1-q43 | 50%–60% | AD |
| CPVT 2 | 611938 | CASQ2 | Calsequestrin 2 | 1p13.1 | Rare | AR |
| CPVT 3 | 614021 | TECRL | Trans-2,3-enoyl-CoA reductase-like | 7p22-p14 | Rare | AR |
| CPVT 4 | 614916 | CALM1 | Calmodulin 1 | 14q31-q32 | Rare | AD |
| CPVT 5 | 603283 | TRDN | Triadin | 6q22.31 | Rare | AR |
Subsequent studies rapidly expanded the spectrum of RYR2 mutations in CPVT which account for ≈50% to 60% of all cases.56 Pathogenic mutations most often alter a single amino acid (missense mutations) and are inherited in autosomal-dominant pattern. CPVT-associated mutations in RYR2 almost always result in increased SR Ca2+ leak, which is amplified in the setting of increased sympathetic drive.58 This increased propensity to SR Ca2+ leak can be detected as an increase in the frequency of elementary Ca2+-release events (ie, Ca2+ sparks).59 It is thought that diastolic SR Ca2+ leak can lead to increased intracellular Ca2+ that activates NCX during diastole, leading to DADs and triggering of ventricular arrhythmias.60 Several aspects of the pathophysiology of CPVT caused by RyR2 mutations remain controversial, including the potential role of reduced binding of FKBP12.6 to RyR2, channel gating deficits in the absence of βAR stimulation, and the potential involvement of SR Ca2+ overload as an additional mechanism. For example, the role of FKBP12.6 in regulating RyR2 Ca2+-release and the role of PKA-mediated phosphorylation on RyR2 in cardiac arrhythmia and HF are subjects of ongoing debate.61
Early studies demonstrated that FKBP12.6 was expressed in the heart, associated with RyR2, and modulated CICR.62 Furthermore, studies found that FKBP12.6 directly bound RyR2 and stabilized the closed conformational state of the protein such that removal caused SR Ca2+ leak.63,64 This stabilizing property of FKBP12.6 was not universally observed.65 As this line of exploration was developing, a separate body of evidence was emerging that RyR2 phosphorylation at serine 2808 (S2808) by PKA could increase channel opening probability as part of the fight-or-flight mechanism.66,67 These studies converged with the observation that PKA-mediated increased channel sensitivity to Ca2+ was based on partial dissociation of FKBP12.6 binding after S2808 phosphorylation and identified lethal exercise-induced arrhythmias in FKBP12.6 knockout mice (Fkbp12.6-/-).58 This observation was expanded to other forms of cardiac disease, including HF, whereby elevated βAR signaling through PKA resulted in hyperphosphorylated S2808 and dissociation of FKBP12.6.68,69 These findings have not been universally observed by other investigators have catalyzed many follow-up studies that have introduced debate in the field.70,71 Some have argued that reduced Ca2+ reuptake into the SR led is the predominant mechanism underlying HF72 or that phospholamban activity and increased SR Ca2+ load is involved.73 There is also evidence that CaMKII phosphorylation of RyR2 may contribute to the development of HF and arrhythmogenesis through increased Ca2+ leak.74 For in-depth review of this topic, please refer to previous articles.75–77 Overall, these studies highlight the complexity of Ca2+ release regulation in the cardiac myocyte.
Studies of several knockin mouse models of human RYR2 mutations have provided additional insights into the pathogenesis of CVPT.59,78–80 Based on some of these studies, it has been proposed that Purkinje cells in a mouse model of CPVT exhibited a higher frequency and amplitude of spontaneous SR Ca2+-release events, suggesting that focal arrhythmias might originate from the specialized conduction system.81 More sophisticated genetic studies are needed to confirm whether Purkinje cells are truly the source of triggered arrhythmias in CPVT mutant mice and in patients with this condition. Finally, recent studies in human induced pluripotent stem cells (iPSC) have confirmed previous studies on recombinantly expressed channels and studies in mouse models, while providing additional mechanistic insights. For example, it has been shown that iPSC-derived cardiomyocytes (iPSC-CM) from patients with CPVT exhibit an increased susceptibility to DADs because of abnormal SR Ca2+-release events.82 Overall, these studies demonstrate that exacerbation of DADs after sympathetic stimulation is the key mechanism and that β-blockers, dantrolene, CaMKII inhibitors like KN-93s, and RyR2-inhibiting compounds such a S107 all represent potential therapeutic options for CPVT.82–84 Subsequent clinical studies in patients with CPVT confirmed the antiarrhythmic potential of dantrolene.85 Thus, iPSC-CM from patients with CPVT may represent a valuable system for preclinical drug screening.
CASQ2-Encoded CASQ2 (CPVT-2)
A second rare genetic subtype of CPVT (CPVT-2) is caused by autosomal-recessive variants in CASQ2-encoded CASQ2, the most abundant Ca2+-buffering protein in the SR. These mutations are relatively rare among CPVT cases, accounting for only ≈3% to 5% of all patients with CPVT.86 This genetic subtype, initially identified in 7 families of a Bedouin tribe in northern Israel, is characterized by resting bradycardia and VT by treadmill or βAR activation with isoprenaline infusion.87 Recently, a family with a unique autosomal-dominant form of CPVT was found to be caused by a CASQ2 mutation.88 CASQ2 is the cardiac-specific isoform of a family of proteins that directly and indirectly regulate SR Ca2+ storage and release.89 CASQ2 has a high-binding capacity (40–50 mol of Ca2+/mol) but a moderate affinity (Kd of 1 mmol/L) for free Ca2+ and serves as molecular sink for Ca2+ that has been sequestered into SR after cardiac contraction.90 With an increased prevalence of acidic amino acid residues, it is thought that the negatively charged CASQ2 directly binds free Ca2+.91
All CASQ2 mutations identified to date are missense, deletion, or nonsense mutations that lead to a severe reduction, or complete loss of, the CASQ2 protein.92 RyR2 channels that lack CASQ2 open spontaneously without being triggered by ICa,L-mediated Ca2+ influx.93 Studies in isolated rat cardiomyocytes transfected with mutant CASQ2 protein revealed a reduced SR store Ca2+ capacity with spontaneous Ca2+ transient generation and evidence of DADs.94 This effect was abrogated by addition of citrate, a low-affinity Ca2+ buffer, suggesting that mutant CASQ2 destabilizes SR-store Ca2+ capacity that alters the Ca2+-sensitivity of RyR2 resulting in proarrhythmic DADs.94 Other studies utilizing knockin mice carrying missense or radical loss-of-function human mutations demonstrated reduced CASQ2 expression with elevated resting cytosolic Ca2+ levels and reduced SR-store Ca2+ that was further exacerbated by βAR stress.95 CASQ2 is part of the RyR2 macromolecular complex that also involves the SR proteins TRDN and JCTN.96,97 The levels of these proteins are often dramatically altered when CASQ2 is genetically ablated or mutated.96,98 Moreover, increased levels of CALR and RyR2, which increases SR Ca2+ leak, have been reported in mice with mutant CASQ2.95 Therefore, it cannot be excluded that some of the RyR2 functional changes in CASQ2 mutant mice are, at least in part, mediated by changes in TRDN, JCTN, or CALR levels. Finally, the mechanisms of increased arrhythmogenesis have been confirmed in human iPSC-CM. For instance, the βAR agonist isoprenaline caused DADs, oscillatory arrhythmic prepotentials, and aftercontractions in cardiomyocytes derived from CPVT patients with CASQ2 variants but not from individuals with normal CASQ2.99,100
TECRL-Encoded Trans-2,3-Enoyl-CoA Reductase-Like Protein (CPVT-3)
A third genetic subtype of CPVT is the gene encoding TECRL (trans-2,3-enoyl-CoA reductase-like protein). Initially identified by linkage analysis in a consanguineous Sudanese family with multiple SCDs among children while playing, subsequent whole-exome sequencing (WES) identified mutations in a handful of families and probands in TECRL.101,102 Each patient demonstrated VT and VF, particularly with exertion, and had SCD. Interestingly, although the subjects had normal QT intervals at baseline, adrenergic stimulation caused QT interval prolongation. As such, mutations in the TECRL gene seem to cause an overlap syndrome with features clearly associated with not only CPVT but also congenital LQTS (see below).
Creation of a mouse model of TECRL mutations is necessary to examine arrhythmia mechanisms in the experimental setting. Studies of iPSC-CM generated from the Sudanese proband demonstrated reduced systolic Ca2+-transient amplitudes and reduced caffeine-stimulated Ca2+ transient amplitudes (an index of SR Ca2+ content) along with elevated resting cytosolic Ca2+ levels, consistent with presence of SR Ca2+ leak as seen in CPVT-1 and CPVT-2.82,99 In addition, mutant iPSC-CMs demonstrated slower Ca2+-transient upstroke velocity and impaired SR Ca2+-reuptake when compared with both heterozygous and wild-type controls. Interestingly, stimulation with norepinephrine resulted in an increased propensity for DADs, which was suppressed by flecainide. AP recordings revealed prolonged APD also suggesting a clinical overlap between TECRL mutation-positive individuals with features of both CPVT and LQTS.102 At present, the mechanisms by which loss of TECRL function alters SR Ca2+-handling or ionic currents resulting in prolonged APD remain unknown.
CALM1-Encoded Calmodulin Type-1 (CPVT-4)
A fourth subtype of CPVT (CPVT-4) is caused by inherited mutations in CALM1-encoded CaM. The locus for this variant, 14q31-q31, was initially found by linkage analysis in a large, multigenerational Swedish family.103 Family members demonstrated multiple episodes of syncope and sudden death, particularly with exercise and exertion. On clinical evaluation, affected individuals demonstrated ventricular ectopy and evidence of VT/VF that was suppressed by β-blockers. The genetic haplotype was inherited in an autosomal dominant fashion and was completely penetrant. Subsequent genetic analysis of the ≈70 known genes within the locus demonstrated a heterozygous CaM-N53I mutation that segregated with incidence of disease within the family. A second mutation, CaM-N97S, was identified in an unrelated proband from Iraq who was diagnosed with CPVT and was negative for mutations in RYR2.
Calmodulin is a ubiquitously expressed Ca2+-sensitive signaling molecule that is found in all eukaryotic cells.104 There are 3 CAM genes in humans, CALM1, CALM2, and CALM3, which all encode a single protein—CaM. CaM is a relatively small, 148-amino acid α-helical protein with 4 classical Ca2+ binding EF hands that each bind to a single Ca2+ cation. This direct Ca2+-binding property allows conformational shifts in the N- and C-terminal domains of the protein that mediate a variety of interactions with a large number of intracellular binding targets.105 A dumbbell-shaped molecule, CaM, can sense both local and global Ca2+ levels, which allows for exquisite sensitivity to a variety of Ca2+-signaling events with downstream regulation of many Ca2+-handling proteins.106 Within the heart, CaM plays a key role in EC coupling and is critical for the SR Ca2+ release and subsequent Ca2+ reuptake into the SR. The LTCC and RyR2 are both important binding partners of CaM.107 Ca2+ entering the cardiomyocyte via LTCCs binds to CaM which, in turn, binds to the C-terminal IQ domain of the Cav1.2 channel α pore subunit (α1C) of LTCC. This process allows Cav1.2 channels to cluster and interact with each other, allowing for sufficient Ca2+ entry to initiate EC coupling.108 CaM also binds to RyR2, and binding of CaM reduces the open probability of RyR2. Conversely, impaired binding of CaM to RyR2 caused by a mutated binding domain on RyR2 leads to a variety of cardiac pathologies.109
In vitro experiments have revealed that mutations in the gene encoding CaM compromise Ca2+-binding and result in an aberrant interaction with the CaM-binding domain of RyR2.103 Subsequent studies revealed that the CaM-N97S mutation in the C domain reduced Ca2+-binding affinity of the C-domain and impaired binding to RyR2 at low Ca2+ concentrations, which was predicted to lead to an increased RyR2 open state. This impaired inhibitory gating regulation was confirmed by subsequent studies of RyR2 single-channel recordings in the presence of mutant CaM and functionally resulted in an increased susceptibility for RyR2-mediated store overload–induced Ca2+ release.110,111 In contrast, the CaM-N53I variant, which localized to the opposing N domain, demonstrated a small yet significant increase in the Ca2+-saturation of the C domain with an alteration to RyR2 binding affinity. These findings demonstrated that mutations in CALM1 are associated with CPVT through 2 distinct mechanisms of RyR2 dysregulation and support a model whereby the Ca2+-saturated C-lobe is constitutively bound to RyR2 while the N lobe senses fluctuations in cellular Ca2+.111
TRDN-Encoded Triadin (CPVT-5)
Finally, a fifth subtype of CPVT (CPVT-5) is caused by mutations in TRDN-encoded TRDN. Mutations in TRDN were first identified by candidate gene approach, and a small number of probands were identified with either homozygous loss-of-function mutations or compound heterozygous mutations. For example, a homozygous frameshift mutation, TRDN-D18Afs*13, was noted in a proband with cardiac arrest at age of 2 years who was found to have polymorphic VT.112 A second independent proband hosted 2 mutations, TRDN-Q205X and TRDN-T59R, and demonstrated proximal muscle weakness, syncope with exertion and bidirectional ventricular ectopy.112 Thus, TRDN mutations can cause CPVT in an autosomal-dominant manner.
As discussed above, TRDN is a transmembrane protein on the SR that forms a macromolecular complex with RyR2, CASQ2, and JCTN.113 TRDN is a multiprotein family arising from alternative splicing of a single TRDN gene. Two isoforms are exclusively expressed in skeletal muscle, whereas a third isoform (also known as Trisk 32 or CT1) is expressed mainly in cardiac muscle.114 Interestingly, all 3 TRDN mutations localized to a region of the protein that is common to all isoforms, including skeletal muscle isoforms.112 The link between TRDN mutations and skeletal myopathy remains unknown. In vitro functional analysis of the TRDN-T59R mutation in nonmuscle COS-7 cells demonstrated intracellular retention and degradation of the mutation protein. Furthermore, viral transduction of TRDN-T59R mutant protein into Trdn-/- mice demonstrated no expression of the protein by immunofluorescence of isolated cardiomyocytes.112 Thus, functionally CPVT-associated mutations lead to a severe TRDN function in cardiomyocytes. Electron microscopy studies of cardiomyocytes from Trdn-/- mice revealed fragmentation and overall reduction in contacts between the junctional SR and T-tubules.115 The function of CRU channels was impaired with reduced negative feedback of SR Ca2+ release on ICa,L. This uninhibited sarcolemmal Ca2+ influx via ICa,L likely caused SR Ca2+ overload leading to spontaneous SR Ca2+-release events on βAR stimulation.
Congenital LQTS
Congenital LQTS refers to a distinct group of cardiac channelopathies characterized by delayed cardiac repolarization, which places affected individuals at risk for syncope, seizures, and SCD. A relatively common arrhythmia syndrome, affecting as many as 1 in 2500 patients, this delay in cardiac repolarization occurs in the absence of an underlying syndrome or structural heart disease.116,117 Approximately 75% of LQTS cases are because of mutations in 3 genes: KCNQ1-encoded IKs potassium channel (Kv7.1, LQTS-1), KCNH2-encoded IKr potassium channel (Kv11.1, LQTS-2), and SCN5A-encoded INa sodium channel (NaV1.5, LQTS-3).118 These ion channels play key roles in the cardiac AP and genetic defects in these channels delay repolarization. Several channel interacting proteins, such as ANK2-encoded ankyrin B (LQTS-4), KCNE1-encoded min-K (LQTS-5), and KCNE2-encoded min-K-related protein 1 (LQTS-6), among others, interact with these major channels and have been implicated as rare causes of LQTS.119,120 To date, hundreds of mutations have been identified in 17 LQTS-susceptibility genes (Table 2). In addition, large population-based GWAS (genome-wide association study) analysis exploring common genetic variants associated with QT prolongation have identified many loci that encode Ca2+-signaling proteins that were associated with longer QT durations.121 Although the majority of the accepted LQTS genes encode proteins that govern the flux of Na+ and K+ about the sarcolemma, there is mounting evidence that Ca2+ fluxes and intracellular Ca2+ signaling are associated with prolonged cardiac repolarization and LQTS.
| Type | MIM* | Gene | Protein | Genetic Locus | Frequency | Inheritance |
|---|---|---|---|---|---|---|
| LQTS 1 | 192500 | KCNQ1 | Kv7.1 | 11p15.5-p15.4 | 30–35 | AD |
| LQTS 2 | 613688 | KCNH2 | KV11.1 | 7p36.1 | 25–30 | AD |
| LQTS 3 | 603830 | SCN5A | NaV1.5 | 3p22.2 | 5–10 | AD |
| LQTS 4 | 600919 | ANK2 | Ankyrin B | 4q25-q26 | Rare | AD |
| LQTS 5 | 613695 | KCNE1 | MinK | 21q22.12 | Rare | AD |
| LQTS 6 | 613693 | KCNE2 | MinK related protein 1 | 21q22.12 | Rare | AD |
| LQTS 7 | 170390 | KCNJ2 | Kir2.1 | 17q24.3 | Rare | AD |
| LQTS 8 | 601005 | CACNA1C | CaV1.2† | 12p13.33 | Rare | AD |
| LQTS 9 | 611818 | CAV3 | Caveolin 3 | 3p25.3 | Rare | AD |
| LQTS 10 | 611819 | SCN4B | Sodium channel β4 | 11p23 | Rare | AD |
| LQTS 11 | 611820 | AKAP9 | Yotiao | 7p21.2 | Rare | AD |
| LQTS 12 | 612955 | SNTA1 | Syntrophin α1 | 20q11.21 | Rare | AD |
| LQTS 13 | 613485 | KCNJ5 | Kir3.4 | 11q24.3 | Rare | AD |
| LQTS 14 | 616247 | CALM1 | Calmodulin 1† | 14q32.11 | Rare | AD |
| LQTS 15 | 616249 | CALM2 | Calmodulin 2† | 2p21 | Rare | AD |
| LQTS 16 | 114183‡ | CALM3 | Calmodulin 3† | 19q13.32 | Rare | AD |
| LQTS 17 | 603283‡ | TRDN | Triadin† | 6q22.31 | Rare | AR |
CACNA1C-Encoded L-Type Calcium Channel (LQTS-8)
The CACNA1C gene encodes the Cav1.2 (α1C) channel subunit of the LTCC, a macromolecular channel complex responsible for ICa,L and EC coupling.3 The Cav1.2 protein comprised 4 homologous domains (DI through DIV) that are connected by intracellular linker regions (I–II, II–III, and III–IV loops) and 6 transmembrane segments (S1 through S6).122 Mutations in CACNA1C have been associated with many human diseases that have cardiac manifestations. Classically, mutations in CACNA1C have been associated with Timothy syndrome—a disease characterized by extreme QT interval prolongation, syndactyly, neurodevelopmental delay, and SCD predisposition.123–126 Expansion of clinical genetic testing has identified many CACNA1C mutations in individuals demonstrating only cardiac abnormalities (QT prolongation, structural heart disease, and cardiomyopathy), without extracardiac abnormalities, so-called cardiac-only TS.127 Individuals with only QT prolongation, and a diagnosis of LQTS, have been identified in a large number of independent cohorts.
Many CACNA1C mutations have been characterized in vitro through heterologous expression in cell lines such as HEK293 and TSA201 cells and demonstrate either increased peak ICa,L, decreased current density with increased window current, or negative activation/positive inactivation shifts.128 Experimental and modeling studies have demonstrated that mutant CACNA1C can lead to enhanced ICa,L, and DAD-mediated triggered activity.129 In addition, they can steepen the APD restitution curve, disrupt rate-dependent cardiac excitation dynamics, and promote the development of alternans.130 Finally, CACNA1C mutations can amplify dispersion of repolarization across the tissue, which produces T-wave alternans and T-wave inversion on the ECG.130,131
Although the overall functional impact of these mutations is the prolongation of phase 2 of the AP causing delayed repolarization, there does not seem to be a clear mechanistic difference between the CACNA1C mutations that lead to Timothy syndrome (TS), cardiac-only TS, or LQTS. Indeed, this is reflected in the recent identification of a CACNA1C-I1166T in a proband with TS and independently identified CACNA1C-I1166V mutation, localizing to the identical residue, in a patient with LQTS.132,133 Given the lack of robust mechanistic studies, it remains unclear how a near-identical genetic substrate can lead to variable expressivity and severity of a disease phenotype. It is likely that genetic modifiers contribute to the differential phenotype manifestations. Additional mechanistic studies, perhaps utilizing iPSC-CM derived from Timothy syndrome, cardiac-only TS, and LQTS patients with CACNA1C mutations may yield insight into genomic, epigenomic, molecular, and biophysical changes that are specific to each disease presentation.
CALM1-, CALM2-, and CALM 3-encoded calmodulin 1, 2, and 3 (LQTS-14–16)
In 2013, the first mutations in the CALM1 and CALM2 genes were associated with LQTS.134 Two unrelated infant probands were described with a severe phenotype of recurrent cardiac arrests with markedly elevated QTc intervals. They were each found to host a heterozygous mutation—CaM-D130G and CaM-D96V mutations, respectively.134 Subsequent validation genotyping in a cohort of LQTS patients yielded an unrelated proband with CaM-D130G and a second subject with CaM-F142L. These mutations were all found to localize either within, or immediately adjacent to, the third and fourth EF hand domains of the C-terminal lobe, resulting in impaired Ca2+-binding of the domain.134 Interestingly, subsequent biochemical investigations have elucidated 2 distinct mechanisms of CaM and RyR2 dysregulation. CaM-D130G and CaM-D96V both impaired CaM-dependent inhibition of RyR2, resulting in an increased open state when single channels were recorded and an increased propensity for store overload–induced Ca2+ release.110 In contrast, although CaM-F142L demonstrated reduced Ca2+ binding, it was unexpectedly found to enhance CaM-dependent gating inhibition of RyR2 and related RyR2-mediated store overload–induced Ca2+ release. Specialized thermodynamic and NMR spectral analysis of the interaction between CaM-F142L and the reciprocal binding domain of RyR2 demonstrated unique alterations in the protein–protein interface suggesting that the mutation does not disrupt the negative regulatory role of CaM despite an impaired ability to bind free Ca2+.110 In addition to mutations identified in CALM1 and CALM2, the first reports of LQTS-associated mutations in CALM3 have been recently reported. Specifically, a CaM-D130G mutation was identified in a neonate with a profoundly elevated QTc interval.135 To date, mutations in CALM3 have not been widely identified and there have been no robust mechanistic studies to evaluate the role of CaM in LQTS. Taken together, these studies identify divergent mechanisms of disease pathogenesis that can, nonetheless, result in altered RyR2 inhibition by CaM.
As described previously, the loss of RyR2 gating inhibition is classically associated with the development of CPVT, and the link between these mutations and LQTS remains unexplored. One explanation for this dichotomy is that there are additional molecular effects to impaired CaM activity, such as increased ICa,L, which can prolong the APD. This possibility is supported by early studies in guinea pig cardiomyocytes, which demonstrate reduced CaM-dependent inactivation of ICa,L with expression of LQTS-associated CAM mutations. In addition, LQTS-associated CAM mutations result in electric alternans in a high dispersed manner across and within cells consistent with the electric remodeling observed in canonical LQTS-associated mutations.136 Given the clear role of these mutations on RyR2 gating, it is likely that there is a significant molecular overlap between the LQTS- and CPVT-associated mutations. However, the effect of CPVT-associated mutations in other sarcolemmal ionic currents that shape APD and cardiac repolarization are largely unexplored although the Nav1.5 and delayed rectifying IK currents are strong candidates.
Recently, the first attempts to derive patient-specific therapies to mitigate the abnormally prolonged repolarization have been reported. In 2017, human iPSC-CMs were derived from a subject who was diagnosed with LQTS shortly after birth after a cardiac arrest with a markedly elevated QTc of 740 who hosted a CaM-D130G mutation.137 Human iPSC-CMs derived from dermal fibroblasts demonstrated prolonged APD and larger Ca2+ transients with slower rise and decay kinetics when compared to wild-type iPSCs from an unrelated ostensibly healthy donor.138 Furthermore, CaM-D130G imparted a significant decrease to CaM-dependent inactivation of the LTCC. The authors utilized CRISPR-mediate interference of the transcription of CALM2, which specifically reduced expression of the mutant protein without altering expression of either CALM1 or CALM3. This selective expression inhibition rescued the prolonged APD in iPSC-derived cardiomyocytes.138 Although this study represents a major step forward in gene therapy approaches to altering monogenic disease expression, translating this technique to an in vivo model of arrhythmia remains an active and challenging area of exploration.
TRDN-Encoded Triadin (LQTS-17)
The most recent gene associated with LQTS is TRDN-encoded TRDN, which has been previously also linked to CPVT-5. Identified after WES of probands negative for the known LQTS-associated genes, a handful of TRDN null variants were identified. As with CPVT-5, each mutation-positive proband demonstrated either homozygous inheritance of loss-of-function allele or a compound heterozygous mutation with a loss-of-function allele.112,139 Both entities clinically manifest as SCD with either QT prolongation (LQTS-17) or signs of ventricular ectopy in the absence of QT prolongation (CPVT-5) diagnosed at an early age. This combination of clinical findings, in addition to the skeletal muscle weakness occasionally noted with CPVT-5, and the TRDN genetic substrate has been labeled the so-called triadin knockout syndrome. To date, there have been no mechanistic studies involving LQTS-associated TRDN mutations, and while Trdn-/- mice have a known propensity for arrhythmogenesis with βAR stimulation, QT prolongation has not been detected.115,140 Given the previously described possibility that Trdn-/- mice likely demonstrate reduced negative feedback of RyR2-mediated SR Ca2+-inhibition of ICa,L, an interesting possibility is that the increased Cav1.2 current might lead to APD prolongation. This would be an indirect mechanism of QT prolongation that is analogous to the CACNA1C mutations described in LQTS-8 that produce an increased ICa,L current. Further extensive studies are needed to delineate these hypotheses.
Idiopathic VF
Idiopathic VF (IVF) is a genetic disease characterized by a documented VF event that is otherwise unexplained. Comprising ≈1% of out-of-hospital cardiac arrest survivors presenting with a shockable rhythm, IVF can often be challenging to diagnosis.141,142 Furthermore, in the setting of a normal ECG, the affected status of an individual can only be known after an arrhythmic event, which makes genetic studies difficult to interpret. Traditionally associated with mutations in the SCN5A-encoded Nav1.5, the first IVF-associated mutations were often described in sporadic cases presenting with VF and had significant clinical overlap with a group of Nav1.5-mediated channelopathies known as Brugada syndrome.143,144 New genetic testing platforms have allowed for the identification of other IVF genes implicated in families with the arrhythmia (Figure 5), and recent advances in WES have identified the first genes encoding Ca2+-handling proteins in children with IVF.
In 2014, a family with a history of VF and SCD with normal ECG and echocardiograms was subjected to WES after kindred were found to be genotype negative for the major LQTS, CPVT, and arrhythmogenic right ventricular cardiomyopathy (ARVC)–associated genes. This identified a CALM1-F90L mutation in a proband who experienced out-of-hospital arrest because of VF at the age of 16 years with no clinical evidence of LQTS, CPVT, cardiomyopathy, or other SCD-predisposing cause.145 Subsequent functional evaluation of the CALM1-F90L mutation demonstrated impaired CaM stability and impaired Ca2+ binding cooperativity.109 It was concluded that the F90L mutation likely perturbs the position of 2 Ca2+ EF hands within the C-lobe relative to each. As a result, the ability of the first occupied site to induce a favorable conformational shift in the second, which is needed to facilitate Ca2+-binding, is impaired. The authors concluded that this creates a relatively insensitive CaM protein that is not responsive over small changes in Ca2+ concentration.109
Although the impact of the F90L on the function of CaM is known, the ultimate effect of this perturbation on RyR2 gating or other Ca2+-handling proteins is still unknown. While there has been some incremental progress in identifying the genetic and molecular causes of IVF, mutations remain rare and IVF remains enigmatic as a disease entity. As with the development of CPVT and LQTS, one possibility is that altered CaM function associated with IVF selectively impairs some ion channels while leaving other channels unaltered. A tempting target is Nav1.5, which contains many IVF-associated mutations. SCN5A-associated IVF and Brugada syndrome mutations demonstrate a diverse array of biophysical effects in heterologous cell line overexpression models. For example, some SCN5A IVF/Brugada syndrome mutations create depolarizing shifts in channel inactivation, whereas others create hyperpolarization shifts in both activation and inactivation, all with the ultimate effect of loss-of-function effect on Nav1.5 and VF predisposition.143,146 It is possible that IVF-associated CAM mutations results in loss of Nav1.5 depolarizing current and dispersion of excitability—a known molecular substrate for reentry-mediated VF. This possibility is supported by structural evidence that CaM directly binds Nav1.5 and is a critical player in channel inactivation and permitting channel activation. However, a direct link between CaM mutations and VF has not been clearly demonstrated.105 Ultimately, subsequent studies are needed to link CAM mutations to INa current and a reentry substrate in IVF.
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder characterized by asymmetrical hypertrophy of the heart, with a prevalence of 1 in 500.147 This disease represents the most common cause of arrhythmogenic SCD in the young, particularly in young athletes.148 HCM is associated with not only lethal ventricular arrhythmias but also AF.149,150 Since the association of the first gene mutation with HCM, that of MYH7-encoded β-myosin heavy chain, multiple studies have determined that the majority of HCM cases are because of mutations in genes encoding components of the cardiac sarcomere.151–153 Although the genetic mutations in proteins encoding cardiac myofilaments are the major cause of HCM, Ca2+ dysregulation plays a significant role in the pathological remodeling and hypertrophy. Furthermore, abnormal Ca2+-signaling and the myofilament sensitivity to Ca2+ are both known triggers for ventricular arrhythmias. Sarcomeric HCM genes are divided into subgroups based on the location of the encoded protein in the cardiac sarcomere consisting of the thick, intermediate, and thin myofilaments. Mutations in genes encoding the thick myofilament (MYH7-encoded beta myosin heavy chain, MYL2-encoded regulatory myosin light chain, and MYL3-encoded essential myosin light chain), the intermediate myofilament (MYPBC3-encoded cardiac myosin binding protein C), and the thin filament proteins (ACTC-encoded actin, TPM1-encoded α-tropomyosin, TNNT2-encoded cardiac troponin T [TnT], TNNI3-encoded cardiac troponin I [TnI], and TNNC1-encoded TnC) have been linked with development of HCM.154–160 Mechanisms of sarocomeric HCM pathogenesis have been extensively reviewed.161,162
Arrhythmia Predisposition in Sarcomeric HCM
Early in the exploration of the sarcomeric gene association with HCM, it was proposed that the arrhythmia burden, manifest in SCD, might be higher with certain mutations. For example, early studies identified individuals in large families of HCM hosting either the MYH7-R403Q or MYH7-R453C missense mutations with increased sudden deaths compared to those hosting a MYH7-V606M mutation.163 Furthermore, early genotype–phenotype studies of TNNT2 suggested an association with decreased life expectancy and a high incidence of SCD despite minimal cardiac hypertrophy.164 These studies proposed that individual mutations, or mutations in specific genetic loci, may predispose to lethal arrhythmic events in HCM. As the field has matured, these associations were not universally observed, and there is significant heterogeneity in the expression and penetrance of sarcomeric HCM disease.165–168 This controversy has been reviewed previously.169,170 Overall, these genotype–phenotype correlations did not have mechanistic support for the arrhythmia burden observed in some cases; however, a growing body of evidence suggests myofilament Ca2+-sensitivity as a major arrhythmic mechanism which is independent of gene mutation. As a molecular unit, the troponin complex and thin filament proteins are responsible for sensing intracellular Ca2+ fluctuations and triggering sarcomeric contraction.171 Although many myofilament proteins have been linked to HCM arrhythmogenesis, alterations in Ca2+-sensitivity of the components of the thin filament have been most clearly linked with potentially fatal ventricular arrhythmias.172 This is detailed below.
Although HCM carries an increased risk of lethal ventricular arrhythmias,173 AF is found commonly with a frequency of 20% to 25% of all patients with HCM.174 The hemodynamic mechanism of this may be related to atrial dilation secondary to elevated left ventricular filling pressures resulting in left atrial dilation; however, the cellular mechanism of this is unexplored among sarcomeric HCM. Furthermore, although there have been some suggestions that the sarcomeric mutations may predispose individuals for early and more severe AF,175,176 there have not been conclusive studies linking specific genotype to AF predisposition.150
TNNT2-Encoded Cardiac TnT and TNNC1-Encoded Cardiac TnC
Troponins are the Ca2+-sensing molecule of the myofilament. After CICR, free Ca2+ binds TnC, which increases its binding affinity for TnI, pulling the TnI inhibitory domain away from its binding site on actin through its interaction with the molecular linker TnT.177 This permits the troponin–tropomyosin complex to move further into the actin groove fully exposing the myosin binding sites on actin. Active actin–myosin cross-bridging then occurs and contraction begins.177
Traditionally, mutations in TNNT2 were thought to be more arrhythmogenic compared with other genetic subtypes of HCM.178 Although this belief has been called into question recently,169 a significant body of evidence has linked HCM-associated TNNT2 mutations with the development of fatal arrhythmias in the absence of other known predictors of arrhythmia predisposition such as significant hypertrophy or fibrosis. Many TnT mutations have been described that nearly universally increase Ca2+ sensitivity, and thus Ca2+-binding of TnT and the sarcomeric thin filament. It is thought that TnT serves as a molecular sink for dynamic Ca2+-buffering and that increased Ca2+-sensitivity may lead to altered Ca2+-transient dynamics. Overall, the degree of arrhythmia susceptibility seems to be directly correlated to the degree of increased Ca2+ sensitivity.179
For example, a mouse model of HCM (transgenic overexpression of I79N mutant TnT) exhibits increased cardiac contractility with reduced diastolic relaxation in the absence of significant fibrosis, as well as increased myofilament Ca2+ sensitivity.180 This increased Ca2+-sensitivity was associated with increased diastolic Ca2+ levels and intracellular Ca2+ overload in isolated cardiomyocyte studies.181 Furthermore, TnT-I79N was associated with decreased Ca2+-transient amplitudes in the face of elevated resting Ca2+ levels that caused ventricular ectopy and VT.182 Although the precise mechanism has not been clarified, the increased TnT Ca2+ sensitivity may lead to DAD-mediated VT resulting from reduced myofilament Ca2+ buffering or could cause reentrant arrhythmia through a still undefined mechanism. The first option is supported in other models of increased thin filament Ca2+ sensitivity. For example, the transgenic expression of fetal slow skeletal troponin I in place of TnI increased Ca2+ sensitivity in a manner analogous to the electric remodeling found in pathological hypertrophy.183 In this model, constitutive increase in Ca2+ sensitivity is associated with increased expression of NCX, which might result in increased INCX current to maintain Ca2+ homeostasis during diastole when SERCA2a is also reduced.184 Interestingly, this observation was noted in younger but not in older mice, reflecting the early age of onset of arrhythmias in TNNT2-positive subjects. The reentry hypothesis is supported by evidence that TNNI3 mutations can increase spatial dispersion of activation times across the myocardium, thereby promoting reentry. For example, TNNT2 mutations, including TnT-I19N, have been shown to associate with a short effective refractory period along with beat-to-beat variability in APD with increased spatial dispersion of conduction velocity.179 Additional studies are required to directly prove 2 suggested hypotheses and delineate the underlying arrhythmogenic mechanisms associated with TNNT2 mutations.
Mutations in TNNC1, a rare cause of HCM, have been also linked with a predisposition to fatal arrhythmias. A TnC-A31S mutation was identified in 3-year-old boy who had HCM and an out-of-hospital VF event. Despite being on β-blocker therapy, he had multiple breakthrough VF events with appropriate ICD discharged. This mutation is located within the inactive Ca2+-binding domain of TnC. When reconstituted in skinned porcine cardiac fibers, this resulted in increased Ca2+-sensitivity of both TnC and the thin filament compared with wild-type.185 Should future studies confirm the presence of increased cellular Ca2+ levels, this also raises the possibility of either a DAD-mediated trigger or formation of an arrhythmogenic substrate for reentry. In addition, although rare, identification and characterization of human mutations affecting other thin filament components will add additional mechanistic understanding to this process.
JPH2-Encoded JPH2
A small subset of patients without mutations in sarcomeric genes host a genetic mutation in genes encoding Ca2+-handling proteins, and some have been linked with a predisposition to arrhythmia.186JPH2-encoded JPH2 is a member of the junctophilin family of proteins, which plays a critical role in maintaining the JMC in excitable cells, including striated muscle.6,7 JPH2 is the major family member found in the heart and spans the JMC, tethering the SR to the sarcolemma creating a fixed cardiac dyad distance and serving a key role in negatively regulating RyR2 opening (Figure 1B).7,187 Reflective of the critical role that this protein plays in maintain CICR and Ca2+ homeostasis by RyR2 gating regulation, JPH2 plays a prominent role in cardiomyopathy development, HF progression, and development of EC coupling in the immature myocyte.188–191 These diverse roles have been reviewed previously.192,193 An emerging role of JPH2 is the development of Ca2+-mediated arrhythmias, in particular congenital AF. Although the vast majority of AF is acquired, reviewed in detail below, a specific mutation (E169K) in JPH2 was linked with AF development in a small family with HCM.194 Expression of JPH2-E169K in mice demonstrated a higher incidence of pacing-induced AF with increased SR Ca2+ leak and propensity of ectopic Ca2+ transients after rapid pacing.194 This was associated with increased RyR2-mediated SR Ca2+ leak because of loss of direct binding between RyR2 and JPH2.189,194 This contributed to increased diastolic Ca2+, increased NCX activity, and a predisposition to DADs. Additional studies are needed to more thoroughly dissect the molecular underpinnings of JPH2-mediated atrial electric remodeling.
CASQ2-Encoded CASQ2 and CALR3-Encoded CASQ3
Rare mutations in other members of the JMC and RyR2 macromolecular complex have been linked to HCM. Genetic interrogation of an Australian cohort of 252 unrelated individuals with HCM revealed a single mutation, D63E in CASQ2 and 2 mutations in the CALR3 gene (CALR3-R73Q and CASQ2-K82R) that were not identified in the ostensibly healthy control population.195 To our knowledge, these are the only mutations described in these genes among individuals with cardiomyopathy. The CASQ2-D63E was found in compound heterozygosity with 2 MYBPC3 mutations, which decrease the likelihood of a truly causative biomarker. Conversely, the 2 CALR3 mutations were found in genotype-negative individuals. CALR is a Ca2+-binding chaperone in the sarcoplasmic/endoplasmic reticulum, where it buffers Ca2+ and plays an important role in the quality control of intracellular secretory pathway processes.196 CALR has 2 major isoforms, and little is known about the expression levels of CALR3 in myocardial tissue. The functional implications of the CALR3 variants are presently unknown. In embryonic stem cell knockout model, CALR3 deficiency compromised the nuclear pore complex and disrupted the nuclear import of the cardiac transcription factor MEF2C in a Ca2+-dependent manner.186,197
Arrhythmogenic Cardiomyopathy
ARVC, also referred to as arrhythmogenic cardiomyopathy or arrhythmogenic right ventricular dysplasia, is a relatively rare type primary myocardial disease characterized by fibro-fatty replacement of myocardial tissue, cardiac arrhythmias, and an increased risk of SCD. This clinical entity has been recently reviewed.198 Traditionally, ARVC is considered a disease of the cardiac desmosome, whereby mutations in components of this cell–cell adhesion structure are commonly identified in individuals with disease.199,200 There is some evidence that RYR2 mutations may be a rare cause of ARVC or are present with a prevalence that is significantly higher than rare RYR2 variants in a control population.201,202 These clinical observations suggests that RYR2 variants play a role in the genetic basis of traditional ARVC as either disease-causing mutations or as a modifier susceptibility allele. In a mouse model of an ARVC-linked RYR2 variant, a reduced right ventricular end-diastolic volume was observed, but pathognomic fibrofatty infiltration or structural abnormalities seen in patients with ARVC were absent.59 Despite the possible link between RyR2 and ARVC, currently there is insufficient evidence to implicate primary defects in Ca2+-signaling in the pathogenesis of this disorder.203
Dilated Cardiomyopathy
Familial dilated cardiomyopathy (DCM) is a genetic heart muscle disease characterized by progressive dilation and dysfunction of the left or both ventricles. Mutations in >30 genes can cause congenital DCM, and most of these genes encode proteins that are part of the sarcomere or are structural proteins needed to conduct mechanical force in the cardiomyocyte.204 The remaining genes encode proteins that play various roles within cardiomyocytes to ensure proper contractile function. Various studies suggest that mutations in sarcomeric genes205–207 and nonsarcomeric genes208,209 can alter Ca2+ homeostasis, although the affected proteins are not directly involved in Ca2+ handling. On the contrary, there is a clear role of defective Ca2+ handling in DCM pathogenesis among patients with inherited mutations in phospholamban (PLN) and HRC.
PLN-Encoded PLN
Rare mutations and polymorphisms localizing to PLN have been linked to patients with inherited cardiomyopathy. In a large family with multiple generations of cardiomyopathy, kindred homozygous for a PLN-L39X nonsense (early stop) mutation developed DCM and HF requiring cardiac transplantation as adolescents.210 Interestingly, individuals heterozygous for this mutation tended to demonstrate HCM. This raises the possibility of a dose-dependent effect with loss of PLN expression. In addition, multiple small genotyping studies identified a handful of heterozygous PLN mutations in individuals that were missense.211,212 Moreover, PLN mutations have been identified in individuals with HCM exclusively. These include a handful rare PLN promoter have been identified in multiple independent cohorts.213–215 Overall, it seems that mutations in PLN are a rare cause of both DCM and HCM accounting for <1% of all individuals with disease.213
As discussed previously, myocyte relaxation during diastole is an active process mediated by ATP-expending pumping of cytosolic Ca2+ into the SR lumen via SERCA2a, which is negatively regulated by PLN. Moreover, PLN inhibitory action can be reduced by PKA and CaMKII-mediate phosphorylation.216,217 Since the discovery of cardiomyopathy-associated mutations, several mouse models have been made expressing putatively pathogenic mutations. For example, transgenic overexpression of the PLN-R14del mutation, initially identified in a large family of DCM, leads to cardiac dilation, myocyte disarray, fibrosis, and early death in a mouse model.211 In vitro studies of PLN-R14del expressed in HEK293 cells demonstrated superinhibition of Ca2+ affinity for SERCA2a that was not relieved by PKA phosphorylation. Although the precise mechanism of PLN-mediated DCM remains unclear, it is possible that chronic suppression of SERCA2a activity leads to increased cytosolic Ca2+ and a substrate for DAD arrhythmogenesis and, perhaps concurrently, pathological myocardial remodeling resulting in HF. This possibility is supported by recent work exploring a PLN-R25C mutation. Originally identified by WES of a DCM family with significant ventricular arrhythmias requiring ICD placement, this mutation caused superinhibition of SERCA2a when virally overexpressed in adult cardiomyocytes.218 This resulted in decreased SR Ca2+ content and reduced Ca2+ transient amplitude, which is consistent with the loss of systolic function observed in DCM. Furthermore, increased Ca2+ spark frequency and spontaneous Ca2+ waves were seen, suggesting DAD-type arrhythmia susceptibility.218 Although the mechanism of increased SR Ca2+ leak is unknown, it is possible that CaMKII activity is increased in the setting of elevated myocyte Ca2+ levels. Additional studies specifically exploring the interaction between SERCA2a function and RyR2 gating are needed to clarify this relationship.
HRC-Encoded HRC
Candidate gene-based genetic interrogation of a cohort of patients with DCM for HRC-encoded HRC identified an S96A polymorphism that was statistically associated with the development of ventricular arrhythmias. The presence of the minor allele variant conferred a hazard ratio of 4.2 for VT or VF among individuals with DCM.219 HRC is part of the SERCA2a macromolecular complex and serves as a regulator of SR Ca2+ reuptake (Figure 4). It has been shown to bind the SR luminal side of SERCA2a and interact with TRDN.32,33 Subsequent studies utilizing adenoviral overexpression in rat ventricular myocytes demonstrated reduced SR store Ca2+ reuptake and increased Ca2+ sparks with HRC-S96A expression compared with wild-type.220 Interestingly, this phenotype was exacerbated after myocardial ischemia and resulted in spontaneous Ca2+ waves.220 This suggested an arrhythmia-susceptibility allele that may alter RyR2 gating function in the setting of ischemic stress. Although in vivo studies are needed to validate these observations, the findings together suggest a relatively common variant that may be clinically silent until an acquired myocardial stress or injury. Furthermore, these findings suggest a molecular mechanism of cross talk between SR reuptake via SERCA2a and SR release via RyR2. Whether this association is direct through common binding partners, indirect through signal transduction molecules, or a combination of both, remains unknown.
Calcium-Dependent Acquired Arrhythmias
Although many arrhythmias can be caused by heritable mutations in cardiac ion channels and channel-interacting proteins, Ca2+-mediated arrhythmias can also develop in the setting of acquired diseases of the myocardium. These common types of arrhythmias include AF and ventricular tachyarrhythmias encountered in patients with structural heart disease.75,221 In this review, we will not discuss arrhythmias that occur in conjunction with structural heart disease.
Heart Failure
HF is a clinical diagnosis, which is defined as any abnormality in cardiac structure or function that results in failure of the heart to meet the metabolic demands of the body. Affecting millions of people worldwide, an estimated 1 in 5 people will develop HF during their lifetime, making it one of the most deadly, morbid, and expensive diseases known.222 Although gains have been made in reducing mortality, there is recent evidence that these gains have plateaued and that global burden of HF remains high.223,224 Given this, there have been rapid advances in the pharmacological management of HF, as well as guidelines shifts for recommended therapies, which target a growing number of molecular mechanisms.225 Pathological alterations in cardiomyocyte Ca2+ cycling have emerged as a prominent component of the molecular dysfunction that occurs in HF. Understanding these mechanisms has been central to the development of recent novel therapies. These topics have been heavily reviewed.226–228 Furthermore, a substantial body of evidence exists linking these pathological alterations in Ca2+ cycling to arrhythmic predisposition during HF remodeling. These arrhythmias are the cause of a significant proportion of SCD that occurs during HF.229,230 Just as HF is a complex and varied disease, the arrhythmic substrate from aberrant Ca2+ signaling is a broad subject and has been the topic of multiple comprehensive reviews.15,231,232
Atrial Fibrillation
AF represents the most common type of cardiac arrhythmia observed in the general population.233 This disease often progresses from a more intermittent form (paroxysmal AF) to persistent (chronic) AF (cAF) that lasts for >7 days at a time.36,221 Numerous factors can promote the occurrence of AF, including genetic determinants (Figure 6), extracardiac factors (ie, sleep apnea, obesity, hypertension, autonomic imbalance), as well as remodeling of the cardiac tissue.36,234 In this section, we will focus on the potential involvement of Ca2+ in the development of AF. The primary arrhythmia mechanisms contributing to AF are focal ectopic firing and reentrant activity (Figure 7).
Figure 7. Calcium-dependent arrhythmia mechanisms in atrial fibrillation (AF). Schematic diagram delineating which changes in intracellular Ca2+-handling promote arrhythmia mechanisms leading to AF. Enhanced ryanodine receptor type-2 (RyR2)–mediated Ca2+ release leads to activation of Na+/Ca2+-exchanger (NCX), which in turn can cause a delayed afterdepolarization (DAD)–mediated triggered action potential (AP). Shortening of the AP duration (APD) because of reduction of ICa,L (L-type Ca2+ current) and membrane hyperpolarization because of upregulation of IK1 (inward rectifier K+ current) promote reentry. See main text for further details. CaM indicates calmodulin; CaMKII, Ca2+/calmodulin-dependent protein kinase II; Cav1.2, L-type Ca2+ channels; Cn, calcineurin; FKBP12.6, FK506-binding protein 12.6; miR-26, micro–RNA-26; NFAT, nuclear factor of activated T cells; and SERCA2a, sarco/endoplasmic reticulum ATPase type-2a.
Ca2+-Dependent Triggered Activity in AF
Experimental studies in animal AF models and atrial samples from patients with AF revealed that abnormal atrial Ca2+-signaling likely plays a role in AF pathophysiology by contributing to afterdepolarization-mediated triggered activity, conduction block, and Ca2+-driven subcellular alternans.36,235 Cellular DAD-mediated triggered activity was demonstrated in atrial myocytes from patients with paroxysmal AF (Figure 7A).236 These patients were in sinus rhythm at the time of tissue collection for weeks, thus excluding confounding effects of high atrial rate-induced atrial remodeling. Several factors contribute to the increased incidence of spontaneous SR Ca2+ release events, including increased SR Ca2+ load and enhanced RyR2-mediated SR Ca2+ release. The SR Ca2+ stores are overloaded because of increased SERCA2a activity secondary to PLN phosphorylation resulting in inactivation of the inhibitory protein.236 Increased SR Ca2+ leak was caused by increased RyR2 protein levels and RyR2 activity levels, whereas RyR2 phosphorylation levels were unaltered.194,237 Enhanced RyR2 protein expression during paroxysmal AF seems to be caused, in part, by a reduced expression of the micro-RNA cluster miR-106b-25, which enhances post-transcriptional regulation of RyR2.238 Consistent with these data is the finding that miR-106b-25–deficient mice are more susceptible to pacing-induced AF, atrial ectopy, and increased SR Ca2+ release events.238 Recent transcriptomic analyses suggest that there may be additional alterations in miRNA and mRNA that have not been fully explored in patients with paroxysmal AF.239 Taken all of these studies together, it is clear that additional investigation is needed to assess the potential effects of intracellular Ca2+ modulation on the pathogenesis and progression of AF.
In patients with persistent AF, an increased prevalence of spontaneous SR Ca2+ release events and DADs have also been reported.235,240,241 The activity of single RyR2 channels was found to be increased in patients with cAF.242,243 Increased levels of PKA and CaMKII-mediated phosphorylation of RyR2 have been reported in patients and large animal models of cAF.242,244,245 Functionally, however, it seems that mainly CaMKII phosphorylation of RyR2 promotes excessive channel activation and SR Ca2+ leak.243 In addition, reduced interactions of RyR2 with channel-stabilizing subunits such as FKBP12.6 and JPH2 may contribute to increased diastolic SR Ca2+ leak and triggered activity.194,246 The enhanced SR Ca2+ leak is more likely to lead to triggered activity because of upregulation of NCX in patients with cAF.243
Finally, AF has been reported in patients with CPVT, which is not surprising because mutant RyR2 channels cause SR Ca2+ leak in both the atria and ventricles.247,248 Studies in mouse models of CPVT caused by an RyR2 mutant confirmed enhanced SR Ca2+ leak in atrial myocytes, consistent with DADs and triggered activity.249,250 In addition, atrial conduction slowing has been reported in an RyR2 knockin mouse model of CVPT, which may be caused by acute Ca2+-dependent inhibition of Na+-channels and a chronic downregulation of Nav1.5 expression.251,252 This study suggests a possible mechanistic link between abnormal SR Ca2+ release and reduced conduction velocity and a slower AP upstroke, which might contribute to reentry. Overall, abnormal Ca2+ signaling and enhanced diastolic SR Ca2+ leak along with cellular DAD-mediated triggered activity may support AF induction by producing DADs and could promote AF persistence by increasing heterogeneity (dispersion) of excitability, thereby causing conduction block that increases the susceptibility to AF-maintaining reentry.
In addition to DADs, late phase 3 EADs have been observed in dogs after rapid atrial pacing (which causes Ca2+ loading of the cells; Figure 7B).239 This is somewhat surprising because EADs typically occur in the setting of APD prolongation, whereas the atrial APD is usually abbreviated in most models of AF. Several changes favor the development of EADs in cAF, including SR Ca2+ leak via RyR2 can promote ICa,L reactivation, the upregulation of INa,L, and enhancement of INCX.243,253–255 Nevertheless, the potential role of late phase 3 EADs in the development of AF requires further investigation. Other mechanisms may also contribute to the formation of triggered activity, including cytosolic Ca2+ alternans (see below), which play a critical role in the initiation of AF in humans.256
Ca2+-Dependent Reentry in AF
Reentry requires a suitable vulnerable substrate, as well as a trigger that acts on the substrate to initiate reentry (discussed above). Atrial remodeling is induced by atrial arrhythmias and has the potential to increase the likelihood of ectopic activity and reentry through multiple mechanisms. The persistence of abnormal Ca2+ signaling and enhanced diastolic SR Ca2+ leak can activate ion channels and trigger Ca2+-dependent signaling pathways, thereby promoting the evolution of atrial remodeling and the progression of AF to more persistent forms.257 For example, small-conductance Ca2+-dependent K+-channels (SK channels) govern the risk of human AF likely by decreasing APD and promoting reentry,258 and the association between SK channels and RyR2 as the potential internal source of SK channel activation, position SK channels as an important Ca2+-dependent link between triggered activity with reentry.259,260 Furthermore, reduced ICa,L in AF causes APD shortening and promotes reentry.235 Its reduction is complex and involves downregulation of the Cav1.2 subunit expression by the calcineurin-NFAT system and Cav1.2 breakdown by Ca2+-dependent calpain proteases.235 Reduced Ca1.3 might also contribute.261 Reentry-promoting increased IK1 may result from a Ca2+-dependent enhancement in expression of Kir2.1-subunits because of a calcineurin-NFAT–mediated decrease in micro–RNA-26.235
In atria, the primary mechanism leading to alternans results from abnormalities in Ca2+ signaling (Ca2+-driven alternans), with APD alternans being secondary to Ca2+-alternans.262 Despite some controversies about whether Ca2+-alternans results from fluctuations in SR Ca2+ content or from changes in RyR2 refractoriness, Ca2+-alternans can be observed in both animal models of AF and in humans with AF. For instance, SR Ca2+ leak increases the susceptibility to Ca2+-alternans and atrial arrhythmias in mice with CPVT mutations in RyR2,263 and in rabbits with chronic myocardial infarction or hypertension-induced atrial remodeling Ca2+-alternans is a prominent feature of the arrhythmogenic substrate.264,265 Atrial cardiomyocytes from patients with cAF are also more prone to Ca2+-alternans, an effect that seems to involve an increased activation of adenosine A2A receptors with subsequent enhancement of RyR2-mediated SR Ca2+ leak.266 Overall, computer modeling clearly suggests that elevated Ca2+-driven APD alternans leads to increased arrhythmia vulnerability, complexity and persistence because of increased heterogeneity of repolarization in atria.267
There is evidence that abnormal intracellular Ca2+-handling promotes atrial remodeling. Mice with cardiac-restricted overexpression of a repressor form of the cAMP-response element modulator (CREM-Tg mice) develop atrial dilatation, abnormal cardiomyocyte growth, atrial fibrosis along with conduction disturbance leading to spontaneous AF.268 By crossing the CREM-Tg mice with RyR2-S2814A mice, in which RyR2 phosphorylation by CaMKII is inhibited, the development of a substrate for spontaneous AF was prevented.269 These studies suggest that RyR2-mediated SR Ca2+ leak is involved in atrial remodeling, potentially by activation of calcineurin-NFAT–mediated changes in gene transcription.269
In addition, there is emerging evidence that intracellular Ca2+ signaling regulates the proliferation and the transition of fibroblasts to collagen-secreting myofibroblasts, thereby promoting reentry.235 Transient-receptor potential canonical-3 channels are key mediators of the fibroblast-to myofibroblast transition and their increase in AF involves the NFAT-micro–RNA-26 pathway.270 Overall, these findings indicate that abnormal RyR2-mediated SR Ca2+ leak and the related Ca2+-dependent signaling may drive AF progression via these and possibly other unrecognized remodeling pathways, leading to the evolution of AF-maintaining substrate for reentry (Figure 7).
In summary, despite some controversies about the precise role of RyR2 in AF, there is good evidence for contribution of abnormal Ca2+ signaling to the formation of the trigger and the substrate for reentry in both animal models and humans with AF.221 However, it is unknown whether intracellular Ca2+ oscillations are required and sufficient to sustain high-frequency foci once the arrhythmia persists. During high-frequency pacing of normal Langendorff-perfused whole rabbit hearts, RyR2 refractoriness initiates SR Ca2+-release alternans in the ventricle without concomitant changes in diastolic SR Ca2+ alternans, which points to a potential role of RyR2 dysfunction in Ca2+ alternans during pacing.271 However, in this model, RyR2-related Ca2+ alternans did not play a major role for the transition of spatially concordant to spatially discordant alternans and the transition of alternans to VF, which rather depended on APD and CV restitution.271 These findings can be interpreted to suggest that although RyR2-related Ca2+ alternans is involved in the initiation of arrhythmias, the maintenance of VF might be less dependent on intracellular SR Ca2+-release oscillations. Of note, studies using optical mapping of voltage and Ca2+ were not yet performed in the diseased ventricle or atrium, thus the consequences of dysfunctional RyR2 (and other ECC components) for arrhythmia maintenance, particularly in the diseased atrium, remain unknown and require thorough addressing in subsequent studies. Simultaneous high-resolution optical mapping of voltage and Ca2+ in perfused intact human atria of sinus rhythm and patients with AF should be performed to obtain first hints about the putative role of intracellular Ca2+ oscillations for the fibrillatory process during pacing-induced AF.272
Therapeutic Approaches to Correcting Calcium Mishandling
Ca2+-handling within cardiomyocytes has been recognized as a potential target for the treatment of cardiac disease for a long time. One class of drugs known as Ca2+ channel antagonists targets the voltage-gated sarcolemmal Ca2+ channels and is currently being used clinically to treat hypertension, angina pectoris, cardiomyopathy, and cardiac arrhythmias. Fleckenstein273 described the first Ca2+ channel blockers as new drugs for the treatment of coronary disease ≈50 years ago. During decades of subsequent studies, the role of Ca2+ channels in cardiac muscle contraction was elucidated (for review, see274). Moreover, the biophysical and genetic identities of various voltage-gated Ca2+ channels were subsequently described.275,276 Several classes of antagonists have been described (ie, benzothiazepines, phenylalkylamines, and dihydropyridines), and are now part of the formulary for the treatment of cardiac diseases including arrhythmias. Ca2+ channel blockers are able to decrease the automaticity of ectopic foci in the heart and have emerging uses in many arrhythmias. For example, T-type Ca2+ channel blockers and LTCC blockers have efficacy in reducing AF arrhythmia burden and can prevent electric remodeling.277–279 Moreover, although mainstay for treatment of CPVT is β-blockade, there has been early evidence that also blocking ICa,L with the LTCC blocker verapamil prevented ventricular arrhythmias.279 Overall, it is thought that reduced ICa,L results in less Ca2+ overload of the myocyte, reducing predisposition to ectopy that can trigger arrhythmias.
During the past 15 years or so, several groups including our own have tried to develop pharmaceutical agents that target the intracellular Ca2+ release channel. To our knowledge, the first example of an experimental small molecule is K201 (also referred to as JTV519), a 1,4-benzothiazepine shown to normalize RyR2 gating in a canine model with tachycardia-induced HF.280 Subsequently, K201 was shown to prevent lethal ventricular tachyarrhythmias in a mouse model of CPVT by stabilizing RyR2 channels.281 Studies using recombinantly expressed RyR2 channels with CPVT-linked missense mutations showed that K201 can normalize mutant channel activity.282 In addition, K201 was shown to exert antiarrhythmic effects against AF in an experimental guinea pig model.283 Although K201 normalizes defective RyR2 channels, this compound also inhibits various other targets including annexin V and K+ channels, raising concerns about potential off-target and proarrhythmic side-effects.284,285 The proposed mechanism of RyR2 stabilization, through normalization of the binding stoichiometry of RyR2 and FKBP12.6, remains controversial. For example, the role of FKBP12.6 in reducing RyR2-mediated Ca2+ leak has been debated and this topic has been robustly reviewed.77,286 Furthermore, dissociating FKBP12.6 from RyR2 by FK506 did not affect suppression of spontaneous Ca2+ release events in rat ventricular myocytes questioning the role of FKBP12.6 binding in the mechanism of FK506.287 Although debate exists in the field, there is a preponderance of datam, which suggests that RyR2 stabilization can be achieved by small molecules. Since discovery of this first molecule, newer generations of RyR2 stabilizing molecules have been developed. For example, a 1,4-benzothiazepine named S107—a more specific RyR2-blocker—was shown to prevent ventricular arrhythmias in a CPVT mouse model heterozygous for mutation R2474S.80 Moreover, S107 has been shown to inhibit the RyR2-mediated diastolic SR Ca2+ leak in atrial myocytes in many RYR2 mutation knockin models and decreased the incidence of burst pacing-induced AF.250 Although thought to have less off-target effects on a host of other receptors than K201, there have yet to be comprehensive studies on the major ion channels responsible for EC-coupling and Ca2+ homeostasis.80
Although flecainide is a class IC antiarrhythmic drug with Na+ channel–blocking properties, this drug has also been shown to inhibit RyR2 and exert therapeutic effects in mouse models of, and patients with, CPVT.288 This is most salient in patients for whom β-blockade is less effective. For example, flecainide has been shown to inhibit aberrant RyR2 activity and reduce spontaneous Ca2+ waves in both patients with CPVT refractory to β-blocker therapy and in Casq2-/- mouse models of CPVT in numerous independent studies.289–291 Although the suppression of aberrant SR Ca2+ release seems a consistent effect of flecainide, other investigators have questioned whether RyR2 is the primary molecular target. For example, increasing the threshold for triggered activity by action on the cardiac Na+ channels with minimal effect on intracellular Ca2+ flux has been proposed.291 In addition, reducing elevated intracellular Ca2+ levels through reduction of INa leading to increased net Ca2+ influx via NCX has also been proposed.292 In an attempt to reconcile these various mechanisms, a so-called triple mode of action of flecainide has been proposed whereby all these various mechanisms are incorporated with the predominant effect being reduction of spontaneous Ca2+ release from RyR2.293,294
In addition to these molecules, other classes of RyR2 inhibitors with antiarrhythmic effects have been described, including dantrolene,295 carvedilol analogues,296 and tetracaine derivatives.297 In addition to LTCC and RyR2, other Ca2+ channels, Ca2+ transporters, and Ca2+-dependent signaling molecules (such as CaM, CaMKII) are potential therapeutic targets.
Concluding Remarks
The past 3 decades have seen a remarkable expansion in identifying the genetic and molecular causes of both congenital and acquired cardiac arrhythmias. Although the specific molecular mechanisms of arrhythmic remodeling of the heart are as diverse as the many ways in which arrhythmia can present, Ca2+ is a critical and central player in many. Progress into identifying the role of Ca2+ in arrhythmias has led to novel understanding of the physiological and pathological regulation of the cardiomyocyte. When coupled to rapid advancement in genetic sequencing platforms, and recent breakthroughs in the development of both in vitro and in vivo models of disease, these advances offer the possibility of revolutionizing the diagnosis and treatment of these common and potentially life-threatening conditions.
Calcium Signaling Series
Donald M. Bers, Guest Editor
Nonstandard Abbreviations and Acronyms
| AF | atrial fibrillation |
| AP | action potential |
| ARVC | arrhythmogenic right ventricular cardiomyopathy |
| CaM | calmodulin |
| CASQ2 | calsequestrin-2 |
| CaMKII | Ca2+/calmodulin-dependent protein kinase II |
| CICR | Ca2+-induced Ca2+-release |
| DCM | dilated cardiomyopathy |
| EC | excitation–contraction |
| FKBP12.6 | FK506-binding protein-12.6 |
| HRC | histidine-rich Ca2+-binding protein |
| iPSC | induced pluripotent stem cells |
| iPSC-CM | iPSC-derived cardiomyocytes |
| JCTN | junctin |
| JMCs | junctional membrane complexes |
| JPH2 | junctophilin-2 |
| LQTS | long QT syndrome |
| LTCCs | L-type Ca2+ channels |
| NCX | sodium-calcium exchanger type 1 |
| PKA | protein kinase A |
| SERCA2a | SR Ca2+-ATPase type-2a |
| SR | sarcoplasmic reticulum |
| TnC | troponin C |
| TnI | troponin I |
| TnT | troponin T |
| TRDN | triadin |
| RyR2 | ryanodine receptor type-2 |
| WES | whole-exome sequencing |
Sources of Funding
Dr Landstrom is supported by the National Institutes of Health (NIH) L40-HL129273 and K08-HL136839, Baylor College of Medicine Department of Pediatrics Pilot Grant Award, and the Pediatric and Congenital Electrophysiology Society Paul C. Gillette Award. Dr Dobrev is supported by DZHK (German Center for Cardiovascular Research), the German Research Foundation DFG (Do 769/4-1), and a NIH grant (R01-HL131517). Dr Wehrens is supported by NIH grants R01-HL089598, R01-HL091947, R01-HL117641, and R41-HL129570, and American Heart Association grant 13EIA14560061.
Disclosures
Dr Wehrens is a founding partner of Elex Biotech, a start-up company that developed drug molecules that target ryanodine receptors for the treatment of cardiac arrhythmia disorders. The other authors report no conflicts.
Footnotes
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