The Pathophysiological Implications of TRP Channels in Cardiac Arrhythmia (The Cardiac Ion Channels) Part 1


The cardiac arrhythmia is a common cause of morbidity and mortality in the present world, especially in developed countries. The etiology of cardiac arrhythmia is quite broad involving both hereditary and secondary backgrounds. An increasing number of rare but lethal arrhythmogenic mutations have been identified by genome-wide association assays in genes associated with cardiac excitation, conduction and morphogenesis. Such well-characterized examples include causative mutations in voltage-dependent Na+, Ca2+ or K+ channel (Nav, Cav, Kv) genes for the prolongation of QT interval which sometimes result in premature sudden death and may act as predisposing factors to drug-induced arrhythmia (Chen et al., 1998; Roden, 2004; Saenen & Vrints, 2008; Towbin & Vatta, 2001; Zareba et al., 2004). Furthermore, some of heart malformations (e.g. atrial septal defect) and idiopathic cardiomyopathy (e.g. dilated cardiomyopathy) with symptoms of arrhythmias have also proved to have some genetic linkage to impaired impulse conduction (Benson et al., 1999; Bonne, et al.,2001; Schott et al., 1998). However, much more prevalent are rhythm disturbances and conduction failures occurring in ‘remodeling’ hearts which progressively undergo structural and electrical changes in prolonged metabolically and mechanically stressed states, e.g. chronic heart failure and myocardial infarction (Nattel, 2007; Olson, 2005). The well-known consequences of cardiac remodeling are; altered expression and gating properties of ion channels shaping the action potential and generating pace-making activities; reduced electrical coupling which leads to aberrant conduction of excitation. These changes are thought to work as the ‘substrates’ increasing the risk of lethal cardiac arrhythmia (Janse, 2004; Nattel, 2007). It has also been known that abnormal handling of intracellular Ca2+ occurring in the remodeled heart may cause spontaneous membrane depolarizations triggering ectopic excitations (Dobrev, 2010; Janse, 2004; Nattel, 2007). However, the available knowledge is still limited largely to ion channels/transporters/pumps whose roles in the cardiac excitation-contraction cycle have relatively been well established.

The transient receptor potential (TRP) channels constitute a newly-emerging non-selective cation channel (NSCC) superfamily activated by a plethora of physico-chemical stimuli other than voltage change. Because of this unique activation profile as well as the ability to permeate Ca2+ (except for TRPM4/TRPM5), TRP channels have attracted great attention as promising candidate molecules elucidating a variety of biological functions and disorders associated with slow sustained Ca2+ influx initiated by neurohormonal factors, pheromones, mechanical (membrane stretch/bending, osmotic change, shear force etc.) and thermal (from cold through cool and warm to heat) stresses, noxious stimuli (acid, respiratory irritants and toxicants) and many gustatory and pungent/cooling agents (camphor, citral, capsaicin, eucalyptol, icilin, menthol, allicin, mustard oil, sweet, umami and bitter tastants etc.) (Holzer, 2011; Vay et al., 2011; Wu et al., 2010). In the cardiovascular system, recent investigations have revealed pathophysiological implications of TRP channels in vasospasm, hypertension, occlusive vascular diseases, cardiac hypertrophy, cardiomyopathy and cardiac arrhythmia (Dietrich et al., 2010; Inoue et al, 2009b; Watanabe et al., 2008). Especially, as will be described below, involvement of some TRP channels in abnormal intracellular Ca2+ handling and increased responses to mechanical and noxious stresses may make them particularly relevant to the pathogenesis of acquired cardiac arrhythmias tightly associated with cardiac hypertrophy and failure, myocardial infarction and atrial fibrillation (Nattel, 2007; Ter Keurs & Boyden, 2007).

This topic will deal with the arrhythmogenic potential of several TRP isoforms identified in the cardiovascular system, with brief introduction to the general concepts of cardiac arrhythmia and its connection to cardiac diseases and with several examples in which the roles of TRP channels have been established or suggested.

Factors contributing to cardiac arrhythmia

Cardiac arrhythmia is the abnormality of cardiac rhythm, the highly coordinated and integrated electrophysiological behavior of multiple ion channels/transporters/exchangers residing in tens of billions of myocytes and non-myoctes consisting of the heart. Clinically, cardiac arrhythmia can be defined as any anomalous excitations out of normal sinus control, and is conventionally classified into bradyarrhythmia (<50 beats per minute) and tachyarrhythmia (>100). Faulty or abnormal excitation of sinus node and various extents of conduction blocks mainly explain the former. In contrast, ectopic excitations occurring outside the sinus node (triggered activity, ectopic automaticity) and perpetuation of spiral/scroll waves rotating around a central core/filament (reentry) are thought to contribute to the latter. Although the mechanism remains still incompletely understood, shortened refractoriness, slowed and anisotropic conduction facilitate the occurrence of reentry (Jalife, 2000). Thus, altered expression or activities of ion channels contributing to the upstroke (Nav) and repolarization of action potential (Kv) as well as those determining the conduction velocity and cell-to-cell coupling [Nav and connexins (Cx), respectively] are involved in the reentrant mechanism.

Ectopic excitations result from premature depolarizations before the next normal excitation arrives. Early afterdepolarization (EAD) occurs before the repolarization of action potential completely terminates, thereby prolonging it and evoking premature action potentials due to re-opening of Nav and/or Cav channels. This is a mechanistic background for the initiation of a specific form of polymorphic ventricular arrhythmias (Torsades de pointes) observed in both congenital and drug-induced Long QT syndromes; the function of ‘repolarization reserve’, i.e. Kv channels, is compromised, or residual activity of Nav channel sustains because of its incomplete inactivation (Roberts & Gollob, 2010).

Delayed afterdepolarization (DAD) is thought to reflect the generation of transient inward currents (Iti) activated by diastolic Ca2+ release from the sarcoplasmic reticulum (SR) of myocytes (Venetucci et al., 2008). If the magnitude of DAD exceeds the threshold of Nav channel activation, an extrasystolic discharge of action potentials occurs. Sustained discharges from one or more foci may propagate around to cause tachyarrhythmias (focal excitation). In ventricular myocytes from rabbit failing heart which shows spontaneous ventricular tachyarrhythima, Iti has been ascribed exclusively to enhanced forward-mode Na+/Ca2+ exchanger type 1 (NCX1) current (Pogwizd et al., 2001; Pogwizd & Bers, 2004). However, there is evidence that implicates Ca2+-dependent Cl- and nonselective cationic conductances in the genesis of DAD (Han & Ferrier, 1992; Hill et al., 1988; Kass et a., 1978; Laflamme & Becker, 1996; Wu & Anderson, 2000). The mechanism underlying the diastolic Ca2+ release is likely to reflect Ca2+ overload into the sarcoplasmic reticulum (SR) caused by a net increase in Ca2+ uptake into the SR (increased Ca2+ influx and SRECA2a Ca2+-ATPase activity), or the dysfunction of ryanodine type 2 receptor (RyR2) which may, especially when intensively phosphorylated by protein kinase A (Wehrens et al., 2003) or Ca2+/calmodulin-dependent kinase II (Ai et al, 2005), causes a diastolic Ca2+ leak from the SR (Bers, 2006). Thus, under excessive sympathetic activities (hard exercise, mental stress, chronic heart diseases) or upon the application of drugs increasing the cAMP level (caffeine, catecholamines, phosphodiesterase inhibitors) or [Na+]i (digitalis) in cardiomyocytes which increase Ca2+ loading into the SR, the occurrence of DAD and resultant tachyarrhythmias may be greatly enhanced (Pogwizd, 2003; Sipido, 2007; Venetucci, 2008). In addition, in some pathological settings such as unphysiologically decreased extracellular K+ level and excessive sympathetic activity, ectopic automaticity, particularly in the Purkinje fiber, can also be abnormally increased to cause tachyarrhythmias (Osadchii, 2010).

Clinical significance of mechanical loading in inducing arrhythmia has been well recognized (Dean & Lab, 1989). It is widely accepted that both acute and chronic stretch of myocardial tissue significantly affects its electrophysiological properties to increase the propensity for arrhythmia (Janse, 2003; Ravens, 2003). Experimentally, a transient diastolic stretch of isolated left ventricle was shown to induce ventricular arrhythmia which was inhibited by micromolar Gd3+ (Hansen et al. 1991; Stancy et al, 1992). Atrial fibrillation elicited by an acute increase in intra-atrial pressure in isolated rabbit hearts was also found effectively blocked by MSCC blockers, Gd3+ and a Tarantula toxin GsMTx-4 (Franz and Bode, 2003; Suchyna, 2000). At the single cell level, Kamkin et al. (2000a) demonstrated that direct stretch of a ventricular myocyte could cause membrane depolarization and prolongation of action potential resembling EAD, which, at extensive stretch, led to an extrasystolic depolarization. This stretch-induced depolarization was attributed to the activation of Gd3+-sensitive mechanosensitive NSCCs (MSCCs) (Hamill & Martinac, 2001; Inoue et al., 2009b). The stretch sensitivity of MSCCs was significantly enhanced in hypertrophied cardiomyocytes with increased susceptibility to stretch-induced arrhythmia (Kamkin et al., 2000a). Considering that the heart is continuously subjected to hemodynamic stresses and deformation due to contraction, mechanical stresses may play a significant role in the causality and severity of arrhythmia, particularly under pressure- and volume-overloaded conditions.

Connection of cardiac diseases to cardiac remodeling and arrhythmia

The cardiac remodeling can be defined as the restructuring and reactivation of differentiated cardiac tissues comprised of myocytic and non-myocytic populations, and is initiated and progressed by a complex interplay of genetic, environmental and aging factors (Cohn, et al., 2000; Fedak, et al., 2005; Swynghedauw, 1999). Chronic heart failure, myocardial infarction and atrial fibrillation (AF) are three common pathological states accompanying the remodeling process with arrhythmic changes; in which excessively activated sympathetic nervous and renin-angiotensin-aldosterone systems, increased generation of inflammatory cytokines and reactive oxygen/nitrogen species, and sustained mechanical stresses likely play active roles. The remodeling process is initially ‘adaptive’ to compensate the impaired pumping function, but gradually becomes ‘maladaptive’ with disturbances in rhythm formation and conduction as common clinical complications.

The key consequences of cardiac remodeling associated with the appearance of arrhythmia include both structural and electrical alterations. Enhanced collagen synthesis promotes the fibrotic replacement of damaged myocardial tissues thereby increasing the electrical heterogeneity. Altered expression and activities of ion channels, transporters and exchangers also bring about significant changes in the shape of action potential and its conduction properties as well as induce the susceptibility to premature excitations (Nattel, et al., 2007; Janse, 2004).

In chronic heart failure, the major electrophysiological changes are pronounced prolongation of action potential which often accompanies EAD-like membrane oscillations. These changes likely occur through decreased expression or activity of transient outward current (Ito; Kv4,3) and voltage-dependent K+ channels forming the repolarization phase of action potential (Ik, Iks) (Bers, 2006; Janse, 2004; Nattel, et al.,2007; Ravens, 2010). The reduced inward rectifying K+ current (IK1) may also destabilize the membrane (i.e. increases the diastolic membrane resistance) and thereby enhance extrasystolic depolarizing responses (DAD) (Nattel, et al., 2007; Pogwitz et al, 2001). Furthermore, upregulation of hyperpolarization-activated current (If) and its mRNA (HCN2/4) (Cerbai, 1994; Fernandez-Velasco et al., 2003) and reduced expression of gap junction channel (Cx43; Dupont et al, 2001) have been reported to contribute to abnormally enhanced automaticity and impaired conduction, respectively. However, more notable changes observed in failing heart are abnormalities in intracellular Ca2+ handling (Bers, 2006; Janse, 2004). Despite a reduction in the SR Ca2+ content due to decreased expression of SERCA2a, the propensity for triggered activity based on DAD is enhanced. This likely reflects the other two major changes in Ca2+ handling, i.e. (1) the increased Ca2+ sensitivity of RyR2 under intensive phosphorylation by protein kinase A (however controversial now; Wehrens et al, 2003) or Ca2+/calmodulin kinase II (Ai et al, 2005) which causes diastolic Ca2+ leak from the SR, and (2) upregulation of Na+/Ca2+ exchanger (NCX1) protein which can carry depolarizing inward currents in the diastole. It has been suggested that increased P-adrenergic drive, which is prominent in chronic heart failure, may greatly facilitate the occurrence of DAD by increasing the Ca2+ content in the SR above the threshold of spontaneous Ca2+ release (Bers, 2006; Pogwizd, 2003).

Myocardial infarction is initiated by a sudden cessation of blood supply to heart tissues (i.e. myocardial ischemia), most frequently by thrombotic obstruction of coronary arteries. The time course of ischemic changes in the heart is variable and complex, and can mechanistically be distinguished between early and late acute phases, and subsequent postinfarction period vulnerable to structural and electrical remodeling (Clements-Jewery et al., 2005; Janse & Wit, 1989; Nattel et al., 2007). In acute phases, rapid depletion of intracellular ATP and accumulation of intracellular ADP, extracellular K+ and lactate occur because of anaerobic glycolysis, and loss of intracellular K+ and intracellular acidosis follows. The extracellular accumulation of K+ leads to the depolarization of myocyte membrane that attenuates the amplitude and upstroke velocity of action potential (facilitated Nav inactivation) and the shortening of action potential duration (due to enhanced Kv activities) or refractoriness. Simultaneously, intercellular accumulation and release of many biochemical substances occurs including catecholamines, ATP, lysophosphatidylcholine, cytokines (e.g., TNFa), reactive oxygen species (ROS), and platelet-activating factors (Clements-Jewery et al., 2005; de Jong & Dekker, 2010). All these possess arrhythmogenic potential to induce ventricular premature excitations (DAD, EAD) and reentry. In postinfarction period, down-regulation of K+ channels (Ito, IKs, IKr, IK1) occurs in border-zones adjacent to infarct areas which impairs the repolarization of action potential leading to EAD, and altered intracellular Ca2+ handling facilitates spontaneous subcellular Ca2+ release events that can trigger arrhythmic episodes (Nattel, et al., 2007).

Atrial fibrillation (AF) is a common supraventicular tachyarrhythmia with rapid and highly irregular firing, being closely associated with aging and cardiovascular diseases such as heart failure, myocardial infarction, valvular diseases and hypertension (Nattel et al, 2007; Ravens, 2010). AF per se is thought to serve as an arrhythmogenic remodeling process, because the occurrence of AF itself progressively aggravates electrophysiological features and facilitates fibrotic changes of atrial tissues in favor of more frequent and sustained occurrences. This clinical feature is described "AF begets AF" and experimentally confirmed by the finding that rapid atrial pacing causes significant shortening of atrial refractoriness and persistent AF (Wijffels, et al. 1995). The major arrhythmogenic changes found for AF are marked shortening of action potential duration which reduces the refractoriness and increases the susceptibility to reentry (Nattel et al, 2007; Ravens, 2010). In AF, this change is combined with abnormal Ca2+ handling with increased Ca2+ release from the SR and augmented NCX1 expression which facilitates ectopic premature depolarizations (i.e. DAD) that serve as a trigger to initiate the reentry (Dobrev, 2010). Both reduced/increased or unchanged expression of gap-junction channels have been reported, but their increased regional heterogeneity may contribute to various extents of conduction failure and reentry (Nattel, et al., 2007).

TRP channels and cardiac arrhythmia

The above considerations strongly suggest that, although alterations in the genesis and conduction properties of action potential are undoubtedly of central importance, other factors, e.g. Ca2+ overload, increased stretch sensitivity and noxious stimuli generated in ischemia/reperfusion, may also play a vital role in arrhythmogenicity. It is also possible that structural remodeling (necrotic/ apoptotic and fibrotic changes) may contribute to the electrical heterogeneity of the myocardium which may act as the pro-arrhythmic substrates for altered conduction and reentry. As described above, Ca2+- and stretch-sensitivities, nociception as well as association to remodeling are the hallmark features of TRP channel members (Inoue et al., 2009b; Nishida & Kurose, 2008; Watanabe et al., 2008; Wu et al, 2010; Vay et al., 2011). Therefore, in the following, we would like to discuss about the pathophysiological relevance of several TRP isoforms particularly in these aspects of acquired arrhythmogenicity (see Table 1).

Intrinsic activator/modulator

possible arrhythmogenic mechanisms

chemical agonists



store depletion, stretch?, GPCR stimulation (TRPC1/TRPC4 or C5), Ca2+/CaM

Cardiomyo cyte

strecth-induced EAD/DAD in hypertrophy?

Gd3+, SKF, GsMTX-4?


const-act., store depletion, GPCR stimulation, BDNF, DAG, oxidative stress (TRPC3/C4), Ca2+/CaM, PKC, PKG, Src

oxidative stress? and other mediators (ATP, UTP) during


Gd3+, La3+, SKF, 2-APB, flufenamate, Pyr-3


const-act, store depletion, GPCR stimulation, LPC – S1P – EGF, neurosteroids, oxdized phospholipids, Ca2+/CaM, PGE2 • S-nitrosylation, thioredoxin, oxidative stress (H2O2)

possible relation to ischemia/oxidative stress in failing heart

Gd3+, SKF, GsMTX-4?

Gd3+, La3+ (high), SKF, 2-APB, BTP-2, ML-7, ML-9, propfol, halothane, chloroform


store depletion, stretch?, GPCR stimulation, GF, DAG, 20-HETE, PIP3/PIP2, Ca2+/CaM, CaMKII, PKC, PKG – Fyn

stretch-inudced EAD/DAD in hypertrophy?


Gd3+, La3+, SKF, 2-APB, ML-9, ML-7, GsMTX-4?


oxidative stress (e.g. H2O2), ADPR, cADPR, NAADP, AMP, [Ca2+]i, pH

oxidative stress in ischemia/reperfusion?

flufenamate, ACA, 2-APB


[Ca2+]i, GPCR stimulation, PIP2, MgATP, ATP, ADP, AMP, voltage, PKC • CaM, spermine,

familial conduction block (PFHBI, ICCD), stretch-inudced EAD/DAD?, QT-elongation in hypertrophy, DAD in AF?

decavanadate, BTP-2

Gd3+, flufenamate, clotrimazol, 9-PA


see above

cardiac fibroblast


see above

see above


const-act, GPCR stimulation, [Mg2+]i, MgATP, ATP, CTP, GTP, UTP, pH, PIP2, cAMP, PKA, spermine,

fibrogenesis in AF

2-APB (high)

Gd3+, SKF, 2-APB (low), L0E908,


cold (<17°C), [Ca2+]i, alkalosis, stretch, GPCR, PIP2, PKA.

respiratory sensory neuron

autonomic imbalance




allicin, allyl


citral, NSAIDs,







heat (>43°C) – acidity (pH<5.9) – 12-HETE, 12-LOX metabolites, anandamide, chemokines • GPCR (e.g. bradykinin, ATP, PAR2) – NGF, GDNF, PKA, PKC, PI3K, Ca2+/CaM, CaMK II, src, calcineurin, Ras/MAPK, SCF

autonomic imbalance

enviromental irritants,

capsaicin, 2-APB • camphor, allicin, citral, resiniferatoxin, gingerol, eugenol, EtOH

capasazeine, ABT-102, AMG-517, GRC-6211, MK-2295, SB-366791, SB-705498,

Table 1. Arrhythmogenic TRP channels

Abbreviations; CaM, calmodulin: GPCR, G-protein-coupled receptor (Gq-coupled): const-act, constitutively active: BDNF, brain-derived neurotrophic factor: DAG, diacylglycerol: PKC, protein kinase C: PKG, protein kinase G: LPC, lysophosphatidylcholine: S1P, sphingosin 1-phosphate: EGF, epidermal growth factor: PGE2, prostaglandin E2: 20-HETE, 20-hydroxytetraenoic acid: PIP3, phosphatidylinositol 3,4,5-trisphospate: PIP2, phosphatidylinositol 4,5-trisphospate: CaMKII, calmodulin-dependent kinase II: ADPR, ADP ribose: cADPR, cyclic ADP ribose: NAADP, nicotinic acid adenine dinucleotide phosphate: PKA, protein kinase A: 12-HETE, 12-hydroxy-5,8,10,14-eicosatetraenoic acid: LOX, lipooxygenase: PAR2, Proteinase-activated receptor 2: NGF, nerve growth factor: GDNF, glial cell-line derived neurotrophic factor: MAPK, mitogen-activated protein kinase: SCF, stem cell factor: SKF, SK&F96365: BTP-2, 4-methyl-4 -[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1,2,3-thiadiazole-5-carboxanilide: Pyr-2, Ethyl-1-(4-(2,3,3-trichloroacrylamide)phenyl)-5-(trifluoroluoromethyl)-1H-pyrazole-4-carboxylate: 2-APB, 2-aminoethoxydiphenyly boroate, 9-PA, 9-phenanthrol.

Stretch-induced arrhythmia in pathological settings

As described above, acute stretch of cardiac muscle can induce arrhythmic responses in both atrium and ventricle, which are inhibited by widely used MSCC blockers Gd3+ and GsMTx-4. This has led to the speculation that activation of nonselective cationic MSCCs causes premature depolarizations. There are at least three candidates for these MSCCs in TRPs expressed in the heart, i.e. TRPC1, TRPC6 and TRPM4.

In both heterologous and native overexpression systems, TRPC1 and TRPC6 have been found to activate in response to mechanical stimuli (Maroto et al.,2005; Spassova et al., 2006). Albeit controversial (e.g. Inoue et al., 2009a), the so-called MSCC-selective peptide blocker GsMTx-4 has been found to inhibit the mechanical activation of both TRPC1- and TRPC6-mediated MSCC activities (Maroto et al.,2005; Spassova et al., 2006). TRPC1 and TRPC6 are ubiquitously expressed in whole myocardial tissues (Huang et al, 2009; Ward et al., 2008), and GsMTx-4 suppresses stretch-induced force development and concomitant [Ca2+]i increase in mouse left ventricular trabecular muscle (Ward et al., 2008) and pressure-induced atrial fibrillation (Franz and Bode, 2003). Moreover, the expression of TRPC1 and TRPC6 is greatly increased in hypertrophied heart under prolonged pressure overload (Kuwahara, et al; 2006; Ohba, et al., 2007), where the susceptibility to mechanically-induced arrhythmia is also enhanced (Kamkin et al., 2000a). All these observations favor the view that TRPC1 and TRPC6 contribute to stretch-induced arrhythmias as MSCCs in some pathological settings. However, there is controversy over the mechanosensitivity of these two TRPC channels. In knock-out mice deficient in TRPC1 or TRPC6 expression, pressure-induced vasoconstriction (myogenic response), which is believed to reflect the depolarizing effects of MSCC activation, was found intact (Dietrich et al., 2005; Gottlieb et al., 2007). Although this fact could not totally negate the roles of these TRP channels in the heart, it is essential to test whether mechanical activation of myocardial MSCCs and mechanical arrhythmogenicity are indeed impaired in these knock-out mice or vice versa in TRPC1- or TRPC6-overexpressing mice. Alternatively, it may also deserve to test the possible involvement of a recently identified GsMTx-4-sensitive MSCC, Piezo1/Piezo2, in stretch-induced arrhythmia in the heart (Bae et al., 2011).

In cerebral arterial myocytes, TRPM4 has been proposed as a MSCC responsible for myogenic response (Earley et al., 2004). However, again, the results from TRPM4-deficient mice do not support this role (for more detail, see below) (Mathar et al., 2010). Nevertheless, it is noteworthy that TRPM4 can be secondarily activated by mechanical stretch through stretch-induced Ca2+ release from ryanodine-sensitive stores in arterial myocytes (Morita et al., 2007), since similar axial stretch-induced Ca2+ release from the SR has been demonstrated in cardiomyocytes (Iribe, et al., 2009). Considering that heart wall is periodically distended by diastolic filling pressure, this mechanosensitive mechanism may have considerable pathophysiological significance for the genesis of DAD in remodeled heart in which the expression of TRPM4 and Ca2+ loading into SR are prominently enhanced (see below). It has been shown that repeated cyclic stretch induces hypertrophic responses of cardiac myocytes, which are significantly attenuated by antagonists for a PLC-linked G-protein coupled receptor (GPCR), angiotensin type 1 (AT1) receptor (Komuro and Yazaki, 1993). This is explained by direct mechanical activation of unoccupied AT1 receptor as demonstrated by the substituted cysteine accessibility mapping technique (Yasuda et al., 2008). Similar mechanical activation also appears to occur for many other PLC-linked GPCRs including endothelin ETA, vasopressin V1A and muscarinic M5 receptors (Mederos y Schnitzler et al., 2008). TRPC6 and its homologue TRPC3 are activated by stimulation of PLC-coupled GPCRs via generation of diacylglycerol (DAG) (Hofmann, et al., 1999) and Ca2+ influx through activated TRPC3 and TRPC6 channels has been shown to be essential for hypertrophic responses of caridomyocyte via calcineurin/NFAT pathway (Kuwahra et al., 2006; Bush et al., 2006; Onohara et al., 2006). In failing hearts where pressure overload is sustained, the release of catecholamines from sympathetic nerves and adrenal gland is increased (see above), and the production of angiotensin II (AngII) and expression of AT1 receptor and angiotensin converting enzyme are greatly enhanced (Goette, A et al., 2000; Ihara M et al, 2000; Kaprielian RR et al., 1997). Moreover, the mechanosensitivity of TRPC6 channel is remarkably enhanced by the simultaneous stimulation of PLC-linked GPCRs via concerted actions of two lipid messengers DAG and 20-HETE (Inoue et al., 2009a). Thus, taken together, it is highly conceivable that sustained mechanical loads promote the hypertrophic remodeling of cardiomyocytes through synergistic interplay between excessive activation of GPCR-PLC pathways and enhanced receptor/mechanical activation of TRPC6 (and TRPC3) channels. This would in turn exacerbate Ca2+ overload into the myocyte SR to increase the propensity for pro-arrhythmic depolarizations. Consistent with this scenario, cardiac-specific TRPC6 transgenic mice have been found to exhibit much increased susceptibility to mechanical stress with increased incidence of sudden death accompanied by severe macroscopic and histological signs of cardiomyopathy (Kuwahara et al., 2006). The same study also found that expression of TRPC6 was several-fold upregulated in human failing heart. Obviously, detailed electrophysiological analyses are required to corroborate whether the above changes could indeed induce the arrhythmogenicity.

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