Electrical and Structural Insights into Right Ventricular Outflow Tract Arrhythmogenesis

Abstract

The right ventricular outflow tract (RVOT) is the major origin of ventricular arrhythmias, including premature ventricular contractions, idiopathic ventricular arrhythmias, Brugada syndrome, torsade de pointes, long QT syndrome, and arrhythmogenic right ventricular cardiomyopathy. The RVOT has distinct developmental origins and cellular characteristics and a complex myocardial architecture with high shear wall stress, which may lead to its high vulnerability to arrhythmogenesis. RVOT myocytes are vulnerable to intracellular sodium and calcium overload due to calcium handling protein modulation, enhanced CaMKII activity, ryanodine receptor phosphorylation, and a higher cAMP level activated by predisposing factors or pathological conditions. A reduction in Cx43 and Scn5a expression may lead to electrical uncoupling in RVOT. The purpose of this review is to update the current understanding of the cellular and molecular mechanisms of RVOT arrhythmogenesis.

1. Introduction

The right ventricular outflow tract (RVOT) tachycardia is a form of monomorphic or polymorphic ventricular tachycardia originating from the RVOT and accounts for the majority (80%) of outflow tract ventricular arrhythmias. The RVOT is a dominant site of origin of premature ventricular contractions and ventricular tachyarrhythmias that are often observed in patients without structural heart diseases, including idiopathic ventricular arrhythmias, Brugada syndrome, torsade de pointes, and long QT syndrome. The RVOT is also one of the origins of malignant ventricular tachycardia caused by structural heart disease, such as arrhythmogenic RV cardiomyopathy (ARVC) [1,2,3,4]. It typically presents in young patients and its incidence is increasing notably [5]. The majority of patients of RVOT arrhythmias are initially diagnosed between the age of 30 and 50 years [6]. RVOT arrhythmias can originate from different sites of the RVOT, including the rightward (free wall), anterior, leftward and posterior (septal) parts, but carry common ECG characteristics. General features of ventricular tachycardia from RVOT are left bundle branch block morphology, an inferior axis, and an rS complex in V1 and R complex in V6. However, the intimate and complex anatomy of the outflow tract limits the predictive value of ECG criteria alone to distinguish RVOT tachycardia from supraventricular tachycardia with left bundle branch block or ventricular tachycardia originating from areas closed to the RVOT, such as the left ventricular outflow tract and the aortic sinus cusp, etc. For clinical purposes, ECG characteristics to differentiate these arrhythmias from RVOT tachycardia have been studied [7,8,9]. Except for ECG, late potentials on the SAECG were present in 78% of the patients with ARVC/D but were not present in any patient with RVOT tachycardia, and ventricular tachycardia in ARVC does not terminate with adenosine [10]. Buxton et al. published the first description of RVOT tachycardia in 1983, and a quarter of patients were asymptomatic [11]. RVOT arrhythmias are usually considered benign and may result in recurrent symptoms of palpitation and dizziness. A small subset of patients with RVOT arrhythmias have tachycardias that are extremely rapid or result in loss of consciousness, and very rarely, aborted sudden death [12]. Triggering beats from the RVOT have a crucial role in initiating ventricular fibrillation associated with Brugada syndrome, as confirmed by the elimination of triggers and malignant arrhythmias after ablation [13]. Emerging laboratory evidence has found that rabbit RVOT myocytes contain distinctive electrophysiological characteristics, which may lead to their high vulnerability to arrhythmogenesis [14]. Moreover, structural heart diseases, the dysfunction of autonomic nervous activity, and sex hormones have a great impact on RVOT arrhythmogenesis due to electrical and structural remodeling. In this review, we update the current understanding of the electrical and structural insights into RVOT arrhythmogenesis, and discuss the impact of predisposing factors and pathological conditions on RVOT arrhythmogenesis.

2. Predisposing Factors of RV Arrhythmogenesis

2.1. Anatomical and Dynamic Perceptions on RVOT Arrhythmogenesis

The RVOT refers to the region of the right ventricle (RV) between the supraventricular crest and the pulmonary valve and antero-cephalad to the left ventricle, resulting in a characteristic “crossover” relationship between the right and left ventricular outflows. The RVOT is a thin, smooth-walled, tubular structure, and comprises a complex three-dimensional network of myocardial fibers arranged circumferentially in the sub-epicardium and longitudinally in the sub-endocardium [15]. Muscular distribution of the RVOT is relatively thin in the free wall and immediate subpulmonary valve portions and thicker in the proximal posterior portion, where it is directly opposite the left ventricular outflow tract and the anterior interventricular septum. Patients with idiopathic RVOT tachycardia were found to have structural anomalies in magnetic resonance imaging, with the RV free wall being the most often aberrant origin [16]. The RVOT would seem more susceptible to dynamic muscular obstruction given the presence of a circumferential, muscular, contractile infundibulum in contrast to the partly fibrous, non-contractile left ventricular outflow tract. The presence of an RVOT gradient was more common in younger, male patients [17]. In a healthy athletic male heart, the RVOT is exposed to high shear stress, which is higher at the proximity of the RVOT free wall compared to the septal RVOT and other RV regions [18]. A relative increase in wall shear stresses in the RVOT, particularly in the RVOT free wall, may contribute to adverse remodeling, scar formation, and arrhythmia. At higher cardiac-output levels, the RVOT wall shear stress increases in a somewhat linear manner. The identified regions of elevated hemodynamic stress at resting and exercise conditions correlate with the common site of RVOT tachycardia in athletes and diseased regions in patients with ARVC [18].

2.2. Embryonic Development Relates to RVOT Arrhythmogenesis

The RVOT and left ventricular outflow tract have a common origin. The subpulmonary myocardium, which corresponds to the adult RVOT, is formed during the fetal period when a large inferior portion of the muscular embryonic outflow tract is incorporated into the RV free wall, and shows different gene expression from the superior part of the embryonic outflow tract [19]. The inferior part of the muscular embryonic outflow tract expresses Sema3C and the subpulmonary myocardium is specifically affected and possibly largely absent in Tbx1 mutant mice [19,20]. During development, Hey2 is expressed in the ventricular working myocardium in a transmural gradient and represses the expression of Scn5a and is absent from the outflow tract. Hey2 is expressed in the RVOT of adult mouse heart. The gene variants may influence the expression of HEY2, leading to reduced SCN5A expression and a reduced sodium (Na⁺) current, thereby mimicking a loss of function mutation in SCN5A as found in a minority of patients with Brugada syndrome [21]. Embryological studies have shown that the RVOT and RV myocytes have different origins, and the conducting phenotype of the RVOT differs from that of the RV free wall and of the left ventricle. In the developing embryonic heart, the myocardial outflow tract presents “transitional zones” with slow conducting properties. Working myocardial genes involved in fast conduction, for example, Cx43 and Scn5a, are less expressed in the adult mouse RVOT [22]. The slow conducting phenotype of the embryonic RVOT in hearts with the Brugada syndrome-linked Scn5a mutation is maintained in the adult heart, resulting in a lower conduction reserve in the RVOT [22]. Additionally, the hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) has been found to be expressed in the RVOT of the developing heart, and the re-expression of an embryonic phenotype or embryonic remnants of tissue may provide the arrhythmogenic potential of this area [23]. These findings may contribute to the increased propensity for arrhythmias to arise there.

2.3. Histopathological Perceptions on RVOT Arrhythmogenesis

The RVOT tissue structure is interspersed with the heterogeneous distribution of fibrous and fat tissue [24,25], and comprises a complex myocardial architecture [15]. The musculature sleeves of RVOT with fibrous and fatty connective tissue possess a unique arrhythmogenic substrate or triggered activity that results in ventricular arrhythmias [26]. Idiopathic RVOT tachycardia often arise from myocardial sleeves and are catecholamine-sensitive, suggesting that automaticity or triggered activity may contribute to RVOT arrhythmogenesis [27]. Myocardial fibrosis has been suggested by abnormal, low-voltage, fractionated electrograms localized to the RVOT at the epicardium [28]. Among patients with Brugada syndrome, interstitial fibrosis of the RVOT with conduction delay and the epicardial–endocardial gradient of collagen deposition has been reported [29,30]. Connexin 43 is poorly expressed in rabbit RVOT with electrical uncoupling, and may therefore be important in the pathogenesis of Brugada syndrome [31]. Intramural fibrosis is an exacerbating factor for the appearance of RVOT arrhythmias. A greater density of intramural clefts being associated with a reduced Na⁺ channel function was found in mouse RVOT myocytes, resulting in an increased vulnerability to conduction abnormalities [32]. Given the complex anatomic makeup and the presence of the endocardial Purkinje network [33], the RVOT could be predisposed to reentry [34]. Moreover, fat not only covers the RVOT epicardial surface but also infiltrates the underlying myocardium (i.e., fatty infiltration) and localizes around vessels and nerves or separate strands of myocardial fibers [25]. Intramyocardial fatty infiltration increased most extensively in the RVOT in human hearts with ARVC [35].

2.4. Cellular Electrophysiology Perceptions on RVOT Arrhythmogenesis

Triggered activity is considered to be the mechanism underlying adenosine-sensitive RVOT tachycardia due to catecholamine-induced delayed afterdepolarization (DAD). Catecholamine stimulation causes increases in intracellular cyclic adenosine monophosphate (cAMP), L-type calcium (Ca²⁺) current (I_Ca-L), and a spontaneous oscillatory release of Ca²⁺ from the sarcoplasmic reticulum that activates a transient inward current, giving rise to a DAD [36]. The functional dynamics of action potentials (APs) and repolarization heterogeneity in the RVOT are believed to be major contributors to Brugada-type electrocardiographic changes [37,38]. In patients with Brugada syndrome, there was a negative voltage gradient between the epicardium and endocardium of the RVOT, with significantly prolonged activation time in the endocardium and the activation-recovery interval in the epicardium, resulting in a larger area of ST-segment elevation >2 mV and T-wave inversions [39]. Compared to RV apex myocytes, RVOT myocytes had a wider range of AP duration (APD) in a rabbit model [40]. Longer APD in RVOT myocytes may contribute to ventricular arrhythmias arising mainly from RVOT in patients with long QT syndrome [41]. Spatial heterogeneity exists in repolarization and APD between epicardial and endocardial RVOT and the RV apical region under physiological conditions [34]. Arrhythmia in the RVOT is associated with positive spatiotemporal autocorrelation between the epicardial–endocardial arrhythmic wave fronts and reentrant rotors [34]. Moreover, regional and tissue transcript signatures of ion channel genes also play a role in RVOT arrhythmogenesis. Higher expression of the Na⁺ channel was found at the basal endocardium of RVOT in non-diseased human hearts [42]. As shown in Figure 1, our previous study identified, for the first time, distinctive electrophysiological characteristics in RVOT myocytes with a longer APD compared to that in the RV apex [14]. The late Na⁺ current (I_Na-Late) flows during the late-phase of AP to prolong APD and plays an important role in the genesis of cardiac arrhythmias as a result of enhanced triggered activity. A single Scn5a insertion mutation produces an early Na⁺ channel closure but augments the I_Na-Late, which may present in patients with features of both Brugada syndrome and long QT-3 syndrome [43]. As the transient outward potassium (K⁺) current (I_to) plays a pivotal role in the genesis of Brugada syndrome, the larger I_to in RVOT myocytes may mediate a more prominent phase 1 notch in AP morphology [14], resulting in a high arrhythmogenesis in those patients [37]. Liang S. et al. showed a wider range of APDs in rabbit RVOT myocytes than in rabbit RV myocytes. The I_Ca-L was obviously larger in the long-APD-RVOT myocytes, which is correlated with the occurrence of early afterdepolarization (EAD) [40]. In our previous study, rabbit RVOT myocytes had a reduced I_Ca-L that relates to Ca²⁺ overload_. Moreover, the smaller rapid component of the delayed rectifier K⁺ current (I_Kr) may produce a delay in phase 3 repolarization of the AP and the I_Na-Late flows during the late phase of the AP in RVOT myocytes, resulting in their longer APD. Both reduced I_Kr and increased I_Na-Late are known to cause long QT syndrome, a clinical condition associated with an increased risk for torsades de pointes-type of ventricular tachycardia.

2.5. Ca²⁺ Homeostasis Perceptions on RVOT Arrhythmogenesis

An imbalance in Ca²⁺ homeostasis in a cardiomyocyte can lead to electrical disturbance. Normally, depolarization opens voltage-gated Na⁺ channels that lead to large Ca²⁺ influxes after opening the L-type Ca²⁺ channels and some Ca²⁺ through the T-type Ca²⁺ channels and the reverse mode Na⁺-Ca²⁺ exchanger (NCX), leading to an increase in the intracellular Ca²⁺ concentration. The increased Ca²⁺ concentration triggers Ca²⁺ to release from the sarcoplasmic reticulum into the cytoplasm via the ryanodine receptor, a process known as Ca²⁺-induced Ca²⁺ release [44]. The increased cytosolic Ca²⁺ level then decreases through Ca²⁺ reuptake into the sarcoplasmic reticulum by the sarco/endoplasmic reticulum Ca²⁺-ATPase and Ca²⁺ extrusion by the sarcolemmal NCX and plasma membrane Ca²⁺-ATPase [45], given that the level of resting intracellular Ca²⁺ represents the balance between Ca influx and extrusion. In some pathological conditions, Ca²⁺ overload is found when intracellular Ca²⁺ removal becomes impaired with increased sarcoplasmic reticulum and intracellular Ca²⁺ concentrations, leading to the increased Ca²⁺ leak by ryanodine receptors [46]. DAD and EAD by spontaneous Ca²⁺ release from the sarcoplasmic reticulum are observed under the conditions of Ca²⁺ overload, induce triggered activity, resulting in ventricular tachycardia and ventricular fibrillation [47]. Late-phase 3 EAD combines the properties of both EAD and DAD and induces triggered activity in isolated canine Purkinje fibers [48]. Late-phase 3 EAD occurs under Ca²⁺ overload and the lengthening of the Ca²⁺ transient duration and is associated with a shortening in APDs [49,50]. Late-phase 3 EAD can occur immediately after the conversion to sinus rhythm from ventricular tachycardia or fibrillation [50]. A higher expression of Ca²⁺-handling genes was found at the basal epicardium of human RVOT [42]. Ca²⁺ overload is known to play a major role in RVOT arrhythmogenesis. The potential Ca²⁺ dysregulation in RVOT myocytes suggests that the RVOT may have a propensity for ventricular arrhythmias. RVOT myocytes had a faster decline in the intracellular Ca²⁺ transient, suggesting that sarcoplasmic reticulum Ca²⁺ uptake is faster in RVOT myocytes. A higher sarcoplasmic reticulum Ca²⁺ load may lead to a spontaneous Ca²⁺ wave and produce the triggered activity of DAD [51]. The NCX plays a major role in removing intracellular Ca²⁺ and decreasing sarcoplasmic reticulum Ca²⁺ content. The larger I_Na-Late in RVOT myocytes may alter the rate of Na⁺ extrusion/Ca²⁺ entry and lead to intracellular Ca²⁺ overload in different species [52], resulting in the genesis of EAD. Ouabain inhibits the Na⁺-K⁺ pump and increases I_Na-Late by Ca²⁺ calmodulin-dependent protein kinase II (CaMKII) that causes Ca²⁺ overload in ventricular myocytes [53,54]. Ouabain infusions have triggered DAD and induced sustained ventricular tachycardia during in vivo and in vitro studies [14,51]. Either the CaMKII inhibitor (KN-93) or an I_Na-Late inhibitor (ranolazine) can terminate ouabain-induced ventricular arrhythmias in rabbit RVOT but not in rabbit RV apex. Accordingly, CaMKII and I_Na-Late inhibition on RVOT tissues ameliorates ouabain-induced ventricular tachycardia with Na⁺ and Ca²⁺ overload (Figure 2) [14].

2.6. Excitation–Contraction Coupling on RVOT Arrhythmogenesis

Cardiac excitation–contraction coupling links cardiac mechanics and electrophysiology with the integration of APD and muscle contractility [55,56]. In the steady state without stimulation, the level of resting intracellular Ca²⁺ is controlled entirely by the surface membrane because there is no net Ca²⁺ flux across the membrane of the sarcoplasmic reticulum [57]. When heart beat is increasing, the amplitude of the systolic Ca²⁺ transient decreases and is accompanied by an increase in diastolic intracellular Ca²⁺ [58]. Rapid activation rates mean that the previous Ca²⁺ transient has insufficient time to decay and cause the increased intracellular Na⁺ activated reverse mode NCX to increase the intracellular Ca²⁺ load. Upon the return to a normal rate after rapid activation, augmented levels of sarcoplasmic reticulum Ca²⁺ loading and release stimulate the extrusion of Ca²⁺ through the forward mode NCX, resulting in a transient period of hypercontractility, APD prolongation and EAD development [52,55]. RVOT arrhythmogenesis resulting from the altered excitation–contraction coupling of RVOT tissue substrate has been reported in patients with Brugada syndrome [59]. Our previous studies demonstrated that a concurrent prolonged post-pacing phase 2 of APD and an enhanced contractility may trigger ventricular tachycardia, resulting from persistent inward Ca²⁺ currents in the short QT tissue model in rabbit RVOT [60]. In contrast, RVOT tachycardia is less likely to occur in those with post-pacing trivially enhanced contractility or APD prolongation. In the drug-induced long QT syndrome model, an increase in contractility, rather than an increase in APD, is critical for the genesis of ventricular tachyarrhythmias at the RVOT [61]. The occurrence of post-pacing-induced ventricular arrhythmias could be ameliorated by an NCX inhibitor, suggesting that NCX plays a role in disruption of the intracellular Ca²⁺ homeostasis in the cardiac excitation–contraction coupling as a crucial mechanism in triggering ventricular arrhythmias [62].

2.7. Role of Autonomic Nervous Activity in RVOT Arrhythmogenesis

Autonomic-nervous-system abnormality may provide a pathophysiological basis for inherited sudden cardiac arrest syndrome [63]. The autonomic dysfunction associated with sympathovagal imbalances has been suggested to play a critical role in the generation of RVOT arrhythmia [64]. Sympathetic fibers of the ventromedial cardiac nerve and branches of the ventrolateral cardiac nerve innervate the myocardium with the proximal pulmonary artery and the RVOT [65]. The sympathetic nerve innervations were found to increase in canine RVOT, especially at the site of arrhythmogenic origin [66]. Moreover, the reduced reuptake of norepinephrine into the nerve terminal or its increased release into the synaptic cleft leads to an increase in local norepinephrine concentrations in the synaptic cleft and the stimulation of postsynaptic beta-adrenoceptors, leading to increased cAMP concentrations. The increase in cAMP will produce Ca²⁺ overload and trigger RVOT tachycardia [67]. The induced sustained RVOT tachycardia is adenosine-sensitive and verapamil-sensitive and is caused by an automatic mechanism [4]. The response of the sustained RVOT tachycardia to catecholamine is usually attenuated by beta-blockers, Ca²⁺ channel blockers and adenosine [68], which provides indirect evidence of a sympathetic tone in the arrhythmogenesis of RVOT arrhythmia. Accordingly, sympathetic hyperactivity could influence the initiation and perpetuation of RVOT tachycardia in the tachypacing-induced ventricular arrhythmias. Recently, Aras et al. reported that ventricular cholinergic innervation crossed the human RVOT transmural wall, and cholinergic stimulation counteracted the sympathetic effects of adrenergic stimulation on the change in APD and the frequency of premature ventricular contractions [34].

2.8. Sex Hormones

Gender differences have been observed in the epidemiology, pathogenesis and clinical presentation of various types of idiopathic RVOT tachycardia [69,70]. Women have RVOT tachycardia initiation with recognized states of hormonal flux. Men more commonly have RVOT initiated by exercise or stress [70]. Idiopathic RVOT tachycardia, long QT syndrome and drug-related torsade de pointes are more common in women than in men, while Brugada syndrome is more common in men. Male patients with ARVC have a higher mortality rate and sudden death rate than in female patients with the same mutation [71]. Brugada syndrome is common in men than in women and a higher mortality rate has been documented in male patients with ARVC [69]. The shortening of the corrected QT interval during puberty in males implies that androgens (specifically testosterone) also contribute to gender differences in the corrected QT interval [72]. Androgen receptor ablation has been shown to regulate electrophysiology and enhance tachyarrhythmia [73]. Our previous study found that androgen-receptor knockout mice had lower levels of serum testosterone, and longer corrected QT interval, with a longer APD in RVOT myocytes [74]. RVOT tissues from androgen-receptor knockout mice had a higher incidence of EADs and faster burst firing. RVOT myocytes from androgen-receptor knockout mice have an increased CaMKII and ryanodine receptor phosphorylation, which increases spontaneous Ca²⁺ release and subsequent ventricular arrhythmias. Accordingly, sex hormones change RVOT electrophysiology and Ca²⁺ homeostasis, with increased ventricular arrhythmogenesis.

2.9. Mutations in Various Signaling Pathways Leading to RVOT Arrhythmogenesis

Genetic defects play an important role in the genesis of inherited RVOT arrhythmogenesis and have been widely reviewed [75,76]. Inherited genetic channelopathy is a significant cause of sudden death in children and adolescents, such as ARVC, and family history and genetic screening may help identify asymptomatic carriers and are essential for early diagnosis in RVOT tachycardia [77,78]. In addition to inherited genetic channelopathy, rare variants in gap junction and transcription factor genes have been associated with RVOT arrhythmogenesis (Table 1).

3. Pathological Conditions for RVOT Arrhythmogenesis

Pathological precipitating factors, resulting in acquired channelopathy, are vital to trigger the genesis of RVOT tachyarrhythmia due to electrical and structural remodeling (Figure 3).

3.1. Obesity/Epicardial Adipose Tissue (EAT) Accumulation in the RVOT

Overweight and obesity are important risk factors for a wide range of chronic diseases, including cardiovascular diseases, type 2 diabetes, and several types of cancer, as well as all-cause mortality [87]. Obesity has been documented to be an independent risk factor for sudden death and other cardiovascular mortality [88]. Obesity is associated with an increasing EAT amount or EAT phenotype modulation [89], and induces electrical and structural remodeling with increasing arrhythmogenic potential [90]. The prevalence of premature ventricular contractions is 30 times higher in obese patients with eccentric left ventricular hypertrophy compared with lean subjects [91]. EAT and the associated increased fibrosis could anatomically disrupt the cell-to-cell electrical conduction of cardiomyocytes, which might result in slow conduction, facilitating arrhythmogenesis. Obesity and overweight slightly increased the RVOT diameter [92]. RVOT, commonly covered with EAT, is vital for ventricular arrhythmia genesis [93]. The fat accumulation on the RVOT epicardial surface could be associated with a higher density and frequency and more fractionations of wave fronts in the epicardium compared with the endocardium [34]. Our previous study showed that EAT-connected rabbit RVOT myocytes had longer APD and an increased resting membrane potential (RMP), suggesting that EAT may change RVOT electrophysiological characteristics [94]. The decreased I_Ca-L might be responsible for the long APD in EAT-connected rabbit RVOT. The inward rectifier K⁺ current was more depressed in EAT-connected rabbit RVOT myocytes, which might lead to a less-negative RMP and make EAT-connected rabbit RVOT myocytes more excitable, leading to high arrhythmogenesis. These findings are in line with clinical observations in patients with Brugada syndrome [2]. Moreover, EAT-connected rabbit RVOT myocytes had larger I_to. I_to exists in large amounts at the epicardial site of the RV, and is suggested to enhance phase 2 reentry like in the model of Brugada syndrome, as suggested in the repolarization disorder hypothesis [38].

3.2. Heart Failure (HF)

HF is a clinical syndrome with multiple etiologies leading to cardiac function impairment. It is associated with significant morbidity and mortality. The most common cause of RV dysfunction is chronic left-sided HF [95]. A previous study found that there is less RVOT fractional shortening in HF patients than healthy controls [96]. HF may have an impact on RVOT electrophysiological characteristics. The ligation of the left anterior descending coronary artery has been widely used to establish the model of HF [97]. Human HF increases the RVOT apex-to-base APD gradient, and regions of long and short APDs cause non-uniform wave propagation, which may initiate ventricular arrhythmias until unidirectional conduction block and reentry [98]. HF increases I_Na-Late in rabbit RVOT myocytes that allow the sustained entry of Na⁺ into the myocardial cells throughout systole, which prolongs APD and increases the risk of arrhythmogenesis [99]. HF increases NCX in rabbit RVOT myocytes [99], and upregulated NCX creates conditions that facilitate arrhythmia formation through DAD in a spontaneous Ca²⁺ wave that elevates intracellular Ca²⁺ levels during the diastolic phase [100]. The increased NCX in HF RVOT myocytes may arise from the increased I_Na-Late levels and compensates for the decrease in Ca²⁺ entry through I_Ca-L during depolarization [101]. The I_to and I_Kr reduction in HF RVOT myocytes are accompanied by APD prolongation [99]. Dysregulated Na⁺ and K⁺ currents have been demonstrated to play an important role in ventricular arrhythmogenesis in HF [99].

3.3. Chronic Kidney Disease (CKD)

CKD is a major burden in patients with cardiovascular diseases, and it has been demonstrated that even mild forms of CKD may be associated with cardiovascular morbidity and mortality [102]. Sudden death is common in CKD and accounts for approximately one-quarter of deaths in patients undergoing dialysis [103]. CKD induces adverse ventricular remodeling that provides the substrate for ventricular arrhythmia [104]. In the ARIC study, patients with CKD had a significant prevalence of non-sustained ventricular tachycardia (30.2%), and >90% of patients had ectopy according to 2-week cardiac monitor recording [105]. Rautavaara et al. monitored CKD patients with an implanted device for 34 months, and 23% of patients had ventricular tachyarrhythmias [106]. Recently, the RV function has been particularly highlighted for dialyzed patients [107]. Hemodialysis is associated with an increased risk of pulmonary hypertension, which causes RV structure abnormalities and dysfunction and is recognized as a predictor of mortality in these patients [108]. Comparative research by Schleberger et al. revealed that the incidence of CKD was 14% in patients undergoing catheter ablation for outflow tract arrhythmias in the absence of structural heart disease [109]. Patients with advanced CKD have been reported to have Ca²⁺ handling abnormalities, abnormal electrophysiological characteristics, and a low induction threshold of ventricular fibrillation [104]. Moreover, a significant interdialytic change in the RVOT velocity time integral was found in CKD patients on hemodialysis, resulting in a high interdialytic hemodynamic change that may contribute to an increase in RVOT wall shear stresses and subsequent RVOT remodeling [110]. Combined cephalosporin and aminoglycoside cause tubular necrosis and induce rabbit kidney injury, which have been used as a CKD animal model [111,112]. The RVOT from CKD rabbits (induced by neomycin and cefazolin) exhibit a shorter APD and a higher incidence of non-sustained ventricular tachycardia [112]. The shortened APD in CKD RVOT myocytes may have been caused by large I_to and I_Kr, which commonly facilitate the repolarization of APs.

In contrast, left ventricular free wall myocytes have been shown to have a prolonged APD in CKD rats, which is caused by the downregulation of cardiac K⁺ currents [113]. The increased regional differences of APD in CKD may contribute to an enhanced APD dispersion and facilitate the genesis of the reentry circuits that result in ventricular arrhythmia. Furthermore, the long QRS duration observed in CKD rabbits may be caused by its small Na⁺ current, gap junction uncoupling and the reduced expression of connexin 43, respectively, contributing to ventricular arrhythmia [114]. A large I_to in CKD RVOT myocytes can be consistent with the prominent spike-and-dome morphology of the APs required for phase 2 reentry [115].

The larger I_Ca-L in CKD RVOT myocytes can increase Ca²⁺ entry and promote Ca²⁺ loading [112], which may cause Ca²⁺ dysregulation and CaMKII signaling pathway activation. Similar to that in HF, CKD RVOT tissues also exhibited increased levels of NCX, and the increasing Ca²⁺ leak in CKD RVOT myocytes, which leads to the genesis of triggered activity. In addition, CKD-enhanced RVOT arrhythmogenesis can be reduced by an NCX inhibitor [112]. The CKD RVOT tissues exhibited high expressions of phosphorylated CaMKII and protein kinase A and a decrease in sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a (SERCA2a) expression, leading to Ca²⁺ handling abnormalities. The increase in NCX function possibly originated through CaMKII-dependent phospholamban phosphorylation.

The CKD RVOT myocytes also show an increased level of oxidative stress, which may have promoted kinase activity and CaMKII expression to cause Ca²⁺ dysregulation. The protein expression of SERCA2a and SERCA2a activity may have been inhibited by the generation of oxidative stress. The hypersympathetic innervation in the CKD RVOT suggests that the RVOT may play a role in the induction of ventricular arrhythmia in CKD through enhanced sympathetic activity. The CKD RVOT with higher oxidative stress and autonomic hyperactivity exhibited distinctive electrophysiological characteristics and Ca²⁺-handling abnormalities, which contributed to the induction of ventricular tachycardia.

4. Conclusions

The RVOT becomes highly arrhythmogenic because RVOT myocytes have unique electrical and Ca²⁺-handling properties that are known to cause arrhythmias. Multiple intrinsic and extrinsic factors are linked to RVOT arrhythmogenesis, which is easily induced in pathological states (Figure 4). As a result, tackling these causes and underlying diseases may provide therapeutic prospects for treating arrhythmias originating from the RVOT.

Author Contributions

Conceptualization, Y.-Y.L., Y.-C.C. and Y.-J.C.; validation, Y.-K.L. and S.-A.C.; writing—original draft preparation, Y.-Y.L., Y.-C.C. and Y.-J.C.; writing—review and editing, Y.-Y.L. and Y.-J.C. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors have no conflict of interest related to this work.

Footnotes

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Figures and Table

Figure 1. Distinctive electrophysiological features of right ventricular outflow tract (RVOT) myocytes relative to right ventricular (RV) apex myocytes. RVOT myocytes had longer action potential duration (APD) at 90% and 50% repolarization (APD90 and APD50) than RV apex myocytes. RVOT myocytes were characterized by a larger late sodium current (INa-Late), transient outward potassium current (Ito), and smaller the rapid component of the delayed rectifier potassium current (IKr-tail), L-type calcium current (ICa-L) and nickel-sensitive Na+-Ca2+ exchanger (NCX). The differences in the properties of the INa-Late, the Ito, the IKr-tail, the ICa-L and the NCX current might contribute to the differences in APD between RVOT myocytes and RV apex myocytes. (Adapted with permission from [14]).

Figure 2. Effects of KN93 (a CaMKII inhibitor) and ranolazine (a late sodium current inhibitor) on ouabain (a cardiac glycoside)-induced ventricular tachycardia (VT). (A) Ouabain induces sustained VT in the right ventricular outflow tract (RVOT) and non-sustained VT in the right ventricular (RV) apex. (B) KN93 or ranolazine can terminate ouabain-induced sustained VT in RVOT preparations. Arrows (↑) indicate electrical stimuli. (Adapted with permission from [14]).

Figure 3. Electrical ventricular remodeling in pathological conditions, such as heart failure, chronic kidney disease and obesity/epicardial adipose tissue (EAT) accumulation, contributes to right ventricular outflow tract (RVOT) arrhythmogenesis. In heart failure, RVOT myocytes have a smaller L-type calcium (Ca2+) current (ICa-L) and a rapid component of delayed rectifier potassium current (IKr-tail) and a larger late sodium (Na+) current (INa-Late) than RV apex myocytes, which prolongs action potential duration (APD). Moreover, an increase in intracellular Na+ by INa-Late may drive the Ca2+ inside by the reverse mode of Na+-Ca2+ exchanger current (NCX), which increases intracellular Ca2+ ([Ca2+]i) and induces delayed afterdepolarization (DAD). In chronic kidney disease, RVOT myocytes have a larger transient outward potassium current (Ito), which causes APD dispersion and phase 2 reentry. CKD RVOT myocytes have a larger ICa-L and NCX than RV apex myocytes that increase Ca2+ load and Ca2+ leak, resulting in Ca2+ calmodulin-dependent protein kinase II (CaMKII) activation and inducing triggered activity. Moreover, chronic kidney disease increases oxidative stress and causes autonomic hyperactivity. In obesity/epicardial adipose tissue (EAT) accumulation, a smaller ICa-L and inwardly rectifying the potassium current (IK1) of RVOT myocytes result in a prolonged APD and a more positive resting membrane potential (RMP) than that of RV apex myocytes. RVOT myocytes have a larger Ito than RV apex myocytes, which causes phase 2 reentry.

Figure 4. Schematic illustration of the intrinsic and extrinsic factors and possible mechanisms resulting in right ventricular outflow tract (RVOT) arrhythmogenesis due to electrical and structural remodeling. The idiopathic (autonomic, gender, genetic, embryonic, anatomical, and histological) and pathological conditions (obesity/epicardial adipose tissue (EAT) accumulation, heart failure (HF), and chronic kidney disease (CKD)) cause RVOT electrical and structural remodeling and are prone to induce triggered activity and reentry, resulting in RVOT arrhythmogenesis. APD, action potential duration; Ca2+, calcium; CV, conduction velocity.

Table 1

Genetic risk factors associated with right ventricular outflow tract arrhythmogenesis.

Associated Gene	Inheritance	Mechanism	Model	Reference
ATP1A2, CACNA1C, PPP2R2C, PLCD3, GNAO1, Solute Carrier Family 6 (Transporter, Norepinephrine), Member 2(SLC6A2), CAMK2B, PIK3R2	Down regulation	Myocardial intracellular Ca2+ regulation	Human	Hasdemir C. et al. [79]
CAMKK2 and ITPR3	Up regulation
TBX3, BMP2, BMPR1B, MYH6, ANKRD23–39	Down regulation	Cardiovascular functions	Human	Hasdemir C. et al. [79]
RGS1	Up regulation
Scn5a	Heterozygous missense mutation	Na+ channel dysfunction	Mouse	Boukens BJ. et al. [22]Zhang Y. et al. [80]Martin CA. et al. [81]Pannone L. et al. [82]Chen Q. et al. [76]
			Human
Gja1	Down regulation	Lower expression of gap junction	Mouse	Boukens BJ. et al. [22]
A1 ADO receptor (R296C)	Somatic mutation	Adenosine insensitive	Human	Cheung JW. et al. [83]
Inhibitory G protein Gαi2 (F200L)	Somatic mutation	Increase intracellular cAMP concentrationAdenosine insensitive	Human	Cheung JW. et al. [83]Lerman BB. et al. [84]
TREK-1 (I267T)	Heterozygous point mutation	Stretch-activated K2P K+ channel TREK-1	Human	Decher N. et al. [85]
Androgen receptor	Knockout	Myocardial intracellular Ca2+ regulation	Mouse	Tsai WC. et al. [74]
Stimulatory G protein alpha-subunit Gsα (W234R)	Somatic mutation	Increase intracellular cAMP concentration	Human	Ip JE. et al. [86]

ANKRD23–39, Ankyrin Repeat Domain 23 and 39; BMP2, Bone Morphogenetic Protein 2; BMPR1B, Bone Morphogenetic Protein Receptor, Type IB; Ca²⁺, calcium; cAMP, cyclic adenosine monophosphate; K⁺, potassium; Na⁺, sodium; PPP2R2C, Protein Phosphatase 2, Regulatory Subunit B, Gamma Isoform; TBX3, T-box 3; TREK-1, TWIK-related potassium channel 1.

References

1. Kamakura, S.; Shimizu, W.; Matsuo, K.; Taguchi, A.; Suyama, K.; Kurita, T.; Aihara, N.; Ohe, T.; Shimomura, K. Localization of optimal ablation site of idiopathic ventricular tachycardia from right and left ventricular outflow tract by body surface ECG. Circulation; 1998; 98, pp. 1525-1533. [DOI: https://dx.doi.org/10.1161/01.CIR.98.15.1525] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9769306]

2. Morita, H.; Fukushima-Kusano, K.; Nagase, S.; Takenaka-Morita, S.; Nishii, N.; Kakishita, M.; Nakamura, K.; Emori, T.; Matsubara, H.; Ohe, T. Site-specific arrhythmogenesis in patients with Brugada syndrome. J. Cardiovasc. Electrophysiol.; 2003; 14, pp. 373-379. [DOI: https://dx.doi.org/10.1046/j.1540-8167.2003.02365.x]

3. Tsai, C.F.; Chen, S.A.; Tai, C.T.; Chiang, C.E.; Lee, S.H.; Wen, Z.C.; Huang, J.L.; Ding, Y.A.; Chang, M.S. Idiopathic monomorphic ventricular tachycardia: Clinical outcome, electrophysiologic characteristics and long-term results of catheter ablation. Int. J. Cardiol.; 1997; 62, pp. 143-150. [DOI: https://dx.doi.org/10.1016/S0167-5273(97)00198-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9431865]

4. Kim, R.J.; Iwai, S.; Markowitz, S.M.; Shah, B.K.; Stein, K.M.; Lerman, B.B. Clinical and electrophysiological spectrum of idiopathic ventricular outflow tract arrhythmias. J. Am. Coll. Cardiol.; 2007; 49, pp. 2035-2043. [DOI: https://dx.doi.org/10.1016/j.jacc.2007.01.085]

5. Sirichand, S.; Killu, A.M.; Padmanabhan, D.; Hodge, D.O.; Chamberlain, A.M.; Brady, P.A.; Kapa, S.; Noseworthy, P.A.; Packer, D.L.; Munger, T.M. et al. Incidence of Idiopathic Ventricular Arrhythmias: A Population-Based Study. Circ. Arrhythm. Electrophysiol.; 2017; 10, e004662. [DOI: https://dx.doi.org/10.1161/CIRCEP.116.004662]

6. Lerman, B.B.; Stein, K.M.; Markowitz, S.M.; Mittal, S.; Slotwiner, D.J. Ventricular arrhythmias in normal hearts. Cardiol. Clin.; 2000; 18, pp. 265-291. [DOI: https://dx.doi.org/10.1016/S0733-8651(05)70141-7]

7. Dixit, S.; Gerstenfeld, E.P.; Callans, D.J.; Marchlinski, F.E. Electrocardiographic patterns of superior right ventricular outflow tract tachycardias: Distinguishing septal and free-wall sites of origin. J. Cardiovasc. Electrophysiol.; 2003; 14, pp. 1-7. [DOI: https://dx.doi.org/10.1046/j.1540-8167.2003.02404.x]

8. Anderson, R.D.; Kumar, S.; Parameswaran, R.; Wong, G.; Voskoboinik, A.; Sugumar, H.; Watts, T.; Sparks, P.B.; Morton, J.B.; McLellan, A. et al. Differentiating Right- and Left-Sided Outflow Tract Ventricular Arrhythmias: Classical ECG Signatures and Prediction Algorithms. Circ. Arrhythm. Electrophysiol.; 2019; 12, e007392. [DOI: https://dx.doi.org/10.1161/CIRCEP.119.007392]

9. Mariani, M.V.; Piro, A.; Della Rocca, D.G.; Forleo, G.B.; Pothineni, N.V.; Romero, J.; Di Biase, L.; Fedele, F.; Lavalle, C. Electrocardiographic Criteria for Differentiating Left from Right Idiopathic Outflow Tract Ventricular Arrhythmias. Arrhythm. Electrophysiol. Rev.; 2021; 10, pp. 10-16. [DOI: https://dx.doi.org/10.15420/aer.2020.10]

10. O’Donnell, D.; Cox, D.; Bourke, J.; Mitchell, L.; Furniss, S. Clinical and electrophysiological differences between patients with arrhythmogenic right ventricular dysplasia and right ventricular outflow tract tachycardia. Eur. Heart J.; 2003; 24, pp. 801-810. [DOI: https://dx.doi.org/10.1016/S0195-668X(02)00654-1]

11. Buxton, A.E.; Waxman, H.L.; Marchlinski, F.E.; Simson, M.B.; Cassidy, D.; Josephson, M.E. Right ventricular tachycardia: Clinical and electrophysiologic characteristics. Circulation; 1983; 68, pp. 917-927. [DOI: https://dx.doi.org/10.1161/01.CIR.68.5.917]

12. Calvo, N.; Jongbloed, M.; Zeppenfeld, K. Radiofrequency catheter ablation of idiopathic right ventricular outflow tract arrhythmias. Indian Pacing Electrophysiol. J.; 2013; 13, pp. 14-33. [DOI: https://dx.doi.org/10.1016/S0972-6292(16)30585-X]

13. Haissaguerre, M.; Extramiana, F.; Hocini, M.; Cauchemez, B.; Jais, P.; Cabrera, J.A.; Farre, J.; Leenhardt, A.; Sanders, P.; Scavee, C. et al. Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes. Circulation; 2003; 108, pp. 925-928. [DOI: https://dx.doi.org/10.1161/01.CIR.0000088781.99943.95]

14. Lu, Y.Y.; Chung, F.P.; Chen, Y.C.; Tsai, C.F.; Kao, Y.H.; Chao, T.F.; Huang, J.H.; Chen, S.A.; Chen, Y.J. Distinctive electrophysiological characteristics of right ventricular out-flow tract cardiomyocytes. J. Cell. Mol. Med.; 2014; 18, pp. 1540-1548. [DOI: https://dx.doi.org/10.1111/jcmm.12329]

15. Ghonim, S.; Voges, I.; Gatehouse, P.D.; Keegan, J.; Gatzoulis, M.A.; Kilner, P.J.; Babu-Narayan, S.V. Myocardial Architecture, Mechanics, and Fibrosis in Congenital Heart Disease. Front. Cardiovasc. Med.; 2017; 4, 30. [DOI: https://dx.doi.org/10.3389/fcvm.2017.00030]

16. Tandri, H.; Bluemke, D.A.; Ferrari, V.A.; Bomma, C.; Nasir, K.; Rutberg, J.; Tichnell, C.; James, C.; Lima, J.A.; Calkins, H. Findings on magnetic resonance imaging of idiopathic right ventricular outflow tachycardia. Am. J. Cardiol.; 2004; 94, pp. 1441-1445. [DOI: https://dx.doi.org/10.1016/j.amjcard.2004.07.150]

17. van Riel, A.; Systrom, D.M.; Oliveira, R.K.F.; Landzberg, M.J.; Mulder, B.J.M.; Bouma, B.J.; Maron, B.A.; Shah, A.M.; Waxman, A.B.; Opotowsky, A.R. Hemodynamic and metabolic characteristics associated with development of a right ventricular outflow tract pressure gradient during upright exercise. PLoS ONE; 2017; 12, e0179053. [DOI: https://dx.doi.org/10.1371/journal.pone.0179053]

18. Gulan, U.; Saguner, A.M.; Akdis, D.; Gotschy, A.; Tanner, F.C.; Kozerke, S.; Manka, R.; Brunckhorst, C.; Holzner, M.; Duru, F. Hemodynamic Changes in the Right Ventricle Induced by Variations of Cardiac Output: A Possible Mechanism for Arrhythmia Occurrence in the Outflow Tract. Sci. Rep.; 2019; 9, 100. [DOI: https://dx.doi.org/10.1038/s41598-018-36614-7]

19. Theveniau-Ruissy, M.; Dandonneau, M.; Mesbah, K.; Ghez, O.; Mattei, M.G.; Miquerol, L.; Kelly, R.G. The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning. Circ. Res.; 2008; 103, pp. 142-148. [DOI: https://dx.doi.org/10.1161/CIRCRESAHA.108.172189]

20. Rana, M.S.; Theveniau-Ruissy, M.; De Bono, C.; Mesbah, K.; Francou, A.; Rammah, M.; Dominguez, J.N.; Roux, M.; Laforest, B.; Anderson, R.H. et al. Tbx1 coordinates addition of posterior second heart field progenitor cells to the arterial and venous poles of the heart. Circ. Res.; 2014; 115, pp. 790-799. [DOI: https://dx.doi.org/10.1161/CIRCRESAHA.115.305020]

21. Bezzina, C.R.; Barc, J.; Mizusawa, Y.; Remme, C.A.; Gourraud, J.B.; Simonet, F.; Verkerk, A.O.; Schwartz, P.J.; Crotti, L.; Dagradi, F. et al. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat. Genet.; 2013; 45, pp. 1044-1049. [DOI: https://dx.doi.org/10.1038/ng.2712] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23872634]

22. Boukens, B.J.; Sylva, M.; de Gier-de Vries, C.; Remme, C.A.; Bezzina, C.R.; Christoffels, V.M.; Coronel, R. Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract. Circ. Res.; 2013; 113, pp. 137-141. [DOI: https://dx.doi.org/10.1161/CIRCRESAHA.113.301565]

23. Jongbloed, M.R.; Mahtab, E.A.; Blom, N.A.; Schalij, M.J.; Gittenberger-de Groot, A.C. Development of the cardiac conduction system and the possible relation to predilection sites of arrhythmogenesis. Sci. World J.; 2008; 8, pp. 239-269. [DOI: https://dx.doi.org/10.1100/tsw.2008.40]

24. Miles, C.; Westaby, J.; Ster, I.C.; Asimaki, A.; Boardman, P.; Joshi, A.; Papadakis, M.; Sharma, S.; Behr, E.R.; Sheppard, M.N. Morphometric characterization of collagen and fat in normal ventricular myocardium. Cardiovasc. Pathol.; 2020; 48, 107224. [DOI: https://dx.doi.org/10.1016/j.carpath.2020.107224]

25. Basso, C.; Thiene, G. Adipositas cordis, fatty infiltration of the right ventricle, and arrhythmogenic right ventricular cardiomyopathy. Just a matter of fat?. Cardiovasc. Pathol.; 2005; 14, pp. 37-41. [DOI: https://dx.doi.org/10.1016/j.carpath.2004.12.001]

26. Pytkowski, M.; Maciag, A.; Sterlinski, M.; Jankowska, A.; Kowalik, I.; Farkowski, M.M.; Kuteszko, R.; Zajac, D.; Firek, B.; Chmielak, Z. et al. Novel algorithm for arrhythmogenic focus localization in patients with right ventricular outflow tract arrhythmias. Cardiol. J.; 2014; 21, pp. 284-292. [DOI: https://dx.doi.org/10.5603/CJ.a2013.0111]

27. Lerman, B.B. Mechanism, diagnosis, and treatment of outflow tract tachycardia. Nat. Rev. Cardiol.; 2015; 12, pp. 597-608. [DOI: https://dx.doi.org/10.1038/nrcardio.2015.121]

28. Ohkubo, K.; Watanabe, I.; Okumura, Y.; Takagi, Y.; Ashino, S.; Kofune, M.; Sugimura, H.; Nakai, T.; Kasamaki, Y.; Hirayama, A. et al. Right ventricular histological substrate and conduction delay in patients with Brugada syndrome. Int. Heart J.; 2010; 51, pp. 17-23. [DOI: https://dx.doi.org/10.1536/ihj.51.17]

29. Coronel, R.; Casini, S.; Koopmann, T.T.; Wilms-Schopman, F.J.; Verkerk, A.O.; de Groot, J.R.; Bhuiyan, Z.; Bezzina, C.R.; Veldkamp, M.W.; Linnenbank, A.C. et al. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: A combined electrophysiological, genetic, histopathologic, and computational study. Circulation; 2005; 112, pp. 2769-2777. [DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.105.532614]

30. Nademanee, K.; Raju, H.; de Noronha, S.V.; Papadakis, M.; Robinson, L.; Rothery, S.; Makita, N.; Kowase, S.; Boonmee, N.; Vitayakritsirikul, V. et al. Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome. J. Am. Coll. Cardiol.; 2015; 66, pp. 1976-1986. [DOI: https://dx.doi.org/10.1016/j.jacc.2015.08.862]

31. Ou, B.; Nakagawa, M.; Kajimoto, M.; Nobe, S.; Ooie, T.; Ichinose, M.; Yonemochi, H.; Ono, N.; Shimada, T.; Saikawa, T. Heterogeneous expression of connexin 43 in the myocardium of rabbit right ventricular outflow tract. Life Sci.; 2005; 77, pp. 52-59. [DOI: https://dx.doi.org/10.1016/j.lfs.2004.12.030]

32. Kelly, A.; Salerno, S.; Connolly, A.; Bishop, M.; Charpentier, F.; Stolen, T.; Smith, G.L. Normal interventricular differences in tissue architecture underlie right ventricular susceptibility to conduction abnormalities in a mouse model of Brugada syndrome. Cardiovasc. Res.; 2018; 114, pp. 724-736. [DOI: https://dx.doi.org/10.1093/cvr/cvx244]

33. De Almeida, M.C.; Stephenson, R.S.; Anderson, R.H.; Benvenuti, L.A.; Loukas, M.; Aiello, V.D. Human subpulmonary infundibulum has an endocardial network of specialized conducting cardiomyocytes. Heart Rhythm; 2020; 17, pp. 123-130. [DOI: https://dx.doi.org/10.1016/j.hrthm.2019.07.033]

34. Aras, K.; Gams, A.; Faye, N.R.; Brennan, J.; Goldrick, K.; Li, J.; Zhong, Y.; Chiang, C.H.; Smith, E.H.; Poston, M.D. et al. Electrophysiology and Arrhythmogenesis in the Human Right Ventricular Outflow Tract. Circ. Arrhythm. Electrophysiol.; 2022; 15, e010630. [DOI: https://dx.doi.org/10.1161/CIRCEP.121.010630]

35. Burke, A.P.; Farb, A.; Tashko, G.; Virmani, R. Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: Are they different diseases?. Circulation; 1998; 97, pp. 1571-1580. [DOI: https://dx.doi.org/10.1161/01.CIR.97.16.1571]

36. Lerman, B.B.; Belardinelli, L.; West, G.A.; Berne, R.M.; DiMarco, J.P. Adenosine-sensitive ventricular tachycardia: Evidence suggesting cyclic AMP-mediated triggered activity. Circulation; 1986; 74, pp. 270-280. [DOI: https://dx.doi.org/10.1161/01.CIR.74.2.270]

37. Morita, H.; Zipes, D.P.; Morita, S.T.; Wu, J. Differences in arrhythmogenicity between the canine right ventricular outflow tract and anteroinferior right ventricle in a model of Brugada syndrome. Heart Rhythm; 2007; 4, pp. 66-74. [DOI: https://dx.doi.org/10.1016/j.hrthm.2006.08.030]

38. Morita, H.; Zipes, D.P.; Fukushima-Kusano, K.; Nagase, S.; Nakamura, K.; Morita, S.T.; Ohe, T.; Wu, J. Repolarization heterogeneity in the right ventricular outflow tract: Correlation with ventricular arrhythmias in Brugada patients and in an in vitro canine Brugada model. Heart Rhythm; 2008; 5, pp. 725-733. [DOI: https://dx.doi.org/10.1016/j.hrthm.2008.02.028]

39. Rudic, B.; Chaykovskaya, M.; Tsyganov, A.; Kalinin, V.; Tulumen, E.; Papavassiliu, T.; Dosch, C.; Liebe, V.; Kuschyk, J.; Roger, S. et al. Simultaneous Non-Invasive Epicardial and Endocardial Mapping in Patients With Brugada Syndrome: New Insights Into Arrhythmia Mechanisms. J. Am. Heart Assoc.; 2016; 5, e004095. [DOI: https://dx.doi.org/10.1161/JAHA.116.004095]

40. Liang, S.; Lin, C.; Li, Y.; Liu, T.; Wang, Y. L-type calcium current in right ventricular outflow tract myocytes of rabbit heart. Sci. China Life Sci.; 2012; 55, pp. 41-46. [DOI: https://dx.doi.org/10.1007/s11427-012-4265-3]

41. Bonatti, V.; Rolli, A.; Botti, G. Recording of monophasic action potentials of the right ventricle in long QT syndromes complicated by severe ventricular arrhythmias. Eur. Heart J.; 1983; 4, pp. 168-179. [DOI: https://dx.doi.org/10.1093/oxfordjournals.eurheartj.a061436] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/6190653]

42. Gaborit, N.; Le Bouter, S.; Szuts, V.; Varro, A.; Escande, D.; Nattel, S.; Demolombe, S. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. J. Physiol.; 2007; 582, pp. 675-693. [DOI: https://dx.doi.org/10.1113/jphysiol.2006.126714] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17478540]

43. Veldkamp, M.W.; Viswanathan, P.C.; Bezzina, C.; Baartscheer, A.; Wilde, A.A.; Balser, J.R. Two distinct congenital arrhythmias evoked by a multidysfunctional Na⁺ channel. Circ. Res.; 2000; 86, pp. E91-E97. [DOI: https://dx.doi.org/10.1161/01.RES.86.9.e91] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10807877]

44. Kohomoto, O.; Levi, A.J.; Bridge, J.H. Relation between reverse sodium-calcium exchange and sarcoplasmic reticulum calcium release in guinea pig ventricular cells. Circ. Res.; 1994; 74, pp. 550-554. [DOI: https://dx.doi.org/10.1161/01.RES.74.3.550] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8118963]

45. Bers, D.M. Calcium fluxes involved in control of cardiac myocyte contraction. Circ. Res.; 2000; 87, pp. 275-281. [DOI: https://dx.doi.org/10.1161/01.RES.87.4.275]

46. Eisner, D.A.; Caldwell, J.L.; Kistamas, K.; Trafford, A.W. Calcium and Excitation-Contraction Coupling in the Heart. Circ. Res.; 2017; 121, pp. 181-195. [DOI: https://dx.doi.org/10.1161/CIRCRESAHA.117.310230]

47. Song, Z.; Ko, C.Y.; Nivala, M.; Weiss, J.N.; Qu, Z. Calcium-voltage coupling in the genesis of early and delayed afterdepolarizations in cardiac myocytes. Biophys. J.; 2015; 108, pp. 1908-1921. [DOI: https://dx.doi.org/10.1016/j.bpj.2015.03.011]

48. Damiano, B.P.; Rosen, M.R. Effects of pacing on triggered activity induced by early afterdepolarizations. Circulation; 1984; 69, pp. 1013-1025. [DOI: https://dx.doi.org/10.1161/01.CIR.69.5.1013]

49. Patterson, E.; Lazzara, R.; Szabo, B.; Liu, H.; Tang, D.; Li, Y.H.; Scherlag, B.J.; Po, S.S. Sodium-calcium exchange initiated by the Ca²⁺ transient: An arrhythmia trigger within pulmonary veins. J. Am. Coll. Cardiol.; 2006; 47, pp. 1196-1206. [DOI: https://dx.doi.org/10.1016/j.jacc.2005.12.023]

50. Burashnikov, A.; Antzelevitch, C. Late-phase 3 EAD. A unique mechanism contributing to initiation of atrial fibrillation. Pacing Clin. Electrophysiol.; 2006; 29, pp. 290-295. [DOI: https://dx.doi.org/10.1111/j.1540-8159.2006.00336.x]

51. Furukawa, T.; Kimura, S.; Catstellanos, A.; Bassett, A.L.; Myerburg, R.J. In vivo induction of “focal” triggered ventricular arrhythmias and responses to overdrive pacing in the canine heart. Circulation; 1990; 82, pp. 549-559. [DOI: https://dx.doi.org/10.1161/01.CIR.82.2.549] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2372901]

52. Bers, D.M.; Bassani, J.W.; Bassani, R.A. Na-Ca exchange and Ca fluxes during contraction and relaxation in mammalian ventricular muscle. Ann. N. Y. Acad. Sci.; 1996; 779, pp. 430-442. [DOI: https://dx.doi.org/10.1111/j.1749-6632.1996.tb44818.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8659859]

53. Aronson, R.S.; Nordin, C. Arrhythmogenic interaction between low potassium and ouabain in isolated guinea-pig ventricular myocytes. J. Physiol.; 1988; 400, pp. 113-134. [DOI: https://dx.doi.org/10.1113/jphysiol.1988.sp017114] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/3418524]

54. Maier, L.S. A novel mechanism for the treatment of angina, arrhythmias, and diastolic dysfunction: Inhibition of late I(Na) using ranolazine. J. Cardiovasc. Pharmacol.; 2009; 54, pp. 279-286. [DOI: https://dx.doi.org/10.1097/FJC.0b013e3181a1b9e7]

55. Jafri, M.S. Models of excitation-contraction coupling in cardiac ventricular myocytes. Methods Mol. Biol.; 2012; 910, pp. 309-335. [DOI: https://dx.doi.org/10.1007/978-1-61779-965-5_14] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22821602]

56. Lu, Y.Y.; Chen, Y.C.; Lin, Y.K.; Chen, S.A.; Chen, Y.J. Mechanoelectrical feedback in pulmonary vein arrhythmogenesis: Clinical challenges and therapeutic opportunities. J. Arrhythm.; 2020; 36, pp. 608-614. [DOI: https://dx.doi.org/10.1002/joa3.12391]

57. Rios, E. The cell boundary theorem: A simple law of the control of cytosolic calcium concentration. J. Physiol. Sci.; 2010; 60, pp. 81-84. [DOI: https://dx.doi.org/10.1007/s12576-009-0069-z]

58. Antoons, G.; Mubagwa, K.; Nevelsteen, I.; Sipido, K.R. Mechanisms underlying the frequency dependence of contraction and [Ca(2+)](i) transients in mouse ventricular myocytes. J. Physiol.; 2002; 543, pp. 889-898. [DOI: https://dx.doi.org/10.1113/jphysiol.2002.025619]

59. Monasky, M.M.; Pappone, C.; Piccoli, M.; Ghiroldi, A.; Micaglio, E.; Anastasia, L. Calcium in Brugada Syndrome: Questions for Future Research. Front. Physiol.; 2018; 9, 1088. [DOI: https://dx.doi.org/10.3389/fphys.2018.01088]

60. Liu, C.M.; Lin, F.Z.; Chen, Y.C.; Lin, Y.K.; Lu, Y.Y.; Wu, C.I.; Higa, S.; Chen, S.A.; Chen, Y.J. Concurrent increases in post-pacing action potential duration and contractility predict occurrence of ventricular arrhythmia. Pflugers Arch.; 2020; 472, pp. 1783-1791. [DOI: https://dx.doi.org/10.1007/s00424-020-02445-7]

61. Liu, C.M.; Lin, F.J.; Chen, Y.C.; Lin, Y.K.; Lu, Y.Y.; Chan, C.S.; Higa, S.; Chen, S.A.; Chen, Y.J. Modulation of post-pacing action potential duration and contractile responses on ventricular arrhythmogenesis in chloroquine-induced long QT syndrome. Eur. J. Pharmacol.; 2023; 941, 175493. [DOI: https://dx.doi.org/10.1016/j.ejphar.2023.175493] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36621600]

62. Fu, M.; Wu, M.; Wang, J.F.; Qiao, Y.J.; Wang, Z. Disruption of the intracellular Ca²⁺ homeostasis in the cardiac excitation-contraction coupling is a crucial mechanism of arrhythmic toxicity in aconitine-induced cardiomyocytes. Biochem. Biophys. Res. Commun.; 2007; 354, pp. 929-936. [DOI: https://dx.doi.org/10.1016/j.bbrc.2007.01.082] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17276394]

63. Verberne, H.J.; Blom, M.T.; Bardai, A.; Karemaker, J.M.; Tan, H.L. An inherited sudden cardiac arrest syndrome may be based on primary myocardial and autonomic nervous system abnormalities. Heart Rhythm; 2022; 19, pp. 244-251. [DOI: https://dx.doi.org/10.1016/j.hrthm.2021.10.026] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34757187]

64. Fukuda, K.; Kanazawa, H.; Aizawa, Y.; Ardell, J.L.; Shivkumar, K. Cardiac innervation and sudden cardiac death. Circ. Res.; 2015; 116, pp. 2005-2019. [DOI: https://dx.doi.org/10.1161/CIRCRESAHA.116.304679]

65. Randall, W.C.; Armour, J.A.; Geis, W.P.; Lippincott, D.B. Regional cardiac distribution of the sympathetic nerves. Fed. Proc.; 1972; 31, pp. 1199-1208.

66. Chang, H.Y.; Lo, L.W.; Chen, Y.R.; Chou, Y.H.; Lin, W.L.; Lin, Y.J.; Yin, W.H.; Feng, A.N.; Chen, S.A. The autonomic neural mechanism of right ventricular outflow tract tachycardia. Auton. Neurosci.; 2018; 212, pp. 10-16. [DOI: https://dx.doi.org/10.1016/j.autneu.2018.03.006]

67. Schafers, M.; Lerch, H.; Wichter, T.; Rhodes, C.G.; Lammertsma, A.A.; Borggrefe, M.; Hermansen, F.; Schober, O.; Breithardt, G.; Camici, P.G. Cardiac sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia. J. Am. Coll. Cardiol.; 1998; 32, pp. 181-186. [DOI: https://dx.doi.org/10.1016/S0735-1097(98)00213-7]

68. Iwai, S.; Cantillon, D.J.; Kim, R.J.; Markowitz, S.M.; Mittal, S.; Stein, K.M.; Shah, B.K.; Yarlagadda, R.K.; Cheung, J.W.; Tan, V.R. et al. Right and left ventricular outflow tract tachycardias: Evidence for a common electrophysiologic mechanism. J. Cardiovasc. Electrophysiol.; 2006; 17, pp. 1052-1058. [DOI: https://dx.doi.org/10.1111/j.1540-8167.2006.00539.x]

69. Nakagawa, M.; Takahashi, N.; Nobe, S.; Ichinose, M.; Ooie, T.; Yufu, F.; Shigematsu, S.; Hara, M.; Yonemochi, H.; Saikawa, T. Gender differences in various types of idiopathic ventricular tachycardia. J. Cardiovasc. Electrophysiol.; 2002; 13, pp. 633-638. [DOI: https://dx.doi.org/10.1046/j.1540-8167.2002.00633.x]

70. Marchlinski, F.E.; Deely, M.P.; Zado, E.S. Sex-specific triggers for right ventricular outflow tract tachycardia. Am. Heart J.; 2000; 139, pp. 1009-1013. [DOI: https://dx.doi.org/10.1067/mhj.2000.106164]

71. Hodgkinson, K.A.; Parfrey, P.S.; Bassett, A.S.; Kupprion, C.; Drenckhahn, J.; Norman, M.W.; Thierfelder, L.; Stuckless, S.N.; Dicks, E.L.; McKenna, W.J. et al. The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5). J. Am. Coll. Cardiol.; 2005; 45, pp. 400-408. [DOI: https://dx.doi.org/10.1016/j.jacc.2004.08.068]

72. Rautaharju, P.M.; Zhou, S.H.; Wong, S.; Calhoun, H.P.; Berenson, G.S.; Prineas, R.; Davignon, A. Sex differences in the evolution of the electrocardiographic QT interval with age. Can. J. Cardiol.; 1992; 8, pp. 690-695.

73. Tsai, W.C.; Yang, L.Y.; Chen, Y.C.; Kao, Y.H.; Lin, Y.K.; Chen, S.A.; Cheng, C.F.; Chen, Y.J. Ablation of the androgen receptor gene modulates atrial electrophysiology and arrhythmogenesis with calcium protein dysregulation. Endocrinology; 2013; 154, pp. 2833-2842. [DOI: https://dx.doi.org/10.1210/en.2012-2265] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23748361]

74. Tsai, W.C.; Lu, Y.Y.; Chen, Y.C.; Chang, C.J.; Kao, Y.H.; Lin, Y.K.; Chen, Y.H.; Chen, S.A.; Yang, L.Y.; Chen, Y.J. Ablation of androgen receptor gene triggers right ventricular outflow tract ventricular tachycardia. Int. J. Cardiol.; 2015; 189, pp. 172-181. [DOI: https://dx.doi.org/10.1016/j.ijcard.2015.04.080]

75. Towbin, J.A.; Vatta, M.; Li, H. Genetics of brugada, long QT, and arrhythmogenic right ventricular dysplasia syndromes. J. Electrocardiol.; 2000; 33, (Suppl. S1), pp. 11-22. [DOI: https://dx.doi.org/10.1054/jelc.2000.20361] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11265709]

76. Chen, Q.; Kirsch, G.E.; Zhang, D.; Brugada, R.; Brugada, J.; Brugada, P.; Potenza, D.; Moya, A.; Borggrefe, M.; Breithardt, G. et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature; 1998; 392, pp. 293-296. [DOI: https://dx.doi.org/10.1038/32675] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9521325]

77. Malcic, I.; Kniewald, H.; Pivac, V.T.; Jelasic, D.; Buljevic, B. Right Ventricular Arrhytmogenic Cardiomyopathy—Have We Avoided a Family Tragedy by Applying Contemporary Diagnostic and Treatment Approach?. Lijec. Vjesn.; 2016; 138, pp. 339-344.

78. Zhou, Y.; Bai, K.; Wang, Y.; Meng, Z.; Zhou, S.; Jiang, S.; Wang, H.; Wang, J.; Yang, M.; Wang, Q. et al. Identification of Rare Variants in Right Ventricular Outflow Tract Obstruction Congenital Heart Disease by Whole-Exome Sequencing. Front. Cardiovasc. Med.; 2021; 8, 811156. [DOI: https://dx.doi.org/10.3389/fcvm.2021.811156]

79. Hasdemir, C.; Aydin, H.H.; Celik, H.A.; Simsek, E.; Payzin, S.; Kayikcioglu, M.; Aydin, M.; Kultursay, H.; Can, L.H. Transcriptional profiling of septal wall of the right ventricular outflow tract in patients with idiopathic ventricular arrhythmias. Pacing Clin. Electrophysiol.; 2010; 33, pp. 159-167. [DOI: https://dx.doi.org/10.1111/j.1540-8159.2009.02606.x]

80. Zhang, Y.; Guzadhur, L.; Jeevaratnam, K.; Salvage, S.C.; Matthews, G.D.; Lammers, W.J.; Lei, M.; Huang, C.L.; Fraser, J.A. Arrhythmic substrate, slowed propagation and increased dispersion in conduction direction in the right ventricular outflow tract of murine Scn5a+/- hearts. Acta. Physiol.; 2014; 211, pp. 559-573. [DOI: https://dx.doi.org/10.1111/apha.12324]

81. Martin, C.A.; Grace, A.A.; Huang, C.L. Spatial and temporal heterogeneities are localized to the right ventricular outflow tract in a heterozygotic Scn5a mouse model. Am. J. Physiol. Heart Circ. Physiol.; 2011; 300, pp. H605-H616. [DOI: https://dx.doi.org/10.1152/ajpheart.00824.2010]

82. Pannone, L.; Monaco, C.; Sorgente, A.; Vergara, P.; Gauthey, A.; Calburean, P.A.; Bisignani, A.; Paparella, G.; Ramak, R.; Overeinder, I. et al. SCN5A mutation in Brugada syndrome is associated with substrate severity detected by electrocardiographic imaging and high-density electroanatomic mapping. Heart Rhythm; 2022; 19, pp. 945-951. [DOI: https://dx.doi.org/10.1016/j.hrthm.2022.01.034] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35124229]

83. Cheung, J.W.; Ip, J.E.; Yarlagadda, R.K.; Liu, C.F.; Thomas, G.; Xu, L.; Wilkes, D.; Markowitz, S.M.; Lerman, B.B. Adenosine-insensitive right ventricular tachycardia: Novel variant of idiopathic outflow tract tachycardia. Heart Rhythm; 2014; 11, pp. 1770-1778. [DOI: https://dx.doi.org/10.1016/j.hrthm.2014.06.014]

84. Lerman, B.B.; Dong, B.; Stein, K.M.; Markowitz, S.M.; Linden, J.; Catanzaro, D.F. Right ventricular outflow tract tachycardia due to a somatic cell mutation in G protein subunitalphai2. J. Clin. Investig.; 1998; 101, pp. 2862-2868. [DOI: https://dx.doi.org/10.1172/JCI1582]

85. Decher, N.; Ortiz-Bonnin, B.; Friedrich, C.; Schewe, M.; Kiper, A.K.; Rinne, S.; Seemann, G.; Peyronnet, R.; Zumhagen, S.; Bustos, D. et al. Sodium permeable and “hypersensitive” TREK-1 channels cause ventricular tachycardia. EMBO Mol. Med.; 2017; 9, pp. 403-414. [DOI: https://dx.doi.org/10.15252/emmm.201606690] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28242754]

86. Ip, J.E.; Xu, L.; Dai, J.; Steegborn, C.; Jaffre, F.; Evans, T.; Cheung, J.W.; Basson, C.T.; Panaghie, G.; Krogh-Madsen, T. et al. Constitutively Activating GNAS Somatic Mutation in Right Ventricular Outflow Tract Tachycardia. Circ. Arrhythm. Electrophysiol.; 2021; 14, e010082. [DOI: https://dx.doi.org/10.1161/CIRCEP.121.010082] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34587755]

87. Guh, D.P.; Zhang, W.; Bansback, N.; Amarsi, Z.; Birmingham, C.L.; Anis, A.H. The incidence of co-morbidities related to obesity and overweight: A systematic review and meta-analysis. BMC Public Health; 2009; 9, 88. [DOI: https://dx.doi.org/10.1186/1471-2458-9-88]

88. Aune, D.; Schlesinger, S.; Norat, T.; Riboli, E. Body mass index, abdominal fatness, and the risk of sudden cardiac death: A systematic review and dose-response meta-analysis of prospective studies. Eur. J. Epidemiol.; 2018; 33, pp. 711-722. [DOI: https://dx.doi.org/10.1007/s10654-017-0353-9]

89. de Divitiis, O.; Fazio, S.; Petitto, M.; Maddalena, G.; Contaldo, F.; Mancini, M. Obesity and cardiac function. Circulation; 1981; 64, pp. 477-482. [DOI: https://dx.doi.org/10.1161/01.CIR.64.3.477]

90. Tam, W.C.; Lin, Y.K.; Chan, W.P.; Huang, J.H.; Hsieh, M.H.; Chen, S.A.; Chen, Y.J. Pericardial Fat Is Associated With the Risk of Ventricular Arrhythmia in Asian Patients. Circ. J.; 2016; 80, pp. 1726-1733. [DOI: https://dx.doi.org/10.1253/circj.CJ-16-0047] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27301329]

91. Messerli, F.H.; Nunez, B.D.; Ventura, H.O.; Snyder, D.W. Overweight and sudden death. Increased ventricular ectopy in cardiopathy of obesity. Arch. Intern. Med.; 1987; 147, pp. 1725-1728. [DOI: https://dx.doi.org/10.1001/archinte.1987.00370100039008]

92. Pan, X.; Chen, X.; Ren, L.; Li, Z.; Chen, S. Correlation between Cardiac Ultrasound Index and Cardiovascular Risk in Healthy Obese and Overweight Populations. Int. J. Clin. Pract.; 2022; 2022, 2235994. [DOI: https://dx.doi.org/10.1155/2022/2235994] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36212053]

93. Maury, P. Why is the right ventricular outflow tract so arrhythmogenic? (.. or is it really?..). Heart; 2011; 97, pp. 1631-1633. [DOI: https://dx.doi.org/10.1136/heartjnl-2011-300465]

94. Lu, Y.Y.; Huang, S.Y.; Lin, Y.K.; Chen, Y.C.; Chen, Y.A.; Chen, S.A.; Chen, Y.J. Epicardial adipose tissue modulates arrhythmogenesis in right ventricle outflow tract cardiomyocytes. Europace; 2021; 23, pp. 970-977. [DOI: https://dx.doi.org/10.1093/europace/euaa412] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33463675]

95. Haddad, F.; Doyle, R.; Murphy, D.J.; Hunt, S.A. Right ventricular function in cardiovascular disease, part II: Pathophysiology, clinical importance, and management of right ventricular failure. Circulation; 2008; 117, pp. 1717-1731. [DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.107.653584]

96. Deveci, B.; Baser, K.; Gul, M.; Sen, F.; Kafes, H.; Avci, S.; Temizer, O.; Ozeke, O.; Tufekcioglu, O.; Golbasi, Z. Right ventricular outflow tract function in chronic heart failure. Indian Heart J.; 2016; 68, (Suppl. S1), pp. S10-S14. [DOI: https://dx.doi.org/10.1016/j.ihj.2015.07.028]

97. Chang, S.L.; Hsiao, Y.W.; Tsai, Y.N.; Lin, S.F.; Liu, S.H.; Lin, Y.J.; Lo, L.W.; Chung, F.P.; Chao, T.F.; Hu, Y.F. et al. Interleukin-17 enhances cardiac ventricular remodeling via activating MAPK pathway in ischemic heart failure. J. Mol. Cell. Cardiol.; 2018; 122, pp. 69-79. [DOI: https://dx.doi.org/10.1016/j.yjmcc.2018.08.005] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30096409]

98. Bayer, J.D.; Lalani, G.G.; Vigmond, E.J.; Narayan, S.M.; Trayanova, N.A. Mechanisms linking electrical alternans and clinical ventricular arrhythmia in human heart failure. Heart Rhythm; 2016; 13, pp. 1922-1931. [DOI: https://dx.doi.org/10.1016/j.hrthm.2016.05.017]

99. Lu, Y.Y.; Cheng, C.C.; Tsai, C.F.; Lin, Y.K.; Lee, T.I.; Chen, Y.C.; Chen, S.A.; Chen, Y.J. Discrepant effects of heart failure on electrophysiological property in right ventricular outflow tract and left ventricular outflow tract cardiomyocytes. Clin. Sci.; 2017; 131, pp. 1317-1327. [DOI: https://dx.doi.org/10.1042/CS20170121]

100. Reinecke, H.; Studer, R.; Vetter, R.; Holtz, J.; Drexler, H. Cardiac Na⁺/Ca²⁺ exchange activity in patients with end-stage heart failure. Cardiovasc. Res.; 1996; 31, pp. 48-54. [DOI: https://dx.doi.org/10.1016/S0008-6363(95)00176-X]

101. Hobai, I.A.; Maack, C.; O’Rourke, B. Partial inhibition of sodium/calcium exchange restores cellular calcium handling in canine heart failure. Circ. Res.; 2004; 95, pp. 292-299. [DOI: https://dx.doi.org/10.1161/01.RES.0000136817.28691.2d] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15217911]

102. Boriani, G.; Savelieva, I.; Dan, G.A.; Deharo, J.C.; Ferro, C.; Israel, C.W.; Lane, D.A.; La Manna, G.; Morton, J.; Mitjans, A.M. et al. Chronic kidney disease in patients with cardiac rhythm disturbances or implantable electrical devices: Clinical significance and implications for decision making-a position paper of the European Heart Rhythm Association endorsed by the Heart Rhythm Society and the Asia Pacific Heart Rhythm Society. Europace; 2015; 17, pp. 1169-1196. [DOI: https://dx.doi.org/10.1093/europace/euv202] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26108808]

103. Chiu, D.Y.; Sinha, S.; Kalra, P.A.; Green, D. Sudden cardiac death in haemodialysis patients: Preventative options. Nephrology; 2014; 19, pp. 740-749. [DOI: https://dx.doi.org/10.1111/nep.12337] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25231407]

104. Bonato, F.O.; Lemos, M.M.; Cassiolato, J.L.; Canziani, M.E. Prevalence of ventricular arrhythmia and its associated factors in nondialyzed chronic kidney disease patients. PLoS ONE; 2013; 8, e66036. [DOI: https://dx.doi.org/10.1371/journal.pone.0066036]

105. Kim, E.D.; Soliman, E.Z.; Coresh, J.; Matsushita, K.; Chen, L.Y. Two-Week Burden of Arrhythmias across CKD Severity in a Large Community-Based Cohort: The ARIC Study. J. Am. Soc. Nephrol.; 2021; 32, pp. 629-638. [DOI: https://dx.doi.org/10.1681/ASN.2020030301]

106. Rautavaara, J.; Kerola, T.; Kaartinen, K.; Vilpakka, M.; Aitkoski, A.; Anttonen, O.; Ahvonen, J.; Koistinen, J.; Vaaraniemi, K.; Miettinen, M. et al. Asystole episodes and bradycardia in patients with end-stage renal disease. Nephrol. Dial. Transplant.; 2022; 37, pp. 575-583. [DOI: https://dx.doi.org/10.1093/ndt/gfab023]

107. Stallworthy, E.J.; Pilmore, H.L.; Webster, M.W.; Sidhu, K.K.; Curry, E.M.; Brown, P.; Scaria, A. Do echocardiographic parameters predict mortality in patients with end-stage renal disease?. Transplantation; 2013; 95, pp. 1225-1232. [DOI: https://dx.doi.org/10.1097/TP.0b013e31828dbbbe]

108. Yigla, M.; Fruchter, O.; Aharonson, D.; Yanay, N.; Reisner, S.A.; Lewin, M.; Nakhoul, F. Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients. Kidney Int.; 2009; 75, pp. 969-975. [DOI: https://dx.doi.org/10.1038/ki.2009.10]

109. Schleberger, R.; Riess, J.; Brauer, A.; Pinnschmidt, H.O.; Rottner, L.; Moser, F.; Moser, J.; Kany, S.; My, I.; Lemoine, M.D. et al. Ablation of Outflow Tract Arrhythmias in Patients With and Without Structural Heart Disease-A Comparative Analysis. Front. Cardiovasc. Med.; 2022; 9, 910042. [DOI: https://dx.doi.org/10.3389/fcvm.2022.910042] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35694678]

110. Sarafidis, P.A.; Kamperidis, V.; Loutradis, C.; Tsilonis, K.; Mpoutsiouki, F.; Saratzis, A.; Giannakoulas, G.; Sianos, G.; Karvounis, H. Haemodialysis acutely deteriorates left and right diastolic function and myocardial performance: An effect related to high ultrafiltration volumes?. Nephrol. Dial. Transplant.; 2017; 32, pp. 1402-1409. [DOI: https://dx.doi.org/10.1093/ndt/gfw345]

111. Browning, M.C.; Hsu, C.Y.; Wang, P.L.; Tune, B.M. Interaction of ischemic and antibiotic-induced injury in the rabbit kidney. J. Infect. Dis.; 1983; 147, pp. 341-351. [DOI: https://dx.doi.org/10.1093/infdis/147.2.341] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/6827149]

112. Huang, S.Y.; Chen, Y.C.; Kao, Y.H.; Lu, Y.Y.; Lin, Y.K.; Higa, S.; Chen, S.A.; Chen, Y.J. Calcium dysregulation increases right ventricular outflow tract arrhythmogenesis in rabbit model of chronic kidney disease. J. Cell. Mol. Med.; 2021; 25, pp. 11264-11277. [DOI: https://dx.doi.org/10.1111/jcmm.17052] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34761510]

113. Hsueh, C.H.; Chen, N.X.; Lin, S.F.; Chen, P.S.; Gattone, V.H., 2nd; Allen, M.R.; Fishbein, M.C.; Moe, S.M. Pathogenesis of arrhythmias in a model of CKD. J. Am. Soc. Nephrol.; 2014; 25, pp. 2812-2821. [DOI: https://dx.doi.org/10.1681/ASN.2013121343]

114. Waks, J.W.; Tereshchenko, L.G.; Parekh, R.S. Electrocardiographic predictors of mortality and sudden cardiac death in patients with end stage renal disease on hemodialysis. J. Electrocardiol.; 2016; 49, pp. 848-854. [DOI: https://dx.doi.org/10.1016/j.jelectrocard.2016.07.020] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27554424]

115. Volders, P.G.; Sipido, K.R.; Carmeliet, E.; Spatjens, R.L.; Wellens, H.J.; Vos, M.A. Repolarizing K+ currents ITO1 and IKs are larger in right than left canine ventricular midmyocardium. Circulation; 1999; 99, pp. 206-210. [DOI: https://dx.doi.org/10.1161/01.CIR.99.2.206]