Bidirectional Ventricular Tachycardia Research Articles

Management of Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary electrical heart disease characterized by the development of polymorphic (including bidirectional) ventricular tachycardia in response to adrenergic stimulation. The leading clinical sign of CPVT is syncope provoked by physical or emotional stress, or adrenergic drugs administration. This disease is characterized by high mortality if not treated. The main treatment approach for CPVT is drug therapy with beta-blockers. Recently, however, there are more and more works stating that beta-blockers have lack of efficacy. Combination therapy with the antiarrhythmic drug of the IC class is one of the approaches before implementing the interventional treatment methods in several patients. Interventional methods include cardioverter defibrillator implantation and left side sympathectomy. This paper presents the modern view on the efficacy, safety, and indications for every management method for patients with CPVT.

Transcriptome analysis of effects of Tecrl deficiency on cardiometabolic and calcium regulation in cardiac tissue.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a hereditary heart disease characterized by bidirectional or polymorphic ventricular tachycardia and an increased risk of sudden cardiac death. Although trans-2,3-enoyl-CoA reductase like (TECRL) is a newly reported pathogenic gene leading to CPVT that can influence intracellular calcium regulation, the unidentified mechanism underlying the pathogenesis of TECRL deficiency-mediated CPVT remains mainly elusive. In the present study, Tecrl knockout (KO) mice were established and the differentially expressed genes (DEGs) were investigated by RNA-sequencing from the heart tissues. In addition, 857 DEGs were identified in Tecrl KO mice. Subsequently, a weighted gene co-expression network analysis was conducted to discern the pivotal pathways implicated in the Tecrl-mediated regulatory network. Moreover, pathway mapping analyses demonstrated that essential metabolism-related pathways were significantly enriched, notably the fatty acid metabolic process and calcium regulation. Collectively, the data suggested a synergistic relationship between Tecrl deficiency and cardiometabolic and calcium regulation during the development of CPVT. Therefore, further studies on the potential function of TECRL in cardiac tissues would be beneficial to elucidate the pathogenesis of CPVT.

Dual effect of cardiac FKBP12.6 overexpression on excitation-contraction coupling and the incidence of ventricular arrhythmia depending on its expression level

FKBP12.6, a binding protein to the immunosuppressant FK506, which also binds the ryanodine receptor (RyR2) in the heart, has been proposed to regulate RyR2 function and to have antiarrhythmic properties. However, the level of FKBP12.6 expression in normal hearts remains elusive and some controversies still persist regarding its effects, both in basal conditions and during β-adrenergic stimulation. We quantified FKBP12.6 in the left ventricles (LV) of WT (wild-type) mice and in two novel transgenic models expressing distinct levels of FKBP12.6, using a custom-made specific anti-FKBP12.6 antibody and a recombinant protein. FKBP12.6 level in WT LV was very low (0.16 ± 0.02 nmol/g of LV), indicating that <15% RyR2 monomers are bound to the protein. Mice with 14.1 ± 0.2 nmol of FKBP12.6 per g of LV (TG1) had mild cardiac hypertrophy and normal function and were protected against epinephrine/caffeine-evoked arrhythmias. The ventricular myocytes showed higher [Ca2+]i transient amplitudes than WT myocytes and normal SR-Ca2+ load, while fewer myocytes showed Ca2+ sparks. TG1 cardiomyocytes responded to 50 nM Isoproterenol increasing these [Ca2+]i parameters and producing RyR2-Ser2808 phosphorylation. Mice with more than twice the TG1 FKBP12.6 value (TG2) showed marked cardiac hypertrophy with calcineurin activation and more arrhythmias than WT mice during β-adrenergic stimulation, challenging the protective potential of high FKBP12.6. RyR2R420Q CPVT mice overexpressing FKBP12.6 showed fewer proarrhythmic events and decreased incidence and duration of stress-induced bidirectional ventricular tachycardia. Our study, therefore, quantifies for the first time endogenous FKBP12.6 in the mouse heart, questioning its physiological relevance, at least at rest due its low level. By contrast, our work demonstrates that with caution FKBP12.6 remains an interesting target for the development of new antiarrhythmic therapies.

Significant delayed conduction and characteristic ventricular tachycardias in patients with cardiac sarcoidosis and electrical storm.

Electrical storm (ES) of ventricular tachyarrhythmias (VTAs) is an important cause of sudden death in patients with cardiac sarcoidosis (CS). VTAs in CS are associated with myocardial scarring and inflammation. However, little is known about the risk factors of ES in patients with CS and VTAs. The objective of this study is to clarify the characteristics and risk factors for the development of ES in patients with CS. The study population included consecutive 52 patients with CS and sustained VTA. Twenty-five out of 52 patients experienced ES. We evaluated clinical characteristics, imaging modalities, and electrocardiogram (ECG) parameters to determine the risk factors associated with ES. Half of the patients experienced VTAs as the initial symptom of sarcoidosis, and eight patients had ES as the initial VTA episode. There were no differences in cardiac imaging abnormalities between patients with and without ES. Among ECG markers, significant QRS fragmentation (odds ratio [OR]: 7.9, p = .01) and epsilon waves (OR: 12.24, p = .02) were associated with ES. Among the ventricular tachycardia (VT) characteristics, multiple morphologies of monomorphic VTs (OR: 10.9, p < .01), short VT cycle lengths (OR: 12.5, p < .01), and polymorphic VT (OR: 13.5, p < .01) were associated with ES. Bidirectional VTs were detected in 10 patients with ES and one patient without ES. Immunosuppressive therapy relieved ES in some patients. ES was common in patients with CS and VTAs. Significant depolarization abnormalities that appeared as QRS fragmentation, epsilon waves, and specific VT characteristics were associated with ES.

Characterization of the cardiac and non-cardiac phenotype associated with genetic variants in KCNJ2

Abstract Introduction Sequence variants in KCNJ2 are associated with Andersen-Tawil syndrome (ATS), a rare, multisystem disorder characterized by a triad of cardiac arrhythmia, periodic paralysis, and craniofacial-skeletal developmental anomalies. Purpose To define the cardiac and non-cardiac features of ATS associated with KCNJ2 variants. Methods Patients with KCNJ2 variants and features within the spectrum of ATS were identified from a detailed literature search between 2001 and 2020. Demographic, clinical and genetic data were collected. To avoid double counting the same proband, publications from the same authors or institutions were cross referenced and only included once unless it was evident that cases were not previously reported based on age, sex and specific KCNJ2. Minor allelic frequency was assessed in the Genome Aggregation Database (gnomAD). Results 296 patients (aged 25.5 ± 15.6 years) were identified from 66 publications. 136 (44%) were male and 162 (55%) probands. Age of symptom onset (reported in 100) was 10.7 ± 6.4 years. There were 162 probands. A family history of sudden death was reported for 23 probands. There were 69 different variants (fig 1a): missense (n=57), inframe deletion (n=5) and insertion (n=2), truncating (n=3), frameshift (n=1), copy number variant (n=1). Overall, penetrant disease was reported in 288 (96%), and only 2 (Arg312Cys, Pro415Leu) were seen in gnomAD. Variants at 2 residues (Arg67 and Arg218) were seen in 43 (26%) probands and 120 (41%) of all patients. Clinical data for all 3 major phenotypes was available for 289 individuals, with the full triad reported in 99 (34%) (fig 1b). A cardiac phenotype seen in 244 (84%), which was an isolated finding in 37 (13%). There was no difference in the phenotypic spectrum in those with variants Arg67 and Arg218 (fig 1c). An isolated cardiac phenotype was seen in 13/120 (11%) at these residues. Cardiac symptoms included palpitations (34/91; 37%), syncope (44/131; 34%). Cardiac arrest was reported in 20 (6.7%). ECG features included ventricular premature beats (VPB) (214/243; 90%), U wave (123/141; 87.2%), bidirectional (82/119; 68.9%), polymorphic (68/118; 57.6%) and monomorphic (7/35; 20.0%) ventricular tachycardia (VT). Arrhythmia-mediated cardiomyopathy was reported in 8. In 37 patients with an isolated cardiac phenotype, features included VPB (29/36; 81%), U waves (21/24; 88%), bidirectional (6/13; 43%), polymorphic (11/17; 65%) and monomorphic (2/7; 29%) VT. Cardiac arrest occurred in 5 (10%) cases. Conclusion The cardiac phenotype associated with KCNJ2 is highly varied. U-waves and VPB are prevalent features, and there is significant arrhythmic burden and morbidity. Identified KCNJ2 variants are highly penetrant and very rarely observed in the population. DIsease-associated variants are especially prevalent at the key functional residues 67 and 218. Improved recognition of this rare disorder will help further define the cardiac features and associated risk.

Bidirectional Ventricular Tachycardia and Prominent U Waves: Look at Fingers and Muscles and Use Flecainide.

We present a case of bidirectional ventricular tachycardia in a 15-year-old boy asymptomatic for arrhythmias, whose major complaint was muscle weakness. At our first evaluation he was receiving sotalol for his ventricular arrhythmias. In addition to bidirectional tachycardia, electrocardiogram during sinus rhythm showed prominent U waves and prolonged QT-U interval. These electrocardiographic signs, along with the evidence of clinodactyly and mild hypertelorism, led us to the diagnosis of Andersen-Tawil syndrome, confirmed by genetic analysis that revealed a "de novo" missense mutation of KCNJ2 gene. Monotherapy with flecainide was rapidly effective and almost eliminated ventricular arrhythmias. After a 4-year follow-up there were no adverse events, flecainide has been well tolerated without significant modification of the QRS or repolarization, and ventricular arrhythmias have not been relapsed to date. The case highlights the importance of a correct clinical diagnosis, which is crucial for the optimal selection of the most appropriate drug therapy, which is expected not to be harmful, before being beneficial.

Unmasking the uncommon: bidirectional ventricular tachycardia in two rare paediatric cardiomyopathies.

We present two exceptional cases of 14-year-old girls diagnosed with rare cardiomyopathies (left ventricular non-compaction, and arrhythmogenic right ventricular cardiomyopathy), both presenting with the unusual finding of bidirectional ventricular tachycardia.

Slow bidirectional ventricular tachycardia associated with immune checkpoint inhibitor myocarditis.

Slow bidirectional ventricular tachycardia associated with immune checkpoint inhibitor myocarditis.

Insights on the mechanism of flecainide in catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by defective cardiac ryanodine receptor (RyR2) calcium release during times of adrenergic stimulation, resulting in bidirectional or polymorphic ventricular tachycardia. Flecainide is a class 1c anti-arrhythmic drug that has demonstrated therapeutic efficacy in treating CPVT. However, its mechanism of action remains disputed. One group proposes a direct effect of flecainide on RyR2-mediated calcium release, while another proposes an indirect effect via sodium channel blockade and modulation of intracellular calcium dynamics. In light of recent studies, this commentary aims to explore and discuss the evidence base for these potential mechanisms.

Elderly male with nausea and vomiting.

A 75-year-old male with a history of atrial fibrillation, type 2 diabetes, congestive heart failure, and cardiomyopathy presented with 1 day history of nausea and vomiting. On physical examination, the patient was afebrile with a blood pressure of 103/59 mm Hg, heart rate of 107, respiration 12, and oxygen saturation 98% on room air. He was frail appearing and awake but confused with pupils at 4 mm. His heart was tachycardic, lungs clear to auscultation, and abdomen soft and non-tender. Neurological examination revealed generalized weakness but was non-focal. An electrocardiogram (ECG) was obtained (Figure 1), which demonstrated a rare example of bidirectional ventricular tachycardia (BiVT), which is most commonly seen with digoxin toxicity. It can also be caused by catecholaminergic polymorphic ventricular tachycardia (a genetic dysrhythmia induced by exercise, physical, or emotional stress), acute myocardial ischemia, ischemic cardiomyopathy, myocarditis, and cardiac sarcoidosis.1 On further questioning, the patient admitted to overdosing on his apixaban, digoxin, and dapagliflozin 24 hours prior. His digoxin level was markedly elevated at 7.2 ng/mL. He had a normal renal function and blood glucose. The patient was treated with 2 doses of digoxin immune fab with improvement in his symptoms. Digoxin is derived from the foxglove plant. Its positive inotropic effects are used to improve systolic function in patients with congestive heart failure, and its atrioventricular nodal blocking effect is used to control atrial tachydysrhythmias.2 It has a narrow therapeutic window and is renally excreted. Signs and symptoms of digoxin toxicity include confusion, decreased appetite, nausea, vomiting, diarrhea, and visual changes (rare). BiVT is a rare finding, but highly suggestive of digoxin toxicity.

CPVT and Complete Atrio-Ventricular Block: The Flipside of the Same Coin

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare electrical genetic disease characterized by ventricular polymorphic tachycardia and/or bidirectional ventricular tachycardia induced by the release of catecholamines caused by intense physical or emotional stress in structurally normal hearts. Mostly, it is caused by mutations in genes that are involved in calcium homeostasis, in particular in the gene encoding for cardiac ryanodine receptor (RyR2). Our observation is the first description of familial CPVT caused by mutation of the RyR2 gene, linked to the complete AV block.

Spatially discordant alternans occurring when cardiac tissue is paced alternatively from two sites.

Cardiac alternans are a precursor to arrhythmias. Spatially discordant alternans (SDA) in ventricles are especially arrhythmogenic as they can lead to ventricular tachycardia and fibrillation. Bidirectional ventricular tachycardia (BVT) is one of the rare arrhythmias. However, the underlying mechanism is still not clear. The normal electrical activity generated by the sinoatrial node propagates as an action potential wave in the heart. BVT occurs when the route of conduction changes in every other beat. In this study, we investigated the mechanism of BVT using mathematical models of cardiac tissue. The two-dimensional tissue was paced from two sites at a constant pacing cycle length. The stimulation site alternated every pacing cycle. We measured electrical alternans, which are defined as an alternating sequence of the action potential durations. We varied parameters in the model such as the distance between two sites and the pacing cycle length. We found that alternans amplitude was significantly amplified when the tissue was paced alternatively from two sites. SDA was formed even at slow heart rates. The alternans amplitude increased with the distance between the pacing sites. The nodal line was formed in the middle of the two pacing sites. This is arrhythmogenic since it can easily lead to a wave break that may initiate a spiral wave. Fast pacing with steep APD restitution is another mechanism of SDA. However, the nodal line is parallel to the wavefront. When tissue is paced rapidly and alternatively from two sites, APD distribution becomes more complex. Our study demonstrates that alternans can be formed by alternating pacing from two sites that mimics BVT.

Phenytoin as treatment for bidirectional ventricular tachycardia in a patient with anterior myocardial infarction and digoxin toxicity

Phenytoin as treatment for bidirectional ventricular tachycardia in a patient with anterior myocardial infarction and digoxin toxicity

Catecholaminergic Polymorphic Ventricular Tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterised by adenergically mediated bidirectional and/or polymorphic ventricular tachycardia. CPVT is a significant cause of autopsy-negative sudden death in children and adolescents, although it can also affect adults. It is often caused by pathogenic variants in the cardiac ryanodine receptor gene as well as other rarer genes. Early identification and risk stratification is of major importance. β-blockers are the cornerstone of therapy. Sodium channel blockers, specifically flecainide, have an additive role. Left cardiac sympathetic denervation is playing an increasing role in suppression of arrhythmia and symptoms. Concerns have been raised, however, about the efficacy of implantable cardioverter defibrillator therapy and the risk of catecholamine driven proarrhythmic storms. In this review, we summarise the clinical characteristics, genetics, and diagnostic and therapeutic strategies for CPVT and describe recent advances and challenges.

Experimental hypothyroidism induces cardiac arrhythmias and ranolazine reverts and prevents the phenotype

AimsHypothyroidism is associated with an increased risk of cardiovascular disease and enhanced susceptibility to arrhythmias. In our investigation, we evaluated the potential involvement of late sodium current (INa,late) in cardiac arrhythmias in an experimental murine model of hypothyroidism. Main methodsMale Swiss mice were treated with methimazole (0.1 % w/vol, during 21 days) to induce experimental hypothyroidism before ECG, action potential (AP) and intracellular Ca2+ dynamics were evaluated. Susceptibility to arrhythmia was measured in vitro and in vivo. Key findingsThe results revealed that hypothyroid animals presented ECG alterations (e.g. increased QTc) with the presence of spontaneous sustained ventricular tachycardia. These changes were associated with depolarized resting membrane potential in isolated cardiomyocytes and increased AP duration and dispersion at 90 % of the repolarization. Aberrant AP waveforms were related to increased Ca2+ sparks and out-of-pace Ca2+ waves. These changes were observed in a scenario of enhanced INa,late. Interestingly, ranolazine, a clinically used blocker of INa,late, restored the ECG alterations, reduced Ca2+ sparks and aberrant waves, decreased the in vitro events and the severity of arrhythmias observed in isolated cardiomyocytes from hypothyroid animals. Using the in vivo dobutamine + caffeine protocol, animals with hypothyroidism developed catecholaminergic bidirectional ventricular tachycardia, but pre-treatment with ranolazine prevented this. SignificanceWe concluded that animals with hypothyroidism have increased susceptibility to developing arrhythmias and ranolazine, a clinically used blocker of INa,late, is able to correct the arrhythmic phenotype.

Bidirectional Ventricular Tachycardia: Challenges and Solutions.

Bidirectional ventricular tachycardia (BiVT) is a rare form of ventricular tachycardia that manifests on surface electrocardiogram by dual QRS morphologies alternating on a beat-to-beat basis. It was first reported in the 1920s as a complication of digoxin, and since then, it has been reported in other conditions including fulminant myocarditis, sarcoidosis, catecholaminergic polymorphic ventricular tachycardia, and Andersen-Tawil syndrome. The mechanism for BiVT is not as well known as other forms of ventricular tachycardia but appears to include typical mechanisms including triggered activity from afterdepolarizations, abnormal automaticity, or reentry. This review will go beyond the definition, surface electrocardiogram, mechanisms, causes, and treatment of BiVT as per our current understanding.

Anesthetic Management of a Patient With Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmogenic disorder induced by adrenergic stress. Electrophysiologically, it is characterized by emotional stress- or exercise-induced bidirectional ventricular tachycardia that may result in cardiac arrest. Minimizing perioperative stress is critical as it can reduce fatal arrhythmias in patients with CPVT. Dexmedetomidine (DEX), a centrally acting sympatholytic anesthetic agent, was used in the successful intravenous (IV) moderate sedation of a 27-year-old female patient with CPVT, a history of cardiac events, and significant dental fear and anxiety scheduled to undergo mandibular left third molar extraction. Oral surgery was successfully performed under DEX-based IV sedation to reduce stress, and no arrhythmias were observed. IV sedation with DEX provided a sympatholytic effect with respiratory and cardiovascular stability in this patient with CPVT who underwent oral surgery.

Caffeine Induces Spontaneous Ventricular Tachyarrhythmias and Bidirectional Ventricular Tachycardia: Increased Vulnerability with Aging

IntroductionCaffeine is generally suspected to trigger or exacerbate cardiac arrhythmias in patients, but so far clinical data have been conflicting. We have demonstrated previously that caffeine plus dobutamine challenge can induce ventricular tachyarrhythmias in normal rats (Heart Rhythm O2 2020;1:359‐367). However, whether caffeine alone can induce cardiac arrhythmias has not been investigated. We hypothesize that caffeine alone could trigger spontaneous cardiac arrhythmias, which may be affected by aging and sexes. In this study we have investigated the effect of caffeine on spontaneous cardiac arrhythmias in younger and older adult rats of both sexes.MethodsThis study used Sprague‐Dawley rats. Younger (5‐month‐old) and older (1‐year‐old) adult rats of both sexes were enrolled. The study consisted of the following groups: 5‐month‐old male rats (younger male, n=8) and 1‐year‐old male rats (older male, n=9), 5‐month‐old female rats (younger female, n=6) and 1‐year‐old female rats (older female, n=5). These rats received caffeine (80mg/kg, IP) injection. In addition, a group of 5‐month‐old rats (both sexes, n=8) receiving saline injection without caffeine served as the control group. Surface electrocardiogram (ECG, standard Lead II) was continuously monitored and recorded during the experiments.ResultsNo arrhythmia was induced in the control group with saline injection. Caffeine injection induced ventricular tachyarrhythmias in 8/9 older male rats, while only in 2/8 younger male rats (younger versus older male rats, p=0.0152, Fisher's exact test). Similarly, ventricular arrhythmias were induced in 5/5 older female rats, and only in 1/6 younger female rats (older versus younger female rats, p=0.0152). There were no significant differences in male versus female rats in both age groups. Induced ventricular arrhythmias include various premature ventricular contractions (PVC, Figure‐Panel A) in all rats, monomorphic ventricular tachycardia (VT, Panel B) in 3 rats and polymorphic VT and bidirectional VT (Panel C) in all rats. No atrial arrhythmia was observed.ConclusionCaffeine can induce spontaneous ventricular arrhythmias in normal rats, and the younger rats are more resistant to arrhythmia induction. Arrhythmia inducibility increases significantly in older rats. There is no sex difference in caffeine induced ventricular arrhythmias. Although different types of ventricular arrhythmias are induced, the characteristic bidirectional VT is highly prevalent among the caffeine induced arrhythmias and no atrial arrhythmia was observed.

PO-657-05 AN UNCOMMON IDIOPATHIC ETIOLOGY OF BIDIRECTIONAL VENTRICULAR TACHYCARDIA

Bidirectional ventricular tachycardia (VT) is an uncommon arrhythmia which occurs most commonly in the setting of digoxin toxicity, catecholaminergic polymorphic VT, or Andersen-Tawil Syndrome. We present a case of bidirectional VT due to idiopathic premature ventricular complexes (PVCs) from two distinct foci treated with catheter ablation.

A very rare cause of sudden cardiac arrest in children: triadin knockout syndrome.

A 7.5-year-old male patient was referred to our clinic with a history of recurrent syncope and aborted cardiac arrest. There was no family history of sudden death, syncope, or arrhythmia. Physical examination, electrocardiography, echocardiography, and 24-hour rhythm Holter monitoring were normal, and bidirectional ventricular tachycardiaT was detected during the exercise stress test. Genetic analysis revealed a homozygous mutation of c.531_533delinsGG, p.(Lys179Asnfs * 44) frameshift variant in TRDN(NM_006073) gene. A 4.5-year-old male was admitted due to syncope during exertion and underwent cardiopulmonary resuscitation due to sudden cardiac arrest. He had family history about sudden cardiac death. Physical examination was normal, and there was borderline QTc prolongation. Bidirectional non-sustained polymorphic ventricular tachycardia was observed at adrenaline provocation test. In genetic analysis, c.568dupA, pII190Asnfs * 2 frameshift variant homozygous mutation was detected in TRDN(NM_006073) gene. Intracardiac defibrillator implantation were performed for both cases. There has not been any event under propranolol and flecainide combination treatment. Triadin knockout syndrome (TCOS) is a rare overlap syndrome characterized by highly malignant arrhythmias, and it is a deadly combination of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia that affects primarily young children. Since lethal arrhythmias are frequently described, genetic testing is very important in these patients. Because, identification of a genetic mutation may be a guide in treatment.