Contributions of Israel to the field of clinical cardiac electrophysiology and implantable devices

Introduction

When I was invited by the Editor of Heart Rhythm O² to write an article dealing with the contributions of my country to clinical electrophysiology, I did immediately accept. What an honor to summarize >45 years of activity in Israel of a field that has known a prodigious growth since the first publication in 1967 by Dirk Durrer and Hein Wellens from Amsterdam of the case of a patient with Wolff-Parkinson-White (WPW) syndrome whose arrhythmias could be initiated and terminated by programmed electrical stimulation.¹ Coumel and coworkers² from Lariboisière Hospital in Paris (who closely worked with my future mentor Gilbert Motté) published similar results in the same year. At the same period, Scherlag and coworkers³ were the first to report the technique of recording of His bundle activity in humans. As Wellens⁴ wrote in his reflections from a Dutchman on an exciting journey while celebrating the 40th Heart Rhythm Society anniversary: “Together these observations from those 3 centers from both sides of the Atlantic resulted in the birth of clinical cardiac electrophysiology, a new subspecialty in cardiology. The findings were incredible. Each time I entered the catheterisation laboratory I found something new, leading to exciting, inspiring, and friendly discussions with my colleagues from the United States and France” (p 803).

After training during years 1973–1978 in cardiology and electrophysiology at Fernand Widal Hospital (10-minute walk from Lariboisière), under the mentorship of Gilbert Motté, I had the privilege to open the first electrophysiology (EP) laboratory in Tel Aviv in 1978, a few years before my friends Boris Strasberg in 1982 and Michael Eldar in 1985 did the same in Belinson and Tel Hashomer hospitals, respectively. In the former hospital, Samuel Sclarovsky, an Argentina-born cardiologist fervent electrocardiogram (ECG) specialist, already flooded the cardiology literature with multiple original articles dealing with the conduction disturbances and arrhythmias encountered in the setting of acute myocardial infarction (Online Supplement).

This review will summarize the most important clinical contributions of Israeli groups in the field of clinical cardiac EP and implantable devices, from 1981 to 2023. For simplicity reasons, these contributions will be classified as topics covering usually chronological order and only those mainly “Made in Israel” considered.

Antiarrhythmic medications

In 1981, the Sclarovsky’s group⁵ reported the first series of 6 patients with atrial fibrillation/atrial flutter (AF/AFl) and rapid ventricular rates associated with WPW syndrome treated with intravenous (IV) ajmaline. In another study from the same group,⁶ IV amiodarone was found to be effective in slowing ventricular response and/or restoring sinus rhythm in 26 patients with paroxysmal or new AF with fast ventricular response. In 1982, with Heshi Rotmensch⁷ we reviewed the benefits and risks of amiodarone therapy. Strasberg et al⁸ reported the second ever reported series of 3 patients with AF and WPW syndrome who had severe deleterious effects after receiving IV verapamil. Rapid suppression of flecainide-induced incessant ventricular tachycardia (VT) (resistant to various IV antiarrhythmic drugs and to cardiac pacing) with high-dose IV amiodarone was reported in 1 patient by Sagie et al.⁹

Polymorphous VT—Torsades de pointes

“Torsades de pointes” (TdP), also called “atypical VT” or “polymorphous VT” (Sclarovsky’s group) is a unique type of ventricular tachyarrhythmia, which comprises a changing QRS configuration and axis during repetitive episodes. This arrhythmia was first described by a French cardiologist, François Dessertenne,¹⁰ who worked with Philippe Coumel and Gilbert Motté at Lariboisière Hospital. Interestingly, his observations were made in 8 patients, including 7 with complete or paroxysmal atrioventricular block (AVB) unrelated to myocardial infarction or to antiarrhythmic medications.

Most specialists in the field, including Israeli workers,^11,12 considered that QT prolongation (congenital or acquired) should be part of the appellation of TdP, even though Dessertenne et al¹⁰ did not recognize the causal association between the long QT interval and the arrhythmia he described.

TdP has been associated with many causes,¹² among them antiarrhythmic drugs (mainly classes 1A and 3), electrolytes disturbances (hypokalemia and hypomagnesemia), various medications (antibiotics, tricyclic antidepressants, phenothiazines, lithium carbonate, anthracycline chemotherapeutic agents, etc), as well as marked bradycardias (mainly high-degree AVB).

Israeli cardiologists have actively contributed to the field of TdP. The Sclarovsky’s group reported 7 cases of procainamide-induced polymorphous VT¹³ and 5 cases of amiodarone-induced polymorphous VT.¹⁴ The group of Bikur Cholim Hospital (Jerusalem) was the first to report on the etiology, warning signs, and therapy of TdP in 10¹⁵ and 16¹⁶ patients, emphasizing the causative role of antiarrhythmic medications in >90% of their cases and the effective management using isoproterenol infusion and ventricular pacing. A few years later, the same group reported the first large series of patients with acquired TdP successfully treated by a bolus of 2 g of magnesium sulfate (n = 9) and eventually an additional bolus dose after a few minutes (n = 3).¹⁷

Bradycardia-dependent TdP was first reported in Israel by Strasberg et al¹⁸ in 9 patients, all with various degrees of AVB. Interestingly, when compared to a similar control group with AVB but without TdP, the ventricular cycle length was similar but the QT and corrected QT (QTc) intervals were significantly longer. Topilski et al¹⁹ found that the prolonged QT interval, QTc interval, and T_peak–T_end interval correlate with an increased risk of TdP during acquired bradyarrhythmias (78% complete AVB), particularly when accompanied by long QT syndrome (LQTS) type 2 (LQT2)–like notched T waves. Finally, Chorin et al²⁰ found that women are at an increased risk of developing TdP during acquired AVB (≥2:1) unrelated to myocardial infarction, vagal syncope, or drug toxicity. However, this increased risk is independent of their longer QT interval. Women develop TdP with QT intervals that are not necessarily arrhythmogenic for men.

Idiopathic verapamil-sensitive right bundle branch block–left axis VT

In 1981, we reported the case of a 30-year-old man with a long history of recurrent sustained VT having a morphology of right bundle branch block (RBBB) and left axis deviation.²¹ The patient had no obvious heart disease. His baseline ECG was normal except for T-wave anomalies that were frequently transiently observed after the termination of episodes of tachycardia. The latter exhibited the particularity to be reproducibly slowed and terminated within 3 minutes of IV verapamil administration while they were only slowed by IV ajmaline and not affected by IV lidocaine and adenosine triphosphate (ATP). During EP study (EPS), VT could be initiated with rapid atrial pacing, ventricular extrastimulation, and burst of ventricular pacing. It could also be terminated with ventricular extrastimulation and ventricular pacing burst. Finally, IV verapamil prevented its subsequent reinitiation by atrial and ventricular pacing.

Taking into consideration that Zipes and coworkers²² published 2 years before 3 cases of idiopathic VT showing the same QRS morphology and similar response to atrial and ventricular pacing, I recommended treating such patients by verapamil to determine whether this ECG entity corresponds to a particular electrophysiological mechanism. Three years later, we could confirm in 3 patients that this VT type represented a unique ECG-electrophysiological entity.²³ How much it is rewarding to see the great amount of electrophysiological work achieved over the years for getting insight into the diagnosis and mechanism of this specific VT and many other affiliated types^24,25 as well as achieving their definite cure with radiofrequency ablation (RFA).25, 26, 27

Idiopathic ventricular fibrillation: Diagnosis and management

As with the preceding case, the experience I acquired in the field of idiopathic ventricular fibrillation (VF) and its treatment with quinidine began incidentally. On February 23, 1979, just before leaving the emergency department after examining a 75-year-old patient with acute inferior myocardial infarction, I found an ECG on the floor that I rushed to pick up. Out of curiosity, I took a look and was surprised to note very short coupled premature ventricular complexes (PVCs) in the setting of an otherwise strictly normal ECG.²⁸

I was told that the ECG belonged to a 29-year-old man admitted with recurrent syncope who was on the way to be discharged home after a consulting neurologist referred him for ambulatory electroencephalogram for suspected epilepsy. After discussing with the patient and his wife, I had the feeling that an arrhythmic event (AE) rather than epilepsy could be responsible for the syncopal events and admitted him in the cardiac care unit. The arrhythmic storms documented a few hours later and during the following 36 hours gave me reason. Quinidine was extremely effective in this patient. It also prevented reinducibility of VF with programmed ventricular stimulation (PVS) and enabled him to live 40.5 years arrhythmia-free on that medication, without an implantable cardioverter-defibrillator (ICD), despite severe additional pulmonary problems requiring lung transplantation.²⁹

This case was the first of a series of patients with apparently idiopathic VF who underwent PVS and were found to have a >90% inducibility rate. This high inducibility rate enabled us to test the efficacy of class 1A drugs (mainly quinidine) and to demonstrate the high clinical and EP efficacy of these medications.^30,31 This positive response associated with an arrhythmia-free long-term follow-up in treated patients formed the basis of our policy to recommend EP-guided quinidine therapy during several decades in my department. Despite the current widespread use of ICD implantation in this type of patients, I still believe that there is a place for such a therapeutic option with quinidine in selected patients, especially those patients who refuse the ICD option, and who have inducible VF during baseline EPS that is prevented by quinidine. Such patients also need to exhibit an excellent tolerance and compliance to the medication.³²

Extensive reviews dealing with idiopathic VF were reported by Viskin and myself.^33,34

An important paper by Viskin et al³⁵ compared the QT intervals of patients with idiopathic VF and healthy controls. Short QTc values were commonly seen in male patients with idiopathic VF. However, short QTc values were also not rare in healthy adults, especially at slow heart rates.

Viskin et al³⁶ studied the mode of onset of ventricular arrhythmias initiating idiopathic VF in 22 VF episodes in 9 patients. In all instances, spontaneous VF followed rapid polymorphic VT, which was initiated by PVCs with very short coupling intervals (302 ± 52 ms). Pause-dependent arrhythmias were never observed. They concluded that non–pause-dependent initiation of the arrhythmia may be of diagnostic value in differentiating idiopathic VF from LQTS.

Finally, in a recent literature review with an extended follow-up of 86 patients with short-coupled idiopathic VF published during the last 40 years, Tovia-Brodie and I³⁷ found several interesting results: (1) an almost equal sex occurrence at a mean age of 40 years; (2) a tendency for later occurrence of the arrhythmia by 4 years in females; (3) a history of syncope in 45.3% of patients, whereas arrhythmic storm occurred in 42% at presentation; (4) for the first time, the presence of “not so short” coupling intervals (≥350 ms) initiating VF in a significant proportion of patients (17.4%); and (5) finally, the slightly higher success rate of quinidine over RFA in arrhythmia control during long-term follow-up.

Brugada syndrome: Diagnosis and risk stratification

All studies dealing with the diagnosis and risk stratification of Brugada syndrome (BrS) originated from Tel Aviv Medical Center under Sami Viskin’s mentorship. The first paper aimed to determine the prevalence of the Brugada sign—RBBB with ST-segment elevation in leads V₁–V₃—in patients with idiopathic VF and in an age-matched healthy population.³⁸ ECGs from 39 consecutive patients with idiopathic VF and 592 healthy controls were reviewed. Eight patients with idiopathic VF (21%) but none of the 592 controls had a definite Brugada sign (P < .005).

The second paper assessed the prevalence of Brugada ECG pattern in consecutive patients with fever and compared the ECGs of 402 patients with fever and 909 those without.³⁹ Type I Brugada ECG pattern was 20 times more common in the febrile group than in the afebrile group.

The third paper aimed to identify clinical and ECG risk markers for drug-induced BrS in 74 cases of drug-induced BrS from noncardiac medications.⁴⁰ These were predominantly observed in adult males, frequently because of drug toxicity, and occurred late after the onset of therapy.

The fourth paper is a comprehensive review of the data on arrhythmic risk stratification in BrS.⁴¹ A history of aborted cardiac arrest (CA) or malignant syncope was found to be a strong predictor of spontaneous VF, whereas the prognostic value of a history of familial sudden death and the presence of an SCN5A mutation were less well defined. The presence of type 1 Brugada ECG increased the risk of VF in all studies, whereas the presence of fragmented QRS complexes and early repolarization correlated with increased risk in several studies. The value of PVS for predicting spontaneous VF remained controversial. Risk prediction was particularly challenging in children and women.

Finally, 1 review paper summarized the history of BrS⁴² and 1 viewpoint paper summarized the top 10 reasons to avoid EPS in BrS.⁴³

Management of BrS: Quinidine and ICD

As for the previous section, all papers dealing with the management of BrS originated from Tel Aviv Medical Center.

It should be noted that we observed our first 3 patients with aborted CA and BrS before the Brugada brothers’ publication in 1992.⁴⁴ These were initially reported as having idiopathic VF in our 1987 paper³⁰ (cases 3, 4, and 5). At this time, our definition of idiopathic VF was not incompatible with ECG changes in right precordial leads and drug challenge with a sodium channel blocker drug was not available yet.

Considering that quinidine decreases the transient outward potassium current, which may play an important role in the arrhythmogenesis of BrS, we tested the EP effects of quinidine bisulfate (mean dose 1483 ± 240 mg) on 25 patients with BrS (1 woman) with baseline inducible VF,⁴⁵ including 7 CA survivors. Quinidine prevented VF reinduction in 22 of 25 patients (88%). After a follow-up period of 6 months to 22.2 years, all patients were alive. Nineteen patients were treated with quinidine for 6–219 months. None had an AE. Administration of quinidine was associated with a 36% incidence of side effects that resolved after drug discontinuation. In a second paper published 5 years later,³¹ we showed the excellent long-term reproducibility of the EP efficacy of quinidine in 5 patients with BrS. In a more recent paper, we reported our 33-year experience of using EP-guided therapy with class 1A antiarrhythmic drugs (mainly quinidine) in 96 patients (88% males; mean age 39.8 ± 15.9 years).⁴⁶ Ten patients were CA survivors, 27 had presented with syncope, and 59 were asymptomatic. VF was induced in 100%, 74%, and 61% of patients with aborted CA, syncope, and no symptoms, respectively. Fifty-four patients (90%) were EP responders to ≥1 antiarrhythmic drug with similar efficacy rates (≈90%) in all patient groups. Patients with no inducible VF at baseline were left on no therapy. After a follow-up of 113.3 ± 71.5 months, 92 patients were alive whereas 4 died of noncardiac causes. No AE occurred during class 1A drugs therapy in any of the EP-drug responders and in patients with no baseline inducible VF. AEs occurred in only 2 aborted CA survivors treated with ICD alone but did not recur on quinidine. All cases of recurrent syncope (n = 12) were attributed to a vasovagal (n =10) or nonarrhythmic (n = 2) mechanism. Class 1A drugs resulted in a 38% incidence of side effects that resolved after drug discontinuation. Our data confirmed that EP-guided therapy with class 1A drugs have a place in our therapeutic armamentarium for all types of patients with BrS.

On the basis of our experience with EP-guided therapy, we strongly stated that an ICD is not the only therapeutic option for treating BrS,⁴⁷ including in the debate I had with Pedro Brugada.⁴⁸

However, I was aware that the quinidine option would be possible for only a few centers considering its inaccessibility in many countries.^49,50

The role of ICD in the management of BrS was also assessed in 2 nationwide Israeli surveys.

In the first paper, Rosso and coworkers⁵¹ assessed the efficacy and complications of ICD therapy in 59 patients with BrS who underwent ICD implantation in 12 Israeli centers between 1994 and 2007. It was found that appropriate device therapy was limited to CA survivors while none of the other patients including those with syncope and/or inducible VF had an AE. The overall ICD complication rate was high.

In the second paper, Leshem and coworkers⁵² conducted the first nationwide survey focused on patients with BrS and documented AE. Israeli centers participated if they had treated patients with BrS who had aborted CA or lethal CA (group 1) or received appropriate therapy for tachyarrhythmias after prophylactic ICD implantation (group 2). The cohort comprised 31 patients: 25 in group 1 and 6 in group 2. During 143 ± 119 months of follow-up, 8 group 1 patients experienced appropriate shocks (none while on quinidine). During long-term follow-up, 5 group 2 patients received ≥1 appropriate shock and 1 had antitachycardia pacing for sustained VT (none taking quinidine). In conclusion, CA from BrS is apparently a rare occurrence on a national scale and no AE occurred in any patient treated with quinidine.

Finally, in 2009, Viskin and coworkers⁵³ called for a prospective registry dealing with empirical quinidine therapy for asymptomatic Brugada ECG type 1. The study encourages empirical therapy with hydroquinidine hydrochloride (600–900 mg/d; Serecor, Sanofi-Aventis, France).

BrS: Survey on arrhythmic events in Brugada syndrome

Considering the relatively small number of patients with BrS and AE reported worldwide, I took the initiative in April 2016 to launch an international survey involving the major BrS centers. Twenty-three of the 27 contacted centers (85%) agreed to participate. The number of patients provided by each of the 23 centers ranged from 7 to 105. The survey gathered 678 patients in total: 415 (61.2%) from 10 Western countries and 263 (38.8%) from 4 Asian countries. The success obtained by this great scientific adventure is mainly due to the exceptional participation of these 23 centers and the outstanding works provided by Anat Milman and Yoav Michowitz who accompanied me in this task.

General results

The Survey on Arrhythmic Events in Brugada Syndrome confirmed the previously reported male prevalence (91.3%), the mean age at the time of AE between the fourth and fifth decades (41.9 ± 14.8 years), the lower rate of spontaneous type 1 Brugada ECG, and VF inducibility rates in women.54, 55, 56 The survey showed several new findings dealing with age at the time of AE, patient sex, and patient profile.54, 55, 56

• 1.the paucity of AEs in the pediatric and elderly populations (4.3% and 1.5%, respectively);
• 2.the absence of male predominance in pediatric and elderly patients;
• 3.an earlier age at the onset of AE (by a mean of 6.7 years; 46.1 ± 13.3 years vs 39.4 ± 15.1 years) in patients who presented with aborted CA (group A) compared with those who experienced an AE documented after prophylactic ICD implantation (group B);
• 4.a later presentation (by a mean of 6.5 years) of the first AE in women;
• 5.no difference in age at the onset of AE between white and Asian patients;
• 6.a higher incidence of family history of sudden cardiac death (SCD) and SCN5A mutations in group B patients;
• 7.of the 252 group B patients, 189 (75%) complied with the Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society ICD indications whereas the remaining 63 (25%) did not, suggesting that efforts are still required for improving risk stratification; and
• 8.finally, higher SCN5A mutation rates in female patients with BrS and AE.

Fever-related AE in BrS

In 35 of 588 patients (6%) with available information, the AE occurred during febrile illness.⁵⁷ The mean age at the time of AE was 29 ± 24 years (range 0.3–76 years). The highest proportion of fever-related AEs was observed in the pediatric population (age <16 years), with a disproportionally higher event rate in the very young (age 0–5 years) (65%). Males were involved in all age groups and females only in the pediatric and elderly groups. Fever-related AEs affected 17 white patients younger than 24 years but no Asians younger than 24 years. Most patients (80%) presented with aborted CA and 6 (17%) with arrhythmic storm. Family history of SCD, history of syncope, and spontaneous Brugada ECG type 1 were noted in 17%, 40%, and 71% of patients, respectively. VF was induced at EPS in 9 of 19 patients (47%). An SCN5A mutation was found in 14 of 28 patients (50%).

Characterization and management of AE in young patients with BrS

A total of 57 patients younger than 20 years, all with BrS and AE, were divided into children (age <12 years; n = 26) and adolescent (age 13–20 years; n = 31) groups.⁵⁸ The children group differed from the adolescent group, with a higher proportion of females, whites, fever-related AEs, and spontaneous type 1 Brugada ECG. During follow-up, 68% of children and 64% of adolescents had recurrent AE, with a median time of 9.9 and 27.0 months, respectively. Approximately one-third of recurrent AEs occurred on quinidine therapy, and in children, 60% of recurrent AEs were fever related. Risk factors for recurrent AE included sinus node dysfunction, atrial arrhythmias, intraventricular conduction delay, or large S wave on ECG lead I in children and the presence of SCN5A mutation in adolescents.

Ethnic differences in patients with BrS and AE

There was no difference in age at AE onset (41.3 ± 16.1 years in whites vs 43.3 ± 12.3 years in Asians).⁵⁹ Higher proportions of whites were observed in pediatric and elderly populations. Asians were predominantly men (98.1% vs 85.7% in whites) and frequently presented with aborted CA (71.1% vs 56%). Asians tended to display a more spontaneous type 1 Brugada ECG (71.5% vs 64.3%). A family history of SCD was noted more in whites, with a higher rate of SCN5A mutation carriers (40.1% vs 13.2% in Asians) as well as more fever-related AEs (8.5% vs 2.9%). No difference was observed between the 2 groups with regard to history of syncope and ventricular arrhythmia inducibility.

Time-to-first appropriate shock in patients implanted prophylactically with an ICD

The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months.⁶⁰ A shorter time was observed in patients from Asian ethnicity, those with syncope, and those with class IIa indication for ICD. A longer time was associated with a positive family history of SCD. Multivariate Cox regression revealed shorter time-to-ICD therapy in patients with syncope. In 193 patients (76.6%), therapy was delivered during the first 5 years. Factors associated with this time were syncope, spontaneous type 1 Brugada, and class IIa indication as opposed to class IIb. A near-significant trend for female sex was also noted.

Genotype-phenotype correlation of SCN5A genotype in patients with BrS and AE

The study group comprised 392 probands: 92 (23.5%) SCN5A+ (44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A−. SCN5A missense variants and the patients hosting them were similar regardless of adjudication.⁶¹ A higher proportion of patients with P/LP were pediatric (<16 years) than SCN5A−. The proportion of females was higher in patients with P/LP than in SCN5A−. P/LP probands were more likely to have a family history of SCD than SCN5A−. A higher proportion of patients with P/LP were white than SCN5A−. Ethnicity and family history of SCD were independent variables associated with P/LP genotype after logistic regression.

Characteristics of patients with spontaneous vs drug-induced Brugada ECG

Of the 678 Survey on Arrhythmic Events in Brugada Syndrome participants, 451 (66.5%) had spontaneous type 1 Brugada ECG and 227 (33.5%) had drug-induced (DI)–Brugada ECG.⁶² Patients with DI-BrS represented a third of BrS cohort with AEs. They differed from patients with spontaneous BrS in sex, ethnicity, and VF inducibility rates. The most important observation is that this group of patients is less studied, and identifying high-risk patients with DI-BrS is not an easy task. We encourage seeking new risk markers in this group in future studies.

Early repolarization syndrome

All 4 papers dealing with the topic of early repolarization also originated from Tel Aviv Medical Center. Two of them were excellent review papers dealing with the malignant form of early repolarization.^63,64 The 2 others were original papers.

In the first original paper, Rosso et al⁶⁵ compared the ECGs of 45 patients with idiopathic VF with those of 124 age- and sex-matched control subjects and with those of 121 young athletes. They found that J-point elevation is found more frequently in patients with idiopathic VF than in healthy control subjects. The frequency of J-point elevation in young athletes is intermediate (higher than that in healthy adults but lower than that in patients with idiopathic VF).

In the second paper, Rosso et al⁶⁶ reanalyzed their case-control study showing that the presence of J waves strongly correlates with a history of idiopathic VF in 45 patients with this disorder, 124 controls matched for age and sex (“matched-control” group), and 121 young athletes. They found for the first time that the presence of J waves was associated with a history of idiopathic VF with an odds ratio of 4.0, but having both J waves and horizontal ST segment yielded an odds ratio of 13.8 for having idiopathic VF.

LQTS

Two Israeli cardiologists have played a tremendous role in the field of LQTS: Sami Viskin and Jesaia Benhorin. Back in Israel after his electrophysiology training in the Melvin Scheinman’s laboratory in San Francisco during which he first authored 2 important papers on LQTS,^67,68 Viskin published in The Lancet an outstanding review on LQTS and TdP⁶⁹ and continued with 2 contributions dealing with the role of cardiac pacing in the treatment of LQTS and especially of rate smoothing with cardiac pacing in preventing TdP.^70,71 Rate smoothing down values of 9%–20% were used, and β-blocker therapy was continued in all 12 studied patients.⁷¹ After 21 ± 11 months of follow-up, all patients (except 1, who died of cancer) are alive. Two patients had recurrent arrhythmias.

Prompted by the observation that many patients with LQTS are not identified by ECG, Viskin and coworkers⁷² presented the ECGs of 2 patients with LQTS and 2 healthy females to 902 physicians (25 world-renowned QT experts, 106 arrhythmia specialists, 329 cardiologists, and 442 noncardiologists) from 12 countries. The correct classification of all QT intervals as either “long” or “normal” was achieved by 96% of QT experts and 62% of arrhythmia experts, but by only <25% of cardiologists and noncardiologists.

One of the major contributions of Viskin was the design of provocative tests that may improve the diagnosis of LQTS. In 1 paper, adenosine or ATP injection was used to provoke heart rate oscillations (bradycardia followed by sinus tachycardia).⁷³ The test triggered QT changes that appeared to be useful in distinguishing patients with LQTS from healthy controls; the best discriminator was the QTc interval during maximal bradycardia. Notched T waves were observed in 72% of patients with LQTS, but in only 5% of controls during adenosine-induced bradycardia. In a second paper, Viskin and coworkers⁷⁴ showed that in response to quick standing, the QTc interval of patients with LQTS was longer than that of control patients, especially for LQT2. In a third paper, Adler et al⁷⁵ showed that the abnormal response observed during the quick-standing stress test persisted (“QT stunning”) even after the heart rate slows back to baseline. In a fourth paper, Chorin et al⁷⁶ used a quick-standing test to determine whether T-wave morphology changes provoked by standing aided in the diagnosis of LQTS and determination of the genotype in 100 patients with LQTS. They found that during quick standing, a QTc interval stretched ≥490 ms increased the odds of correctly identifying LQTS. T-wave morphology changes provoked by standing were most helpful for identifying LQT2, less helpful for LQT1, and least helpful for LQT3. Other important papers were published:

• 1.Birati and coworkers⁷⁷ reviewed ECG traces of TdP associated with LQTS, which were collected at Tel Aviv Medical Center and the Academic Medical Center of Amsterdam. Multiple lead recordings of 1025 LQTS-related arrhythmias, including 151 episodes of TdP and 874 QT-related extrasystoles (“impending TdP”), were available for 50 patients. Most episodes of TdP (56%) and most QT-related extrasystoles (70%) were suspected to originate from the right/left ventricular (RV/LV) outflow tract. These results show some concordance with those recently published by Pappone et al⁷⁸ in 11 high-risk patients with LQTS.
• 2.Rosso and coworkers⁷⁹ studied 91 patients who presented with AVB and who also had an ECG predating the bradyarrhythmia for comparison. They found that patients who developed a change in QRS morphology at the time of AVB had a 7-fold higher risk of developing long QT. This risk nearly doubled when the change in QRS morphology was accompanied by a change in QRS axis. They concluded that cardiac memory resulting from a change in QRS morphology during AVB is independently associated with QT prolongation and may be arrhythmogenic during AVB.
• 3.Chorin et al⁸⁰ studied the effects of ranolazine, a sodium channel blocker that preferentially reduces the late components (I_NaL) of the sodium current, both experimentally and in a clinical study of 8 patients. They showed that ranolazine blocks I_NaL in experimental models of LQT3 harboring the SCN5A D1790G mutation and shortens the QT interval of patients with LQT3.
• 4.To predict the QT interval in the presence of normal QRS duration for patients with left bundle branch block (LBBB), Yankelson et al⁸¹ measured the QT interval in 48 patients with new-onset LBBB who had a recent ECG with narrow QRS duration for comparison. They found that in patients with LBBB, replacing of the QRS duration after deriving the QTc interval with a fixed value of 88 ms for females and 95 ms for males provides a simple and reliable method for predicting the QTc interval before the development of LBBB.
• 5.Considering the increasing number of drugs that result in the prolongation of the QT interval mainly by blocking a specific rapid delayed rectifier potassium current (“I_Kr”) on the myocardial cell membrane and a similar observation observed in healthy subjects after drinking grapefruit juice, Chorin et al⁸² studied 30 healthy volunteers and 10 adult patients with congenital LQTS. Healthy volunteers drank 2 L of grapefruit juice (in divided doses), or received 400 mg of oral moxifloxacin, in a randomized crossover study. Patients with LQTS were tested with only grapefruit. They found that grapefruit juice, at doses tested, prolongs the QT interval. The effect was significant in healthy volunteers, greater in female patients, and more so in patients with LQTS.
• 6.Viskin and Halkin⁸³ also discussed the role of ICD in the management of LQTS.
• 7.Finally, Havakuk and Viskin⁴² wrote an interesting paper dealing with the history of LQTS.

Flecainide in LQT3

After describing a large LQT3-affected kindred with a new SCN5A mutation (D1790G), Benhorin and coworkers⁸⁴ were the first to assess the ECG effects of flecainide acetate, a type 1C sodium channel blocker, in 8 asymptomatic carriers of this mutation and 5 control subjects. Flecainide significantly shortened all heart rate–corrected repolarization duration parameters only in mutation carriers and not in control subjects. Flecainide also normalized marked baseline repolarization dispersion in most mutation carriers. These effects in carriers were maintained during long-term (9–17 months) outpatient flecainide therapy with no adverse effects.

In a long-term study involving 30 D1790G carriers who were treated with flecainide and followed for 1–215 months, Chorin and coworkers⁸⁵ confirmed the safety and efficacy of the medication. All carriers while being compliant with flecainide therapy had no cardiac events during an average follow-up of 83 ± 73 months. Six of 20 carriers (30%) who discontinued flecainide had cardiac events 1–11 months after discontinuing flecainide. Interestingly, flecainide induced the appearance of the Brugada ECG pattern in 6 carriers (20%; 5 males), was discontinued in 3, and was not associated with arrhythmia. Also, sinus node dysfunction was evident in 6 carriers (20%) and was fully corrected by flecainide in 3.

Polymorphic VT in various settings

Several outstanding original and review articles dealing with the issue of polymorphic VT in various settings have been published between 1998 and 2021 by the Tel Aviv Medical Center group: (1) polymorphic VT in the absence of organic heart disease⁸⁶; (2) polymorphic VT/TdP after acute myocardial infarction⁸⁷; (3) quinidine-responsive polymorphic VT in patients with coronary heart disease⁸⁸; (4) quinidine-responsive out-of-hospital polymorphic VT in patients with coronary heart disease⁸⁹; (5) importance of the QT and coupling intervals in the differential diagnosis of polymorphic VT, ischemic VF, and TdP⁹⁰; and (6) polymorphic VT: terminology, mechanism, diagnosis, and emergency therapy.⁹¹

Adenosine and ATP

In 1984, during a sabbatical in Hahnemann University (Philadelphia), I published with Amir Pelleg an extensive review on the “Electrophysiologic Effects of Adenosine Triphosphate and Adenosine on the Mammalian Heart: Clinical and Experimental Aspects.”⁹² The great efficacy of ATP on paroxysmal supraventricular tachycardia (PSVT) was already known since the first reports of Hungarian physicians on hundreds of patients in the early 50s.⁹² Two French groups including 1 led by Gilbert Motté also reported a series in which ATP—because of its strong dromotropic negative atrioventricular (AV) nodal effect—was found to terminate PSVT in >95% of the cases and slowed and enabled the diagnosis of atrial tachyarrhythmias. When the tachycardia did not respond to the medication, this allowed to consider VT or an AT with antegrade accessory conduction.⁹²

Considering the lack of clinical EP studies on the effects of ATP, we studied them in a series of patients with atrioventricular nodal reentry tachycardia (AVNRT) and atrioventricular reentry tachycardia (AVRT)⁹³ and compared them with those of verapamil.⁹⁴ Later a comparative study was made with IV magnesium.⁹⁵ The superiority of adenosine compounds was demonstrated and emphasized in a review.⁹⁶

Concomitantly, we compared the mechanism of action of adenosine and ATP on the negative chronotropic and dromotropic actions in experimental studies in dogs before and after chemical or surgical vagotomy, β-blockade, as well as after administration of dipyridamole and aminophylline, agonist and antagonist of adenosine, respectively.97, 98, 99 We found that in the intact canine heart, contrary to humans, there is a strong vagal involvement in the mechanism of action of ATP but not of adenosine and only a small part of the electrophysiological effects of ATP is the result of its degradation to adenosine.97, 98, 99, 100

We also investigated the effects of the bolus administration of ATP during sinus rhythm in patients with various mechanisms of PSVT. We found interesting results: (1) Antegrade dual AV nodal physiology was observed in 76% of patients with inducible AVNRT¹⁰¹; (2) AV reentrant echo beats and even AVRT could be observed in 73% of patients with inducible AVRT¹⁰²; and (3) this enabled us to extend the diagnostic use of ATP as a bedside test for identifying the mechanism of PSVT in patients suffering from nondocumented palpitations.¹⁰³ Also, we could assess the incidence of dual AV nodal physiology after the termination of AVNRT and compare it with drug administration in sinus rhythm.¹⁰⁴ Finally, we were able to successfully use the ATP test for assessing the results of slow pathway ablation in patients with AVNRT.¹⁰⁵ All these therapeutic and diagnostic uses of ATP were summarized in a paper.¹⁰⁶

PVS and risk stratification

In 1990, we reported the high sensitivity and specificity of a PVS protocol using up to 2 extrastimuli and repetition (n = 10) of double extrastimulation at shortest coupling intervals for induction of VT.¹⁰⁷ In 2009, we reported that an “aggressive” protocol of PVS including high stimulus current with repetition of double (n = 10) and triple (n = 5) extrastimulation could effectively be used for selecting patients with old myocardial infarction and a low ejection fraction who may not require an ICD.¹⁰⁸

Two studies performed in Tel Aviv and Sheba medical centers assessed the prognostic value of inducible ventricular flutter and found it comparable to that of sustained monomorphic VT.^109,110

We also found that laboratory induction of sustained nonclinical VT in amiodarone-treated patients does not imply the likelihood of their future spontaneous occurrence and therefore their prevention may not be required.¹¹¹ Finally, we extensively reviewed the noninvasive and invasive strategies for the prevention of sudden death after myocardial infarction.^112,113

VT: Mapping and ablation

The first world series of transcatheter electrical shock VT ablation including 8 patients was reported by our center in 1986¹¹⁴ after the tremendous success obtained by this technique in a patient with recent myocardial infarction and incessant VT refractory to drugs, pacing, and direct current shocks.¹¹⁵

Eldad and coworkers116, 117, 118 conducted in Sheba Medical Center the first world experiments of a transcutaneous multielectrode basket catheter for endocardial mapping and ablation of VT in a closed chest postinfarction pig model.

Boulos and his colleagues^119,120 from Rambam Hospital (Haifa) were the first to provide electroanatomic mapping of arrhythmogenic RV dysplasia and to differentiate between RV outflow tract tachycardia and arrhythmogenic RV dysplasia.

Michowitz and I¹²¹ reviewed the main ECG characteristics of epicardial arrhythmias.

Tovia-Brodie and coworkers¹²² assessed the clinical characteristics and site of origin of LV outflow tract arrhythmias in 42 patients who underwent RFA. The same group¹²³ subsequently reported the use of new imaging CARTO segmentation module software (CARTO Segmentation Module, Biosense Webster, Diamond Bar, CA) to facilitate ablation of ventricular arrhythmias in 18 patients with idiopathic ventricular arrhythmias or ischemic VT.

The approach for challenging ablation of outflow tract ventricular arrhythmia originating from the aortic cusps was reported by Ibrahim Marai on behalf the Rambam team.¹²⁴

Havakuk and colleagues¹²⁵ from Tel Aviv Medical Center aimed to evaluate the symptomatology of sustained monomorphic VT with an emphasis on the prevalence of palpitations. They found that despite similar heart rate, patients with VT rarely report having palpitations whereas patients with PSVT do so commonly.

Finally, 3 important works dealing with VT ablation were published by the team of Sheba Medical Center.

• 1.In a multicenter study of VT ablation in patients with The HeartMate3 (Abbott Laboratories, Chicago, IL), an LV assist device system with a magnetically levitated pump, Nof and coworkers¹²⁶ found that ablation in patients with HeartMate3 is feasible and safe when done in the appropriate setup. They concluded that long-term arrhythmia-free survival is acceptable but not well predicted by noninducibility at the end of the procedure.
• 2.Sabbag and coworkers¹²⁷ performed VT ablation in 46 venoarterial extracorporeal membrane oxygenation (VA-ECMO)–assisted patients. They found that decannulation from VA-ECMO may be done immediately at the conclusion of VT ablation in most cases. Failure to timely wean off VA-ECMO is a strong predictor of mortality.
• 3.Nissan and coworkers¹²⁸ found that the inducibility of >2 VTs during a VT ablation procedure remains a predictor of VT recurrence even after successful VT ablation. This group of patients remains at high risk of VT and should be followed up and treated more vigorously.

AFl/AF ablation

In a series of 845 patients undergoing 913 procedures of cavotricuspid isthmus ablation,¹²⁹ we found that 16 patients (1.9%) experienced AVB lasting ≥3 seconds: in 12 patients during delivery of radiofrequency (RF) pulses (group 1) and in 4 patients, all with preexisting LBBB, during manipulation of catheters in the cardiac chambers (group 2). The site of AVB was intranodal in group 1 and infranodal in group 2. Permanent pacemaker implantation (PPI) was required in 1 patient in group 1 and in all 4 patients in group 2 for a total PPI rate of 0.6%.

In a large worldwide survey involving 34,943 AF ablation procedures (72% men), Michowitz and associates¹³⁰ found that tamponade during AF ablation procedures is relatively rare (0.9%). Women have an ≈2-fold higher risk of developing this complication (1.24% vs 0.67% in men). Noteworthy was that the risk of tamponade in women decreased substantially in high-volume centers.

Two papers were devoted to a new irrigated multipolar nMARQ (Biosense Webster, Diamond Bar, CA) ablation catheter. The first by Rosso et al,¹³¹ which aimed to verify intracardiac signals with a second circular mapping catheter, and the second by Laish-Farkash and coworkers¹³² from Barzilai Medical Center (Ashkelon), which dealt with the safety and feasibility of contrast injection during pulmonary vein isolation with the catheter.

Two other papers by Laish-Farkash and associates^133,134 involved both the phased RF Pulmonary Vein Ablation Catheter (PVAC, Medtronic, Minneapolis, MN) and the irrigated nMARQ catheter.

The 2 most recent original papers dealing with AF ablation originate from Shaare Zedek Hospital (Jerusalem). Tovia-Brodie and coworkers¹³⁵ reported the anatomical accuracy of the KODEX-EPD (Philips, Netherlands) novel 3D mapping system of the left atrium during pulmonary vein isolation and its excellent correlation with computer tomography imaging. In the second paper, Rav Acha and colleagues¹³⁶ showed that cryoballoon AF ablation results in circumferential pulmonary vein fibrosis in the majority of pulmonary veins, as assessed by a new clinically relevant magnetic resonance imaging (MRI) analysis. A significant correlation was found between major pulmonary veins gaps on postablation MRI and AF recurrence, suggesting that MRI might have the ability to predict AF recurrence.

Finally, Ayzenberg et al¹³⁷ from Kaplan Hospital (Rehovot) reviewed the success rate and complications of 300 consecutive pulmonary vein isolation procedures performed in 291 patients during 2014–2015 in 8 medical centers (85% RFA). The overall 2-year success rate was 56% with a complication rate of 6.6% (2.5% serious), among them 2 deaths, 1 procedure related.

Ablation of AVNRT and accessory pathways

The 14-year Tel Aviv center results of RFA of AVNRT and accessory pathways in 901 and 508 patients were reported in 2006 and 2007, respectively.^138,139

Swissa et al140, 141, 142 and Fogelman et al¹⁴³ reported the results of ablation in the pediatric population at Schneider Hospital (Petach Tikva). This includes cryotherapy ablation of parahisian accessory pathways,¹⁴⁰ ablation of AVNRT with limited fluoroscopy,^141,142 and catheter ablation of left-sided accessory pathways in small children.¹⁴³

Wagshal et al¹⁴⁴ from Soroka Hospital (Beer-Sheva) reported that the ablation temperature correlates with the pattern of accelerated junctional rhythm produced during slow pathway ablation.

Iakobishvili et al¹⁴⁵ from Beilinson Hospital (Petach Tikva) found that the amount and duration of accelerated junctional rhythm is correlated with the total abolition of slow pathway conduction.

Finally, 2 original studies from Tel Aviv Medical Center conclude this subsection. Topilski and coworkers¹⁴⁶ found that spontaneous or inducible AVNRT is relatively common in patients with idiopathic outflow tract ventricular arrhythmias (17 of 68 [25%]).

Michowitz and associates¹⁴⁷ studied 1587 patients with AVNRT, of whom 20 had ≥1 first-degree relatives with AVNRT. This indicates a familial AVNRT prevalence of 127 cases per 10,000 (95% confidence interval 82–196 cases per 10,000). First-degree relatives of patients with AVNRT presented a hazard ratio of at least 3.6 for exhibiting AVNRT compared with the general population. After inclusion of 4 families with familial AVNRT who underwent ablation at another hospital, the population study comprised a total of 24 families (50 patients) with AVNRT. Familial AVNRT prevalence is higher than previously believed, suggesting that this arrhythmia may have a genetic component.

Catheter-induced trauma and ablation

All papers dealing with catheter-induced trauma during ablation originate from Tel Aviv Medical Center. We reported this phenomenon during most types of ablation: accessory pathways,^148,149 fast and slow nodal pathways,¹⁵⁰ ablation of AFl,¹²⁹ and outflow tract ventricular arrhythmias.¹⁵¹

Pacemakers/leads/ICDs/cardiac resynchronization therapy defibrillators

Among the 30 selected publications dealing with this field, two-thirds originate from the Michael Glikson’s group (in Sheba and Shaare Zedek hospitals). I have selected the following 11 papers:

• 1.After reviewing complete ICD follow-up data from 82 patients who received an ICD for stable VT, Glikson and coworkers¹⁵² found that these patients are at risk of subsequent unstable VT during follow-up. The estimated 2- and 4-year probabilities of any VT and unstable VT were 67% and 77% and 11% and 25%, respectively. These findings support ICD treatment for stable VT survivors.
• 2.Nof and coworkers¹⁵³ compared different coronary sinus leads and delivery systems for LV pacing (Medtronic, Guidant). They did not find significant differences in complication rates between systems and leads.
• 3.Rozen et al¹⁵⁴ evaluated a novel multipole method of the heart rate variability analysis in the prediction of imminent ventricular tachyarrhythmias in 28 patients with ICD. They found that the method emerges as a highly specific, possible predictor of imminent ventricular tachyarrhythmias.
• 4.Abu Sham'a and coworkers¹⁵⁵ found that the presence of baseline moderate or severe tricuspid valve regurgitation is associated with increased mortality but does not predict clinical or echocardiographic response to cardiac resynchronization therapy (CRT). Patients with worsened tricuspid regurgitation are less likely to clinically respond to CRT. Pacing leads passing through the tricuspid valve may worsen regurgitation.
• 5.Buber and coworkers¹⁵⁶ collected data of 300 ICD recipients of various manufacturers; 160 devices were strategically programmed to reduce shocks and 140 were not. Utilization of strategically chosen VT/VF detection and therapy parameters was found to be effective and safe in ICDs of various manufacturers at a median follow-up period of 2 years in primary prevention ICD recipients.
• 6.Younis and associates¹⁵⁷ analyzed data of 217 consecutive patients who underwent transvenous lead extraction with no intraprocedural complications. They found that 17 patients (9%) developed delayed shock during the first 24 hours. Reasons for shock were sepsis (47%) or no apparent cause (53%). In multivariate analysis, patients with delayed shock had a significantly lower glomerular filtration rate and more signs of systemic infection before extraction had more lead/tip remnants. Patients presenting with delayed shock had significantly higher mortality rates at 1-year follow-up.
• 7.Sabbag and coworkers¹⁵⁸ analyzed the baseline ECGs of 239 patients implanted with a CRT device between 2007 and 2010 and classified them into 3 groups: (a) typical LBBB according to the accepted guidelines (n = 67); (b) atypical LBBB pattern (n = 74); and (c) all other types of intraventricular conduction disturbances (n = 98). They found that patients with typical and atypical LBBB exhibited a similar echocardiographic response to CRT (75%–72%), higher than the group with other types of intraventricular conduction defect (52%).
• 8.Beinart and coworkers¹⁵⁹ analyzed the data of 1481 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial – Reduce Inappropriate Therapy and found that systolic blood pressure (≤120 mm Hg) predicted higher rates of ventricular tachyarrhythmias. However, low systolic blood pressure was not associated with an increased risk of atrial arrhythmias and inappropriate ICD therapy.
• 9.In a multicenter study involving 8 Israeli and 1 US (Mayo clinic) centers, Glikson and coworkers¹⁶⁰ prospectively evaluated the benefit of speckle tracking radial strain imaging–guided LV lead positioning in CRT in patients with ischemic cardiomyopathy and CRT indication. A total of 172 patients were enrolled with 2:1 randomization into 2 groups (guided vs control). The results showed that echocardiography-guided implantation of an LV lead using speckle tracking radial strain imaging does not improve the clinical or echocardiographic response compared with conventional implantation.
• 10.Milman and coworkers¹⁶¹ prospectively evaluated the outcome and safety of intraoperative defibrillation threshold testing (DFT) during device replacement (the Simpler trial) in 92 patients. The primary outcome was a failure to terminate induced VF with a single shock 10 J below the maximum capacity of the device. Secondary outcomes included complications of DFT. They found that induction of VF was successful in 84 patients as was successful conversion on the first attempt in all. There were no procedure-related complications.
• 11.Amitai Segev and coworkers¹⁶² retrospectively analyzed the incidence and predictors of failed shocks in 99 patients with hypertrophic cardiomyopathy wearing an ICD. Of the 18 patients who received an appropriate shock, 6 patients experienced at least 1 failed shock. The only predictor of failed shock was increased wall thickness. A maximum wall thickness of ≥25 mm was associated with a 20-fold (2.2- to 182-fold) increase in the risk of failed shock. While in all cases a second shock successfully terminated the clinical arrhythmia, this scenario may justify dual-coil leads or DFTs in selected individuals.

Of the remaining papers, I have selected the following:

• 1.The paper by Zeidan-Shwiri and coworkers¹⁶³ from Rambam Hospital who found that patients with an ICD and sleep-disordered breathing have a striking increase in the onset of life-threatening ventricular AEs during sleeping hours. These findings provide a rationale for sleep-disordered breathing screening in patients with appropriate ICD therapy if device interrogation reveals a predominance of nocturnal onset of arrhythmias.
• 2.The viewpoints by Viskin and Rosso¹⁶⁴ dealing with the top 10 reasons to avoid DFT during ICD implantation and that by Adler et al¹⁶⁵ dealing with wearable cardioverter-defibrillators.

Device complications: Infection, extraction, and perforation

Four important papers have been devoted to the issue of device complications.

In a multicenter study of lead perforation after cardiac implantable electronic devices (CIEDs), Rav Acha and coworkers¹⁶⁶ found that a conservative management of CIEDs lead perforation is associated with increased complications compared with early lead revision.

Nof and coworkers¹⁶⁷ sought to determine the predictors for success and outcomes of patients who underwent CIEDs extraction indicated for systemic or local CIEDs-related infection where complete lead removal could not be achieved. They used the results of a European prospective lead extraction registry involving 1865 CIEDs extractions. A total of 6.5% patients with infected CIEDs failed attempted extraction. Only those in which >4 cm of the lead remained resulted in higher procedural complications and mortality rates.

Also, using the data from the European lead extraction registry, Levi and coworkers¹⁶⁸ aimed to compare the safety, efficacy, and ease of extracting active fixation with those of passive fixation right atrial and RV leads. They found that the mechanism of fixation affects the ease of transvenous lead extraction of right atrial and RV leads and rates of complete radiological success in the right atrium but not clinical success.

Finally, Topaz and coworkers¹⁶⁹ evaluated the efficacy of delivering continuous, in situ–targeted, ultrahigh concentration of antibiotics into the infected subcutaneous device pocket, obviating the need for device/lead extraction. They treated a total of 80 patients with pocket infection with this method during 2007–2021. The extraction could be avoided in 90.8% of extraction-eligible patients treated with this method (59 of 65).

ICD Israel Registry

Under the direction of Mahmud Suleiman (Rambam Hospital, Haifa) and on behalf of the Israeli Working Group of Pacing and Electrophysiology, an Israeli ICD Registry has been settled and a total of 2807 consecutive patients undergoing ICD/CRT device implantation were prospectively enrolled between July 2010 and June 2012. To my best knowledge, there is no similar registry at the national scale. Twelve papers have been published between 2014 and 2019. I have summarized them below:

• 1.In a real-world scenario, elderly patients (age >75 years) who comprised ≈20% of ICD/cardiac resynchronization therapy defibrillator (CRT-D) recipients had a device reintervention rate similar to that of their younger counterparts. The association between advanced age and adverse clinical outcomes was attenuated in elderly patients implanted with a CRT-D.¹⁷⁰
• 2.No significant differences in the incidence of mortality, malignant ventricular arrhythmias, or inappropriate ICD discharges were observed between patients who underwent DFT and those who did not. These results may support avoiding DFT during ICD placement.¹⁷¹
• 3.In the real-world setting, women implanted with an ICD significantly differed from men in their baseline characteristics and in the use of CRT-D devices. This, however, did not translate into outcome differences.¹⁷²
• 4.Chronic kidney disease is associated with adverse prognosis after ICD implantation, but not after CRT-D implantation. The glomerular filtration rate decreased in patients with ICD, but not in those with CRT-D.¹⁷³
• 5.Israeli Arab patients who comprise ∼20% of the Israeli population constituted 15.7% of the ICD registry cohort. They display unique clinical features with a higher prevalence of nonischemic cardiomyopathy characterized by an early-onset and rapid deterioration.¹⁷⁴
• 6.Rates of lifesaving appropriate ICD shock therapies in patients implanted with an ICD for the primary prevention of SCD in the registry are lower than those reported previously (1.1% at 1 year of follow-up and 2.6% at 30 months in primary prevention patients, whereas the corresponding rates in the secondary prevention group were 3.8% at 1 year and 7.4% at 30 months).¹⁷⁵
• 7.Despite a significant excess of cardiac hospitalizations and mortality in the diabetic population, there was no difference in the rate of ICD treatments, suggesting that the outcome difference is not related to arrhythmias.¹⁷⁶
• 8.The presence of anemia in patients with ICD is associated with an increased risk of ventricular arrhythmias during long-term follow-up.¹⁷⁷
• 9.In octogenarians with systolic heart failure, CRT pacemaker therapy is associated with similar morbidity and mortality outcomes as CRT-D therapy.¹⁷⁸
• 10.Real-life rates of single-coil lead implantation are rising while adding no additional risk. These results of single-coil safety are reassuring and obtained, despite low and contemporary rates of DFT.¹⁷⁹
• 11.In a large real-life registry, implantation of quadripolar LV leads in patients with CRT-D (suggested to improve LV remodeling and overall mortality) did not influence heart failure hospitalization rates.¹⁸⁰
• 12.Patients with ischemic cardiomyopathy without heart failure symptoms have a higher risk of appropriate ICD therapy than do symptomatic patients after adjustment for the competing risk of death, suggesting a possible incremental benefit of primary ICD implantation in this population.¹⁸¹

Catecholaminergic polymorphic ventricular tachycardia

The Israeli contribution to the field of catecholaminergic polymorphic ventricular tachycardia (CPVT) has been significant in both laboratory and clinical settings.

Lahat and colleagues¹⁸² described an autosomal recessive form of CPVT with assignment of the disease gene to chromosome 1p13-21. They also reported that a missense mutation in a highly conserved region of calsequestrin-2 (CASQ2) is associated with autosomal recessive CPVT in Bedouin families from Israel.¹⁸³ Rosso and coworkers¹⁸⁴ reported the preliminary evidence of the superiority of combined β-blockers and calcium blockers over β-blockers alone for preventing exercise-induced arrhythmias in 5 patients. Khoury and colleagues¹⁸⁵ from Rambam Hospital found that flecainide can completely prevent ventricular arrhythmia during exercise and partially prevent recurrent ICD shocks in high-risk patients with CASQ2 mutation–associated CPVT. Marai and colleagues¹⁸⁶ from the same group provided interesting information on a series of patients with CPVT with mutations in CASQ2. Four of 5 patients who received an ICD had VT storms treated but not terminated by recurrent ICD shocks. These VT storms (2 episodes in 2 patients and 1 episode in each of 2 patients) terminated spontaneously after finishing the programmed ICD shocks, without degeneration to VF.

Blich and colleagues,¹⁸⁷ also from Rambam Hospital, compared the ECG characteristics of PVCs during the exercise test in 16 patients with CASQ2 mutation–associated CPVT with those in 36 healthy subjects. They found that several ECG criteria can help distinguish PVCs originating from CPVT compared to healthy subjects.

Nof and coworkers¹⁸⁸ reported an atypical type of CPVT in a large family carrying an RYR2-p.M4109R variant, wherein affected members developed marked and transient cardiac repolarization changes (QT prolongation associated with a tall and broad T wave) after pacing-mediated tachycardia and a subsequent pause. In vitro characterization of the RYR2-p.M4109R variant has revealed that it causes a loss of function and the familial diagnosis has been revised to calcium release deficiency syndrome, a recently discovered inherited arrhythmia syndrome.

Miscellaneous genetics

Along with new mutations associated with several inherited arrhythmias,189, 190, 191, 192 2 clinical papers, both by Blich and colleagues, should be pointed out. One deals with the role of 12-lead Holter, family screening, and genetic testing in 104 index cases of nonischemic sudden CA.¹⁹³ The second deals with the use of ECG, 12-lead Holter, exercise testing, cardiac imaging, familial study, and genetic testing to study 29 families in whom a child experienced sudden CA.¹⁹⁴

Arrhythmogenic cardiomyopathy

The prevalence of LBBB and RBBB morphology VT in patients with arrhythmogenic cardiomyopathy (ACM) and sustained VT was assessed from a European survey on ACM that we conducted.¹⁹⁵ Twenty-six centers from 11 European countries provided information on 954 patients with ACM who had ≥1 episode of sustained VT spontaneously documented during patients’ clinical course. We found that 882 patients (92.5%) displayed LBBB-VT alone and 72 (7.5%) RBBB-VT (alone in 42 [4.4%] or in combination with LBBB-VT in 30 [3.1%]). In conclusion, RBBB-VT accounts for a significant proportion of sustained VTs in ACM. Sex and type of pathogenic mutations were associated with VT type, female sex with LBBB + RBBB-VT, and DSP mutation with RBBB-VT. In a further analysis of the results of this survey, Laredo and coworkers¹⁹⁶ found that in patients with ACM and RBBB-VT, RBBB-VTs originated mainly from the inferior and lateral LV walls. Sinus rhythm depolarization and repolarization abnormalities were frequent and associated with underlying variants.

Transcatheter aortic valve replacement

The Israeli contribution to the field of pacing and electrophysiology dealing with transcatheter aortic valve replacement (TAVR) has been remarkable for a procedure that was been first Food and Drug Administration–approved for the indication of severe aortic stenosis in prohibitive risk patients in 2011.

In 2013, Goldenberg and coworkers¹⁹⁷ from Beilinson Hospital reported their results with PPI after TAVR in 191 patients undergoing the procedure between 2009 and 2011.

Hochstadt and coworkers¹⁹⁸ from Tel Aviv Medical Center analyzing a cohort of 1489 consecutive patients undergoing TAVR showed that postprocedure PPI was not associated with increased long-term mortality. This conclusion was not altered by ventricular pacing burden.

Natanzon and coworkers¹⁹⁹ from Sheba Medical Center found in a series of 1239 patients undergoing TAVR that PPI after TAVR was associated with higher 1-year adverse outcome, but this attenuated over time. Interestingly, pacing burden was associated with adverse clinical course.

Yankelson and coworkers²⁰⁰ analyzing a registry of 380 patients undergoing TAVR found that previous AF at baseline but not new-onset AF significantly increased stroke and mortality rates after the procedure.

In 2017, Tovia-Brodie and colleagues²⁰¹ from Tel Aviv Medical Center published what I do consider to be one of the best reviews on the value of EPS in decision making regarding the need of PPI after TAVR.

Younis and colleagues²⁰² from Sheba Medical Center showed that in patients undergoing TAVR who received chronic β-blocker therapy, drug discontinuation before the procedure was independently associated with a significant increase in the rate of adverse AEs, including high-degree AVB, new-onset AF, and the need for PPI.

Yagel and coworkers^203,204 from Hadassah Medical Center brought recent original contributions dealing with the prediction of AVB after TAVR. The R-wave amplitude in lead V₁ on the baseline ECG was found to correlate with the occurrence of high-degree AVB following LBBB after TAVR.²⁰³ Also, they found that although post TAVR-LBBB is associated with a leftward QRS axis shift in most patients, a non-negligible proportion of patients (27%) exhibited a rightward or no QRS axis shift.²⁰⁴ More interestingly, the latter group tended to have a higher risk of developing high-degree AVB.

Finally, Danone and colleagues²⁰⁵ from Carmel and Hadassah hospitals reported the first world series of RBBB after TAVR in 5 patients, outlining that this rare subset of patients may be at an increasing risk of AVB after TAVR, which may benefit from prophylactic PPI.

Coronavirus disease 2019

Tovia-Brodie et al²⁰⁶ reported the results of an international survey dealing with implantation of CIEDs in patients with active coronavirus disease 2019, showing that patients with active coronavirus disease 2019 who underwent CIED implantation had high complication and mortality rates.

Guidelines/expert consensus statement

Glikson and associates²⁰⁷ reported the outstanding 2021 European Society of Cardiology guidelines on cardiac pacing and CRT. Michowitz et al²⁰⁸ summarized them as the “10 commandments.” Finally, Sabbag and coworkers²⁰⁹ reported an European Heart Rhythm Association expert consensus statement on arrhythmic mitral valve prolapse.

Outstanding case reports

Among the case reports published by Israeli centers, I have selected the 10 following ones:

• 1.A fetal tachyarrhythmia was discovered at the 32nd week of gestation of a 22-year-old woman.²¹⁰ Fetal echocardiography revealed AF with rapid ventricular rate without any other demonstrable cardiac abnormality. Despite therapeutic maternal blood levels of digoxin, the fetal ventricular rate and cardiac size increased, which prompted one to perform cesarean section at the 34th week of gestation. A baby with WPW syndrome but no other cardiac anomaly was delivered. Recurrent episodes of nonsustained AF with conduction over the accessory pathway occurred in the first hours of life.
• 2.A previously asymptomatic and healthy 22-year-old man suffered in July 1994 an aborted CA during which VF was recorded.²¹¹ After successful defibrillation, Brugada ECG type 1 was present. During the exercise test, when the sinus rate was 180 beats/min, an LBBB-VT suggesting an RV outflow tract origin appeared, and the test discontinued. The tachycardia terminated spontaneously 1 minute later and could not be reproduced during the exercise test after administration of propranolol. We believe that this patient was the first reported case of sustained RV monomorphic VT associated with BrS.
• 3.A 35-year-old woman had a history of convulsions and syncopal episodes due to TdP related to LQTS, which responded to ventricular pacing.²¹² After PPI, while she was getting ready to leave the hospital, she had VF and CA. After defibrillation, her blood pressure was 190/130 mm Hg. The ECG (with the pacemaker temporarily off) showed deep T-wave inversion. She was scheduled for ICD implantation. Meanwhile, she was found to be pregnant and surgical abortion was performed. During and after the procedure, several episodes of both hypertension and hypotension were documented. The diagnosis of pheochromocytoma was raised and confirmed. A large tumor of the right adrenal gland was found and resected. The ECG normalized, suggesting that pheochromocytoma was the cause of LQTS.
• 4.An 18-year-old woman with recurrent idiopathic catecholamine-sensitive paroxysmal AF underwent ablation.²¹³ Recordings of multiple initiations of rapid atrial tachycardia/flutter (300 beats/min) at the proximal part of the right superior pulmonary vein using a single ablation catheter suggested local reentry in the vein as the mechanism of arrhythmia. A single RF pulse delivered at this site resulted in definitive cure of the arrhythmia.
• 5.A 67-year-old woman collapsed during swimming and was transferred to the hospital where a diagnosis of cardiac tamponade was made.²¹⁴ During the previous 3 years, she underwent multiple ablation procedures for AFl and AF, the latest procedure 3 months before the present collapse. Pericardiocentesis yielded minimal improvement, prompting emergency sternotomy. A large tear of the inferior vena cava and the right atrial free wall was observed and repaired. After surgery, the patient fully recovered. The last successful ablation line delivered was at the very lateral part of the cavotricuspid isthmus and probably played a critical role in the late cardiac rupture, along with exercise-induced mechanical tension over the atrial tissue.
• 6.A 38-year-old man with BrS and aborted CA was treated with quinidine without ICD on the basis of the results of EP drug testing.²¹⁵ Six months later, after suffering from vasovagal syncope, he opted to receive an ICD and decided to discontinue quinidine against our recommendation. Sixty-seven months later, he had recurrent VF that was terminated only by the 6th maximal energy shock delivered by the device (which has the capability to deliver a maximum of 8 shocks). This case suggests the possible risk in relying only on an ICD in the management of CA survivors with BrS.
• 7.An apparently healthy 78-year-old man presented with a 40-year history of rapid, regular, nondocumented palpitations very suggestive of PSVT, lasting up to 15 minutes, and always provoked by stress.²¹⁶ He refused to undergo EPS. About 1 month later, after a stressful event, the patient felt rapid palpitations resembling those he had experienced previously; however, this episode was unusually prolonged prompting hospitalization. The ECG showed unexpected monomorphic LBBB-VT (220/min) associated with moderate hypotension that required cardioversion. Coronary angiography and echocardiography showed normal findings. However, MRI was consistent with the diagnosis of RV cardiomyopathy/dysplasia without LV involvement. During EPS, sustained clinical VT was induced, but not SVT. Sotalol (80 mg thrice daily) prevented the reinduction of VT and was given during 14 years without ICD. The patient remained arrhythmia-free on that medication during follow-up. A pathogenic or likely pathogenic mutation in the desmosomal gene PKP2 [c.1613G>A (p.Trp538∗)] was identified.
• 8.A 68-year-old man was admitted to the hospital because of syncope.²¹⁷ He had no cardiac history. On questioning, he reported that his only brother (age 85 years) was apparently healthy but was hospitalized in our department 7 years earlier with no further medical information. At admission, his ECG showed monomorphic RBBB-VT (210/min). After cardioversion, sinus rhythm resumed with narrow QRS complexes. Coronary anatomy was unremarkable. MRI showed thinning of the LV anterolateral wall with akinesia as well as subendocardial and transmural late gadolinium enhancement. The RV had normal systolic function with suspected mild dyskinesia at the outflow tract area and a few microaneurysms at the free wall. Considering that the patient was the brother of the patient described above²¹⁶ and that genetic testing identified the same PKP2 mutation that was present in his older brother, we believe that he suffered from left-dominant ACM in the setting of familial ACM.
• 9.A 74-year-old man underwent successful TAVR for severe symptomatic aortic stenosis.²¹⁸ The preprocedural ECG displayed a borderline PR interval and normal QRS duration. Only mild PR prolongation was seen at day 1 after the procedure, with additional RBBB at day 2. On day 3, alternating RBBB and LBBB were documented, justifying PPI. On day 4, multiple episodes of nonsustained wide QRS tachycardia, at rates of 187–200 beats/min, lasting 10 to 15 seconds were observed. All these episodes had an LBBB morphology like the spontaneous LBBB complexes, but were clearly not paced beats. Interrogation of the pacemaker demonstrated ventriculoatrial dissociation during tachycardia, which suggests its ventricular origin. Bundle branch reentry VT, similar in morphology and rate to the patient’s clinical VT, was induced with double ventricular extrastimulation. RFA of the RBB resulted in complete AVB and prevented VT reinduction.
• 10.During routine follow-up, a 52-year-old man with known coronary artery disease was found to have a baseline asymptomatic VT at a rate of 190 beats/min.²¹⁹ The VT morphology (RBBB-left axis) prompted physicians to suspect a diagnosis of fascicular VT, which was confirmed by its immediate termination after IV verapamil (5 mg). The patient underwent RFA, and after a total number of 10 RF applications, VT could no longer be induced. A moderate pericardial effusion was drained. In the following hours, short-coupled PVCs ultimately resulting in VF were documented. These arrhythmias were suppressed by IV and then oral quinidine. Twenty-four hours later, the patient developed asystolic CA necessitating prolonged resuscitation, atropine, epinephrine, bicarbonates, and ventricular pacing. The patient condition improved. An ICD was implanted and quinidine discontinued 1 month later. No arrhythmias recurred at 6 months of follow-up. The mechanism of this exceptional “Purkinje angry syndrome” and the CA are discussed in length. Ironically, this exceptional non-previously reported major complication of ablation of verapamil-sensitive left posterior fascicular VT occurred in the same department where this arrhythmia had been first described >40 years earlier.²¹

Outstanding review

Cardiac memory is assumed to be an innocent ECG curiosity. However, during cardiac memory, reduction of repolarizing potassium currents increases LV repolarization gradients. Therefore, when cardiac memory occurs in patients who already have a prolonged QT interval (for whatever reason), it can lead to a frank LQTS with QT-related ventricular arrhythmias (TdP). These arrhythmogenic effects of cardiac memory have been reviewed here for the first time by Viskin and coworkers.²²⁰

Shlomo Ben-Haim and the CARTO system

The CARTO cardiac mapping systems (CARTO RMT TM, Biosense Webster, Diamond Bar, CA) have revolutionized the fields of therapeutic electrophysiology and interventional cardiology. This is the fruit of the outstanding and innovative work by Ben-Haim, Gepstein, and colleagues,221, 222, 223, 224 which began ≈30 years ago at the Cardiovascular Research Laboratory of Technion-Israel Institute of Technology, Haifa. Nowadays, more than 6000 electrophysiological centers worldwide are using CARTO systems for complex (and even less complex) ablation procedures.

Note: The colossal contribution of Michel Mirowski, a great Israeli cardiologist, was not recognized in this review. The only reason is that if Mirowski conceptualized the idea of ICD while he was working in Israel, the technology and funding of his invention could be possible only in the United States.^225,226