Ventricular fibrillation (VF) is an emergency condition that, without immediate treatment, leads to death. In the event of this malignant ventricular arrhythmia chaotic, disorganized electrical activity appears in the ventricular myocardium. In such cases the heart is unable to transport blood effectively, which leads to circulatory collapse, clinical death, and if left unattended, biological death. Sudden cardiac death (SCD) is a leading death cause all over the world, affecting some 5 million people a year (Berdowski et al., 2010; Glinge et al., 2016) with a low survival rate of approximately 10% (Kim et al., 2016). In the United States 300–400 thousand, while in Europe 700 thousand cases of sudden cardiac death are registered a year. Its incidence is 100/100000 in the case of 50-year-old men, it is as high as 800/100000 among men 75 years of age. SCD is more frequent among men than women (6.68/100000 vs. 1.4/100000) (Eckart et al., 2011; Priori et al., 2015). VF is the arrhythmia to manifest first and with the highest frequency in relation to registered circulatory collapses (Rea et al., 2004), which accounts for about 30% of the cases (Bourque et al., 2007).

The most common factors that may contribute to the development of VF are acquired risk factors, e.g., ischemic heart disease, cardiomyopathies, electrolyte imbalances, certain drug therapies affecting myocardial repolarization, and less frequently inherited disorders, e.g., ion channel abnormalities (channelopathies), congenital valvular diseases, and coronary artery anomalies. ( Table 1 ) (Garson and McNamara, 1985; Jouven et al., 1999; Thompson et al., 2000; Frothingham, 2001; Haddad and Anderson, 2002; Taylor, 2003; Yap and Camm, 2003; Vieweg and Wood, 2004; Owens and Ambrose, 2005; Haissaguerre et al., 2008; Priori et al., 2015; Aiba, 2019; Coutinho Cruz et al., 2019).

Channelopathies listed under inherited primary arrhythmia syndromes, like long and short QT syndromes and Brugada-syndrome (BrS), are important pathogenetic factors (Aiba, 2019). In 70% of long QT syndromes (LQTS) the mutation of the KCNQ1 or the KCNH2 (hERG) genes have been clarified. These genes encode the potassium channels responsible for the slow (I_Ks) and rapid component (I_Kr) of the delayed rectifier repolarising potassium current, respectively. Beyond KCNQ1 (LQT1) and KCNH2 (LQT2), SCN5A (LQT3) is the third most frequently affected gene that plays a role in the genesis of LQTS. Mutation of the SCNA5 contributes to an increase in the depolarising sodium inward current leading to the consequent prolongation of the QT interval (Priori et al., 2013). Furthermore, the role of mutations of the L-type calcium channel and other structural proteins was described in the pathogenesis of LQTS, however the triggering mutation has not been identified yet in many other cases (Schwartz et al., 2012). In the case of catecholaminergic polymorphic ventricular tachycardia (CPVT) the autosomal dominant inherited mutation of the type-2 cardiac ryanodine receptor has been identified as a possible cause. Moreover, the mutation of the Kir2.1 inward rectifier potassium channel encoded by KCNJ2 gene can also lead to CPVT (Priori et al., 2013). The Brugada syndrome is known as a familial disease which is inherited in an autosomal dominant pattern with incomplete penetration, however in 60% of the cases occurs sporadically (Campuzano et al., 2010). Nearly 400 gene mutations have been described as a possible underlying factor in the genesis of this disease, nevertheless, in more than 80% of the cases the mutation and/or copy number variation of SCN5A gene encoding the Kv1.5 voltage gated sodium channel have been found (Kapplinger et al., 2010; Eastaugh et al., 2011). However, recently a thorough evaluation of the routine genetic testing panels was made. As a result, mutation of SCNA5 gene was proven to be the only real, clinically valid disease-causing gene in case of BrS. Other gene-disease associations appeared to be debatable (Hosseini et al., 2018). The highest occurence of ECG alterations and cardiac events were reported in case of SCNA5 mutation among BrS patients (Yamagata et al., 2017). Several gene polymorphisms, epigenetic factors and posttranslational modifications were also revealed as a pathogenic condition of BrS in the past few years (Kim et al., 2013; Webster et al., 2013) Arrhythmogenic right ventricular dysplasia (ARVD) may also have an effect in arrhythmogenesis and the development of SCD (Marcus et al, 2010). The single nucleotide polymorphisms (SNPs) located in the 21q21 and 2q24.2 loci also contribute to an increased risk for SCD (Bezzina et al., 2010; Arking et al., 2011).

The electrical (repolarization) heterogeneity and secondary anisotropy of the ventricular myocardium play a crucial role in the genesis of VF. The monophasic action potentials (MAPs) characterising the electrical feature of a myocardial cell in the endocardial, mid-myocardial, and epicardial layers differ from each other, where types and expression levels of potassium channels responsible for transient outward currents (I_to) are also different. These dissimilarities can form a transmural voltage gradient during the activation of the ventricular myocardium. As a result, increased ventricular electrical anisotropy and an enhanced ventricular arrhythmia vulnerability may appear (Antzelevitch et al., 2000). Anisotropy can also be influenced by the differences in the distribution of intercellular electrical signal transducer gap junctions (Rohr, 2004). The macroscopic discontinuity of the myocardium (e.g., presence of septa, trabecula, papillary muscles), and the accumulation of connective tissue due to hypertrophy or infarction may also generate ventricular anisotropy (Antzelevitch et al., 2000). Scars and fibrotic tissues deposited parallel (not perpendicular) to the myocardial fibers can cease intercellular connections, consequently electrical conduction may turn irregular (Spach and Josephson, 1994). In the case of myocardial hypertrophy and heart failure (HF) the prolongation of action potential duration (APD) may consequently form early afterdepolarizations (EADs) (Nabauer and Kaab, 1998) Heart failure can cause a significant decrease in the repolarising I_to and delayed rectifier potassium currents (I_Kr and I_Ks currents of K channels encoded by KCNH2 and KCNQ1 genes) that may enhance the effect of proarrhythmic factors (e.g., hypokalemia, hypomagnesemia, class III antiarrhythmic drugs) (Nuss et al., 1996; Anumonwo and Lopatin, 2010). In the case of LQTS the mutation of potassium channels decreases their function by at least 50% leading to a prolonged repolarization, APD and QT interval. Class III antiarrhythmic drugs have a similar APD prolonging effect, that may contribute to an increased ventricular proarrhythmic susceptibility (Nuss et al, 1996; Peters et al., 2000). In the cases of heart failure and left ventricular hypertrophy, the downregulation of potassium channels, the decrease of transient outward currents (I_to) and the decrease of rapid and slow components of the delayed rectifier currents (I_Kr, I_Ks) can contribute to the prolongation of APD. Regarding HF, the overexpression of HCN2 and HCN4 genes can appear resulting in an increased pacemaker current (I_f) not only in the SA node, but in the ventricular tissue, too. The electrical remodeling of the heart can lead to a reduced ventricular repolarization reserve, increasing the risk of ventricular arrhythmias based on triggered activity, ectopic automaticity, and reentry mechanisms (Cerbai et al., 2001; Stillitano et al., 2008). ATP-sensitive potassium channels (K_ATP channels) localized in the sarcolemmal membrane may be activated by metabolic stress or ischemia causing the shortening of APD, preventing the heart from calcium overload and contraction abnormalities. Moreover, myocardial hypertrophy and ischemia can increase the expression levels of Kir 6.1 and Kir 6.2 K_ATP channels, leading to an increased risk for ventricular dysrhythmias based on heterogeneous shortening of the AP (Akrouh et al., 2009; Tinker et al., 2018). In 1998 repolarization reserve has been defined by Roden et al. as a defensive mechanism of the myocardium, which protects the heart from the emergence of arrhythmias in particular circumstances where APD has already been prolonged. For instance, enhanced inward Na⁺ currents contributes to an increase in delayed rectifier outward potassium current (especially I_Kr) as a compensatory mechanism in order to prevent the prolongation of repolarization. Furthermore, congenital alterations in ion currents of the myocardium, heart failure, cardiac hypertrophy, bradycardia, increased sympathetic activation, female gender, recent pharmacological conversion from atrial fibrillation to sinus rhythm, use of diuretics, hypokalemia, hypomagnesemia, administration of class IA, IC or III antiarrhythmic drugs or agents with I_Kr blocking effect can decrease repolarization reserve. Co-occurence of certain conditions which affect more than one type of ion currents involved in regular repolarization may critically reduce repolarization reserve and can result in proarrhythmia (Roden, 1998; Varró and Baczkó, 2011).

The underlying electrophysiological mechanisms of ventricular fibrillation consequently include ectopic automaticity, reentry and triggered activity (due to early and late afterdepolarizations) ( Figure 1 ) (Bayes De Luna et al., 1989; Peters et al., 2000).

Ectopic automaticity is the result of spontaneous diastolic depolarization, where current of injury (local alterations in K⁺ gradient) due to acute ischemic damage is an important provoking mechanism (Thygesen and Uretsky, 2004). In the case of ectopic automaticity it is a ventricular premature beat caused by inherited or acquired ectopic impulse-generating foci that most frequently play a role in triggering VF (Van Camp, 1992; Singh and Noheria, 2018). Ventricular premature beats may arise from any part of the electrical conducting system of the heart, especially from the Purkinje fibers, and may also originate from the right or left ventricular outflow tract, or the papillary muscles. Nevertheless, monomorphic ventricular tachycardia or atrial fibrillation as part of a preexcitation syndrome may also contribute to VF (Viskin et al., 2013).

A frequent underlying cause of the unidirectional block serving as the basis of reentry mechanism may be the prolongation of the monophasic action potential of the myocyte and the consequential heterogeneity of ventricular repolarization. This process may be facilitated by myocardial ischemia and may trigger an increase in the monophasic AP duration restitution slope as well as changes in the amplitude of AP (electrical alternans) (Krummen et al., 2016).

Triggered activity may also appear as a consequence of early (EAD) or delayed afterdepolarization (DAD). EAD is caused by the early reactivation of L-type Ca-channels, a consequence of a decrease in repolarising potassium currents or an increase in the activity of positive currents toward the intracellular space (Roden, 2016). Furthermore, oxidative stress, hypokalemia may also play an additive role in the pathomechanism of EAD (Antzelevitch et al., 1991; Karagueuzian et al., 2013; Antzelevitch et al., 2014; Markandeya and Kamp, 2015). In contrast, DAD develops after the repolarization of the myocyte membrane due to intracellular calcium excess or an increased sensitivity of intracellular ryanodine receptors (Priori and Chen, 2011). Delayed after depolarizations often serve as a background for ventricular arrhythmias caused by heart failure or digoxin toxicity and can also play a role in the genesis of CPVT (Priori and Chen, 2011).

Several diagnostic tools are available for the risk stratification of ventricular arrhythmias and sudden cardiac death. Certain parameters of the 12-lead surface ECG (e.g., QT interval and dispersion, T wave peak-to-end interval, arrhythmogeneity index, epsilon wave, delta wave, Brugada sign, J point elevation, etc.) may be of help in predicting life-threatening ventricular dysrhythmias and clarifying the underlying arrhythmia mechanism. Holter ECG may be useful in arrhythmia risk stratification (by determining T wave alternans, heart rate variability, QT variability, etc.). Echocardiography is widely used to determine structural and functional abnormalities of the heart. Accumulation of connective tissue in the left ventricle (scar burden) and fatty tissue in the right ventricle (ARVD) can be examined by MRI. Coronary CT angiography and coronarography may be of help to recognize coronary artery disease as a possible underlying arrhythmogenic factor. Electrophysiological testing is suitable for the examination of VT/VF inducibility and for the definition of the arrhythmia foci. Serum level of certain biomarkers may also be taken into consideration as part of ventricular arrhythmia risk assessment (Deyell et al., 2015).

The most effective therapies for ventricular fibrillation and pulseless ventricular tachycardia (pVT) are immediate high-quality chest compression as well as early defibrillation, which latter plays a key role in terminating these arrhythmias ( Figure 2 ) (Neumar et al., 2015).

Survival rate by early defibrillation in the case of resuscitation performed by lay people is 37.4% (Benjamin et al., 2017). The necessity of earliest possible electrical treatment is underpinned by the fact that the rate of successful resuscitation falls by 7%–10% per min from the circulatory collapse (Larsen et al., 1993). The availability of automated external defibrillators (AED) in public spaces and broad-scale training for lay persons about the use of the device may increase the current survival rate of 10% (Berg et al., 2019). In Scandinavia, there have been experiments with simulation practices using drones for the speedy delivery of AEDs with positive results and applying this method in real situations in future may improve the success rate of life saving as well (Sanfridsson et al., 2019). During a practice simulating out-of-hospital circulatory collapse the results of resuscitations performed by elderly bystanders (average age: 75.5 years) were compared considering several aspects. The bystanders did not have any prior training and the primary goal was to find out how modern telecommunication tools (smartphones, drones, AED) would affect their performance. Results showed that from the time of the circulatory collapse AED was placed on the simulated patients within 10 min and resuscitation started within 2.25 min (Sanfridsson et al., 2019).

An improvement in the chance of long-term survival and the least neurological damage were found in the case when the initial rhythm observed on site was ventricular fibrillation (Daya et al., 2015). Another important element of improving the neurological outcome is post-resuscitation care started in time, which includes coronary intervention and targeted temperature management (TTM) (Link et al., 2015). Based on the examination of 136 patients, the Hypothermia after Cardiac Arrest Study Group showed that the application of TTM clearly improved neurological outcome (based on CPC) and reduced mortality (Hypothermia after Cardiac Arrest Study Group, 2002). Stanger et al. examined 570 patients resuscitated after out-of-hospital sudden cardiac death who were administered TTM therapy in hospital. The patients were put into two groups depending on how many minutes after arrival in hospital TTM was started. The greatest difference between the early (20–81 min) and the late (167–319 min) groups was in survival. The early group had 1.59 times higher chance for survival compared to the late group, while they had only 1.49 times higher chance for a good neurological outcome, which did not prove clearly significant (Stanger et al., 2019). The 2015 resuscitation guideline recommends earliest possible PCI in the case of sudden cardiac death with acute coronary syndrome as the underlying cause (Nikolaou et al., 2015). Kahn et al. had found already that early PCI performed on patients who had suffered SCD due to STEMI could help survival with a good neurological outcome (Kahn et al., 1995). Examining 35 and 190 patients respectively, Nanjayya et al. and Bro-Jeppesen et al. compared patients who underwent and others who did not undergo immediate angiography and PCI in hospital, after out-of-hospital sudden death. Both studies found that early PCI had no significant positive effect on mortality (Bro-Jeppesen et al., 2012; Nanjayya and Nayyar, 2012). In contrast, Strote et al. found by retrospectively analyzing the data of 270 patients who had suffered sudden cardiac death that acute PCI (if performed within 6 h after the emergence of symptoms) ensured significantly better survival than PCI performed beyond 6 h (Strote et al., 2012).

Regarding long-term treatment of malignant ventricular arrhythmias, the application of implantable cardioverter defibrillator (ICD) is an important element, which releases an antitachycardia pacing or an electric shock at the occurrence of the rhythm disturbance ( Figure 3 ).

In a study with 2,521 patients involved Bardy et al. found that the implantation of an ICD able to deliver only shocks, combined with conventional conservative therapy, reduced total mortality rate by 23% in the case of NYHA II and III heart failure patients with EF <35% compared to conservatively treated patients (Bardy et al., 2005). Antitachycardia pacing (ATP) is in fact meant to reduce the number of superfluous or inappropriate shocks, whereby patients’ quality of life improves, and the lifetime of the device also grows. Most often the device delivers superfluous shocks due to supraventricular arrhythmias, which occurred in 8%–40% of the patients despite appropriate drug therapy. Moreover, ATP is also successful in stopping slow and fast ventricular tachycardia in almost 85%–90% of the cases, although it may happen in both cases if timing or setting are inappropriate that the ATP itself generates a malignant ventricular arrhythmia (Fisher et al., 1978; Schuger et al., 2012). In the CASCADE study cardiac dysrhythmias due to ICD dysfunction have been shown to be significantly reduced by long-term administration of amiodarone (CASCADE study, 1991). This favourable effect of amiodarone is more pronounced compared to class IC antiarrhythmic drugs, e.g., quinidine, procainamide, and flecainide (Huang et al., 1991). However, there are cases reporting the effectiveness of long-term quinidine therapy administered shortly after intravenous infusion of β-adrenoceptor agonist isoproterenol in the case of VF storms in patients with BrS, when amiodarone was ineffective (Jongman et al., 2007; Dakkak et al., 2015). According to further observations the number of appropriate and inappropriate ICD shocks can be reduced by sotalol, nevertheless overall mortality seems not to improve compared to placebo (Kühlkamp et al., 1999; Bollmann et al., 2005). Azimilide, another class III antiarrhythmic drug equally inhibits the rapid and slow components of delayed rectifier K⁺ currents. It has the same positive effects as amiodarone, but it is known to cause less proarrhythmic effect. Additionally, azimilide has not been proven to reduce left ventricular systolic function during long-term antiarrhythmic treatment (Dorian et al., 2004). Positive effects of dronaderone and dofetilide (blocker of the rapid component of delayed rectifier K⁺ current) were also described, but less antiarrhythmic and mortality reducing effects were verified compared to amiodarone and sotalol (Bollmann et al., 2005). Recurrent VF episodes were registered in more than one third of ICD patients treated with amiodarone alone. Importantly, more favorable results were found in patients on combined β-adrenoceptor antagonist and amiodarone management (Connolly et al., 2006).

Newest ICDs are suitable for the purpose of cardiac resynchronization therapy (CRT) as well. Tang et al. examined 1798 patients, half of whom were grouped, in a randomized way, into the category ‘only ICD’, while the other half into the category ICD complemented by CRT. In the course of the 40-month examination period they found that the relative risk of cardiovascular death in the CRT group fell by 24% compared to the ‘only ICD’ group, and the frequency of hospitalization was also signifcantly lower (Tang et al., 2010).

The European Society of Cardiology has issued recommendations for subcutaneous ICDs as well. The malfunctioning of these devices develops rarely, although the application of ATP or cardiac resynchronization is not available.

The implantation of ICD’s is mainly performed as secondary prevention combined with β-adrenoceptor antagonist therapy (e.g. metoprolol 100 mg/die, carvedilol 50 mg/die or bisoprolol 10 mg/die) for patients who suffered malignant ventricular arrhythmia episodes (Connolly et al., 2006). For the purpose of primary prevention ICD’s are implanted primarily for patients with congenital heart diseases, but according to the AHA protocol currently in force it is to be considered for patients suffering from heart failure as well (Al-Khatib et al., 2018). MADIT, MADIT-II, and SCD-HeFT trials proved that populations suffering from heart failure and ischemic heart disease, ICD implanation significantly improved overall mortality without any additional therapies (Moss et al., 1996; Moss et al., 2002; Mark et al., 2006). Accordingly, ICD implantation as a primary prevention is recommended for NYHA I heart failure patients where left ventricular ejection fraction is under 30%, for NYHA II and III patients where EF is under 35% and in the case of ischemic heart disease where EF is less than 40% (Al-Khatib et al., 2018).

The administration of β-adrenoceptor antagonists has especially great significance in the case of congenital heart disease patients and primary ion channel diseases. Both the short- and long-term survival of inherited long QT syndrome patients is clearly positively influenced β-adrenoceptor antagonist therapy unless it is the LQT3 type. The suggested β-adrenoceptor antagonists are propranolol (2–4 mg/kg/die) or the long-acting nadolol (1.5 mg/kg/die), while other β-adrenoceptor antagonists, e.g., metoprolol or atenolol seem to be ineffective in this particular indication. Regarding LQT3, drugs decreasing the late sodium current, e.g., flecainide, dofetilide, mexiletine, or ranolazine can be administered (Schwartz et al., 2012; Antzelevitch et al., 2014). Wilde et al. examined 118 LQT3-type LQT syndrome patients who had suffered some cardiac event (SCD, syncope, aborted cardiac death). They found that the administration of β-adrenoceptor antagonist reduced the development of a similar cardiac event among these patients later on by 83% in the case of women, while no such difference was found in the case of men (Wilde et al., 2016). The study of Shimizu et al. also emphasises the difference between the two sexes. They sequenced the clinical genomes of 1,124 patients including the pathological mutations causing the long QT syndrome. The retrospective data and the genetic findings together highlight the fact that LQT1 and LQT2 mutations much more frequently involve malignant ventricular arrhythmias in the case of women, while as regards the other 3 major types of mutation no differences can be detected between the two sexes (Shimizu et al., 2019). This is one reason why a widening range of attempts have been made for the genetically based risk assessment of channelopathies as it may be of use in the selection of closer observation and specific drug therapy.

ACE-inhibitors and aldosterone antagonists (eplerenone), which protect from ventricular arrhythmias associated to ischemic heart disease primarily, reduce the heterogeneity of APD and left ventricular reverse remodelling and lower the risk of sudden cardiac death (Alberte and Zipes, 2003; Pitt et al., 2003). It was confirmed in the CONSENSUS study already that in the period examined the administration of enalapril in the case of 253 patients suffering from NYHA IV heart failure reduced the development of SCD by 27% (CONSENSUS Trial Study Group, 1987). In the SOLVD study examining 2569 patients Lam et al. found that the administration of 20 mg enalapril per day reduced overall mortality by 12% and cardiovascular mortality by 4% in the case of heart failure patients (Lam et al., 2018). In the SAVE trial on 2,231 patients the administration of 3x25 mg captopril daily reduced overall cardiovascular mortality by a few percent compared to the placebo group but it did not meaningfully affect the risk of sudden cardiac death (Pfeffer et al., 1992). In the HOPE study 9,297 patients with preserved left ventricular function, but high cardiovascular risk were examined. Patients taking 10 mg of ramipril daily had a relative risk of 0.62 for SCD compared to placebo group (The Heart Outcomes Prevention Evaluation Study (HOPE) Investigators, 2000). Based on PROGRESS, EUROPA and ASCOT-BLPA trials the administration of 4–10 mg perindopril daily (individual dose is required based on kidney function and other taken drugs) significantly reduced cardiovascular mortality and the occurence of sudden cardiac death (Campbell, 2006). On the contrary, in the IMAGINE study 2,553 patients with left ventricular ejection fraction ≥40% were examined who underwent CABG, where 40 mg quinapril were given daily early after the operation. Compared to the placebo group there were no significant positive effects on cardiovascular mortality and on the occurrence of ventricular arrhythmias up to 3 years after surgery. However, ACE-I treatment increased the incidence of adverse events, mainly early after CABG (Rouleau et al, 2008).

The angiotensin-receptor blocker candesartan was proven, based on the CHARM low LVEF study published in 2004, to signifcantly reduce overall mortality as well as cardiovascular mortality when added to the base therapy of chronic heart failure patients with left ventricular EF of lower than 40% (Young et al., 2004). The same was confirmed by the favorable findings of the RESOLVD study where candesartan was added to the ACE-inhibitor (enalapril) and β-adrenoceptor antagonist (metoprolol) and the triple combination produced more favorable prognosis (McKelvie et al., 2003). Based on the data of ONTARGET, PROFESS and TRANSCEND studies the positive effects of angiotensin receptor blocker telmisartan at the daily dose of 80 mg on cardiovascular mortality and on the occurence of ventricular arrhythmias were confirmed. At the same time the superior effects of ACE-Is (e.g., ramipril, perindopril) compared to telmisartan were also noted (DiNicolantonio and O’Keefe, 2014).

Statins are inhibitors of the hydroximethylglutaryl coenzyme A reductase, i.e., they reduce the serum cholesterole level, in addition to which, thanks also to their pleiotropic effect, they reduce the likelihood of malignant ventricular arrhythmias. The DEFINITE study examined 229 non-ischemic heart disease patients undergoing ICD therapy where the administration of statins significantly reduced ventricular arrhythmogenesis and sudden cardiac death compared to patients without statin administration (Goldberger et al., 2006).

Furthermore, in the case of arrhythmias triggered by EADs, inhibitors of the L-type Ca⁺⁺ currents may be administered as part of the long-term therapy. Morita et al. found that the late type Na channel blocker ranolazine reduced repolarization heterogeneity, and increased the threshold potential value required for the development of VF. In addition, its non-selective blocking property on L-type Ca channels and I_Kr, I_Ks currents was detected, too. Ranolazine is also effective in the case of VF with underlying reentry mechanism (Morita et al., 2011) and has been furthermore proven to signifcantly reduce the delivery of inappropriate ICD shocks (Bunch et al., 2011; Zareba et al., 2018). However, further data are needed to clearly evaluate the exact role of ranolazine in the prevention of SCD. According to the latest ESC guideline, ranolazine is recommended only in the case of LQTS3 patients as a preventive treatment of ventricular fibrillation (Priori et al., 2015).

The cyclin-dependent kinase inhibitor roscovitine, originally developed as a chemotherapeutic agent, accelerated the inactivation of L-type Ca channels in the course of model experiments, thereby reducing the likelihood of the development of ventricular arrhythmias (Krummen et al., 2016). Further research is however needed with reference to these agents.

In the cases of recurrent or refractory VF and ICD storms secondary to repeated VF episodes, ablation of VF triggers and substrates have to be taken into consideration. In these circumstances electrophysiological testing, and intracardiac mapping are performed (Cheniti et al., 2017). In order to clearly localize the ablation site, beyond classical pace mapping, entrainment and phase mapping, lately, activation, or substrate mapping have been accomplished (deBakker, 2019). Radiofrequency ablations of both VF triggers and subtrates have to be achieved. Endocardial data can be completed with epicardial maps served by electrocardiographic imaging (ECGI) method. During ECGI process a special vest with 252 surface electrodes is worn by the patients. Data of ECGI combined with computer tomography raise the opportunity of a more exact localization of arrhythmia foci. During ECGI procedure together with intracardiac mapping, both endo- and epicardial maps can be gained by the investigator (Singh and Noheria, 2018).

In VF patients with ischemic heart disease, non-ischemic cardiomyopathies, valvulopathies, amyloidosis, long QT syndromes and IVF, short-coupling triggering ventricular premature beats originating from the Purkinje system were identified and ablated (Cheniti et al., 2018; Singh and Noheria, 2018). In 2011, successful epicardial ablations of premature beats of the right ventricular outflow tract (RVOT) were published in patients with BrS. In 2019, another study provided data on the VF ablation of 52 ERS patients. These interventions were carried out in the right ventricle, RVOT and Purkinje fibres. In both studies, during a 3-year follow-up period, 90% of patients were reported to be free of recurrent VF episodes (Nademanee et al., 2011; Nademanee et al., 2019).

Sudden cardiac death is a leading death cause in developed countries, its fast and effective treatment as well as prevention are therefore high priority tasks. There are several non-invasive diagnostic opportunities serving the timely detection of diseases increasing susceptibility to inherited and acquired ventricular arrhythmia, and earliest possible detection is followed, as part of a long-term therapeutic strategy, by the assessment and application of drug and device therapy on an individual basis. In the case of cardiopulmonary resuscitation early defibrillation in addition to minimally interrupted chest compression has been proven to improve the outcome of patients. Radiofrequency ablation of VF triggers and substrates is also a feasible and emerging therapeutical opportunity.

All authors confirm that they have read and approved the paper and they have met the criteria for authorship. ZS: wrote the manuscript. DU: took part in preparing the manuscript. TÖ: took part in preparing the manuscript. VS: took part in preparing the manuscript. PN: prepared and reviewed the manuscript before publication.

This work was funded by GINOP-2.3.2-15-2016-00062.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.