In early reports showing the onset of idiopathic VF [3, 33, 52], a similar ECG pattern of the first short-coupled ventricular extrasystole was observed, namely left bundle branch block pattern and left axis (Fig. 36.2). However, later reports [34, 35], showed that extrasystoles with other patterns do exist, suggesting various possible origin sites. Interestingly, when multiple episodes of polymorphic VT are recorded with 12-lead recordings, the morphology of the initiating beats of all these episodes is similar. This applies not only to the first complex, but to the second and third complexes of the polymorphic arrhythmias as well (Fig. 36.2). The last observation supports the notion that idiopathic VF has a focal origin (see below) [34, 35].

Excluding all forms of organic heart disease is essential before the diagnosis of idiopathic VF is considered. However, it should be noted that some forms of organic heart disease may cause malignant ventricular arrhythmias at a time when the anatomic abnormalities are minimal and difficult to detect by imaging modalities. For example, patients with hypertrophic cardiomyopathy due to Troponin-T mutations may be at risk for arrhythmic death at a time when left ventricular hypertrophy is still mild [79, 80]. Similarly, right ventricular dysplasia is sometimes identified as the underlying cause of sudden death only during forensic examination and despite negative extensive diagnostic workup [81]. Of note, subtle anatomic abnormalities, like mitral valve prolapse without hemodynamic significance, should not necessarily be accepted as the cause of cardiac arrest. On the other hand, signs of severe left ventricular dysfunction after resuscitation should not necessarily be used to exclude the diagnosis of idiopathic VF because prolonged resuscitation may result in transient electrocardiographic and echocardiographic abnormalities that are indistinguishable from those seen in patients with dilated cardiomyopathy [82, 83]. If such abnormalities resolve, the diagnosis of idiopathic VF should obviously be considered.

Patients with atrioventricular accessory pathways may have minimal or no ventricular preexcitation (i.e., may have narrow QRS complexes) if they also have fast conduction along the AV node or if their accessory pathways is located on the left lateral wall (far away from the sinus node). Yet, these pathways may have short refractory periods. Such patients may develop atrial fibrillation with rapid ventricular rates that may deteriorate to VF. If the preexcited atrial fibrillation is not recorded and the patient is found in VF, the near-normal electrocardiogram during sinus rhythm may lead to a wrong diagnosis of “idiopathic VF” because all imaging tests will be normal. The wrong diagnosis of idiopathic VF may gain further support from electrophysiologic studies if atrial stimulation is not performed prior to ventricular pacing because programmed ventricular stimulation is likely to induce VF in patients with WPW [84]. Therefore, excluding accessory pathways – either with adenosine injection as a bedside test or with atrial pacing during electrophysiologic studies – is a mandatory step in the work-up of VF survivors even when the electrocardiogram is judged to be “normal”. Of note, rare cases of cardiac arrest caused by very rapid supraventricular tachyarrhythmias in patients without Wolff-Parkinson-White have also been described [85].

Physicians may opt to skip performance of exercise testing in cardiac arrest survivors reasoning that coronary angiography will eventually reveal any significant coronary lesion. We have encountered patients with CPVT who were erroneously diagnosed as “idiopathic VF” only because exercise stress testing was not performed. Since all other tests, including electrophysiologic studies, are invariably normal in this disease, exercise stress test is a mandatory test in cardiac arrest survivors. Although the majority of patients with CPVT have a pathognomonic response to exercise (exercise-induced atrial fibrillation followed my multifocal ventricular extrasystoles, bidirectional VT and polymorphic VT), it was recently recognized that some patients with genetically proven CPVT have only single ventricular extrasystoles that look like typical “benign right ventricular outflow tract (RVOT) extrasystoles” during maximal exercise [86, 87]. More recently, a family with CPVT in which affected individuals had negative exercise stress tests but were identifiable by marked post-pause QT prolongation, was described [88]. Such patients could easily be misdiagnosed as “idiopathic VF.”

The QTc intervals of the healthy population, as well as the QTc of patients with LQTS have a normal distribution and there is considerable overlapping between the QTc of both populations. Importantly, 12 % of patients with genetically proven LQTS have “normal” QT when the latter is defined as QTc <440 ms [89]. Identifying patients with LQTS who have borderline QT is especially challenging in the LQT1 genotype because the T-wave morphology, which is frequently abnormal in LQT2 and LQT3, is most often normal in LQT1. Fortunately, the epinephrine challenge test is especially effective for unraveling abnormal QT responses in LQT1 [76, 77]. We recently described that the sudden tachycardia induced by standing unmasks LQTS in borderline cases and use that as a bedside test [73].

The newly described SQTS [15, 16, 23] is caused by genetic mutations involving the same potassium channels that cause the LQTS but with an opposite effect [90–93]. In other words, in the SQTS there is excessive outflow of potassium currents, shortening the action potential duration and the effective ventricular refractory period. Distinguishing idiopathic VF from SQTS is not easy. Although the original cases of SQTS had extremely short QT intervals (QTc shorter than 300 ms [15, 16, 23] more recently described cases of genetically proven SQTS have QTc intervals of 360 ms [25]. Also, we recently showed that “relatively short” QT intervals (QTc <360 ms) are frequently observed in healthy males but are statistically more common in males with idiopathic VF [18]. Moreover, patients with idiopathic VF have normal QT intervals at normal heart rates, but their QT fails to lengthen as their heart rate slows down, leading to abnormally short QTc values during bradycardia [26, 27]. Finally, patients with SQTS and patients with idiopathic VF share the following clinically characteristics: (1) Both patient groups have similar spontaneous [5, 17] and inducible [3, 23] ventricular arrhythmias; (2) both patient groups appear to respond especially well to quinidine therapy [33, 52, 54, 94, 95]; (3) both patient groups are at risk for inappropriate ICD-shocks because of intracardiac T-wave oversensing [96, 97]. Patients with SQTS may be misdiagnosed as “idiopathic VF” if the QT interval is measured only during relatively rapid heart rates. This is because the main problem in the SQTS is failure of appropriate QT lengthening during bradycardia [23].

We estimated that one out five patients originally diagnosed as “idiopathic VF” have in fact Brugada syndrome [13] and very similar numbers were reported by others [98]. Moreover, if all patients with idiopathic VF undergo systematic testing with repeated electrocardiograms [99] and Holter recordings [100] with the right precordial electrodes placed at higher positions, as well as pharmacological challenge tests using sodium-channel blockers, as many as 40 % with idiopathic VF could be diagnosed as Brugada syndrome [101].

The right ventricular outflow tract (RVOT) is the site of origin of the most common type of ventricular tachycardia (VT) occurring in patients without organic heart disease [33]. This RVOT-VT has a distinctive morphology (QRS complexes with left bundle branch block pattern and tall R waves in the inferior leads) and, in general, does not lead to hemodynamic decompensation. Therefore, RVOT-VT is considered a benign arrhythmia [33]. However, our group [65] and the group of Noda and Shimizu [66] recently described patients with otherwise typical “benign RVOT ectopy” who went on to develop spontaneous VF or polymorphic VT. It is not clear if patients with idiopathic VF and patients with this newly described form of “polymorphic VT from the RVOT” represent different aspects of one disease or two distinct disorders [102]. However, several characteristics differ among both groups: (1) otherwise typical monomorphic RVOT-VT is also seen in patients with malignant polymorphic RVOT-VT [65, 66] but is never seen in idiopathic VF. (2) Only 5 % of patients with “malignant polymorphic VT” have inducible VF [65, 66] by programmed ventricular stimulation, whereas the majority of patients with idiopathic VF have inducible VF [33, 52]. (3) the coupling interval of the ventricular extrasystoles initiating the malignant ventricular arrhythmias is invariably very short in idiopathic VF [3, 5] but is longer, varying from “relatively short” [65] to “normal,” [66] in the “polymorphic RVOT-VT” [103]. The last observation is consistent with the results of intracardiac mapping performed by Haissaguerre [35]: In that series, idiopathic VF originated from Purkinje fibers in 86 % of the patients and from the RVOT in the remaining 14 %. Again, the coupling interval of the extrasystoles initiating VF was longer for arrhythmias originating in the RVOT than for arrhythmias triggered by Purkinje fibers (355  ±  30 ms vs. 280  ±  26 ms, p  <  0.01) [35].

The very first patients with idiopathic VF described in the literature, back in 1929 [1] and 1949 [105], were treated with quinidine after multiple episodes of spontaneous polymorphic VT and VF were clearly documented. Both patients had an excellent response [1, 105]. In fact, a second publication reporting the long term follow-up of the patient initially reported in 1949, established that this patient eventually died of cancer at old age, without ever experiencing arrhythmia recurrence while on quinidine therapy for 40 years [106]. In 1987, Belhassen pioneered the therapy of idiopathic VF with EPS-guided quinidine after observing that VF is easily inducible at the baseline state but no longer inducible after quinidine therapy [2]. Of note, one of the patients included in that original report [52], has completed >25 uneventful years of electrophysiologic-guided therapy with amiodarone and quinidine after experiencing arrhythmic storms of VF in the absence of therapy and recurrent arrhythmic syncope on amiodarone alone [94].

In 1990, when we first reviewed the topic of idiopathic VF [3], we found that the recurrence rate of cardiac arrest was high during therapy with other antiarrhythmic drugs (including amiodarone, beta-blockers or verapamil) [3]. The high-rate of arrhythmia recurrence with verapamil is worth noting because that drug was empirically proposed by Leenhardt and Coumel to treat the “short-coupled variant of torsade de pointes” [4], an entity that probably represents idiopathic VF. In contrast, we found that the recurrence rate with quinidine was nil [3]. By the time the ICD became commercially available, we continued to recommend quinidine as the sole therapy for appropriately selected patients with idiopathic VF, including patients resuscitated from spontaneous cardiac arrest [107]. Our criteria for quinidine therapy in VF survivors includes all the following: (1) diagnosis of idiopathic VF with or without Brugada syndrome; (2) inducible VF in the absence of drugs with programmed ventricular stimulation (Fig. 36.3); (3) no-inducible arrhythmias during oral quinidine therapy despite a very aggressive protocol of ventricular stimulation (Fig. 36.3) [2, 108, 109] (4) informed consent by a patient who is well informed of the risk and benefits of ICD and quinidine therapy for this disease [107]; (5) repeated assertion of drug compliance during long-term follow-up (compliance is assessed with quinidine serum levels and quinidine-effect on the QT interval). Our results using such approach were published in 1999 [53]. These results are shown in Fig. 36.5 and may be summarized as follows: Of 34 patients with idiopathic VF (all after resuscitation from cardiac arrest), 26 (80 %) had inducible VF at baseline electrophysiologic study and all but one of them were rendered non-inducible with quinidine. Side effects from quinidine led to discontinuation of quinidine therapy in 14 % of our patients. Nevertheless, 23 patients (2 out of 3 patients from the original cohort of cardiac arrest survivors) remained on quinidine therapy (without ICD back-up) and all are alive and completely free of arrhythmic symptoms that now exceeds 10 years. The long-term effectiveness of quinidine for preventing VF induction has been confirmed [110]. Relatively early in our experience, three patients who had negative electrophysiologic studies in the absence of drugs received empiric quinidine. All these patients died 4–8 years after the original VF episode. These 3 patients discontinued follow-up long before they died. Therefore, we do not know if the fatalities were due to poor compliance or due to drug failure and weather such failure was related to the fact that quinidine therapy for these particular patients was empiric and not guided by electrophysiologic studies (since these 3 patients were non-inducible at baseline). Nevertheless, we no longer recommend empiric use of quinidine for non-inducible patients after spontaneous cardiac arrest, a subgroup of patients for whom ICD implantation is mandatory. However, we have successfully used quinidine to control arrhythmic storms of ventricular fibrillations in patients who originally received an ICD either because of non-inducibility in the baseline EPS or because of (the extremely rare) persistence of inducibility while on quinidine therapy. The excellent response of VF storms in idiopathic VF with Brugada syndrome has also been repeatedly reported [60, 111–113]. Of note, the fatalities that occurred 4–8 years after the first VF event clearly demonstrate that patients with idiopathic VF remain at risk for fatal arrhythmia-recurrence even after long asymptomatic periods. Thus, long asymptomatic periods after the first VF episode should not be interpreted as resolution of an unidentified “myocarditis” and cannot be taken as a “good prognostic sign.”