Epicardial Anatomic Correlates of Electrocardiographic Abnormalities in Brugada Syndrome

CHAPTER
26		Epicardial Anatomic Correlates of Electrocardiographic Abnormalities in Brugada Syndrome
		Carlo Pappone, MD, PhD; Vincenzo Santinelli, MD; Josep Brugada, MD, PhD

INTRODUCTION

The Brugada syndrome (BrS) was first reported as a unique set of abnormal electrocardiogram (ECG) signs associated with an unpredictable risk of sudden cardiac death due to ventricular fibrillation (VF) in the absence of overt structural heart disease.^1–3 Unfortunately, there are no reliable methods to identify the potential victims within the large pool of BrS patients. The predictive value of several ECG markers, including but not limited to coved-type ST-segment elevation in precordial leads and QRS fragmentation or late potentials, still needs to be confirmed in large, prospective studies to increase both specificity and sensibility. Although the typical BrS ECG pattern seems to be the best predictor, it commonly fluctuates overtime, frequently changing from type 1 to type 2 or type 3, or even can be transiently normal, requiring serial ECGs as a guide for the prognosis.⁴ Therefore, it is not surprising that a heated debate is ongoing about both pathophysiology and anatomical location of coved-type ST-segment elevation in the management of patients with BrS. It is over 30 years since clinical and experimental observations were first made about the existence of a selected “special” anatomical area of the RV involved in the BrS phenotype and VT (ventricular tachycardia)/VF inducibility.^1–3 After the pioneering results of recent studies, many electrophysiologists and cardiologists are now discussing the role of an arrhythmic substrate potentially responsible for the typical BrS ECG pattern and VT/VF inducibility as a target for catheter ablation.^5,6 New relevant anatomical, electrophysiological, and mechanical data begin to continue leading further information on our understanding of this apparently complex disease.⁷ This chapter describes a comprehensive analysis of a new multimodality 3D imaging applied to patients with BrS, which provides a foundation to establish a correlation between anatomical, electrocardiographic, and electro-physiological findings. We then discuss how the complex electrophysiological milieu of Brugada substrate might set the scene for understanding the physiopathology and care of BrS, considering that precise anatomic, electrocardiographic, and electrophysiological correlates have been sufficiently elucidated. This chapter also discusses the role of overt or silent electrical substrates in order to have more confidence in treating BrS patients in the near future—and in the absence of other associated cardiomyopathies—with catheter ablation alone without implantable cardioverter-defibrillator. We should be aware of the potential for repeating past mistakes if we do not learn from them as we seek an appropriate therapy based on these new relevant insights.

BRUGADA SYNDROME HISTORICAL PRECEDENTS

Despite the results of several experimental and clinical studies in BrS for more than two decades, many questions remain unanswered. Indeed, both the anatomical explanation and underlying pathophysiology that gives rise to the typical ECG pattern are still pending.¹ Although the genetic abnormalities implicated in the syndrome affect individual ion channel functioning across the heart uniformly, the right ventricular outflow tract (RVOT) has been supposed to be the site that gives rise to the BrS phenotype and ECG pattern changes. One explanation likely lies in differences during embryonic development and ion channel expression between the RVOT, right ventricle (RV), and left ventricle (LV). Few studies have examined the electrophysiological changes in these regions simultaneously to accurately determine the differential behavior of different segments of RV or LV to sodium channel blockade. Anecdotal reports first proposed the RVOT area as the primary site of inducibility of ventricular fibrillation and the origin of spontaneous premature ventricular complexes.1,2 As a result, the knowledge of the complex anatomy and physiology of the RV, particularly of the whole RVOT area becomes indeed crucial when evaluating a potential correlation between anatomic, electrocardiographic, and electrophysiological characteristics of the syndrome. Studies using body-surface mapping in patients with BrS after ajmaline infusion showed an increase in body surface filtered QRS duration in the precordial leads overlying the RV but not the LV.¹ Several theories based on RV repolarization and depolarization abnormalities have been proposed to explain the coved-type ST segment elevation in BrS.^1,2 Clinical observations suggested that BrS may be a functional rather than fixed structural disease, and this was initially supported by the fact that commonly, BrS-type 1 ECG pattern or VF/VT episodes are consistently provoked by fever, and that prompt and aggressive control of fever by antipyretics may be helpful. Finally, more recently, the presence of unexpected high rates of mechanical abnormalities in patients with BrS has been suggested repeatedly but never demonstrated conclusively.⁸

THE DISCOVERY OF THE BRUGADA SUBSTRATE

Despite decades of research and many publications on BrS contributing to our knowledge of the syndrome, pathophysiology and management have remained a mystery to clinicians with few therapeutic options. Indeed, implantable cardioverter-defibrillator and quinidine are currently the only two mainstay therapies for BrS.^1,2 In the last 3 years, pioneering studies by our group using 3D electroanatomic imaging techniques have provided new insights into better understanding pathophysiology, mechanisms, and management of BrS.^5–7 The very promising results of these studies have revolutionized our approach, which is now readily available for the majority of symptomatic patients with BrS. Multivariate analysis revealed the substrate size as the only independent predictor of inducibility of malignant VT/VF regardless of clinical presentation or presence of spontaneous typical BrS ECG pattern.⁷ It is possible now to determine and accurately localize the Brugada substrate, which consists of a prolonged fractioned electrical activity over highly variable areas of the RV epicardium, ranging from a small area corresponding to the superior part of RVOT towards an extensive area from the medial to inferior aspect of the anterior RV free wall without involving other regions of the RV or LV (Figures 26.1–26.7; Videos 26.1 and 26.2). Of interest, there is a correlation between Brugada substrate and coved ST-segment elevation, both of which are well correlated with VT/VF inducibility.⁷ These findings are clinically relevant as they demonstrate that higher coved-type ST-segment elevation actually reflects larger and more complex substrates that are more commonly found in patients who are inducible with a less aggressive protocol.⁷ Patients inducible with a single or double extrastimuli have up to three times larger substrates than those patients inducible with three extrastimuli (Figure 26.5). Of note, many other patients become inducible only after ajmaline-induced a consistent increase of the substrate size and analysis of ROC curve demonstrated that a substrate size of 4 cm² best differentiated inducible from noninducible patients.⁷ These observations are clinically important, indicating that in BrS, fatal arrhythmias are less likely to develop in small or silent substrates, which are commonly found among patients with concealed or intermittent typical ECG pattern, who represent the vast majority of patients with BrS. These findings can reasonably explain why in BrS the occurrence of VF is a very rare event, because, unlike traditional stable substrates characterized by “low-voltage” scar or fibrosis as in postischemic VT, in patients with BrS the occurrence of unstable malignant arrhythmias requires a consistent substrate expansion and activation. The time, magnitude, and persistence of substrate activation in BrS is highly variable, mostly depending on the initial substrate size and location as well as on the presence and duration of triggers. In our experience, about 50% of the induction of VT/VF is achieved from the RVOT, a site that has been previously reported to induce mainly false-positive testing. Our observation is not surprising if one considers the RVOT area as the commonest site of the Brugada substrate, as revealed by electroanatomic maps. More extensive substrates, particularly after ajmaline, can drive consistent mechanical changes in the same regions of the RV that are not anatomically uniform, with the anterior free wall of the RVOT showing the greatest impairment of movement/deformation during contraction (Figure 26.7). The predominant involvement of the RV anterior free wall in BrS emphasizes the concept that additional precordial leads, rather than the traditional ones alone, are more likely to accurately detect the entire substrate size, and this consistently increases the sensitivity of ECG to detect type 1 Brugada pattern, largely depending on the surrounding anatomic location and real size of fully activated substrate. Unlike small substrates, larger substrates show the highest elevation of the coved ST segment in the lower right leads (third or fourth intercostal space), coinciding with the anterior region of the RVOT in the electroanatomic maps (Figures 26.8 and 26.9).