Predicting lethal ventricular arrhythmias in hypertrophic cardiomyopathy using non-electrophysiologic methods: Invasive EGM vs. non-invasive ECG analysis of fragmentation

Abstract

We read with interest the study by Saumarez et al. 1 evaluating the utility of tightly coupled ventricular extrastimuli to improve risk stratification in patients with hypertrophic cardiomyopathy (HCM) beyond that achieved with the American College of Cardiology/American Heart Association risk markers 2 and European Society of Cardiology (ESC) risk score. 3 The authors demonstrated an impressive ROC–area under the curve of 0.89 using paced electrogram (EGM) delay and fragmentation at four right ventricular (RV) endocardial sites to predict ventricular tachycardia (VT)/ventricular fibrillation (VF). This dynamic EGM response arises from non-uniform anisotropic conduction through multiple conducing pathways, 4 and has also been demonstrated at the critical isthmus of VT circuits in patients with ischaemic and non-ischaemic cardiomyopathy. 5 Thus, close-coupled pacing is a rational approach to identify abnormal substrate and VT/VF risk in a variety of cardiomyopathy subtypes, including HCM. However, this approach is quite invasive and time-consuming, making it challenging to implement in clinical practice for risk stratification. Moreover, the endocardium and epicardium of the LV free wall are not sampled where abnormal HCM substrate is common. 6 A more feasible approach is to assess QRS fragmentation on the surface ECG during sinus rhythm, which is influenced by conduction heterogeneity much like EGM fragmentation. 4 Non-invasive risk stratification with QRS fragmentation also has the advantage of assessing LV and RV conduction abnormalities more globally and can be easily repeated to evaluate disease progression. We have recently developed a novel QRS fragmentation metric, known as QRS peak (QRSp), that quantifies low-amplitude intra-QRS peaks during sinus rhythm. 7 QRSp is quantified from the precordial leads of a 3-minute high-resolution 12-lead ECG after selective filtering and signal-averaging to maximize signal to noise (Figure 1A ). In a prospective study of 134 HCM patients (mean age 52 ± 13 years, ESC risk score 4.6 ± 2.7) with prophylactic defibrillators and no history of VT/VF, maximum QRSp across the precordial leads was greater in patients with VT/VF than those without during the 5-year follow-up [6.0 (4.0–7.0) vs. 4.0 (2.0–5.0), P < 0.001]. In multivariable Cox analysis, QRSp predicted VT/VF such that each peak increased VT/VF risk by 40%, while non-ECG-based risk factors and scores were not predictive. Among all patients with QRSp < 4, the annual event rate for VT/VF was <1% (Figure 1B ). These findings further support the importance of evaluating ventricular substrate with electrophysiological (EP) metrics that outperform clinical risk markers and suggest that invasive EP manoeuvres may not be necessary. By analogy, activation mapping during sinus rhythm has identified deceleration zones that co-localize to critical isthmus of VT circuits in patients with ischaemic cardiomyopathy. 8 Figure 1 QRSp quantification and relation to VT/VF events in HCM. (A) Illustration of the QRSp method applied to lead V5 of a representative patient. Five positive (blue circles) and five negative (red squares) abnormal QRS peaks are identified on the QRS signal average (bold black line) after excluding three normal peaks (green diamonds) that correspond to those found on a smoothed QRS template (dashed black line). The sum of the negative and positive abnormal peaks is the QRSp count for the lead. A patient’s QRSp score is defined as the greatest QRSp count detected in any precordial lead (V1–V6). (B) Kaplan–Meier survival curves for VT/VF events in patients with HCM stratified by QRSp ≥ 4. After 5 years of follow-up, patients with QRSp < 4 had greater freedom from VT/VF compared to patients with QRSp ≥ 4 (total events: 2/46 vs. 19/88; annual event rate: 0.98 vs. 4.4%, P = 0.012). HCM, hypertrophic cardiomyopathy; KM, Kaplan–Meier; QRSp, QRS peak; VT/VF, ventricular tachycardia/ventricular fibrillation. The assessment of EGM or ECG fragmentation should also consider myocardial scar burden, as defined by late gadolinium enhancement (LGE) magnetic resonance imaging (MRI), which is an important risk marker in HCM. 9 Heterogeneous scar will cause conduction slowing, and higher LGE signal intensity has been associated with slower conduction velocity in ischaemic cardiomyopathy. 10 Saumarez et al. 1 did not relate their paced EGM fragmentation with scar imaging. In our study, QRSp was greater in HCM patients with extensive (>15%) LGE MRI than those without [4.0 (3.0–6.0) vs. 3.5 (2.0–4.0), P < 0.001]. 7 As such, non-invasive EP metrics of fragmentation in combination with LGE MRI may provide a more practical, robust approach to HCM risk stratification than paced EGM fragmentation, which should be the focus of future prospective studies.