Clinical study of 39 Chinese patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy
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1 Chinese Medical Journal 2009;122(10): Original article Clinical study of 39 Chinese patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy MA Ke-juan, LI Ning, WANG Hong-tao, CHU Jian-min, FANG Pi-hua, YAO Yan, MA Jian, HUA Wei, ZHANG Shu, WANG Fang-zheng, Li Zhang and PU Jie-lin Keywords: arrhythmogenic right ventricular dysplasia/cardiomyopathy; ventricular tachycardia; sudden cardiac death; electrocardiograph; Chinese A Background There are few studies on the clinical profile of Chinese patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The purpose of this study was to describe the clinical characteristics of ARVD/C patients from China, particularly to define the features of electrocardiograph and treatment outcomes. Methods Thirty-nine patients hospitalized in Fu Wai Cardiovascular Hospital from 1998 to 2006 were included. The data were obtained from the medical archive and the follow-up records. Results Of these patients 33 were male and 6 female (age at the first presentation was (34.9 ± 9.8) years). The most common symptoms were palpitation (62%) and syncope (44%). Right precordial QRSd 110 ms was detected in 69% of the patients, epsilon wave in 59%, and a ratio of QRSd in V 1 +V 2 +V 3 /V 4 +V 5 +V in 82%. The most frequent features of electrocardiogram in patients without right bundle-branch block were T-wave inversions and S-wave upstroke in V 1 V 3 55 ms (96% and 90% of 28 patients, respectively). Radiofrequency catheter ablation (RFCA) for ventricular tachycardia (VT) was successful in 15 (68%) of 22 patients. The recurrence rate of VT was 46% (7/15) during the follow-up of (16.7 ± 11.2) months. Seven patients had cardioverter/defibrillator (ICD) implanted plus drug therapy and 17 patients took antiarrhythmic drugs alone. During the follow-up of (35.6 ± 19.0) months, all patients with ICD implanted received at least one appropriate ICD shock. One patient died of ventricular fibrillation suddenly and one patient underwent heart transplantation for progressive biventricular heart failure during the drug therapy alone. Conclusions This study demonstrated the clinical and ECG features of the 39 ARVD/C Chinese patients. ICD provided life-saving protection by effectively terminating malignant arrhythmias, and the high recurrence of VT was the major problem of RFCA therapy. rrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C) is an inherited disease pathologically characterized by progressive replacement of the right ventricular myocardium with adipose and fibrous tissue, which often induces ventricular arrhythmias in the early phase or leads to heart failure in the later stage. It has been recognized as an important cause for sudden cardiac death among young individuals, 1 especially in competitive athletes. 2,3 Since the first description of ARVD/C 24 years ago, 4 remarkable progress has been made in pathogenesis, genetics and diagnosis. However, the natural history of ARVD/C reported varies greatly, especially in different races. The majority of studies in the literature have involved western populations, 5-7 except one which described 11 Chinese patients from Hong Kong, China. 8 In this paper, we characterized the clinical profiles of 39 ARVD/C Chinese patients, particularly focused on the diagnostic values of specific electrocardiograph (ECG) patterns and the outcomes of these patients under the current invasive and noninvasive treatments. METHODS Diagnosis of ARVD/C The diagnosis of ARVD/C was based on the criteria established by the Task Force of the Working Group of Myocardial and Pericardial Disease of the European Society of Cardiology and the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. 9 Briefly, the criteria are subdivided into major and minor criteria and are classified into 6 categories: (1) global and/or regional dysfunction and structural alterations; (2) fibrofatty replacement of the myocardium; (3) repolarization abnormalities; (4) depolarization/conduction abnormalities; (5) arrhythmias; DOI: /cma.j.issn Center for Arrhythmia Diagnosis and Treatment, Fu Wai Cardiovascular Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing , China (Ma KJ, Li N, Wang HT, Chu JM, Fang PH, Yao Y, Ma J, Hua W, Zhang S, Wang FZ and Pu JL) Cardiac Electrophysiology Department, Beijing Anzhen Hospital, Capital Medical University, Beijing , China (Ma KJ) University of Utah School of Medicine, Department of Medicine, LDS Hospital, th Avenue, Suite 130, Salt Lake City, UT 84103, USA (Zhang L) Correspondence to: Dr. PU Jie-lin, Centre for Arrhythmia Diagnosis and Treatment, Fu Wai Cardiovascular Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing , China (Tel: , Fax: jielinpu@yahoo.com) This study was supported by grants from the National Basic Research Program of China (973 Program, No. 2007CB512000, 2007CB512008)
2 1134 and (6) family history. The diagnosis of ARVD/C can be established when 2 major criteria or 1 major plus 2 minor criteria, or at least 4 minor criteria have been met. Study population and clinical data Thirty-nine patients hospitalized in Fu Wai Cardiovascular Hospital from 1998 to 2006 were included. The data obtained from their medical archive included demographic data (age, sex, race), clinical data (familial history, presentation of the disease, age at onset of symptoms, physical examination), and ECG recordings (12-lead ECG and 24-hour Holter recordings). Structure and function of the ventricular myocardium were assessed by noninvasive (echocardiography, magnetic resonance imaging (MRI)) and invasive (ventricular angiography, electrophysiological study (EPS)) examinations. Diffuse lesion was defined when imaging study revealed a widespread right ventricular (RV) involvement resulting in global RV dilatation and a reduction in ejection fraction. Regional lesion was diagnosed when the disease was localized in the RV, such as segmental wall-motion abnormalities (hypokinetic or dyskinetic areas) with mild or no decrease in RV ejection fraction. ECG analysis Standard 12-lead ECG was registered at 25 mm/s and 1 mv/cm. ECG parameters and standards for measurements are described in Table 1. All parameters were measured in 3 consecutive beats; the mean value was used for analysis. Table 1. ECG parameters and definitions Variables Definition QRS complex Beginning of QRS complex to its end S-wave upstroke Nadir of S wave to isoelectric line QRS dispersions Difference between maximum and minimum QRS values in any of the 12 ECG leads Epsilon waves Distinct waves of small amplitude that occupy the ST segment Parietal block QRSd in V 1 V 3 that exceeds the QRSd in lead V 6 by 25 ms T-wave inversions T-wave negativity in V 1 and beyond Complete RBBB/ QRSd 0.12 s / QRSd 0.10 s and < 0.12 s, Incomplete RBBB secondary R wave in right precordial leads, and wide S wave in leads I and V 6 Treatment and follow-up Clinical treatment included antiarrhythmic drugs, radiofrequency catheter ablation (RFCA), implantable cardioverter-defibrillator (ICD) and heart transplantation. Patients were followed up in out-patient clinic every 6 to 12 months with regard to the recurrence of cardiac arrhythmias and assessment of cardiac structure and function. Cardiac events recorded by ICD were also collected. Statistical analysis Categorical variables were expressed as frequency (percentage). Continuous variables were expressed as mean ± standard deviation (SD). Statistical analyses were performed with SPSS statistical software (version 11.0). P < 0.05 was considered statistically significant. RESULTS Clinical characteristics The clinical data of the 39 patients are summarized in Table 2. All the patients were Chinese Han ethnic, 33 males and 6 females (5.5:1). Their mean age at the first presentation was (34.9 ± 9.8) years (range years). All of the patients met the international standardized diagnostic criteria. Twenty (51%) of the patients presented with 2 major diagnostic criteria, 12 (31%) patients with 1 major criterion plus at least 2 minor criteria, and 7 (18%) patients with 4 minor criteria. Four (11%) of the patients had a family history of either sudden cardiac death (3 patients) or ventricular tachycardia (VT) (1 patient). Table 2. Clinical characteristics of 39 patients with ARVD/C Characteristics Number (%) Age at onset of symptoms (years) < >50 Gender Male Female Familial history sudden death, VT Presenting symptoms Palpitations Syncope Atypical chest pain Clinical signs of right ventricular failure Resuscitated VF cardiac arrest 4 (10) 6 (15) 18 (46) 9 (23) 2 (5) 33 (85) 6 (16) 4 (10) (62) 17 (44) 2 (5.1) 1 (2.5) 2 (5.1) Actively involved in athletic activity 19 (53) Arrhythmia Left bundle-branch block VT Sustained monomorphic VT Sustained polymorphic VT Nonsustained monomorphic VT VF MRI Normal Abnormal Diffuse RV involvement Localized form RVOT dilation Fibrofatty infiltration LV involvement EPS Inducible VT with one morphology Inducible VT with more than one morphology Fragmented potentials 36 (92) (5) 5 (13) 34 (87) 18/34 (53) 16/34 (47) 24/34 (71) 16/34 (47) 6/34 (18) 22 3 (14) 19 (86) 13 (59) The most common symptoms of the patients were palpitation (62%) and/or syncope (44%). In more than half (54%) of the patients, the symptoms were induced by physical exercise. Ventricular fibrillation (VF) as the first manifestation was seen in 2 patients.
3 Chinese Medical Journal 2009;122(10): Ventricular tachycardia with left bundle-branch block (LBBB-VT) was the most frequent arrhythmic event. Sustained VT was documented by 24 hours Holter recording in 36 patients with a 2:1 ratio of monomorphic VT to polymorphic VT. Dilated RV and wall thinning were detected in 34 patients by echocardiography or MRI with global RV involvement in 18 (53%) and regional lesion in 16 (47%) patients. Twenty-four patients (71%) showed right ventricular outflow tract (RVOT) dilation and 6 patients (18%) exhibited left ventricle (LV) involvement. Typical morphologic changes were seen in the RV of the patient with the episode of polymorphic VT (Figures 1, 2). Abnormalities of the RV demonstrated by echocardiography could also be detected by MRI, but minor lesions were only revealed by MRI in 12 patients (35%). Figure 2. Magnetic resonance imaging of the same patient in Figure 1, showing RV wall thinning and dilation with the enlarged RVOT as well as the regional thinning (marked by slim arrow) and the fatty replacement (marked by wide arrow) of LV myocardium. RA: right atrium. RV: right ventricle. RVOT: right ventricle outflow tract. LV: left ventricle. Prolonged S-wave upstroke in V 1 through V 3 55 ms was another common feature (25 patients, 90%). Figure 1. ECGs from a 44-year-old man diagnosed with ARVD/C at 40 years of age. A: His baseline ECG demonstrated sinus rhythm with T-wave inversion in leads V 1 to V 4, epsilon wave and S-wave upstroke prolongation in right precordial leads. B: Episode of polymorphic VT. In 21 patients older than 35 years or with chest pain, coronary angiography revealed no significant coronary artery disease. In 22 patients who underwent EPS study, more than one type of VT was induced in 19 patients (86%) from multi-site origins in RV. At least one of them matched clinical VT morphologically. The fragmented potentials could be registered in 13 patients (59%) by ablation catheter before energy delivery. ECG analysis The detailed ECG features of all patients are summarized in Table 3, and the typical ECG recordings are shown in Figures 1, 3, 4. Complete and incomplete right bundle-branch blocks (RBBBs) were present in 11 patients (30%). In 28 patients (72%) without RBBB, the T-wave inversion was the most prominent findings (27/28, 96%), which were limited to V 1 V 3 in 14 patients (52%) and beyond V 3 in the remaining 13 patients (48%). Present with RBBB Complete RBBB Incomplete RBBB Absent of RBBB QRSd in V 1 V ms 110 ms 120 ms Table 3. ECG features of patients with ARVD/C ECG parameters Number (%) 11 (28) 7 (18) 4 (10) 28 (72) 35 (90) 26 (67) 14 (36) Epsilon wave in precordial leads 23 (59) T-wave inversion in ECG absent of RBBB V 1 V 3 Beyond V 3 T-wave inversion beyond V 3 In the cases of diffuse RV disease In the cases of localized RV disease QRSd V 1 +V 2 +V 3 /V 4 +V 5 +V Parietal block (QRSd V 1-3 V 6 25 ms) In the cases with RBBB In the cases without RBBB S-wave upstroke in V 1 V 3 in ECG without RBBB 55 ms 60 ms 70 ms 27/28 (96) /18 (78) 6/16 (38) 36 (92) 32 (82) 13 (33) 20 8/11 (72) 15/28 (54) (90) 20 (71) 11 (39) ST-segment elevation 1 (2.6) QRS dispersion 40 ms 18 (46) QRS duration (QRSd) 110 ms in V 1 V 3 was present in 67% of all patients. The ratio of QRSd in V 1 +V 2 +V 3 /V 4 +V 5 +V (called localized right precordial QRS prolongation) was detected in 32 patients (82%). Another marker indicating delayed activation was the presence of parietal block (defined as the QRSd in leads V 1 to V 3 that exceeded the QRSd in lead V 6 by 25 ms). A parietal block was more commonly observed in patients with RBBB than in those without RBBB (72% (8/11), versus 54% (15/28),
4 1136 dispersion 40 ms was detected in 46% of all patients. Figure 3. A: ECG from a patient characterized by the T-wave inversion in leads V 1 to V 4, epsilon wave (as indicated with an arrow) and S-wave upstroke prolongation in right precordial leads. B: The epsilon wave on ECG with crbbb from another patient. Treatment and follow-up The acute success was achieved in 15 (68%) out of 22 patients who underwent RFCA for VT. During the follow-up of (16.7 ± 11.2) months, VT recurred in 7 patients (47%). There were 24 patients under sotalol/amiodarone therapy for prevention of VT including 7 patients implanted with an ICD and 7 patients for RFCA failure. During the follow-up of (35.6 ± 19.0) months, all patients implanted with ICD received at least one appropriate shock. All patients taking drugs only experienced 1 or more episodes of VT and most of VTs were terminated by external cardioversion. One patient died of VF and one underwent heart transplantation because of the progressive biventricular heart failure during a later follow-up. The follow-up data are summarized in Table 4. Table 4. Treatment and outcomes Treatment and outcomes Number (%) Treatment RFCA Acute success Failure ICD Drugs only Outcomes VT/VF recurrent with RFCA At least one appropriate shock by ICD Heart transplantation for HF Cardiac sudden death DISCUSSION 22 15/22 (68) 7/22 (32) 7 17 (7 for ablation failure) 7/15 (47) 7/7 (100) 1/17 1/17 We have described in detail the clinical and ECG features of the 39 ARVD/C Chinese patients, a large cohort of ARVD/C patients. The results of the study are representative, and comparable with those of the studies in the western populations. The results also provide important insights into the natural history and the efficacy of current treatments for this life-threatening cardiomyopathy. Figure 4. ECGs from a 40-year-old man diagnosed with ARVD/C and diffuse RV involvement at 38 years of age. A: Baseline ECG shows sinus rhythm with RBBB. B: Monomorphic VT with LBBB was documented during his syncope event. P < 0.05). The prevalence of epsilon waves was 59%. Mean QRS dispersion was (35.0 ± 13.9) ms and QRS The most common symptoms in our patients were palpitation and syncope. The age at the first presentation of these symptoms ranged from 17 to 60 years and the majority of the patients typically showed the symptoms during the third and fourth decade of life. It was notable that the patients presented with syncope or resuscitated VF cardiac arrest at the first onset (total 13 patients) were younger than those with repeated palpitations. It was also worth pointing out that the documented VT/VF events were triggered by sports activity in 54% of the patients with symptoms. This observation may confirm the previous findings in other studies that the incidence of sudden cardiac death (SCD) in ARVD/C patients declined after the fourth decade of life. 1,10 This also suggests the higher risk in the young patients and the potential role of physical activity in triggering cardiac arrhythmia in ARVD/C.
5 Chinese Medical Journal 2009;122(10): A familial history of sudden cardiac death or LBBB-VT was found in 4 patients in our series. The incidence was less than the range of 15% to 50% reported in the literature. 11,12 It might be underestimated in our study because we did not perform systematic screening of all family members for ARVD/C. The higher prevalence in male than female (5.5:1) in our cohort was similar to that reported elsewhere. 5-8 Our study suggested that MRI is more sensitive than echocardiography to find the structural abnormalities in the early stage of ARVD/C. However, the advantage is limited in patients with a larger amount of fibrosis, and the specificity is also challenged in the situation such as pure lipomatosis, which is completely different in pathology from ARVD/C. 13 Marcus et al 4 first reported the ECG features of patients with ARVD/C 24 years ago. Subsequently, several specific ECG features were introduced by McKenna et al 9 to the diagnostic criteria for ARVD/C including (1) T-wave inversions in V 1 through V 3, (2) QRS duration (QRSd) 110 ms in V 1 through V 3, and (3) the presence of an epsilon wave. In our study, 95% of the patients (all except two) showed 1 or more ECG features of the criteria. The epsilon wave, a marker of delayed right ventricular activation, is considered a major diagnostic criterion for ARVD/C. Although this criterion is highly specific, it is observed in only 25% to 35% of patients in previous studies The minor criterion of T-wave inversion in the right precordial leads (in the absence of RBBB) is reported in 55% to 95% of patients. 14,16-18 The higher prevalence of epsilon wave and T-wave inversion in our study (59% and 96%, respectively) indicated the later stage of the disease. Most of our patients showed RV anatomic abnormalities, particularly diffuse RV involvement in 18 patients (53%). Nava et al 18 reported that the extent of right precordial T-wave inversion correlates with the degree of RV involvement. In our study, T-wave inversion beyond V 3 lead was seen in 78% (14/18) of patients with diffuse RV disease and in 38% (6/16) of patients with localized form (P < 0.05). Hence T-wave inversion is not specific for ARVD/C, and it can be seen in normal individuals, particularly in children under 12 years of age. QRSd 110 ms in V 1 V 3, a major criterion for the diagnosis of ARVD/C, indicates delayed right ventricular activation. In one study, QRSd 110 ms in lead V 1 measured during sinus rhythm had a sensitivity of 55% and a specificity of 100% for the diagnosis of ARVD/C. If QRSd 110 ms appeared in both V 1 and V 3, the sensitivity would increase to 60% but the specificity decreased to 82%. 19 Another study 14 reported that QRSd 110 ms in V 1 through V 3 was presented in 64% of patients. This finding is comparable with that in our study. The additional ECG features of ARVD/C we have analyzed include QRS dispersion, parietal block and a ratio of the QRSd in leads V 1 +V 2 +V 3 /V 4 +V 5 +V We did not find any significant difference in the prevalence of these predictors between our study and other studies. 11,14-16 Recently, Nasir et al 14 described a novel ECG finding termed as delayed S-wave upstroke in the right precordial leads. Prolonged S-wave upstrokes 55 ms in leads V 1 through V 3 were observed in 95% of patients in the absence of RBBB, and became the most prevalent ECG pattern for ARVD/C during the sinus rhythm. In our study, this ECG feature was seen in 90% of patients and showed a significant relationship with the degree of RV involvement. QRS dispersion was considered to represent regional inhomogeneity of depolarization as a consequence of a ventricular conduction defect. QRS dispersion 40 ms was the strongest independent predictor of sudden death in ARVD/C. 15 In the present study, we found 80% of the patients presenting with syncope (13/17) and two patients with SCD showed QRS dispersion 40 ms, which further confirmed that this ECG feature is a strong predictor for malignant arrhythmic events. Currently, no guidelines are available for the best management of patients with ARVD/C. Most therapeutic protocols target to prevent ventricular arrhythmia or sudden cardiac death. Current treatment choices include antiarrthymic drugs such as beta-blockers or amiodarone, ICD therapy, and radiofrequency catheter ablation. Our study indicated that the success of catheter ablation was limited by the progressive and diffuse nature of the disease, resulting in multiple arrhythmogenic foci, which are difficult to be abolished. The high recurrence rate of VT should be the major problem associated with RFCA. Although our study highlighted the benefit of ICD therapy with respect to terminating arrhythmic events and preventing sudden death, a larger clinical trial is needed to prove the long-term benefit and to evaluate the side-effects. 20 The efficacy of antiarrhythmic drug therapy is difficult to assess because of the individual variability on drug combination. In conclusion, our study demonstrated the clinical characteristics of 39 ARVD/C Chinese patients. Ninety-five percent of the patients had 1 or more ECG features described in the task force criteria, and other ECG markers once reported for ARVD/C were also observed in our series. The majority of patients experienced LBBB-VT, and ICD therapy provided life-saving protection by effectively terminating life-threatening arrhythmias. Low acute success and high recurrence of VT were the major problem for RFCA therapy. The small number of patients and short follow-up
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