Author + information
- Received September 13, 2002
- Revision received January 15, 2003
- Accepted February 10, 2003
- Published online September 3, 2003.
- Lorenzo Monserrat, MD†,
- Perry M Elliott, MD, MRCP, FACC*,* (, )
- Juan R Gimeno, MD*,
- Sanjay Sharma, BSc, MRCP*,
- Manuel Penas-Lado, MD† and
- William J McKenna, MD, FACC, FESC, FRCP*
- ↵*Reprint requests and correspondence:
Dr. Perry M. Elliott, Department of Cardiological Sciences, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, United Kingdom.
Objectives The aim of this study was to examine the characteristics of non-sustained ventricular tachycardia (NSVT) episodes during Holter monitoring and to determine their relationship to age and prognosis.
Background It has been suggested that NSVT is only of prognostic importance in patients with hypertrophic cardiomyopathy (HCM) when repetitive, prolonged, or associated with symptoms.
Methods We studied 531 patients with HCM (323 male, 39 ± 15 years). All underwent ambulatory electrocardiogram monitoring (41 ± 11 h).
Results A total of 104 patients (19.6%) had NSVT. The proportion of patients with NSVT increased with age (p = 0.008). Maximum left ventricular wall thickness and left atrial size were greater in patients with NSVT. Mean follow-up was 70 ± 40 months. Sixty-eight patients died, 32 from sudden cardiac death (SCD). Twenty-one patients received an implantable cardioverter defibrillator (ICD). There were four appropriate ICD discharges. In patients ≤30 years (but not >30), five-year freedom from sudden death was lower in those with NSVT (77.6% [95% confidence interval (CI): 59.8 to 95.4] vs. 94.1% [95% CI: 90.2 to 98.0]; p = 0.003). There was no relation between the duration, frequency, or rate of NSVT runs and prognosis at any age. The odds ratio of sudden death in patients ≤30 years of age with NSVT was 4.35 (95% CI: 1.54 to 12.28; p = 0.006) compared with 2.16 (95% CI: 0.82 to 5.69; p = 0.1) in patients >30 years of age.
Conclusions Non-sustained ventricular tachycardia is associated with a substantial increase in sudden death risk in young patients with HCM. A relation between the frequency, duration, and rate of NSVT episodes could not be demonstrated.
Although a number of studies have reported an association between non-sustained ventricular tachycardia (NSVT) and the risk of SCD in patients with hypertrophic cardiomyopathy (HCM) (1–4), its utility as a clinical risk marker remains controversial. Most recently, it has been suggested that NSVT is of prognostic importance only when repetitive, prolonged, or associated with symptoms (5,6). In order to test this hypothesis, we studied the relation between the characteristics of NSVT detected during Holter monitoring and prognosis in a large single-center population studied over a period of 13 years.
A total of 630 consecutive patients (37 ± 16 years, 382 male) with HCM were assessed at St. George's Hospital, London, U.K., between 1988 and 2000 (3,4). The reasons for referral were clinical management (37.8%), family screening (25.3%), risk stratification (23.8%), and diagnosis clarification (13.2%). The diagnosis of HCM was based on the presence of unexplained left ventricular (LV) hypertrophy more than two standard deviations from normal ranges corrected for age and body size, or on the presence of unexplained electrocardiographic and echocardiographic abnormalities in relatives of patients with unequivocal disease (7,8). Patients in this study were selected from the cohort of 630 patients using the following criteria: 1) age 14 to 75 years; 2) follow-up for more than one day; and 3) successful completion of Holter monitoring. A detailed family pedigree and clinical history were obtained from all patients. A history of syncope was defined as one or more episodes of unexplained loss of consciousness within the 12 months preceding the first visit to St. George's Hospital. Chest pain was classified as exertional, or atypical if it occurred at rest and/or lasted more than 30 min at rest in the absence of myocardial infarction. The New York Heart Association classification was used to grade dyspnea. A family history of sudden death was defined as SCD in two or more first-degree relatives <40 years of age.
Two-channel (CM1 on channel 1 and V2 on channel 2) 24 to 48 h (mean, 41 ± 11 h) ambulatory electrocardiogram monitoring was performed in all patients (Marquette Electronics, Milwaukee, Wisconsin). Non-sustained ventricular tachycardia was defined as three or more consecutive ventricular beats at a rate of ≥120 beats/min, lasting for <30 s. One investigator (L.M.) reviewed all the studies, identifying and printing all episodes of NSVT on 25 mm/s speed paper, including the three beats immediately preceding each episode. The same investigator (L.M.), unaware of the clinical, echocardiographic, and follow-up data, made the following measurements for each episode of NSVT: 1) number of consecutive ventricular beats; 2) rate of the VT; and 3) the number of runs during each recording.
Two-dimensional and M-mode echocardiography were performed using standard methods (9). In brief, end-diastolic LV wall thickness was recorded at mitral valve and papillary muscle level in the anterior and posterior septum, and in the lateral and posterior LV wall using short-axis two-dimensional images. Anterior and posterior wall thickness at the apex was measured in the two-chamber and short-axis apical views. Left ventricular outflow tract velocities were measured using continuous-wave Doppler, and LV outflow tract gradients were calculated using the modified Bernouilli equation (LV outflow tract gradient = 4 × [LV outflow tract velocity]2).
Patients were exercised to exhaustion on a treadmill using the Bruce or modified Bruce protocols (1988 to 1994), or on an upright bicycle ergometer (Sensormedics ergometrics 800S, Bitz, Germany) using an incremental ramp protocol (1994 onwards). Blood pressure was measured by auscultation of the brachial artery during deflation of a mercury sphygmomanometer at rest, every minute during exercise and for the first 5 min of recovery. Blood pressure response to exercise was considered abnormal when systolic blood pressure failed to increase by more than 25 mm Hg from baseline, or when there was a decrease of more than 10 mm Hg from the maximum blood pressure during exercise (3,10).
Follow-up started with the date of the initial Holter recorded at St. George's Hospital. Survival data were collected in routine clinic visits and where necessary by direct communication with patients and their attending physicians. Additional information was obtained using a written questionnaire sent to all patients' general practitioners. In order to assess the influence of amiodarone on the relation between NSVT and prognosis, patients who had received the drug for the majority (>50%) of their follow-up were compared with patients who had never taken the drug or who had received the drug for <50% of their follow-up period.
As previously described (3,4), for the end point classification, we considered sudden death a witnessed death within 1 h of new symptoms and nocturnal deaths with no antecedent history of worsening symptoms. Deaths preceded by new signs and/or symptoms of heart failure of more than 1 h duration and/or cardiogenic shock were considered as heart failure deaths. Deaths secondary to stroke, pulmonary or systemic embolism, or myocardial infarction were also considered as cardiovascular deaths.
SPSS for PC statistical program (SPSS Inc., Chicago, Illinois) was used for the analysis. Continuous variables are presented as mean ± SD. Student ttest (paired or unpaired) was used to compare continuous variables in patients with and without NSVT. Mann-Whitney Utest was used to compare NSVT characteristics in patients with and without events. Chi-square test was used to compare categorical variables. Log-rank test was used to compare survival curves from different groups. A multivariate Cox regression model was used to analyze the relation between NSVT and survival. A p value <0.05 was considered statistically significant.
From a total of 630 patients assessed between 1988 and 2000, 531 patients (39 ± 15 years, 323 male) fulfilled the selection criteria. Exclusions comprised 31 patients younger than 14, three patients older than 75, nine patients without follow-up data, and 56 patients with insufficient Holter data to permit analysis of NSVT characteristics. The mean age at Holter was 39 ± 15 years. Fifty-four patients (10%) were <20 years old, 109 (20%) were age 20 to 29, 114 (21%) were between 30 and 39, 121 (23%) were age 40 to 49, and 82 (15%) were between 50 and 59. Fifty-one (10%) patients were age 60 to 75. Symptoms at initial assessment and the results of noninvasive testing in the study cohort of 531 patients are shown in Table 1.
Relation to clinical features
A total of 104 patients (19.6%) had NSVT during their initial Holter recording. The proportion of patients with NSVT at their first Holter increased with age (p = 0.008) (Fig. 1). The youngest patient with NSVT was 17 years old. Maximum LV wall thickness and left atrial size were greater in patients with NSVT: 22.6 ± 5.9 mm versus 20.3 ± 6.8 mm (p = 0.001) and 45.6 ± 8.3 mm versus 41.8 ± 8.2 mm (p = 0.0001), respectively. Non-sustained ventricular tachycardia was more frequent in patients with atrial fibrillation (38% of patients with NSVT vs. 19% in patients in sinus rhythm; p = 0.046).
Number and rate of runs
The median number of runs of NSVT in 48 h was one (mean, 3.3 ± 8; range, 1 to 69). A total of 88% of the patients with NSVT had four or less runs in 48 h (Fig. 2). The mean maximum rate of the NSVT runs was 157 ± 26 beats/min (range, 120 to 240), and the mean rate of all the runs was 150 ± 22 beats/min (range, 120 to 222). The mean number of beats of the longest run was 6.3 ± 4 beats (range, 3 to 29; median, 5 beats) and of all runs 4.7 ± 2 (range, 3 to 15; median, 4). There was a correlation between LV end-systolic diameter and the number of beats of the longest run of NSVT (r = 0.267, p = 0.02). No other significant relation was detected between NSVT characteristics and echocardiographic features or age.
Mean follow-up was 70 ± 40 months (one day to 160 months). There were 68 deaths in the 531 study patients. Thirty-two patients died suddenly, eight patients died with progressive heart failure, and eight patients died from other disease-related complications. Twenty patients died from noncardiovascular or unknown causes. In addition to this, six patients underwent orthotopic cardiac transplantation, and four patients received an appropriate implantable cardioverter defibrillator (ICD) discharge. Five-year cumulative freedom for all-cause mortality, cardiac transplantation, or appropriate ICD discharge was 88.9% (95% confidence interval [CI]: 85.9 to 91.9).
Treatments and interventional procedures
A total of 168 patients (31.6%) received amiodarone during their follow-up, and 92 (17.3%) were on amiodarone for 50% of their follow-up or more. Eleven of these 92 patients died (three sudden deaths, four cardiovascular cause, four noncardiovascular or unknown cause), two received an appropriate ICD discharge, and one received a cardiac transplant. The reasons for amiodarone therapy were supraventricular tachycardia (including paroxysmal atrial fibrillation), n = 26 (28.3%); sudden death prophylaxis, n = 40 (43.5%); and both supraventricular tachycardia and sudden death prophylaxis, n = 15 (16.3%). In the remaining 11 patients, amiodarone therapy had been started by referring physicians before their evaluation at St. George's Hospital.
Five-year cumulative survival for all-cause mortality, heart transplantation, or appropriate ICD discharge was 88.3% (95% CI: 85.0 to 91.6) in patients who had never taken amiodarone or who had taken the drug for <50% of follow-up and 91.5% (95% CI: 85.4 to 97.6) in patients who had taken amiodarone for the majority of follow-up (p = 0.6). The corresponding five-year cumulative survival estimates for sudden death were 93.9% (95% CI: 91.4 to 96.4) and 97.7% (95% CI: 94.6 to 100) (p = 0.1).
Myectomy (20 patients, 2 with NSVT), alcohol septal ablation (14 patients, 4 with NSVT), and dual chamber pacemaker implantation (36 patients, 8 with NSVT) were performed in patients with severe LV outflow tract obstruction for the treatment of severe symptoms refractory to medical therapy. Thirty patients (7 with NSVT) received a pacemaker for the treatment of conduction system disease or chronotropic incompetence. Five patients (2 with NSVT) underwent mitral valve replacement. An ICD was implanted in 21 patients considered to be at high risk for sudden death: four with previous ventricular fibrillation (none of them with NSVT on Holter) and 17 with two or more recognized risk factors of SCD (3 with NSVT on Holter).
NSVT and mortality
Forty-two (9.8%) of the 427 patients without NSVT, and 26 (25%) of the 104 patients with NSVT died (p = 0.0001). Of the 32 patients that died suddenly, thirteen had NSVT (p = 0.005). Five-year cumulative freedom from all-cause mortality, heart transplantation, or appropriate ICD discharge was 90.6% (95% CI: 87.5 to 93.7) in patients without NSVT and 82.3% (95% CI: 74.3 to 90.3) in those with NSVT (p = 0.001). Five-year cumulative freedom from sudden death was 95.6% (95% CI: 93.4 to 97.8) in patients without NSVT and 90.7% (95% CI: 84.4 to 97.0) in patients with NSVT (p = 0.003). The overall relative risk for sudden death in patients with NSVT was 2.8 (95% CI: 1.4 to 5.6), p = 0.005.
Nine of the 13 patients with NSVT who died suddenly had only one or two episodes in 48 h. The remaining patients had 6, 9, 31, and 69 episodes. In seven of the 13 patients, there were no more than three or four beats in the longest run, and only three patients had runs of more than five beats. There was no significant difference in any NSVT variable in patients with and without sudden death or all-cause mortality (Table 2).
All but one of the 13 patients with NSVT that died suddenly were in New York Heart Association functional class I or II at diagnosis, and only one had a family history of sudden death. Four of these 13 patients with NSVT had reported previous syncopal episodes, and four had an abnormal blood pressure response during upright exercise testing. Three of these 13 patients had a maximal LV wall thickness ≥30 mm. In 5 of the 13 patients with NSVT that died suddenly, there was no other risk factor for sudden death but the presence of NSVT. Two of them had a LV outflow tract >90 mm Hg.
Two of the 28 patients with NSVT who received amiodarone for more than 50% of their follow-up died suddenly (one having stopped treatment three months before her death because of side effects), compared with 11 of the 76 patients with NSVT not receiving amiodarone, p = 0.5. Five-year sudden death discharge freedom was 96.3% (95% CI: 89.2 to 100) in amiodarone-treated patients with NSVT and 88.4% (95% CI: 80.2 to 96.6) in patients with NSVT not treated with amiodarone, p = 0.2.
There was 1 sudden death and 2 appropriate ICD discharges in the 64 patients without NSVT who received amiodarone for more than 50% of their follow-up, and 18 sudden deaths and two appropriate ICD discharges in the remaining 363 patients, p = 1. In patients without NSVT, five-year sudden death freedom was 98.3% (95% CI: 95.0 to 100) in amiodarone-treated patients and 95.1% (95% CI: 92.7 to 97.6) in patients not treated with amiodarone for the majority of follow-up, p = 0.2.
Interaction of age, NSVT, and survival
The relative risk of sudden death in patients with NSVT varied with age, being highest in those age ≤30 years. Fifteen of 174 patients age 30 or younger (6 of 26 with NSVT) and 17 of 357 patients older than 30 at the time of Holter monitoring (7 of 78 with NSVT) died suddenly during follow-up. Five-year cumulative freedom for sudden death was 91.6% (95% CI: 87.3 to 95.9) in patients age 30 or younger versus 96.2% (95% CI: 93.8 to 98.6) in patients older than 30 at Holter (p = 0.2). There was no relation between NSVT and freedom for sudden death in patients older than 30 (five-year cumulative freedom 96.5% [95% CI: 94.0 to 99.0] without NSVT and 95.2% [95% CI: 89.9 to 100] with NSVT; p = 0.1). The odds ratio of sudden death in patients >30 years of age with NSVT was 2.16 (95% CI: 0.82 to 5.69; p = 0.1). In patients younger than 30, five-year freedom from sudden death was lower in the NSVT group (77.6% [95% CI: 60.2 to 95.0] with NSVT vs. 94.1% [95% CI: 90.2 to 98.0] without NSVT; p = 0.003), with an odds ratio for sudden death in patients with NSVT of 4.35 (95% CI: 1.54 to 12.28; p = 0.006) (Fig. 3).
Twenty-eight of 174 patients age 30 or younger (11 of 26 with NSVT) and 50 of 358 patients older than 30 at the time of Holter monitoring (15 of 78 with NSVT) died or received a cardiac transplantation or an appropriate ICD discharge during follow-up (p = 1). Figure 4presents the freedom functions from all-cause mortality, cardiac transplantation, or appropriate ICD discharge in patients older and younger than 30 with and without NSVT. In older patients there was no significant difference in all-cause mortality between patients with NSVT (5-year cumulative freedom 89.8% [95% CI: 82.5 to 97.1]) versus without NSVT (5-year cumulative freedom 88.9% [84.8 to 93.0]); p = 0.2. In patients younger than 30 years, freedom was lower in the NSVT group (5-year cumulative freedom 61.3% [95% CI: 41.1 to 81.5] with NSVT vs. 93.5% [95% CI: 89.4 to 97.6] without NSVT; p < 0.0001).
For patients ages 30 or younger at Holter, we introduced NSVT in a multivariate Cox regression model with other recognized predictors for sudden death (Table 3). In a model including all these variables, NSVT with an odds ratio of 4 (95% CI: 1.3 to 12.8, p = 0.02) and wall thickness >30 mm with an odds ratio of 3.5 (95% CI: 1.2 to 10.7, p = 0.03) were the only independent predictors of sudden death.
The identification of patients with HCM who are at risk of SCD has been challenging because of the relatively low disease prevalence and the low annual sudden death rates. We have previously suggested that patients with multiple clinical risk markers have an annual risk of dying suddenly sufficient to consider ICD implantation (3). The use of NSVT as a risk marker has, however, remained controversial because of conflicting data in the published literature (1–6). Two studies have demonstrated a significant association between NSVT in patients with HCM and sudden death risk (1,2). In a study of 86 patients, McKenna et al. (1)found that NSVT was significantly associated with an increased risk of sudden death during a mean follow-up period of 2.6 years. In a similar study, Maron et al. (2)demonstrated that 67% of patients who died suddenly had NSVT compared with 17% of survivors. In both studies the majority of patients had fewer than four episodes of NSVT during the recording period (1,2). Two more recent independent studies have, however, failed to demonstrate a statistically significant association between sudden death and NSVT, and it has been suggested that the findings in the earlier studies reflect referral center bias towards symptomatic high-risk patients (5,6). Although factors such as patient selection, changing diagnostic criteria, and treatment protocols may explain the discrepancy in the literature, it is of note that the mean age of patients in the more recent reports was over 40 years of age. The demonstration in this study that the association between NSVT and sudden death risk is particularly strong in patients <30 years of age may provide another explanation for the failure of some studies to demonstrate statistically significant relations between NSVT and prognosis.
The explanation for the complex relation between age, NSVT, and sudden death risk is unclear. In older patients progressive myocyte loss and fibrosis may account for the increased incidence of NSVT in this age group. Conversely, fibrosis and myocyte loss has had less time to develop in younger patients, and, thus, ventricular arrhythmia at an early age may be rarer. However, when NSVT is present in young patients, it probably reflects a more potent arrhythmogenic substrate caused by myocyte disarray, myocardial ischemia, and abnormal autonomic function (11–13).
The implication of this study is that when NSVT occurs in isolation in young patients, it may justify prophylactic therapy to prevent SCD. In contrast, the same arrhythmia in older patients may not justify therapy when it occurs in isolation. A limitation to the study is the small sample size that could account for the lack of significant association between NSVT and sudden death in the group of more than 30 years, and studies with larger numbers of patients will be required to evaluate the prognosis value of the presence of NSVT in this age group.
Although the association between sudden death risk and NSVT in young patients is striking, it should be borne in mind that the majority of sudden deaths, even in young patients, occurred in patients without NSVT. In other words, Holter monitoring identifies only one subset of young patients at high risk, and other recognized risk factors need to be excluded in order to reassure individual patients (14). The infrequent occurrence of symptomatic or sustained ventricular tachycardia during Holter monitoring in this study means that we were unable to make any comment on their prognostic importance. However, data from other studies suggest that prolonged runs of symptomatic ventricular tachycardia are prognostically important in patients with HCM (15). When long multiple episodes of NSVT are present, further investigations to exclude coronary artery disease and to identify possible underlying mechanisms such as LV apical aneurysms are warranted (15,16).
Non-sustained ventricular tachycardia is associated with a substantial increase in all-cause mortality and sudden death risk in young patients with HCM. This risk is independent of the frequency, duration, and heart rate of NSVT episodes.
- confidence interval
- hypertrophic cardiomyopathy
- implantable cardioverter defibrillator
- left ventricular
- non-sustained ventricular tachycardia
- sudden cardiac death
- Received September 13, 2002.
- Revision received January 15, 2003.
- Accepted February 10, 2003.
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