The prognostic significance of incidental non-sustained ventricular tachycardia (NSVT) in subjects without apparent heart disease is unknown. We aimed to evaluate short- and long-term prognosis of NSVT in the Copenhagen Holter Study cohort. From the study, 678 middle-aged and elderly subjects had minimum 48 hours of Holter-recording, laboratory testing and physician-based examination and questionnaire performed. Median follow-up time was 14.7 years. NSVT was defined as runs of minimum three premature ventricular complexes. The primary end-point was a combination of cardiovascular mortality, acute myocardial infarction, coronary revascularization or stroke. Secondary endpoints were all-cause mortality and components of the primary end-point. We found that 72 (10.6%) had minimum one NSVT event on 48-hour Holter-recording. The primary end-point occurred more frequently in patients with NSVT than those without: 38.3 versus 17.7 events per 1,000 patient-years, hazard ratio 2.1, 95% CI 1.37 to 3.20 after adjustment for risk factors. Secondary end-points also occurred more frequently in the NSVT-group. A shorter-term follow-up revealed similar event rates for the primary outcome; 47.5 versus 21.2 events per 1,000 patient-years, hazard ratio 1.9, 95% CI 0.69 to 5.24. Besides stroke other secondary end-points occurred more frequently in the short-term follow-up. The prognosis in subjects with NSVT was not dependent of the length of the VT. In conclusion, incidental asymptomatic NSVT on Holter-recording in subjects without apparent or manifest structural heart disease is associated with increased risk of mortality and cardiovascular events, however the increased risk is not imminent but with a slow and steady pace over time.
Clinicians are regularly confronted with the results of Holter-ECG recordings, unexpectedly showing runs of asymptomatic non-sustained ventricular tachycardia (NSVT). This may put the physician in a difficult position since there are no solid data guiding us how to interpret such findings in patients without known structural heart disease. In subjects with heart failure some studies find NSVT associated with increased mortality while others find the association only in univariate analyses but not after adjustment for other risk factors. The short- and long-term prognosis of NSVT in the general population and in those with risk factors is unclear. Subjects from the general population, without known heart disease, normally are not on anti-arrhythmic medication and the etiology for NSVT could be multifactorial and thus the prognosis quite different. In the light of unclear prognosis some physicians may react promptly by setting up acute or subacute work-up and adjusting/prescribing medication to avoid imminent cardiac events while others may have a more relaxed attitude towards this phenomenon. We aimed to evaluate the long-term and short-term prognosis of NSVT in the cohort of the Copenhagen Holter Study.
Methods
The Copenhagen Holter Study was launched in 1998 and continued until year 2,000. The aim of the study was to address the value of 48-hour Holter recording, in the assessment of future adverse events in middle-aged and older men and women. Information about the study protocol and the selection procedures have been published previously. In brief, all men 55 years and all men and women 60, 65, 70, and 75 years of age (n = 2,969) who were living within 2 well-defined postal regions in the city of Copenhagen were contacted with a questionnaire regarding cardiovascular risk factors, medication use, and medical history. All responding individuals with >1 risk factor, and 60% of randomly selected subjects with 0 to 1 risk factors were invited to follow-up consisting of a physician-based questionnaire, physical examination, laboratory testing, ECG and 48-hours continuous ECG recording. Subjects with known ischemic heart disease, congestive heart failure, valvular heart disease, atrial fibrillation, congenital heart disease, stroke, cancer, or other life-threatening conditions were excluded. This resulted in a study population of 678 middle aged and elderly subjects with no manifest or apparent structural heart disease. Participants underwent fasting laboratory tests, a physical examination, and up to 48 hours of Holter-recording. Holter recording was performed using a 2-channel Space Labs tape recorder (9025, Space Labs, Inc., Redwood, Washington). Recordings were edited and interpreted by trained personnel. The interobserver variability showed kappa values between 0.91 and 0.94. Median value of technically acceptable recording was 44.1 hours, and first and third quartiles (Q1, Q3) were 41.4 to 45.5 hours; 98% of the subjects had >24 hours of recording.
The Framingham ten-year risk was calculated on the basis of age, gender, total cholesterol, HDL-cholesterol, diabetes mellitus and systolic blood-pressure, as described by Wilson et al Definitions : Identification of Ventricular premature complexes (VPC) was based on three criteria: prematurity, post contraction pause, and morphology. Coupling interval to preceding QRS complex had to be 70% or less of mean RR interval of basic rhythm prior to the event. Undisturbed sinus node or atrial ectopic impulse formation demonstrated by a full compensatory pause, or on rare occasions interposition of the premature complex between two normally conducted beats of the regular basic rhythm. QRS complexes widened above 0.10 second and were morphologically different from those of the basic rhythm. NSVT was defined as runs of three or more consecutive complexes of abnormal QRS complexes of which the first complies with the above-mentioned criteria, and the duration being <30 second. The RR intervals of runs are shorter than the basic rhythm. Standard Deviation of the Normal to Normal beats (SDNN) for a 24-hour period was used as a marker of heart rate variability.
Follow-up: Primary endpoint was a combined cardiovascular event consisting of cardiovascular death, acute myocardial infarction (AMI), coronary revascularization, or stroke. Secondary endpoints were all cause mortality and components of the primary endpoint. Events of AMI, revascularization, stroke, and death were retrieved from the national central patient registry and from discharge letters and were validated by reviewing patients’ files. The diagnosis of stroke was made on the basis of clinical findings with a confirmed diagnosis by computed tomography or magnetic resonance imaging. Last follow-up was performed in June 2013. For the short-term follow up, August 1, 2,000 was chosen arbitrarily as the censoring date so the last included patient would have at least six months of follow-up.
Statistical analyses: For continuous variables with a normal distribution mean and standard deviation (SD) values are reported. Data that are not normally distributed are presented as median with interquartile ranges. Pearson chi-square test, Fisher exact test, 2-tailed Student t test, and Wilcoxon rank-sum test (Mann-Whitney U test) were used for the comparison of groups as appropriate. Kaplan-Meier survival function was used to compare event-free survival in different groups according to VT, and the log rank test (Mantel-Cox test) was used to test for equality of the survivor function. Cox proportional hazards model estimated the hazard of VT in relation to the endpoint of death, or cardiovascular events. The assumption of proportional hazards was assessed by visual judgement of the log-minus-log survival plots. Covariates were entered as continuous variables when possible. The assumption of linearity for a continuous variable was checked by entering the transformed variable in addition to the variable of interest. The selection of potentially confounding covariates in Cox regression models and competing risk models was made on the basis of existing knowledge about their relationship with mortality and cardiovascular events. Statistical analysis was performed using STATA version 13.0 (Stata Corp, College Station, Texas) and SAS statistical software program (SAS Enterprise, version 7.11; SAS Institute Inc., Cary, NC).
Ethics : All participants provided written informed consent. The regional ethical committee of Copenhagen and Frederiksberg approved the study. The study is in compliance with the Helsinki Declaration.
Results
In this cohort of 678 community dwelling middle-aged and elderly subjects from Copenhagen city, without apparent or manifest heart disease, 10.6% (72) had at least one event of NSVT on a 48-hour Holter recording. Runs of NSVT had a length of 3 to maximum 9 complexes with the following distribution: 30 patients (41.5%) had only runs of 3 complex, 17 (23.5%) max 4 complexes, 11 (15%) max 5 complexes, 4 (5%) max 6 complexes, 5 (7%) max 7 complexes, 3 (4%) max 8 complexes, and 3 (4%) max 9 complexes. Table 1 displays how baseline characteristics of subjects with versus without NSVT were characterized by mildly lower age and systolic blood pressure, HDL-cholesterol, and triglycerides together with a higher NT-pro BNP and a lower heart rate variability as expressed by SDNN.
| Non-sustained ventricular tachycardia | |||
|---|---|---|---|
| Covariates | All(n = 678) | Yes(n = 72) | No(n = 606) |
| Age (years) | 64.5 (6.8) | 64.2 (6.8) ⁎⁎ | 66.9 (6.6) |
| Men | 397 (58.5%) | 53 (72%) * | 344(56.8%) |
| Current smoker | 314 (46.5%) | 33 (46%) | 281(46.4%) |
| Diabetes mellitus | 75 (11.0%) | 10 (14%) | 65 (10.7%) |
| Systolic Blood pressure (mm Hg) | 156.3 (24.2) | 155.7 (24.4) * | 161.4(21.9) |
| Diastolic Blood pressure (mm Hg) | 90.9 (10.9) | 90.6 (10.9) | 92.7 (10.7) |
| Body mass index (Kg/m 2 ) | 26.8 (4.4) | 26.8 (4.4) | 26.7 (4.0) |
| Low density lipoprotein Cholesterol (mmol/l)/(mg/dL) | 3.8 (1.0)/146.9 (38.7) | 3.87 (0.9)/149.7 (34.8) | 3.73 (1.1)/144.2 (41.4) |
| High density lipoprotein Cholesterol (mmol/l)/(mg/dL) | 1.51 (0.5)/58.4 (17.8) | 1.50 (0.4) ⁎⁎ /58.0 (15.5) ⁎⁎ | 1.66 (0.5)/64.2 (17.7) |
| Triglycerides (mmol/l)/(mg/dL) | 1.25 (0.92–1.82)/48.3 (35.6–70.4) | 1.02 (0.80–1.62) ⁎⁎ /39.4 (30.9–62.7) ⁎⁎ | 1.26 (0.93–1.82)/48.7 (35.9–70.4) |
| P-Sodium (mmol/l) | 141 (140–142) | 141 (140–142 | 141(140–142) |
| P-Potassium (mmol/l) | 3.9 (0.3) | 3.90 (0.3) | 3.88(0.31) |
| P-Creatinine (µmol/l) | 93 (19) | 92.5 (18.8) | 94.3 (21.0) |
| Alcohol (units/week) | 13 (0–26) | 14 (6–33) | 13 (0–26) |
| Aspirin use | 103 (15.2%) | 19 (26%) ⁎⁎ | 84 (13,9%) |
| β-blocker use | 34 (5.0%) | 6 (8%) | 28 (4.6%) |
| Diuretics use | 121 (17.8%) | 14 (19%) | 107 (17.7%) |
| ACE-inhibitor use | 32 (4.7%) | 7 (10%) * | 25 (4.1%) |
| High sensitive CRP (µg/ml) | 2.45 (1.14–4.59) | 2.68 (1.19–3.94) | 2.43(1.11–4.61) |
| NT-pro BNP ( p mol/l) | 6.9 (3.6–13.8) | 11.7 (5.7–29.2) ⁎⁎⁎ | 6.4 (3.5–12.9) |
| Low level of physical activity | 174 (25.6%) | 18 (25%) | 156 (26%) |
| Resting heart rate (bpm) | 72.5 (12.3) | 72.4 (12) | 73.7(14.1) |
| SDNN (ms) | 125 (35) | 124 (35) * | 131 (36) |
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