The Prevalence and Prognostic Value of Rest Premature Ventricular Contractions

This chapter discusses research conducted to evaluate the prognostic significance of premature ventricular contractions (PVCs) on a routine electrocardiogram (ECG), and to evaluate their relationship to heart rate, heart failure and sport participation. Identifying parameters to help risk stratify patients and provide prognostic implications can help identify individuals who may benefit from early diagnosis and intervention. Our discussion utilizes research from a large database of computerized 12-lead ECGs, including 45,402 members of the US Veterans Administration, of which 352 were known to have heart failure. In addition, 750 athletes were analyzed. Echocardiograms and treadmill tests were performed on all those with heart failure and echocardiograms were part of the annual physical exam of the college athletes. Briefly, there were 1731 patients with PVCs (3.8%) in the total veteran population. Twentynine of the 352 with heart failure exhibited a PVC (8%) and 5 of the 750 athletes exhibited a PVC (0.7%). Compared to patients without PVCs, those with PVCs had significantly higher all-cause (39% vs. 22%, p<0.001) and cardiovascular mortality (20% vs. 8%, p<0.001). PVCs remain a significant predictor even after adjustment for age and other ECG abnormalities. The presence of multiple PVCs or complex morphologies did not add significant additional prognostic information. Those patients with PVCs had a significantly higher heart rate than those without PVCs (meanSD: 78.615 vs. 73.516 bpm, p<0.001). When patients were divided into groups by heart rate (<60, 60-79, 80-99 and >100 bpm) and by the presence or absence of PVCs, mortality increased progressively with heart rate and doubled with the presence of PVCs. Using regression analysis, heart rate was demonstrated to be an independent and significant predictor of PVCs. We identified 352 patients (64 ± 11 years; 7 females) with a history of clinical HF undergoing treadmill testing for clinical reasons at the VAPAHCS (1987-2007). Patients with rest PVCs were defined as having ≥1 PVC on the ECG prior to testing (n=29; 8%).During a median follow-up period of 6.2 years, there were 178 deaths of which 76 (42.6%) were due to CV causes. At baseline, compared to patients without rest PVCs, those with rest PVCs had a lower ejection fraction (EF) (30% vs. 45%) and the prevalence of EF≤35% was higher (75% vs. 41%). They were more likely to have smoked (76% vs. 55%).The all-cause and CV mortality rates were significantly higher in the rest PVCs group (72% vs. 49%, p=0.01 and 45% vs. 20%, p=0.002; respectively). After adjusting for age, beta-blocker use, rest ECG findings, resting heart rate (HR), EF, maximal systolic blood pressure, peak HR and exercise capacity,


Introduction
This chapter discusses research conducted to evaluate the prognostic significance of premature ventricular contractions (PVCs) on a routine electrocardiogram (ECG), and to evaluate their relationship to heart rate, heart failure and sport participation.Identifying parameters to help risk stratify patients and provide prognostic implications can help identify individuals who may benefit from early diagnosis and intervention.Our discussion utilizes research from a large database of computerized 12-lead ECGs, including 45,402 members of the US Veterans Administration, of which 352 were known to have heart failure.In addition, 750 athletes were analyzed.Echocardiograms and treadmill tests were performed on all those with heart failure and echocardiograms were part of the annual physical exam of the college athletes.Briefly, there were 1731 patients with PVCs (3.8%) in the total veteran population.Twentynine of the 352 with heart failure exhibited a PVC (8%) and 5 of the 750 athletes exhibited a PVC (0.7%).Compared to patients without PVCs, those with PVCs had significantly higher all-cause (39% vs. 22%, p<0.001) and cardiovascular mortality (20% vs. 8%, p<0.001).PVCs remain a significant predictor even after adjustment for age and other ECG abnormalities.The presence of multiple PVCs or complex morphologies did not add significant additional prognostic information.Those patients with PVCs had a significantly higher heart rate than those without PVCs (meanSD: 78.615 vs. 73.516 bpm,p<0.001).When patients were divided into groups by heart rate (<60, 60-79, 80-99 and >100 bpm) and by the presence or absence of PVCs, mortality increased progressively with heart rate and doubled with the presence of PVCs.Using regression analysis, heart rate was demonstrated to be an independent and significant predictor of PVCs.We identified 352 patients (64 ± 11 years; 7 females) with a history of clinical HF undergoing treadmill testing for clinical reasons at the VAPAHCS .Patients with rest PVCs were defined as having ≥1 PVC on the ECG prior to testing (n=29; 8%).During a median follow-up period of 6.2 years, there were 178 deaths of which 76 (42.6%) were due to CV causes.At baseline, compared to patients without rest PVCs, those with rest PVCs had a lower ejection fraction (EF) (30% vs. 45%) and the prevalence of EF≤35% was higher (75% vs. 41%).They were more likely to have smoked (76% vs. 55%).The all-cause and CV mortality rates were significantly higher in the rest PVCs group (72% vs. 49%, p=0.01 and 45% vs. 20%, p=0.002; respectively).After adjusting for age, beta-blocker use, rest ECG findings, resting heart rate (HR), EF, maximal systolic blood pressure, peak HR and exercise capacity, rest PVCs was associated with a 5.5 -fold increased risk of CV mortality (p=0.004).Considering the presence of PVCs during exercise and/or recovery did not affect our results.All five athletes with at least one PVC on a routine screening ECG as part of the annual physical exams had normal echocardiograms and no clinical manifestations of heart disease.Thus, we concluded that PVCs on a resting ECG are a significant and independent predictor of all-cause and cardiovascular mortality.Increased heart rate predicts mortality in patients with and without PVCs and the combination dramatically increases mortality.These findings together with the demonstrated independent association of heart rate with PVCs suggest that a hyper-adrenergic state is present in patients with PVCs and that it likely contributes to their adverse prognosis.In patients with heart failure the presence of PVCs on a resting ECG is associated with a significant increase in risk of CV death independent of age and exercise capacity.PVCs are rare in young athletes and do not appear to be associated with cardiac disease.

Background
Premature ventricular contractions (PVCs) are common electrocardiographic findings in patients with and without structural heart disease.Prior evidence suggests that the presence of PVCs has prognostic value but it is unclear what underlying process they represent.A surprising observation in some studies has been an apparent association between higher mean resting heart rates and the presence of PVCs.Activation of the sympathetic nervous system is an important factor in the genesis of ventricular arrhythmias (Anderson, 2003;Podrid, Fuchs & Candinas, 1990).Enhanced automaticity, triggered activity, and reentry are all mechanisms generating rhythm abnormalities; all three mechanisms are markedly potentiated by the action of catecholamines.We sought to make use of our large database of electrocardiogram (ECG) data to confirm the prognostic significance of PVCs and analyze the interaction between heart rate and PVCs.We hypothesized that both elevated heart rate and the presence of PVCs are markers of sympathetic nervous system (SNS) activity and would, therefore, be correlated with each other and predictive of mortality.This would support the other lines of evidence suggesting that the sympathetic nervous system is active in the genesis of PVCs.
O f t h e E C G s o r i g i n a l l y c l a s s i f i e d a s h a v i n g P V C s p r e s e n t , 1 4 % w e r e f o u n d t o b e misclassified as having PVCs when none were present.The most common reason for these errors was misclassification of artifact or of aberrantly-conducted supraventricular beats.All the misclassified patients were reclassified into the 'PVC absent' group, leaving 1731 patients for analysis in the 'PVC present' group.The 'PVC present' ECGs were then reviewed to categorize the patterns and morphologic characteristics of confirmed PVCs.These characteristics included presence of multiple PVCs on a single 10-sec ECG, presence of couplets or salvos (≥3 consecutive PVCs), presence of bigeminal or trigeminal rhythm, and presence of multiform PVC morphologies.For the purposes of this study, complex PVCs were defined as repetitive PVCs (≥2 consecutive) and multiform morphologies.Non-sustained ventricular tachycardia was rarely documented on these short recordings and the few short runs of 3 or more consecutive beats were not analyzed separately.Heart rate was determined by the program by counting all QRS complex templates in 10 seconds and multiplying by six.When PVCs were present, the R-R interval between the normal, dominant sinus QRS complexes (NN) was manually measured except when the pattern of PVCs made it impossible (i.e., bigeminy).This NN interval was used to calculate the intrinsic sinus rate.An 'abnormal' ECG was defined as the presence of one or more of the following: pathologic Q waves, left or right bundle branch block, intraventricular conduction delay, Wolff-Parkinson-White syndrome, right or left ventricular hypertrophy (Romhilt-Estes), left atrial enlargement, or abnormal ST segments.All remaining ECGs were classified as 'normal'.

Follow-up
The Social Security Death Index and California Health Department Service were used to ascertain vital status as of 12/31/00.Cause of death was available from the latter and deaths determined by the Social Security Death Index were classified by review of the Veteran's Affairs clinical data base.All-cause death and cardiovascular death were used as endpoints.Mean follow-up was 5.5 years.Data regarding cardiac interventions or events was not available.

Statistical methods
Number Crunching System SoftwareÔ (Kaysville, UT) was used for all statistical analyses after transferring the data from a Microsoft ACCESS (Redmond, WA) database.Unpaired two-tailed t tests were used for univariate comparison of variables.Cox proportional hazard analysis was performed to evaluate those with and without PVCs and those with multiple and complex PVCs.Multivariate Cox hazard function analysis was performed to demonstrate if the various PVC characteristics were independently and significantly associated with time until death after considering age and other ECG abnormalities.Analysis was repeated using data from only those patients with normal ECGs.Kaplan Meier survival analysis was again performed after patients were divided into groups by heart rate (<60, 60-79, 80-99 and >100 bpm) and by the presence or absence of PVCs.Multivariate regression analysis was performed with heart rate as the dependent variable and with the following independent variables: age, gender, abnormal/normal ECG classification, in-or outpatient status and PVCs present or not.Logistic regression was performed with PVCs as the dependent variable and with the following independent variables: age, gender, abnormal/normal ECG classification, PVCs present or absent and in-or outpatient status.

Results
After exclusion of patients with atrial fibrillation and paced rhythms, there were 43,671 patients without PVCs and 1731 patients with PVCs (3.8%).Demographic and ECG characteristics of the groups are shown in Table I.The group with PVCs was older than those without PVCs (mean age  SD: 65  12 vs.56  15, P<0.001).As this was a VA study, the patients are 90% male but there was a slightly higher percentage of men among those with PVCs (90% vs. 94%, p=0.01).There were no significant differences between height, weight or BMI.Patients with PVCs had a significantly higher prevalence of Q waves, LVH, LAE, bundle branch blocks and ECGs classified as abnormal.Of the ECG characteristics evaluated, only RVH was similar between the groups.Table II.Demographics and ECG findings in patients with single versus multiple and noncomplex versus complex PVCs.

Variable
Multiple PVCs (≥2 PVC per ECG) were present in 47% patients with PVCs.Of these 10% were couplets or salvos, 21% had multiform morphologies, and 15% had ventricular bigeminal or trigeminal patterns.The demographics and prevalence of ECG abnormalities for these patients are shown in Table II.Patients with multiple PVCs were older than those with only single PVCs present on the ECG.Those with complex forms were older than those with non-complex morphologies.There were no statistically significant differences in the prevalence of Q waves, LVH, right or left bundle branch block between those patients with or without multiple PVCs.Patients with complex PVCs had statistically significantly more Q waves on their ECGs than those without complex PVCs (p=0.007).
The average annual all-cause mortality in the total population was 3.9% with mortality in those with PVCs (6.7%) significantly higher than for those without PVCs (3.8%) (Table III).
The average annual CV mortality in the total population was 1.5% (39% of the deaths) with CV mortality in those with PVCs (3.5%) significantly higher than for those without PVCs (1.4%).Those with complex PVCs had an annual CV mortality rate of 5.1%.The hazard ratios for patients with all types of PVCs were significantly increased when compared to patients having no PVCs on an ECG.The age-adjusted hazard ratios in patients with any PVCs versus those with no PVCs was 1.39 (95% CI 1.29 -1.50) for all cause mortality and 1.81 (95% CI 1.62 -2.01) for cardiovascular mortality.There was no statistically significant difference in mortality between patients who had multiple (≥2) PVCs per ECG and those with only single PVCs.The age-adjusted hazard ratio for complex PVCs (versus no PVCs) for all-cause and cardiovascular mortality in all patients was 1.6 (95% CI 1.3-1.9)and 2.1 (95% CI 1.6-2.8),respectively.Patients with complex PVCs appeared to have increased allcause and CV mortality as compared to those with non-complex PVCs but the difference in survival did not achieve statistical significance.Similar findings resulted when the analysis was limited to patients with normal resting ECGs.After considering age, BMI, and ECG findings in a Cox hazard model, the presence of any resting PVCs were found to be independent predictors of mortality with a hazard ratio of 2.0 (95% CI 1.1-2.8)Table III.Mortality in patients with and without PVCs.
When patients were divided into groups by heart rate (<60, 60-79, 80-99 and >100 bpm) and by the presence or absence of PVCs, mortality increased progressively with heart rate and doubled with the presence of PVCs (Table IV, Figure 1).Cardiovascular mortality ranged from a low of 6.3% in those with heart rates less than 60 bpm and no PVCs to a high of 26.1% in those with a heart rate > 100 bpm and PVCs.Within each heart rate group, there was a significant increase in mortality when PVCs were present (p<0.001).The differences in event free survival between groups is also clearly demonstrated with Kaplan-Meier cumulative survival curve (Figure 2).The PVC and heart rate stratifications performed similarly when patients were divided into those with normal and abnormal ECGs.

PVCs
The "PVC hypothesis" that PVC suppression would prevent sudden death was popularized by Lown and others in the 1960's and 1970's and was accepted as dogma well into the late 1980's.It was based on seemingly sound logic that that sudden death in myocardial infarction survivors is due to ventricular fibrillation (Nikolic & Bishop 1982;Pratt, Francis & Luck, 1983) and that PVCs precede and therefore identify those patients who are susceptible to these episodes (Lown, 1971).It was assumed that the suppression of PVCs with antiarrhythmic drugs would be beneficial but the disappointing results of the CAST trials (CAST Investigators, 1989, 1992) negated the causal role theory of PVCs.In fact, the negating of the "PVC hypothesis" by the CAST results is a classic example of why hypothetical Heart Rate Group mechanisms cannot replace the evidence based approach.Partly due to these results, PVCs are generally ignored on a routine ECG.But, PVCs may still have an important role in risk stratification even if treatment with antiarrhythmic medications is not appropriate.A higher prevalence of PVCs has been seen in patients with coronary artery disease (Bikkina, Larson, & Levy, 1992), hypertension (Vogt et al., 1990), accompanying ECG abnormalities (Fisher & Tyroler, 1973), and nearly every form of structural heart disease.PVCs also increase with age (Flegg, 1988;Kostis et 1982).In the acute phase of myocardial infarction, PVCs are seen in 80-90% of patients and have been related to residual ischemia (Mukharji et al., 1984), degree of coronary narrowing (Minisi et al., 1988), degree of left ventricular involvement (Bigger et al., 1984;Tracy et al., 1987), and age of infarction (Kostis et al., 1987).
In patients without established cardiovascular disease, there have been conflicting findings with some authors concluding that PVCs are benign in this population (Fleg & Kennedy, 1992;Rodstein, Wolloch, & Gubner, 1971) and others reporting increased mortality (Abdalla et al., 1987;Bikkina, Larson, & Levy, 1992;Rabkin, Mathewson & Tate, 1981) although the methods used to determine true absence of coronary artery disease varied greatly between studies.Our results are consistent with the Framingham Heart Study of 6,033 men and women who underwent one hour ambulatory electrocardiography (Bikkina, Larson, & Levy, 1992).After adjusting for age and traditional risk factors for coronary artery disease, there was a significant and independent association between asymptomatic ectopy in men without clinically apparent coronary heart disease and the risk for all-cause mortality (RR 2.3) as well as death from coronary heart disease (RR 2.1).Such an association was not seen in women or in men with known coronary artery disease.
The idea that looking at the frequency and morphology of PVCs might provide additional predictive power has been investigated.Ismaile et al. reported findings from a prospective study of 15,637 apparently healthy white men who underwent screening for the Multiple Risk Factor Intervention Trial (MRFIT) (Abdalla et al., 1987).They used 2 minute resting rhythm strips and concluded that the presence of frequent or complex PVCs is associated with a significant and independent risk for sudden cardiac death (RR 4.2; RR 3.0 for the presence of any PVCs).Our study confirms the risk predicted by any PVC but only shows a non-significant trend towards worse outcome with complex or multiple PVCs.This may be because we looked at all-cause and cardiovascular mortality but did not limit our outcome to sudden death.

Heart rate
Gillman et al. evaluated 4,530 untreated hypertensives using 36-year follow-up data from the Framingham Study (Gillman et al., 1993).Regression analysis, after adjustment for age and systolic blood pressure, showed that there was a two-fold increase in cardiovascular mortality for each heart rate increment of 40 beats/min.In a French study of 19,386 subjects undergoing routine health examinations, resting tachycardia was demonstrated to be a predictor of non-cardiovascular mortality in both genders, and of cardiovascular mortality in men, independent of age and blood pressure (Benetos et al., 1999).Heart rate on the initial ECG after acute myocardial infarction has also been shown to be an independent predictor of prognosis (Hathaway et al., 1998).Our results add to the evidence that heart rate is an important prognostic variable.
Several large studies confirm our finding of heart rate not being related to age (Gillum, 1988;Morcet et al., 1999;Simpson et al., 2002;Spodick et al., 1992).There are conflicting reports in the literature as to the association of gender and heart rate.Some studies suggest that heart rate is higher in women (Gillum, 1988;Morcet et al., 1999) while others confirm our finding of heart rate being lower in women (Simpson et al., 2002).

PVCs and heart rate
Few studies have evaluated the relationship of resting PVCs with increased heart rate on an ECG.The Atherosclerosis Risk In Communities (ARIC) study reported the prevalence of PVCs in 15,792 individuals aged 45-65 years on a longer than normal ECG recording of 2minutes (Simpson et al., 2002).PVCs were present in 6% of these middle-aged adults and faster sinus rates were directly related to PVC prevalence.The relationship of PVCs to heart rate has been described in a series of studies using Holter monitoring.The relationship between the frequency of PVCs and underlying heart rate was reported in patients with frequent PVCs; the most frequent relationship was an increase in PVCs with increasing heart rate (Acanfora et al., 1993;Winkle, 1982) It has also been shown that there are three reproducible trends characterizing the dynamic behavior of PVCs: a tachycardia-enhanced pattern (28%), a bradycardia-enhanced pattern (24%), and an indifferent pattern in the remainder of patients (48%) (Pitzalis et al. 1997).Another study suggested that beta-blockers were most effective in reducing PVC frequency in the tachycardia and indifferent groups (Pitzalis et al., 1996).Propafenone has also been shown to be most effective in tachycardia-enhanced patients (Saikawa et al., 2001).

Sympathetic nervous system
Several lines of evidence suggest that activation of the sympathetic nervous system (SNS) plays a primary role in the generation of PVCs, ventricular arrhythmias and sudden cardiac death (Grassi et al., 2003;Podrid, Fuchs & Candinas, 1990).Circulating catecholamines and increased heart rate are known to interact with all three major mechanisms involved in the generation of arrhythmias: enhanced automaticity, triggered automaticity, and reentry (Stein et al., 1998).Substantial experimental data from animal studies shows that activation of the SNS is a strong stimulus for the development of ventricular tachyarrhythmias.It is well established that medications with beta-blocking properties help to decrease the frequency of PVCs (Krittayaphong et al, 2002) and prevent sudden death (JAMA, 1982;Pederson, 1985).Decreased sympathetic tone and improvement of cardiac autonomic regulation appear to play a major role in the ability of beta-blockers to reduce PVCs (Acanfora et al., 2000).Studies of genetic disorders, animal models, and spontaneous human arrhythmias have helped to create a better understanding of this relationship.1Infusion of nerve growth factor into animal models, designed to mimic long-term elevations of sympathetic activity and signaling, resulted in apoptosis, hypertrophy, and fibrosis.In human studies, changes in heart rate have been shown to occur prior to the onset of PVCs and ventricular arrhythmias (Anderson et al., 1999;Nemec, Hammill & Shen, 1999;Pitzalis et al, 1997;Sapoznikov, Luria & Gotsman, 1999).The propensity for PVCs and ventricular arrhythmias is highest when there are superimposed effects of short-, intermediate, and long-term changes.Parasympathetic inhibition of SNS activity may be part of a normal regulatory process that is lost in patients with severe heart failure and other disorders.
Some investigators have proposed the nerve sprouting hypothesis of ventricular arrhythmia to explain arrhythmic events seen in patients with a history of myocardial infarction (Chen et al, 2001).The theory is that myocardial damage results in nerve injury which is followed by sympathetic nerve sprouting and regionally increased sympathetic tone.The increased SNS activity in the local area of remodeled myocardium results in PVCs, ventricular tachycardia/fibrillation and sudden death.Support for this hypothesis was provided by an evaluation of cardiac nerves in explanted native hearts of human transplant recipients (Cao et al., 2000).Infusion of nerve growth factor into the left stellate ganglion of dogs was also shown to result in increased development of ventricular arrhythmias (Cao et al., 2000).The recurring theme of research in this area is that the response to injury results in heterogeneous sympathetic innervation which is highly arrhythmogenic (Verrier & Antzelevitch, 2004).

Study limitations
The population in our study included a relatively diverse group of all consecutive inpatients and outpatients who had a 12-lead ECG for any reason; the only exclusion criteria were the presence of atrial fibrillation or a paced rhythm.This differs from many previous studies of either more narrowly defined high-risk populations of patients referred to electrophysiologists or more broadly defined low-risk community epidemiological cohorts.These differences may be an advantage as our study is clinically based and includes all patients at our facility referred for an ECG.Base-line clinical data, laboratory studies and diagnostic tests such as echocardiograms or cardiac catheterizations were not available.Information on medications, especially beta-blockers, would have been very useful.The ECGs were obtained over the span of more than a decade during which time there were changes in practice patterns and beta-blocker usage.However, there is no reason to think that beta-blocker usage would be less in those with PVCs (such that this would explain their higher heart rate).We also lack other markers of sympathetic activity to confirm our hypothesis.An important limitation of the study is that PVCs are identified on a single 10 second ECG recording.This 'snapshot' might not be expected to provide as much clinically meaningful information as longer term ambulatory ECG monitoring but, the extremely large number of patients available for analysis allows significant results to be obtained.The 4% prevalence of PVCs found in our study compares favorably with a rate of 2-7% in previous epidemiologic studies including those using 2-min rhythm strips.(Crow et al., 1975;Fisher & Tyroler, 1973;Kostis et al., 1987;Simpson et al., 200).Overall, this is a retrospective analysis and, as such, should be considered hypothesis generating rather than conclusive evidence of a cause and effect relationship.The predictive models generated here should be validated using other electrocardiographic databases and in prospective evaluations.

Conclusions
Our study suggests that the simple 12-lead ECG provides valuable information and can complement more advanced strategies for arrhythmic risk stratification.The presence of any PVC on a single ECG is a powerful predictor of all-cause and cardiovascular mortality.The presence of multiple or complex PVCs was not a significantly better predictor although there was a trend towards worse prognosis in patients with complex forms.These observations are true even in those patients with otherwise normal baseline ECGs.
Regression analysis demonstrates that heart rate is a significant and independent predictor of the presence of PVCs.Our findings support the hypothesis that activation of the sympathetic nervous system is an important factor in the genesis of PVCs and ventricular arrhythmias.The presence of elevated heart rate is a significant prognostic factor and the combination of increased heart rate and PVCs dramatically increases mortality.

Table I .
Demographics and ECG findings in patients with and without PVCs.Those patients with PVCs had a significantly higher heart rate than those without PVCs (mean  SD: 78.6  15 vs. 73.5  16 bpm, P<0.001).This heart rate difference persisted when patients were sub-grouped by gender, race, outpatient vs. inpatient status and those with otherwise normal ECGs (i.e., least likely to have structural heart disease).Those patients with PVCs always had a significantly higher mean heart rate.Further analysis of heart rate differences showed that women had a significantly lower mean HR than men (71.1 ± 13.7 vs 74.0 ± 16.2, p<0.001), outpatients had a lower mean heart rate than inpatients (72.5 ± 15.0 vs 76.9 ± 17.7, p<0.001), and those with an otherwise normal ECG had a lower heart rate than those with an abnormal ECG (73.2 ± 15.6 vs 75.2 ± 16.8, p<0.001).