Higher High-Sensitivity C Reactive Protein is Associated with Future Premature Ventricular Contraction: a Community Based Prospective Cohort Study

We aimed to determine whether hs-CRP is a predictor of future premature ventricular contraction (PVC) events in a community based population. A total of 101,510 participants were recruited at baseline (2006–2007). The follow-up visits were conducted every two years. Participants who were free from PVC at baseline and achieved the fourth visit, or diagnosed of PVC during the subsequent visits were included for analyses. Diagnosis of PVC was based on standard supine resting, 10-s 12-lead ECG. Cox regression was applied to evaluate the association between quartiles of hs-CRP and the incidence of PVCs. 60710 participants (male: 79.9%, mean age 49.4 years) were included for analyses. During a mean follow-up of 74.9 ± 7.4 months, 908 (1.5%) participants were diagnosed with PVC. Participants of the highest quartile of hs-CRP had significantly increased risk of PVC events as compared with the lowest quartile (HR 1.36; 95% CI 1.12–1.66); and stratified analyses showed similar result in males (HR 1.45; 95% CI 1.16–1.80), but not in females (HR 1.12; 95% CI 0.71–1.79). Moreover, elevated serum hs-CRP was associated with future PVC in participants without history of myocardial infarction or stroke (HR 1.34; 95% CI 1.09–1.65). Elevated hs-CRP was an independent predictor of PVC in Chinese population, especially in men.

Premature ventricular contractions (PVC) have been reported as a frequent arrhythmia, with the prevalence of up to 50% in asymptomatic people depending on the different populations evaluated 1,2 . The incidence of PVC varies from 1% to over 10% in healthy population, and tents to be higher in older people 3,4 . Accumulating evidence suggests that patients with PVC are at higher risk for many adverse cardiovascular events, such as impaired ventricular systolic function or congestive heart failure (CHF), overall cardiac mortality, as well as sudden death 5,6 . Indeed, PVC has been considered as an equivalent risk factor for many other risk factors for CHF 7 . Particularly, PVCs detected on 12-lead electrocardiogram (ECG) was demonstrated to have a relatively high sensitivity to predict frequent PVCs detected from Holter monitoring 8,9 . Despite the clinical findings that PVC increases the risk of adverse cardiovascular outcomes, the potential mechanisms underlying this association remain to be determined. Many mechanisms, including myocardial fibrosis, electrophysiological and structural remodeling and inflammation 10 have been involved. However, the association between systematic inflammation and incidence of PVC has not been well evaluated.
As a classic marker of systematic inflammation, high-sensitive c reactive protein (hs-CRP) has been linked to many chronic disorders, such as hypertension, metabolic syndrome, coronary artery disease (CAD), myocardial infarction, and stroke [11][12][13] . In view of the fact that hs-CRP has been involved in the pathogenesis of many cardiovascular events, we hypothesized that elevated hs-CRP may predict PVC events. Therefore, in this community based prospective cohort study, we evaluated the effects of baseline hs-CRP level on the incidence of future PVC Smoking status was classified as never, former or current according to self-reported information. In the present study, we defined smokers as those who were current smokers. Hypertension was defined as presence of a history of hypertension, using antihypertensive medications, a systolic blood pressure > = 140 mmHg, or a diastolic pressure > = 90 mmHg. Diabetes mellitus (DM) was defined as a self-reported disease or the use of insulin, or oral hypoglycemic agents or FBG ≥ 7 mmol/L. Body weights (accurate to 0.1 kg) and heights (accurate to 0.1 cm) were measured, and the body mass indexes (BMI) were calculated. The estimated glomerular filtration rate (eGFR), which was calculated by the Modification of Diet in Renal Disease (MDRD) formula as follows: 186 × (serum creatinine −1.154 ) × (age −0.203 ) × (0.742 if female), with the serum creatinine concentration expressed in milligram per deciliter (mg/dl) 17 .
Anthropometric measurements. Height and weight were measured while subjects wearing light clothing without shoes and hats. Height was measured to the nearest 0.1 cm using a portable stadiometer and weight was measured to the nearest 0.1 kg using calibrated platform scales. Blood pressure (BP) was measured to the nearest 1 mm Hg using mercury sphygmomanometers following the standard recommended procedures. Two readings each of systolic and diastolic blood pressures were recorded at 5-min intervals. The average of two readings was used for subsequent analysis. If the 2 measurements differed by more than 5 mmHg, an additional reading was taken. 12-lead electrocardiography was measured at rest for 5 minutes for the detection of arrhythmias including PVC. Statistical Analysis. Statistical analyses were performed using SAS software, version 9.1 (SAS Institute, Cary, North Carolina, USA) and SPSS 13.0 (SPSS Inc, Chicago, IL). Continuous variables were described by mean ± standard deviation (SD) and compared using one-way ANOVA analysis among multiple groups. Categorical variables were described by percentages and compared via Chi-Squared tests. Hs-CRP was divided into 4 categories according to the quartile 18 . Hazards ratio (HR) and 95% confidence intervals (CI) of incident PVC were estimated according to different hs-CRP concentrations and 1-SD increment of hs-CRP with Cox regression models. A two-tailed p value of <0.05 was considered statistically significant.

Results
A total of 60710 participants (46700 men, 79.9%) with a mean age of 49.36 ± 11.56 years old were finally included in the analyses. The subjects were categorized into four groups according to the quartiles of hs-CRP concentrations. The demographic and clinical characteristics of the subjects are summarized in Table 1. In the present study, thresholds dividing the first and second, second and third, and third and fourth hs-CRP quartiles were 0.29, 0.71 and 1.80 mg/l for the whole population, 0.28, 0.77 and 2.1 mg/l for women, and 0.29, 0.70 and 1.73 mg/l for men. SDs of hs-CRP concentration for was 2.02 mg/l, 1.99 mg/l and 2.12 mg/l for the overall participants, women and men, respectively. Male subjects were in higher proportion (76.9%) in the study. Compared with the first hs-CRP quartile, Participants of the higher quartile of hs-CRP were associated with higher prevalence of cardiovascular risk factors, including hypertension, DM, MI, stroke, high BMI, advanced age, and elevated concentrations of systolic BP, diastolic BP, FBG.
During a mean follow-up of 74.9 ± 7.4 months, 908(1.5%) participants were diagnosed of PVC. The incidence of PVC increased with increment of baseline hs-CRP concentration in total subjects and in men. From the first to the fourth hs-CRP quartile, the incidence of PVC was 1.2%, 1.4%, 1.5% and 2.0% in all participants, 1.2%,  Fig. 2).

Discussion
In this prospective cohort study based on community populations, we found that elevated baseline hs-CRP was an independent risk factor for PVC risk. The association between increased baseline hs-CRP and subsequent PVC events remained sigfnicaint in men and in those without history of myocardial infarction or stroke. Result of our study may be reflective of the pathophysiological association between systematic inflammation and risk of PVC. In our study, we were not able to detect a significant correlation between hs-CRP and PVC in women. One possible reason was the relatively low proportion of women in this cohort study which may limit the statistical power. One reason might be the ethnic heterogeneity which may suggest the different association between inflammation and PVC in different populations 19 . Another important reason likely was the difference of age-related risk patterns in men and women. A recent review study showed that women seemed to have a lower risk of cardiovascular disease until older age as compared to men. The potential mechanism might be related to the iron loss/ deficiency during fertile years due to menstruation 20 . In the present study, we enrolled a total of 14010 women with a mean age of 48.15 ± 10.99 years old, which were relatively young. Hence, the relative protection from cardiovascular disease in fertile women probably contributed to the non-significant relationship between hs-CRP and PVC. In the sensitivity analysis, the relationship remained significance in participants without myocardial infarction or stroke. Of interest, we found lower hs-CRP concentration was a predictor of PVC incidence in men without myocardial infarction or stroke, compared with hs-CRP concentration in predicting further PVC in the whole population. It implied a cut off of hs-CRP concentration specificity in the particular population.
Results of our study may be reflective of the role of systematic inflammation in the pathogenesis of PVCs. It has been proposed that hs-CRP as a biomarker of inflammation, could stimulate the recruitment of monocytes into atheromatous plaque and induce endothelial dysfunction by suppressing basal and induced nitric oxide release, and finally contributes to the atherosclerotic process 21,22 . Recently, hs-CRP has been suggested to be of prognostic predictor in participants with CAD as well as in general populations [23][24][25] . Moreover, higher plasma hs-CRP has also been proposed as an independent risk factor of myocardial infarction, stroke, peripheral arterial disease and atrial fibrillation recurrence [26][27][28] . Our results suggest that hs-CRP was a significant predictor of PVC incidence, which were consistent with the previous findings of Biasucci et al. 29 , who found that hs-CRP concentration >3 mg/l is significantly associated with the occurrence of ventricular tachycardia (VT) or ventricular fibrillation (VF) in patients with implantable cardioverter defibrillator (ICD). Moreover, Blangy et al. 30 also showed that increased hs-CRP was associated with a higher VT incidence. Indeed, Bonny et al. 31 found that systemic inflammation expressed by high CRP concentration was a more active process after spontaneous ventricular arrhythmia in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. Furthermore, hs-CRP has also been suggested as a useful indicator of long term risk of sudden cardiac death in healthy men 32 , and in patients with chronic heart failure and reduced LVEF 33 . Interestingly, sudden death is reported to be mainly related to acute coronary event, but only isolated areas of myocardial fibrosis could be found in an autopsy case, suggesting that these areas might provide a myocardial substrate prone to develop arrhythmias 22 . Additionally, recent studies showed that elevated hs-CRP participated in atrial fibrillation recurrence via leading to electrophysiological and structural remodeling in the atrial and ventricular myocardium 10,34,35 . Hence, it could be speculated that elevated hs-CRP may accelerate the pathogenesis of ventricular arrhythmia via inducing of myocardial fibrosis. These facts may be reflective the potential mechanisms of statins administration for the prevention of ventricular arrhythmia in patients with ICDs, which may involve the anti-fibrotic effects following the anti-inflammatory benefits of the medications 36 . Further researches should be conducted to confirm the detail mechanisms for PVC induced by elevated hs-CRP.
Several researches demonstrated a poor prognosis in population with frequent PVCs 9,37 , and increased burden of PVCs has been linked to left ventricular dysfunction [38][39][40] . Sajadieh et al. 41 demonstrated a hs-CRP concentration > or = 2.5 mg/l was associated with a significantly higher risk of death and acute myocardial infarction. In the present study, higher hs-CRP was related to higher risk of PVC incidence. Further studies should clarify whether there were particular groups of subjects who would have a worse prognosis. For this purpose, long-term follow-up may be the first step forward.
Limitations and strengths. Possible study limitations should be considered. Firstly, participants enrolled in our study were from the Kailuan Mine Corporation, which included more men than women. The representativeness of the study was limited by the higher proportion of male subjects. Secondly, the prognosis of subjects with PVC and higher hs-CRP concentration was not known, further follow-up are need to confirm the results. Notwithstanding these limitations, our survey has important strengths including its large sample size, population-based research and relatively long time of follow-up.

Conclusion
Elevated hs-CRP was an independent predictor of PVC in a Chinese population, especially in men, which may be reflective of the pathophysiological association between systematic inflammation and risk of PVC.