Use of C-reactive protein for prediction of sinus rhythm maintenance after pharmacologic cardioversion in patients with Metabolic Syndrome

Atrial Fibrillation (AF) has increasingly become a focus of attention in recent years because it is the most encountered arrhythmia in clinical practice, a major cause of morbidity and mortality, and has adverse effects on overall quality of life. Several studies reported that Metabolic Sydrome (MS), a cluster of atherogenic risk factors, could influence the development of atrial fibrillation. An association between atrial fibrillation and metabolic syndrome has been suggested¹, but the mechanisms that relate metabolic syndrome to the increased risk of atrial fibrillation occurrence are not completely understood.^{2, 3}

Approximately 50% of patients undergoing cardioversion usually present with recurrence of AF within 3–6 months of cardioversion despite ongoing antiarrhythmic treatment.⁴ The precise mechanisms of AF recurrence have not been fully elucidated. Many studies have indicated that inflammatory changes are essential for the recurrence of AF^5,6, and an increased level of markers of inflammation, such as CRP, is associated with a greater risk of AF recurrence. However, there was significant heterogeneity across the studies.^7–10 Therefore, identifying patients at high risk of AF recurrence remains challenging.

We set out to use CRP levels to predict sinus rhythm maintenance after Pharmacologic Cardioversion (PCV) in patients with Metabolic Syndrome (MS). We tested the hypothesis that increased CRP levels are associated with a greater risk of AF recurrence after PCV in MS patients.

For evaluation of the data obtained from the study, descriptive statistical methods of mean ± standard deviation, frequency, and ratio values were used. The distribution of variables was tested for normality using the Kolmogorov-Smirnov test, and the heterogeneity of variances was evaluated by Levene’s test. Analysis of quantitative variables with normal distribution was performed using the Student-t test and analysis of variance (ANOVA). Continuous variables with abnormal distribution and qualitative variables were analyzed using the Fisher test and Χ² test. The association between variables was analyzed using logistic regression, odds ratio (OR),and 95% confidence interval (CI) were estimated. A p value <0.05 was considered statistically significant for a confidence interval of 95%. Statistical analyses were performed with the SPSS software package (SPSS 19.0).

A total of 215 patients with MS, after pharmacologic cardioversion, were stratified in two groups: 105 participants (51 females and 54 males) with CRP<3mg/L and 110 participants (59 females and 51 males) with level of CRP>3mg/L, completed the survey. (Table 2)

After the follow-up at one year, only 35 (31.8%) of patients with MS and CRP levels above 3.0mg/L remain in sinus rhythm, compared to 68 (64.7%) of patient with MS and CRP levels below 3.0mg/L (Fisher exact p=0. 002) (Table 1 and Fig. 1). The recurrence rate of AF in participants with MS and CRP levels above 3.0mg/L was higher when compared with participants with MS and CRP levels below 3.0mg/L [75 (68. 1%) vs. 37 (35. 2%)] (Fisher exact p=0. 002).

Figure 1

Of all recurrences of atrial fibrillation, 45% occurred within the first three months with significant difference between the two groups (55% in patients with MS and CRP levels above 3.0mg/L vs. 24% patients with MS and CRP levels below 3.0mg/L, Fisher exact p=0. 003) and the last three months (12% in patients with MS and CRP levels above 3.0mg/L vs. 35% in patients with MS and CRP levels below 3.0mg/L, Fisher exact p=0.04).

There was no significant difference between groups using antiarrhythmic drugs (AADs) after PCV during follow-up period. Amiodarone was used in (49% of patients with MS and CRP levels above 3.0mg/L vs. 44% patients with MS and CRP levels below 3.0mg/L, p=0.48), Flekainide (13%vs. 16%, p=0. 47), Propaphenon (21% vs. 22%, p=0. 34), and Metoprolol (2% vs. 3%, p=0.52). Also, there was no significant difference between participants those that did not use any AADs during the follow-up period, regarding maintenance in sinus rhythm (SR) (17% vs. 11.7%, Fisher exact p=0.38).

The baseline demographic, clinical, electrocardiographic, echocardiographic, and laboratoric characteristics of each study group are summarized in Table 2. There were no statistically significant differences between the participants with level of CRP >3mg/L and participants with level of CRP <3mg/L in: gender (p=0.96), ages (58. 8±5.2 vs. 56. 9±5.4; p=0.5), systolic and diastolic blood pressure (142±26 vs. 132±15 p=0.47; 89±10 vs. 83±7) (p=0. 31), WC (94±3. 4 vs. 92. 4±5. 2 p=0. 18), Trig (2. 1±0. 5vs 1. 9±0. 4 p=0. 29); HDL (0.89 vs. 0.86, p=0.46), three risk factors of MS (p=0.19), four risk factors of MS (p=0.09) and five risk factors of MS (p=0.06), type of AF (paroxysmal p=0.51; persistence p=0.50), presence of disease (coronary disease p=0.42, heart failure p=0.34; kidney disease p=0.61, stroke p=0.54), AADs used for pharmacological cardioversion (Amiodarone p=0.46, Flecainide p=0.44, Propaphenone p=0.49; Metoprolol p=0.24, oral medications (pill-in-the-pocket), Propaphenone p=0.54, Flecainide p=0.36), AADs used after pharmacological cardioversion (Amiodarone p=0, 55, Flecainide p=0.32, Propaphenone p=0.35, Metoprolol p=0.24).

Of all participants included in the study, 167 (77. 6%) participants had no evidence of organic heart disease (85 (81%) in group with level of CRP <3mg/L and 82 (74. 5%) participants in group with level of CRP >3mg/L, p=0.38). In the remaining 48 (22.3%) participants, the underlying heart disease was: coronary artery disease in 12 (5.5%) participants (5 in group with level of CRP <3mg/L and seven in group with level of CRP >3mg/L, p=0. 42), Heart failure in 15 (6.9%) participants (6 in group with level of CRP <3mg/L and nine in group with level of CRP >3mg/L, p=0. 34), Kidney disease in 9 (4.1%) participants (4 in group with level of CRP <3mg/L and five in group with level of CRP >3mg/L, p=0. 53), stroke in 19 (8.8%) participants (9 in group with level of CRP <3mg/L and 10 in group with level of CRP >3mg/L, p=0. 54). There was no significant difference in patient characteristics between either study group.

Significant differences between groups were observed in relation to: BMI – significantly higher in participants with level of CRP >3mg/L than participants with level of CRP <3mg/L (2, 7±0, 13 vs. 9, 8±9. 1 p=0. 00); glycemia level – significantly higher in participants with level of CRP >3mg/L than participants with level of CRP <3mg/L (6, 8±0.9 vs. 6, 5±0.8 p=0. 006).

Echocardiographic data of cardiac structure and function according to CRP levels are presented in Table 2. There were no significant changes between groups in relation to left ventricular dimensions and ejection fraction, but in relation to LVMI, there was significant difference. Patients who had CRP levels above the cut-off of 3 mg/L had higher LVMI than patients with levels below 3 mg/L respectively (96.8±1.1 vs. 66.8±5.2, p=0.001). There were significant changes between groups in relation to dimension and function of LA. Patients who had CRP levels above the cut-off of 3 mg/L had increased dimension of LA (4.1±0.3 vs. 3.9±0.2, p=0.001), higher prevalence of enlargement of LA [LAVI (30.6±4.6 vs. 28.5±4.3, p=0.0009)].

In a logistic regression (Table 3), there was observed significant association of CRP levels above the cut-off of 3 mg/L with a rate of AF recurrence (OR=3.938, 95%CI 2.234-6.942), LAd (OR=3.817, 95%CI 0.989-1.544), LAVI (OR=1.74;95% CI 1.549-1.975), LVMI (OR=1.041, 95% CI 1.022-1.061), and BMI (OR=2.072, 95%CI 1.203-3.571).

In the present study, we observed that frequency of maintaining sinus rhythm after the follow-up of one year of pharmacologic cardioversion in participants with MS and CRP levels above the cutoff of 3 mg/L was significantly lower than among participants with MS and CRP levels below 3 mg/L, indicating that increased CRP levels are associated with greater risk of AF recurrence after pharmacologic cardioversion in patients with MS. Results that confirmed our hypothesis and suggests the possibility that degree of systemic inflammation may be more proarrhythmic. A positive association between CRP levels and AF recurrence has been demonstrated in several studies^18–20, but some of reports failed to demonstrate such a relationship.^{21, 22}

It is well-established that inflammation is independently associated with the development of AF.^23,24 Experimental and clinical data indicate that inflammation may have been involved in the pathogenesis of both metabolic syndrome and atrial fibrillation²⁵; this makes inflammation one of many possible cofactors of AF. Markers of inflammation (CRP, leukocyte infiltrates)have been found in atrial tissue samples of subjects with AF.²⁶ In both cross-sectional and longitudinal studies, CRP has been consistently and significantly predictive of early AF relapse after successful cardioversion, even after adjustment for risk factors for AF, such as hypertension and CAD.²⁷ Even in the present study, we found that of all recurrences of atrial fibrillation, the greatest incidence of AF recurrence occurred within the first three months with significant different occurrence between the two groups, and higher AF recurrence occurred in participants with CRP levels above a cut-off at 3 mg/L. It has also been suggested that atrial electrical remodeling resolves during the first days after cardioversion of persistent AF and may be related to early recurrence rates.²⁸

LA remodeling is a key process in AF generation and is a consequence of structural and functional maladaptation against external stress. LA remodeling, in turn, promotes electrical disturbance that can increase incident AF.²⁹ In the present study, we found significant association of increased rate of AF recurrence in participants with CRP levels above a cut-off at 3 mg/L and LA remodeling (LA dimensions and LAVI). Similar results have been found in others studies.³⁰

Several placebo-controlled studies have demonstrated the absolute efficacy of AADs as superior to placebo in maintenance of SR after rhythm cardioversion.³¹ In the present study, maintenance rate of SR after rhythm cardioversion in participants who are not received any AADs in a 1-year follow-up, were observed in 13.5%. A 13-25% maintenance rate of sinus rhythm after cardioversion of atrial fibrillation in a 1-year follow-up without antiarrhythmic drug therapy has been reported.³² It is well known that inflammatory processes have been associated with AF but uncertain whether this represents the course or the effect of inflammation.³³ Although mechanisms by which AF cause inflammation are unknown.³⁴ Regardless of the presence of a causal relationship, the study of baseline CRP levels may provide significant prognostic information regarding sinus rhythm maintenance.³⁵

Pharmacologic cardioversion is a widely conducted procedure that restores the AF to SR in a patients with AF, despite AADs in clinical practice. The clinical significance of this study is that CRP is an easily determined marker in everyday clinical practice worldwide that may be helpful for predicting early AF recurrence after successful pharmacologic cardioversion, even with various AADs. Therefore, this approach could guide clinicians to determine treatment plans from a simple rate control strategy to a more effective rhythm control therapy, such as catheter ablation for patients with AF refractory to AADs and pharmacologic cardioversion.

Understanding the pathogenesis of AF and the relationships between inflammation and AF is of both academic and clinical interest because insights might lead to better prevention and treatment of this common but dangerous dysrhythmia. The detailed imaging of inflammation by positron emission tomographic or molecular means might help to clarify the role of inflammation in AF, and microRNA could prove to be of substantial value in the study of tissue and circulating biomarkers. If a causal link between inflammation and AF is proved, novel approaches to targeting inflammation might lead to better therapeutic options.

Firstly, the cross-sectional design precludes the assessment of causal relationships between inflammation (CRP levels) and maintenance of SR. Secondly, detection of AF recurrence was based on ECG recordings acquired on a systematic basis and/or 24 hour Holter registration. Importantly, patients were encouraged to obtain an ECG registration when experiencing palpitations in order to confirm AF as the cause of these complaints. Nevertheless, asymptomatic episodes may have been missed. Thirdly, the present study comprised a relatively small group of patients. Therefore, the present findings need to be validated in a larger group of patients.

CRP, an easily determined marker in everyday clinical practice, may provide significant prognostic information regarding sinus rhythm maintenance and could be useful for predicting recurrence of AF after successful pharmacologic cardioversion in clinical practice. Atrial Fibrillation patients with CRP levels above a cut-off at 3 mg/L should be observed closely after successful pharmacologic cardioversion, even with various AADs and anti-inflammatory therapeutic strategies, and may be a next logical step in AF care, one not burdened by proarrhythmic risk.