Article Text
Abstract
Objective Plasma norepinephrine (NE) level can be a guide to mortality in patients with heart failure. This study aimed to evaluate the significance of plasma NE level compared with plasma natriuretic peptides (atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) levels in patients with atrial fibrillation (AF).
Methods Included in this study were 137 consecutive patients referred for catheter ablation of lone AF (paroxysmal in 90 and persistent in 47 patients). Blood samples for measurements of ANP, BNP and NE were drawn in the supine position before the procedure.
Results ANP, BNP and NE levels were greater in patients with persistent AF than in patients with paroxysmal AF (median (25th–75th centile)=28 (18–49) vs 69 (36–106), p<0.0001; 28 (15–50) vs 94 (39–156), p<0.0001; and 315 (223–502) vs 382 (299–517) pg/mL, p=0.04, respectively). NE level correlated weakly with ANP and BNP levels (r=0.28 and r=0.23, respectively, p<0.01 for both). BNP and NE levels differed between patients with and without recurrence of AF (55 (26–135) vs 35 (18–64), p=0.005 and 431 (323–560) vs 302 (225–436) pg/mL, p<0.001, respectively). Of note, only NE level was significantly greater in patients with symptomatic sick sinus syndrome (SSS) (n=21) than in those without SSS (560 (466–632) vs 321 (242–437) pg/mL, p<0.0001). Logistic regression analysis showed NE level to be the only independent discriminator for SSS (OR 1.006, 95% CI 1.002 to 1.010, p=0.001).
Conclusions An increase in plasma NE level was observed in patients with AF and SSS. Although this implies a pathophysiological link between clinical manifestation of SSS and the autonomic nervous dysfunction, further studies are needed to clarify the mechanisms for this novel finding.
Statistics from Altmetric.com
Introduction
Autonomic nervous activities play an important role in the development of various types of cardiovascular and non-cardiovascular diseases.1–6 Modulation of autonomic nerve function may contribute to suppression of atrial fibrillation (AF) because simultaneous sympathetic and parasympathetic activations are the most common triggers in AF.2 ,7–9 Recently, ganglionated plexus ablation and renal sympathetic denervation have become one of the potential therapeutic applications.10–12
Activity of the sympathetic nervous system is difficult to evaluate in clinical practice. To date, no technique available to measure it can be viewed as the ‘gold standard’. Norepinephrine (NE) is the neurotransmitter released from sympathetic nerve endings. Its measurement in circulating plasma can be easily performed, but it may be a crude guide to assess sympathetic neural function particularly in healthy subjects because it depends on the rate of immediate NE reuptake and NE clearance from the circulation. Under particular conditions with marked adrenergic overdrive (eg, untreated heart failure), however, increased plasma NE levels may reflect, at least in part, sympathetic hyperactivity and thus can be a guide to mortality in patients with chronic heart failure.4 ,13
Now, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are commonly used as helpful predictors of prognosis in patients with heart failure or AF13–15 and were reported to be predictive for clinical outcome after catheter ablation of AF.16 However, the relation of plasma catecholamine levels to the characteristics and prognosis of patients with AF has not been assessed. The purpose of this study was to evaluate the significance of plasma NE level in comparison with natriuretic peptides in patients with drug-resistant symptomatic AF who were referred for catheter ablation of AF.
Methods
Study subjects
The study subjects comprised 137 consecutive patients with symptomatic AF (90 (66%) with paroxysmal AF and 47 (34%) with persistent AF) who were referred for catheter ablation of AF at the University of Tsukuba from April 2011 to December 2013. Patients who had long-standing persistent AF, structural heart disease, reduced LVEF of<55%, sleep disorder, or moderately to severely decreased renal function (estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2) were excluded from the study.17 Antihypertensive drugs except for β-blockers were not discontinued during the periprocedure period. All antiarrhythmic drug therapy was discontinued four to five half-lives before the procedure except for amiodarone, which was discontinued 8 weeks beforehand.
Data acquisition
Blood samples for the measurements of ANP, BNP and NE levels were drawn with the patient in the supine position 1 day before the procedure. ANP and BNP levels were measured using chemiluminescent enzyme immunoassay, and NE level was measured using high-performance liquid chromatography (SRL, Tokyo, Japan). Transthoracic and transoesophageal echocardiography was performed in all patients to exclude structural heart diseases and left atrial (LA) thrombus before the procedure.
Electrophysiological study and catheter ablation
A 7F 14-pole dual-site mapping catheter (Irvine Biomedical, Irvine, California, USA) was positioned in the coronary sinus and the low lateral wall of the right atrium throughout the procedure. Two long sheaths (SL0; AF Division, St. Jude Medical, Minnetonka, Minnesota, USA) were advanced into the left atrium. Following pulmonary vein (PV) angiography, a decapolar ring catheter (Lasso; Biosense Webster, Diamond Bar, California, USA) was placed in the PVs. An open-irrigation 3.5-mm-tip deflectable catheter (ThermoCool; Biosense Webster) was used for mapping and ablation. Bipolar electrograms were displayed and recorded at filter settings of 30–500 Hz during the procedure (EP-WorkMate; St. Jude Medical).
The ipsilateral PV antrum was circumferentially ablated under fluoroscopic, electrogram, 3D cardiac CT, and CARTO (Biosense Webster) guidance. Radiofrequency energy was delivered at a power of 25 W at the posterior aspect, at 20 W at the sites adjacent to the oesophagus and at 30 W at the anterior aspect of the PV antrum. Maximum irrigation flow rate was 30 mL/min and maximum temperature was 42°C. PV isolation was confirmed with the Lasso catheter. If atrial premature contractions originating from the superior vena cava were observed, it was also isolated. In patients with persistent AF, continuous fractionated atrial electrogram ablation in the left atrium and linear ablations at the LA roof and cavotricuspid isthmus were performed. Biphasic external cardioversion was used to restore sinus rhythm if AF was still present after ablation.
Postablation care and follow-up
Patients were discharged on anticoagulation at ≥4 days after ablation. During the hospitalisation, patient monitoring was continued to document any episodes of AF, sinus bradycardia and sinus arrest. Patients were seen in an outpatient clinic 2 weeks and 6 weeks after hospital discharge and every 2 months thereafter. Holter (DSC-3300; Nihon Kohden, Tokyo, Japan) or event recorder (HCG-901; Omron, Kyoto, Japan) recordings were undertaken before the outpatient visits, and treatment success was defined as freedom from all atrial tachycardias in the absence of antiarrhythmic drug therapy after a blanking period of 2 months.
Definition of sick sinus syndrome
In patients with presyncope or syncope suggestive of cerebral hypoperfusion associated with bradycardia, a link between the bradycardia and symptoms was confirmed by Holter recordings or 12-lead ECGs before ablation. Symptomatic persistent sinus bradycardia with a heart rate of <40 bpm or symptomatic sinus arrest of >3 s after the termination of AF (tachycardia-bradycardia syndrome) was defined as sick sinus syndrome (SSS).18
Statistical analysis
Continuous variables are expressed as mean±SD or median (25th–75th centile), and categorical variables are reported as number and percentage. Differences between groups were tested using unpaired Student's t test, Mann-Whitney U-test or Fisher's test as appropriate. Correlation analysis was calculated using the Spearman's correlation test. A receiver operating characteristic curve for SSS discrimination was constructed, and the best cut-off of NE level was identified using the Youden index. Variables with p<0.05 in the univariable model were included in logistic regression analysis to identify the possible discriminators of the clinical manifestation of SSS. The discriminatory ability of the multivariable models was also evaluated using the concordance index (C-index). A two-tailed p value of <0.05 indicated statistical significance. All statistical analyses were carried out using JMP V.11.0 (SAS Institute, Cary, North Carolina, USA).
Results
Patient characteristics (paroxysmal vs persistent AF)
Blood samples were drawn between 10:00 and 12:00 in 54 (39%) patients or between 13:00 and 15:00 in 83 (61%). There was no difference in plasma NE level between the different sampling times (p=0.7). The heart rhythm at blood sampling was sinus rhythm in 93 (68%) patients and AF in 44 (32%). ANP, BNP and NE levels were higher in patients in whom blood samples were drawn during AF than in patients in whom the samples were drawn during sinus rhythm (median (25th–75th centile)=85 (55–130) vs 27 (18–48), 120 (61–184) vs 28 (16–46), and 442 (342–531) vs 299 (226–434) pg/mL, p<0.0001 for all). Patients with paroxysmal AF had a shorter history of AF (24 (12–57) vs 36 (18–90) months, p=0.02), higher EF (67±7 vs 65±6%, p=0.04), and smaller LA volume indexed to body surface area (LAVi) (30±9 vs 39±11 mL/m2, p<0.0001) than patients with persistent AF (table 1). Levels of all plasma biomarkers were greater in patients with persistent AF than in patients with paroxysmal AF. However, the differences in ANP level (28 (18–49) vs 69 (36–106) pg/mL, p<0.0001) and BNP level (28 (15–50) vs 94 (39–156) pg/L, p<0.0001) between the groups were more significant than the difference in NE level (315 (223–502) vs 382 (299–517) pg/mL, p=0.04) (table 1). ANP and BNP levels were correlated (r=0.76, p<0.0001). The correlations of NE level with natriuretic peptides levels were significant but weak (r=0.28, p=0.001 for ANP and r=0.23, p=0.007 for BNP). ANP or BNP, but not NE, correlated with LAVi (r=0.45, p<0.0001; r=0.56, p<0.0001; and r=0.10, p=0.25, respectively). The prevalence of SSS did not differ significantly between the paroxysmal and persistent AF groups (19% vs 9%, p=0.14). There was a linear correlation between age and plasma NE level (r=0.33, p=0.0002). There was a trend towards higher plasma NE levels in the hypertensive than in the normotensive patients (365 (285–542) vs 316 (244–456) pg/mL, p=0.06)
Procedural outcomes and plasma biomarkers
During a median follow-up period of 27 months, 24 (27%) patients with paroxysmal AF and 24 (51%) patients with persistent AF experienced recurrence of AF. Characteristics of patients with and without recurrence of AF are summarised in table 2. ANP, BNP and NE levels were significantly higher in patients who had recurrence of AF than in patients who did not (57 (25–113) vs 29 (21–55), p=0.007; 55 (26–135) vs 35 (18–64), p=0.005; and 431 (323–560) vs 302 (225–436) pg/mL, p<0.001, respectively) (figure 1A).
SSS and plasma biomarkers
Twenty-one (15%) patients were diagnosed as having SSS, including tachycardia-bradycardia syndrome in 17 patients and persistent sinus bradycardia in 4 patients. All patients with SSS had syncope (n=12) or presyncope (n=9). The mean duration of sinus arrest following termination of AF was 5.3±2.9 sec. A pacemaker had been implanted before AF ablation in two patients and was implanted after AF ablation in five patients. SSS was more common in women (43% vs 15%, p=0.005), in the elderly (70±8 years old vs 62±10 years old, p=0.0003) and in patients with hypertension (67% vs 38%, p=0.02) and lower eGFR (68±14 mL/min/1.73 m2 vs 77±18 mL/min/1.73 m2, p=0.03) (table 3). Neither the percentage of patients with sinus rhythm during blood samplings (57% vs 71%, p=0.3) nor the heart rate during sinus rhythm (57±10 bpm vs 61±9 bpm, p=0.14) differed significantly between patients with and without SSS. Most interestingly, the NE level was significantly higher in patients with SSS than in patients without SSS (560 (466–632) vs 321 (242–437) pg/mL, p<0.0001), whereas neither ANP nor BNP was associated with the presence of SSS (62 (21–125) pg/mL vs 30 (22–70) pg/mL, p=0.19 and 49 (25–116) pg/mL vs 39 (20–78) pg/mL, p=0.27, respectively) (figure 1B). In multivariable logistic regression analysis using the variables of sex, age, hypertension, eGFR and NE level, NE level was the only independent predictor of the coexistence of SSS in patients with AF (OR, 1.006; 95% CI 1.002 to 1.010; p=0.001) (table 4). Aging was also a possible independent predictor (p=0.06). The C-indices for SSS discrimination in the multivariable model including and not including NE level were 0.86 and 0.81, respectively. Receiver operating characteristic analysis determined the best cut-off value of NE level to be 452 pg/mL for manifestation of SSS, with a sensitivity of 81%, specificity of 77%, positive predictive value of 39% and negative predictive value of 96% (area under the curve=0.82) (figure 2). In a sensitivity analysis performed only among patients with paroxysmal AF, the major results, including the discrimination value of the NE level for SSS, were similar to those of all patients (data not shown).
Discussion
Main findings
In patients with lone AF referred for catheter ablation, levels of natriuretic peptides were associated with the type of AF (paroxysmal or persistent), LA volume and procedural outcomes, consistent with results from previous studies. As a novel finding, increased plasma NE level was observed in patients with symptomatic SSS. Multivariable analysis also determined that plasma NE level was the only independent discriminator for the presence of SSS in this selected patient group. Although neither the mechanisms responsible for plasma NE elevation nor the reasons for its relation to SSS are clear, these findings may provide a clue to further clarify the multifactorial mechanisms for clinical manifestation of SSS.
Sick sinus syndrome
SSS was more prevalent in women, the elderly, and the patients with hypertension or lower eGFR in this study. These findings were consistent with the results from prior studies,19–21 and their mechanisms can be explained in part by the studies by Sanders et al.21 They clearly demonstrated that sinus node disease was associated with structural and anatomical abnormalities characterised by atrial enlargement and scarring, widespread conduction abnormalities and increased atrial refractory period.21 These atrial abnormalities and SSS were also observed in patients with paroxysmal lone AF despite being remote from an arrhythmic event.9 Because such a milieu underlying SSS is also involved as a substrate of AF, it was reasonable that the patients with SSS had an increased risk of recurrence of AF in this study, as also reported in a prior study.22
Natriuretic peptides
BNP is secreted by ventricular myocytes during periods of increased ventricular stretch and wall tension. It is well known that BNP is elevated even in patients with lone AF. A previous study found that BNP correlates with AF burden (chronicity, altered haemodynamics and LA dilation), and there is a strong relation between BNP level at baseline and arrhythmia recurrence after AF ablation among patients with lone AF.23 These results were consistent with the results from the present study. Although the mechanisms of elevated BNP level in lone AF are not yet fully understood, subclinical altered haemodynamics associated with ventricular filling due to atrial mechanical dyssynchrony, atrial inflammation, atrial fibrosis and atrial microvascular dysfunction24 may increase the BNP level and the predisposition to the recurrence of AF. No study, to the best of our knowledge, has evaluated an association of natriuretic peptides with SSS in patients with AF.
Norepinephrine
NE is the neurotransmitter released from sympathetic nerve endings. Plasma NE level is not always a surrogate measure of the sympathetic activity. A higher plasma NE level may be a reflection of reduced clearance or reuptake of NE and increased release of NE. Several changes with age could contribute to reduced chronotropic responsiveness to NE, including reductions in β-1 adrenergic receptor density. However, in the complicated conditions resulting in marked adrenergic overdrive, such as heart failure, hypertension, diabetes mellitus, sleep disorder, obesity (metabolic syndrome) and AF, an increase in the heart rate and plasma NE level provides valuable information reflecting sympathetic hyperactivity.25 Prior studies reported that plasma NE level can be a guide to mortality in patients with chronic heart failure.4 ,13 It may also be of pathophysiological importance that plasma NE levels are significantly higher in essential hypertension than in normotension.11
NE, type of AF and clinical outcome
Plasma NE level was significantly higher in patients with persistent AF than in patients with paroxysmal AF. Persistent AF is likely to suffer from more advanced atrial remodelling. Impaired atrial mechanical function may induce haemodynamic deterioration characterised by high LA pressure. Yoshida et al26 invasively compared LA pressure between paroxysmal and persistent AF and found that mean LA pressure in the persistent AF group was significantly higher than that in the paroxysmal AF group. This implies that patients with persistent AF are under a compromised haemodynamic condition. Although there is a chicken-egg dilemma, a haemodynamic factor may be one of the possible reasons for a higher plasma NE level in patients with persistent AF, consistent with the higher plasma BNP level in persistent AF. Moreover, autonomic dysfunction or autonomic remodelling, which might affect the plasma NE level, is the most common trigger of AF.7 Therefore, it is reasonable that plasma NE level was a significant predictor for clinical outcome after catheter ablation of AF.
NE and SSS
The primary and novel finding in the present study was that the plasma level of NE, and not that of ANP or BNP, was independently increased in patients with AF and symptomatic SSS. Although the mechanisms responsible for plasma NE elevation in SSS were not clear, we hypothesised two scenarios.
Psychological stress
More than 80% of patients with SSS had tachycardia-bradycardia syndrome in this study. Most such patients suffered severely from syncope or presyncope. Repeated switching between palpitations and syncope results in psychological stress. Plasma NE may be sensitive to the haemodynamic stress4 and to psychological stress, whereas BNP is sensitive only to the haemodynamic stress associated with impaired LV function. Lampert et al6 performed a mental stress protocol in patients with structural heart disease and observed a significant increase in blood pressure, heart rate and plasma NE level, suggesting a pathophysiological link between emotion and arrhythmia.
Impaired autonomic function or cardiopulmonary baroreflex are associated with symptoms of AF and occurrences of AF. It is possible that the patients with AF and SSS underwent more advanced remodelling of the atria that may play a role in the reflex control of sympathetic drive to the heart than the patients with AF alone.27 AF symptoms such as dizziness resulting from disordered cardiopulmonary baroreflex could also result in psychological stress.28
Compensated heart rate by increased sympathetic tone
SSS was more prevalent in the elderly, and there was a linear relation between age and plasma NE level in the present study. Heart rate during stable sinus rhythm is not always low in patients with tachycardia-bradycardia syndrome, as shown in this study and as commonly observed. A previous study from our laboratory investigated the contribution of sympathetic tone to intrinsic sinus node function (heart rate, sinus node recovery time and sinoatrial conduction time).5 Basic sinus node function was not observed to change with age, whereas intrinsic sinus node function deteriorated with age. This fact suggested that age-related enhancement of sympathetic tone masks the age-related deterioration of intrinsic sinus node function. The compensated baseline heart rate in patients with tachycardia-bradycardia syndrome in the present study may be due to an increase in sympathetic tone.
Limitations
The present study results do not provide satisfactory evidence for the mechanisms contributing to the increased plasma NE level in patients with AF and SSS. Lack of data from 24-h blood pressure and heart rate monitoring to analyse their variability and arterial baroreflex sensitivity was a major limitation. The clinical diagnosis of SSS was not confirmed using invasive measures such as sinus node recovery time or sinoatrial conduction time. However, an underestimation of SSS is unlikely because sinus arrest results in haemodynamic collapse, and asymptomatic sinus arrest is unusual. Sleep disorder is known to cause the elevation of sympathetic tone. Patients who had been diagnosed as having sleep disorder were excluded from the study. However, polysomnography studies were not performed systematically in this study, and thus the diagnosis may be underestimated. Recent studies have demonstrated the ability of an MRI as an in vivo technique to quantify LA fibrosis.29 However, this modality is not yet considered the gold standard to detect atrial fibrosis and is not universally available because current methods to identify atrial scar require specialised software and operator knowledge, experience, techniques, and proper judgment. Finally, because we evaluated SSS in conjunction with AF, results from the present study may not be applicable to patients with SSS alone.
Conclusion
An increase in plasma NE level was observed in patients with lone AF and symptomatic SSS. This implies a pathophysiological link between the clinical manifestation of SSS and autonomic nervous dysfunction. Further studies are needed to clarify the mechanisms responsible for this novel finding.
Key messages
What is already known on this subject?
Plasma norepinephrine level can be a guide to mortality in patients with heart failure and is higher in hypertensive subjects than in normotensive subjects.
What might this study add?
Plasma norepinephrine level is increased in patients with lone atrial fibrillation and symptomatic sick sinus syndrome.
How might this impact on clinical practice.
The findings may provide a clue to further clarify the multifactorial mechanisms for the clinical manifestation of sick sinus syndrome.
References
Footnotes
Contributors KY contributed to study design, recruitment, data collection, data analysis, interpretation of results, drafting, review and final approval of the manuscript. TK, YI, AK, NK, DH, MB, MM, and NT contributed to planning, data collection and data analysis. IY and KA contributed to final approval of the manuscript.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ibaraki Prefectural Central Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.