|Year : 2019 | Volume
| Issue : 1 | Page : 11-16
Atrial electrical remodeling induced by chronic ischemia and inflammation in patients with stable coronary artery disease
Răzvan Constantin Serban1, Alkora Ioana Balan2, Marcel Perian2, Irina Pintilie3, Cristina Somkereki1, Adina Huţanu4, Alina Scridon4
1 Department of Physiology, University of Medicine and Pharmacy of Tîrgu Mureş; Laboratory of Cardiac Catheterization, Angiography and Electrophysiology, Emergency Institute for Cardiovascular Diseases and Transplantation, Tîrgu Mureş, Romania
2 Department of Physiology, University of Medicine and Pharmacy of Tîrgu Mureş, Tîrgu Mureş, Romania
3 Laboratory of Cardiac Catheterization, Angiography and Electrophysiology, Emergency Institute for Cardiovascular Diseases and Transplantation; Center for Advanced Medical and Pharmaceutical Research Tîrgu Mureş, Tîrgu Mureş, Romania
4 Department of Physiology, University of Medicine and Pharmacy of Tîrgu Mureş; Center for Advanced Medical and Pharmaceutical Research Tîrgu Mureş, Tîrgu Mureş, Romania
|Date of Submission||23-Aug-2018|
|Date of Decision||09-Jan-2019|
|Date of Acceptance||10-Jan-2019|
|Date of Web Publication||22-Feb-2019|
Dr. Alina Scridon
Department of Physiology, University of Medicine and Pharmacy of Tîrgu Mureş, 38, Gheorghe Marinescu Street, 540139 Tîrgu Mureş
Source of Support: None, Conflict of Interest: None
The pathophysiology of coronary artery disease (CAD) includes low-grade chronic inflammation. At its turn, inflammation is known to promote myocardial structural remodeling and to increase vulnerability to atrial arrhythmias. Meanwhile, the impact of chronic inflammation on the electrophysiological properties of the atria remains unknown. We aimed to evaluate the impact of low-grade chronic inflammation on atrial electrophysiology in patients with stable CAD undergoing elective coronary artery bypass grafting (CABG). Circulating levels of several inflammatory, angiogenesis, and endothelial dysfunction markers were determined 1 day before CABG in 30 consecutive CAD patients. Right atrial appendage samples were collected during the CABG procedure; action potential recordings were performed in six study patients using the microelectrode technique. Interleukin (IL)-1b (r = 1.00, P = 0.01), IL-6 (r = 0.98, P < 0.01), vascular endothelial growth factor (VEGF) (r = 0.98, P < 0.01), and hemoglobin (r = 0.98, P < 0.01) levels significantly positively correlated with the duration of atrial depolarization. Consequently, IL-6, VEGF, and hemoglobin (r = −0.86, P = 0.03 for all) levels significantly negatively correlated with the velocity of atrial depolarization. There was no significant correlation between any of the studied markers levels and any of the other parameters of the action potential (all P > 0.05). The present study is the first to demonstrate that in patients with stable CAD, chronic inflammation and ischemia are associated with pro-arrhythmic atrial electrical remodeling. These changes may contribute to the increased propensity to postoperative atrial arrhythmias seen in some of the patients undergoing CABG.
Keywords: Action potential, coronary artery bypass grafting, inflammation, ischemia, pro-arrhythmic electrical remodeling
|How to cite this article:|
Serban RC, Balan AI, Perian M, Pintilie I, Somkereki C, Huţanu A, Scridon A. Atrial electrical remodeling induced by chronic ischemia and inflammation in patients with stable coronary artery disease. Chin J Physiol 2019;62:11-6
|How to cite this URL:|
Serban RC, Balan AI, Perian M, Pintilie I, Somkereki C, Huţanu A, Scridon A. Atrial electrical remodeling induced by chronic ischemia and inflammation in patients with stable coronary artery disease. Chin J Physiol [serial online] 2019 [cited 2019 Nov 12];62:11-6. Available from: http://www.cjphysiology.org/text.asp?2019/62/1/11/252835
| Introduction|| |
Despite considerable advances in treatment strategies, coronary artery disease (CAD) remains a major cause of cardiac arrhythmias and one of the most important causes of death in people above the age of 35 years. Many investigations have associated stable CAD with an increase in inflammatory markers levels. At its turn, inflammation has been shown to promote both atrial fibrillation (AF) occurrence and persistence., In patients undergoing cardiac surgery, the postoperative inflammatory surge has been associated with pro-arrhythmic changes in the electrophysiology of the atria and with increased risk of AF,,, whereas preoperative corticosteroid therapy has been shown to decrease the risk of postoperative AF.
On the other hand, the effects of chronic inflammation on pro-arrhythmic atrial remodeling in patients with stable CAD are less clear. Over the long term, chronic inflammation has been shown to induce extracellular matrix deposition and atrial fibrosis, favoring the occurrence of AF., Meanwhile, changes in the electrophysiological properties of the atrial myocardium under the influence of a chronic inflammatory status have not been evaluated to date. Therefore, we aimed to assess the impact of preoperative inflammatory status on atrial action potential parameters using right atrial appendage samples from patients with stable CAD undergoing elective coronary artery bypass grafting (CABG).
| Materials and Methods|| |
The study enrolled 30 consecutive patients with stable CAD admitted to the Cardiovascular Surgery Department of the Emergency Institute for Cardiovascular Diseases and Transplantation of Tîrgu Mureş, Romania, for a first-time elective CABG procedure. All patients were ≥18 years of age and were hemodynamically stable at the moment of inclusion. Patients with systemic inflammatory diseases or on ongoing anti-inflammatory therapy (except for low-dose aspirin), patients with a history of AF, and those requiring valve replacement or other surgery concomitant with the CABG procedure were not eligible for this study. Each patient gave written informed consent. The study was performed according to the Declaration of Helsinki; the study protocol was approved by the Local Ethics Committee (decision no. 845/08.02.2016).
Age, gender, history of arterial hypertension and diabetes mellitus, and ongoing drug therapy were recorded for all patients included in the study. Patients' weight and height were noted and the body mass index (BMI) was calculated. The left ventricular ejection fraction (LVEF) was assessed by transthoracic echocardiography and the SYNergy between percutaneous coronary intervention (PCI) with TAXUS™ and Cardiac Surgery (SYNTAX I) score was calculated for each study participant.
Evaluation of the preoperative inflammatory status
Venous blood samples were collected from each patient 1 day before CABG surgery and were used to quantify the circulating levels of several inflammatory, angiogenesis, and endothelial dysfunction markers levels. Plasma high-sensitivity C-reactive protein (hs-CRP) concentrations were determined using the immunoturbidimetric method (Automated Analyzer Cobas Integra 400; Roche Diagnostics, Basel, Switzerland), as described previously. Interleukins 1b (IL-1b), 2 (IL-2), 6 (IL-6), 8 (IL-8), and 17A (IL-17A) and vascular endothelial growth factor (VEGF) levels were measured with the xMAP Luminex technology (Flexmap 3D analyzer; Luminex Corporation, Austin, TX, USA) and EMD Millipore Corp (Burlington, MA, USA) kits. Transforming growth factor beta and von Willebrand factor levels were determined by enzyme-linked immunosorbent assay (ELISA) using the Dynex DSX ELISA Analyzer (Dynex Technologies Inc., Chantilly, VA, USA) and DRG Instruments GmbH (Marburg, Germany) kits. Standard automated complete blood count analysis was performed using the Sysmex XP–300 Automated Hematology Analyzer (Sysmex Corporation, Hyogo, Japan).
Action potential recordings
During the CABG procedure, the tissue segment (i.e., right atrial appendage) removed to fix the cavoatrial cannula during extracorporeal circulation, usually considered “surgical waste”, was collected and placed into oxygenated Krebs-Henseleit solution (118 mM NaCl, 4.7 mM KCl, 25 mM NaHCO3, 2.5 mM CaCl2, 1.2 mM MgSO4, 1.2 mM KH2 PO4, and 11 mM glucose). The sample was immediately transferred to the electrophysiology laboratory and placed into the Steiert organ bath, in oxygenated Krebs-Henseleit solution, at 37°C. After a 30-min equilibration period, electrical stimulation was performed at a rate of 60 stimuli/min. The duration of the stimuli was set as 0.05 ms, and the amplitude was set one-third above the stimulation threshold. Intracellular action potentials recordings were performed in the right atrial appendage preparations using the microelectrode technique.
The amplitude of the resting and the action potential was measured, as well as the duration of depolarization and the action potential duration to 25% (APD25), 50% (APD50), and 90% (APD90) of complete repolarization. The duration of depolarization was measured as the interval of time elapsed between the beginning of the upstroke and the peak of the action potential; APD25, APD50, and APD90 were defined as the intervals of time elapsed between the beginning of the action potential and the moment when action potential amplitude decreased by 25%, 50%, and 90%, respectively, of its maximum value. The velocity of the depolarization and that of the repolarization were also calculated. Out of the total of 30 patients included in the study, right atrial appendage samples were successfully collected in nine patients. Viable atrial myocytes were found in six of these nine samples (i.e., in 3 of the 9 samples electrical stimulation did not trigger any electrical response from the cells).
Statistical analysis was performed using the GraphPad InStat 3 Software (San Diego, CA, USA). Categorical variables are expressed as absolute values and percentages. Continuous data are expressed as means ± standard error of the mean or median and interquartile range, as appropriate. For assessment of electrophysiological parameters, a minimum of 10 action potentials was recorded for each of the six right atrial appendage samples. For each sample, the mean values of all action potentials' parameters were calculated and included in the group analysis. To assess whether the six patients in whom the electrophysiological study was performed were representative for the entire study population, clinical and laboratory parameters were compared between these six patients and the remaining 24 patients using Student's t-test for the continuous variables and the Chi-square test for the categorical variables. For the six patients in whom electrophysiological study was performed, correlations were ascertained between action potential parameters, on the one hand, and clinical and blood parameters, on the other hand. Spearman's rank correlation method was used for correlations analysis due to the low number of samples (n = 6) included in the electrophysiological study. A P < 0.05 was considered statistically significant.
| Results|| |
Characteristics of the study population
The mean age of the 30 study patients was 60.6 ± 1.7 years. Out of the total of 30 patients included in the study, 24 patients (80%) were male, 29 (96.7%) were hypertensive, and 11 (36.7%) were diabetics. The mean BMI was 27.5 ± 0.7 kg/m2. The median LVEF was 50% (45%–55%), and SYNTAX I score was 24.8 ± 1.6 points.
Inflammatory, angiogenesis, and endothelial dysfunction markers levels and blood count parameters were assessed in all study patients (n = 30), and the values are presented in [Table 1]. None of the tested clinical and laboratory parameters was significantly different (all P > 0.05) in the six patients in whom the electrophysiological study was performed compared to the remaining 24 patients included in the study [Table 1].
|Table 1: Clinical characteristics, complete blood count, inflammatory, angiogenesis, and endothelial dysfunction markers levels in the entire study population|
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[Figure 1] depicts representative action potentials recorded in the right atrial appendage samples of the study patients. Atrial action potential parameters are presented in [Table 2].
|Figure 1: Representative action potentials (green tracings) recorded in the right atrial appendage samples of the study patients. (a-d) Action potentials triggered by electrical stimulation (stimulation spikes can be observed in front of each action potential) in the right atrial appendage samples of four different patients. Similar action potentials were also recorded in the other two patients in whom electrophysiological study was performed. In three of the six patients, spontaneous action potentials could also be observed (examples are provided in [e and f]). The occurrence of spontaneous action potentials during the electrophysiological study is not unusual and could be related to mechanical stretch, electrolyte imbalance, ischemia, and/or microelectrode manipulation|
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There was no significant correlation between any of the clinical parameters and any of the parameters of the action potential (n = 6; all P > 0.05). Furthermore, there were no significant correlations between white blood cell or platelet count and any of the parameters of the action potential (n = 6; all P > 0.05). However, hemoglobin levels significantly positively correlated with the duration of atrial depolarization (r = 0.98, P < 0.01) and negatively correlated with the velocity of atrial depolarization (r = −0.86, P = 0.03). There was no significant correlation between any of the inflammatory, angiogenesis, or endothelial dysfunction markers levels and the resting potential or the action potential amplitude (all P > 0.05). Furthermore, no significant correlation was observed between the inflammatory, angiogenesis, or endothelial dysfunction markers levels and APD25, APD50, and APD90 (all P > 0.05). However, IL-1b (r = 1.00, P = 0.01), IL-6 (r = 0.98, P < 0.01), and VEGF (r = 0.98, P < 0.01) levels significantly positively correlated with the duration of atrial depolarization, whereas this was not the case for any of the other inflammatory, angiogenesis, or endothelial dysfunction markers, including hs-CRP (all P > 0.05). Consequently, IL-6 (r = −0.86, P = 0.03) and VEGF (r = −0.86, P = 0.03), but not IL-1b (P > 0.05) levels were also significantly negatively correlated with the velocity of atrial depolarization.
| Discussion|| |
Substantial evidence has shown an association between chronic inflammation and pro-arrhythmic structural remodeling of the atria via induction of myocardial fibrosis. High levels of VEGF, CRP, heat shock protein 27, and IL-6 have also been associated with an increase in atrial size, as well as with an increased risk of developing AF.,, In addition, inflammatory cytokines have recently been shown to impact on the autonomic nervous system of the heart, promoting atrial arrhythmias via stimulation of the acetylcholine-dependent K current and heterogeneous atrial refractory period shortening.,, Increased NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity, which mediates IL-1b release in immune cells, has recently been reported in atrial cardiomyocytes from AF patients. Meanwhile, cardiomyocyte-specific knock-in mice expressing constitutively active NLRP3 showed increased ectopic activity, abnormal sarcoplasmic reticulum Ca2+-release, atrial effective refractory period shortening, atrial hypertrophy, and inducible AF, which was attenuated by a specific NLRP3-inflammasome inhibitor. In acute settings, inflammation has also been shown to alter atrial electrophysiology, promoting inhomogeneous atrial conduction and action potential shortening., However, the impact of low-grade, chronic inflammation on atrial electrophysiology in patients with stable CAD remained to date unknown.
The present study indicates for the first time that chronic ischemia and inflammation may have a negative impact on atrial electrophysiology. Higher severity of the inflammatory process (as reflected by IL-1b and IL-6 levels) and of tissue ischemia (as reflected by VEGF levels) were associated with an increase in the duration of atrial depolarization and consequently with a reduction in the velocity of atrial depolarization, both of which depend on a number of factors, including the conductance of sodium channels and the intracellular architecture. Among these factors, voltage-gated fast sodium currents are the major determinants of membrane depolarization duration and velocity, creating the electrochemical gradient that drives ion diffusion. Therefore, our findings are likely to reflect the impact of chronic inflammation and ischemia on voltage-gated sodium channels activity. Previous experimental studies have already demonstrated an inhibiting effect of ischemia on sodium channels activity. Although the effect of chronic inflammation on atrial myocytes has never been evaluated, previous studies have demonstrated a negative effect of numerous pro-inflammatory ILs on the activity of neuronal voltage-gated sodium channels. At their turn, increased duration and reduced velocity of atrial depolarization are likely to contribute to the typical intra-atrial conduction slowing seen in AF patients, providing a pro-arrhythmogenic atrial electrical remodeling. Such changes could also explain, at least partially, the increased propensity to AF seen in up to 40% of patients undergoing CABG. Unfortunately, the low number of atrial samples on which the electrophysiological study was performed did not allow us to assess a potential relationship between the observed atrial electrical changes and the occurrence of post-CABG AF. Further studies will have to assess this hypothesis. Evaluating the effects of anti-inflammatory therapies on pro-arrhythmic atrial electrical remodeling and elucidating whether the antiarrhythmic effects of these drugs reported in previous studies are related, at least partially, to a reverse atrial electrical remodeling process, would also be of interest.
Interestingly, despite the significant positive correlation found between IL-1b and IL-6 levels and the duration of atrial depolarization, no significant correlation was found between hs-CRP levels and atrial depolarization duration. These discrepant findings may be due to the small sample size, which could have led to the loss of potentially relevant pro-arrhythmic factors, such as hs-CRP. However, similar discrepancies have been reported previously. In the study by Marcus et al., although IL-6 levels were significantly associated with AF, this was not the case for CRP, suggesting that while certain inflammatory markers, including CRP, may represent a simple epiphenomenon in the inflammation-AF relationship, others, such as IL-6 and/or IL-1b, may play active roles in AF pathophysiology.
Another interesting observation in the present study was the significant positive association between hemoglobin levels and the duration of atrial depolarization, and consequently, the significant negative association between hemoglobin levels and the velocity of atrial depolarization. Anemia, often encountered in the setting of chronic inflammatory diseases, has been shown to increase the risk of AF via adrenergic activation, increased cardiac output, and ischemic injury to atrial myocytes. However, in the present study, mean hemoglobin levels were within the normal range. Moreover, our data showed a significant positive correlation between hemoglobin levels and atrial depolarization duration, indicating more prominent pro-arrhythmic atrial electrical remodeling with increased, and not decreased, hemoglobin levels. These data are in line with those of several previous studies, which have demonstrated a significant association between increased postoperative hemoglobin levels and AF occurrence., In that setting, red blood cell transfusion has been incriminated as a contributor to the increased AF risk., However, similar findings have also been reported in apparently healthy individuals with increased hemoglobin levels, which displayed higher rates of incident AF and intra-ventricular conduction disorders, as well as in patients following acute myocardial infarction, who did not beneficiate of blood transfusions and whose hemoglobin levels were also within the normal range. Our study therefore extends the aforementioned results, suggesting pro-arrhythmic atrial electrical remodeling as a potential link between increased hemoglobin levels and AF occurrence. Although to date there is no obvious mechanistic explanation for this finding, factors such as smoking, obstructive sleep apnea, or chronic pulmonary disease could provide an answer; all these factors have been associated with chronic inflammation, oxidative stress, and increased risk of AF  and have also been shown to affect hemoglobin levels. Decreased plasma volume could also affect hemoglobin levels and favor AF occurrence, particularly if overlapped by adrenergic activation or oxidative stress. Regardless of the underlying mechanism, hemoglobin levels are likely to be a simple reflection of subjacent conditions already known to be associated with increased AF risk. Future studies are required to fully elucidate the relationship between hemoglobin levels, atrial remodeling, and AF in patients with chronic ischemic heart disease.
The main limitation of the present study is related to the small number of patients evaluated. This was mostly due to the strict inclusion criteria and to the continuous reduction in the number of CABG procedures performed in patients with stable CAD in favor of percutaneous coronary angioplasty over the past years. The small sample size, and particularly the small number of right atrial appendage samples subjected to electrophysiological study, could have reduced the statistical power of the study and could have led to the loss of potentially relevant pro-arrhythmic factors. However, in terms of clinical and laboratory parameters, there was no significant difference between the six patients in whom electrophysiological study was performed and the remaining 24 study patients, suggesting that those six patients could be seen as representative for the entire study population. Assessing the atrial structural remodeling in relation to chronic inflammation would also have been of interest.
| Conclusions|| |
The present study is the first to demonstrate that in patients with stable CAD chronic inflammation and ischemia are associated with pro-arrhythmic atrial electrical remodeling. These changes are likely to contribute to the increased propensity to postoperative AF seen in some of the patients undergoing CABG.
The first two authors contributed equally to the manuscript and both should be viewed as first authors.
Financial support and sponsorship
This work was supported by a grant of the Ministry of Research and Innovation, CNCS-UEFISCDI, project number PN-III-P1-1.1-TE-2016-0382, within PNCDI III.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]