Aim: In this study, we aimed to investigate the effect of preoperative low-dose (0.3 mg/kg) intravenous (IV) ketamine administration on fetal oxidative stress markers including Superoxide Dismutase (SOD), Glutathione Peroxidase (GPx), Malondialdehyde (MDA), and Ischemia-modified albumin (IMA) in patients undergoing cesarean section with combined spinal epidural anesthesia (CSEA).

Material and Methods: A total of 60 parturients aged 18–45 years, and undergoing elective cesarean section with CSEA were included. Two groups (n=30, for each group) were formed by randomization. Before the CSEA procedure, the ketamine group received an IV of 0.3 mg/kg ketamine diluted with 10 ml normal saline and the control group received an IV10 ml normal saline. Then, CSEA was performed using 1.8 ml 0.5% isobaric bupivacaine (9 mg) and 15 µg fentanyl. Immediately after delivery, the umbilical cord was doubly clamped, and a 5 ml of cord blood sample was drawn for biochemical analysis of fetal oxidative stress markers. The socio-demographic, anesthetic characteristics, and biochemical analysis results of the participants were recorded. The results were compared with appropriate statistical methods.

Results: There were no significant differences between the groups in terms of socio-demographic and anesthetic characteristics. Also, both groups had similar values in terms of cord blood GPx, MDA, SOD, and IMA levels.

Discussion: Preoperative low-dose IV ketamine administration has no influence on cord blood oxidative stress markers.

Keywords: Ketamine, Cord blood; Oxidant, Antioxidant, Cesarean Section, Anesthesia

Introduction

In response to surgical stress, many metabolic reactions occur in the body [1]. As a result of these reactions, the maternal blood levels of oxidative products in the form of free radicals and non-radicals increase. These oxidative products formed in response to surgical stress in the mother may pass to the fetus via cord blood, cause damage to cells and tissues, and increase postoperative maternal and fetal morbidity and mortality [2-4].
In order to prevent cellular damage in the tissues, defense mechanisms called the antioxidative system activates, and harmful oxidative products are tried to be destroyed by enzymatic and non-enzymatic antioxidant systems [5]. Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) main enzymes with antioxidant activity and these enzymes protect the cells against damage [6]. Malondialdehyde (MDA) is a reactive metabolic product that occurs during lipid peroxidation and is an indicator of oxidative stress [7]. Ischemia-modified albumin (IMA), modified serum albumin is a biological marker of ischemia and is formed under oxidative stress [8]. Researchers reported the beneficial effects of some anesthesia techniques and anesthetic agents in reducing the surgery-induced inflammatory response [9-11].
Ketamine is used for induction of anesthesia with a rapid onset and short-term effect in patients undergoing cesarean section surgery [12]. Studies found that ketamine provides less fetal depression, so it may be preferred in cases of fetal distress [13,14]. Also, a systematic review [15] reported that low-dose ketamine (0.25 mg/kg) may inhibit postoperative stress response.
Based on the above findings, this present study aimed to investigate the effect of preoperative low dose (0.3 mg/kg) intravenous (IV) ketamine administration on fetal oxidative stress markers including SOD, GPx, MDA, IMA in patients undergoing cesarean section with combined spinal epidural anesthesia (CSEA).

Material and Methods

This randomized, double-blind study was approved by the Ethical Committee of Atatürk University, Medical Faculty, Erzurum, Türkiye. A total of 60 pregnant women undergoing elective cesarean section with CSEA in the Anesthesiology and Reanimation Department at Atatürk University, Medical Faculty, Erzurum, Türkiye from October 2021 to February 2022 were enrolled in the study.
A total of 60 parturients aged 18–45 years, classified as ASA I or II, and undergoing elective cesarean section with CSEA were included. Participants with a complicated pregnancy, such as fetal anomaly, hypertension, contraindications to study drugs, mul-tiple pregnancies, and coagulation abnormalities were excluded. Prior to the study, participants were informed about the study protocol, and written informed consent was obtained from every participant. Patients fasting for 8 hours before surgery were transferred to the operating room. Intravenous access was provided using a 16-gauge/18-gauge cannula and 500 ml of preloaded Ringer’s lactate was administered intravenously. Oxygen supplementation of 2 L/min via a nasal cannula was given to all patients. Premedication was not applied. Before the anesthesia procedure, demographic characteristics (age, weight, height, ASA physical status), systolic and diastolic blood pressure values, and heart rate of patients were recorded. Two groups (n=40 for each group) were formed by randomization using a computer-generated table of random numbers. Patients and investigators were blinded to groups. An investigator prepared the studied drugs diluted with 10 ml of normal saline and supplied them in similar syringes. An anesthetist blinded to group allocation injected the drugs within 30 seconds before the CSEA procedure and collected intraoperative data. The ketamine group received an IV of 0.3 mg/kg ketamine diluted with 10 ml of normal saline, and the control group received an IV10 ml normal saline. Then, patients were placed in a sitting position for CSEA. After skin sterilization and local anesthetic infiltration (2% lidocaine), CSEA was performed using an 18-gauge Tuohy needle (Set for CSEA, Braun, Melsungen, Germany) in the L2-3 or L3-4 intervertebral space with a midline approach using the negative pressure method. The subarachnoid cavity was entered with a 27-gauge pencil-point needle using the needle-through-needle technique. After cerebrospinal fluid flow was observed, 1.8 ml 0.5% isobaric bupivacaine (9 mg) and 15 µg fentanyl was injected over 30 seconds. Then, the spinal needle was pulled out, an epidural catheter was advanced 3–5 cm into the epidural space. At the end of the anesthesia procedure, the patient was placed in the left supine position. A Pin-prick test was performed to assess the sensory block level. Surgery was allowed when the sensory block reached the T6 dermatome. If the sensory block was not observed within 20 minutes, 5 ml of 2% lidocaine solution was injected via the epidural catheter and these patients were not included in the study. A modified Bromage scale was used to evaluate the motor block level. General anesthesia protocol was planned for patients with three unsuccessful attempts to reach the intrathecal space. Intravenous ephedrine (6 mg) was used in case of hypotension (a 20% decrease in systolic blood pressure compared to preoperative values), and intra¬venous atropine (1 mg) was used in case of bradycardia (the HR < 45 beats/minute). Intraoperative nausea and vomiting were treated with IV metoclopramide (10 mg). Mean arterial pressure (MAP) and HR values were recorded every 2 minutes after spinal injection for 20 minutes and then every 5 minutes until the end of surgery. The operation time (the time from the beginning of the surgery to surgery end time), anesthetic complications, delivery time (the interval between the end of the spinal anesthesia procedure and delivery), and, the number of patients requiring ephedrine and atropine were recorded. Immediately after delivery, the umbilical cord was doubly clamped, and a 5 ml of cord blood sample was drawn into serum separator tubes and centrifuged at 3000 g for 10 minutes. Then, the obtained serum samples were kept at -80 OC for biochemical analysis of fetal oxidative stress markers. Also, umbilical artery blood gas values and neonatal APGAR scores at 1 and 5 minutes after delivery were recorded. After the operation, patients were transferred to the recovery room. Postoperative pain was evaluated with the Visual analog scale (VAS; 0 cm= no pain, 10 cm= worst pain). In the case of VAS > 3 in a patient, 10 ml of 0.1% bupivacaine solution was given through the epidural catheter. Anesthesia-related side effects and sensory block time (from the spinal anesthetic injection to the recovery of T10 dermatome) were evaluated postoperatively by an anesthetist blinded to the group assignment. When the sensory block had regressed to the T10 level, patients were transferred to the inpatient service.

Biochemical analysis

Cord blood SOD levels were measured using a “Human SOD ELISA Kit” produced by Bioassay Technology Laboratory (BT LAB, Cat. No:E0700Hu, China). Cord blood GPx levels were determined via a “Human GPX ELISA Kit” produced by Bioassay Technology Laboratory (BT LAB, Cat. No.E3921Hu, China). Cord blood MDA levels were measured with a “Human MDA ELISA Kit” produced by Bioassay Technology Laboratory (BT LAB, Cat. No.E1371Hu, China). Cord blood IMA levels were determined using a “Human IMA ELISA Kit” produced by Bioassay Technology Laboratory (BT LAB, Cat. No.E1172Hu, China). All measurements were made according to the manufacturer’s instructions. The SOD, GPx, IMA, and MDA levels were expressed as ng/mL, µU/mL, nmol /mL, ng /mL, respectively.

Statistical Analysis

The primary endpoint was the difference in cord blood IMA levels between groups. Sample size estimation was based on the study performed by Omür et al. [16]. To detect a 25% difference between groups in terms of IMA levels, with an α error of 0.05 and a power of 85%, it was calculated that the sample size should be 25 subjects per group (available at: http://www.stat.uiowa.edu/~rlenth/Power). Thirty patients were enrolled in each group to allow dropouts.
Statistical analysis was performed using SPSS software 12.0 (SPSS Inc., Chicago, IL, USA). The data were presented as mean ± standard deviation, median (minimum-maximum), or n (%), and P < 0.05 was considered statistically significant. To assess the normal distribution of data, the Kolmogorov-Smirnov test was performed. When data were not normally distributed, comparisons were done with the Mann-Whitney U-test. The Independent T test was used when comparing non-normally distributed data and the Chi-squared test was used for the analysis of categorical variables.

Results

During the study period, 90 parturients were eligible, 18 did not meet the inclusion criteria and 12 declined to participate in the study. A total of 60 parturients, who were scheduled for elective cesarean section, were recruited. The CSEA was successful for all parturients. All patients had sufficient anesthesia during surgery. Data collection was completed in 60 patients (n=30, for each group) (Figure 1).
Patients in the two groups were comparable in concerning socio-demographic, anesthetic, and surgical characteristics (Table 1).
There were no significant differences between groups in terms of mean arterial blood pressure values (Figure 2).
Patients in the control group had significantly lower heart rate values at the 4th, 6th and 8th minutes of the surgery compared to the ketamine group (Table 2). Neonatal parameters and cord blood arterial blood gas analysis results were similar in both groups. Also, both groups had similar values in terms of cord blood GPx, MDA, SOD, and IMA levels (Table 3).

Discussion

This present study aimed to investigate the effectiveness of preoperative low-dose intravenous ketamine (0.3 mg/kg) in attenuating oxidative stress response in the fetus in patients undergoing elective cesarean section with CSEA. We observed similar cord blood GPx, MDA, SOD, and IMA levels in the ketamine group in comparison with the control group.
Surgical stress increases cytokine release and leads to an increase in oxidative products. It was reported that these oxidative products increase postoperative maternal and fetal morbidity and mortality [1-4]. For this reason, researchers investigated the effects of different anesthesia methods and drugs on the surgical stress response. In a study, Vosoughian et al. [11] compared maternal serum levels of interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) in general and spinal anesthesia among patients undergoing cesarean section. They reported postoperative higher IL-6 and TNF-α levels in the general anesthesia group compared to the spinal anesthesia group. They concluded that the spinal anesthesia technique may be a better option for reducing maternal surgical stress in patients undergoing cesarean section. In another study, Kang et al. [17] reported that Dexmedetomidine administration during surgery reduces cytokine release and postoperative leukocyte and CRP levels in patients undergoing laparoscopic cholecystectomy.
Ketamine, an N-Methyl-D-Aspartate (NMDA) receptor antagonist is frequently used for induction and maintenance of anesthesia. Experimental studies revealed the anti-inflammatory effects of ketamine [18,19]. Spencer et al. [20] reported that sub-anesthetic doses of an IV ketamine infusion reduce TNF-alpha levels in both male and female rats. In an in vivo experiment, Zhou et al. [21] revealed the protective effect of ketamine against hypoxia-induced injury in human umbilical vein endothelial cells. Therefore, we hypothesized that preoperative low-dose IV ketamine might reduce the surgical stress response in the fetus. For this purpose, we compared the effects of adding preoperative small-dose ketamine during CSEA on cord blood GPx, MDA, SOD, and IMA levels in patients undergoing cesarean section. We reported no differences between groups in terms of these oxidant and antioxidant parameters. Inconsistent with our results, Senapathi et al. [10] reported that low-dose intravenous ketamine decreases maternal CRP levels in patients undergoing emergency cesarean section under spinal anesthesia. Gokcinar et al. [22] investigated the anti-inflammatory and antioxidant efficacy of ketamine in a rat model of acute lung injury. They reported that ketamine decreases oxidative stress and inflammation in both plasma and lung tissue. Xingwei et al. [23] showed that low-dose ketamine before general anesthesia protects organs from potential oxidative damage and inflammation caused by pneumoperitoneum. However, this present study failed to demonstrate the antioxidant activity of ketamine in cord blood. In this instance, we speculated that the time might not enough for the ketamine to cross the placenta and reach the cord blood. But it is known that showed that ketamine rapidly passes the placenta and that ketamine levels in cord blood reach the same levels as in the mother’s venous blood approximately one and a half minutes after IV ketamine injection [24].
Ischemia-modified albumin has been reported to be an important indicator of hypoxia, ischemia, and oxidative stress response. Omür et al. [16] have suggested that different anesthesia techniques may have different effects on cord blood IMA levels in patients undergoing cesarean section. They reported similar values in IMA levels during cesarean section with general anesthesia or CSEA. Consistent with these results, we observed similar cord blood IMA levels in the ketamine group compared to the control group.
This is the first study in the literature evaluating the effect of preoperative low-dose ketamine on cord blood SOD, GPx, MDA, and, IMA levels. There is a limitation in this current study. It would be interesting to measure cord blood oxidant and antioxidant levels in different groups, such as preeclampsia or diabetes, following administration of preoperative low-dose ketamine. Comprehensive studies including different patient groups may be planned.

Conclusion

This present study showed that preoperative low-dose IV ketamine administration has no influence on cord blood oxidative stress markers. Further studies need to evaluate the effects of low-dose ketamine on cord blood oxidant and antioxidant parameters.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: This study was supported by the Research Fund of Ataturk University. Project Number: TSA-2021-9904.

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Mehmet Aksoy, Gamze Nur Cımıllı Senocak, Esra Laloglu, Ayse Nur Aksoy, Aysenur Dostbıl. Effect of low-dose ketamine on fetal oxidative stress: A randomized trial. Ann Clin Anal Med 2022;13(12):1359-1363

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Aim: Atrial fibrillation (AF) causes structural, electrical, and cellular remodeling in the atrium. Evaluation of intra- and interatrial conduction time, indicates structural and electrical remodeling in the atrium. This study aimed to evaluate the effect of pulmonary vein isolation applied with radiofrequency ablation (RF) therapy on intra- and interatrial conduction time and to investigate the structural and electrically remodeling after treatment.

Material and Methods: Fifty-two patients with symptomatic PAF despite at least one antiarrhythmic drug and without structural heart disease were included in the study. Two patients were excluded because of complications developed during and after the operation. Fifty patients (28 female; mean age: 51.68 ± 11.731; mean left atrial diameter: 36.79 ± 4.318) who underwent CARTO® 3D pulmonary vein isolation applied with the RF ablation system were followed-up. Intra- and inter-atrial electromechanical delay was measured in all patients using tissue doppler echocardiography before and three months after RF ablation.

Results: All intra- and interatrial conduction times were significantly decreased 3 months after RF ablation procedure (PA lateral p = 0.022; PA septum p = 0.002; PA tricuspid p = 0.019, interatrial conduction delay p= 0,012, intra-atrial conduction delay p = 0.029).

Discussion: The results of our study suggest that providing stable sinus rhythm with RF ablation may slow down, stop or even improve structural remodeling at substrate level secondary to AF even in patients with paroxysmal AF who did not yet develop atrial fibrosis and permanent structural changes.

Keywords: Pulmonary Vein Isolation, Radiofrequency Ablation, Atrial Conduction Time, Tissue Doppler Echocardiography

Introduction

Atrial fibrillation (AF) is a supraventricular tachyarrhythmia resulting from the irregular activity of the atria and is characterized by atrial mechanic functional loss [1].On the electrocardiogram, rapid, irregular fibrillation waves of different shapes and sizes are seen instead of P waves [2].
In developed countries, the prevalence of AF is estimated between 1.5-2% in the general population, and the mean age of patients with this disease is steadily increasing. This arrhythmia is associated with a five-fold increase in the risk of stroke, a three-fold increase in the incidence of congestive heart failure, and high mortality. AF usually starts as paroxysmal AF (PAF) and transforms into persistent AF[2]. The mechanism of PAF consists of initiating factors [3, 4].
Two main targets in AF treatment are protection against thromboembolic complications and rate or rhythm control. Among two important studies comparing rhythm and rate control, in the randomized controlled AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) study, no difference could be demonstrated between the two groups in terms of mortality and stroke from all causes [5]. The RACE (Rate Control versus Electrical cardioversion for persistent atrial fibrillation) study showed that rate control was not worse than rhythm control in preventing cardiovascular mortality and morbidity [6]. However, in the subgroup analysis of the RACE study, left ventricular function improved in patients with heart failure and rhythm control with catheter ablation for AF [7]. Long-term rhythm control can be achieved with antiarrhythmics or ablation. In a study evaluating recurrence of atrial fibrillation (AF) in The Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA), it was stated that catheter ablation was effective in reducing recurrence of any AF by 48% and symptomatic AF by 51% compared to drug therapy over 5 years of follow-up. Furthermore, AF burden was also significantly reduced in catheter ablation patients, regardless of their baseline AF type [8]. Despite optimal medical therapy, ablation can be performed in symptomatic patients [9].
Atrial fibrillation is thought to occur due to electrophysiological, metabolic, ischemic, hemodynamic, and genetic factors. Persistent AF causes electrical remodeling characterized by shortening of atrial refractoriness caused by changes in the expression of ion channels in the atria, contractile remodeling resulting in disruption of atrial contraction, and structural remodeling leading to changes in the cellular structure of atrial myocytes. All these changes affect each other, leading to continuity of the AF process [10]. While electrical activity foci in the pulmonary vein (PV) cause the development of AF, structural changes in the left atrium due to chronic or recurrent AF cause remodeling, leading to fibrosis and continuing rhythm disturbance [11]. Atrial conduction time that can be easily measured simply by tissue Doppler echocardiography can give us an idea about the arrhythmogenic substrate changes that make AF sustained [12, 13].
The objective of this study was to evaluate the effect of PV electrical activity foci isolation treatment with the RF ablation method on the left atrial arrhythmogenic substrate through tissue Doppler echocardiography and to investigate the structural remodeling process due to AF by the termination of electrical remodeling using RF ablation method.

Material and Methods

A total of 52 patients aged ≥ 18 presented to and were hospitalized in the Abant Izzet Baysal University Medical Faculty, cardiology outpatient clinic, diagnosed with paroxysmal AF and symptomatic despite at least one antiarrhythmic drug were included in the study. Two patients were excluded from the study due to complications developed during and after the procedure. A detailed physical examination and 12-lead ECG were performed on all patients. All patients underwent transthoracic echocardiography and transesophageal echocardiography within 48 hours to confirm the absence of left atrial appendage (LAA) thrombus. Intra- and inter-atrial electromechanical delay was studied with the tissue Doppler method three months after the procedure. Identification of AF ≥ 30 seconds following the procedure was considered a failure.
Patients with acute coronary syndrome, previous myocardial infarction (MI) and coronary artery disease, congestive heart failure, decreased LV ejection fraction (EF<55%), chronic obstructive pulmonary disease, significant valvular disease, pacemaker implantation, hypertension (resting blood pressure ≥ 140/90 mm Hg), diabetes mellitus, peripheral vascular diseases, respiratory or neurologic disorders, pericarditis, congenital heart disease, alcohol addiction, renal or hepatic disease and those with poor echocardiographic imaging were excluded from the study.
Before the beginning, the study protocol was approved by the local ethics committee of our hospital. All patients were informed about the study’s objectives and signed consent forms. The study was conducted under the ethical principles of the Declaration of Helsinki.

Echocardiographic Examination and Measurement of Atrial Conduction Time

Echocardiographic examination was performed in all patients before pulmonary vein RF ablation and three months after the ablation with the GE VividS6 system (GE Vingmed, Horten, Norway) using a probe of 2-4 MHz frequency. Echocardiographic examination was performed with the patient in the supine position and lying on the left side, using appropriate echocardiographic windows with M mode, two-dimensional (2D), pulse wave doppler, continuous wave doppler, color flow, and tissue doppler imaging (TDI) methods.

M-mode echocardiography: Left ventricular end-systole and diastole sizes and ejection fraction, end-diastole septum and posterior wall thicknesses were measured with M-mode echocardiography.

2D echocardiography: Wall motion of both ventricles, valvular structure and functions, and the pericardial window were examined with 2D echocardiography. Mitral flow parameters were measured at the end of expiration by averaging three cardiac cycles.

Tissue Doppler Echocardiography: Simultaneous ECG recordings were taken during tissue Doppler echocardiographic examination. The time from the beginning of the P wave on the ECG to the onset of the A’ wave on tissue Doppler (wave indicating atrial contraction) was defined as the PA distance (electromechanical atrial time) (Figure 1). Atrial electromechanical time was measured separately from the lateral mitral annulus, septal mitral annulus, and lateral tricuspid annulus; and defined as PA lateral, PA septum, and PA tricuspid, respectively. The difference between PA lateral and PA tricuspid (PA lateral – PA tricuspid) was defined as interatrial conduction delay, and the difference between PA septum and PA tricuspid (PA septum – PA tricuspid) as interatrial conduction delay.
Transesophageal Echocardiography: All patients underwent TEE within 48 hours before the ablation. The echogenic mass in the LAA that continued in more than one plane and distinguished from the surrounding tissues was considered a thrombus, and patients with thrombi in the LAA were excluded.

Electrophysiological Procedure

Pulmonary vein isolation was performed under anesthesia and noninvasive mild sedation. Vascular access was obtained using the bilateral femoral veins and left femoral artery. Intracardiac and superficial electrocardiograms were recorded at 100 mm/second (Prucka, GE Medical Systems). Transseptal punctures were made with the Brockenbrough needle transseptal needle (St. Jude Medical, Minnetonka, MN, USA) under fluoroscopy. First, pulmonary vein electrical mapping was performed with a circular mapping catheter (Lasso, Biosense Webster, Diamond Bar, CA, USA) via the single transseptal sheath and pulmonary vein potentials (it was paced from the coronary sinus to separate from atrial potential [AP]) were determined. The ablation catheter (SF-Contact force, Biosense Webster, Diamond Bar, CA, USA) was inserted through the other transseptal sheath; right and left pulmonary vein isolation was performed, respectively (Figure 2).

Statistical Analysis

Biostatistical analysis of the data obtained was performed with SPSS (Statistical Package for Social Sciences) for Windows v. 21.0 package software. The normality of the data was analyzed with the Kolmogorov-Smirnov test. Continuous variables were expressed as mean ± standard deviation and categorical variables with frequency and percentage (%). Descriptive statistics regarding normally distributed variables were expressed as mean ± standard deviation. Whereas non-normally distributed variables were given with median, minimum, and maximum values. In the statistical evaluations, correlations between categorical variables were examined with the Chi-square test. Normally distributed variables were analyzed using the Student t-test, and non-normally distributed variables were analyzed using Mann-Whitney U and Kruskal-Wallis tests. Pearson’s correlation analysis was used to determine the direction and level of the correlations between the variables. p<0.05 values considered statistically significant.

Results

A total of 52 patients with PAF despite at least one antiarrhythmic drug were included. One patient developed acute pericardial tamponade during 3D pulmonary vein isolation and the process was terminated. In another patient, pericardial tamponade was observed 12 hours after the successful process then the patient was taken to the surgery. Finally, 50 patients who underwent RF ablation with the CARTO® 3D pulmonary vein isolation system were analyzed. All patients had received at least one antiarrhythmic drug, with 34 (68%) having received propafenone and the remaining 16 (32%) amiodarone. Of all patients, 28 (56%) were female, and the mean age of the patients was 51.68±11.731 years. PAF attack was observed at follow-up after the ablation in six (12%) patients.
Basal echocardiographic findings of the patients are given in Table 1.
Comparison of Atrial Conduction Times Before and After Ablation
A comparison of atrial conduction times measured with tissue Doppler echocardiographic examination before and three months after the ablation is shown in Table 2a.
PA lateral, septum, tricuspid, intra-, and interatrial conduction delay times significantly decreased after the RF ablation procedure (Figure 3a.)
Comparison of Atrial Conduction Times Before and After Ablation According to Sexes
A comparison of atrial conduction times before and after ablation according to sexes is shown in Table 2b.
When atrial conduction times before and after RF ablation were compared according to sexes, no significant difference was found between the two groups in male patients, while there was a significant difference in all parameters except for intra-atrial conduction delay in female patients (Figure 3b).
In the correlation analysis of atrial conduction times before and after RF ablation; a significant negative correlation was found in all values including PA lateral (r=-0.763; p<0.001), PA septum (r=-0.734; p<0.01), PA tricuspid (r=-0.812; p<0.001), interatrial conduction time (r=-0.594; p=0.00) and intra-atrial conduction time (r=-0.563; p=0.002) (Table 3).

Discussion

AF is a disease characterized by the disruption of cardiac mechanical functions due to irregular atrial activation. There are initiating factors that cause the onset of AF and an anatomical substrate that maintains it. An essential feature of AF is that the arrhythmia sustains itself when it begins. It is possibly caused by remodeling occurring in the atrium. Atrial remodeling occurs at electrophysiological, cellular, and anatomic levels [14]. Many studies have shown the association between intra- and interatrial conduction blocks and AF [15]. It is thought that a shortening in the atrial effective refractory period, inconsistency of the atrial effective refractory period with changes in heart rate, and a prolongation in atrial conduction time occur as a result of electrical remodeling in AF [16]. Delay in interatrial and intra-atrial conduction leads to heterogeneity of atrial refractoriness.
A study by Bayar et al. showed that left intra-atrial mechanical delay increased in patients with PAF and was an independent risk factor for PAF [17]. Van Staveren et al. showed that inter and intra-atrial conduction was prolonged following electrical cardioversion in patients with lone AF [18]. In a study by Lizewska et al. with patients who underwent cryoballoon, the intra-atrial delay before and after the procedure was a predictor of late AF recurrence [19].
There may be fibrosis in the left atrium in AF, which causes anisotropy, maintain anisotropic atrial conduction delay, changes intra-atrial refractoriness, and leads to the continuity of reentrant arrhythmia. The persistence of AF during the structural atrial remodeling process leads to a reduction in the amount of connexin 40 and thus causing regional conduction abnormalities that lead to reentrant pathways maintaining themselves [20]. Radiofrequency (RF) catheter ablation has recently been introduced as an important therapeutic option in patients with drug-resistant atrial fibrillation (AF), with about a 75% success rate [21]. In our study, significant decreases were observed in intra- and interatrial conduction times after RF ablation (PA lateral p: 0.022; PA septum p: 0.002; PA tricuspid p: 0.019; interatrial conduction delay p:0.012; and intra-atrial conduction delay p:0.029). This result suggests that providing stable sinus rhythm by eliminating the AF triggering mechanisms with RF ablation of pulmonary vein isolation may slow down, stop or even improve structural remodeling at substrate level secondary to AF even in patients who did not yet develop atrial fibrosis and permanent structural changes. There is a linear relationship between electrophysiological, structural, and cellular remodeling with the increase of AF duration during the day in PAF patients, and this process progresses toward permanent AF [4, 10]. However, it is unclear whether AF can produce additional forms of remodeling, especially when arrhythmia remains sustained for extended periods [22]. As also seen in our study, preservation of sinus rhythm after pulmonary vein RF ablation is expected to affect this process.
Sex differences may affect diagnostic and therapeutic interventions in various medical conditions, including cardiac arrhythmias [23]. In our study, when atrial conduction times were compared before and after RF ablation according to sexes, no significant difference was observed between the two groups in male patients. At the same time, there were significant differences in all parameters except for intra-atrial conduction delay in female patients. The reason was probably the low number of male patients (14 patients; 28%) who had atrial conduction time measured after the procedure.

Limitation

In this study, the number of patients was relatively small. Long-term results could be better analyzed with a more extensive series of patients and longer follow-ups. Clearer information about fibrosis and left atrial structural changes could be obtained by adding cardiac MRI and echocardiography.

Conclusion

As the clinical emphasis in this study, providing stable sinus rhythm with successful RF ablation may slow down, stop or even improve structural remodeling at substrate level secondary to AF in patients with PAF who did not yet develop atrial fibrosis and permanent structural changes.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: None

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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İbrahim Dönmez, Tolga Memioğlu, Emrah Acar, Fatma Erdem. Evaluation of the effects of 3D mapping ablation on atrial conduction times in patients with paroxysmal atrial fibrillation. Ann Clin Anal Med 2022;13(12):1373-1377

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