Atrial Pacing Improves Mitochondrial Function in Peripheral Blood Mononuclear Cells in Patients with Cardiac Implantable Electronic Devices.

Mitochondrial dysfunction contributes significantly to the development of atrial fibrillation (AF). Conflicting data regarding the atrial pacing and the risk of AF existed and the impact of atrial pacing on mitochondrial function remains unknown. Therefore, we sought to examine the association between atrial pacing percentage and mitochondrial function in patients with cardiovascular implantable electronic devices (CIED) with atrial pacing capability. This is a cross-sectional study involving 183 patients with CIED with atrial pacing capability. The oxidative stress and mitochondrial function were determined in peripheral blood mononuclear cells (PBMCs). Among 183 patients, 55.7% had permanent pacemakers, 7.7% had defibrillators and 36.6% had cardiac resynchronization therapy. Mean age was 67.5±14.7 years with 51% being male. Mean left ventricular ejection fraction (LVEF) was 53.9 ± 16.8%. We demonstrated that the presence of atrial pacing above 50% correlated with higher levels of mitochondrial spared respiratory capacity (P=0.043) and coupling efficiency (P=0.045). After adjusting with multiple linear regression for age, sex, LVEF, history of AF, sick sinus syndrome, co-morbidities, eGFR, CRT, and percentage of ventricular pacing, our findings revealed a statistically significant association between a higher percentage of atrial pacing and increased spared respiratory capacity (ß 0.217, P=0.046), lower non-mitochondrial respiration (ß -0.230, P=0.023) and proton leak (ß -0.247, P=0.022). We demonstrated that atrial pacing enhances mitochondrial performance in PBMCs and left ventricular contractile performance in patients with CIED. This observation may serve as additional support for the preventive effect of atrial pacing in the prevention of atrial arrhythmia.

Safety and efficacy of adaptive atrial pacing regulated by blood pressure during low-level exercise: a proof-of-concept study.

AIMS: Despite half of all heart failure patients suffering from heart failure with preserved ejection fraction (HFpEF), treatment options are limited. This study aims to compare safety and efficacy of standard pacemaker programming (DDD or DDDR) and a novel pacing algorithm PressurePace™ (BaroPace Inc, Issaquah, WA, USA) which modulates atrial pacing rate based on blood pressure (BPAP). METHODS: This prospective, randomized, double-blind, non-significant risk proof of concept study was conducted at two large cardiology clinics in Los Angeles, California, USA. Subjects underwent two modified Bruce protocol graded treadmill exercise tests in which pacemaker programming was randomized to either standard programming (DDD or DDDR), or BPAP at least 1 week apart. Physiological measurements of heart rate (HR), and systolic and diastolic blood pressure (BP) were collected at 2 min intervals. During the BPAP treadmill test, the pacemaker activity sensor was disabled. The PressurePace algorithm instructed the pacemaker technician to modify or leave unchanged the atrial pacing rate based on these BP measurements. Subjects and clinical staff were blinded to pacemaker programming, only the pacemaker technician was unblinded. RESULTS: Ten subjects with HFpEF associated with hypertension who also had permanent dual-chamber pacemakers, previously implanted for standard clinical indications, participated in the study. Mean age was 70.1 ± 6.8 years, left ventricular ejection fraction of 54.8 ± 1.9%. Exercise duration increased in all 10 subjects, when paced in the BPAP mode compared with standard pacemaker programming, showing a mean increase of 117 s (26%, P = 0.0016). The algorithm could adjust HR at each 2 min interval. The majority of subjects (60%) had their atrial pacing rate increased an average of 20% at t = 2 min. In the remaining 40% of subjects, the algorithm instructed HR to be unchanged. In two subjects, the pacing rate was not increased until t = 6 min. In contrast, subjects programmed to DDDR experienced an average of 45% increase in atrial pacing rate at t = 2 min. In the post-treadmill recovery period, SBP was higher for subjects who underwent BPAP. This difference in SBP was most pronounced immediately post-treadmill and diminished as subjects progressed through the 30 min recovery period. Statistical significance was achieved at t = 0, 20, and 30 min post-treadmill. CONCLUSIONS: An increase in exercise duration was reported in HFpEF subjects using a pacing algorithm that modulated HR based on BP compared with standard programming. These encouraging results form the basis for a larger, randomized cross-over trial to confirm these initial observations, further characterize the safety, efficacy, and possible mechanisms of action in both acute and longer-term treatment.

Impact of weight adjusted high frequency low tidal volume ventilation and atrial pacing in lesion metrics in high-power short-duration ablation: Results of a pilot study.

INTRODUCTION: Lesion size index (LSI) was introduced with the use of Tacticath™ and as a surrogate of lesion quality. The metric used to achieve the predetermined values involves combined information of contact force (CF), power and radiofrequency time. Rapid atrial pacing (RAP) and high-frequency low-tidal volume ventilation (HFLTV) independently or in combination improve catheter stability and CF and quality of lesions. Data of the impact of body weight adjusted HFLTV ventilation strategy associated with RAP in the lesion metrics still lacking. The study aimed to compare the results of high-power short-duration (HPSD) atrial fibrillation ablation using simultaneous weight adjusted HFLTV and RAP and standard ventilation (SV) protocol. METHODS: Prospective, nonrandomized study with 136 patients undergoing de novo ablation divided into two groups; 70 in RAP (100 ppm) + HFLTV with 4 mL/kg of tidal volume and 25 breaths/min (group A) and 66 patients with SV in intrinsic sinus rhythm (group B). Ablation using 50 W, CF of 5-10 g/10-20 g and 40 mL/minute flow rate on the posterior and anterior left atrial wall, respectively. RESULTS: No procedure-related complications. Group A: Mean LSI points 70 ± 16.5, mean total lower LSI 3.4 ± 0.5, mean total higher LSI 8.2 ± 0.4 and mean total LSI 5.6 ± 0.6. Anterior and posterior wall mean total LSI was 6.0 ± 0.4 and 4.2 ± 0.3, respectively. Mean local impedance drop (LID) points were 118.8 ± 28.4, mean LID index (%) 12.9 ± 1.5, and mean LID < 12% points 55.9 ± 23.8. Anterior and posterior wall mean total LID index were 13.6 ± 2.0 and 11.9 ± 1.7, respectively. Recurrence in 11 (15.7%) patients. Group B: Mean LSI points 56 ± 2.7, mean total lower LSI 2.9 ± 0.7, mean total higher LSI 6.9 ± 0.9, and mean total LSI 4.8 ± 0.8. Anterior and posterior wall mean total LSI was 5.1 ± 0.3 and 3.5 ± 0.5, respectively. Mean LID points were 111.4 ± 21.5, mean LID index (%) 11.4 ± 1.2, and mean LID < 12% points 54.9 ± 25.2. Anterior and posterior wall mean total LID index were 11.8 ± 1.9 and 10.3 ± 1.7, respectively. Recurrence in 14 (21.2%) patients. Mean follow up was 15.2 ± 4.4 months. CONCLUSION: Weight adjusted HFLTV ventilation with RAP HPSD ablation produced lower recurrence rate and better LSI and LID parameters in comparison to SV and intrinsic sinus rhythm.

The power of three: Atrial rate limit power-on-reset - A non-electromagnetic cause of pacemaker-induced extracardiac stimulation.

BACKGROUND: Power-on reset (PoR) is most commonly due to electromagnetic interference. Full PoR results in a switch to an inhibited mode (VVI) pacing and resets pacing outputs to maximal unipolar settings, leading to extracardiac stimulation. METHODS: We present a case of PoR occurrence in the absence of electromagnetic interference, resulting in pectoral stimulation triggered by violation of the atrial rate limit. CONCLUSIONS: It is useful for clinicians to recognizethe occurrence of PoR in the setting of atrial limit violation andthe appropriate management in such circumstances.

Rapid atrial pacing above the maximum sensor rate: a case report.

Background: While ventricular-based timing modes are known to cause elevated atrial pacing above the lower rate when intrinsic atrioventricular (AV) conduction is shorter than programmed AV delay, there is one case report in 2015 by Jafri et al. where rapid atrial pacing was induced in an Abbott device set DDI with a lower rate of 90 by an unsensed premature atrial complex and slow intrinsic AV conduction allowing pacemaker 'crossover.' Case summary: We present a very unusual case of rapid atrial pacing at >180 b.p.m. due to a perfect storm of events that we believe has not been previously reported. A patient with a St. Jude Abbott DCPPM set DDDR had an atrial tachyarrhythmia causing a mode switch to DDIR, which uses ventricular-based timing. This was followed by a period of rapid atrial pacing that terminated spontaneously. Discussion: This phenomenon depended on an initial atrial tachyarrhythmia causing a mode switch to DDIR. In addition, the set lower rate would not have led to a short enough calculated ventriculo-atrial interval (VAI), but because rate responsive pacing was enabled, the calculated VAI was short enough to promote the crossover in setting of slow AV conduction and allow the rapid atrial pacing. Understanding this unique mechanism requires careful attention to pacemaker timing cycles and appreciation of the limitations of device programming. While it appears that a similar phenomenon was reported once in the literature, we believe that this episode of rapid atrial pacing was even more serendipitous due to the unlikely series of events required for its inception.

Transient loss of atrial capture: the "atrial pacemaker stunning" phenomenon.

Atrial loss of capture in the chronic phase after implantation may be permanent due to various causes, e.g. technical lead problems or increased scar tissue formation around the lead tip. However, it may also be transient after atrial ischemia in the context of occlusion of the right coronary artery. In this case, it may be preferable to wait for recovery, which may take up to 45 days, instead of immediately performing an atrial lead revision.

Alternative atrial pacing site to improve cardiac function: focus on Bachmann's bundle pacing.

Pacing from the right atrial appendage (RAA) prolongs the P wave duration and can induce interatrial and especially left-sided atrio-ventricular dyssynchrony. Pacing from Bachmann's bundle closely reproduces normal physiology and has the potential to avoid the electromechanical dysfunction associated with conventional RAA pacing. Interatrial conduction delay is associated with an increased risk of stroke, heart failure, and death. In addition to a reduction in atrial fibrillation, Bachmann's bundle pacing has emerging applications as a hemodynamic pacing modality. This review outlines the pathophysiology of atrial conduction disturbances and their potential remedies and provides the reader with a practical guide to implementing Bachmann's bundle pacing with an emphasis on the recapitulation of normal electrical and mechanical function.

Atrial pacing minimization in sinus node dysfunction and risk of incident atrial fibrillation: a randomized trial.

BACKGROUND AND AIMS: High percentages of atrial pacing have been associated with an increased risk of atrial fibrillation. This study is aimed at evaluating whether atrial pacing minimization in patients with sinus node dysfunction reduces the incidence of atrial fibrillation. METHODS: In a nationwide, randomized controlled trial, 540 patients with sinus node dysfunction and an indication for first pacemaker implantation were assigned to pacing programmed to a base rate of 60 bpm and rate-adaptive pacing (DDDR-60) or pacing programmed to a base rate of 40 bpm without rate-adaptive pacing (DDD-40). Patients were followed on remote monitoring for 2 years. The primary endpoint was time to first episode of atrial fibrillation longer than 6 min. Secondary endpoints included longer episodes of atrial fibrillation, and the safety endpoint comprised a composite of syncope or presyncope. RESULTS: The median percentage of atrial pacing was 1% in patients assigned to DDD-40 and 49% in patients assigned to DDDR-60. The primary endpoint occurred in 124 patients (46%) in each treatment group (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.76-1.25, P = .83). There were no between-group differences in atrial fibrillation exceeding 6 or 24 h, persistent atrial fibrillation, or cardioversions for atrial fibrillation. The incidence of syncope or presyncope was higher in patients assigned to DDD-40 (HR 1.71, 95% CI 1.13-2.59, P = .01). CONCLUSIONS: Atrial pacing minimization in patients with sinus node dysfunction does not reduce the incidence of atrial fibrillation. Programming a base rate of 40 bpm without rate-adaptive pacing is associated with an increased risk of syncope or presyncope.

Overview of programmed electrical stimulation to assess atrial fibrillation susceptibility in mice.

Atrial fibrillation (AF) is the most common human arrhythmia and is associated with increased risk of stroke, dementia, heart failure, and death. Among several animal models that have been used to investigate the molecular determinants of AF, mouse models have become the most prevalent due to low cost, ease of genetic manipulation, and similarity to human disease. Programmed electrical stimulation (PES) using intracardiac or transesophageal atrial pacing is used to induce AF as most mouse models do not develop spontaneous AF. However, there is a lack of standardized methodology resulting in numerous PES protocols in the literature that differ with respect to multiple parameters, including pacing protocol and duration, stimulus amplitude, pulse width, and even the definition of AF. Given this complexity, the selection of the appropriate atrial pacing protocol for a specific model has been arbitrary. Herein we review the development of intracardiac and transesophageal PES, including commonly used protocols, selected experimental models, and advantages and disadvantages of both techniques. We also emphasize detection of artifactual AF induction due to unintended parasympathetic stimulation, which should be excluded from results. We recommend that the optimal pacing protocol to elicit an AF phenotype should be individualized to the specific model of genetic or acquired risk factors, with an analysis using several definitions of AF as an endpoint.

The impact of chronotropic incompetence on atrioventricular conduction times in heart failure patients.

BACKGROUND: Intrinsic atrioventricular (AV) conduction is used to optimize AV intervals with cardiac resynchronization therapy (CRT) in most device algorithms. Atrial pacing and heart rate affect conduction times, but little is known regarding differeces among chronotropic incompetent(CI) and competent(CC) patients to guide programming. METHODS: RAVE was a multicenter prospective trial of CRT patients. Heart rate was increased with incremental atrial pacing and with submaximal exercise. According to the maximal heart rate achieved during exercise, patients were classified as either CI or CC. For CI patients, an additional symptom-limited exercise with rate-adaptive pacing activated was performed. Intracardiac intervals were measured from the implantable lead electrograms in multiple postures. RESULTS: There were 12 subjects with CI and 24 with CC. With atrial pacing, AV interval immediately increased and gradually increased with incremental atrial pacing in all patients. However, the changes in the atrial to right ventricular (ARV) and atrial to left ventricular (ALV) intervals with increasing atrial pacing rates were about threefold greater in CI patients compared to CC patients (24.3 ± 28.9 vs. 7.2 ± 5.5 ms/10 bpm for ARV and 22.7 ± 25.6 vs. 7.1 ± 5.7 ms/10 bpm for ALV in the standing position, p < 0.05). In CI pacing with rate-adaptive pacing during exercise, AV interval changes with paced heart rate were variable. CONCLUSIONS: The AV response to overdrive atrial pacing at rest may provide a simple means of identifying chronotropic competence in CRT patients. For patients with CI, who often require rate-adaptive atrial pacing, rate-adaptive AV algorithms should be adjusted individually.

Efficacy of Coronary Sinus Pacing for Cardiogenic Shock Due to Percutaneous Coronary Intervention-induced Sick Sinus Syndrome: Two Case Reports.

We herein report two cases of atrial pacing with coronary sinus (CS) pacing performed to improve hemodynamic instability in cardiogenic shock due to percutaneous coronary intervention (PCI)-induced sick sinus syndrome (SSS). Ventricular pacing alone made it difficult to stabilize hemodynamics due to SSS, which had been caused by the lack of reflow and slow flow of the sinus node artery (SNA) jailed with a stent. Adding atrial pacing with CS pacing may be useful, as in our two cases, where ventricular pacing alone was unable to stabilize hemodynamics.

Regions of Highly Recurrent Electrogram Morphology With Low Cycle Length Reflect Substrate for Atrial Fibrillation.

Traditional anatomically guided ablation and attempts to perform electrogram-guided atrial fibrillation (AF) ablation (CFAE, DF, and FIRM) have not been shown to be sufficient treatment for persistent AF. Using biatrial high-density electrophysiologic mapping in a canine rapid atrial pacing model of AF, we systematically investigated the relationship of electrogram morphology recurrence (EMR) (Rec% and CLR) with established AF electrogram parameters and tissue characteristics. Rec% correlates with stability of rotational activity and with the spatial distribution of parasympathetic nerve fibers. These results have indicated that EMR may therefore be a viable therapeutic target in persistent AF.

Mapping-guided atrial lead placement determines optimal conduction across Bachmann's bundle: a rationale for patient-tailored pacing therapy.

AIMS: Conventional right atrial appendage (RAA) pacing is associated with increased atrial activation time resulting in higher incidences of atrial tachyarrhythmia. Optimal pacing sites ideally shorten inter-atrial conduction delay, thereby decreasing atrial excitation time. We therefore examined the impact of programmed electrical stimulation (PES) from the right atrium (RA) and left atrium (LA) on the electrophysiological properties of Bachmann's bundle (BB). METHODS AND RESULTS: High-resolution epicardial mapping of BB was performed during sinus rhythm (SR) and PES in 34 patients undergoing cardiac surgery. Programmed electrical stimulation was performed from the RAA, junction of the RA with inferior caval vein (LRA), and left atrial appendage (LAA). Pacing from either the RAA or LAA resulted in, respectively, right- and left-sided conduction across BB. However, during LRA pacing in most patients (n = 15), activation started in the centre of BB. The total activation time (TAT) of BB during RAA pacing [63 (55-78) ms] was similar to that of SR [61 (52-68) ms, P = 0.464], while it decreased during LRA [45 (39-62) ms, P = 0.003] and increased during LAA pacing [67 (61-75) ms, P = 0.009]. Reduction of both conduction disorders and TAT was most often achieved during LRA pacing (N = 13), especially in patients who already had a higher amount of conduction disorders during SR [9.8 (7.3-12.3) vs. 4.5 (3.5-6.6)%, P < 0.001]. CONCLUSION: Pacing from the LRA results in a remarkable decrease of TAT compared with pacing from the LAA or RAA. As the most optimal pacing site varies between patients, individualized positioning of the atrial pacing lead guided by mapping of BB may be one of the new frontiers for atrial pacing.

Effects and pharmacological mechanism of Zhigancao Decoction on electrical and structural remodeling of the atrium of rabbits induced by rapid atrial pacing.

BACKGROUND: Zhigancao decoction (ZD) has a long history in China as a traditional Chinese medicine compound for the treatment of tachyarrhythmias. This study mainly explored the pharmacological mechanism of Zhigancao Decoction in preventing atrial fibrillation by altering the electrical and structural remodeling of the atrial in rabbits. METHODS: In total, 30 male New Zealand white rabbits were randomly divided into 3 groups (ten rabbits for each). The first group was sham-operated (control group). The second group was intervened by the rapid right atrium pacing (RAP) to induce atrial fibrillation (AF group), while the third group was given ZD gavage and RAP (AF + ZD group). All rabbits were anesthetized before two monophasic action potential (MAP) catheters were sequentially inserted into the right atrium. After 8 h of rapid right atrial pacing, the electrophysiological indexes and the induction rate of atrial fibrillation were observed in the three groups of rabbits, and the left atrial myocardium samples were taken to observe the ultrastructure. Single atrial myocytes were separated by enzymolysis, and the L-type calcium current (ICa-L) of atrial myocytes in different experimental groups was observed by whole-cell patch clamp technique. The fluorescence intensity of Ca2+ in atrial myocytes was observed after Fluo-3/AM fluorescent staining. The main components of ZD were identified by liquid chromatography-mass spectrometry-mass spectrometry (LC-MS/MS) method. RESULTS: Compared with the AF group, the maximum ascent rate (Max dV/dt) and plateau potential were significantly reduced in the ZD group, the action potential duration at 10% and 20% (APD10, APD20) were significantly shortened (P < 0.01), action potential duration at 50%, 70%, and 90% (APD50, APD70, APD90) were significantly prolonged, and atrial effective refractory period (AERP) was significantly prolonged (P < 0.01) in the ZD group. In the ZD group, the ICa-L amplitudes of rabbit atrial myocytes under each clamping voltage were significantly smaller than those in the AF group (P < 0.01) and the control group (P < 0.05). The Ca2+ fluorescence intensity in the rabbit atrial myocytes in the ZD group was significantly weaker than that in the AF group (P < 0.01) and the control group (P < 0.05). Electron microscopy displayed that the control group had neatly arranged atrial tissue myofilaments and intact mitochondria. However, the ultrastructural damage of the AF group was severe compared with that of the ZD group. LC-MS/MS analysis confirmed that ZD contained several antiarrhythmic compounds including ginsenoside, isoliensinine, catalpol, glycyrrhizinate and hesperetin. CONCLUSION: Rapid atrial pacing (RAP) could cause the electrical and structural remodeling of rabbit atrial myocytes. ZD might reverse the atrial electrical remodeling but could have little effect on structural remodeling, which might be the mechanism of ZD treatment on atrial fibrillation.

Alpha-lipoic acid prevents atrial electrical and structural remodeling via inhibition of NADPH oxidase in a rabbit rapid atrial pacing model.

BACKGROUND: Alpha-lipoic acid (ALA) is a natural compound, one of the natural antioxidants with high activity. In the NADPH oxidase family, NADPH oxidase 4 (NOX4) is an important subunit participating in the production of ROS. NADPH oxidase 2 (NOX2) can form active NADPH oxidase complexes when binding to several other subunits in the cytoplasm, and NOX2 is its major functional subunit. Rapid atrial pacing (RAP) model was constructed to study the effects of ALA on electrical and structural remodeling in rabbits. METHODS: Thirty rabbits were divided into SHAM group, RAP group and ALA+RAP group. Their right atriums were paced at a speed of 600 beats/min for 12 h in the RAP and ALA+RAP groups, and the atrial effective refractory period (AERP) and AERP frequency adaptability were determined during the pace. In ALA+RAP group, ALA (30 mg/kg) was administered intraperitoneally daily to the rabbits for 3 days before RAP. Atrial tissue was collected from each group to detect malondialdehyde (MDA), superoxide dismutase (SOD) and reactive oxygen species (ROS) to observe the effect of oxidative stress. The pathological structure of the atrial tissue was observed through hematoxylin-eosin (HE) staining. Ultrastructural changes in the atrial myocytes were observed by transmission electron microscopy (TEM), and the expression levels of Nox2 and Nox4 were detected by immunohistochemistry, western blot and ELISA. RESULTS: AERP gradually shortened, while ALA injection could remarkably delay this process. HE staining showed that the most of the nuclei appeared normal, the myocardial fibers did not show ruptures, and their arrangement was slightly ordered, and myofilament dissolution and mitochondrial swelling and deformation were rarely observed by TEM in the ALA+RAP group. Compared with the RAP group, the contents of MDA and ROS were reduced, SOD activity was enhanced, and the expression of NOX2 and NOX4 was decreased in the ALA+RAP group. DISCUSSION: ALA can inhibit atrial electrical remodeling and structural remodeling, and its mechanism may be related to inhibiting the activity of NADPH oxidase.

Left Bundle Area Pacing for Tachycardia-Bradycardia Syndrome in a Patient With Dextrocardia.

We present the case of an 81-year-old woman with a background of situs inversus with dextrocardia who was successfully treated for tachycardia-bradycardia syndrome with left bundle area pacing. This report describes how this approach can circumvent the limitations of other pacing approaches to optimize patient outcomes. (Level of Difficulty: Intermediate.).

Atrial Fibrillation, thromboembolic risk, and the potential role of the natriuretic peptides, a focus on BNP and NT-proBNP - A narrative review.

Atrial fibrillation (AF) is one of the most commonly encountered arrythmia in clinical practice. AF itself can be driven by genetic predisposition, ectopic electrical activity, and abnormal atrial tissue substrates. Often there is no single etiological mechanism, but rather a combination of factors that feed back to remodel and worsen tissue substrate, "AF begets AF". The clinical consequences of AF can often include emboli, heart failure, and early mortality. The classical AF cardioembolic (CE) concept requires thrombus formation in the left atrial appendage, with subsequent embolization. The temporal dissociation between AF occurrence and CE events has thrown doubt on AF as the driver of this mechanism. Instead, there has been a resurgence of the "atrial cardiomyopathy" (ACM) concept. An ACM is proposed as a potential mechanism of embolic disease through promotion of prothrombotic mechanisms, with AF instead reflecting atrial disease severity. Regardless, AF has been implicated in 25% to 30% of cryptogenic strokes. Natriuretic peptide(NP)s have been shown to be elevated in AF, with higher levels of both NT-proBNP and BNP being predictive of incidental AF. NPs potentially reflect the atrial environment and could be used to identify an underlying ACM. Therefore, this narrative review examines this evidence and mechanisms that may underpin the role of NPs in identifying atrial dysfunction, with focus on both, BNP and NTproBNP. We explore their potential role in the prediction and screening for both, ACM and AF. Moreover, we compare both NPs directly to ascertain a superior biomarker.