Cryoballoon cardioneuroablation: New electrophysiological insights.

Background: Cardioneuroablation (CNA) targeting ganglionated plexi has shown promise in treating vasovagal syncope. Only radiofrequency ablation has been used to achieve this goal thus far. Objective: The purpose of this study was to investigate the utility of cryoballoon ablation (CBA) of the pulmonary veins (PVs) as a potential simplified approach to CNA. Methods: We report our observations of autonomic modulation in a series of 17 patients undergoing CBA for atrial fibrillation and our early experience using CBA of the PVs in 3 patients with malignant vagal syncope. In 17 patients undergoing CBA of AF, sinus cycle length was recorded intraprocedurally after ablation of individual PVs. Results: The most pronounced shortening of the sinus cycle length was observed after isolation of the right upper PV, which was ablated last. Reduced sinus node recovery time and atrioventricular (AV) nodal effective refractory period were observed after CBA. Resting heart rate was elevated by 6-7 bpm after CBA and persisted during 12-month follow-up. CBA of the PVs was performed in 3 patients with recurrent vagal syncope mediated by sinus arrest (n = 2) and AV block (n = 1). In all patients, isolation of the right upper PV resulted in marked shortening of sinus cycle length. During follow-up of 178 ± 43 days (134-219 days), CNA resulted in abolition of pauses, bradycardia-related symptoms, and syncope in all patients. Conclusion: CBA of the PVs (particularly the right upper PV) may be a predictable anatomic CNA approach in patients with refractory vagal syncope due to sinus arrest and/or AV block and may warrant systematic investigation as a tool to perform CNA.

Transvenous extraction of conduction system pacing leads: An international multicenter (TECSPAM) study.

BACKGROUND: Conduction system pacing (CSP) by His bundle pacing or left bundle branch area pacing (LBBAP) is incorporated into Heart Rhythm Society guidelines for the management of bradycardia and cardiac resynchronization therapy. Despite increasing adoption with both lumenless leads and stylet-driven leads, concerns regarding the feasibility and safety of the extraction of CSP leads remain. OBJECTIVE: The aim of the study was to report on the safety, feasibility, and clinical outcomes of the extraction of CSP leads. METHODS: Patients undergoing the extraction of CSP leads from 10 international centers were enrolled in this retrospective study. Data regarding indications, lead location, lead type, extraction tools, procedural success, complications, and reimplantation in the conduction system were collected. RESULTS: Overall, 341 patients (age 69 ± 15 years; female 34%; cardiomyopathy 46%; lead dwell time 22 ± 26 months) underwent the extraction of 224 His bundle pacing and 117 LBBAP leads (lumenless leads 321; stylet-driven leads 20). Complete procedural success was achieved in 338 (99%), while clinical success was 100% with retained distal fragments in 3 patients (1%). Among patients with a lead dwell time of >6 months (6-193 months; n = 226), manual extraction was successful in 198 (87%), mechanical tools in 22 (10%), and laser in 6 (3%). Femoral tools were necessary in 3 patients. Minor complications occurred in 7 patients (2.1%). CSP reimplantation was successful in 233 of 244 patients attempted (95%). CONCLUSION: The overall success rates of the extraction of CSP leads were very high (although the LBBAP lead dwell time was <3 years), with a low need for extraction tools and minimal complication. Reimplantation in the conduction system is feasible and safe.

Centennial of the original description of Mobitz type II second-degree atrioventricular block.

The year 2024 marks the centenary of Mobitz's description of type II second-degree atrioventricular block. Its definition remains valid to this day with only minor modification for the diagnosis of infranodal conduction block. Mobitz a century ago indicated that his type II atrioventricular block was associated with Stock-Adams attacks and a prolonged duration of the QRS complex before the eventual description of bundle branch block.

Arrhythmic Risk in Biventricular Pacing Compared With Left Bundle Branch Area Pacing: Results From the I-CLAS Study.

BACKGROUND: Left bundle branch area pacing (LBBAP) may be associated with greater improvement in left ventricular ejection fraction and reduction in death or heart failure hospitalization compared with biventricular pacing (BVP) in patients requiring cardiac resynchronization therapy. We sought to compare the occurrence of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) and new-onset atrial fibrillation (AF) in patients undergoing BVP and LBBAP. METHODS: The I-CLAS study (International Collaborative LBBAP Study) included patients with left ventricular ejection fraction ≤35% who underwent BVP or LBBAP for cardiac resynchronization therapy between January 2018 and June 2022 at 15 centers. We performed propensity score-matched analysis of LBBAP and BVP in a 1:1 ratio. We assessed the incidence of VT/VF and new-onset AF among patients with no history of AF. Time to sustained VT/VF and time to new-onset AF was analyzed using the Cox proportional hazards survival model. RESULTS: Among 1778 patients undergoing cardiac resynchronization therapy (BVP, 981; LBBAP, 797), there were 1414 propensity score-matched patients (propensity score-matched BVP, 707; propensity score-matched LBBAP, 707). The occurrence of VT/VF was significantly lower with LBBAP compared with BVP (4.2% versus 9.3%; hazard ratio, 0.46 [95% CI, 0.29-0.74]; P<0.001). The incidence of VT storm (>3 episodes in 24 hours) was also significantly lower with LBBAP compared with BVP (0.8% versus 2.5%; P=0.013). Among 299 patients with cardiac resynchronization therapy pacemakers (BVP, 111; LBBAP, 188), VT/VF occurred in 8 patients in the BVP group versus none in the LBBAP group (7.2% versus 0%; P<0.001). In 1194 patients with no history of VT/VF or antiarrhythmic therapy (BVP, 591; LBBAP, 603), the occurrence of VT/VF was significantly lower with LBBAP than with BVP (3.2% versus 7.3%; hazard ratio, 0.46 [95% CI, 0.26-0.81]; P=0.007). Among patients with no history of AF (n=890), the occurrence of new-onset AF >30 s was significantly lower with LBBAP than with BVP (2.8% versus 6.6%; hazard ratio, 0.34 [95% CI, 0.16-0.73]; P=0.008). The incidence of AF lasting >24 hours was also significantly lower with LBBAP than with BVP (0.7% versus 2.9%; P=0.015). CONCLUSIONS: LBBAP was associated with a lower incidence of sustained VT/VF and new-onset AF compared with BVP. This difference remained significant after adjustment for differences in baseline characteristics between patients with BVP and LBBAP. Physiological resynchronization by LBBAP may be associated with lower risk of arrhythmias compared with BVP.

Sex-Specific Outcomes of LBBAP Versus Biventricular Pacing: Results From I-CLAS.

BACKGROUND: Cardiac resynchronization therapy (CRT) using biventricular pacing (BVP) has been associated with greater clinical improvement in women than men. Recently, left bundle branch area pacing (LBBAP) has been shown to be an alternative form of CRT. OBJECTIVES: The purpose of this study was to investigate sex-specific outcomes for death and heart failure events in a large, international, multicenter, cohort of patients undergoing CRT with BVP or LBBAP. METHODS: In this international study of 1,778 patients (575 female and 1203 male), sex-specific survival analysis was performed to compare the effect of LBBAP-CRT relative to BVP-CRT on the combined endpoint of death or heart failure hospitalization (HFH), and secondary endpoints of HFH only, and death alone. RESULTS: Female patients were more likely to have nonischemic cardiomyopathy and left bundle branch block (LBBB) and less likely to have hypertension, diabetes, or coronary artery disease than were male patients. Overall, female patients had a better result with LBBAP compared with BVP than did male patients, with a significant 36% reduction in death or HFH (HR: 0.64; 95% CI: 0.43 to 0.97; P = 0.03) and a significant 60% reduction in HFH alone (HR: 0.4; 95% CI: 0.24 to 0.69, P < 0.01). Women had a greater reduction in death or HFH among those with nonischemic cardiomyopathy (HR: 0.45 95% CI: 0.26 to 0.79; P < 0.01) and LBBB (HR: 0.49; 95% CI: 0.27 to 0.87; P < 0.01). Sex-specific echocardiographic outcomes were better in women than in men. CONCLUSIONS: Women obtained significantly greater reductions in the combined endpoint of death or HFH (primarily driven by reduction in HFH) with LBBAP compared with BVP among patients requiring CRT than did men.

Adjunct posterior wall isolation reduces the recurrence of atrial fibrillation in patients undergoing cryoballoon ablation: A systematic review and meta-analysis.

BACKGROUND: Recurrence rates of atrial fibrillation (AF) remain high even after complete wide area circumferential pulmonary vein isolation (PVI). In recent years adjunct posterior wall isolation (PWI) has been performed in patients with more persistent forms of AF but the benefits remain unclear. AIM: The objective of this meta-analysis was to evaluate the efficacy of adjunct posterior wall isolation in reducing recurrence rates of AF using cryoballoon ablation (CBA). METHODS: We searched PubMed, Google Scholar, Clinicaltrials.gov and Cochrane CENTRAL. We included studies comparing PVI to PVI + PWI in patients with either persistent or paroxysmal AF (PAF) undergoing CBA. After data extraction and quality assessment of the studies, we assessed recurrence rates of atrial tachy-arrhythmias (AF, atrial flutter, and atrial tachycardia) as well as total ablation time and procedural adverse events. Risk ratio (RR), mean difference (MD), and 95% confidence interval (CI) were calculated using Review Manager. RESULTS: Concomitant PWI exhibited a substantial reduction in the risk of AF recurrence (RR: 0.51; 95% CI: 0.42-0.63, p < .00001), as well as all atrial arrhythmias (RR: 0.58; 95% CI: 0.49-0.68, p < .00001). On subgroup analysis, in patients with only PAF, adjunct PWI resulted in significant reduction in recurrence risk of AF (RR: 0.56; 95% CI: 0.41-0.76, p = .0002) as well. There was no significant difference in adverse events between both groups (RR: 0.90; 95% CI: 0.44-1.86; p = .78), whereas total ablation time was significantly increased in PVI + PWI group (MD: 21.75; 95% CI: 11.13-32.37, p < .0001). CONCLUSION: Adjunct PWI when compared to PVI alone decreases recurrence rates of atrial fibrillation after CBA of patients with persistent as well as paroxysmal atrial fibrillation.

Cardiac Conduction System Pacing: A Comprehensive Update.

The field of cardiac pacing has changed rapidly in the last several years. Since the initial description of His bundle pacing targeting the conduction system, recent advances in pacing the left bundle branch and its fascicles have evolved. The field and investigators' knowledge of conduction system pacing including relevant anatomy and physiology has advanced significantly. The aim of this review is to provide a comprehensive update on recent advances in conduction system pacing.

Comparison of Left Bundle Branch Area Pacing and Biventricular Pacing in Candidates for Resynchronization Therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) with biventricular pacing (BVP) is a well established therapy in patients with reduced left ventricular ejection fraction (LVEF), heart failure, and wide QRS or expected frequent ventricular pacing. Left bundle branch area pacing (LBBAP) has recently been shown to be a safe alternative to BVP. OBJECTIVES: The aim of this study was to compare the clinical outcomes between BVP and LBBAP among patients undergoing CRT. METHODS: This observational study included patients with LVEF ≤35% who underwent BVP or LBBAP for the first time for Class I or II indications for CRT from January 2018 to June 2022 at 15 international centers. The primary outcome was the composite endpoint of time to death or heart failure hospitalization (HFH). Secondary outcomes included endpoints of death, HFH, and echocardiographic changes. RESULTS: A total of 1,778 patients met inclusion criteria: 981 BVP, 797 LBBAP. The mean age was 69 ± 12 years, 32% were female, 48% had coronary artery disease, and mean LVEF was 27% ± 6%. Paced QRS duration in LBBAP was significantly narrower than baseline (128 ± 19 ms vs 161 ± 28 ms; P < 0.001) and significantly narrower compared to BVP (144 ± 23 ms; P < 0.001). Following CRT, LVEF improved from 27% ± 6% to 41% ± 13% (P < 0.001) with LBBAP compared with an increase from 27% ± 7% to 37% ± 12% (P < 0.001) with BVP, with significantly greater change from baseline with LBBAP (13% ± 12% vs 10% ± 12%; P < 0.001). On multivariable regression analysis, the primary outcome was significantly reduced with LBBAP compared with BVP (20.8% vs 28%; HR: 1.495; 95% CI: 1.213-1.842; P < 0.001). CONCLUSIONS: LBBAP improved clinical outcomes compared with BVP in patients with CRT indications and may be a reasonable alternative to BVP.

Left bundle branch area pacing in patients with heart failure and right bundle branch block: Results from International LBBAP Collaborative-Study Group.

Background: Cardiac resynchronization therapy (CRT) using biventricular pacing has limited efficacy in patients with heart failure (HF) and right bundle branch block (RBBB). Left bundle branch area pacing (LBBAP) is a novel physiologic pacing option. Objective: The aim of the study was to assess the feasibility and outcomes of LBBAP in HF patients with RBBB and reduced left ventricular systolic function, and indication for CRT or ventricular pacing. Methods: LBBAP was attempted in patients with left ventricular ejection fraction (LVEF) <50%, RBBB, HF, and indications for CRT or ventricular pacing. Procedural, pacing, and electrocardiographic parameters; clinical response (no HF hospitalization and improvement in NYHA class); and echocardiographic response (≥5% increase in ejection fraction) to LBBAP were assessed. Results: LBBAP was attempted in 121 patients and successful in 107 (88%). Patient characteristics included age 74 ± 12 years, female 25%, ischemic cardiomyopathy 49%, and ejection fraction 35% ± 9%. QRS axis at baseline was normal in 24%, left axis 63%, right axis 13%. LBBAP threshold and R-wave amplitudes were 0.8 ± 0.3 V @ 0.5 ms and 10 ± 9 mV at implant and remained stable during mean follow-up of 13 ± 8 months. LBBAP resulted in narrowing of QRS duration (156 ± 20 ms to 150 ± 24 ms (P = .01) with R-wave peak times in V6 of 85 ± 16 ms. LVEF improved from 35% ± 9% to 43% ± 12% (P < .01). Clinical and echocardiographic response was observed in 60% and 61% of patients, respectively. Female sex and reduction in QRS duration with LBBAP were predictive of echocardiographic response and super-response. Conclusion: LBBAP is a feasible alternative to deliver CRT or physiologic ventricular pacing in patients with RBBB, HF, and LV dysfunction.

Conduction System Pacing for Cardiac Resynchronization Therapy.

Although conventional biventricular pacing has been shown to benefit patients with heart failure and conduction system disease, there are limitations to its therapeutic success, resulting in widely variable clinical response. Limitations of conventional biventricular pacing evolve around myocardial scar, fibrosis, and inability to effectively stimulate diseased tissue. Several observational and acute hemodynamic studies have demonstrated improved electrical resynchronization and echocardiographic response with conduction system pacing. This article provides a systematic review of conduction system pacing as a physiologic alternative to conventional CRT, which is currently undergoing rigorous investigation.

Rescue left bundle branch area pacing in coronary venous lead failure or nonresponse to biventricular pacing: Results from International LBBAP Collaborative Study Group.

BACKGROUND: Cardiac resynchronization therapy (CRT) using biventricular pacing (BVP) is effective in patients with heart failure, left bundle branch block (LBBB), and reduced left ventricular function. Left bundle branch area pacing (LBBAP) has been reported as an alternative option for CRT. OBJECTIVE: The purpose of this study was to assess the feasibility and outcomes of LBBAP in patients who failed conventional BVP because of coronary venous (CV) lead complications or who were nonresponders to BVP. METHODS: At 16 international centers, LBBAP was attempted in patients with conventional CRT indication who failed BVP because of CV lead complications or lack of therapeutic response to BVP. Heart failure hospitalization (HFH) and death, echocardiographic outcomes, procedural data, pacing parameters, and lead complications including CV lead failure are reported. RESULTS: LBBAP was successfully performed in 200 patients (CV lead failures 156; nonresponders 44) (age 68 ± 11 years; female 35%; LBBB 55%; right ventricular pacing 23%; ischemic cardiomyopathy 28%; nonischemic cardiomyopathy 63%; left ventricular ejection fraction [LVEF] ≤35% in 80%). Procedural duration was 119.5 ± 59.6 minutes, and fluoroscopy duration was 25.7 ± 18.5 minutes. LBBAP threshold and R-wave amplitudes were 0.68 ± 0.35 V @ 0.45 ms and 10.4 ± 5 mV at implant, respectively, and remained stable during mean follow-up of 12 ± 10.1 months. LBBAP resulted in significant QRS narrowing from 170 ± 28 ms to 139 ± 25 ms (P <.001) with V6 R-wave peak times of 85 ± 17 ms. LVEF improved from 29% ± 10% at baseline to 40% ± 12% (P <.001) during follow-up. The risk of death or HFH was lower in those with CV lead failure than in nonresponders (hazard ratio 0.357; 95% confidence interval 0.168-0.756; P = .007) CONCLUSION: LBBAP is a viable alternative to CRT in patients who failed conventional BVP due to CV lead failure or who were nonresponders.

Left bundle branch-optimized cardiac resynchronization therapy (LOT-CRT): Results from an international LBBAP collaborative study group.

BACKGROUND: Cardiac resynchronization therapy (CRT) based on the conventional biventricular pacing (BiV-CRT) technique sometimes results in broad QRS complex and suboptimal response. OBJECTIVE: We aimed to assess the feasibility and outcomes of CRT based on left bundle branch area pacing (LBBAP, in lieu of the right ventricular lead) combined with coronary venous left ventricular pacing in an international multicenter study. METHODS: LBBAP-optimized CRT (LOT-CRT) was attempted in nonconsecutive patients with CRT indications. Addition of the LBBA (or coronary venous) lead was at the discretion of the implanting physician, who was guided by suboptimal paced QRS complex, and/or on clinical grounds. RESULTS: LOT-CRT was successful in 91 of 112 patients (81%). The baseline characteristics were as follows: mean age 70 ± 11 years, female 22 (20%), left ventricular ejection fraction 28.7% ± 9.8%, left ventricular end-diastolic diameter 62 ± 9 mm, N-terminal pro-B-type natriuretic peptide level 5821 ± 8193 pg/mL, left bundle branch block 47 (42%), nonspecific intraventricular conduction delay 25 (22%), right ventricular pacing 26 (23%), and right bundle branch block 14 (12%). The procedure characteristics were as follows: mean fluoroscopy time 27.3 ± 22 minutes, LBBAP capture threshold 0.8 ± 0.5 V @ 0.5 ms, and R-wave amplitude 10 mV. LOT-CRT resulted in significantly greater narrowing of QRS complex from 182 ± 25 ms at baseline to 144 ± 22 ms (P < .0001) than did BiV-CRT (170 ± 30 ms; P < .0001) and LBBAP (162 ± 23 ms; P < .0001). At follow-up of ≥3 months, the ejection fraction improved to 37% ± 12%, left ventricular end-diastolic diameter decreased to 59 ± 9 mm, N-terminal pro-B-type natriuretic peptide level decreased to 2514 ± 3537 pg/mL, pacing parameters were stable, and clinical improvement was noted in 76% of patients (New York Heart Association class 2.9 vs 1.9). CONCLUSION: LOT-CRT is feasible and safe and provides greater electrical resynchronization as compared with BiV-CRT and could be an alternative, especially when only suboptimal electrical resynchronization is obtained with BiV-CRT. Randomized controlled trials comparing LOT-CRT and BiV-CRT are needed.

Immuno-Electrophysiological Mechanisms of Functional Electrical Connections Between Recipient and Donor Heart in Patients With Orthotopic Heart Transplantation Presenting With Atrial Arrhythmias.

[Figure: see text].

Left Bundle Branch Area Pacing for Cardiac Resynchronization Therapy: Results From the International LBBAP Collaborative Study Group.

OBJECTIVES: The aim of this study was to assess the feasibility and outcomes of left bundle branch area pacing (LBBAP) in patients eligible for cardiac resynchronization therapy (CRT) in an international, multicenter, collaborative study. BACKGROUND: CRT using biventricular pacing is effective in patients with heart failure and left bundle branch block (LBBB). LBBAP has been reported as an alternative option for CRT. METHODS: LBBAP was attempted in patients with left ventricular ejection fraction (LVEF) <50% and indications for CRT or pacing. Procedural outcomes, left bundle branch capture, New York Heart Association functional class, heart failure hospitalization, echocardiographic data, and lead complications were recorded. Clinical (no heart failure hospitalization and improvement in New York Heart Association functional class) and echocardiographic responses (≥5% improvement in LVEF) were assessed. RESULTS: LBBAP was attempted in 325 patients, and CRT was successfully achieved in 277 (85%) (mean age 71 ± 12 years, 35% women, ischemic cardiomyopathy in 44%). QRS configuration at baseline was LBBB in 39% and non-LBBB in 46%. Procedure and fluoroscopy duration were 105 ± 54 and 19 ± 15 min, respectively. LBBAP threshold and R-wave amplitudes were 0.6 ± 0.3 V at 0.5 ms and 10.6 ± 6 mV at implantation and remained stable during mean follow-up of 6 ± 5 months. LBBAP resulted in significant QRS narrowing from 152 ± 32 to 137 ± 22 ms (p < 0.01). LVEF improved from 33 ± 10% to 44 ± 11% (p < 0.01). Clinical and echocardiographic responses were observed in 72% and 73% of patients, respectively. Baseline LBBB (odds ratio: 3.96; 95% confidence interval: 1.64 to 9.26; p < 0.01) and left ventricular end-diastolic diameter (odds ratio: 0.62; 95% confidence interval: 0.49 to 0.79; p < 0.01) were independent predictors of echocardiographic response. CONCLUSIONS: LBBAP is feasible and safe and provides an alternative option for CRT. LBBAP provides remarkably low and stable pacing thresholds and was associated with improved clinical and echocardiographic outcomes.

The evolution of cardiac resynchronization therapy and an introduction to conduction system pacing: a conceptual review.

In chronic systolic heart failure and conduction system disease, cardiac resynchronization therapy (CRT) is the only known non-pharmacologic heart failure therapy that improves cardiac function, functional capacity, and survival while decreasing cardiac workload and hospitalization rates. While conventional bi-ventricular pacing has been shown to benefit patients with heart failure and conduction system disease, there are limitations to its therapeutic success, resulting in widely variable clinical response. Limitations of conventional CRT evolve around myocardial scar, fibrosis, and inability to effectively simulate diseased tissue. Studies have shown endocardial stimulation in closer proximity to the specialized conduction system is more effective when compared with epicardial stimulation. Several observational and acute haemodynamic studies have demonstrated improved electrical resynchronization and echocardiographic response with conduction system pacing (CSP). Our objective is to provide a systematic review of the evolution of CRT, and an introduction to CSP as an intriguing, though experimental physiologic alternative to conventional CRT.

In vitro and in vivo cardiac toxicity of flavored electronic nicotine delivery systems.

The usage of flavored electronic nicotine delivery systems (ENDS) is popular, specifically in the teen and young adult age-groups. The possible cardiac toxicity of the flavoring aspect of ENDS is largely unknown. Vaping, a form of electronic nicotine delivery, uses "e-liquid" to generate "e-vapor," an aerosolized mixture of nicotine and/or flavors. We report our investigation into the cardiotoxic effects of flavored e-liquids. E-vapors containing flavoring aldehydes such as vanillin and cinnamaldehyde, as indicated by mass spectrometry, were more toxic in HL-1 cardiomyocytes than fruit-flavored e-vapor. Exposure of human induced pluripotent stem cell-derived cardiomyocytes to cinnamaldehyde or vanillin-flavored e-vapor affected the beating frequency and prolonged the field potential duration of these cells more than fruit-flavored e-vapor. In addition, vanillin aldehyde-flavored e-vapor reduced the human ether-à-go-go-related gene (hERG)-encoded potassium current in transfected human embryonic kidney cells. In mice, inhalation exposure to vanillin aldehyde-flavored e-vapor for 10 wk caused increased sympathetic predominance in heart rate variability measurements. In vivo inducible ventricular tachycardia was significantly longer, and in optical mapping, the magnitude of ventricular action potential duration alternans was significantly larger in the vanillin aldehyde-flavored e-vapor-exposed mice than in controls. We conclude that the widely popular flavored ENDS are not harm free, and they have a potential for cardiac harm. More studies are needed to further assess their cardiac safety profile and long-term health effects.NEW & NOTEWORTHY The use of electronic nicotine delivery systems (ENDS) is not harm free. It is not known whether ENDS negatively affect cardiac electrophysiological function. Our study in cell lines and in mice shows that ENDS can compromise cardiac electrophysiology, leading to action potential instability and inducible ventricular arrhythmias. Further investigations are necessary to assess the long-term cardiac safety profile of ENDS products in humans and to better understand how individual components of ENDS affect cardiac toxicity.

The Antimalarial Chloroquine Reduces the Burden of Persistent Atrial Fibrillation.

In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (IK1 and IKACh) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking IK1 and IKACh with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC50 of IK1 and IKACh block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of IK1 and IKACh. We then tested, as a proof of concept, if oral chloroquine administration to a patient with persistent atrial fibrillation can decrease the arrhythmia burden. We also simulated the effects of chloroquine in a 3D model of human atria with persistent atrial fibrillation. In patch clamp the IC50 of IK1 block by chloroquine was similar to that of IKACh. A 14-day regimen of oral chloroquine significantly decreased the burden of persistent atrial fibrillation in a patient. Mathematical simulations of persistent atrial fibrillation in a 3D model of human atria suggested that chloroquine prolonged the action potential duration, leading to failure of reentrant excitation, and the subsequent termination of the arrhythmia. The combined block of IK1 and IKACh can be a targeted therapeutic strategy for persistent atrial fibrillation.