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Introduction: Anterior cruciate ligament (ACL) injury is frequently accompanied by quadriceps muscle atrophy, a process closely linked to mitochondrial health and mitochondria-specific autophagy. However, the temporal progression of key quadricep atrophy-mediating events following ACL injury remains poorly understood. To advance our understanding, we conducted a longitudinal study to elucidate key parameters in quadriceps autophagy and mitophagy. Methods: Long-Evans rats were euthanized at 7, 14, 28, and 56 days after non-invasive ACL injury that was induced via tibial compression overload; controls were not injured. Vastus lateralis muscle was extracted, and subsequent immunoblotting analysis was conducted using primary antibodies targeting key proteins involved in autophagy and mitophagy cellular processes. Results: Our findings demonstrated dynamic changes in autophagy and mitophagy markers in the quadriceps muscle during the recovery period after ACL injury. The early response to the injury was characterized by the induction of autophagy at 14 days (Beclin1), indicating an initial cellular response to the injury. Subsequently, at 14 days we observed increase in the elongation of autophagosomes (Atg4B), suggesting a potential remodeling process. The autophagosome flux was also augmented between 14- and 28 days (LC3-II/LC3-I ratio and p62). Notably, at 56 days, markers associated with the elimination of damaged mitochondria were elevated (PINK1, Parkin, and VDAC1), indicating a possible ongoing cellular repair and restoration process. Conclusion: These data highlight the complexity of muscle recovery after ACL injury and underscore the overlooked but crucial role of autophagy and mitophagy in promoting the recovery process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Noh, Ahn, Davi, Lepley and Kwon.)

Background: Although pulmonary vein isolation (PVI) gaps contribute to recurrence after atrial fibrillation (AF) catheter ablation, the mechanism is unclear. We used realistic computational human AF modeling to explore the AF wave-dynamic changes of PVI with gaps (PVI-gaps)., Methods: We included 40 patients (80% male, 61.0 ± 9.8 years old, 92.5% persistent AF) who underwent AF catheter ablation to develop our realistic computational AF model. We compared the effects of a complete PVI (CPVI) and PVI-gap (2-mm × 4) on the AF wave-dynamics by evaluating the dominant frequency (DF), spatial change of DF, maximal slope of the action potential duration restitution curve (Smax), and AF defragmentation rate (termination or change to atrial tachycardia), and tested the effects of additional virtual interventions and flecainide on ongoing AF with PVI-gaps., Results: Compared with the baseline AF, CPVIs significantly reduced extra-PV DFs ( p  < 0.001), but PVI-gaps did not. COV-DFs were greater after CPVIs than PVI-gaps ( p  < 0.001). Neither CPVIs nor PVI-gaps changed the mean Smax. CPVIs resulted in higher AF defragmentation rates (80%) than PVI-gaps (12.5%, p  < 0.001). In ongoing AF after PVI-gaps, the AF defragmentation rates after a wave-breaking gap ablation, extra-PV DF ablation, or flecainide were 60.0, 34.3, and 25.7%, respectively ( p  = 0.010)., Conclusion: CPVIs effectively reduced the DF, increased its spatial heterogeneity in extra-PV areas, and offered better anti-AF effects than extra-PV DF ablation or additional flecainide in PVI-gap conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jin, Hwang, Lim, Kwon, Park, Yu, Kim, Joung, Lee and Pak.)

Introduction: Despite rigorous rehabilitation aimed at restoring muscle health, anterior cruciate ligament (ACL) injury is often hallmarked by significant long-term quadriceps muscle weakness. Derangements in mitochondrial function are a common feature of various atrophying conditions, yet it is unclear to what extent mitochondria are involved in the detrimental sequela of quadriceps dysfunction after ACL injury. Using a preclinical, non-invasive ACL injury rodent model, our objective was to explore the direct effect of an isolated ACL injury on mitochondrial function, muscle atrophy, and muscle phenotypic transitions., Methods: A total of 40 male and female, Long Evans rats (16-week-old) were exposed to non-invasive ACL injury, while 8 additional rats served as controls. Rats were euthanized at 3, 7, 14, 28, and 56 days after ACL injury, and vastus lateralis muscles were extracted to measure the mitochondrial respiratory control ratio (RCR; state 3 respiration/state 4 respiration), mitochondrial reactive oxygen species (ROS) production, fiber cross sectional area (CSA), and fiber phenotyping. Alterations in mitochondrial function and ROS production were detected using two-way (sex:group) analyses of variance. To determine if mitochondrial characteristics were related to fiber atrophy, individual linear mixed effect models were run by sex., Results: Mitochondria-derived ROS increased from days 7 to 56 after ACL injury (30-100%, P < 0.05), concomitant with a twofold reduction in RCR ( P < 0.05). Post-injury, male rats displayed decreases in fiber CSA (days 7, 14, 56; P < 0.05), loss of IIa fibers (day 7; P < 0.05), and an increase in IIb fibers (day 7; P < 0.05), while females displayed no changes in CSA or phenotyping ( P > 0.05). Males displayed a positive relationship between state 3 respiration and CSA at days 14 and 56 ( P < 0.05), while females only displayed a similar trend at day 14 ( P = 0.05)., Conclusion: Long-lasting impairments in quadriceps mitochondrial health are present after ACL injury and play a key role in the dysregulation of quadriceps muscle size and composition. Our preclinical data indicate that using mitoprotective therapies may be a potential therapeutic strategy to mitigate alterations in muscle size and characteristic after ACL injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Davi, Ahn, White, Butterfield, Kosmac, Kwon and Lepley.)

Background: The ZFHX3 gene (16q22) is the second most highly associated gene with atrial fibrillation (AF) and is related to inflammation and fibrosis. We hypothesized that ZFHX3 is associated with extra-pulmonary vein (PV) triggers, left atrial (LA) structural remodeling, and poor rhythm outcomes of AF catheter ablation (AFCA). Methods: We included 1,782 patients who underwent a de novo AFCA (73.5% male, 59.4 ± 10.8 years old, 65.9% paroxysmal AF) and genome-wide association study and divided them into discovery ( n = 891) and replication cohorts ( n = 891). All included patients underwent isoproterenol provocation tests and LA voltage mapping. We analyzed the ZFHX3 , extra-PV trigger-related factors, and rhythm outcomes. Result: Among 14 single-nucleotide polymorphisms (SNPs) of ZFHX3 , rs13336412, rs61208973, rs2106259, rs12927436, and rs1858801 were associated with extra-PV triggers. In the overall patient group, extra-PV triggers were independently associated with the ZFHX3 polygenic risk score (PRS) (OR 1.65 [1.22-2.22], p = 0.001, model 1) and a low LA voltage (OR 0.74 [0.56-0.97], p = 0.029, model 2). During 49.9 ± 40.3 months of follow-up, clinical recurrence of AF was significantly higher in patients with extra-PV triggers (Log-rank p < 0.001, HR 1.89 [1.49-2.39], p < 0.001, model 1), large LA dimensions (Log-rank p < 0.001, HR 1.03 [1.01-1.05], p = 0.002, model 2), and low LA voltages (Log-rank p < 0.001, HR 0.73 [0.61-0.86], p < 0.001, model 2) but not the ZFHX3 PRS (Log-rank p = 0.819). Conclusion: The extra-PV triggers had significant associations with both ZFHX3 genetic polymorphisms and acquired LA remodeling. Although extra-PV triggers were an independent predictor of AF recurrence after AFCA, the studied AF risk SNPs intronic in ZFHX3 were not associated with AF recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hwang, Kwon, Hong, Yang, Park, Yu, Kim, Uhm, Joung, Lee and Pak.)

Background: We previously reported that a computational modeling-guided antiarrhythmic drug (AAD) test was feasible for evaluating multiple AADs in patients with atrial fibrillation (AF). We explored the anti-AF mechanisms of AADs and spatial change in the AF wave-dynamics by a realistic computational model. Methods: We used realistic computational modeling of 25 AF patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal AF) reflecting the anatomy, histology, and electrophysiology of the left atrium (LA) to characterize the effects of five AADs (amiodarone, sotalol, dronedarone, flecainide, and propafenone). We evaluated the spatial change in the AF wave-dynamics by measuring the mean dominant frequency (DF) and its coefficient of variation [dominant frequency-coefficient of variation (DF-COV)] in 10 segments of the LA. The mean DF and DF-COV were compared according to the pulmonary vein (PV) vs. extra-PV, maximal slope of the restitution curves (Smax), and defragmentation of AF. Results: The mean DF decreased after the administration of AADs in the dose dependent manner ( p < 0.001). Under AADs, the DF was significantly lower ( p < 0.001) and COV-DF higher ( p = 0.003) in the PV than extra-PV region. The mean DF was significantly lower at a high Smax (≥1.4) than a lower Smax condition under AADs. During the episodes of AF defragmentation, the mean DF was lower ( p < 0.001), but the COV-DF was higher ( p < 0.001) than that in those without defragmentation. Conclusions: The DF reduction with AADs is predominant in the PVs and during a high Smax condition and causes AF termination or defragmentation during a lower DF and spatially unstable (higher DF-COV) condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hwang, Park, Kwon, Lim, Lee, Jin, Yu, Kim, Joung and Pak.)

Catheter ablation is the most effective rhythm control method for patients with atrial fibrillation (AF); however, it inevitably causes atrial tissue damage. We previously reported that AF catheter ablation (AFCA) increases left atrial (LA) pressure without changes in symptom scores. We hypothesized that extensive LA ablation increased the risk of stiff LA physiology. We included 1,720 patients (69.1% male, 60.0 [53.0-68.0] years old, 66.2% with paroxysmal AF) who underwent de novo AFCA and echocardiography before and 1-year after the procedure. Stiff LA physiology was defined, when the amount of the estimated pulmonary arterial pressure increase between the pre-procedural and the 1-year post-procedural follow-up echocardiography was >10 mmHg and when right ventricular systolic pressure (RVSP) was >35 mmHg at 1-year follow-up echocardiography. The failed rhythm control within 1 year was defined as recurrent AF despite using anti-arrhythmic drugs or cardioversion within a year of AFCA. We explored the incidence and risk factors for stiff LA physiology and the rhythm outcome of AFCA. Among the 1,720 patients, 64 (3.7%) had stiff LA physiology 1 year after AFCA. Stiff LA physiology was independently associated with diabetes (odds ratio [OR], 2.36 [95% CI, 1.14-4.87], p = 0.020), the ratio of the peak mitral flow velocity of the early rapid filling to the early diastolic velocity of the mitral annulus (E/Em; OR, 1.04 [95% CI, 1.00-1.10], p = 0.049), LA pulse pressure (Model 2: OR, 1.05 [95% CI, 1.00-1.11], p = 0.049), low LA voltage (OR, 0.36 [95% CI, 0.18-0.74], p = 0.005), empirical extra-pulmonary vein (PV) LA ablation (OR, 2.60 [95% CI, 1.17-5.74], p = 0.018), and radiofrequency (RF) ablation duration (Model 2: OR, 1.02 [95% CI, 1.01-1.03], p = 0.003). Although the incidence of post-AFCA stiff LA physiology was 3.7% and most of the cases were subclinical, the empirical extra-PV ablation was associated with this undesirable condition. In addition, patients who had low mean LA voltage before AFCA could be susceptible to stiff LA physiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Kwon, Yu, Kim, Uhm, Joung, Lee and Pak.)

Atrial stretch may contribute to the mechanism of atrial fibrillation (AF) recurrence after atrial fibrillation catheter ablation (AFCA). We tested whether the left atrial (LA) wall stress (LAW-stress [ measured ] ) could be predicted by artificial intelligence (AI) using non-invasive parameters (LAW-stress [AI] ) and whether rhythm outcome after AFCA could be predicted by LAW-stress [AI] in an independent cohort. Cohort 1 included 2223 patients, and cohort 2 included 658 patients who underwent AFCA. LAW-stress [ measured ] was calculated using the Law of Laplace using LA diameter by echocardiography, peak LA pressure measured during procedure, and LA wall thickness measured by customized software (AMBER) using computed tomography. The highest quartile (Q4) LAW-stress [ measured ] was predicted and validated by AI using non-invasive clinical parameters, including non-paroxysmal type of AF, age, presence of hypertension, diabetes, vascular disease, and heart failure, left ventricular ejection fraction, and the ratio of the peak mitral flow velocity of the early rapid filling to the early diastolic velocity of the mitral annulus (E/Em). We tested the AF/atrial tachycardia recurrence 3 months after the blanking period after AFCA using the LAW-stress [ measured ] and LAW-stress [AI] in cohort 1 and LAW-stress [AI] in cohort 2. LAW-stress [ measured ] was independently associated with non-paroxysmal AF ( p < 0.001), diabetes ( p = 0.012), vascular disease ( p = 0.002), body mass index ( p < 0.001), E/Em ( p < 0.001), and mean LA voltage measured by electrogram voltage mapping ( p < 0.001). The best-performing AI model had acceptable prediction power for predicting Q4-LAW-stress [ measured ] (area under the receiver operating characteristic curve 0.734). During 26.0 (12.0-52.0) months of follow-up, AF recurrence was significantly higher in the Q4-LAW-stress [ measured ] group [log-rank p = 0.001, hazard ratio 2.43 (1.21-4.90), p = 0.013] and Q4-LAW-stress [AI] group (log-rank p = 0.039) in cohort 1. In cohort 2, the Q4-LAW-stress [AI] group consistently showed worse rhythm outcomes (log-rank p < 0.001). A higher LAW-stress was associated with poorer rhythm outcomes after AFCA. AI was able to predict this complex but useful prognostic parameter using non-invasive parameters with moderate accuracy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Kwon, Shim, Lee, Han, Yu, Kim, Uhm, Joung, Lee, Kim and Pak.)

Background: The efficacy of antiarrhythmic drugs (AAD) can vary in patients with atrial fibrillation (AF), and the PITX2 gene affects the responsiveness of AADs. We explored the virtual AAD (V-AAD) responses between wild-type and PITX2 +/- -deficient AF conditions by realistic in silico AF modeling. Methods: We tested the V-AADs in AF modeling integrated with patients' 3D-computed tomography and 3D-electroanatomical mapping, acquired in 25 patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type). The ion currents for the PITX2 +/- deficiency and each AAD (amiodarone, sotalol, dronedarone, flecainide, and propafenone) were defined based on previous publications. Results: We compared the wild-type and PITX2 +/- deficiency in terms of the action potential duration (APD 90 ), conduction velocity (CV), maximal slope of restitution (Smax), and wave-dynamic parameters, such as the dominant frequency (DF), phase singularities (PS), and AF termination rates according to the V-AADs. The PITX2 +/- -deficient model exhibited a shorter APD 90 ( p < 0.001), a lower Smax ( p < 0.001), mean DF ( p = 0.012), PS number ( p < 0.001), and a longer AF cycle length (AFCL, p = 0.011). Five V-AADs changed the electrophysiology in a dose-dependent manner. AAD-induced AFCL lengthening ( p < 0.001) and reductions in the CV ( p = 0.033), peak DF ( p < 0.001), and PS number ( p < 0.001) were more significant in PITX2 +/- -deficient than wild-type AF. PITX2 +/- -deficient AF was easier to terminate with class IC AADs than the wild-type AF ( p = 0.018). Conclusions: The computational modeling-guided AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF. AF wave-dynamic and electrophysiological characteristics are different among the PITX2 -deficient and the wild-type genotype models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hwang, Park, Kwon, Lim, Hong, Kim, Yu, Kim, Uhm, Joung, Lee and Pak.)