Electrophysiological Studies Research Articles

Electrophysiological Phenotype-Genotype Study of Sustained Monomorphic Ventricular Tachycardia in Inherited, High Arrhythmic Risk, Left Ventricular Cardiomyopathy.

Among inherited cardiomyopathies involving the left ventricle, whether dilated or not, certain genotypes carry a well-established arrhythmic risk, notably manifested as sustained monomorphic ventricular tachycardia (SMVT). Nonetheless, the precise localization and electrophysiological profile of this substrate remain undisclosed across different genotypes. Patients diagnosed with cardiomyopathy and left ventricle involvement due to high-risk genetic variants and SMVT treated by electrophysiological study were recruited from 18 European/US centers. Electrophysiological study, imaging, and outcomes data after ablation were assessed in relation to genotype. Seventy-one patients were included (49.6 Q1-Q3 [40-60] years, 76% men). They were divided into 4 groups according to the affected protein: desmosomal (DSP, PKP2, DSG2, and DSC2), nuclear membrane (LMNA and TMEM43), cytoskeleton (FLNC and DES), and sarcoplasmic reticulum (PLN). Desmosomal genes, TMEM43, and PLN were associated with biventricular disease, while variants in LMNA and cytoskeleton genes had predominant left ventricle involvement (P=0.001). The location of the clinical-SMVT substrate was significantly different based on genotype (P=0.005). DSP and cytoskeleton genes presented SMVTs with right bundle branch block morphology, which origin was identified in the inferolateral segments of the left ventricle. The other desmosomal genes (PKP2 and DSG2), along with TMEM43, showed SMVTs with left bundle branch block morphology and predominantly right ventricular substrate. In contrast, LMNA substrate was mainly observed in the interventricular septum. During a median of 26 Q1-Q3 (10.6-65) months, 27% of patients experienced recurrences of clinical SMVT with differences between genotypes (log-rank 0.016). Nuclear membrane genes demonstrated the highest recurrence rate compared with desmosomal genes (hazard ratio, 4.56 [95% CI, 1.5-13.8]). The anatomic substrate of SMVTs shows a strong correlation with the underlying genotype, electrocardiographic morphology, and recurrence rate. Particularly, patients with nuclear membrane gene variants have a significantly higher recurrence rate compared with those with desmosomal gene variants.

Electrophysiological predictors of susceptible atrial substrate for the onset and recurrence of atrial fibrillation.

The atrial electroanatomic substrate is an essential component in the pathogenesis of atrial fibrillation (AF). However, the electrophysiological markers of susceptible atria for AF are not well-characterized. This study aimed to assess atrial conduction indices on surface electrocardiogram (ECG) and intracardiac electrogram (EGM) as predictors of initiation and recurrence of AF after successful ablation. We studied all consecutive patients who underwent electrophysiological study and catheter ablation for AF (study group) or atrioventricular nodal reentrant tachycardia (AVNRT) (control group) from 2013 to 2018. Atrial conduction indices were measured on ECG and EGM during the electrophysiology study. Clinical data was obtained from the medical record. A total of 387 patients with AF (mean age 63years, 31% female) were studied and compared to 94 patents in control group. The initiation of AF was associated with significant prolongation of atrial conduction indices on ECG and EGM (p < 0.05). During a mean follow up of 5 ± 2years, recurrence of AF (48%) after successful ablation occurred in patients with prolonged P wave duration, left atrial (LA) conduction interval, proximal to distal coronary sinus (pCS-dCS) interval, and P wave to dCS interval (p < 0.05). Machine learning modeling determined that pCS-dCS interval, QRS duration, and LA duration in leads V1 and II are most impactful conduction indices in association with AF recurrence. Prolonged atrial conduction intervals, particularly LA (pCS-dCS), indicate susceptible substrate for the onset and the recurrence of AF after ablation. LA conduction indices can facilitate early detection and management of AF.

Co-occurrence of Charcot-Marie-Tooth disease type 1 and glomerulosclerosis in a patient with a de novo INF2 variant

BackgroundRenal disease is associated with Charcot-Marie-Tooth disease (CMT), a common inherited neurological disorder. Three forms of CMT have been identified: CMT1 of the demyelinating type, CMT2 of the axonal defect type, and intermediate type (Int-CMT). INF2 is an important target for variants that cause the complex symptoms of focal segmental glomerulosclerosis (FSGS) and CMT.Case presentationWe report the case of a 13-year-old female Chinese patient (born in 2011) with a rare co-occurrence of CMT1 and glomerulosclerosis (GS) (CMT1-GS). The patient presented with slowly progressive gait disorder with unsteadiness during walking, pes cavus, and kyphoscoliosis since the age of 1 year. Electrophysiological studies and brain magnetic resonance imaging revealed demyelinating features consistent with CMT1. At 12 years of age, she was hospitalised for hypertension and dizziness; her serum albumin was 27.9 g/L, serum creatinine was 87 μmol/L, estimated glomerular filtration rate was 88.6 mL/min, and 24-h urine protein was 4.95 g. A renal biopsy showed glomerulosclerosis. Renal function deteriorated further during the follow-up period, and she received a kidney transplant at the age of 13. Whole-exome sequencing identified a de novo heterozygous c.326T > G (p.Met109Arg) variant in exon 2 of INF2. The variant was classified as “pathogenic” according to the American College of Medical Genetics and Genomics criteria.ConclusionsWe describe a rare clinical phenotype of CMT1-GS associated with a de novo variant of INF2. Our findings expand the phenotypic and genotypic spectrums of INF2-associated disorders.

Microglia-Impaired Phagocytosis Contributes to the Epileptogenesis in a Mouse Model of Dravet Syndrome

Dravet syndrome (DS) is a genetic disorder caused by a deficit in the Nav1.1 channel, leading to drug-resistant epilepsy. The Nav1.1 channel plays a crucial role in microglial cell activation, and microglia are recognized as key mediators of seizures. In this study, we explored the role of microglia in DS-related epileptogenesis using a knock-in mouse model (Scn1aE1099X/+) that mimics a subset of DS patients. In these DS mice, we observed a significant downregulation of the Nav1.1 channel in microglia. This channel deficit led microglia to adopt a pro-inflammatory state in their quiescent phase. In the LPS-activated state, microglia predominantly exhibited an intermediate morphology rather than the expected fully activated form. The reduced expression of pro-inflammatory cytokines was detected in microglia following treatment with LPS. Notably, we found a significant decrease in the phagocytic ability of microglia in DS mice. Electrophysiological studies revealed an increased immature synaptic activity in the dentate gyrus in DS mice. The impaired microglial phagocytosis of damaged cells, combined with reduced cytokine secretion, may result in an excess of immature synaptic connections, neuronal hyperexcitation, and the formation of abnormal neural circuits in the hippocampus of Scn1aE1099X/+ mice. These changes could potentially contribute to mechanisms relevant to epileptogenesis in DS.

Design and In Vivo Testing of an Anatomic 3D-Printed Peripheral Nerve Conduit in a Rat Sciatic Nerve Model.

Background: Three-dimensional (3D) printer technology has seen a surge in use in medicine, particularly in orthopedics. A recent area of research is its use in peripheral nerve repair, which often requires a graft or conduit to bridge segmental defects. Currently, nerve gaps are bridged using autografts, allografts, or synthetic conduits. Purpose: We sought to improve upon the current design of simple hollow, cylindrical conduits that often result in poor nerve regeneration. Previous attempts were made at reducing axonal dispersion with the use of multichanneled conduits. To our knowledge, none has attempted to mimic and test the anatomical topography of the nerve. Methods: Using serial histology sections, 3D reconstruction software, and computer-aided design, a scaffold was created based on the fascicular topography of a rat sciatic nerve. A 3D printer produced both cylindrical conduits and topography-based scaffolds. These were implanted in 12 Lewis rats: 6 rats with the topographical scaffold and 6 rats with the cylindrical conduit. Each rodent's uninjured contralateral limb was used as a control for comparison of functional and histologic outcomes. Walking track analysis was performed, and the Sciatic Functional Index (SFI) was calculated with the Image J software. After 6 weeks, rats were sacrificed and analyses performed on the regenerated nerve tissue. Primary outcomes measured included nerve (fiber) density, nerve fiber width, total number of nerve fibers, G-ratio (ratio of axon width to total fiber width), and percent debris. Secondary outcomes measured included electrophysiology studies of electromyography (EMG) latency and EMG amplitude and isometric force output by the gastrocnemius and tibialis anterior. Results: There were no differences observed between the cylindrical conduit and topographical scaffold in terms of histological outcomes, muscle force, EMG, or SFI. Conclusion: This study of regeneration of the sciatic nerve in a rat model suggests the feasibility of 3D-printed topographical scaffolds. More research is required to quantify the functional outcomes of this technology for peripheral nerve regeneration.

Impact of growth on electrophysiological properties of ventricular pre-excitation in paediatric athletes.

Risk stratification is recommended for patients with ventricular pre-excitation, particularly when sports eligibility is required. Few studies have examined the changes in the electrophysiological properties of the accessory pathway during growth. This study investigates the evolution of electrophysiological properties of the ventricular pre-excitation in young athletes referred for sports eligibility. Between January 2011 and July 2022, 44 paediatric patients (32 males; mean age, 10 ± 2.42) with ventricular pre-excitation underwent an electrophysiological study, both at rest and during adrenergic stress at two different times (T0 and T1) within a minimal interval of 2 years. Transcatheter ablation was not performed between the two electrophysiological studies. Electrophysiological data were collected and compared. Electrophysiological study under basal conditions showed a significant decrease in the anterograde accessory pathway effective refractory period and 1:1 conduction over the accessory pathway from T0 to T1. The shortest pre-excited R-R interval during atrial fibrillation did not significantly change at the basal condition; however, it decreased during the stress test. Furthermore, six patients (13.6%) changed the risk profile of their accessory pathway: two "high-risk" patients at T0 became "low-risk" and four "low-risk" patients became "high-risk" at T1. Atrioventricular re-entry tachycardia inducibility did not differ significantly between the two electrophysiological studies. This study highlights the importance of repeating electrophysiological study (transesophageal or intracardiac) in paediatric athletes with ventricular pre-excitation because significant and clinically relevant changes in the conduction and refractoriness of accessory pathway can occur. This could influence risk stratification for sports eligibility and the correct indication and timing for accessory pathway ablation.

Design, Synthesis, and Insecticidal Activity of Novel meta-Diamide Compounds Bearing a Phthalimide as a Potential GABA Receptor Antagonist.

In pursuit of potent and environmentally benign insecticides targeting the γ-aminobutyric acid (GABA) receptor, a series of novel meta-diamide compounds bearing a phthalimide were rationally designed and synthesized. Bioassay studies revealed that most of the target compounds exhibited promising larvicidal activity against Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). Notably, the most active compound N15 displayed exceptional potency with LC50 values of 3.82 and 3.42 mg·L-1 against M. separata and P. xylostella, respectively. Electrophysiological studies using Xenopus oocytes confirmed that compound N15 exerted its insecticidal activity by targeting the GABA receptors.

Functional block in the initiation and maintenance of common flutter: detailed electrophysiological study and electro-anatomical mapping.

The precise pathophysiology of common atrial flutter remains imperfectly known. The mechanisms of arrhythmia initiation and the role of areas of slow conducting myocardium and functional block are still debated topics. We conducted a detailed electrophysiological study of a patient to illustrate and refine these concepts. Prior to CTI ablation, electrophysiological study and electro-anatomical mapping were performed, focusing on initiation and maintenance mechanisms of the arrhythmia. The initiation of common atrial flutter takes place on the septal aspect of the cavo-tricuspid isthmus where functional unidirectional conduction block occurs. The direction of activation is therefore frequently counter-clockwise, and the arrhythmia stabilizes around the vena cavas and sinus venosus/crista terminalis region. No conduction slowing is present. Common atrial flutter initiates when functional unidirectional conduction block occurs on the septal cavotricuspid isthmus. Its rotation is limited by anatomical and functional boundaries.

Incomplete ablation as a mechanism of atrial fibrillation recurrence and atrial tachycardia development after maze procedure

ObjectiveAtrial tachyarrhythmias are the most frequent complication after the maze procedure. We examined the mechanism of atrial tachyarrhythmias in association with the ablation energy and technique used at each lesion and by the findings of postoperative electrophysiological study. MethodsFour-hundred fifty-three patients who underwent the maze procedure with biatrial incisions and bilateral pulmonary vein (PV) isolation were examined for the incidence and mechanism of recurrence of atrial fibrillation (AF) and development of atrial tachycardia (AT). PV isolation was performed by radiofrequency (RF) ablation, cryothermia, or cut-and-sew technique. The atrioventricular isthmi and the coronary sinus (CS) were ablated by RF, cryothermia, or a combination of these. ResultsOf 443 patients who survived surgery (98%), 54 patients (12.2%) had recurrent AF and 36 patients (8.1%) developed AT during the median of 28 months (interquartile range, 3-75) postoperatively. Multivariate logistic regression analysis showed preoperative left atrial dimension and nonperformance of intraoperative PV pacing were the independent predictors for AF recurrence. Electrophysiologic study in patients with AT demonstrated incomplete ablation in 24 patients (67%), most frequently at the CS in 16 patients (67%), and non-PV focal activations in 16 patients (44%). Preoperative New York Heart Association functional class of 1 and nonperformance of additional epicardial ablation of the CS were the independent predictors for postoperative AT development. ConclusionsIncomplete ablation is a cause of AF recurrence and AT development after the maze procedure. Intraoperative PV pacing prevents AF recurrence and additional epicardial CS ablation prevents AT development.

Mitigating ibrutinib-induced ventricular arrhythmia and cardiac dysfunction with metformin.

Ibrutinib is a first-line drug that targets Bruton's tyrosine kinase for the treatment of B cell cancer. However, cardiotoxicity induced by ibrutinib is a major side effect that limits its clinical use. This study aimed to investigate the mechanism of ibrutinib-induced cardiotoxicity and evaluate the protective role of metformin. The study utilized male C57BL/6 J mice, which were administered ibrutinib at a dosage of 30 mg/kg/day via oral gavage for 4 weeks to induce cardiotoxicity. Metformin was administered orally at 200 mg/kg/day for 5 weeks, starting 1 week before ibrutinib treatment. Cardiac function was assessed using echocardiography and electrophysiological studies, including surface electrocardiography and epicardial electrical mapping. Blood pressure was measured using a tail-cuff system. Western blot analysis was conducted to evaluate the activity of the PI3K-AKT and AMPK pathways, along with apoptosis markers. C57BL/6 J mice were treated with ibrutinib for 4 weeks to assess its effect on cardiac function. We observed that ibrutinib induced ventricular arrhythmia and abnormal conduction while reducing the left ventricular ejection fraction. Furthermore, pretreatment with metformin reversed ibrutinib-induced cardiotoxicity. Mechanistically, ibrutinib decreased PI3K-AKT activity, resulting in apoptosis of cardiomyocytes. Administration of metformin upregulated AMPK and PI3K-AKT activity, which contributed to the improvement of cardiac function. The study concludes that metformin effectively mitigates ibrutinib-induced cardiotoxicity, including ventricular arrhythmia and cardiac dysfunction, by enhancing AMPK and PI3K-AKT pathway activity. These findings suggest that metformin holds potential as a therapeutic strategy to protect against the adverse cardiac effects associated with ibrutinib treatment, offering a promising approach for improving the cardiovascular safety of patients undergoing therapy for B cell cancers.

Wearable Patch ECG monitors and transesophageal electrophysiological study for diagnosing palpitations of unknown origin.

To analyze the application value of wearable adhesive Patch ECG monitors combined with transesophageal electrophysiological study (TEPS) in the diagnosis of palpitations of unknown origin. This was a retrospective study of patients with suspected arrhythmia who were admitted to Henan Provincial People's Hospital between October 2021 and July 2023 due to recurrent paroxysmal palpitations of unknown origin, with or without accompanying symptoms such as dizziness, amaurosis, and syncope. All patients underwent TEPS. Those who did not exhibit arrhythmia during the TEPS were selected for Patch ECG monitoring, which lasted several weeks (depending on the duration of symptom capture). The results of TEPS, Patch ECG monitors, and clinical diagnoses were observed and recorded. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value (NPV) for diagnosing palpitations of unknown origins was analyzed based on clinical diagnostic outcomes for (1) TEPS alone, (2) Patch ECG monitoring in patients with negative TEPS results, and (3) the combination of both methods. A total of 569 patients were included in this study. The TEPS results exhibited that 227 of the 569 patients did not detect arrhythmias and 342 detected arrhythmias. Of the 569 patients, 102 refused to undergo Patch ECG monitors, and 467 patients completed the entire study process. Among them, 379 cases (66.61%) were clinically diagnosed as arrhythmias. TEPS shows good performance in most evaluation indices except NPV (69.60%, 95% CI, 61.54%-77.66%). The combined diagnosis was strongly consistent with clinical diagnosis. The accuracy, sensitivity, and NPV of TEPS combined with Patch ECG monitors in the diagnosis of palpitations of unknown origin were significantly higher than those of TEPS alone. Wearable adhesive patch ECG monitors combined with TEPS can enhance the diagnostic efficiency of palpitations of unknown origin.

Abstract 4125701: Race and Ethnicity Are Associated with Diagnosis and Management of Wolff-Parkinson-White Pattern in Children

Background: Racial and ethnic disparities have been reported in catheter ablation in adults. There are limited data on the impact of race/ethnicity on the diagnosis and management of children with Wolff-Parkinson-White pattern (WPW). Hypothesis: Diagnosis of WPW by electrocardiogram (ECG) and risk stratification by exercise stress test (EST) and electrophysiology study (EPS) will differ by race/ethnicity in children. Methods: We performed a retrospective cohort study of patients 0-21 years old, excluding those with congenital heart disease, at a children’s hospital from 1991-2021. The primary exposure was race/ethnicity. Outcomes were 1) diagnosis of WPW on ECG, 2) undergoing EST, and 3) undergoing EPS. Likelihood and time to outcome were assessed with multivariable logistic regression adjusted for birth year and Cox regression, respectively. Results: The cohort consisted of 1,638,746 patients (White 53.0%, Black 21.0%, Hispanic 6.8%, Asian 4.2%, Multi-racial 2.0%, Other 11.0%, and Missing 1.7%). WPW was diagnosed in 898 patients (0.05%). After adjusting for birth year, Asian, Black, and Other race were associated with lower odds of WPW diagnosis compared to White patients (OR 0.57, 0.66, 0.70; p≤0.01). There was no association between race and age at first diagnosis (p=0.2). A total of 616 WPW patients (69%) underwent EST. Compared with White patients, Asian, Hispanic, and Other race were less likely to undergo EST (OR 0.39, 0.59, 0.62; p≤0.04), and those who did had their EST at later ages (HR 0.59, 0.65, 0.46; p≤0.04). A total of 739 WPW patients (82%) underwent EPS. Compared with White patients, Black, Hispanic, and Other race were less likely to undergo EPS (OR 0.44, 0.53, 0.59; p≤0.02), and those who did had their EPS at later ages (HR 0.60, 0.63, 0.66; p≤0.004). Conclusion: This analysis found that non-White racial and ethnic groups are less likely to be diagnosed with WPW. This may reflect differences in WPW prevalence by race/ethnicity, but differential access to ECG cannot be ruled out. Among WPW patients, however, Asian and Hispanic patients are approximately half as likely to undergo EST, while Black and Hispanic patients are approximately half as likely to undergo EPS, compared to White patients.

Abstract 4133324: Socioeconomic status, race, and ethnicity in management of pediatric SVT

Introduction: Electrophysiology study and ablation (EPS) is often the preferred approach to management of supraventricular tachycardia (SVT) and/or ventricular pre-excitation (WPW) in older children/adolescents. There are inequities in arrhythmia management in adults, and in other areas of pediatric cardiology, but little is known about disparities in management of SVT in children. Research question: Do racial/ethnic and socioeconomic inequities affect referral for EPS in patients with SVT and/or WPW? Methods: This retrospective observational study utilized the Pediatric Health Information System of 49 children’s hospitals’ administrative data from 2016-2022. We included patients with SVT or WPW seen in the emergency department, admitted for observation, or inpatient. We excluded patients with congenital heart disease. The outcome was having a procedure code for EPS. The childhood opportunity index (COI, scale 1-100) based on zip code was used to measure socioeconomic status (SES). Results: Among 37,818 patients with primary diagnosis of SVT (27620, 73%) or WPW (10198, 27%), 9840 (26%) underwent EPS (Table 1). COI was higher in patients who underwent EPS than those who did not (median 59 [IQR 34,82] vs 57 [IQR 30,81]). In addition, time from initial visit with diagnosis of SVT/WPW to EPS was longer in patients with lower COI (beta= -0.026, p=0.007). Black (21.2%), Hispanic (23.8%), and American Indian (19.8%) patients were less likely to undergo EPS than White (26.5%) and Asian (28.31%) patients and those with other (28.4%) or unknown/missing (35.7%) race (p&lt;0.001, Figure 1). In both subgroups of patients with SVT and WPW, EPS differed by race and COI, and higher COI predicted shorter time to EPS. Conclusions: In this hospital database of pediatric patients, we found disparities in use of EPS for the management of SVT and/or WPW. Patients of minoritized race/ethnicity and lower SES were less likely to undergo EPS.

Induction of supraventricular tachycardias in patients undergoing pulmonary vein isolation for paroxysmal atrial fibrillation is safe and reasonable.

Patients with atrial fibrillation (AF) may experience other supraventricular tachycardias (SVT) that can trigger AF and cause similar symptoms. The aim of this study was to assess the safety and effectivity of inducing SVT in patients undergoing catheter ablation (CA) for AF. In 61 patients with paroxysmal AF undergoing CA between January 2022 and March 2023, an electrophysiological study was performed after pulmonary vein isolation (PVI) to induce SVT. Induced arrhythmias were mapped and ablated. All patients were followed up at 3, 6, and 12 months after the procedure; seven-day ECG Holter monitoring was carried out 6 and 12 months after the procedure. In 24 patients (39%) an SVT was induced during the stimulation protocol. There was no significant difference in procedure time (P=0.408) or fluoroscopy dose (P=0.458) between patients with and without inducible arrhythmia. Further, none of the echocardiographic variables such as left atrial volume index (LAVI) (P=0.936), left ventricular ejection fraction (LVEF) (P=0.586), or right atrial (RA) area (P=0.716), differed significantly in these subgroups. Age was a significant factor in patients with arrhythmia inducibility compared with those without (64.5 ± 7.6 and 58.2 ± 10.5, P=0.04). SVT inducibility after successful PVI was 39%. Ablation of nonclinical arrhythmia is safe and did not prolong the total procedure or fluoroscopy time.

Abstract 4144530: IL-37 promotes resolution of Right Heart Disease-induced inflammation and atrial fibrillation.

INTRODUCTION: Atrial Fibrillation (AF) is the most common cardiac arrhythmia. Hypertension, obesity, diabetes or right heart disease (RHD) are important risk factors for AF. Inflammation stands as a common denominator among most AF risk factors. Studies have shown that patients with AF present high levels of circulating IL-18. Our group recently described that inflammation-resolution may prevent AF in RHD, however, the mechanism remains unclear. To inhibit IL-18-induced inflammation, IL37, a specific antagonist of IL-18-receptor was shown to attenuate cardiac fibrosis in a mice model of myocardial infarction, but little is known about its efficacy to prevent AF. HYPOTHESIS: IL-37 curbs RHD-induced atrial inflammation and AF vulnerability. METHODS: To induce right-sided cardiac hypertrophy and dilation, pulmonary artery banding (PAB) was performed in male and female Wistar rats (250-300g). Sham animals did not receive the ligation. Animals were randomized into four groups: Sham and PAB treated or not with IL37 (100 ng/ml/kg). Electrophysiological studies and echocardiography were performed in vivo before sacrifices at day (D)0, D7, D14 and D21. To analyze the atrial conduction, right atrial (RA) optical mapping was performed on Langendorff-perfused hearts. Histology, western blot, and qPCR were performed to study the expression of proteins and genes involved in atrial inflammation, fibrosis, and electrical remodeling. RESULTS: Twenty-one days after surgery, PAB rats were more vulnerable to AF and developed severe right-sided hypertrophy and dilation compared to Sham. Reliable to clinical evidence, female rats might be more resistant to AF than males. AF was associated with increased RA levels of inflammatory biomarkers including IL18, IL1β, and IL6. IL37 treatment was associated with decreased atrial expression of inflammatory markers. CONCLUSION: IL37 is a potential new therapeutic strategy to reduce atrial inflammation and prevent AF vulnerability in RHD.

Abstract 4139187: Electrophysiological and Mechanical Characterization of Human Ventricular Myocardium from Patients with Primary or Secondary Cardiac Hypertrophy

Left-ventricular hypertrophy (LVH) is an adaptive condition to hemodynamic stress often involving the left ventricle (LV). This pathological condition is associated with clinical complications such as ventricular arrhythmias and diastolic dysfunction, the molecular and cellular mechanisms of which have been poorly investigated in the human heart. We collected myocardial samples from the upper interventricular septum of 132 patients with hypertrophic cardiomyopathy (HCM), 42 patients with aortic stenosis and severe LVH (AoS-LVH) and 12 non-failing non-hypertrophic patients with valve disease (NF-NH), who underwent myectomy operations at our cardiac surgery center. Samples were used to isolate single viable cardiomyocytes from the left ventricle to perform patch-clamp electrophysiological studies and intracellular calcium measurements with fluorescent dyes. Intact trabeculae were also dissected to perform isometric force measurements of electrically-stimulated twitches. Single-cell patch-clamp studies revealed a marked prolongation of action potential duration (APD) in HCM (N=82, mean APD at 90% repolarization=763±252ms at 0.5Hz) and AoS-LVH (N=22, APD90%=579±147ms) samples with respect to NF-NH (N=12, APD90%=447±88ms). In both HCM and AoS-LVH cardiomyocytes, APD prolongation was associated with increased late-Na + current with respect to NF-NH, while L-type Ca 2+ current was enlarged only in HCM samples. Ca 2+ -fluorescence studies revealed markedly slower Ca-transient (CaT) kinetics in myocardial samples from HCM (N=38, mean CaT 50% decay time at 0.5 Hz = 658±179ms) and AoS-LVH patients (N=9, CaT50%= 568±187ms), when compared with NF-NH samples (N=8, CaT50%=283±59ms), paralleled by elevated diastolic [Ca 2+ ]. Twitch force measurements in intact trabeculae revealed prolonged isometric contractions in HCM (N=78, overall twitch duration at 0.5Hz= 730±147ms) and in AoS-LVH patient-samples (N=24, TwD=669±116ms), as compared with NF-NH (N=7, TwD=511±73ms). Force-frequency relationship was flat in pathological samples, while NF-NH trabeculae showed a clear increase in twitch amplitude while increasing pacing rate to 2Hz. Our results suggest that the main features of functional cardiomyocyte remodeling (that is, changes in the expression and/or function of ion-channel and EC-coupling proteins) are qualitatively similar in primary vs. secondary LVH, albeit abnormalities are quantitatively more extensive in HCM samples.

Abstract 4129195: Mechanisms of Healthy Aging in the Prevention of Atrial Fibrillation

Introduction: Atrial Fibrillation (AF) is the most frequent cardiac arrhythmia. AF can lead to severe complications such as myocardial infarction, strokes, and sudden death. With 70% of AF patients aged 65 and older, aging stands as the major risk factor for AF. Our group have recently contributed to reveal that old Wistar rats (20 months) are more susceptible to AF than younger rats (5 months). Interestingly, Lou/c/jall (LOU) rats, a model of healthy aging derived from Wistar rats, can live up to ~35 months old (equivalent to 100 human years). LOU rats have been identified as resistant to age-related diseases such as obesity, hypertension, and neurodegenerative disorders, which are major risk factors for AF. However, the susceptibility of LOU rats to AF have never been reported. Hypothesis: LOU rats may carry specific molecular adaptations conferring resistance to age-related cardiac remodeling and low AF vulnerability. Objectives: Characterize the vulnerability of very old LOU rats (32 months) to AF compared to old Wistar rats (22 months). Determine the atrial inflammatory profile of LOU rats and identify the molecular adaptations that may explain their resistance to AF Methods: Male and Female rats were divided into five groups: LOU and Wistar rats of 5 months (young), 20 months (old), and 32 months (very old: LOU/c rats only). AF inducibility was assessed in vivo using transesophageal electrophysiological study and cardiac structure and function were analyzed by in vivo echocardiography. Atrial electrical conduction was examined using ex vivo optical mapping. Histological analyses were performed to assess atrial fibrosis. Additionally, immunoblot analysis, qPCR, and RNA sequencing were employed to investigate the levels of biomarkers involved in atrial inflammation and fibrosis. Result: Old Wistar rats were more vulnerable to AF than young rats. Old and very old LOU were significantly more resistant to AF than old Wistar animals. LOU rats’ low susceptibility to AF was accompanied with absence of cardiac structural and functional remodeling and low levels of atrial fibrosis compared to old Wistar. Additionally, advanced age did not affect LOU rats’ atrial electrical conduction properties as compared to old Wistar rats. Conclusion: Promotion of healthy aging conditions mimicking LOU rats’ resistance to cardiac remodeling and reduction of atrial fibrosis may contribute to prevent AF in subjects with pathological aging.

Adverse Effects of Aβ1-42 Oligomers: Impaired Contextual Memory and Altered Intrinsic Properties of CA1 Pyramidal Neurons.

Aβ1-42 (amyloid beta) oligomers, the major neurotoxic culprits in Alzheimer's disease, initiate early pathophysiological events, including neuronal hyperactivity, that underlie aberrant network activity and cognitive impairment. Although several synaptotoxic effects have been extensively studied, neuronal hyperexcitability, which may also contribute to cognitive deficits, is not fully understood. Here, we found several adverse effects of in vivo injection of Aβ1-42 oligomers on contextual memory and intrinsic properties of CA1 pyramidal neurons. Male rats underwent behavioral and electrophysiological studies 1 week after microinjections into the dorsal CA1 region, followed by histological analysis. After 1 week, Aβ1-42 oligomers impaired contextual learning without affecting basic physiological functions and triggered training-induced neuronal excitability. Furthermore, riluzole, a persistent sodium current (INaP) blocker, dose-dependently reduced Aβ1-42 oligomer-induced hyperexcitability. Congo red staining, which detects insoluble amyloid deposits, further identified labeling of CA1 pyramidal neurons while immunohistochemistry with lecanemab, which detects soluble Aβ oligomers, revealed immunoreactivity of both pyramidal and non-pyramidal cells in the target area. Therefore, our study suggests that a single injection of Aβ1-42 oligomers resulted in contextual memory deficits along with concomitant neuronal hyperexcitability and amyloid deposition in the CA1 region after 1 week.

Mechanisms of lipid-mediated regulation of the pore-forming activity of antimicrobial agents: studies on planar lipid bilayers

Planar lipid bilayers are unique tools designed for modeling cell membranes and electrophysiological studies of incorporated ion channels. Such model systems are designed to limit the number of components taking part in the functioning of biological membranes in order to characterize in detail the occurring processes under well-controlled experimental conditions. Planar lipid bilayers make it possible to record single events with a measured current of more than a tenth of a picoampere. The relative simplicity of the method, the ability to observe single molecular events, and the high reproducibility of the results obtained determines the unprecedented effectiveness of using planar lipid bilayers to identify key physical and chemical factors responsible for regulating the functioning of ion channels. This review represents an analysis of literature data concerning the mechanisms of lipid-associated regulation of ion channels formed by various antimicrobial agents. The examination allows us to consider the lipids as molecular chaperones that ensure the formation of pores in target membranes by antimicrobials.

The Parkinson's disease DJ-1/PARK7 gene controls peripheral neuronal excitability and painful neuropathy.

Parkinson's disease is a progressive neurodegenerative disease with well-documented motor symptoms as well as less recognised, but significant, non-motor symptoms. These non-motor symptoms include prodromal pain and peripheral neuropathy, the causes of which are unknown. We investigated the role of DJ-1/PARK7, a Parkinson's disease-associated gene, in prodromal pain and peripheral neuropathy. Using DJ-1 deficient mice, we conducted comprehensive sensory tests, cutaneous staining, molecular analyses and electrophysiological studies on mouse and human primary sensory neurons from dorsal root ganglia. We found that these mice exhibited cold hypersensitivity, oxidative stress, and neuropathy of the cutaneous fibres of primary sensory neurones before any motor impairments were observed. Mechanistically, DJ-1 in primary sensory neurones regulated this hypersensitivity and neuropathy via TRPA1 signalling. Interestingly, we discovered that DJ-1 also plays a role in the progression of chemotherapy-induced peripheral neuropathies. Pain and mechanisms associated with these neuropathies were exacerbated in DJ-1 deficient mice but were significantly reduced by the pharmacological activation of DJ-1. Importantly, we also confirmed the expression of DJ-1 and its therapeutic potential in human primary sensory neurons. Thus, we uncover a peripheral mechanism of DJ-1 and propose that it may serve as a new target for developing therapeutic approaches for Parkinson's disease-linked and other painful neuropathies.