Reduced Conduction Velocity Research Articles

Clinical and Electrophysiological Characteristics of 23 French Patients With Neurolymphomatosis.

Neurolymphomatosis is a hematological condition defined by the direct infiltration of malignant lymphomatous cells into the peripheral nervous system. Since nerve conduction studies may disclose demyelinating features, clinicians may misdiagnose neurolymphomatosis as chronic inflammatory demyelinating polyneuropathy (CIDP). This study aimed to determine whether patients with neurolymphomatosis met the 2021 revised criteria for CIDP. We retrospectively analyzed 23 patients with primary or secondary neurolymphomatosis from nine French hospitals. We analyzed whether patients with a diagnosis of neurolymphomatosis met the 2010 and 2021 CIDP criteria. 152 motor nerves were analyzed, and conduction blocks were found in 13.8% of them. Eight patients (34.7%) demonstrated at least one conduction block. Other demyelinating parameters fulfilling the 2021 CIDP criteria were rare, including reduced conduction velocities (1.7%), prolonged distal motor latencies (3%), absent F-waves (12.4%), and prolonged F-wave latencies (7.7%). Five patients met the 2010 CIDP criteria, whereas only one met the 2021 CIDP criteria. Demyelinating features are rare in neurolymphomatosis, and a conduction block is the most frequent abnormality. Consequently, only one patient met the 2021 criteria for CIDP diagnosis. This is likely attributable to the inclusion of sensory criteria. Furthermore, the new criteria emphasize the importance of identifying red flags, such as pain or monoclonal gammopathy, which could suggest an alternative diagnosis to CIDP. Clinicians should consider neurolymphomatosis in patients who present with red flags or atypical CIDP.

Long-term glucosamine supplementation aggravates atrial fibrillation susceptibility by impairing AMPK signaling.

Glucosamine, a widely used dietary supplement, has been linked to potential cardiovascular risks, including atrial fibrillation (AF). This study aimed to investigate the effects of long-term glucosamine supplementation on AF susceptibility and the underlying mechanisms. C57BL/6 J mice were treated with low-dose (15 mg/kg/day) or high-dose (250 mg/kg/day) glucosamine via drinking water for 6 weeks. AF susceptibility was assessed through transesophageal electrical stimulation. Atrial remodeling was characterized through electrophysiological and echocardiography studies, histological analysis, and molecular examination. AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) was used to validation the underlying mechanism in mice and isolated neonatal atrial cardiomyocytes. Long-term high-dose glucosamine supplementation increased AF susceptibility in mice, as indicated by an elevated AF incidence and duration. Glucosamine induced notable electrical remodeling, evidenced by intra-atrial conduction slowing (P wave duration, amplitude, and area), likely attributable to reduced conduction velocity, as confirmed by two-dimensional electrical mapping. Structural remodeling including increased left atrial weight, cardiomyocyte hypertrophy and fibrosis was evident in the atria of glucosamine-treated mice, despite unaffected cardiac function. Mechanistically, glucosamine suppressed atrial AMPK signaling, leading to lipid and glycogen accumulation. Intriguingly, despite impaired atrial AMPK signaling, high-dose glucosamine improved systemic insulin sensitivity. Pharmacological activation of AMPK with AICAR mitigated glucosamine-induced AF susceptibility and associated pathological changes both in vivo and in vitro. Our findings demonstrate that long-term glucosamine supplementation enhances AF susceptibility, potentially by impairing atrial AMPK signaling, underscoring the importance of caution in the utilization of glucosamine.

A Comparative Study of the Electroneurographic Findings in Amyloidotic Polyneuropathy in Patients with Light-Chain Amyloidosis and Glu54Gln Transthyretin Amyloidosis

Background and Objectives: Amyloidosis is a disorder characterized by the abnormal folding of proteins, forming insoluble fibrils that accumulate in tissues and organs. This accumulation disrupts normal tissue architecture and organ function, often with serious consequences, including death if left untreated. Light-chain amyloidosis (AL) and hereditary transthyretin-type amyloidosis (hATTR) are two of the most common types. In amyloidosis, peripheral nervous system involvement is a significant diagnostic feature, particularly when it manifests as polyneuropathy, carpal tunnel syndrome (CTS), and dysautonomia. These neurological symptoms often point to the involvement of amyloid deposits in the peripheral and autonomic nervous systems, which can help identify and differentiate between the various types of amyloidosis. Materials and Methods: This retrospective study focused on the evolution of electrophysiological parameters in two groups: AL (n = 22) and hATTR-Glu54Gln patients (n = 14), with mixed axonal polyneuropathy. Patients were followed for two consecutive years to assess disease progression. The PND scale (polyneuropathy disability) was also used to assess motor impairment for each patient. Results: In our study AL amyloidosis patients presented with mixed, axonal polyneuropathy associated with CTS in 63.6% of cases and cardiomyopathy (45.5%). Serial EMGs (electromyography) showed decreased motor amplitudes of the common peroneal and tibial nerves and sensory amplitude of the superficial peroneal nerve, with mostly preserved conduction velocities. The patients maintained stage I PND throughout the monitoring period. The entire hATTR group displayed mixed, axonal polyneuropathy and cardiomyopathy; 85.7% of them had CTS, and 42.9% had orthostatic hypotension. EMG data showed decreased motor amplitudes of the tibial and common peroneal nerves, decreased sensory amplitudes of the superficial peroneal nerve, and mildly reduced conduction velocities, with significant progression at 12 and 24 months. The patients displayed additional reduced muscle strength, some reaching stage 3A and 3B-PND at the end of the study. Conclusions: The amyloidotic polyneuropathy found in the groups was similar in its axonal, sensory-motor, and length-dependent characteristics, but the study showed significant differences in its progression, with more abrupt changes in the hATTR-Glu54Gln group. The amyloidosis AL patients remained in stage 1 PND, while the hATTR-Glu54Gln patients progressed to stage 3 PND at 24 months.

Median nerve impairment in leprosy: how does it differ from the classic carpal tunnel syndrome?

Carpal tunnel syndrome (CTS) has already been described as a possible form of neural leprosy presentation. However, the median nerve can be involved in this neuropathy in proximal segments and, sometimes, with an asymmetric impairment of the digital branches. To detail the pattern of median nerve impairment through nerve conduction study (NCS) and ultrasound evaluation. This cross-sectional study comprises 15 primary neural leprosy (PNL) patients and 14 patients with CTS who underwent peripheral nerve ultrasonography and NCS evaluation. From the total, 92.8% of patients with CTS and 80% with PNL had bilateral impairment of the median nerve, with 27 nerves in each group. Considering the cross-sectional area (CSA) of the tunnel (Mt) segment, 63% of the nerves in the CTS and 74.1% in the PNL groups were found to be thickened, with an average CSA of 13.4 ± 4.4 and 12.4 ± 4.6, respectively (p = 0.18). The CSA of the proximal tunnel (Mpt) segment showed thickening in only 3.7% in the CTS group and 96.3% in the PNL (p < 0.0001), with an average of 6.6 ± 1.3 and 17.0 ± 6.7, respectively (p < 0.001). Finally, 88.9% of the nerves in the PNL group and only 7.4% in the CSA (p < 0.0001) showed a reduction in conduction velocity in the distal forearm, with an average of 41.0 ± 6.3 and 53.2 ± 5.2, respectively (p < 0.0001). The presence of neural thickening and demyelinating impairment in the segments proximal to the carpal tunnel favors the diagnosis of leprosy.

Nerve conduction velocity studies in diabetic peripheral neuropathy involving sural nerve—A meta-analysis

ABSTRACT Introduction: Diabetes mellitus (DM) poses a significant health burden globally, impacting millions due to its metabolic disruptions. Among its complications, diabetic peripheral neuropathy (DPN) is a prevalent concern, affecting sensory and motor nerves. While various diagnostic methods exist, discrepancies persist in prevalence estimates of DPN among diabetic populations. Objective: This meta-analysis aimed to assess the prevalence of DPN in individuals with DM, focusing on sural nerve conduction velocity (NCV) measurements. Additionally, the study explored how different evaluation techniques influenced prevalence estimates. Methods: A systematic literature search was conducted following PRISMA guidelines across multiple databases. Studies reporting sural nerve NCV measurements in diabetic patients were included. Data extraction, quality assessment, and statistical analyses were performed to synthesize findings. Results: Twenty-six studies met the inclusion criteria, providing insights into sural nerve NCV among diabetic individuals. Pooled analysis revealed a mean sural nerve NCV of 42.12 m/s (95% CI: 39.87-44.36), indicative of reduced conduction velocity in diabetic populations. Furthermore, sural nerve amplitude was significantly lower in diabetic individuals, with a pooled mean of 4.68 μV (95% CI: 3.11-6.25). Conclusion: Individuals with type 2 DM exhibit impaired sural nerve function, as evidenced by reduced NCV and amplitude measurements. Timely NCV assessment, alongside glycemic monitoring, is crucial for identifying and managing DPN to prevent further complications. Interventions addressing glycemic control, dietary regulation, and lifestyle modifications are recommended to mitigate the progression of neuropathy in diabetic populations.

Non-invasive mapping of atrial slow-conduction areas and validation by endocardial isochronal mapping to predict atrial fibrillation recurrence after ablation

Abstract Background Atrial arrythmogenic substrate is a key determinant of arrhythmia recurrence after pulmonary vein isolation (PVI), and reduced conduction velocities have been linked to adverse outcome. However, a non-invasive method to assess such electrical substrate is not available to date. Purpose We have developed and validated a non-invasive mapping system based on electrocardiographic imaging (ECGi) to assess local conduction velocities and their predictive value regarding 12-months arrhythmia-free survival following PVI. Methods A novel ECGi-based non-invasive mapping system obviating the need of additional CT- or CMR-imaging was developed. 52 consecutive patients scheduled for AF ablation (PVI-only) and 19 healthy controls were prospectively included and local left and right atrial conduction velocities determined in sinus rhythm through non-invasive mapping. In 36 of the patients high density endocardial mapping was performed to define areas of slow conduction based on isochronal late activation maps. AF ablation patients were systematically followed and monitored for 12 months post ablation. Results Mean ECGi-determined atrial conduction velocities were significantly lower in AF patients (54% paroxysmal) than in healthy controls (1.45±0.15 vs. 1.64±0.15 m/s; p&amp;lt;0.0001). Differences were even more pronounced in a regional analysis (Fig. 1A). In this analysis we focused only on the segment with the slowest average conduction velocity in a given patient, i.e. the region that was most likely to harbour arrhythmogenic substrate. Multivariable regression analyses and c-statistics found this average conduction velocity of the „slowest" segment (AUC 0.74) to predict 12-months arrhythmia recurrence after PVI better than previously proposed non-invasive predictors including left atrial size (AUC 0.71) or the left atrial extent of late gadolinium enhancement (MRI) (AUC 0.70). A ROC analysis found a regional conduction velocity threshold of 0.78 m/s to best discriminate PVI responders from non-responders. Patients without slow-conduction areas (mean conduction velocity &amp;lt;0.78 m/s) showed significantly higher 12-months arrhythmia-free survival than those with one or more slow-conduction areas (88.9% versus 48.0%, p=0.002) (Fig. 1B). For validation we compared slow-conduction areas determined by non-invasive mapping with slow-conduction areas as defined by invasive isochronal mapping. Interrater reliability testing revealed good agreement between non-invasive mapping-determined slow-conduction areas and those defined by isochronal mapping (kappa 0.63, Fig. 2). Conclusions ECGi-based non-invasive mapping reliably identifies areas of slow conduction. The presence of ECGi-determined slow-conduction areas well discriminates PVI-responders from non-responders. Such non-invasive assessment of electrical arrhythmogenic substrate may guide treatment strategies and could be a step towards personalised AF therapy.Figure 1Figure 2

Regional conduction velocities determined by noninvasive mapping are associated with arrhythmia-free survival after atrial fibrillation ablation

BackgroundAtrial arrhythmogenic substrate is a key determinant of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI), and reduced conduction velocities have been linked to adverse outcome. However, a noninvasive method to assess such electrophysiologic substrate is not available to date. ObjectiveThis study aimed to noninvasively assess regional conduction velocities and their association with arrhythmia-free survival after PVI. MethodsA consecutive 52 patients scheduled for AF ablation (PVI only) and 19 healthy controls were prospectively included and received electrocardiographic imaging (ECGi) to noninvasively determine regional atrial conduction velocities in sinus rhythm. A novel ECGi technology obviating the need of additional computed tomography or cardiac magnetic resonance imaging was applied and validated by invasive mapping. ResultsMean ECGi-determined atrial conduction velocities were significantly lower in AF patients than in healthy controls (1.45 ± 0.15 m/s vs 1.64 ± 0.15 m/s; P < .0001). Differences were particularly pronounced in a regional analysis considering only the segment with the lowest average conduction velocity in each patient (0.8 ± 0.22 m/s vs 1.08 ± 0.26 m/s; P < .0001). This average conduction velocity of the “slowest” segment was independently associated with arrhythmia recurrence and better discriminated between PVI responders and nonresponders than previously proposed predictors, including left atrial size and late gadolinium enhancement (magnetic resonance imaging). Patients without slow-conduction areas (mean conduction velocity <0.78 m/s) showed significantly higher 12-month arrhythmia-free survival than those with 1 or more slow-conduction areas (88.9% vs 48.0%; P = .002). ConclusionThis is the first study to investigate regional atrial conduction velocities noninvasively. The absence of ECGi-determined slow-conduction areas well discriminates PVI responders from nonresponders. Such noninvasive assessment of electrical arrhythmogenic substrate may guide treatment strategies and be a step toward personalized AF therapy.

Mannitol and hyponatremia regulate cardiac ventricular conduction in the context of sodium channel loss of function.

Scn5a heterozygous null (Scn5a+/-) mice have historically been used to investigate arrhythmogenic mechanisms of diseases such as Brugada syndrome (BrS) and Lev's disease. Previously, we demonstrated that reducing ephaptic coupling (EpC) in ex vivo hearts exacerbates pharmacological voltage-gated sodium channel (Nav)1.5 loss of function (LOF). Whether this effect is consistent in a genetic Nav1.5 LOF model is yet to be determined. We hypothesized that loss of EpC would result in greater reduction in conduction velocity (CV) for the Scn5a+/- mouse relative to wild type (WT). In vivo ECGs and ex vivo optical maps were recorded from Langendorff-perfused Scn5a+/- and WT mouse hearts. EpC was reduced with perfusion of a hyponatremic solution, the clinically relevant osmotic agent mannitol, or a combination of the two. Neither in vivo QRS duration nor ex vivo CV during normonatremia was significantly different between the two genotypes. In agreement with our hypothesis, we found that hyponatremia severely slowed CV and disrupted conduction for 4/5 Scn5a+/- mice, but 0/6 WT mice. In addition, treatment with mannitol slowed CV to a greater extent in Scn5a+/- relative to WT hearts. Unexpectedly, treatment with mannitol during hyponatremia did not further slow CV in either genotype, but resolved the disrupted conduction observed in Scn5a+/- hearts. Similar results in guinea pig hearts suggest the effects of mannitol and hyponatremia are not species specific. In conclusion, loss of EpC through either hyponatremia or mannitol alone results in slowed or disrupted conduction in a genetic model of Nav1.5 LOF. However, the combination of these interventions attenuates conduction slowing.NEW & NOTEWORTHY Cardiac sodium channel loss of function (LOF) diseases such as Brugada syndrome (BrS) are often concealed. We optically mapped mouse hearts with reduced sodium channel expression (Scn5a+/-) to evaluate whether reduced ephaptic coupling (EpC) can unmask conduction deficits. Data suggest that conduction deficits in the Scn5a+/- mouse may be unmasked by treatment with hyponatremia and perinexal widening via mannitol. These data support further investigation of hyponatremia and mannitol as novel diagnostics for sodium channel loss of function diseases.

Electrophysiological variations of Guillain-Barre syndrome in Bangladesh- Hospital based study

Introduction: Guillain-Barre syndrome (GBS) is an immune mediated disorder of peripheral nerves which usually presents by rapidly evolving ascending weakness &amp; mild sensory loss and hypo- or areflexia. Electrodiagnostic study (EDS) is the basis for classification of different subtypes of the disease. EDS also has a crucial role in diagnosis, ruling out of some differential diagnosis like myopathic and motor neuron disorders and confirming the neuropathic nature of GBS. The benefit of immunotherapy is greatest when introduced early. In addition, electrophysiological characteristic can predict the prognosis of patients with GBS. This study was conducted to determine the predominant subtype and electrophysiological pattern of GBS in the context of Bangladesh. Objectives: Objective of this study was to compare the electrophysiological variations among different electrophysiological subtypes of GBS. Methods: It is an observational cross sectional study conducted in Department of Medicine and Neurology, Sir Salimullah Medical College &amp; Mitford Hospital and National Institute of Neuroscience (NINS), Dhaka, over a period of one year &amp; four months. Total 30 patients were selected by purposive sampling technique. Demographic data were collected from the patients and recorded in structured case report form. Clinical examination and relevant investigations were done meticulously. Collected questionnaire were checked to identify any error in data. Data was analyzed with SPSS version 21 software. Result: In this study, maximum numbers of patients 53% were between 21-30 years of age group with mean value 27.47±8.1 years. Male to female ratio was 1.7:1. Frequency of Guillain-Barre syndrome is predominance at middle age group. Commonest presentation was limb weakness (parapledgia or quadripledgia) in 60% patients, paresthesias &amp; numbness (40%), pain (100%) and deviation of mouth (63%) of GBS patients. Cerebrospinal fluid shows a mild pleocytosis (5 to 50 cells/µl) in majority of cases was found in 76% of patients. Whereas elevated CSF Protein (&gt;45 mg/dl) was seen in all GBS patient. Increased distal motor latency (DML) was found in 93% patients, whereas 7% patients had normal DML. In the case of the lower limbs, increased distal motor latency was predominant. Decreased amplitude of sensory nerve action potential (SNAP) was seen in 83% patients while 16% patients had normal. Slowing of motor conduction velocities, decreased amplitude as well as increase in distal motor latencies were observed, being more pronounced in the lower limbs. F-wave was completely absent in 20.0% patients while 20% patients showed decreased conduction velocity with prolonged latency. Sensory nerve action potential revealed that decreased sensory conduction velocity (SCV) was seen in 26%, absent SCV in 10% and normal SCV in 63% patients. Present study demonstrated that Acute inflammatory demyelinating polyneuropathy (AIDP) was the commonest type of Guillain-Barré syndrome, present in 56% of patient. Around 30% of the patients belonged to acute motor axonal polyneuropathy (AMAN) and 13% were acute motor sensory axonal polyneuropathy (AMSAN). Conclusion: In this study AIDP was the most frequent subtype. The characteristic findings supportive of AIDP include prolonged distal motor latencies, reduced conduction velocities, conduction blocks at non-entrapment sites, temporal dispersion and prolonged F wave latencies. J MEDICINE 2024; 25: 11-16

Impact of 2021 European Academy of Neurology/Peripheral Nerve Society diagnostic criteria on diagnosis and therapy of chronic inflammatory demyelinating polyradiculoneuropathy variants.

There are different criteria for the diagnosis of different variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines provide specific clinical criteria for each CIDP variant even if their therapeutical impact has not been investigated. We applied the clinical criteria for CIDP variants of the 2021 EAN/PNS guidelines to 369 patients included in the Italian CIDP database who fulfilled the 2021 EAN/PNS electrodiagnostic criteria for CIDP. According to the 2021 EAN/PNS clinical criteria, 245 patients achieved a clinical diagnosis of typical CIDP or CIDP variant (66%). We identified 106 patients with typical CIDP (29%), 62 distal CIDP (17%), 28 multifocal or focal CIDP (7%), four sensory CIDP (1%), 27 sensory-predominant CIDP (7%), 10 motor CIDP (3%), and eight motor-predominant CIDP (2%). Patients with multifocal, distal, and sensory CIDP had milder impairment and symptoms. Patients with multifocal CIDP had less frequently reduced conduction velocity and prolonged F-wave latency and had lower levels of cerebrospinal fluid protein. Patients with distal CIDP more frequently had reduced distal compound muscle action potentials. Patients with motor CIDP did not improve after steroid therapy, whereas those with motor-predominant CIDP did. None of the patients with sensory CIDP responded to steroids, whereas most of those with sensory-predominant CIDP did. The 2021 EAN/PNS criteria for CIDP allow a better characterization of CIDP variants, permitting their distinction from typical CIDP and more appropriate treatment for patients.

Mechanisms of pulmonary arterial hypertension-induced atrial fibrillation: insights from multi-scale models of the human atria.

This study aimed to use multi-scale atrial models to investigate pulmonary arterial hypertension (PAH)-induced atrial fibrillation mechanisms. The results of our computer simulations revealed that, at the single-cell level, PAH-induced remodelling led to a prolonged action potential (AP) (ΔAPD: 49.6 ms in the right atria (RA) versus 41.6 ms in the left atria (LA)) and an increased calcium transient (CaT) (ΔCaT: 7.5 × 10-2 µM in the RA versus 0.9 × 10-3 µM in the LA). Moreover, heterogeneous remodelling increased susceptibility to afterdepolarizations, particularly in the RA. At the tissue level, we observed a significant reduction in conduction velocity (CV) (ΔCV: -0.5 m s-1 in the RA versus -0.05 m s-1 in the LA), leading to a shortened wavelength in the RA, but not in the LA. Additionally, afterdepolarizations in the RA contributed to enhanced repolarization dispersion and facilitated unidirectional conduction block. Furthermore, the increased fibrosis in the RA amplified the likelihood of excitation wave breakdown and the occurrence of sustained re-entries. Our results indicated that the RA is characterized by increased susceptibility to afterdepolarizations, slow conduction, reduced wavelength and upregulated fibrosis. These findings shed light on the underlying factors that may promote atrial fibrillation in patients with PAH.

Abstract 16957: PRKAG2 Directly Interacts With Myosin Heavy Chains to Modulate Myocyte Electrical and Morphological Changes in Cardiac Hypertrophy

Introduction: Mutations in the PRKAG2 gene cause a complex myocardial disorder characterized by hypertrophic cardiomyopathy (HCM) and conduction disturbances. While prior studies associated PRKAG2 -linked hypertrophy with increased glycogen storage, many HCM phenotypes in the disorder remain unexplained by this effect alone. We aimed to uncover the molecular mechanisms by which PRKAG2 mutations induce myocyte hypertrophy and electrical changes during cardiac development. Methods: We created transgenic zebrafish expressing WT (Tg WT ) and pathological mutant (Tg R299Q ) murine Prkag2 cDNA under a myocardium-specific promoter. Using these models, we studied the impact of Prkag2 variant on myocyte electrical activity, metabolism, and cytoarchitecture across cardiogenesis and in mature hearts. Results: Tg R299Q adult fish showed hypertrophic cardiomyocytes, swollen mitochondria, and shortened sarcomere length compared to Tg WT and WT, mirroring human HCM phenotypes. The glycogen content was elevated in adult hearts but not during early cardiogenesis. Despite the absence of glycogen accumulation at 6-day post fertilization, Tg R299Q hearts showed electrical abnormalities, including a reduced conduction velocity, decreased Ca 2+ amplitude, and prolonged action potential durations in both atria and ventricles, compared to Tg WT and WT. Co-immunoprecipitation and proximity ligation assay revealed physical interactions between Prkag2 and myosin heavy chain (MYH), with the R299Q variant enhancing this interaction and altering the subcellular localization of Prkag2 from mitochondria to sarcomeres. Knockdown of the fish homolog of MYH7 ( vmhcl ) restored the early electrical disturbances caused by Tg R299Q . This abnormal MYH-Prkag2 interaction disturbed mitochondria and sarcomere organization contributing to altered myocyte cytoarchitecture observed in Tg R299Q . Conclusions: Mutant PRKAG2 altered cardiac excitability and Ca 2+ handling during embryogenesis, preceding glycogen accumulation. Enhanced binding between Prkag2 and MYHs contributed to these early changes. Our study revealed a novel link between sarcomere proteins and metabolic regulators in cardiac hypertrophy, suggesting a new therapeutic avenue for treating HCM.

Chronic diastolic stretch unmasks conduction defects in an in vitro model of arrhythmogenic cardiomyopathy.

We seek to elucidate the precise nature of mechanical loading that precipitates conduction deficits in a concealed-phase model of arrhythmogenic cardiomyopathy (ACM). ACM is a progressive disorder often resulting from mutations in desmosomal proteins. Exercise has been shown to worsen disease progression and unmask arrhythmia vulnerability, yet the underlying pathomechanisms may depend on the type and intensity of exercise. Because exercise causes myriad changes to multiple inter-dependent hemodynamic parameters, it is difficult to isolate its effects to specific changes in mechanical load. Here, we use engineered heart tissues (EHTs) with iPSC-derived cardiomyocytes expressing R451G desmoplakin, an ACM-linked mutation, which results in a functionally null model of desmoplakin (DSP). We also use a novel bioreactor to independently perturb tissue strain at different time points during the cardiac cycle. We culture EHTs under three strain regimes: normal physiological shortening; increased diastolic stretch, simulating high preload; and isometric culture, simulating high afterload. DSPR451G EHTs that have been cultured isometrically undergo adaptation, with no change in action potential parameters, conduction velocity, or contractile function, a phenotype confirmed by global proteomic analysis. However, when DSPR451G EHTs are subjected to increased diastolic stretch, they exhibit concomitant reductions in conduction velocity and the expression of connexin-43. These effects are rescued by inhibition of both lysosome activity and ERK signaling. Our results indicate that the response of DSPR451G EHTs to mechanical stimuli depends on the strain and the timing of the applied stimulus, with increased diastolic stretch unmasking conduction deficits in a concealed-phase model of ACM.

Left atrial conduction times and regional velocities in persistent atrial fibrillation patients with and without fibrotic atrial cardiomyopathy

Despite the progress in understanding left atrial substrate and arrhythmogenesis, only little is known about conduction characteristics in atrial fibrillation patients with various stages of fibrotic atrial cardiomyopathy (FACM). This study evaluates left atrial conduction times and conduction velocities based on high-density voltage and activation maps in sinus rhythm (CARTO®3 V7) of 53 patients with persistent atrial fibrillation (LVEF 60% (55–60 IQR), LAVI 39 ml/m2 (31–47 IQR), LApa 24 ± 6 cm2). Measurements were made in low voltage areas (LVA ≤ 0.5 mV) and normal voltage areas (NVA ≥ 1.5 mV) at the left atrial anterior and posterior walls. Maps of 28 FACM and 25 no FACM patients were analyzed (19 FACM I/II, 9 FACM III/IV, LVA 14 ± 11 cm2). Left atrial conduction time averaged to 110 ± 24 ms but was shown to be prolonged in FACM (119 ms, + 17%) when compared to no FACM patients (101 ms, p = 0.005). This finding was pronounced in high-grade FACM (III/IV) (133 ms, + 31.2%, p = 0.001). In addition, the LVA extension correlated significantly with the left atrial conduction time (r = 0.56, p = 0.002). Conduction velocities were overall slower in LVA than in NVA (0.6 ± 0.3 vs. 1.3 ± 0.5 m/s, -51%, p < 0.001). Anterior conduction appeared slower than posterior, which was significant in NVA (1 vs. 1.4 m/s, -29%, p < 0.001) but not in LVA (0.6 vs. 0.8 m/s, p = 0.096). FACM has a significant influence on left atrial conduction characteristics in patients with persistent atrial fibrillation. Left atrial conduction time prolongs with the grade of FACM and the quantitative expanse of LVA up to 31%. LVAs show a 51% conduction velocity reduction compared to NVA. Moreover, regional conduction velocity differences are present in the left atrium when comparing anterior to posterior walls. Our data may influence individualized ablation strategies.

Renal denervation reverses ventricular structural and functional remodeling in failing rabbit hearts

Renal denervation (RDN) suppresses the activity of the renin–angiotensin–aldosterone system and inflammatory cytokines, leading to the prevention of cardiac remodeling. Limited studies have reported the effects of renal denervation on ventricular electrophysiology. We aimed to use optical mapping to evaluate the effect of RDN on ventricular structural and electrical remodeling in a tachycardia-induced cardiomyopathy rabbit model. Eighteen rabbits were randomized into 4 groups: sham control group (n = 5), renal denervation group receiving RDN (n = 5), heart failure group receiving rapid ventricular pacing for 1 month (n = 4), and RDN-heart failure group (n = 4). Rabbit hearts were harvested for optical mapping. Different cycle lengths were paced (400, 300, 250, 200, and 150 ms), and the results were analyzed. In optical mapping, the heart failure group had a significantly slower epicardial ventricular conduction velocity than the other three groups. The RDN-heart failure, sham control, and RDN groups had similar velocities. We then analyzed the 80% action potential duration at different pacing cycle lengths, which showed a shorter action potential duration as cycle length decreased (P for trend < 0.01), which was consistent across all groups. The heart failure group had a significantly longer action potential duration than the sham control and RDN groups. Action potential duration was shorter in the RDN-heart failure group than the heart failure group (P < 0.05). Reduction of conduction velocity and prolongation of action potential duration are significant hallmarks of heart failure, and RDN reverses these remodeling processes.

Right atrial collision time (RACT): A novel marker of propensity for typical atrial flutter.

The risk of typical atrial flutter (AFL) is increased proportionately to right atrial (RA) size or right atrial scarring that results in reduced conduction velocity. These characteristics result in propagation of a flutter wave by ensuring the macro re-entrant wave front does not meet its refractory tail. The time taken to traverse the circuit would take account of both of these characteristics and may provide a novel marker of propensity to develop AFL. Our goal was to investigate right atrial collision time (RACT) as a marker of existing typical AFL. This single-centre, prospective study recruited consecutive typical AFL ablation patients that were in sinus rhythm. Controls were consecutive electrophysiology study patients >18 years of age. While pacing the coronary sinus (CS) ostium at 600 ms, a local activation time map was created to locate the latest collision point on the anterolateral right atrial wall. This RACT is a measure of conduction velocity and distance from CS to a collision point on the lateral right atrial wall. Ninety-eight patients were included in the analysis, 41 with atrial flutter and 57 controls. Patients with atrial flutter were older, 64.7 ± 9.7 versus 52.4 ± 16.8 years (<.001), and more often male (34/41 vs. 31/57 [.003]). The AFL group mean RACT (132.6 ± 17.3 ms) was significantly longer than that of controls (99.1 ± 11.6 ms) (p < .001). A RACT cut-off of 115.5 ms had a sensitivity and specificity of 92.7% and 93.0%, respectively for diagnosis of atrial flutter. A ROC curve indicated an AUC of 0.96 (95% CI: 0.93-1.0, p < .01). RACT is a novel and promising marker of propensity for typical AFL. This data will inform larger prospective studies.

Local conduction velocities determined by non-invasive electrocardiographic imaging predict arrhythmia-free survival after pulmonary vein isolation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This project has received funding from the European Union's Horizon Research and Innovation Programme under the Marie-Sklodowska Curie Grant Agreement No. 860974 Background Recurrence rates after atrial fibrillation (AF) ablation are still unsatisfactory. As catheter ablation is primarily targeting pulmonary vein (PV) ectopic activity, it is not surprising that extra-PV arrythmogenic substrate is a key determinant of arrhythmia recurrence. Against this background, several studies have proposed assessment of extra-PV substrate in terms of atrial fibrosis or locally reduced conduction velocities (CV) to guide treatment. However, to date no non-invasive method directly assessing electrical arrhythmogenic substrate has been established in clinical practice, and treatment decisions are commonly based on crude surrogates like AF type or left atrial size. Here we establish and validate a novel non-invasive method based on electrocardiographic imaging (ECGi) to determine atrial arrhythmogenic substrate in terms of reduced local CVs and its predictive value regarding arrhythmia recurrence after PVI. Methods and results 52 consecutive patients scheduled for AF ablation (PVI-only) and 19 healthy controls were prospectively included and received ECGi to assess left and right atrial arrhythmogenic substrate. This ECGi-based method uses 64 electrodes placed on the torso. Subsequently, a 3D model of the torso is acquired as an anatomical reference using a 3D reconstruction camera. A personalised 3D atrial geometry is then derived from a database of human atria using an artificial intelligence-based algorithm. Finally, unipolar surface electrograms are projected onto the cardiac geometry and local CVs are estimated. Mean ECGi-determined atrial CVs were significantly lower in AF patients than in healthy controls, both in a global analysis (1.45±0.15 m/s vs. 1.64±0.15 m/s; p&amp;lt;0.0001) and a regional analysis of 19 predefined left and right atrial segments (Fig. 1). Considering only the segments with the lowest average CV in each patient, differences in CVs were more pronounced (0.80±0.22 vs. 1.08±0.26 m/s; p&amp;lt;0.0001). Multivariate logistic regression analyses combined with c-statistics including other previously proposed predictors found this mean CV of the "slowest" segment to be the strongest predictor of arrhythmia recurrence. A ROC analysis revealed that a cut-off for this variable of 0.72 m/s best discriminates PVI responders from non-responders: patients with a mean CV &amp;gt;0.72 m/s in all atrial regions showed a 6-months arrhythmia-free survival of 90.9%, whereas patients with one or more atrial regions with a mean CV &amp;lt;0.72 m/s had a poor outcome with an arrhythmia-free survival rate of only 57.9% (Fig. 2). Conclusion This was the first study to investigate local atrial CV non-invasively and to validate their predictive value regarding outcome after PVI. The absence of ECGi-determined areas of slow conduction well discriminated PVI responders from non-responders. Such non-invasive assessment of electrical arrhythmogenic substrate may guide treatment strategies and be an important step towards personalised AF therapy.

A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart.

Tamoxifen, a selective estrogen receptor modulator, was initially used to treat cancer in women and more recently to induce conditional gene editing in rodent hearts. However, little is known about the baseline biological effects of tamoxifen on the myocardium. In order to clarify the short-term effects of tamoxifen on cardiac electrophysiology of myocardium, we applied a single-chest-lead quantitative method and analyzed the short-term electrocardiographic phenotypes induced by tamoxifen in the heart of adult female mice. We found that tamoxifen prolonged the PP interval and caused a decreased heartbeat, and further induced atrioventricular block by gradually prolonging the PR interval. Further correlation analysis suggested that tamoxifen had a synergistic and dose-independent inhibition on the time course of the PP interval and PR interval. This prolongation of the critical time course may represent a tamoxifen-specific ECG excitatory-inhibitory mechanism, leading to a reduction in the number of supraventricular action potentials and thus bradycardia. Segmental reconstructions showed that tamoxifen induced a decrease in the conduction velocity of action potentials throughout the atria and parts of the ventricles, resulting in a flattening of the P wave and R wave. In addition, we detected the previously reported prolongation of the QT interval, which may be due to a prolonged duration of the ventricular repolarizing T wave rather than the depolarizing QRS complex. Our study highlights that tamoxifen can produce patterning alternations in the cardiac conduction system, including the formation of inhibitory electrical signals with reduced conduction velocity, implying its involvement in the regulation of myocardial ion transport and the mediation of arrhythmias. A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart（Figure 9）. A working model of tamoxifen producing acute electrical disturbances in the myocardium. SN, sinus node; AVN, atrioventricular node; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.

PO-02-243 IMPACT OF PARTIAL CONSTRICTION OF THE ARTERIAL PULMONARY TRUNK ON THE DEVELOPMENT OF SUSCEPTIBILITY TO ATRIAL FIBRILLATION IN RATS

Atrial Fibrillation (AF) is the most frequent and clinically important form of cardiac arrhythmia. It has been demonstrated that cardiovascular comorbidities such as myocarditis, myocardial infarction, obesity, or pulmonary hypertension (PH) promote cardiac remodeling associated with the development of atrial arrhythmogenic substrates. Right-heart disease (RHD), characterized by chronic right-sided cardiac structural and functional anomalies, has also been designated among AF risk factors. Inflammation is one of the common denominators between cardiovascular risk factors and AF vulnerability. However, no study has described the progression of the molecular and cellular changes involved in the causal link relating RHD, the activation of atrial inflammation, and the development of AF substrate. This study aims to establish the characterization of the progression of atrial arrhythmogenic inflammation in a rat model of RHD. Hypothesis Permanent constriction of the pulmonary artery trunk (PAT) provokes severe RHD associated with progressive atrial inflammation and fibrosis responsible for enhanced AF vulnerability. Pulmonary Artery Banding (PAB) reducing the PAT diameter to 1 mm, was surgically performed on 225-275g Wistar rats to induce permanent PH and severe RHD. Sham animals received PAB-mimicking intervention without ligation. Echocardiography and electrophysiological studies (EPS) were performed in vivo, on all the animals at Day0, Day7, Day14 and Day21 post-surgery. The atrial tissues were analyzed by optical mapping, histology (Masson's Trichrome), qPCR and immunoblotting. Within three weeks, PAB rats developed severe right heart remodeling characterized by progressive ventricular and atrial hypertrophy and dilation. Right atrial (RA) optical mapping revealed a reduction in conduction velocity and refractory periods in PAB rats compared to Sham. PAB rats were more vulnerable to AF than Sham starting at 7th-day until the 21st-day post-surgery. Histological analysis shows that since the 14th day until the 21st-day post-surgery RA fibrosis significantly increased in PAB rats compared to sham. Quantitative polymerase chain reaction performed on inflammation and fibrosis-related genes such as IL6, Tgfb1 or Col1a1 revealed a progressive aggravation of RA inflammatory and fibrotic status in PAB rats from Day7, Day14 to Day2 Severe RHD is associated with progressive and unresolved RA inflammation and fibrosis provoking an aggravation of AF vulnerability overtime

Biallelic pathogenic variants in the mitochondrial form of phosphoenolpyruvate carboxykinase cause peripheral neuropathy.

Phosphoenolpyruvate carboxykinase (PCK) plays a critical role in cytosolic gluconeogenesis, and defects in PCK1 cause a fasting-aggravated metabolic disease with hypoglycemia and lactic acidosis. However, there are two genes encoding PCK, and the role of the mitochondrial resident PCK (encoded by PCK2) is unclear, since gluconeogenesis is cytosolic. We identified three patients in two families with biallelic variants in PCK2. One has compound heterozygous variants (p.Ser23Ter/p.Pro170Leu), and the other two (siblings) have homozygous p.Arg193Ter variation. All three patients have weakness and abnormal gait, an absence of PCK2 protein, and profound reduction in PCK2 activity in fibroblasts, but no obvious metabolic phenotype. Nerve conduction studies showed reduced conduction velocities with temporal dispersion and conduction block compatible with a demyelinating peripheral neuropathy. To validate the association between PCK2 variants and clinical disease, we generated a mouse knockout model of PCK2 deficiency. The animals present abnormal nerve conduction studies and peripheral nerve pathology, corroborating the human phenotype. In total, we conclude that biallelic variants in PCK2 cause a neurogenetic disorder featuring abnormal gait and peripheral neuropathy.