Class 1C Research Articles

#1723 Genetic landscape of polycystic kidney disease in a Chinese cohort – experience using whole genome sequencing in a tertiary renal unit

Abstract Background and Aims Genetic testing has increasingly been employed to provide definitive diagnoses and prognostic information in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). We aim to explore the genetic landscape of ADPKD in a Chinese cohort utilizing whole genome sequencing and study its real-world clinical utility. Method From 1st January 2022 to 31st March 2023, we recruited 50 adult Chinese patients who had the clinical diagnosis of ADPKD followed up at Queen Mary Hospital and consented to the study protocol. The study was approved by the University Institution Review Board and local ethics committees. Genomic DNA was isolated from samples obtained from patients per standard protocol. Whole-genome sequencing was performed and analysed through the germline analysis pipeline. Diagnostic analysis was performed per American College of Medical Genetics (ACMG) guidelines and ClinGen variant curation expert panel specifications. Diagnostic variants were defined as those classified as ‘pathogenic’ or ‘likely pathogenic’. Potential clinical utility of genetic findings were studied case-by-case based on the Kidney Disease Improving Global Outcomes (KDIGO) 2023 Clinical Practice Guideline for the Evaluation, Management and Treatment of ADPKD. Results Among the 50 unrelated probands with ADPKD, half were males and the mean age at presentation was 38. 38% patients had incidental finding of kidney cysts on abdominal imaging performed for unrelated symptoms or health screening, 32% presented for screening due to positive family history and only 30% presented with typical symptoms of ADPKD. Cystic complications were present in 30%, with cyst haemorrhage being the most common, followed by kidney stones, cyst rupture and infection. 80% patients also had liver cysts and none had a history of cerebral aneurysms. The majority of our cohort (72%) had a family history of ADPKD. We identified diagnostic variants in 35 individuals, reaching a diagnostic yield of 70%. Diagnostic variants were identified in PKD1 (20/35), PKD2 (11/35), IFT140 (3/35) and ALG9 (1/35). The majority of diagnostic variants were protein-truncating (32/35), while non-truncating variants consisted of 1 in-frame deletion and 2 missense variants in PKD1. We identified 3 copy number variation:NC_000016.10:g.2110587_2111851del,NC_000016.10:g.2132339_2137621del,NC_000016.10:g.2036427_2101117del. The genetic findings allowed physicians to make definitive diagnosis in 9 patients with negative family history of ADPKD. The genetic findings provided important prognostic information as protein-truncating variants in PKD1 or PKD2 were associated with more severe disease compared to non-truncating variants. For the 3 patients harbouring heterozygous pathogenic variants in IFT140 (NM_014714.4:c.2659G>T, NM_014714.4:c.3780del, NM_014714.4:c.1035_1036del), they demonstrated a milder PKD phenotype with stable kidney function, normal kidneys size and absence of liver cysts 10 years after the diagnosis. The patient with heterozygous likely pathogenic ALG9 variant (NM_024740.2:c.1225del) also had milder PKD phenotype with normal kidney function and normal sized kidneys on USG 5 years after the diagnosis. In another male patient with young hypertension who was classified as Mayo Class 1C according to kidney imaging, identifying the pathogenic protein-truncating variant in PKD1 (NM_001009944.3:c.7288C>T) would render him eligible to tolvaptan treatment in view of the high PROPKD score (7). Furthermore, the genetic findings enabled an earlier diagnosis in a number of family members by cascade testing and genetic results were important to identify suitable living-related kidney donors. Conclusion Genetic testing utilizing whole genome sequencing has multiple clinical utility in ADPKD patients. It could provide a definitive diagnosis in those with atypical presentation or without family history, inform prognosis, guide treatment, determine living-related donor suitability and allow earlier diagnosis in other family members.

CLASS 1C AGENTS ARE EFFECTIVE AND SAFE IN TERMINATING RECENT–ONSET ATRIAL FIBRILLATION IN ELDER PATIENTS TOO

Abstract Background Amiodarone is still widely used in recent–onset atrial fibrillation (AF), mainly in elder people, for its presumed safety. Nevertheless the growing experience with class 1c agents could encourage their use in order to improve the management of AF in elderly too. Aim: To assess whether class 1c agents could be considered effective and safe in elder people, as well in younger, in terminating recent–onset AF. Methods We retrospectively evaluated a three–years experience in over 75 patients treated in the Emergency Department of University Hospital of Verona for recent–onset AF (< 48 h). We excluded patients submitted to electrical cardioversion and those in whom the choice of treatment was forced by clinical conditions or coronary and structural heart disease. Then we compared the results in terms of effectiveness and safety between the two groups of treatment, class 1c agents vs amiodarone. Statistical analysis was performed using Chi–square test, with significance level set at p<0.05. Results We attempted at restoration of sinus rhythm in 264 patients older than 75 years observed for recent–onset AF from January 2018 to December 2020. According to exclusion criteria, the study population was restricted to 147 patients (53 males, 94 females; mean age 80 years, range 75–95) where the treatment depended on the physician‘s choice only. Most of these patients (61.2%) was treated with amiodarone, while in 38.8% class 1c agents were administered. Mean age was not significantly different between the groups (81 vs 78.5). After treatment, stable restoration of sinus rhythm was reported in 43 patients (47.7%) in amiodarone and in 47 (82.4%) in class 1c group (p<0.01). Median time of conversion was 240 minutes (range 30–680) in amiodarone while 60 (range 15–530) in class 1c group (p<0.01), as shown in fig. 1. Surprisingly, even the narrow sample did not allow any significance, the incidence of adverse events was notably superior in amiodarone patients, both in number (5 cases) and seriousness (2 cases). Whereas in class 1c group we reported only one mild adverse event. At the end of observation, 43 patients (75.4%) in class 1c but only 38 (42.2%) in amiodarone group were discharged with stable sinus rhythm (p<0.02). Conclusions Class 1c agents appear to be more effective and as safe as amiodarone in terminating recent–onset AF even in selected elder people. However these preliminary results need to be confirmed in a larger and prospective study.

Class 1C Antiarrhythmics for Premature Ventricular Complex Suppression in Nonischemic Cardiomyopathy With Implantable Cardioverter-Defibrillators

BackgroundPremature ventricular complexes (PVCs) are common and associated with worse outcomes in patients with heart failure. Class 1C antiarrhythmic drugs (AADs) effectively suppress PVCs, but guidelines currently restrict their use in structural heart disease. ObjectivesThis study aimed to assess the safety and efficacy of class 1C AADs in patients with nonischemic cardiomyopathy (NICM) and implantable cardioverter-defibrillators (ICDs). MethodsAll patients with NICM and an ICD treated with flecainide or propafenone at the Hospital of the University of Pennsylvania between 2014 and 2022 were identified. PVC burden, left ventricular ejection fraction (LVEF), and biventricular pacing percentage were compared before and during class 1C AAD treatment. Safety outcomes included sustained atrial and ventricular arrhythmias, heart failure admissions, and death. ResultsWe identified 34 patients, 23 receiving flecainide and 11 propafenone. Most patients (62%) had failed other AADs or catheter ablation (68%) prior to class 1C AAD initiation. PVC burden decreased from 20% ± 13% to 6% ± 7% (P < 0.001), LVEF increased from 33% ± 9% to 37% ± 10% (P = 0.01), and biventricular pacing percentage increased from 85% ± 9% to 93% ± 7% (P = 0.01). Sustained ventricular tachycardia (2 vs 9 patients) and admissions for decompensated heart failure (2 vs 3 patients) decreased compared with the 12 months prior to class 1C AAD initiation. ConclusionsClass 1C AADs effectively suppressed PVCs in patients with NICM and ICDs, leading to increases in LVEF and biventricular pacing percentage. In this limited sample, their use was safe. Larger studies are needed to confirm the safety of this approach.

Effect of concomitant usage of alteplase and mechanical thrombectomy for M1 middle cerebral artery occlusion on clinical outcome: a retrospective analysis of 457 patients from two centers.

Endovascular thrombectomy (EVT) and concomitant usage of intravenous alteplase (alteplase) in large vessel occlusion stroke may produce unwanted excess intracerebral hemorrhage (ICH). Whether this applies specifically to isolated occlusion of the M1 segment of the middle cerebral artery (MCA) is unknown. A retrospective study from two tertiary thrombectomy centers. ICH was determined according to Heidelberg Bleeding Classification (HBC). Factors associated with the occurrence of ICH in EVT alone vs. EVT with alteplase were evaluated using logistic regression analysis. Factors related to the clinical outcome as determined with a modified Rankin scale (mRS) were investigated with univariate and adjusted multivariate logistic regression analysis. The interaction between clinical variables and the usage of alteplase on the occurrence of ICH was evaluated. Any ICH occurred in 156/457 (34.1%) patients Class 1a bleeding in 37 (8.1%), type 2 in 45 (9.8%) Class 1c in 22 (4.8%), Class 2 in 25 (5.5%), and Class 3 (extraparenchymal) in 27 (5.9%). ICH occurred in similar frequency between alteplase-treated patients vs. EVT alone (85/262 [32%] vs. 71/195 [36%]; OR 1.19 (95% CI 0.81-1.76). After adjustment, odds for clinical outcome were lower in ICH patients (OR 0.44 [95% CI 0.25-0.74]), p = 0.002). Higher ICH rate was associated with more EVT steps (p for interaction -0.005), and usage of only stent-retriever (p for interaction =0.005). Utilization of alteplase alongside EVT for MCA M1 occlusion did not result in excessive ICH occurrences or clinical deterioration.

Abstract TP274: Challenging the Guidelines or Merely an Observation on Transthoracic Echocardiography

Introduction: Accurate detection of left atrial appendage (LAA) clot is critical in patients before Balloon Mitral Valvotomy (BMV). There is an elevated risk of thrombus formation and ischemic stroke in Rheumatic Heart Disease (RHD). The yearly prevalence of new stroke is 3-7.5% in RHD. Transesophageal Echocardiogram (TEE) has traditionally been the gold standard for LAA clot detection. But it is semi-invasive and have risks. The need for alternatives in this clinical context has prompted this comparative study. Hypothesis: Visualizing LAA on Transthoracic Echocardiogram (TTE) is facile in severe mitral stenosis due to increased LAA size, which is vital for stroke prevention. Methods: In this comparative study, we assessed the diagnostic accuracy of TTE as a non-invasive alternative to TEE for LAA clot detection in patients scheduled for BMV. A total of 150 patients admitted to a tertiary hospital underwent both TTE and TEE before BMV, with TEE as the reference standard for evaluation. Results: The mean age of our study population was 41.4 years, the majority were females (64.7%). The incidence of thrombus in TEE was 30%, with a significant difference in females (37%) vs. males (17%). TTE missed LAA clots in 18.8%, this discrepancy rate was 6% in males and 26% in females, signifying a significant reduction in clot detection in females. TEE exhibited no such limitations in clot detection between genders. TTE displayed sensitivity of 98% and specificity of 81%. The accuracy rate of TTE was 43.3%.Pearson Correlation coefficient and Fishers Exact test confirms significance. The non-invasive nature of TTE, devoid of procedural complexities, positions it as a Cost-effective option. Conclusion: Our study provides compelling evidence supporting the hypothesis that TTE is an effective and practical alternative to TEE for LAA clot detection in RHD patients Further studies are needed in this regard so that the current Class 1C recommendation for TEE before any BMV may need to be revised.

Effect of early cryoballoon ablation on atrial fibrillation recurrence - a nationwide register study

Abstract Introduction Cryoballoon ablation seems a viable first-line therapy in atrial fibrillation (AF) patients and outperforms antiarrhythmic drugs (AAD) regarding sinus rhythm maintenance. Despite this, guidelines in general recommend AAD use before ablation for AF, delaying a potential ablation. Therefore, data regarding the impact of the timing of cryoballoon ablation on AF recurrence in large, unselected cohorts is highly warranted. Purpose To examine AF recurrence after AF cryoballoon ablation by time from AF diagnosis to AF ablation. Methods From nationwide registers, we included all AF patients above 18 years who underwent first-time cryoballoon ablation from January 2010 to December 2018. The AF patients were stratified by ablation timing: Early ablation (&amp;lt; 1 year after AF diagnosis) and late ablation (≥1 year after AF diagnosis). The primary endpoint was recurrent AF, defined as a composite endpoint of AF hospitalization, claimed prescriptions of AAD, re-ablation or electrical cardioversions. The cumulative incidence of recurrent AF at 5-year follow-up after a blanking period of 90 days was estimated using the Aalen-Johansen estimator, taking the competing risk of death into account. The relative rates of recurrent AF were examined using cox models adjusted for sex, age, procedure-year, left atrial size, body mass index, AF-type (paroxysmal or persistent), hypertension, heart failure, ischemic heart disease, and chronic obstructive pulmonary disease. Results The study cohort consisted of 677 patients, 204 in the early ablation group and 473 in the late ablation group. Median age increased from 59 in the early ablation group to 65 in the late ablation group. In the early ablation group 71% had paroxysmal AF compared to 66% in the late ablation group. Use of amiodarone and Class 1C antiarrhythmic medication were higher in the late ablation group. The 5-year cumulative incidence of recurrent AF was 41% and 51% in the early and late ablation groups. The Hazard ratio (HR) and 95% confidence interval (95% CI) were 1.44 and (CI 1.10-1.89) in the late ablation group compared to the early ablation group (Figure 1). For paroxysmal AF the 5-year cumulative incidence of recurrent AF was 41% and 49% in the early and late ablation groups with a HR of 1.32 (CI 0.95-1.84) in the late ablation group compared to the early ablation group. For persistent AF the 5-year cumulative incidence of recurrent AF was 39% and 59% in the early and late ablation groups with a HR of 1.74 (CI 1.05-2.87) in the late ablation group compared to the early ablation group (Figure 2). Conclusion In this nationwide register study examining recurrent AF after cryoballoon ablation, we found lower recurrence rates when early ablation was performed. Based on this, early cryoballoon ablation could potentially provide considerable benefits and improve outcomes after ablation, indicating that cryoballoon ablation as first-line therapy might be ideal.Figure 1Figure 2

Abstract 14930: A Case of Flecainide Toxicity Causing Wide Complex Tachycardia, Unresponsiveness, Hemodynamic Instability and Pacemaker Under-Sensing

Introduction: Flecainide toxicity (FT) is an uncommon yet potentially lethal complication. We report a case of FT precipitated by acute kidney injury (AKI) in a patient with paroxysmal atrial fibrillation (AF) and a permanent pacemaker (PPM), who presented with wide complex tachycardia (WCT) and PPM under-sensing. Case presentation: An above 85-year-old female with paroxysmal AF and a PPM presented with an episode of unresponsiveness. While en route to the ED via ambulance, she had another episode associated with hemodynamic instability precipitated by a WCT. She regained consciousness after 1 biphasic DC shock. An EKG in the ED revealed sinus rhythm with atrial under-sensing and pacing spikes during ventricular refractory period (see picture). Laboratory data were consistent with AKI and normal electrolytes levels. PPM interrogation showed atrial under-sensing. Flecainide was discontinued and following drug washout the EKG changes resolved and the QRS normalized. She was discharged on amiodarone with no recurrence of arrhythmias on follow up. Discussion: Flecainide is Class 1C Antiarrhythmic drug that blocks fast the sodium channels. Prolongation of PR interval and QRS duration, in addition to supraventricular and ventricular arrhythmias, may occur with FT. Left ventricular dysfunction, myocardial scar, and high serum levels are considered risk factors for proarrhythmia. The drug half-life is prolonged in patients with renal disease/AKI. There are limited data on PPM malfunction due to FT, but it may cause increased pacing thresholds and failure to capture. Sodium bicarbonate, lidocaine, and ECMO have been used in treatment. Conclusion: FT can lead to lethal arrhythmias and PPM malfunction. Since flecainide serum levels are not always readily available, its diagnosis can be challenging. Therefore, physicians should be aware of the clinical presentation and EKG changes that accompany FT.

Problematika Peserta Didik dalam Operasi Hitung di Kelas 1 SD Negeri 80 Muara Bulian

Mathematics is widely used in various fields of life. However, in reality, activities for every individual cannot always run as they should, there will be some problems, even in learning mathematics. This situation is influenced by a person's comprehension of a lesson. Examples of problems in learning mathematics can be seen in the technique of adding derivatives, which is the result of dozens or tens or two-digit numbers (often called storing numbers), which results in incorrectly determining the results of further arithmetic operations. This research activity uses a qualitative approach. When referring to the problems studied, using qualitative methods makes it possible to gain an understanding of the reality on the ground. Based on the results of observations at SDN 80 Muara Bulian in class 1C in learning to count there were some students who wrote numbers from below which should have been from above so that they looked neat in writing and the prohibition on writing numbers starting from the early grades, so that later students could write numbers correctly. Correct. Learning withdrawal is an activity that is accompanied by symptoms that hinder achieving the desired goal, so efforts are needed to overcome these symptoms. Completion of learning is a disability or imperfection that causes a person to have difficulty carrying out learning activities so that the learning process becomes ineffective. Expansion of learning is a collection of various disorders that vary in manifestations, which are inability to listen, speak, read, write, think, and do arithmetic. Students with learning difficulties tend to have low interest and motivation in learning mathematics, this is shown by students who are not active during class learning, they tend not to want to ask questions when the teacher gives them the opportunity to ask questions. In addition, students are lazy to do exercises or assignments given by the teacher. Students who have difficulties are also often noisy in class and do not pay attention to the teacher's explanation.

Multifocal ectopic purkinje-related premature contractions and related cardiomyopathy.

In the past 20 years, genetic variants in SCN5A encoding the cardiac voltage-gated sodium channel Nav1.5 have been linked to a range of inherited cardiac arrhythmias: variants resulting in loss-of-function of Nav1.5 have been linked to sick sinus syndrome, atrial stand still, atrial fibrillation (AF) impaired pulse generation, progressive and non-progressive conduction defects, the Brugada Syndrome (BrS), and sudden cardiac death. SCN5A variants causing increased sodium current during the plateau phase of the cardiac action potential is associated with Long QT Syndrome type 3 (LQTS3), Torsade de Pointes ventricular tachycardia and SCD. Recently, gain-of-function variants have been linked to complex electrical phenotypes, such as the Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC) syndrome. MEPPC is a rare condition characterized by a high burden of premature atrial contractions (PACs) and/or premature ventricular contractions (PVCs) often accompanied by dilated cardiomyopathy (DCM). MEPPC is inherited in an autosomal dominant fashion with an almost complete penetrance. The onset is often in childhood. The link between SCN5A variants, MEPPC and DCM is currently not well understood, but amino acid substitutions resulting in gain-of-function of Nav1.5 or introduction of gating pore currents potentially play an important role. DCM patients with a MEPPC phenotype respond relatively poorly to standard heart failure medical therapy and catheter ablation as the PVCs originate from all parts of the fascicular Purkinje fiber network. Class 1c sodium channel inhibitors, notably flecainide, have a remarkable positive effect on the ectopic burden and the associated cardiomyopathy. This highlights the importance of genetic screening of DCM patients to identify patients with SCN5A variants associated with MEPPC. Here we review the MEPPC phenotype, MEPPC-SCN5A associated variants, and pathogenesis as well as treatment options.

Development and Validation of a Simple and Sensitive ICP-MS Method for the Quantification of Elemental Impurities in Propafenone Hydrochloride Drug Substance

Elemental impurities are substances present in drug products, excipients, or drug formulations. They may be formed by the presence of catalysts and environmental contaminants. Elemental impurities can be detected by a sophisticated method such as Inductively Coupled Plasma Mass Spectrometry (ICP–MS). ICP-MS is an advanced method to detect elemental impurities in drug substances. In this study Propafenone hydrochloride drug was used, Propafenone Hydrochloride is an antiarrhythmic medication belonging to class 1C used to prevent supraventricular and ventricular arrhythmias. The present study was aimed to develop and validate inductively coupled plasma mass spectroscopic (ICP–MS) method for detection of elemental contaminants, i.e., Class 1, Cd, Pb, As, Class 2A, Hg, Co, V, and Class 2B impurities such as Ni, T1, Se, Ag, Au, Pd, Ir, Os, Rh, Ru, and Pt. Total 17 elemental impurities were detected in Propafenone Hydrochloride and this method was employed for the regular sample analysis of 17 elemental impurities in Propafenone Hydrochloride for pharmaceutical use. The instrument conditions were set using RF power of 1550 W, auxiliary gas of 0.5 L/min, and nebulizer flow of 1.01 L/min nebulizer pump pressure was 0.10 rps, spray chamber temperature was 2°C, and mode used was He, He flow rate was 4.3 mL/min and the energy discrimination rate was 3.0 V. The technique is sensitive and may identify desirable elemental impurities within permissible regulatory limits when additional elements are present. The proposed ICP-MS approach has been found to be accurate, precise, linear, rugged, robust, and convenient for the quality control of the drug substance propafenone hydrochloride. The linearity results for each impurity were 0.9990. The methods were validated according to USP requirements and International Council for Harmonization ICH guidelines. The suggested approach is an excellent quality control tool for the concurrent quantitative assessment and detection of elemental contaminants at low levels in the drug substance propafenone hydrochloride.

#3593 COEXISTENCE OF 2 (DE NOVO) MUTATIONS IN 2 DIVERSE GENES (PKD1, LRP5) IN A PATIENT WITH RENAL AND LIVER POLYCYSTIC DISEASE

Abstract Introduction In Autosomal Dominant Polycystic Kidney Disease (ADPKD) the phenotype is variable. The most common extrarenal manifestation of the disease is the presence of hepatic cysts. Parallel cysts appearance in two different organs is possibly related to the genetic injury. We present in this report the case of a patient without family history of ADPKD and 2 different mutations related to cyst formation. Case report A 53 year old woman came to our outpatient ADPKD clinic with known multiple hepatic and renal cysts, diagnosed 11 years ago. She had no family history of ADPKD, both her parents aged 89 years old, had no renal or liver cysts on recent ultrasound scans. The patient had a background of recurrent UTIs, nephrolithiasis and hypertension diagnosed at 40 years old. Currently she was found to have e-GFR 49ml/min and liver function tests within normal range. Genetic testing and Magnetic Resonance Imaging (MRI) for estimating Total Kidney Volume (TKV) and hepatic imaging were conducted. In the genetic testing with a second generation sequencing, two heterozygous mutations in two different genes were depicted. The first was found in PKD1 gene: c.1396G&amp;gt;A (p.Val466Met) and causes the amino acid valine to be replaced by methionine at position 466 of the produced protein (Polycystin 1). It is reported as a variant of uncertain clinical significance because while it has been described in the literature in individuals with ADPKD, no functional studies have been performed to confirm its pathogenetic role. The second mutation concerned the LRP5 gene: c.3586G&amp;gt;A (p.Ala1196Thr) and causes the replacement of the amino acid alanine by threonine at position 1196 of the produced protein (Low density lipoprotein Receptor-related Protein-5). It is also referred as a variant of uncertain clinical significance, and exhibits autosomal dominant inheritance also. The MRI shows a particularly high cystic load in the liver (innumerable cysts) and multiple renal cysts in the two large kidneys, in a quite atypical form (not innumerable but many large cysts). The TKV was 1842 ml (1071 ml/m) and classified her in the class 1C (or possibly 2C because of the atypical form) according to the Mayo Clinic imaging classification system for ADPKD. The estimated prediction of the End-Stage Chronic Kidney Disease (ESCKD) (as long as the disease is not atypical) was according to the Mayo Clinic formula, 11 years. Discussion In a recent publication, pathological nucleotide variants of the LRP5 gene were associated with hepatic cystogenesis. Coexistence of PKD1 and LRP5 mutations was also identified in 2 families with polycystic kidney and liver disease. The underlying pathogenetic mechanism appears to be related to the connection between Polycystin-1 (the product of PKD1 involved in the pathogenesis of ADPKD) and the Wnt signaling pathway (affected by LRP5 gene mutations and linked to hepatic cystogenesis). The coexistence of the two mutations possibly means synergistic action. Unique facts and important phenotypic characteristics in this particular patient, is the de novo simultaneous appearance of the two mutations (the parents were not genetically tested but do not have cysts in very old age), the particularly large cystic liver load (which is also observed in typical ADPKD, especially in women), the atypical renal cyst imaging and the moderate to severe renal disease (expected ESCKD at 64 years, which it is more than expected in a PKD1 mutation only, but less than in a solitary PKD2 mutation). In conclusion, genetic complexity appears to go hand in hand with phenotype diversity in ADPKD and polycystic liver disease.

#5783 REAL-LIFE USE OF TOLVAPTAN IN ADPKD: A RETROSPECTIVE ANALYSIS OF A LARGE CANADIAN COHORT

Abstract Background and Aims Tolvaptan is the first disease-modifier therapy proven to slow eGFR decline in high-risk patients with ADPKD. However, barriers to its use in real-life settings have not been examined. Method Single-center, retrospective study of 523 current or new patients with ADPKD followed at the Center for Innovative Management of PKD in Toronto, Ontario between January 1, 2016 to December 30, 2018. All patients had clinical assessment and total kidney volume measurements; those deemed to be at high risk based on their Mayo Clinic Imaging Class (MCIC) 1C, 1D, or 1E, were offered tolvaptan with their preference (yes or no) and reasons for their choices recorded. Results Overall, 315/523 (60.2%) patients had MCIC 1C-1E; however, only 96 (30%) of them were treated with tolvaptan at the last follow-up. Among these high-risk patients, those treated with tolvaptan were more likely to have a higher eGFR (61 ±27 vs. 82 ±26 ml/min/1.73 m2), CKD stages 1–2 (41% vs. 79%), and MCIC 1D-1E (69% vs. 37%). The most common reasons provided for not taking tolvaptan were lifestyle preference related to the aquaretic effect (51%), older age ≥60 (12%), and pregnancy or family planning (6%). Conclusion In this real-world experience, at least 60% of patients with ADPKD considered to be at high risk for progression to ESKD by imaging were not treated with tolvaptan; most of them had earlier stages of CKD with well-preserved eGFR. The most common reason for their refusal to consider tolvaptan is a concern for intolerability of the aquaretic side-effect; strategies to mitigate this side-effect may help to reduce the barrier to tolvaptan therapy.

Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: Primary Results of a Double-Blind, Placebo-Controlled, Phase 2/3 Randomized Clinical Trial

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9mL/min/1.73m2. Enrollment included 236 and 242 patients in stages 1 and 2, respectively. In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8mg; venglustat, 15mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15mg (highest dose identified as safe and well tolerated in stage 1), or placebo. Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2). A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early. The short follow-up period after the end of treatment and limited generalizability of the findings. In patients with rapidly progressing ADPKD, treatment with venglustat at either 8mg or 15mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels. This study was funded by Sanofi. Registered at ClinicalTrials.gov with study number NCT03523728.

Safety of Pill-in-the-Pocket Class 1C Antiarrhythmic Drugs for Atrial Fibrillation.

Guidelines recommend that initial trial of a "pill-in-the-pocket" (PIP) Class 1C antiarrhythmic drug (AAD) for cardioversion of atrial fibrillation (AF) be performed in a monitored setting because of the potential for adverse reactions. This study sought to characterize real-world, contemporary use of the PIP approach, including the setting of initiation and incidence of adverse events. This retrospective cohort study included all patients at the Hospital of the University of Pennsylvania treated with a PIP approach for AF between 2007 and2020. A total of 273 patients (age 56 ± 13 years; 182 [67%] male; CHA2DS2VASc score 1.1 ± 1.2) took a first dose of PIP AAD. Flecainide was used in 151 (55%) and propafenone in 122 (45%). The first dose of PIP AAD was taken in a monitored setting in 167 (62%). Significant adverse events occurred in 7 patients (3%), 2 of whom had taken the doseinamonitored setting. Significant adverse events included unexplained syncope (1 of 7), symptomatic bradycardia/hypotension(4 of 7), and 1:1 atrial flutter (2 of 7). All occurred in patients taking 300mg of flecainide (n=4) or 600mg of propafenone (n=3). Electrical cardioversion was performed in 29 (11%) patients because of failure of the AAD to terminate AF. One patient required intravenous fluids and vasopressors for 2 hours because of persistent hypotension andbradycardia. Two patients required permanent pacemakers for bradycardia. The remaining patients required no intervention. Our data support the current recommendation to initiate PIP AAD in a monitored setting because ofrare significant adverse reactions that can require urgent intervention.

Use of flashcard media in English learning topic knowing numbers in class 1c students at SDITA El Mamur school

Background: English subjects at the SD/MI level emphasize the introduction of vocabulary as a foundation or basis in learning English. English ability can be seen from the wealth of vocabulary that a person has. One of the creative efforts in making learning interesting is using media flash cards.&#x0D; Purpose: This study aims to determine the application of flashcards media about numbers in English in grade 1C at SDITA EL MAMUR.&#x0D; Design and methods: The researcher collected data using a qualitative approach, the type of research was descriptive narrative, and the data collection technique was interviews with informants, namely the homeroom teacher of class 1C. at SDITA EL MAMUR.&#x0D; Results: The results of this study indicate that the use of flashcard media can assist students in pronouncing vocabulary numbers in English because the use of flashcard media is easy to understand and attractive to students.

Recurrence rates of atrial fibrillation ablation according to body mass Index, a nationwide, registry-based danish study

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Novo Nordisk supported the project. Background The proportion of people with obesity is rapidly rising, and the number of overweight patients undergoing ablation for atrial fibrillation (AF) is also increasing. The link between body mass index (BMI), and AF prevalence is well-established but the impact of BMI on the risk of recurrent AF after ablation is less elucidated. Therefore, data pertaining to recurrence rates of ablations according to BMI in large, unselected cohorts of patients is still warranted. Purpose To examine the risk of recurrent AF after AF ablation by BMI. Method Using Danish nationwide registries, all Danish patients above 18 years who underwent first-time AF ablation from January 1st 2010 to December 31st 2018 were identified and included at the date of ablation. The patients were categorized by BMI; underweight: &amp;lt; 18.5 kg/m2; normal weight: 18.5-24 kg/m2; overweight 25-29 kg/m2; obese 30-34 kg/m2; morbidly obese &amp;gt; 34 kg/m2. Recurrent AF was defined using a composite endpoint comprising claimed prescriptions of anti-arrhythmic drugs, hospital admissions due to AF, re-ablation, or electrical cardioversions. The cumulative incidence of recurrent AF by BMI at 1- and 5-year follow-up after a blanking period of 90 days, was estimated using the Aalen-Johansen estimator, takin death as competing risk in to account. The relative rates of recurrent AF by BMI were examined using Cox models adjusted for sex, age, procedure-year, heart failure, ischemic heart disease, chronic obstructive pulmonary disease, chronic kidney disease, hypertension, and diabetes. Results The study cohort consisted of 9,229 patients. Median age [IQR] decreased from 64 [60, 75] in the normal weight group to 60 [53, 66] in the morbidly obese. The number of patients with a CHA2DS2-VASc score of 2 or more increased from 48% in normal-weight to 65% in morbidly obese. Use of amiodarone increased by BMI category, while the use of Class 1C anti-arrhythmic medication remained stable. Figures 1 and 2 show the 1- and 5-year cumulative incidence of recurrent AF, Hazard Ratios (HR), and 95% Confidence Intervals (CI 95%) stratified by BMI categories and depict that the risk of recurrent AF increased incrementally and significantly in overweight groups compared to normal weight patients, both in 1- and 5-year follow-up. Underweight patients demonstrated non-significantly increased risk of recurrent AF, both in 1- and 5-year follow-up. Conclusion In this large nationwide study examining recurrent AF post AF ablation, we found that recurrence rates of AF increased incrementally according to BMI, both in short- and long-term follow-up. Therefore, aggressive weight management in overweight patients could potentially provide substantial benefits and improve short- and long-term outcomes after ablation.

MO016: Feasibility and Effectiveness of Short-Term Ketogenic Interventions in Autosomal Dominant Polycystic Kidney Disease (ADPKD): Results from the Reset-Pkd Study

Abstract BACKGROUND AND AIMS Over the last years, there has been increasing evidence that defects in the energy metabolism of polycystic kidney disease (PKD) cyst lining cells, especially increased glucose dependency and defects in fatty acid oxidation, may underlie the pathogenesis of ADPKD, Rowe et al. (Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat Med 2013; 19(4): 488–493). Based on these data, ketogenic dietary interventions have effectively been used in PKD animal models, Kipp et al. (A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease. Am J Physiol Renal Physiol 2016;310(8):F726-F31), Torres et al. (Ketosis ameliorates renal cyst growth in polycystic kidney disease. Cell Metab 2019;30(6):1007–23 e5) and Warner et al. (Food restriction ameliorates the development of polycystic kidney disease. J Am Soc Nephrol 2016;27(5):1437–1447). As a first-in-human pilot study, the RESET-PKD study now strives to translate these promising results in the clinical setting. METHOD The present study enrolled 10 ADPKD patients with rapid disease progression. After a screening visit (V1), patients followed their usual carbohydrate-rich diet for up to 4 weeks. In a second visit (V2), patients chose to either perform a 3-day water fast (WF) or a 14-day ketogenic diet (KD) until a third study visit (V3), after which they returned to their normal high-carbohydrate diet for 3–6 weeks until a final visit (V4). At all visits, total kidney volume (TKV) and total liver volume (TLV) were monitored using MRI; anthropometric parameters, body composition and biochemical parameters (i.e. serum creatinine, complete blood cell count, glucose, β-hydroxybutyrate in fingerstick blood and acetone in breath) were measured. Ketone bodies were evaluated at all visits and in between. Feasibility was examined using respective questionnaires. Undesirable effects such as feelings of hunger and discomfort were documented in a study diary. RESULTS All participants (KD: n = 5, WF: n = 5; age: 39.8 ± 11.6 years; eGFR: 82 ± 23.5 mL/min; TKV: 2224 ± 1156 mL) were classified as Mayo Class 1C to 1E. Serum creatinine values were not altered by the ketogenic dietary interventions (V2: 1.17 ± 0.33 mg/dL versus V3: 1.20 ± 0.35 mg/dL, P = 0.826), but serum glucose levels decreased significantly (V2: 84 ± 3 mg/dL, V3: 70 ± 13 mg/dL, P = 0.004). BHB blood levels as well as acetone levels in breath increased in both study arms (V1 to V2 average acetone: 2.6 ± 1.18 ppm, V2 to V3: 22.8 ± 11.9 ppm, P &amp;lt; 0.0001; V1 to V2 average BHB: 0.22 ± 0.08 mmol/L, V2 to V3: 1.89 ± 0.92 mmol/L, P &amp;lt; 0.0001). Nine out of 10 patients reached a ketogenic state during the intervention and 90% evaluated ketogenic interventions as being feasible while 80% of patients both reached the metabolic endpoint and rated ketogenic dietary interventions as feasible. TKV changes during KD and WF did not show any significant differences compared to the period on carbohydrate-rich diet (ΔTKV V1 to V2: 0.75 ± 0.54%, ΔTKV V2 to V3: −1.06 ± 1.16%). CONCLUSION The RESET-PKD study demonstrates feasibility of short-term ketogenic interventions both regarding reliable attainment of ketosis and patient-reported feasibility of this intervention in everyday life. In this proof of principle study, short-term ketogenic interventions could not show a significant reduction in TKV. However, this endpoint is likely to require long-term exposure to ketogenesis. Future large-scale clinical trials examining such long-term dietary interventions—e.g. the KETO-ADPKD study—will be of great importance to further evaluate long-term feasibility and the therapeutic potential of ketogenic diets in ADPKD.

Effect of Rythmol (propafenone HCl) administration during pregnancy in Wistar rats.

Propafenone is a well-known Class 1C antiarrhythmic agent that has sodium channel blocking properties as well as the ability to block 13 other channels and a modest calcium antagonistic effect. Propafenone has a profound electrophysiologic effect on auxiliary atrioventricular circuits and in patients with atrioventricular nodal reentry tachycardia can obstruct conduction in the fast conducting pathway. Furthermore, propafenone is less likely than other Class 1C drugs to cause proarrhythmia. However, although this medicine can pass through the placenta, the effects during pregnancy remain unknown. Here, we investigated the potential teratogenic and genotoxic effects of Rythmol during rat development. Pregnant Wistar rats received 46.25 mg/kg body weight of propafenone daily by gavage from Gestation Day (GD) 5 to GD 19. At GD 20, the dams were dissected, and their fetuses were assessed via morphologic, skeletal, and histologic investigation. In addition, a comet assay was used to measure DNA impairment of fetal skull osteocytes and hepatic cells. The study showed that propafenone treatment of pregnant rats led to a marked decrease in gravid uterine weight, number of implants/litter, number of viable fetuses, and bodyweight of fetuses but a clear increase in placental weight and placental index in the treated group. Frequent morphologic abnormalities and severe ossification deficiency in the cranium bones were observed in the treatment group. Various histopathological changes were observed in the liver, kidney, and brain tissues of maternally treated fetuses. Similarly, propafenone induced DNA damage to examined samples. Thus, our study indicates that propafenone may be embryotoxic in humans.

398 Right ventricular cardiogenic shock induced by propafenone intoxication: a case report

Abstract Aims Propafenone is a Class 1C antiarrhythmic drug recommended in the treatment of supraventricular or ventricular tachycardia and paroxysmal atrial fibrillation (AF). Most common cardiological features associated with propafenone intoxication include heart failure and conduction disturbances while other clinical findings range from nausea and vomiting to seizures and coma. Methods We report a case of atypical presentation of propafenone intoxication occurred in 88-year-old woman who presented at Emergency Department with severe ECG abnormalities and prevalent acute right ventricular with massive tricuspidalic regurgitation and cardiogenic shock. The patient underwent urgent coronary angiography that revealed a stable 90% coronary plaque that was treated with a single stent and then brought to Intensive Care Unit where she was successfully treated with inotropic and mechanical circulatory support (intra-aortic balloon pump, IABP). Results The patient progressively achieved hemodynamic stability with complete ECG normalization and biventricular function recovery. Conclusions Our case further expands the vast spectrum of presentations of Class 1c antiarrhythmic drugs overdose. In an emergency setting it is difficult to rule out other causes of cardiogenic shock but propafenone toxicity needs to be suspected in every case of hemodynamic instability in patients in chronical treatment. Patients in chronical treatment with propafenone who have kidney or liver dysfunction might be at higher risk of drug accumulation: in such cases, the real utility of propafenone must be evaluated before therapy initiation.

Long-term outcomes in patients treated with flecainide for atrial fibrillation with stable coronary artery disease

Class 1C antiarrhythmic drugs (AAD) have been associated with harm in patients treated for ventricular arrhythmias with a prior myocardial infarction. Consensus guidelines have advocated that these drugs not be used in patients with stable coronary artery disease (CAD). However, long-term data are lacking to know if unique risks exist when these drugs are used for atrial fibrillation (AF) in patients with CAD without a prior myocardial infarction. In 24,315 patients treated with the initiation of AADs, two populations were evaluated: (1) propensity-matched AF patients with CAD were created based upon AAD class (flecainide, n=1,114, vs class-3 AAD, n=1,114) and (2) AF patients who had undergone a percutaneous coronary intervention or coronary artery bypass graft (flecainide, n=150, and class-3 AAD, n=1,453). Outcomes at 3 years for mortality, heart failure (HF) hospitalization, ventricular tachycardia (VT), and MACE were compared between the groups. At 3 years, mortality (9.1% vs 19.3%, P < .0001), HF hospitalization (12.5% vs 18.3%, P < .0001), MACE (22.9% vs 36.6%, P < .0001), and VT (5.8% vs 8.5%, P=.02) rates were significantly lower in the flecainide group for population 1. In population 2, adverse event rates were also lower, although not significantly, in the flecainide compared to the class-3 AAD group for mortality (20.9% vs 25.8%, P=.26), HF hospitalization (24.5% vs 26.1%, P=.73), VT (10.9% vs 14.7%, P=.28) and MACE (44.5% vs 49.5%, P=.32). Flecainide in select patients with stable CAD for AF has a favorable safety profile compared to class-3 AADs. These data suggest the need for prospective trials of flecainide in AF patients with CAD to determine if the current guideline-recommended exclusion is warranted.