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Background: Standard-of-care (SoC) medications for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) are recommended as first-line therapy despite the lack of evidence from controlled clinical trials and well known off-target side effects., Objectives: We describe the impact of SoC therapy downtitration and withdrawal in patients already receiving aficamten in FOREST-HCM (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy; NCT04848506)., Methods: Patients receiving SoC therapy (beta-blocker, nondihydropyridine calcium-channel blocker, and/or disopyramide) were eligible for protocol-guided SoC downtitration and withdrawal at the discretion of the investigator and after achieving a stable dose of aficamten for ≥4 weeks. Successful SoC withdrawal was defined as at least a 50% dose-reduction in ≥1 medication. Adverse events (AEs) were prospectively evaluated 1 to 2 weeks after any SoC withdrawal., Results: Of 145 patients with oHCM who were followed for at least 24 weeks (mean age 60.5 ± 13.2 years; 44.8% female; 42% NYHA functional class III), 136 (93.8%) were receiving ≥1 SoC therapy; of those, 64 (47%) had an attempt at withdrawal, with 59 (92.2%) successful. Thirty-eight (64.4%) patients completely discontinued ≥1 medication, and 27 (45.8%) achieved aficamten monotherapy with 2 later restarting a SoC medication. There were no significant differences in baseline characteristics on day 1 in FOREST-HCM in those with a SoC-withdrawal vs no-withdrawal attempt. In patients who underwent successful SoC therapy withdrawal, NYHA functional class improved by ≥1 class in 79.2% from baseline, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score improved to 83.0 ± 15.8 points, and resting and Valsalva left ventricular outflow tract gradient improved to 14.3 ± 10.9 and 32.9 ± 21.4 mm Hg, respectively. N-terminal pro-B-type natriuretic peptide levels improved to a median of 220.0 pg/mL (Q1-Q3: 102.0-554.0.0 pg/mL) and high-sensitivity troponin I improved to a median of 6.0 ng/L (Q1-Q3:3.5-10.7 ng/L). Downtitration and withdrawal of SoC therapy did not impact these results (all P values for change were >0.05), and these changes were similar in patients who did not undergo SoC therapy withdrawal. There were no serious AEs attributed to SoC withdrawal and treatment emergent AEs were similar between groups., Conclusions: In FOREST-HCM, one-half of the patients with oHCM attempted downtitration and withdrawal of SoC medications while receiving aficamten treatment, with infrequent instances of resumption of SoC. Stopping and dose reduction of SoC medications were well tolerated with no adverse consequences in clinical measures of efficacy (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506)., Competing Interests: Funding Support and Author Disclosures The FOREST-HCM trial is funded by Cytokinetics, Incorporated. Dr Masri has received consulting/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, Haya, Lexion, BioMarin, Alexion, and Ionis; and has received research grants from Ionis, Pfizer, Cytokinetics, and Attralus. Dr Choudhury has received advisor fees from Cytokinetics. Dr Barriales-Villa has received consulting/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Elliott has received consulting fees from Bristol Myers Squibb, Pfizer, and Cytokinetics; has received speaker fees from Pfizer; and has received an unrestricted grant from Sarepta. Dr Maron has received consulting/advisor fees from Imbria, Edgewise, and Biomarin; and has received steering committee fees for SEQUIOA-HCM from Cytokinetics, Incorporated. Dr Nassif has received research and grant support from AstraZeneca and Cytokinetics; and has received consulting/advisory fees from Vifor and Cytokinetics. Dr Oreziak has received investigator fees from Cytokinetics and MyoKardia/Bristol Myers Squibb. Dr Owens has received consulting/advisor fees from Bristol Myers Squibb; and has received research grants from Bristol Myers Squibb, Cytokinetics, Novartis, and Actelion Pharmaceuticals. Dr Saberi has received consulting fees from Bristol Myers Squibb and Cytokinetics. Dr Tower-Rader has received research grants from Bristol Myers Squibb and Cytokinetics. Dr Rader has received consulting fees/honoraria from Medtronic, Cytokinetics, Bristol Myers Squibb, and Recor. Dr Garcia-Pavia has received Speakers Bureau fees from Bristol Myers Squibb, Pfizer, BridgeBio, Ionis, AstraZeneca, NovoNordisk, Intellia, and Alnylam; has received consulting fees from Bristol Myers Squibb, Cytokinetics, Rocket Pharma, Lexeo Therapeutics, Pfizer, BridgeBio, Daiichi-Sankyo, Neurimmune, Alnylam, AstraZeneca, Novo Nordisk, Attralus, Intellia, Idoven, General Electric, and Alexion; and has received research/educational support to his institution from Pfizer, BridgeBio, NovoNordisk, AstraZeneca, Intellia, and Alnylam. Dr Olivotto has received Speakers Bureau fees from Bristol Myers Squibb, Amicus, and Genzyme; has received consulting/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma, and Lexeo; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, Chiesi, and Boston Scientific. Dr Wang has received Speakers Bureau fees from Bristol Myers Squibb; has received consulting/advisor fees from Bristol Myers Squibb and Cytokinetics; and has received research grants from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular. Drs Heitner, Jacoby, Kupfer, Malik, Melloni, Meng, and Wei are employees of and hold stock in Cytokinetics Incorporated. Dr Sherrid has received consulting fees/honoraria from Pfizer Inc; and has served as a consultant for Cytokinetics Inc without payment. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: For symptomatic obstructive hypertrophic cardiomyopathy (oHCM), limited evidence exists on healthcare resource utilization (HRU) and cost for patients with symptomatic oHCM by treatment categories. We evaluated whether HRU and costs vary by initial treatment in symptomatic oHCM., Methods: This is a retrospective study of medical and pharmacy claims from 2016 to 2021 to identify (per International Classification of Disease Tenth Revision diagnosis codes) adult patients in the USA with symptomatic oHCM. Patients included in the study cohort were required to be treatment naïve (≥ 12 months' activity before first treatment) and symptomatic (fatigue, chest pain, syncope, dyspnea, heart failure, or palpitations within 3 months of index date). Patients were grouped by first index treatment [beta blocker (BB), calcium channel blockers (CCB), disopyramide, combination therapy], and HRU and costs [per person per year (PPPY), in USD] by initial treatment were reported., Results: Among 7334 patients with symptomatic oHCM, initial treatment included BB (65.8%), CCB (21.1%), disopyramide (1.2%), or BB + CCB (11.9%). Overall, 87.2% were prescribed monotherapy. Outpatient visits were the main driver of all-cause HRU (mean 11.5 PPPY), and varied by initial treatment (BB: 11.0, CCB: 10.5, disopyramide: 7.2, combination therapy: 12.1). All-cause urgent care visits were more frequent than inpatient visits (means: 5.4 and 0.83 PPPY, respectively). All-cause incurred costs were $46,628 PPPY overall and varied by treatment (BB: $47,029, CCB: $42,124, disopyramide: $27,007, combination therapy: $54,024)., Conclusions: In this large, US-based cohort of patients with symptomatic oHCM, initial therapy was most commonly BB and CCB monotherapy. Costs and HRU were high for most patients, but greater for those treated initially with combination therapy., (© 2024. The Author(s).)

Pediatric hypertrophic cardiomyopathy (HCM) has a wide range of clinical manifestations. Left ventricular outflow tract obstruction (LVOTO) at rest is present in up to one-third of children with HCM, with a further 50-60% of symptomatic children developing a gradient under exertion. Treatment options are limited, and there is a relative lack of data on the pediatric population. Disopyramide is a sodium channel blocker with negative inotropic properties. This therapy effectively reduces LVOTO in adults with HCM and delays surgical interventions, but it is not licensed for use in children. We aimed to review and analyze the influence of disopyramide over the pathophysiological, clinical, electrocardiographic, and echocardiographic characteristics of patients with HCM in infancy, childhood, adolescence, and adult age. While disopyramide remains a cornerstone in the management of pediatric HCM, the advent of mavacamten and aficamten heralds a new era of potential advancements. These emerging therapies could significantly improve the quality of life and prognosis for young patients with HCM.

Background: Left ventricular outflow tract obstruction (LVOTO) is present in 1/3 of children with Hypertrophic Cardiomyopathy (HCM). Disopyramide improves symptoms associated with LVOTO and delays surgical intervention in adults, but it is not licensed in children., Aim: To describe a single-centre thirty-year experience of using disopyramide to treat LVOTO-related symptoms in a paediatric HCM cohort., Methods: Clinical data were collected for all patients meeting diagnostic criteria for HCM (<18 years) at the time of initiation, 6 months after, and last follow-up or end of disopyramide treatment. It included demographics, clinical history, 12‑lead electrocardiography, and echocardiography. Comparisons between baseline and 6 month follow up, and end of follow up respectively were performed., Results: Fifty-one patients with HCM were started on disopyramide at a mean age 10.2±5.3 years. At 6 months, of those previously symptomatic, 33(86.8%) reported an improvement of symptoms and 12(31.6%) were asymptomatic. PR interval, corrected QT interval and maximal LVOT gradient had not significantly changed, but fewer participants were noted to have systolic anterior motion of the mitral valve 31 (72.1%) vs. 26 (57.80%). Patients were followed up for a median of 1.9 years (IQR 0.83-4.5). Nine patients (17.6%) reported side effects, and eleven patients (33.3%) with initial improvement in symptoms reported a return or worsening of symptoms requiring a change in medication (n = 4, 12.1%) or left ventricular septal myomectomy (n = 7, 21.2%) during follow up., Conclusion: Disopyramide is a safe and effective treatment for LVOTO-related symptoms in childhood obstructive HCM. Any delay in the need for invasive intervention, particularly during childhood, is of clear clinical benefit., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: To evaluate the role of bisoprolol to control symptoms and left ventricular outflow tract obstruction (LVOTO) in a consecutive cohort of adults with hypertrophic cardiomyopathy (HCM)., Methods and Results: In this retrospective study, patients with HCM with an LVOT gradient ≥50 mmHg after Valsalva manoeuvre and New York Heart Association (NYHA) class II-III symptoms were assigned to receive bisoprolol (starting at 1.25 mg daily). The initial dose was increased every two weeks to achieve the target in LVOT gradient <30 mmHg or the maximum tolerated dose. The primary endpoint was the achievement of a LVOT gradient <30 mmHg and ≥ 1 NYHA class improvement. The secondary endpoints were proportion of patients with LVOT gradient <30 mmHg or < 50 mmHg, proportion of patients with ≥1 NYHA class improvement, and change from baseline in LVOT gradient. Between December 2001 and December 2020, 92 patients were enrolled into the study. Sixteen (17%) patients on bisoprolol met the primary endpoint. Bisoprolol reduced the LVOT gradient to less than 30 mmHg in 33 (36%) patients, to less than 50 mmHg in 57 (62%), and improved NYHA class in 30 (33%). The mean reduction of LVOT gradient on bisoprolol was 28 (±14) mmHg and the percentage reduction was 42 (±21) %. In 35 (38%) patients, bisoprolol did not reduce the gradient to less than 50 mmHg requiring disopyramide and/or myectomy to achieve this goal., Conclusion: Treatment with bisoprolol was well-tolerated and effective in relieving obstruction and improving symptoms in a significant proportion of patients with symptomatic obstructive HCM., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Highly reliable identification of adults with hypertrophic cardiomyopathy (HC) at risk for sudden death (SD) has been reported. A significant controversy remains, however, regarding the most reliable risk stratification methodology for children and adolescents with HC. The present study assesses the accuracy of SD prediction and prevention with prophylactic implantable cardioverter-defibrillators (ICDs) in young HC patients. The study group is comprised of 146 HC patients <20 years of age evaluated consecutively over 17 years with prospective risk stratification and ICD decision-making. We relied on ≥1 established individual risk markers considered major within each patient's clinical profile, based on an enhanced American College of Cardiology /American Heart Association (ACC/AHA) guidelines algorithm. Of the 60 largely asymptomatic patients implanted with primary prevention ICDs at age 15 ± 4 years, 9 (15%) experienced device therapy terminating potentially lethal ventricular tachyarrhythmias and restoring sinus rhythm at 19 ± 6 years (range 9 to 29), 5.1 ± 6.0 years after implant; 3 patients had multiple appropriate ICD discharges. The individual risk marker algorithm was associated with 100% sensitivity in predicting SD events (95%CI: 69, 100) and 63% specificity for identifying patients without events (95%CI: 54, 71). Of these patients with device therapy, massive left ventricular hypertrophy (absolute wall thickness ≥30 mm) was the most common predictor, present in 70% of patients either alone or in combination with other risk markers. Each of the 146 study patients have survived to date at 22 ± 5 years, including all 86 without ICD recommendations. In conclusion, an enhanced ACC/AHA risk stratification strategy, based on established individual risk markers, was highly reliable in prospectively predicting SD events in children and adolescents with HC, and preventing arrhythmia-based catastrophes in this susceptible high risk population., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Significant left-ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) may result in symptoms and is associated with adverse outcomes. Although disopyramide can reduce resting gradients, nearly 30% of HCM patients do not respond. We sought to study the clinical and echocardiographic variables associated with disopyramide-induced LVOT-gradient reduction., Methods: Forty-one disopyramide-treated HCM patients (average daily-dose 305 mg) were subdivided into two groups: (1) nineteen responders, with a reduction of LVOT-gradients of at least 30% from baseline, and (2) twenty-two non-responders, in whom LVOT-gradients did not change or increased following treatment. All patients had a thorough clinical and echocardiographic assessment pre- and post-treatment initiation., Results: Patients who responded to disopyramide had better pretreatment left ventricular (LV) systolic function (LV ejection fraction of 67.9 ± 5.6% vs. 59.7 ± 5.8%, p = 0.0001), better LV global longitudinal strain (-17.9 ± 2.3% vs. -16.1 ± 2.5%, p = 0.048), less mitral regurgitation, smaller LV size (indexed LV end-systolic volume of 16.2 ± 5.1 ml/m 2 vs. 23.2 ± 6.8 ml/m 2 , p = 0.001), and lower LV maximal wall thickness (17.2±3 mm vs.19.2 ± 3.4 mm, p = 0.046). Baseline left atrial (LA) volumes were significantly lower in the responders, with higher indices of LA ejection fraction (62 ± 11.2% vs. 50.5 ± 12.2%, p = 0.005), systolic LA strain (34 ± 12.4% vs. 25.8 ± 10.6%, p = 0.04), and LA strain-rate (1.34 ± 0.49%/sec vs. 0.99 ± 0.24%/sec, p = 0.012). In multivariable analysis, the presence of reduced LV systolic function and systolic LA strain-rate remained independently associated with poor response to disopyramide., Conclusions: Obstructive HCM patients with more severe disease at baseline tend to respond less to disopyramide treatment. In those patients, early referral for alcohol septal ablation or myectomy surgery should be considered., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Hypertrophic cardiomyopathy is a heterogenous condition associated with a myriad of symptoms. Just as in other disease states, the aim of medical therapy is the alleviation of suffering, improvement of longevity, and the prevention of complications. This article focuses on the associated comorbidities seen in patients with hypertrophic cardiomyopathy, potential lifestyle interventions, and conventional medical treatments for symptomatic hypertrophic cardiomyopathy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Early repolarization (ER) has been associated with an increased risk of sudden cardiac arrest. Interestingly, ventricular arrhythmias seem to be triggered by parasympathetic stimulation. In the present case report, we describe complete control of highly frequent malignant ventricular arrhythmias after adding theophylline to ineffective oral hydroquinidine and high-rate pacing in a patient suffering from malignant ER. We hypothesize that the theophylline-mediated enhanced beta-adrenergic stimulation could reduce the transmural myocardial voltage discrepancy by increasing the inward I Ca,L current., (© 2017 Wiley Periodicals, Inc.)

Objective: Short QT syndrome (SQTS) is an inherited cardiac channelopathy, but at present little information is available on its pharmacological treatment. SQT3 variant (linked to the inward rectifier potassium current I K1 ) of SQTS, results from a gain-of-function mutation (Kir2.1 D172N) in the KCNJ2-encoded channels, which is associated with ventricular fibrillation (VF). Using biophysically-detailed human ventricular computer models, this study investigated the potential effects of quinidine, disopyramide, and E-4031 on SQT3., Approach: The ten Tusscher et al model of human ventricular myocyte action potential (AP) was modified to recapitulate the changes in I K1 due to heterozygous and homozygous forms of the D172N mutation. Wild-type (WT) and mutant WT-D172N and D172N formulations were incorporated into one-dimensional (1D) and 2D tissue models with transmural heterogeneities. Effects of drugs on channel-blocking activity were modelled using half-maximal inhibitory concentration (IC 50 ) and Hill coefficient (nH) values. Effects of drugs on AP duration (APD), effective refractory period (ERP) and QT interval of pseudo-ECGs were quantified, and both temporal and spatial vulnerability to re-entry was measured. Re-entry was simulated in the 2D ventricular tissue., Main Results: At the single cell level, the drugs quinidine, disopyramide, and E-4031 prolonged APD at 90% repolarization (APD 90 ), and decreased maximal transmural voltage heterogeneity (δV); this caused the decreased transmural dispersion of APD 90 . Quinidine prolonged the QT interval and decreased the T-wave amplitude. Furthermore, quinidine increased ERP and reduced temporal vulnerability and increased spatial vulnerability, resulting in a reduced susceptibility to arrhythmogenesis in SQT3. In the 2D tissue, quinidine was effective in terminating and preventing re-entry associated with the heterozygous D172N condition. Quinidine exhibited significantly better therapeutic effects on SQT3 than disopyramide and E-4031., Significance: This study substantiates a causal link between quinidine and QT interval prolongation in SQT3 Kir2.1 mutations and highlights possible pharmacological agent quinidine for treating SQT3 patients.

Aims: Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology., Methods: The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue., Results: At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide., Conclusions: The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.

Systolic anterior motion of the mitral valve (SAM) occurs intraoperatively after mitral valve repair (MVRr) in up to 14% of cases and typically resolves in the operating room with conservative measures. Less commonly SAM may also occur in the early or late postoperative period. The clinical course and optimal management of such cases is poorly defined, but reoperation is common. We describe our experience using disopyramide to successfully treat postoperative SAM refractory to beta blockade. Seven patients were retrospectively identified with mitral valve prolapse who underwent MVRr from 2003 to 2015 and were found during follow-up to have severe SAM with a left ventricular outflow tract (LVOT) gradient not observed intraoperatively. All 7 patients were successfully managed medically. In 5 cases, SAM persisted even after maximization of beta blockade, and the addition of disopyramide led to significant improvement or resolution of SAM, the LVOT gradient, and mitral regurgitation. The postoperative LVOT gradient initially exceeded 30 mm Hg in 6 of 7 patients. In 2 patients, the LVOT gradient exceeded 100 mm Hg, and both were managed medically with disopyramide with complete resolution of SAM. In conclusion, SAM after MVRr typically follows a benign clinical course and can be managed medically in most cases. When an initial treatment strategy of beta blockade is insufficient, the addition of disopyramide can effectively alleviate and terminate this condition and should be considered before reoperation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

HCM is the most common inherited heart condition occurring in 1:500 individuals in the general population. Left ventricular outflow obstruction at rest or after provocation occurs in 2/3 of HCM patients and is a frequent cause of limiting symptoms. Pharmacologic therapy is the first-line treatment for obstruction, and should be aggressively pursued before application of invasive therapy. Beta-blockade is given first, and up-titrated to decrease resting heart rate to between 50 and 60 beats per minute. However, beta-blockade is not expected to decrease resting gradients; its effect rests on decreasing the rise in gradient that accompanies exercise. For patients who fail beta-blockade the addition of oral disopyramide in adequate dose often will decrease resting gradients and offer meaningful relief of symptoms. Disopyramide vagolytic side effects, if they occur, can be greatly mitigated by simultaneous administration of oral pyridostigmine. This combination allows adequate dosing of disopyramide to achieve therapeutic goals. Verapamil utility in obstructive HCM with high resting gradients is limited by its vasodilating effects that can, infrequently, worsen gradient and symptoms. As such, we tend to avoid it in patients with high gradients and limiting heart failure symptoms. In a head-to-head comparison of intravenous drug administration in individual obstructive HCM patients the relative efficacy for lowering gradient was disopyramide > beta-blockade > verapamil. Severe symptoms in non-obstructive HCM are caused by fibrosis or severe myocyte disarray, and often by very small LV chamber size. Severe symptoms caused by these anatomic and histologic abnormalities, in the absence of obstruction, are less amenable to current pharmacotherapy. New pharmacotherapeutic approaches to HCM are on the horizon, that are to be evaluated in formal therapeutic trials.

It was reported that antiarrhythmic drugs (AADs) can be useful in controlling refractory seizures in humans or in enhancing the action of antiepileptic drugs (AEDs) in animal models. Disopyramide phosphate (DISO) is an AAD that blocks sodium channels in cardiac myocytes. We evaluated a DISO derivative, 2-(2-chlorophenyl)-2-(pyridin-2-yl)acetamide (ADD424042) for its anticonvulsant activity in a battery of rodent models of epileptic seizures. The compound displayed a broad spectrum of activity in the 'classical' models as well as in the models of pharmacoresistant seizures. Furthermore, ADD424042 showed good therapeutic indices between the anticonvulsant activity and the motor impairment. On the contrary, no anticonvulsant effects but severe lethality were observed in the primary anticonvulsant testing of the parent DISO. By performing the whole-cell voltage-clamp experiments in dispersed cortical neurons we demonstrated that ADD424042 decreased the maximal amplitude of voltage-gated sodium channels with an IC50 value in nM range. Moreover, the compound enhanced use-dependent block and decreased excitability in pyramidal neurons in the current-clamp experiments in cortical slices. Importantly, we found that ADD424042 possessed either no, or very small cardiotoxic effect. In contrast to DISO, ADD424042 did not produce any apparent changes in electrocardiogram (ECG) and arterial blood pressure recordings. ADD424042 had no effect on QT and corrected QT intervals, at a dose which was 15 times higher than ED50 for the anticonvulsant effect in the MES model. Taken together, these data suggest that ADD424042 has the potential to become a lead structure for novel broadly acting AEDs with wide margin of cardiac safety., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by unexplained left ventricular hypertrophy in the absence of other cardiac or systemic etiologies. Approximately two-thirds of patients with HCM develop left ventricular outflow tract (LVOT) obstruction with or without provocation, whereas nearly half develop heart failure with preserved ejection fraction. Medical management of heart failure with preserved ejection fraction is based on the presence of symptoms and LVOT obstruction and frequently includes β-blockers or verapamil. Disopyramide is a class Ia antiarrhythmic that historically was used for the treatment of arrhythmias; however, its contemporary use is often reserved for patients with HCM who are persistently symptomatic despite β-blockers or verapamil and have evidence of LVOT obstruction. The pharmacologic rationale for use of disopyramide is largely based on its strong negative inotropic property. Three clinical studies have showed significant improvements in heart failure symptoms and a reduction in the need for invasive therapy in patients treated with disopyramide. Appropriate dosing and monitoring of disopyramide are important to mitigate the potential for anticholinergic adverse events and proarrhythmias. Disopyramide is a safe and effective medication that reduces heart failure symptoms and LVOT gradient and delays the need for invasive therapy in patients with obstructive HCM., (© 2015 Pharmacotherapy Publications, Inc.)

We reviewed the natural history of patients with hypertrophic cardiomyopathy (HCM). The effect of medical treatments on natural history, left ventricular (LV) functions and LV remodeling was also evaluated. Sudden cardiac death and end-stage heart failure are the most serious complications of HCM. Age <30 years and a family history of sudden premature death are risk factors for sudden cardiac death in HCM patients. End-stage heart failure is not a specific additional phenomenon observed in patients with HCM, but is the natural course of the disease in most of those patients. After the occurrence of heart failure, the progression to cardiac death is very rapid. Young age at diagnosis, a family history of HCM, and greater wall thickness are associated with a greater likelihood of developing end-stage heart failure. Neither beta-blockers nor calcium antagonists can prevent this transition. The class Ia antiarrhythmic drugs, disopyramide and cibenzoline are useful for the reduction of LV pressure gradient. Unlike disopyramide, cibenzoline has little anticholinergic activity; therefore, this drug can be easily adapted to long-term use. In addition to the reduction in LV pressure gradient, cibenzoline can improve LV diastolic dysfunction, and induce regression of LV hypertrophy in patients with HCM. A decrease in intracellular Ca(2+) concentration through the activation of the Na(+)/Ca(2+) exchanger associated with cibenzoline therapy is likely to be closely related with the improvement in HCM-related disorders. It is possible that cibenzoline can prevent the progression from typical HCM to end-stage heart failure., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: There is controversy about preferred methods to relieve obstruction in hypertrophic cardiomyopathy patients still symptomatic after β-blockade or verapamil., Methods and Results: Of 737 patients prospectively registered at our institution, 299 (41%) required further therapy for obstruction for limiting symptoms, rest gradient 61 ± 45, provoked gradient 115 ± 49 mm Hg, and followed up for 4.8 years. Disopyramide was added in 221 (74%) patients and pharmacological control of symptoms was achieved in 141 (64%) patients. Overall, 138 (46%) patients had surgical relief of obstruction (91% myectomy) and 6 (2%) alcohol septal ablation. At follow-up, resting gradients in the 299 patients had decreased from 61 ± 44 to 10 ± 25 mm Hg (P<0.0001); New York Heart Association class decreased from 2.7 ± 0.7 to 1.8 ± 0.5 (P<0.0001). Kaplan-Meier survival at 10 years in the 299 advanced-care patients was 88% and did not differ from nonobstructed patients (P=0.28). Only 1 patient had sudden death, a low annual rate of 0.06%/y. Kaplan-Meier survival at 10 years in the advanced-care patients did not differ from that expected in a matched cohort of the US population (P=0.90)., Conclusions: Patients with obstruction and symptoms resistant to initial pharmacological therapy with β-blockade or verapamil may realize meaningful symptom relief and low mortality through stepped management, adding disopyramide in appropriately selected patients, and when needed, by surgical myectomy.

Pharmacologic therapy is the first line approach to relieve symptoms in obstructive hypertrophic cardiomyopathy. There are no randomized trials to evaluate their effect on prognosis. Gradient reduction by surgical septal myectomy is associated with excellent prognosis, but not all patients have symptoms severe enough to require surgery; and, guidelines recommend operation only for patients with high gradients and symptoms unresponsive to pharmacologic therapy. The combination of disopyramide and beta-blockade is effective in reducing resting gradients (though not to the extent of surgery). This review examines the question of whether pharmacologic reduction of gradient in asymptomatic patients or those with milder symptoms might decrease HCM-related mortality., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) occurs in 1 in 500 individuals. Treatment options for HCM differ from those administered in coronary disease, heart failure, and valvular disease patients that comprise the core of many cardiology practices. In this article, we offer a concise summary of the therapeutic use of disopyramide for reducing gradients and relieving symptoms in obstructive HCM., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aims: Patients undergo ablation for focal atrial fibrillation (AF) as a result of failure of anti-arrhythmic drugs. Our basic studies have implicated cholinergic and adrenergic neurotransmitter release as the underlying mechanism for focal AF. Therefore, we tested the efficacy of a combination of sodium channel-blocking agents with additional vagolytic properties and a β-blocker to terminate and prevent focal AF., Methods and Results: In 18 Na-pentobarbital-anaesthetized dogs, after a right or left thoracotomy, acetylcholine (Ach, 0.5 cc, 100 mM) was injected into a fat pad containing ganglionated plexi (GP) or applied on an atrial appendage (AA) to induce focal firing at the pulmonary veins (PVs) or AA, respectively. Disopyramide (2-4 mg/kg, n= 6) or quinidine (3-6 mg/kg, n= 12) combined with esmolol or propranolol (1 mg/kg, n= 13 and 5, respectively) were slowly injected to terminate (Group I, n= 12) or prevent (Group II, n= 6) Ach-induced sustained focal AF. In another four dogs, only the sodium channel-blocking agents with additional vagolytic properties or only the β-blocker was injected prior to or after the initiation of focal AF. At baseline, the mean duration of AF induced by Ach was 26 ± 4 min. Group I: After drugs, Ach-induced AF duration was 3 ± 1 min (P< 0.001). Group II: Prior to drugs, Ach-induced AF lasted for 19 ± 3 min. With the drug combination the duration of Ach-induced AF, decreased to 6 ± 1/min, P< 0.001. Either quinidine or propranolol alone did not change the duration of Ach-induced AF, mean 25 ± 10 min compared with Ach alone, 28 ± 16 min, P= 0.2., Conclusions: Type IA (cholinergic antagonist) plus Type II (β-adrenergic antagonist) provides significant prevention and suppression of focal AF arising at PV and non-PV sites.

Negative inotropic agents are often administered to decrease the left ventricular (LV) pressure gradient in patients with obstructive hypertrophic cardiomyopathy (HC). Little information is available regarding comparisons of the effects on LV pressure gradient among negative inotropic agents. The present study compared the decrease in the LV pressure gradient at rest in patients with obstructive HC after treatment with pilsicainide versus treatment with disopyramide or cibenzoline. The LV pressure gradient and LV function were assessed before and after the intravenous administration of each drug. In 12 patients (group A, mean pressure gradient 90 ± 24 mm Hg), the effects of disopyramide, propranolol, and verapamil were compared. In another 12 patients (group B, mean pressure gradient 98 ± 34 mm Hg), a comparison was performed among disopyramide, cibenzoline, and pilsicainide. In group A, the percentage of reduction in the LV pressure gradient was 7.7 ± 9.9% with verapamil, 19.0 ± 20.2% with propranolol, and 58.6 ± 15.0% with disopyramide, suggesting that disopyramide was more effective than either verapamil or propranolol. In group B, the percentage of reduction in the LV pressure gradient was 55.3 ± 26.6% with disopyramide, 55.3 ± 20.6% with cibenzoline, and 54.7 ± 15.4% with pilsicainide, suggesting an equivalent effect on the LV pressure gradient for these 3 agents. In conclusion, these results indicate that the acute efficacy for the reduction of the LV pressure gradient at rest by pilsicainide (a pure sodium channel blocker) was equivalent to that of disopyramide or cibenzoline (combined sodium and calcium channel blockers). Accordingly, sodium channel blockade might be more important for reducing the LV pressure gradient at rest in patients with obstructive HC than calcium channel blockade or β blockade., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The patient was a 57-year-old man with Brugada syndrome, who had been implanted with a implantable cardioverter defibrillator (ICD). The frequency of ventricular fibrillation (VF) started to increase about 4 years after ICD implantation, occurring, at worst, six times in one night. Immediately after starting oral administration of disopyramide, VF stopped occurring. He then discontinued taking disopyramide, but immediately after the discontinuation VF started occurring again, so he restarted taking disopyramide. Thereafter, VF completely stopped occurring. Findings observed in our case suggest that disopyramide could be added in our arsenal of medications for treating arrhythmic storms in patient with Brugada syndrome.

It remains unclear whether the combination of dual-chamber (DDD) pacing and disopyramide can achieve prolonged left ventricular outflow tract (LVOT) gradient reduction and symptom relief in patients with obstructive hypertrophic cardiomyopathy (HCM). In an HCM patient with a severe LVOT gradient, the combination of DDD pacing and disopyramide achieved marked improvement of gradient in the catheter laboratory and also after medium-term follow-up. The patient's severe dyspnoea was alleviated during the follow-up period. This combination might enable physicians to treat and manage elderly symptomatic obstructive HCM patients with a severe LVOT gradient more effectively and less invasively.

Background: Cibenzoline (CBZ), a class I antiarrhythmic drug, has been widely used to maintain sinus rhythm in patients with paroxysmal atrial fibrillation (P-AF). This agent has an anticholinergic action and will become the drug of first choice for vagally mediated P-AF. We assessed its efficacy quantitatively by analyzing the frequency-domain heart rate variability (FD-HRV) of the Holter electrocardiogram (ECG) in patients with vagal P-AF., Methods: We enrolled 65 consecutive patients with vagal P-AF, but 31 patients were excluded because of the occurrence of significant arrhythmias during the 24-h Holter recordings. Accordingly, CBZ was administered to the remaining 34 patients. After administration, a Holter ECG recording was made again. High frequency (HF) components, i.e., vagal tone index, on the FD-HRV analysis from 00:00 h to 06:00 h were used for assessment. In 14 patients, the treatment was changed to disopyramide (DSP) and the same analyses were performed., Results: In two patients, the FD-HRV analysis was not utilized after administration. Finally, 32 patients were available for evaluation. CBZ was considered effective for vagal P-AF in 24 patients (75%). After administration, the HF component levels decreased (1589+/-795 ms(2) vs. 850+/-524 ms(2), p<0.0001). Comparison of the pre-administration HF component levels between the CBZ-responsive group and the CBZ-non-responsive group showed higher levels in the CBZ-responsive group (1766+/-758 ms(2) vs. 1058+/-690 ms(2), p=0.026). Although no significant difference in the reduction of the HF component levels was found between CBZ and DSP, DSP had anticholinergic side effects in two patients (14%)., Conclusions: In vagal P-AF patients, larger HF components on the FD-HRV analysis could be a hallmark of the antiarrhythmic action of CBZ. The reduction in the HF component levels after drug administration is useful for a quantitative assessment of anticholinergic action.

Drug treatment of hypertrophic cardiomyopathy is the first-line treatment, at the onset of clinical signs and symptoms. Beta-blockers are proposed for symptomatic patients with no gradient or with a gradient that appears only on exertion. Verapamil is the standard second-line drug,when the beta-blockers are insufficient or ineffective but must be avoided when there is blockage at rest with severe symptoms. Disopyramide is indicated for patients with obstruction who do not respond to beta blockers and/or verapamil. Treatment with anticoagulants is widely prescribed because this disease is highly emboligenic.

We report here on the successful treatment for right ventricular outflow tract obstruction after bilateral lung transplantation in a patient with primary pulmonary hypertension. A 31-year-old female patient with primary pulmonary hypertension underwent successful bilateral lung transplantation. She had a pressure gradient of 30 mmHg through the right ventricular outflow tract one week after transplantation, but was successfully treated with atelenol and disopyramide. Long-term follow-up cardiac catheterization did not show any significant right ventricular outflow tract obstruction. The actual cause of the right ventricular outflow tract obstruction remained unknown, but longstanding pulmonary hypertension might have induced significant structural changes in the heart, such as right ventricular hypertrophy and enlargement.

Although high-degree atrioventricular (AV) block in patients with a history of syncope usually requires pacemaker implantation, therapeutic strategies should also be considered. A 35-year-old man presented with complaints of palpitations, nausea and dysgeusia. Since aged 30, the patient had experienced three episodes of syncope. Holter monitoring showed transient high-degree AV block (up to 5:4 block) associated with nausea, eructation and dysgeusia irrelevant to posture as well as ventricular ectopic beats with palpitation. A head-up tilt test revealed neurally mediated vasodepression but electrophysiological study showed no abnormalities. These results indicated that his transient high-degree AV block was functional, and syncope would have been because of neurally mediated vasodepression, not bradycardia. After administration of disopyramide at 300 mg daily, the symptoms subsided and ventricular ectopic beats and AV block disappeared. He has been well for 20 months.

It is important to identify patients with hypertrophic cardiomyopathy (HC) who have labile left ventricular outflow tract (LVOT) obstruction for consideration of ventricular septal reduction therapy. Although Doppler echocardiography has become the diagnostic modality to assess LVOT obstruction, it may not identify all patients with labile obstruction. This study assessed the diagnostic value of cardiac catheterization using isoproterenol challenge in 25 patients with HC in whom an LVOT obstruction (gradient >or=50 mm Hg) was clinically suspected, but not diagnosed using Doppler echocardiography. These patients underwent cardiac catheterization using a transseptal approach with isoproterenol challenge. During isoproterenol infusion, the gradient increased to >or=50 mm Hg in 14 patients and remained <50 mm Hg in 11 patients. Ten patients subsequently underwent surgical myectomy, 6 patients underwent alcohol septal ablation, and 9 patients were managed medically. Median follow-up was 26 months. Of patients who had a provoked gradient >50 mm Hg during isoproterenol infusion, 8 patients who underwent septal myectomy and 5 of 6 patients who underwent alcohol septal ablation had sustained alleviation of symptoms at follow-up. In conclusion, cardiac catheterization with isoproterenol challenge may identify patients with HC who may benefit from septal reduction therapy for whom the initial noninvasive evaluation does not show severe obstruction.

Introduction: Quinidine has been evaluated in patients with a short QT-1 syndrome caused by an IKr gain-of-function mutation of HERG. Recently, in vitro data with disopyramide showed an even stronger effect on the N588K mutant current. The aim of the present study was to test the in vivo effects of disopyramide in patients with short QT-1 syndrome caused by a N588K mutation in HERG., Methods and Results: Repetitive ECGs were recorded in two female patients with short QT-1 syndrome with a N588K-HERG mutation off drugs, on oral quinidine, and on oral disopyramide. One patient underwent exercise testing on drugs to determine the QT interval to heart rate relation, whereas the QT interval was calculated to the peak of the T wave in lead V3. In the same patient, drug-induced changes in ventricular effective refractory periods were determined by programmed ventricular stimulation via the ICD lead. Disopyramide increased the QT interval from QTc 329 ms/QTc 315 ms, respectively, off drugs to QTc 358 ms/QTc 333 ms in both patients and restored the heart rate dependence of the QT interval toward normal subjects (-0.39 ms/bpm off drugs, -0.58 ms/bpm on disopyramide vs. 1.29 +/- 0.33 ms/bpm in normal subjects). The ventricular effective refractory period increased under disopyramide by 40 ms., Conclusion: These preliminary observations suggest that oral disopyramide may be a suitable alternative to quinidine for prolonging the QT interval and ventricular effective refractory periods in patients with short QT-1 syndrome. Further studies of this pharmacologic approach are warranted.

Physicians treating hypertrophic cardiomyopathy (HCM) are faced with unique management challenges. Understanding pathophysiology and overall good prognosis forms the basis for medical treatment. Treatment is tailored by the presence or absence of outflow tract gradient and individual symptoms. In all patients, formal stratification for sudden death risk is necessary, with consideration of defibrillator implantation in patients deemed to be at high risk. In patients with no or only mild symptoms the approach of watchful waiting is often appropriate. For symptomatic patients with non-obstructed disease medical treatment with calcium channel blockers and beta-blockers is aimed to improve heart failure symptoms, and ischemia. Verapamil is the most often used, with likely benefit of relieving ischemia. Obstruction, most commonly due to systolic anterior motion of the mitral valve (SAM) and mitral-septal contact, occurs in >/=50% of all HCM patients, worsening symptoms and increasing mortality. Successful medical treatment of obstruction with negative inotropes slows acceleration of left ventricular ejection with delay in SAM, ultimately yielding a lower pressure gradient. Beta -blockers are the first line treatment in obstructive HCM predominantly by mitigating provocable gradients. The magnitude of symptom relief with verapamil is similar to the effect of beta -blockade. Disopyramide combined with beta -blockade is thought by some to be the most effective medical treatment of obstruction, and has been shown to be safe and not pro-arrhythmic. Most symptomatic HCM patients with significant obstruction at rest or provocation can be successfully managed with long-term medication alone.

Aims: We studied changes in atrial pacing threshold after termination of atrial fibrillation (AF) by acute administration of disopyramide phosphate (DP) to elucidate the suitable setting for atrial pacing output before AF termination., Methods and Results: Four patients with sick sinus syndrome implanted with AAI mode pacemakers were examined. Disopyramide phosphate (2 mg/kg body weight) was injected intravenously for termination of a total of eight AF episodes. The maximal pacing threshold after AF termination (5.2+/-0.8 V at 0.45 ms) was significantly higher than that at baseline (1.3+/-0.2 V at 0.45 ms; P<0.01) and the average increment was 433+/-68%. During a period free from AF, an acute administration of DP did not increase the atrial pacing threshold and serum disopyramide levels were not toxic., Conclusion: The increased atrial pacing threshold observed after AF termination cannot be explained by the action of DP alone. However, our results suggest that atrial pacing output should be set at the maximum value before DP is administered to induce AF termination in patients with AAI pacemaker-dependent bradyarrhythmias.

Amrubicin is a novel synthetic 9-aminoanthracycline derivative and is converted enzymatically to its C-13 hydroxy metabolite, amrubicinol, whose cytotoxic activity is 10-100 times that of amrubicin. We aimed to determine the maximum tolerated dose (MTD) of amrubicin and to characterize the pharmacokinetics of amrubicin and amrubicinol in previously treated patients with refractory or relapsed lung cancer. The 15 patients were treated with amrubicin intravenously at doses of 30, 35, or 40 mg/m(2) on three consecutive days every 3 weeks for a total of 43 courses. Neutropenia was the major toxicity (grade 4, 67%). The MTD was 40 mg/m(2), with the specific dose-limiting toxicities being grade 4 neutropenia persisting for >4 days, febrile neutropenia, or grade 3 arrhythmia in the three patients treated at this dose. A patient with non-small-cell lung cancer showed a partial response, and ten individuals experienced a stable disease. The area under the plasma concentration versus time curve (AUC) for amrubicin and that for amrubicinol increased with amrubicin dose. The amrubicin AUC was significantly correlated with the amrubicinol AUC. The recommended phase II dose of amrubicin for patients with lung cancer refractory to standard chemotherapy is thus 35 mg/m(2) once a day for three consecutive days every 3 weeks.

This article summarizes current understandings and therapies for both arrhythmias. Atrial flutter is most often arising from a macroreentry circuit in the right atrium or around scar tissue in case or previous cardiothoracic surgery. As a macroreentrant tachycardia it is regular and can lead to higher heart rates, especially if occurring with 1:1 conduction. In contrast atrial fibrillation, especially when occurring paroxysmal at the beginning, is arising from triggers within the pulmonary veins. Ablation strategies to electrically isolate those triggers have a treatment success rate of 80%, which is much more than can be achieved with antiarrhythmic medication (success rates 30-50%). Emergency treatment of both arrhythmias include cardioversion and pacemaker implantation with AV node ablation if necessary.

A 72-year-old man was referred for further assessment of a chronic cough. He noticed an association between the episodes of coughing and palpitations. Electrocardiography (ECG) revealed normal sinus rhythm and sporadic unifocal ventricular premature contractions (VPCs). Each cough was preceded by a premature beat. Continuous wave Doppler echocardiography revealed a VPC-induced transient increase in the pulmonary artery blood flow. He was successfully treated for VPCs with oral disopyramide, resulting in subsidence of both the coughing and palpitations. We suspect that the VPC-induced hemodynamic changes in the pulmonary circulation might be responsible for coughing in our patient. Premature contractions should be considered as a possible cause of chronic dry cough in the clinical setting.

The electrocardiographic parameters relating occurrence of ventricular fibrillation (VF) episodes in patients with idiopathic VF (IVF) are still unknown. The aim of this study was to clarify efficacy of pharmacological therapy in patients with IVF with respect to repolarization dynamics. The study group consisted of 8 men (age 43.6 +/- 9.1 years) with IVF (Brugada type 5 patients, prominent J wave in the inferior leads 3 patients) who had documented spontaneous episodes of VF, 7 of whom had implantable cardioverter defibrillators. The relation between QT and RR interval was analyzed from 24-hour Holter ECG using an automatic analyzing system before and after pharmacological therapy (bepridil 5 and disopyramide 3). From QT-RR linear regression lines, QT intervals were determined at RR intervals of 0.6 second [QT(0.6)], 1.0 second [QT(1.0)], and 1.2 seconds [QT(1.2)]. Pharmacological therapy increased the slope of QT-RR regression line from 0.105 +/- 0.020 to 0.144 +/- 0.037 (P < 0.05). Accordingly, QT(1.0) and QT(1.2) became longer after drug therapy [QT(1.0), 0.382 +/- 0.016 seconds vs 0.414 +/- 0.016 seconds (P < 0.01); QT(1.2), 0.403 +/- 0.017 seconds vs 0.442 +/- 0.021 seconds (P < 0.01)]. However, QT(0.6) did not change after drug administration. Before drug therapy the average episodes of VF were 5.5 +/- 5.8 (range 1 to 17) during the observation period of 19.3 +/- 17.6 months (range 6 to 60 months). After drug therapy, 6 patients had no episode of VF for 24 to 120 months (66.0 +/- 38.5 months). Two patients had a single episode of VF for 12- and 96-month follow-ups. Pharmacological therapy decreased the frequency of VF episodes in association with prolongation of QT intervals at slower heart rates. Not only J wave and ST elevation but also shorter QT intervals at slower heart rates may represent an electrophysiological substrate for development of VF episodes in these specific IVF patients.

Atrial pacing failure occurred after termination of atrial fibrillation by acute administration of disopyramide phosphate in a 71-year-old woman implanted with an AAI pacemaker for sick sinus syndrome. The atrial pacing threshold showed an 810% increase; however, the serum concentration of disopyramide corresponded to therapeutic level. Infusion of the same dose of disopyramide phosphate used during the period of atrial pacing rhythm did not increase the atrial pacing threshold. In the present patient, we supposed that atrial pacing failure did not occur by the effect of disopyramide alone, but rather was a reciprocal action in response to atrial fibrillation.

Objectives: In this study we assessed the long-term efficacy and safety of disopyramide for patients with obstructive hypertrophic cardiomyopathy (HCM)., Background: It has been reported that disopyramide may reduce left ventricular outflow gradient and improve symptoms in patients with HCM. However, long-term efficacy and safety of disopyramide has not been shown in a large cohort., Methods: Clinical and echocardiographic data were evaluated in 118 obstructive HCM patients treated with disopyramide at 4 HCM treatment centers. Mortality in the disopyramide-treated patients was compared with 373 obstructive HCM patients not treated with disopyramide., Results: Patients were followed with disopyramide for 3.1 +/- 2.6 years; dose 432 +/- 181 mg/day (97% also received beta-blockers). Seventy-eight patients (66%) were maintained with disopyramide without the necessity for major non-pharmacologic intervention with surgical myectomy, alcohol ablation, or pacing; outflow gradient at rest decreased from 75 +/- 33 to 40 +/- 32 mm Hg (p < 0.0001) and mean New York Heart Association functional class from 2.3 +/- 0.7 to 1.7 +/- 0.6 (p < 0.0001). Forty other patients (34%) could not be satisfactorily managed with disopyramide and required major invasive interventions because of inadequate symptom and gradient control or vagolytic side effects. All-cause annual cardiac death rate between disopyramide and non-disopyramide-treated patients did not differ significantly, 1.4% versus 2.6%/year (p = 0.07). There was also no difference in sudden death rate, 1.0%/year versus 1.8%/year (p = 0.08)., Conclusions: Two-thirds of obstructed HCM patients treated with disopyramide could be managed medically with amelioration of symptoms and about 50% reduction in subaortic gradient over >/=3 years. Disopyramide therapy does not appear to be proarrhythmic in HCM and should be considered before proceeding to surgical myectomy or alternate strategies.

We present the case of 38-year-old woman who experienced palpitations on swallowing, which were later found to be atrial fibrillation. Her symptoms improved on treatment with disopyramide and verapamil. Within 9 months, she was weaned from both medications without recurrence of symptoms.

Background: Fetal supraventricular tachycardia confers an increased risk of cardiac failure, hydrops, and eventual intrauterine death. Although protocols for prenatal anti-arrhythmic treatment are now well established, few published reports discuss this condition in the setting of multiple pregnancies., Case Report: A 20-year-old primigravida woman with a twin pregnancy presented at 31 weeks of gestation for routine obstetrical check-up which revealed simultaneous supraventricular tachycardia in both fetuses. She was treated with oral digoxin, resulting in successful cardioversion in both of the fetuses, which was maintained until they were delivered by caesarian section at 38 weeks gestation. However, several hours after birth, tachyarrhythmias recurred in each of the infants. Combined disopyramide therapy with digoxin was necessary to control their heart rates., Conclusion: The treatment of arrhythmia in fetuses of a multiple gestation presents unique issues, particularly when diagnosed prior to fetal lung maturity.

Right ventricular (RV) outflow tract obstruction (RVOTO) is an uncommon complication of lung transplantation in patients with pulmonary hypertension (PH) and both medical management and surgical intervention are required. A 28-year-old female with primary PH was referred and because she did not respond to medical treatment, living-donor lobar lung transplantation was performed. The operation was successful, but dyspnea and exercise intolerance developed during rehabilitation and transthoracic echocardiography revealed RVOTO. Intravenous disopyramide during cardiac catheterization reduced the pressure gradient from 35 mmHg to 16 mmHg without decreasing RV systolic pressure. However, electrical and hemodynamic parameters were adversely affected by disopyramide and thus, after cardiac catheterization, administration of fluid and a low dose of atenolol was started, and her symptoms improved. Transthoracic echocardiography showed improvement in the RVOTO. This case suggests that disopyramide should be avoided for patients with RVOTO following lung transplantation and that other negative inotropic agents, such as beta-blockers, are more effective for relief of RVOTO.

Patient education, identification of possible triggers of syncope and reassurance are a central feature of the management of patients with reflex syncope. Patients should be advised as to the importance of adequate hydration and taught physical countermaneuvers to enhance cardiac venous return. These maneuvers are sufficient for most patients, however, for a small number of patients who continue to have recurrent syncopal events, pharmacological intervention may be considered. Volume expansion can be enhanced with salt and fludrocortisone. Agents from diverse pharmacological classes have been used to attenuate the reflex response, enhance vasoconstriction and attenuate vagal outflow. Alpha adrenoreceptor agonists, anticholinergic agents, theophylline, beta adrenoreceptor antagonists, serotonin reuptake inhibitors and disopyramide are the most widely studied. None of these agents has shown a consistent therapeutic benefit in clinical trials.