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Journal of Clinical Medicine Apr 2023Although disopyramide has been widely used to reduce left ventricular outflow obstruction (LVOTO) and to improve symptoms in patients with obstructive hypertrophic...
Although disopyramide has been widely used to reduce left ventricular outflow obstruction (LVOTO) and to improve symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM), its use in real world as well as patient characteristics associated with a positive treatment response are still unclear. From 1980 to 2021, 1527 patients with HCM were evaluated and 372 (23%) had a LVOTO with active follow-up. The efficacy and safety of disopyramide were assessed systematically during 12 months (2-, 6-, and 12-month visits). Responders were patients with a final NYHA = I and a LVOTO < 30 mmHg; incomplete responders were those patients with NYHA > I and a LVOTO < 30 mmHg; and non-responders were symptomatic patients with no change in functional class NYHA and a LVOT gradient > 30 mmHg. Two-hundred-fifty-four (66%) patients were in functional class NYHA I/II and 118 (34%) in NYHA III/IV. A total of 118/372 (32%, 55 ± 16 years) underwent disopyramide therapy. Twenty-eight (24%) patients responded to therapy, 39 (33%) were incomplete responders, and 51 (43%) did not respond. Responder were mainly patients in functional NYHA class I/II (24/28, 86%), whereas incomplete responders and non-responders were more often in functional NYHA class III/IV (50/54 (93%)). An independent predictor of response to disopyramide treatment was the presence of NYHA I/II at the initiation of therapy (HR 1.5 (95% CI 1.1-4.5), = 0.03). No major life-threatening arrhythmic events or syncope occurred, despite 19 (16%) patients showing reduced QTc from baseline, 19 (16%) having no difference, while 80 (69%) patients had prolonged QTc interval. Thirty-one (26%) patients experienced side effects, in particular, 29 of the anticholinergic type. Disopyramide was underused in oHCM but effective in reducing LVOTO gradients and symptoms in slightly symptomatic patients with less severe disease phenotype with a safe pro-arrhythmic profile.
PubMed: 37048808
DOI: 10.3390/jcm12072725 -
Current Cardiology Reviews 2016HCM is the most common inherited heart condition occurring in 1:500 individuals in the general population. Left ventricular outflow obstruction at rest or after... (Review)
Review
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.
Topics: Animals; Cardiomyopathy, Hypertrophic; Disopyramide; Electrocardiography; Humans; Hypertension; Ventricular Outflow Obstruction
PubMed: 26818487
DOI: 10.2174/1573403x1201160126125403 -
Archives of Cardiovascular Diseases May 2009The management of patients with hypertrophic cardiomyopathy (HCM) has evolved markedly over the past 20 years, particularly with the rising number of indications for... (Review)
Review
The management of patients with hypertrophic cardiomyopathy (HCM) has evolved markedly over the past 20 years, particularly with the rising number of indications for implantable cardiac defibrillators (ICDs) and alcohol septal ablation (ASA). However, medical therapies targeted to improve quality of life are underused; when resting and/or exercise obstruction is present, an incremental and additive approach should be used based on a high dosage of beta-blockers, verapamil and/or disopyramide. Radiofrequency catheter ablation of atrial fibrillation or A-V node has been proposed in some instances. Treatment of syncope or presyncope due to an abnormal blood pressure response during exercise remains challenging. Only patients with obstruction who remain severely symptomatic despite maximal medical therapy should be considered for invasive procedures, including dual-chamber (DDD) pacing, ASA or surgery. The reported complication rates of ASA (essentially complete A-V block, incidence above 5-10%, with mortality rates ranging from 0-4%) and the benefits at medium-term follow-up appear comparable to those observed after myectomy, which, according to guidelines, should remain the primary treatment for most severely symptomatic drug-refractory young patients with obstruction. While the overall survival of patients with HCM is similar to that of the general population, detection of patients at high risk of sudden cardiac death remains challenging, particularly in the young, and indications for ICDs in high risk patients without prior cardiac arrest should be patient- and family-orientated.
Topics: Cardiac Pacing, Artificial; Cardiology; Cardiomyopathy, Hypertrophic; Cardiovascular Agents; Catheter Ablation; Death, Sudden, Cardiac; Defibrillators, Implantable; Electric Countershock; Embolization, Therapeutic; Ethanol; Heart Transplantation; Humans; Mitral Valve; Patient Selection; Quality of Life; Risk Assessment; Treatment Outcome
PubMed: 19520330
DOI: 10.1016/j.acvd.2009.03.008 -
British Journal of Clinical Pharmacology Sep 1978
Clinical Trial Randomized Controlled Trial
Topics: Adult; Biological Availability; Disopyramide; Half-Life; Humans; Kinetics; Male; Pyridines; Time Factors
PubMed: 687507
DOI: 10.1111/j.1365-2125.1978.tb04598.x -
Pharmaceutics Feb 2023Cardiomyopathy is associated with structural and functional abnormalities of the ventricular myocardium and can be classified in two major groups: hypertrophic (HCM) and...
Cardiomyopathy is associated with structural and functional abnormalities of the ventricular myocardium and can be classified in two major groups: hypertrophic (HCM) and dilated (DCM) cardiomyopathy. Computational modeling and drug design approaches can speed up the drug discovery and significantly reduce expenses aiming to improve the treatment of cardiomyopathy. In the SILICOFCM project, a multiscale platform is developed using coupled macro- and microsimulation through finite element (FE) modeling of fluid-structure interactions (FSI) and molecular drug interactions with the cardiac cells. FSI was used for modeling the left ventricle (LV) with a nonlinear material model of the heart wall. Simulations of the drugs' influence on the electro-mechanics LV coupling were separated in two scenarios, defined by the principal action of specific drugs. We examined the effects of Disopyramide and Dygoxin which modulate Ca transients (first scenario), and Mavacamten and 2-deoxy adenosine triphosphate (dATP) which affect changes of kinetic parameters (second scenario). Changes of pressures, displacements, and velocity distributions, as well as pressure-volume (P-V) loops in the LV models of HCM and DCM patients were presented. Additionally, the results obtained from the SILICOFCM Risk Stratification Tool and PAK software for high-risk HCM patients closely followed the clinical observations. This approach can give much more information on risk prediction of cardiac disease to specific patients and better insight into estimated effects of drug therapy, leading to improved patient monitoring and treatment.
PubMed: 36986654
DOI: 10.3390/pharmaceutics15030793 -
Journal of the American Heart... May 2017Disopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns...
BACKGROUND
Disopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns about its use in the ambulatory setting. The risk of initiating disopyramide in this manner has never been evaluated.
METHODS AND RESULTS
All charts of patients seen in the outpatient hypertrophic cardiomyopathy clinic between 2010 and 2014 were screened for initiation of disopyramide and data were extracted. Disopyramide in our clinic is usually initiated at a dose of 300 mg daily and titrated during follow-up. A total of 2015 patients were seen in the clinic, including 168 who were started on disopyramide. There were no cardiac events within 3 months of disopyramide initiation. During long-term follow-up (255 patient-years; mean, 447 days; interquartile range, 201-779), only 2 patients developed cardiac events (syncope of unknown cause in both). Thirty-eight patients (23%) developed side effects of disopyramide and 18 (11%) stopped the drug because of these side effects. Of the patients continuing disopyramide long term, 63% remained free of septal reduction interventions at end of follow-up. Disopyramide at a dose of 300 mg prolonged the mean QTc interval by 19±23 ms; however, increasing the dose to 600 mg had no further significant effect.
CONCLUSIONS
Initiation of disopyramide in the outpatient setting is safe and the risk of subsequent sudden cardiac death is low. Because of its QT-prolonging effect, precautions may be necessary in patients at higher risk of torsades de pointes.
Topics: Action Potentials; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Cardiomyopathy, Hypertrophic; Databases, Factual; Disopyramide; Electrocardiography; Female; Heart Rate; Humans; Male; Middle Aged; Risk Factors; Syncope; Time Factors; Torsades de Pointes; Treatment Outcome; Voltage-Gated Sodium Channel Blockers
PubMed: 28550094
DOI: 10.1161/JAHA.116.005152 -
JACC. Basic To Translational Science Nov 2019Disopyramide is effective and safe in patients with obstructive hypertrophic cardiomyopathy. However, its cellular and molecular mechanisms of action are unknown. We...
Disopyramide is effective and safe in patients with obstructive hypertrophic cardiomyopathy. However, its cellular and molecular mechanisms of action are unknown. We tested disopyramide in cardiomyocytes from the septum of surgical myectomy patients: disopyramide inhibits multiple ion channels, leading to lower Ca transients and force, and shortens action potentials, thus reducing cellular arrhythmias. The electrophysiological profile of disopyramide explains the efficient reduction of outflow gradients but also the limited prolongation of the QT interval and the absence of arrhythmic side effects observed in 39 disopyramide-treated patients. In conclusion, our results support the idea that disopyramide is safe for outpatient use in obstructive patients.
PubMed: 31998849
DOI: 10.1016/j.jacbts.2019.06.004 -
Clinical Cardiology May 1990Mexiletine is a Class IB antiarrhythmic which has basic and clinical electrophysiologic properties similar to lidocaine. Like other Class I antiarrhythmic agents,... (Review)
Review
Mexiletine is a Class IB antiarrhythmic which has basic and clinical electrophysiologic properties similar to lidocaine. Like other Class I antiarrhythmic agents, mexiletine blocks the rapid inward sodium current responsible for phase 0 of the action potential. It has been noted in the clinical electrophysiology laboratory to have minimal effect on sinus node function and AV nodal and His-Purkinje system conduction. Pharmacokinetic studies have shown that oral absorption is rapid with bioavailability of 80-90%. Mexiletine is predominantly metabolized by the liver with elimination half-life of 9 to 12 hours. The antiarrhythmic effects of the primary drug's metabolites remain to be defined. Hemodynamic studies have shown mexiletine to have a lesser negative inotropic effect than procainamide or disopyramide. Although mexiletine as a single agent successfully suppresses 60 to 80% of spontaneous ventricular arrhythmias, it has lower efficacy in suppression of induced ventricular arrhythmias. Multiple studies have shown that as monotherapy mexiletine is effective in preventing the induction of ventricular tachycardia in approximately 20% of patients. When used in combination with a Class IA antiarrhythmic drug for suppression of induced ventricular arrhythmias, multiple investigators have reported greater efficacy. Neurological side effects (tremor, dizziness, memory loss) occur in approximately 10% of patients while gastrointestinal side effects (nausea, anorexia, gastric irritation) occur in up to 40% of patients. Proarrhythmia or other serious toxicity from the drug is uncommon.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Therapy, Combination; Hemodynamics; Humans; Mexiletine
PubMed: 2189614
DOI: 10.1002/clc.4960130509 -
Molecular Psychiatry Jul 2023Anxiety disorders are increasingly prevalent, affect people's ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed...
Anxiety disorders are increasingly prevalent, affect people's ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed and sub-optimally treated, resulting in adverse life events and/or addictions. We endeavored to discover blood biomarkers for anxiety, using a four-step approach. First, we used a longitudinal within-subject design in individuals with psychiatric disorders to discover blood gene expression changes between self-reported low anxiety and high anxiety states. Second, we prioritized the list of candidate biomarkers with a Convergent Functional Genomics approach using other evidence in the field. Third, we validated our top biomarkers from discovery and prioritization in an independent cohort of psychiatric subjects with clinically severe anxiety. Fourth, we tested these candidate biomarkers for clinical utility, i.e. ability to predict anxiety severity state, and future clinical worsening (hospitalizations with anxiety as a contributory cause), in another independent cohort of psychiatric subjects. We showed increased accuracy of individual biomarkers with a personalized approach, by gender and diagnosis, particularly in women. The biomarkers with the best overall evidence were GAD1, NTRK3, ADRA2A, FZD10, GRK4, and SLC6A4. Finally, we identified which of our biomarkers are targets of existing drugs (such as a valproate, omega-3 fatty acids, fluoxetine, lithium, sertraline, benzodiazepines, and ketamine), and thus can be used to match patients to medications and measure response to treatment. We also used our biomarker gene expression signature to identify drugs that could be repurposed for treating anxiety, such as estradiol, pirenperone, loperamide, and disopyramide. Given the detrimental impact of untreated anxiety, the current lack of objective measures to guide treatment, and the addiction potential of existing benzodiazepines-based anxiety medications, there is a urgent need for more precise and personalized approaches like the one we developed.
Topics: Humans; Female; Precision Medicine; Pharmacogenetics; Quality of Life; Anxiety Disorders; Biomarkers; Risk Assessment; Benzodiazepines; Serotonin Plasma Membrane Transport Proteins
PubMed: 36878964
DOI: 10.1038/s41380-023-01998-0 -
The Cochrane Database of Systematic... Aug 2015Coronary artery disease is a major public health problem affecting both developed and developing countries. Acute coronary syndromes include unstable angina and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Coronary artery disease is a major public health problem affecting both developed and developing countries. Acute coronary syndromes include unstable angina and myocardial infarction with or without ST-segment elevation (electrocardiogram sector is higher than baseline). Ventricular arrhythmia after myocardial infarction is associated with high risk of mortality. The evidence is out of date, and considerable uncertainty remains about the effects of prophylactic use of lidocaine on all-cause mortality, in particular, in patients with suspected myocardial infarction.
OBJECTIVES
To determine the clinical effectiveness and safety of prophylactic lidocaine in preventing death among people with myocardial infarction.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 3), MEDLINE Ovid (1946 to 13 April 2015), EMBASE (1947 to 13 April 2015) and Latin American Caribbean Health Sciences Literature (LILACS) (1986 to 13 April 2015). We also searched Web of Science (1970 to 13 April 2013) and handsearched the reference lists of included papers. We applied no language restriction in the search.
SELECTION CRITERIA
We included randomised controlled trials assessing the effects of prophylactic lidocaine for myocardial infarction. We considered all-cause mortality, cardiac mortality and overall survival at 30 days after myocardial infarction as primary outcomes.
DATA COLLECTION AND ANALYSIS
We performed study selection, risk of bias assessment and data extraction in duplicate. We estimated risk ratios (RRs) for dichotomous outcomes and measured statistical heterogeneity using I(2). We used a random-effects model and conducted trial sequential analysis.
MAIN RESULTS
We identified 37 randomised controlled trials involving 11,948 participants. These trials compared lidocaine versus placebo or no intervention, disopyramide, mexiletine, tocainide, propafenone, amiodarone, dimethylammonium chloride, aprindine and pirmenol. Overall, trials were underpowered and had high risk of bias. Ninety-seven per cent of trials (36/37) were conducted without an a priori sample size estimation. Ten trials were sponsored by the pharmaceutical industry. Trials were conducted in 17 countries, and intravenous intervention was the most frequent route of administration.In trials involving participants with proven or non-proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences regarding all-cause mortality (213/5879 (3.62%) vs 199/5848 (3.40%); RR 1.02, 95% CI 0.82 to 1.27; participants = 11727; studies = 18; I(2) = 15%); low-quality evidence), cardiac mortality (69/4184 (1.65%) vs 62/4093 (1.51%); RR 1.03, 95% CI 0.70 to 1.50; participants = 8277; studies = 12; I(2) = 12%; low-quality evidence) and prophylaxis of ventricular fibrillation (76/5128 (1.48%) vs 103/4987 (2.01%); RR 0.78, 95% CI 0.55 to 1.12; participants = 10115; studies = 16; I(2) = 18%; low-quality evidence). In terms of sinus bradycardia, lidocaine effect is imprecise compared with effects of placebo or no intervention (55/1346 (4.08%) vs 49/1203 (4.07%); RR 1.09, 95% CI 0.66 to 1.80; participants = 2549; studies = 8; I(2) = 21%; very low-quality evidence). In trials involving only participants with proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences in all-cause mortality (148/2747 (5.39%) vs 135/2506 (5.39%); RR 1.01, 95% CI 0.79 to 1.30; participants = 5253; studies = 16; I(2) = 9%; low-quality evidence). No significant differences were noted between lidocaine and any other antiarrhythmic drug in terms of all-cause mortality and ventricular fibrillation. Data on overall survival 30 days after myocardial infarction were not reported. Lidocaine compared with placebo or no intervention increased risk of asystole (35/3393 (1.03%) vs 14/3443 (0.41%); RR 2.32, 95% CI 1.26 to 4.26; participants = 6826; studies = 4; I(2) = 0%; very low-quality evidence) and dizziness/drowsiness (74/1259 (5.88%) vs 16/1274 (1.26%); RR 3.85, 95% CI 2.29 to 6.47; participants = 2533; studies = 6; I(2) = 0%; low-quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. Trial sequential analyses suggest that additional trials may not be needed for reliable conclusions to be drawn regarding these outcomes.
AUTHORS' CONCLUSIONS
This Cochrane review found evidence of low quality to suggest that prophylactic lidocaine has very little or no effect on mortality or ventricular fibrillation in people with acute myocardial infarction. The safety profile is unclear. This conclusion is based on randomised controlled trials with high risk of bias. However (disregarding the risk of bias), trial sequential analysis suggests that additional trials may not be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might require additional higher trials.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bradycardia; Humans; Lidocaine; Myocardial Infarction; Randomized Controlled Trials as Topic; Ventricular Fibrillation
PubMed: 26295202
DOI: 10.1002/14651858.CD008553.pub2