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Cardiology Research Aug 2023Hypertrophic cardiomyopathy is one of the most common genetic inherited diseases of myocardium, which is caused by mutation in genes encoding proteins for the cardiac... (Review)
Review
Hypertrophic cardiomyopathy is one of the most common genetic inherited diseases of myocardium, which is caused by mutation in genes encoding proteins for the cardiac sarcomere. It is the most frequent cause of sudden death in young people and trained athletes. All diagnostic methods, including heart catheterization, transthoracic and transesophageal echocardiography, magnetic resonance imaging, genetic counseling and tissue biopsy are required for risk and therapy stratification and should be individualized depending on phenotype and genotype. Current therapy has not been tested adequately. Beta-blockers and verapamil can cause hypotension which can make hypertrophic cardiomyopathy worse. Disopyramide has been inadequately studied, and mavacamten was only studied in small trials. More definitive trials are currently ongoing. Novel invasive and noninvasive diagnostics, medical therapies, interventional and surgical approaches tend to influence the natural history of the disease, favoring a better future for this patient population.
PubMed: 37559708
DOI: 10.14740/cr1514 -
American Journal of Cardiovascular... Sep 2023Aficamten is a novel cardiac myosin inhibitor that has demonstrated its ability to safely lower left ventricular outflow tract (LVOT) gradients and improve heart failure... (Review)
Review
Aficamten is a novel cardiac myosin inhibitor that has demonstrated its ability to safely lower left ventricular outflow tract (LVOT) gradients and improve heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM). Based on the REDWOOD-HCM open label extension (OLE) study, participants receiving aficamten had significantly reduced resting and Valsalva LVOT gradient within 2 weeks after initiating treatment, with ongoing improvements over 24 weeks, and recent evidence suggests effects can sustain up to 48 weeks. While beta-blockers, calcium channel blockers, and disopyramide have shown some benefits in managing HCM, they have limited direct impact on the underlying disease process in patients with obstructive HCM. Aficamten achieves its therapeutic effect by reducing hypercontractility and improving diastolic function in obstructive HCM. Mavacamten was the first cardiac myosin inhibitor approved for symptomatic obstructive HCM. However, aficamten has a shorter human half-life (t) and fewer drug-drug interactions, making it a preferable treatment option. This review evaluates the long-term clinical value and safety of aficamten in patients with obstructive HCM based on available data from completed and ongoing clinical trials. Additionally, the molecular basis of sarcomere-targeted therapy in reducing LVOT gradients is explored, and its potential in managing obstructive HCM is discussed.
Topics: Humans; Cardiomyopathy, Hypertrophic; Calcium Channel Blockers; Adrenergic beta-Antagonists; Cardiac Myosins
PubMed: 37526885
DOI: 10.1007/s40256-023-00599-0 -
Journal of Cardiac Failure Nov 2023
Topics: Humans; Disopyramide; Sequoia; Heart Failure; Anti-Arrhythmia Agents; Cardiomyopathy, Hypertrophic
PubMed: 37473912
DOI: 10.1016/j.cardfail.2023.07.003 -
Journal of Pharmacological and... 2023Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia....
Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia. Various computational tools including machine learning models (MLM) for the prediction of hERG inhibition have been developed to facilitate the throughput screening of drugs in development and optimise thus the prediction of hERG liabilities. The use of MLM relies on large libraries of training compounds for the quantitative structure-activity relationship (QSAR) modelling of hERG inhibition. The focus on inhibition omits potential effects of hERG channel agonist molecules and their associated QT shortening risk. It is instructive, therefore, to consider how known hERG agonists are handled by MLM. Here, two highly developed online computational tools for the prediction of hERG liability, Pred-hERG and HergSPred were probed for their ability to detect hERG activator drug molecules as hERG interactors. In total, 73 hERG blockers were tested with both computational tools giving overall good predictions for hERG blockers with reported ICs below Pred-hERG and HergSPred cut-off threshold for hERG inhibition. However, for compounds with reported ICs above this threshold such as disopyramide or sotalol discrepancies were observed. HergSPred identified all 20 hERG agonists selected as interacting with the hERG channel. Further studies are warranted to improve online MLM prediction of hERG related cardiotoxicity, by explicitly taking into account channel agonism as well as inhibition.
Topics: Humans; Potassium Channel Blockers; Ether-A-Go-Go Potassium Channels; Arrhythmias, Cardiac; Machine Learning; Internet
PubMed: 37468081
DOI: 10.1016/j.vascn.2023.107293 -
Heart International 2023Hypertrophic cardiomyopathy (HCM) is a common heridetary cardiac disorder characterized by a wide range of symptoms. The pharmacological treatment of HCM is currently...
Hypertrophic cardiomyopathy (HCM) is a common heridetary cardiac disorder characterized by a wide range of symptoms. The pharmacological treatment of HCM is currently limited to beta blockers, non-dihydropyridine calcium channel blockers and disopyramide. Mavacamten is a novel cardiac myosin inhibitor, which was recently added to the limited pharmacological list of treatment options for HCM. This editorial elaborates on current evidence evaluating the use of mavacamten in patients with symptomatic obstructive HCM, comments on its current use and its expanded potential applications in the future.
PubMed: 37456351
DOI: 10.17925/HI.2023.17.1.2 -
Drug Design, Development and Therapy 2023Hypertrophic cardiomyopathy (HCM) is a condition with abnormal hypertrophy of the left ventricle in the absence of common causes. The most common form involves the basal... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a condition with abnormal hypertrophy of the left ventricle in the absence of common causes. The most common form involves the basal septum and can lead to obstruction of the left ventricular outflow tract. Patients can experience exertional symptoms such as chest pain, dyspnea and syncope. Traditional treatment has included beta blockers and nondihydropyridine calcium channel blockers with second-line therapy being disopyramide. Recently, mavacamten, a cardiac myosin inhibitor, has demonstrated improvement in quantitative measures of obstruction and symptom relief to such a degree that patients were able to defer invasive management of the disease. This review focuses on the pharmacology of mavacamten, its clinical trial data and guidance on how to incorporate this drug into clinical practice. Furthermore, it discusses emerging therapies currently being investigated for HCM.
Topics: Humans; Cardiomyopathy, Hypertrophic; Heart; Benzylamines; Calcium Channel Blockers
PubMed: 37064432
DOI: 10.2147/DDDT.S368590 -
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