Medical Therapies to Improve Left Ventricular Outflow Obstruction and Diastolic Function in Hypertrophic Cardiomyopathy

Zhu, Mason; Reyes, Klevin Roger L.; Bilgili, Gizem; Siegel, Robert J.; Lee Claggett, Brian; Wong, Timothy C.; Masri, Ahmad; Naidu, Srihari S.; Willeford, Andrew; Rader, Florian

doi:10.1016/j.jacadv.2023.100622

Cited by 3 publications

(1 citation statement)

References 60 publications

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“…While payor costs will be increased, use of mavacamten in patients without prior history of therapy may also be reasonable given there is a lack of robust clinical data supporting the use of beta blockers, calcium channel blockers, and disopyramide in oHCM. 33 Future studies comparing mavacamten to these alternatives are needed.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of a Multidisciplinary Approach to Management of Mavacamten in Obstructive Hypertrophic Cardiomyopathy

Jensen,

Yousif,

Huynh

et al. 2024

Preprint

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BackgroundTraditional treatments for obstructive hypertrophic cardiomyopathy (oHCM) include beta-blockers, calcium channel blockers, and disopyramide. Mavacamten, a novel cardiac myosin inhibitor, is a promising oHCM therapy but has practical challenges limiting its use. This study aimed to describe a clinic workflow for mavacamten management in a real-world setting, addressing challenges such as cost, drug interactions, and monitoring requirements. The focus was on reducing patient-level costs while ensuring feasibility and efficiency.MethodsA retrospective analysis was conducted on 34 oHCM patients considered for mavacamten between May 2022 and May 2023. The clinic workflow involved cardiologist assessment, pharmacist evaluation of drug interactions, enrollment in the mavacamten REMS program, cost reduction measures, and initiation monitoring through scheduled echocardiograms. An algorithm detailing steps and tools used in this workflow is provided.ResultsOf the 34 patients, 21 (62%) were initiated on mavacamten and followed for up to 1 year on therapy. Cost assessments indicated reduced out-of-pocket expenses with assistance programs. The median time from referral to first fill was 22 days. Patients demonstrated high adherence (99.1%) measured by proportion of days covered. Echocardiogram follow-ups showed significant improvements in left ventricular outflow tract parameters with no patients having a decrease in left ventricular ejection fraction to less than 50%.ConclusionsThe described workflow effectively addressed challenges associated with mavacamten management, emphasizing roles for clinic personnel, cost reduction strategies, and structured patient monitoring. While the workflow’s specifics may need adaptation in different settings, this report provides valuable insights for clinics implementing structured mavacamten management approaches.

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Section: Discussionmentioning

confidence: 99%

Outcomes of a Multidisciplinary Approach to Management of Mavacamten in Obstructive Hypertrophic Cardiomyopathy

Jensen,

Yousif,

Huynh

et al. 2024

Preprint

Self Cite

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Stereoselective block of the hERG potassium channel by the Class Ia antiarrhythmic drug disopyramide

Zhang,

El Harchi,

James

et al. 2024

Cell. Mol. Life Sci.

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Potassium channels encoded by human Ether-à-go-go-Related Gene (hERG) are inhibited by diverse cardiac and non-cardiac drugs. Disopyramide is a chiral Class Ia antiarrhythmic that inhibits hERG at clinical concentrations. This study evaluated effects of disopyramide enantiomers on hERG current (IhERG) from hERG expressing HEK 293 cells at 37 °C. S(+) and R(−) disopyramide inhibited wild-type (WT) IhERG with IC50 values of 3.9 µM and 12.9 µM respectively. The attenuated-inactivation mutant N588K had little effect on the action of S(+) disopyramide but the IC50 for the R(−) enantiomer was ~ 15-fold that for S(+) disopyramide. The enhanced inactivation mutant N588E only slightly increased the potency of R(−) disopyramide. S6 mutation Y652A reduced S(+) disopyramide potency more than that of R(−) disopyramide (respective IC50 values ~ 49-fold and 11-fold their WT controls). The F656A mutation also exerted a stronger effect on S(+) than R(−) disopyramide, albeit with less IC50 elevation. A WT-Y652A tandem dimer exhibited a sensitivity to the enantiomers that was intermediate between that of WT and Y652A, suggesting Y652 groups on adjacent subunits contribute to the binding. Moving the Y (normally at site 652) one residue in the N- terminal (up) direction in N588K hERG markedly increased the blocking potency of R(−) disopyramide. Molecular dynamics simulations using a hERG pore model produced different binding modes for S(+) and R(−) disopyramide consistent with the experimental observations. In conclusion, S(+) disopyramide interacts more strongly with S6 aromatic binding residues on hERG than does R(−) disopyramide, whilst optimal binding of the latter is more reliant on intact inactivation.

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Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy

Hegde,

Claggett,

Wang

et al. 2024

Journal of the American College of Cardiology

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Medical Therapies to Improve Left Ventricular Outflow Obstruction and Diastolic Function in Hypertrophic Cardiomyopathy

Cited by 3 publications

References 60 publications

Outcomes of a Multidisciplinary Approach to Management of Mavacamten in Obstructive Hypertrophic Cardiomyopathy

Outcomes of a Multidisciplinary Approach to Management of Mavacamten in Obstructive Hypertrophic Cardiomyopathy

Stereoselective block of the hERG potassium channel by the Class Ia antiarrhythmic drug disopyramide

Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy

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