1. Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non-β-Blocking R-Enantiomer Carvedilol.
- Author
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Seo K, Yamamoto Y, Kirillova A, Kawana M, Yadav S, Huang Y, Wang Q, Lane KV, Pruitt BL, Perez MV, Bernstein D, Wu JC, Wheeler MT, Parikh VN, and Ashley EA
- Subjects
- Humans, Mice, Animals, Carvedilol pharmacology, Carvedilol therapeutic use, Ryanodine Receptor Calcium Release Channel metabolism, Arrhythmias, Cardiac drug therapy, Arrhythmias, Cardiac metabolism, Adrenergic beta-Antagonists pharmacology, Adrenergic beta-Antagonists therapeutic use, Myocytes, Cardiac metabolism, Verapamil therapeutic use, Receptors, Adrenergic metabolism, Metoprolol therapeutic use, Cardiomyopathy, Hypertrophic complications, Cardiomyopathy, Hypertrophic drug therapy
- Abstract
Background: Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown., Methods: We screened 21 β-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM ( Myh6
R403Q /+ and induced pluripotent stem cell (iPSC)-derived cardiomyocytes from patients with HCM ( MYH7R403Q/+ )., Results: We identified that carvedilol, a β-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a β1 -blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α1 -adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of β-blocking effect, retains the ability to inhibit both α1 -receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In Myh6R403Q/+ mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in MYH7R403Q/+ iPSC-derived cardiomyocytes., Conclusions: R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α1 -adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction., Competing Interests: Disclosures K.S., V.N.P., and E.A.A. filed a US patent related to this work (Application No. 63/479,523; filed January 11, 2023). K.S. and S.Y., previously affiliated with Stanford University at the time of the study and manuscript preparation, are now employees of Bristol Myers Squibb. V.N.P. receives research funding from BioMarin, as well as consulting fees from Lexeo Therapeutics, Nuevocor, and Viz.ai and is a shareholder in Constantiam Bio. M.T.W. has consulted for, received clinical trial support from, and received in kind support from MyoKardia (which was acquired by Bristol Myers Squibb), and received clinical trial support from Novartis and CytoKinetics. E.A.A. is a founder of Personalis, Inc, DeepCell, Inc, and Svexa Inc; a founding advisor of Nuevocor; a nonexecutive director at AstraZeneca; and an advisor to SequenceBio, Novartis, Medical Excellence Capital, Foresite Capital, and Third Rock Ventures. The remaining authors declare no competing interests.- Published
- 2023
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