Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non-β-Blocking R-Enantiomer
Kinya Seo1, Yuta Yamamoto1, Anna Kirillova1
1From the Departments of Medicine (K.S., Y.Y., A.K., M.K., S.Y., Y.H., Q.W., M.V.P., M.T.W., V.N.P., E.A.A.), Stanford University School of Medicine, CA.
Insights
R-carvedilol, a novel therapeutic agent, effectively suppresses hypercontractility and arrhythmia in hypertrophic cardiomyopathy (HCM) models. This agent improves cardiac output without reducing heart rate, offering a unique therapeutic option for HCM patients.
Area of Science:
- Cardiology
- Pharmacology
- Genetics
Background:
- Hypertrophic cardiomyopathy (HCM) is characterized by hypercontractility and arrhythmia, with beta-blockers as first-line therapy.
- Current beta-blockers can cause adverse effects like reduced cardiac output and fatigue.
- Mavacamten shows promise for hypercontractility but is limited to specific patient groups and its antiarrhythmic effects are unknown.
Purpose of the Study:
- To screen beta-blockers for their impact on myocyte contractility and antiarrhythmic properties.
- To evaluate the in vivo efficacy of a promising drug in a mouse model of HCM.
- To compare the efficacy of the identified drug with existing HCM therapies.
Main Methods:
- Screened 21 beta-blockers for effects on myocyte contractility and antiarrhythmic properties.
- Evaluated in vivo cardiac function using hemodynamic pressure-volume loop analysis in an established mouse model of HCM.
- Tested efficacy in vitro and in vivo against metoprolol, verapamil, and mavacamten using patient-derived iPSC-cardiomyocytes.
Main Results:
- Carvedilol, a beta-blocker not typically used for HCM, was identified to suppress contractile function and arrhythmia by inhibiting RyR2.
- The R-enantiomer of carvedilol inhibited both RyR2 and alpha1-adrenergic receptors, reducing contractility without lowering heart rate or cardiac output.
- R-carvedilol demonstrated superior efficacy in normalizing hyperdynamic contraction, suppressing arrhythmia, and increasing cardiac output in mouse and iPSC models compared to existing therapies.
Conclusions:
- R-enantiomer carvedilol attenuates hyperdynamic contraction and suppresses arrhythmia by dual blockade of alpha1-adrenergic receptor and RyR2.
- This dual action improves cardiac output without reducing heart rate, a unique therapeutic profile for HCM.
- R-carvedilol may benefit HCM patients, particularly those without left ventricular outflow tract obstruction.
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 (Myh6R403Q/+ 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.
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