Cardiac myosin inhibitors are a novel class of medication designed to address the underlying cause of certain heart muscle conditions, rather than managing symptoms. Cardiac myosin is a specialized protein within heart muscle cells (cardiomyocytes) that converts chemical energy into mechanical force for contraction. This protein interacts with actin to facilitate the cycle of muscle contraction and relaxation. By targeting this fundamental component, these inhibitors offer a precise therapeutic approach to modulate muscle function.
The Molecular Mechanism of Action
The heart’s ability to contract relies on the cyclical interaction between the thick filament protein, myosin, and the thin filament protein, actin, known as the cross-bridge cycle. Energy from adenosine triphosphate (ATP) hydrolysis powers the myosin heads to bind to actin and generate the force that shortens the muscle fiber. In certain disease states, this cycle is overactive, leading to excessive and forceful contraction of the heart muscle.
A cardiac myosin inhibitor works by selectively binding directly to the myosin protein. This binding stabilizes the myosin head in the “off” or “super-relaxed” state, making it less available to interact with actin and form force-generating cross-bridges. By shifting the myosin population into this relaxed conformation, the drug effectively reduces the total number of cross-bridges formed during contraction. This molecular modulation decreases the hypercontractility of the heart muscle and lowers the overall force of contraction, reducing the heart’s workload.
Primary Therapeutic Application in Heart Disease
The primary condition treated by this class of drugs is Hypertrophic Cardiomyopathy (HCM), a genetic disorder characterized by unexplained thickening of the heart wall. This thickening is often caused by mutations in sarcomeric proteins, including cardiac myosin, leading to hypercontractility. The excessive force generated by the heart muscle can create a physical obstruction, particularly in the left ventricular outflow tract (LVOT), where blood exits the heart.
This obstruction impedes the flow of blood from the left ventricle into the aorta (obstructive HCM). This restriction forces the heart to work harder, causing symptoms like shortness of breath, chest pain, and fatigue. By reducing the heart’s contractility, cardiac myosin inhibitors alleviate the physical obstruction in the LVOT.
Alleviating this obstruction improves the heart’s efficiency and allows blood to flow more freely. Clinical studies show this intervention leads to physiological benefits, including a reduction in the LVOT pressure gradient and improved functional capacity. Reducing the mechanical stress on the heart can also lead to beneficial structural changes, such as decreased left ventricular mass and improved diastolic function.
Specific Medications and Administration Requirements
Mavacamten (Camzyos) was the first medication in this class to receive regulatory approval; a second-generation compound, aficamten, is also in advanced development. These drugs are taken orally, typically once daily, with the specific dose determined through careful, individualized titration. Dosing is adjusted based on the patient’s clinical response and specific echocardiographic measurements.
Administration requires a structured approach to prevent excessive reduction in heart function due to the drug’s mechanism. Titration involves starting at a low dose (e.g., 5 mg for mavacamten) and adjusting based on the patient’s left ventricular ejection fraction (LVEF) and the measured LVOT gradient.
This stringent monitoring is often mandated through specialized regulatory frameworks, such as the Risk Evaluation and Mitigation Strategy (REMS) program in the United States. The REMS program ensures that only certified prescribers and pharmacies dispense the medication. Patients must undergo regular assessments to confirm the drug provides therapeutic benefit without compromising the heart’s overall pumping function, ensuring safe management of the drug’s powerful effect.
Safety Profile and Necessary Patient Monitoring
The primary safety concern relates directly to the drug’s mechanism: the potential for excessive reduction in heart muscle contractility. If the dose is too high, the reduction in force can lead to a decrease in the Left Ventricular Ejection Fraction (LVEF). A low LVEF signifies reduced pumping efficiency, which can cause symptoms of heart failure.
To manage this risk, mandatory and frequent echocardiogram assessments are required before and throughout treatment. Echocardiograms establish a baseline LVEF and are repeated at specific intervals (e.g., weeks four, eight, and twelve, then every twelve weeks thereafter). The medication is generally contraindicated for initiation if the LVEF is already below 55%.
If a patient’s LVEF drops below a specific threshold, typically 50%, the drug must be temporarily interrupted to allow heart function to recover. Commonly reported side effects include dizziness and fainting (syncope), which may also signal an overly aggressive reduction in contractility. The strict monitoring protocol ensures the drug is delivered at the lowest effective dose to reduce hypercontractility while maintaining sufficient global heart function.