Efficacy of Mavacamten in Reducing Cardiac Obstruction in an Elderly Patient with Hypertrophic Cardiomyopathy: A Case Study

Introduction

Hypertrophic cardiomyopathy (HCM) is a chronic and progressive myocardial disorder that, in some cases, is characterized by progressively worsening dyspnea and reduced exercise capacity due to dynamic left ventricular outflow tract (LVOT) obstruction [1]. While European, American, and Japanese guidelines for the pharmacological management of symptomatic HCM recommend therapies such as beta blockers, calcium channel blockers, and disopyramide, evidence supporting their ability to provide complete symptom relief, prevent disease progression, or alter the natural course of the condition remains limited [1]. This highlights the pressing need for further research into novel therapies to more effectively manage symptoms and tackle the challenges associated with this debilitating and potentially life-threatening cardiac condition.

Mavacamten is the first cardiac myosin adenosine triphosphatase (ATPase) inhibitor to be approved by the Food and Drug Administration for the treatment of adults with symptomatic obstructive HCM classified as New York Heart Association (NYHA) functional class II or III [2]. Mavacamten lowers myocardial filling pressures by limiting the number of myosin heads that can bind with actin, effectively reducing excessive contractility and alleviating dynamic LVOT obstruction [2,3].

A recent phase 3 clinical study revealed that Mavacamten provided significant relief from symptoms and LVOT obstruction in patients with HCM [4]. With a post-exercise LVOT gradient reduction of 50% compared to placebo, Mavacamten has demonstrated notable improvements in quality of life, as assessed by various health-related quality of life indexes [5]. While these findings are encouraging for HCM patients, data on older patients remain limited, as most HCM trials predominantly included younger populations [4,6].

We present the case of a geriatric patient with severe HCM who achieved a dramatic reduction in LVOT pressure within just 4 weeks of treatment with Mavacamten, exceeding our expectations for improvement.

Case Report

A 91-year-old man with HCM, NYHA II–III heart failure, and grade II diastolic dysfunction, under our clinic’s care for the past 15 years, had presented multiple times since March 2024 with worsening shortness of breath. The patient reported experiencing shortness of breath for many years, which gradually worsened despite treatment. He described it as debilitating, occurring even at rest and intensifying with minimal walking. It was accompanied by deep, dull chest pain that lasts for hours and resolves spontaneously.

After an extensive clinical evaluation, results of pulmonary and cardiovascular examinations were normal. The pulmonary work-up to assess pulmonary involvement included multiple chest computed tomography scans, chest X-rays, and a pulmonology evaluation, all of which were unremarkable. Furthermore, potential coronary involvement was considered; the patient’s last computed tomography angiography of the coronary arteries, performed in 2020, revealed non-obstructive coronary arteries. However, serial ultrasound examinations showed subtle progressive changes in cardiac wall measurements. Initial findings in 2011 demonstrated an interventricular septum (IVS) measuring 2.1 cm and a posterior wall (PW) measuring 1.0 cm.

Subsequent measurements in 2024 revealed a modest increase in the IVS to 2.3 cm, while the PW measurement remained consistent at 1.0 cm. Echocardiography also revealed trace mitral regurgitation, systolic anterior motion (SAM) of the mitral valve, asymmetric septal hypertrophy (ASH), and the scimitar sign. Conditions that may contribute to abnormal cardiac load, such as hypertension (which was present in this patient) or aortic stenosis, were ruled out as the cause of his symptoms. On the one hand, hypertension would not explain his baseline and Valsalva-induced increase in LVOT gradients, nor would it account for echocardiographic findings such as SAM, ASH, and the scimitar sign. On the other hand, his echocardiographic findings never suggested a significant elevation in aortic transvalvular gradients. Using both the continuity equation and planimetry, there was no evidence suggestive of aortic stenosis. Based on these findings, worsening HCM was determined to be the most likely diagnosis. After unsuccessful management with the beta-blocker Atenolol and due to his numerous intolerances and the inability to adjust his dose or add a new regimen, we opted to initiate treatment with Mavacamten (Camzyos) in August 2024.

On Day 0, the patient began Mavacamten at a dose of 5 mg PO QD. An echocardiogram performed the week before revealed a LVOT velocity of 3.9 meters per second at rest (corresponding to a pressure gradient [PG] of approximately 61 mmHg), and 6.4 meters per second during Valsalva (PG of 164 mmHg – see Figures 1, 2). At that time, the left ventricular ejection fraction (LVEF) was 60%. A follow-up echocardiogram on Day 9 showed an LVOT velocity of 2.0 meters per second at rest (PG of approximately 16 mmHg), 6.2 meters per second during Valsalva (PG of approximately 154 mmHg) and a LVEF of 55%. At that time, the patient reported no significant change in symptoms.

During a follow-up visit on Day 14, there was minimal improvement in shortness of breath, with no change in chest pain. No echocardiogram was performed at that time. During his next follow-up on Day 19, the patient appeared well, without signs of heart failure, and reported further improvement in shortness of breath both at rest and during exercise. An echocardiogram from that visit indicated an LVOT velocity of 1.6 meters per second at rest (PG of approximately 10 mmHg) and 2.6 meters per second during Valsalva (PG of approximately 27 mmHg – see Figures 3, 4, and Videos 1, 2). LVEF remained stable at 55%, consistent with the previous echocardiogram.

After 3 months at the same dose, his PG were still not within guideline-directed targets, though the patient remained clinically well. Since his ejection fraction remained unchanged and no adverse effects were observed, we decided to increase the Mavacamten dose to 10 mg, as recommended by guidelines. This further improved his clinical condition, normalized his PG. LVOT rest showed a Vmax of 1.1 m/s which corresponds to a PG of 5 mmHg, and LVOT Valsalva showed a Vmax of 1.3 m/s, which corresponds to a maximum PG of 6 mmHg. LVEF remained at 50% (Figures 5, 6, and Videos 3, 4), and resulted in no more evidence of SAM or mitral regurgitation.

The patient is being closely monitored and has demonstrated good compliance with his treatment regimen. He reports tolerating Mavacamten therapy well, with constant improvement of his shortness of breath and no significant adverse effects noted. Following treatment initiation, the patient’s heart failure was classified as NYHA I–II, while his grade II diastolic dysfunction and chest pain did not improve. Regular follow-up appointments are scheduled to assess his progress and adjust medications as necessary. The patient’s engagement in his treatment plan has been encouraging, as he actively participates in discussions about his care and expresses a willingness to adhere to the prescribed therapies. This collaborative approach is crucial in managing his complex medical history and optimizing his overall health outcomes. Continuous assessment will help ensure that any emerging issues are addressed promptly, contributing to the ongoing improvement of his symptoms and quality of life.

Discussion

We report the case of an elderly patient who showed a far better than expected response to Mavacamten treatment. While previous studies report an average reduction of about 50% in LVOT pressure gradient in HCM patients after 4 weeks of Mavacamten treatment [4,6], our case demonstrates a reduction of over 80% in LVOT obstruction, both at rest and during Valsalva (83.6% and 83.5%, respectively) in the same time frame. This remarkable outcome was accompanied by significant improvement in his shortness of breath and overall health.

With an upward trend in the diagnosis of HCM in the elderly [7], evidence suggests that LVOT obstruction is more prevalent and resistant in older patients with HCM compared to younger ones [8]. This makes clinical management crucial, as most HCM-related complications tend to occur later in life [9]. As a long-term follow-up patient and after excluding other possible diagnoses such as coronary obstruction or pulmonary involvement, we believe that the substantial reduction in LVOT pressure gradient in our HCM patient could be attributed to a genetic predisposition affecting the drug’s mechanism of action. While recent studies have shown that metabolic variability in the drug’s pharmacokinetics can lead to increased plasma concentrations and, consequently, a higher risk of systolic dysfunction [10,11], no studies have yet explored the pharmacogenetic factors that enhance a patient’s responsiveness to the drug’s pharmacodynamics.

Although we do not have information about this patient’s CYP2C19 genotype, we relied on robust echocardiogram-based follow-ups to titrate the dosage to 5 mg PO QD, as recommended in the literature [6,11]. The significant reduction in pressure gradient and improvement in the patient’s symptoms at this relatively low dose may be attributed to heightened drug efficacy, possibly due to increased sensitivity of the patient’s myosin ATPase to the medication. This expands on the work of Giudicessi et al, who showed that genotype-positive obstructive HCM patients tend to have a more favorable clinical response to Mavacamten [12]. While we cannot confirm that our patient falls into this category, our case suggests that his response to the drug may be due to a particular genetic susceptibility. Further pharmacogenetic studies are needed to confirm this hypothesis.

This represents a significant advancement in the management of severe HCM patients with LVOT obstruction above a 50 mmHg pressure gradient who are refractory to medical therapy [13]. Previously, achieving similar results would have required surgical intervention, making this a crucial non-invasive option for such patients. Notably, the VALOR-HCM trial demonstrated a strong preference among enrolled patients for medical therapy over invasive procedures [6], which aligns with our approach in managing this elderly patient. While we are mindful of the many adverse effects that could impair our patient’s overall health, such as the risk of LVEF reduction, syncope, atrial fibrillation, chest pain, and dyspnea [5], our rigorous safety assessments through regular echocardiogram monitoring allow us to manage this patient closely and safely.

Our study has several strengths. First, the same trained echocardiographers have consistently monitored the patient, minimizing bias in measurement techniques. Second, our ability to perform frequent echocardiograms allows us to optimize dosage titration for this elderly patient. However, the study also has limitations. Due to time constraints and the clinic-based setting, we were only able to assess HCM-related parameters on the echocardiogram, such as LVOT and LVEF, without evaluating other factors like aortic valve areas or common comorbidities in HCM, such as mitral regurgitation. To address these limitations, we have established a protocol to conduct a full echocardiogram every 6 months for this patient to reduce potential biases. Second, as the patient is AV-paced and to facilitate management for our elderly patient, we based our clinical evaluation on clinical signs and echocardiographic measurements, and did not use electrocardiograms and NT-proBNP measurements to assess the response to Mavacamten. Moreover, due to the significant cost and limited clinical relevance for this patient, genetic testing was not performed, restricting our ability to determine which genes or proteins may be responsible for his enhanced response to the drug. Finally, given the patient’s advanced age, multiple treatment intolerances, and the low likelihood of influencing management strategies, we chose not to explore potential phenocopies of this patient’s HCM.

Conclusions

In conclusion, we present the case of an elderly patient with advanced HCM, refractory to first-line medications, who responded to Mavacamten more significantly than reported in the literature within the first 4 weeks of treatment. Using an echocardiogram-based follow-up for dosage titration and safety assessments, we suspect that the patient’s genotype sensitivity may explain the marked reduction in LVOT obstruction and symptom improvement. Further studies are needed to better understand the pharmacodynamic variability of the drug and how to more effectively tailor its use for HCM patients.