28th September, 2023, Dr Chee L Khoo
In June this year, we saw how our understanding of the pathophysiology of hypertrophic cardiomyopathy (HCM) (formerly known as hypertrophic obstructive cardiomyopathy or HOCM) has significantly changed. In particular, we saw how not all patients with HCM have “obstruction” in the left ventricular tract. In other words, the primary defect in HCM is no longer “structural”. HCM is now generally recognised as a disease caused by dysfunction of the sarcomere, the basic contractile apparatus of the heart muscle. We now have a drug, Mavacamten that claim to target that molecular defect.
Before we can look into what Mavacamten does, we need to visit the key pathophysiological feature contributing to outflow tract obstruction in HCM. Not all patients with HCM have left ventricular outflow tract (LVOT) obstruction. Instead, systolic hyperactivity and diastolic dysfunction in HCM is usually present and often herald the clinical onset of the disease (2). In most cases, the cause of the systolic and diastolic dysfunction is myofibrillar dysfunction (see below).
We will need to revisit some medical school basics. According to the sliding filament theory, the myosin (thick filaments) of muscle fibres slide past the actin (thin filaments) during muscle contraction, while the two groups of filaments remain at relatively constant length.
Myofibrillar dysfunction occurs when there is excessive sarcomeric myosin–actin cross-bridge formation during systole and diastole which leads to hypertrophy, hypercontractility, and impaired relaxation as well as to myocardial inefficiency and unproductive energy consumption [3].
The molecular defect in HCM
Approximately 40% of affected individuals, and a significant portion of those with a family history of clinical disease, have at least one mutation in one or more genes that encode sarcomere proteins.
In the healthy heart, 40–50% of the myosin heads are in the ‘off state’ with negligible energy consumption, whereas in HCM there is a shift in this ratio, with only 15–20% of the myosin heads being in this ‘off state’. The extra myosin heads in the ‘on state’ not only consume more adenosine triphosphate (ATP) (i.e., energy), but are also primed to interact with actin. These effects combine to cause excess myosin–actin cross-bridges during both systole and diastole, leading to inefficient hyperdynamic contraction and diastolic dysfunction. This sustained sarcomeric hyperactivity activates pro-hypertrophic, pro-inflammatory, and pro-fibrotic pathways, resulting in progressive myocardial remodeling, characterised by fibrosis, myofilament disarray, and elevated stresses.
The mechanism of action of Mavacamten
Mavacamten is an allosteric, selective, and reversible inhibitor of cardiac myosin, the motor unit of the sarcomere. It decreases the number of myosin heads that can enter the on-actin (power-generating) state, thus reducing the probability of cross-bridge formation in HCM, and shifts the overall myosin population towards the energy-sparing ‘off state’.
Mavacamten decreases overall ATP turnover at the sarcomere level, reduces diastolic tensions, and promotes relaxation. As a result of these direct, salutary diastolic, systolic, and energy-sparing attributes, mavacamten increases the ventricular chamber size and reduces the velocity of myocardial contraction. This reduces anteriorly displacing forces that favour septal anterior motion (SAM) and, therefore, creates an optimal intraventricular mechanical environment to reduce LVOT obstruction.
Does Mavacamten work in clinical practice?
There have been 5 Phase2/3 clinical trials looking at the efficacy and safety of Mavacamten. The numbers at this stage are small. 331 unique patients in 5 trials:
- PIONEER-HCM [4]
- PIONEER-open-label extension (OLE) [5]
- MAVERICK-HCM [6]
- EXPLORER-HCM [7] and its cardiac magnetic resonance (CMR) sub-study [8]; and
- MAVA-long-term extension (LTE)
All patients must have received a diagnosis of HCM (hypertrophied and non-dilated left ventricle in the absence of systemic or other known cause) with a maximum LV wall thickness of 15 mm or more at screening, or 13 mm or more with a positive family history of HCM. In some of the studies, participants had obstruction while in other studies, there were no obstruction in the LVOT. Thus, mavacamten were tested in patients with or without LVOT obstruction.
Outcomes
Mavacamten lowered the LVEF in patients with HCM, bringing it within the normal range in PIONEER, MAVERICK-HCM, EXPLORER-HCM, and MAVA-LTE. In patients with obstruction, it decreased peak and post exercise LVOT gradients. In the EXPLORER-HCM, Mavacamten showed complete resolution of mitral valve SAM after 30 weeks.
Mavacamten treatment significantly reduced plasma NT-proBNP levels irrespective of whether there was obstruction or not, indicating a reduction in left ventricular wall tension and thus, left ventricular filling pressure. Reduction in left ventricular filling pressure is expected to reduce left atrial volume and pulmonary pressure. Indeed, Mavacamten showed reduction in both.
Mavacamten also demonstrated a reduction in cardiac troponin indicating a reduction in myocardial ischaemia.
Summary
Data collected from the above and other studies have consolidated our understanding of the pathophysiology of HCM: sarcomeric hyperactivity and hypercontractility. Mavacamten reduces hypercontractility by returning more myosin heads to the ‘off state.’ There are a number of novel drugs coming up targeting the other parts of the molecular defects in HCM.
References
- Edelberg, J.M., Sehnert, A.J., Mealiffe, M.E. et al. The Impact of Mavacamten on the Pathophysiology of Hypertrophic Cardiomyopathy: A Narrative Review. Am J Cardiovasc Drugs 22, 497–510 (2022).
- Ho CY. New paradigms in hypertrophic cardiomyopathy: insights from genetics. Prog Pediatr Cardiol. 2011;31(2):93–8
- McNamara JW, Li A, Smith NJ, et al. Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes. J Mol Cell Cardiol. 2016;94:65–71
- Heitner SB, Jacoby D, Lester SJ, et al. Mavacamten treatment for obstructive hypertrophic cardiomyopathy: a clinical trial. Ann Intern Med. 2019;170(11):741–8
- Heitner SB, Lester S, Wang A, et al. Abstract 13962: precision pharmacological treatment for obstructive hypertrophic cardiomyopathy with mavacamten: one-year results from PIONEER-OLE. Circulation. 2019;140(Suppl_1):A13962-A.
- Ho CY, Mealiffe ME, Bach RG, et al. Evaluation of mavacamten in symptomatic patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2020;75(21):2649–60
- Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759–69
Saberi S, Cardim N, Yamani MH, et al. Mavacamten favorably impacts cardiac structure in obstructive hypertrophic cardiomyopathy: EXPLORER-HCM CMR substudy analysis. Circulation. 2021;143:606–8.