Treatment of RAF1-Related Obstructive Hypertrophic Cardiomyopathy by MEK Inhibition Using Trametinib

Abstract

RASopathies cause nonsarcomeric hypertrophic cardiomyopathy via dysregulated signaling through RAS and upregulated mitogen-activated protein kinase activity. We provide the first report of the successful treatment of an adult with RAF1-associated hypertrophic cardiomyopathy using trametinib, a MEK inhibitor.

Keywords: Noonan syndrome; RASopathies; cardiovascular genetics; hypertrophic cardiomyopathy.

Graphical abstract

Figure 1

Electrocardiogram Showing Left Ventricular Hypertrophy Electrocardiogram shows normal sinus rhythm, right atrial abnormality, left ventricular hypertrophy with repolarization abnormality, and nonspecific T-wave abnormality.

Figure 2

Echocardiogram Showing an LVOT Gradient of 213 mm Hg Transthoracic echocardiogram (apical 3-chamber) spectral Doppler assessment showing a peak left ventricular outflow tract gradient of 213 mm Hg while on therapy with beta-blockers and disopyramide.

Figure 3

Cardiac Magnetic Resonance Imaging Showing Severe Ventricular Hypertrophy Cardiac magnetic resonance imaging with late gadolinium enhancement showing septal dominant hypertrophy with a maximal wall thickness of 36 mm, leading to systolic anterior motion of the mitral leaflets, a left ventricular apical aneurysm and a small (approximately 9%) burden of late gadolinium enhancement.

Figure 4

Echocardiogram Post-Trametinib Showing a Marked Improvement in the LVOT Gradient Transthoracic echocardiogram (apical 3-chamber) spectral Doppler assessment showing a peak left ventricular outflow tract gradient of 41 mm Hg following treatment with trametinib.

Figure 5

Cardiac MRI After Treatment With Trametinib Cardiac magnetic resonance imaging following treatment with trametinib showed no objective differences with respect to maximal wall thickness, global left ventricular mass, left ventricular aneurysm, or myocardial fibrosis; however, a visible reduction in severity of systolic anterior motion was present.