Stern JA, Markova S, et al. A small molecule inhibitor of sarcomere contractility acutely relieves left ventricular outflow tract obstruction in feline hypertrophic cardiomyopathy. PLoS ONE, 2016 Dec 14;11(12).
Hypertrophic cardiomyopathy (HCM) is the most common heritable heart disease in both cats and humans. In HCM, the walls of the heart’s left ventricle thicken asymmetrically, and the disease is considered idiopathic in that the lesion is not explained by another cardiac or systemic disease. Due to the hypertrophy of the left ventricular muscle, the heart experiences hyperdynamic contraction and impaired ventricular relaxation, which in turn does not facilitate normal ventricular filling in diastole. In some cases the HCM is subclinical and in others clinical signs and symptoms are severe, including exercise intolerance, congestive heart failure, atrial fibrillation, and sudden cardiac death.
HCM is a disease of the sarcomere, which is the basic structural unit of striated skeletal and cardiac muscle; sarcomeres actually give muscle its striated appearance. Muscle cells, or myofibers, are composed of linear organelles, the myofibrils, which are in turn made up of repeating sections of sarcomeres. In mice, cats, and humans, mutations in the genes that code for sarcomere proteins are ultimately responsible for the development of HCM and its sequelae. Humans and cats with HCM share mutations in the MYBPC3 gene, which produces a hypercontractile sarcomere.
One of the most worrisome complications of HCM is the development of left ventricular outflow tract (LVOT) obstruction , which occurs in both cats and humans, but not in mice, with HCM. When one or both mitral valve leaflets contact the interventricular septum during systole, then the systolic anterior motion (SAM) of these structures impedes blood flow into the LVOT, increasing the pressure gradient through the LVOT. In turn, the increased pressure gradient through the LVOT potentiates a worsening of the left ventricular hypertrophy.
Those feline and human patients with HCM who develop SAM/LVOT obstruction (LVOTO) have a greater tendency to become symptomatic. In humans with HCM, approximately 1/3 have LVOTO at rest, and another 1/3 of these patients develop LVOTO only after a provocative stress such as exercise. For those human patients with LVOTO and congestive heart failure who are not helped by medical therapy, invasive septal reduction therapy is available, but this is inconsistently successful, does not address the underlying muscular pathology of the disease, and is not available for feline patients with similar disease. Medical therapies used in both cats and humans such as beta blockers and calcium channel blockers also may help some patients, but still do not really target the underlying sarcomeric pathology, have inconsistent results as well as side effects, and do not change the natural history of the disease.
In this study, the effects of MYK-461, a small molecule that acts directly at the level of the sarcomere to inhibit contractility, were evaluated in five male cats ranging in age from 0.9 to 3.7 years from a research colony of mixed breed domestic shorthair/Maine Coon cross cats with HCM and LVOTO identified on baseline awake echocardiography. In studies on mice with HCM, MYK-461 was found to act directly on myosin, the sarcomeric protein that generates the force of muscle contraction, and as a result it attenuated ventricular hypertrophy, myofibrillar disarray, and fibrosis early in the course of HCM. The investigators hypothesized that the use of MK-461 in their feline subjects, who already had HCM and LVOTO, would actually eliminate SAM and reduce LVOTO.
The five feline subjects were anesthetized in order to get accurate LVOT velocities from subcostal echocardiographic views, which are not considered comfortable in conscious cats. In order to return the anesthetized animals’ hearts to baseline conscious LVOT obstruction, adrenergic stimulation was provided as intravenous isoproterenol, and all cats then developed heart rates similar to those they had when conscious, as well as SAM and LVOT obstruction. In other studies in both animals and humans, isoproterenol has been shown to not induce SAM or LVOTO in normal hearts, but will do so in those with HCM. Following anesthetic induction and and administration of isoproterenol, MYK-461 was given by intravenous infusion, and changes in heart function were monitored.
Changes in cardiac function observed after administration of MYK-461 included decreases in fractional shortening (FS) from 52+ 3% to 38 + 7%, which in turn were associated with an increase in end-systolic ventricular diameter. Plasma concentrations of MYK-461 were measured throughout the procedure and a linear relationship between FS and MYK-461 plasma concentrations was identified when both isoproterenol and MYK-461 were administered simultaneously and when only MYK-461 and vehicle were infused. In all 5 cats, SAM was eliminated when MYK-461 was administered, while SAM persisted in 3/3 animals receiving vehicle alone. The MYK-461 was also associated with reductions in the LVOT pressure gradient. A mild simultaneous increase in systolic blood pressure from 96 + 9 mm Hg to 108 + 8 mm Hg suggests a hemodynamic benefit from reduction of LVOTO.
This study demonstrates that the use of direct sarcomere inhibitors such as MYK-461 selectively reduces cardiac contractility and in turn relieves provokable SAM and LVOTO without negative chronotropy, which is a common effect of other pharmaceuticals used in HCM such as beta blockers and calcium channel blockers. Obvious limitations of the study include the small number of subjects and the fact that the investigation was performed under general anesthesia, which has multiple impacts on cardiovascular function. However, this fascinating research has paved the way for chronic studies on conscious humans and cats, including client-owned cats, under normal physiologic conditions, to determine the potential effect of MYK-461 on modification and progression of HCM and the possibility of remodeling of already diseased hearts. [PJS]