To start, I spoke to cardiologist Dr. Robert Plenge to get a better sense of his work, as I planned on interviewing him. He introduced me to hypertrophic cardiomyopathy (also known as HCM) and the rising drug mavacamten and sent me some starter articles. Before I read them, I familiarized myself with the heart and how it functions. I watched YouTube informational videos and looked at visuals. Then, I read, annotated, and took notes on all the articles, learning more about the heart, discovering HCM and pharmaceutical approaches to treating HCM, like mavacamten, a new drug undergoing testing before FDA approval. After that, I watched some more YouTube videos focusing specifically on HCM; these visuals helped me visualize and understand better what happened to a heart with HCM. Following my research process, I interviewed Dr. Plenge via Zoom, asking him more questions about mavacamten and his work with genetics. After the interview, I finalized all my website work and posted it online.

Throughout my research process, I learned a lot about HCM, heart functions and problems, mavacamten, and the drug testing process. In the heart, there are four main parts: the right atrium, the right ventricle, the left atrium, and the left ventricle. There is also the septum, a muscular wall that divides the heart’s two sides (1). Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disorder that is characterized by primary left ventricular hypertrophy (2). Common symptoms of HCM include, but are not limited to: tiredness, shortness of breath, chest pain, lightheadedness, heart pounding, and fainting (3). Hypertrophy is “the enlargement of an organ or tissue from the increase in size of its cells,” (4). In other words, with HCM, the walls of the heart thicken because heart muscle cells grow bigger, so the left ventricle of the heart therefore contracts harder and cannot hold as much blood. There are two different kinds of HCM: non-obstructive and obstructive. In non-obstructive HCM, the heart has thickened walls, but the walls and mitral valve do not block blood flow out of the left ventricle (5). The mitral valve is the valve that allows for blood flow from the left atrium to the left ventricle. In obstructive HCM, however, the heart has thickened walls and the septum may bulge into the path where blood leaves the left ventricle, known as the outflow tract (6). During heart muscle contraction in obstructive HCM, the mitral valve is pushed toward the septum, narrowing the outflow tract and possibly preventing closing of the mitral valve, hence causing backflow of blood into the left atrium. A narrowed outflow tract results in more pressure and heart-work needed to push blood out of the left ventricle. This pressure is called a gradient (7).

HCM is caused by mutations in sarcomeric contractile proteins (myosin)(8). Myosin is the heart’s motor; it is “a fibrous protein that forms (together with actin) the contractile filaments of muscle cells and is also involved in motion in other types of cells,” (9). When myosin is mutated, its power production in the heart is enhanced and ATPase activity is increased. Therefore, a treatment solution would be to intervene early, using a small molecule inhibitor of myosin power generation to prevent hypertrophy in the heart (10). Meet mavacamten: a first-class, small molecule, selective allosteric inhibitor of cardiac myosin ATPase specifically developed to target underlying pathophysiology of HCM by reducing actin-myosin cross-bridge formation, therefore reducing contractility and improving myocardial energetics (11). Essentially, mavacamten aims to block the myosin protein from interacting with other motor proteins, allowing the heart muscle to contract and then relax at a more normal, steady rate (12).

HCM affects a large portion of the population and often goes undiagnosed and inadequately treated in patients, as it is passed down genetically and can be asymptomatic. It’s important to raise awareness for HCM to encourage everyone to get genetic tests and even echocardiograms. My research means that there are solutions to problems difficult to treat in the past. With studying and testing, new drugs can be created, approved by the FDA, and used later on to help others.

Project Summary Endnotes:

1. Hypertrophic Cardiomyopathy (HCM) Mechanism of Disease Video, HCM Care, 2017.

2. Iacopo Olivotto, Artur Oreziak, and Ahmad Marsi, "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial," The Lancet, August 29, 2020, 1, accessed April 13, 2021, https://doi.org/10.1016/S0140-6736(20)31792-X.

3. Hypertrophic Cardiomyopathy.

4. Google Definition

5. Hypertrophic Cardiomyopathy.

6. Hypertrophic Cardiomyopathy.

7. Hypertrophic Cardiomyopathy.

8. David M. Warshaw, "Throttling back the heart's molecular motor," Science 351, no. 6273 (February 5, 2016): 1, accessed April 13, 2021, https://doi.org/10.1126/science.aaf1636.

9. Google Definition

10. Warshaw, "Throttling back," 1.

11. Olivotto, Oreziak, and Marsi, "Mavacamten for treatment," 1.

12. Michigan Medicine - University of Michigan. "A change of heart: New drug for HCM reduces heart mass." ScienceDaily. ScienceDaily, 16 November 2020. <www.sciencedaily.com/releases/2020/11/201116184440.htm>.