Pathophysiology and Therapeutic Needs in Nonobstructive Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a common inherited heart condition in which the heart muscle becomes abnormally thick. This can make it harder for the heart to fill properly with blood and pump it efficiently around the body. In many patients, the thickened heart muscle, together with changes in the mitral valve (the valve between the left atrium and the left ventricle), interferes with blood flow leaving the heart. This situation is called left ventricular outflow tract obstruction (obstructive HCM).
However, many people with HCM do not have this obstruction. This form is known as nonobstructive HCM and is estimated to affect between 30% and 70% of patients, depending on the population being studied. It is the focus of a recent review by Dr. Desai and colleagues, published in JACC: Heart Failure.
In most cases, nonobstructive HCM is a familial disease caused by genetic mutations affecting proteins that help the heart muscle contract. The most common mutations involve the genes MYH7 and MYBPC3, which together account for about 40–60% of patients with an identified genetic cause. However, people carrying the same genetic mutation can have very different symptoms and disease severity. This suggests that additional genetic and environmental factors influence how the condition develops and progresses.
Nonobstructive HCM is a highly heterogeneous disease. Some individuals remain asymptomatic and have a low risk of complications, while others experience a more aggressive course. Symptoms may include shortness of breath, chest pain, fatigue, palpitations, and dizziness. Over time, some patients may develop serious complications such as atrial fibrillation, dangerous ventricular arrhythmias, heart failure, stroke, or sudden cardiac death. However, many people with nonobstructive HCM live full and active lives with regular specialist follow-up and appropriate treatment.
These symptoms are mainly caused by the heart muscle becoming stiffer and relaxing less effectively between heartbeats (known as diastolic dysfunction), reduced energy efficiency of heart muscle cells, abnormalities of the small blood vessels, and progressive scarring of the heart muscle. In advanced cases with severe heart failure that does not respond to standard treatments, heart transplantation may become necessary. Fortunately, this is required only for a small number of patients with very advanced disease.
Despite this substantial disease burden, treatment options for nonobstructive HCM remain limited. In general, patients with HCM—both obstructive and nonobstructive—are encouraged to engage in regular mild-to-moderate physical activity, because of its overall health benefits. However, more research is needed to better define the risks and benefits of exercise, and the type and intensity of physical activity should always be tailored to each individual patient.
Current medical treatments mainly aim to relieve symptoms rather than target the underlying disease mechanisms. Commonly used medications such as beta-blockers, calcium channel blockers, and diuretics often provide only partial relief and may cause side effects. Unlike obstructive HCM, there are currently no approved treatments specifically designed to slow or modify the disease process in nonobstructive HCM.
Encouragingly, the review highlights a growing number of clinical trials investigating new targeted therapies. These include cardiac myosin inhibitors (medicines that act directly on the heart muscle to improve how it works), drugs that improve heart muscle energy use, and other novel treatments aimed at slowing or altering disease progression. Early studies suggest these approaches may be safe and beneficial, but larger clinical trials are needed to confirm their long-term safety and effectiveness before they become part of routine clinical care.
Authors: Milind Y. Desai, Niccolo Maurizi, Elena Biagini, Philippe Charron, Fabio Fernandes, Esther González-
López, Paul L. van Haelst, Kristina Hermann Haugaa, Christopher M. Kramer, Benjamin Meder, Michelle
Michels, Anjali Owens, Shinsuke Yuasa, Perry Elliott.
JACC Heart Fail. 2025 Nov;13(11):102658. doi: 10.1016/j.jchf.2025.102658.
Prepared by Raffaello Dilarante and Francesca Musso