A Better Idea of When Mild HCM Is Likely to Go Downhill Fast

If therapies were to expand to people with mild hypertrophic cardiomyopathy (HCM), the first in line should be specific groups more prone to disease worsening, suggested one registry study.

Out of 2,500 people with phenotypically mild HCM, 23% subsequently developed symptoms and 21% went on to experience major adverse cardiovascular events (MACE; most commonly atrial fibrillation [Afib]) over a 7-year follow-up, reported Carolyn Ho, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues.

In this natural history study, there was a relatively low overall MACE incidence rate of 3.4 events per 100 patient-years — though MACE rates were especially high in outliers with the largest or steepest increases in left atrial (LA) diameter, left ventricular (LV) maximal wall thickness, or LV outflow tract gradient.

“Our intent was to study patients with HCM who are not currently eligible for treatments aimed at improving symptoms, but may be a target for disease-modifying therapy in the future,” study authors wrote in the Journal of the American College of Cardiology. “These findings highlight dynamic disease progression as an important feature of risk prediction.”

“We advocate for a paradigm shift in surveillance strategies, focusing on trajectory in addition to cross-sectional measures at individual timepoints. Such an approach could identify individuals experiencing more aggressive myocardial remodeling who may benefit from more frequent follow-up and earlier intervention, even if their absolute values may be within the normal range,” Ho’s group noted.

HCM is a myocardial disorder characterized by unexplained left ventricular hypertrophy. Therapeutic advancements in HCM have long focused on symptom relief and prevention of malignant ventricular arrhythmias and advanced heart failure, whereas an unmet need remains in disease-modifying therapies in early-stage HCM.

Mark Russell, MD, and Joshua Meisner, MD, PhD, both of University of Michigan in Ann Arbor, called the present work “extremely timely, as there are now an increasing number of therapies that may have the ability to modify the course of HCM.”

Examples already on the market — albeit approved for other indications — include valsartan, SGLT2 inhibitors, GLP-1 receptor agonists, and finerenone, Russell and Meisner cited in an accompanying editorial. In fact, given that “increasing outflow tract obstruction is an important determinant of future MACE, myosin inhibitors may ultimately have a role in altering the course of the disease in patients with mild HCM who are at risk for progression,” the duo wrote.

The disease course of mild HCM had been analyzed by Ho and colleagues based on the international Sarcomeric Human Cardiomyopathy Registry.

Phenotypically mild HCM was defined as shorter disease duration (<10 years since diagnosis or age ≤30 years), no previous MACE, New York Heart Association (NYHA) functional class I symptoms, and having a LV maximal wall thickness <25 mm.

Participants were followed prospectively for the development of symptoms or MACE, the latter defined as Afib, malignant ventricular arrhythmia, heart failure, stroke, or all-cause mortality. A subset of participants underwent genetic testing to identify variants in HCM-associated genes.

Of the 2,500 patients with phenotypically mild HCM (mean age 43 years, 31% women) followed for an average 7 years, 289 developed Afib, 69 malignant ventricular arrhythmia, and 193 heart failure.

The 23% of individuals who progressed from NYHA functional class I to ≥II symptoms during follow-up were significantly at greater risk of experiencing MACE (HR 2.79, 95% CI 2.30-3.39).

Other predictors of incident MACE were older age at baseline, higher body mass index, larger LA diameter, greater LV maximal wall thickness, higher LV outflow tract gradient, and presence of LV late gadolinium enhancement on cardiac MRI.

Study authors noted limitations in the registry study: it being subject to potential missing data and bias and failing to capture undiagnosed people in the general population.

Given the rarity of observed events in mild HCM, however, it would be impractical to proceed to a randomized trial with broad inclusion criteria, Ho and colleagues suggested. They said studies would be more likely to show treatment benefit by “preferentially” recruiting people with the aforementioned echocardiographic metrics instead.

“These patients are at higher risk for adverse events in the medium term, and therefore may both receive the greatest benefit from treatment and be able to demonstrate response to therapy,” the investigators reasoned.

“Future work could develop these data into a risk calculator for clinical progression of disease, similar to the highly beneficial and widely adopted sudden cardiac death-risk calculators in HCM, which will help guide clinical monitoring and treatment,” Russell and Meisner added.