Inching Toward a Blood Test for Hypertrophic Cardiomyopathy

A small panel of circulating biomarkers may reliably distinguish hypertrophic cardiomyopathy (HCM) from similar conditions that cause left ventricular hypertrophy (LVH), researchers found.

From proteomic profiling of nearly 5,000 proteins, five were selected as potential flags for HCM based on protein concentrations being disproportionately higher or lower in HCM relative to three control diseases: hypertensive LVH, transthyretin amyloid cardiomyopathy (ATTR-CM), and aortic stenosis (AS).

The five-protein model had an area under the receiver-operating-characteristic curve of 0.86 (95% CI 0.82-0.89) for distinguishing HCM in a test cohort, reported Yuichi Shimada, MD, MPH, of Columbia University Irving Medical Center in New York City, and colleagues in Circulation: Heart Failure.

“The present study represents the largest-scale (n=1,415) and the most comprehensive (4,979 proteins) proteomic HCM investigation to date, elucidating plasma circulating biomarkers that are independently associated with HCM compared with other cardiomyopathies with LVH that are commonly encountered in clinical practice,” the authors wrote.

Their study will also be presented as an abstract at the upcoming American Heart Association (AHA) annual meeting.

Shimada’s group found that dysregulated MAPK and HIF-1 pathways were implicated in the five candidate HCM biomarkers: pleiotrophin, SPARC-related modular calcium-binding protein 2, spondin-1, transgelin, and ribonuclease pancreatic. These proteins are associated with cell proliferation, inflammation, and angiogenesis, the authors noted.

HCM is a relatively common genetic cardiomyopathy that can be a challenge to diagnose, with about one in three patients misdiagnosed as having another cardiomyopathy. Genetic testing identifies a pathogenic gene mutation in only 30% to 60% of patients with HCM, according to Shimada and colleagues.

U.S. recommendations say that patients with suspected HCM should undergo diagnostic imaging with both echocardiography and cardiac MRI, as well as a 12-lead ECG. The initial comprehensive HCM evaluation aims for diagnosis with assessment of LV morphology and function, symptom severity, sudden death risk, family history, lifestyle modification, and a surveillance plan.

“The difficulty in diagnosing HCM is partly due to the lack of specific plasma biomarkers that differentiate HCM from other cardiomyopathies with LVH. Moreover, signaling pathways that are uniquely dysregulated in HCM have not been well elucidated,” the study authors wrote.

For their study, Shimada and colleagues included patients from two tertiary care centers who underwent plasma proteomics profiling: 879 had HCM, 331 had hypertensive LVH, 169 had ATTR-CM, and 36 had AS.

Each patient had one protein measurement. There was a training and test set for each cohort.

The five identified biomarkers remained independently associated with HCM after adjustment for demographic and clinical factors.

Even so, the investigators cautioned, they could not rule out the potential for any false positives or residual confounding in their analysis. Additionally, not all patients underwent myocardial biopsy for a definitive diagnosis, so misclassification is another possible limitation to the study.

Finally, “the present study only included cardiomyopathies with LVH that are most frequently encountered in clinical practice and did not involve HCM phenocopies with lower prevalence, such as Fabry disease, Danon disease, and Noonan syndrome,” Shimada’s group acknowledged.