New Proteomics Tool Reveals Novel Biomarkers for Cardiovascular Risk

BOSTON – Proteomics, the large-scale study of the body’s proteins, is used to identify molecules associated with certain conditions and can help clinicians diagnose, monitor or screen for a wide range of diseases. These telltale molecules, known as biomarkers, may also help researchers understand the origins of disease like cancer and heart disease and could open the door for new ways to treat them.

In a study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and the Broad Institute of Harvard and MIT, researchers identified more than 200 new biomarkers linked to cardiovascular disease using an emerging proteomics technology. The paper, published yesterday in the journal Circulation, demonstrates that the promising proteomics tool – an aptamer-based platform that uses single stranded DNA like a fly strip to bind to specific targets – can analyze more than 1,100 proteins in a single blood sample, with both high sensitivity and high precision.

"Many individuals with coronary artery disease don’t exhibit any of the traditional cardiac risk factors, such as smoking, hypertension, high cholesterol or diabetes. The presence of these new biomarkers indicates an elevated risk of cardiac disease even in individuals who have no outward symptoms,” said corresponding author Robert E. Gerszten, MD, Chief of Cardiovascular Medicine at BIDMC, senior faculty member at the Broad Institute and Professor of Medicine at Harvard Medical School.” “With this new technology, we were able to identify novel proteins associated with damage to the cardiovascular tissues.”

In what’s known as a perturbational study, the investigators assessed clinical and biochemical changes in study subjects before and after a cardiac procedure. In this case, the researchers used the aptamer-based proteomics platform to analyze blood samples from patients who had undergone alcohol septal ablation, a treatment for hypertrophic cardiomyopathy (thickening of the heart muscle). The technique also serves as a model of planned myocardial injury (PMI), causing the body to mimic the symptoms of a heart attack.

“Alcohol septal ablation reproduces key clinical features of spontaneous myocardial infarction – commonly known as a heart attack – including chest pain, electrocardiographic changes, and the release of established markers of myocardial injury,” said Gerszten.

The results not only confirmed the existence of established biomarkers of myocardial injury, including creatine kinase MB and troponin, but also identified more than 200 proteins that increased in the study subjects’ blood within one hour following PMI.

“Many of these proteins appeared in the blood samples within 10 minutes of injury,” said Gerszten. “This new information might ultimately help guide treatment by providing clinicians with additional information on top of established biomarkers and electrocardiographic changes.”

Using archived blood samples from a cohort of more than 5,000 participants of the long-running Framingham Heart Study, the investigators next tested whether the aptamer proteomics platform could detect these same proteins and risk factors in individuals who did not have overt cardiovascular disease.

“This analysis confirmed the links between the novel proteins and cardiovascular risk traits in patient samples archived for more than 20 years,” said Gerszten. “This suggests there are many previously unknown pathways that are awry in individuals who had numerous risk factors.”

“Our overall findings provide important human data to support the use of this promising proteomics technology for the diagnosis and screening of cardiovascular conditions, and they highlight a broad spectrum of protein biomarkers associated with cardiometabolic risk that can be explored in future studies,” said Gerszten. “Ultimately, they may even enable us to identify pathways for therapeutic intervention.”

Study coauthors include co-corresponding author Steven A. Carr, PhD, of the Broad Institute; BIDMC investigators Debby Ngo, MD, Sumita Sinha, PhD, Dongxiao Shen, PhD, Michelle J. Keyes, PhD, Xu Shi, MD, PhD, and Laurie A. Farrell, RN; John F. O’Sullivan, MD, PhD, and Michael A. Fifer, MD, of Massachusetts General Hospital; Eric W. Kuhn, PhD, and Hasmik Keshishian, PhD, of the Broad Institute; Marc S. Sabatine, MD, MPH, and Mark D. Benson, MD, PhD, of Brigham and Women’s Hospital; Ramachandran S. Vasan, MD, of Boston University School of Medicine; Martin G. Larson, ScD, of Boston University School of Public Health; and Thomas J. Wang, MD, of Vanderbilt University.

This work was supported by grants from the National Institutes of Health (N01HC25195, HH-SN268201000033C) and the National Cancer Institute (U24CA60034)