Test Aims to Identify Heart Attacks Before They Occur

Neil Osterweil

March 09, 2015

LA JOLLA, California — A point-of-care assay to detect a heart attack about to happen, which would give clinicians time to intervene before myocardial damage occurs, is being developed by genomics researchers.

Cardiologists are very good at identifying people at risk for acute myocardial infarction (AMI) and figuring out when a patient has experienced acute coronary syndrome, but they are at a loss when it comes to predicting when a major cardiovascular event is imminent, said Evan Muse, MD, from the Scripps Translational Science Institute in La Jolla, California.

"While the diagnosis of coronary disease or acute myocardial infarction is pretty simple on the spectrum of things, we think it's a little too little, a little too late," he said here at the Future of Genomic Medicine VIII. "Wouldn't it be nice to have a signal that comes up before you have that ultimate heart damage?"

Since the late 1990s, it has been known that there is a significant elevation in circulating endothelial cells after an AMI. These cells are also elevated in patients with unstable angina, who don't exhibit ST-segment elevations on electrocardiogram and who have no evidence of myocardial damage on assays such as cardiac troponins, Dr Muse said.

His team assembled a cohort consisting of 23 AMI patients 18 to 80 years of age who had an ST-elevation myocardial infarction and had undergone coronary angiography, and a control group of 22 healthy adult blood donors 18 to 35 years of age with no history of chronic disease.

They used immunomagnetic separation to enrich circulating endothelial cells, and then created genetic microarrays from the enriched cells to compare gene expression in the blood of the AMI patients with that in the blood of control subjects.

As expected, in circulating endothelial cells from AMI patients, there was an upregulation of genes in pathways for platelet activation and thrombosis and inflammation, "but that's not telling us anything more than we already knew," Dr Muse said.

The investigators wanted to create a discovery set that would identify whether a specific combination of genes, expression patterns, or both, is predictive of a cardiac event.

They found 11 genes that were either significantly upregulated or significantly downregulated in patients with AMI, compared with control subjects. Their panel had a perfect discriminative ability, as indicated by the 1.0 area under the curve (AUC) of receiver operating characteristics (ROC).

"We thought that was pretty awesome, but seemingly unbelievable, so we went back and recruited another 25 healthy volunteers, in addition to the 23 crashing patients with acute myocardial infarction. Using this 11-gene model, we were able to see an AUC of ROC analysis of 0.99, which we felt was quite fantastic," Dr Muse reported.

Many of the genes included in the panel have already been recognized as being involved in inflammatory signaling and vesicular trafficking, such as endothelin-1, an endothelium-specific protein implicated in the risk for cardiac disease.

The team also tested the concept on whole blood samples from AMI patients and healthy control subjects, using quantitative real-time polymerase chain reaction (PCR) on a test panel of seven of the genes, and found an AUC of 0.998.

The seven-gene test was a little less robust when they tested it on a third cohort of patients who had stable coronary disease. Nearly two-thirds of that control set had previously undergone coronary angioplasty with stenting or coronary artery bypass graft, and one-quarter had atrial fibrillation. For this test run, the AUC was 0.85 — not perfect, but still quite impressive.

"We moved from having to use immunomagnetic separation techniques and microarrays of thousands of genes to a real-time PCR of just seven genes from whole blood, something that could potentially be moved into a real clinical setting for relevance," Dr Muse explained.

Beyond Statins

"I think it's the wave of the future," said Dan Harper, MD, a physician in family practice and integrative medicine in Solana Beach, California, who was not involved in the study.

"We're going to have to start looking at more than just cholesterol as being the enemy, and the American Heart Association's answer — getting everybody on statins — only decreases adverse events 20% to 30%," he told Medscape Medical News.

Keeping patients healthy is the ultimate goal. In those with a genetic weakness, "what can I do to support patients so that the weakness doesn't manifest?" Dr Harper asked. "That's the bottom line. I think these guys are right on with what they're saying."

The work described by Dr Muse is supported by the Scripps Translational Science Institute, and Dr Muse is an employee of Scripps. Dr Harper has disclosed no relevant financial relationships.

Future of Genomic Medicine (FoGM) VIII. Presented March 5, 2015.

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