Blood Biomarker Discovery Study

The Blood Biomarker Discovery Study was HRP's first research study with the aim to discover blood biomarkers that suggest the presence of vulnerable plaque or increased risk of developing the condition.

The Blood Biomarker Discovery Study used stored blood samples from the Duke University CATHGEN research project. The Duke CATHGEN research project recruited research participants from those patients who were undergoing a coronary angiogram because of suspected coronary disease. Angiograms can reliably detect stenosis of the coronary arteries but can not identify the presence of vulnerable plaque, which is the type of plaque prone to rupture and the generation of thrombosis. Coronary stenosis is an important cause of cardiac symptoms, such as angina and a contributing cause of heart attacks. The participants provided blood samples and informed consent for use of their samples and data for research purposes.

It is well known that 20-25 % of patients who undergo a coronary angiogram for suspected coronary disease are found to have limited or no coronary disease. Interestingly, despite these normal or near normal angiograms, some of the patients developed a documented heart-attack in the two year period following the angiogram. One likely explanation is that the patient had a vulnerable plaque in one of the coronary arteries, not detectable with an angiogram, and that the vulnerable plaque ruptured resulting in the heart attack.

The Study used a case-control design involving a total of 136 subjects. The cases had a normal or near normal angiogram and despite this developed a documented heart-attack or stroke over the two-year period following the angiogram. Controls were selected because they matched the cases on relevant parameters except that they had no sign of heart attack or stroke over the two years. The study was conducted by BG Medicine on behalf of the HRP Initiative and with collaboration of researchers at Duke University.

The following laboratory tests were performed by on the samples of cases and controls:

• Proteomics:
  • Mass-spectrometry-based proteomic profiling - this advanced technology allows one to find all proteins in plasma that are present over a certain threshold level
  • Targeted proteomics - targeted proteomics uses standard laboratory technologies (ELISA) to measure a predefined list of plasma proteins.
• Metabolomics:
  • Mass-spectrometry-based profiling of small molecules (metabolites) in plasma - this advanced technology allows one to find a variety of smaller molecules such as amino acids, lipids, fatty acids, sugars, etc.
• DNA:
  • DNA is the principal genetic material of the body and study looked at genetic variants among a number of important genes between the cases and controls.

A preliminary analysis was completed in Q3 of 2007 and results were very promising. Additional analyses are being performed, a replication study is being planned and a manuscript will be prepared and submitted for publication.

There were a number of single laboratory measurements that were consistently higher or lower in the cases than controls. These are measurements of one specific molecule in plasma whereby the range of values among cases was statistically different from the controls, called univariate biomarkers - a single molecule measurement correlates with the risk. As with many blood tests, such as cholesterol, the individual predictive value is somewhat limited. For example some controls may have values that are in the same range as the cases.

The following figure shows the performance of the test. The perfect test would follow the left vertical axis and the top axis. A test that has no value and is as good as a coin toss would follow the red diagonal. The line marked "conventional" illustrates the current standard of relying on information based on smoking, obesity, blood pressure, etc. while the other line indicates the performance of the 20-marker panel discovered in the Blood BioMarker Discovery Study.

An important word of caution: These are preliminary results on a single relatively small study. Although very promising, the results need to be validated, for example by repeating these measurements in the large HRP BioImage study. However, if these results are confirmed, the HRP might have discovered an improved method of finding those at the highest risk of heart attacks and stroke. These 20 measurements can easily be combined in a single blood test that can be done in the doctor's office or hospital laboratory, possibly even on a single drop of blood.