Diagnostics & Imaging Week Associate

The Cleveland Clinic (Cleveland) has been awarded a five-year, $17.22 million grant from the National Institutes of Health (NIH; Bethesda, Maryland) to advance its research into the science of heart attacks.

The federal funding will support Cleveland Clinic studies in four key areas: the genetics of heart attacks, the genetics of atherosclerosis, the role of proteins in arterial disease and the role of inflammation markers in the formation of coronary plaques.

Eric Topol, MD, chairman of the Department of Cardiovascular Medicine and chief academic officer of the Cleveland Clinic, will serve as program director for the new NIH grant. Individual projects will be led by Qing Wang, PhD; Jonathan Smith, PhD; Edward Plow, PhD; and Stanley Hazen, MD.

"This grant will give us a phenomenal and unprecedented opportunity to build on our early successes of identifying key genes and proteins implicated in causing heart attacks still the leading cause of death and disability," Topol said.

He told Diagnostics & Imaging Week that the tests that can be extracted from successful completion of these projects will help fuel the transformation of healthcare to an era of "smart medicine," in which people are diagnosed with a predisposition for a condition virtually at birth and treated accordingly rather than diagnosing a condition after it has advanced to a degree where treatment becomes much more difficult and expensive.

"If we can, in a pretty comprehensive way, nail down the rest of the genes and proteins that are implicated in heart attacks that will give us a way to really prevent this condition and also fashion much better strategies for individualized treatment," Topol said.

Two large-scale clinical research studies in cardiovascular disease GeneBank and GeneQuest helped to lay the groundwork for the the Cleveland Clinic to carry out these four projects and other revolutionary cardiovascular research.

GeneBank and GeneQuest were designed to foster investigator-initiated basic, translational and clinical research into the genetic and molecular origins of heart disease. They are centralized shared resources created specifically to assist Cleveland Clinic researchers in advancing genetics research.

GeneBank is a repository of genetic material, including DNA samples. Since its inception in 2001, GeneBank has enrolled more than 8,500 patients who have undergone cardiac catheterization.

GeneQuest, initiated in 1995, is the first large-scale prospective collection of families with premature coronary artery disease and heart attack. GeneQuest's population database currently includes more than 2,000 individuals from 500 multiplex families and more than 500,000 genotypes. A genome-wide scan of the population was completed in collaboration with National Heart, Lung and Blood Institute (also Bethesda) Genotyping Service.

Topol noted that the GeneBank and GeneQuest studies laid the foundation for the NIH grant money. "Those were, in many ways, what we had to seed our program with to show that they were effective before we could get successful peer review of the work."

In 2003, Cleveland Clinic researchers announced the first gene confirmed as a cause of coronary heart disease in humans. The gene, MEF2A, was discovered by methodically studying the genetic makeup of members of an Iowa family plagued for generations by coronary artery disease and heart attacks.

Subsequent studies of MEF2A have revealed that mutations on the gene are prevalent in about 2% of the population, considerably more than once believed. In addition, the severity of the mutation may impact the severity of heart disease in people who carry it.

Led by Topol and Wang, the genetics of heart attacks project will study patients with premature familial coronary disease. Using GeneQuest and GeneBank, researchers will study 16 key families with multiple generations of at least 10 to 12 siblings in each generation. Both affected and unaffected family members will participate.

In another project, atherosclerosis-susceptibility genes discovered in a mouse model will be tested to determine whether the effect is comparable in humans.

Smith will lead this project, which will use both the GeneQuest and GeneBank samples and clinical databases. The study will determine the specific sites of common variation in genes used in a subsequent association study performed with controls from the GeneBank cohort. The control group consists of a large group of men and women who have no coronary disease and who are a minimum of 50 and 55 years of age, respectively.

In the third project, the role of thrombospondins in atherothrombosis will be studied. Thrombospondins are a family of related, adhesive glycoproteins that are synthesized, secreted and incorporated into the extracellular matrix of a variety of cells. They interact with a number of blood coagulation factors and anticoagulant factors and are involved in a variety of functions including cell adhesion, platelet aggregation, cell proliferation and tissue repair.

This project will include two types of analyses to measure the effect of thrombospondins in atherothrombosis, a term that refers to a series of acute and chronic events in arterial disease.

Led by Plow, the first set of analyses will use the GeneBank case-cohort population and the GeneBank control population described above. The samples will be analyzed for disease associated with thrombospondin types 2 and 4 (there are five types total). The second set of analyses will examine the relationship between thrombospondins and second cardiac events, including heart attacks or other events requiring cardiac intervention.

The fourth project involves the role of inflammation markers in the formation of coronary plaques.

In 2003, Cleveland Clinic researchers identified a blood test to determine whether a person is in imminent danger of heart attack or death. The test is especially valuable for identifying at-risk patients not recognized by current diagnostic laboratory testing. The test measures the level of myeloperoxidase (MPO) in the bloodstream. MPO is an enzyme found in disease-fighting white blood cells.

Led by Hazen, this project will build upon knowledge previously gathered on MPO and other inflammation markers by examining the relationship between inflammation and specific oxidation pathways to incident cardiovascular risks. Using a series of intravascular ultrasound studies, researchers will measure coronary plaque and regression as it relates to inflammation.

"In the future, we will be able to use a simple panel of genes and proteins to assess the heart-attack risk of an individual early in life," said Topol. "This has a great potential to radically change and improve preventive medicine."

He noted that getting to this vision of a comprehensive testing panel for the detection of heart attack is possible in the not-to-distant future. At this point he estimated that perhaps 10% of the heart attack "puzzle" has been solved, but that in the next four or five years, The Cleveland Clinic projects that in conjunction with the work of other programs, the majority of the other pieces will be found. "Not all, but much, much closer."

No Comments