OREF grant recipient studies intrinsic causes of tendon problems
High cholesterol presents a significant health risk in the United States. More than 16 percent of adults have hypercholesterolemia, generally defined as a concentration of 240 milligrams or more of cholesterol per deciliter of blood. Although high cholesterol is a known risk factor for heart disease and stroke, its potential role in musculoskeletal health is not well understood.
Understanding intrinsic causes of tendon damage
Dr. Abboud noted that extrinsic causes of tendon damage—such as mechanical impingement, overloading the tendon, sports injury, or trauma—are relatively easy to identify in patients. Intrinsic causes pose a greater challenge. These intrinsic causes may include the aging process, blood supply, or the deposition of materials in the tendon that changes its mechanical properties.
Several studies, including one by Dr. Abboud and his colleagues looking at cholesterol and rotator cuff tears, have found a positive correlation between hypercholesterolemia and tendon injury. Studies of tendon injuries in people with familial hypercholesterolemia, a genetic disorder that results in extremely high blood cholesterol, have provided evidence that may be relevant to more typical cases of high cholesterol in the general population.
Research on fatty deposits in tendons (xanthomas), which are often associated with familial hypercholesterolemia, also provides details about cholesterol’s potential contribution to tendon injury. These fatty lesions increase tendon size and may alter the biomechanics of tendons.
Tendinous xanthomas are accumulations of lipid-laden macrophages (foam cells) in tendons (Fig. 1). These foam cells are immune-system cells that have “consumed” deposits of cholesterol. The composition of tendinous xanthomas is remarkably similar to lesions found in atherosclerotic plaques, which increase the risk of cardiovascular disease. Studies of cholesterol-lowering statins have shown that these drugs, usually prescribed to reduce cardiovascular risk, can reduce the size of tendinous xanthomas in people with familial hypercholesterolemia.
Learning from animal models
Experiments with animal models should further clarify the impact of cholesterol on tendons.
“If you add impurity to any structure, it changes the mechanical properties whether positively or negatively,” Dr. Abboud explained.
Dr. Abboud—along with a team that includes his mentor Louis J. Soslowsky, PhD—are working with mice that have normal blood cholesterol levels and transgenic mice that have approximately 50 percent higher blood cholesterol levels than normal mice when exposed to the same diet.
Researchers inflict a reproducible surgical injury to one patellar tendon at 10 months of age—late middle age for mice—to a subset of mice from both the study and control groups. After a recovery period, the mice are euthanized and the patellar tendons are dissected for analysis (Fig. 2).
A qualitative analysis of tissue slides is performed using a microscopic technology that assesses the organization of collagen fibers and identifies the presence of foam cells. Immunofluorescence is used to determine the concentration of various lipids, as well as proteins that would indicate localized immune system activity. A computerized biomechanical test measures the elasticity and stiffness of a segment of the patellar tendon. This series of tests is also performed on the remaining mice in the control and study groups that did not receive the surgical injury. A comparison of the data from each group thus far has shown that the hypercholesterolemic mice have reduced baseline elastic modulus and healing strength at 3 weeks postinjury compared to controls.
Dr. Abboud’s team is also conducting a parallel investigation in a rat model. The control and study groups are made up of rats of the same breed, but the study group is fed a high-cholesterol diet. In this model, the surgical injury is to the supraspinatus tendon, often the site of rotator cuff injuries in humans.
Translating research to the clinic
Dr. Abboud’s work may lay the foundation for future clinical studies—to clarify the role of high cholesterol in tendon injury risk and to test the potential of cholesterol-lowering drugs for modifying that risk or improving healing after injury. “If we truly find a link in patients, we could change the extent of tendon disease or damage over a patient’s lifetime,” he said.
A more immediate impact may be on the role of orthopaedic surgeons in a patient’s overall health care. “One of the challenges orthopaedists have is developing tunnel vision. We see the tendon, we see the bone, and that’s all we focus on. Often, we fix a tendon without exploring the underlying etiology for that tendon disease,” noted Dr. Abboud.
If a well-established association is found between high cholesterol and tendon injury risk, suggested Dr. Abboud, an orthopaedist might recommend a lipid test when he or she sees a patient with such an injury—especially if there is no apparent extrinsic cause. He added, “Orthopaedists may have the opportunity to treat a patient before the cardiovascular manifestations of hypercholesterolemia become obvious.”
Supporting research, shaping careers
OREF funding, said Dr. Abboud, enabled him to translate his questions about cholesterol from an interesting observation into a well-sustained investigation and a potential long-term focus for his career.
“I’m very indebted to OREF,” he stated. “I see my career going in a different direction now because of this grant. It helped me pursue my research interests and it gives me credibility in applying for additional grants to look at this question further in the future. OREF is a tremendously important funding source for orthopaedic surgeons.” Support for Dr. Abboud’s grant was made possible by the Orthopaedic Surgeons Network of Arizona.
Jay D. Lenn is a contributing writer for OREF and can be reached at firstname.lastname@example.org