Heart disease hits people with diabetes twice as often as people without diabetes. In those with diabetes, cardiovascular complications occur at an earlier age and often result in premature death, making heart disease the major killer of diabetic people. But why is heart disease so prevalent among diabetics?

To help answer that question, researchers at Washington University School of Medicine in St. Louis have been analyzing the fat (lipid) composition of heart tissue from laboratory mice with diabetes. They have found that heart cells of diabetic mice lose an important lipid from cellular components that generate energy for the heart, and their latest research shows this happens at the very earliest stages of diabetes.

"Diabetic hearts run mostly on fats for fuel because glucose isn't readily available to them," says Richard Gross, M.D., Ph.D., director of the Division of Bioorganic Chemistry and Molecular Pharmacology and professor of medicine, of chemistry and of molecular biology and pharmacology.

"Unfortunately, this change in metabolism distorts the lipid composition of cell membranes causing abnormal physical properties and cellular dysfunction." The important lipid that the researchers found to be decreased in diabetes is cardiolipin.

"Cardiolipin" literally means heart fat, and the term was coined because cardiolipin was first discovered in beef hearts and is one of the most abundant lipids in heart tissue. This lipid has unusual physical properties that are essential for the operation of the energy-producing cell structures called mitochondria. When mitochondria lose a lot of their cardiolipin, they malfunction.

Their malfunction not only interferes with the energy supply of heart muscle cells, it also increases the amount of damaging oxygen-containing substances in the cells, creating unhealthy conditions that can lead to heart problems. Interestingly, a rare genetic disorder — Barth syndrome — held a key to identifying cardiolipin decrease in diabetic hearts. Children born with Barth syndrome have weak hearts and often die young from heart failure. These children have mutations that prevent cells from producing enough cardiolipin.

The connection between cardiolipin and heart disease in Barth syndrome led the Washington University researchers to wonder if cardiolipin was also affected in diabetic hearts. But in order to measure cardiolipin, the researchers needed a way to distinguish it from the numerous other lipids found in heart cells. Fortunately, Gross and his colleagues have been developing and refining a highly sophisticated set of techniques that allow them to separate and quantify thousands of different lipids based on their subtle structural differences.

The set of techniques has been termed "shotgun lipidomics" because they very rapidly determine which lipids are in tissues and blood. "Shotgun lipidomics provide a precise way to measure changes in heart lipid content," says first author Xianlin Han, Ph.D., assistant professor of medicine. "We found a dramatic depletion of cardiolipin in heart muscle as early as five days after diabetes was induced in mice."

"These results suggest that cardiolipin alterations underlie heart dysfunction in diabetic heart disease and may be a useful biomarker for diagnosing cardiovascular disease in diabetes," Gross says. "Measuring alterations may be a way to tell the severity of heart disease and to evaluate how well therapies work. In addition, these findings suggest potential new therapeutic approaches."

Even though the research team found a depletion of an important type of lipid in diabetic heart tissue, diabetic heart muscle cells actually take in excess lipids. But as these lipids enter cells they activate lipid-digesting enzymes. In previous studies, Gross and colleagues identified a particular lipid-digesting enzyme that becomes more active in diabetic heart muscle and contributes to the breakdown of cardiolipin.

Recently, Gross and his colleague David Mancuso, Ph.D., member of the division, found that mice engineered to produce too much of this enzyme in their hearts developed defects in mitochondrial function which became worse when they were fasted — a condition that, like diabetes, causes the heart to use lipids for fuel. A 16-hour fast caused significant problems with the mouse hearts' ability to pump blood, again implicating altered lipid metabolism, cardiolipin scarcity and mitochondrial impairment in heart disease using lipid as predominant fuel. Gross adds that in addition to the effects on mitochondria, many of the membranes in heart cells, which are built from fatty molecules, are also adversely affected by the diabetic heart's abnormal lipid metabolism. Furthermore, because fatty molecules are part of cells' signaling mechanisms, numerous aspects of cellular physiology become altered.

"The pieces of the puzzle of diabetic heart disease are now rapidly falling into place," Gross says. "By exploiting the novel technology of shotgun lipidomics, we have identified the increased activation of certain lipid-digesting enzymes and the decrease of cardiolipin as central aspects of this disorder. We hope that these kinds of studies will enable physicians to diagnose diabetic cardiovascular disease sooner and treat it earlier."

Han X, Yang J, Yang K, Zhao Z, Abendschein DR, Gross RW. Alterations in myocardial cardiolipin content and composition occur at the very earliest stages of diabetes: a shotgun lipidomics study. Biochemistry 2007;46:6417-6428.

Mancuso DJ, Han X, Jenkins CM, Lehman JJ, Sambandam N, Sims HF, Yang J, Yan W, Yang K, Green K, Abendschein DR, Saffitz JE, Gross RW. Dramatic accumulation of triglycerides and precipitation of cardiac hemodynamic dysfunction during brief caloric restriction in transgenic myocardium expressing human calcium-independent phospholipase A2γ. Journal of Biological Chemistry 2007 Mar;282(12):9216-9227.

Funding from the National Institutes of Health supported this research.