Dallas, TX - The use of magnetic resonance spectroscopy (MRS), an imaging technology used primarily in research, has allowed investigators to detect the accumulation of triglycerides in the hearts of patients with impaired glucose tolerance, as well as those with type 2 diabetes mellitus [1]. The storing of excess lipids in human cardiac myocytes is an early manifestation in the pathogenesis of type 2 diabetes, say investigators, also evident in those with impaired glucose handling, and might help explain the myocardial dysfunction often observed in type 2 diabetic patients.

"This study is based on previous studies where we previously showed the buildup of fat in skeletal muscle and in the liver of patients with insulin resistance," said senior investigator Dr Lidia Szczepaniak (University of Texas Southwestern Medical School, Dallas, TX). "This is a more ambitious task, measuring the fat in a beating heart, but the study is inspired by research done in animal models showing that as animals become insulin resistant, they have more fat in the heart, and that these hearts are extremely dysfunctional. In patients with insulin resistance and with diabetes, the buildup of fat is occurring way before that function is affected."

The results of the study are published in the September 4, 2007 issue of Circulation.

In discussing the study with heartwire, Szczepaniak said that in addition to contributing to coronary artery disease risk, the metabolic abnormalities associated with diabetes also lead to abnormalities in cardiac function. This cardiac dysfunction, she said, is believed to be independent of the effects of diabetes on the vasculature. More than 30 years ago, in fact, Framingham investigators first suggested that patients with type 2 diabetes had an increased risk of congestive heart failure, an association that remained even after adjustment for atherosclerotic disease.

Szczepaniak said that while the mechanisms in which diabetes causes cardiac dysfunction are unclear, animal studies have suggested that abnormalities in diastolic and systolic function are the result of an excessive storing of lipids and lipotoxic injury to cardiomyocytes. The overstorage of lipids, known as cardiac steatosis, produces lipotoxic substances that result in oxidative stress and can cause apoptosis, but investigators point out that it is not known whether this overstorage of lipids is the cause or consequence of heart failure in type 2 diabetes.

To clinically evaluate the diabetic heart, the investigators, led by Dr Jonathan McGavock (University of Texas Southwestern Medical School), used MRS to detect cardiac steatosis throughout the progressive stages in the natural history of diabetes. Overall, investigators stratified 134 individuals to undergo MRS and included lean and obese subjects with normal glucose tolerance, those with abnormal glucose tolerance, and those with diabetes mellitus.

As measured by spectroscopy, the myocardial triglyceride content was elevated in the obese subjects but was higher in subjects with impaired fasting glucose levels and diabetes. Subcutaneous and visceral fat was lowest in the lean groups, elevated only among the obese and those with metabolic abnormalities. The amount of fat in the heart was unrelated to the amount of fat in the blood or liver and suggests that these measures are not sufficient to predict cardiac steatosis or possible cardiac dysfunction, say investigators.

The investigators say the data emphasize that in the presence of normal glucose tolerance, obesity is not necessarily enough to cause cardiac steatosis, mainly because the myocardial triglyceride levels were not associated with body mass index. Also, given that the buildup of fat in the heart of those with impaired glucose tolerance precedes the onset of diabetes mellitus as well as ventricular dysfunction associated with diabetes, the detection of overstorage of lipids might be used a means to screen for cardiac dysfunction prior to the onset of heart failure in diabetic patients.

"The main message of our work is that we can test the abnormalities in the heart way before the symptoms of heart failure are detected," said Szczepaniak.

MRS uses the same principles as MR imaging, allowing researchers to observe protons in fat and water and quantify the amount of lipids in cardiac cells. Spectroscopy provides information about the metabolites, explained Szczepaniak, while MRI is the two-dimensional application of spectroscopy that creates the images. Spectroscopy is not in high demand, thus making the hardware and software for spectroscopy scarce. However, this type of imaging is used frequently for measuring hepatic triglyceride levels, she noted.

Writing in an editorial accompanying the paper [2], Dr Frederick Ruberg (Boston University School of Medicine, MA) notes that these data contradict smaller studies suggesting the myocardial triglyceride levels are related to age or body mass index but make sense given animal and human studies showing the accumulation of lipids in other organs in diabetes mellitus.

"This study does not imply causality but does strongly suggest that accumulation of myocardial triglyceride is at least a marker of early cardiac dysfunction in patients with insulin resistance," writes Ruberg. "More rigorous studies of diastolic characterization in subjects with more advanced heart failure and diabetes mellitus would be interesting to test whether increased lipid content is associated with more profound dysfunction."

One limitation, he suggests, relates to the clinical significance of the study. In contrast to MRI, MR spectroscopy is technically challenging to perform, requiring high sensitivity and a precision that might be difficult to reproduce, and is unlikely to be widely applied clinically. However, it is an excellent research tool, writes Ruberg, "one that will continue to provide a window into the potential mechanism(s) of cardiac dysfunction in insulin-resistant states."

The study by the Texas study group, he adds, is of "significant importance because it provides strong evidence linking observations from animal models of cardiac lipotoxicity to humans with diabetes mellitus. With future simplification of spectroscopic techniques, it is foreseeable that myocardial lipid content may one day be used as a biomarker to predict the development of cardiac dysfunction in patients with insulin-resistant states and may serve as a measurable target for intervention before the development of diabetic cardiomyopathy."

In terms of patients enrolled in the study, Ruberg noted that subjects taking thiazolidinediones, agents known to modulate intracellular lipid content, were excluded from the study to avoid confounding the results.