Gene-altered mice boost studies of cardiomyopathy
June 1, 1998
University of Chicago cardiologists have created the first transgenic mouse that closely reproduces the clinical, anatomical, and pathological features of dilated cardiomyopathy, allowing scientists an unprecedented opportunity to study the early changes associated with this fairly common disorder and to develop and test new therapies.
The finding is reported in the June 1, 1998 issue of the Journal of Clinical Investigation.
"This is a big step toward better understanding and better treatments for a prevalent and very deadly disease," said cardiologist Jeffrey Leiden, MD, PhD, Frederick H. Rawson Professor of Medicine and Pathology at the University of Chicago and director of the study.
Dilated cardiomyopathy is an important cause of congestive heart failure, which affects more than 4 million Americans. Congestive heart failure is the most common cause of hospitalization for patients over age 65 and a leading cause of death.
In dilated cardiomyopathy the heart muscle expands and weakens -- ballooning out like an over-stretched rubber band--until it can no longer pump blood efficiently. Patients complain of overwhelming fatigue, shortness of breath, and chest pains. Lack of adequate circulation, in turn, can damage the lungs, liver, and other body systems.
Although cardiomyopathy has been associated with many possible triggers, such as viral infections or alcohol abuse, the cause is usually unknown. Idiopathic (of unknown cause) dilated cardiomyopathy (IDC), affects an estimated 36 of every 100,000 people. Recent studies show that as many as 40 percent of those patients have a family history of the disorder, suggesting a genetic predisposition to the disease.
Dilated cardiomyopathy, like all forms of heart failure, tends to be diagnosed late in the course of the disease and to progress rapidly. There is no cure. Up to 50 percent of patients die or require a heart transplant within five years of diagnosis.
"This disease has remained extremely frustrating for patients and physicians," said Dr. Leiden, "because there has not been major scientific or therapeutic progress for decades."
The lack of an animal model has severely limited physicians' ability to understand the causes and mechanism of this disease and to develop new, more effective treatments. Since patients are usually diagnosed with advanced disease, knowledge of the early stages of cardiomyopathy is particularly limited.
"Without sufficient understanding," said Dr. Leiden, "we can only treat the symptoms--not the underlying disorder."
Even the value of diet and exercise as therapy for heart failure remain unsettled.
By altering one mouse gene, however, the research team has created a very accurate animal model of the disease. They introduced a mutant form--active only in the heart--of a gene called CREB, which controls the activity of several other genes that regulate the growth and development of cardiac muscle.
The altered gene--which blocks the normal effects of CREB--is turned on only after the mice mature. The mice are normal at birth; but a few weeks later, mice with the altered gene develop a severe and progressive form of dilated cardiomyopathy that precisely mirrors the human disease.
In gene-altered mice, the heart muscle expands and loses pumping strength. This results in an accumulation of fluid in the lungs, liver, and legs. Like patients with IDC, these mice die prematurely, from 20 to 35 weeks after birth (about one-third the normal life span).
"The clinical behavior, the anatomical changes, and the microscopic evidence at autopsy are identical to human cardiomyopathy," said Dr. Leiden. "The progress of the disease is remarkably similar to the way heart failure affects humans."
For example, all four chambers of the mouse heart dilate--just like the human disorder. The muscle loses the ability to squeeze out blood or to refill after contracting. Fluid backs up, causing congestion in the lungs, liver, legs, and abdomen.
Under the microscope, the cardiac tissue from the mice is indistinguishable from human heart tissue; it shows the standard markings of cardiomyopathy: cellular drop out, the appearance of fibrous tissue between muscle cells, the odd intermingling of oversized and tiny muscle cells, and the appearance of empty spaces within remaining muscle cells. The mice even develop "nutmeg liver," a classic finding in human cardiomyopathy, caused by the back-up of blood flow through that organ.
Diagnostic images of affected mice, taken with ultrasound or cardiac catheterization, also are identical to human disease. In fact, the researchers--working with engineers from Hewlett Packard--developed non-invasive ultrasound heart-imaging equipment sensitive enough to follow the course of the disease in mice. Although mouse hearts beat eight to 10 times a second and are no bigger than an M&M candy (that's plain, not peanut), the new technology allows sequential monitoring of these mice with echocardiography.
This mouse model should "hasten scientific understanding for dilated cardiomyopathy and improve therapy for heart failure," suggest the researchers. It should allow controlled testing of the effects of exercise and diet and permit more rapid testing of new medications.
"We are particularly excited about the opportunity to learn about the early stages of the disease," said Dr. Leiden, "which should gives us valuable clues about the biochemistry of cardiomyopathy and possible suggest ways to intervene before the damage is done."
Although CREB mutations have not been detected in human IDC, the similarity of the mouse and human versions suggests that the cardiac genes that CREB controls--a pathway that has not yet been mapped out--may play a crucial role in the development of IDC.
This research was supported by a grant from the National Heart, Lung, and Blood Institute. Additional authors of the paper include Richard Fentzke, Claudia Korcarz, Roberto Lang and Hua Lin, all of the University of Chicago.
University of Chicago cardiologists have created the first transgenic mouse that closely reproduces the clinical, anatomical, and pathological features of dilated cardiomyopathy--allowing scientists an unprecedented opportunity to study the early changes associated with this fairly common disorder and to develop and test new therapies.
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