The genetics of dilated cardiomyopathy
Volume 8, Issue 1
Through collaboration and a strong foundation of cardiology expertise, Mayo Clinic researchers have identified the genetic underpinnings of one of the major and potentially deadly forms of heart disease.
Within millions of Americans lies a silent killer — an enlarged and weakened heart that with every beat moves closer and closer to failing. When people eventually notice symptoms and seek medical care, the heart defect may be so subtle that their doctors are left struggling to pinpoint a cause.
Researchers at Mayo Clinic were the first to figure out the puzzle, determining that this enigmatic condition is a genetic disorder called idiopathic dilated cardiomyopathy. Now, their work is helping doctors diagnose the disease earlier than ever so that patients can receive appropriate medical care.
A different kind of heartbreak
Jeanne Theis, Ph.D., and Timothy Olson, M.D., are cardiovascular researchers seeking genetic answers.
Heart failure is usually equated with coronary artery disease and clogged arteries, which is often a result of an unhealthy diet and too little exercise. But that isn't the case with idiopathic dilated cardiomyopathy and other forms of dilated cardiomyopathy — people with this condition generally have normal blood pressure and clear arteries. Dilated cardiomyopathy is caused by an intrinsic abnormality in the cells underlying their heart muscle, which causes its main pumping chamber to become enlarged or dilated. In cases of idiopathic dilated cardiomyopathy, though, the cause is unknown.
It can take years or decades for that very subtle but critical defect to affect the pumping ability of the heart. But eventually, blood no longer flows as easily as it should, and patients start to experience symptoms, such as shortness of breath, fatigue and swelling of the extremities. Unfortunately, once patients know they're sick, the damage to their heart is sometimes so extensive that their only hope is a heart transplant. In fact, dilated cardiomyopathy is the most common reason that both children and adults need a heart transplant.
Mayo Clinic pediatric cardiologist Timothy M. Olson, M.D., has been motivated to seek better treatments by the heartbreaking history of the condition.
"This condition is different from coronary artery disease, which is far more common and for which we have strategies to halt the progression of heart failure," says Dr. Olson, whose research program investigates genetic mutations that lead to heart problems. "For dilated cardiomyopathy, we don't have that. I want to understand why the disease occurs in the first place, with the hope that understanding the biological underpinnings of the disease will lead to new ways to treat and prevent it."
Dr. Olson's latest discovery connects dilated cardiomyopathy to a gene linked to packaging unruly DNA strands into tight little chromosomes. He says the gene, called GATAD1, is unlike anything that has been linked to the disease so far. And he should know, considering that this is the seventh gene that Mayo Clinic investigators have found to cause dilated cardiomyopathy. The foundation for each of those findings can be traced to a seminal study published in 1992 in the New England Journal of Medicine by Virginia Michels, M.D., a medical geneticist at Mayo Clinic in Rochester, Minn.
It's in the genes
Virginia Michels, M.D., the Mayo Clinic medical geneticist whose seminal study provided the foundation for recent discoveries.
Image scan comparison of normal and dilated hearts.
Pathology specimen comparison of normal and dilated hearts.
Back then, most clinicians considered dilated cardiomyopathy to be extremely rare. There was only a small glimmer of evidence tying genetics to the disease, and it was certainly not enough to flag family members of the affected as also being at risk. Dr. Michels, who over the years has treated a number of patients and their relatives, began to suspect that the dilated cardiomyopathy was much more common in families than a simple family history would indicate. So she began running echocardiograms to look for enlarged ventricles in the hearts of seemingly healthy family members.
Dr. Michels found that a fourth of individuals with dilated cardiomyopathy had at least one relative who also had the disease. Her results were disputed at first, but they eventually became a turning point for the field. Clinicians came to realize that if they looked more closely, they could catch this disease at an earlier stage, when medication had a better chance of slowing its progression. Now it's standard clinical practice to perform screening echocardiograms on all individuals who might be at risk of dilated cardiomyopathy.
"The effect that her publication had on the field can't be understated," Dr. Olson says. "That study provided a rationale for changing clinical practice, but it also had a major impact on research in this area. At the time, researchers in human genetics were starting to make some important discoveries with regard to cardiovascular disease, such as identifying genes for hypertrophic cardiomyopathy and Marfan syndrome. But in terms of dilated cardiomyopathy, this study alone set the ball into motion and provided a heightened level of interest in applying molecular genetics to decipher the cause of this, disease."
In a way, Dr. Michels' seminal study gave Mayo Clinic a head start in the race to identify the genes behind dilated cardiomyopathy. She not only performed echocardiograms on her patients and their families, but she also gathered blood samples from every willing participant who walked through the clinic doors. That unparalleled source of samples, which continues to accumulate today, has given scientists the material they need to perform a number of exhaustive DNA studies.
For example, Dr. Olson's most recent research, published in the September 2011 issue of the journal Circulation: Cardiovascular Genetics, uncovered a new gene in a family that had been recruited to the research study more than 20 years ago. Dr. Olson and his colleagues had long been interested in this particular family because it demonstrated what the researchers considered to be a unique form of inheritance. The vast majority of families with dilated cardiomyopathy have a dominant form of inheritance, meaning they have a mutation in one of the two copies of a gene. This family, however, displayed a recessive form of inheritance, meaning that the disease was caused by mutations in both copies of a gene.
The researchers were unable to pinpoint the disease-causing gene in this family or to understand why it tracked so differently than other families with dilated cardiomyopathy until the advent of next-generation sequencing technology. With the help of Mayo Clinic genomics researcher Eric D. Wieben, Ph.D., Dr. Olson and his colleagues were able to take their classical genetic tactics and combine them with the latest sequencing tools to first narrow down the location of the defective gene to chromosome 7 and then identify the exact mutation in its DNA sequence. By combining these techniques, the researchers took a project that essentially sat idle for a couple of decades and brought it to completion within a year.
"What we are doing now is melding the old data from family-based studies with the new data from sequencing to get results much faster than ever before," says Dr. Michels, who was a co-author of the paper in Circulation: Cardiovascular Genetics. "This way, none of the old approaches gets tossed out; everything just builds on something from before. Our knowledge and experience in studying dilated cardiomyopathy disease is expanding in tremendous ways. When we first started out we thought we might find one or two genes that cause it; we had no idea it there could be so many."
All the good ones are gone
Dr. Theis, a Mayo Clinic research fellow, was first author of the article that revealed the new gene.
Family members with dilated cardiomyopathy had a point mutation in both copies of the GATAD1 gene, altering the genetic blueprint for a highly conserved region of the protein that it encodes.
Over the years, scientists have found more than 30 different genes that play a role in dilated cardiomyopathy. Some of the earliest discoveries were defects in genes coding for contractile proteins, which could alter the contraction of the heart muscle required to keep blood pumping. Those were followed by the discovery of mutations in genes that coded for the cytoskeletal proteins, which could compromise the structural integrity of the heart muscle cells.
Then the latest sequencing technologies brought a wave of discoveries in genes that researchers wouldn't normally have anticipated, such as those involved in regulating the flux of different ions, such as sodium, potassium and calcium, across heart muscle. Still, most of the genes linked to dilated cardiomyopathy make sense when understanding the physiology of the heart. That isn't the case with the most recent discovery, GATAD1.
"This gene certainly wasn't on anyone's candidate list when we started drawing up this project. It just goes to show that the easy genes have all been discovered, and now it is the hard ones that are left," Dr. Wieben says. "None of us have any idea how this defect could lead to this particular disease. Figuring that out is the exciting part and will involve defining new mechanisms of disease that could, in turn, give us a new understanding of how the heart develops and how it functions."
In other words, gene discovery is just a first step. It will take years of research to truly delineate how this defect leads to heart failure, and even more to use that knowledge to halt the progression of dilated cardiomyopathy. But this research does have a more immediate benefit: It adds one more gene to the ever-expanding list used to help diagnose the condition. Already, there are commercially available tests that can check for defects in the genes that cause dilated cardiomyopathy. The problem is those genetic tests will miss a lot of diagnoses because only one-third of those genes are known.
"We certainly have our work cut out for us in terms of discovering what genes account for the other two-thirds of the cases," Dr. Olson says. "One of the challenges is to try to identify as many genes as possible for the condition, such that they can be incorporated into a standardized genetic testing panel that will catch more cases. My prediction is that the era of gene discovery is going to be dramatically accelerated. Perhaps within the next 10 years, we will be in a position of knowing the vast majority of genes for dilated cardiomyopathy rather than just 30 percent of them. With that knowledge, we not only can diagnose heart failure risk in more people but also develop more effective therapies that can halt the disease process entirely and give these patients a chance at a longer and better life."
Other Mayo Clinic cardiology research
In addition to cardiovascular genetics, Mayo Clinic researchers are furthering knowledge in many other areas of cardiovascular research, including cardiovascular biomarkers, contractility and signaling and cardiovascular molecular imaging.