Understanding the genetics of disturbed heart rhythms and sudden cardiac death
In March 2006, Davis Nwankwo nearly joined the list.
It was a routine Monday morning practice. The Vanderbilt Commodores were heading to the Southeastern Conference Men’s Basketball tournament later in the week. Nwankwo arrived for practice about an hour early, as usual, to visit the trainer and have his ankles iced and taped.
He felt fine.
About 20 minutes into the practice, “my mind went blank and I started to walk away from the drill,” recalls Nwankwo, 21, a 6-foot, 10-inch tall senior from College Park, Md. He learned later that he collapsed, stopped breathing, and had no pulse. His heart’s normal rhythmic contraction was gone, replaced by rapid, uncoordinated twitching: ventricular fibrillation.
Nwankwo was lucky. Athletic trainer Mike Meyer sent someone racing to get the automated external defibrillator (AED) from the training room. A jolt from the AED and two breaths from Meyer saved Nwankwo’s life.
Without these measures, “he would have died on the spot,” says Dan Roden, M.D., director of the John A. Oates Institute for Experimental Therapeutics at Vanderbilt University Medical Center and one of the cardiologists who cared for Nwankwo during his hospital stay.
All in the family
Though the unexpected collapse and death of a young athlete in prime physical condition garners national attention, it is a rare event. But sudden cardiac death in the general population is all too common.
“About 15 percent of all deaths in adults in the United States—almost one death every minute—are sudden cardiac deaths, most due to ventricular fibrillation,” Roden says. “That’s a major public health problem.”
For patients with known heart disease, the “cardiovascular world has gotten very good at projecting risk of sudden cardiac death,” Roden says. Patients who are considered high risk generally undergo surgery to place an implantable cardioverter defibrillator, an electronic watchdog that monitors heart rhythm and delivers a shock in the event of cardiac arrest. Nwankwo had a defibrillator implanted two days after his collapse.
“But very good (at determining risk) is not perfect,” Roden adds. To complicate matters further, fewer than half of all sudden cardiac deaths occur in patients with known heart disease or conventional markers. That means that for a majority of those who suffer sudden cardiac death, it is the first symptom they experience.
Wilde and colleagues performed a case-control study in patients with a defined type of myocardial infarction (ST-elevation MI) who underwent percutaneous coronary intervention (angioplasty or stent placement). The case patients were those who survived ventricular fibrillation that occurred within the first 12 hours of the myocardial infarction. Control patients were matched for age, gender and infarct size, but did not experience ventricular fibrillation.
“The most intriguing finding of this case-control study… is that sudden cardiac death among parents and siblings is such a strong predictor of primary ventricular fibrillation,” Wilde and colleagues wrote in their 2006 Circulation report. The previous epidemiological studies had also suggested that a family history of sudden cardiac death increases a person’s risk for sudden death.
“What a ‘family history’ means to me,” Roden says, “is that there’s a relatively common genetic variant, or set of variants, in people who have sudden death that is different from people who don’t have sudden death. And that risk shows up when a coronary artery is occluded.”
Roden and Jean-Jacques Schott, Ph.D., of the French INSERM (National Institute of Health and Medical Research Center) in Nantes, France, are co-coordinators of a five-year, $6 million initiative funded by the Paris-based Leducq Foundation to search for the genetic variations that increase risk for sudden cardiac death. The network of sites in Europe and the United States aims to generate a genetic risk profile that will make it possible to calculate a patient’s risk for sudden cardiac death based on a genetic test.
“For these kinds of genetic screens, you need large, well-characterized patient and control populations, and the resources to do complicated genetic and statistical analyses,” Roden says. The network, whose core members include Amsterdam’s Wilde, Eduardo Marban, M.D., Ph.D., and Peter Spooner, Ph.D., both of Johns Hopkins University, and Robert Myerburg, M.D., of the University of Miami, plans to carry out its first screen for genetic variations associated with sudden cardiac death within the next six months.
Rare diseases offer insight
Genetic screening can be done at the single gene or genome-wide level, or somewhere in between. The Leducq-funded investigators will take the middle road, looking for “places in the genes we know and love, so-called candidate genes, where variation might explain susceptibility to arrhythmias and sudden death,” Roden says.
Ion channels control the flow of electrically-charged ions acoss the cell membrane and thus can affect heart rhythm. Red and green figures show closed and open channels. The yellow figure shows a mutation that inhibits ion flow.
In 1995, Mark Keating, M.D., and colleagues at the University of Utah reported that mutations in two ion channel genes—one encoding a sodium channel, the other a potassium channel—cause congenital long QT syndrome. This disorder, named for the longer than normal time between two points—Q and T—on the electrocardiogram, affects about one in 1000 individuals in the United States and can cause a potentially fatal arrhythmia called torsades de pointes. Over the last decade, hundreds of distinct mutations that cause long QT syndrome have been identified in 11 different genes, almost all of them encoding ion channels in the heart.
Likewise, other rare inherited arrhythmias and heart muscle diseases like hypertrophic cardiomyopathy have been linked to mutations in ion channels, calcium-regulating proteins, and components of the muscle cell’s contractile apparatus.
The rare cardiac diseases were once only interesting for purposes of “hospital roundsmanship,” Roden says, but “their importance now goes well beyond that.” They have revealed that the heart is composed of highly interconnected and interdependent systems, and that a defect in just one component of the system can cause a dramatic phenotype.
The rare syndromes have pointed to new components in cardiac physiology. And what's more, variations in the genes implicated by the rare syndromes have turned out to be more common than previously believed and to only sometimes cause disease, a phenomenon called “variable penetrance.”
“There’s a lot of commonality to these arrhythmia syndromes because the majority of them are caused by ion channel defects,” says Dawood Darbar, M.D., Ph.D., “but whether you get the congenital long QT syndrome or Brugada syndrome or atrial fibrillation, no one really knows why that is, and that’s something we’re trying to understand.”
Darbar, assistant professor of Medicine at Vanderbilt, focuses on atrial fibrillation, the most common arrhythmia observed in clinical practice. Atrial fibrillation carries a substantial risk of stroke and affects between two and three million people in the United States, a number that may climb up to eight million as the population ages. Symptoms range from nothing at one extreme to tremendous disability in terms of shortness of breath on exertion and heart failure on the other.
The fact that atrial fibrillation has a genetic basis has only been recently appreciated. “In the last five years there have been some fairly dramatic findings, and we now believe that up to a third of patients with atrial fibrillation probably have a genetic basis for their disease,” Darbar says.
Darbar and colleagues have conducted genetic screens in families with atrial fibrillation, identifying several DNA regions of interest. They also are building a database of clinical information and DNA samples for patients with atrial fibrillation, not just those who are part of large affected families. With more than 900 patients enrolled, this may be the largest such population in the country, he says.
“We’re trying to get to the point where we can do a genome-wide screen so that we can look beyond candidate genes to genes that intuitively don’t make any sense,” Darbar says.
Understanding the genetic causes of arrhythmia disorders will ultimately improve treatments, the investigators argue.
Antiarrhythmic medications are not terribly effective, Roden says, and are famous for causing a wide range of side effects, including actually worsening the heart rhythm and even creating new abnormal rhythms. And antiarrhythmic drugs are not alone in having these “proarrhythmic” effects. A wide range of non-cardiovascular drugs including antihistamines, antibiotics, and antipsychotics also can create life-threatening abnormal heart rhythms.
It was one of these drug-induced arrhythmias—torsades de pointes—that first captivated Roden. What intrigued him, he recalls, was that the same unique pattern on the electrocardiogram occurred in a congenital syndrome (long QT) and a drug-induced arrhythmia. The connection suggested that the genome may hold clues for why drugs elicit this kind of adverse reaction in some individuals but not others.
Roden has pursued the idea that there are genetic contributors to variability in drug response—“pharmacogenomics”—for most of his career, and last year he was named assistant vice chancellor for Personalized Medicine at Vanderbilt. He leads the Pharmacogenomics of Arrhythmia Therapy project, part of the Pharmacogenetics Research Network, a national effort to understand the genetics of drug responses supported by the National Institute of General Medical Sciences. Roden’s arrhythmia-focused team is poised to screen DNA samples from patients who have experienced drug-induced arrhythmias.
“The idea (of personalized medicine) has gone from an intellectual curiosity kind of thing to the notion that it may one day be possible to have generalized genetic profiles of every patient and the informatics infrastructure that will allow you to interrogate that genetic information,” Roden says.
“We could predict, based on genotype at one marker, how a patient will respond to the medication,” Darbar says. “This is the first example I know of a pharmacogenetic effect in atrial fibrillation.”
“In all of these spheres—arrhythmia management, drug-induced arrhythmias, sudden death,” Roden says, “the mantra is: knowing what the genetic variants are will make us smarter in terms of predicting who is at risk or not, and in terms of tailoring therapy with available drugs or tailoring new therapies.”
A tall order, perhaps, but one for which these investigators are game.
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