ONE night in 1991 my 26-year-old brother suddenly and inexplicably died. There was no warning. He was generally fit and pretty healthy. Yet he just died in his sleep. The coroner was so perplexed he ordered three post-mortems and eventually called my family to apologise for his failure to find a cause. Losing a loved one is bad enough. But on top of the anger, frustration and deep sense of loss at James’s death, we were left with a lingering fear that whatever happened to him could happen to any of us. It’s a fear that has proved justified.
Now, 11 years and three near-death experiences later, I’ve finally got some answers. Like my brother, it seems I have a rare genetic disease called Brugada syndrome that can suddenly stop my heart beating properly. Discovered only a decade ago, Brugada syndrome is so obscure that most doctors and coroners have never even heard of it. It is a disease that affects only the electrical activity of the heart, so that physically, the heart looks perfectly healthy. This makes it almost impossible to detect. The first symptom can be the last: failure of the heart to beat properly. And to make matters worse, the condition leaves no clues as to the cause of its victims’ untimely demise.
But now scientists are scrambling to understand Brugada syndrome. In part their endeavours are fuelled by the suspicion that Brugada could be jeopardising clinical trials of a host of new drugs unrelated to heart problems. And there is evidence that it may also be behind some cot deaths in babies. Researchers are hoping that data from the Human Genome Project will help them devise new, reliable ways of detecting Brugada syndrome. That would help not only the people who, often unknowingly, carry the gene or genes that cause it. It would also lift the shadow hanging over so many drugs trials, and thereby bring benefits to all of us. Until those tests materialise, however, my family and thousands of others face some difficult decisions.
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It’s hard to know exactly how many people have Brugada syndrome. What we do know is that it is much more common in some ethnic groups than in others. Current estimates are that as many as 1 in 2000 Japanese have it, mostly men, while in Thailand it is thought to be the biggest killer of healthy males under the age of 50, second only to traffic accidents. The Thais are so familiar with it that it has entered folklore. Since it mainly affects men, they have nicknamed it the “widow ghost” – the legend says that a disquieted spirit, searching for a new groom, steals the souls of men while they sleep. Desperate to evade the widow’s clutches, some Thai men used to dress in women’s clothes before going to bed, in the hope that she would be fooled into sparing them.
For me it’s a little less dramatic. I now have a metal box in my chest called an implantable cardioverter defibrillator, or ICD. The sophisticated electronics inside it continuously monitor the electrical activity of my heart, and will zap it back to life if the widow strikes again. If I am lucky, I will have passed out before this happens, and so avoid a shock that some have compared to being kicked in the chest. But in many respects I am already fortunate, because unlike my brother and many other Brugada victims I have at least had some warning signs.
No one knows why, but some people with Brugada syndrome survive an attack as the heart somehow naturally recovers its rhythm. To date I have undergone three such “spontaneous abortive sudden deaths” that I know of. I may have had more that I’m not even aware of– perhaps in my sleep, or while lazing in front of the TV.
My first two attacks were written off by doctors as common-or-garden fainting episodes. But just a year ago, when I collapsed at a conference in Washington DC, things went a little differently. On this occasion, perhaps because I was seen by doctors almost immediately, a routine electrocardiogram revealed mildly suspicious electrical activity. I was told that there was probably nothing to worry about but that I should “check it out” when I got home to London.
The timing of my ECG was lucky because Brugada doesn’t always show up in the ECG trace. “It depends a lot on the activity of the heart: how excited it is, how fast or how slow it goes,” explains Ramon Brugada, one of the three Spanish brothers who discovered the disease in 1992. “You have to diagnose it at the right time.” Otherwise the ECG will look normal. In the immediate aftermath of the attack, the electrical activity in my heart was still slightly abnormal, alerting the doctors to a potential problem.
Anatomy of an attack
Abnormal heart beats, or arrhythmias, are a fairly common heart problem, especially in older people. They are often caused by damage to the heart, such as coronary heart disease. But some arrhythmias are caused by genetic faults that disrupt electrical activity in the heart. One of the best known of these is “long QT syndrome”, which has also been implicated as a cause of unexplained sudden death. Unlike Brugada, however, it is easy to diagnose and treat. Both Brugada and long QT exert their deadly effects by stopping heart muscle cells from working as a team.
A Brugada syndrome attack occurs when heart muscle cells in the right ventricle, one of the heart’s four chambers, fail to conduct electrical signals properly (see Diagram). These cells are normally “paced” by regular electrical pulses from the heart’s natural pacemaker, the sinus node, to ensure that they all contract together and that the two sets of chambers beat rhythmically. But a Brugada attack deprives cells in the right ventricle of this signal. With nothing to keep them in order, anarchy prevails. They contract faster and faster until very quickly they lose their rhythm altogether and beat independently. Instead of beating, the chamber just quivers and the heart stops pumping blood effectively. To make best use of the little oxygen available, the brain quickly shuts down higher cognitive functions and the person faints.
At this point their life hangs in the balance. Sometimes the heart spontaneously regains its rhythm and the person recovers. If it doesn’t, the heart itself begins to suffer from the lack of oxygen, and in just a few minutes the patient is in real trouble. “If it doesn’t spontaneously abort and you don’t have a defibrillator nearby you are going to die,” says Ramon Brugada, currently at the Masonic Medical Research Laboratory in Utica, New York. And because the disease results solely from abnormal electrical activity– activity that ceases once you are dead– it leaves no traces in the body to explain what killed you.
Having gone through it myself I am at least comforted, through dim recollections of the experience, that my brother did not suffer. In fact, perversely, the whole experience is quite pleasant. What’s more, the standard tests I was given to rule out any underlying physiological problems revealed that my heart was actually in great shape, despite a youth spent smoking and eating fatty foods. But during the six months it took doctors to make a diagnosis, I was nevertheless filled with dread that if the widow struck again her blow could be fatal.
The standard test, called the ajmaline challenge, involves injecting the drugs ajmaline or flecainide into the bloodstream before carrying out an ECG. Paradoxically, these drugs are normally used to treat certain types of arrhythmia. But in the challenge test their role is to trigger the heart into revealing the classic Brugada ECG trace. During a Brugada attack the flow of sodium ions through the membranes of nerve cells in the right ventricle is disrupted, blocking the flow of charge into the heart muscle cells. Flecainide and ajmaline appear to provoke something similar in people with Brugada.
The challenge test is needed to diagnose the vast majority of cases, because most of the time the ECGs of people with Brugada look normal. But the test is far from infallible: in particular, it sometimes gives a positive result for people who turn out not to have the condition. And because there is no other way of diagnosing Brugada, it is impossible to do controlled tests on the test itself. This uncertainty has led to fears that some people have been treated for Brugada unnecessarily. So to pin down the diagnosis doctors also rely heavily on the patient’s family history and any history of fainting. Only reliable genetic screening will solve the issue of diagnosis.
But that’s only half the problem. We already know that not everyone with Brugada has fainting episodes, and such people put doctors in a quandary because it is unclear how you distinguish between a someone who carries the Brugada gene but will never have an attack, and someone who has simply yet to have their first attack. Should they all be given an ICD? Views on the precise risk vary, but the consensus now seems to be that some people may not have their first attack until they are well into their 40s. “What is clear is that among the asymptomatic patients and those with a normal ECG the risk is extremely low,” says Silvia Priori, cardiologist at the University of Pavia, in Italy.
While genetic screening is possible in some cases, only one gene has so far been linked to Brugada, and there could be others we don’t know about. The gene that has been identified codes for an ion channel protein that regulates the flow of sodium ions through cell membranes. But researchers have also found Brugada patients who have a normal version of this gene, meaning that other genes must be involved. Researchers hope that information from the Human Genome Project will help track them down.
Watertight diagnosis
But for now the ajmaline challenge is really all we have to go on. It may be fallible, but it has certainly saved many lives. Because scientists have only known about Brugada for a decade or so, they haven’t yet been able to monitor large number of Brugada patients over the course of their lives to discover the risk factors for having an attack. Until they get this information, it will be impossible to tell how well the challenge test works, says Charles Antzelevitch, a Brugada expert also at the Masonic Medical Research Laboratory.
In my own case, family history and my own history of fainting make my Brugada diagnosis seem pretty watertight. But given the questionable reliability of the challenge there must be some people who have been needlessly treated with ICDs. You might think it’s better to be safe than sorry, but try saying that to one particular 42-year-old asymptomatic man with no family history of Brugada. His defibrillator went off by mistake 32 times in quick succession while he was still conscious.
It’s considerations like this that are forcing members of my family to make difficult decisions about getting tested. It now turns out that one of my many cousins has a history of fainting. What’s more, his father died of a suspected heart attack in his forties. Because it is impossible to know whether this was a Brugada attack, my cousin is in an odd predicament. The only confirmed history of Brugada in his family is in two cousins: myself and my brother. Also, his fainting could well have been a bad reaction to antibiotics, and so unrelated to Brugada.
But it’s equally possible that antibiotics and other drugs, both legal and recreational, could induce a Brugada attack or other kinds of arrhythmia. The suspicion that this might happen has huge implications for the world beyond Brugada patients. According to Denis Noble at the Cardiac Electrophysiology Group at Oxford University, people with a genetic propensity for arrhythmias are costing the drugs industry billions of dollars a year. In 1998 more than half the drug withdrawals required by the US Food and Drug Administration have been attributed to cardiac side effects, most of them arrhythmias, he says.
These are not just drugs developed for cardiac patients but include antihistamines, antibiotics and medicines to counter vomiting and migraine. The problem is that many drugs are attracted to ion channel openings, and so can cause them to block, says Rod MacKinnon, a biochemist at the Rockefeller Institute in New York and the man who revealed the molecular structure of ion channels (żěè¶ĚĘÓƵ, 20 July, p 46). “If you block them you create instability in the electrical rhythm of the heart,” he says. With people genetically predisposed to arrhythmias this could be all it takes to bring on an attack.
The number of people who suffer arrhythmias while taking part in drugs trials is pretty low– usually fewer than 1 per cent– and the episodes are usually harmless. But occasionally they can be fatal, and Noble suspects that in these cases there is a distinct, underlying cause unrelated to the drug being tested. “It has to be the case that these people are predisposed to these problems either genetically or because of lifestyle,” he says.
When a single failed drug can represent a half-a-billion-dollar investment going to waste, it is clearly in drugs companies’ interests to start trying to understand conditions like Brugada. If they were able to pre-screen test subjects before recruiting them into trials, then their drugs would stand a much greater chance of making it to market.
So the hunt is on for reliable diagnostic tests. One way of doing this would be to track down all the genes involved in Brugada syndrome, and find out which mutations cause the disease. Then it would be easy to screen patients for these mutations.
But finding the genes isn’t easy. Researchers first compare the chromosomes of relatives in families where some members have Brugada. They look to see whether any chromosomal “markers”– small stretches of known DNA sequences– are found only in Brugada patients and not their healthy relatives. This helps them focus their search on an area of the genome where the culprit gene must lie. Now that we have the full sequence of the human genome at our fingertips, this process is much faster than it used to be. “The Human Genome Project is helping tremendously in the identification of candidate genes for the disease,” says Ramon Brugada. “We now have more than 5000 informative chromosomal markers.” This is making it possible to track down the genes even in small Brugada families, while in the past only large families could have yielded enough data to track down the genes.
By providing a more accurate diagnosis, these developments promise improvements in treating all kinds of arrhythmia. At present these treatments are something of a lottery. Because we know so little about the biology of arrhythmias, drugs you might expect to work could actually make the condition worse. This becomes clear when you consider that the same dose of flecainide used to induce an arrhythmia in the challenge test is also used to produce an almost opposite effect– stopping arrhythmias– under different conditions.
In an effort to discover more about what happens in the heart cells of someone with arrhythmia, Andrew Grace and colleagues at Cambridge University are manipulating the gene that encodes for sodium channels in mice to produce similar mutations to the ones responsible for Brugada in people. Having a mouse model for the disease will help researchers understand the basic biology of Brugada. But the obvious drawback of this approach is that mice aren’t people, and the physiology of their hearts is quite different.
Problems like this mean that the prospects of finding a drug to treat Brugada aren’t great. And because Brugada is rare in the rich Western world, drugs companies don’t see it as a profitable area for investment.
So for now, implanting an ICD is the only treatment. And I’m thankful to know that these devices work. “Every single person with a defibrillator is still alive,” says Ramon Brugada. My biggest risk now, apparently, is of getting an infection when I go back under the knife sometime in the next 6 to 10 years to have my defibrillator’s batteries changed. But doctors readily admit that kicking a misbehaving heart into line with a defib is still a very crude way to treat the disease. I am certainly not looking forward to the first time mine zaps me back to life, and I fervently hope that this doesn’t become a legacy that my three-year-old daughter ends up dreading too.
And here’s where the decisions hit hardest. My wife and I were previously considering having a second child. Now we are not so sure. With our first baby, we didn’t mind whether we had a boy or a girl. But now we know that males are more likely to develop Brugada, should we wish for another daughter?
And there’s something worse preying on our minds. “Brugada is also one of the causes of sudden infant death,” says Ramon Brugada. Indeed the Brugada brothers’ first case was a three-year-old, whose two-year-old sister had already died without warning. Evidence for a link between sudden infant death syndrome and long QT syndrome has also been mounting in recent years– so much so that the Italian government is considering making it compulsory for newborns to have an ECG.
So if we do choose to have another child, we’ll inevitably watch them far more nervously than we watched their sister. Do we really want to be terrified that when we put our baby to bed each night we may wake the following morning to find it dead?
The answers to these dilemmas won’t come easily. As it stands, Brugada is an enigma. We don’t know what causes an attack, we don’t know how to treat it, we don’t know why it mainly affects males, and we don’t know why some attacks are fatal and others not. And we have still only one highly questionable test with which to identify the condition.
In an odd way, I think I should feel grateful to my brother James. If he had not died, then I and the rest of my family might never have found out about the widow ghost, and the chances are that some of us would have ended up mysteriously dying too. But instead of gratitude I feel only guilt for unleashing this knowledge on my family, and pray that I am the only one with the disease.
No doubt some of the answers will come. But the genetic research and long-term studies of Brugada patients will take decades to bear fruit. “You can’t make time go faster,” says Priori. As my family submit to the gruelling process of being tested, I wonder how many people will slip through the net while we wait for answers.