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A signpost for sudden death A family struggles with a genetic flaw that can fatally stop the heart Sunday, July 02, 2000 By Byron Spice, Science Editor, Post-Gazette
As Vin recollects, he had just sat down to have a cup of coffee with a coworker when he was first confronted by his family curse.
"I suddenly felt hot and started sweating -- and I never sweat," he said. He walked inside the small Erie machine shop where he worked in maintenance. "Gosh, I don't know," he told a secretary, "something's going ..."
And he was out like a light. When he awoke 20 minutes later, ambulance crew members were huddled over him. He protested that he could drive himself home, but they hustled him off to St. Vincent Medical Center.
That fainting spell in late September 1997 would prove to be a warning for Vin and his entire family, who have asked to remain anonymous. A sharp-eyed cardiologist at St. Vincent, Dr. Jeff Buetikofer, suspected that Vin was suffering from a little known but deadly genetic condition called Brugada syndrome.
That diagnostic detective work set in motion a National Institutes of Health-sponsored hunt by University of Pittsburgh physicians to find the culprit gene in Vin's family. Less than three years later, Drs. Barry London and Raul Weiss believe they've identified the gene, which affects at least two of Vin's brothers and nine other family members.
People with Brugada syndrome have seemingly healthy but electrically unstable hearts, London said. Without warning, their hearts can start racing until the pumping muscles flutter futilely, a condition called fibrillation. Oddly, it tends to strike while a person is at rest, just as Vin was when his first episode occurred.
Sometimes, Brugada patients may simply suffer fainting episodes. But it can also result in sudden cardiac death. A quarter million Americans die of sudden cardiac death each year; most are people with hearts already diseased or weakened by previous heart attacks. Brugada probably represents a small fraction of the U.S. total, but the exact proportion is unknown.
Elsewhere, however, Brugada may be a major killer. Dr. Ramon Brugada, a cardiologist at Baylor Medical Center in Houston, Texas, and one of a trio of Spanish-born physician brothers who have studied the disease, said it ranks second only to auto accidents as a killer of young men in Taiwan, Vietnam and much of Southeast Asia.
A widespread disorder
Since 1991, when brother Pedro identified the syndrome in a 3-year-old Polish child at his clinic in Belgium, at least 700 families with Brugada syndrome have been identified worldwide. "We've found it everywhere we have looked," Ramon Brugada said.
It's become well-known in the research community, London said, but many heart specialists still don't know much about it. Certainly Vin and his wife Mary didn't have a clue about how serious Vin's condition might be when Weiss first urged Vin to come to Pittsburgh to be tested.
Weiss called the Monday evening after Vin was released from the hospital in Erie. "He said, 'You have to get him to Pittsburgh right now,' " Mary recalled. She gave the doctor "such a hard time. I was downright nasty. I said, 'There's no reason for us to rush down there.' And he said, 'Oh yes there is.' "
When they finally made the trip a week later, Vin ended up spending 10 days in UPMC Presbyterian. He wasn't released until surgeons had implanted an automatic defibrillator in his chest -- a device that could shock his heart back into action if it should start fluttering again.
The value of that defibrillator was proven the next spring, when Vin and Mary were on their way back to Presby for a routine doctor's visit. Traveling down I-79 with one of their sons at the wheel, they had stopped for dinner in Cranberry. Afterward, Mary was in the backseat and Vin was in the passenger seat, chatting away as his son merged the car back into the southbound I-79 traffic.
"I don't remember what he was talking about," Mary said, "but he was probably giving advice to our son about what lane to get into." In mid-sentence, Vin suddenly slumped over. Almost as suddenly, Mary said, the defibrillator kicked in and her husband stiffened and jerked, as if he were having a seizure.
"I said, 'Are you OK?' and he said, 'Yeah, what's the matter?' "
Vin said he had no idea what had happened. "It scares the hell out of the wife, though. One minute I'm talking and the next I'm slumped over," he said. "It's so peaceful going out, but it's a son of a gun coming back."
Ten minutes later, he had a second attack. "I said, 'Something's going to happen,' " Vin recalled, and then he slumped and stiffened again.
Though the defibrillator can shock Vin back to life, these brief periods of unconsciousness meant that it was no longer safe for him to climb ladders or drive cars. So Vin, 59, retired from his maintenance job, and he rides a bike to get around when Mary can't drive him.
One of Vin's older brothers also has had attacks, one day fainting while on the golf course. He got back up and finished the round, but he's subsequently had a defibrillator implanted. A brother in California also has had episodes and now has a defibrillator too.
Expensive solution
But the implant is by no means a perfect solution, Weiss said. Though they work well, they eventually have to be replaced, a big concern, particularly for younger people. And the cost is considerable -- about $50,000, although it is generally covered by insurance. Other family members who display Brugada traits have not opted for the implant.
Complicating matters is that the family tends to be long-lived, Vin said. He said he had a 51-year-old nephew who died alone in his chair one Christmas, but no one can be certain if Brugada was the cause.
Soon after seeing Vin, Weiss and London set off to find the gene responsible. They've gone to Erie County a couple of times each year and visited family members in other states to gather blood samples and perform electrocardiography. Some have been invited to Pittsburgh for extensive study in Presby's electro-physiology lab, where Weiss uses drugs to try to trigger an episode under controlled conditions.
People with Brugada syndrome have EKG patterns that are often interpreted as normal but to the trained eye are distinctive, Weiss said. The Brugada traits in this family only appear in middle age or later, however, so Weiss is trying to tease out subtle EKG patterns that would let him identify the syndrome in young patients who are not yet in danger of sudden death.
By comparing genetic markers in DNA samples from affected and unaffected family members, London believes he has tracked down this family's Brugada gene. Like genes discovered in other families with the syndrome, it appears to control the sodium channels in cell membranes. Sodium channels are involved in changing the electrical properties of heart muscle cells, which is necessary to control the impulses that start and stop a heartbeat.
London won't reveal the exact location of the gene until he can publish his findings in a scientific journal. But he said it lies in an area of a chromosome that up until now has been "only vaguely" mapped. Completion of the Human Genome Project and its sequencing of the entire genome should allow him to rapidly pin down the gene and identify the mutation that causes it to malfunction.
Ramon Brugada said at least 10 genetic mutations have been isolated in Brugada patients. All involve sodium channel genes, but every family so far has had a different mutation.
The genetic studies give doctors a tool to identify family members who lack the gene for Brugada, but it hasn't led to a foolproof test for all families, and it hasn't yet led to a breakthrough in treatment.
Ramon Brugada is optimistic that genetic studies eventually will identify common biological pathways that cause the syndrome. That will help researchers find drugs that restore proper function of the pathway, preventing sudden deaths.
"It's just a matter of time," he said.
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