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Mending Broken Hearts (part 2)
Don Steffensen was putting duck-hunting decoys out on a small lake one fall afternoon in southwestern Iowa when his heart attack hit. The infarction was massive and unexpected. It's likely that Steffensen survived only because a buddy was carrying nitroglycerin tablets and quickly slipped one under his friend's tongue. Nitroglycerin is used to make dynamite; in the body, a heavily diluted form releases nitric oxide, which signals the smooth muscle cells in veins and arteries to relax, dilating the vessels.
The Steffensen clan is enormous: more than 200 relatives spread over three generations, many of the youngest are now dispersed from Iowa to New York and beyond. Although heart trouble is common in the family, it had never struck anyone as unusual. "I attributed it to diet," shrugs Tina, a slim 38-year-old and the family's only vegetarian.
It was a reasonable conclusion. The Steffensens were raised on the kind of farm food that the state is famous forham balls, meatloaf, pie, macaroni and cheeseand still popular even as careers have moved indoors. Driving north through cornfields to meet some of the family in Buffalo Center, I dined at a restaurant offering deep-fried sandwiches. A single ham and cheese hoagiedunked in hot fat and served sizzlingseemed capable of stopping a heart all on its own.
But could the high incidence of heart trouble among the Steffensens be related to something else besides high-fat diets? Eleven years after Don's attack, his wife, Barbara, happened to overhear a doctor describing a study about the genetics of heart attacks.
Curious, Don and 20 of his relatives each sent a vial of blood to the Cleveland Clinic, where the research was being conducted. Eric Topol, a cardiologist and genetics researcher at the clinic, spent a year studying their DNA. Each person's genome comes with millions of individual variations, but Topol was looking for something distinctiveand shared only by the members of the clan with heart trouble. The mutation he and his team finally spotted, in a gene called MEF2A, produced a faulty protein. "We knew we had something," Topol says. "But the question was: How does this sick protein, present at birth, lead to heart attacks 50 years later in life?"
Topol himself is as lean as a greyhound and weathered in a cowboyish way. He talks slowly and eats minimally: salads for dinner and high-fiber cereal for breakfast. He doesn't eat lunch at all. Like almost every cardiologist I've talked to, he takes statins preventively, and his cholesterol count is a low 135. His children, 22 and 25, also eat uncommonly well for their ages. "People have looked at the cadavers of men in their 20s who died in car accidents or as casualties of war, and nearly all had arterial cholesterol deposits," Topol said as we walked to his lab. "This disease starts much earlier than people realize."
Using endothelial cells (which line the inside of the artery wall) grown in culture, Topol set about figuring out what the MEF2A mutation does. He and his coworkers created some cells carrying the Steffensen variant, and others with the normal form of the protein. Both cell proteins were tagged fluorescent green so their locations could be visualized on a computer screen. The resulting images revealed a striking difference.
In a normal cell, all the MEF2A protein was inside the nucleus; on the screen, the cell resembled a fried egg with a fluorescent green yolk. But in the cells carrying the mutated version, the nucleus did not glow; instead the cell membrane was edged by a thin, luminous green line: a layer of MEF2A protein, trapped where it cannot serve its usual purpose. Topol believes that this defect affects the integrity of the coronary artery walls, rendering them more vulnerable to cracking when the plaque embedded in them ruptures. And each crack brings an increased chance of a heart attack.
Since this discovery, the Steffensens have become famous, appearing on shows like 60 Minutes II. Their mutant gene turns up in a Robin Cook novel titled Marker, about a health insurance company in New York that secretly screens patients for the MEF2A mutation and then kills them to preempt future medical-care payouts. Lively reading, but the Steffensen gene is an unlikely target for an insurance company, in part because it is an uncommon genetic defect.
Topol's study did find that although dysfunctional MEF2A is very rare, the chance of heart disease in those carrying it may approach 100 percent. Most other genetic variations identified thus far increase the risk by much less. As it turns out, Topol himself carries a bum gene: apoE4, which affects inflammation in the arteries. Unlike MEF2A, it is common; every fourth person has it.
"Heart disease is not a one- or two-gene problem," says Steven Ellis, a Cleveland Clinic cardiologist who oversees a 10,000-person genetic study known as GeneBank that collects DNA samples from patients who enter hospitals with atherosclerosis. Ellis, like most cardiac researchers, suspects that dozens of genes end up contributing to a predisposition: Some affect arterial integrity, others inflammation (which both causes and exacerbates arterial cracks), and still others the processing of lipids (the fats and cholesterol that turn into plaques). Of the several dozen genes, each may contribute just one percent to a person's total riskan amount that may be compounded, or offset, by outside factors like diet. As one doctor told me, any person's heart attack risk is "50 percent genetic and 50 percent cheeseburger."
The point of tracking down all these small mutations, Ellis explains, is to create a comprehensive blood testone that could calculate a person's genetic susceptibility by adding up the number of risky (and, eventually, beneficial) variables. Combined with other important factors, such as smoking, weight, blood pressure, and cholesterol levels, doctors could decide which patients need aggressive treatment, such as high-dose statins, and which ones are likely to benefit from exercise or other lifestyle changes. Some genes already can predict whose cholesterol level will respond strongly to dietary changes and whose won't. Assessing risk is crucial, Ellis says, because heart disease is often invisible. In fact, 50 percent of men and 64 percent of women who die of heart disease die suddenly, without experiencing any previous symptoms.
Although standard tests can detect atherosclerosis, they aren't foolproof. They may reveal plaques, but give no indication whether or not they are life-threatening. Tests like angiography, for example, where doctors inject a dye into the bloodstream and track it with x-rays, can show how much blood is flowing through an artery, but not discern the plaques embedded inside the artery walloften the culprit in a heart attack.
Researchers have been working to solve this problem with scanners that provide pictures of the arterial wall itself, but it's a tricky task. Normal cardiac artery walls are about a millimeter thick. Coronary arteries move with every beat of the heart, 70 times a minute. It's tough to get a clear image of something so small in constant motion.
Difficult, but not impossible. As I walk through the basement of the Cleveland Clinic, I pass a room containing a large, blue, plastic doughnut as tall as I am, with a woman's legs sticking out of the middle. The doughnut is a computed tomography (CT) scanner, a kind of three-dimensional x-ray machine that's also used for imaging tumors. The scanner, aided by medications that reduce a patient's heart rate and an injectable dye that highlights the arteries, can produce startlingly clear pictures.
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Kurre mos debato me nje idiot!Njerezit mund te mos e bejne dallimin! (Ligj i Marfit)
Think Different!Think Again! (National Geographic Channel)
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