Can We End Heart Disease?

The volume and variety of research will allow many more to survive

It's 7:30 a.m. in Operating Room 8 at Stanford Medical Center. Amid the preoperative bustle, beeping monitors, and the staff's black humor as they don gloves and gowns, the elderly patient's body on the table is an island of stillness. I see her hand, relaxed, ghostly pale, and gently upturned. I imagine it pruning a rosebush or caressing a grandchild's cheek. I cannot bring myself to look above the green drape to the patient's face. I wish her well, but during the next three hours, I will see more than a stranger should. I will look into her heart.

This patient, call her Patricia, is battling heart disease, the nation's No.1 killer. And she has been losing. In recent months, gardening or chasing a grandchild would have been unthinkable for her. She barely has the strength to walk around her house. Patricia is 75, and her heart is wearing out. A crucial valve is failing to shut properly, and so her heart is working overtime for a fraction of the pumping benefit. Untreated, she would be dead in less than a year from congestive heart failure.

Instead, technology is about to save her. In the next three hours, surgeons will open her heart and insert a small mechanical device to replace that leaky valve. It should be snapping open and shut well past her 90th birthday, if nothing else goes wrong. Valve replacements are miraculous enough, but they have been done for years. The new, so-called minimally invasive approach her doctors are using, however, doesn't require that her breastbone be cut and her entire chest be opened, as is done in conventional open-heart surgery. Instead, doctors will work through a single, three-inch incision, and she should be home feeling normal in three days.

Innovative new surgeries such as this are part of explosive progress being made in the fight against heart disease. It's happening not only in operating rooms but also in fluid-engineering labs, British pigpens, and on the cutting edge of biotechnology. And it comes none too soon. About 1 million Americans die of heart disease each year, including about 300,000 who die of cardiac arrest before they can get to a hospital. Around the world heart disease kills more people than any other ailment, accounting for 15 million deaths a year, according to the World Health Organization. That's about 30% of all deaths. This is happening despite the knowledge that at least half of all heart disease can be prevented by simple and obvious lifestyle changes such as quitting smoking, eating better, and exercising.

It's a good time for a miracle, and the good news is there seems to be more than one on the horizon. The volume and variety of research projects--aiming to understand heart disease from the earliest stages of conception through the heart's last few heroic beats--is staggering:

-- To ease the strains and complications of surgery, doctors are perfecting a variety of less traumatic and more effective procedures, some using robots.

-- Geneticists are unraveling the microscopic dance of DNA that governs blood-vessel development, and they may soon be able to correct genetic errors.

-- Molecular biologists are conjuring new blood vessels out of diseased and dying tissue in a promising procedure dubbed "biobypass."

-- Researchers are devising a new generation of artificial hearts, some of which could be humming in patients' chests before the turn of the century.

-- Researchers are exploring the potential of transplants of animal hearts as alternatives to artificial hearts. Such hearts could be pumping human blood within five years.

-- New technology is transforming the pacemaker and opening the door to treatment with a wide variety of high-tech devices.

With the success of existing technologies, more and more people are surviving heart attacks and living with heart disease. "We're seeing a shift in heart attacks from acute, fatal diseases to chronic diseases," says Rockefeller University Professor Jan L. Breslow, the president of the American Heart Assn. "The number of people living with congestive heart failure has tripled in the last 20 years." Indeed, the phenomenon of heart patients nowadays undergoing multiple crises--each of which previously might have killed them--is part of what has driven America's heart health-care tab to $259 billion annually.

The biggest heart problem in the U.S. by far is congested plumbing: coronary artery disease. More than 13 million Americans are afflicted with the disorder, in which arteries that supply the heart muscle become gummed up and narrowed by waxy deposits, or plaques, that ultimately lead to clots, blocking arteries and causing a heart attack.

Medicine has made dramatic advances against coronary disease with such innovations as antihypertensives, clot-busting drugs, pacemakers, and bypass surgeries. Here are some of the next-generation technologies that are contributing to the emerging heart-disease miracle:


The door to the O.R. where Patricia awaits swings open and surgeon John H. Stevens, 36, greets his Stanford staff with a boyish grin. Historically, heart surgeons have been plucked from the brightest and most surgically talented medical students. With such attention come big egos, intense competition, and sometimes resentment. In hospital halls, they're referred to as cowboys, prima donnas, and occasionally (and not flatteringly) as "God."

As co-founder of a company called Heartport Inc., the personable Stevens and a group of surgeons at Stanford are pushing the boundaries of what thousands of "Gods" before him thought was either possible or wise. With Patricia, Stevens--who recently left Stanford to become Heartport's chief technical officer--does most of his work through what Heartport calls a "port" incision, about three inches wide beneath her right breast.

Such minimally invasive procedures, first used in the early 1990s, are becoming the rage in cardiac surgery, although they have their detractors. Well-known heart surgeon O.H. "Bud" Frazier of the Texas Heart Institute says that while he supports their use experimentally, "a small incision is not the most important thing" to be concerned with when doing heart surgery--he's not sure surgeons should sacrifice good visibility of the heart for a small scar. Heartport says it has data showing that the rates of complications or deaths with the new techniques are no higher than those for conventional surgery.

After his opening incision, Stevens makes two clicks with what look like pliers and pulls out a small piece of rib. "Spare rib?" cracks the nurse. She flips it into a pan.

Variations on minimally invasive approaches are red-hot. Well over 1,000 patients have had heart operations using other less-traumatic techniques, such as CardioThoracic Systems Inc.'s "beating heart" bypass surgery, which uses special instruments to hold the beating heart still. That eliminates an occasional nightmarish consequence of conventional surgery--some patients' hearts never start beating again.

Other surgical innovations are also appearing. Dr. Patrick M. McCarthy, director of the Cardiac Assist Program at the Cleveland Clinic, is experimenting with a radical procedure invented by Argentine surgeon Randas J. Batista. In failing hearts, the left ventricle becomes enlarged and pumps inefficiently. In the Batista procedure, surgeons carve out a golf-ball-size section of the enlarged ventricle and tighten its valve. By reducing the volume of muscle, what's left pumps more efficiently. It doesn't always save lives, but some patients have improved dramatically.

In another exotic procedure, surgeons at the University of California at Los Angeles, are making older or slightly damaged donor hearts usable by repairing the disembodied hearts before transplanting them. The reconditioned hearts are given to patients who, according to current guidelines, would be ineligible for transplants because they are over 65. So far, seven reconditioned hearts have been transplanted. Recipients' three-year survival rates are comparable to those for recipients of conventional transplants.


Wander into cardiologist Mark C. Fishman's lab at Harvard University, and you may confuse it with the marine biology department. Fishman's experimental subjects, as befits his name, are not humans but fish--zebra fish, to be specific. The value of these tiny creatures is that their embryos are transparent, and their hearts develop within one day of fertilization. That provides a unique window to study how the cardiovascular system develops.

Theoretically, hundreds of genes might contribute to heart problems. To Fishman's delight, however, the zebra fish have shown that mutations in a single gene can provoke quite specific heart problems. One mutation, for example, causes a heart to form without any valves. Another makes blood vessels loop the wrong way. Yet another makes the heart beat slowly. With that information in hand, "it's conceivable that one could make parts of hearts again" and regenerate damaged tissue, he says.

Important genetic clues are also coming from such unexpected places as the quaint Italian village of Limone sul Garda. Many villagers, descendants of an 18th century resident named Giovanni Pomaroli, have eternally young hearts. Although they smoke and drink, have high cholesterol levels, and gobble fats and salt with abandon, Pomaroli's descendants have virtually no heart disease and often live well into their 90s.

The reason seems to be a genetic mutation researchers have dubbed "Apo-A-1 Milano." It produces some kind of protective protein akin to high-density lipoproteins (HDLs), the so-called good cholesterol associated with a reduced risk of heart disease. Elide Fava, 36, has the Milano gene, and so do her two children. She lets them eat all the potato chips they want. Because of the Milano gene, "Limone is full of little old people who look young," she says.

P.K. Shah of Cedars-Sinai Medical Center in Los Angeles has created a gene-spliced version of that protein. Injected into mice prone to develop atherosclerosis, the drug prevented clogging of the arteries in some and even reversed it in others. "The results are very exciting," he says.

At the University of Utah, researcher Mark Keating is examining the terrifying phenomenon of sudden death caused by an erratic heart rhythm called tachycardia. By combing Mormon genealogical records, Keating has uncovered three mutant genes related to proper functioning of the heart's electrical circuitry. Simple measures, such as prescribing potassium supplements and the heart drugs called beta blockers, are believed to disarm these genetic time bombs. The treatment is already being given to people with the mutations.


About 300,000 patients each year undergo bypass surgery to try to restore good blood flow to their hearts. Now comes a revolutionary development: At New York Hospital/Cornell Medical Center, gene-therapy pioneer Ronald G. Crystal, surgeon Todd K. Rosengart, and others are working with genes and human proteins that spark "angiogenesis"--the growth of new blood vessels. The idea is to prompt the growth of new arteries when existing coronary arteries are failing. Crystal calls it "biobypass."

In studies with pigs, Crystal has used genetically engineered viruses to transfer a gene called VEG-F to the heart. It made new vessels grow and restored blood flow in pigs whose coronary arteries were clamped shut. He hopes to begin human trials within a year. Biotech pioneer Genentech is experimenting with a gene-spliced form of VEG-F that could be given as a drug.

A related phenomenon has emerged unexpectedly from a surgical technique doctors began performing several years ago to route more blood into oxygen-starved areas of the heart. Using lasers, doctors drilled about two dozen tiny holes in the heart to create physical channels to bring more blood in. The researchers have since learned that the physical disruption of the heart tissue by the lasers stimulated angiogenesis. Cardiogenesis Corp., a maker of cardiac lasers, is joining biotech company Chiron Corp. to explore how the laser technique could be paired with biobypass, with the hope of obviating some surgical bypass.


Early efforts to create artificial hearts, going as far back as 1969, were resounding failures--patients felt miserable, they suffered repeated strokes, and many had trouble even getting out of bed. But the picture has changed. "This technology has made a lot of strides and will make even more in the next decade," says pioneer surgeon Frazier of the Texas Heart Institute in Houston. By 2000, Frazier hopes to implant a total replacement heart made by ABIOMED Inc. in Danvers, Mass. It's a long way from the primitive Jarvik-7 heart that dentist Barney Clark received at the University of Utah in 1982. ABIOMED's device is one of several designs that will be fully implantable, with no wires or tubes protruding from the skin. The Jarvik-7, in contrast, was tethered to a device the size of a washing machine.

Another innovative design is a smaller assist pump called the Streamliner under development by Bartley Griffith, a cardiologist at the University of Pittsburgh. The Streamliner, about the size of a D-cell battery, whirls like a tiny turbine, pumping blood not in heartbeats but in a continuous flow: patients who get it will have no pulse.

"The perception is that the artificial heart failed and is dead," says David M. Lederman, chief executive of ABIOMED. In fact, he says, advances in electronics and materials technology have sparked dramatic progress.


Not everyone agrees with Lederman, and some are hedging their bets. They are working hard on another promising, but also controversial, approach: xenotransplants, or transplants of animal hearts into humans.

As with artificial hearts, the first xenotransplants were failures. One of the most notable was the infamous "Baby Fae" transplant of a baboon heart into an infant in 1984. The infant died shortly thereafter.

There has been quiet progress since then, however, much of it the result of advances in preventing transplant rejection. Today, 30,000 patients per year receive heart valves from pigs. The next frontier is to produce pig hearts genetically engineered to carry human immune system proteins. The chances of rejection should be no higher than with human hearts.

Remember cover girl Dolly, the cloned Scottish sheep? PPL Therapeutics, which owns rights to that technology, is planning to develop transplantable hearts in animals and then to clone the animals that produce the best match. Another group of British researchers working with a Novartis subsidiary called Imutran has transplanted pig hearts into monkeys and shown the hearts can survive more than 60 days.

Dr. David H. Sachs, professor of surgery and immunology at Harvard, says it will be at least five years before animal hearts begin to be used for transplants. One worry is that xenotransplants will inadvertently transfer animal viruses into human recipients.


Sometimes near miracles can spring from the simplest innovations. A device called a "stent," aimed at keeping clogged arteries open, is a single wire shaped to create a filigreed metal tube smaller than a paper clip. It is inserted into arteries during angioplasty, in which a balloon is threaded into a clogged artery and inflated to force the artery open. Stents reduce reclogging of treated arteries by 30% to 50% or more, and newer stents may be even better. A San Carlos (Calif.) company called Isostent is actually irradiating the filigreed metal tubes, which seems to improve their ability to resist reclogging.

Another gadget undergoing improvement is the pacemaker. It will become more sophisticated, says Medtronic CEO William W. George. "We will upgrade the pacemaker to a heart management device," adapting it to treat not only rhythm disorders but also heart failure.

Dramatically improved computing power is behind the spidery robot in a small room at Intuitive Surgical in Mountain View, Calif. There, founder and physician Frederic H. Moll sits at a console, peering into a three-dimensional imaging scope, his hands attached by Velcro to two scissor-like controllers. A couple of feet away on a table, robot arms control two extremely tiny pincers, no more than half an inch long, poised over a pig heart.

As Moll's fingers move, so do the pincers, one of which holds a suture needle. In a wink, Moll has sewn several stitches. Originally designed to allow military surgeons to perform operations remotely on downed soldiers, the technology is now being adapted to push the frontier for minimally invasive surgery: It could mean that only tiny puncture-wound-size incisions are needed. Privately held Intuitive hopes to begin human trials of heart surgery in early 1998.

Three hours after Stevens began surgery, he has restored almost normal blood flow with the new valve and is ready to close. All eyes turn to a monitor above Patricia's body. Rhythmic spikes flash across the videoscreen, and the monitor beeps the same pattern.

"Nice beat," says a nurse.

"You can dance to it," says the operator of the bypass machine.

I look back to the operating field and there, inside the open port, I can see Patricia's trembling, pumping heart. I can see her heart is less taut, less blue, less diseased than when Stevens began. She went home three days later.

None of these remarkable new surgeries, experimental drugs, or genetic discoveries will end heart disease in this generation. It's possible, however, to contemplate such an eventuality. Each advance reveals more clues that will help prevent killing and crippling heart attacks and counteract the slow and miserable years of decline that Patricia endured. If this isn't the end of heart disease, it's surely the beginning of the end.

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