At first, Kathy Kastan's symptoms just seemed weird. An avid athlete, she would get oddly tired, struggle to catch her breath, and wince at the pain in her shoulder and back when she exercised. She tried shaking it off, but the problems kept nagging her, so the 41-year-old consulted a cardiologist.
"He said, 'You're healthy as a horse. I never want to see you again,' " said Kastan, who lives in Cordova, Tenn.
But she got worse -- so bad that crushing chest pain knocked her down every time she tried to work out. Finally, she went to specialists who discovered that Kastan did have serious heart disease -- just not the familiar, clogged-up-artery kind. Instead, her arteries would mysteriously spasm, strangling the blood flow to her heart muscle.
"It's amazing how many women have been through this. They have these symptoms, and nobody can figure out what's wrong," she said. "I was one of the lucky ones. I escaped an actual heart attack."
Doctors are starting to realize that many women probably have Kastan's kind of heart disease, as well as other forms that differ in essential ways from the well-known pattern that strikes most men. This new understanding -- that heart disease may be a fundamentally different disease in many women -- has far-reaching implications for medicine's ability to defend women against the nation's No. 1 killer. Contrary to persistent misconceptions, heart disease claims the lives of more women than men.
"The whole disease is poorly understood in women, from the expression of the symptoms all the way down to some of the basic mechanisms," said Carl J. Pepine, a cardiologist at University of Florida's College of Medicine in Gainesville. "The disease has a very broad spectrum, and more men are at one side and more women are at the other side."
Instead of one main blockage, arteries in many women go into spasm or have smaller, easily missed buildups along their entire lengths, which can be just as dangerous as one big one. And often the problems lie not in the major arteries that nourish the heart muscle but in the frequently overlooked smaller branches.
These differences, frequently found in younger women, could help explain why the symptoms are often so different than in men, why women are often misdiagnosed -- or never diagnosed -- why they commonly are not treated until much later, and why women are more likely to die from their heart disease even when they are treated. The standard tests, drugs and procedures simply may not work as well for many women.
"We are just now starting to describe this really for the first time," said C. Noel Bairey Merz, a heart expert at Cedars-Sinai Medical Center in Los Angeles. "We hear about how women are treated less aggressively than men, and how they eventually have worse heart attacks and are more likely to die with their heart disease. We can see how this could culminate in that way."
This new understanding is emerging only now because heart disease research has traditionally focused almost exclusively on men. Experts assumed that women's tendency to fare so poorly was the result of not being treated as early or as thoroughly as men.
"In the past, we had the assumption of equality -- that everything was equal between the genders and there were no differences," said George Sopko of the National Heart, Lung, and Blood Institute. "Now that's beginning to unravel."
Experts stress that most women who get heart disease are struck by the same form that hits men, which can be prevented and treated the same way. But a new generation of research is urgently needed, Bairey Merz and other experts say, to better understand the other ways women's arteries start to become diseased, zero in on the most important risk factors, develop new diagnostic tests and find treatments tailored specifically for women.
"Men and women are very similar, but like many other areas of health, when we've bothered to do the research there are differences that sometimes can have clinically significant importance," Bairey Merz said.
One of the main sources of this new understanding is the federally funded Women's Ischemia Syndrome Evaluation (WISE) study, which is tracking about 1,000 women in Florida, Pennsylvania and Alabama who have chest pain or other symptoms but who mostly seem fine on standard tests.
"In general, people think these ladies are crazy. They are not infrequently told they are nuts," Bairey Merz said. They often are sent to stomach specialists or for psychotherapy and end up in a maddening hunt for the source of their ills until finally, weeks, months or years later, they are in an emergency room with a heart attack.
The WISE study found that in nearly half of these women, their hearts are not getting enough blood, and one-third are likely to go on to have a heart attack or other serious heart problems -- three times the usual risk.
"Women appear more likely to more diffusely lay out their plaque throughout the wall of the artery, whereas men are more likely to lay it down a lumpy-bumpy pattern," Bairey Merz said. "This could explain the delayed diagnoses, the missed diagnoses, the never diagnoses."
The reason for this difference is unclear, but it may be a result of women's unique hormonal chemistry and differences in how women's arteries respond to stress.
"What we believe is that women's bodies remodel their arteries to accommodate the . . . plaque," Pepine said. "If you think about the whole female picture, they are designed to do that. They remodel their arteries to accommodate blood flow when they are pregnant."
Detailed studies of the arteries of women who died of heart attacks have found that the disease often looks much different in women in another way.
"In men, it's like a sore, like a pimple, that breaks and leads to the formation of a blood clot, that causes a heart attack," said Renu Vermani of the Armed Forces Institute of Pathology in Washington. "In women, we don't see this pimple. We see erosion. It's a malformation -- like a scab, like a scar."
Vermani speculates that when arteries spasm, the innermost lining, called the endothelium, momentarily rubs against itself. "Over time, that causes it to erode," he said. "The endothelium is disturbed, it's eroded, which leads to clot formation."
Doctors have long known that women are prone to blood vessel spasms and the ailments they cause, such as migraine headaches. When it happens to an artery feeding the heart, it produces pain or, in severe instances, a heart attack.
"It's like putting a rubber band around the artery: It narrows so that you can't get enough blood to supply the muscle to keep it viable," said Marianne J. Legato, a women's health expert at Columbia University.
The same bad actors that cause better-known forms of heart disease -- high cholesterol, high blood pressure, smoking, obesity -- may also damage the endothelium, making arteries prone to spasms or to diffuse plaques that diminish their ability to dilate properly. But there may be other factors that are particularly dangerous for women.
Because estrogen plays a role in processing nitric oxide, which helps arteries function properly, the endothelium may suffer when estrogen levels wane due to menopause. Another key player may be inflammation -- an overreaction by the immune system.
"Let's say you have somewhat high cholesterol and just slightly high blood pressure. The likelihood would be that you should have a low risk," Sopko said. "However, if you take some of these novel risk factors, like inflammation, it is possible that they act as amplifiers . . . that are gender-specific or gender-related."
Some researchers suspect that the crucial oxygen-carrying protein in blood, hemoglobin, may also be important. Women tend to have less hemoglobin than men because of their monthly menstrual cycles, and low hemoglobin may further starve the heart muscle. Hemoglobin deficits may also reduce nitric oxide levels.
"Hemoglobin turns out to be a major independent predictor of outcome," Pepine said.
Researchers have also found that in many women, plaques, spasms and tiny clots clog up the smaller branches of arteries, which are not routinely examined by doctors.
"They are very important, but we don't typically look at them," Bairey Merz said. "This appears to be dominantly a women's problem."
That was the case with Laura Luxemberg, 40, of San Diego. Bairey Merz diagnosed her with "microvascular disease" after she was initially told that her shortness of breath, headaches, chest tightness and other symptoms might be a digestive problem.
"That's what happened to my sister, too, three years ago. She went to the emergency room and was told to take Maalox," said Luxemberg, whose sister subsequently died from a heart attack.
One of the most disturbing implications is that many women would not be helped by the most aggressive treatments used to treat heart disease: surgery to bypass blocked major arteries and angioplasty, a procedure that wedges open clogged arteries and often keeps them open with tiny scaffolding called stents.
"If you don't have a discrete blockage, you have nothing to bypass. Sticking in a bypass may actually make things worse. You can't put a stent in the whole length of the vessel," said Sharonne N. Hayes, who runs a women's heart clinic at the Mayo Clinic in Rochester, Minn.
Women do respond to many of the drugs used to treat heart disease, including aspirin, cholesterol-lowering statins and vessel-dilating "ACE inhibitors," perhaps by reducing inflammation and improving blood vessel function. But doctors such as Hayes have also started using new combinations of these drugs, as well as other, alternative treatments such as an amino acid called L-arginine, specifically to reduce inflammation and keep arteries functioning properly.
But much more research is needed, experts say. Researchers are developing ultrasound and other imaging techniques to help diagnose women earlier, for example. Drugs that boost hemoglobin might help treat them.
"Basically," Legato said, "we're doing a whole different kind of research, looking at women instead of just looking at men, which is what we have been wont to do."
said Kathy Kastan, 41, of her initially misdiagnosed heart disease.