People with cardiovascular disease live longer, healthier lives than ever before, thanks to the advances of modern medicine. But about 950,000 Americans still die annually of heart attacks or other forms of cardiovascular disease, reports the U.S. Centers for Disease Control. That’s as many as all other causes of death combined.

Those living with cardiovascular disease are even more numerous: about 61 million Americans, or nearly 25 percent of the population. About 6 million of them are hospitalized each year.

Another eye-opener: local research has shown a link between cardiovascular disease, obesity and the most common form of diabetes. The implications of controlling all these diseases is hard to overstate. American obesity costs $117 billion in direct and indirect losses, says the 2001 Surgeon General’s Report on Overweight and Obesity.

These grim statistics may soon change. Many of the improvements will come thanks to research and better diagnostic techniques pioneered in San Diego. Players include UCSD, the Salk Institute and other local institutions, doctors and biomedical companies. All hope to knock cardiovascular disease off of its fearsome perch as the country’s leading cause of death.

Molecular Roots

Recognizing the close relationship between obesity, diabetes and other related disease, medical researchers have coined the term “Syndrome X” for metabolic disorders that put people at higher risk of developing these diseases. Now many researchers simply call it “the metabolic syndrome” in recognition of how common it is.

Ronald M. Evans, a top researcher at the Salk Institute, believes he and his colleagues have found the precise biological cause for this metabolic syndrome. “We discovered a molecular switch, the so-called ‘fat switch’ in the body, that detects what we eat,” Evans says. “We know there is a direct link between a high-fat diet and heart disease, and Type II diabetes.

“We believe one of these molecular switches that we discovered is the central regulator of this process. We have worked to characterize the nature of this switch, and how it contributes to normal energy control and metabolism, and then what goes wrong when we eat excessive amounts of calories and fail to exercise.”

The discovery was made and extended in three highly influential papers written in the 1990s by Evans, Barry Forman and other Salk scientists. The papers explain why certain drugs to treat insulin-resistant diabetes also reduce the severity of heart disease. The drugs promote removal of a harmful form of cholesterol called oxidized low-density lipoprotein, a known risk factor for heart disease.

These discoveries raised the possibility of creating a new family of drugs that would block forms of cardiovascular disease and insulin-resistant diabetes. That’s exactly what numerous pharmaceutical and biotechnology companies are now trying to do.

Amylin’s Contribution

San Diego-based Amylin Pharmaceuticals edged into the cardiovascular arena by way of developing drugs for diabetes. Amylin first developed a new drug for Type I, or childhood-onset diabetes, called Symlin. Based on a hormone called amylin, the drug works together with insulin to control blood glucose levels, preventing many complications of the disease. However, Symlin proved very difficult to develop. Clinical results appeared marginal to some, and its development partner, Johnson & Johnson, abandoned the Symlin program. For a time, Amylin appeared close to going out of business. Now, Symlin appears likely to gain approval.

But the real buzz comes over another Amylin drug that treats Type II diabetes, a much larger market. The drug, derived from lizard venom, is called AC2993. In clinical trials, it helps those with Type II diabetes use insulin without the weight gain and abnormally low blood sugar that often occur. The drug’s potential excited Eli Lilly & Co., which in September committed $325 million to develop it with Amylin.

Amylin also has licensed the rights to develop two cardiovascular drugs. One, called AC3056, has been shown in animals to reduce harmful LDLs, but not the beneficial high-density lipoproteins. It is now in early human clinical trials. A second cardiovascular drug was licensed in December for the treatment of congestive heart failure, which afflicts some 5 million Americans. The drug is in Phase II trials.

Investors have applauded Amylin’s progress: its stock closed in late January at about $17.25 per share, valuing the company at $1.57 billion. The stock has steadily climbed since late September of 2001, when it closed below $5 per share.

Finding What’s Broke

San Diego-based research not only has helped bring on new treatments, it has discovered that some accepted treatments weren’t effective, says Elizabeth Barrett-Connor, professor of family and preventive medicine at the UCSD School of Medicine.

Barrett-Connor is a master of multidisciplinary research. She founded the Rancho Bernardo Heart and Chronic Disease study in the early 1970s. The ongoing study looked at such conditions as diabetes and osteoporosis as well as cardiovascular disease, and the issues involved in treating the latter two simultaneously in women.

Barrett-Connor’s research helped prove that hormone replacement therapy did not lower the risk of heart disease in women, and in some cases increased the risk. She also was principal investigator of the Multiple Outcomes of Raloxifene Evaluation, which showed that a non-hormone drug for osteoporosis did not increase the risk of heart disease, and could actually lower the incidence in women at high risk for heart disease.

“That was a really important discovery, because had those trials not gone on, I think half of women in America would have been taking hormones, at some cost and risk, and at no cardiovascular benefit,” she says. “Those studies were the reason why the American Heart Association, for example, changed its recommendations, as has every other professional organization, about the use of hormones for preventing heart disease. That means women at risk will now get more appropriate treatment instead of estrogen, which just doesn’t work.”

Improving Diagnosis

While medical doctors applaud these striking advances, they have a more immediate concern: how to better diagnose cardiovascular disease at an earlier stage. The earlier the treatment, the better the prognosis.

Anthony N. DeMaria, a professor of medicine and chief of the cardiology division at UCSD Medical Center, is a pioneer in developing better diagnostics. In addition to teaching at UCSD Medical Center, DeMaria is the editor in chief of the Journal of the American College of Cardiology and has authored more than 180 research papers. He’s also on the board of directors of Biosite Diagnostics, a San Diego-based medical device company.

DeMaria says Biosite sought his cardiologist’s perspective on new diagnostic products.

“I told them I didn’t know much about business,” DeMaria says. “They said, ‘that’s OK. You teach us about cardiology, and we’ll teach you about business.’”

DeMaria is world-known for his expertise in ultrasound imaging as a diagnostic tool. “Ultrasound is a marvelous thing,” he says. “It’s relatively inexpensive, it’s small and portable. You could do it every hour if you wanted to. It’s dynamic in that it not only shows you the internal anatomy of the heart, but it shows it continuously, so you can see the movement of the heart.”

DeMaria and his colleagues in UCSD’s cardiology division have extensively tested new ultrasound devices, the latest of which are about as small as a laptop computer. “The anticipation is that as time goes by, they’ll get as small as personal digital organizers, and will be used in every single physical exam to detect disease earlier and earlier.”

DeMaria has participated in clinical trials of ultrasound contrast agents put into the blood that give a clearer picture of the heart, including the first such agent, Albunex, developed by San Diego-based Molecular Biosystems Inc. Clinical success didn’t bring financial success. Molecular Biosystems ran low on cash and was acquired by another San Diego biotechnology company, Alliance Pharmaceutical. In turn, Alliance is floundering, its stock at 15 cents per share as of Jan. 24, and a market capitalization of just $2.7 million.

Regardless of the fate of Alliance, DeMaria predicts cardiac ultrasound and contrast agents will become ubiquitous diagnostic tools.

“There absolutely are things you can detect with a contrast agent that you could not detect without the contrast agent,” DeMaria says. “Sometimes you just don’t get adequate signals back to define the walls of the heart or the borders of the chambers. These new contrast agents, when they go through the capillaries of the heart muscle, they produce a signal so that during our (ultrasound) echocardiogram we can actually assess blood flow to the heart muscle itself. That’s a huge advance. We haven’t been able to do this until just recently.”

DeMaria says he and his colleagues at UCSD’s cardiology division were the first to show that it was feasible to measure blood flow to the heart in this manner, and other laboratories have since helped improve this technique.

A Collaborative Effort

Describing his own research is just the start for DeMaria. At length, he details the activities of doctors and researchers at UCSD, both in the cardiology division and other parts of the university. Some examples:

• UCSD cardiology Dr. Kirk Hammond teamed up with other doctors and developed a way to use a virus to carry a gene into heart cells. The gene triggers the growth of new blood vessels, of obvious use in treating or preventing heart attacks.
  
  That technology was the scientific basis of Collateral Therapeutics, a San Diego-based biotech that was purchased last year by Schering AG in a stock swap that valued Collateral at $159 million. Collateral’s gene therapy product, called Generx, is in Phase II/III human clinical trials to treat angina.
  
  
• Another physician in the cardiology department, Dr. Gregory Feld, has collaborated with the bioengineering department on methods to control irregular heartbeats, or arrhythmias.

Cardiology research at UCSD stretches far beyond just that program. The university’s top-ranked Department of Bioengineering, for example, has patented a method to prevent arteries from clogging up again after they have been opened by angioplasty, a process called restenosis. The university is looking for a company to license the technology for clinical trials.

The technique was developed by Shu Chien, director of the Whitaker Institute of Bioengineering at UCSD. Chien developed a procedure to insert genes into the cell walls of arteries during angioplasty. The genes block production of a protein that promotes restenosis.

“There’s a lot of interface between bioengineering and the clinical cardiology program, particularly in examining the way the heart contracts,” DeMaria says. “We’re trying to get a complete understanding of what determines normal cardiac performance and how to assess abnormalities.”

With so much going on, DeMaria admits it’s become complicated to keep up with all the cardiovascular research just at UCSD. So the university is in the early stages of forming a new cardiovascular center to become a focus for all cardiovascular-related research.

From Mice To Men

Evans jokes, “My patients are mice,” meaning that no matter how exciting the discovery, it won’t result in improved health care until it is developed through clinical trials, accepted by doctors and used in humans. As a doctor and researcher, DeMaria has the credentials to push the process along. Wearing multiple hats makes DeMaria conversant with three very different interested parties in cardiology: the researchers who make basic breakthroughs, the cardiologists themselves and the patients the cardiologists treat.

DeMaria is worrying that patients may be drawing the wrong lessons from the great advances in cardiovascular care. While people with cardiovascular disease are living longer than ever, DeMaria points out it is still the leading cause of death in the United States. Moreover, the longer people live with cardiovascular disease, the more treatment they’ll need.

The stereotypical heart attack death used to occur to men in their 50s. Now it’s more likely to take place in men and women in their 60s and older. “Surveys time and time again have shown that women are very afraid of developing breast cancer,” DeMaria says. “But in fact, their chances of developing heart disease and dying of heart disease are much much greater than of dying of breast cancer. Cardiovascular disease remains an enormous problem.”

Although its cross-section of research and clinical practice is perhaps the most impressive, UCSD is far from the only game in town when it comes to heart treatment. The Integrative Cardiology program at the Scripps Center for Integrative Medicine explicitly takes a holistic approach to patient care.

Scripps’ Healing Hearts program, modeled after the famous dietary approach of Dean Ornish, gives patients stress testing and lipid analysis, an individualized exercise plan supervised by a nurse and exercise physiologist, lectures, group support and even spiritual counseling. Its stress-reducing therapies include acupuncture, biofeedback and hatha yoga.

On the research side, Scripps Clinic’s scientists are vying with UCSD and Salk, indeed the entire world, in unraveling more clues to safe ways of lowering cholesterol levels and exactly how obesity contributes to heart disease.

Scripps professor Joel Buxbaum is researching a congenital form of premature heart aging also referred to as Alzheimer’s of the heart. About 1.5 million African-Americans have a gene that predisposes them to this condition.

The Underlying Cause

All the research and treatment aside, one fact is behind the country’s growing problems in obesity, diabetes and cardiovascular disease: We’re growing fat.

Americans eat more and exercise less than we used to, says the Salk’s Evans. However, we have virtually the same genes as did our more athletic ancestors, genes attuned to an environment of food scarcity and physical exertion.

Evolutionary biology gives insights into why this is so: Ancient humans whose genes were not as efficient in metabolizing and storing food tended not to leave as many descendants. Humans also are fond of fatty foods, also explainable as a byproduct of natural selection. Fats are energy dense, meaning that ounce for ounce, they contain more energy than other foods.

Add another factor: improved health care that allows Americans and Westerners in general to live longer than their remote ancestors. Not only has their environment changed, they now live long enough to experience the harmful effects of inactivity.

“Heart disease begins with the first bite,” says the wiry and trim Evans.

San Diego researchers are well positioned and working hard to turn that around and put a big bite on this killer.