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Detecting Secrets
of the Failing Heart
by Eve Jacobs

The cardiologist has been a principal investigator on more than 70 clinical research studies in heart failure and other cardiovascular diseases.

Mark Klapholz, MD, director of cardiology, UMDNJ-University Hospital, and associate professor of medicine, UMDNJ-New Jersey Medical School.

Other people's hearts keep Marc Klapholz ticking 'round-the-clock. In fact, they're both his passion and his lifeblood. He works to fix hearts whose rhythms are no longer strong and steady, that falter and plummet and skip out of control, damaged hearts too weak to pump enough blood for the body's workings.

Klapholz calls curing heart failure one of "the holy grails of medicine." This mission has enormous repercussions. Five million people in the U.S. have failing hearts - unarguably an epidemic. And the numbers are rising. There are more than half a million new cases diagnosed annually. It's estimated that advanced heart failure kills 20 percent within a year of diagnosis, and 50 percent within five years. The growing number of aging Americans - particularly those who survive recurrent heart attacks, but with grave damage to their organs - is the largest contributor to the escalating numbers. Uncontrolled, or undiagnosed, high blood pressure is also a major player. Sometimes there is no identifiable cause.

Heart failure does not mean the heart has stopped or threatens an imminent shutdown, but that it has been damaged. And since the pump cannot yet be fixed, Klapholz says "the resistance against which the heart has to work needs to be decreased and metabolic derangements that occur because the pump is impaired need to be corrected." The symptoms - chief among them difficulty breathing, extreme fatigue when exercising and sometimes even at rest, and swelling of legs and feet - often stop people in their tracks, setting off alarms of dire illness that bring them panicked into the emergency room.

"To slow it down, prevent it, perhaps to reverse it - what a tremendous challenge," says Klapholz. "Of course, our ultimate goal is to stop this major killer."

As heart failure progresses, the question of when to transplant is a valid one. Each year, 4,000 Americans are sick enough to be placed on an urgent heart transplant waiting list, but unfortunately, the organs are hard to come by, and only 2,000 heart transplants are performed in this country annually. In most cases, heart failure must be managed by medications. As a cardiologist who specializes in the medical management of this disease, Klapholz's aim is to find the best drugs to do the job in each individual case. This is a tough assignment.

While many do well on conventional therapies, Klapholz says the "art is in combining drugs and knowing how to work with dosages, and being able to tell when a person's condition is worsening even slightly," which warrants immediate attention. But some patients are not responsive to the traditional drugs or lose responsiveness over time, as the condition worsens. It is these patients whom cardiologists refer to heart failure specialists like Klapholz - who has been a principal investigator on more than 70 clinical research studies in heart failure and other cardiovascular diseases - for therapies not yet generally available.

Just recently, he participated in a major clinical trial to determine the value of a drug specifically aimed to treat heart failure in black patients. Called BiDil, the drug was determined to be so effective that it was considered unethical to continue giving some patients a placebo. The clinical trial was halted early and all 1,050 participants will be offered the medication. The drug will be going forward for FDA approval, which may be granted as early as the beginning of 2005.

There are an estimated 750,000 blacks with heart failure and many are not being helped by the standard medications. Blacks are more likely than whites to die of the disease. BiDil works by enhancing the level of nitric oxide, a gas that is released from the lining of arteries and which may be more commonly deficient in black patients with heart failure. "However," Klapholz cautions, "the differences in terms of treating heart failure have to do with genetics, not skin color."

Among his other recent efforts to diminish the impact of heart failure was participation - as a principal investigator - in a clinical trial of the novel compound tolvaptan, a "selective vasopressin receptor antagonist." According to Klapholz, it is a "fascinating drug that addresses fluid overload that is part and parcel of heart failure."

There are roughly one million hospitalizations yearly for chronic heart failure, most related to worsening congestion, or fluid build-up, particularly in the lungs. "Diuretics are used ubiquitously for this congestion but unfortunately they are drugs with very bad side effects," he says. Diuretic use is linked to electrolyte imbalances and worsening kidney function.

The congestive symptoms experienced by heart failure patients may be due, in part, to elevated vasopressin levels. By blocking the action of vasopressin, the experimental drug was successful in lessening congestion in these patients without having deleterious effects on blood pressure, heart rate, potassium levels, or kidney function. Results of this study were published this year in the Journal of the American Medical Association. Klapholz was one of the authors. Further studies are underway to ascertain if the drug actually extends survival in heart failure patients.

Developing and heading up sites for national and international research trials of new heart failure medicines is only one facet of this cardiologist's work. He is also board certified in echocardiography and interventional cardiology. "I am trying to develop as much expertise as possible in many areas," he says.

Klapholz, recently appointed director of cardiology at UMDNJ's University Hospital and New Jersey Medical School, plans to "grow a premier cardiology program here." He also aims to develop new programs in pulmonary hypertension, percutaneous cardiovascular defect repair (placing plugs to close up holes in the heart), percutaneous left ventricular assist devices (miniaturized pumps to support failing hearts) and peripheral vascular disease management, including repair of blockages in carotid arteries with the use of stents.

In addition, he believes a great opportunity exists to partner with basic scientists at the Cardiovascular Research Institute at UMDNJ-New Jersey Medical School to work on cardiovascular repair. "We have the underpinnings of turning around heart failure," he says. His goal is to establish UMDNJ as a leading center in the country for the treatment of cardiovascular disease.

He also looks forward to "developing a strong relationship with the pharmaceutical industry, which is so prominent in New Jersey, in the quest to develop new medications for cardiovascular disease," he says. "I feel the sky's the limit."

While Klapholz keeps his own heart exercised by bicycling in Central Park, what really keeps him going is the "drive to be very good at something in a context of doing something of real value," he comments. Finding better drugs to regenerate millions of failing hearts, while successfully applying the standard therapies, is certainly a mission of real value. "And working well with the people around me and enjoying those interactions every day are also very important to me," he says.

It is this total dedication to keeping the hearts around him beating healthfully - and happily - that makes him one of America's "top docs."