Midway through the story of his heart troubles, Scott Radabaugh hesitates, gently placing a hand on his chest. He feels a twinge there, he says with a frown. He leans in a bit over the table in the San Ramon, Calif., café and tells me the questions flooding his mind: Could it just be a sore muscle from his workout? Or a sensitivity to the wires supporting his sternum, a remnant of his quadruple bypass surgery? Or is it a more ominous sign?

At 6 feet tall with a weightlifter’s physique and a ruddy complexion, Radabaugh appears to be the epitome of a healthy man. But he has what he calls a “sleeping giant” of a disease, a gene that makes him prone to soaring blood levels of low-density lipoprotein, known as LDL — the so-called bad cholesterol. At age 46, he’s already had two major surgeries to clear arteries blocking blood flow to his brain and his heart, and he is on the lookout for signs that he will need a third.

“I’m on hyper alert,” says the human resources manager and single father of three from Danville, Calif. “Once I have chest pains it may be time…. What’s scary is that I don’t go anywhere without nitroglycerin or aspirin [to help defuse a blood clot or heart attack]. I think about my own mortality many times a day.”

His condition, known as familial hypercholesterolemia, or FH, is a genetic disease in which individuals are born with high levels of LDL that build up in the arteries and can ultimately choke off blood flow to the heart if not treated. Radabaugh hadn’t heard of FH until a few years ago, though it’s highly prevalent in the United States. It’s thought to affect more than 600,000 adults and children — or one in 500 — and is far more common than other widely known genetic diseases, such as cystic fibrosis or breast cancer among women with a mutation in the BRCA1 gene.

Cardiologist Joshua Knowles, MD, PhD, an FH expert at Stanford, says FH is a condition that has been seriously neglected in this country — under-reported, under-treated and under-researched. Sadly, he says, many people don’t learn about it until they have a heart attack.

“It’s an invisible disease,” says Knowles, an instructor in medicine. “If you don’t have your cholesterol checked and get treatment, you’re a ticking time bomb until something happens.”

Though cholesterol is essential to body function, genetic changes can affect how people clear it from the blood. People with FH lack receptor proteins on the surfaces of their cells that help regulate the amount of circulating LDL. Without functioning receptors, the cells can’t latch on to the harmful protein, and that allows it to flood the bloodstream and accumulate in the artery walls. High-density lipoprotein, or HDL, on the other hand, is considered the “good” cholesterol because it helps remove these dangerous deposits.

 

FH is often the cause of premature heart attacks in young people, including athletes who seemingly out of the blue drop dead on the field. (Among the best known is Darryl Kile, pitcher for the St. Louis Cardinals, who died of a heart attack in 2002 at age 33, shortly before a big game in Chicago. Kile’s father died of a heart attack at age 44.) The disease is an underlying cause for some 24,000 heart attacks each year among people under age 60 in the United States, Knowles says. It often affects multiple family members, as children have a 50 percent chance of inheriting it from their parents. In rare instances, children inherit two copies of the gene — one from each parent — making them unusually vulnerable, at risk for heart attack in childhood.

Because it’s an asymptomatic disease, it often goes unnoticed by patients and their caregivers, says cardiologist Robert Harrington, MD, professor and chair of medicine at Stanford. “When you are a busy pediatrician or primary care provider, you don’t really see the disease. And until patients have a problem, they don’t complain about their high cholesterol,” Harrington says. Cholesterol is a major risk factor for heart disease, though it’s not the only contributor, as diet, exercise, smoking, blood pressure and stress all may play a role.

Photograph: Colin Clark

Scott Radabaugh, Heart disease taught him to cherish life and family.

Knowles and his colleagues follow some 60 FH patients at Stanford Hospital & Clinics, diligently tracking their cholesterol numbers. A faculty member in his 40s, he is reserved and thoughtful, saying his aim is to get patients to a place where their risk of a major heart event is low. Radabaugh first visited him as a patient in early 2013 at Stanford’s Familial Hypercholesterolemia Clinic for a second opinion on whether he’d need another bypass operation. “He was comforting. He took a lot of the fear away,” Radabaugh says of Knowles. Before then, he says, he had no clear sense of what his risks were. “He’s given me some assurances that I don’t have issues in the short term and could go years without another bypass. But of course nobody can say for sure.”

Radabaugh says that because of his family history, he long suspected he was prone to high cholesterol. As a child, he remembers his mother coming home from the doctor, upset to learn that her cholesterol was out of range. By age 52, she had suffered a blockage in an artery that was propped open by a stent, followed eight years later by a double bypass. Radabaugh watched as she emerged from the painful procedure, determined that he would do everything possible to avoid bypass surgery for himself.

‘I fell into the mistaken belief that if I ate a low-fat diet and exercised — and doctors reinforced this — I could reduce my risk to that of the general population.’

A Texas native, he was 27 when he got his first human resources job in Houston in 1995 and decided he should be checked out. When his cholesterol results came back, his doctor was alarmed, as his LDL level was high, nearly 300 mcg/dl. The American Heart Association defines LDL levels of below 100 mcg/dl as ideal; people with FH commonly have levels of 200 to 400. He was prescribed cholesterol-lowering statin drugs — the mainstay of FH treatment — and advised to watch his intake of fat.

He is still very much the Texan, arriving for our meeting in black cowboy boots, black Wrangler jeans and a work shirt with pockets. Radabaugh works out regularly, and he looks it. He also played football and baseball in high school and lifted weights while in college at Texas A&M, he says, all of which made him feel he was doing the right thing for his health.

“I fell into the mistaken belief that if I ate a low-fat diet and exercised — and doctors reinforced this — I could reduce my risk to that of the general population,” says Radabaugh, who maintains a strict dietary and exercise routine. “They were missing that one important piece: that if it’s genetic it begins the day you are born.”

 

One day in 2010, while he was pedaling on the elliptical machine at the gym, he felt a burning sensation in his chest. He stepped off the machine, and the pain subsided. But he was terrified, he says, as he stood in the crowded facility in San Ramon, Calif.

He dialed his primary care physician, who scheduled him for a stress test at 7 a.m. the next day at John Muir Medical Center in Walnut Creek, Calif. He failed miserably, barely able to sustain three minutes on the treadmill before his legs started to burn, as his heart wasn’t delivering enough oxygen to his extremities. That test was followed by an angiogram, an X-ray of the arteries, which showed blockages in four major vessels, including one directly leading to the heart. He was stunned to hear that he needed immediate bypass surgery — that “brutal” procedure (in which the sternum is split in half and later stapled together) that he’d tried so hard to avoid.

“My surgeon said, ‘You were really lucky. You would have had a heart attack in two to three weeks, and where the blockage was located it would have been fatal,’” he says. “You hear about these guys at the gym who work out and they’re in great shape and they drop dead. That would have been me.”

He was just 43. Radabaugh had assumed he was one of the many people with garden-variety high cholesterol. He did not realize then that he was an FH carrier and had been building up stores of cholesterol since birth.

“If you’re a normal person, you begin worrying about heart disease when you’re in your 60s or 70s,” Knowles says, “but if you’re an FH patient, the heart attacks start happening in your 30s and 40s.” Men with FH have a 50 percent risk of heart attack by age 40, while women have a 30 percent risk by the time they are 60.

As Radabaugh now says, “I may be 46, but I have the cardiovascular system of a 76-year-old.”

Because of his family history, his doctor suggested he have his three children tested as well, though they were just 5, 8 and 12 at the time. So in April 2011 — on the first anniversary of his bypass surgery — Radabaugh took them on a family outing to the lipid clinic at UCSF. Astonishingly, all three children proved to have high LDL numbers and were prescribed statins. For the first time Radabaugh heard the term, familial hypercholesterolemia. There was some relief in knowing the source of his problems, he says. “At least I had a name for this monster I was fighting. I felt empowered.” He resolved to become an advocate, educating others about the condition and encouraging them to go for testing.

“If you have any possibility of high cholesterol or family history, get yourself and your family members checked,” he tells people. “Once you have the knowledge, you can do something. If you don’t, the hand of God may reach down and grab you at any moment.”

FH may not be widely recognized today, but it has lurked in the background for decades. Its scientific roots go back to 1938, when a Norwegian scientist linked high cholesterol with the odd, yellowish swellings or bumps that appeared on patients’ limbs and around their eyes. Known as xanthomas or in the case of the eyes, arcus, these are often a hallmark of the condition: cholesterol-laden deposits that pillow under the skin and may pop up on the elbows, hands, feet, Achilles tendons or other body parts.

 

In the 1970s, scientists began to explain some of the underlying biology of the disease. At that time, Michael Brown, MD, and Joseph Goldstein, MD, at the University of Texas Southwestern Medical Center, discovered that cells have surface receptors that regulate how much LDL circulates in the bloodstream. The cause of FH was a shortage, or complete absence, of these receptors, they learned. The finding earned them the Nobel Prize in 1985.

The following year, Thomas Südhof, MD, who was working then in their lab, succeeded in cloning the gene for the LDL receptor — one of the genes that when mutated is responsible for FH. The discoveries laid the groundwork for the development in the late 1980s of the first statin drugs to lower cholesterol, revolutionizing cardiovascular medicine and leading to what Südhof, who is now a Stanford professor of molecular and cellular physiology and winner of a 2013 Nobel Prize, calls “one of the major medical advances of mankind.”

Since identifying the first LDL receptor gene, known as LDLR, scientists have pinpointed two other, less common genes important for FH. When a person with FH is tested, 60 to 80 percent of the time a disease-causing mutation in one of these genes shows up, says Knowles. All told, at least 1,500 mutations are known that affect LDLR, while just a few affect the other two genes.

Genetic testing for FH in Europe has been found to be cost-effective, as it saves the cost of major procedures, tests and hospitalizations. But in the United States, this testing is uncommon because it’s expensive — $800 to $1,300 — and not typically covered by insurance, Knowles says. Because the condition is so prevalent and treatable, the U.S. Centers for Disease Control and Prevention has made screening for the disease a top priority, encouraging first-degree relatives of people with FH to be screened, though not necessarily to get a genetic test.

Some European countries with national health-care systems also have launched campaigns to identify and treat patients with the disease. In the Netherlands, for instance, a government-led effort has identified 71 percent of patients thought to have FH, based on an estimated prevalence of one in 500 in the general population. A similar campaign in Norway has pinpointed 43 percent of affected individuals, while in the United States, that number is less than 1 percent, according to a recent European Heart Journal study.

 

Knowles has been working with the 2-year-old FH Foundation, a nonprofit patient advocacy group, to help change that. As the foundation’s chief medical officer, a voluntary position, he spearheaded its September 2013 launch of a national online registry to gather information about affected individuals and their family members. The goal is to help document the number of patients, learn about their history, their treatment, their participation in clinical trials and how the disease is impacting their lives, all in the interest of improving patient care and developing new therapies. The registry is a collaboration with the Duke Clinical Research Institute, which Harrington directed before he came to Stanford in 2012.

Harrington says the database is unusual in that it is driven by patients, who anonymously supply their own information. “It’s a next step in terms of empowering patients,” he says. “It will allow the FH Foundation and the academic community to provide valuable insights into the disease.”

The first person to sign up for the registry was Radabaugh, who met Knowles through the foundation. More than 100 people are now in the registry, which is accessed through the foundation’s website: http://thefhfoundation.org/.

Cardiologist Euan Ashley, MD, PhD, says the registry offers a rare opportunity. “Here you have a very straightforward and relatively benign intervention — cholesterol testing and treatment — that can be done very early on and save lives. That is very unusual for any genetic disease. So it’s a great opportunity — if you can find people with the disease,” says Ashley, associate professor of medicine and director of the Center for Inherited Cardiovascular Disease at Stanford.

Knowles is seeking other ways to identify FH patients and funnel them into treatment. He recently completed a study in which he and his colleagues reviewed the electronic medical records for all Stanford Hospital patients who have had cholesterol testing in the last 10 years, tagging those with “very suspicious” LDL levels. He was able to identify some 150 patients, whose health-care providers were then notified. About 10 patients have since come in to Stanford for follow-up, though others may have seen caregivers elsewhere, he says.

He is now seeking funding to apply that same model in other health-care systems, such as the massive Veterans Affairs Health Care System, with the hopes of identifying a broader swath of individuals with FH.

“I think it’s an area where electronic medical records could be very valuable,” says Michael McConnell, MD, a professor of medicine and co-director of the Preventive Cardiology Clinic at Stanford. “We want to be careful and not alarm patients, but there is a public benefit not only to the patient but also to the family members who may not have been screened.”

Ashley also is working with the American Heart Association on guidelines to encourage information sharing among insurance companies. The goal is to identify family members who may be dispersed across the country, covered by different health plans, and unaware that FH is a common family trait.

“It’s much cheaper for them to pay for a simple test than to pay for the heart attack, the heart bypass and the coronary care unit,” he says. “And it’s much better for the patient.”

 

The American Academy of Pediatrics also recommends that all children between the ages of 9 and 11 get a cholesterol panel, but the guideline is not widely implemented, Knowles says. Some pediatricians may not be aware of the guidelines or are reluctant to draw blood in a child, while others may not want to do cholesterol testing unless they are prepared to give the child medication. But Knowles says at the very least, a child found to have high cholesterol could benefit from diet and lifestyle changes, while knowing the child’s cholesterol status could help identify other family members at risk. “If you did that and screened a lot of kids at an early age, you’d pick up a lot of the FH cases,” he says.

‘Here you have a very straightforward and relatively benign intervention — cholesterol testing and treatment — that can be done very early on and save lives. That is very unusual for any genetic disease.’

Once patients are identified, they must follow a particularly aggressive drug regimen, typically based on the use of a high-potency statin. The statin drugs work by inhibiting an enzyme that is key to the liver’s production of cholesterol. Major studies from the Netherlands and Great Britain have shown that taking statins and controlling cholesterol are highly effective in reducing mortality among FH patients to levels similar to the general population, Knowles notes.

The goal for FH patients is to bring their LDL down at least 50 percent and ideally even lower (perhaps as low as 70 mg/dl) to compensate for the body’s long-term cholesterol exposure, Knowles says. But fewer than 20 percent of patients actually reach healthy cholesterol levels because doctors, often unaware of a patient’s FH status, may not pursue aggressive treatment, while patients don’t always take their pills. The drugs also may carry side effects, with up to 10 to 20 percent of patients experiencing problems such as muscle aches, which limit their use.

“Compliance is a challenge for everyone,” says Mary Ann Champagne, RN, a Stanford nurse who has worked with FH patients for 20 years. “It’s a silent and asymptomatic disease and people don’t see or feel an immediate benefit from taking their prescribed medication.”

Statins have been the dominant treatment for decades and are among the country’s most widely prescribed drugs, with Lipitor (atorvastatin), the leading statin, commanding a market of $7.2 billion in 2010, according to the pharmaceutical research firm IMS Health. Most statins, including atorvastatin, are now generic and, as a result, inexpensive. 

But more recently, drug development has focused on an entirely new class of compounds that could have huge implications for treatment, Harrington says. These drugs target PCSK9, an enzyme that makes it difficult for the body to clear cholesterol. Early-stage trials have shown that when the enzyme is blocked, LDL levels drop to unprecedented levels. Several companies are sponsoring large-scale clinical trials with variants of the drug to assess their impact on heart disease. Results are expected in the next year or two.

Radabaugh clings to the promise of these potent new medications. Though he is diligent in taking his pills — he and his children down their “vitamins” daily — he still struggles to bring his LDL into a low range, he says.

 

Much of his life these days revolves around management of the disease and his preoccupation with what the future will bring. In late 2012, a CT scan of his carotid arteries, which carry oxygen and blood through the neck into the brain, showed that the artery on his left side was 90 percent blocked, putting him at serious risk of stroke. He underwent a procedure known as carotid endarectomy, in which surgeons opened up the vessel to clear the deposits. The procedure left him with a 3-inch scar on his neck and a slight swelling there that gives him a throaty voice at times.

Then in the spring of 2013, he learned that two of his bypass grafts had failed; this is not entirely uncommon, as about half of bypass grafts fail within 10 years because the substitute vessels, typically veins taken from the leg, aren’t equipped to deal with high arterial pressure. So Radabaugh faces the prospect of another procedure. A second bypass operation could be complex because doctors would have to steal arteries from another part of his body, likely his arms. They are hoping to postpone the procedure for as long as possible.

And so Radabaugh waits, as the prospect of a major heart event hovers in the background.

“I’m waiting for chest pains and another bypass or, God forbid, I could have a massive heart attack,” he says.

In the meantime, he harks back to an experience in the hospital’s intensive care unit when he was awaiting his bypass procedure. A woman in the next room suffered a fatal heart attack that marshaled the entire staff and left family members swooning in grief. Watching the incident unfold, he says, gave him an entirely new perspective, as he could savor the joy of his own survival.

“I’ve had the chance to stand on the cliff with my toes on the edge, but thank God I didn’t fall in. So it’s given me a good perspective. I realize now it’s only our relationships in life that matter.”

He has learned to cherish what he has. “Every day I appreciate the time with my kids and my life,” he says. “I don’t wait to tell them how I feel about them. My life is focused on what is important.” SM

 

Contact Ruthann Richter