Cindy Kostreba admits now that she had a sometimes sporadic relationship with statins, even after a routine physical in her early 20s revealed a total cholesterol level that was twice the optimal amount.
Already active and thin, she reluctantly took the statins, medications that are used to lower cholesterol levels, for long stretches, but with a few gaps that extended a year or longer. She worried about potential side effects and grew weary of what she describes as the “merry-go-round of medicines,” with doctors frequently changing her prescriptions in an effort to squelch her elevated cholesterol. Then her college-aged son, a fit ice hockey player, shocked his pediatrician during a checkup three years ago with an elevated cholesterol level of his own.
After learning of Kostreba’s lifelong struggles, the pediatrician referred them both to a lipid specialist, who suggested genetic testing. The results came back positive for familial hypercholesterolemia (FH), an inherited disorder that’s believed to affect roughly one in every 300 Americans.
Genetic tests for FH typically look for variants in one of three genes linked to cholesterol levels, LDLR, APOB, and PCSK9, the most common being the LDLR gene. People with FH are afflicted with cholesterol levels that dwarf the concerns of those of us who fret when our LDL (low density lipoprotein) readings — dubbed the “bad” cholesterol — drift north of 100 mg/dL. When untreated, LDL levels in people with FH can range from 190 mg/dL to 400 mg/dL. Yet, the diagnosis is frequently missed. Only 1 to 10 percent of those with the disorder realize that their cardiovascular deck is prematurely stacked against them.
“I wish he didn’t have that gene, but he does,” says Kostreba, whose 22-year-old son now takes a statin. “I feel like my son has an advantage by catching it early and hopefully preventing heart disease.”
Along with trying to flag inherited cardiovascular vulnerabilities such as FH, researchers are working hard to identify genes that might improve the efficacy and reduce the side effects of commonly used drugs in cardiovascular disease patients. Blood testing also can assess the activity of specific genes to determine the likelihood that a patient’s chest pain is being caused by a worrisome blockage in the heart.
Flagging Genetic Culprits
For researchers, finding the genetic basis of cardiovascular disease, also referred to as heart disease, has posed a steep challenge. Cardiovascular disease encompasses a range of conditions that affect the heart valves, heart muscle (cardiomyopathies), rhythm (arrhythmias), and blood vessels (coronary artery disease). Each of these conditions is complex, influenced by a combination of genetics, lifestyle, and the environment. In some cases, such as FH, research has focused on genes underlying coronary artery disease risk factors such as high cholesterol.
While some heart conditions can be attributed to a single mutation in a gene, these “single gene,” or “Mendelian,” diseases are less prevalent. For example, the genetically linked Brugada syndrome, which causes heart rhythm disruptions, affects five out of every 10,000 people worldwide, while FH, which falls into the same category of Mendelian heart diseases, is more common. Deciphering the genetic underpinnings of the more garden-variety forms of heart disease, especially coronary heart disease, which takes nearly 380,000 American lives annually, has proven far more complex.
Family history remains one of the strongest risk factors for coronary heart disease. One analysis found that adults who had at least one biological parent with coronary heart disease were 40 to 60 percent more likely to develop it themselves, compared with those whose parents didn’t have the disease. Despite efforts by researchers to understand the genetic basis of a family history of coronary heart disease, the genes discovered to date do not fully account for its strong effect.
Shedding pounds and making other smart lifestyle choices still matter, but they are only roughly half of the heart disease equation, says Joseph Hill, chief of the division of cardiology at the University of Texas Southwestern Medical Center in Dallas. The rest of an individual’s vulnerability is shaped by the mixed stew of subtle genetic changes that we all carry around to varying degrees. Together they can potentially add up to significant heart risk.
“That’s why some people can smoke all of their lives and never have heart disease,” Hill says. “Others develop heart disease, and they’ve never touched a cigarette.”
The Great Mutation Hunt
Over the last two decades, researchers have begun to discover specific and typically rare genetic variants, or mutations, that can be connected to sometimes quite severe heart conditions. One potentially fatal form, called hypertrophic cardiomyopathy, which involves a thickening of the heart muscle. It has been linked to mutations in several genes, including MYH7 and MYBPC3. Another condition, long QT syndrome, can cause serious heart arrhythmias; it has been linked to another set of genetic mutations, including KCNQ1, KCNH2, and SCN5A, among others.
As more mutations have been identified, increasing numbers of genes have been added to genetic testing panels, says Elizabeth McNally, who directs the Center for Genetic Medicine at Northwestern University Feinberg School of Medicine in Chicago. Physicians were excited, McNally recalls, when cardiomyopathy panels were released in 2007 that could look at up to five genes at a time. These days, some panels can screen for as many as 80 genes, and she says she expects that number to soon climb.
But even with these so-called single-gene disorders, mutations are not destiny. For one thing, not all genetic mutations have been identified, so a negative result shouldn’t rule out the condition, according to a 2011 consensus statement by the Heart Rhythm Society and the European Heart Rhythm Association.
Moreover, family members with the same mutation may experience significantly different degrees of heart disease, McNally says. One family member with a mutation linked to hypertrophic cardiomyopathy may be living with worrisome arrhythmias starting in young adulthood, while others in the same family who are several decades older may have virtually no signs, even on heart imaging tests, she says.
Identifying a mutation, though, is only half of the equation. The other half is whether that knowledge is beneficial. In their 2011 statement, the two heart organizations stressed that cardiovascular genetic testing should be limited to individuals for whom other tests already point to a particular condition and to tests whose accuracy is relatively high or whose results might influence medical care.
With some inherited heart conditions, there are still relatively few treatment options, says Euan Ashley, who directs the Stanford University School of Medicine’s Center for Inherited Cardiovascular Disease in Stanford, California. A genetic confirmation of hypertrophic cardiomyopathy, which is a common cause of sudden death in young athletes, can open the door to screening for other family members, he says. Those who test positive may be advised to stop high-intensity exercise, depending on what further tests, such as heart imaging, reveal, Ashley says. “But we don’t have a medication that clearly reverses or interrupts the progression of the disease,” he says, adding, “Actually, in most people the disease doesn’t progress.”
However, people with another form of cardiomyopathy, called familial dilated cardiomyopathy (named for its characteristic enlarged heart), appear to benefit from starting medication early, Ashley says. Mutations in more than 30 genes have been linked to familial dilated cardiomyopathy. When a young patient has a dilated heart and other causes, like a prior heart attack, have been ruled out, genetic testing can help solve the puzzle, he says.
If the results come back positive, further testing is typically recommended for that individual’s first-degree family members, such as siblings, parents, and children. If some of them test positive, another set of first-degree relatives will be screened, and so on, a process that may identify as many as 30-some carriers in an extended family, Ashley says. Along with closer heart monitoring, those with familial dilated cardiomyopathy could be prescribed heart drugs, such as beta blockers and angiotensin-converting enzyme (ACE) inhibitors, he says. These drug therapies can reduce risk of heart failure.
For individuals with FH, diet and lifestyle changes are the first line treatment, but nearly all patients will also need to take medications to prevent or slow coronary artery disease. It is recommended to start treatment with statins as soon as possible after diagnosis, with one set of guidelines suggesting beginning as early as 8 years old in some severe cases. A recently published study, which followed 214 children with FH for a decade, found that prolonged statin use appeared to be safe and prevented the worsening of heart disease.
In addition, a new class of cholesterol-lowering drug is already in the pipeline, targeting the gene PCSK9, which plays a key role in regulating blood cholesterol levels. Three pharmaceutical companies are vying to be the first to commercialize a PCSK9 drug, which is expected to make its debut this year, with potential blockbuster status.
Before her genetic results came back, Kostreba said that she wasn’t living in denial about her familial vulnerability. She already knew that some relatives on her mother’s side had developed high cholesterol or suffered heart attacks at relatively young ages. But the 53-year-old believes that knowing the name and genetic mutation that underlies her perplexingly high cholesterol bolsters her commitment to stick with the medication. “Before, I just thought, ‘Oh, they’re just giving me all of these drugs. Every time I go in, they give me a new one. I’m tired of this,’” she says.
Working these days with the lipid specialist near her South Carolina home, Kostreba has found a combination that’s working well. Her reading last fall was her lowest ever: a cholesterol total of 223 mg/dL, which is only slightly above normal.
Drugs, Dosing, and Side Effects
Genetic testing also may help avoid some of the biggest stumbling blocks to preventing heart disease — the troubling side effects associated with statins, the problem of dosing with some anticoagulants, and the question of whether a patient will respond to a drug. Statins have long been the go-to drug to reduce elevated LDL levels, an affliction of 71 million Americans, or roughly one in three adults. And statins may be even more frequently prescribed in the wake of the latest set of cholesterol-lowering guidelines, published in 2013 by the American College of Cardiology and the American Heart Association.
Those guidelines, which center on statins, moved away from a specific target number for LDL cholesterol and focus more on a broader analysis of heart risk to assess an individual’s long-term vulnerability. Nearly 13 million more Americans between the ages of 40 to 75 could become eligible for the cholesterol drugs, according to a study published in an April 2014 issue of The New England Journal of Medicine analyzing the new guidelines.
Side effects remain a persistent problem, with some patients complaining about varying degrees of muscle aches, cramping, and pain. Between 10 and 15 percent of patients taking the drugs may experience at least mild muscle pain, called statin-induced myopathy, which may lead them to stop taking the drug. For the estimated 50 percent of all patients who discontinue statins for reasons that range from side effects to cost, the therapeutic benefits are lost.
Too frequently patients and their providers abandon the drugs entirely, says Deepak Voora, a cardiologist with Duke University’s Center for Applied Genomics and Precision Medicine in Durham, North Carolina. “It turns out that a lot of people are often denied cardiovascular benefits of these drugs.”
Voora has been studying how side effects are influenced by a mutation in SLCO1B1, a drug transporter gene that assists the liver with removing drug molecules like statins from the body. The mutation in question handicaps the liver’s cleansing ability, he says. “And as a consequence, not as much drug is taken up by the liver, and instead more drug is delivered to the rest of the body,” he says. “The muscles are essentially exposed to a higher concentration of the drug in people who carry this [mutation].”
Even among mutation carriers, though, their side effect vulnerability appears to vary depending upon the statin involved, says Voora, who published a related study in 2009. The risk of side effects was greatest among SLCO1B1 mutation carriers on Zocor (simvastatin) and negligible in those taking Pravachol (pravastatin). Another study also found no increased side effects with the statin Crestor (rosuvastatin) in SLCO1B1 mutation carriers.
Such genetic insights open the door to more personalized drug prescribing, Voora says. If someone tests positive for SLCO1B1, the patient could be started on drugs less associated with side effects, he says.
Could sharing SLCO1B1 results with patients who are vulnerable to side effects, and recommending that they take the optimal statin instead, convince them to try the drugs again? An ongoing research study, which Voora leads at Duke, in collaboration with Travis Air Force Base in California, is looking at whether such an approach improves adherence. “Maybe they may be more likely to try, or retry, a statin medication, and take it more regularly,” Voora says. “It’s a testable hypothesis.”
Researchers are also investigating genetic testing to solve the tricky dosing dilemma of the blood thinner drug, warfarin. Too much of the drug can cause excessive bleeding, while too little fails to prevent blood clots. Finding mutations in VKORC1 and CYP2C9 genes can help determine a patient’s sensitivity to the drug and determine the optimal dosage. While the test is moving in the right direction, some feel that it is not ready for clinical practice and that more research needs to be done.
The anticoagulant clopidogrel is another drug whose efficacy can vary according to a person’s genetic makeup. Research has shown that people harboring a mutation in the CYP2C19 gene may not respond as well to the drug and may be at risk for cardiac events. As with warfarin, studies are still under way to pinpoint which patients will respond to clopidogrel and which ones won’t.
Genetic Detective Work
While carrying certain genetic variants may reveal whether you are at increased risk of heart disease, such knowledge isn’t very helpful when you feel tightness in your chest. Other molecular markers can help with that. In certain disease states, cells make some proteins in abnormal amounts, not because of a gene mutation, but because the gene is either turned on or off by the disease process. It’s called gene expression, and it can be measured in a blood sample. People suffering from coronary artery disease have a specific gene expression signature in their blood that is a telltale sign of disease.
Available through CardioDx, Corus CAD is a blood test that looks at the expression level of specific genes and produces a score indicating the likelihood that a patient’s chest discomfort or other symptoms might be caused by a narrowing or blockage in the arteries of the heart. The test, which can help determine whether imaging and other tests are needed, is covered by Medicare and some commercial insurance companies.
As for the far rarer inherited heart conditions, genetic confirmation can sometimes be helpful with getting reimbursed by insurers, says Nathan Stitziel, a cardiologist and the director of the Center for Cardiovascular Genetics at Washington University School of Medicine in St. Louis. It also might provide a measure of comfort for someone who has been living with a worrisome heart problem from a young age, he points out. “They can say, ‘Oh look, I didn’t do anything to cause my thick heart — it’s a genetic thing.’”
But patients also need to keep in mind that the heart panel might produce more questions than answers, he says. It might identify only mutations unrelated to the heart condition in question — or nothing at all. “The third scenario, which we’re often stuck in, honestly,” he says, “is that we find mutations in genes that are related to the syndrome, but we don’t know what those mutations do.”
The good news is that if a mutation is found, the genetic detective work will prove less costly for other family members who are searching for answers, says Josh Knowles, a cardiologist at the Stanford University School of Medicine’s Center for Inherited Cardiovascular Disease and chief medical officer of the FH Foundation. “We never find an individual with FH — we find families with FH,” he says.
For that first individual, it will cost $1,000 to $2,000 to sort through three potential genes and isolate the mutational culprit, Knowles says. But once that’s been achieved, any subsequent testing looking for that specific mutation is far cheaper, typically less than $200 per individual, he says.
Two years after her positive results, Kostreba hasn’t been able to convince any members of her extended family to get screened, including those with daunting cholesterol readings. They figure that they’re already taking cholesterol drugs, she says, so what’s the point? But the mom, and perhaps future grandmother, is thankful that her son carries the genetic knowledge forward for future generations. “When he has children, he can let their pediatrician know when they are young.”