AHA president: genetics will revolutionize heart disease treatment, but for now, eat better

Cardiologists are increasingly checking patients’ unique genetic profiles as a first step in caring for them. This may partly explain why the American Heart Association last year elected a UAB genetic epidemiologist as its president in Donna Arnett, Ph.D. As her term ends this week, we thought to talk to her about her year in office and what's next in the treatment of massive, global health problems like high blood pressure.

Within the UAB School of Public Health, Dr. Arnett is chair of the Department of Epidemiology, the science that examines patterns in populations, including who is at risk for major diseases and why. She leads several nationwide studies looking at whether genetic variations in each person make them more at risk for heart diseases – or less likely to respond to commonly used anti-cholesterol or anti-inflammatory drugs.

What came across is her passion for scientific inquiry and determination to find better treatments for the families at higher risk for heart disease thanks to their genes. At the same time, she is the first to recommend that Americans get some exercise and eat better, rather than depend on genetics to eventually yield cures.

Show notes for the podcast:

1:40  Dr. Arnett began her career as a clinical research nurse working in a veterans hospital, and proceeded to become a leading genetic epidemiologist in cardiology and AHA president. Much of her inspiration has come from her strong curiosity, a need to ask questions. Early in her career at the veterans hospital, she wanted to know, for instance, why African Americans with the same level of high blood pressure as whites often had more serious kidney damage. Why were African Americans also more likely to have left ventricular hypertrophy. It's a thickening of the muscle in the left ventricle, one of the heart's chambers, that comes with fibrosis (scarring) and increased risk for heart attack and stroke. Why did people have different responses to the same doses of the same drug?

2.04  Unanswered questions drove her forward into the field of genetic epidemiology just as it was being founded. She said it was just good luck that she got into a field just as it was taking off.

3:00  She worked as a research nurse in general cardiovascular studies, but her office at the time was down the hall from the hospital's dialysis center. She got to know some of the veterans, and was struck by how many of the dialysis patients with severe kidney damage were African Americans. The experience brought home the human cost of the genetic contribution to disease.

4:15 Dr. Arnett said cardiology as a field is behind neurology and oncology, not only in genetic epidemiology, but also in pharmacogenomics, the study of the effect of each person's genetic variations on their response to drug treatments.

5:25  In her speech last year as began her term as AHA president, Dr. Arnett spoke about on the theme of  “transforming cardiovascular health through genes and environment.”  As a genetic epidemiologist she has a passionate interest in searching for genetic clues that may influence each person's disease risk. Some families with no traditional risk factors (not overweight; don't smoke) have struggled with tremendous disease burden and premature deaths. So learning how genes contribute to that is a must. That said, the thing that could save most lives from heart disease in America today would be a focus on environmental factors like the obesity epidemic. Our lifestyle is dominated by processed foods and sedentary inactivity, so Dr. Arnett believes we need to be "battling at both ends."

6:50  A focus of Dr. Arnett's tenure as AHA president has been hypertension or high blood pressure.  It affects more than a billion people in the world, and does tremendous damage. On the bright side, nations and  international institutions are starting to pay attention. The United Nations has held summits in recent years on diseases like hypertension that are caused by diet and lifestyle, where past efforts focused on infectious diseases. The World Health Organization has launched a campaign meant to reduce non-communicable diseases by 25 percent by 2025, with hypertension as a major focus.

7:25 In the U.S., the American Heart Association this year has partnered with the Million Hearts Initiative led by the Department of Health and Human Services, in an effort to prevent one million heart attacks in the next four years. The partnership will seek to achieve this goal through a combination of awareness campaigns, better access to care, new monitoring programs and initiatives that help people to take their medicine. Dr. Arnett said only a multi-pronged approach that include individuals, physicians, pharmacists, employers, companies and government agencies, combined with culture change, has a chance of making a difference.  New technologies may help the cause, including smart phone apps that monitor blood pressure and upload it directly to a patient's electronic medical record.

9:45 The field of genetics within cardiology continues its high-speed evolution, she said. It's moving toward analysis of each person's entire gene code, or genome, to look for small differences that contribute to that person's risk for heart disease. Past approaches that tried to find a  few genetic differences that placed large numbers of people at risk across populations are giving way to the study of individuals. Technologies have evolved to the point that whole genome sequencing of individuals is becoming affordable. It is being used around the country, said Dr. Arnett, to help diagnose diseases that seemingly have no cause. She and her colleagues are also using it to search for rare genetic variations that cause higher risk for left ventricular hypertrophy in some families.  

11:45 Dr. Arnett has focused on left ventricular hypertrophy in her work because it is one of the four basic causes of heart disease -- along with smoking, high blood pressure and high cholesterol -- first identified by the landmark Framingham Heart Study in 1967.  It is also the only one of the four that still has no known treatment for it (apart from lowering blood pressure).

12:38  The modern day life of the human body has changed drastically from the one in which it evolved, said Dr. Arnett.  We went from running constantly to hunt and eating mostly plants during the first 8,000 generations of human existence, to sitting on the couch eating a steady diet of fatty, heavily salted food for the last four generations.  Looking back even further, Dr. Arnett said, we evolved from saltwater fish, and with fine-tuned bodily mechanisms for regulating salt. The refrigeration and processing of food came about after World War II, drastically changing the way we eat. Heavily salted foods have changed the fluid balance in our bodies, which is regulated by the kidneys, to result in pandemic high blood  pressure. Our genes may be slowly evolving to better handle salt but it will take many generations. .

The illusion of a single perfect dose

Imagine if the recommended dose of a medication, the dose printed on its package, was correct for only about half of the people taking it. Then picture some people needing 30 times as much of the drug as others. What if either too high or too low a dose could have life-threatening consequences?

This worrisome scenario is the reality for patients taking warfarin, the 59-year-old blood thinner meant to help people avoid blood clots.

It serves as an example of the fact that, for many drugs, the idea of one correct dose for everyone is an illusion. In this light, I find it strange to think that the doses of medications I took growing up were best guesses, based on things like body weight, age, sex and race.

A wave of studies in recent years revealed that each person's genetic quirks greatly influence how well his or her body uses a drug, and on top of the classic factors mentioned above. How each person processes a drug determines not only whether or not that drug will work for them at all, but also how much of it is needed. Human genetic material is always changing, and many small variations at key spots in genes across a population create a range of responses to the same drug. Complicating matters, some of the variations with an impact on drug response are different for people with different ancestries.

That brings us to a study published this week and co-led by a UAB researcher. It found that a new genetic marker can better predict the right starting dose of warfarin dose in African-Americans. If confirmed in further studies, the finding may help avert more of the bleeds and blood clots that come when a patient’s  dose misses the drug’s narrow safety window.

Clots form to patch holes in blood vessels. Unfortunately, clotting can also be triggered by atrial fibrillation, cancer, surgery, aging and inactivity. Once formed, clots can float through the circulatory system to clog blood vessels elsewhere, causing heart attacks and strokes.

For these reasons, 33 million Americans got a prescription for warfarin in 2012, most of whom started on an average starting dose of 5 mg. The drug is very effective at preventing clots, but if the dose is too-high for any individual, that patient is at risk for internal bleeding. If the dose is too small, they may not be protected against clots. Doctors monitor patients' clotting speed closely in the first few weeks of treatment, trying to get each person's dose right before serious side effects occur. Such efforts fail often enough that warfarin made a recent top-ten list of drugs causing side-effect related hospitalizations in the United States, mostly because of bleeds.

Most of why dose varies so greatly across the population remained unexplained. A study just published in The Lancet and co-led by UAB's Nita Limdi, Pharm.D., associate professor in the Department of Neurology within the UAB School of Medicine, chipped away at this mystery.

The new study was a genome-wide association (GWA) study, a kind of analysis that looks at differences in genetic code to see if one or more variations are found more often across a population with a given trait. Traits can be high risk for a disease, needed drug dose or how tall you are. Even the smallest genetic variations, called single nucleotide polymorphisms (SNPS), can have a major impact on a trait by swapping just one of 3.2 billion “letters” making up the human DNA code.

The current GWA study found a statistically significant association between a SNP called rs12777823 and reduced warfarin dose requirements in African-Americans. Patients with this SNP needed 20 percent less warfarin, an effect not seen in patients of European or Asian ancestry. When incorporated into dosing algorithms, the new variant enabled the prediction of best dose with 21 percent greater accuracy than the standard formula. Past GWA studies had sought to identify genetic factors that could improve warfarin dose prediction, but none of them included patients of African ancestry.

For more information, see our press release on the study.