Faculty Spotlight: Gregory Marcus, MD

Is alcohol good or bad for the heart? The short answer: it depends, it.s complicated, and Dr. Gregory Marcus is trying to find out more.

"Alcohol is fascinating as it relates to cardiovascular health," said Dr. Marcus, a cardiac electrophysiologist who studies atrial fibrillation, an abnormal heart rhythm in which the upper chambers of the heart quiver ineffectively, rather than pumping blood efficiently. "On one hand, there's evidence that moderate alcohol consumption might prevent heart attacks, be beneficial in heart failure, and help the cholesterol profile. Also, red wine might have beneficial components like antioxidants, which can help the health of blood vessels.

"On the other hand, there's pretty good evidence that alcohol increases risk for atrial fibrillation and may raise blood pressure," said Dr. Marcus. However, some of the data is anecdotal, drawn from clinical experience of so-called "holiday heart syndrome," in which patients develop atrial fibrillation after drinking, often following a holiday or weekend.

"The question is, is alcohol just triggering atrial fibrillation in those who already have the disease, or is it actually causing atrial fibrillation?" asked Dr. Marcus. "That's one of the things we need to figure out." He and his team hypothesize that there may be two dynamics at play: an acute effect, caused by a specific drinking episode, and a chronic effect, which unfolds over years of drinking.

Alcohol and Atrial Fibrillation

Although about 85 percent of Americans drink alcohol, little is known about how it affects the electrical properties of the heart. At the same time, while atrial fibrillation is the most common arrhythmia, how it develops is poorly understood. Dr. Marcus recently received a grant from the National Institutes of Health (NIH) to discover more about both these areas. "If we could really understand the mechanisms by which alcohol leads to atrial fibrillation, we might learn something that could reveal a new target for therapies," he said.

The grant includes several projects:

• Alcohol vs. placebo: Patients with atrial fibrillation can sometimes be helped or even cured through ablation — a catheter-based procedure to strategically burn or freeze the heart tissue producing the faulty electrical signals causing an arrhythmia. In this study, patients who are already scheduled to have an ablation are randomly divided into two groups.
  
  Just before the ablation, one group receives an infusion of intravenous alcohol, which is titrated by repeated breathalyzer tests to achieve a blood alcohol concentration of .08%. The other group receives a placebo infusion. The electrophysiologists performing the procedures do not know whether the patient is receiving alcohol or the placebo. They perform tests before and after the infusion to determine the electrophysiologic properties of the upper chambers of the heart, and to see whether they can induce atrial fibrillation. "The idea is to see how alcohol versus placebo changes the electrical properties of the heart," said Dr. Marcus. Dr. Jeffrey Olgin, chief of the Division of Cardiology, Gallo-Chatterjee Distinguished Professor of Medicine, and a co-investigator on Dr. Marcus's NIH-funded study, is performing a similar set of experiments on rat hearts.
   
• Framingham collaboration: Dr. Marcus and his team are collaborating with investigators at the landmark Framingham Heart Study, which was established in 1948 and has closely studied three generations of participants over decades to learn more about cardiovascular risk factors. Participants fill out detailed questionnaires and return to the study's headquarters every two years for a detailed medical history, physical examination and laboratory tests.
  
  Dr. Marcus is working with Framingham to review many years of serial alcohol surveys and echocardiograms, which are ultrasound images of the heart. "The hypothesis is that consuming alcohol over a long period of time leads to an enlargement of the left atrium, which then leads to atrial fibrillation," said Dr. Marcus. His group is also conducting animal experiments to complement this investigation.
   
• Close monitoring: In the third project, Dr. Marcus and his team have recruited patients with intermittent atrial fibrillation to wear a heart monitor for a month to record their heart rhythm, as well as wrist and ankle monitors that detect the alcohol level in their sweat. By comparing the monitor readings, they hope to learn whether there is a relationship between alcohol consumption and atrial fibrillation, and if so, what the timing of that relationship is. An acute effect might produce atrial fibrillation shortly after alcohol enters the bloodstream, whereas a "hangover" effect might trigger the arrhythmia a day or two later. Participants will also provide a blood sample that can help determine whether they had any binge drinking episodes in the previous two weeks.
  
  The investigators also want to find out if there is a threshold concentration . a tipping point that sets off the arrhythmia — and whether there are signature characteristics of the heart rhythm just before an alcohol-associated atrial fibrillation episode begins, which might provide insight into how atrial fibrillation occurs.

 

Additional Investigations

Dr. Marcus also leads other related studies:

• Dry to wet: Many previous investigations of alcohol and heart disease have a major limitation: they often rely on self-reports of how much participants drink. Because of social taboos, participants may downplay the amount or frequency of their consumption, or feel pressured to inflate their drinking habits.
  
  Dr. Marcus and one of his research mentees, cardiac electrophysiology fellow Dr. Jonathan Dukes, have pursued an alternative route. They conducted a study of every hospitalization in Texas over five years using a database called the Healthcare Cost and Utilization Project. Texas is of special interest because a number of its counties prohibit the sale of alcohol, likely a holdover from Prohibition. (Although alcohol consumption is legal in "dry" counties, people must purchase it in "wet" counties.) "This legal patchwork within a single state has provided a rich opportunity for us to leverage those differences and conduct a natural experiment," said Dr. Marcus.
  
  Dr. Marcus's group compared the rates of heart attack, atrial fibrillation and heart failure in dry versus wet counties. "We found that in wet counties, where alcohol sales were most liberal, there was more atrial fibrillation, but less heart attacks and less heart failure," said Dr. Marcus.
  
  Interestingly, during the study's five-year period, several counties changed their laws to legalize alcohol sales. "When counties went from dry to wet, there was more atrial fibrillation when they became wet than when they were dry," said Dr. Marcus. "Atrial fibrillation was always associated with more access to alcohol."
  
  Their group also found that in counties where alcohol sales were permitted, there was an increase in the number of hospital diagnoses for alcohol abuse and alcoholic liver disease, suggesting that there was a relationship between availability and consumption of alcohol and likely validating their original approach to this research question. They recently submitted their findings for publication.
   
• Health eHeart Study: Dr. Marcus also serves as co-principal investigator of the web-based Health eHeart Study, which has enrolled nearly 20,000 participants to date and uses Big Data approaches, smartphones, mobile health apps and other technology to better predict, prevent and treat heart disease.
  
  Dr. Marcus and another mentee, cardiology fellow Dr. Isaac "Ziggy" Whitman, analyzed data from the alcohol-related questionnaire that all Health eHeart participants receive. About one-third of participants thought alcohol was good for the heart, one-third thought it was bad, and one-third were unsure. "In a separate survey, the one-third that thought it was good for the heart reported drinking more alcohol than other respondents, and their number one source of information was the lay press — not their physician," said Dr. Marcus. This is the first known study to assess these beliefs. Dr. Marcus believes it may be particularly important that such beliefs are associated with increased alcohol consumption, and that these beliefs are based primarily on information in the popular media rather than physician recommendations.

 

All these studies underscore the need to understand more about the relationship between alcohol consumption and heart health, as well as how arrhythmias develop. "If we could understand which patients are prone to what heart conditions, and knew exactly how alcohol affects the heart, we could personalize our recommendations," said Dr. Marcus. "We might say, 'Mr. Smith, you would do better if you drank one to two glasses of wine a night,' or 'Mr. Jones, you should avoid alcohol.' But we don't yet know the answer, and we're very interested in figuring that out."

An Ideal Study

If he had unlimited funds, Dr. Marcus would like to conduct a randomized controlled trial — the "gold standard" of research. The study would enroll volunteers who would be willing to either drink alcohol or not, and randomize them to either a moderate drinking group or a non-drinking group. "If we had sufficient funding to enroll thousands of people and follow them for at least five years, that would be an outstanding opportunity to learn a lot about the relationship between alcohol and heart disease," said Dr. Marcus.

The Health eHeart Study may provide an infrastructure to support such an ambitious study, using mobile health apps, smartphone messaging, and other tech tools to gather a rich pool of data. "This would be a completely innovative and very clinically meaningful research study," said Dr. Marcus, noting that randomized controlled trials are the best way to answer research questions. For example, a large, randomized controlled trial run by the Women's Health Initiative found in 2002 that hormone replacement therapy was more likely to harm than help women, overturning the conventional wisdom at the time.

"An alcohol randomized study would be of interest far beyond cardiovascular health, gathering a humongous wealth of information that would be of interest to oncologists, gastroenterologists, endocrinologists, psychiatrists and many others," said Dr. Marcus.

Health eHeart Collaborations

In addition to his investigations about alcohol and heart disease, Dr. Marcus is enthusiastic about the growing scope of the Health eHeart Study, which he co-directs along with Dr. Olgin and Dr. Mark Pletcher, a cardiovascular epidemiologist. The study has enrolled participants from every state, as well as six continents and about 90 countries.

"We are very excited by President Obama's Precision Medicine Initiative that he mentioned in this year's State of the Union address, and think that what we're building is exactly what they're looking for," said Dr. Marcus. "The Health eHeart Study is not just a cohort study, but a new paradigm for collecting clinical research." Dr. Olgin has been invited to be a member of the President's and NIH panel for this Precision Medicine Initiative.

Dr. Marcus and his team are collaborating with a number of other institutions, including UC Berkeley, the Childhood Cancer Survival Study and the Duke Clinical Research Institute. The Health eHeart Study also has established a close working relationship with the American Heart Association (AHA), which prominently featured the study at its most recent annual meeting, and helped enroll several thousand participants. In collaboration with EmPowered to Serve, an AHA initiative that works with faith-based and community partners, the Health eHeart Study is recruiting more participants from underrepresented groups while providing tailored aggregate recommendations for community leaders about opportunities for members to improve their health.

The Health eHeart Study also works with the Patient-Centered Outcomes Research Institute, a federally funded organization that promotes patient involvement in research studies. Led by Dr. Pletcher, the recently formed Health eHeart Alliance convened a patient-investigator summit with about 50 patients and 20 researchers. Together they developed ideas for patient-initiated research questions, such as creating a smartphone-based algorithm to help determine the triggers for a particular patient's atrial fibrillation.

Driven by Curiosity

Dr. Marcus grew up in Berkeley, and majored in philosophy at UC San Diego. He also took pre-med classes, and wrote his honors thesis on medical ethics. "I wanted there to be meaning in my life, and felt that saving lives was the simplest way to do that," he said.

After earning his medical degree at George Washington University in Washington, DC, he completed his residency and chief residency at Stanford University. He did his cardiology and cardiac electrophysiology fellowships at UCSF, where he also earned a master's degree in clinical research. Dr. Marcus joined the UCSF faculty in 2006. In addition to his research, Dr. Marcus sees patients in clinic, performs ablation procedures, and implants pacemakers and defibrillators.

Dr. Marcus has a son in his 20s, and he and his wife, Jenny, have two young daughters. In addition to medicine and spending time with his family, Dr. Marcus enjoys playing basketball, skiing, and playing the drums.

"I've always been very curious," said Dr. Marcus. "I question things when the answer is, 'Well, that's just the way it is.' There's got to be a reason, and if we don't know it, it's just because we haven't figured it out yet. I love solving puzzles and challenging conventional wisdom."

– Elizabeth Chur