stanford medicine




Prevent the stent

Doctors may be implanting too many artery-opening stents and could improve patient outcomes — and ultimately save lives — if they did more in-depth measurements of blood flow in the vessels to the heart.

A study published Jan. 15 in the New England Journal of Medicine evaluated the benefits of a new diagnostic tool to measure blood flow and determine whether stenting was the best option. More than 1.2 million procedures to unclog arteries and implant stents are performed each year in the United States, according to the American Heart Association.

Illustration by David Plunkert
Man with watch on bicep

“Not only were the outcomes better, the cost was less,” says William Fearon, MD, co-principal investigator of the multicenter international study called FAME and assistant professor of cardiovascular medicine at the School of Medicine. “Now there’s scientific support for cardiologists to apply this new technique.”

The study suggests that doctors should go one step beyond relying solely on X-rays from a coronary angiogram to determine which arteries should be stented for patients with coronary artery disease. It’s not uncommon to see narrowing of the arteries in coronary angiograms, but in most cases the narrowing doesn’t limit the oxygen supply to the heart.

By using a method called fractional flow reserve, or FFR, which involves inserting a coronary pressure guidewire into a patient’s artery, doctors can measure whether blood flow is truly reduced to a dangerous level. If the flow is not too restricted, a patient can usually be treated with statins or aspirin instead.

Patients included in the study either suffered from chest pains or were recovering from mild heart attacks. All patients had multiple coronary arteries with narrowings. Half of the participants were treated with the traditional method of using an angiogram to decide which narrowings to stent, while the other half underwent the angiogram with the additional pressure-wire technique.

Researchers found that patients who received the additional test received one-third fewer stents than the group examined only with an angiogram. After one year, 18.4 percent of the patients within the traditional group had died, suffered a heart attack, or needed a bypass surgery or repeat stent procedure, compared with 13.2 percent among those who received the additional pressure-wire test.


The study was funded by Radi Medical Systems, one of two companies that make the pressure wires used in the study to measure blood flow inside arteries. Radi was recently acquired by St. Jude Medical.

Life blood

A new technique neatly sidesteps a major barrier to creating organs from stem cells: the lack of a reliable blood supply for the developing structure.

“Efforts to use tissue engineering to generate whole organs have largely failed,” says Geoffrey Gurtner, MD, associate professor of surgery, “primarily due to the lack of available blood vessels. Now we’ve essentially hijacked an existing structure to overcome this problem.”

David PlunkertBig man with veins

Stanford researchers have found that stem cells can thrive in pieces of tissue temporarily removed from lab animals, as long as the segments are fed by plenty of blood vessels. The key is to keep the tissue adequately supplied with oxygen and nutrients while outside of the body.

Once the cells nestle into the tissue’s nooks and crannies, the so-called bioscaffold can then be reconnected to the animal’s circulatory system. Gurtner is the senior author of the study, featured in the March FASEB Journal.

How they did it

Gurtner and colleagues made the bioscaffold from a piece of an extra fold of tissue in the groin of laboratory rats, about the size of a half-dollar coin. They attached the ends of the two main blood vessels to a modified bioreactor, an appliance designed to keep livers and kidneys healthy when they’re outside of a body. The device pumps an oxygenated soup of nutrients into one vessel and recovers it from the other.

First the scientists showed that the bioreactor could keep the tissue healthy enough for reimplantation into a second, genetically identical animal for up to 24 hours. In many cases, the tissue became nearly indistinguishable from surrounding skin within 28 days of transplant, though the success rate decreased as time spent on the bioreactor increased.

The team then used the bioreactor to pump stem cells through the tissue, and the cells were able to migrate out of the vascular spaces and into the surrounding tissue. Once there, they began to form colonies and continued to thrive even eight weeks after reimplantation.

The researchers believe that in the near future they will induce the stem cells in the tissue to produce healthy, specialized cells churning out proteins missing in people with genetic conditions such as hemophilia or diabetes. In the long run, they hope to encourage the cells to become entire transplantable organs. — KRISTA CONGER

The research was supported by grants from the National Institutes of Health and the National Institute of Biomedical Imaging and Bioengineering.

Do ask, do tell

Jonathan RabinovitzMitchell LunnMitchell Lunn is an advocate for more training in caring for gay patients.

Every time he goes to a new doctor, Mitchell Lunn faces the question: Should he tell his doctor he’s gay?

“The question always comes up,” says Lunn, 27, a Stanford medical student from North Dakota. “Do I want to come out or not?” This hesitancy is common with lesbian, gay, bisexual and transgender patients when meeting a doctor for the first time. And often they’re driven away by homophobic comments, or simply by a basic lack of knowledge on the part of their doctor as to their unique health-care concerns, says Lunn.

Surveying the scene

Lunn would like to see better training of medical students on health-care needs within the LGBT community, so he and three classmates have organized an on-campus research group, called the Lesbian, Gay, Bisexual & Transgender Medical Education Research Group.

In the spring, the group sent surveys to the deans of medical education at schools in the United States and Canada to determine what is being taught, before moving forward with recommended improvements.

“Taking a really comprehensive sexual history for any patient is essential. Medical students need to learn to ask these questions with every patient, from the 89-year-old grandmother to the 16-year-old wearing a rainbow T-shirt.”

“We have a little bit of content at Stanford, which is good. But nobody knows for sure what other schools are teaching,” Lunn says.

Questions on the survey range from, “When learning how to conduct a sexual history, are students at your institution taught to obtain information about same-sex relations, e.g., asking ‘do you have sex with men, women, or both?’” to, “Is there a clinical clerkship site that is specifically designed to facilitate LGBT patient care?” Next they plan to send a similar survey to all medical students.

Stanford medical student Juno Obedin-Maliver, 30, from New York City, says she knows firsthand just how important a sensitive and well-informed medical interview is to adequate care for LGBT people.

“I routinely get asked about birth control,” says Obedin-Maliver, discussing her experiences as a lesbian meeting with a new doctor. “I awkwardly stumble through explaining that that’s not necessary and why. But they don’t ask the necessary follow-up questions like, ‘Are you monogamous?’ ‘Have you been screened for sexually transmitted infections?’ ‘Are you practicing safe sex?’”

She adds, “Taking a really comprehensive sexual history for any patient is essential. Medical students need to learn to ask these questions with every patient, from the 89-year-old grandmother to the 16-year-old wearing a rainbow T-shirt.”

More information on the research group is available at: — TRACIE WHITE


The chatterbox

People with a genetic condition called Williams syndrome are famously gregarious. Scientists, looking carefully at brain function in such individuals, think they may now have a better understanding of why this is so.

Williams syndrome affects one in 10,000 individuals, and manifests in a distinctive pattern of physical and behavioral abnormalities. It includes greatly reduced spatial and mathematical reasoning but relatively less loss of certain verbal abilities or capacity to read others’ emotions.

People with Williams syndrome are also invariably sociable — so much so that they will strike up conversations with strangers.

In a study published Jan. 28 in the Journal of Neuroscience, medical school researchers reasoned that the link between this sociability and the characteristic genetic deletion causing the condition might be mediated by the amygdala, a brain region known to be key to social and emotional processing.

The researchers found that parts of the amygdala react more powerfully in Williams syndrome patients than in developmentally normal subjects when they’re exposed to facial expressions conveying positive emotions.

Postdoctoral scholar Brian Haas, PhD, was the co-first author of the study along with Bangor University researcher Debra Mills, PhD. Haas works in the lab of senior author Allan Reiss, MD, the Howard C. Robbins Professor of Psychiatry and Behavioral Sciences.

Using two techniques for objectively measuring brain response, the team showed that when 14 individuals with Williams syndrome looked at photos of faces judged by an independent team of normal reviewers to be especially reflective of a positive emotional state, their amygdalas responded much more forcefully than did those of 13 age-matched normally developing subjects.

One of the two techniques, functional magnetic resonance imaging, allowed the researchers to localize the increased activity to specific nerve clusters in the amygdala. The other technique, involving monitoring the brain’s electrical signals with a device placed on subjects’ heads, charted the course of this activity over time.

Friendliness explained?

The study also confirmed work by others showing that Williams syndrome patients’ amygdalas respond less vigorously to negatively charged stimuli (such as a face exhibiting fear) than do those of developmentally normal subjects. This may provide a physiological basis for Williams syndrome patients’ relative lack of reticence about approaching and engaging strangers, says Haas. Likewise, the amygdala’s heightened response to faces showing positive expressions suggests that exposure to these smiling faces may be profoundly rewarding to these patients.

This research holds implications for neurologically normal individuals, too. “The more we understand about what makes us more or less social beings,” says Reiss, “the better we may be able to tolerate one another’s differences.” — BRUCE GOLDMAN

The work was funded by the National Institute of Child Health and Human Development.

Woof woof wolf

Slipping through trees or across snow, the wolf has glided into legend on paws of white, gray or — in North America — even black. This last group owes an unexpected debt to the cousins of the domestic dog, say medical school researchers. In an unconventional evolutionary twist, dogs that bred with wolves thousands of years ago ceded a genetic mutation encoding dark coat color to their canine ancestors. As a result, the Gray Wolf, or Canis lupus, is no longer just gray.

Marco MusianiWolves fightingA domestic dog gene gives wolves their dark coat.

Black wolves, which are found nearly exclusively in North America, seem to have a selective advantage over lighter-colored wolves in forested areas. It’s a rare instance of domestic animals — in this case, probably the dogs of the earliest Native Americans — contributing to the genetic variability of their wild counterparts in a way that affects both the recipients’ appearance and survival.

Genetics professor Greg Barsh, MD, PhD, and graduate student Tovi Anderson collaborated with researchers in the United States, Sweden and Italy on the study,
which was published in the Feb. 5 Science.

The team compared DNA collected from 41 black, white and gray wolves in the Canadian Arctic and 224 black and gray wolves in Yellowstone National Park with that of domestic dogs and gray and black coyotes. Their intention was to build on previous work in the Barsh lab that identified a mechanism controlling pigmentation in dogs that differs from most other mammals.

“It may have been easier for dogs to interact with wolves in North America than in Europe. There was probably a higher concentration of wolves, and the dogs, like the humans, were more migratory.”

The researchers used a variety of genetic tests to determine that the mutation was likely introduced into wolves by dogs sometime in the last 10,000 to 15,000 years, about the same time the first Americans crossed the Bering land bridge from Siberia. These humans were probably accompanied by dogs, some of which carried the black-coat mutation estimated to have arisen about 50,000 years ago.

“It may have been easier for dogs to interact with wolves in North America than in Europe,” says Anderson. “There was probably a higher concentration of wolves, and the dogs, like the humans, were more migratory.”

The research underscores the idea that evolution may involve other instances in which traits are passed in unexpected directions. “We now know that dogs have been the caretakers of a genetic legacy that may be beneficial to wolves,” says Barsh. “It should lead us to think more broadly as to how this might apply to other animals and plants.” — KRISTA CONGER

The research was funded by the National Institutes of Health, the National Science Foundation and the Swedish Research Council.

Precision warfarin

Scientists have taken a small but important step toward folding a patient’s genetic profile into doctors’ everyday practice. Most immediately, the advance will likely lead to the safer, more effective use of the common but notoriously difficult-to-dose anti-clotting drug warfarin, taken by 30 million people in the United States each year. In the future, it could affect how doctors prescribe dozens of medications.

Because the right amount of warfarin can vary by as much as tenfold among individuals, physicians currently start most of their patients on a low dose and ramp up gradually until blood tests indicate the dose is correct — a process that can take months. A dose that’s too high can lead to severe bleeding.

David PlunkertWolves fighting

“It appears that up to 46 percent of people will require a warfarin dose that is significantly higher or lower than average,” says Russ Altman, MD, PhD, professor of bioengineering, genetics and medicine, noting that about 800,000 people are likely to be affected in the United States alone. “We’re hoping that our research will help clinicians get it right on the first try.”

Altman and his colleagues solicited warfarin dose-response information from over 21 sites in nine countries for inclusion in the study, which was published in the Feb. 19 New England Journal of Medicine.

The researchers collected a variety of demographic, clinical and genetic information from about 5,000 patients at risk for stroke, heart disease or other blood-clotting problems for whom the ideal doses of warfarin had already been established by trial and error.

They combined this information with the pre-determined ideal warfarin dose in about 4,000 of these patients to develop a computerized dose-prediction algorithm. They then tested the algorithm with and without the genetic data on the additional 1,000 patients.

“We found that even just including demographic and clinical information … yielded initial doses that were closer to the final, ideal dose, than the standard, ‘fixed-dose’ regimen,” says Altman.

“But including the genetic data enabled us to be much more accurate.”

Tailoring the dose

Incorporating this kind of genetic information in a standard office visit will be a challenge, Altman admits, but the fact that patients are currently recalled for weekly blood tests might make a combination approach workable. A physician could start a patient on a standard dose of warfarin and take a DNA sample during the first visit. The results could be ready when the patient returns the following week.

And it’s a strategy that would work with many other drugs, Altman adds. — KRISTA CONGER

The study was funded by the National Institutes of Health Pharmacogenetics Research Network; the National Institute of General Medical Sciences; the National Heart, Lung and Blood Institute; the National Institute of Neurological Disorders and Stroke; the National Center for Research Resources; the National Research Program for Genomic Medicine; and several international granting agencies.







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