Originally developed in 1897 as a painkiller, aspirin has become a valuable cardiology tool in the 21st century for preventing and treating cardiovascular disease. Because of the drug’s ability to reduce blood clotting, doctors commonly recommend a daily aspirin to patients at high risk or with a history of heart attacks, strokes, and other cardiovascular ailments. Extensive research has largely supported the drug as a cheap and effective way to prevent these life-threatening events and to help nullify what remains the leading cause of death in the United States.

But in 2000, a group of Boston cardiologists trying to identify risk factors that might predict poor outcomes after a heart attack made a strange discovery. Most of the predictive risk factors they discovered and ultimately incorporated into their well-known 7-point “TIMI risk score” made perfect sense. For example, if you came to the emergency room with chest pain and had an abnormal electrocardiogram or elevated levels in the blood signaling heart damage, you were more likely to be at risk for future adverse events. But the team also discovered one risk factor for predicting worse outcomes that was far from expected: the prior use of aspirin. According to their analysis, patients who were taking aspirin to prevent cardiovascular disease actually did worse after suffering a heart attack.

“It seemed to make little sense, because aspirin had clearly proven itself in other settings to be protective against heart attacks,” said Jonathan Rich, an instructor of medicine in the section of cardiology at the University of Chicago Medical Center. “If you suffered a heart attack, to prevent you from having another, your doctor invariably puts you on aspirin. So this unexpected discovery caught everyone’s attention. Did this mean that aspirin use could actually be hurting people?”

Dubbed the “aspirin paradox,” this observation did not deter doctors from continuing to prescribe aspirin for the prevention of cardiovascular disease. But the mystery caused some to wonder whether there was a biological reason for aspirin’s unexpected role as a risk factor, such as “aspirin resistance” in some patients, or if there was instead an epidemiological or statistical explanation. While working in Boston with the TIMI study group, Rich took charge of an effort to comb through the data for a way to explain the paradox.

The research ultimately led to a study, published last month in the Journal of the American College of Cardiology, which seems to take aspirin off the hook. When researchers controlled for a long list of potential confounding variables such as age, sex, smoking, and previous history of cardiovascular events, the association of prior aspirin use with a higher chance of post-event mortality entirely disappeared. Aspirin, they concluded, was not directly causing worse outcomes after a heart attack. Instead, it was simply a common drug that people with previous cardiovascular disease - by definition, a population at high risk for poorer outcomes, were frequently taking.

“Aspirin is probably an innocent bystander,” Rich said. “The reason people who take aspirin do worse than those not taking aspirin is because those taking aspirin have already suffered a heart attack, a stroke, or have heart failure for which they were prescribed the drug. In actuality, when we looked closer at the heart attacks that people suffered, those who were taking aspirin actually had less severe heart attacks than those not taking aspirin, suggesting that perhaps aspirin was indeed beneficial, but simply insufficient to prevent the heart attack entirely.”

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Yesterday we talked about how Kathleen Cagney’s research appeared to reveal an effect of the 9/11 terrorist attacks on the body mass index of people more than a thousand miles away in Dallas. By coincidence, Discover magazine published a book excerpt (from “Origins: How the Nine Months Before Birth Shape the Rest of Our Lives” by Annie Murphy Paul) yesterday that touches on how the fall of the World Trade Center might have caused post-traumatic stress disorder not just in people near the towers that morning, but also the fetuses being carried by pregnant women near the towers. Can PTSD be transmitted from mother to unborn child? And did 9/11 leave a wide swath of medical impact across the country? Fascinating research.

Oh cruel search for alien habitable worlds: new data released at an astronomy symposium this week appears to refute the existence of Gliese 581g, the “Goldilocks” planet that had everyone daydreaming of intergalactic travel two weeks ago. Though the debate over the planet’s existence is far from settled, it’s a quick, nasty reminder that leaping from a handful of data points to bold claims of Earth-like planets and alien life is a dangerous gamble. (Also, Google News hits for original Gliese 581g story = 1407 articles. For the “Gliese 581g may not exist” story = 91.)

As part of the “It Gets Better” campaign reacting to the recent run of tragic suicides by homosexual teenagers, Scientific American’s psychology blogger Jesse Bering begins a long, detailed look at the evolutionary history of suicide. Why would an organism evolve the capacity to kill itself? Bering dials down to insects that are cannibalized after copulation and explains a mathematical equation for suicidal motivation in the first part of his series.

If University of Chicago evolutionary biologist Jerry Coyne is too prolific for you on his blog, Why Evolution is True, you can get a primer on his views regarding the incompatibility of science and religion from his USA Today editorial this week. There were, of course, letters,  and a blog response from Albert Mohler of the Southern Baptist Theological Seminary.

An in-depth Reuters article about the increasing use of cardiac assist devices and the end-of-life ethics questions they raise talks to our chief of cardiac and thoracic surgery Valluvan Jeevanandam, among other experts. For more on the topic, see our post on ethicist Daniel Sulmasy, who has written about when it is ethical for physicians to turn off a person’s cardiac device, knowing that it may hasten death.

When the FDA adds a “Boxed Warning” to a drug - known casually and more dramatically as a “black box” - it can have dramatic consequences. The information is intended to warn physicians of potential adverse effects associated with the drug, issues that are not deemed serious enough to pull the drug from the market but which should prompt extra attention and care. Antidepressants, the diabetes drug Avandia, and Depo-Provera birth control have all received black boxes in recent years, prompting widespread media coverage and medical comment.

Earlier this year, the anticoagulant medication clopidogrel (marketed as Plavix) became the latest drug to be black-boxed by the FDA. The warning fit the purported age of genetic medicine, as it was meant to draw attention to certain patients for whom the anti-clotting drug is less effective due to the presence of a gene variant for an important enzyme. These “poor metabolizers” exhibited reduced ability to convert the drug into its active components, and the black box warned that physicians should run genetic tests and consider alternative treatments in patients with the polymorphism.

But clopidogrel has become an important medical tool, used in millions of patients at high risk for heart attack, stroke, and other cardiovascular events. The drug has increasingly been incorporated into the long-term care of patients with drug-eluting stents - devices implanted to keep arteries open that secrete medication to prevent the vessels from re-narrowing. In patients where genetics renders clopidogrel less effective, the lost protection can lead to a stent thrombosis (where a clot forms on the device and blocks the artery) or other grave problems. Those concerns, and the expense of conducting genetic tests in every patient, have sent ripples through the field of interventional cardiology, said Sandeep Nathan, assistant professor of medicine at the University of Chicago Medical Center.

“There’s a growing recognition that this sort of formulaic approach to anti-platelet therapy is probably not a good idea,” Nathan said. “What has been brewing as a suspicion for well over a decade has come to an explosive head in the past one or two years.”

In response, Nathan has launched a two-pronged research and clinical effort to rethink current use of clopidogrel while seeking the best possible way to address risk in the future. Instead of waiting for a post-stent adverse event to tragically prove a patient’s insensitivity to clopidogrel, Nathan’s group has become one of the first to offer anti-platelet testing before the stent is implanted in patients at high-risk for the drug being ineffective.

“I view this as testing a parachute. You better be sure that the pack you just strapped on before you jumped out of a plane actually contains a parachute and not camping gear,” Nathan said. “If somebody implanted a drug-eluting stent in me, you better believe that I’m going to want to know if the drug that is my sole protection against a catastrophic, potentially life-ending event, is working.”

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A great deal of attention has been paid in recent years to the issue of racial and ethnic health disparities. Statistic after statistic reveals that minorities in the United States, particularly African-American and Hispanic populations, are in poorer health on average compared to American whites. Infant mortality, heart disease, diabetes, obesity, cancer and other maladies appear in often shockingly higher rates in minority populations, reflecting differences frequently attributed to socioeconomic factors and access to quality health care. But a new study by University of Chicago Medical Center researchers finds that a major contributor to those disparities might be traced back to what’s in the medicine cabinet.

The National Social Life, Health, and Aging Project (NSHAP) is a research effort launched out of the University of Chicago to study a large sample of older Americans. In 2005 and 2006, more than 3,000 in-home interviews were conducted across the country with people between the ages of 57 and 85 about their social activity, their health, and their medical care. As part of the interview, researchers not only asked the subject what medications they were currently taking, they looked at the drugs with their own eyes, taking a medication inventory “by direct observation.”

That thorough scan allowed Dima Qato, Caleb Alexander, and colleagues to analyze racial and ethnic patterns of medication use with unprecedented high fidelity. Previous studies which used insurance claims or prescriptions written to measure medication usage missed a key human factor, said Alexander, assistant professor of medicine.

“As we all know from own experience, what you are prescribed and what you take are often quite different,” Alexander said. “This data was unique in that it allowed for us to observe, from a nationally representative sample of individuals, the medicines people were actually taking.”

The analysis focused on medications prescribed to people at high risk for cardiovascular disease, a condition that has seen great progress recently in preventive medicine. Those included both the cholesterol-lowering prescription drug class of statins and the well-known over-the-counter drug aspirin, which is recommended to people at risk of heart attack and stroke for its anti-clotting abilities. Before the researchers even got to comparing different races and ethnicities, a disturbing overall trend appeared regarding use of these medicines.

“We found that across the board, regardless of race, there was evidence of under-use of both stains and aspirin,” said Qato, a research associate in the Department of Obstetrics & Gynecology.

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The Kv1.2 channel (image courtesy Fatemeh Khalili-Araghi/Theoretical and Computational Biophysics Group at UIUC)

Inside the human body are millions of miniature machines, the gatekeepers of the electrical impulses that keep our hearts beating and our minds thinking. They’re called ion channels; portals that allow small ions such as sodium, potassium, calcium, and chloride, to pass in or out of cells. A simple responsibility, with a complex and crucial outcome, as the flow of ions allows muscles to contract and action potentials to fire along the length of neurons.

While the job of an ion channel may seem straightforward, their design is anything but. Because the channels are awfully tiny, scientists have been forced to determine their workings through indirect experiments. A handful of pictures of the channels have also been taken, via the method of X-ray crystallography, but the photos can only capture an ion channel at rest - imagine trying to figure out how a car engine works from a single photograph.

But what if you could take the volumes of indirect information about an ion channel and instruct a computer to fill in the blanks? That was the approach taken recently by a team of scientists from the University of Illinois and the University of Chicago to tackle a target at the top of the list for ion channel researchers: the potassium channel voltage sensor.

“A potassium channel is a switch that opens and lets ions flow,” said Benoît Roux, professor of biochemistry and molecular biophysics at the University of Chicago and an author of the paper. “And that voltage dependence switch is necessary to understand how the nerve impulse works.”

Think of the ion channel as a garage door, and the voltage sensor as the control box. The channel only opens at a particular voltage, so it needs a way of both detecting voltage changes and powering the transition from closed to open states. It does so with the voltage sensor, a group of positively-charged amino-acids that can be pushed a small distance inward or outward by changes in voltage.

Scientists have a fuzzy idea of how that voltage sensor works from electrophysiological experiments, but the fine points of the mechanism are still unclear. As with any unknown territory in science, competing theories with colorful names like the paddle model, the helical-screw model and the transporter model attempt to fill the void. But Roux and his colleagues decided to test the movement of the voltage sensor with a complex computer simulation of one particular potassium channel, called Kv1.2, found in the heart and brain.

“This is not something you can do on a desktop computer,” Roux said. “Other people have had access to big computers, but it’s the strategy to compute that quantity that has never been done. This shows that it’s possible to address this kind of question at the most quantitative level with an atomistic model, and that has never been shown before.”

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In the first part of his “The Genome at 10″ series on Sunday, Nicholas Wade of the New York Times wrote about frustration in the wake of the Human Genome Project. Despite optimistic promises at its unveiling in 2000, scientists haven’t found as many of the answers to disease in DNA as was initially hoped. Instead, our knowledge of the genome has created even more questions and complexity in the search for the genetic sources of disease.

As a result, more and more attention has been paid in recent years to epigenetics, the non-genetic control of gene expression. Through processes such as DNA methylation and histone acetylation, biology has developed ways of controlling the volume of protein production - silencing or activating a particular gene when its protein is needed.

“Picture the reading of DNA (gene transcription) as the opening of a zipper,” described Stephen Archer, chair of cardiology at the University of Chicago Medical Center. “Transcription factors must run along this DNA zipper to allow the DNA to open so the gene can be read. Methylation blocks this reading, much like having a thread stuck in the zipper prevents its opening. This way, methylation silences a perfectly normal gene.”

For a disease such as pulmonary arterial hypertension (PAH), which Archer studies, the search for a straight genetic cause has been unsatisfactory. PAH is marked by blockage of blood vessels to the lungs, and is known to run in families. 10 years ago, when a PAH-linked genetic mutation was found in a gene called BMPR2, researchers hoped that aberrant genetics were to blame for the disease. But at most, only a quarter of people with that mutation developed PAH, and not all people with PAH carried that mutation, Archer said. That led PAH researchers  to look elsewhere for answers, including at a mitochondrial protein called superoxide dismutase 2 (SOD2), which is known to be lower in PAH patients.

But when researchers looked at the SOD2 gene in people with PAH, they found no mutation. That suggested epigenetics may be to blame, Archer said.

“The question was why is SOD2 downregulated?,” Archer said. “So we began looking at the possibility it might be present but functionally inhibited.”

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For the next month, the world’s attention (and mine) will be focused on South Africa for the 2010 World Cup. Though it’s just starting to break through the public consciousness in the States, the World Cup is such a massive cultural force in the rest of the world that its tremors are felt even in scientific circles. A recent psychology study on how to take the best penalty kick got a lot of media play this week, and at least two different economists developed models to predict the winner via a country’s GDP and other factors (both picked Brazil).

I jumped into PubMed to see what other World Cup-related research could be found, and it turned out the water there was very deep. Since the last World Cup in 1996, dozens of scientific and medical articles have been published, ranging from editorials advising fans about potential diseases they need to be immunized against in South Africa to surveys of injuries suffered by referees during the tournament. But one topic appeared to drive much of the World Cup-related scientific debate, and it explains just how seriously the competition is taken around the world: does watching important World Cup games cause heart attacks?

The controversy started with a 2008 New England Journal of Medicine article called “Cardiovascular Events During World Cup Soccer.” A team of German researchers looked at emergency medicine records from June 9 to July 9, 2006, when the last World Cup was taking place in Germany, and compared the period to two control months free from international tournaments. According to the authors, “six of the seven games in which the German team participated were associated with an increase in the number of cardiac emergencies,” averaging out to a 2.5-fold increase in heart attacks. People with a history of coronary artery disease had an even higher health risk of watching their countrymen on the pitch: a four times increase in events. Blog founding father Jeremy Manier wrote about the study for the Chicago Tribune, and related it to local stress about the Cubs and Bears.

But wait - a counter-attack was sprung this year by an Italian team of researchers, who focused upon their own population during not only the 2006 World Cup, but the 2002 event as well as the 2004 European Championships. Studying more than 25,000 hospital admissions, the authors failed to find any uptick in heart-related events, even when Italy’s national team defeated France in a tense penalty shootout to win the ‘06 Cup (there was, however, at least one Italian with a chest injury that day). The Italian authors claim that their negative results are more in line with previous literature, including an English study that found only a small (but significant) increase in heart attacks and strokes during club soccer matches.

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Last October, a group of Illinois legislators visited the University of Chicago Medical Center for two days of education and discussion about cardiovascular medicine and health care reform, part of a nationwide “Legislator in the Lab” program. In addition to laboratory tours and panel discussions, the legislators and their staffs heard a series of brief, informative lectures on different cardiology topics, from prevention of sudden cardiac death to the use of stem cells for heart tissue regeneration. Many of these lectures were videotaped and posted to the Medical Center’s YouTube channel, and I thought I’d share a couple of them here today.

Dr. Matthew Sorrentino on Risk Factors for  Cardiovascular Disease

Everyone knows a little bit about risk factors for heart disease, such as obesity, age, family history, and tobacco use. But it’s important to remember that these factors don’t exist in isolation - instead, they interact in a way that can dramatically increase a person’s risk for heart attack or stroke. As such, cardiologists keep a scoresheet on their patients, adding up risk factors to determine a patient’s risk for heart attack. Matthew Sorrentino, professor of medicine in the section of cardiology, breaks down how doctors use these risk assessments, and how they can guide interventions that offer fast, powerful risk reduction.

Dr. Rupa Mehta on Heart Disease in Women

The undisputed leaders in the arena of women’s health awareness are breast cancer organizations, which routinely organize charity walks and fundraisers that draw thousands of participants and light city buildings pink. But as Rupa Mehta, assistant professor of medicine in the section of cardiology, reminded the audience in her talk, breast cancer and other diseases trail far behind cardiovascular disease as a killer of women. 460,000 women in the United States die from heart disease each year, which breaks down to about one death a minute. Mehta talks about the challenges that face physicians and patients in recognizing and treating heart disease in women, including watching out for the different set of symptoms - including fatigue, sleep disturbances, and shortness of breath - that signal an oncoming heart attack in females.

Venomous animals such as snakes, scorpions and spiders are typically the stuff of phobias for most people. But the toxins those creatures have developed to immobilize and kill their prey are actually some of nature’s most finely-tuned weapons, sharpened by millions of years of evolution to hit a particular molecular target. For Zoltan Takacs, an Assistant Professor at the University of Chicago Medical Center, it’s those qualities that have made snakes and venom a life-long source of fascination, not fear. From expeditions around the world to catch and collect tissue from venomous animals to laboratory experiments that seek to unlock the potential of those toxins for research and clinical use, Takacs has turned a childhood love of creepy-crawlies into a career.

Acknowledging Takacs’ unique existence as half-scientist/half-adventurer, National Geographic today announced him as one of their 2010 Emerging Explorers. With 13 other award recipients, Takacs earns $10,000 to put toward expeditions that have already taken him to over 130 countries in pursuit of venomous species. Takacs brings tissue from those animals back to Chicago for further study, looking to repurpose the venomous tricks of nature into highly-selective ligands that could have therapeutic value.

“It’s a straight connection between rain forest and lab bench,” Takacs said last week, from a snake-free conference room in Hyde Park. “Nature is not limited to the African savannah with elephants and lions. There is also the underlying molecular biodiversity, and if that’s erased then we lose the potential for new drugs.”

That potential is vast: Takacs estimated that 10 to 20 million different toxins exist in nature. Only 10,000 or so of those toxins have been discovered, and of those only 500 have been thoroughly studied. But from the small supply of well-characterized toxins, at least 12 drugs have already been derived and are currently in use for treating blood pressure, heart failure, heart attacks, and diabetes.

“If you face a heart attack in the United States and go to the emergency room, there are three drugs for emergency treatment and two of them are derived from snake venom,” Takacs said. “These are truly lifesaving drugs.”

Finding more drugs means cataloging more toxins, so Takacs teamed up with biophysicist Steve Goldstein, Professor of Pediatrics and an expert on ion channels, to create libraries of toxins based on templates obtained from nature. A recently published example from Takacs’ research is a vivid demonstration of how those toxins can be reshuffled by scientists to create new compounds even more specific - and potentially useful in the lab and clinic - than their natural counterparts.

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Last month, we told you about a new cardiac defibrillator device that was implanted for the first time in the United States here at the University of Chicago Medical Center. That procedure - performed by Martin Burke, professor of cardiology, on 38-year-old mother of four Brooke Bergeron - was also the first of a global clinical trial that hopes to test the subcutaneous implantable cardioverter-defibrillator (S-ICD) in more than 300 people. But a new medical device doesn’t just jump straight to the world-testing stage; the current trial was built on the foundation of several smaller trials that worked out the kinks of the device and proved its effectiveness in smaller pools of patients.

The data from those trials were published this week in the New England Journal of Medicine, and portray an instructive case study in how a new device is developed and tested without endangering the patient. In trials conducted in New Zealand and Europe over the last 10 years, different configurations of the device were compared, software was refined, and a slow, careful roll-out of the S-ICD in more and more patients was achieved. With a majority of successes along the way, the researchers set the stage for the wider testing of the device currently in progress while exciting many in the field of cardiology.

“This could be a game changer, if indeed this is the direction this technology goes,” Richard Page, president of the Heart Rhythm Society, told Bloomberg News.

Interestingly, the first step was an engineering challenge - figuring out the best configuration for the device’s leads, which both sense the heart’s rhythms and deliver the shock if necessary. The classic implantable defibrillators have an advantage in this respect, since the leads are actually placed inside the heart. But with subcutaneous leads placed under the skin near the sternum, the same task can be accomplished from farther away with a stronger, but still safe, shock. All the same, the device’s designers wanted to minimize the amount of electricity required to reset the heart’s rhythm, and thus tested four different configurations (pictured above) to find the one that performs its function with the least firepower.

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There’s no such thing as a perfect drug. Physicians know that for every treatment benefit a drug provides, there will also be side effects that must be taken into consideration. Ideally, these side effects can be controlled with careful dosing of the drug or close monitoring of the patient, such that the drug’s good side can be maximized while its potential toxic effects are minimized. But because every individual patient will respond to a given drug in a different way, that balance is easier said than done.

As such, the guidelines for dealing with common side effects of a particular drug aren’t always obvious, especially when the drug in question is new or its side effect is atypical. That was the case recently with a class of drugs called angiogenesis inhibitors, the first of which was approved in 2004 for cancer treatment. Angiogenesis inhibitors, such as bevacizumab and sorafenib, were developed to be more tolerable cancer drugs than the classic chemotherapy agents known for having several difficult side effects. But these drugs - which act by blocking the growth of new blood vessels around a tumor - presented with a potentially dangerous side effect of their own: hypertension. Studies found that anywhere from a quarter to 72 percent of patients given one of the these angiogenesis inhibitor drugs experienced elevated blood pressure, with the effect occasionally severe enough that the drug had to be stopped.

But as a cancer-fighter, these drugs have been very successful. So a panel, including two University of Chicago Medical Center physician-researchers, was convened by the National Cancer Institute to come up with recommendations for physicians eager to use angiogenesis inhibitors in cancer patients but concerned about the potential for hypertension. Led by Michael Maitland, assistant professor of medicine, and George Bakris, professor of medicine, the 13-member panel released their findings this month in the Journal of the National Cancer Institute. The purpose, the researchers said, was to reassure physicians that a promising new drug class can be safely used if certain precautions are taken.

“If carefully managed, I think these drugs are a huge move forward in our armory against cancer,” said Bakris, who directs the Medical Center Hypertensive Diseases Unit.

That a cardiologist such as Bakris was involved in a discussion of how to best use a cancer drug reflects the broad approach taken by the panel. Cancer drugs are most often prescribed by - you guessed it - cancer specialists, for whom hypertension is generally not a primary concern. By bringing oncologists and cardologists to the table together, Maitland said that the panel was able to come up with guidelines that satisfied both specialties and made sure the patient was being treated for both diseases. As a result, physicians can feel more comfortable treating treating patients with angiogenesis inhibitors even if they have a history of hypertension, or are at elevated risk for high blood pressure due to age, family history or diet.

“Often the case is those patients aren’t seeking medical attention for hypertension until they find that they have a tumor and need treatment for cancer,” Maitland said. “If a patient is hypertensive, a physician should not dismiss that as irrelevant just because they have advanced cancer. We already know that ignoring co-morbidities in a cancer patient can generate as much risk for their long term survival as the stage of the cancer.”

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Climate Scientists to Politicians: Enough Already

A pretty remarkable letter was published in the journal Science this week, signed by 250 members (including4 University of Chicago scientists) of the National Academy of Sciences and calling for “an end to McCarthy-like threats” surrounding climate change. The letter makes a stand for reason on both climate change specifically and science in general, arguing that the scientific process of constantly questioning and improving the knowledge of a particular subject should not be misinterpreted as flaws.

When someone says that society should wait until scientists are absolutely certain before taking any action, it is the same as saying society should never take action. For a problem as potentially catastrophic as climate change, taking no action poses a dangerous risk for our planet.

The letter comes on the heels of Oklahoma Sen. James Inhofe suggesting in March that U.S. and British scientists should be criminally investigated for their role in the “ClimateGate” hacked e-mails incident. Michael Mann, the Penn State climatologist who created the famous hockey stick graph showing the recent rise in global temperatures, was cleared by his university of any misconduct charges, but was targeted this week by Virginia Attorney General Ken Cuccinelli. Such efforts are political grandstanding at its most despicable, and seriously endanger the ability of scientists to conduct research in an open and unpolitical forum. Great coverage, as always, by Andrew Revkin at Dot Earth.

2010 BIO Coverage Roundup

To wrap up BIO week, I thought I’d cast a net for some of the other commentary from this week’s conference in Chicago. Bruce Japsen of the Chicago Tribune saw part of Al Gore’s speech and focused on how the global recession wounded the biotechnology industry. Tuesday’s keynote session with George W. Bush and Bill Clinton was controversially closed to the media, but Forbes ran a perspective on the event from a conference attendee. Industry magazine Fierce Biotech and the San Diego Biotechnology Network were also grinding out gavel-to-gavel coverage alongside our own.

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Typically, when a clinical trial is stopped early, it’s bad news. The drug being tested may show unexpected side effects too harmful to continue, the trial may fall short of its patient recruitment goals, or the early results may reveal too marginal a benefit to make the study worth the cost and time. But good news can also bring a clinical trial to a premature halt. One recent example is the ACCOMPLISH trial - a study of combination drug therapies for hypertension that was called short after three years basically for being too successful.

The lengthy acronym ACCOMPLISH stands for Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension. In short, the trial was designed to find the best two-drug combination for people with high blood pressure to reduce the frequency of strokes and heart attacks in such patients. The trial compared a previously-established combination of a diuretic and a drug called an ACE inhibitor to a new combination: ACE inhibitor plus calcium-channel blocker. Both two-drug combos were effective at reducing patients blood pressure, but the new combination (benazepril + amlodipine) won out on reducing cardiovascular events, decreasing the numbers of deaths, hospital visits and other serious incidents by 20 percent.

That result was so promising that the study’s data safety monitoring board - an independent panel of scientists who act as a kind of clinical trial lifeguard team - brought the study to its early end. In essence, the results were so positive for the new treatment combination that it would be unethical to continue treating patients with the older combination. Those positive results, announced in 2008 and published in the New England Journal of Medicine, established a new standard treatment for hypertensive patients.

But hypertension was only one of the targets that the ACCOMPLISH trial was designed to study. High blood pressure doesn’t always appear in isolation, sometimes it is accompanied by other diseases as bad or worse for the patient. Because of the trial’s very large size - over 11,000 patients - it was possible to break out some subgroups that had both hypertension and another disease to test the two drug combinations in their effect on that secondary condition.

In comes George Bakris, a professor of medicine and director of the hypertensive diseases unit at the University of Chicago Medical Center. Bakris, an expert in kidney disease, was one of the researchers who designed the ACCOMPLISH trial - and just as importantly, helped seek out the funding (which eventually came from the drug company Novartis) to make it possible. As such, Bakris was able to incorporate a sub-trial within the larger study to look at the effect of these drug combinations on chronic kidney disease, which affects more than 15 percent of Americans.

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Implantable pacemakers and defibrillators have been a staple of cardiology for decades. Offering round-the-clock protection against heart attacks and other issues, it’s not hyperbole to say that the devices have been a lifesaver for hundreds of thousands of people. But the majority of these implantable devices are still placed predominantly in older patients with heart conditions, with the average age of recipients consistently in the high 60’s in clinical trials. Because of the finite lifetime of an internal cardoverter defibrillator (ICD) or pacemaker and the difficulties associated with removing or replacing those devices, many doctors prefer to avoid those options in younger patients.

“That’s crazy,” said Martin Burke, director of the heart rhythm center at the University of Chicago Medical Center. “You have more to gain from a defibrillator if it saves your life when you’re 50 rather than when you’re 80.”

But some of the concerns over implantable defibrillators are legit. Classic ICDs and pacemakers require the electrical leads that deliver the shock to be placed inside the heart, where any infection can be a serious complication. The sensory system that tells the defibrillator to fire sometimes overreacts to benign changes in heart rhythm, causing unnecessary shocks. Flexible materials must also be used due to the hostile environment inside the heart - “It’s a 98.6 degree, dynamic environment that pumps like a piston 60 to 100 times a minute; it’s a miracle they last 15-20 years in my mind,” said Burke, who is a specialist at removing ICDs as well as implanting them.

So Burke has been part of a lengthy effort to improve the technology of ICDs, with a new device - the subcutaneous-ICD, or S-ICD - that finally reached the clinical trial stage this year. Last month, Burke performed the first S-ICD implantation in the United States upon 38-year-old Brooke Bergeron, who suffered a heart attack last year while giving birth to her fourth child.

The subcutaneous ICD changes the location of the leads from inside the heart to just beneath the skin over the sternum. If an infection should occur in that location, it would be less dangerous, and removing the leads would be a less difficult process. While the added distance from the heart means a more powerful shock is delivered by the S-ICD (about 2.5 times stronger than traditional ICDs), the power is still well within a safe range, Burke said. And patients should experience fewer of those shocks, thanks to an improved monitor system that measures more complex heart rhythm characteristics to separate out dangerous cardiac events from false positives.

“We’ve been shocking people like this for 40 years, that’s no different. The big change is the position of the electrodes under the skin and the sensor,” Burke said. read more

If asked to define women’s health, what would you say? If you answered obstetrics/gynecology, you’d only be partially right. Sure, you’re not going to find too many male patients in an Ob/Gyn clinic, but the effect of sex upon health is not restricted to the reproductive organs.

“Every cell has a sex,” said Paula Johnson, chief of the Division of Women’s Health at Brigham and Women’s Hospital in her talk at the University of Chicago Medical Center this week. “There are sex differences influencing disease and we are only at the very tip of the iceberg of understanding the extent of those differences.”

Johnson spoke to the Department of Medicine Grand Rounds Tuesday about the growing field of women’s health and how it can be better integrated into academic medical centers. Trained as a cardiologist, Johnson used predominantly examples from her own discipline, where female deaths due to cardiovascular disease have outnumbered male deaths for the last 25 years. But her message applied to nearly any branch of medicine and science, as research shows again and again that the same diseases can often differ in many significant respects between men and women.

However, much of that research was only recently done, Johnson said, pointing out that it wasn’t until 1993 that the National Institutes of Health formally required clinical trials to include women among the subject pool. Even with that requirement, only a minority of studies break down trial results by sex to reveal whether there are differences in how men and women respond to a new drug treatment or therapy.

Such omissions are looking increasingly ridiculous as more physiological differences between men and women are found. Returning to the example of heart disease, Johnson acknowledged that some of the difference between cardiac deaths in men and women can be attributed to the longer lifespan of females. But women are more likely to die of previously-undetected heart disease than men, suggesting that the course of the disease - and, potentially, its origins - are different in the female population. One study even found that the most common mechanism of arterial blockage differs between sexes, with plaque rupture seen traditionally in men and older women while younger women present with plaque erosion. The difference may sound subtle to the layperson, but it could mean that heart disease in younger women might be overlooked by diagnostic tests, Johnson said.

“The end result is myocardial infarction and you would not be able to tell the difference,” Johnson said. “What we don’t understand is why [plaque erosion] is more common in women, whether there are differences in biology of what incites either of these, and if potentially there are, do those differences have implications for treatment or prevention.”

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