From Uncharted Region of Human Genome, Clues Emerge About Origins of Coronary Artery Disease

Scientists from the U.S. Department of Energy's Lawrence Berkeley National Laboratory have learned how an interval of DNA in an unexplored region of the human genome increases the risk for coronary artery disease, the leading cause of death worldwide.
Their research paints a fuller picture of a genetic risk for the disease that was discovered only three years ago and which lurks in one out of two people.
It also reinforces the tantalizing possibility that many more disease risks -- and potential therapies -- are hidden in the vast and uncharted part of the genome that doesn't contain instructions for making proteins.
The research is reported in the February 21 advance online publication of the journal Nature.
The team focused on an interval of DNA in chromosome 9p21. People who carry variations of this interval have an increased chance of developing coronary artery disease, which is an accumulation of plaque in coronary arteries that restricts blood flow to the heart and causes heart attacks.
Determining how this DNA contributes to the disease is difficult because it's in the poorly understood part of the genome that doesn't code for proteins, the workhorses of cellular function.
In groundbreaking research, the Berkeley Lab scientists found that the DNA interval regulates a pair of genes that inhibit cell division, and that bad copies of the interval reduce the genes' expression. Although more work is needed to understand how this mechanism contributes to coronary artery disease, the researchers speculate that the hobbled genes allow vascular cells to proliferate unchecked and narrow coronary arteries.
"We show that this non-coding interval affects the expression of two cell cycle inhibitor genes located almost 100,000 base pairs away. We believe that something goes awry in variants of this interval, causing vascular cells to divide and multiply more quickly than usual," says Len Pennacchio, a geneticist with Berkeley Lab's Genomics Division who conducted the research with Axel Visel and several other scientists from Berkeley Lab, as well as Jonathan Cohen of the University of Texas Southwestern Medical Center.
The link between an interval of DNA in chromosome 9p21 and a risk for coronary artery disease was established in several recent studies, one of which was published in the journal Science in 2007. In that study, led by Cohen and co-authored by several scientists including Pennacchio, the researchers scoured the human genome for differences in people who have coronary artery disease versus people who don't.
This genome-wide association analysis alighted on a stretch of DNA in chromosome 9p21 that spans 58,000 base pairs of DNA. The study found that people with bad copies of this interval have a moderately higher risk of developing coronary artery disease. In addition, 50 percent of people have one bad copy and 25 percent have two bad copies.
"The risk of coronary artery disease isn't very high in any give person with bad copies. But they are so common that population-wide the effect is significant," says Pennacchio.
Remarkably, the study also found that the DNA interval isn't associated with known risks for coronary artery disease such as diabetes, high blood pressure, and high cholesterol level. An unknown mechanism was at work.
"We landed on this risk interval and immediately said 'wow!' why doesn't it link to problems that we know cause coronary artery disease?" says Pennacchio. "So the big question became: what is this DNA doing?"
Adding to the mystery, the DNA interval is among the 98 percent of our genome that doesn't code for proteins. Most efforts to determine the function of the genome have focused on the two percent of our DNA that overlaps protein-coding genes. Scientists are just now beginning to explore the non-coding region, once referred to as "junk DNA."
As part of this effort, the Berkeley Lab scientists set out to determine the function of the DNA interval in chromosome 9p21 that's linked to coronary artery disease. They removed an analogous section of DNA from mice, then tracked what happened.
The expression level of two genes located far away, Cdkn2a and Cdkn2b, plummeted by about 90 percent in the "knock-out" mice compared to normal mice. These genes are important in controlling cell cycles and have been linked to cancer when mutated, but they had never been linked to coronary artery disease.
The scientists also studied heart tissue of the "knock-out" mice and found that the smooth muscle cells from their aortas had increased proliferation, a hallmark of coronary artery disease.
"Our research shows that the DNA interval plays a pivotal role in regulating the expression of two genes that control cell cycles. It also suggests that variants of the interval spur the progression of coronary artery disease by altering the dynamics of vascular cells," says Pennacchio.
With this mechanism identified, scientists can develop therapies that fight coronary artery disease by targeting the two genes and jumpstarting them into action, says Pennacchio. He also believes that the genetic roots of many other diseases will be unearthed as scientists learn how to decipher the function of non-coding DNA.
"Non-coding DNA is a huge area of the genome, waiting to be explored, which could have huge dividends for understanding and treating disease," says Pennacchio.

Smoking Bans Reduce Risk Of Heart Attacks Associated With Secondhand Smoke

Smoking bans are effective at reducing the risk of heart attacks and heart disease associated with exposure to secondhand smoke, says a new report from the Institute of Medicine. The report also confirms there is sufficient evidence that breathing secondhand smoke boosts nonsmokers' risk for heart problems, adding that indirect evidence indicating that even relatively brief exposures could lead to a heart attack is compelling."It's clear that smoking bans work," said Lynn Goldman, professor of environmental health sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, and chair of the committee of experts that wrote the report. "Bans reduce the risks of heart attack in nonsmokers as well as smokers. Further research could explain in greater detail how great the effect is for each of these groups and how secondhand smoke produces its toxic effects. However, there is no question that smoking bans have a positive health effect."

About 43 percent of nonsmoking children and 37 percent of nonsmoking adults are exposed to secondhand smoke in the United States, according to public health data. Despite significant reductions in the percentages of Americans breathing environmental tobacco smoke over the past several years, roughly 126 million nonsmokers were still being exposed in 2000.

A 2006 report from the U.S. Surgeon General's office, The Health Consequences of Involuntary Exposure to Tobacco Smoke, concluded that exposure to secondhand smoke causes heart disease and indicated that smoke-free policies are the most economical and effective way to reduce exposure. However, the effectiveness of smoking bans in reducing heart problems has continued to be a source of debate.

The IOM committee conducted a comprehensive review of published and unpublished data and testimony on the relationship between secondhand smoke and short-term and long-term heart problems. Eleven key studies that evaluated the effects of smoking bans on heart attack rates informed the committee's conclusions about the positive effects of smoke-free policies. The studies calculated that reductions in the incidence of heart attacks range from 6 percent to 47 percent. Given the variations in how the studies were conducted and what they measured, the committee could not determine more precisely how great the effect is. Only two of the studies distinguished between reductions in heart attacks suffered by smokers versus nonsmokers. However, the repeated finding of decreased heart attack rates overall after bans were implemented conclusively demonstrates that smoke-free policies help protect people from the cardiovascular effects of tobacco smoke, the committee said.

The report also provides a detailed discussion of the evidence from animal research and epidemiological studies showing a cause-and-effect relationship between secondhand smoke exposure and heart problems. The committee was not able to determine the exact magnitude of the increased risk presented by breathing environmental tobacco smoke, but noted that studies consistently indicate it increases the risks by 25 percent to 30 percent. Although there is no direct evidence that a relatively brief exposure to secondhand smoke could precipitate a heart attack, the committee found the indirect evidence compelling. Data on particulate matter in smoke from other pollution sources suggest that a relatively brief exposure to such substances can initiate a heart attack, and particulate matter is a major component of secondhand smoke.

The report was sponsored by the U.S. Centers for Disease Control and Prevention. Established in 1970 under the charter of the National Academy of Sciences, the Institute of Medicine provides independent, objective, evidence-based advice to policymakers, health professionals, the private sector, and the public. The National Academy of Sciences, National Academy of Engineering, Institute of Medicine, and National Research Council make up the National Academies.

Police Work Undermines Cardiovascular Health, Comparison To General Population Shows

It is well documented that police officers have a higher risk of developing heart disease: The question is why.In the most recent results coming out of one of the few long-term studies being conducted within this tightly knit society, University at Buffalo researchers have determined that underlying the higher incidence of subclinical atherosclerosis -- arterial thickening that precedes a heart attack or stroke -- may be the stress of police work.

"We took lifestyle factors that generally are associated with atherosclerosis, such as exercise, smoking, diet, etc., into account in our comparison between citizens and the police officers," said John Violanti, Ph.D., UB associate professor of social and preventive medicine, who has been studying the police force in Buffalo, N.Y., for 10 years.

"These lifestyle factors were statistically controlled for in the analysis. This led to the conclusion that it is not the 'usual' heart-disease-related risk factors that increase the risk in police officers. It is something else. We believe that 'something else' is the occupation of policing."

Results of the study appear in the June issue of the Journal of Occupational and Environmental Medicine.

Violanti and colleagues have been studying the role of cortisol, known as the "stress hormone," in these police officers to determine if stress is associated with physiological risk factors that can lead to serious health problems such as diabetes and cardiovascular disease.

In a study accepted for publication in Psychiatry Research that looked at the male-female differences in stress and signs of heart disease, Violanti found that female police officers had higher levels of cortisol when they awoke, and the levels remained high throughout the day. Cortisol normally is highest in the morning and decreases to its lowest point in the evening. The constantly high cortisol levels were associated with less arterial elasticity, a risk factor for heart disease, Violanti noted.

"When cortisol becomes dysregulated due to chronic stress, it opens a person to disease," he said. "The body becomes physiologically unbalanced, organs are attacked and the immune system is compromised as well. It's unfortunate, but that's what stress does to us."

In the current study, the researchers used carotid artery thickness to assess heart disease risk. Participants were 322 clinically healthy active-duty police officers from the Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) study and 318 healthy persons from the ongoing UB Western New York Health Study matched to the officers by age.

All measurements were taken in the morning after a 12-hour fast. In addition to testing carotid thickness via ultrasound, investigators measured blood pressure, body size, cholesterol (both total and HDL) and glucose. They collected information on physical activity, symptoms of depression, alcohol consumption and smoking history. These are the factors that typically cause heart disease.

Results showed that police work was associated with increased subclinical cardiovascular disease -- there was more plaque build-up in the carotid artery -- compared to the general population that could not be explained by those conventional heart disease risk factors.

Subclinical atherosclerosis means that the disease shows progression but does not qualify yet as overt heart disease.

"In this case we examined the thickness of the carotid artery as an indicator of increasing risk for atherosclerosis," noted Violanti. "The plaque buildup was greater in police than the citizen population.

"In future work, we will measure the carotid artery thickness again to see how much it has increased. At some point in time, the thickness may reach a stage of possible blockage, which will require medical intervention and treatment. We think that police officers will likely reach that stage quicker than the general population."

P. Nedra Joseph, Ph.D., a former postdoctoral researcher at UB, now at the Centers for Disease Control and Prevention (CDC), is first author on the study. Additional contributors to the study were: from UB -- Richard Donahue, Ph.D., and Joan Dorn, Ph.D., from the UB School of Public Health and Health Professions; Michael E. Andrew, Ph.D., and Cecil M. Burchfiel, from the CDC; and Maurizio Trevisan, M.D., formerly of UB, now head of the University of Nevada Health Sciences System.

The BCOPS study is funded by the National Institute for Occupational Safety and Health.

Red Wine Compound Resveratrol Demonstrates Significant Health Benefits

The benefits of alcohol are all about moderation. Low to moderate drinking – especially of red wine – appears to reduce all causes of mortality, while too much drinking causes multiple organ damage. A mini-review of recent findings on red wine's polyphenols, particularly one called resveratrol, will be published in the September issue of Alcoholism: Clinical & Experimental Research; the review is also available at Early View.Reports on the benefits of red wine are almost two centuries old," said Lindsay Brown, associate professor in the School of Biomedical Sciences at The University of Queensland and corresponding author for the study. "The media developed the more recent story of the French paradox in the early 1990s. However, studies on the actions of resveratrol, one of the active non-alcoholic ingredients, were uncommon until research around 1997 showed prevention of cancers. This led to a dramatic interest in this compound."

Red wine contains a complex mixture of bioactive compounds, including flavonols, monomeric and polymeric flavan-3-ols, highly colored anthocyanins, as well as phenolic acids and the stilbene polyphenol, resveratrol. Brown said that some of these compounds, particularly resveratrol, appear to have health benefits.

"The breadth of benefits is remarkable – cancer prevention, protection of the heart and brain from damage, reducing age-related diseases such as inflammation, reversing diabetes and obesity, and many more," said Brown. "It has long been a question as to how such a simple compound could have these effects but now the puzzle is becoming clearer with the discovery of the pathways, especially the sirtuins, a family of enzymes that regulate the production of cellular components by the nucleus. 'Is resveratrol the only compound with these properties?' This would seem unlikely, with similar effects reported for other components of wine and for other natural products such as curcumin. However, we know much more about resveratrol relative to these other compounds."

Stephen Taylor, professor of pharmacology at the University of Queensland, agreed that resveratrol is the "compound du jour."

"I think that red wine has both some mystique and some historical symbolism in the west," said Taylor, "and of course, some various pleasures attached to its ingestion, all of which give it a psychological advantage edge, food-wise. Not many of us can or will eat a couple of cups of blueberries a day for years on end, but if we could do a population study for a decade or so on such a group, you might actually see similar results."

Key points of the review include:

* Resveratrol exhibits therapeutic potential for cancer chemoprevention as well as cardioprotection.

"It sounds contradictory that a single compound can benefit the heart by preventing damage to cells, yet prevent cancer by causing cell death, said Brown. "The most likely explanation for this, still to be rigorously proved in many organs, is that low concentrations activate survival mechanisms of cells while high concentrations turn on the in-built death signals in these cells."

* Resveratrol may aid in the prevention of age-related disorders, such as neurodegenerative diseases, inflammation, diabetes, and cardiovascular disease.

"The simplest explanation is that resveratrol turns on the cell's own survival pathways, preventing damage to individual cells," said Brown. "Further mechanisms help, including removing very reactive oxidants in the body and improving blood supply to cells."

* Low doses of resveratrol improve cell survival as a mechanism of cardio- and neuro-protection, while high doses increase cell death.

"The key difference is probably the result of activation of the sirtuins in the nucleus," said Brown. "Low activation reverses age-associated changes, while high activation increases the process of apoptosis or programmed cell death to remove cellular debris. Similar changes are seen with low-dose versus high-dose resveratrol: low-dose resveratrol produces cellular protection and reduces damage, while high-dose resveratrol prevents cancers."

In summary, noted Brown, current scientific research is starting to explain reports from the last 200 years that drinking red wine improves health. "It is a cliché that 'nature is a treasure trove of compounds,' but studies with resveratrol show that this is correct! We need to understand better the vast array of compounds that exist in nature, and determine their potential benefits to health."

"There is one particular point that deserves fleshing out," added Taylor. "Resveratrol is largely inactivated by the gut or liver before it reaches the blood stream, where it exerts its effects – whatever they may be – good, bad, or indifferent. Thus, most of the reseveratrol in imbibed red wine does not reach the circulation. Interestingly, absorption via the mucous membanes in the mouth can result in up to around 100 times the blood levels, if done slowly rather than simply gulping it down. Of course, we don't know if these things matter yet, but issues like this are real and generally ignored by all."

BPA Found In Many Plastics May Cause Heart Disease In Women

New research by a team of scientists at the University of Cincinnati (UC) shows that bisphenol A (BPA) may be harmful for the heart, particularly in women.Results of several studies are being presented in Washington, D.C., at ENDO 09, the Endocrine Society's annual meeting, June 10-13.

A research team lead by Scott Belcher, PhD, Hong Sheng Wang, PhD, and Jo El Schultz, PhD, in the department of pharmacology and cell biophysics, found that exposure to BPA and/or estrogen causes abnormal activity in hearts of female rats and mice.

In addition, these researchers found that estrogen receptors are responsible for this affect in heart muscle cells.

"There is broad exposure to bisphenol A, despite recognition that BPA can have harmful effects," Belcher says. "We had reason to believe that harmful cardiovascular affects can be added to the list."

BPA, an environmental pollutant with estrogen activity, is used to make hard, clear plastic and is common in many food product containers. It has been linked to neurological defects, diabetes and breast and prostate cancer.

Using live cultures of cells isolated from rat or mouse hearts, researchers briefly exposed the cardiac cells to BPA and/or estrogen. Both compounds caused striking changes in the activity of cardiac muscle cells from females but not males. Additional studies revealed that these cellular changes in activity caused improperly controlled beating in the female heart.

"Low doses of BPA markedly increased the frequency of arrhythmic events," Belcher says. "The effect of BPA on these cardiac arrhythmias was amplified when exposed to estradiol, the major estrogen hormone in humans."

The mechanism underlying this harmful effect was investigated using cellular imaging techniques.

"BPA and/or estrogen rapidly stimulated contraction by altering control of the concentrations of free calcium inside the heart cell but only in heart muscle cells from females, showing that these effects were sex-specific," Belcher says. "BPA's presence increased the frequency of calcium 'sparks' from the sarcoplasmic reticulum—the part of the cardiac muscle that stores and releases calcium ions—indicating spontaneous release or 'leak' that's likely causing the heart arrhythmias and may have other harmful actions, especially following heart attack."

Belcher and colleagues also investigated the nature of the mechanisms that mediated the responses of the cardiac muscle cells to estrogen and BPA.

"Pharmacological studies using selective estrogen receptor drugs and animal models lacking estrogen receptors were used to investigate the role of each estrogen receptor in mediating the rapid sex-specific function effects of E2 and BPA in cells," he says. "Our findings suggest that estrogen has opposing actions in cardiac cells.

"In female cardiac muscle cells, the blocking or genetic removal of estrogen receptor beta completely blocked the contractile effects of BPA and estrogen, while in males, blockade of the effects of estrogen receptor alpha caused the male heart to become more 'female-like' and become responsive to estrogen and BPA.

"These studies have identified new and important potential cardiac risks associated with BPA exposure that may be especially important for women's heart health," he says.

This study was funded by grants from the National Institutes of Health and the UC Center for Environmental Genetics.

Feeling Close To A Friend Increases Progesterone, Boosts Well-being And Reduces Anxiety And Stress

Why does dishing with a girlfriend do wonders for a woman's mood?

A University of Michigan study has identified a likely reason: feeling emotionally close to a friend increases levels of the hormone progesterone, helping to boost well-being and reduce anxiety and stress.

"This study establishes progesterone as a likely part of the neuroendocrine basis of social bonding in humans," said U-M researcher Stephanie Brown, lead author of an article reporting the study findings, published in the current (June 2009) issue of the peer-reviewed journal Hormones and Behavior.

A sex hormone that fluctuates with the menstrual cycle, progesterone is also present in low levels in post-menopausal women and in men. Earlier research has shown that higher levels of progesterone increase the desire to bond with others, but the current study is the first to show that bonding with others increases levels of progesterone. The study also links these increases to a greater willingness to help other people, even at our own expense.

"It's important to find the links between biological mechanisms and human social behavior," said Brown, is a faculty associate at the U-M Institute for Social Research (ISR) and an assistant professor of internal medicine at the U-M Medical School. She is also affiliated with the Ann Arbor Veterans Affairs Hospital. "These links may help us understand why people in close relationships are happier, healthier, and live longer than those who are socially isolated."

Progesterone is much easier to measure than oxytocin, a hormone linked to trust, pair-bonding and maternal responsiveness in humans and other mammals. Oxytocin can only be measured through an invasive spinal tap or through expensive and complex brain imaging methods, such as positron emission tomography scans. Progesterone can be measured through simple saliva samples and may be related to oxytocin.

In the current study, Brown and colleagues examined the link between interpersonal closeness and salivary progesterone in 160 female college students.

At the start of the study, the researchers measured the levels of progesterone and of the stress hormone cortisol in the women's saliva, and obtained information about their menstrual cycles and whether they were using hormonal contraceptives or other hormonally active medications.

To control for daily variations in hormone levels, all the sessions were held between noon and 7 p.m.

The women were randomly assigned to partners and asked to perform either a task designed to elicit feelings of emotional closeness or a task that was emotionally neutral.

In the emotionally neutral task, the women proofread a botany manuscript together.

After completing the 20-minute tasks, the women played a computerized cooperative card game with their partners, and then had their progesterone and cortisol sampled again.

The progesterone levels of women who had engaged in the emotionally neutral tasks tended to decline, while the progesterone levels of women who engaged in the task designed to elicit closeness either remained the same or increased. The participants' cortisol levels did not change in a similar way.

Participants returned a week later, and played the computerized card game with their original partners again. Then researchers measured their progesterone and cortisol. Researchers also examined links between progesterone levels and how likely participants said they would be to risk their life for their partner.

"During the first phase of the study, we found no evidence of a relationship between progesterone and willingness to sacrifice," Brown said. "But a week later, increased progesterone predicted an increased willingness to say you would risk your life to help your partner."

According to Brown, the findings are consistent with a new evolutionary theory of altruism which argues that the hormonal basis of social bonds enables people to suppress self-interest when necessary in order to promote the well-being of another person, as when taking care of children or helping ailing family members or friends.

The results also help explain why social contact has well-documented health benefits---a relationship first identified nearly 20 years ago by U-M sociologist James House.

"Many of the hormones involved in bonding and helping behavior lead to reductions in stress and anxiety in both humans and other animals. Now we see that higher levels of progesterone may be part of the underlying physiological basis for these effects," Brown said.

Stem Cells Transplanted From Marrow Into Heart May Improve Heart's Performance

The Cardiology department and the Area of Cell Therapy of Cordoba hospital Reina Sofia are carrying out clinical tests with patients who have suffered from a severe heart attack. With the implantation of the patient's stem cells, the heart regenerates thus improving its wall motion, that is, its cardiac performance. Indeed for the last four years, the Area of Cell Therapy of Cordoba hospital, led by haematologist Dr. Concha Herrera, has been implementing a therapy program with adult stem cells in patients with heart-related problems. However, this therapy is not a service the hospital offers yet. More specifically, at the end of 2007 the hospital ended a clinical test with patients who had suffered a severe myocardial infarction, that is, an obstruction of one of the main coronary arteries that stops the blood pump to the heart.

The test consisted of treating 30 people split into three groups of ten each at random. The first group was the control group, where patients received standard treatment for acute myocardial infarction; the second group was treated with stem cells directly implanted into the coronary artery affected using a catheterization; the third group was treated with a medicine called G-CSF, which makes cells move from the marrow to the blood, so that they get to the heart in a natural way, without having to do so through a catheter.

At the end of the test, the results revealed that the two groups treated without cells improved slightly, whereas patients transplanted with stem cells through the coronary arteries (vessels which bring the blood to the Herat muscle) did improve their ventricular function much more. This was interpreted as a significant decrease of the cardiac failure symptoms such as pain, fatigue and breathlessness when making small efforts.

Moreover, with this process it is possible to prevent some acute arrhythmias (change or irregularity in the rhythm of the heartbeat), which in many cases could result in the patient's death. ‘However, it does not prevent a future heart attack', Dr. Herrera assures.

In short, the stem cells transplanted from the marrow into the heart muscle have a double function: on the one hand they regenerate the heart cells, the cardiomiocites. In addition to this, they segregate a series of proangiogenic factors that produce blood vessels (angiogenesis) and can also produce the recruitment of stem cells that are in the myocardium itself.

The Are of Cell Therapy, led by Dr. Herrera, is currently developing other trials in the cardiology department, both in patients with acute myocardial infarction (35) and in those with chronic ischemic cardiopathy, due to one or more heart attacks suffered in the past, either months or years ago (20 patients). Moreover, in the last few months a new clinical trial has been started - so far in eight patients- who suffer from a disease called Dilated Myocardiopathy. The origin of this disease is unknown but it causes a very severe cardiac failure which conditions the need for a heart transplant in many cases. So far, ‘the results in these first patients are very satisfactory'.

'We will start shortly a clinical test where we will use stem cells from the marrow in diabetic patients who have the artery taking the blood to the lower limbs blocked. This pathology, called peripheral ischemia, can result in a limb being amputated'.

This work, published in Revista Española de Cardiología journal, has been awarded with a prize by the Sociedad Española de Cardiología.

Molecule Prompts Damaged Heart Cells To Repair Themselves After A Heart Attack

A protein that the heart produces during its early development reactivates the embryonic coronary developmental program and initiates migration of heart cells and blood vessel growth after a heart attack, researchers at UT Southwestern Medical Center have found.The molecule, Thymosin beta-4 (TB4), is expressed by embryos during the heart's development and encourages migration of heart cells. The new findings in mice suggest that introducing TB4 systemically after a heart attack encourages new growth and repair of heart cells. The research findings indicate that the molecule affects developmental gene expression as early as 24 hours after systemic injection. The UT Southwestern study is online and will appear in an upcoming issue of the Journal of Molecular and Cellular Cardiology.

"This molecule has the potential to reprogram cells in the body to get them to do what you want them to do," said Dr. J. Michael DiMaio, associate professor of cardiothoracic surgery at UT Southwestern and senior author of the study. Obviously, the clinical implications of this are enormous because of the potential to reverse damage inflicted on heart cells after a heart attack."

Tremendous medical progress has been made to counter the damaging effects of heart attacks, but ordinarily, mammalian hearts are incapable of repairing themselves following damage. They are also limited in their ability to form new blood vessels. Earlier studies demonstrated that TB4 is expressed in the embryonic heart and stimulates cardiac vessels to form. It was therefore thought that introduction of TB4 might activate new vessel growth in the adult heart.

In this mouse study researchers found that TB4 initiates capillary tube formation of adult coronary endothelial cells in tissue culture. The molecule also encourages cardiac regeneration by inhibiting death in heart cells after an injury such as a heart attack and by stimulating new vessel growth.

"We observed that by injecting this protein systemically, there was increased cardiac function after a heart attack," said Dr. Ildiko Bock-Marquette, assistant professor of cardiothoracic surgery at UT Southwestern and the study's lead author. "We hope this protein can inhibit cell death that occurs during a heart attack in the short term, and that it may initiate new growth of coronary vessels by activating progenitor cells in the long term."

Researchers assessed the effect of TB4 on new vessel growth in adult mice after inducing heart attacks and then following up by introducing TB4 into the animals. An examination of the capillary smooth muscle cells following treatment with TB4 showed a significant increase in capillary density in the heart three days afterward near the site of the heart attack, the scientists reported.

Further studies will examine whether the same events occur in larger mammals and which receptors are responsible for the action of this molecule.

Other UT Southwestern researchers involved in the study were Santwana Shrivastava, research assistant; and John Shelton, senior research scientist. Study authors also included Dr. Teg Pipes, former postdoctoral fellow; Jeffrey Thatcher, a doctoral candidate in biomedical engineering; Dr. Cristi Galindo, postdoctoral research fellow; and co-senior author, Dr. Eric Olson, chairman of molecular biology.

The work was supported by the Ted Nash Long Life Foundation, the American Heart Association, and the National Institutes of Health.

Waist Size Found To Be Predictor Of Heart Failure In Both Men And Women

Adding to the growing evidence that a person's waist size is an important indicator of heart health, a study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found that larger waist circumference is associated with increased risk of heart failure in middle-aged and older populations of men and women.The findings, published online in the April 7 Rapid Access Report of the journal Circulation: Heart Failure, showed that increased waist size was a predictor of heart failure even when measurements of body mass index (BMI) fell within the normal range.

"Currently, 66 percent of adults in the United States are overweight or obese," explains Emily Levitan, ScD, the study's first author and a Research Fellow in the Cardiovascular Epidemiology Research Unit at BIDMC. "Knowing that the prevalence of heart failure increased between 1989 and 1999, we wanted to better understand if and how this increase in obesity was contributing to these rising figures."

A life-threatening condition that develops when the heart can no longer pump enough blood to meet the body's needs, heart failure (also known as congestive heart failure) is usually caused by existing cardiac conditions, including high blood pressure and coronary artery disease. Heart failure is the leading cause of hospitalization among patients 65 and older, and is characterized by such symptoms as fatigue and weakness, difficulty walking, rapid or irregular heartbeat, and persistent cough or wheezing.

The researchers examined two Swedish population-based studies, the Swedish Mammography Cohort (made up of 36,873 women aged 48 to 83) and the Cohort of Swedish Men (43,487 men aged 45 to 79) who responded to questionnaires asking for information about their height, weight and waist circumference. Over a seven-year period between January 1998 and December 2004 the researchers reported 382 first-time heart-failure events among the women (including 357 hospital admissions and 25 deaths) and 718 first-time heart-failure events among men (accounting for 679 hospital admissions and 39 deaths.)

Their analysis found that based on the answers provided by the study participants, 34 percent of the women were overweight and 11 percent were obese, while 46 percent of the men were overweight and 10 percent were obese.

"By any measure – BMI, waist circumference, waist to hip ratio or waist to height ratio –our findings showed that excess body weight was associated with higher rates of heart failure," explains Levitan.

Further breakdown of the numbers showed that among the women with a BMI of 25 (within the normal range), a 10-centimeter higher waist measurement was associated with a 15 percent higher heart failure rate; women with a BMI of 30 had an 18 percent increased heart failure rate. In men with a BMI of 25, a 10-centimeter higher waist circumference was associated with a 16 percent higher heart failure rate; the rate increased to 18 percent when men's BMI increased to 30.

Furthermore, adds Levitan, among the men, each one-unit increase in BMI was associated with a four percent higher heart failure rate, no matter what the man's waist size. In women, she adds, BMI was only associated with increased heart failure rates among the subjects with the largest waists. Finally, the authors found that the association between BMI and heart-failure events declined with age, suggesting that the younger the person, the greater the impact of weight to heart health.

"This study reinforces the importance of maintaining a healthy weight," says Levitan. "Previous research has looked at various types of heart disease and related health issues, and no matter the particulars of the study, they've all been pretty consistent in determining that excess body weight increases a person's risk of heart disease."

Study coauthors include BIDMC investigators Murray A. Mittleman, MD, DrPH (senior author), Amy Z. Yang, BA and Alicja Wok, DrMedSci.

The study was supported by grants from the National Institutes of Health, the Swedish Research Council and the Swedish Foundation for International Cooperation in Research and Higher Education.