Researchers at the McEwen Centre for Regenerative Medicine at Toronto General Hospital have reported discovering what is called the “SOS” distress signal that mobilizes specific heart repair cells from the bone marrow to the injured heart after a heart attack. While it has long been known that bone marrow cells have the ability to clear the dead tissue after a heart attack, what has not been known is the critical role of bone marrow adult stem cells in repairing a damaged heart, restoring its function and enhancing growth of new blood vessels.

“These cells act like generals in a battlefield,” said Shafie Fazel, MD, cardiac surgery resident at TGH, University of Toronto surgeon/scientist program fellow and lead author of the study, “Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines,” in the Journal of Clinical Investigation. “When damaged heart tissue sends out an ‘SOS’ distress signal, this subset of bone marrow cells mobilizes quickly and stimulates the growth of new blood vessels in the heart. This is the first step in repairing the heart and in preventing the vicious downward spiral of heart failure in which the heart progressively thins and dilates, eventually causing death.”

Despite advances in surgical procedures, mechanical assistance devices, drug therapy, and organ transplantation, more than half of patients with congestive heart failure die within five years of initial diagnosis.

“Cardiovascular diseases are the most important cause of mortality in Canada and the western world,” said Dr. Ren-Ke Li, scientist at the McEwen Centre for Regenerative Medicine and professor of cardiovascular surgery at the University of Toronto. “Each year, 70,000 Canadians suffer from a heart attack and many of them are left with crushing disabilities, mainly because the heart muscle is not able to regenerate after a heart attack. This study identifies the method the body employs to repair the heart and provides new therapies to stimulate cardiac regeneration and prevent heart failure in patients who have suffered a heart attack.” The research was performed in Li’s laboratory.

Li’s team used genetically engineered mice in which bone marrow cells were modified to carry a green fluorescent marker allowing researchers to easily track them. The researchers demonstrated that these bone marrow cells are quickly mobilized to the damaged heart region following a heart attack. Once in the damaged area, the cells produce chemicals that trigger the growth of new blood vessels – an important step in repairing the injured heart.

The research also demonstrated that a specific molecule, called c-kit, located on the surface of a subset of bone marrow cells, plays a central role in this mobilization. The molecule c-kit is the “switch” that needs to be turned on by the “SOS” signals sent by the damaged heart. By binding to another molecule called the stem cell factor – much like a lock and key – the “turned on” c-kit activates the bone marrow cells to migrate to the heart to help stimulate new blood vessel growth.

In the study, mice with defective c-kit bone marrow cells could not mobilize these cells to race toward the injured site and regenerate the injured heart. Their heart function was dramatically impaired and, 42 days after a heart attack, their hearts dilated to twice the size of the normal mouse heart. However, the heart function of the c-kit defective mice could be restored to normal by restoring the c-kit cells in their bone marrow, confirming the importance of these cells in repairing the heart. This suggests that a similar treatment of an infusion of bone marrow cells after a heart attack may prevent progression of heart failure in patients who survived a heart attack.

Dr. Richard Weisel, director of the Toronto General Research Institute, professor and chairman of cardiac surgery at the University of Toronto and co-author of the study, said, “Based on the knowledge we gained from this study, we can now design new strategies to enhance normal repair and regeneration for patients who suffered a heart attack. One treatment resulting from this discovery was to inject cells genetically modified to release large amounts of stem cell factor into the region of the heart injured by the heart attack. These cells increased the ‘SOS’ signals from the heart and enhanced the intrinsic regeneration of the heart and restored function nearly to normal.”

Quality measures don’t tell AMI death story

Hospital quality measures do not fully account for the variation in hospital death rates for heart attack patients, according to a study in the July issue of the Journal of the American Medical Association. As part of the national effort to improve hospital quality, the Centers for Medicare & Medicaid Services (CMS; Baltimore) and the Joint Commission on Accreditation of Healthcare Organizations (JCAHO; Oakbrook Terrace, Illinois) monitor and report hospital performance on acute myocardial infarction (AMI) “core” process measures approved by the Hospital Quality Alliance, according to the article.

Although the CMS/JCAHO process measures are considered indicators of quality of AMI care, little is known about how these measures track with each other. And the degree to which process measure performance conveys meaningful information about short-term death rates remains unclear.

Elizabeth Bradley, PhD, of the Yale University School of Medicine (New Haven, Connecticut), and colleagues used data from the National Registry of Myocardial Infarction (NRMI) and CMS claims data to determine the correlations among AMI process measures and the association between hospital performance on process measures and hospital-specific, risk-standardized, 30-day death rates, derived from Medicare claims data. The researchers used 2002-2003 data from 962 hospitals participating in the NRMI and used information on AMI patients aged 66 years or older.

Moderately strong correlations were found between beta-blocker use at admission and discharge, aspirin use at admission and discharge, and angiotensin-converting enzyme (ACE) inhibitor use, and weaker, but statistically significant, correlations between these medication measures and smoking cessation counseling and time to reperfusion therapy measures. Some process measures were significantly correlated with risk-standardized, 30-day death rates but together explained only 6% of hospital-level variation in risk-standardized, 30-day death rates for patients with AMI.

“This finding suggests that a hospital’s short-term mortality rates after AMI cannot be reliably inferred from performance on the publicly reported process measures,” the authors write. “Our results highlight that the current process measures provide information that is complementary to, but not redundant with, a measure of 30-day mortality.

“Although the core measures are important in pursuing improved AMI outcomes, they capture in aggregate only a small proportion of the hospital-level variation in short-term 30-day mortality rates. Until additional process measures are developed that explain more of the variation, reporting not only the current core measures but also short-term risk-standardized mortality rates is a reasonable approach to characterize hospitals’ overall quality of care.”

Ashish Jha, MD, of the Harvard School of Public Health and Brigham and Women’s Hospital (Boston), in an accompanying editorial, wrote: “More information is needed on processes and outcomes across a large number of conditions for hospitals, physician practices, and other health care settings and practitioners. Much of these data are on their way, led by major payers such as Medicare and coalitions of employers who want greater accountability for the care they purchase ... In the most expensive healthcare system in the world, patients and physicians should expect nothing less.”

AHRQ reports on CABG trends

The percentage of patients who underwent coronary artery bypass graft surgery (CABG) in high-volume hospitals fell from 63% in 1997 to 41% in 2003, according to a new report by the Agency for Healthcare Research and Quality (AHRQ; Washington). AHRQ tracked data on 10 surgical procedures because research suggests that patients undergoing certain operations are more likely to have better outcomes when done in hospitals where their type of procedure is performed frequently.

The report found that:

• In 2003, about 45,000 more patients nationwide had CABG in low-volume hospitals compared with 1997.
• The percentage of patients undergoing abdominal aortic aneurysm repair in high-volume hospitals also declined, from 53% to 38%.
• In contrast, the percentage of patients undergoing procedures for cerebral aneurysms in high-volume hospitals increased from 35% to 53%.

The percentages of patients who underwent the seven other procedures in high-volume hospitals tracked by AHRQ did not change significantly between 1997 and 2003. These procedures were carotid endarterectomy; lower extremity arterial bypass; percutaneous transluminal coronary angioplasty (PTCA); heart transplantation; pediatric heart surgery; pancreatic cancer surgery; and esophageal cancer surgery.

ACE inhibitors linked to congenital malformations

Infants born to mothers who took angiotensin-converting enzyme (ACE) inhibitors during the first trimester of pregnancy had an increased risk of major congenital malformations compared with infants whose mothers didn’t take these drugs, according to a new study funded by AHRQ and the FDA. The study, published in the June 8 issue of the New England Journal of Medicine, is considered the first to find an adverse impact of ACE inhibitors on a fetus when taken only during the first trimester of pregnancy.

ACE inhibitors carry an FDA “black box” warning that they can cause injury and even death to the developing fetus when used during the second and third trimesters of pregnancy. The warning states that use of ACE inhibitors should be discontinued as soon as possible when pregnancy is detected. According to data from the National Ambulatory Medical Care Survey, in 1995 there were more than 1.4 million prescriptions for ACE inhibitors written in physicians’ offices for women ages 15 to 44, increasing to more than 2.7 million in 2002 for the same age group.

Carolyn Clancy, MD, director of AHRQ, said, “Clinicians who treat women of childbearing age and pregnant women should be aware of these new findings and consider whether to use other treatment options to control hypertension or kidney damage from diabetes.”

The study was conducted by researchers at the AHRQ-sponsored Vanderbilt University Center for Education and Research on Therapeutics (CERTs; Nashville, Tennessee). Researchers, led by William Cooper, MD, of Vanderbilt Children’s Hospital, examined data gathered from the Tennessee Medicaid program on 29,507 infants born between 1985 and 2000. Of the total population, 209 infants were identified as having been exposed to ACE inhibitors during the first trimester, 202 had comparable exposure to other anti-hypertensive medications, and 29,096 had no maternal use of anti-hypertensive drugs.

The researchers found that major congenital malformations were diagnosed in 856, or 2.9% of infants, and that 203 infants had more than one malformation. Among infants exposed to ACE inhibitors in the first trimester, the proportion born with major congenital malformations was 7.1%, compared with 1.7% among infants exposed to other anti-hypertensive medications. The rate of major congenital malformations in the general population is about 3%.

The chance of a major congenital malformation among infants exposed to ACE inhibitors during the first trimester was 2.71 times higher than in infants whose mothers did not use any hypertension medications. The increased overall risk seen with ACE inhibitors was due primarily to higher risks for cardiovascular and central nervous system malformations, including atrial septal defects, patent ductus arteriosus, hydrocephalus and spina bifida. The risk for all other types of malformations, including those of the musculoskeletal, gastrointestinal and genital systems, was not significantly increased by first-trimester exposure to ACE inhibitors, the researchers found.

“This study raises the important issue of a woman and her physician being aware of potential risks of medications that she might be taking before she becomes pregnant,” Cooper said.

AHRQ said it is sponsoring follow-up studies on the effects of drug exposures during pregnancy.

Older transfused blood increases risk

Older stored blood transfused into patients undergoing repeat heart surgery is associated with a significant increased risk of death, both during a patient’s hospital stay and over the longer term following discharge, according to a new analysis by researchers from Duke University Medical Center (Durham, North Carolina) and Columbia University College of Physicians & Surgeons (New York).

Use of older blood also is associated with an increased risk for kidney problems, acute respiratory distress and longer confinement to intensive care units, the researchers found.

The findings may hold important health implications, but they should be viewed with caution, the researchers said.

“We did find a significant association between older blood and adverse outcomes,” said Elliott Bennett-Guerrero, MD, a Duke anesthesiologist who was the study’s lead investigator. “However, there have been no large, randomized clinical trials conducted to uncover links between age of transfused blood and patient outcomes, so we cannot say for certain that older blood causes the adverse effects we found in our study.”

He added, “Our results show that the number of transfusions given is a robust predictor of long-term mortality, and that the duration of storage also has independent adverse effects as well. We believe our findings provide intriguing avenues for future study.”

The researchers published their findings in the June 22 issue of Anesthesia & Analgesia.

Patients routinely receive transfusions during and after surgery to replace lost blood. Of the 12 million units of blood administered to patients each year in the U.S., more than 2 million units are transfused into heart surgery patients.

National blood banks require that blood can be stored for only 42 days after donation. After that time, unused blood must be discarded.

“Scientists have long known that red blood cells undergo significant changes during their storage, but little had been known about whether or not these changes have any clinical implications for patients,” Bennett-Guerrero said.

Previous studies of lower-risk cardiac surgical patients found a link between age of transfused blood and adverse outcomes, but no risk of increased mortality, he said. “We hypothesized that the effects of storage duration would be more pronounced in patients who are more likely to receive multiple blood transfusions, such as those undergoing a repeat open-heart procedure.”

Lower-risk heart patients use an average of two units of blood, compared to the current study’s high-risk population that received an average of five units of blood. The more units of blood a patient receives increased the probability of receiving an older unit of blood, Bennett-Guerrero said.

The researchers retrospectively analyzed the medical files of 321 patients who underwent a repeat open-heart procedure for coronary artery bypass or valve replacement between 1995 and 2001 and who received donated blood during surgery or recovery.

The study indicated that increasing age of the blood corresponded significantly with an increased risk of death. “In terms of mortality, kidney damage and length of stay in the intensive care unit and hospital, we saw the rate of risk increase with each successive quartile,” Bennett-Guerrero said. Specifically, the in-hospital mortality rate for patients who received the “freshest” blood was about 4%, compared with a 25% rate for patients in the oldest blood group. In terms of kidney damage, the rate increased from about 7% in the freshest blood group to almost 45% in the oldest group.

Patients in the freshest blood group spent an average of 3.5 days in the intensive care unit, compared to about seven days for those in the oldest blood group. In terms of overall hospital stay, patients in the freshest blood group had a 12-day stay, compared to 17 days for the oldest group.