From This Week’s Circulation
Detecting Vulnerable Plaque
Intravascular elastography, the measurement of the elasticity of soft tissue by use of ultrasound, can detect vulnerable plaque with high sensitivity and specificity in the laboratory setting, said researchers from the Netherlands in this week’s issue of the journal Circulation (Circulation. 2003;108:2636–2641OpenUrl).
The researchers, led by Johannes A. Schaar, MD, Thoraxcenter Erasmus MC, in Rotterdam, the Netherlands, used intravascular elastography to investigate coronary artery specimens acquired from patients after death. The arteries were later processed for histological evaluation. Vulnerable plaque was defined histologically as having a thin cap of less than 250 μg, with moderate to great infiltration by macrophages and at least 40% of atheroma. By elastography, vulnerable plaque was plaque with a high-strain region at the surface surrounded by low-strain regions.
In 54 sections of 24 diseased coronary arteries, the researchers found 26 vulnerable plaques and 28 nonvulnerable plaques by histology. Twenty-three of the 26 histologically vulnerable plaques were also considered vulnerable by elastography. Of the 28 nonvulnerable plaques, 25 were detected by elastography. The researchers calculated that intravascular elastography has a positive predictive value of 88% and a negative predictive value of 89% compared with histology.
“There is a need for a technique to diagnose the vulnerability of a plaque,” they wrote. “With the availability of such a technique, a vulnerable plaque can be identified and followed and treatment can be monitored. . . . Intravascular elastography identifies successfully vulnerable plaque features in postmortem coronary arteries. Thus, intravascular elastography may play an important role in diagnosing the vulnerable plaque and help to gain deeper insight in the pathophysiology of acute coronary syndrome and identify the high-risk patient. If unstable angina, plaque progression, and myocardial infarction are to be understood and prevented, vulnerable plaques must be identified and stabilized. Endeavors to prevent acute events are limited by identifying the high-risk plaque. The identification of vulnerable plaques may allow establishing therapies to reduce the risk of cardiac death in the future and opens the door to a preventive strategy for our patients.”
From the 2003 Scientific Sessions of the American Heart Association
From Cell to Heart
ORLANDO, Fla—Fifty years ago, a damaged or ailing heart was a sentence to a slow death. Opening a patient’s chest and replumbing the heart took the courage of pioneering heart surgeons. Developing medications that would change the timing of the heart as well as its biochemistry took intellect and bravura. New devices can change the rhythms of ailing hearts and even shock one back into action. Today, the hope is that primordial cells—those early in differentiation—can be reprogrammed to grow new heart muscle and new blood vessels. Even a decade ago, that would have been a dream. Today, as scientists take their dreams closer to reality, it is happening in the laboratory, in animals, and even in patients, and it was the subject of many sessions of the 2003 Scientific Sessions of the American Heart Association meeting here November 9–12, 2003.
Finding a population of stem cells resident in the heart that can be used to repair its damage has been the objective of Piero Anversa, MD, Professor and Director of the Cardiovascular Research Institute at New York Medical College in Valhalla, for the past 5 years. He and his colleagues believe they may have found such a population, and now their aim is to get those cells to move from normal tissue into that which is damaged.
In rats that had had heart attacks, he and his colleagues used a fluorescent label to identify cardiac stem cells located in the atria and apex of the left ventricle. In a treatment group of animals, Dr Anversa and his colleagues injected the animal with human growth factor and insulin growth factor 1 at increasing doses from the area where the cardiac stem cells are located to the middle of the left ventricle to create a chemical pathway that prompted the stem cells to move to the injured area of the heart. The control group received injections of saline. Studies of the rats showed that hearts functioned better, expressing troponin T. The treated rats had thicker ventricles than the control rats and less fibrosis.
Human bone marrow–derived multipotent stem cells formed both blood vessels and heart muscle when implanted in animal hearts, said Young Sup Yoon, MD, PhD, Assistant Professor of Medicine at Tufts University School of Medicine in Boston. The cells represent a novel population derived from bone marrow, said Dr Yoon.
The researchers implanted the cells into areas of rat hearts that were affected by a heart attack. Bone marrow cells and saline were injected into controls. After 28 days, heart function was better in the animals that received the human bone marrow–derived multipotent stem cells than in the control rats. The transplanted cells had differentiated into both heart muscle and blood vessels.
Two years ago, Bodo E. Strauer, MD, Professor of Medicine at Heinrich Heine University in Düsseldorf, Germany, used a heart catheter to implant autologous bone marrow stem cells into the damaged muscle of a patient who had had a heart attack. Three months later, he and his colleagues found that the size of the infarct had decreased by approximately 30%, accompanied by a concomitant increase in heart functions. Since that time, Dr Strauer and his colleagues have implanted cells in 20 heart attack patients who underwent percutaneous intervention with the implantation of a stent. Twenty patients who did not consent to the experimental procedure were used as controls.
After 3 months, the area of infarct in the patients who received the stem cells had decreased from 33% of the left ventricle’s circumference to 14%. Ejection fractions increased from 55% to 65%.
“We had good long-term results,” said Dr Strauer. “There was no deterioration of function after treating patients with the stem cells, and we saw long-term prevention of the remodeling process. We conclude this may represent a new fundamental outlook for patients with acute myocardial infarction that can be offered to these patients. The outlook is that the therapy is also possible in chronic coronary disease in patients with old infarcts and stable coronary disease.”
In a similar study, researchers from the Texas Heart Institute in Houston and Brazil have injected mononuclear bone marrow cells into the hearts of Brazilian patients with severe ischemic heart failure, said Emerson Perin, MD, Director of Cardiovascular Interventional Technology at the Heart Institute. The injections were performed under guided imaging and a mapping system and were aimed at the area of the heart in which blood flow was blocked. Nine patients in a control group received no treatment.
The amount of muscle tissue not getting enough blood flow in the heart decreased from 15% at baseline to 4.5% at 2 months and 8.8% at 6 months. In the control groups, the percentage was 10% at baseline and increased to 32% at 2 and 6 months.
“Given that this is an initial experience, we were concerned about safety,” said Dr Perin. “There were no significant arrhythmias, which is a significant issue when you inject stem cells into people. We also did not see any evidence of infection or inflammation.”
“The objective findings are encouraging,” he said. “The patients who got the cells decreased the amount of heart tissue lacking blood flow. We can measure this carefully and target the area of hibernating myocardium that can return to normal but is lacking flood flow. Peak oxygen consumption tests that measure the amount of work the heart can do were also increased in patients who received the stem cells.”
“We hope to follow this up with a trial in Houston soon,” he said.
In a trial at several US medical centers, Nabil Dib, MD, of the Arizona Heart Institute in Phoenix, and his colleagues transferred thigh muscle cells from the legs of 27 patients into their ailing hearts. The patients involved were all either undergoing coronary artery bypass graft surgery or receiving a left ventricular assist device at the time of the cell transplantation.
All 21 patients in the bypass group had had a myocardial infarction and had an ejection fraction of less than 40%. Those in the left ventricular assist device group were all candidates for heart transplantations, said Dr Dib.
One patient in the bypass graft died when the vein grafted in the procedure failed 5 days after the procedure. One patient in the group has an irregular rhythm, said Dr Dib. Two patients in the left ventricular assist device group died of device-related complications.
Tests in the hearts of 3 patients who received heart transplantations showed that the thigh muscles had engrafted. In the bypass group, positron-emission tomographic scanning and magnetic resonance imaging showed evidence of “new life” in the area of the heart where there had been damage, he said.
“The myoblast cell transplant is safe and feasible,” said Dr Dib. “Preliminary results are encouraging enough to proceed to a larger trial to test the efficacy of cell transplant on heart problems.”
In the midst of an epidemic of obesity, physicians are under increasing pressure to help their patients eliminate this major risk factor. In a sea of conflicting information about what works and what does not, it seems as though the research in the area has been scant. In recent years, some have tried to rectify that by comparing popular diets, evaluating supplements, and looking at the characteristics of those who are chronically obese.
When researchers at Tufts University New England Medical Center randomly assigned 160 overweight men and women to one of 4 popular diet plans, they did not know which would work. The four diets tested were Atkins, Ornish, Weight Watchers, and The Zone.
“All 4 popular diets can work for weight loss in the best-case scenario,” said Michael L. Dansinger, MD, Assistant Professor of Medicine at Tufts. “All diets looked favorable for reducing the risk of heart attack. None was impressive for lowering blood pressure, although not everyone in the trial was hypertensive.”
After one year, mean percent weight loss was 2.1% for the Atkins diet, 3.1% for the Ornish, 3% for Weight Watchers, and 3% for The Zone. Framingham scores were reduced 6.4% for Atkins, 3.3% for Ornish, 9.6% for Weight Watchers, and 6.9% for The Zone. Not all in the trial followed the diets for a year. Completion rates were 52% for Atkins, 50% for Ornish, 65% for Weight Watchers, and 65% for The Zone. Of those who completed the diet, weight reduction and Framingham risk scores were 3.9% and 12.3%, Atkins; 6.2% and 6.6%, Ornish; 4.5% and 14.7%, Weight Watchers; and 4.6% and 10.5%, The Zone. Weight loss was statistically significant for all diets, and reductions in the Framingham risk scores were significant for all but the Ornish diet.
“A wide variety of eating strategies look favorable,” said Dr Dansinger. “With further study, the challenge for physicians will be to match individuals with food plans that work best for them rather than matching everyone with one plan. The best way to boost adherence is to learn to match a person’s food preferences and lifestyle with their diets.”
Dean Ornish, MD, the physician who developed the Ornish diet, said, “When people go on the Ornish diet program, their heart disease reverses.”
He said he is concerned that the study will be misinterpreted. The Framingham risk score includes measurement of high-density lipoprotein, which can decline when a person goes on a low-fat diet, he said.
“It would discourage me to see people making changes that are not good for them,” said Dr Ornish. “I’ve said all along, you can lose weight on any diet if you burn more calories than you take in.”
Care should be exercised when using weight loss supplements, said Brian F. McBride, PharmD, a Fellow in Cardiovascular Pharmacy and Adjunct Assistant Professor of Pharmacy Practice at the University of Connecticut School of Pharmacy. When he studied the effect of the popular supplement Metabolife 356 on blood pressure and markers for development of arrhythmia, he found that there was an increase in blood pressure in 15 healthy subjects who took the supplement. In the study, he said, 60% of patients who received Metabolife 356 had a prolonged QT interval. He pointed out that the US Food and Drug Administration had removed drugs from the market because they prolonged the QT interval less than Metabolife 356 did in his study. He said he also identified risks for developing atrial arrhythmias.
He said his study was limited because his subjects were young and took only a single dose of the supplement. “I don’t know if the effects intensify or decrease with prolonged dosage.”
Because Metabolife 356 contains 18 different herbs, including ephedra, Dr Dansinger said it is difficult to determine what is causing the effects he saw. He recommended more studies involving markers of arrhythmia and blood pressure with this and other weight loss supplements.
Kazuko Masuo, MD, PhD, from the Department of Geriatric Medicine at Osaka University Graduate School of Medicine, found that individuals with overactive sympathetic nervous systems and higher levels of insulin are more likely to regain weight they have lost.
Subjects in the study followed a low-calorie diet for 2 years. Every 6 months, researchers measured their weight, blood pressure, leptin levels, norepinephrine, and insulin levels. They found that 32% of patients with successful weight loss at 6 months had gained weight at 12 months. Thirty-six percent had rebounded by 2 years.
“Sympathetic responsiveness was higher in the group with rebound than in the group that sustained their weight loss,” he said.