(Circulation. 2000;102:e9041.)
© 2000 American Heart Association, Inc.
Cardiovascular News |
Cardiovascular News
American Heart Association 2000: Touching Hearts Through Science
The 73rd Scientific Sessions of the American Heart Association (AHA) opened Sunday in the "Big Easy" (New Orleans, La), but the problems and solutions faced by clinicians and researchers treating patients with heart disease are anything but easy. As the association’s president reminded colleagues during the opening session: "The completion of the human genome project was a race not to the finish line, but to the starting line."
In the future, the president said, there will be new medicines and new procedures for treating the various forms of heart disease. However, in the current healthcare environment, many patients cannot afford the treatments available now. It is a reasonable question to ask whether they will be able to afford those of the future.
The promise of new therapies was demonstrated early in the Sessions when leaders in the field described novel new approaches to solving the problems of heart failure. Philippe Menasche, MD, of the Hopital Bichat in Paris has already used cell therapy to treat a 73-year-old heart failure patient who was not a candidate for surgical or percutaneous revascularization.
On June 15, 2000, he and his colleagues topped 7 years of preclinical research when they took a sample of muscle from the patient’s thigh and grew the myocytes in culture. Then, the expanded group of cells was reimplanted into the scarred tissue of the patient’s heart.
"It is now 5 months later, and there is some objective evidence of new contraction," said Dr Menasche during a press conference at the AHA conference. However, this contraction is useful but different from that expected from heart muscle cells. He has permission to treat a total of 9 patients with the novel new therapy but is cautious about the effect of this new treatment until there are more patients and longer follow-up. "I think this concept of cell therapy can now be moved into the clinical arena," he said.
Most researchers think of embryonic stem cells as the best beginning point for the growth of new differentiated cells, noted Ray C.J. Chiu, MD, PhD, of McGill University Health Centre in Montreal. "However, adults have stem cells, too." Stromal cells found in the bone marrow can differentiate into heart muscle cells when directed into hearts. In his animal studies of the phenomenon, Dr Chiu injected labeled stromal cells into the hearts of rats that were manipulated to be immunologically the same as their donors. "Within 5 weeks, there were heart muscle cells with a clear gap junction between the implanted cell and the native muscle." A few weeks later, the implanted cells had aligned and integrated themselves with normal muscle.
However, when the cells were injected into scar tissue in the heart, 2 populations resulted. Those directly in the scar "did not develop well," he said. These findings lead him to believe that the normal cells initiate some signal that causes the stromal cells to begin differentiation. For example, these stromal cells can become blood vessel cells as well as muscle cells.
Jeffrey Isner, MD, of St Elizabeth’s Medical Center in Boston, said his group has been focusing on the development of new blood vessels. There are 2 sources of blood vessels: endothelial cells in blood vessels that can multiply and migrate away from their parent vessel to form collateral arteries and circulating endothelial progenitor cells that can go directly to where new blood vessels need to be formed and engraft to make new blood vessels.
He and his colleagues are developing a method to harvest immature cells from patient blood, grow these in a culture dish, and return them to the patient. By doing this, he said, we avoid immunological intolerance by giving a patient his or her own cells. In animal studies, these cells incorporated into the native vasculature and formed blood vessels around the site of infarction.
Dr Isner said his angiogenesis trials have been on hold for several months but should be released from that situation soon. "In this coming week, we should be able to resume our clinical trials of gene therapy."
New results from the VIVA trial (VEGF in Ischemia for Vascular Angiogenesis) of vascular endothelial growth factor (VEGF) protein are more positive than preliminary findings announced last year, said Timothy Henry, MD, of the University of Minnesota in Minneapolis. At the 1999 AHA scientific sessions, Dr Henry said the study at 60 days appeared negative because the 3 groups in the study (placebo, high-dose VEGF, and low-dose VEGF) had the same results in analyses of exercise status, angina, and quality of life. All 3 groups had improved.
At 1-year follow-up, the placebo group had lost all indications of benefit. In fact, half of the patients had class IV angina. However, both the high-dose and low-dose VEGF groups had significant improvement in chest pain from baseline. At 1 year, 40% of the high-dose group had little or no angina.
Because of concerns that angiogenesis would encourage the growth of cancer or even cause a condition that could result in a heart attack, information about side effects was very important, said Dr Henry. At 1 year, 4 patients in the placebo group, 1 in the low-dose group, and none in the high-dose group had developed cancer. One patient in the placebo group and 2 in the high-dose group had myocardial infarctions. Overall, there were 3 deaths in the placebo group and 1 in the low-dose group. There were 37 patients in the placebo group, 34 in the low-dose group, and 35 in the high-dose group.
Genes That May Aid in Heart Disease Prevention
A form of the gene that codes for endothelial nitric oxide synthase (eNOS) could reduce the risk of heart disease, said Julian Halcox, MD, head of the heart catheterization laboratory at the National Heart, Lung, and Blood Institute. In his study, Dr Halcox identified 2 forms of the eNOS gene, one called 894T and another called 894G. Individuals can be homozygous for either gene or heterozygous for each gene.
To test the hypothesis that one form of the gene might reduce the risk of atherosclerosis, Dr Halcox and his colleagues genotyped 253 patients who had come to the hospital for coronary revascularization. They also measured how easily the patients’ blood vessels dilated in response to stimuli and compared this to the form of the gene they carry. Of the patients, 123 had atherosclerosis and 130 had clear arteries. The researchers found that the blood vessels from the individuals with the homozygous TT form of the gene relaxed better than those from patients who were homozygous for GG or were heterozygous. "This impaired relaxation in GG or GT patients make them more likely to develop atherosclerosis," Dr Halcox said. People with the TT genotype seem to be protected against coronary vascular disease. However, this hypothesis needs to be tested in a larger population to determine if there are implications on a population level.
In a study of another form of the eNOS gene, C. Paul Leeson of the Institute of Child Health in London tested the effects of environmental factors on forms of the Glu298 gene. They studied the effects of smoking and a heart-healthy diet containing n-3 fatty acids on 248 people with 2 different forms of the gene Glu298-Asp-Asp (specifically, Glu298-GluGlu and Glu298-GluAsp). When they genotyped the patients, the researchers found that male smokers with the AspAsp and GluAsp phenotypes had poorer blood vessel flexibility when compared with GluGlu smokers. Higher blood levels of the fatty acid related to improved blood vessel function in the AspAsp and GluAsp groups but not in the GluGlu groups.
"This is an early study and it is small," said Dr Leeson. "We need bigger studies in other populations." However, it does show that underlying genetic makeup can be modified by environment. This has profound implications for patient counseling about risk factors in the future. "We hope that our studies will open the door to more genotype-specific types of interventions."
Three forms of the thrombospondin genes (TSP-1, TSP-2 and TSP-4) increase the risk of developing early coronary artery disease and heart attack, said Eric Topol, MD, chairman of the Department of Cardiology at The Cleveland Clinic Foundation. He and his colleagues analyzed DNA from 347 people who had had a heart attack or revascularization before the age of 40 (in men) or 45 (in women). They compared their study subjects to 422 matched controls from the general population.
Among those who had coronary artery disease, 42.6% carried at least 1 copy of the TSP-4 gene compared with 33.6% of the controls. The association was even stronger for those who had had early heart attack: 48.6% had at least 1 copy of TSP-4. TSP-1 was a rare gene but, when people had 2 copies of it, they were at extremely high risk of early atherosclerosis. "I think this is highly interesting and needs to be replicated in other populations," said Dr Topol.
FDA Warns of Stroke Risk Associated With Phenylpropanolamine; Cold Remedies and Drugs Removed From Store Shelves
On November 6, 2000, the US Food and Drug Administration (FDA) asked drug companies to stop marketing products containing phenylpropanolamine (PPA) and announced that it was taking steps to see the chemical removed from all drug products. This sparked a move to remove cold remedies and diet medications containing the nasal decongestant from store shelves. The reason for the removal is that the medication has been linked to an increased risk of hemorrhagic stroke in women.
The history of phenylpropanolamine has been clouded by reports of stroke associated with the drug. For that reason, the FDA said in a statement that it had not finalized the "safe and effective" status for PPA, despite the opinion of one expert panel in 1976 that it was generally recognized as safe and effective as a decongestant and the opinion of another such group in 1982 that it had that reputation when used in weight control.
As reports of hemorrhagic stroke continued (30 since 1979), the FDA asked the pharmaceutical industry to conduct a study to determine the stroke risk associated with PPA. The results of that study ("Phenylpropanolamine and Risk of Hemorrhagic Stroke: Final Report of the Hemorrhagic Stroke Project") was given to the agency in October 2000. It was also published on a fast-track basis online by the New England Journal of Medicine on November 6, 2000. The printed version of the study by researchers from Yale and Brown Universities, the Mayo Clinic, and the University of Texas Medical School at Houston will appear on December 21, 2000. The article can be found at http://www.nejm.org.
The case-control study compared the histories of 702 hospitalized men and women who had suffered a very recent stroke with 1376 matched control subjects who were chosen randomly. The study found an increased risk of hemorrhagic stroke in women within 3 days of beginning to use PPA for weight control and within 1 day of using the medication as a nasal decongestant. The analysis showed no stroke risk in men using remedies containing PPA as a decongestant, and no men reported using the medication as an appetite suppressant. The FDA said there may be a risk to men, although the study did not show one. The study was supported by Novartis Consumer Health (formerly Ciba Consumer Pharmaceuticals), Thompson Medical Company, and Chattem.
The FDA noted that the risk was low but that the event (hemorrhagic stroke) is extremely serious, and the agency is unable to determine who is at risk. It agreed with the conclusion of its Nonprescription Drugs Advisory Committee on October 19, 2000, that PPA not be recognized as generally safe for over-the-counter use. In agreeing, the FDA said that the use of PPA is not justified for the conditions for which it is used. The agency said it is also concerned about the use of PPA in prescription medications and plans to remove it from both over-the-counter and prescription medications.
Drug companies reacted quickly and, within hours of the FDA announcement, they were asking stores to remove the medications from stores where they could be sold to consumers.
Two Intravascular Brachytherapy Systems Approved by FDA
Two devices that deliver radiation directly to the site of in-stent stenosis received approval by the FDA on November 6, 2000. The use of stents has revolutionized the clinical use of coronary angioplasty for the treatment of angina.
In most patients, stents remain open, keeping the coronary arteries clear. However, when the artery renarrows—a situation called in-stent stenosis—the problem is difficult to treat. The renarrowing occurs because of an exaggerated healing response in the stented area of the coronary artery.
When in-stent stenosis occurs, the area is reopened with a balloon catheter. Then, the brachytherapy device is temporarily placed in the narrowed area, which receives radiation treatment that halts the overly vigorous healing process and prevents the recurrence of blockage that can cause chest pain.
Clinical studies showed that the 2 brachytherapy devices were safe and effective, prompting the FDA to approve them. The approved devices are the Cordis Checkmate System made by Cordis Corporation of Miami, Fla, and the Novoste Beta-Cath System made by the Novoste Corporation of Norcross, Ga.
Community Intervention Can Prevent Risky Drinking and Car Crashes and Trauma Associated With Alcohol Abuse
Aggressive, community-wide alcohol-prevention strategies can reduce alcohol-related automobile accidents as well as injuries from the car crashes and assaults according to a 5-year study published in the November 8, 2000 issue of the Journal of the American Medical Association (JAMA. 2000;284:2341-2347).
In a study known as the Community Prevention Trial, Harold D. Holder, PhD, and colleagues at the Prevention Research Center in Berkeley, California, and the Pacific Institute for Research and Evaluation involved local city government, police, and media in their prevention study. Institutions that sold and served alcohol were also recruited into the study. The researchers encouraged communities to build coalitions to advocate preventive actions. The media was encouraged to advocate responsible beverage service. Governments were encouraged to work harder to limit alcohol access by teens, enforce drinking and driving laws, and limit alcohol access by using municipal zoning ordinances. The communities in which these interventions were put into place were compared with others in which no such activity was stimulated.
Over the 5-year period, those in communities with no interventions continued to drink, but those in the cities where the intervention was put into effect reported imbibing less each time they drank. After 5 years, the researchers discovered that night car crashes with injuries had declined by 10%, crashes by drunk drivers were reduced 6%, injuries by assault were reduced 43%, and the numbers of people hospitalized because of assault dropped 2% in the intervention communities when compared with the control cities.
"Dr Holder and his colleagues demonstrate that complex community systems can be studied rigorously—a formidable achievement given the complexity of the environment," said Enoch Gordis, MD, director of the National Institution of Alcohol Abuse and Addiction, which sponsored the study. "The Community Prevention Trial provides powerful new evidence that comprehensive, coordinated environmental prevention programs can be effective in reducing alcohol-related injuries and accidents in the community."
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