Two Paradoxical Syndromes; One Mutation
Proving the axiom that answers are not always the solution, a mutation in the cardiac sodium (Na+) channel can cause both long-QT and Brugada syndromes. Although both lead to life-threatening cardiac arrhythmias, long-QT is associated with enhanced Na+ channel function and Brugada with reduced Na+ channel function.
In this week’s issue of Circulation, Colleen E. Clancy, PhD, and Yoram Rudy, PhD, of the Cardiac Bioelectricity Research and Training Center in the Departments of Biomedical Engineering and Physiology and Biophysics at Case Western University in Cleveland, Ohio, used a computational approach to determine how the same mutation could lead to such dissimilar results (Circulation. 2002;105:1208–1213). They posited that the mutation 1795insD in the C-terminus of the cardiac Na+ channel exerts its variable effects depending on the myocardial substrate.
Using a computer, the scientists developed models of the Na+ channel as it exists normally and as it is mutated and incorporated into virtual transgenic cells. The mutation, said the authors in their paper, “disrupts the Na+ current by enhancing channel inactivation states and stabilizing inactivation states, which reduces channel availability. The mutation also promotes channel bursting resulting in a persistent component of noninactivating current.”
The authors point out that ion channel proteins exist haphazardly in the heart muscle, which results in “intrinsic electrophysiological heterogeneity.” Through their computer analysis, the authors demonstrate that this heterogeneity is the reason that two seemingly opposite syndromes can result from a single mutation.
Younger Women More Likely to Die After Bypass Surgery
Viola Vaccarino, MD, PhD, and colleagues from Emory University School of Medicine, Atlanta, Ga, demonstrate a second oddity in another study in this week’s Circulation with their finding that younger women face an increased mortality after coronary artery bypass graft surgery (Circulation. 2002;105:1176–1181).
In this study, the authors mined the National Cardiovascular Network database to determine that young women (those under the age of 50 years) were 3 times more likely to die after the operation than were men of the same age, and women aged 50 to 59 years were 2.4 times more likely to die than were men. However, as members of each sex got older, the mortality differences became less apparent, said the scientists from the Division of Cardiology in the Department of Medicine at Emory University School of Medicine and the Departments of Epidemiology and Health Policy and Management at Rollins School of Public Health at Emory University.
In their study, the researchers evaluated information from 51 187 patients from 23 participating hospitals. However, they said, their study did not pinpoint the exact causes of the differences in mortality in the different age groups. They did find that younger women who underwent the bypass grafting had more comorbid conditions and risk factors than men. These included stroke, heart failure, diabetes, kidney problems, and valve disease. On average, they were also in a higher angina class. However, these differences became less apparent with age.
The authors noted that they had anticipated that such conditions would be responsible for the higher rates of death in younger women. However, they found that these factors explained <30% of the mortality difference between younger women and men. They also found that women had less severe coronary artery disease and better left ventricular ejection fractions, negating an expected difference based on severity of disease.
As a result, said the authors, “it remains difficult to explain why coronary artery anatomy would have a larger impact on in-hospital mortality in the younger than in the older women.”
Fine Particulate Air Pollution Associated With Deaths From Lung Cancer and Heart Disease
By linking vital statistic and cause-of-death data with information on risk factors and demographics on 1.2 million adults in the 1982 Cancer Prevention II Study of the American Cancer Society to air pollution data from the US metropolitan areas, researchers from Utah’s Brigham Young University, Health Canada, the University of Ottawa in Canada, the American Cancer Society, and New York University School of Medicine were able to find a definite association between deaths from lung cancer and heart disease (JAMA. 2002;287:1132–1141).
The risk of long-term exposure to fine particular matter is less than that of cigarette smoking but is very real, the researchers said. The risk is not as large as that posed by significant obesity, the researchers said. However, they said, it is “comparable to the estimated effect of being moderately overweight.”
“In conclusion, the findings of this study provide the strongest evidence to date that long-term exposure to fine particulate air pollution common to many metropolitan areas is an important risk factor for cardiopulmonary mortality . . . Elevated fine particulate air pollution exposures were associated with significant increases in lung cancer mortality.”
Alzheimer’s Vaccine Trials Halted
The Irish pharmaceutical firm Elan Corporation suspended trials of its experimental Alzheimer’s vaccine in late February after 12 of those who had received the medication showed evidence of severe brain inflammation. On March 1, 2002, the company and its collaborator, Wyeth-Ayerst Laboratories, the pharmaceutical division of American Home Product Corporation, announced that they were ending the trial of the drug known as AN-1792.
The company had halted its studies in January when 4 French patients demonstrated symptoms of inflammation of the central nervous system. In the interim, at least 11 more patients have had the symptoms, the company noted in a released statement on its website.
In consultation with their Data Safety and Monitoring Committee, the two companies decided to give no more patients the medication. However, they said that patients who had already been treated would be followed to assess ongoing safety.
“We will continue to monitor all patients who have received the drug in these studies,” said Ivan Lieberburg, MD, Elan’s chief scientific and medical officer, in a released statement. “The well-being of patients is always our paramount concern. Our decision to first suspend dosing, and now permanently discontinue dosing in this exploratory phase of clinical research with this single compound, in our opinion, remains in the best interest of the health and safety of patients. There are additional compounds under preclinical evaluation as part of this collaboration. We believe that these alternative therapeutic candidates may result in a treatment for Alzheimer’s disease.”