A paper in the Jan. 16 issue of the Proceedings of the National Academy of Sciences casts Alzheimer’s disease (AD) against type: as a cardiovascular disorder at its root.
Reduced blood flow is a well-known symptom of Alzheimer’s disease, but that has been interpreted as an effect of the disorder. Senior author Berislav Zlokovic described the prevailing opinion that “the brain is atrophying because of the disease, so not as much blood as usual is needed.” But he believes that the opposite cause/effect relationship is true: “the brain [may be] dying because of the reduced blood flow.”
The researchers studied the role of two cardiovascular proteins: serum response factor (SRF) and myocardin, the chief regulators of arterial contraction. They found that both are over-expressed in tissues from patients with late-stage Alzheimer’s disease.
“We don’t know exactly why,” Zlokovic said, adding that hypoxia or a genetic polymorphism are just two possibilities. But the result, he said, is clear: “Blood flow regulation is disrupted.” That disruption, in turn, may be a contributing factor in the dementia that makes Alzheimer’s so devastating. “Normally, with attention there is an increase in blood flow to parts of the brain,” Zlokovic said. But with high levels of myocardin and SRF, blood vessels are no longer able to dilate to accommodate blood flow. And this state of affairs “doesn’t support brain function.”
The work was done by Zlokovic, a professor of neurological surgery, and his colleagues from biotech startup Socratech Research Laboratories (Rochester, New York), the University of Rochester Medical School and the State University of New York at Stony Brook. They first did tissue studies and found that both myocardin and SRF genes are more highly expressed in vascular smooth muscle cells from the brains of AD patients than in control brains, and that such high expression led to arterial wall muscles contracting more than usual.
The scientists next did in vivo studies — challenging in this case. Knockouts lacking either gene never make it past early embryonic development, since they have severe cardiac abnormalities, and over-expressing the SRF gene is lethal for the same reason. Zlokovic and colleagues got around this by delivering genes to the brain surface via a cranial window, which, Zlokovic explained, is “not gene transfer to the brain itself” but targets the blood vessels on the brain surface. Using this technique they found that when either gene was expressed more strongly than usual, blood flow in the brain was reduced, much like it is in AD in people. Conversely, when they used short hairpin RNAs to silence SRF, the phenomenon was reversed, and blood flow increased.
Exposing cells to A-beta peptides, which form amyloid plaques, did not lead to increased expression of SRF, suggesting that increases in blood vessel contractility cause the protein accumulations, rather than the other way around.
The technology has been licensed to Socratech, a spinout from the University of Rochester where Zlokovic is chief scientific officer. The company, which Zlokovic said has identified gene targets and is currently doing high-throughput screening to find molecules that are active against those targets, is focused on new treatments for AD and stroke.
Lethal mutations identified as cause of sudden cardiac death
In 49 young people who died suddenly and inexplicably at an average age of 14, conventional autopsies found no cause of death. But when Clinic researchers at Mayo Clinic (Rochester, New York) conducted molecular autopsy — a sophisticated form of postmortem genetic testing — they found that more than one-third died due to potentially heritable genetic defects that impair the heart’s rhythm center. The defects were caused by mutations, which can be thought of as “spelling” errors in the genetic code. The defects produced one of two abnormal heart rhythm conditions: long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).
Both syndromes can declare their presence silently and catastrophically with a sudden death episode as the first symptom. Because they leave no structural or physical clues, the defects can’t be detected with conventional autopsy methods — so families have been left with the additional grief of wondering what caused the premature death.
Mayo Clinic’s molecular autopsy is a detailed examination at a molecular level of heart function and can determine if such mutations are the cause of death in 35% of cases in which conventional autopsies could not determine a cause. “The fact that conventional autopsy fails to provide an answer is, in fact, a key clue that the killer may be LQTS or CPVT,” said Michael Ackerman, MD, PhD, the study’s chief author who heads the Windland Smith Rice Sudden Death Genomics Laboratory at Mayo. The laboratory reported that between 1998 and 2004, 42 coroners’ offices in the U.S. referred to it 49 cases of unexplained death.
“To prevent further tragic, premature deaths, the standard of care for the evaluation of sudden unexplained death must now change,” Ackerman said. “Surviving members in a family in which there’s been this tragedy should receive medical attention that is equal to a ‘full-court press.’ It must involve a careful and sleuth-like search for these inherited glitches in the heart’s electrical system.”
The Mayo Clinic report appears as the featured article and editorial topic in the Jan. 16 issue of the Journal of the American College of Cardiology.
Ackerman said that to identify at-risk relatives, all immediate family members of the person who died inexplicably must undergo comprehensive cardiac evaluation that includes, at minimum, an electrocardiogram and an exercise stress test as initial screens for LQTS and CPVT.
If evidence of heart problems is found, family members need to act immediately by getting screened for the lethal mutations, and treated, if necessary, he said.
“Families who have lost a loved one to sudden unexplained death should now know that they can do more if the coroner or medical examiner is unable to provide an explanation for their loved one’s sudden and unexplained death,” Ackerman said. “Postmortem genetic testing could be performed on the victim of sudden death in search of the cause. Now, one-third of the time, we can find the cause.”
MRI found superior to CT for emergency diagnosis of acute stroke
MRI can provide a more sensitive diagnosis than computed tomography (CT) for acute ischemic stroke, according to a study comparing the two imaging techniques for the emergency diagnosis of suspected acute stroke, that study described as “the most comprehensive” of its kind. The difference between MRI and CT was attributable to MRI’s superiority for detection of acute ischemic stroke — the most common form of stroke, caused by a blood clot. The study was conducted by physicians at the National Institute of Neurological Disorders and Stroke (NINDS), of the National Institutes of Health.
“These NIH research findings on acute stroke imaging are directly applicable to real-world clinical practice,” said NIH Director Elias Zerhouni, MD. “The patients involved in this study were the typical cross-section of suspected stroke patients that come into emergency rooms on a daily basis.”
The findings appear in the Jan. 27 edition of The Lancet.
The study has good news for patients, according to Walter Koroshetz, MD, deputy director of NINDS. “This study shows that about 25% of stroke patients who come to the hospital within three hours of onset, the time frame for approved clot-busting therapy, have no detectable signs of damage. In other words, brain injury may be completely avoided in some stroke victims by quick re-opening of the blocked blood vessel,” said Koroshetz.
A contrast dye may be used in both imaging techniques to enhance visibility of certain areas or tissues. Study results show immediate non-contrast MRI is about five times more sensitive than and twice as accurate as immediate non-contrast CT for diagnosing ischemic stroke. Non-contrast CT and MRI were equally effective in the diagnosis of acute intracranial hemorrhage. Non-contrast CT has been the standard in emergency stroke treatment, primarily to exclude hemorrhagic stroke, which cannot be treated with clot-busting therapies.
“Most possible stroke victims are first evaluated by non-specialists, who may be reluctant to treat a patient for stroke without greater confidence in the accuracy of the diagnosis,” said Steven Warach, MD, PhD, director of the NINDS Stroke Diagnostics and Therapeutic Section and senior investigator of the study. “Our results show that MRI is twice as accurate in distinguishing stroke from non-stroke. Based on these results, MRI should become the preferred imaging technique for diagnosing patients with acute stroke.”
The study included 356 consecutive patients with suspected stroke arriving at the NIH Stroke Center at Suburban Hospital (Bethesda, Maryland), a primary stroke center. Stroke specialists conducted emergency clinical assessments with all patients, including the NIH Stroke Scale, used to measure stroke severity. MRI was done prior to CT in 304 patients. Scans were initiated within 2 hours of each other, with a median difference of 34 minutes.
Four readers were unanimous in their agreement on the presence or absence of acute stroke in 80% of patients using MRI compared to 58% using non-contrast CT. No significant difference using the two technologies was seen in the diagnosis of acute intracranial hemorrhage.
“Although MRI is remarkably accurate in detecting early stroke damage, it can’t substitute for doctor’s clinical judgment in making a stroke diagnosis and deciding upon treatment,” said Koroshetz. “Future studies are needed to determine whether advanced contrast enhanced CT techniques can afford the same level of clinical information more quickly and with less expense.”
Aggressive BP control for cost savings seen as ‘debatable’
High blood pressure is controlled better in the U.S. than in five Western European countries, according to a recent study, and the researchers credit American doctors’ more aggressive prescribing of drugs. The authors conclude that spending on blood pressure drugs in the U.S. is probably less than the costs of the heart attacks and strokes prevented.
But other experts questioned the cost-effectiveness of treating mildly high blood pressure. “That’s very debatable,” countered Dr. William Elliott of Chicago’s Rush University Medical Center, specializing in preventive medicine, called the cost-savings conclusion “debatable — only in specific subsets of patients does it save money . . . for very high-risk people, older people, people with previous heart attack and strokes.”
The study was conducted by researchers at the University of Pennsylvania (Philadelphia), University of Chicago and Stanford University (Palo Alto, California) and was published in a recent issue of the Archives of Internal Medicine.
The researchers looked at reports of more than 21,000 patients treated for hypertension and found that post-treatment blood pressure was 134 over 79 on average in the U.S.; 139/80 in France; 141/83 in Germany; 143/84 in Italy; 141/83 in Spain; and 144/82 in Britain.
The study also found that the use of more than one blood pressure drug per patient was highest in the U.S., with 64% of the patients getting more than one class of drug, compared with a low of 44% in Spain and 59% in Germany and Britain.
Study co-author Caleb Alexander, MD, of the University of Chicago, said treating high blood pressure aggressively and early is “a good thing, given the burden of hypertension among the population.”
But the study did not take into account the potential harmful side effects of aggressive medical treatment for hypertension, according to Lisa Schwartz, MD, of the VA Outcomes Group, made up of researchers trying to promote straightforward presentation of medical information. Blood pressure drugs can cause low blood pressure, weakness, depression and chronic cough.
In addition, some experts said the study simply reflects the fact that American doctors are treating less severe hypertension, while Europeans in the study started with higher blood pressure before treatment. For example, 87% of the French started with levels over 160/100. In contrast, 65% of Americans started treatment with levels that high.
Also, the study did not involve a representative sample of the nations’ people, but instead looked only at those people who go to the doctor for hypertension. That means the study probably missed uninsured Americans who cannot afford regular care. The data came from a 2004 survey in which doctors filled out diaries about the first 15 cardiovascular patients they saw in one week.
The study was supported by grants from the National Institute on Aging and the Agency for Healthcare Research and Quality (Washington).
Lack of gender-specific study analysis undercuts cardio data for women
Heart disease differences in men and women continue to be poorly understood because women are included in clinical trials far less than men, and even when women are included, study results are not reported by sex, according to a study in a recent issue of Mayo Clinic Proceedings. The study shows that three-fourths of clinical cardiovascular trials published in leading general medical and cardiology journals during the last six months of 2004 did not provide gender-based analysis.
In a review of 645 cardiovascular clinical trials published from July 1 through Dec. 31, 2004, only 153 provided sex-specific reporting — defined as reporting results for women and men in a format that allows data to be specifically extracted for each sex. In addition, the authors found that 7% of the studies did not report the participants’ sex, and 3% included no women, despite studying conditions that affect both sexes.
Sharonne Hayes, MD, an author of the study and director of Women Heart Clinic of the Mayo Clinic (Rochester, Minnesota), said, “We hope this analysis will drive the behavior of researchers. If more women are included in trials and the results are reported by sex, it will help physicians provide the best care possible to both men and women.”
Policy changes in 1986 by the National Institutes of Health were aimed at increasing participation by women and minorities in research. Little progress was made until 1993, however, when NIH-funded research required that women and minorities be included in trials unless a clear reason was given for their exclusion. The law required inclusion of women and minorities but did not require reporting the data.
The authors of the Proceedings report found that clinical trials funded by the NIH were more likely to report results by sex than non-NIH-funded trials (51% vs. 22%). While sex-based reporting has increased as a result of the NIH requirement, the authors challenge journal editors to create a similar policy of reporting sex-based results, regardless of the funding source.
Mary Norine Walsh, MD, another study author, and a cardiologist at The Care Group (Indianapolis) siad, “More sustained change will occur when those planning large clinical trials include enrollment of enough women to allow for pre-specified endpoint analysis, and when journal editors and reviewers uniformly require such analysis.”
The authors reviewed clinical trials published in Annals of Internal Medicine, Archives of Internal Medicine, Journal of the American Medical Association, The New England Journal of Medicine, Journal of the American College of Cardiology, The American Journal of Cardiology and Circulation.
On a more positive side, The National Heart, Lung, and Blood Institute (NHLBI) recently reported that the number of heart disease deaths in American women is decreasing. New data indicates that the number of women who die from heart disease has shifted from 1 in 3 women to 1 in 4 — a decrease of nearly 17,000 deaths from 2003 to 2004.
NHLBI experts analyzed preliminary data for 2004, the most recent year for which data are available. This analysis showe a steady decline in the number of heart disease deaths in women in each of the five years from 2000 to 2004, a consecutive yearly decline which had never occurred before.