Obstructive Sleep Apnea Linked to Blood Vessel Abnormalities
Obstructive sleep apnea may cause changes in blood vessel function that reduces blood supply to the heart in people who are otherwise healthy, according to new research reported in Hypertension: Journal of the American Heart Association.
However, treatment with 26 weeks of continuous positive airway pressure (CPAP) improved study participants’ blood supply and function.
Obstructive sleep apnea, which causes periodic pauses in breathing during sleep, affects about 15 million adults in the United States, according to the American Heart Association. The sleep disorder may be a contributing factor to high blood pressure and cardiovascular diseases.
“The findings should change how doctors treat patients with obstructive sleep apnea,” said Gregory Y.H. Lip, MD, lead author of the study and professor of cardiovascular medicine at the University of Birmingham in the United Kingdom. “Even apparently healthy patients with sleep apnea show abnormalities of small and large blood vessels, as well as impaired blood supply to the heart muscle, and these can improve with CPAP therapy.”
CPAP treatment provides a constant airflow that holds the airway open to maintain uninterrupted breathing during sleep. This eliminates sleep apnea events and allows the patient to get a restful sleep.
The study is the first to show blood vessel abnormalities in sleep apena patients. Previous studies have linked blood vessel dysfunction to cardiovascular disorders.
Reversing blood vessel abnormalities could help patients with obstructive sleep apnea who are otherwise healthy avoid developing and dying from cardiovascular disorders, researchers said.
Researchers looked for changes in blood vessel function in 108 participants who were otherwise healthy, with no differences in age, sex, body mass index and smoking status across three groups:
- 36 people with moderate or severe obstructive sleep apnea without high blood pressure;
- 36 high blood pressure patients without obstructive sleep apnea;
- 36 patients with neither high blood pressure nor obstructive sleep apnea.
Researchers used several techniques to assess blood vessel function, including myocardial contrast echocardiography.
All the sleep apnea patients received CPAP therapy; so proper randomized studies will still be needed to confirm the intervention’s beneficial effects on the blood vessels, Lip said.
Furthermore, patients in the control groups weren’t treated with CPAP therapy, which would have been clinically unjustified because none had obstructive sleep apnea, researchers said.
Lip hopes his research will bring greater awareness to the relationship between obstructive sleep apnea and cardiovascular diseases. “The condition can be treated, and it is important that clinicians look out for it,” he said.
The study was partially funded by Bracco Research, Sa, Switzerland.
Gene Therapy Delivered Once to Blood Vessel Wall Protects Against Atherosclerosis in Rabbit Studies
Medicine has been at an impasse in the search for therapies that prevent plaque growth and rupture. Statin drugs that lower bad cholesterol work, but they have not eliminated heart attacks and strokes, must be taken daily for life, and some patients do not tolerate statins.
Trials of newer interventions such as niacin have been disappointing, according to Dr. David A. Dichek, senior author of a study of a one-dose method for delivering gene therapy into an arterial wall, published July 19th in Molecular Therapy.
Dichek is the John Locke Professor of Cardiovascular Research at the University of Washington (UW) and associate director for research in the Division of Cardiology, UW Department of Medicine. Dichek practices cardiology at UW Medicine.
“Introducing into the blood vessel wall genes that protect against atherosclerosis is potentially an effective means of preventing or reversing plaque formation and inflammation,” Dichek said. “As applied in our study, the introduced genes can produce proteins that counteract the fundamental processes that drive atherosclerosis, including preventing lipid accumulation inside the artery wall and decreasing recruitment of inflammatory cells. We found both of these effects.”
Gene transfer would move the production of the therapeutic “drug” (in this case a therapeutic gene) directly to the site of atherosclerosis development: the blood vessel wall. The approach maximizes delivery of the drug to the artery wall and minimizes side effects in the rest of the body, the research team noted.
The deployed gene produces a protein that is likely responsible for the beneficial effects of high-density lipoprotein, or HDL. This substance is apolipoprotein A-1, or apoA-1. It pumps out harmful cholesterol from the scavenger-type cells that ingest fats and congregate in early atherosclerotic lesions. ApoA-1 appears to remove cholesterol from the lesions and is capable of transporting it to the liver, where it can be excreted from the body.
Lack of a suitable vector to transfer apoA-1-manufacturing genes into the cells lining the arterial wall has hampered the progress of this approach. Normally apoA-1 is produced by cells in the liver, stomach and intestine and enters the artery wall only after circulating through the blood.
The UW researchers successfully used a helper-dependent adenovirus (HDAd) as the vehicle to transfer a genomic clone of rabbit apo-A1 into the carotid artery. This large blood vessel sends oxygenated blood to the brain. After the vector was infused into the artery, the gene was taken up almost exclusively by the cells in the thin layer that lines the carotid’s inner surface and is in contact with circulating blood.
At two weeks, atherosclerosis in the carotid artery, as measured by lesion size and lipid content, was minimal and similar in fat-fed rabbits with or without gene therapy. Between weeks two and four, disease measurements increased in control arteries, but were stable or decreased in treated ones.
A lengthier study of chow-fed rabbits revealed that apo-A1 production from a treated artery continued for at least 48 weeks after a single dose of gene therapy.
The researchers concluded, “HDAd vectors provide for prolonged, stable expression of therapeutic transgenes in the artery wall. The transgene’s production of apo-A1 in cells lining the artery wall significantly retards atherosclerosis.”
What made this approach continually effective — far longer than reported for any other gene therapy efforts of this type — was the type of gene delivery vector and the type of receiving cell. Past attempts at gene therapy for atherosclerosis delivered to the artery wall were effective for only a few days. Then body’s immune system recognized and wiped out the foreign protein vector.
The HDAd vector, and the production of Apo-1, persisted because, unlike most other vectors, HDAd does not produce any viral proteins. It remains under the radar of the immune system and does not provoke serious inflammation. Also, the long-living cells that took up the gene transfer have very low turnover and proliferation rates. Even if some initial cell loss occurs after vector infusion, most of the cells seem to stay alive at the site of gene therapy, for the duration.
Another hopeful experimental finding: This vector didn’t set up gene factories in other parts of the body. The vector genome was at or below the limit of detection in multiple samples of different tissues and organs. Its presence in the artery didn’t upset normal blood values. Keeping vectors restricted “on location” can avoid provoking harmful systemic inflammatory reactions or other unwanted side effects.
The researchers plan to test whether HDAd treatment provides persistent protection against atherosclerosis (at least six months in fat-fed rabbits) and test whether HDAd can be efficiently delivered into vein segments before surgically grafting the veins into the arterial circulation.
“Vein grafts are an attractive setting for gene therapy because they can be treated efficiently and completely after they are removed from the body and before surgical reimplantation,” Dichek said.
Overall, this week’s reported findings suggest that delivering the ApoA-1 gene once via the HDAd vector might protect blood vessels against atherosclerosis and potentially provide life-long benefits. Further experiments will show whether the approach is effective for years or works in vein grafts. If gene therapy can eliminate or reduce existing plaques, as well as prevent their formation, it would have even greater clinical usefulness.
The researchers pointed out that efficient catheter-based or other targeted delivery of gene therapy to the three main locations where atherosclerosis is most harmful — the carotid, coronary, and femoral arteries — might significantly reduce disability and mortality from atherosclerosis.
“Localized one-time gene therapy might someday be an alternative or an important adjunct to systemic drugs such as statins that patients take for decades,” Dichek said. “In gene-therapy trials for other diseases, one-time treatments have shown efficacy for at least nine years and will likely continue to be effective indefinitely. Because atherosclerosis is a life-long threat, gene therapy that protects blood vessels for a lifetime makes a lot of sense.”
Receptor ‘Ties’ Blood Flow, Atherosclerosis Together
Atherosclerotic lesions often occur in areas of turbulent blood flow — for example, after an artery splits into two branches. A multi-disciplinary team of Vanderbilt University (Nashville, Tenn.) investigators has discovered that a receptor on the surface of endothelial cells lining the blood vessels senses the turbulent flow and promotes atherosclerosis. The findings, reported in the Journal of Clinical Investigation, suggest that the receptor, Tie1, may be a novel target of therapy for atherosclerosis.
H. Scott Baldwin and his colleagues have studied the role of the Tie1 receptor during development for a number of years. They learned that it is required for the survival of vascular endothelial cells and that mice without the Tie1 gene die before birth. Tie1 expression in endothelial cells drops as an animal develops from a newborn to an adult, except in the endothelial cells in areas of turbulent blood flow.
“The fact that Tie1 is expressed in virtually every endothelial cell in the embryo, but only in these pathological sites in the adult was intriguing,” said Baldwin, professor of pediatrics and cell and developmental biology. “We wanted to know what it was doing in the adult.”
The investigators thought that Tie1 might have a role in the response of endothelial cells to shear stress — the force exerted by blood flowing through the blood vessels.
Kel Vin Woo, a student in Vanderbilt’s Medical Scientist Training Program who has an undergraduate background in biomedical engineering, developed methods to study the effects of shear stress on endothelial cells in vitro and in vivo.
He also used mouse breeding strategies to establish a line of mice prone to developing atherosclerosis, in which the Tie1 gene could be selectively eliminated in endothelial cells at desired times in adult mice.
The researchers found that laminar (non-turbulent) flow turned off Tie1 expression, both in vitro and in vivo. They showed that reducing Tie1 expression in mice prone to developing atherosclerosis decreased atherosclerosis lesions, and that these effects were dose-dependent. They demonstrated in vitro and in vivo that Tie1 has a pro-inflammatory role.
In sum, Baldwin said, “Tie1 appears to sense blood flow, whether it’s fast and laminar or slow and turbulent, and transmit that signal via endothelial cells to enhance the inflammatory state that is conducive for atherosclerosis.”
The findings suggest that eliminating Tie1 or somehow blocking its signaling could have a favorable therapeutic impact on atherosclerosis.
“A potentially exciting thing is that because Tie1 is not expressed by many endothelial cell populations in the adult, a drug that blocks its activity may be less likely to have bad side effects,” Baldwin said.
Baldwin said that the collaborative environment at Vanderbilt was key to the studies.
“Basically you have a developmental biologist and pediatric cardiologist, who teams up with a student trained in biomedical engineering, who connects with a vascular surgeon, and all three join with the atherosclerosis experts to do the research,” he said. “And it can all happen here because we’re bumping into each other every day. There is a unique culture of collaboration…going out of your way to help your colleagues succeed.”
The National Institutes of Health and American Heart Association supported the research.
Patient Enrollment in U.S. Clinical Trial of Renal Denervation with Symplicity® Catheter System™ for Treating Resistant Hypertension to Start Soon
Medtronic, Inc. announced that the U.S. Food and Drug Administration (FDA) has conditionally approved the protocol for SYMPLICITY HTN-3, the company’s U.S. clinical trial of renal denervation with the Symplicity® Catheter System™ for the treatment of resistant hypertension (high blood pressure in the presence of three or more medications), affecting hundreds of millions of people worldwide. Patient enrollment in the landmark study is expected to start soon.
Having received Europe’s CE (Conformité Européene) mark and a listing with Australia’s Therapeutic Goods Administration (TGA), Medtronic’s Symplicity Catheter System is commercially available in Europe and Australia.
FDA approval of the SYMPLICITY HTN-3 protocol enables Medtronic to conduct a randomized, controlled trial of renal denervation in the United States. The Symplicity Catheter System is not approved by the FDA for U.S. commercial distribution.
The principal investigators of SYMPLICITY HTN-3 are George Bakris, MD, professor of medicine and director of the Hypertension Center at the University of Chicago Medical Center; and Deepak L. Bhatt, MD, MPH, associate professor of medicine at Harvard Medical School, chief of cardiology for the VA Boston Healthcare System, and director of the Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the VA Boston Healthcare System.
“The imminent start of this clinical trial marks a pivotal point in the study of hypertension treatments,” said Dr. Bakris, who also serves as president of the American Society of Hypertension. “SYMPLICITY HTN-3 will assess the efficacy and safety of renal denervation with the Symplicity Catheter System — a treatment approach that represents a first in our field: a catheter-based intervention for patients with resistant hypertension who have been unable to achieve target blood pressure levels despite multiple medications.”
SYMPLICITY HTN-3 is a single-blind, randomized, controlled trial designed to evaluate the safety and effectiveness of renal denervation with the Symplicity Catheter System in patients with resistant hypertension. Across 60 U.S. medical centers, the study will enroll approximately 500 patients who will be randomized to receive either renal denervation and treatment with anti-hypertensive medications or treatment with anti-hypertensive medications alone. The primary endpoints of the study are the change in blood pressure from baseline to six months following randomization and incidence of major adverse events one month following randomization.
Renal denervation is a minimally invasive procedure that modulates the output of the sympathetic nerves located outside the renal artery walls. The Symplicity Catheter System consists of a proprietary generator and a flexible catheter. The catheter is introduced through the femoral artery and is threaded up into the renal artery near each kidney. Once in place, the tip of the catheter delivers low-power radio-frequency (RF) energy according to a proprietary algorithm, to modulate the surrounding sympathetic nerves. Renal denervation does not involve a permanent implant.
Clinical research to date shows that renal denervation with the Symplicity Catheter System may provide a significant and sustained reduction in blood pressure levels for many patients with uncontrolled blood pressure despite multiple medications. Results from SYMPLICITY HTN-2, a randomized, controlled trial of 106 patients in Europe, Australia and New Zealand, showed that patients with resistant hypertension randomized to renal denervation achieved a mean blood pressure reduction of 32/12 mm Hg at 6 months, whereas the patients in the control group randomized to anti-hypertensive medications alone had blood pressures that did not vary from baseline (1/0 mm Hg). The overall occurrence of adverse events did not differ between groups.
Despite lifestyle changes and the availability of modern antihypertensive agents, approximately 50 percent of patients with hypertension remain uncontrolled, and approximately 15–20 percent of those are resistant.1
More information about the SYMPLICITY HTN-3 trial is available online at www.SymplifyBPtrial.com.
- Lloyd-Jones D, Adams RJ, Brown TM, and members of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics — 2010 update: a report from the American Heart Association. Circulation 2010 Feb 23;121(7):e46-e215.
First Report from Public-Private Partnership Shows Variability in How Clinical Trials Are Monitored
Results from a study assessing how clinical trial quality is monitored in the U.S. reveal a variety of monitoring approaches, the choice of which appears to relate to the type of organizational sponsor for the trial.
Furthermore, the rationale behind any specific monitoring approach does not appear to be evidence-based, raising the possibility that there could be more effective and efficient ways to ensure the reliability of clinical trial results and patient safety.
This possibility suggests potential for addressing the current high costs and complex nature of clinical trial conduct.
The study is the first component of an effort undertaken by the Clinical Trials Transformation Initiative (CTTI), a partnership of over 60 organizations founded by the U.S. Food and Drug Administration and Duke University Medical Center (DUMC).
CTTI’s mission is to identify practices that through broad adoption will improve the quality and efficiency of clinical trials. Its members include leaders in academia, industry, government agencies, clinical research organizations, patient advocacy groups, and others engaged in the clinical trials enterprise.
Little information has been previously reported about how sponsors ensure a trial is properly conducted and answers the questions outlined at the outset of the trial. International monitoring guidelines are in place, but it appears that different types of organizations have interpreted the guidelines differently.
“This study and subsequent recommendations by CTTI reinforce the importance of exploration, analysis, and validation of innovative and efficient monitoring techniques,” said Rachel Behrman Sherman, MD, associate director for medical policy at the FDA’s Center for Drug Evaluation and Research.
“Generation of such evidence will contribute to the growing body of information referred to as ‘regulatory science,’ and should improve the quality of clinical trial results.”
The new study, published in the journal Clinical Trials, coincides with recently announced recommendations for improving clinical trial monitoring processes, which were presented by CTTI representatives at the Society for Clinical Trials Annual Meeting in Vancouver, BC.
The report is based on data collected from 65 organizations that conduct or sponsor clinical trials (18 academic or government institutions, 11 clinical research organizations, and 36 organizations from the pharmaceutical and device industries). Each organization completed a survey to obtain information about methods for study oversight and quality assurance.
“Given the investment in time and resources spent on monitoring activities, all stakeholders are responsible for ensuring the methods we use are achieving their desired intent of protecting patients and data integrity,” said Briggs W. Morrison, MD, senior vice president of worldwide medical excellence at Pfizer and the study’s first author.
”Through further investigation, we will assess the potential impact of the variations in the monitoring practices observed, with the goal of generating widely adopted evidenced-based approaches.”
While 83 percent of respondents acknowledge using central monitoring practices made possible through the advent of new technologies, only 12 percent said they always or frequently use them.
In contrast, 87 percent of respondents report always performing on-site visits to participating study sites. This practice was most commonly associated with industry and clinical research organizations (84 percent combined) versus academic, government, or cooperative groups (31 percent combined).
“The frequency of on-site monitoring is one of the biggest drivers of cost in monitoring a clinical trial and an excellent example of an inefficiency that does not always lead to increased quality in clinical trials,” said Judith M. Kramer, MD, executive director of CTTI.
“Broader adoption of recent technological enhancements, such as electronic data capture and clinical trial management systems, may provide an effective and efficient method to target or replace on-site visits.”
Blame Game Doesn’t Help Obese Patients
Doctors should be more understanding when it comes to obese patients and their lack of success, according to a team of Vanderbilt University Medical Center (Nashville, Tenn.) obesity researchers.
Kevin Niswender, assistant professor of medicine and molecular physiology & biophysics, is two years into a line of basic research that indicates the challenges overweight and obese persons face are really similar to those faced by people with drug addictions.
“People with substance abuse problems have changes in certain parts of the brain and this causes them to continue to use substances and to increase their substance use in order to feel normal, or to have that sense of pleasure that people would get otherwise from healthier activities,” he said.
“Our idea is that people who have similar behaviors with regard to eating may be more predisposed to the development of obesity because they don’t experience that sense of reward or pleasure that an individual should feel from eating a more balanced meal.”
Niswender is teaming with Malcolm Avison, professor of radiology and radiological sciences, and translational nutrition scientist Heidi Silver on a new study designed to investigate the effects of insulin on energy balance, body composition, brain function and other risk factors for cardiometabolic disease.
The study will compare how a weight loss diet, with or without a newer type of insulin, affects areas of the brain’s dopamine system that are involved in food intake and the sense of pleasure people get from eating.
“This line of basic science research is really opening up a new way of thinking about the problems of obesity and overeating,” Niswender said.
“We think now that when one overeats, insulin has a different function. Insulin acts on those areas of the brain where dopamine normally functions to decrease the reward aspect of food intake, thereby helping to limit food intake.
“It is likely that this novel function of insulin is compromised in obese people.”
Coronary Heart Disease Can Go Unrecognized by Family Physicians, Study Finds
In a new study, researchers found that of 180 patients in whom a reference committee later identified coronary heart disease (CHD), 31.7% had originally been misdiagnosed by their family doctors as not having CHD (“false negative”).
Stefan Bösner and his colleagues presented the results of their cross-sectional study in Deutsches Ärzteblatt International.
When a patient presents with chest pain as the main symptom, the family doctor has to decide whether immediate action is called for or whether watchful waiting is an option. In this diagnostic cross-sectional study, the authors evaluated the data of a total of 1,249 patients over the age of 35 years who presented to 74 participating family doctors with chest pain. From this data pool, Bösner and colleagues extracted the doctors’ initial suspected diagnosis in respect of coronary heart disease (CHD). In a total of 57 patients, the doctor wrongly suspected another cause than CHD for the chest pain.
Nevertheless, the family doctors still referred one in three of the patients given such a false negative diagnosis to a cardiologist. In view of the number of missed cases of CHD, there is an argument for considering a diagnosis of CHD in patients with less pronounced symptoms. However, the researchers believe that if the “diagnostic threshold” were to be lowered, the result would be a dramatic rise in false positive diagnoses.
- Bösner S, Haasenritter J, Keller H, et al. The diagnosis of coronary heart disease in a low-prevalence setting: follow-up data from patients whose CHD was misdiagnosed by their family doctors. Deutsches Ärzteblatt International, 2011; DOI: 10.3238/arztebl.2011.0445