Clinical and Industry News: Part II

Genes Can Influence Where Plaque Happens in Heart Arteries Heredity sometimes influences where fatty deposits develop in a coronary artery, researchers reported. Different locations of disease show different degrees of inheritance, said Ulrich Broeckel, MD, one of the study’s authors. The most hazardous ones have a high heritability. The new findings, if confirmed, could affect heart disease screening strategies for close relatives of coronary heart patients. Coronary heart disease involves a complex combination of genetic and environmental factors. Physicians have long known that a family history of the disease is a major risk factor for a heart attack. But, researchers have devoted scant attention to whether genes might partially govern where the fatty deposits develop within the heart’s arteries. As far as we can determine, we are the first to do a large study of the genetic contribution to the location and pattern of coronary lesions, said Broeckel, assistant professor of medicine at the Medical College of Wisconsin in Milwaukee. He and his colleagues conducted their study as part of a 10-year collaboration that includes the Medical College of Wisconsin, the University of Regensburg in Germany and the University of Luebeck, also in Germany. The researchers studied angiograms of 882 siblings with coronary artery disease from 401 families. One person from each family had had a heart attack before age 60 and at least one sibling had had a heart attack or coronary revascularization. The team compared the angiograms of the 401 people who’d had a heart attack before age 60 (one from each family) to that of a sibling who’d had a heart attack or revascularization procedure. They found that a large number of sibling groups had shared disease patterns, indicating a genetic influence. After considering several factors that affect the risk of coronary disease, such as age, gender, hypertension, and diabetes, an analysis showed a statistically significant association between inheritance and: Coronary heart disease at the point where the coronary arteries branch off from the aortic artery, as well as in the upper parts of the left and right coronary arteries. A blockage there shuts off blood flow to a greater proportion of the heart than one lower down. The degree of artery ectasia; that is, abnormally widened portions of the vessels, which are associated with coronary heart disease. The amount of calcified artery deposits. The researchers found a lesser degree of statistically significant influence, or none at all, between heredity and: Coronary disease in the lower parts of the heart’s left and right arteries. Diffuse disease; that is, heart disease spread throughout at least two-thirds of an artery. When the right and left coronary arteries were compared separately, there was a higher heritability in the left artery. The pattern of blood supply, as determined by whether the right or left artery dominated the flow of blood. Whether a person had disease in one, two or three arteries. The researchers did not design the study to reveal the actual genes that might influence disease development at different artery sites. That is our next step, Broeckel said. The study findings may help improve screening for relatives of people with coronary heart disease, he said. For example, the genetic link to disease in the left main artery may offer a more precise way to predict a relative’s risk of having or developing the same problem. The researchers noted several limitations of the study that could affect its results. All the participants were white and of northern European origin, which means the genetic findings might not apply to other ethic groups. Moreover, the study did not consider to what degree the siblings shared the same living environment, which could mean an overestimation of the genetic role in disease at specific sites. Heart Repair Linked to Migraine Relief Provocative results of retrospective studies prompt calls for randomized controlled trials Migraine headache patients reported the painful attacks eased or even vanished after they underwent procedures to close abnormalities that allow blood to flow between the atria of their hearts, according to the results of two new studies. What we observed is that after closing the opening between heart atria, there was a dramatic reduction in the incidence of migraine headaches in those patients who had complained of headaches prior to the inter-atrial closure procedure, said Jonathan Tobis at the University of California in Los Angeles. Dr. Tobis and his colleagues, including lead author Babak Azarbal, MD, reviewed 89 cases in which a device was threaded through a catheter into an abnormal intra-atrial opening. Almost half the patients (37 of 89) reported suffering migraine headaches before the procedure. By contrast, only 12 percent of the general population reports suffering migraines. Three months after the procedure, three-quarters of the migraine sufferers (28 of 37) reported their migraines were gone or significantly improved. In the second study, Mark Reisman, MD, and his colleagues in Seattle, Wash., reviewed 162 cases of patients who underwent a transcatheter procedure to close an intra-atrial opening (patent foramen ovale) because they had suffered a stroke or transient ischemic attack. The results were extraordinary. We’ve been able to see a significant number of patients who have had not just a reduction in the frequency of headaches but actually complete relief, said Mark Reisman, MD at Swedish Medical Center in Seattle, Wash. This study further supports a link between a common heart abnormality and migraine headache. Of the 162 patients studied, 57 (35 percent) reported suffering migraines before undergoing the procedure. A year after the procedure, the researchers contacted 50 of the migraine suffers. More than half (28 of 50) said their migraines were gone and another seven patients said the frequency of migraine attacks had dropped by more than 50 percent. Although many migraine suffers are eager for any procedure that could offer them potential relief from the debilitating attack, both Dr. Reisman and Dr. Tobis stressed that randomized, controlled clinical trials are needed before recommending heart procedures as a possible migraine treatment. They also noted that there are migraine suffers who do not have heart abnormalities, and people with intra-atrial holes who do not suffer migraines; so the link seen in these studies, even if confirmed, does not explain all migraines. The studies involved patients receiving treatment for patent foramen ovale or atrial septal defect. Dr. Reisman said his team decided to look into possible links between heart abnormalities and migraines after patients began spontaneously telling them that their headaches had disappeared after the catheter procedures. This is a huge leap in our understanding about the potential causes of migraine headaches. For centuries there have been explanations for migraine headaches that run the gamut from demons to vascular spasm. However, there has been no good scientific explanation for these headaches, Dr. Tobis said. These studies were not designed to uncover how a hole in the wall between heart chambers could cause migraines, but researchers have some suspicions. The blood normally circulates through the lungs on its way from the right atrium to the left atrium, but the atrial wall hole short-circuits that usual route. So the researchers said future studies should look for signs of impurities or tiny clots passing through the intra-atrial hole that may be filtered or metabolized by the lungs in a person with normal circulation. Because of the dramatic nature of the changes reported by patients in these observational studies, Dr. Reisman said a more definitive clinical trial could be done with in a couple of years. The population for this study would be patients who suffer from frequent and severe migraines, those who are unresponsive to current medications or have significant side effects due to the medications. That would be the population to focus on, he said. Sotirios Tsimikas, MD, at the University of California in San Diego, cautioned that while these studies provide a strong rationale for further investigation, a healthy skepticism should be in place until randomized, controlled trials are performed. From the migraine patient perspective, I would suggest patients stay tuned for more studies before we know whether this may be of benefit. Patients with severe migraines and PFO may consider enrolling in trials that will be forthcoming in the future, Dr. Tsimikas said. This is the first chapter in a very interesting story that may have a happy ending where some migraine patients may ultimately benefit from closure of patent foramen ovale or atrial septal defects. It also suggests new hypotheses on how migraines occur, and this is exciting from a research perspective. Spencer King, MD, at the Fuqua Heart Center in Atlanta, said the study results support the observations of others who noted improvements in migraine symptoms following the closure of intra-atrial holes. There are many examples, however, of treatments that relieve symptomatic conditions but are not effective when subjected to randomized trials. There does not seem to be any question that many patients are better, but it is less clear that closure of the defect is the reason. A double-blind randomized trial will be necessary, Dr. King said. Dr. Tobis said that he will be the cardiology principal investigator for a future randomized clinical trial sponsored by the manufacturer of one of the PFO occluder devices used in the procedure, but that the company (AGA Medical Corporation) did not provide funding for this study. Drug-Eluting Stents Stretch Limits, Remain Effective, No Ill Effects Observed From Overexpansion A recent study provides evidence that expanding a drug-eluting stent (DES) up to 1 mm beyond its intended diameter to ensure a snug fit does not weaken the stent or increase the risk of restenosis. Overexpansion of a stent could distort its geometry, causing a loss of scaffolding strength and intrusion of plaque through the wire mesh. With a DES, there is the additional possibility of uneven release of the drug coating. These concerns do not appear to be justified, according to the study from researchers from EMO Centro Cuore Columbus and San Raffaele Hospital, both in Milan, Italy. The need to overdilate a stent is frequently present when the artery is larger than the stent balloon system, said Dr. Antonio Colombo. It is important to know that such a procedure is not deleterious. The study involved 254 patients who were treated with a sirolimus-coated stent. The stent was expanded to its intended 3.0mm diameter in 168 patients, but required overexpansion with a high-pressure balloon to 3.5-4mm in 86 patients. The researchers found no difference between the two groups in the rate or of restenosis during follow-up angiography. In addition, during the first 6 months, a similar proportion of patients about 9% in each group experienced a major cardiac illness, including heart attack, death, and the need for repeat angioplasty, stenting, or coronary artery bypass graft surgery.

Source: Catheterization and CardiovascularInterventions: Journal of the Society for Cardiovascular Angiography and Interventions, February 2005.