Last month's 73rd scientific sessions of the American Heart Association (AHA; Dallas, Texas), held this year in New Orleans, didn't exactly throw a bright light on medical devices in the cardiovascular sector. Most of the press briefings were focused on genetic therapy and tissue engineering, on the clinical side, and on the higher risks of heart disease among women and African-Americans, in new epidemiology studies. In the device sector, attendees did show considerable interest in just-approved brachytherapy treatments for in-stent restenosis (see Product Pipeline, page 21, for more on these approvals) and several sessions helped to promote the new market potential for automated external defibrillators (AEDs).
The emphasis on deploying an increasing number of defibrillators – especially in high-stress, high-traffic areas – was heightened just before the AHA meeting with congressional approval of a bill directing the department of Health and Human Services to develop guidelines for placing AEDs in federal buildings. Those guidelines are expected to provide standards for their placement in a broad variety of other public and private venues. The federal legislation in turn was supported by the AHA's recent adoption of guidelines stressing the need to provide defibrillation for heart attack within three minutes of onset, and the November publication of research in the New England Journal of Medicine concerning the ability of AEDs to save lives in casinos and other public locations.
The brief window of therapeutic opportunity following heart attack was addressed in a variety of ways at the AHA sessions and on the conference's exhibition floor.
On the theoretical side, an academic presenter told a large conference room audience that the primary need was for a device that would monitor the onset of a heart attack and would then signal emergency personnel concerning the precise location of the victim. But such an approach was considered highly unrealistic by the AED manufacturers at the AHA sessions. They pointed out that location of the victim is far from guaranteeing life-saving defibrillation within the first, precious three minutes afterwards. Not even the close presence of a defibrillator guarantees that, said Raymond Cohen, president of Cardiac Science (Irvine, California), who noted that research indicates "you have a better chance of surviving a heart attack in a casino than you do in a hospital." According to research spotlighted by Cardiac Science, hospital defibrillation takes between five and six minutes to reach victims, and the rate of survival-to-discharge is an anemic 15%, figures which Cohen termed "abysmal." Cardiac Science is attempting to improve these statistics with a combination monitor/AED for the high-risk hospital patient, which is attached to the patient and provides defibrillation automatically.
But then most heart attacks don't occur in the hospital. The large majority happen outside the hospital, most of them in the home. Wherever they occur, they are not witnessed, more often than not. To address this problem, Cardiac Science and LifeCor (Pittsburgh, Pennsylvania) are developing "wearable" defibrillators designed for high-risk patients. Cardiac Science is developing a Walkman-type device that is worn on a belt, with sensors attached to the chest. The LifeCor device, currently in clinical trials and closer to FDA approval, is a type of harness that can be worn underneath clothing, with sensors that provide a warning of any arrhythmia that may lead to an attack. When this happens, the wearer holds a sensor between thumb and forefinger and dropping it – for instance, if unconsciousness occurs – triggers a defibrillating shock.
Whatever the particular strategy used, the AED manufacturers at the AHA meeting said that the new federal legislation will provide a growing awareness of what AEDs can do, and, just as important, the need for quick response. According to one company representative, the new guidelines will provide a "cookbook" for broad deployment of the devices, further reinforced by extensive training in their use. Additionally, liability issues that have so far provided a barrier to general usage could eventually work as an incentive for their adoption.
Serotonin receptor and heart development
The discovery that absence of one of the many receptors for serotonin causes congenital heart defects in mice may lead to new drugs for treating some types of heart disease. French researchers predict that their discovery will lead to a better understanding of how and why certain heart defects develop, and how to improve treatment of heart disease. Luc Maroteaux, research director of the Centre National de la Recherche Scientifique at the Universite Pasteur de Strasbourg (Illkirch, France), said, "Our study provides the first genetic evidence that a molecule such as serotonin, which is a well-known neurotransmitter involved in human pathologies such as depression, is also used to control the proper development of organs such as the heart. As a result of this finding, we will be able to pursue investigations on serotonin in organ development and functioning."
The work was reported in the National Academy of Sciences in a paper titled, "Serotonin 2B receptor is required for heart development." Serotonin is an alternative name for 5-hydroxytryptamine (5-HT), found mainly in the intestinal wall, in platelets and in the central nervous system. In the vascular system, it acts as a vasoconstrictor, while in the central nervous system it has a role as a neurotransmitter, influencing diverse behaviors including appetite, sleep, memory and learning. Studies have also suggested that it is required for normal embryonic development, including craniofacial development and development of the heart.
There are at least 15 receptors to which 5-HT is known to bind to mediate its actions. Researchers have classified these into four families. Attempts to generate knock out mice lacking the genes for these receptors have resulted in animals where the only apparent abnormality is in their behavior.
Now, Maroteaux and his colleagues have reported that mice lacking a receptor belonging to the 5-HT2 family have abnormal heart development. That receptor, called 5-HT2B, is a G protein-coupled, seven transmembrane-spanning receptor expressed in the heart, intestines and brains of both embryonic and adult rats, mice and humans. "Our results identify a 5-HT2B receptor-mediated pathway by which 5-HT interacts with ErbB-2 [the receptor for the peptide growth factor called neuregulin] to control differentiation in [the] developing heart," they said in the research paper. "These results reveal 5-HT via 5-HT2B receptor as an important regulator of cardiac myocyte differentiation and proliferation."
Maroteaux and his group prepared mice lacking both copies of the gene encoding the 5-HT2B receptor. When mice heterozygous for the deleted gene were crossed with each other, only 16.7% of the pups were homozygous, compared to the expected 25%, figures which they suggested show "some embryonic lethality."