While the media spotlight has shone brightly on implantable cardioverter defibrillators (ICDs) of late, their external cousins – automated external defibrillators (AEDs) - have grown in numbers and in technological complexity. AEDs have saved thousands of lives, but their increased prevalence has not been without increased problems, and the authors of an article appearing Aug. 9 in the Journal of the American Medical Association (JAMA) make the case that the FDA should push manufacturers to more closely track their equipment. The agency wasted no time in responding to the recommendation, posting a statement on its web site stating that while it agrees with the bulk of the article’s findings, it noted “a few points on which the agency differs.”

The study in JAMA, authored by Jignesh Shah, MD, and William Maisel, MD, both of Beth Israel Deaconess Medical Center (Boston), based its findings on a review of FDA enforcement reports of recalls and safety alerts “to identify trends in these rates and to identify the types of malfunctions” leading to those actions. Shah and Maisel reviewed recall reports (available at the FDA web site) between January 1996 and December 2005, covering “2.78 million AED device-years.” According to the authors, “21.2% of AEDs distributed during the study period were recalled, most often because of electrical or software problems.”

The article notes that “confirmed fatal AED-related device malfunctions occurred in 370 patients,” but it does not specify the total number of times that the AEDs were actually used during the period studied. Maisel and Shah also do not specify how many of the 370 were directly attributable to operation of the defibrillators - or some other circumstance that might be counted as an adverse event - because such data are not often available for device adverse event reports due to difficulties in attribution of cause.

Of the 52 recalls, which affected almost 386,000 AEDs and AED accessories, 15 were for accessories, such as cables and pads, and the balance of 37 were for the defibrillator unit itself. Among the unit failures were failure to detect and failure to shock, both of which could include software failures. Software also is listed in its own category, however.

Of the 37 recalls for defibrillator units, the largest number in any one category was for failure to shock, the reason for five recalls that covered more than 51,000 defibrillators. Eight recalls were for electrical problems, pulling in almost 32,000 defibrillators. Recalls for “failure to detect” were in a near tie for the second spot with electrical problems, also at just under 32,000. Class I recalls accounted for four of the 37 unit recalls, and 31 were class II recalls.

As for accessory recalls, seven were for cables accounting for a total of somewhat more than 148,000 defibrillators, and four recalls for pad problems caught almost 51,000 defibrillators. All but one of the accessory recalls were class IIs.

The article reminds readers that class I recalls are those that involve a “reasonable probability that use of the product will cause serious adverse health consequences” and class II recalls are for devices that “may cause temporary or medically reversible adverse health consequences or the probability of adverse consequences is remote.”

Shah and Maisel point out that FDA advisories deal with “the potential for a device to malfunction, not [necessarily with] an actual device malfunction.” They assert that “as such, they are a surrogate marker of device reliability.” Qualifying this assertion, they acknowledge that “some advisories are issued even when the risk of device failure is less than 1%.”

The article also claims that “while a patient’s ICD is routinely registered with the manufacturer ... no such process occurs with AEDs” and that “the inability to track devices and end users makes it impossible to know how many AED units were actually fixed or taken out of service.”

This is one of the points that the agency disagrees with, insisting that it can document that “more than 95% of the AEDs affected by class I recalls in 2005 were returned to the manufacturers or taken out of service. Fewer than 3% were lost or stolen.”

As to the JAMA article’s argument that the number of AEDs affected by recalls has gone up, the FDA rebuts that, too. It says that “improvements in the devices’ ability to self-diagnose hardware and software problems may contribute to this trend,” which often brings units out of distribution “before a device is ever used on a patient.”

Anne Devine, a communications specialist for Medtronic (Minneapolis) said, “Overall, Medtronic thinks it was a balanced article” but insisted that “we do track [AEDs] very carefully.” She told CDU that the company does not favor a different regulatory approach.

Stress testing combined with stress agent

Heart problems can be easier to diagnose when the heart is working harder and beating faster than when it is at rest. During stress testing, an individual exercises (or is given a pharmacologic stress agent if unable to exercise) to make the heart work harder and beat faster while blood flow to the heart is being examined.

A research team from the Netherlands used stress testing with exercise or a pharmacologic stress agent (dobutamine in conjunction with radiolabeled tetrofosmin, a widely available radiotracer) to assess perfusion (blood flow) to the heart muscle and determine risk of heart events in obese patients.

”Prognostic Stratification of Obese Patients by Stress 99mTc-Tetrofosmin Myocardial Perfusion Imaging” appeared in the August issue of the Journal of Nuclear Medicine. Abdou Elhendy, of the Marshfield Clinic (Marshfield, Wisconsin), was joined by co-authors Arend Schinkel, Ron van Domburg, Elena Biagini and Don Poldermans, all with Thoraxcenter, University Hospital Rotterdam; Jeroen J. Bax, Leiden University Hospital, the Netherlands; and Roelf Valkema, nuclear medicine department at the University Hospital Rotterdam.

PKA, jellyfish protein aid cell imaging

Scientists studying heart cells have devised a new way to visualize and quantify the rise and fall in the activity of a key enzyme linked to heart failure, offering a window to the inner workings of heart cells that is expected to help in the development of more effective drugs to treat heart failure.

In a paper appearing in the August online edition of Proceedings of the National Academy of Sciences, the researchers at the University of California, San Diego describe the use of an engineered protein partly derived from a jellyfish that fluoresces within heart cells in tandem with activation of the key enzyme called PKA (protein kinase A). By combining computer modeling with the novel fluorescence-imaging technique in living cells, the researchers were able to uncover new details in the molecular control of PKA.

PKA is an intensely studied regulatory enzyme whose activity in heart cells rises sharply in response to exercise or various stresses, priming the heart to beat faster and with more power, and to increase its metabolic rate to meet the increased energy demands.

”For the first time, this innovative visualization technique allowed us to refine our computational models and get a better understanding of the interacting biochemical pathways in heart cells that involve PKA,” said Andrew McCulloch, a professor and chair of the department of bioengineering at UCSD’s Jacobs School of Engineering. “Now we’re in a good position to do similar experiments with mutant strains of mice that experience heart failure in ways that mimic human disease.”

Fluorescence-tagged proteins have been used before to probe heart cells; however, the results reported in PNAS were the first in which the proteins have been used to visualize PKA activity in those cells. The most recent visualizations, combined with mathematical models, provide more detailed and quantitative measurements of PKA activation.

PKA affects the heart rhythm in ways that are readily detectable with an electrocardiogram. However, a better understanding of how the PKA-dependent regulatory system works in healthy heart cells, and how it is altered in diseased cells, may reveal underlying causes of heart failure.

The key enzyme in heart muscle signaling, PKA is a member of a huge class of regulatory proteins called kinases. Each kinase is specialized to attach a phosphate molecule to a specific set of target proteins. These phosphorylation reactions switch targeted proteins from an inactive state to an active state. PKA actually activates other kinases, which in effect amplify the effect of PKA through a signaling cascade.

The activity of kinases is delicately balance by a group of enzymes called protein phosphatases, which simply remove phosphate groups from specific proteins, inactivating them. About 30% of all human proteins are regulated by kinases and phosphatases.

Activation of PKA is actually initiated at the exterior surface of heart cells where neurotransmitters and hormones bind to beta-adrenergic receptors. However, while drugs that boost PKA activity temporarily increased cardiac contractions, they also led to higher patient mortality in the long term.

While the series of PKA signaling behaviors reported in the PNAS paper confirmed parts of a sophisticated computer model of myocytes regulation, there were surprises as well. “The devil is in the details of a biochemical system so complex, but by pursuing those details we may be able to help develop therapies designed to treat patients with inherited or acquired defects in this important system,” said McCulloch.

He added, “The improvement of our computer models goes hand-in-hand with the ability to test them in living heart muscle cells with these novel visualization tools. This combined approach takes advantage of what we already know, but also opens up new opportunities to find missing pieces of the puzzle.”