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High rate of serious infections among findings
Acquiring a heart for transplant, no matter how badly a patient needs one, is a dicey prospect. Of the 40,000 people each year with end-stage heart failure who could be helped with a transplant, only about 3,000 manage to get one. Left-ventricular assist devices (LVAD) are used as bridges to transplant, and researchers continue to investigate their use as an alternative permanent therapy for those patients. But there’s a problem: Long-term device implantation is rarely an option because of the high rate of serious infections that the devices carry.
A group of investigators at Columbia-Presbyterian Medical Center in New York City recently examined the relation between LVAD-related infection and the immune responses of LVAD recipients.1 They compared the rate of candidal infection in 78 patients with New York Heart Association class IV heart failure who received either an LVAD or medical management.
Three months after LVAD implantation, the risk of developing candidal infection was 28% in LVAD recipients, compared with 3% in the control group. T-cell death rate was higher in LVAD recipients than in controls. The investigators concluded that LVAD implantation results in an aberrant state of T-cell activation, heightened susceptibility of some T-cells to activation-induced cell death, progressive defects in cellular immunity, and increased risk of opportunistic infection.
"It is important to emphasize," says Silviu Itescu, MD, a cardiothoracic surgeon and one of the study’s authors, "that these abnormalities occur in heart failure patients only after LVAD implantation. They are specific to the device implantation. They do not occur in other patients undergoing heart surgery or bypass."
"Apoptosis is programmed cell death," says Mehmet C. Oz, MD, also a cardiothoracic surgeon at Columbia-Presbyterian and one of the investigators. "The cell turns off its basic life mechanism, and it dies as a result." He says that’s mainly what aging is, but the phenomenon the investigators wrote about is programmed cell death of a rapidly growing, then shrinking, population of cells.
The T-cell apoptosis appears to result from excessive T-cell stimulation by the LVAD itself, almost as though the recipient’s T-cells are attempting to reject the device but cannot do so and consequently enter into a pro-apoptotic pathway. These are not phenomena that are seen in transplant recipients, perhaps because they routinely receive drugs that inhibit T-cell activation. However, says Itescu, it is likely that in the absence of immunosuppression, many of these phenomena would also be seen in recipients of any organ.
Oz explains the phenomena this way: "The LVAD patients were doing two things. They were developing a hyperacute immune response — a very aggressive immunologic response — and at the same time, they were prone to certain types of infections, more than we anticipated. When we investigated this, we found that there were two T-cell lines. One T-cell line was overresponding, and because it was overresponding, the other T-cell line was underresponding." He says there’s usually a balance between the different levels of immune response, but the LVAD seems to stimulate one arm more than the other.
Death of T-cells, says Itescu, promotes infection by viruses, fungi, and other opportunistic patho-gens because one needs T-cells to combat these organisms. The prototypic disease where loss of T-cells leads to infection is HIV-1. In that disease, also, T-cells die through apoptosis in addition to other mechanisms. LVAD patients who undergo transplantation do not have an increased risk for infection compared to other transplant recipients. Therefore, "one can consider the immune defects and risk for infection we have described as only a problem for potential long-term LVAD use, as permanent therapy," explains Itescu. He describes therapeutic use as LVAD implantation for years, not months as with bridge-to-transplant use.
The research done by Oz and colleagues was not at the level of trying to define markers or tell-tales of LVAD infection. That was beyond the scope of the investigators’ study. "That’s not the level of our research," says Oz. "It’s much more basic. We’re just describing the phenomenon and epiphenomenon — what’s going on and the other signs of it."
"In the short term, all patients not responding to medical therapy can benefit from LVADs," says Itescu. "There are no predictive variables that would help decide whether LVAD or medical therapy is optimal for an individual patient."
Designing a treatment strategy is perhaps the next step in this research. For that next step, researchers will look at medications that specifically block whatever is overstimulating the one arm of the T-cells," Oz says. "If we can block them from being overstimulated, the other arm won’t be understimulated."
He says that participants in the study were waiting for heart transplants. Patients with LVADs are weakened, but they can survive. "They’re better off without the device and the infection than with the device," he says. "Our findings don’t help us decide in whom to place the device, just to deal with the problems once it’s in."
"The major positive impact of using LVADs as bridges to transplant," says Itescu, "is on patient survival while on the waiting list." Without LVADs, about 30% of patients die while waiting several months for an organ, whereas with an LVAD, waiting-list mortality is almost negligible.
"The immune problems during this short period do not generally lead to life-threatening infections since the defects need to accumulate over time," he says. "In LVAD patients with immune activation/T-cell apoptosis, we have observed an increased incidence of concomitant B cell activation and production of anti-HLA antibodies. This sensitized’ state is associated with a greater risk of cellular rejection post-transplant. For these patients, we have developed immunosuppressive protocols pre-transplant [while on LVAD support], and now their post-transplant outcome is as good as any nonsensitized transplant recipient."
1. Ankersmit HJ, Tugulea S, Spanier T, et al. Activation-induced T-cell death and immune dysfunction after implantation of left-ventricular assist device. Lancet 1999; 354:550-555.