Laura J. Pinderski

Infection in ventricular assist devices: prevention and treatment

Infection is one of the most important challenges to the use of implanted mechanical circulatory support systems (MCSS), particularly as we enter the era of permanent device use in patients who are not candidates for cardiac transplantation. This paper describes the pathogenesis of MCSS infection, with particular attention to the role of biofilm-forming bacteria. Suggestions are presented for the prevention and treatment of infections in implanted MCSS.

Selection of patients and techniques of heart transplantation

Cardiac transplantation remains the primary therapeutic choice for most patients under 65 years of age with advanced heart failure who remain symptomatic despite maximal medical therapy. Cardiac transplantation should be reserved for those patients most likely to benefit in terms of both life expectancy and quality of life. The concept of survival benefit margin must be balanced with the principles of utility in the selection process. A critical component of outcomes research for advanced heart failure will be the generation of accurate data and analyses which predict long-term survival and quality of life with various therapeutic modalities. Patients with multiple comorbidities have inferior survival and might be considered for alternative therapies. We currently recommend the bicaval techniques as the transplant technique of choice except in small infants and children.

Donor PAI-1 expression inhibits the intimal response of early allograft vascular disease.

BACKGROUND The development of allograft vascular disease (AVD) may be related to altered expression of the fibrinolytic system. We determined the extent to which plasminogen activator inhibitor type 1 (PAI-1) expression in donor tissue influences intimal proliferation (IP) in a mouse model of AVD. METHODS We utilized an end-to-end abdominal aortic transplant model in mice to investigate the development of IP in 3 groups of 6 recipients. Group A (negative control) utilized C57BL/6J strain mice as both donors and recipients. In Groups B (positive control) and C, C57BL/6J mice were vessel donors and CBA/J mice were recipients. Both groups received intraperitoneal anti-CD4 and anti-CD8 monoclonal antibodies (250 microg/week for 5 weeks). Group C recipients, however, were transplanted with vessels from C57BL/6J PAI-1 knockout mice. Animals were killed at 50 days. Transplanted aortas were removed and intimal areas calculated using morphometric analysis. RESULTS Group A (mean intimal area 6421 +/- 8507 microm(2)) demonstrated very little IP in comparison to the other groups. IP was significantly higher in Group B (mean intimal area 56357 +/- 35629 microm(2)) than Group A (p = 0.008). Group C (mean intimal area 288195 +/- 123279 microm(2)) demonstrated significantly more intimal proliferation than either Groups A or B (vs B, p = 0.003; vs A, p < 0.001). The significance of these results is maintained if intimal thickness is measured as a stand-alone reference for the intimal response. CONCLUSIONS Lack of PAI-1 expression in donor tissue greatly exaggerates the extent of IP after allogeneic transplantation and suggests that PAI-1 is important in limiting the early phase of AVD.

Allogeneic bone marrow inhibits T-cell activation and clonal expansion in vitro.

Background. Donor bone marrow infusion has long been used to enhance graft survival or induce tolerance in T cell depleted solid organ allograft recipients. However, the mechanisms through which bone marrow cells affect tolerance remain obscure. We studied the affect of allogeneic bone marrow cells on the activation of allospecific T cells in vitro. Methods. Carboxyfluorescein‐diacetate succinimidyl ester‐labeled CBA/Ca strain CD8+ splenocytes, bearing T‐cell receptor &agr; and &bgr; transgenes from the BM3.3 T‐cell clone specific for the major histocompatibility complex class I antigen Kb, were placed in culture with irradiated C57BL/6J stimulator cells in the presence of increasing numbers of C57BL/6J or Balb/cJ bone marrow cells for 1 to 3 days. Responder cells were individually analyzed for proliferative history, expression of activation‐associated antigens, and intracellular cytokine production. Results. Allogeneic bone marrow cells exert a dosedependent inhibitory effect on proliferation of allospecific CD8+ T cells in mixed lymphocyte culture. However, the inhibited T‐cell subpopulations show physiologic changes associate with the early stages of T‐cell activation, including expression of CD69 and early decrease of surface T‐cell expression. Unlike cells not co‐cultured with bone marrow, these cells fail to reexpress the T‐cell receptor (TCR) by 72 hr of culture. The observed inhibitory effect is also associated with a decrease in the proportion of CD8+ cells expressing interleukin‐2 and interferon‐&ggr;. Conclusions. Collectively, these results suggest that peripheral allospecific T cells undergo the initial stages of activation on exposure to antigen in the presence of bone marrow cells, but the cell cycle is arrested and TCR reexpression is inhibited. We speculate that bone marrow cells effect this inhibition through a receptor‐ligand interaction that modulates the transmembrane signal pathway for the TCR.

The use of bosentan and a prostacyclin analog in the treatment of primary pulmonary hypertension

early (range 3-7 fractions) due to minor marrow suppression or infectious complications. The mean (sd) nadir leukocyte count was 2.98 (1.34) x 10 and platelet nadir 114 (41) x 10. Seven (19%) required blood transfusion and only 2(5%) had serious infections as complications. Duration of TLI course was mean (sd) 62.8 (41.7) days. Mean (sd) rate of decline in FEV1 was 122.7 (21.6) mls/month before TLI and 25.1(7.7) mls/month after TLI, (difference in rate of decline 95% CI 48.2-146.7), p 0.0004 (students paired t-test). Total survival in the 37 treated recipients is median (range) 59 (6-146) months and the post TLI survival is 27 (0-93) months. TLI is a well tolerated treatment with only mild marrow suppression and a low incidence of serious infection. It results in a significant reduction in the rate of FEV1 decline in rapidly progressive BOS. TLI should form part of the immunosuppressive armoury in patients with aggressive BOS.

Response of doxorubicin-induced cardiomyopathy to the current management strategy of heart failure

BACKGROUND Doxorubicin (D) (Adriamycin) is a potent and efficacious chemotherapeutic agent in the treatment of various forms of cancer, but its use has been limited by the development of cardiac toxicity. Historically, D-induced cardiomyopathy (CMP) has been refractory to therapy. We report our experience with this form of CMP at the University of Alabama at Birmingham. METHODS Twenty-five patients (20 women, 5 men) with a clinical diagnosis of D-CMP were referred to our program from 1990 to 2003. Patient data were extracted from office charts. RESULTS Patients were followed-up for 71 +/- 58 months. On presentation, the average left ventricular ejection fraction (LVEF) was 26 +/- 9.2%, and 88% of patients were New York Heart Association (NYHA) Class III or IV. Patients were treated with angiotensin-converting enzyme inhibitors (ACEi; n = 23) or angiotensin-receptor blocker (ARB; n = 2), and 15 were treated with a combination of ACEi and beta-blockers (BB). With medical therapy, LVEF improved significantly (26 +/- 9.2% vs 35 +/- 16.5%, p = 0.022), as did the NYHA class (p < 0.003). All survivors (n = 19) were NYHA Class I or II with medical therapy, with 10 (53%) being Class I. In the group of patients treated with ACEi + BB, there was a statistically significant improvement in LVEF (26 +/- 10.0% vs 37 +/- 17.6%, p = 0.028), which not seen in the ACEi group, with a strong trend toward normalization of LV function (47% vs 10%, p = 0.054). CONCLUSIONS In the current era of management of heart failure, D-CMP carries a better prognosis than previously described. Early addition of BB may further improve LVEF.