Fatal outcome after heart transplantation caused by Aspergillus lentulus.

Opportunistic invasive fungal infections are a major cause of mortality in immunocompromised patients. Early diagnosis of invasive aspergillosis and proper identification of the causative agent is crucial for guidance of therapy. Accurate differentiation of Aspergillus lentulus, a filamentous fungus often misidentified as atypical Aspergillus fumigatus, is of concern as multiple antifungal drugs show a reduced susceptibility. This is the first report, to our knowledge, of a proven pulmonary invasive fungal infection caused by A. lentulus after heart transplantation.

Activation of the heart by donor brain death accelerates acute rejection after transplantation.

BACKGROUND: Donor brain death upregulates expression of inflammatory mediators in the heart. It is hypothesized that these nonspecific changes trigger and amplify acute rejection in unmodified recipients compared with hearts from normal living donors. We examined the inflammatory and immunological consequences of gradual-onset donor brain death on cardiac allografts after transplantation. METHODS AND RESULTS: Functioning hearts were engrafted from normotensive donors after 6 hours of ventilatory support. Hearts from brain-dead rats (Fisher, F344) were rejected significantly earlier (mean+/-SD, 9. 3+/-0.6 days) by their (Lewis) recipients than hearts from living donor controls (11.6+/-0.7 days, P=0.03). The inflammatory response of such organs was accelerated, with rapid expression of cytokines, chemokines, and adhesion molecules and brisk infiltration of associated leukocyte populations. Upregulation of major histocompatibility class II antigens increased organ immunogenicity. Acute rejection evolved in hearts from brain-dead donors more intensely and at a significantly faster rate than in controls. CONCLUSIONS: Donor brain death is deleterious to transplanted hearts. The resultant upregulation of inflammatory factors provokes host immune mechanisms and accelerates the acute rejection process in unmodified hosts.

The impact of anti-endotoxin core antibodies on endotoxin and cytokine release and ventilation time after cardiac surgery.

OBJECTIVES: We hypothesized that a temporary cardiopulmonary bypass (CPB)-induced reduction of endotoxin antibody levels contributes to elevated endotoxin levels and the associated inflammatory consequences, with a significant influence on the postoperative ventilation time period. BACKGROUND: Cardiac surgery using CPB induces a systemic inflammatory response syndrome with an associated risk of increased postoperative morbidity and mortality. METHODS: A total of 100 consecutive patients undergoing elective coronary artery bypass graft surgery using CPB were prospectively investigated. Endotoxin core antibodies (immunoglobulin [Ig] M/IgG against lipid A and lipopolysaccharide), endotoxin, interleukin (IL)-1-beta, IL-6, IL-8 and tumor necrosis factor-alpha were measured serially from 24 h preoperatively until 72 h postoperatively. RESULTS: Eighty-five patients had no complications (group 1), whereas 15 patients required prolonged ventilation (group 2). In both groups, there was a decrease of all antibodies 5 min after CPB onset, compared with baseline values (p < 0.001), an increase of endotoxin and IL-8 peaking at 30 min postoperatively (p < 0.001) and an increase of IL-6 peaking 3 h postoperatively (p < 0.001). In group 2, preoperative antibody levels were lower (p < 0.01)--specifically, the decrease in IgM was significantly stronger and of longer duration (p < 0.002)--and levels of endotoxin (p < 0.001) and IL-8 (p < 0.001) were higher at 30 min postoperatively. CONCLUSIONS: We conclude that an CPB-associated temporary reduction of anti-endotoxin core antibody levels contributes to elevated endotoxin and IL-8 release. Furthermore, lower levels of IgM anti-endotoxin core antibodies were associated with a greater rise in endotoxin and IL-8, as well as prolonged respirator dependence.

Factors associated with methicillin-resistant coagulase-negative staphylococci as causing organisms in deep sternal wound infections after cardiac surgery.

Established preoperative antibiotic prophylaxis in cardiac surgery is ineffective against methicillin-resistant coagulase-negative staphylococci (CoNS). This case-control study aimed to determine factors predicting deep sternal wound infections due to methicillin-resistant CoNS. All cardiac surgery patients undergoing sternotomy between June 2009 and March 2013 prospectively documented in a Swiss tertiary care center were included. Among 1999 patients, 82 (4.1%) developed deep sternal wound infection. CoNS were causal in 36 (44%) patients, with 25/36 (69%) being methicillin resistant. Early reintervention for noninfectious causes (odds ratio (OR) 4.3; 95% confidence interval (CI) 1.9-9.5) was associated with methicillin-resistant CoNS deep sternal wound infection. Among CoNS deep sternal wound infection, perioperative antimicrobial therapy (p 0.002), early reintervention for noninfectious causes (OR 7.9; 95% CI 0.9-71.1) and time between surgery and diagnosis of infection over 21 days (OR 10.8; 95% CI 1.2-97.8) were associated with methicillin resistance. These findings may help to better tailor preoperative antimicrobial prophylaxis.

Endogenous tissue renin-angiotensin systems. From molecular biology to therapy.

Expression of the genes for renin and angiotensinogen has been documented in the heart and brain of several species, including rodents and primates. In the same tissues, local generation of angiotensin II has also been demonstrated. Neuropeptidergic brain angiotensin and local cardiac angiotensin participate in cardiovascular regulation. Inhibition of cardiac angiotensin II protects against deleterious arrythmogenic and metabolic effects of transient regional myocardial ischemia, and blockade of brain angiotensin II effectively lowers blood pressure in spontaneously hypertensive rats. It is surmised therefore that the therapeutic effects of converting enzyme inhibitors are, in part, brought about by inhibition of local tissue angiotensin II generation in addition to their interference with the hormonal plasma renin-angiotensin system. This would help to explain their therapeutic efficacy in pathophysiologic conditions in which hypertension is associated with low plasma renin activity.

Angiotensin formation in the isolated rat hindlimb.

Local vascular generation of angiotensin was investigated in isolated perfused rat hindquarters. Extraction and combined high-performance liquid chromatography (HPLC)/radioimmunoassay analysis of hindlimb perfusate showed a spontaneous release of angiotensin I (Ang I; 5.0 +/- 3.4 fmol/h) and angiotensin II (Ang II; 31.8 +/- 7.9 fmol/h). Angiotensin converting enzyme (ACE) inhibition with captopril abolished Ang II release while Ang I levels increased more than 10-fold. Perfusion with purified hog renin caused a dose-dependent angiotensin release and vasoconstriction. The renin inhibitor H-142 abolished all effects of renin whereas ACE inhibition prevented Ang II formation and vasoconstriction but increased Ang I levels. Metabolism and pressor effects of synthetic tetradecapeptide renin substrate (TDP), Ang I and Ang II were studied using a recirculating rat hindlimb perfusion system. TDP-dependent formation of Ang I and II, and an increase in perfusion pressure was shown; ACE inhibition reduced but did not abolish Ang II formation and vasoconstriction. Ang I was converted to Ang II by about 50% during one pass through a hindlimb. This conversion was abolished by ACE inhibition. These data add support to the presence of a functional vascular renin-angiotensin system.

A model of gradual onset brain death for transplant-associated studies in rats.

BACKGROUND: The relatively few studies that have examined the systemic events after brain death have primarily involved large animals. For more precise definition of the physiology of this central catastrophe and its influence on peripheral organs, we have established a reproduceable model of gradual onset brain death in rats. METHODS: The central injury is induced by graded inflation of a Fogarty catheter placed intracranially under EEG and blood pressure monitoring. The rats were mechanically ventilated for 6 hr before removal of their kidneys. Complications and mortality are discussed. RESULTS: The majority (83%) of the 100 experimental animals could be used as organ donors. After a transient period of autonomic storm, the mean arterial blood pressure remained consistently between 80-100 mmHg, not appreciably different from controls. Despite normotension, the transplanted kidneys from brain dead donors showed a significantly longer interval to regain uniform cortical color and turgor than kidneys from control animals. CONCLUSIONS: We describe a controlled model of gradual onset brain death in the rat in which normotension can be sustained for several hours before the kidneys are removed for transplantation. Despite stable donor blood pressure, ischemia of peripheral organs may explain in part the increased incidence of delayed graft function of cadaver kidneys compared with those from living donors. This model is suitable for transplant-related studies involving organs from donors with irreversible central injury.

Activation of inflammatory mediators in rat renal isografts by donor brain death.

BACKGROUND: Brain death (BD) has been thought to influence the early course of transplanted organs by triggering a series of nonspecific inflammatory events that in turn may increase the kinetics and intensity of the immunological host responses. In this study early nonspecific, cellular, and molecular changes occurring in kidney isografts from BD donors are compared with those from normal anesthetized, ventilated controls. METHODS: After induction of brain death, the animals were mechanically ventilated for 6 hr before organ removal. Only rats with stable blood pressure (mean arterial pressure >80 mmHg) were included. Serum creatinines were measured daily. Representative grafts were harvested 6 hr after brain death and between 1 hr and 5 days after engraftment for morphology, immunohistology, and reverse transcriptase-polymerase chain reaction. The presence of serum cytokines was assessed by enzyme linked immunoabsorbant assay. RESULTS: Serum creatinine levels rose slightly in recipients from BD donors. Serum interleukin-1beta levels increased within 6 hr versus controls (P<0.05). mRNA levels of interleukin-1beta and macrophage inhibitory protein-1 in the kidneys were up-regulated transiently before engraftment (6 hr after BD) and 1 hr after revascularization (P<0.05). By immunohistology, numbers of infiltrating polymorphonuclear leukocytes peaked at 24 hr in parallel with intragraft induction of P- and E-selectin, complement, and other proinflammatory chemokines and cytokines. At 5 days, the isografts from BD donors were highly infiltrated by host leukocyte populations associated with intense up-regulation of their products. In contrast, those from control donors remained relatively normal through this initial follow-up period. CONCLUSIONS: The intense nonimmune inflammation produced in isografts after donor BD may represent the initial stages of a continuum between an initial nonspecific and later immune reactivity, when placed in the context of allotransplantation.

Inducible heat shock protein 70 in rat cardiac allograft and its immunohistochemical localization in cardiac myocytes.

BACKGROUND: Heat shock proteins (HSP) are induced by a variety of stress and are presumed to play an important role in protecting cells from the effects of stress. Some evidence exists that HSP is involved in allograft rejection. Recently, an increase of inducible HSP 70 in heterotopic rat heart allografts was shown by quantitative Western blotting. To determine a possible mRNA induction and the localization of inducible HSP 70, we examined 19 heart transplants in rats. METHODS: Fisher F344 rat hearts were heterotopically transplanted into Lewis recipients (n=10), and nine cardiac isografts (Fisher to Fisher) were performed. The 19 native hearts of the recipients served as controls. Animals were killed on posttransplantation days 1, 3, and 5. The hearts were examined immunohistologically for inducible HSP and analyzed by a semiquantitative polymerase chain reaction for inducible mRNA. RESULTS: The level of HSP 70 mRNA in the allograft increased from day 1 to 3 and day 3 to 5 after transplantation and was significantly higher than that of time-matched isografts (0.92+/-0.49 vs. 0.49+/-0.05 and 1.14+/-0.53 vs. 0.53+/-0.15; P<0.05). The native hearts showed no elevated HSP 70 expression compared with isografts. Immunohistochemically, the majority of inducible HSP was located in cardiomyocytes adjacent to infiltrating lymphocytes, which where consistently negative. CONCLUSIONS: These results demonstrate that HSP mRNA expression in cardiac allografts is time-dependent, and its protein is expressed in cardiomyocytes.

Prediction of clinical outcome after cardiac surgery: the role of cytokines, endotoxin, and anti-endotoxin core antibodies.

Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) can lead to a systemic inflammatory response syndrome with organ failure and increased morbidity and mortality. The mechanisms of these findings are still under discussion. We investigated whether anti-endotoxin core antibodies, endotoxin, and proinflammatory cytokines influence the clinical course after cardiac surgery. Seventy-eight patients undergoing CABG using CPB were investigated. Anti-endotoxin core antibodies, endotoxin, interleukin (IL)-6, IL-8, IL-1beta, and TNF-alpha were measured 24 h preoperatively and up to 72 h postoperatively. Patients with a postoperative mechanical ventilation time below 24 h (n = 65; Group A) were compared to patients with prolonged respirator therapy (>24 h; n = 13; Group B). Preoperative antibody levels were significantly lower in Group B (P < 0.001). In this group, antibody levels remained decreased during the observation period (P < 0.001). Endotoxin significantly increased 30' postoperatively in both groups (P < 0.002). The increase in Group B was 3-fold higher (P< 0.001). IL-8 increased postoperatively in both groups, peaking 3 h after surgery (P < 0.001). In Group B, the IL-8 release was significantly higher than in Group A (P < 0.001). IL-6 significantly increased in both groups, reaching its maximum 24 h postoperatively (P < 0.001). No differences between groups were observed. No significant changes of IL-1beta and TNF-alpha were observed. We conclude that anti-endotoxin core antibodies may be predictive of adverse outcome after cardiac surgery. The imbalance between antibodies and endotoxin results in an exaggerated increase in endotoxin and IL-8 with an impact on clinical outcome.

Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172.

BACKGROUND: In patients with heparin-induced thrombocytopenia undergoing cardiac operations, anticoagulation with heparin should be avoided. The low-molecular-weight glycosaminoglycan Orgaran has been used as an alternative, but the overall experience is limited. METHODS: Two patients with heparin-induced thrombocytopenia underwent cardiopulmonary bypass using Orgaran for anticoagulation. A 30-year-old woman suffered from emboli to her brain through a secondary atrial septal defect, a 14-year-old boy from ischemia of his left leg due to recurrent embolism originating from the mitral valve. In both cases, cardiopulmonary bypass was performed in a routine manner, except for using low-dose Orgaran instead of heparin. Anticoagulation was monitored during cardiopulmonary bypass by measuring Orgaran plasma levels and activated clotting time. RESULTS: No thromboembolic or bleeding complications occurred during and after atrial septal defect repair and mitral valve replacement, respectively. In the former case, thrombotic material from the inferior vena cava was removed during hypothermic circulatory arrest within the same procedure. Activated clotting time did not correlate with plasma levels of Orgaran. CONCLUSIONS: Orgaran might be a useful alternative for anticoagulation during extracorporeal circulation. Adequate dosages and measurement of plasma levels are recommended for its use in cardiopulmonary bypass.

Cardiac pacemaker infection: surgical management with and without extracorporeal circulation.

BACKGROUND: Pacemaker infections are rare, but serious complications of pacemaker therapy. The generator pocket, the pacing leads, or both may be involved. METHODS: We report on 12 patients with infected pacemaker systems. Four patients suffered from localized generator pocket infections, 6 had infected leads, and 2 patients had both. Pacemaker systems were completely removed in all patients. When the infection was limited to the generator pocket, the pacemaker system was removed at the original implantation site. Extracorporeal circulation was employed for the explantation of infected pacing leads. RESULTS: No complications occurred in patients with localized generator pocket infections. One patient with infected leads who was preoperatively already in a serious clinical condition died of septic shock in the early postoperative period; another patient died of pulmonary complications after tricuspid valve replacement 14 months after pacemaker explantation. No recurrent infections were observed. CONCLUSIONS: Explantation of the complete pacemaker system has proved a reliable method to eradicate infection. Complications have been rare, except in patients in a critically ill state who undergo cardiopulmonary bypass.

Chronic rejection: increasing evidence for the importance of allogen-independent factors.

Chronic rejection is a process caused by an interplay of different risk factors. Early injury regardless of type, seems to be an important prognostic event. Later insults appear to contribute. As the individual components of the process are increasingly dissected and understood, means to modulate or normalize them will be forthcoming.

Molecular and cellular events associated with ischemia/reperfusion injury.

I/R is an important non-specific, antigen independent event, which significantly influences the outcome of transplanted organs. Increasing graft immunogenicity and host alloresponsiveness inflicts additional deleterious effects. Ischemia has also been associated with donor conditions such as brain death and the non-heart-beating donor. As an event surrounding organ procurement, preservation and revascularization occurring early in the transplant process, it initiates a cascade of molecular and cellular events which trigger the release of proinflammatory mediators and attraction of various cell types infiltrating the tissues. This inflammatory event influences both acute functional and structural changes in the organ which contributes to reduced graft survival. Eventually, attenuation of I/R by strategies targeting various mediators and cell populations at different levels of the inflammatory cascade may constitute a means to improve both short and long-term success of solid organ grafts.

Tissue renin-angiotensin systems: focus on the heart.

Recent findings support the existence of independently functioning, local renin-angiotensin systems in a number of tissues. The clinical importance that inhibitors of the renin-angiotensin system have gained in the treatment of hypertension and cardiac failure, as well as molecular biology data, suggest that a functional, tissue renin-angiotensin system is present in the heart. Using several experimental approaches we present evidence to support the existence and the possible physiopathological relevance of such a cardiac renin-angiotensin system. Tissue angiotensins were documented and quantified in different regions of the heart by high performance liquid chromatography combined with specific radio-immunoassay. Reduction of cardiac angiotensin after administration of converting enzyme inhibitors in nephrectomized animals indicates that these peptides are generated locally. Effects of converting enzyme inhibitors on angiotensin II-dependent facilitation of cardiac sympathetic tone further support this concept and emphasize the potential physiological role of a cardiac renin-angiotensin system. Further, direct evidence for local generation of angiotensin II in the myocardium is provided by assessment of the intracardiac conversion of angiotensin I to angiotensin II and by measurement of the activity of angiotensin converting enzyme in the heart.

The impact of pretransplantation urgency status and the presence of a ventricular assist device on outcome after heart transplantation.

INTRODUCTION: There are conflicting reports on the posttransplantation morbidity and mortality of patients listed urgently and/or supported by a ventricular assist device (VAD). The aim of this study was to analyze the outcomes with regard to pretransplantation condition (elective, urgent, VAD). METHODS: All adult recipients between January 1, 2005, and October 31, 2012, were included. Demographics; preoperative, operative, and postoperative data; outpatient follow-up; and donor characteristics were collected and analyzed. RESULTS: Of a total of 74 patients, 19 were listed urgently, 20 had a Berlin Heart EXCOR BVAD (biventricular assist device) (Berlin Heart, Berlin, Germany) (8 urgent), 7 had a Berlin Heart INCOR left VAD (Berlin Heart, Berlin, Germany) (2 urgent), and 2 had a HeartWare left VAD (HeartWare International, Framingham, Mass, USA) (none urgent). Mean age was 52 ± 12years. The overall 30-day, 1-year, and 3-year survival was 90% ± 3%, 79% ± 5%, and 66% ± 7%. There was no difference in survival when comparing urgently listed (95% ± 5%, 84% ± 8%, 74% ± 12%) and elective patients (89% ± 4%, 77% ± 6%, 63% ± 8%; P = .4), and VAD patients (86% ± 6%, 76% ± 8%, 63% ± 11%) and those without mechanical support (93% ± 4%, 81% ± 6%, 69% ± 9%; P = .6). In-hospital outcomes and long-term complications were also comparable. CONCLUSIONS: Our series suggests that urgent patients and patients on a VAD have a posttransplantation outcome comparable to elective patients and patients without a VAD. These data support the effectiveness of the current practice of listing for heart transplantation.