Left ventricular aneurysm in a four-year-old child: a diagnostic challenge.

We describe spontaneous rupture of a congenital left ventricular (LV) aneurysm with subsequent tamponade and cardiac arrest in a 4-year-old male with staphylococcal septicemia. Emergency resuscitation, thoracotomy, and oversewing were successfully undertaken in the pediatric intensive care unit. There was complete cardiovascular recovery without adverse neurodevelopmental sequelae.  This article details the difficulties in determining the etiology of ventricular aneurysms but highlights the importance of attempting to do so, particularly in distinguishing between congenital and acquired forms. Congenital aneurysms are usually a stable pathology; mycotic aneurysms are not and should be managed emergently, as survival after rupture is rare.

Left ventricular volume reduction surgery for heart failure: a physiologic perspective.

BACKGROUND: Ventricular volume reduction surgery for idiopathic cardiomyopathy fails to improve cardiac output and is associated with a high incidence of recurrent heart failure. Volume reduction surgery achieved by removing akinetic or dyskinetic myocardium after myocardial infarction appears to be associated with better outcomes. The reasons for the differences in outcomes are not clear. METHODS AND RESULTS: The hemodynamic effect of the major forms of volume reduction surgery were predicted by using a composite model of the left ventricle in which 20% of the myocardium was given properties of either weak but contracting muscle, an akinetic scar, or a dyskinetic scar (aneurysm). The end-systolic and end-diastolic pressure-volume relationships were determined numerically for each simulated operation. Any volume reduction procedure reduced chamber size, shifting end-systolic and end-diastolic pressure-volume relationships leftward. With resection of weak but contracting muscle, the leftward shift was greater for the end-diastolic than for the end-systolic pressure-volume relationship. Conversely, with resection of dyskinetic scar, the leftward shift was greater for end-systolic than for end-diastolic pressure-volume relationships. In contrast, resection of stiff scar shifted the 2 relationships equally. The effect on overall pump function was indexed by the relationship between total ventricular mechanical work and end-diastolic pressure. There was a beneficial effect on this relationship of resecting dyskinetic tissue, an equivocal effect of akinetic scar resection, and a negative effect of removing contracting myocardium. CONCLUSIONS: The effect of volume reduction surgery on overall ventricular pumping characteristics is determined by the differential effects on end-systolic and end-diastolic properties, which in turn are determined by the material properties of the region being removed.

Direct cardiac compression for cardiogenic shock with the CardioSupport system.

Epicardial direct cardiac compression for cardiogenic shock avoids a blood surface interface with associated thromboembolic and immunologic sequelae and could be placed rapidly with technical ease. The Cardio Technologies device provides synchronized biventricular cardiac compression, is placed via a thoracotomy, and remains on the heart without need for sutures. In preclinical work, the system has successfully restored cardiac function to near normal in the setting of heart failure. The CardioSupport system offers an attractive and novel alternative for treating cardiogenic shock and is being prepared for upcoming clinical trials.

Maximizing hemodynamic effectiveness of biventricular assistance by direct cardiac compression studied in ex vivo and in vivo canine models of acute heart failure.

OBJECTIVE: Direct cardiac compression improves effective ventricular contractility. However, associated reductions in filling volumes and increases in arterial pressure occurring at the onset of direct cardiac compression limit the degree to which cardiac output is augmented. We tested the hypothesis that active preload and afterload control maximizes the hemodynamic effectiveness of direct cardiac compression. METHODS AND RESULTS: Studies in isolated canine hearts loaded with a computer-controlled volume servo system that mimicked heart failure were used to clearly define the hemodynamic effects of direct cardiac compression. Immediately on initiation of direct cardiac compression, ventricular end-diastolic pressure and volume decreased substantially, arterial pressure increased, but stroke volume did not change significantly. When end-diastolic pressure was restored to about 20 mm Hg, stroke volume doubled; decreasing afterload resistance further increased stroke volume by about 30%. Such load adjustments were then tested in vivo in a canine model of acute heart failure induced by coronary artery microembolizations titrated to decrease cardiac output to 33% +/- 9% of control as end-diastolic pressure rose to 20.6 +/- 2.2 mm Hg. Direct cardiac compression decreased end-diastolic pressure to 11.4 +/- 2.6 mm Hg while increasing cardiac output from 0.8 +/- 0.2 to 1. 4 +/- 0.5 L/min (to only approximately 55% of normal). Restoring end-diastolic pressure to 19.6 +/- 2.2 mm Hg by infusions of saline solution increased cardiac output to 1.9 +/- 0.5 L/min. Afterload reduction (nitroprusside), while maintaining end-diastolic pressure at 19.8 +/- 1.3 mm Hg, increased cardiac output to its baseline, 2.8 +/- 1.1 L/min. CONCLUSIONS: Direct cardiac compression significantly improves ventricular pumping capacity and can restore cardiac output to about 60% of normal in the setting of acute heart failure. When combined with active preload and afterload manipulations, direct cardiac compression can restore cardiac output to normal.

The diagnosis and management of aortic dissection occurring years after open heart surgery.

Aortic dissection occurring after open heart surgery is an uncommon but well recognized complication. Unfortunately, it is associated with a high morbidity and mortality. Pre-existing aortic wall pathology, intraoperative aortic manipulations and hypertension are known to predispose to the development of this condition. We report a case of aortic dissection occurring 2 years after coronary artery bypass surgery and complicated by acute saphenous vein graft occlusion and severe mitral insufficiency. We review the diagnosis and management of this complication.

Physiological and hemodynamic evaluation of nonuniform direct cardiac compression.

BACKGROUND: Biventricular direct cardiac compression (DCC) has the potential to support the failing heart without the complications associated with a blood/device interface encountered with the use of current ventricular assist devices. A clinically designed DCC device that provides compression pressure around the base of the heart in synchrony with native ventricular contractions was evaluated with the use of an ex vivo and in vivo canine model of heart failure. METHODS AND RESULTS: The device was tested over a series of ventricular preloads with the use of an ex vivo canine heart preparation and computerized afterload system that mimicked the conditions of heart failure. The end-systolic pressure-volume relation of the left and right ventricles was shifted upward in parallel by DCC, with the magnitude of the shift averaging 40% of the device compression pressure. The device was tested in vivo with the use of a canine model of acute ischemic heart failure in which graded reductions in ventricular function were created through serial coronary artery embolizations. Under the most severe condition of heart failure, DCC improved cardiac output (CO) by 104% (0.80+/-0.33 to 1.63+/-0.40 L/min) and mean arterial pressure by 95% (45.6+/-11 to 89.0+/-18.2 mm Hg). The CO was typically restored to approximately 60% of the normal baseline value, despite attempts to further increase CO by increasing the amount or duration of compression pressure. CONCLUSIONS: Nonuniform DCC significantly improves the left and right ventricular pressure-generating capability and, in the setting of acute heart failure, can increase CO and mean arterial pressure. Such DCC devices can potentially avoid the complications associated with currently available ventricular support devices that involve a blood/device interface.

Vasopressin deficiency and pressor hypersensitivity in hemodynamically unstable organ donors.

BACKGROUND: Solid organ donors often develop hypotension due to vasodilation, and recently we observed that a variety of vasodilatory states are characterized by vasopressin deficiency and hypersensitivity. Thus, we investigated the prevalence of vasopressin deficiency in hypotensive solid organ donors without clinical evidence of diabetes insipidus; we also investigated the vasopressor effect of vasopressin replacement in hypotensive donors. METHODS AND RESULTS: Fifty organ donors were evaluated for hemodynamic instability, (mean arterial pressure [MAP]

Activation-induced T-cell death and immune dysfunction after implantation of left-ventricular assist device.

BACKGROUND: Cardiac transplantation is a limited option for end-stage heart failure because of the shortage of donor organs. Left-ventricular assist devices (LVADs) are currently under investigation as permanent therapy for end-stage heart failure, but long-term successful device implantation is limited because of a high rate of serious infections. To examine the relation between LVAD-related infection and host immunity, we investigated immune responses in LVAD recipients. METHODS: We compared the rate of candidal infection in 78 patients with New York Heart Association class IV heart failure who received either an LVAD (n=40) or medical management (controls, n=38). Fluorochrome-labelled monoclonal antibodies were used in analyses of T-cell phenotype. Analysis of T-cell function included intradermal responses to recall antigens and proliferative responses after stimulation by phytohaemagglutinin, monoclonal antibodies to CD3, and mixed lymphocyte culture. We measured T-cell apoptosis in vivo by annexin V binding, and confirmed the result by assessment of DNA fragmentation. Activation-induced T-cell death was measured after T-cell stimulation with antibodies to CD3. All immunological tests were done at least 1 month after LVAD implantation. Between-group comparisons were by Kaplan-Meier actuarial analysis and Student's t test. FINDINGS: By 3 months after implantation of LVAD, the risk of developing candidal infection was 28% in LVAD recipients, compared with 3% in controls (p=0.003). LVAD recipients had cutaneous anergy to recall antigens and lower (<70%) T-cell proliferative responses than controls after activation via the T-cell receptor complex (p<0.001). T cells from LVAD recipients had higher surface expression of CD95 (Fas) (p<0.001) and a higher rate of spontaneous apoptosis (p<0.001) than controls. Moreover, after stimulation with antibodies to CD3, CD4 T-cell death increased by 3.2-fold in LVAD recipients compared with only 1.2-fold in controls (p<0.05). INTERPRETATION: LVAD implantation results in an aberrant state of T-cell activation, heightened susceptibility of CD4 T cells to activation-induced cell death, progressive defects in cellular immunity, and increased risk of opportunistic infection.

Hemodynamic effects of direct biventricular compression studied in isovolumic and ejecting isolated canine hearts.

BACKGROUND: Biventricular direct cardiac compression (DCC) can potentially support the failing heart without the complications associated with a blood/device interface. The effect of uniform DCC on left and right ventricular performance was evaluated in 7 isolated canine heart preparations. METHODS AND RESULTS: A computer-controlled afterload system either constrained the isolated heart to contract isovolumically or simulated hemodynamic properties of physiological ejection. Biventricular DCC was provided by a chamber surrounding the heart that allowed adjustment of the compression pressure, onset time, and duration. Through a series of ventricular preloads, the effect of DCC on the end-systolic pressure-volume relationship (ESPVR) was evaluated under isovolumic and ejecting conditions. Under both conditions, DCC shifted the ESPVR of the left and right ventricles upward by an amount approximately equal to the compression pressure. The augmentation of end-systolic pressure for each initial preload tested, however, was less under ejecting conditions, because reductions in end-systolic and end-diastolic volumes occurred with ejection. Nevertheless, the net effect was to increase stroke volume. Measurement of M&f1;O2 demonstrated that at a given ventricular volume, M&f1;O2 did not change with DCC; however, peak ventricular pressure increased substantially, so that the effective pressure-volume area increased. CONCLUSIONS: Biventricular DCC can augment end-systolic pressure with no added costs of M&f1;O2. Under ejecting conditions, this augmentation of ventricular contracting ability manifests as increases in stroke volume. Thus, DCC represents a feasible alternative form of ventricular assist, and devices that support the heart in this manner should be further explored.

Target cell susceptibility to lysis by human natural killer cells is augmented by alpha(1,3)-galactosyltransferase and reduced by alpha(1, 2)-fucosyltransferase.

Susceptibility of porcine endothelial cells to human natural killer (NK) cell lysis was found to reflect surface expression of ligands containing Gal alpha(1,3)Gal beta(1,4)GlcNAc [corrected], the principal antigen on porcine endothelium recognized by xenoreactive human antibodies. Genetically modifying expression of this epitope on porcine endothelium by transfection with the alpha(1,2)-fucosyltransferase gene reduced susceptibility to human NK lysis. These results indicate that surface carbohydrate remodeling profoundly affects target cell susceptibility to NK lysis, and suggest that successful transgenic strategies to limit xenograft rejection by NK cells and xenoreactive antibodies will need to incorporate carbohydrate remodeling.

Induction of swine major histocompatibility complex class I molecules on porcine endothelium by tumor necrosis factor-alpha reduces lysis by human natural killer cells.

BACKGROUND: Natural killer (NK) cells have been implicated in a process of delayed xenograft rejection occurring in pig-to-primate organ transplants. As tumor necrosis factor-a (TNF-a) induces expression of both adhesion receptors and major histocompatibility complex class I molecules on porcine endothelium, we investigated the effects of TNF-alpha on human NK cell adherence to and cytotoxicity of porcine aortic endothelial cell (PAEC) monolayers. METHODS: Adherence of human NK cells was measured after PAEC treatment with increasing concentrations of TNF-alpha. Monoclonal antibodies (mAbs) against adhesion molecules on NK cells and PAEC were used in inhibition studies. Resting or TNF-alpha-treated PAEC were used as targets for NK lysis. Increasing titers of anti-swine leukocyte antigen (SLA) class I antibodies or pooled human immune globulin (IVIg) were used to reverse the effects of TNF-alpha on NK lysis. RESULTS: NK cell adhesion to TNF-a-treated PAEC increased in a dose-dependent manner by a maximum of 44%, and was inhibited by mAbs against CD49d, CD11a, CD11b, CD18, and CD2, as well as porcine vascular cell adhesion molecules. In contrast, TNF-alpha treatment of PAEC reduced human NK lysis in a dose-dependent manner. Preincubation of TNF-a-treated PAEC with increasing concentrations of anti-SLA class I mAb increased NK lysis in a titer-dependent manner, and reversed the protective effect on human NK lysis by 77%. Treatment with IVIg, containing antibodies against an a-helical region of HLA class I molecules, had a similar effect. CONCLUSIONS: These results imply that SLA class I molecules can bind to inhibitory receptors on human NK cells, and that these interactions can be augmented by increasing the level of SLA class I molecule expression on porcine endothelium. Strategies that can increase porcine endothelial cell expression of either swine or human major histocompatibility complex class I molecules may reduce human NK activity against porcine xenografts.

High-level porcine endothelial cell expression of alpha(1,2)-fucosyltransferase reduces human monocyte adhesion and activation.

BACKGROUND: Monocyte binding to and activation by human endothelium requires a number of interactions, including those involving sialylated endothelial cell ligands. As porcine endothelial cell transfection with alpha(1,2)-fucosyltransferase has been shown to reduce terminal sialylation, we investigated whether high-level expression of alpha(1,2)-fucosyltransferase by porcine endothelium would reduce human monocyte adhesion and functional activation. METHOD: Purified human monocytes were labeled with 51Cr, and measured for adherence to human or porcine endothelial cell monolayers in the presence of either medium or monoclonal antibodies against monocyte lectins or sialylated endothelial cell ligands. Monocyte production of prostaglandin E2 (PGE2) and interleukin-1beta (IL-1beta) was measured by enzyme-linked immunosorbent assay, using supernatants collected from cultures performed between human monocytes and human or porcine endothelial cell monolayers. Finally, monocyte adhesion and activation were measured after culture with a porcine endothelial cell line transfected with alpha(1,2)-fucosyltransferase, expressing reduced surface expression of terminal Gal alpha(1,3)-Gal and sialic acid residues. RESULTS: Human monocytes adhered by 50% higher levels to porcine endothelium than to human endothelium. This increased level of adherence was associated with augmented monocyte activation, as defined by 3.3-fold higher levels of PGE2 production and 7.3-fold higher levels of IL-1beta production. Monoclonal antibodies against CD62L (L-selectin) on monocytes or CD15s (sialylated Lewis X) on porcine endothelium reduced monocyte adhesion by 38% and 52%, respectively. Porcine endothelial cell transfection with alpha(1,2)-fucosyltransferase reduced terminal sialic acid expression by 65%, monocyte adherence by 50%, and the production of PGE2 and IL-1beta by 67% and 38%, respectively. CONCLUSIONS: Together, these results demonstrate that human monocytes use surface lectins to bind to sialylated carbohydrate structures on porcine endothelium, and indicate that reduction in porcine endothelial cell surface expression of terminally sialylated structures by high-level alpha(1,2)-fucosyltransferase activity reduces monocyte adherence and activation.

Importance of CD49d-VCAM interactions in human monocyte adhesion to porcine endothelium.

By using a primate model of natural antibody depletion, we have previously shown that delayed rejection of porcine cardiac xenografts in unmodified primate recipients resulted from xenograft infiltration with monocyte/macrophage lineage cells. In the present study, we initially showed that human monocytes/macrophages demonstrated significantly greater adherence to unstimulated pig aortic endothelial cells (PAEC) than to human umbilical vein endothelial cells (HUVEC). Human TNF-alpha augmented monocyte adhesion to HUVEC by 5-fold higher levels than to PAEC. This effect could not be explained on the basis of incompatibility between human TNF-alpha and its receptor on PAEC since porcine VCAM expression increased by 75-85% after stimulation with TNF-alpha. TNF-augmented monocyte adherence was abrogated by either treatment of PAEC with an anti-VCAM Mab or monocytes with an anti-CD49d Mab. These results suggest that VCAM-CD49d interactions are important in adhesion of human monocytes to PAEC but may not be as effective as those between human monocytes and allogeneic endothelium, perhaps because of structural differences across species. Other interactions, as yet undefined, must explain the relative increase in adhesiveness of human monocytes for unstimulated PAEC versus HUVEC. In experiments investigating the functional consequences of this enhanced monocyte adherence, PAEC stimulation induced 10-fold higher levels of macrophage-derived IL-1 beta and 3-fold higher levels of T cell proliferation compared with HUVEC. Using an anti-DR Mab to interrupt antigen presentation by autologous macrophages markedly reduced the T cell proliferative response to PAEC. Together, these results indicate that the enhanced adherence of human monocytes to PAEC contributes to xenograft rejection beyond the hyperacute period by leading to tissue infiltration, elaboration of cytokines, and an augmented indirect pathway of T cell xenoantigen recognition.

Preformed IgG antibodies against major histocompatibility complex class II antigens are major risk factors for high-grade cellular rejection in recipients of heart transplantation.

BACKGROUND: Preformed anti-HLA antibodies reacting specifically with donor lymphocytes have been associated with acute vascular rejection and early cardiac allograft failure. However, the effect of preformed anti-HLA antibodies directed against allogeneic major histocompatibility complex (MHC) class I or II antigens of a donor panel on heart transplantation outcome has not been extensively studied. METHODS AND RESULTS: The study group consisted of 68 patients who received cardiac transplants between 1989 and 1996 and who were at high risk for developing anti-HLA antibodies before transplantation. The effect of preformed antibodies against allogeneic MHC class I or class II antigens on the development of early high-grade cellular rejection and on cumulative annual rejection frequency was determined. Both patients with left ventricular assist devices and retransplantation candidates had a similar increase in the frequency of IgG anti-MHC class II antibodies (IgG anti-II) compared with control subjects (P<0.0001), whereas the frequency of IgG anti-MHC class I antibodies (IgG anti-I) was elevated only in patients with left ventricular assist devices. Pretransplantation IgG anti-II predicted early development of high-grade cellular rejection (P=0.006) and higher cumulative annual rejection frequency (P<0.001) in both of these sensitized patient groups. Among retransplantation recipients, a match between donors 1 and 2 at HLA-A additionally predicted an earlier time to a high-grade cellular rejection. CONCLUSIONS: These results emphasize the importance of specifically screening heart transplantation candidates for the presence of IgG antibodies directed against MHC class II molecules and suggest that strategies aimed at their reduction may have an impact on the onset and frequency of high-grade cellular rejections after transplantation.

Role of natural killer cells, macrophages, and accessory molecule interactions in the rejection of pig-to-primate xenografts beyond the hyperacute period.

Pig-to-primate cardiac xenografts surviving beyond the period of hyperacute rejection succumb after 3-4 days to a secondary immunologic response characterized by xenograft infiltration with NK cells and macrophages. Circulating baboon mononuclear cells contain NK cell precursors which mediate lysis of porcine endothelium by two distinct mechanisms: antibody-dependent cellular cytotoxicity and lymphokine activation. IL-2 activated NK lysis of porcine endothelium was 2.4-fold stronger than lysis occurring following engagement of FcRIII by xenoreactive IgG. IL-2 augmented NK lysis involved interactions between CD2 and CD49d on baboon NK cells and their respective ligands on porcine endothelium, since NK lysis was reduced either by using Mabs against CD2, CD49d, or porcine VCAM, or by treating endothelial cells with PIPLC to cleave GPI-linked molecules. These results imply that interactions between accessory molecule receptor-ligand pairs on primate NK cells, macrophages and porcine endothelium are of critical importance in delayed xenograft rejection.

Triple immunosuppression reduces mononuclear cell infiltration and prolongs graft life in pig-to-newborn baboon cardiac xenotransplantation.

OBJECTIVE: Pig hearts transplanted into unmedicated newborn baboons do not undergo hyperacute rejection by preformed xenoantibody and complement. These grafts are rejected at days 3 to 4 in association with the infiltration of macrophages and natural killer cells. We investigated whether an immunosuppressive regimen used widely in cardiac allotransplantation could reduce this cellular response and prolong xenograft life. METHODS: Ten newborn baboons underwent heterotopic pig cardiac xenotransplantation. Five baboons were immunosuppressed with mycophenolate mofetil (100 mg/kg), methylprednisolone acetate (0.8 mg/kg), and cyclosporine A (INN: ciclosporin; 10 mg/kg). Xenograft rejection was studied by light microscopy and immunofluorescence. The induced humoral response to porcine xenoantigens was documented by enzyme-linked immunosorbent assay using synthetic alpha-1,3-galactosyl epitopes coupled to bovine serum albumin. RESULTS: Graft life was extended from a mean of 3.6 +/- 0.5 days (n = 5) to a mean of 6.2 +/- 1.1 days (n = 5, p = 0.01). In comparison with controls, explanted grafts from medicated baboons demonstrated reduced infiltration with natural killer cells and macrophages, but increased evidence of complement-mediated rejection substantiated by increased deposition of immunoglobulin M, complement, and fibrin. In all baboons receiving transplants, levels of both immunoglobulin M and immunoglobulin G anti-galactose were significantly increased after transplantation, with immunoglobulin G levels remaining persistently elevated. CONCLUSIONS: These results indicate that cyclosporine-based triple immunosuppression marginally prolonged xenograft survival and appears to have reduced the natural killer cell and macrophage infiltrates. The immunosuppressive protocol, however, was not adequate to prevent the induced immunoglobulin M humoral response and prevent complement-mediated graft injury.

Induction of tolerance in rodent cardiac allotransplantation using an MHC class I-derived peptide and cyclosporin A.

BACKGROUND: The synthetic peptide corresponding to residues 75-84 of the human major histocompatibility complex class I molecule HLA-B7 (Allotrap 07) has been shown to inhibit differentiation of cytotoxic T lymphocyte precursors. Subsequent treatment of LEW-1A rats with this peptide was associated with a reduction in the level of cytotoxic activity directed to donor alloantigens. This study was undertaken to investigate the effect of Allotrap 07 on rodent heart allograft survival in LEW-1A recipients. METHODS: Heart allografts from Lewis rats were heterotopically transplanted into the infrarenal abdominal aorta of ACI recipients. The treatment groups consisted of different regimens of short-term intravenous Allotrap 07 and oral cyclosporin A. All grafts were palpated daily, with rejection defined as the cessation of palpable contractions. RESULTS: Cardiac allografts transplanted from Lewis to ACI rats survived indefinitely after administration of intravenous Allotrap 07 and oral cyclosporin A. Tolerance induction was donor-specific because third-party Brown-Norway, but not Lewis, grafts were rapidly rejected after implantation into ACI recipients. CONCLUSIONS: Because donor-specific tolerance persisted long after cessation of peptide administration and did not occur when cyclosporin A was omitted from the immunosuppressive regimen, the mechanism may involve induction of clonal anergy.