Renal cell carcinoma with tumor thrombus extension into the proximal pulmonary artery.
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Carcinoma, Renal Cell↗
Biomedical subjects
Hillel Laks
Publications and source records attributed to Hillel Laks.
Dual upregulation of Fas and Bax promotes alloreactive T cell apoptosis in IL-10 gene targeting of cardiac allografts.
Activation-induced cell death and cytokine deprivation are demonstrated by peripheral T cell populations at the conclusion of natural immune responses, and each of these processes is modulated by the immunosuppressive cytokine interleukin (IL)-10 in vitro. This study employs a clinically relevant in vivo model of IL-10 gene transfer with heterotopically transplanted cardiac allografts to determine the mechanisms of the effects of IL-10 on T cell survival. IL-10 protein overexpression within allografts 4-5 days after gene transfer augments apoptosis of CD4+ and CD8+ graft-infiltrating lymphocytes by 7.1-fold (P < 0.001) and 6.0-fold (P < 0.001), respectively. Graft-infiltrating T cells express 10-fold more proapoptotic Fas (P < 0.01) and 30-fold more Bax (P < 0.01) than controls. The fractions of activated caspase-8 (FADD-like IL-1beta-converting enzyme) and activated caspase-9 were increased 7- and 2.3-fold, respectively, in IL-10 gene-treated allografts at postoperative day 4-5. These changes in the Fas-Fas ligand pathway and Bcl-2 mitochondrial apoptosis regulation are enhanced by complete suppression of antiapoptotic FADD-like IL-1beta-converting enzyme inhibitory protein (FLIP) (from 30.5 to 0.0%, P < 0.01) and Bcl-xL (from 22.5 to 0.1%, P = 0.03) expression among these cells from the earliest days after gene transfer. Although changes in proteins of Fas- and Bcl-2-mediated apoptosis signaling occur, only the levels of Fas and FLIP correlate to the rate of apoptosis of graft-infiltrating CD3 lymphocytes and histological rejection scores. These results indicate that dichotomous apoptosis-regulatory pathways are affected by IL-10 gene therapy, but Fas-mediated mechanisms of activation-induced cell death more substantially contribute to the greater cell death of graft-infiltrating T cells after ex vivo IL-10 gene transfer.
Animals↗
Support with the BVS 5000 assist device during treatment of acute giant-cell myocarditis.
Giant-cell myocarditis is a rare and aggressive form of myocarditis with a high mortality rate. Our purpose is to summarize 3 cases of acute giant-cell myocarditis that illustrate possible outcomes with mechanical support. We reviewed the cases of 3 patients, aged 39 to 59 years, who had giant-cell myocarditis (confirmed by myocardial biopsy). The indication for ventricular assist was circulatory failure despite maximal medical treatment with 2 or more inotropic agents and intraaortic balloon pump support. Immunosuppression and a biventricular mechanical assist (BVS 5000) were used to treat all these patients. The mean duration of mechanical support was 15.7 days (range, 10 to 19 days). One patient had recovery of myocardial function and was weaned from mechanical support. This case is, to our knowledge, the first reported of ventricular support leading to cardiac recovery after diagnosis of giant-cell myocarditis. The 2nd patient was not a candidate for further surgery and died of multisystem organ failure. The 3rd patient underwent orthotopic heart transplantation after 18 days of support and was discharged. We conclude that patients with giant-cell myocarditis tend to have biventricular involvement and can recover myocardial function on mechanical support and immunosuppression. If recovery is not observed, transplantation is warranted. By avoiding left ventricular cannulation, the BVS 5000 is well suited for bridging to recovery, transplantation, or long-term support.
Acute Disease↗
Indirect alloreactivity and chronic rejection.
BACKGROUND: The relative contribution of the direct versus indirect pathway of T-lymphocyte alloreactivity to the development of chronic rejection is incompletely understood. Utilizing a murine model of cardiac allograft vasculopathy (CAV) and a recipient strain with markedly reduced capacity for indirect alloreactivity, we sought to define the importance of indirect allorecognition in CAV. METHODS: The cells from H2-M mutant mice are unable to present intact protein antigens via class II molecules and have a markedly reduced capacity to present exogenous peptides. B6C.H-2(bm12) strain donor hearts were transplanted into either C57Bl/6 wild-type (WT) or H2-M mutant mice (on C57Bl/6 background). Recipients were killed on day 24. T lymphocyte and macrophage infiltration were graded immunohistochemically. Intimal lesions were measured morphometrically. RESULTS: Donor hearts in WT recipients developed significant intimal lesions, as expected (50+/-7%). Moreover, the donor hearts in H2-M mutant mice also developed comparable intimal lesions (52+/-9%, P=NS vs. WT). Furthermore, the extent of T lymphocyte and macrophage infiltration was similar in both groups. CONCLUSIONS: This study demonstrates that a markedly reduced capacity for indirect alloreactivity does not affect the severity of intimal lesions in this model of CAV. The findings of this study question the role of indirect alloreactivity as the sole pathway of allorecognition leading to chronic rejection.
Animals↗
Outcome of staged surgical approach to neonates with single left ventricle and moderate size bulboventricular foramen.
Neonates with double-inlet left ventricle or tricuspid atresia with transposed great arteries and a bulboventricular foramen (BVF) area <2 cm(2)/m(2) develop BVF obstruction. This study examined the outcome of neonates with BVF area between 1 and 2 cm(2)/m(2) whose BVF was bypassed after the neonatal period. We reviewed 29 neonates with double-inlet left ventricles (n = 18) or tricuspid atresia (n = 11) and transposed great arteries. The study group consisted of 9 patients with neonatal BVF areas of 1 to 2 cm(2)/m(2) who did not undergo repair of the BVF obstruction as a neonate. The comparison group consisted of 8 "ideal" patients without BVF obstruction. Precavopulmonary shunt data from cardiac catheterization and echocardiogram and outcomes of the cavopulmonary shunt were compared. Study group patients developed a mild BVF gradient (18 +/- 10 mm Hg by cardiac catheterization) by a mean of 7 months. Left ventricular wall thickness, however, remained in the normal range (4.2 +/- 0.3 mm) and was not statistically different from the comparison group (4.1 +/- 0.4 mm). No difference was found in the precavopulmonary mean pulmonary artery pressure (15 +/- 5 vs 15 +/- 6 mm Hg), transpulmonary gradient (8 +/- 4 vs 8 +/- 5 mm Hg), and left ventricular end-diastolic pressure (7 +/- 2 vs 8 +/- 3 mm Hg). One patient in the study group died from respiratory syncytial virus pneumonia while awaiting cavopulmonary shunt. Neither group had mortality from the cavopulmonary shunt. The lengths of hospital stay were comparable (8.3 +/- 3.7 vs 8.9 +/- 6.0 days). Thus, neonates with BVF area between 1 and 2 cm(2)/m(2) develop mild but hemodynamically insignificant BVF gradient by 7 months of age. This group of patients can be managed safely with relief of BVF obstruction later in infancy.
Heart Defects, Congenital↗
Localized interleukin-10 gene transfer induces apoptosis of alloreactive T cells via FAS/FASL pathway, improves function, and prolongs survival of cardiac allograft.
We hypothesized that localized IL-10 gene transfer can induce alloreactive T cell apoptosis and tested this hypothesis with liposome-mediated ex vivo intracoronary IL-10 gene transfer using a functional heterotopic allograft heart transplant model in rabbits. Localized IL-10 overexpression prolonged cardiac allograft survival over three folds. In parallel with the time-course of IL-10 overexpression, the percentage of apoptotic CD3+ cells among total CD3+ cells was significantly increased in the gene therapy group (36.5+/-3.9%) compared with that in the control group (6.2+/-2.6%, P<0.01) on postoperative day (POD) 3-6, and it was further increased (45.8+/-5.7%) on POD7-10. Apoptotic CD4+ and CD8+ cells were also significantly increased in the gene group (P<0.01). In contrast, the percentage of apoptotic myocytes significantly decreased from 10.1+/-0.8% in the control group to 3.5+/-0.4% in the gene group on POD7-10 (P<0.01). This reduction was inversely correlated with the increase in the percentages of apoptotic CD4+ and CD8+ cells (P<0.01). The percentage of caspase-3 positive myocytes was significantly reduced, although percentages of caspase-3 positive CD4+ and CD8+ cells were markedly increased in the gene group (P<0.01). Moreover, about 60-80% of apoptotic T lymphocytes expressed Fas in the gene group compared with less than 10% in the control group (P<0.01). These results suggest that localized IL-10 gene transfer induces alloreactive T cell apoptosis via the Fas/FasL pathway that may contribute to the alleviated acute rejection, improved cardiac function, and prolonged survival in the IL-10 gene-treated cardiac allografts.
Animals↗
The role of MIG/CXCL9 in cardiac allograft vasculopathy.
T lymphocytes play a critical role in chronic rejection of transplanted hearts, or cardiac allograft vasculopathy (CAV). However, the molecular mediators of T lymphocyte recruitment in CAV are incompletely defined. We hypothesized that the chemokine, monokine induced by interferon-gamma (MIG/CXCL9), which induces T lymphocyte migration in vitro, participates in T lymphocyte recruitment in CAV. In a previously characterized MHC II-mismatched murine model of CAV, intragraft MIG/CXCL9 gene transcript and protein levels increased on days 7, 14, and 24 days after transplantation, paralleling T lymphocyte recruitment and preceding intimal thickening. Antibody neutralization of MIG/CXCL9 significantly reduced CD4(+) T lymphocyte infiltration and intimal thickening in this model. MIG/CXCL9 was produced by graft-infiltrating MOMA-2+ macrophages in early and late stages of CAV. And, although T lymphocytes did not produce MIG/CXCL9, recipient CD4(+) T lymphocytes were required for sustained intragraft MIG/CXCL9 production and CAV development. These findings demonstrate that 1) MIG/CXCL9 plays an important role in CD4(+) T lymphocyte recruitment and development of CAV, 2) MOMA-2+ macrophages are the predominant recipient-derived source of MIG/CXCL9, and 3) recipient CD4 lymphocytes are necessary for sustained MIG/CXCL9 production and CAV development in this model. Neutralization of the chemokine MIG/CXCL9 may have therapeutic potential for the treatment of chronic rejection after heart transplantation.
Animals↗
Seventeen-year experience with 1,083 heart transplants at a single institution.
BACKGROUND: Heart transplantation is the most accepted treatment for end-stage heart disease. A review of 1,083 consecutive transplants (1984 to 2001) was undertaken. METHODS: Adult recipients were divided into quartiles. The last 540 transplants were combined. Three eras were created from these, 1984 to 1991, 1991 to 1995, and 1995 to 2001, with three age groups: 0 to 18 years, 19 to 61 years, and 62 to 74 years. All patients have at least 1 year of follow-up time. End points were survival, rejection, and graft coronary artery disease. RESULTS: There were 1,012 patients. Donor age, graft ischemic time, and the proportion of elderly recipients and nonstandard donor hearts have increased in the current era. Actuarial 60-month survivals of recipients after 1995 were 80.7% (0 to 18 years); 75.3% (19 to 61 years); and 76.2% (>62 years). The current era children and younger adult groups demonstrated improved results when compared with previous eras (p = 0.003 and p = 0.05). Rejection episodes equal to or greater than ISHLT grade 3A per person per year improved to 0.15 in the current era (p < 0.001). During the three eras, older recipients (>62 years) demonstrated fewer episodes of rejection when compared with other adults (0.13 versus 0.58, p = 0.03). Deaths attributed to graft coronary artery disease decreased from 11% to 5% from era 2 to era 3. Regression analysis revealed a mild effect of donor age on survival and graft coronary artery disease (hazard ratio = 1.02, p = 0.001; hazard ratio = 1.039, p < 0.001, respectively). Recipient predictors of graft coronary artery disease were diagnosis of ischemic cardiomyopathy (hazard ratio = 1.6, p = 0.014) and congenital heart disease (hazard ratio = 3.41, p = 0.02). CONCLUSIONS: Improved survival in the current era may be attributed to better organ preservation, improved immunosuppression and control of infection, and less life-threatening graft coronary artery disease.
Adolescent↗
Use of hearts transplanted from donors with atraumatic intracranial bleeds.
BACKGROUND: Donor atraumatic intracranial bleed (aICB) is associated with older age and may reflect a history of hypertension. Hearts from donors who died of aICB may be at increased risk for graft failure because of the associated catecholamine surge. We evaluated whether receiving a heart from a donor who had an aICB independently affected the outcome of transplantation. METHODS: We reviewed adult patients (>18 years) who underwent heart transplantation between July 1994 and December 1999. We excluded patients who received non-standard hearts (e.g., donor age >55 years). Group 1 received hearts from donors with aICB (n = 80), and Group 2 received hearts from donors who did not have aICB (n = 171). RESULTS: Recipient age, gender, United Network for Organ Sharing status, and indication for transplantation were similar for both groups. Donors in Group 1 were older (41 vs 26 years, p = 0.001), more commonly women (55% vs 20%, p = 0.001), and more often had history of hypertension (26% vs 2%, p = 0.001). Survival to discharge was 86% in Group 1 and 95% in Group 2. Actuarial 5-year survival was 72% for Group 1 and 81% for Group 2 (p = 0.52). Regression analysis showed that receiving a heart from a donor with aICB was a risk factor for early recipient mortality but not for long-term outcome (odds ratio = 3.25, p = 0.02, and hazard ratio = 1.16, p = 0.69, respectively). Donor aICB, female gender, and abnormal initial echocardiogram (global hypokinesia) were selected as clinically relevant independent risk factors for early mortality of the recipient, using a fitted multifactor logistic regression model (goodness-of-fit chi-square p value = 0.94). Donor age, accident-to-retrieval time interval, and borderline left ventricular hypertrophy did not significantly differ. Five-year freedom from transplant coronary artery disease in Group 1 was 74% (vs 80% in Group 2, p = 0.05). CONCLUSIONS: The trend observed in this series suggests that receiving a heart from a donor with aICB is a potential independent risk factor for early mortality after transplantation independent of age. Caution should be used when evaluating such donors, particularly when other risk factors such as female donor or depressed ejection fraction are present.
Female↗
Use of assist devices and ECMO to bridge pediatric patients with cardiomyopathy to transplantation.
BACKGROUND: Pulsatile ventricular assist devices (VADs) are used to bridge adults with end-stage heart disease to transplantation. A combination of external implantable pulsatile and continuous-flow external mechanical support now can be used to bridge pediatric patients with end-stage cardiomyopathy to orthotopic heart transplantation (OHT). METHODS: We reviewed consecutive pediatric patients with cardiomyopathy (n = 28) who required mechanical cardiac support from July 1995 to February 2001. All were OHT candidates with severe hemodynamic compromise despite maximal medical support. We excluded from this series patients who had undergone cardiotomy. RESULTS: Nineteen patients received support from external continuous-flow devices, either with extracorporeal membrane oxygenation or with centrifugal VADs, and 9 patients received pulsatile support. Nineteen of 28 (68%) patients were successfully bridged to transplant (17) or weaned (2) from their devices after recovery. Of the patients successfully bridged to transplant or recovery, 89% are alive to date. Univariate analysis revealed that a lower bilirubin concentration after 2 days of support was associated with a favorable outcome (p = 0.006). As expected, the patients with pulsatile VADs had significantly higher rates of extubation and oral feeding. CONCLUSION: Pulsatile and continuous-flow devices can complement each other to significantly extend the lives of a wide range of pediatric patients with severe cardiomyopathies.
Adolescent↗
Localized immunosuppression in the cardiac allograft induced by a new liposome-mediated IL-10 gene therapy.
BACKGROUND: Overexpression of interleukin 10 (IL-10) in the donor heart prolongs allograft survival in animals. Interleukin-10 has many immunosuppressive effects; however, the mechanism(s) of its protective effect on allograft rejection remains unknown. METHODS: Recently, we optimized an ex vivo, intracoronary infusion of the GAP:DLRIE, liposome-mediated, IL-10 gene method using a rabbit, cervical, heterotopic heart transplant model. RESULTS: The efficiency of this new-generation, liposome-mediated, IL-10 gene transfer to the donor hearts was 15% in hypothermic conditions, which represents a 30% increase from the efficiency of other liposomes, such as DOSPA/DOPE, DOGS/DOPE, and DMRIE/DOPE. Cardiac allograft survival was prolonged from 6.0 +/- 0.7 days to 14.3 +/- 1.8 days. Infiltrating lymphocyte sub-populations CD3+, CD4+, and CD8) decreased significantly in the gene therapy group compared with the control group. Local IL-10 overexpression correlated significantly with decreased CD4+ and CD8+ responsiveness and Type-1 helper (Th1) cytokine gene (IL-2, interferon-gamma, and tumor necrosis factor alpha) expression level and correlated inversely with the allograft rejection grade. In the gene therapy group, the cytotoxic activity of infiltrating T cells in the allograft decreased greatly, but the time course of this decrease did not parallel the rejection process. CONCLUSION: We conclude that GAP:DLRIE is the best cationic liposome for ex vivo gene transfection in hypothermic conditions. The effects of IL-10 gene therapy on antigen-specific T-lymphocyte proliferation and Th1-cytokine expression may play an important role in localized immunosuppression and tolerance induction.
Animals↗
Hepatitis C-positive donors in heart transplantation.
Hepatitis C virus (HCV) can be transmitted to heart transplant recipients by donor organs. Mid-term results were reported using HCV-positive donors in patients at risk of imminent death (group I, n = 10), or in patients who otherwise would not have been offered heart transplantation (group II, n = 10) because of age (9/10) or associated medical risk (1/10). Medical records pertaining to patients receiving HCV-positive allografts between July 1994 and December 1999 were reviewed. The recipients consisted of 19 males and one female, with a median age of 54 years for group I and 66 for group II. The HCV RNA level, seroconversion of anti-HCV antibody, biochemical liver dysfunction, and causes of death were examined. Older recipients received reduced immunosuppression. Two patients in group II were HCV positive and were also retransplants. The hospital mortality rate was 10% in group I and 20% in group II; both hepatitis C-positive recipients died postoperatively prior to discharge. All predischarge deaths were related to multi-system organ failure (MSOF). All 17 survivors were HCV negative prior to transplant. Of these, 4/17 seroconverted. HCV RNA was detected in two of them. At a median follow-up of 26.4 months, 2/11 current survivors continue to test anti-HCV positive and are RNA negative. Three-year actual survival was 40% for group I and 70% in group II. Transplant coronary artery disease (TCAD) accounted for one postoperative death in group I. Current data show that four out of 11 survivors had developed TCAD at 3-year follow-up, yielding an actual freedom from TCAD rate of 12/17 (70%) at 3-year follow-up. Hepatitis C transmission using a donor heart as the reservoir is moderate (25%). Limited use of such donors is justified in selected patients. The risk for hepatic disease may be reduced by tailoring immunosuppression specifically for such recipients, particularly if they are at low risk of rejection. Further studies are necessary to define a possible association between HCV and TCAD.
Aged↗
Recent trends in early outcome of adult patients after heart transplantation: a single-institution review of 251 transplants using standard donor organs.
Older age, prior transplantation, pulmonary hypertension, and mechanical support are commonly seen in current potential cardiac transplant recipients. Transplants in 436 consecutive adult patients from 1994 to 1999 were reviewed. There were 251 using standard donors in 243 patients (age range 18-69 years). To emphasize recipient risk, 185 patients who received a nonstandard donor were excluded from analysis. The indications for transplant were ischemic heart disease (n = 123, 47%), dilated cardiomyopathy (n = 82, 32%), and others (n=56, 21%). One hundred and forty-nine (57%) recipients were listed as status I; 5 and 6% were supported with an intra-aortic balloon and an assist device, respectively. The 30-d survival and survival to discharge were 94.7 and 92.7%, respectively; 1-year survival was 89.1%. Causes of early death were graft failure (n = 6), infection (n = 4), stroke (n = 4), multiorgan failure (n = 3) and rejection (n = 2). Predictors were balloon pump use alone (OR= 11.4, p =0.002), pulmonary vascular resistance > 4 Wood units (OR = 5.7, p = 0.007), pretransplant creatinine > 2.0 mg/dL (OR = 6.9, p = 0.004) and female donor (OR = 8.3, p = 0.002). Recipient age and previous surgery did not affect short-term survival. Heart transplantation in the current era consistently offers excellent early and 1-year survival for well-selected recipients receiving standard donors. Early mortality tends to reflect graft failure while hospital mortality may be more indicative of recipient selection.
Adolescent↗
Short-term bridge to heart transplant using the BVS 5000 external ventricular assist device.
From January 1995 to April 2001, 71 patients with cardiogenic shock using the BVS 5000 were treated or accepted in transfer. Of the 24 transplanted, nine had dilated cardiomyopathy, ischemic cardiomyopathy, acute myocardial infarction, giant cell myocarditis and previous Fontan procedure (group I, n = 13). The others had postcardiotomy shock (group II, n = 11); seven were transferred to our center after device implantation. Age ranged from 8 to 67 years. Ten (77%) patients in group I were implanted without cardiopulmonary bypass. The mean duration of support was 6.7 (2-24) d. Twelve patients were extubated before transplantation and 13 (five in group I, eight in group II) received nonstandard donor organs. Survival to discharge and 1-year actuarial survival was 85 and 77% for group I and 73 and 64% for group II, respectively. Patients with post-implant serum bilirubin levels > 10 mg/dL had a tendency to expire from multiple systemic organ failure. Patients not ventilator-dependent at the time of transplant had the best outcomes. Short-term bridge to transplantation using the BVS 5000 is feasible in selected patients. Caution is recommended when directing such patients to transplant if they need ventilator support and have high serum bilirubin levels.
Adolescent↗
Parasitic omphalopagus complicated by omphalocele and congenital heart disease.
Conjoined twins occur in approximately one of every 50,000 to 200,000 births. Atypical or parasitic conjoined twins result from the embryonic death of one twin, which leaves behind body parts vascularized by the primary twin. Omphalopagus refers to conjoined twins joined at the level of the umbilicus. The authors report a case of atypical omphalopagus involving an acardiac, acephalic, parasitic twin and a host twin with a large omphalocele, transposition of the great arteries, and aortic coarctation. The authors briefly review reported cases of parasitic omphalopagus and emphasize the role of intensive neonatal care, preoperative planning, and staged surgical intervention in the successful management of complicated variants.
Abnormalities, Multiple↗
Role of CD8+ lymphocytes in chronic rejection of transplanted hearts.
BACKGROUND: The contribution of CD8(+) lymphocytes to the pathogenesis of cardiac allograft vasculopathy, or chronic rejection in heart transplants, remains undefined. We used both major histocompatibility complex class I mismatched and major histocompatibility complex class II mismatched models of cardiac allograft vasculopathy to characterize the role of CD8(+) lymphocytes in the development of cardiac allograft vasculopathy. METHODS: Donor hearts from B10.A mice were transplanted into B10.BR recipients (major histocompatibility complex class I mismatched). Donor hearts were harvested at 1, 7, 14, and 30 days after transplantation and (1) quantitated morphometrically for lesion development, (2) stained immunohistochemically, or (3) digested for isolation of graft-infiltrating cells. The cytotoxic phenotype of graft-infiltrating CD8(+) lymphocytes was determined with flow cytometry. Intracellular cytokine staining of CD8(+) and CD4(+) lymphocytes for interleukin 2, interferon g, interleukin 4, and interleukin 10 was performed with 2-color flow cytometry. Finally, B6.C-H2(bm12) donor hearts were transplanted into either C57BL/6 wild-type (major histocompatibility complex class II mismatched) or CD8 -/- knockout recipients and examined for the development of cardiac allograft vasculopathy. RESULTS: In the major histocompatibility complex class I mismatched model, CD8(+) lymphocytes were the predominant T-lymphocyte subset that infiltrated the allografts and demonstrated markers of activation. The intracellular cytokine-staining assay demonstrated that CD8(+) lymphocytes were the primary sources of allograft interleukin 2 and interferon gamma. Intimal lesions developed in the allografts by day 14 (12.0% +/- 4.0%) and further increased by day 30 (44.0% +/- 5.0%). In the major histocompatibility complex class II mismatched model, the donor hearts in the CD8 -/- knockout recipients had substantially less severe intimal lesions when compared with the donor hearts in wild-type recipients (19.0% +/- 6.0% vs 50.0% +/- 7.0%, respectively; P <.05). CONCLUSIONS: In both major histocompatibility complex class I and II mismatched models, CD8(+) lymphocytes contribute significantly to chronic rejection. The findings of this study suggest that control of chronic rejection requires interventions directed at CD8(+) lymphocytes.
Animals↗
Interatrial septostomy under transesophageal echocardiography guidance: a novel approach.
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Cardiac Catheterization↗
Oxidized lipids as mediators of coronary heart disease.
PURPOSE OF REVIEW: To summarize the recent evidence on the physiological relevance of the view that LDL lipid oxidation may play a major role in the inflammatory reaction that leads to or amplifies atherogenesis. Oxidation of LDL phospholipids containing arachidonic acid at the sn-2 position occurs when a critical concentration of 'seeding molecules' derived from the lipoxygenase pathway is reached in LDL. This generates a series of biologically active, oxidized phospholipids that mediate the cellular events seen in the developing fatty streak. RECENT FINDINGS: We have observed that LDL from mice that are genetically predisposed to diet-induced atherosclerosis is highly proinflammatory when the mice are maintained on an atherogenic diet, when they are injected with LDL-derived oxidized phospholipids, or once they are infected with influenza A virus. Patients with coronary atherosclerosis also had highly proinflammatory LDL, despite having normal blood lipid levels or normal plasma HDL levels. SUMMARY: We and others have hypothesized that HDL and LDL-derived oxidized phospholipids may be part of a system of nonspecific innate immunity. We therefore propose that determination of HDL capacity against LDL oxidation and the detection of proinflammatory HDL may be a useful marker of susceptibility to atherosclerosis.
Animals↗