Obesity and outcomes after left ventricular assist device implantation: insights from the EUROMACS Registry.

OBJECTIVES: The objective was to analyse associations between obesity and outcomes after left ventricular assist device (LVAD) implantation. METHODS: A retrospective analysis of the EUROMACS Registry was performed. Adult patients undergoing primary implantation of a continuous-flow LVAD between 2006 and 2019 were included (Medtronic HeartWare® HVAD®, Abbott HeartMate II®, Abbott HeartMate 3™). Patients were classified into 4 different groups according to body mass index at the time of surgery (body mass index <20 kg/m2: n = 254; 20-24.9 kg/m2: n = 1281; 25-29.9 kg/m2: n = 1238; ≥ 30 kg/m2: n = 691). RESULTS: The study cohort was comprised of 3464 patients. Multivariable Cox proportional cause-specific hazards regression analysis demonstrated that obesity (body mass index ≥30 kg/m2) was independently associated with significantly increased risk of mortality (body mass index ≥30 vs 20-24.9 kg/m2: hazard ratio 1.36, 95% confidence interval 1.18-1.57, overall P < 0.001). Moreover, obesity was associated with significantly increased risk of infection and driveline infection. The probability to undergo heart transplantation was significantly decreased in obese patients (body mass index ≥30 vs 20-24.9 kg/m2: hazard ratio 0.59, 95% confidence interval 0.48-0.74, overall P < 0.001). CONCLUSIONS: Obesity at the time of LVAD implantation is associated with significantly higher mortality and increased risk of infection as well as driveline infection. The probability to undergo heart transplantation is significantly decreased. These aspects should be considered when devising a treatment strategy before surgery.

Long-term continuous flow mechanical biventricular support: 9 years and counting.

We report 2 continuous flow HeartWareTM left ventricular assist devices successfully used in a patient with advanced heart failure of giant cell myocarditis origin in a biventricular configuration. Despite technical challenges of adapting a left ventricular assist device engineered for systemic pressure to function as a right ventricular assist device, the addition of dynamic banding on the right ventricular assist device outflow graft allowed successful adaptation of afterload. This patient has now been on biventricular configuration support for 9 years, and remains stable to this day.

The Predictive Value of Depression in the Years After Heart Transplantation for Mortality During Long-Term Follow-Up.

OBJECTIVE: Current understanding of the prognostic impact of depression on mortality after heart transplantation (HTx) is limited. We examined whether depression after HTx is a predictor of mortality during extended follow-up. Subsequently, we explored whether different symptom dimensions of depression could be identified and whether they were differentially associated with mortality. METHODS: Survival analyses were performed in a sample of 141 HTx recipients assessed for depression, measured by self-report of depressive symptoms (Beck Depression Inventory - version 1A [BDI-1A]), at median 5.0 years after HTx, and followed thereafter for survival status for up to 18.6 years. We used uni- and multivariate Cox proportional hazard models to examine the association of clinically significant depression (BDI-1A total score ≥10), as well as the cognitive-affective and the somatic subscales of the BDI-1A (resulting from principal component analysis) with mortality. In the multivariate analyses, we adjusted for relevant sociodemographic and clinical variables. RESULTS: Clinically significant depression was a significant predictor of mortality (hazard ratio = 2.088; 95% confidence interval = 1.366-3.192; p = .001). Clinically significant depression also was an independent predictor of mortality in the multivariate analysis (hazard ratio = 1.982; 95% confidence interval = 1.220-3.217; p = .006). The somatic subscale, but not the cognitive-affective subscale, was significantly associated with increased mortality in univariate analyses, whereas neither of the two subscales was an independent predictor of mortality in the multivariate analysis. CONCLUSIONS: Depression measured by self-report after HTx is associated with increased mortality during extended follow-up. Clinical utility and predictive validity of specific depression components require further study.

Single centre experience with transapical transcatheter mitral valve implantation.

OBJECTIVES: A transcatheter heart valve technique can be used in failed mitral valve repairs with annuloplasty rings, deterioriated bioprostheses and in mitral annular calcification, all serving as 'docking stations' for balloon-expandable valves. Specially designed transcatheter mitral valve platforms are used in ongoing studies for native mitral valve regurgitation. We present our single centre experience with transcatheter mitral valve implantation-transapical approach procedures in eleven patients. METHODS: Eleven patients were treated between 2011 and 2016. They had severe mitral regurgitation due to either failed repair annuloplasty rings (N = 6), failed bioprostheses (N = 2) or in the native valve (N = 3), all at high risk for open mitral valve surgery. Three different types of transcatheter valves were used: (1) the SAPIEN XT/SAPIEN 3, (2) the Lotus valve and (3) a Tendyne transcatheter mitral valve. Computed tomography reconstruction, echocardiography, 3D printing and bench tests were done in the preoperative evaluation and procedural planning. Transapical approach access was performed via a left minithoracotomy. RESULTS: Implantation success was 100% with no left ventricular outflow tract obstruction. Good haemodynamics and improved New York Heart Association class were demonstrated in all patients. One patient died before 30 days due to sepsis. One patient had a valve thrombosis when switching from Coumadin to new oral anticoagulant and had a second valve implanted into the first one as a 'valve-in-valve' procedure. CONCLUSIONS: The transapical approach is a safe and straight forward procedure for accessing the mitral valve. 'Transcatheter aortic valve implantation' prostheses may be used in redo surgery due to an already sufficient 'docking station'. These specially designed new prostheses may be beneficial for addressing mitral valve regurgitation, but are still under evaluation. Anticoagulation is mandatory.

The Heparan Sulfate Proteoglycan Glypican-6 Is Upregulated in the Failing Heart, and Regulates Cardiomyocyte Growth through ERK1/2 Signaling.

Pressure overload is a frequent cause of heart failure. Heart failure affects millions of patients worldwide and is a major cause of morbidity and mortality. Cell surface proteoglycans are emerging as molecular players in cardiac remodeling, and increased knowledge about their regulation and function is needed for improved understanding of cardiac pathogenesis. Here we investigated glypicans (GPC1-6), a family of evolutionary conserved heparan sulfate proteoglycans anchored to the extracellular leaflet of the cell membrane, in experimental and clinical heart failure, and explored the function of glypican-6 in cardiac cells in vitro. In mice subjected to pressure overload by aortic banding (AB), we observed elevated glypican-6 levels during hypertrophic remodeling and dilated, end-stage heart failure. Consistently, glypican-6 mRNA was elevated in left ventricular myocardium from explanted hearts of patients with end-stage, dilated heart failure with reduced ejection fraction. Glypican-6 levels correlated negatively with left ventricular ejection fraction in patients, and positively with lung weight after AB in mice. Glypican-6 mRNA was expressed in both cardiac fibroblasts and cardiomyocytes, and the corresponding protein displayed different sizes in the two cell types due to tissue-specific glycanation. Importantly, adenoviral overexpression of glypican-6 in cultured cardiomyocytes increased protein synthesis and induced mRNA levels of the pro-hypertrophic signature gene ACTA1 and the hypertrophy and heart failure signature genes encoding natriuretic peptides, NPPA and NPPB. Overexpression of GPC6 induced ERK1/2 phosphorylation, and co-treatment with the ERK inhibitor U0126 attenuated the GPC6-induced increase in NPPA, NPPB and protein synthesis. In conclusion, our data suggests that glypican-6 plays a role in clinical and experimental heart failure progression by regulating cardiomyocyte growth through ERK signaling.

Evaluation of the HeartWare ventricular assist device Lavare cycle in a particle image velocimetry model and in clinical practice.

OBJECTIVES: Ventricular blood stasis is a concern for continuous flow mechanical support devices and might contribute to the formation of thromboembolic events. The HeartWare® Ventricular Assist System (HVAD®) is equipped with the Lavare™ cycle that is a periodic speed modulation feature designed to alter flow patterns within the left ventricle and reduce areas of potential blood stasis. Here, we report in vitro and clinical findings on the effects of the Lavare cycle. METHODS: The effect of pump speed changes on the intraventricular flow field was examined with an in vitro particle image velocimetry model. The clinical impact of the Lavare cycle was evaluated through a retrospective review of the ReVOLVE study which includes 248 patients implanted with the HVAD following Conformité Européenne Mark in nine centres in Europe and Australia. Baseline characteristics, adverse event profiles and Kaplan-Meier survival estimates were stratified by patients using/not using the Lavare cycle. RESULTS: Particle image velocimetry showed increased ventricular washout with an active Lavare cycle as measured by the fluid velocities and angular dispersion parameters. With the Lavare cycle on, there was also a 22% decrease in the stagnation index compared with when the Lavare cycle was off. In the ReVOLVE registry, patients with the Lavare cycle turned on (n = 215) were supported for 497 patient-years, whereas patients who did not use the speed modulation (n = 33) were supported for 39.3 patient-years. The Lavare cycle did not significantly affect patient survival as both groups had approximately an 80% survival after 1 year. Patients using the Lavare cycle had significantly fewer rates of stroke [0.06 vs 0.20 events per patient-year (EPPY), P = 0.0008], sepsis (0.03 vs 0.15 EPPY, P = 0.0003) and right heart failure (0.03 vs 0.18 EPPY, P < 0.0001) with no difference in the transplant or recovery rates among the two cohorts. CONCLUSIONS: The Lavare cycle effectively generates ventricular washout and the adverse event profiles of ReVOLVE patients with the Lavare cycle on were better than those with the Lavare cycle off. Larger studies are warranted to verify the positive effect of the Lavare cycle and to optimize speed modulation settings, so additional clinically relevant improvements can be realized.

Long-term support of patients receiving a left ventricular assist device for advanced heart failure: a follow-up analysis of the Registry to Evaluate the HeartWare Left Ventricular Assist System.

OBJECTIVES: The Registry to Evaluate the HeartWare Left Ventricular Assist System (ReVOLVE) is an investigator-initiated multicentre, prospective, single-arm database established to collect post-Conformité Européenne Mark clinical information on patients receiving the HeartWare® Ventricular Assist System (HVAD®). The number of patients requiring longer periods of mechanical circulatory support is ever increasing and so further investigation into long-term outcomes in bridge-to-transplant populations is necessary. METHODS: Data were collected on 254 commercial implants performed between February 2009 and March 2012 from nine centres in Europe (7 centres) and Australia (2 centres). Patients were followed to device explant, heart transplant or death, and the outcomes of patients who remained on support longer than 2 years were analysed. Summary statistics were used to describe patient demographics, adverse events, length of support and outcomes for this long-term cohort. RESULTS: A total of 124 patients (49% of the original ReVOLVE population) were on support for more than 2 years (range: 731-2108 days), 76 of whom are still alive on support. Overall survival through 5 years was 59%. CONCLUSIONS: Owing to the low rate of heart transplants, a significant number of patients receiving a left ventricular assist device as a bridge to transplant remain on support for prolonged periods, often exceeding 2, 3 and even 4 years. Real-world use of the HVAD system continues to show excellent outcomes for patients on the device, including those on support beyond 2 years.

The homeostatic chemokine CCL21 predicts mortality in aortic stenosis patients and modulates left ventricular remodeling.

BACKGROUND: CCL21 acting through CCR7, is termed a homeostatic chemokine. Based on its role in concerting immunological responses and its proposed involvement in tissue remodeling, we hypothesized that this chemokine could play a role in myocardial remodeling during left ventricular (LV) pressure overload. METHODS AND RESULTS: Our main findings were: (i) Serum levels of CCL21 were markedly raised in patients with symptomatic aortic stenosis (AS, n = 136) as compared with healthy controls (n = 20). (ii) A CCL21 level in the highest tertile was independently associated with all-cause mortality in these patients. (iii) Immunostaining suggested the presence of CCR7 on macrophages, endothelial cells and fibroblasts within calcified human aortic valves. (iv). Mice exposed to LV pressure overload showed enhanced myocardial expression of CCL21 and CCR7 mRNA, and increased CCL21 protein levels. (v) CCR7-/- mice subjected to three weeks of LV pressure overload had similar heart weights compared to wild type mice, but increased LV dilatation and reduced wall thickness. CONCLUSIONS: Our studies, combining experiments in clinical and experimental LV pressure overload, suggest that CCL21/CCR7 interactions might be involved in the response to pressure overload secondary to AS.

Transapical 29-mm Edwards SAPIEN-XT aortic valve in a 34-mm mitral annuloplasty ring.

A 71-year-old woman with severe congestive heart failure and failed mitral valve repair was referred for surgery. Because of her low ejection fraction, a valve-in-ring procedure was suggested. There was a great difference in the given size for the 34-mm Carpentier-Edwards-Physio-Ring and the biggest available transcatheter valve of 29 mm from Edwards. Therefore, we did a "bench test." We expanded a 29-mm Edwards SAPIEN-XT aortic valve in a 34-mm Carpentier-Edwards-Physio-Ring. It fitted well and turned out circular with good coaptation of the leaflets. Thereafter, a successful transapical mitral valve-in-ring implantation on cardiopulmonary bypass was performed, and additional leads for cardiac resynchronization was placed.

Combined repair of upper sternal cleft and transposition of the great arteries in a newborn.

We report the case of a newborn with the unusual association of an upper sternal defect and transposition of the great arteries. Surgical correction of the cardiac disease consisted of the arterial switch procedure. The already less compliant bony thorax of the infant made direct approximation of the upper sternal defect only possible with adjuvant bilateral chondrotomy. Sternal cleft repair is advised during the very first weeks of life.

Hospital costs fell as numbers of LVADs were increasing: experiences from Oslo University Hospital.

BACKGROUND: The current study was undertaken to examine total hospital costs per patient of a consecutive implantation series of two 3rd generation Left Ventricle Assist Devices (LVAD). Further we analyzed if increased clinical experience would reduce total hospital costs and the gap between costs and the diagnosis related grouped (DRG)-reimbursement. METHOD: Cost data of 20 LVAD implantations (VentrAssist™) from 2005-2009 (period 1) were analyzed together with costs from nine patients using another LVAD (HeartWare™) from 2009-June 2011 (period 2). For each patient, total costs were calculated for three phases - the pre-LVAD implantation phase, the LVAD implantation phase and the post LVAD implant phase. Patient specific costs were obtained prospectively from patient records and included personnel resources, medication, blood products, blood chemistry and microbiology, imaging and procedure costs including operating room costs. Overhead costs were registered retrospectively and allocated to the specific patient by predefined allocation keys. Finally, patient specific costs and overhead costs were aggregated into total hospital costs for each patient. All costs were calculated in 2011-prices. We used regression analyses to analyze cost variations over time and between the different devices. RESULTS: The average total hospital cost per patient for the pre-LVAD, LVAD and post-LVAD for period 1 was $ 585, 513 (range 132, 640- 1 247, 299), and the corresponding DRG- reimbursement (2009) was $ 143, 192 . The mean LOS was 54 days (range 12- 127). For period 2 the total hospital cost per patient was $ 413, 185 (range 314, 540- 622, 664) and the corresponding DRG- reimbursement (2010) was $ 136, 963. The mean LOS was 49 days (range 31- 93).The estimates from the regression analysis showed that the total hospital costs, excluding device costs, per patient were falling as the number of treated patients increased. The estimate from the trend variable was -14, 096 US$ (CI -3, 842 to -24, 349, p < 0.01). CONCLUSION: There were significant reductions in total hospital costs per patient as the numbers of patients were increasing. This can possibly be explained by a learning effect including better logistics, selection and management of patients.

Perfusion temperature, thyroid hormones and inflammation during pediatric cardiac surgery.

OBJECTIVES: During cardiopulmonary bypass (CPB) surgery there are several alterations in concentrations of thyroid hormones. Although hypothermia and inflammation have been implicated in the disturbed thyroid axis during CPB, these issues are far from clear. METHODS AND RESULTS: We measured serum/plasma concentrations of thyroid hormones and inflammatory mediators in children with body weight <10 kg, undergoing open heart surgery, randomized to mild (n=15, 32 degrees C) or moderate (n=15, 25 degrees C) hypothermia. During CPB there was a marked decrease in triiodothyronine (T3), free thyroxin (FT4) and thyroid-stimulating hormone (TSH), followed by a slight increase after 24 h, but without normalization 48 h after CPB. There was no difference in the thyroid response between the two hypothermia groups. During CPB the maximal changes in plasma levels of interleukin (IL)-6 and the chemokines, regulated on activation normal T cell expressed and secreted (RANTES) and monocyte chemoattractant protein (MCP)-1 were inversely correlated with the maximal changes in serum levels of T3. CONCLUSION: Our findings in this randomized trial do not support a role for hypothermia as a major cause of altered thyroxin responses in children undergoing CPB. Our finding may also suggest that in addition to IL-6, other inflammatory cytokines, such as chemokines, should be further investigated for their possible influence on the thyroid axis during CPB.

In vitro evaluation of PHISIO-coated sets for pediatric cardiac surgery.

OBJECTIVES: Phosphorylcholine coated cardiopulmonary bypass (CPB) circuits for children have been available for some years, but conflicting results regarding the inflammatory response have been reported. Accordingly, we aimed to investigate the effect of phosphorylcholine coating on the inflammatory response. DESIGN: Ten coated and nine uncoated pediatric CPB sets were tested in an in vitro CPB circuit model. The inflammatory response was assessed by serial assays of hemoglobin, hematocrit, leukocyte counts, platelet counts, activation of the complement system, activation of platelets measured as beta-thromboglobulin, activation of neutrophils measured as myeloperoxidase, activation of coagulation measured as prothrombin fragments 1+2, assessment of hemolysis measured as lactate dehydrogenase, and a panel of seven cytokines. Samples were obtained at baseline and after 15, 30, 60 and 120 minutes. RESULTS: There were no significant differences between the phosphorylcholine coated circuits and the uncoated circuits for any of the parameters during the observation period, although a potentially beneficial effect on platelets could not be ruled out. CONCLUSIONS: Phosphorylcholine coating of CPB equipment did not exert any beneficial effect on the inflammatory markers monitored.

Biomarker profile in off-pump and on-pump coronary artery bypass grafting surgery in low-risk patients.

BACKGROUND: The purpose of this study was to investigate the cytokine and chemokine profile in low-risk patients undergoing off-pump and on-pump coronary artery bypass grafting (CABG) surgery by use of a broad panel of cytokines and chemokines. METHODS: Eight consecutive blood samples were obtained from patients enrolled into a prospective, randomized study comparing off-pump and on-pump CABG in a low-risk population. Eleven patients from each group were randomly selected for analysis of 25 different cytokines and chemokines using multiplex technology. Data were compared using two-way repeated measures analysis of variance. RESULTS: Of the 25 biomarkers analyzed, 11 were not detected while 14 increased significantly in both groups. Only three mediators, eotaxin, macrophage inflammatory protein (MIP)-1beta, and interleukin (IL)-12 were significantly different between the two groups, increasing more in the on-pump than in the off-pump group (p < 0.001, p < 0.01, and p < 0.05, respectively). There was a marked, comparable increase in the concentrations of the cytokines IL-6, IL-10, IL-15, and IL-1Ra as well as the chemokines inducible protein (IP)-10, monokine induced by interferon gamma (MIG), monocyte chemoattractant protein 1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES) in both groups (p < 0.001 for all). There was only a modest, but still statistically significant, increase in IL-8, tumor necrosis factors alpha, and IL-2R, without any intergroup differences. When corrected for hemodilution the production of the antiinflammatory biomarkers IL-1Ra and IL-10 were significantly higher in the on-pump group (p < 0.001 for both). CONCLUSIONS: The cytokine and chemokine production profile of the inflammatory response associated with CABG is largely similar using the off-pump and on-pump techniques in low-risk patients, but slightly higher concentrations of eotaxin, MIP-1beta, and IL-12 were found in the on-pump group.

Increased expression of LIGHT/TNFSF14 and its receptors in experimental and clinical heart failure.

BACKGROUND: Clinical and experimental studies suggest a pathogenic role for inflammation in chronic heart failure (HF). LIGHT is a member of the tumour necrosis factor superfamily involved in innate and adaptive immune responses. AIMS: We sought to investigate a potential pathogenic role of LIGHT in chronic HF. METHODS: We used various clinical and experimental approaches including studies in post-infarction HF rats and in vitro studies of endothelial cells and peripheral blood mononuclear cells (PBMC). RESULTS: Our main findings were: (i) LIGHT and its receptors (i.e., HVEM and lymphotoxin-beta receptor) were regulated during experimental HF, with strong expression in the infarcted area accompanied by up-regulation of HVEM in cardiomyocytes and endothelial cells also in the non-ischaemic part of the left ventricle. (ii) Patients with chronic HF had significantly increased expression of LIGHT on CD3(+) T-cells accompanied by increased expression of HVEM on monocytes and within the failing myocardium. (iii) LIGHT induced interleukin (IL)-6 expression in endothelial cells. In HF patients, but not in healthy controls, such an IL-6-inducing effect was also seen in LIGHT activated PBMC. CONCLUSION: Our findings in both clinical and experimental HF may suggest a role for LIGHT signalling pathways in the progression of chronic HF involving IL-6-related mechanisms.

Effect of perfusion temperature on the inflammatory response during pediatric cardiac surgery.

BACKGROUND: Cardiopulmonary bypass (CPB) triggers the whole body inflammatory response, and it has been suggested that the degree of hypothermia may influence these responses. The aim of this prospective study was to compare the inflammatory response in children undergoing CPB for repair of congenital heart defects, randomized to mild or moderate hypothermia. METHODS: We measured inflammatory markers in blood samples of thirty children with body weight less than 10 kg undergoing open heart surgery randomized to surgery at either mild (32 degrees C) or moderate (25 degrees C) hypothermia. Blood was sampled after induction of anesthesia, at skin closure, 2 hours, 24 hours, and 48 hours postoperatively. RESULTS: Except for an enhanced interleukin-8 response in the moderate hypothermia group, there were no differences in levels of inflammatory mediators between those with mild and those with moderate hypothermia. In contrast to the modest influence of the degree of hypothermia, long CPB time and long aortic cross-clamp time were accompanied by enhanced inflammation involving raised levels of interleukin-8 and myeloperoxidase, as well as increased leukocyte counts. CONCLUSIONS: Only minor differences in cytokine levels were detected between those with moderate and those with mild hypothermia during CPB. Ischemic aortic cross-clamp time and time on CBP should be as short as possible to avoid an excessive inflammatory response and possibly adverse clinical effects.

[Survival after heart transplantation in Norway]. / Overlevelse etter hjertetransplantasjon i Norge.

BACKGROUND: Heart transplantation has been a treatment option in Norway for selected patients with terminal congestive heart failure since 1983. The number of transplants is limited by donor availability. Few Norwegian doctors are aware of the challenges to be expected in taking care of heart transplant recipients. In the present paper we therefore present our experience so far. MATERIAL AND METHODS: We have followed individuals within our patient cohort for up to 22 years. The cohort consists of 522 patients (mean age 48.8 years +/- 13.6), somewhat unequally distributed from various parts of the country, reflecting the local referring practice. We have a complete overview of the patients who are partly followed up locally, but come to a control at least once a year at our hospital. RESULTS AND INTERPRETATION: Mean survival in these patients is 12 years. With an expected survival of less than one year without transplantation, these are strong results that compare well with international figures. Patients younger than 50 years at transplantation have the best prognosis regardless of donor age, while the combination of patients older than 50 years and donor above 35 years have the poorest chance of survival. However, patients are disposed to various severe complications. Initially after transplantation acute rejection, unspecific graft failure and infections are a threat; while complications such as chronic graft sclerosis, renal failure and cancer are complications that appear over time. To optimise results, life-long regular follow up is necessary.

ALCAPA, a possible reason for mitral insufficiency and heart failure in young patients.

OBJECTIVES: ALCAPA, anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital disease. We have from 1990 to 2003 operated on seven patients in our clinic. The objective of this study was to describe our experience of treating the condition and to remind other doctors of it as a possible diagnosis. DESIGN: The patients were identified by a retrospective review of our clinical records. RESULTS: Symptoms and signs varied from discomfort and pathologic heart murmur to ventricular fibrillation. All patients were operated on by use of cardiopulmonal bypass. Two died postoperatively within one week, two were reoperated later on because of pulmonary artery stenosis. CONCLUSION: ALCAPA should be suspected if a young patient with no previous history of heart failure presents with dyspnoe, chest pain or dysrhythmia. ALCAPA must be excluded by coronary angiography in younger patients with mitral insufficiency and no other morphological findings. Patients diagnosed early and operated on have a good prognosis.

Off-pump cardiac surgery abolishes complement activation.

BACKGROUND: This prospective randomized study compared the inflammatory response in patients undergoing elective on-pump and off-pump coronary artery bypass grafting. PATIENTS AND METHODS: Forty-four patients undergoing elective coronary artery bypass grafting were recruited with 22 patients randomized to on-pump heart surgery and 22 patients to off-pump coronary bypass surgery. Plasma levels of C3bc, the terminal SC5b-9 complement complex, myeloperoxidase, beta-thromboglobulin and prothrombin fragment F1 + 2 were measured before the operation, intraoperatively, at termination of the operation, and two hours post-operatively. RESULTS: Complement was markedly activated in the on-pump group as indicated by a significant increase in C3bc and SC5b-9 (p < 0.001 for both), whereas no complement activation was seen in the off-pump group (p = 0.001 between the groups). In contrast, both groups showed significant activation of neutrophils, platelets and coagulation, as indicated by an early increase in myeloperoxidase and a post-operative increase in beta-thromboglobulin and F1 + 2, respectively. Notably, there were no intergroup differences with regard to neutrophil and platelet activation, whereas coagulation activation was more pronounced in the off-pump group (p < 0.01). CONCLUSIONS: Off-pump surgery completely eliminated the heart-lung machine-induced complement activation. Neutrophils and platelets were equally activated in both groups, whereas coagulation was enhanced post-operatively in the off-pump group.

Decreased endomyocardial RANKL expression in transplant coronary artery disease.

Transplant-associated coronary artery disease (TxCAD) appears to be initiated by endothelial cell activation and inflammation involving inflammatory cytokines and chemokines. Osteoprotegerin (OPG) and receptor activator of nuclear Factor-kappaB ligand (RANKL) have been implicated in cardiovascular disease progression and we measured the expression of these mediators in serum and myocardial biopsies taken serially during the first year after heart transplantation (HTx), relating them to the development of TxCAD. Serum OPG as well as myocardial gene expression of RANK and OPG, but not RANKL, were highest early after HTx and declined progressively. Importantly, patients who develop TxCAD or experience episodes of acute rejection showed a lower myocardial RANKL expression throughout the first year after transplantation than patients without these complications. Our findings may suggest an unrecognized role RANKL in maintaining myocardial and/or endothelial integrity and suggest that RANKL should be further investigated as a parameter that may predict development of TxCAD.