Management of ganciclovir resistance cytomegalovirus infection with CMV hyperimmune globulin and leflunomide in seven cardiothoracic transplant recipients and literature review.

Cytomegalovirus (CMV) disease caused by genetically resistant CMV poses a major challenge in solid organ transplant recipients, and the development of resistance is associated with increased morbidity and mortality. Antiviral resistance affects 5%-12% of patients following ganciclovir (GCV) therapy, but is more common in individuals with specific underlying risk factors. These include the CMV D+R- serostatus, type of transplanted organ, dose and duration of (Val)GCV ([V]GCV) prophylaxis, peak viral loads, and the intensity of immunosuppressive therapy. Guideline recommendations for the management of GCV resistance (GanR) in solid organ transplant recipients are based on expert opinion as there is a lack of data from controlled trials. Second-line options to treat GanR include foscarnet (FOS) and cidofovir (CDV), but these drugs are often poorly tolerated due to high rates of toxicity, such as renal dysfunction and neutropenia. Here, we report seven cardiothoracic transplant recipients with GCV resistance CMV infection from our centre treated with CMV immunoglobulin (CMVIG) +/- leflunomide (LEF) and reviewed the literature on the use of these agents in this therapeutic setting.

Modifying dietary patterns in cardiothoracic transplant patients to reduce cardiovascular risk: The AMEND-IT Trial.

BACKGROUND: Cardiovascular disease (CVD) is common after cardiothoracic transplantation and causes substantial morbidity. AIMS: To assess feasibility and potential effectiveness of dietary interventions to reduce CVD risk. MATERIALS AND METHODS: In a pilot intervention, we recruited patients from a tertiary hospital and randomly allocated them to a Mediterranean or low-fat diet for 12 months. Feasibility was measured by patient participation, retention, and adherence. Changes in weight, body mass index (BMI), heart rate, blood pressure, glucose markers, and blood lipids were assessed using longitudinal generalized estimating equation regression models with 95% confidence intervals. RESULTS: Of 56 heart and 60 lung transplant recipients, 52 (45%) consented, 41 were randomized, and 39 (95%) completed the study with good adherence to randomized diets. After 12 months, changes in many risk factors were seen in the Mediterranean and low-fat-diet groups, respectively, including mean BMI (-0.5 vs. 0.0 kg/m2 ), systolic/diastolic blood pressure +0.5/+0.1 vs -4.4/-3.5 mmHg; fasting glucose -0.26 vs -0.27 mmol/L; total cholesterol -0.56 vs -0.40 mmol/L. Changes in BMI and systolic/diastolic blood pressure in 49 eligible patients who did not take part were +0.7 kg/m2 and +2.5/+1.8 mmHg. DISCUSSION: Dietary interventions in cardiothoracic transplant patients are feasible and potentially beneficial. CONCLUSION: A definitive nutritional intervention study in these high-risk patients is warranted.

The use of CMVIg rescue therapy in cardiothoracic transplantation: A single-center experience over 6 years (2011-2017).

Cytomegalovirus (CMV) is the most important infectious agent in solid organ transplant recipients and has a major impact on morbidity and mortality. Most cases are well managed with antiviral agents, but CMV hyperimmune globulin (CMVIg) can be used alongside antiviral therapy for prophylaxis in high-risk thoracic organ recipients and to treat life-threatening CMV infection or disease. CMVIg may also improve antiviral host defences when genetic resistance to antivirals or unwanted side effects occur. In this single-center, retrospective study, we reviewed the CMVIg use to supplement antiviral therapy as a "rescue therapy" in cardiothoracic transplant recipients. These comprised 12 single lung, 11 double lung, and 12 heart transplant recipients. Patients received a median of 2 doses of CMVIg, most often in combination with ganciclovir or valganciclovir, and reduced immunosuppression. One week after rescue therapy was initiated, CMV DNA levels were significantly reduced, and after four weeks, CMV DNA was undetectable in 73% patients. Only one patient died as a result of CMV-related disease. No significant adverse effects were observed. We conclude that CMVIg rescue therapy is safe, well tolerated, and effective at controlling viral replication in cardiothoracic transplant recipients.

Study Comparing Vein Integrity and Clinical Outcomes in Open Vein Harvesting and 2 Types of Endoscopic Vein Harvesting for Coronary Artery Bypass Grafting: The VICO Randomized Clinical Trial (Vein Integrity and Clinical Outcomes).

BACKGROUND: Current consensus statements maintain that endoscopic vein harvesting (EVH) should be standard care in coronary artery bypass graft surgery, but vein quality and clinical outcomes have been questioned. The VICO trial (Vein Integrity and Clinical Outcomes) was designed to assess the impact of different vein harvesting methods on vessel damage and whether this contributes to clinical outcomes after coronary artery bypass grafting. METHODS: In this single-center, randomized clinical trial, patients undergoing coronary artery bypass grafting with an internal mammary artery and with 1 to 4 vein grafts were recruited. All veins were harvested by a single experienced practitioner. We randomly allocated 300 patients into closed tunnel CO2 EVH (n=100), open tunnel CO2 EVH (n=100), and traditional open vein harvesting (n=100) groups. The primary end point was endothelial integrity and muscular damage of the harvested vein. Secondary end points included clinical outcomes (major adverse cardiac events), use of healthcare resources, and impact on health status (quality-adjusted life-years). RESULTS: The open vein harvesting group demonstrated marginally better endothelial integrity in random samples (85% versus 88% versus 93% for closed tunnel EVH, open tunnel EVH, and open vein harvesting; P<0.001). Closed tunnel EVH displayed the lowest longitudinal hypertrophy (1% versus 13.5% versus 3%; P=0.001). However, no differences in endothelial stretching were observed between groups (37% versus 37% versus 31%; P=0.62). Secondary clinical outcomes demonstrated no significant differences in composite major adverse cardiac event scores at each time point up to 48 months. The quality-adjusted life-year gain per patient was 0.11 (P<0.001) for closed tunnel EVH and 0.07 (P=0.003) for open tunnel EVH compared with open vein harvesting. The likelihood of being cost-effective, at a predefined threshold of £20 000 per quality-adjusted life-year gained, was 75% for closed tunnel EVH, 19% for open tunnel EVH, and 6% for open vein harvesting. CONCLUSIONS: Our study demonstrates that harvesting techniques affect the integrity of different vein layers, albeit only slightly. Secondary outcomes suggest that histological findings do not directly contribute to major adverse cardiac event outcomes. Gains in health status were observed, and cost-effectiveness was better with closed tunnel EVH. High-level experience with endoscopic harvesting performed by a dedicated specialist practitioner gives optimal results comparable to those of open vein harvesting. CLINICAL TRIAL REGISTRATION: URL: https://www.isrctn.com. International Standard Randomised Controlled Trial Registry Number: 91485426.

Genetic variants associated with risk of atrial fibrillation regulate expression of PITX2, CAV1, MYOZ1, C9orf3 and FANCC.

Genome-wide association studies (GWAS) have identified genetic variants in a number of chromosomal regions that are associated with atrial fibrillation (AF). The mechanisms underlying these associations are unknown, but are likely to involve effects of the risk haplotypes on expression of neighbouring genes. To investigate the association between genetic variants at AF-associated loci and expression of nearby candidate genes in human atrial tissue and peripheral blood. Right atrial appendage (RAA) samples were collected from 122 patients undergoing cardiac surgery, of these, 12 patients also had left atrial appendage samples taken. 22 patients had a history of AF. Peripheral blood samples were collected from 405 patients undergoing diagnostic cardiac catheterisation. In order to tag genetic variation at each of nine loci, a total of 367 single nucleotide polymorphisms (SNPs) were genotyped using the Sequenom platform. Total expression of 16 candidate genes in the nine AF-associated regions was measured by quantitative PCR. The relative expression of each allele of the candidate genes was measured on the Sequenom platform using one or more transcribed SNPs to distinguish between alleles in heterozygotes. We tested association between the SNPs of interest and gene expression using total gene expression (integrating cis and trans acting sources of variation), and allelic expression ratios (specific for cis acting influences), in atrial tissue and peripheral blood. We adjusted for multiple comparisons using a Bonferroni approach. In subsidiary analyses, we compared the expression of candidate genes between patients with and without a history of AF. Total expression of 15 transcripts of 14 genes and allelic expression ratio of 14 transcripts of 14 genes in genomic regions associated with AF were measured in right atrial appendage tissue. 8 of these transcripts were also expressed in peripheral blood. Risk alleles at AF-associated SNPs were associated in cis with an increased expression of PITX2a (2.01-fold, p=6.5×10(-4)); and with decreased expression of MYOZ1 (0.39 fold; p=5.5×10(-15)), CAV1 (0.89 fold; p=5.9×10(-8)), C9orf3 (0.91 fold; 1.5×10(-5)), and FANCC (0.94-fold; p=8.9×10(-8)) in right atrial appendage. Of these five genes, only CAV1 was expressed in peripheral blood; association between the same AF risk alleles and lower expression of CAV1 was confirmed (0.91 fold decrease; p=4.2×10(-5)). A history of AF was also associated with a decrease in expression of CAV1 in both right and left atria (0.84 and 0.85 fold, respectively; p=0.03), congruent with the magnitude of the effect of the risk SNP on expression, and independent of genotype. The analyses in peripheral blood showed association between AF risk SNPs and decreased expression of KCNN3 (0.85-fold; p=2.1×10(-4)); and increased expression of SYNE2 (1.12-fold; p=7.5×10(-24)); however, these associations were not detectable in atrial tissue. We identified novel cis-acting associations in atrial tissue between AF risk SNPs and increased expression of PITX2a/b; and decreased expression of CAV1 (an association also seen in peripheral blood), C9orf3 and FANCC. We also confirmed a previously described association between AF risk variants and MYOZ1 expression. Analyses of peripheral blood illustrated tissue-specificity of cardiac eQTLs and highlight the need for larger-scale genome-wide eQTL studies in cardiac tissue. Our results suggest novel aetiological roles for genes in four AF-associated genomic regions.

Multiparametric cardiovascular magnetic resonance surveillance of acute cardiac allograft rejection and characterisation of transplantation-associated myocardial injury: a pilot study.

BACKGROUND: Serial surveillance endomyocardial biopsies are performed in patients who have recently undergone heart transplantation in order to detect acute cardiac allograft rejection (ACAR) before symptoms occur, however the biopsy process is associated with a number of limitations. This study aimed to prospectively and longitudinally evaluate the performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting and monitoring ACAR in the early phase post-transplant, and characterize graft recovery following transplantation. METHODS: All patients receiving a heart transplant at a single UK centre over a period of 25 months were approached within one month of transplantation. Multiparametric CMR was prospectively performed on the same day as biopsy on four separate occasions (6 weeks, 10 weeks, 15 weeks and 20 weeks post-transplant). CMR included assessment of global and regional ventricular function, myocardial tissue characterization (T1 mapping, T2 mapping, extracellular volume, LGE) and pixel-wise absolute myocardial blood flow quantification. CMR parameters were compared with biopsy findings. As is standard, grade 2R or higher ACAR was considered significant. RESULTS: 88 CMR-matched biopsies were performed in 22 patients. Eight (9%) biopsies in 5 patients demonstrated significant ACAR. Significant ACAR was associated with a reduction in circumferential strain (-12.7±2.5% vs. -13.7±3.6%, p=0.047) but there was considerable overlap between groups. Whilst trends were observed between ACAR and proposed CMR markers of oedema, particularly after adjusting for primary graft dysfunction, differences were not significant. Significant improvements were seen in markers of graft structure and contractility, oedema and microvascular function over the period studied, although few parameters normalised. CONCLUSIONS: This study provides novel insight into the myocardial injury associated with transplantation, and its recovery, however multiparametric CMR was not able to accurately detect ACAR during the early phase post-transplantation.

A post-preservation vascular flush removes significant populations of donor leukocytes prior to lung transplantation.

BACKGROUND: Donor leukocytes are intrinsically involved in acute lung allograft rejection, via self-presentation of donor antigens to recipient leukocytes. Therapeutic modalities to remove donor leukocytes are currently unavailable. We evaluated if a vascular flush immediately following preservation can be used for this purpose. METHODS: A post-preservation flush was performed with STEEN solution in n = 6 porcine lungs following static cold storage. The first 500 ml effluent from the left atrium was collected and an inflammatory profile performed. RESULTS: A total of 1.17 billion (±2.8 × 108) viable leukocytes were identified within the effluent. T cells were the dominant cell population, representing 82% of the total mobilised leukocytes, of which <0.01% were regulatory T cells. IL-18 was the most abundant cytokine, with a mean concentration of 84,216 pg (±153,552 pg). In addition, there was a mean concentration of 8819 ng (±4415) cell-free mitochondrial DNA. CONCLUSION: There is an immediate transfer of donor leukocytes, cytokines and damage-associated molecular patterns following reperfusion. Such a pro-inflammatory donor load may enhance alloantigen presentation and drive recipient alloimmune responses. A post-preservation flush may therefore be an effective method for reducing the immune burden of the donor lung prior to transplantation.

Ex Vivo Lung Perfusion Improves the Inflammatory Signaling Profile of the Porcine Donor Lung Following Transplantation.

BACKGROUND: Primary graft dysfunction and allograft rejection represent major caveats to successful lung transplantation. Reducing inflammation in donor lungs before transplantation may improve outcomes. Evidence exists that ex vivo lung perfusion (EVLP) can alter the donor lung environment, although the mechanisms remain unclear. This study aimed to characterize the inflammatory signaling profile of the lung following standard and EVLP transplant and delineate the immediate impact on the recipient circulation. METHODS: Female recipient pigs (n = 12) were randomized to undergo left lung transplantation from male donors either using the gold standard protocol (static cold storage) or following 3 hours of EVLP. The relative phosphorylation of 44 phosphokinases and the relative expression of 35 apoptosis-related molecules were profiled within the donor lung 24 hours posttransplantation. RESULTS: A global profile of mitochondrial salvage and cell survival was observed in the EVLP lung tissue compared with lungs undergoing standard transplantation. This included increased phosphorylation of downstream prosignaling kinases, including ERK1/2 and FAK. In addition, there was upregulated expression of the antiapoptotic proteins Bcl-2, HSP-70, LIVIN, and PON2 with downregulation of apoptosis inducing mitochondrial associated molecules, including clusterin, cytochrome C, and HTRA2/OMI. In the early postoperative period, there were significantly lower levels of circulating mitochondrial DNA in recipients receiving EVLP lungs compared with a standard transplant (P = 0.016). Genomic DNA did not differ between groups, with donor DNA undetectable at all time points. CONCLUSIONS: EVLP alters the inflammatory signaling profile of the donor lung before transplantation, with a global cell survival and antiapoptotic signature.

Melatonin--a pleiotropic molecule involved in pathophysiological processes following organ transplantation.

Mammals adjust their physiology in response to seasonal changes to environment (i.e. photoperiod, temperature, food availability). These changes are thought to predominantly occur for the conservation of energy during winter, by pervasive changes such as the inhibition of reproduction. Previous reports have suggested that circannual changes also occur to the immune system. In mammals, this chronological effect may be dependent on photoperiod, and evidence exists to suggest that there is a great deal of immune variation in response to light, or circadian rhythm. This is a clinically relevant, yet under-reported area of human transplantation. The aim of this review is to discuss immune variation, with specific emphasis on melatonin secretion, in the context of organ rejection, infection, neoplasia formation, and immunosuppression.

The interpretation of clinical trial data--wrongly ACCLAIM'ed?

Advances in medicine continue to drive forward through the practice of often impressive and innovative investigation. Through the application of randomized clinical trials, statistical analyses deliver the notorious "P values" to provide evidence of whether an intervention results in the desired clinical effect. However, it would appear that it is becoming increasingly common for trial reports to "cheat" the statistical system, particularly when lucrative industrial reward might be at stake. Fortunately, there is a safety net in place for the clinician who is less well accustomed to critiquing the research manuscript. In the United States, the Food and Drug Administration rigorously analyzes evidence relating to safety and efficacy of new therapies before approving them for general use. In Europe, the European Medicines Agency provides a similar service. Yet of much concern, there appears to be clear differences over the respective level of scrutiny of clinical trial data. This article discusses the unease of how a flawed international trial report appeared to deceive the European Union into approving a device-based product for chronic heart failure despite an important lack of credible data.

Pleiotropic effects and cholesterol-lowering therapy.

HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, or 'statins', have revolutionized the management of patients with atherosclerotic vascular disease. Following 2 large acute coronary syndrome trials, additional clinical benefit outside their effect of low-density lipoprotein (LDL) lowering was proposed. This concept was introduced following the observation of cardiovascular event rate reduction, only weeks after initiation of treatment and supposedly before the effect of LDL lowering could have influenced atheroma volume burden. Furthermore, there has been a substantial compilation of experimental data demonstrating beneficial effects of statins on inflammation, thrombosis, platelet aggregation, immunomodulation and endothelial function. These are hypothesized to occur via the interruption of the mevalonate pathway. However, the absolute benefit of these non-lipid-lowering effects, often referred to as 'pleiotropic effects', has been challenged by meta-analysis data. Anti-inflammatory actions have also been proposed to occur by the process of LDL lowering alone rather than due to a unique property of statins. Furthermore, some experimental data reports have shown evidence of pleiotropic effects in non-statin lipid-modifying agents. In this review article, we consolidate what is known so far and critically analyse the literature in order to highlight the outstanding issues.

Liquid chromatography-mass spectrometry measurement of tacrolimus in finger-prick samples compared with venous whole blood samples.

BACKGROUND: Finger-prick sampling is an alternative strategy for monitoring immunosuppressive drug concentrations that could be useful in reducing outpatient visits. We investigated the correlation between venous and finger-prick samples in a group of adult thoracic transplant patients. METHODS: Blood samples (n = 65) for the measurement of whole blood tacrolimus were collected from adult heart (n = 18) and lung transplant (n = 20) recipients receiving tacrolimus-based immunosuppressive therapy and a finger-prick sample was taken at the same time. RESULTS: Between-batch assay imprecision (coefficient of variation [CV], %) for the last 12 months (n = 270) at concentrations of 3.5, 6.9 and 13.9 microg/L was 8.0%, 5.4% and 5.2%, respectively. Passing and Bablok regression analysis between finger-prick and venous blood showed finger-prick tacrolimus = 1.02 (venous blood tacrolimus) -0.06. Bland-Altman analysis showed good agreement with a bias of 0.114 microg/L and 95% limits of agreement from -1.0 to 1.2 microg/L. CONCLUSIONS: The liquid chromatography mass spectrometry methodology that we have developed has the potential to allow patients or their carers to collect finger-prick blood samples at home and send them to the laboratory using the routine mail service. We believe that finger-prick blood sampling has an important role to play in the care of transplant patients receiving immunosuppressive drugs, including tacrolimus.

Impact of dose reductions on efficacy outcome in heart transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil at 12 months post-transplantation.

Mycophenolic acid (MPA) dose reduction is associated with increased risk of rejection and graft loss in renal transplantation. This analysis investigated the impact of MPA dose changes with enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) in de novo heart transplant recipients. In a 12-month, single-blind trial, 154 patients (EC-MPS, 78; MMF, 76) were randomized to either EC-MPS (1080 mg bid) or MMF (1500 mg bid) in combination with cyclosporine and steroids. The primary efficacy variable was the incidence of treatment failure, comprising a composite of biopsy-proven (BPAR) and treated acute rejection, graft loss or death. Significantly fewer patients receiving EC-MPS required > or =2 dose reductions than patients on MMF (26.9% vs. 42.1% of patients, p = 0.048). Accordingly, the average daily dose of EC-MPS as a percentage of the recommended dose was significantly higher than for MMF (88.4% vs. 79.0%, p = 0.016). Among patients requiring > or =1 dose reduction, the incidence of treated BPAR grade > or =3A was significantly lower with EC-MPS compared with MMF (23.4% vs. 44.0%, p = 0.032). These data suggest that EC-MPS-treated heart transplant patients are less likely to require multiple dose reductions than those on MMF which may be associated with a significantly lower risk of treated BPAR > or =3A.

Clinical characteristics and survival in cardiogenic shock admissions to a UK heart transplant unit.

AIM: We describe the characteristics and outcomes of cardiogenic shock (CS) admissions to a UK transplant unit, which is previously unreported. PATIENTS & METHODS: Fifty-nine unselected, consecutive patients over a 38-month period in CS (INTERMACS ≤2) and potentially eligible for transplant were retrospectively reviewed. RESULTS: Patients were predominantly male (76.3%), young (mean age 42.2 years) and with severe end-organ dysfunction (acute liver/kidney injury 83%, mean lactate 3.5 mmol/l). 57.6% required mechanical support and 28.8% cardiac transplant. 30 days, discharge and 1-year survival were 78, 68 and 63%, respectively. Predictors of death included no transplant, increasing age and increasing creatinine. CONCLUSION: Patients with CS and potential for transplant require significant resource input but demonstrate favorable outcomes in our experience.

Does brain natriuretic peptide interact with the immune system after cardiac transplantation?

Brain natriuretic peptide (BNP) is a marker of diagnosis and prognosis in patients with chronic heart failure. Stored in ventricular myocytes, it is released during ventricular stretch and increased transmural pressure. However, BNP behaves unusually after cardiac transplantation, with a failure to return to normal levels. This raises a question over whether other processes are involved in both its production and secretion. Several studies suggest BNP levels are associated with allograft rejection and coronary graft vasculopathy. Both of these processes have a single denominator in common, the activated immune system. This overview considers further evidence suggesting that BNP interacts with the immune system after cardiac transplantation.

Randomized Study Comparing the Effect of Carbon Dioxide Insufflation on Veins Using 2 Types of Endoscopic and Open Vein Harvesting.

OBJECTIVE: The aim of the study was to assess whether the use of carbon dioxide insufflation has any impact on integrity of long saphenous vein comparing 2 types of endoscopic vein harvesting and traditional open vein harvesting. METHODS: A total of 301 patients were prospectively randomized into 3 groups. Group 1 control arm of open vein harvesting (n = 101), group 2 closed tunnel (carbon dioxide) endoscopic vein harvesting (n = 100) and Group 3 open tunnel (carbon dioxide) endoscopic vein harvesting (open tunnel endoscopic vein harvesting) (n = 100). Each group was assessed to determine the systemic level of partial arterial carbon dioxide, end-tidal carbon dioxide, and pH. Three blood samples were obtained at baseline, 10 minutes after start of endoscopic vein harvesting, and 10 minutes after the vein was retrieved. Vein samples were taken immediately after vein harvesting without further surgical handling to measure the histological level of endothelial damage. A modified validated endothelial scoring system was used to compare the extent of endothelial stretching and detachment. RESULTS: The level of end-tidal carbon dioxide was maintained in the open tunnel endoscopic vein harvesting and open vein harvesting groups but increased significantly in the closed tunnel endoscopic vein harvesting group (P = 0.451, P = 0.385, and P < 0.001). Interestingly, partial arterial carbon dioxide also did not differ over time in the open tunnel endoscopic vein harvesting group (P = 0.241), whereas partial arterial carbon dioxide reduced significantly over time in the open vein harvesting group (P = 0.001). A profound increase in partial arterial carbon dioxide was observed in the closed tunnel endoscopic vein harvesting group (P < 0.001). Consistent with these patterns, only the closed tunnel endoscopic vein harvesting group demonstrated a sudden drop in pH over time (P < 0.001), whereas pH remained stable for both open tunnel endoscopic vein harvesting and open vein harvesting groups (P = 0.105 and P = 0.869, respectively). Endothelial integrity was better preserved in the open vein harvesting group compared with open tunnel endoscopic vein harvesting or closed tunnel endoscopic vein harvesting groups (P = 0.012) and was not affected by changes in carbon dioxide or low pH. Significantly greater stretching of the endothelium was observed in the open tunnel endoscopic open tunnel endoscopic vein harvesting group compared with the other groups (P = 0.003). CONCLUSIONS: This study demonstrated that the different vein harvesting techniques impact on endothelial integrity; however, this does not seem to be related to the increase in systemic absorption of carbon dioxide or to the pressurized endoscopic tunnel. The open tunnel endoscopic harvesting technique vein had more endothelial stretching compared with the closed tunnel endoscopic technique; this may be due to manual dissection of the vein. Further research is required to evaluate the long-term clinical outcome of these vein grafts.

The MDR1/ABCB1 gene, a high-impact risk factor for cardiac transplant rejection.

BACKGROUND: Variations in the expression and activity levels of the multidrug-resistance MDR1/ABCB1 encoded P- glycoprotein (P-gp) have an impact on the therapeutic efficacy of many drugs. C3435T and G2677 polymorphisms of the MDR1/ABCB1 gene correlate with cellular expression levels of P-gp, a membrane-bound efflux pump which removes a multitude of drugs, including chemotherapy drugs and immunosuppressants, from cells. We aimed to investigate whether the phenomenon of drug resistance, mediated by the MDR1/ABCB1 gene and seen in tumor cells to chemotherapeutic agents, is important in the field of transplantation, predisposing some patients to resistance to immunosuppressants. METHODS: G2677 and C3435T polymorphisms of the ABCB1 gene were determined by PCR in 170 heart transplant recipients. We examined the relationship between MDR1/ABCB1 polymorphisms and endomyocardial biopsy-proven rejection (EBPR) determined by biopsy performed at set intervals according to a standard protocol. RESULTS: A significant relationship was found between a patient's C3435T genotype and freedom from first grade > or =3A rejection episode. 3435-CC recipients were 1.8 times (1.05-3.09; P = 0.03) more likely to undergo a > or =3A rejection episode in the first 12 months. Haplotypes derived from the G2677 and C3435T polymorphisms (GG/CC, GT/CT and TT/TT) amplified this phenomenon further (log rank, P = 0.03; HR 2.18; 1.21-4.26; P = 0.02). CONCLUSIONS: ABCB1 polymorphisms correlate with freedom from grade > or =3A EBPR and we believe that this may be attributed to MDR1/ABCB1 encoded P-gp mediating the efflux of immunosuppressants out of leukocytes, with depleted immunosuppressant levels in leukocytes manifesting as increased cellular rejection.

Cytomegalovirus Hyper Immunoglobulin for CMV Prophylaxis in Thoracic Transplantation.

Cytomegalovirus (CMV) infection negatively influences both short- and long-term outcomes after cardiothoracic transplantation. In heart transplantation, registry analyses have shown that CMV immunoglobulin (CMVIG) with or without virostatic prophylaxis is associated with a significant reduction in mortality and graft loss versus no prophylaxis, particularly in high-risk donor (D)+/recipient (R)- transplants. Randomized comparative trials are lacking but retrospective data suggest that addition of CMVIG to antiviral prophylaxis may reduce rates of CMV-related events after heart transplantation, including the incidence of acute rejection or chronic allograft vasculopathy. However, available data consistently indicate that when CMVIG is used, it should be administered with concomitant antiviral therapy, and that evidence concerning preemptive management with CMVIG is limited, but promising. In lung transplantation, CMVIG should again only be used with concomitant antiviral therapy. Retrospective studies have shown convincing evidence that addition of CMVIG to antiviral prophylaxis lowers CMV endpoints and mortality. The current balance of evidence suggests that CMVIG prophylaxis reduces the risk of bronchiolitis obliterans syndrome, but a controlled trial is awaited. Overall, the relatively limited current data set suggests that prophylaxis with CMVIG in combination with antiviral therapy appears effective in D+/R- heart transplant patients, whereas in lung transplantation, addition of CMVIG in recipients of a CMV-positive graft may offer an advantage in terms of CMV infection and disease.

Myocardial recovery with mechanical circulatory support.

Mechanical circulatory support (MCS) is instituted in patients with advanced heart failure, some of who may experience sufficient recovery in cardiac function to allow withdrawal of mechanical support. The incidence of left ventricular recovery with MCS is unclear as reported series in the literature demonstrate widely divergent rates. A number of clinical parameters (including echocardiographic, haemodynamic and physiological) are used to indicate likely left ventricular recovery during pump speed reduction but no internationally agreed definition exists. Withdrawal of MCS is not without risk and so robust clinical and biochemical definitions are important to minimize patient morbidity and mortality. Here we review our current understanding of left ventricular recovery with MCS.

A comprehensive review on learning curve associated problems in endoscopic vein harvesting and the requirement for a standardised training programme.

Endoscopic vein harvesting is becoming one of the most favourable vein harvesting techniques in multiple bypass coronary surgery, due to its short term post-operative benefits with high patient satisfaction. However, long-term graft patency has been both supported and questioned in the literature. Graft failure can be affected by harvesting methods and operator's experience. Endoscopic vein harvesting is associated with a learning curve period, during which the incidence of vein trauma is high due to unfamiliarity with the surgical technique. There is a paucity of structured learning tools for novice practitioners, meaning that training differs significantly between hospital centres. Inconsistent training methods can lead to poor surgical technique, which can have a significant impact on vein quality and stress level of the practitioner. In turn, this can lead to increased postoperative complications and longer surgical duration. The main aim of this literature review is to understand the impact of the learning curve on the vein conduit and whether there is a requirement for a standardised training programme for the novice practitioners.