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Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma.

Wed, 08/09/2017 - 12:45
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Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma.

Mol Cancer Res. 2016 May;14(5):448-57

Authors: Zhou X, Guo J, Ji Y, Pan G, Liu T, Zhu H, Zhao J

Abstract
UNLABELLED: The epidermal growth factor receptor (EGFR) activates downstream mTOR phosphorylation to promote the progression of many different tumor types, thus making it a prime therapeutic target. However, the role of DEP domain-containing mTOR-interacting protein (DEPTOR), a natural mTOR inhibitor, remains unclear in this process. Here, it is reported that EGFR expression is significantly increased in tumors of lung adenocarcinoma patients and is negatively correlated with the expression of DEPTOR. Activation of EGFR signaling, by EGF, in A549 lung adenocarcinoma cells (overexpressing EGFR) significantly enhanced the function of the mTOR autoamplification loop, consisting of S6K, mTOR, CK1α, and βTrCP1, which resulted in downregulation of DEPTOR expression. Gefitinib, a specific EGFR inhibitor, stimulated DEPTOR accumulation by downregulating the function of the mTOR autoamplification loop. Furthermore, a series of assays conducted in DEPTOR knockout or ectopic expression in A549 cells confirmed that DEPTOR inhibited proliferation, migration, and invasion as well as the in vivo tumor growth of lung adenocarcinoma. Importantly, tumor progression mediated by EGFR ectopic expression was diminished by transfection with DEPTOR. This study uncovers the important inhibitory role of DEPTOR in lung adenocarcinoma progression and reveals a novel mechanism that EGFR downregulates DEPTOR expression to facilitate tumor growth.
IMPLICATIONS: DEPTOR acts as a tumor suppressor by limiting EGFR-driven lung adenocarcinoma progression. Mol Cancer Res; 14(5); 448-57. ©2016 AACR.

PMID: 26896556 [PubMed - indexed for MEDLINE]

Factors associated with failure of free gracilis flap in reconstruction of acute traumatic leg defects.

Wed, 08/09/2017 - 12:45
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Factors associated with failure of free gracilis flap in reconstruction of acute traumatic leg defects.

J Plast Surg Hand Surg. 2016 Jun;50(3):125-9

Authors: Wong JZ, Lahiri A, Sebastin SJ, Chong AK

Abstract
BACKGROUND: Possible factors associated with failure of free gracilis flaps were studied.
MATERIALS AND METHODS: All gracilis free flaps used to reconstruct acute traumatic leg defects in a 5 year period were collected. This included open fractures of the tibia and/or fibula in which a gracilis free flap was used for reconstruction. Pre-op factors included age, ethnicity, gender, presence of diabetes, ischaemic heart disease, peripheral vascular disease, or coagulation disorders; days from trauma to flap surgery, Gustilo class, presence of a concurrent ipsilateral femur fracture, and use of CT angiogram to determine adequacy of blood supply. Intra-op factors included type of arterial anastomosis (end to side or end to end), presence of arterial transection, initial arterial anastomotic failure, initial venous anastomotic failure, use of systemic vasoconstrictors by anaesthetists for correction of hypotension, and use of modulators of the coagulation mechanism (dextran/heparin). Post-op factors included post-op day when flap was removed and use of modulators of the coagulation mechanism.
RESULTS: Patients with a concurrent ipsilateral femur fracture had a 9.67 (95% CI of OR = 1.32-70.96) times increased risk of flap failure compared to patients without an associated femur fracture.
CONCLUSION: The finding of increased risk of free gracilis flap failure for coverage of leg defects in patients with ipsilateral femur fractures has implications on flap selection and pre-operative counselling. In such a situation, a non-microvascular option could be safer if it is available as an alternative.

PMID: 26750150 [PubMed - indexed for MEDLINE]

A TSLP-complement axis mediates neutrophil killing of methicillin-resistant Staphylococcus aureus.

Tue, 08/08/2017 - 15:46
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A TSLP-complement axis mediates neutrophil killing of methicillin-resistant Staphylococcus aureus.

Sci Immunol. 2016 Nov 18;1(5):

Authors: West EE, Spolski R, Kazemian M, Yu ZX, Kemper C, Leonard WJ

Abstract
Community-acquired Staphylococcus aureus infections often present as serious skin infections in otherwise healthy individuals and have become a worldwide epidemic problem fueled by the emergence of strains with antibiotic resistance, such as methicillin-resistant S. aureus (MRSA). The cytokine thymic stromal lymphopoietin (TSLP) is highly expressed in the skin and in other barrier surfaces and plays a deleterious role by promoting T helper cell type 2 (TH2) responses during allergic diseases; however, its role in host defense against bacterial infections has not been well elucidated. We describe a previously unrecognized non-TH2 role for TSLP in enhancing neutrophil killing of MRSA during an in vivo skin infection. Specifically, we demonstrate that TSLP acts directly on both mouse and human neutrophils to augment control of MRSA. Additionally, we show that TSLP also enhances killing of Streptococcus pyogenes, another clinically important cause of human skin infections. Unexpectedly, TSLP mechanistically mediates its antibacterial effect by directly engaging the complement C5 system to modulate production of reactive oxygen species by neutrophils. Thus, TSLP increases MRSA killing in a neutrophil- and complement-dependent manner, revealing a key connection between TSLP and the innate complement system, with potentially important therapeutic implications for control of MRSA infection.

PMID: 28783679 [PubMed]

Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation.

Tue, 08/08/2017 - 15:46
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Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation.

Sci Immunol. 2016 Jul 14;1(1):aaf8759

Authors: Marino J, Babiker-Mohamed MH, Crosby-Bertorini P, Paster JT, LeGuern C, Germana S, Abdi R, Uehara M, Kim JI, Markmann JF, Tocco G, Benichou G

Abstract
Transplantation of allogeneic organs and tissues represents a lifesaving procedure for a variety of patients affected with end-stage diseases. Although current immunosuppressive therapy prevents early acute rejection, it is associated with nephrotoxicity and increased risks for infection and neoplasia. This stresses the need for selective immune-based therapies relying on manipulation of lymphocyte recognition of donor antigens. The passenger leukocyte theory states that allograft rejection is initiated by recipient T cells recognizing donor major histocompatibility complex (MHC) molecules displayed on graft leukocytes migrating to the host's lymphoid organs. We revisited this concept in mice transplanted with allogeneic skin, heart, or islet grafts using imaging flow cytometry. We observed no donor cells in the lymph nodes and spleen of skin-grafted mice, but we found high numbers of recipient cells displaying allogeneic MHC molecules (cross-dressed) acquired from donor microvesicles (exosomes). After heart or islet transplantation, we observed few donor leukocytes (100 per million) but large numbers of recipient cells cross-dressed with donor MHC (>90,000 per million). Last, we showed that purified allogeneic exosomes induced proinflammatory alloimmune responses by T cells in vitro and in vivo. Collectively, these results suggest that recipient antigen-presenting cells cross-dressed with donor MHC rather than passenger leukocytes trigger T cell responses after allotransplantation.

PMID: 28783676 [PubMed]

Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts.

Tue, 08/08/2017 - 15:46
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Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts.

Sci Immunol. 2017 Jun 23;2(12):

Authors: Dai H, Friday AJ, Abou-Daya KI, Williams AL, Mortin-Toth S, Nicotra ML, Rothstein DM, Shlomchik WD, Matozaki T, Isenberg JS, Oberbarnscheidt MH, Danska JS, Lakkis FG

Abstract
Mice devoid of T, B, and natural killer (NK) cells distinguish between self and allogeneic nonself despite the absence of an adaptive immune system. When challenged with an allograft, they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce interleukin-12 and present antigen to T cells. However, the molecular mechanisms by which the innate immune system detects allogeneic nonself to generate these DCs are not known. To address this question, we studied the innate response of Rag2(-/-) γc(-/-) mice, which lack T, B, and NK cells, to grafts from allogeneic donors. By positional cloning, we identified that donor polymorphism in the gene encoding signal regulatory protein α (SIRPα) is a key modulator of the recipient's innate allorecognition response. Donors that differed from the recipient in one or both Sirpa alleles elicited an innate alloresponse. The response was mediated by binding of donor SIRPα to recipient CD47 and was modulated by the strength of the SIRPα-CD47 interaction. Therefore, sensing SIRPα polymorphism by CD47 provides a molecular mechanism by which the innate immune system distinguishes between self and allogeneic nonself independently of T, B, and NK cells.

PMID: 28783664 [PubMed]

Induced Pluripotent Stem Cell-Derived Cardiomyocytes Provide In Vivo Biological Pacemaker Function.

Tue, 08/08/2017 - 15:46
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Induced Pluripotent Stem Cell-Derived Cardiomyocytes Provide In Vivo Biological Pacemaker Function.

Circ Arrhythm Electrophysiol. 2017 May;10(5):e004508

Authors: Chauveau S, Anyukhovsky EP, Ben-Ari M, Naor S, Jiang YP, Danilo P, Rahim T, Burke S, Qiu X, Potapova IA, Doronin SV, Brink PR, Binah O, Cohen IS, Rosen MR

Abstract
BACKGROUND: Although multiple approaches have been used to create biological pacemakers in animal models, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have not been investigated for this purpose. We now report pacemaker function of iPSC-CMs in a canine model.
METHODS AND RESULTS: Embryoid bodies were derived from human keratinocytes, their action potential characteristics determined, and their gene expression profiles and markers of differentiation identified. Atrioventricular blocked dogs were immunosuppressed, instrumented with VVI pacemakers, and injected subepicardially into the anterobasal left ventricle with 40 to 75 rhythmically contracting embryoid bodies (totaling 1.3-2×10(6) cells). ECG and 24-hour Holter monitoring were performed biweekly. After 4 to 13 weeks, epinephrine (1 μg kg(-1) min(-1)) was infused, and the heart removed for histological or electrophysiological study. iPSC-CMs largely lost the markers of pluripotency, became positive for cardiac-specific markers. and manifested If-dependent automaticity. Epicardial pacing of the injection site identified matching beats arising from that site by week 1 after implantation. By week 4, 20% of beats were electronically paced, 60% to 80% of beats were matching, and mean and maximal biological pacemaker rates were 45 and 75 beats per minute. Maximum night and day rates of matching beats were 53±6.9 and 69±10.4 beats per minute, respectively, at 4 weeks. Epinephrine increased rate of matching beats from 35±4.3 to 65±4.0 beats per minute. Incubation of embryoid bodies with the vital dye, Dil, revealed the persistence of injected cells at the site of administration.
CONCLUSIONS: iPSC-CMs can integrate into host myocardium and create a biological pacemaker. Although this is a promising development, rate and rhythm of the iPSC-CMs pacemakers remain to be optimized.

PMID: 28500172 [PubMed - indexed for MEDLINE]

Oral Ulcerations Induced by Mycophenolate Mofetil Following Cardiac Transplant.

Tue, 08/08/2017 - 15:46
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Oral Ulcerations Induced by Mycophenolate Mofetil Following Cardiac Transplant.

Exp Clin Transplant. 2016 Oct;14(5):584-585

Authors: Mahdavi M, Hejri GM

PMID: 27733108 [PubMed - indexed for MEDLINE]

Donations After Circulatory Death in Liver Transplant.

Tue, 08/08/2017 - 15:46
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Donations After Circulatory Death in Liver Transplant.

Exp Clin Transplant. 2016 Oct;14(5):463-470

Authors: Eren EA, Latchana N, Beal E, Hayes D, Whitson B, Black SM

Abstract
The supply of liver grafts for treatment of end-stage liver disease continues to fall short of ongoing demands. Currently, most liver transplants originate from donations after brain death. Enhanced utilization of the present resources is prudent to address the needs of the population. Donation after circulatory or cardiac death is a mechanism whereby the availability of organs can be expanded. Donations after circulatory death pose unique challenges given their exposure to warm ischemia. Technical principles of donations after circulatory death procurement and pertinent studies investigating patient outcomes, graft outcomes, and complications are highlighted in this review. We also review associated risk factors to suggest potential avenues to achieve improved outcomes and reduced complications. Future considerations and alternative techniques of organ preservation are discussed, which may suggest novel strategies to enhance preservation and donor expansion through the use of marginal donors. Ultimately, without effective measures to bolster organ supply, donations after circulatory death should remain a consideration; however, an understanding of inherent risks and limitations is necessary.

PMID: 27733105 [PubMed - indexed for MEDLINE]

Association of Maternal Antiangiogenic Profile at Birth With Early Postnatal Loss of Microvascular Density in Offspring of Hypertensive Pregnancies.

Tue, 08/08/2017 - 15:46
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Association of Maternal Antiangiogenic Profile at Birth With Early Postnatal Loss of Microvascular Density in Offspring of Hypertensive Pregnancies.

Hypertension. 2016 Sep;68(3):749-59

Authors: Yu GZ, Aye CY, Lewandowski AJ, Davis EF, Khoo CP, Newton L, Yang CT, Al Haj Zen A, Simpson LJ, O'Brien K, Cook DA, Granne I, Kyriakou T, Channon KM, Watt SM, Leeson P

Abstract
Offspring of hypertensive pregnancies are more likely to have microvascular rarefaction and increased blood pressure in later life. We tested the hypothesis that maternal angiogenic profile during a hypertensive pregnancy is associated with fetal vasculogenic capacity and abnormal postnatal microvascular remodeling. Infants (n=255) born after either hypertensive or normotensive pregnancies were recruited for quantification of postnatal dermal microvascular structure at birth and 3 months of age. Vasculogenic cell potential was assessed in umbilical vein endothelial cells from 55 offspring based on in vitro microvessel tube formation and proliferation assays. Maternal angiogenic profile (soluble fms-like tyrosine kinase-1, soluble endoglin, vascular endothelial growth factor, and placental growth factor) was measured from postpartum plasma samples to characterize severity of pregnancy disorder. At birth, offspring born after hypertensive pregnancy had similar microvessel density to those born after a normotensive pregnancy, but during the first 3 postnatal months, they had an almost 2-fold greater reduction in total vessel density (-17.7±16.4% versus -9.9±18.7%; P=0.002). This postnatal loss varied according to the vasculogenic capacity of the endothelial cells of the infant at birth (r=0.49; P=0.02). The degree of reduction in both in vitro and postnatal in vivo vascular development was proportional to levels of antiangiogenic factors in the maternal circulation. In conclusion, our data indicate that offspring born to hypertensive pregnancies have reduced vasculogenic capacity at birth that predicts microvessel density loss over the first 3 postnatal months. Degree of postnatal microvessel reduction is proportional to levels of antiangiogenic factors in the maternal circulation at birth.

PMID: 27456522 [PubMed - indexed for MEDLINE]

Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival.

Tue, 08/08/2017 - 15:46
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Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival.

Transpl Int. 2016 Aug;29(8):930-40

Authors: Borges CM, Reichenbach DK, Kim BS, Misra A, Blazar BR, Turka LA

Abstract
MyD88 signaling directly promotes T-cell survival and is required for optimal T-cell responses to pathogens. To examine the role of T-cell-intrinsic MyD88 signals in transplantation, we studied mice with targeted T-cell-specific MyD88 deletion. Contrary to expectations, we found that these mice were relatively resistant to prolongation of graft survival with anti-CD154 plus rapamycin in a class II-mismatched system. To specifically examine the role of MyD88 in Tregs, we created a Treg-specific MyD88-deficient mouse. Transplant studies in these animals replicated the findings observed with a global T-cell MyD88 knockout. Surprisingly, given the role of MyD88 in conventional T-cell survival, we found no defect in the survival of MyD88-deficient Tregs in vitro or in the transplant recipients and also observed intact cell homing and expression of Treg effector molecules. MyD88-deficient Tregs also fail to protect allogeneic bone marrow transplant recipients from chronic graft-versus-host disease, confirming the observations of defective regulation seen in a solid organ transplant system. Together, our data define MyD88 as having a divergent requirement for cell survival in non-Tregs and Tregs, and a yet-to-be defined survival-independent requirement for Treg function during the response to alloantigen.

PMID: 27112509 [PubMed - indexed for MEDLINE]

Pretransplant Stable Systolic Cardiac Functions Play an Important Role in Short-term Systolic Cardiac Functions After Kidney Transplant in Children.

Tue, 08/08/2017 - 15:46
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Pretransplant Stable Systolic Cardiac Functions Play an Important Role in Short-term Systolic Cardiac Functions After Kidney Transplant in Children.

Exp Clin Transplant. 2017 Feb;15(1):34-39

Authors: Alparslan C, Yavascan O, Doğan MS, Saritas S, Mutlubas Ozsan F, Kasap Demir B, Bakiler AR, Aksu N

Abstract
OBJECTIVES: In this study, our aim was to evaluate the systolic cardiac parameters and related risk factors in children within 6 months after kidney transplant.
MATERIALS AND METHODS: We retrospectively evaluated 24 children who received kidney transplants. Clinical and laboratory parameters before and after transplant were recorded. Results were evaluated statistically, with a P value less than .05 considered significant.
RESULTS: Before transplant, systolic cardiac functions were within normal limits. After transplant, ejection fraction (63.35% ± 5.38% vs 66.95% ± 4.62%; P = .01) was significantly increased and left ventricular mass index (32.63 ± 17.21 g/m2.7 vs 31.29 ± 15.65 g/m2.7; P = .78) was not significantly decreased, whereas fractional shortening (52.16% ± 15.32% vs 59.8% ± 12.94%; P = .54) did not change. Systolic blood pressure, systolic blood pressure index, diastolic blood pressure, and diastolic blood pressure index values were not statistically different before and after transplant (P > .05). The number of antihypertensive agents was significantly decreased (P = .001). Before and after transplant, cardiac geometry was normal in 15 patients (62.5%) and 17 patients (70.8%).
CONCLUSIONS: Our patients, who had stable systolic cardiac function before transplant, showed further improvements in systolic cardiac function even within 6 months after transplant. Therefore, strictly monitored and controlled blood pressure, volume, anemia, and nutrition in children before transplant may play important roles in achieving better cardiac systolic function after kidney transplant.

PMID: 26867571 [PubMed - indexed for MEDLINE]

The role of free flaps for salvage of the exposed total ankle arthroplasty.

Tue, 08/08/2017 - 15:46
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The role of free flaps for salvage of the exposed total ankle arthroplasty.

Microsurgery. 2017 Jan;37(1):34-37

Authors: Hallock GG

Abstract
Total ankle arthroplasty in the right circumstances cannot only relieve discomfort; but, unlike an ankle arthrodesis, can restore enhanced ambulatory capabilities. Subsequent wound healing issues have the potential to ultimately lead to implant removal, a disaster that can be avoided by as early intervention as possible that will provide sustainable wound closure. Over the past 5 years, 5 patients have presented in a delayed fashion with wound breakdown following total ankle arthroplasty that required a free flap for successful prosthesis salvage. The mean wound size was 78.0 cm(2) (range 14-200 cm(2) ). Two gracilis and 2 latissimus dorsi muscle free flaps were chosen as a malleable means not just to cover but to fill these usually large 3-dimensional wounds. A single radial forearm perforator free flap was selected in one case for a superficial wound that required a long vascular pedicle to reach outside the zone of injury. The postoperative course for all was uneventful, with a minimum follow-up of 4 months. Function preservation following total ankle arthroplasty wound breakdown even after an untimely delay in referral can still be maintained using microsurgical tissue transfers. © 2014 Wiley Periodicals, Inc. Microsurgery 37:34-37, 2017.

PMID: 26069155 [PubMed - indexed for MEDLINE]

Cerebral Microhemorrhage: A Frequent Magnetic Resonance Imaging Finding in Pediatric Patients after Cardiopulmonary Bypass.

Mon, 08/07/2017 - 18:48
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Cerebral Microhemorrhage: A Frequent Magnetic Resonance Imaging Finding in Pediatric Patients after Cardiopulmonary Bypass.

J Clin Imaging Sci. 2017;7:27

Authors: Kim PPC, Nasman BW, Kinne EL, Oyoyo UE, Kido DK, Jacobson JP

Abstract
OBJECTIVES: This study was undertaken to estimate the incidence and burden of cerebral microhemorrhage (CM) in patients with heart disease who underwent cardiopulmonary bypass (CPB), as detected on susceptibility-weighted imaging (SWI), a magnetic resonance (MR) sequence that is highly sensitive to hemorrhagic products.
MATERIALS AND METHODS: With Institutional Review Board waiver of consent, MR imaging (MRI) of a cohort of 86 consecutive pediatric patients with heart failure who underwent heart transplantation evaluation were retrospectively reviewed for CM. A nested case-control study was performed. The CPB group consisted of 23 pediatric patients with heart failure from various cardiac conditions who underwent CPB. The control group was comprised of 13 pediatric patients with similar cardiac conditions, but without CPB history. Ten patients in the CPB group were female (age: 5 days to 16 years at the time of the CPB and 6 days to 17 years at the time of the MRI). The time interval between the CPB and MRI ranged from 11 days to 4 years and 5 months. Six patients in the control group were female, age range of 2 days to 6 years old. The number of CM on SWI was counted by three radiologists (PK, EK and DK). The differences in number of CM between groups were tested for significance using Mann-Whitney U-test, α = 0.05. Using the univariate analysis of variance model, the differences in number of CM between groups were also tested with adjustment for age at MRI.
RESULTS: There are statistically significant differences in CM on SWI between the CPB group and control group with more CM were observed in the CPB group without and with adjustment for age at MRI (P < 0.001).
CONCLUSIONS: Exposure of CPB is associated with increased prevalence and burden of CM among pediatric patients with heart failure.

PMID: 28781924 [PubMed]

Durable mechanical circulatory support in teenagers and adults with congenital heart disease: A systematic review.

Mon, 08/07/2017 - 18:48
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Durable mechanical circulatory support in teenagers and adults with congenital heart disease: A systematic review.

Int J Cardiol. 2017 Aug 02;:

Authors: Steiner JM, Krieger EV, Stout KK, Stempien-Otero A, Mahr C, Mokadam NA, Hermsen JL

Abstract
BACKGROUND: Heart failure is the leading cause of morbidity and mortality for adults with congenital heart disease (ACHD). Many patients are ineligible for transplantation, and those who are eligible often face long wait times with high wait-list morbidity. Durable mechanical circulatory support (MCS) may be an option for many patients. This systematic review evaluates the published literature on the use of durable MCS in teenagers and adults with congenital heart disease.
METHODS: A comprehensive search of MEDLINE (PubMed), EMBASE, and the Cochrane Library was performed electronically in July 2015 and updated in March 2016, guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.
RESULTS: Individual case reports and several case series identified 66 patients with ACHD treated with durable MCS. More than half were INTERMACS 1 or 2 at the time of implantation. Patients with Fontan repairs were more frequently classified as INTERMACS 1 or 2 (89% compared to 59% or less among other groups). Cases published after 2010 showed a trend toward less severe INTERMACS status, and patients were less likely to have received transplants by the time of reporting (31% compared to 61% prior). Durable MCS was implanted as bridge-to-transplant in 77%. Patients with Fontan repair accounted for 14% of cases.
CONCLUSION: Reports of durable MCS utilization in patients with ACHD are becoming more frequent and devices are being implanted in more stable patients. Reports are mostly case reports or small case series so reporting bias is likely and prospective protocoled reporting is needed.

PMID: 28781147 [PubMed - as supplied by publisher]

Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis.

Mon, 08/07/2017 - 18:48
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Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis.

Lancet Diabetes Endocrinol. 2017 Aug 03;:

Authors: Birkeland KI, Jørgensen ME, Carstensen B, Persson F, Gulseth HL, Thuresson M, Fenici P, Nathanson D, Nyström T, Eriksson JW, Bodegård J, Norhammar A

Abstract
BACKGROUND: In patients with type 2 diabetes and a high cardiovascular risk profile, the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin have been shown to lower cardiovascular morbidity and mortality. Using real-world data from clinical practice, we aimed to compare cardiovascular mortality and morbidity in new users of SGLT2 inhibitors versus new users of other glucose-lowering drugs, in a population with a broad cardiovascular risk profile.
METHODS: CVD-REAL Nordic was an observational analysis of individual patient-level data from the Prescribed Drug Registers, Cause of Death Registers, and National Patient Registers in Denmark, Norway, and Sweden. All patients who filled a prescription for glucose-lowering drugs between 2012 and 2015 were included and followed up until Dec 31, 2015. Patients were divided into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs. Each SGLT2 inhibitor user was matched with three users of other glucose-lowering drugs by use of propensity scores. Hazard ratios (HRs) were estimated by country (Cox survival model) and weighted averages were calculated. Cardiovascular outcomes investigated were cardiovascular mortality, major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, and ischaemic or haemorrhagic stroke), hospital events for heart failure (inpatient or outpatient visit with a primary diagnosis of heart failure), non-fatal myocardial infarction, non-fatal stroke, and atrial fibrillation. We also assessed incidence of severe hypoglycaemia.
FINDINGS: Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0·9 (SD 4·1) years (80 669 patient-years) and mean age of 61 (12·0) years; 40% (36 362 of 91 320) were women and prevalence of cardiovascular disease was 25% (22 686 of 91 320). 94% of the total SGLT2 inhibitor exposure time was for use of dapagliflozin, with 5% for empagliflozin, and 1% for canagliflozin. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with decreased risk of cardiovascular mortality (HR 0·53 [95% CI 0·40-0·71]), major adverse cardiovascular events (0·78 [0·69-0·87]), and hospital events for heart failure (0·70 [0·61-0·81]; p<0·0001 for all). We did not identify significant differences between use of SGLT2 inhibitors and use of other glucose-lowering drugs for non-fatal myocardial infarction, non-fatal stroke, or atrial fibrillation. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with a decreased risk of severe hypoglycaemia (HR 0·76 [0·65-0·90]; p=0·001). For cardiovascular mortality, the differences were similar for the 25% of individuals with cardiovascular disease at baseline and those without (HR 0·60 [0·42-0·85] vs 0·55 [0·34-0·90]), while for major adverse cardiovascular events the HR in the group with cardiovascular disease at baseline was 0·70 (0·59-0·83) versus 0·90 (0·76-1·07) in the group without.
INTERPRETATION: In a population of patients with type 2 diabetes and a broad cardiovascular risk profile, SGLT2 inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with use of other glucose-lowering drugs-a finding consistent with the results of clinical trials in patients at high cardiovascular risk.
FUNDING: AstraZeneca.

PMID: 28781064 [PubMed - as supplied by publisher]

Early aspirin use and the development of cardiac allograft vasculopathy.

Mon, 08/07/2017 - 18:48
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Early aspirin use and the development of cardiac allograft vasculopathy.

J Heart Lung Transplant. 2017 Jul 03;:

Authors: Kim M, Bergmark BA, Zelniker TA, Mehra MR, Stewart GC, Page DS, Woodcome EL, Smallwood JA, Gabardi S, Givertz MM

Abstract
BACKGROUND: Cardiac allograft vasculopathy (CAV) remains a leading cause of morbidity and mortality after orthotopic heart transplantation (OHT). Little is known about the influence of aspirin on clinical expression of CAV.
METHODS: We followed 120 patients with OHT at a single center for a median of 7 years and categorized them by the presence or absence of early aspirin therapy post-transplant (aspirin treatment ≥6 months in the first year). The association between aspirin use and time to the primary end-point of angiographic moderate or severe CAV (International Society for Heart and Lung Transplantation grade ≥2) was investigated. Propensity scores for aspirin treatment were estimated using boosting models and applied by inverse probability of treatment weighting (IPTW).
RESULTS: Despite a preponderance of risk factors for CAV among patients receiving aspirin (male sex, ischemic heart disease as the etiology of heart failure, and smoking), aspirin therapy was associated with a lower rate of moderate or severe CAV at 5 years. Event-free survival was 95.9% for patients exposed to aspirin compared with 79.6% for patients without aspirin exposure (log-rank p = 0.005). IPTW-weighted Cox regression revealed a powerful inverse association between aspirin use and moderate to severe CAV (adjusted hazard ratio 0.13; 95% confidence interval 0.03-0.59), which was directionally consistent for CAV of any severity (adjusted hazard ratio 0.50; 95% confidence interval 0.23-1.08).
CONCLUSIONS: This propensity score-based comparative observational analysis suggests that early aspirin exposure may be associated with a reduced risk of development of moderate to severe CAV. These findings warrant prospective validation in controlled investigations.

PMID: 28781013 [PubMed - as supplied by publisher]

Registry of the International Society for Heart and Lung Transplantation: Twentieth Pediatric Lung and Heart-Lung Transplantation Report-2017; Focus Theme: Allograft ischemic time.

Mon, 08/07/2017 - 18:48
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Registry of the International Society for Heart and Lung Transplantation: Twentieth Pediatric Lung and Heart-Lung Transplantation Report-2017; Focus Theme: Allograft ischemic time.

J Heart Lung Transplant. 2017 Jul 19;:

Authors: Goldfarb SB, Levvey BJ, Cherikh WS, Chambers DC, Khush K, Kucheryavaya AY, Lund LH, Meiser B, Rossano JW, Yusen RD, Stehlik J, International Society for Heart and Lung Transplantation

PMID: 28781012 [PubMed - as supplied by publisher]

Pre-operative proteinuria in left ventricular assist devices and clinical outcome.

Mon, 08/07/2017 - 18:48
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Pre-operative proteinuria in left ventricular assist devices and clinical outcome.

J Heart Lung Transplant. 2017 Jul 15;:

Authors: Muslem R, Caliskan K, Akin S, Sharma K, Gilotra NA, Brugts JJ, Houston B, Whitman G, Tedford RJ, Hesselink DA, Bogers AJJC, Manintveld OC, Russell SD

Abstract
BACKGROUND: This study evaluated the association of pre-operative proteinuria before continuous flow left ventricular assist device (CF-LVAD) implantation in relation to mortality and the need for renal replacement therapy (RRT) during the first year of follow-up.
METHODS: This retrospective, multicenter cohort study evaluated all patients (n = 241) who underwent CF-LVAD implantation in the 2 participating tertiary referral centers. Patients were included if a urine dipstick was performed within 7 days before CF-LVAD implantation. Proteinuria was defined as trace or higher.
RESULTS: In total, 173 patients (72%) were included (78% men; mean age, 52.3 ± 13.3; mean estimated glomerular filtration rate, 60.1 ± 25.9 mL/min/1.73 m(2)), and 42 patients (24%) had pre-operative proteinuria. The observed survival in patients with proteinuria vs without proteinuria was 57% vs 86% at 3 months and 52% vs 78% at 1 year (log-rank p < 0.001), respectively. In addition, during the first year after implantation, 32% of the patients with proteinuria and 15% of the patients without proteinuria required RRT (log-rank p = 0.02). Multivariate Cox regression analysis confirmed that pre-operative proteinuria was an independent predictor for mortality (adjusted hazard ratio, 2.09; 95% confidence interval, 1.10-3.80, p = 0.02) and for the need of RRT during the first year (adjusted hazard ratio, 2.23; 95% confidence interval, 1.13-4.84; p = 0.02).
CONCLUSIONS: Proteinuria, which was present in 25% of all tested LVAD patients, predicts worse outcome in all-cause mortality and need of RRT in patients with a CF-LVAD. This warrants the use of proteinuria in risk stratification when selecting patients for CF-LVAD therapy.

PMID: 28781011 [PubMed - as supplied by publisher]

An ISHLT consensus document for prevention and management strategies for mechanical circulatory support infection.

Mon, 08/07/2017 - 18:48
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An ISHLT consensus document for prevention and management strategies for mechanical circulatory support infection.

J Heart Lung Transplant. 2017 Jun 23;:

Authors: Kusne S, Mooney M, Danziger-Isakov L, Kaan A, Lund LH, Lyster H, Wieselthaler G, Aslam S, Cagliostro B, Chen J, Combs P, Cochrane A, Conway J, Cowger J, Frigerio M, Gellatly R, Grossi P, Gustafsson F, Hannan M, Lorts A, Martin S, Pinney S, Silveira FP, Schubert S, Schueler S, Strueber M, Uriel N, Wrightson N, Zabner R, Huprikar S

PMID: 28781010 [PubMed - as supplied by publisher]

Post-transplant lymphoproliferative disease is associated with early sternotomy and left ventricular hypoplasia during infancy: a population-based retrospective review.

Mon, 08/07/2017 - 18:48
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Post-transplant lymphoproliferative disease is associated with early sternotomy and left ventricular hypoplasia during infancy: a population-based retrospective review.

Cardiol Young. 2017 Aug 07;:1-9

Authors: Ekman-Joelsson BM, Wåhlander H, Synnergren M, Sager M, Mellgren K

Abstract
BACKGROUND: Heart transplantation has been an option for children in Sweden since 1989. As our unit faced an increased rate of post-transplant lymphoproliferative disorder, the objective of the study was to identify possible risk factors.
METHODS: This is a retrospective study of all children aged 0-18 years who underwent heart transplantation in Gothenburg from 1989 to 2014.
RESULTS: A total of 71 children underwent heart transplantation. The overall incidence of post-transplant lymphoproliferative disorder was 14% (10/71); however, 17% (6/36) of those undergoing transplantation after 2007 developed lymphoma, compared with only 10% (4/35) of transplantation cases before 2007 (p=0.85). The mean age at transplantation was 9 years (0-17). The mean post-transplant follow-up time was 5.5 years (0.5-21.9) in the group that developed post-transplant lymphoproliferative disorder, compared with 10.2 years (0.02-25.2) in those who did not. In our study group, risk factors for post-transplant lymphoproliferative disorder were surgically palliated CHD (p=0.0005), sternotomy during infancy (p⩽0.0001), hypoplastic left ventricle (p=0.0001), number of surgical events (p=0.0022), mismatch concerning Epstein-Barr virus infection - that is, a positive donor-negative recipient (p⩽0.0001) - and immunosuppressive treatment with tacrolimus compared with ciclosporine (p=0.028). Discussion This study has three major findings. First, post-transplant lymphoproliferative disorder only developed in subjects born with CHD. Second, the vast majority (9/10) of the subjects developing the disorder had undergone sternotomy as infants. Third, the number of surgical events correlated with a higher risk for developing post-transplant lymphoproliferative disorder.

PMID: 28780922 [PubMed - as supplied by publisher]

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