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Can we push the boundaries of ABO-incompatible pediatric heart transplantation?

Tue, 08/01/2017 - 21:53
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Can we push the boundaries of ABO-incompatible pediatric heart transplantation?

J Heart Lung Transplant. 2017 Jul 17;:

Authors: Simpson KE, Canter C

PMID: 28756122 [PubMed - as supplied by publisher]

Distal airway microbiome is associated with immunoregulatory myeloid cell responses in lung transplant recipients.

Tue, 08/01/2017 - 21:53
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Distal airway microbiome is associated with immunoregulatory myeloid cell responses in lung transplant recipients.

J Heart Lung Transplant. 2017 Jul 15;:

Authors: Sharma NS, Wille KM, Athira S, Zhi D, Hough KP, Diaz-Guzman E, Zhang K, Kumar R, Rangarajan S, Eipers P, Wang Y, Srivastava RK, Rodriguez Dager JV, Athar M, Morrow C, Hoopes CW, Chaplin DD, Thannickal VJ, Deshane JS

Abstract
BACKGROUND: Long-term survival of lung transplant recipients (LTRs) is limited by the occurrence of bronchiolitis obliterans syndrome (BOS). Recent evidence suggests a role for microbiome alterations in the occurrence of BOS, although the precise mechanisms are unclear. In this study we evaluated the relationship between the airway microbiome and distinct subsets of immunoregulatory myeloid-derived suppressor cells (MDSCs) in LTRs.
METHODS: Bronchoalveolar lavage (BAL) and simultaneous oral wash and nasal swab samples were collected from adult LTRs. Microbial genomic DNA was isolated, 16S rRNA genes amplified using V4 primers, and polymerase chain reaction (PCR) products sequenced and analyzed. BAL MDSC subsets were enumerated using flow cytometry.
RESULTS: The oral microbiome signature differs from that of the nasal, proximal and distal airway microbiomes, whereas the nasal microbiome is closer to the airway microbiome. Proximal and distal airway microbiome signatures of individual subjects are distinct. We identified phenotypic subsets of MDSCs in BAL, with a higher proportion of immunosuppressive MDSCs in the proximal airways, in contrast to a preponderance of pro-inflammatory MDSCs in distal airways. Relative abundance of distinct bacterial phyla in proximal and distal airways correlated with particular airway MDSCs. Expression of CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP), an endoplasmic (ER) stress sensor, was increased in immunosuppressive MDSCs when compared with pro-inflammatory MDSCs.
CONCLUSIONS: The nasal microbiome closely resembles the microbiome of the proximal and distal airways in LTRs. The association of distinct microbial communities with airway MDSCs suggests a functional relationship between the local microbiome and MDSC phenotype, which may contribute to the pathogenesis of BOS.

PMID: 28756121 [PubMed - as supplied by publisher]

Comparison of two strategies for ex vivo lung perfusion.

Tue, 08/01/2017 - 21:53
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Comparison of two strategies for ex vivo lung perfusion.

J Heart Lung Transplant. 2017 Jul 08;:

Authors: Nilsson T, Gielis JF, Slama A, Hansson C, Wallinder A, Ricksten SE, Dellgren G

Abstract
BACKGROUND: Two clinically used strategies for ex vivo lung perfusion (EVLP) were compared in a porcine model with respect to lung function, metabolism, inflammatory response, oxidative stress, and cell viability.
METHODS: Porcine lungs (n = 20) were preserved, harvested, and kept cooled for 2 hours. After randomization, EVLP was performed using a cellular perfusate and open left atrium (COA group) or an acellular perfusate and a closed left atrium (ACA group). Oxygenation (partial pressure of arterial oxygen/fraction of inspired oxygen), compliance, dead space, weight, and perfusate oncotic pressure were registered before and after a 4-hour period of reconditioning. Lung tissue samples were collected before and after EVLP for quantitative polymerase chain reaction analysis of gene expression for inflammatory markers, measurement of tissue hypoxia (hypoxia inducible factor-1α) and oxidative stress (ascorbyl radical), and viability (trypan blue staining) and lung histopathology.
RESULTS: In 3 of 10 lungs undergoing EVLP in the ACA group, EVLP was terminated prematurely because of severe lung edema and inability to perfuse the lungs. There were no significant differences in changes of lung oxygenation or pulmonary vascular resistance between groups. Compliance decreased and lung weights increased in both groups, but more in the ACA group (p = 0.083 and p = 0.065, respectively). There was no obvious difference in gene expression for hypoxia inducible factor-1α, inflammatory markers, free radicals, or lung injury between groups.
CONCLUSIONS: Lung edema formation and decreased lung compliance occurs with both EVLP techniques but were more pronounced in the ACA group. Otherwise, there were no differences in lung function, inflammatory response, ischemia/reperfusion injury, or histopathologic changes between the EVLP techniques.

PMID: 28756120 [PubMed - as supplied by publisher]

What to do (or not to do) when randomization is not possible.

Tue, 08/01/2017 - 21:53
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What to do (or not to do) when randomization is not possible.

J Heart Lung Transplant. 2017 Jul 17;:

Authors: Naci H

PMID: 28756119 [PubMed - as supplied by publisher]

von Willebrand factor disruption and continuous-flow circulatory devices.

Tue, 08/01/2017 - 21:53
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von Willebrand factor disruption and continuous-flow circulatory devices.

J Heart Lung Transplant. 2017 Jun 12;:

Authors: Proudfoot AG, Davidson SJ, Strueber M

Abstract
Bleeding events remain a significant and frequent complication of continuous-flow left ventricular assist devices (VADs). von Willebrand factor (VWF) is critical to hemostasis by acting as a bridging molecule at sites of vascular injury for normal platelet adhesion as well as promoting platelet aggregation under conditions of high shear. Clinical and experimental data support a role for acquired von Willebrand disease in VAD bleeding episodes caused by shear-induced qualitative defects in VWF. Pathologic shear induces VWF unfolding and proteolysis of large multimers into smaller less hemostatic multimers via ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). This review outlines the pathobiology of VWF disruption in the context of VADs as well as current diagnostic and management strategies of the associated acquired von Willebrand disease.

PMID: 28756118 [PubMed - as supplied by publisher]

Vascular Damage and Kidney Transplant Outcomes: An Unfriendly and Harmful Link.

Tue, 08/01/2017 - 21:53
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Vascular Damage and Kidney Transplant Outcomes: An Unfriendly and Harmful Link.

Am J Med Sci. 2017 Jul;354(1):7-16

Authors: Hernández D, Triñanes J, Armas AM, Ruiz-Esteban P, Alonso-Titos J, Duarte A, González-Molina M, Palma E, Salido E, Torres A

Abstract
Kidney transplant (KT) is the treatment of choice for most patients with chronic kidney disease, but this has a high cardiovascular mortality due to traditional and nontraditional risk factors, including vascular calcification. Inflammation could precede the appearance of artery wall lesions, leading to arteriosclerosis and clinical and subclinical atherosclerosis in these patients. Additionally, mineral metabolism disorders and activation of the renin-angiotensin system could contribute to this vascular damage. Thus, understanding the vascular lesions that occur in KT recipients and the pathogenic mechanisms involved in their development could be crucial to optimize the therapeutic management and outcomes in survival of this population. This review focuses on the following issues: (1) epidemiological data framing the problem; (2) atheromatosis in KT patients: subclinical and clinical atheromatosis, involving ischemic heart disease, congestive heart failure, stroke and peripheral vascular disease; (3) arteriosclerosis and vascular calcifications; and (4) potential pathogenic mechanisms and their therapeutic targets.

PMID: 28755740 [PubMed - in process]

Intracoronary Stem Cell Delivery to the Right Ventricle: A Preclinical Study.

Tue, 08/01/2017 - 21:53
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Intracoronary Stem Cell Delivery to the Right Ventricle: A Preclinical Study.

Semin Thorac Cardiovasc Surg. 2016 Winter;28(4):817-824

Authors: Wehman B, Siddiqui O, Jack G, Vesely M, Li T, Mishra R, Sharma S, Taylor BS, Griffith BP, Kaushal S

Abstract
Clinical protocols for stem cell-based therapies are currently under development for patients with hypoplastic left heart syndrome. An ideal cell delivery method should have minimal safety risks and provide a wide distribution of cells to the nonischemic right ventricle (RV). However, the optimal strategy for stem cell delivery to the RV has yet to be explored in a preclinical model, necessary for a hypoplastic left heart syndrome trial. Human c-kit(+) cardiac stem cells (CSCs) were delivered to healthy Yorkshire swine through the proximal right coronary artery with a stop and reflow technique. The effect of premedication with antiarrhythmic (AA) medications in this model was retrospectively reviewed, with the primary outcome of survival 2 hours after infusion. A group underwent CSC delivery to the RV without prophylactic AA medication (no AA, n = 7), whereas the second group was premedicated with a loading dose and intravenous infusion of amiodarone and lidocaine (AA, n = 13). Cardiac biopsies were obtained from each chamber to ascertain the biodistribution of CSCs. Survival was significantly greater in the prophylactic AA group compared with the group without AA (13/13 [100%] vs 1/7 [14.3%], P < 0.0001). Cardiac arrest during balloon inflation was the cause of death in each of the nonmedicated animals. In the premedicated group, 9 (69.2%) pigs experienced transient ST segment changes in the precordial leads during CSC delivery, which resolved spontaneously. Most c-kit(+) CSCs were distributed to lateral segments of the RV free wall, consistent with the anatomical course of the right coronary artery (lateral RV, 19.2 ± 1.5 CSCs/field of view vs medial RV, 10.4 ± 1.3 CSCs/field of view, P < 0.0001). Few c-kit(+) CSCs were identified in the right atrium, septum, or left ventricle. Prophylactic infusion of AA enhances survival in swine undergoing intracoronary delivery of human c-kit(+) CSCs to the RV. Additionally, intracoronary delivery results in a limited biodistribution of c-kit(+) CSCs within the RV. Human clinical protocols can be optimized by requiring infusion of AA medications before cell delivery.

PMID: 28417870 [PubMed - indexed for MEDLINE]

In Vivo Functional Selection Identifies Cardiotrophin-1 as a Cardiac Engraftment Factor for Mesenchymal Stromal Cells.

Sun, 07/30/2017 - 12:45
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In Vivo Functional Selection Identifies Cardiotrophin-1 as a Cardiac Engraftment Factor for Mesenchymal Stromal Cells.

Circulation. 2017 Jul 28;:

Authors: Bortolotti F, Ruozi G, Falcione A, Doimo S, Dal Ferro M, Lesizza P, Zentilin L, Banks L, Zacchigna S, Giacca M

Abstract
Background -Transplantation of cells into the infarcted heart has significant potential to improve myocardial recovery; however, low efficacy of cell engraftment still limits therapeutic benefit. Here we describe a method for the unbiased, in vivo selection of cytokines that improve mesenchymal stromal cell (MSC) engraftment into the heart in both normal conditions and after myocardial infarction. Methods -An arrayed library of 80 secreted factors, including most of the currently known interleukins and chemokines, were individually cloned into adeno-associated viral (AAV) vectors. Pools from this library were then used for the batch transduction of bone marrow-derived MSCs ex vivo, followed by intra-myocardial cell administration in normal and infarcted mice. Three weeks after injection, vector genomes were recovered from the few persisting cells and identified by sequencing DNA barcodes uniquely labeling each of the tested cytokines. Results -The most effective molecule identified by this competitive engraftment screening was cardiotrophin 1 (Ctf1), a member of the IL6 family. Intra-cardiac injection of MSCs transiently pre-conditioned with Ctf1 preserved cardiac function and reduced infarct size, parallel to the persistence of the transplanted cells in the healing hearts for at least two months after injection. Engraftment of Cft1-treated MSCs was consequent to STAT3-mediated activation of the focal adhesion kinase (FAK) and its associated focal adhesion complex and the consequent acquisition of adhesive properties by the cells. Conclusions -These results support the feasibility of selecting molecules in vivo for their functional properties using AAV vector libraries and identify Ctf1 as a powerful cytokine promoting cell engraftment and thus improving cell therapy of the infarcted myocardium.

PMID: 28754835 [PubMed - as supplied by publisher]

Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis.

Sun, 07/30/2017 - 12:45
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Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis.

Gut. 2017 Jul 28;:

Authors: Rosendahl J, Kirsten H, Hegyi E, Kovacs P, Weiss FU, Laumen H, Lichtner P, Ruffert C, Chen JM, Masson E, Beer S, Zimmer C, Seltsam K, Algül H, Bühler F, Bruno MJ, Bugert P, Burkhardt R, Cavestro GM, Cichoz-Lach H, Farré A, Frank J, Gambaro G, Gimpfl S, Grallert H, Griesmann H, Grützmann R, Hellerbrand C, Hegyi P, Hollenbach M, Iordache S, Jurkowska G, Keim V, Kiefer F, Krug S, Landt O, Leo MD, Lerch MM, Lévy P, Löffler M, Löhr M, Ludwig M, Macek M, Malats N, Malecka-Panas E, Malerba G, Mann K, Mayerle J, Mohr S, Te Morsche RHM, Motyka M, Mueller S, Müller T, Nöthen MM, Pedrazzoli S, Pereira SP, Peters A, Pfützer R, Real FX, Rebours V, Ridinger M, Rietschel M, Rösmann E, Saftoiu A, Schneider A, Schulz HU, Soranzo N, Soyka M, Simon P, Skipworth J, Stickel F, Strauch K, Stumvoll M, Testoni PA, Tönjes A, Werner L, Werner J, Wodarz N, Ziegler M, Masamune A, Mössner J, Férec C, Michl P, P H Drenth J, Witt H, Scholz M, Sahin-Tóth M, all members of the PanEuropean Working group on ACP

Abstract
OBJECTIVE: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.
DESIGN: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.
RESULTS: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.
CONCLUSION: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.

PMID: 28754779 [PubMed - as supplied by publisher]

Impact of Asymmetric Dimethylarginine on Coronary Physiology Early After Heart Transplantation.

Sun, 07/30/2017 - 12:45
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Impact of Asymmetric Dimethylarginine on Coronary Physiology Early After Heart Transplantation.

Am J Cardiol. 2017 Jun 29;:

Authors: Parikh RV, Khush KK, Luikart H, Pargaonkar VS, Kobayashi Y, Lee JH, Sinha S, Cohen G, Valantine HA, Yeung AC, Fearon WF

Abstract
Cardiac allograft vasculopathy is a major cause of long-term graft failure following heart transplantation. Asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction, has been mechanistically implicated in the development of cardiac allograft vasculopathy, but its impact on coronary physiology early after transplantation is unknown. Invasive indices of coronary physiology, namely, fractional flow reserve (FFR), the index of microcirculatory resistance, and coronary flow reserve, were measured with a coronary pressure wire in the left anterior descending artery within 8 weeks (baseline) and 1 year after transplant. Plasma levels of ADMA were concurrently assayed using high-performance liquid chromatography. In 46 heart transplant recipients, there was a statistically significant correlation between elevated ADMA levels and lower FFR values at baseline (r = -0.33; p = 0.024); this modest association persisted 1 year after transplant (r = -0.39; p = 0.0085). Patients with a baseline FFR <0.90 (a prognostically validated cutoff) had significantly higher baseline ADMA levels (0.63 ± 0.16 vs 0.54 ± 0.12 µM; p = 0.034). Baseline ADMA (odds ratio 1.80 per 0.1 µM; 95% confidence interval 1.07 to 3.03; p = 0.027) independently predicted a baseline FFR <0.90 after multivariable adjustment. Even after dichotomizing ADMA (≥0.60 µM, provides greatest diagnostic accuracy by receiver operating characteristic curve), this association remained significant (odds ratio 7.52, 95% confidence interval 1.74 to 32.49; p = 0.006). No significant relationship between ADMA and index of microcirculatory resistance or coronary flow reserve was detected. In conclusion, baseline ADMA was a strong independent predictor of FFR <0.90, suggesting that elevated ADMA levels are associated with abnormal epicardial function soon after heart transplantation.

PMID: 28754566 [PubMed - as supplied by publisher]

Comparison of Different Stem Cell Mobilization Regimen in AL Amyloidosis Patients.

Sun, 07/30/2017 - 12:45
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Comparison of Different Stem Cell Mobilization Regimen in AL Amyloidosis Patients.

Biol Blood Marrow Transplant. 2017 Jul 25;:

Authors: Lisenko K, Wuchter P, Hansberg M, Mangatter A, Benner A, Ho AD, Goldschmidt H, Hegenbart U, Schönland S

Abstract
High-dose melphalan (HDM) and autologous blood stem cell transplantation (ABSCT) is an effective treatment for transplant-eligible patients with systemic light chain (AL) amyloidosis. Whereas most centers use granulocyte colony-stimulating factor (G-CSF) alone for mobilization of peripheral blood stem cells (PBSC), the application of mobilization chemotherapy might offer specific advantages. We retrospectively analyzed 110 patients with AL amyloidosis who underwent PBSC collection. Major eligibility criteria included age <70 years and cardiac insufficiency NYHA ≤III°. Prior to mobilization, 67 patients (61%) had been pre-treated with induction therapy, including 17 (15%) patients who had received melphalan. Chemotherapy mobilization was performed with either cyclophosphamide, adriamycin, dexamethasone (CAD)/G-CSF (n=78, 71%), ifosfamide/G-CSF (n=14, 13%) or other regimens (n=8, 7%). AL amyloidosis patients with predominant heart involvement and/or status post heart transplantation were mobilized with G-CSF only (n=10, 9%). PBSC collection was successful in 101 patients (92%) at first attempt. The median number of CD34(+) cells was 8.7 (range 2.1-45.5) x10(6) CD34(+)/kg collected in a median of one leukapheresis (LP) session. Compared to G-CSF mobilization only a chemo-mobilization with CAD/G-CSF or ifosfamide/G-CSF had a positive impact on the number of collected CD34(+) cell number/kg per LP (P<0.001, multivariate). Melphalan-containing previous therapy and higher age had a significant negative impact on quantity of collected CD34(+) cells. Median common toxicity criteria (CTC) grade of non-hematological toxicity was II (range 0-IV). Life-threatening CTC grade IV adverse events were observed in 3 patients with no fatalities. Cardiovascular events were observed in n=17 patients (22%) upon CAD/G-CSF mobilization (median CTC grade 3, range 1-4). Toxicity in patients undergoing ifosfamide/G-CSF mobilization was higher compared to G-CSF mobilization only. HDM and ABSCT were performed in 100 patients. Compared to >6.5 x10(6) transplanted CD34(+) cells/kg, an ABSCT with <3 x10(6) CD34(+) cells/kg was associated with a longer duration to leucocyte reconstitution >1/nl and a reduced platelet count <150/nl one year after ASCT. Our results show that CAD chemotherapy is very effective in PBSC mobilization and has a tolerable toxicity profile in AL amyloidosis patients. A further toxicity reduction by omission of adriamycin might be considered. Due to the advanced non-hematological toxicity ifosfamide administration cannot be recommended. However, G-CSF mobilization alone is also safe and effective. Considering the hematopoietic reconstitution and long-term stem cell function our results provide a rationale to collect and transplant as much as >6.5 x10(6) CD34+ cells/kg, if feasible with reasonable effort.

PMID: 28754546 [PubMed - as supplied by publisher]

Gender differences and outcomes in left ventricular assist device support: The European Registry for Patients with Mechanical Circulatory Support.

Sun, 07/30/2017 - 12:45
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Gender differences and outcomes in left ventricular assist device support: The European Registry for Patients with Mechanical Circulatory Support.

J Heart Lung Transplant. 2017 Jul 04;:

Authors: Magnussen C, Bernhardt AM, Ojeda FM, Wagner FM, Gummert J, de By TMMH, Krabatsch T, Mohacsi P, Rybczynski M, Knappe D, Sill B, Deuse T, Blankenberg S, Schnabel RB, Reichenspurner H

Abstract
BACKGROUND: Despite the increasing use of ventricular assist devices (VADs), gender differences in indications, hemodynamics, and outcome are not well understood. We examined gender differences and gender-specific predictors for perioperative outcome in patients on ventricular support.
METHODS: Multicenter data of 966 patients (median age 55 years, 151 women) from the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) were analyzed. Median follow-up was 1.26 years.
RESULTS: At the time of VAD implantation, women were more often in an unstable condition (Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] profile 1 and 2) (51.7% vs 41.6% in men), experiencing significantly more often major bleeding (p = 0.0012), arrhythmias (p = 0.022), and right ventricular (RV) failure (p < 0.001) with need for additional RV support. The survival of women on isolated LVAD support was significantly worse (1-year survival 75.5% vs 83.2% in men). Age-adjusted Cox regression analyses showed significant associations with mortality for preoperative inotropic therapy, percutaneous mechanical support, INTERMACS profile 1 and 2, RV dysfunction, major bleeding, cerebral bleeding, ischemic stroke, and RV failure. In women, pump thrombosis was more strongly related with mortality compared to men, while the direction of the association of renal dysfunction with mortality was different for women and men (p-value interaction 0.028 and 0.023, respectively).
CONCLUSIONS: Women and men differ in perioperative hemodynamics, adverse events, and mortality after VAD implantation. A gender-dependent association of pump thrombosis with mortality was seen. The impact on treatment practice needs to be shown.

PMID: 28754423 [PubMed - as supplied by publisher]

Risk of Early, Intermediate, and Late Rejection Following Heart Transplantation: Trends Over the Past 25 Years and Relation to Changes in Medical Management Tertiary Center Experience: The Sheba Heart Transplantation Registry.

Sat, 07/29/2017 - 12:45
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Risk of Early, Intermediate, and Late Rejection Following Heart Transplantation: Trends Over the Past 25 Years and Relation to Changes in Medical Management Tertiary Center Experience: The Sheba Heart Transplantation Registry.

Clin Transplant. 2017 Jul 28;:

Authors: Katz M, Freimark D, Raichlin E, Har-Zahav Y, Arad M, Kassif Y, Peled A, Asher E, Elian D, Kogan A, Shlomo N, Ofek E, Lavee J, Goldenberg I, Peled Y

Abstract
AIM: To explore the trends in the risk for rejection following heart transplantation (HT) over the past 25 years, and their relation to changes in medical management.
METHODS: The study population comprised 216 HT patients. Rejection periods were defined: 0-3 months (early), 3-12 months (intermediate), 12+ months (late). HT era was dichotomized: 1991-1999 (remote era) and 2000-2016 (recent era). Medication combination was categorized as newer (TAC, MMF, everolimus) vs. older therapies (AZA, CSA).
RESULTS: Multivariate analysis showed that patients who underwent HT during the recent era experienced a significant reduction in the risk for major rejection. These findings were consistent for early (OR=0.44 [95% CI 0.22-0.88]), intermediate (OR=0.02 [95% CI 0.003-0.11]), and late rejections (OR=0.18 [95% CI 0.05-0.52]). Using the year of HT as a continuous measure showed that each 1-year increment was independently associated with a significant reduction in the risk for early, intermediate, and late rejections (5%,21%,18% respectively). In contrast, the risk-reduction associated with newer types of immunosuppressive therapies was not statistically significant after adjustment for the treatment period.
CONCLUSIONS: Major rejection rates following HT have significantly declined over the past two decades even after adjustment for changes in immunosuppressive therapies, suggesting that other factors may also play a role in the improved outcomes of HT recipients. This article is protected by copyright. All rights reserved.

PMID: 28753240 [PubMed - as supplied by publisher]

Down regulation of protective genes are associated with cellular and antibody-mediated rejection.

Sat, 07/29/2017 - 12:45
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Down regulation of protective genes are associated with cellular and antibody-mediated rejection.

Clin Transplant. 2017 Jul 28;:

Authors: Lin-Wang HT, Cipullo R, Dinkhuysen JJ, Finger MA, Rossi JM, de Barros Correia E, Hirata MH

Abstract
Despite advances in immunosuppressive therapy, rejection still remains the main obstacle to a successful transplant. This study aims to explore the gene expression profile of the rejection process in order to decrease the number of unnecessary endomyocardial biopsies in stable patients.
METHODS: Total of 300 formalin fixed and paraffin embedded (FFPE) endomyocardial biopsy, sampled from 63 heart allograft recipients were included in this study. Acute cellular rejection (ACR) and antibody mediated rejection (AMR) were diagnosed by histological analysis and immunohistochemical C4d staining, respectively. Analysis of gene expression was performed by quantitative real-time polymerase chain reaction. The samples were grouped according to the ISHLT rejection classification, aiming the statistical analysis.
RESULTS: There was a significant decrease in the HMOX1, AIF1 and CCL2 transcript over the post-transplantation period in non-rejection group (p <0.001). Furthermore, the ADIPOR1, ADIPOR2, BCL2L1 and VEGFA protective genes were significantly down regulated in the ACR group (p<0.05). ADIPOR2, BCL2L1, IL6 and NOS2 genes were also significantly down regulated in the AMR group than in the non-rejection group (p<0.05).
CONCLUSION: The down regulations of the protective genes contribute to the allograft rejection, and the archived FFPE samples are useful for the gene expression analysis aiming the allograft rejection surveillance. This article is protected by copyright. All rights reserved.

PMID: 28752907 [PubMed - as supplied by publisher]

Myocardial Tissue Engineering for Regenerative Applications.

Sat, 07/29/2017 - 12:45
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Myocardial Tissue Engineering for Regenerative Applications.

Curr Cardiol Rep. 2017 Sep;19(9):78

Authors: Fujita B, Zimmermann WH

Abstract
PURPOSE OF REVIEW: This review provides an overview of the current state of tissue-engineered heart repair with a special focus on the anticipated modes of action of tissue-engineered therapy candidates and particular implications as to transplant immunology.
RECENT FINDINGS: Myocardial tissue engineering technologies have made tremendous advances in recent years. Numerous different strategies are under investigation and have reached different stages on their way to clinical translation. Studies in animal models demonstrated that heart repair requires either remuscularization by delivery of bona fide cardiomyocytes or paracrine support for the activation of endogenous repair mechanisms. Tissue engineering approaches result in enhanced cardiomyocyte retention and sustained remuscularization, but may also be explored for targeted paracrine or mechanical support. Some of the more advanced tissue engineering approaches are already tested clinically; others are at late stages of pre-clinical development. Process optimization towards cGMP compatibility and clinical scalability of contractile engineered human myocardium is an essential step towards clinical translation. Long-term allograft retention can be achieved under immune suppression. HLA matching may be an option to enhance graft retention and reduce the need for comprehensive immune suppression. Tissue-engineered heart repair is entering the clinical stage of the translational pipeline. Like in any effective therapy, side effects must be anticipated and carefully controlled. Allograft implantation under immune suppression is the most likely clinical scenario. Strategies to overcome transplant rejection are evolving and may further boost the clinical acceptance of tissue-engineered heart repair.

PMID: 28752277 [PubMed - in process]

Readmissions after continuous flow left ventricular assist device implantation.

Sat, 07/29/2017 - 12:45
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Readmissions after continuous flow left ventricular assist device implantation.

J Artif Organs. 2017 Jul 27;:

Authors: Kimura M, Nawata K, Kinoshita O, Yamauchi H, Hoshino Y, Hatano M, Amiya E, Kashiwa K, Endo M, Kagami Y, Nemoto M, Ono M

Abstract
Continuous flow left ventricular assist device (CF-LVAD) therapy has improved the survival of patients with advanced heart failure. However, the readmission rate of CF-LVAD patients is still relatively high. A total of 90 patients who received CF-LVADs between April 2011 and March 2016 at our institute and were discharged home were analyzed retrospectively. They were followed up through March 2017. Clinical data, including frequency, length and etiology of readmission, were obtained from medical records. The mean observation period after initial discharge was 713 ± 322 days. In total, 73 patients (81%) had 236 readmissions, 214 unplanned and 22 planned. The overall and unplanned readmission rates were 1.34 and 1.22 per patient-year, respectively. The rate of freedom from unplanned first readmission at 1 year after initial discharge was 39%. The median interval between the previous hospital discharge and first and second readmissions was 311 and 213 days, respectively (log-rank test, p = 0.117). The rate of readmission after more than three readmissions was significantly higher than that of first or second readmission (log-rank test, p < 0.001). The most common etiology of readmission was driveline infection (DLI) (36%), followed by stroke (9%). The median length of hospital stay due to DLI was 23 days. The patients with repeated unplanned readmissions had significantly lower EuroQol 5 dimensions questionnaire utility score than those with no or just one readmission. Readmission was common in CF-LVAD patients, and the most common etiology of readmissions was DLI. The interval to the next readmission seemed shorter for patients with repeated readmissions.

PMID: 28752193 [PubMed - as supplied by publisher]

ANMCO/SIC Consensus Document: cardiology networks for outpatient heart failure care.

Sat, 07/29/2017 - 12:45
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ANMCO/SIC Consensus Document: cardiology networks for outpatient heart failure care.

Eur Heart J Suppl. 2017 May;19(Suppl D):D89-D101

Authors: Aspromonte N, Gulizia MM, Di Lenarda A, Mortara A, Battistoni I, De Maria R, Gabriele M, Iacoviello M, Navazio A, Pini D, Di Tano G, Marini M, Ricci RP, Alunni G, Radini D, Metra M, Romeo F

Abstract
Changing demographics and an increasing burden of multiple chronic comorbidities in Western countries dictate refocusing of heart failure (HF) services from acute in-hospital care to better support the long inter-critical out-of- hospital phases of HF. In Italy, as well as in other countries, needs of the HF population are not adequately addressed by current HF outpatient services, as documented by differences in age, gender, comorbidities and recommended therapies between patients discharged for acute hospitalized HF and those followed-up at HF clinics. The Italian Working Group on Heart Failure has drafted a guidance document for the organisation of a national HF care network. Aims of the document are to describe tasks and requirements of the different health system points of contact for HF patients, and to define how diagnosis, management and care processes should be documented and shared among health-care professionals. The document classifies HF outpatient clinics in three groups: (i) community HF clinics, devoted to management of stable patients in strict liaison with primary care, periodic re-evaluation of emerging clinical needs and prompt treatment of impending destabilizations, (ii) hospital HF clinics, that target both new onset and chronic HF patients for diagnostic assessment, treatment planning and early post-discharge follow-up. They act as main referral for general internal medicine units and community clinics, and (iii) advanced HF clinics, directed at patients with severe disease or persistent clinical instability, candidates to advanced treatment options such as heart transplant or mechanical circulatory support. Those different types of HF clinics are integrated in a dedicated network for management of HF patients on a regional basis, according to geographic features. By sharing predefined protocols and communication systems, these HF networks integrate multi-professional providers to ensure continuity of care and patient empowerment. In conclusion, This guidance document details roles and interactions of cardiology specialists, so as to best exploit the added value of their input in the care of HF patients and is intended to promote a more efficient and effective organization of HF services.

PMID: 28751837 [PubMed - in process]

SERCA2a: A potential non-invasive biomarker of cardiac allograft rejection.

Sat, 07/29/2017 - 12:45
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SERCA2a: A potential non-invasive biomarker of cardiac allograft rejection.

J Heart Lung Transplant. 2017 Jul 05;:

Authors: Tarazón E, Ortega A, Gil-Cayuela C, Sánchez-Lacuesta E, Marín P, Lago F, González-Juanatey JR, Martínez-Dolz L, Portolés M, Rivera M, Roselló-Lletí E

Abstract
BACKGROUND: The detection of heart transplant rejection by non-invasive methods remains a major challenge. Despite the well-known importance of the study of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in the heart, its role as a rejection marker has never been analyzed. Our objective in this study was to determine whether circulating SERCA2a could be a good marker of cardiac rejection.
METHODS: We collected 127 consecutive endomyocardial biopsies (EMBs) and serum samples from adult heart transplant recipients (49 without allograft rejection and 78 with the diagnosis of biopsy allograft rejection, including 48 Grade 1R, 21 Grade 2R and 9 Grade 3R). Serum concentrations of SERCA2a were determined using a specific sandwich enzyme-linked immunosorbent assay. We also analyzed SERCA2a expression changes on EMBs using immunofluorescence.
RESULTS: SERCA2a cardiac tissue and serum levels were decreased in patients with cardiac rejection (p < 0.0001). A receiver-operating characteristic analysis showed that SERCA2a strongly discriminated between patients with and without allograft rejection: normal grafts vs all rejecting grafts (AUC = 0.804); normal grafts vs Grade 1R (AUC = 0.751); normal grafts vs Grade 2R (AUC = 0.875); normal grafts vs Grade 3R (AUC = 0.922); normal grafts vs Grade 2R and 3R (AUC = 0.889), with p < 0.0001 for all comparisons.
CONCLUSIONS: We demonstrated that changes in SERCA2a cardiac tissue and serum levels occur in cardiac allograft rejection. Our findings suggest that SERCA2a concentration assessment may be a relatively simple, non-invasive test for heart transplant rejection, showing a strong capability for detection that improves progressively as rejection grades increase.

PMID: 28750934 [PubMed - as supplied by publisher]

Association between antibody functions and human cytomegalovirus (HCMV) replication after lung transplantation in HCMV-seropositive patients.

Sat, 07/29/2017 - 12:45
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Association between antibody functions and human cytomegalovirus (HCMV) replication after lung transplantation in HCMV-seropositive patients.

J Heart Lung Transplant. 2017 Jul 18;:

Authors: Vietzen H, Görzer I, Honsig C, Jaksch P, Puchhammer-Stöckl E

PMID: 28750933 [PubMed - as supplied by publisher]

Pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension.

Sat, 07/29/2017 - 12:45
Related Articles

Pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension.

J Heart Lung Transplant. 2017 Jul 01;:

Authors: Lankeit M, Krieg V, Hobohm L, Kölmel S, Liebetrau C, Konstantinides S, Hamm CW, Mayer E, Wiedenroth CB, Guth S

Abstract
BACKGROUND: Management and outcome of patients with operable chronic thromboembolic pulmonary hypertension (CTEPH) who underwent pulmonary endarterectomy (PEA) at a large German referral center were investigated.
METHODS: In Germany, 394 PEAs were performed in 2014 and 2015 with an in-hospital mortality rate of 5.8%. Of these, 253 patients (64.2%) were treated at the Kerckhoff Clinic, Bad Nauheim, and 237 (93.7%; median age, 62 years [interquartile range [IQR], 52-72 years]; 46.0% female) were included in the present analysis.
RESULTS: On referral, 52 patients (22.0%) were treated with pulmonary arterial hypertension-specific drugs and 95 (40.4%) were treated with non-vitamin K-dependent oral anticoagulants, and 14 (5.9%) had mean pulmonary artery pressure <25 mm Hg and were classified as having chronic thromboembolic pulmonary vascular disease. PEA was feasible in 236 (99.6%) patients with median duration of surgery of 397 minutes (IQR, 363-431 minutes). Periprocedural (0%) and in-hospital (2.5%) mortality rates were very low. Forty-two patients (17.7%) had intraoperative complications, and 60 (25.3%) had post-operative complications. The duration of surgery was the only predictor of in-hospital mortality (≥500 minutes; odds ratio [OR], 32.0; 95% confidence interval [CI], 5.5-187.6) and the only independent predictor of intraoperative (≥440 minutes; OR, 10.8; 95% CI, 4.4-26.5) and post-operative (≥390 minutes; OR, 2.4; 95%CI, 1.1-5.7) complications. Only intraoperative complications independently predicted a longer duration of surgery (≥397 minutes; OR, 5.0; 95% CI, 2.2-11.2).
CONCLUSIONS: In an experienced center with multidisciplinary diagnostic and therapeutic approaches, PEA is safe. Prognosis was mainly determined by occurrence of intraoperative complications and duration of surgery rather than patients' pre-operative status.

PMID: 28750932 [PubMed - as supplied by publisher]

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