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Late graft failure in heart transplant recipients: incidence, risk factors and clinical outcomes.

Tue, 06/06/2017 - 18:45

Late graft failure in heart transplant recipients: incidence, risk factors and clinical outcomes.

Eur J Heart Fail. 2017 Jun 05;:

Authors: López-Sainz Á, Barge-Caballero E, Barge-Caballero G, Couto-Mallón D, Paniagua-Martin MJ, Seoane-Quiroga L, Iglesias-Gil C, Herrera-Noreña JM, Cuenca-Castillo JJ, Vázquez-Rodríguez JM, Crespo-Leiro MG

Abstract
AIM: To analyse the incidence, risk factors and clinical outcomes of late graft failure after heart transplantation.
METHODS AND RESULTS: We conducted an observational, single-centre study based on 547 patients who underwent cardiac transplantation from 1991 to 2014 and who survived the in-hospital postoperative period. Late graft failure was defined as the first hospitalization due to this condition after discharge. Over a mean follow-up of 8.4 ± 6, 178 (32.5%) patients were hospitalized due to late graft failure [incidence rate: 3.6 cases per 100 patient-years, 95% confidence interval (CI) 3.1-4.2]. Pre-transplant diabetes, higher pre-transplant transpulmonary pressure gradient and lower donor-recipient weight ratio were independently associated with higher risk of graft failure. Cardiac allograft vasculopathy, cellular rejection grade ≥1R, and antibody-mediated rejection grade ≥1 were detected in 50.6%, 44.9% and 19.2% patients, respectively, admitted due to graft failure. Left ventricular ejection fraction was ≥50% in 60.1% of these patients. Re-transplant free survival 1, 5, 10 and 15 years after the diagnosis of late graft failure was 72.2%, 38.4%, 18.4%, and 7.5%, respectively; the incidence rate of re-hospitalization due to decompensated heart failure was 40.9 episodes per 100 patient-years (95% CI 36.6-46.1). The need for inotropes, the presence of cardiac allograft vasculopathy, higher creatinine serum levels, lower ejection fraction and lower sodium serum levels were independent predictors of worse outcomes.
CONCLUSIONS: Late graft failure is frequent after heart transplantation, as it is associated with poor outcomes. Rejection and cardiac allograft vasculopathy are the most frequent underlying causes.

PMID: 28580728 [PubMed - as supplied by publisher]

Heart transplantation in patients with dystrophinopathic cardiomyopathy: Review of the literature and personal series.

Tue, 06/06/2017 - 18:45

Heart transplantation in patients with dystrophinopathic cardiomyopathy: Review of the literature and personal series.

Intractable Rare Dis Res. 2017 May;6(2):95-101

Authors: Papa AA, D'Ambrosio P, Petillo R, Palladino A, Politano L

Abstract
Cardiomyopathy associated with dystrophinopathies [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy (XL-dCM) and cardiomyopathy of Duchenne/Becker (DMD/BMD) carriers] is an increasing recognized manifestation of these neuromuscular disorders and notably contributes to their morbidity and mortality. Dystrophinopathic cardiomyopathy (DCM) is the result of the dystrophin protein deficiency at the myocardium level, parallel to the deficiency occurring at the skeletal muscle level. It begins as a "presymptomatic" stage in the first decade of life and evolves in a stepwise manner toward pictures of overt cardiomyopathy (hypertrophic stage, arrhythmogenic stage and dilated cardiomyopathy). The final stage caused by the extensive loss of cardiomyocytes results in an irreversible cardiac failure, characterized by frequent episodes of acute congestive heart failure (CHF), despite a correct pharmacological treatment. The picture of a severe dilated cardiomyopathy with intractable heart failure is typical of BMD, XL-dCM and cardiomyopathy of DMD/BMD carriers, while it is less frequently observed in patients with DMD. Heart transplantation (HT) is the only curative therapy for patients with dystrophinopathic end-stage heart failure who remain symptomatic despite an optimal medical therapy. However, no definitive figures exist in literature concerning the number of patients with DCM transplanted, and their outcome. This overview is to summarize the clinical outcomes so far published on the topic, to report the personal series of dystrophinopathic patients receiving heart transplantation and finally to provide evidence that heart transplantation is a safe and effective treatment for selected patients with end-stage DCM.

PMID: 28580208 [PubMed - in process]

Echocardiography-Derived Left Ventricular Outflow Tract Gradient and Left Ventricular Posterior Wall Thickening Are Associated with Outcomes for Anatomic Repair in Congenitally Corrected Transposition of the Great Arteries.

Tue, 06/06/2017 - 18:45

Echocardiography-Derived Left Ventricular Outflow Tract Gradient and Left Ventricular Posterior Wall Thickening Are Associated with Outcomes for Anatomic Repair in Congenitally Corrected Transposition of the Great Arteries.

J Am Soc Echocardiogr. 2017 Jun 01;:

Authors: Moodley S, Balasubramanian S, Tacy TA, Chan F, Hanley FL, Punn R

Abstract
BACKGROUND: Congenitally corrected transposition of the great arteries is a rare form of congenital heart disease. Management is controversial; options include observation, physiologic repair, and anatomic repair. Assessment of morphologic left ventricle preparedness is key in timing anatomic repair. This study's purpose was to review the modalities used to assess the morphologic left ventricle preoperatively and to determine if any echocardiographic variables are associated with outcomes.
METHODS: A retrospective review of patients with congenitally corrected transposition of the great arteries eligible for anatomic repair at Lucile Packard Children's Hospital from 2000 to 2016 was conducted. Inclusion criteria were (1) presurgical echocardiography, magnetic resonance imaging, and cardiac catheterization and (2) clinical follow-up information. Echocardiographic measurements included left ventricular (LV) single-plane Simpson's ejection fraction, LV eccentricity index, LV posterior wall thickening, pulmonary artery band (PAB)/LV outflow tract (LVOT) pressure gradient, and LV and right ventricular strain. Magnetic resonance imaging measurements included LV mass, ejection fraction, eccentricity index, and LV thickening. LV pressure, PAB/LVOT gradient, right ventricular pressure, pulmonary vascular resistance, and Qp/Qs constituted catheterization data. Outcomes included achieving anatomic repair within 1 year of assessment in patients with LVOT obstruction or within 1 year of pulmonary artery banding and freedom from death, transplantation, or heart failure at last follow-up.
RESULTS: Forty-one patients met the inclusion criteria. PAB/LVOT gradients of 85.2 ± 23.4 versus 64.0 ± 32.1 mm Hg (P = .0282) by echocardiography and 60.1 ± 19.4 versus 35.9 ± 18.9 mm Hg (P = .0030) by catheterization were associated with achieving anatomic repair and freedom from death, transplantation, and heart failure. Echocardiographic LV posterior wall thickening of 35.4 ± 19.8% versus 20.6 ± 15.0% (P = .0017) and MRI LV septal wall thickening of 37.1 ± 18.8% versus 19.3 ± 18.8% (P = .0306) were associated with achieving anatomic repair. Inter- and intraobserver variability for echocardiographic measurements was very good.
CONCLUSIONS: PAB/LVOT gradient and LV posterior wall thickening are highly reproducible echocardiographic measurements that reflect morphologic LV performance and can be used in assessing patients with congenitally corrected transposition of the great arteries undergoing anatomic repair.

PMID: 28579248 [PubMed - as supplied by publisher]

Extended Bridge to Heart and Lung Transplantation Using Pumpless Extracorporeal Lung Assist.

Tue, 06/06/2017 - 18:45

Extended Bridge to Heart and Lung Transplantation Using Pumpless Extracorporeal Lung Assist.

Can J Cardiol. 2017 Mar 25;:

Authors: Vasanthan V, Garg M, Maruyama M, Michelakis E, Freed DH, Nagendran J

Abstract
In end-stage idiopathic pulmonary artery hypertension (iPAH), centrally cannulated Novalung (Novalung GmbH, Hechingen, Germany) pumpless extracorporeal lung assist (pECLA) decompresses the pulmonary artery for bridge to transplantation. We report placing a 45-year-old man with end-stage iPAH and right heart failure on centrally cannulated pECLA for 82 days as a bridge to heart and double-lung transplantation (HLTx). To our knowledge, this is the longest reported bridge to transplantation in Canada and the first successful bridge to HLTx. We demonstrate how pECLA permits mobility, facilitating physiotherapy to ensure fitness for transplantation. Considering the irreversible right heart failure, HLTx remains suitable in iPAH.

PMID: 28579162 [PubMed - as supplied by publisher]

Bleeding and thrombosis associated with ventricular assist device therapy.

Tue, 06/06/2017 - 18:45

Bleeding and thrombosis associated with ventricular assist device therapy.

J Heart Lung Transplant. 2017 May 11;:

Authors: Shah P, Tantry US, Bliden KP, Gurbel PA

Abstract
Over the past decade, continuous-flow rotary pumps have dramatically improved survival for patients with advanced systolic heart failure. Bleeding and thrombosis, however, continue to be the Achilles heel of left ventricular assist device (LVAD) therapy. There is a dynamic and complex interaction between the patient and pump. The net effect of a variety of hematologic derangements, such as hemolysis, high-molecular-weight von Willebrand degradation, platelet activation and diminished pulsatility, is poorly understood. A combination of these factors mediates the common adverse events of gastrointestinal bleeding, device thrombosis and stroke. In this review we incorporate information from translational investigations in LVAD patients to understand how continuous-flow pumps activate the coagulation system and platelets predisposing to thrombosis, while, in parallel, degrade high-molecular-weight von Willebrand factor and trigger abnormal angiogenesis predisposing to bleeding. Finally, we propose novel strategies to develop a personalized approach to anti-thrombotic monitoring and titration of anti-coagulants to minimize the bleeding and thrombotic event rates of future LVAD recipients.

PMID: 28579115 [PubMed - as supplied by publisher]

Potential impact of a shock requirement on adult heart allocation.

Tue, 06/06/2017 - 18:45

Potential impact of a shock requirement on adult heart allocation.

J Heart Lung Transplant. 2017 May 17;:

Authors: Parker WF, Garrity ER, Fedson S, Churpek MM

PMID: 28579114 [PubMed - as supplied by publisher]

Waitlist outcomes in pediatric lung transplantation: Poor results for children listed in adult transplant programs.

Tue, 06/06/2017 - 18:45

Waitlist outcomes in pediatric lung transplantation: Poor results for children listed in adult transplant programs.

J Heart Lung Transplant. 2017 Apr 24;:

Authors: Scully BB, Goss M, Liu H, Keuht ML, Adachi I, McKenzie ED, Fraser CD, Melicoff E, Mallory GB, Heinle JS, Rana A

Abstract
BACKGROUND: Low case volume has been associated with lower survival after pediatric lung transplantation. Our aim was to analyze waitlist outcomes among pediatric lung transplant centers in the USA.
METHODS: We studied a cohort of 1,139 pediatric candidates listed in the Organ Procurement and Transplantation Network for lung transplantation between 2002 and 2014. Of these candidates, 720 (63.2%) received a transplant. Candidates were divided into groups according to the clinical activity of the center of listing: high-volume pediatric (≥4 transplants per year); low-volume pediatric (<4 transplants per year); and adult (transplant volume predominantly in adults). We used multivariate Cox regression analysis to identify independent risk factors for waitlist mortality. We also determined the transplant rate-or likelihood of transplant after listing-over the study period.
RESULTS: Fifty-eight percent of the children and adolescents were listed in adult centers where the resultant transplant rate was low-only 42% received a transplant compared with 93% in pediatric programs. Listing in an adult program was also the most significant risk factor for death on the waiting list (hazard ratio 15.6, 95% confidence interval 5.8 to 42.1).
CONCLUSIONS: Most children (58%) are listed for lung transplantation in adult centers and have a reduced rate of transplantation and a greater chance of waitlist mortality.

PMID: 28579113 [PubMed - as supplied by publisher]

Early mortality after heart transplantation related to IgA anti-β2-glycoprotein I antibodies.

Tue, 06/06/2017 - 18:45

Early mortality after heart transplantation related to IgA anti-β2-glycoprotein I antibodies.

J Heart Lung Transplant. 2017 May 19;:

Authors: Delgado JF, Serrano M, Morán L, Enguita AB, Martínez-Flores JA, Ortiz-Bautista C, Rodríguez-Chaverri A, de Antonio IP, García Cosio MD, Castro Panete MJ, Cortina JM, Serrano A

Abstract
BACKGROUND: The presence of pre-formed IgA anti-β2-glycoprotein I antibodies (IgA-aB2GP1ab) has been related to early graft loss after kidney transplant. Because β2-glycoprotein I is produced in both the kidney and heart, we aimed to assess whether the presence of these antibodies may also be associated with poor outcomes after heart transplantation (HT).
METHODS: A 2-year follow-up retrospective analysis of 151 consecutive patients who underwent HT between 2004 and 2012 was performed to assess the role of this pre-formed antibody type in HT. The population was divided into 2 groups according to the presence of IgA: Group 1 was positive for IgA-aB2GP1ab (47 patients, 31.1%), and Group 2 was negative for IgA-Ab2GP1ab (104 patients, 68.9%).
RESULTS: Early mortality rates within the first 3 months were higher in Group 1 (27.7%) than in Group 2 (9.6%). No differences in donor and recipient characteristics or in causes of death were observed between groups. Multivariate analysis identified the presence of IgA-aB2GP1ab, female gender and blood type A as independent risks factors for early mortality after HT. A greater incidence of thrombotic events during the first 3 months post-HT in Group 1 (23.4% vs 5.8%) and a greater presence of risk factors for thrombotic events, which may have exacerbated them, were observed. After this period, no increase in mortality or in thrombotic events was found when the 2 groups were compared.
CONCLUSION: Pre-transplant presence of IgA-aB2GP1ab is associated with both increased early mortality rates and higher thrombotic events after HT.

PMID: 28579112 [PubMed - as supplied by publisher]

Incremental shuttle walk test distance and autonomic dysfunction predict survival in pulmonary arterial hypertension.

Tue, 06/06/2017 - 18:45

Incremental shuttle walk test distance and autonomic dysfunction predict survival in pulmonary arterial hypertension.

J Heart Lung Transplant. 2017 Apr 24;:

Authors: Billings CG, Hurdman JA, Condliffe R, Elliot CA, Smith IA, Austin M, Armstrong IJ, Hamilton N, Charalampopoulos A, Sabroe I, Swift AJ, Rothman AM, Wild JM, Lawrie A, Waterhouse JC, Kiely DG

Abstract
BACKGROUND: To ensure effective monitoring of pulmonary arterial hypertension (PAH), a simple, reliable assessment of exercise capacity applicable over a range of disease severity is needed. The aim of this study was to assess the ability of the incremental shuttle walk test (ISWT) to correlate with disease severity, measure sensitivity to change, and predict survival in PAH.
METHODS: We enrolled 418 treatment-naïve patients with PAH with baseline ISWT within 3 months of cardiac catheterization. Clinical validity and prognostic value of ISWT distance were assessed at baseline and 1 year.
RESULTS: ISWT distance was found to correlate at baseline with World Health Organization functional class, Borg score, and hemodynamics without a ceiling effect (all p < 0.001). Walking distance at baseline and after treatment predicted survival; the area under the receiver operating characteristic curve for ability of ISWT distance to predict mortality was 0.655 (95% confidence interval 0.553-0.757; p = 0.004) at baseline and 0.737 (95% confidence interval 0.643-0.827; p < 0.001) at 1 year after initiation of treatment. Change in ISWT distance also predicted survival (p = 0.04). Heart rate (HR) and systolic blood pressure (SBP) parameters reflecting autonomic response to exercise (highest HR, change in HR, HR recovery at 1 minute >18 beats/min, highest SBP, change in SBP, and 3-minute SBP ratio) were significant predictors of survival (all p < 0.05).
CONCLUSIONS: In patients with PAH, the ISWT is simple to perform, allows assessment of maximal exercise capacity, is sensitive to treatment effect, predicts outcome, and has no ceiling effect. Also, measures of autonomic function made post-exercise predict survival in PAH.

PMID: 28579006 [PubMed - as supplied by publisher]

Surgical Management of Absent Pulmonary Valve Syndrome.

Tue, 06/06/2017 - 18:45
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Surgical Management of Absent Pulmonary Valve Syndrome.

World J Pediatr Congenit Heart Surg. 2016 Sep;7(5):600-4

Authors: Jonas RA

Abstract
The author's approach to the management of tetralogy of Fallot with absent pulmonary valve is described, including the technique of homograft replacement of the central pulmonary arteries for the neonate who presents with profound respiratory compromise.

PMID: 27587495 [PubMed - indexed for MEDLINE]

Left Isomerism of the Atrial Appendages With Sinus Venosus Defect and Anomalous Systemic Venous Drainage.

Tue, 06/06/2017 - 18:45
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Left Isomerism of the Atrial Appendages With Sinus Venosus Defect and Anomalous Systemic Venous Drainage.

World J Pediatr Congenit Heart Surg. 2016 Sep;7(5):661-4

Authors: Talwar S, Ramakrishnan P, Anderson RH, Choudhary SK, Makhija N, Kumar S, Airan B

Abstract
We present a case with left isomerism, interruption of the inferior caval vein, anomalous systemic venous drainage with partially anomalous pulmonary venous drainage, and a sinus venosus type of atrial septal defect in the absence of a right superior caval vein. This report is of interest because of a rare combination of these anomalies, which was accurately diagnosed and successfully repaired.

PMID: 26884453 [PubMed - indexed for MEDLINE]

Chest Pain and Shortness of Breath in a Previously Healthy Teenager.

Tue, 06/06/2017 - 18:45
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Chest Pain and Shortness of Breath in a Previously Healthy Teenager.

J Pediatric Infect Dis Soc. 2015 Jun;4(2):171-3

Authors: Chaparro J, Murphy E, Davis C, Viani RM, Pong A

PMID: 26407419 [PubMed - indexed for MEDLINE]

Survival and Left Ventricular Function Changes in Fulminant Versus Non-Fulminant Acute Myocarditis.

Sun, 06/04/2017 - 10:06
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Survival and Left Ventricular Function Changes in Fulminant Versus Non-Fulminant Acute Myocarditis.

Circulation. 2017 Jun 02;:

Authors: Ammirati E, Cipriani M, Lilliu M, Sormani P, Varrenti M, Raineri C, Petrella D, Garascia A, Pedrotti P, Roghi A, Bonacina E, Moreo A, Bottiroli M, Gagliardone MP, Mondino MG, Ghio S, Totaro R, Turazza FM, Russo CF, Oliva F, Camici PG, Frigerio M

Abstract
Background -Previous reports have suggested that despite their dramatic presentation, patients with fulminant myocarditis (FM) might have better outcome than those with acute non-fulminant myocarditis (NFM). In this retrospective study, we report outcome and changes in left ventricular ejection fraction (LVEF) in a large cohort of patients with FM compared with NFM. Methods -The study population consists of 187 consecutive patients admitted between May 2001 and November 2016 with a diagnosis of acute myocarditis (onset of symptoms <1 month) of whom 55 required inotropes and/or mechanical circulatory support (FM) whilst the remaining 132 patients were hemodynamically stable (NFM). We also performed a sub-analysis in 130 adult patients with acute viral myocarditis and viral prodrome within 2 weeks from the onset, which includes 34 FM vs. 96 NFM. Patients with giant-cell, eosinophilic myocarditis or cardiac sarcoidosis and subject <15 years of age were excluded from the latter sub-analysis. Results -In the whole population (n=187) in-hospital death or heart transplantation (HTx) was 25.5% vs. 0% in FM vs. NFM, respectively (p<0.0001). Long-term HTx free survival at 9 years was lower in FM than NFM (64.5% vs. 100%, Log Rank p<0.0001). Despite greater improvement in LVEF during hospitalization in FM vs. NFM forms (median: 32%, interquartile: 20-40% vs. 3%, 0-10%, respectively, p<0.0001), the proportion of patients with LVEF<55% at last follow up was higher in FM vs. NFM (29% vs. 9%, Relative risk 3.32, 95% confidence interval: 1.45-7.64, p=0.003). Similar results regarding survival and changes in LVEF in FM vs. NFM were observed in the subgroup (n=130) with viral myocarditis. None of the patients with NFM and LVEF≥55% at discharge had a significant decrease in LVEF at follow up. Conclusions -Patients with FM have an increased mortality and need for HTx, compared to those with NFM. From a functional viewpoint, FM patients have a more severely impaired LVEF at admission that, despite steep improvement during hospitalization, remains lower than that in patients with NFM at long term follow up. These findings hold true also considering only the viral forms and are at odd with previous studies showing better prognosis in FM.

PMID: 28576783 [PubMed - as supplied by publisher]

Outcomes of Ventricular Tachycardia Ablation Using Percutaneous Left Ventricular Assist Devices.

Sun, 06/04/2017 - 10:06
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Outcomes of Ventricular Tachycardia Ablation Using Percutaneous Left Ventricular Assist Devices.

Circ Arrhythm Electrophysiol. 2017 Jun;10(6):

Authors: Kusa S, Miller MA, Whang W, Enomoto Y, Panizo JG, Iwasawa J, Choudry S, Pinney S, Gomes A, Langan N, Koruth JS, d'Avila A, Reddy VY, Dukkipati SR

Abstract
BACKGROUND: Although percutaneous left ventricular assist devices (pLVADs) facilitate mapping and ablation of hemodynamically unstable ventricular tachycardia (VT), there is limited data whether clinical outcomes are improved. We sought to retrospectively compare the outcomes of patients undergoing scar-related VT ablation with and without pLVAD support.
METHODS AND RESULTS: The study population comprised 194 patients (109 pLVAD and 85 non-pLVAD). The pLVAD group more often had dilated cardiomyopathy (33% versus 13%; P=0.001), New York Heart Association heart failure class ≥III (51% versus 25%; P<0.001), lower left ventricular ejection fractions (26±10% versus 39±16%; P<0.001), and electrical storm (49% versus 34%; P=0.04). Procedure times (422±112 versus 330±92 minutes; P<0.001), postablation VT inducibility (20% versus 7%; P=0.02), and length of subsequent hospitalization (median 6 versus 4 days; P=0.001) were all higher in the pLVAD group. During median follow-up of 215 days, the primary end point (recurrent VT, heart transplantation, or death) occurred in 36% of the pLVAD versus 26% of the non-pLVAD groups (P=0.14). After propensity matching for differences between groups, no differences were seen between groups for both acute procedural outcomes and the primary end point.
CONCLUSIONS: In this large single-center scar-related VT ablation experience, despite the worse clinical status of the patients selected for pLVAD support, clinical outcomes were better than expected and were similar to healthier patients not receiving hemodynamic support. Patients with dilated cardiomyopathy presenting with electrical storm, advanced heart failure, and severe left ventricular dysfunction most frequently received hemodynamic support during VT ablation.

PMID: 28576780 [PubMed - in process]

Pediatric post-tonsillectomy hemorrhage in the setting of post-transplantation immunosuppression.

Sun, 06/04/2017 - 10:06
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Pediatric post-tonsillectomy hemorrhage in the setting of post-transplantation immunosuppression.

Int J Pediatr Otorhinolaryngol. 2017 Apr;95:117-120

Authors: Quintanilla-Dieck L, Chinnadurai S, Wootten C, Goudy SL, Virgin FW

Abstract
INTRODUCTION: Long-term immunosuppressants form an integral part of therapy for post-transplantation patients. Immunosuppressants may also have an anticoagulant effect, and little is known about their effects on bleeding risk after adenotonsillectomy. Our objective was to investigate whether there is an increased observed rate of post-tonsillectomy hemorrhage in a population of pediatric patients on long-term immunosuppressants after solid organ transplantation, compared to healthy controls.
METHODS: This was a retrospective chart review of pediatric patients with a history of renal or heart transplant undergoing adenotonsillectomy at our institution between 2000 and 2014. All patients underwent tonsillectomy with monopolar electrocautery. Retrieved data included perioperative medications, occurrence of post-operative bleeding and associated treatment. For comparison, we obtained a population of age-matched controls with no history of immunosuppression who underwent the same procedure.
RESULTS: A total of 34 patients meeting criteria were identified, of which 3 (8.82%) suffered a postoperative bleed. Forty-seven controls were obtained, with a total of 2 (4.26%) postoperative hemorrhages (p = 0.65). Two of the post-transplantation patients who bled postoperatively required cauterization in the operating room. None of the controls required surgical treatment. The incidences of postoperative bleeding requiring surgical treatment were 5.88% and 0%, respectively (p = 0.17).
CONCLUSION: We failed to demonstrate an increased risk of bleeding after undergoing adenotonsillectomy in our cohort of post-transplantation pediatric patients on chronic immunosuppression. Future research, likely requiring a multi-institutional effort, could stratify by immunosuppressive agent to elucidate bleeding risk with specific medications.

PMID: 28576519 [PubMed - in process]

Innovation in pediatric clinical trials: The need to rethink the end-point.

Sun, 06/04/2017 - 10:06
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Innovation in pediatric clinical trials: The need to rethink the end-point.

J Heart Lung Transplant. 2017 May 15;:

Authors: Glass L, Conway J

PMID: 28576400 [PubMed - as supplied by publisher]

Whole genome Cardiac DNA methylation fingerprint and gene expression analysis provide new insights in the pathogenesis of Chronic Chagas disease Cardiomyopathy.

Sat, 06/03/2017 - 12:45
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Whole genome Cardiac DNA methylation fingerprint and gene expression analysis provide new insights in the pathogenesis of Chronic Chagas disease Cardiomyopathy.

Clin Infect Dis. 2017 May 30;:

Authors: Laugier L, Frade AF, Ferreira FM, Baron MA, Teixeira PC, Cabantous S, Ferreira LRP, Louis L, Rigaud VOC, Gaiotto FA, Bacal F, Pomerantzeff P, Bocchi E, Kalil J, Santos RHB, Cunha-Neto E, Chevillard C

Abstract
Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects 10 million people worldwide. Approximately 12,000 deaths attributable to Chagas disease occur annually due to Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy presenting with heart failure and arrythmia; 30% of infected subjects develop CCC years after infection. Genetic mechanisms play a role in differential progression to CCC, but little is known about the role of epigenetic modifications in pathological gene expression patterns in CCC patients' myocardium. DNA methylation is the most common modification in the mammalian genome.
Methods: We investigated the impact of genome-wide cardiac DNA methylation on global gene expression in myocardial samples from end-stage CCC patients, as compared with control samples from organ donors.
Results: In total, 4720 genes were differentially methylated between CCC patients and controls, of which 399 were also differentially expressed. Several of them were related to heart function or to the immune response and had methylation sites in their promoter region. Reporter gene and in silico transcription factor binding analyses indicated promoter methylation modified expression of key genes. Among those, we found potassium channel genes KCNA4 and KCNIP4, involved in electrical conduction and arrythmia, SMOC2, involved in matrix remodeling, as well as enkephalin and RUNX3, potentially involved in the increased Th1 cytokine-mediated inflammatory damage in heart.
Conclusions: Results support that DNA methylation plays a role in the regulation of expression of pathogenically relevant genes in CCC myocardium, and identify novel potential disease pathways and therapeutic targets in CCC.

PMID: 28575239 [PubMed - as supplied by publisher]

Diffuse myocardial fibrosis among healthy pediatric heart transplant recipients: Correlation of histology, cardiovascular magnetic resonance, and clinical phenotype.

Sat, 06/03/2017 - 12:45
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Diffuse myocardial fibrosis among healthy pediatric heart transplant recipients: Correlation of histology, cardiovascular magnetic resonance, and clinical phenotype.

Pediatr Transplant. 2017 Jun 02;:

Authors: Feingold B, Salgado CM, Reyes-Múgica M, Drant SE, Miller SA, Kennedy M, Kellman P, Schelbert EB, Wong TC

Abstract
Fibrosis is commonly described in heart allografts lost late after transplantation. CMR-derived ECV is a validated measure of DMF in native adult hearts that may predict heart failure and mortality. We explored associations of ECV with histologic myocardial fibrosis and clinical features after pediatric heart transplantation. Twenty-five recipients (7.0±6.3 years at transplant and 10.7±6.5 years post-transplant) were prospectively recruited for CMR and BNP measurement at the time of surveillance biopsy. All had normal ejection fractions and lacked heart failure symptoms. Fibrosis was quantified on biopsy after picrosirius red staining as CVF. ECV was quantified using contemporaneous hematocrit on basal and mid-short-axis slices. ECV was moderately correlated with CVF (r=.47; P=.019). We found no associations of ECV with hemodynamics, ischemic time, time since transplantation, or number of prior biopsies or acute rejections. Compared to healthy non-transplant controls, there was no significant difference in ECV (25.1±3.0 vs 23.7±2.0%, P=.09). Log-transformed BNP was correlated with ECV (recipients: r=.46, P=.02; recipients and controls: r=.45, P=.006). These findings suggest ECV quantifies DMF and relates to biological indicators of cardiac function after pediatric heart transplantation.

PMID: 28574157 [PubMed - as supplied by publisher]

Comparative in vivo analysis of the role of the adventitia and the endothelium on arterial mechanical function: relevance for aortic counterpulsation.

Sat, 06/03/2017 - 12:45
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Comparative in vivo analysis of the role of the adventitia and the endothelium on arterial mechanical function: relevance for aortic counterpulsation.

Int J Artif Organs. 2017 May 24;:0

Authors: Bia D, Zócalo Y, Wray S, Cabrera-Fischer EI

Abstract
PURPOSE: The comparative effect of the intimal and adventitial layers on arterial biomechanics control, in basal and altered conditions, remains to be elucidated. This study aimed (1) to characterize the arterial conduit (CF) and buffering (distensibility) function of the iliac arteries in in vivo animals, in which the intimal and adventitial layers were removed; (2) to determine the effects of intra-aortic ballon pumping (IABP) on simultaneously de-adventitialized (DA) and de-endothelialized (DE) iliac arteries before and after induced heart failure.
METHODS: Pressure and diameter signals were measured in the iliac arteries of sheep (n = 7) in which the adventitial and intima layer were removed. Intra-aortic balloon pump (IABP) assistance was used in a control state and after heart failure induction.
RESULTS: Both DE and DA determined significant changes in arterial diameter, distensibility and CF. Changes were higher after DA than after DE in terms of distensibility and CF (p<0.05). DA followed by DE (DA + DE) showed significant increases in arterial diameter and CF, accompanied by a decrease in distensibility (p<0.05) with respect to intact arteries. Heart failure induction caused significant hemodynamic changes without modifying the already impaired local biomechanical parameters. Nonsignificant improvements in the biomechanical parameters of DA + DE iliac arteries were observed during IABP before and after heart failure induction.
CONCLUSIONS: Biomechanical changes caused by DA of iliac arteries were more important than those observed after DE. The DA + DE arteries showed significant differences with respect to intact arteries and with DA or DE arteries. IABP-related effects on arterial mechanics were absent in DA + DE arteries.

PMID: 28574108 [PubMed - as supplied by publisher]

A Hyper-Crosslinked Carbohydrate Polymer Scaffold Facilitates Lineage Commitment and Maintains a Reserve Pool of Proliferating Cardiovascular Progenitors.

Sat, 06/03/2017 - 12:45
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A Hyper-Crosslinked Carbohydrate Polymer Scaffold Facilitates Lineage Commitment and Maintains a Reserve Pool of Proliferating Cardiovascular Progenitors.

Transplant Direct. 2017 May;3(5):e153

Authors: Baio JM, Walden RC, Fuentes TI, Lee CC, Hasaniya NW, Bailey LL, Kearns-Jonker MK

Abstract
BACKGROUND: Cardiovascular progenitor cells (CPCs) have been cultured on various scaffolds to resolve the challenge of cell retention after transplantation and to improve functional outcome after cell-based cardiac therapy. Previous studies have reported successful culture of fully differentiated cardiomyocytes on scaffolds of various types, and ongoing efforts are focused on optimizing the mix of cardiomyocytes and endothelial cells as well as on the identification of a source of progenitors capable of reversing cardiovascular damage. A scaffold culture that fosters cell differentiation into cardiomyocytes and endothelial cells while maintaining a progenitor reserve would benefit allogeneic cell transplantation.
METHODS: Isl-1 + c-Kit + CPCs were isolated as clonal populations from human and sheep heart tissue. After hyper-crosslinked carbohydrate polymer scaffold culture, cells were assessed for differentiation, intracellular signaling, cell cycling, and growth factor/chemokine expression using real time polymerase chain reaction, flow cytometry, immunohistochemistry, and calcium staining.
RESULTS: Insulin-like growth factor 1, hepatocyte growth factor, and stromal cell derived factor 1α paracrine factors were induced, protein kinase B signaling was activated, extracellular signal-regulated kinase phosphorylation was reduced and differentiation into both cardiomyocytes and endothelial cells was induced by scaffold-based cell culture. Interestingly, movement of CPCs out of the G1 phase of the cell cycle and increased expression of pluripotency genes PLOU5F1 (Oct4) and T (Brachyury) within a portion of the cultured population occurred, which suggests the maintenance of a progenitor population. Two-color immunostaining and 3-color fluorescence-activated cell sorting analysis confirmed the presence of both Isl-1 expressing undifferentiated cells and differentiated cells identified by troponin T and von Willebrand factor expression. Ki-67 labeling verified the presence of proliferating cells that remained in situ alongside the differentiated functional derivatives.
CONCLUSIONS: Cloned Isl-1 + c-kit + CPCs maintained on a hyper-cross linked polymer scaffold retain dual potential for proliferation and differentiation, providing a scaffold-based stem cell source for transplantation of committed and proliferating cardiovascular progenitors for functional testing in preclinical models of cell-based repair.

PMID: 28573188 [PubMed - in process]

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