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Nazanin Aghel,1 Diego Hernan Delgado,1 Jeffrey Howard Lipton2 1Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network,University of Toronto, 2Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada Abstract: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment and outcomes of chronic myeloid leukemia (CML). Despite their significant impact on the management of CML, there is growing evidence that TKIs may cause cardiovascular and/or metabolic complications. In this review, we present the current evidence regarding the cardiovascular safety profiles of BCR-ABL TKIs. Methodological challenges of studies that reported the cardiovascular safety of TKIs are discussed. We also propose management strategies for cardiovascular surveillance and risk factor modification during treatment with these agents. Keywords: BCR-ABL, tyrosine kinase inhibitor, peripheral arterial disease, cardiovascular disease, adverse event

Background: Diagnosis of hereditary amyloid transthyretin (hATTR) amyloidosis with cardiomyopathy is frequently delayed, in large part because of symptom overlap with other cardiovascular diseases and limited provider knowledge of this disease. The sponsored and provider referred hATTR Compass Genetic Testing Program (Ionis, Carlsbad, CA; Ambry Genetics, Aliso Viejo, CA) provided no-cost genetic testing to adults with a family history or clinical suspicion of hATTR amyloidosis. This study aims to characterize patients with hATTR amyloidosis and increase awareness of genetic testing for hATTR., Methods and Results: Patients were referred to the hATTR genetic testing program, and a cross-sectional post hoc analysis was performed. A pathogenic TTR variant was identified in 1503 (6.6%) of 22 886 patients referred for genetic testing between June 2018 and March 2022. Patients were identified in all US states, 3 US territories, and Canada. Median age at testing was 63 years, and 44% were female. The p.V142I TTR variant was the most common (n=1263, 84.0%). Only 32% of patients with a pathogenic TTR variant reported a known family history; a lower percentage of Black individuals reported a known family history compared with other racial and ethnic groups. Black patients accounted for 23.7% of all patients referred and 81.9% of patients with the p.V142I variant., Conclusions: This sponsored genetic testing program identified a large number of patients with a pathogenic TTR variant, notably, in geographic regions not previously reported, and demographic groups that are historically underrepresented in the literature.

Introduction: Complementary, alternative and integrative medicine includes a myriad of therapies including herbal medicines, vitamins, dietary interventions and more, that are taken alone or in adjunct to standard conventional treatment. Often the main goals are to slow progression of disease, increase effectiveness of a drug, reduce side effects and improve quality of life. The study of these therapies and their influence in heart failure is not new. However, even for an experienced clinician, a gap exists between the literature and the application of knowledge to make a confident recommendation., Areas Covered: This review has a focus on specific supplements that are commonly used for individuals with HF. It discusses the mechanism of action, expected benefits, potential adverse effects, suggested doses, forms and drug interactions of these therapies. The literature search methodology included using medical subject headings terms to search in PubMed. Articles used were screened and critically appraised by the authors of this review., Expert Opinion: There are promising outcomes pertaining to the use of CAM in patients with HF. Advances in large scale, randomized, placebo-controlled trials are necessary to support evidence-based decision making regarding the use of supplements in conjunction, and in comparison, to conventional therapies for heart failure.

Introduction: The use of cannabis and its derivatives have increased steadily over the past few decades, prompting patients and clinicians to increasingly inquire about its health effects and safety profile. However, despite promising evidence suggesting therapeutic utilization, cannabis remains a controlled substance in most countries and is largely considered to have no medical or recreational benefit; thus, a lack of observational studies and randomized control trials exist to outline positive and negative health implications. Ultimately, this leaves patients, health-care professionals, and policymakers without necessary evidence required to make informed decisions on cannabis use., Areas Covered: This review outlines cannabis in a clinical setting and delves into specific effects of cannabinoids on cardiovascular health and disease. It discusses positive and negative health implications associated with cannabis, mechanisms in cardiovascular disease, and reveals methods guiding cannabis use in the clinical setting., Expert Opinion: Advances in research are necessary to guide decisions regarding cannabinoid use. Countries that have federally legalized cannabis have a unique opportunity to study cardiovascular implications in an unbiased and comprehensive manner. Ultimately, as cannabis use will inevitably increase, researchers, clinicians, and policymakers must work together to ensure cannabis is utilized in a way that is therapeutically beneficial.

Purpose: To evaluate the diagnostic utility of the Look Locker inversion time (TI) sequence on cardiac magnetic resonance imaging in patients with suspected cardiac amyloidosis and to evaluate whether there are differences in the nulling pattern between amyloid types., Materials and Methods: A total of 144 patients with suspected cardiac amyloidosis who had undergone cardiac magnetic resonance imaging were included in this retrospective study. Sixty-four had cardiac amyloidosis (62.1±9.2 y, 70.3% male, 68.8% had light chain amyloid [AL], 18.8% had familial transthyretin amyloid caused by mutant genes [ATTRm], and 12.5% had wild-type transthyretin amyloid [ATTRwt]) and 80 did not have cardiac amyloidosis (61.3±13.3 y, 58.8% male). Time to myocardial and blood pool nulling on the Look Locker TI sequence was classified as normal if blood pool nulled before myocardium or abnormal if blood pool nulling was coincident with or after myocardial nulling., Results: The nulling pattern was abnormal in 26 patients with cardiac amyloidosis compared with none of the patients without cardiac amyloidosis (40.6% vs. 0.0%, P<0.0001). Abnormal nulling had 40.6% sensitivity and 100% specificity for cardiac amyloidosis (area under the receiver operating characteristic curve: 0.703, 95% confidence interval: 0.642-0.764). All patients with cardiac amyloidosis with an abnormal nulling pattern demonstrated late gadolinium enhancement. Among patients with cardiac amyloidosis, there was no significant difference in abnormal nulling between AL, ATTRm, and ATTRwt amyloid types (31.8%, 58.3%, 62.5%, respectively, P=0.10)., Conclusions: An abnormal nulling pattern on the Look Locker TI sequence is highly specific for cardiac amyloidosis when present. However, abnormal nulling is a late finding with low sensitivity and does not differentiate between amyloid types.

Background: After a transplant, cancer is a leading cause of morbidity and mortality. Human leukocyte antigen-G (HLA-G)-an immune checkpoint molecule-reduces allograft rejection by dampening host immune responses. Reports suggest malignant cells utilize HLA-G to evade the immune system and promote cancer development. Our objective was to evaluate HLA-G donor-recipient polymorphism matching and development of cancer after a heart transplant., Methods: Recipients (n = 251) and corresponding donors (n = 196) were genotyped retrospectively to identify HLA-G polymorphisms in the 5' regulatory (-725, -201), 3' untranslated (+3,197, +3,187, +3,142, 14-base pair insertion-deletion polymorphism [14-bp indel]) and coding regions (Haplotypes I-VI). Associations between donor-recipient polymorphism matching and development of cancer were assessed through multivariate proportional hazard regression models., Results: Recipient and donor (48.2 ± 12.1 and 35.5 ± 14.3 years, respectively) mean follow-up was 7.2 ± 4.6 years. Overall, 42 (16.7%) recipients developed de novo post-transplant cancer. 14-bp polymorphism matching significantly reduced the proportion of cancer, revealing an independent protective effect (hazard ratio [95% CI]: 0.26 [0.10-0.75]; p = 0.012). Recipients with the 14-bp insertion sequence, whether homozygous or heterozygous, had a lower proportion of cancer (p > 0.008), matching the INS sequence (INS/INS and INS/DEL) protected against cancer (p = 0.002). No differences were seen between matched vs unmatched cohorts regarding all donor-recipient pre-transplant and post-transplant characteristics. No other polymorphisms showed significant associations., Conclusions: We investigated donor-recipient HLA-G polymorphism matching and development of cancer following a heart transplant. Donor-recipient 14-bp matching was an independent protective factor against cancer development. HLA-G may have a role in therapeutic and diagnostic strategies against cancer. Identifying relevant HLA-G polymorphisms may warrant alterations in immunotherapy to reduce post-transplant cancer risk., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Rejection is a leading cause of mortality following heart transplantation. Human leukocyte antigen-G (HLA-G) is an immune checkpoint which dampens the immune response. Reports suggest elevated HLA-G expression is associated with reduced allograft rejection. Our objective was to evaluate HLA-G polymorphisms and cell mediated rejection (CMR) development., Methods: Recipients (n = 123) were genotyped to identify relevant HLA-G polymorphisms in the 5'regulatory (-725, -201), 3'untranslated (+3197, +3187, +3142, 14-bp indel) and coding regions (haplotypes 1-6). CMR was evaluated via endomyocardial biopsy (grade ≥ 2R). Univariate/adjusted analyses were conducted via Kaplan Meier and proportional hazard models., Results: Mean recipient age was 48 (±12) years, with a median time to CMR of 4.6 years. 55 (45%) recipients had a biopsy grade ≥ 2R. Adjusted analysis revealed the +3196 G allele as a risk factor for CMR (p = 0.03). Compared to the minor GG genotype, CG had a 47.2% reduction in CMR risk (HR[95% CI] = 0.528 [0.235, 1.184]), while CC had a 66.9% reduction (0.331 [0.144, 0.761]). The recessive effect significantly increased CMR likelihood (2.388 [1.128, 5.059], p = 0.02)., Conclusion: The HLA-G +3196 G allele was identified as a risk factor for CMR diagnosis. HLA-G may have a role in therapeutic/diagnostic strategies against transplant rejection., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Amyloidosis is a term used to describe a group of rare heterogeneous diseases that ultimately result in the deposition and accumulation of misfolded proteins. These misfolded proteins, known as amyloids, are associated with a variety of precursor proteins that have amyloidogenic potential. Ultimately, the specific type of amyloidosis is dependent on multiple factors including genetic variability of precursor proteins and the tissue or organ in which the amyloid accumulates. Several types of amyloid have a predilection for the heart and thus contribute to cardiac amyloidosis, a major cause of restrictive cardiomyopathy. Individuals with cardiac amyloidosis present clinically with heart failure with preserved ejection fraction. Although improved diagnostics and increased awareness of cardiac amyloidosis have led to a relative increase in diagnosis, cardiac amyloidosis remains an underrecognized and underdiagnosed cause of heart failure with preserved ejection fraction. It is essential to properly identify cases of cardiac amyloidosis and determine the pathology responsible for the formation of amyloid to appropriately provide management. This review aims to encourage physician awareness of cardiac amyloidosis by focusing on clinical presentation and the distinctions between types. Furthermore, epidemiology is central to understanding the affected demographics and sometimes hereditary nature of the disease. Improved understanding of cardiac amyloidosis will ideally lead to earlier diagnosis and interventions to improve patient outcomes., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Cardiac amyloidosis is an under-recognized and potentially fatal cause of heart failure and other cardiovascular manifestations. It is caused by deposition of misfolded precursor proteins as fibrillary amyloid deposits in cardiac tissues. The two primary subtypes of systemic amyloidosis causing cardiac involvement are immunoglobulin light chain (AL), a plasma cell dyscrasia, and transthyretin (ATTR), itself subdivided into a hereditary subtype caused by a gene mutation of the ATTR protein, and an age-related wild type, which occurs in the absence of a gene mutation. Clinical recognition requires a high index of suspicion, inclusive of the extracardiac manifestations of both subtypes. Diagnostic workup includes screening for serum and/or urine monoclonal protein suggestive of immunoglobulin light chains, along with serum cardiac biomarker measurement and performance of cardiac imaging for findings consistent with amyloid infiltration. Modern cardiac imaging techniques, including the use of nuclear scintigraphy with bone-seeking radiotracer to noninvasively diagnose ATTR cardiac amyloidosis, have reduced reliance on the gold standard endomyocardial biopsy. Disease-modifying therapeutic approaches have evolved significantly, particularly for ATTR, and pharmacologic therapies that slow or halt disease progression are becoming available. This Canadian Cardiovascular Society/Canadian Heart Failure Society joint position statement provides evidence-based recommendations that support the early recognition and optimal diagnostic approach and management strategies for patients with cardiac amyloidosis. This includes recommendations for the symptomatic management of heart failure and other cardiovascular complications such as arrhythmia, risk stratification, follow-up surveillance, use of ATTR disease-modifying therapies, and optimal clinical care settings for patients with this complex multisystem disease., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Introduction : Cardiac amyloidosis is a disorder caused by the accumulation of abnormal protein products, amyloid, in the myocardium which subsequently impairs normal heart function. Heart failure with preserved ejection fraction has been increasingly attributed to amyloidosis and the resultant restrictive cardiomyopathy it creates. Areas covered : Amyloid transthyretin (ATTR) is one of several identified amyloid products that have been pathologically implicated in cardiac amyloidosis through advanced diagnostics. Improvements in nuclear imaging techniques, particularly scintigraphy, have enabled non-invasive diagnosis where previously endomyocardial biopsy was the only option. Despite being considered a rare disease, it is likely that ATTR cardiac amyloidosis is an underdiagnosed condition which has been supported by autopsy findings in heart failure populations. This article will review ATTR cardiac amyloidosis to provide physicians with the tools they need to establish a definitive diagnosis when there is a clinical suspicion of amyloidosis and provide the most appropriate care. Expert commentary : Increased awareness and improved diagnostic techniques will lead to earlier diagnosis and a greater understanding of the clinical presentation. The anticipated increases in the prevalence of this disease due to increased clinical awareness will require, and in-part, facilitate the development of new therapies to manage this patient population.

Human leukocyte antigen-G (HLA-G) expression is modulated by immunosuppressant use and is associated with lower incidence of graft rejection and cardiac allograft vasculopathy (CAV). We examined whether everolimus induces HLA-G expression and inhibits human coronary artery smooth muscle cell (HCASMC) proliferation, a critical event in CAV. Also, we examined whether TNFα-stimulated neutrophil adhesion is inhibited by HLA-G on human coronary artery endothelial cells (HCAECs). HLA-G expression in HCASMCs following everolimus treatment was determined by western-blot densitometric analysis. HCASMCs proliferation following incubation with recombinant HLA-G was determined by automated cell counter detecting 2-10 µm particles. Assessment of recombinant HLA-G on neutrophil adhesion to HCAECs in response to TNF-α induced-injury was determined by nonstatic adhesion assays. HLA-G expression was upregulated in HCASMCs following everolimus exposure (1000 ng/ml; P < .05). HLA-G (500, 1000 ng/ml; both P < .05) reduced HCASMC proliferation and inhibited TNFα-stimulated neutrophil adhesion to endothelial cells at all concentrations (0.1-1 ng/ml; all P < .001). Our study reveals novel regulation of HLA-G by everolimus, by demonstrating HLA-G upregulation and subsequent inhibition of HCASMC proliferation. HLA-G is a potent inhibitor of neutrophil adhesion to HCAECs. Findings support HLA-G's importance and potential use in heart transplantation for preventative therapy or as a marker to identify patients at high risk for developing CAV., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). Although these treatments have changed the natural course of CML and many other cancers, they may cause cardiovascular and/or metabolic complications. In this review, we discuss how overlooking the main drivers of cardiovascular events (CVEs) and lack of standard definitions for cardiovascular adverse events might have affected these event rates in CML trials. Methodological limitations that affect the available data are discussed, with an emphasis on the future direction of cardiovascular safety research in trials of investigational drugs in cancer treatment.

The Human Leukocyte Antigen-G (HLA-G) is a MHC-class Ib molecule with robust immunomodulatory properties; in transplant, it inhibits cytotoxic activity of immune cells and thus has a pivotal role in protecting the allograft from immune attack. The present review details a 10-year experience investigating the influence of HLA-G on heart transplantation, allograft rejection and cardiac allograft vasculopathy development. Exploration of HLA-G in transplantation began with the initial findings of its increased expression in allograft hearts. Since then, HLA-G has been recognized as an important factor in transplant immunology. We discuss inducers of HLA-G expression, and the importance of HLA-G as a potential biomarker in allograft rejection and heart failure. We also highlight the importance of polymorphisms and how they may influence both HLA-G expression and clinical outcomes. There remains much to be done in this field, however we hope that findings from our group and other groups will ignite interest and facilitate further expansion of HLA-G research in transplantation., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: Nilotinib is a highly effective tyrosine kinase inhibitor in the treatment of chronic myeloid leukemia (CML). However, reports of cardiovascular toxicities caused by nilotinib have recently raised critical concerns. The aim of the present study was to evaluate the incidence of cardiovascular events (CVEs) and frequency of asymptomatic peripheral arterial disease (PAD) after long-term exposure to nilotinib., Patients and Methods: In the present retrospective cohort, we evaluated the incidence of CVEs in 63 CML patients treated with nilotinib. The results of Doppler ultrasound examination of the carotid and vertebral and lower extremity arteries with ankle-brachial index measurements were collected in asymptomatic patients. The clinical outcome was a composite endpoint of PAD, acute coronary events, stroke, heart failure, and cardiovascular death., Results: Sixty-three patients with a median age of 60 years were followed up for a median duration of 63 months. After a median nilotinib exposure of 49.30 months (range, 7.00-117.95 months), for a total exposure of 178.7 patient-years, 6 patients (9%) had experienced the clinical outcome. Four patients (8%) had abnormal arterial leg Doppler ultrasound findings. No significant lesions were reported in carotid/vertebral artery ultrasound examinations. Together, hypertension and low-density lipoprotein cholesterol > 2 mmol/L significantly increased the risk of CVEs or abnormal ultrasound findings (odds ratio, 37.65; 95% confidence interval, 4.06-348.9)., Conclusion: The incidence of CVEs and the frequency of asymptomatic PAD in this population was low, and CVEs were associated with cardiovascular risk factors. Aggressive risk factor modification and applying standard definitions for measuring cardiovascular outcomes might have contributed to the findings. Further prospective and adequately powered studies are needed to explore the effect of the cardiovascular risk profile on CVEs in CML patients taking nilotinib., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Both types of sleep-disordered breathing (SDB), obstructive and central sleep apnoea (OSA and CSA, respectively), are common in patients with heart failure and reduced ejection fraction (HFrEF). In such patients, SDB is associated with increased cardiovascular morbidity and mortality but it remains uncertain whether treating SDB by adaptive servo-ventilation (ASV) in such patients reduces morbidity and mortality., Aim: ADVENT-HF is designed to assess the effects of treating SDB with ASV on morbidity and mortality in patients with HFrEF., Methods: ADVENT-HF is a multicentre, multinational, randomized, parallel-group, open-label trial with blinded assessment of endpoints of standard medical therapy for HFrEF alone vs. with the addition of ASV in patients with HFrEF and SDB. Patients with a history of HFrEF undergo echocardiography and polysomnography. Those with a left ventricular ejection fraction ≤45% and SDB (apnoea-hypopnoea index ≥15) are eligible. SDB is stratified into OSA with ≥50% of events obstructive or CSA with >50% of events central. Those with OSA must not have excessive daytime sleepiness (Epworth score of ≤10). Patients are then randomized to receive or not receive ASV. The primary outcome is the composite of all-cause mortality, cardiovascular hospital admissions, new-onset atrial fibrillation requiring anti-coagulation but not hospitalization, and delivery of an appropriate discharge from an implantable cardioverter-defibrillator not resulting in hospitalization during a maximum follow-up time of 5 years., Conclusion: The ADVENT-HF trial will help to determine whether treating SDB by ASV in patients with HFrEF improves morbidity and mortality., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Anthracycline-induced cardiomyopathy (AIC) may progress to end-stage heart failure requiring mechanical circulatory support or orthotopic heart transplantation (OHT). Previous studies have described important clinical differences between AIC and nonischemic cardiomyopathy (NIC) cohorts requiring these advanced interventions. Therefore, we sought to extend this literature by comparing echocardiographic parameters, treatment strategies, and the prognosis between matched patients from these cohorts. This is a retrospective matched cohort study. All patients who received a ventricular assist device or OHT at a large Canadian center were reviewed (n = 421; 1988 to 2015) and subjects with clinical and pathologic evidence of AIC were included (n = 17, 4.0%). A comparison cohort with idiopathic NIC from the same database, matched 3:1 for age, gender, ethnicity, and year of heart failure onset was selected. The Mann-Whitney rank-sum and Fisher's exact tests were used for comparisons. Patients with AIC were predominantly women (70.6%) with heart failure diagnosed at age 40.2 ± 15.8 and 8.3 ± 8.9 years after anthracycline treatment. Compared with NIC, no differences were seen in co-morbidities, echocardiographic measures, the proportion of patients receiving a defibrillator, ventricular assist device, or OHT, the incidence of graft failure, and all-cause mortality. In contrast to other studies, AIC was not associated with a higher incidence of right ventricular dysfunction. A greater proportion of patients with AIC developed cancer (recurrence or new primary) post-OHT (21.4% vs 2.3%, p = 0.042). In conclusion, we demonstrate that when matched cohorts of patients with end-stage heart failure secondary to AIC and idiopathic NIC are compared, they are similar with respect to co-morbidities, degree of ventricular dysfunction, and advanced therapeutics used. The prognosis with OHT is also similar., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Human Leukocyte Antigen-G (HLA-G) is a non-classical class 1b protein, whose gene is located on chromosome 6 (6p21.31). HLA-G inhibits the immune cells' cytotoxic activity by interacting with specific receptors on their membranes. Since it is a naturally occurring immune modulator, HLA-G has been investigated in transplantation. Indeed, a number of investigations reveal that HLA-G expression is influenced by genetic polymorphisms and in turn, those polymorphisms are associated with detrimental or beneficial outcomes in various pathological situations. The present review introduces the HLA-G molecule, the gene and its polymorphisms. It focuses on the expression of HLA-G and the role of polymorphisms primarily in heart transplant outcomes, secondarily in other transplant organs, as well as the role of the allograft and effect of medical therapy. We discuss the limitations in HLA-G transplant investigations and future directions. The immune inhibiting activity of HLA-G has a great deal of potential for its utilization in enhancing diagnostic, preventive and therapeutic strategies against rejection in the setting of transplantation., (Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Introduction: Diminished exercise capacity is a key symptom in heart failure (HF). Exercise predictors (peak VO2, VE/VCO2 slope, and oxygen uptake efficiency slope [OUES]) are prognostic markers but studied in isolation. We evaluated if these exercise variables offer additional prognostic value to clinical predictors in HF., Methods and Results: This was a single-institution retrospective cohort study of 517 consecutive HF patients. We used Cox proportional hazards modeling to determine the additional prognostic value of exercise variables on mortality, HF hospital admissions, and a composite outcome of ventricular assistance device (VAD) implantation, heart transplantation (HT), and death. During a mean follow-up of 2.7 years, 52 deaths, 47 HTs, and 19 VAD implantations occurred. After adjusting for age, New York Heart Association functional class, ejection fraction, body mass index, creatinine, and B-type natriuretic peptide, peak VO2 (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.85-0.96), OUES (HR 0.92, 95% CI 0.87-0.97), and VE/VCO2 (HR 1.03, 95% CI 1.01-1.05) were independent predictors of the composite outcome. Similar discriminatory capacity existed between the exercise variables (c-statistics 0.77, 0.78, and 0.78, respectively). Only VE/VCO2 was an independent predictor of admissions (HR 1.04, 95% CI 1.01-1.07), and only peak VO2 was an independent predictor of mortality (HR 0.90, 95% CI 0.84-0.98)., Conclusions: Peak VO2, OUES, and VE/VCO2 are independent predictors of HF prognosis over recognized clinical variables. However, no single exercise variable was superior., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Clonidine may help prevent cardiac complications in patients undergoing non-cardiac surgery and receiving chronic beta-blocker therapy. We conducted a multicentre pilot randomized trial to estimate recruitment rates for a full-scale trial and to assess the safety and tolerability of combining clonidine with chronic beta-blockade., Methods: Patients who were at elevated perioperative cardiac risk, receiving chronic beta-blockade, and scheduled for major non-cardiac surgery were recruited in a blinded (participants, clinicians, outcome assessors) placebo-controlled randomized trial at three Canadian hospitals. Participants were randomized to clonidine (0.2 mg oral tablet one hour before surgery, plus 0.2 mg·day(-1) transdermal patch placed one hour before surgery and removed four days after surgery or hospital discharge, whichever came first) or matching placebo. Feasibility was evaluated based on recruitment rates, with each centre being required to recruit 50 participants within 12-18 months. Additionally, we reviewed study drug withdrawals and safety outcomes, including clinically significant hypotension or bradycardia., Results: Eighty-two of the 168 participants were randomized to receive clonidine and 86 to receive placebo. The average time to recruit 50 participants at each centre was 14.3 months. Six patients (7%) withdrew from clonidine, while four (5%) withdrew from placebo. Based on qualitative review, there were no major safety concerns related to clonidine. There was a moderate overall rate of cardiac morbidity, with 18 participants (11%) suffering postoperative myocardial infarction., Conclusion: This pilot randomized trial confirmed the feasibility, safety, and tolerability of a full-scale trial of oral and transdermal clonidine for reducing the risk of cardiac complications during non-cardiac surgery. This trial was registered at www.clinicaltrials.gov: NCT00335582.

Autologous stem-cell transplant has been widely used to treat patients with AL amyloidosis. However, transplant-related mortality rates are high, and a recent randomized trial suggested that non-transplant regimens produced comparable results with less toxicity. In order to define the role of patient selection in stem cell transplantation, we evaluated 78 consecutive AL amyloidosis patients transplanted at our centre. Transplant-related mortality occurred in 11·5%. Complete haematological response and organ response were achieved in 56% and 60%. Median overall survival was significantly lower for patients with brain-type natriuretic peptide (BNP) >300 pg/ml (17·5 months vs. not-reached) (P = 0·0004), troponin-I >0·07 ng/ml (13·5 months vs. not-reached) (P = 0·00001) and those not achieving a complete haematological response (88 months vs. not-reached) (P = 0·0345); high BNP and troponin-I were the most important predictive factors in a multivariate analysis. Based on this study, patients with BNP <300 pg/ml and/or normal levels of troponin-I should be considered transplant candidates., (© 2013 John Wiley & Sons Ltd.)

Background: The HeartWare ventricular assist device (HVAD) is a new generation centrifugal flow VAD recently introduced in Canada. The objective of this study was to compare the HVAD device to the HeartMate II (HMII) axial flow device. Very few studies have compared clinical outcomes between newer generation VADs., Methods: All perioperative and follow-up data on LVAD recipients were collected prospectively in our institutional database. Between January 2006 and April 2012, 46 consecutive patients underwent implantation of either an HVAD (n=13) or a HMII (n=33) device. Pre-implant demographics, perioperative and postoperative clinical outcomes were reviewed between groups., Results: Overall, the baseline characteristics, demographics, co-morbidities and laboratory values were comparable between the two groups. The majority of the patients were Interagency Registry for Mechanical Assisted Circulatory Support 3-4 (92% in both groups) and most of the patients were bridge to transplant (75% in HMII vs. 79% in HVAD). Survival and the incidence of perioperative bleeding, renal dysfunction, liver dysfunction, and infection were similar between the groups. However, HVAD devices had a significantly higher incidence of gastrointestinal (GI) bleeding (31% vs. 0% in HMII patients, p<0.01) and stroke (44% vs. 10% in HMII patients, at one year p=0.04). Hemorrhagic strokes were more frequent in patients with HVAD (three of the five episodes vs. one of the three episodes in HMII patients, p=0.06)., Conclusion: While device complications were comparable, patients with HVAD experienced a significantly higher incidence of stroke and GI bleeding and therefore refinement in patients' management may decrease incidence of these complications., (© 2013 Wiley Periodicals, Inc.)

Background: Current available treatment options for advanced heart failure include heart transplantation and ventricular assist device (VAD) therapy. This project aimed to evaluate the cost-effectiveness of a bridge-to-transplantation (BTT)-VAD approach relative to direct heart transplantation in transplant-eligible patients., Methods and Results: A Markov model was used to evaluate survival benefits and costs for BTT-VAD versus nonbridged heart transplant recipients. Three different scenarios were considered according to severity of patients' baseline hemodynamic status (high, medium, and low risk). Results are presented in terms of survival, costs, and cost-effectiveness ratio. Sensitivity analyses were used to analyze uncertainty in model estimates. Over a 20-year time horizon, BTT-VAD therapy increased survival at an increased cost relative to nonbridged heart transplant recipients: $100 841more in costs and 1.19 increased life years (LYs) in high-risk patients ($84 964/LY), $112 779 more in costs and 1.14 more LYs ($99 039/LY) in medium-risk patients, and an additional cost of $144 334 and incremental clinical benefit of 1.21 more LYs ($119 574/LY) in low-risk patients. The sensitivity analysis estimated a 59%, 54%, and 43% chance of BTT-VAD therapy being cost-effective for high-, medium-, and low-risk patients at a willingness-to-pay level of $100 000/LY. Subgroup analyses indicated that risk of post-VAD and transplantation complications, waiting time, renal dysfunction, and patient age substantially affected the cost-effectiveness ratio., Conclusions: BTT-VAD therapy is associated with improved survival and increased costs. On the basis of commonly accepted willingness-to-pay thresholds, BTT-VAD therapy is likely to be cost-effective relative to nonbridged heart transplantation in specific circumstances.

A 14 bp insertion/deletion polymorphism in exon 8 of the HLA-G gene is associated with mRNA stability and HLA-G expression. In cardiac transplantation, the 14 bp deletion polymorphism plays an important role in the expression of HLA-G and is associated with fewer episodes of cellular rejection. We investigated the association between the 14 bp insertion/deletion HLA-G polymorphism and cardiac allograft vasculopathy (CAV) post heart transplantation. There were no statistically significant differences in the presence of the three HLA-G genotypes (-14 bp/-14 bp, +14 bp/-14 bp, +14 bp/+14 bp) between patients without CAV and patients with CAV at 1 year (p=0.61) or 5 years (p=0.76) post-transplant. We found no correlation between HLA-G genotypes and CAV progression from baseline to 5 years post-transplant (p=0.55). HLA-G polymorphism appears to play an important role as a genetic indicator for cellular rejection post-transplant; however, it is not a reliable marker to identify patients at risk of CAV., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Atrial masses postcardiac transplant are not well reported and their diagnosis and treatment can be challenging. In the asymptomatic patient, differentiating thrombus from cardiac tumor can sometimes be difficult and the use of multiple imaging modalities is recommended. Accurate diagnosis is imperative to inform a treatment plan that balances the benefits and risks of a medical versus surgical approach. We present three cases of atrial masses postcardiac transplant to illustrate this clinical dilemma., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

During the H1N1 influenza virus pandemic, vaccination of high risk groups including solid-organ transplant recipients was advised. A retrospective case control study of 60 heart transplant patients, 15 having received the H1N1 virus antigen and ASO3 adjuvant vaccine (GlaxoSmithKline, Mississauga, ON, Canada) within 21 days and 45 having not been vaccinated, all undergoing routine surveillance endmyocardial biopsies, was performed. The overall rate of cellular rejection (all grades) was not statistically different between groups; however, acute cellular rejection, ≥grade 2 (1990 ISHLT criteria), was more frequent among those having recently vaccinated (control: 1/45 vs. 6/15, p = 0.001). On multivariate analysis, the only risk factor found to be associated with acute cellular rejection was recent H1N1 viral antigen and adjuvant vaccination (OR 26.5: 95% CI 02.59-270.5). Vaccine adjuvants increase host response to vaccine antigens by immune upregulation potentially increasing risk of rejection in solid-organ transplant recipients. The potential hazard of vaccination this study raises must be weighed with the clear benefit vaccination has proven to be., (©Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Immune activation and inflammation play critical roles in the development of heart failure (HF). Human leukocyte antigen-G (HLA-G) is a nonclassical, major histocompatibility complex class I (MHC-I) protein, upregulated in the context of transplantation, malignancy, and inflammation, and has been correlated with various clinical outcomes. We sought to evaluate the utility of plasma HLA-G in identifying patients with HF. We conducted a single-center, cross-sectional pilot study involving 82 patients diagnosed with HF and 10 healthy controls. Concentrations of circulating HLA-G and inflammatory markers were detected with specific enzyme-linked immunosorbent assay kits and quantified according to purified protein standards. The mean age of the patients was 49.1 ± 12.0 years and 62.2% were male. The median and interquartile range of HLA-G levels (U/ml) were significantly higher (p < 0.001) in HF patients (63, 36-98) compared with controls (28, 22-40). Moreover, HLA-G levels that were similarly (p = 0.766) upregulated across all New York Heart Association functional classes. There was no significant correlation between serum HLA-G and other biomarkers. In conclusion, HLA-G is upregulated in patients diagnosed with HF. Its marked elevation even in New York Heart Association class I patients might indicate that serum HLA-G is a more sensitive marker than other classical HF biomarkers., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. All rights reserved.)

Background: We investigated the effect of epidermal growth factor-like domain 7 (Egfl7) on nuclear factor-κB activation, intercellular adhesion molecule-1 expression, and neutrophil adhesion to human coronary artery endothelial cells after calcineurin-inhibition-induced injury., Methods and Results: Human coronary endothelial cells were incubated with cyclosporine (CyA) 10 μg/mL with or without Egfl7 (100 ng/mL) or the Notch receptor activator Jagged1 (200 ng/mL) for 6 to 48 hours. CyA upregulated nuclear factor-κB (p65) activity (128 ± 2% of control, P<0.001) in nuclear extracts, as determined with a DNA-binding activity ELISA. This activity was inhibited by Egfl7 (86 ± 3% of control; P<0.001 versus CyA alone). Jagged1 blocked Egfl7-induced nuclear factor-κB inhibition (105 ± 4% of control; P<0.05 versus CyA plus Egfl7). CyA upregulated cell-surface intercellular adhesion molecule-1 expression (215 ± 13% of control; P<0.001), as determined by flow cytometry. This expression was suppressed by Egfl7 (148 ± 5%; P<0.001 versus CyA alone). Jagged1 attenuated the intercellular adhesion molecule-1-suppressive effect of Egfl7 when administered with CyA (193 ± 3% versus 148 ± 5%; P<0.01). CyA increased neutrophil adhesion to human coronary endothelial cells (control 20 ± 5%, CyA 37 ± 3%; P<0.001 versus control) in a nonstatic neutrophil adhesion assay. This increase was attenuated by Egfl7 (22 ± 6%; P<0.001 versus CyA alone). Jagged 1 attenuated the effect of Egfl7 on neutrophil adhesion (31±3%; P<0.001 versus Egfl7 plus CyA)., Conclusions: Our study reveals that Egfl7 is a potent inhibitor of neutrophil adhesion to human coronary endothelial cells subsequent to calcineurin-inhibition-induced injury. Mechanistically, Egfl7 blocked nuclear factor-κB pathway activation and intercellular adhesion molecule-1 expression, which suggests that it may have significant antiinflammatory properties. Because Jagged1 blocked the effect of Egfl7, Notch receptor antagonism may contribute to the mechanism of action of Egfl7.

Introduction: The use of mechanical circulatory support (MCS) in nontransplant eligible candidates remains controversial. Our decision to offer MCS for nontransplant candidates has led to their reevaluation after a period of left ventricular assist device (LVAD) support., Methods: From 2001 to September 2009, we had 37 patients who received an implantable LVAD, 22 (59%) were not deemed to be transplant eligible at the time of LVAD insertion (bridge to candidacy, BTC group)., Results: Fifteen (41%) patients were considered transplant eligible (bridge to transplant, BTT group) at the time of device insertion and received a HeartMate XVE (n = 7), HeartMate 2 (n = 7), or a Novacor LVAS (n = 1). In the BTC group, patients received the HeartMate XVE device (n = 11), HeartMate 2 (n = 5), or the Novacor LVAS (n = 6). The primary criterion for transplant ineligibility was refractory pulmonary hypertension (PH) in 18 patients, 3 patients did not meet our body mass index criteria (>35 kg/m(2)), and 2 patients were dialysis-dependent. Six (27%) BTC patients died on support. Overall, 16/22 patients (73%) were subsequently listed for transplantation, with one listed for combined heart-lung due to refractory PH. Twelve patients (75%) underwent successful heart transplantation. Three patients died during their transplant. Overall posttransplant survival at one year shows lower survival in the BTC group compared to the BTT group (67% vs. 100%, p = 0.05). At two years and three years the survival was lower, but not statistically different (BTC vs. BTT: 67% vs. 90% and 64% vs. 87%, respectively, p = NS)., Conclusions: MCS can successfully convert a large proportion of transplant-ineligible patients into acceptable candidates. , (© 2011 Wiley Periodicals, Inc.)

Background: Human leukocyte antigen G (HLA-G) is a non-classical Ib molecule in the major histocompatibility complex. HLA-G has important immunosuppressive properties, and in the context of cardiac transplantation, is associated with a low risk of cellular rejection. A 14-bp insertion/deletion polymorphism in exon 8 of the HLA-G gene is associated with messenger RNA (mRNA) stability and expression of HLA-G. This study analyzed the relationship between HLA-G polymorphisms and serum HLA-G levels in patients after cardiac transplantation to determine if any specific HLA-G genotype is associated with cellular rejection., Methods: Ninety-four heart transplant patients were genotyped for the 14-bp polymorphism. Serum HLA-G levels and cellular rejection grades were evaluated in all patients., Results: The 14-bp polymorphism was significantly associated with serum HLA-G expression. Patients with the -14-bp/-14-bp genotype had significantly higher mean serum HLA-G levels (88.2 U/ml) than those patients with the +14-bp/-14-bp (52.8 U/ml) and +14-bp/+14-bp (32.2 U/ml) genotypes (p = 0.004). The -14 bp/-14-bp genotype was significantly associated with fewer episodes of cellular rejection., Conclusions: This study suggests that the 14-bp deletion in the HLA-G gene plays an important role in the expression of HLA-G and thus might be a clinically useful genetic indicator for cellular rejection risk after cardiac transplantation., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The increasing prevalence of heart failure and its unpredictable trajectory highlight the need for patients to make their end-of-life care wishes known using advanced care directives (ACDs). The paucity of literature addressing heart failure patients' decision-making processes and knowledge of ACDs underscores the need for investigation. The purposes of this study were to (1) determine patients' awareness, comprehension, and utilization of ACDs and (2) determine their knowledge of the process of cardiopulmonary resuscitation and their current resuscitation preference., Methods: A prospective, single-centre study was designed to collect quantitative data addressing patients' understanding of ACDs and cardiopulmonary resuscitation as well as their current resuscitation preference. Patients who consented were interviewed using a semistructured questionnaire. Data were analyzed using descriptive statistics., Results: Of the 41 participants, 76% did not know what ACDs were and fewer recalled discussing them with their physician. Nearly 80% of the 37 queried participants would have preferred to discuss ACDs. More than 75% of participants wanted full resuscitation if they were to require it at this time. Most participants had not documented their resuscitation preference, and only slightly over half said their substitute decision maker was aware of their preference. Among the 19 with an implantable cardioverter-defibrillator, nearly half would want it deactivated should their condition worsen. Only 2 participants recalled having discussed this option with their physician., Conclusions: There remains a lack of knowledge and utilization of ACDs among this heart failure population. Participants' preferences highlight the importance of discussing ACDs and exploring resuscitation preferences early and often in heart failure., (Copyright © 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: We previously demonstrated that cyclosporine (CyA) impairs endothelial function as a result of alterations in nitric oxide (NO) and endothelin-1 (ET-1) regulation. Bosentan (BOS), an ET-1 antagonist, and tetrahydrobiopterin (BH₄), an eNOS cofactor, may reduce endothelial dysfunction by improving ET-1/NO homeostasis., Methods: Lewis rats received intraperitoneal injections of CyA with BOS or with BOS+BH₄ daily for 2 weeks. Control (Con) animals received saline injections. Thoracic aortic segments were assessed for endothelial-dependent (E(dep)) and -independent (E(ind)) relaxation (E(max%)) after exposure to acetylcholine and sodium nitroprusside. Vessel sensitivity to ET-1-induced vasospasm was evaluated., Results: CyA use resulted in impaired E(dep) vasorelaxation when compared with Con, whereas BOS and BH₄ treatment preserved E(dep) vasorelaxation. CyA significantly altered E(ind) vasorelaxation, whereas BOS and BH₄ therapy attenuated CyA-induced effects. Compared with Con, CyA and BH₄ exposure demonstrated increased sensitivity to ET-1 vasospasm. BOS therapy abrogated the CyA and BH₄-induced sensitivity to vasospasm. CyA treatment resulted in higher 8-isoprostane levels compared with Con. CyA-mediated vascular dysfunction is characterized by impaired NO and ET-1 homeostasis., Conclusions: Our study suggests potential therapeutic strategies to prevent endothelial dysfunction as combined therapy with ET-1 antagonism and NO augmentation completely abrogated CyA-induced vascular injury., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: To identify the impact of the presence of patent foramen ovale (PFO) in patients undergoing liver transplantation., Methods: Twenty-seven pre-liver transplant patients who had a PFO (PFO group) were identified and compared with 61 patients without PFO (NoPFO group). Patients were matched according to age, gender and cause of liver disease. The diagnosis of PFO was made by transthoracic echocardiography prior to liver transplantation. Patient baseline characteristics and complications during the early post-transplant period were analyzed., Results: The mean age in the PFO group was 47 ± 14 (range 18-68) yr and 50 ± 11 (range 12-65) yr in the NoPFO group. The PFO group had a mean model for end-stage liver disease (MELD) score of 15 ± 10 whereas in the NoPFO group the MELD score was 19 ± 10 (p = 0.08). There were non-significant differences in echocardiographic parameters between groups. Duration of mechanical ventilation and the incidence of neurological complications were similar. Thirty-day mortality rate was similar in both groups; only one patient in the NoPFO group died within the first 30 days post-transplantation., Conclusions: The presence of PFO in patients with end-stage liver disease undergoing liver transplantation does not appear to affect patient outcomes during the peri-operative period., (© 2010 John Wiley & Sons A/S.)

Background: Fixed pulmonary hypertension (FPH) is considered a contraindication to cardiac transplantation. Ventricular assist device (VAD) therapy through prolonged left ventricular unloading may reverse FPH. Our aim was to assess post-transplant outcomes and survival in patients with and without FPH undergoing VAD implantation as bridge to transplant., Methods: Fifty-four patients received an intracorporeal left VAD (LVAD) as a bridge to transplant from 2000 to 2008 at two institutions (Rigshospitalet, Denmark, and the Toronto General Hospital, Canada). Twenty-two (41%) patients had fixed FPH (defined as pulmonary vascular resistance [PVR] >3 Wood units and resistant to pulmonary vasodilators) prior to VAD implant (FPH group) and were compared with 32 patients without FPH (NoFPH group). Baseline characteristics, pre- and post-transplant pulmonary pressures, incidence of complications and post-transplant survival were analyzed., Results: Baseline characteristics were similar except that patients in the FPH group were older (46 ± 11 years vs 39 ± 13 years in the NoFPH group, p < 0.05). The mean pre-VAD PVR was 4.3 ± 1.7 Wood units in the FPH group and 1.7 ± 0.5 Wood units in the NoFPH group (p < 0.001). Pulmonary pressures were higher in the FPH group immediately prior to VAD implant, but they were comparable immediately pre-transplant and during the first year post-transplant. The incidence of post-transplant RV failure was not significantly different between groups. Post-transplant survival was similar between groups., Conclusions: VAD therapy successfully decreases pulmonary hypertension, even in patients with "fixed" FPH, allowing candidacy for heart transplantation. Among bridge-to-transplant candidates, the presence of FPH does not reduce post-transplant survival., (Copyright © 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Acute hemodynamic collapse resulting in cardiogenic shock and impending end-organ failure is usually associated with certain death. The introduction of short-term mechanical circulatory support (MCS) devices offers potential therapy to these critically ill patients. The BVS 5000 device (ABIOMED Inc, USA) is widely used in the United States, but rarely in Canada, where device reimbursement remains a barrier., Objective: To present the Toronto General Hospital's (Toronto, Ontario) initial five-year experience with this device to highlight the indications for use, common complications and overall success rates., Methods and Results: The institutional MCS database from 2001 to 2006 was reviewed, and 18 patients who received 30 devices in a variety of configurations were identified. The most common support configuration consisted of biventricular support (n=12), followed by isolated left ventricular support (n=4) and isolated right ventricular support in two recipients of an implantable long-term left ventricular assist device. Overall survival to device explant or transplant was 55% (n=10), of which five (50%) were successfully discharged from the hospital. The overall survival from device implant to hospital discharge was 28% (five of 18). The most common cause of death was multisystem organ failure., Conclusions: MCS with the ABIOMED BVS 5000 can successfully resuscitate critically ill patients; however, earlier institution of this device would avoid irreversible end-organ injury, and lead to higher rates of device explant and hospital discharge. Short-term MCS devices should be available in all cardiac surgical centres in Canada to permit stabilization and evaluation of the acutely ill cardiac patient and subsequent management in a heart transplant facility.

Background: Epidermal growth factor-like domain 7 (Egfl7) is a chemoattractant for endothelial cells, and its expression is restricted to endothelial cells. Hypoxia/reoxygenation (H/R) induced endothelial injury that occurs during transplantation contributes to the subsequent development of allograft vasculopathy. We investigated the effect of Egfl7 on endothelial cell intercellular adhesion molecule 1 expression in response to H/R injury., Methods and Results: Human coronary artery endothelial cells were submitted to hypoxia (0.1% O(2)) followed by normoxia (21% O(2)) in the presence or absence of Egfl7 (100 ng/mL). Hypoxia alone increased the expression of Egfl7×140±8% of control at 3 hours (n=6; P<0.05) and 385±50% of control at 6 hours (n=6; P<0.001). Incubation with Egfl7 during the reoxygenation period prevented intercellular adhesion molecule 1 upregulation (mean fluorescence intensity: 5.37±0.92 versus 3.81±0.21; P<0.05; n=4 per group). Nuclear factor-κB nuclear localization on H/R injury was blocked by Egfl7 administration (cytosolic/nuclear ratio of 0.93±0.01 versus 1.44±0.24; P<0.05; n=4 per group). Inhibitor of nuclear factor-κB protein level was significantly reduced on H/R injury (26±4.6% of control expression; P<0.05; n=4 per group); however, concurrent incubation with Egfl7 attenuated this reduction (46±6.2% of control expression; P<0.05 when compared with H/R injury alone; n=4 per group)., Conclusions: Our study reveals the novel observation that hypoxia upregulates human coronary artery endothelial cells expression of Egfl7 and that Egfl7 inhibits expression of intercellular adhesion molecule 1 subsequent to H/R injury. Mechanistically, Egfl7 prevented nuclear factor-κB nuclear localization and augmented inhibitor of nuclear factor-κB protein levels, suggesting that it inhibits nuclear factor-κB activation, a key step in the inflammatory activation of endothelial cells. Egfl7 may be protective against H/R injury incurred during transplantation and may modulate the events that lead to the development of graft vasculopathy.

Cardiac amyloidosis is a myocardial disease characterized by extracellular amyloid infiltration throughout the heart. Cardiac amyloidosis has a wide spectrum of clinical manifestations but the most frequent presentation is heart failure. Differential diagnoses from other restrictive cardiomyopathies is important. A combination of clinical, electrocardiographic and imaging methods is commonly used to diagnose this disease. Definite diagnosis is based on endomyocardial biopsy and treatment of cardiac amyloidosis is a challenge. Heart transplantation, although controversial, has demonstrated survival benefit.

Background: Acute renal dysfunction (ARD) is a frequent complication after ventricular assist device (VAD) implantation. The purpose was to identify predictors associated with ARD after VAD implantation., Methods and Results: ARD was defined using the risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, end-stage kidney disease (RIFLE) criteria. Patients who developed ARD during VAD support (ARD, n=24) were compared with patients who did not (NoARD, n=29). Patients with ARD before implant were excluded. Patient characteristics pre-VAD implant, incidence of complications during support and survival were analyzed. Baseline characteristics were similar. The ARD group had longer cardiopulmonary bypass (CPB) time, greater need for reoperation and higher risk of bleeding (>1 L) intraoperatively (P < .05). The ARD group had a higher incidence of infections (17% vs. 50%, OR 5, 95%CI 1.3-17), liver injury (58% vs. 17%, OR 7, 95%CI 2-24), ventricular arrhythmias (42% vs. 14%, OR 4, 95%CI 1.1-16), and right ventricular failure (73% vs. 30%, OR 7, 95%CI 2-24). Need for dialysis was associated with higher pre-VAD creatinine and worse outcomes. Survival was significantly lower in the ARD group (HR 8.5, 95%CI 2-29)., Conclusions: Acute renal dysfunction is a common and serious complication post-VAD implantation and is associated with reduced survival. Longer CPB time, higher intraoperative blood loss, and reoperation are associated factors with the development of this disease.