Effects of everolimus and HLA-G on cellular proliferation and neutrophil adhesion in an in vitro model of cardiac allograft vasculopathy.

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.

Cost-effectiveness of ventricular assist device therapy as a bridge to transplantation compared with nonbridged cardiac recipients.

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.

Autologous stem cell transplant is an effective therapy for carefully selected patients with AL amyloidosis: experience of a single institution.

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.

A randomized feasibility trial of clonidine to reduce perioperative cardiac risk in patients on chronic beta-blockade: the EPIC study.

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.

Clinical differences between continuous flow ventricular assist devices: a comparison between HeartMate II and HeartWare HVAD.

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.

Epidermal growth factor-like domain 7 is a novel inhibitor of neutrophil adhesion to coronary artery endothelial cells injured by calcineurin inhibition.

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.

Epidermal growth factor-like domain 7 suppresses intercellular adhesion molecule 1 expression in response to hypoxia/reoxygenation injury in human coronary artery endothelial cells.

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.

Mechanical circulatory support as a bridge to transplant candidacy.

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.

Integrating supplementation in the management of patients with heart failure: an evidence-based review.

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.

The positive and negative cardiovascular effects of cannabis.

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.

Hiding in Plain Sight: Cardiac Amyloidosis, an Emerging Epidemic.

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.

Human leukocyte antigen-G donor-recipient matching of the 14-base pair polymorphism protects against cancer after heart transplant.

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.

HLA-G +3196 polymorphism as a risk factor for cell mediated rejection following heart transplant.

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.

Diagnostic Performance of Abnormal Nulling on Cardiac Magnetic Resonance Imaging Look Locker Inversion Time Sequence in Differentiating Cardiac Amyloidosis Types.

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.

Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on the Evaluation and Management of Patients With Cardiac Amyloidosis.

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.

CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation, SGLT2 Inhibitors, ARNI in HFpEF, and Tafamidis in Amyloidosis.

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.

Progesterone induces human leukocyte antigen-g expression in vascular endothelial and smooth muscle cells.

BACKGROUND: Human leukocyte antigen-G (HLA-G) expression in heart transplant patients has been negatively associated with acute cellular rejection and cardiac allograft vasculopathy. We assessed HLA-G expression in vascular human endothelial and smooth muscle cell cultures to determine if future therapeutic agents can be targeted toward inducing HLA-G expression to protect against allograft rejection and vasculopathy. METHODS AND RESULTS: Human coronary artery endothelial, aortic endothelial, and coronary artery smooth muscle cell cultures were exposed to cytokines (interferon-gamma or interleukin-10), hypoxia/reoxygenation stress, immunosuppressive agents (cyclosporine, sirolimus, or tacrolimus), or progesterone. HLA-G was not expressed by untreated, normoxic cells. Furthermore, maximal doses of interferon-gamma, interleukin-10, cyclosporine, sirolimus, or tacrolimus, as well as exposure to hypoxia/reoxygenation, failed to induce HLA-G expression. HLA-G, which has previously not been detected in adult vascular endothelial and smooth muscle cells, was detected by enzyme-linked immunosorbent assay and flow cytometry in human coronary artery endothelial, human coronary aortic endothelial, and human coronary artery smooth muscle cultures after incubation with progesterone in a dose-dependent manner (P<0.001) with no change in cellular proliferation ability or viability. This effect was partially blocked in the presence of mifepristone, a progesterone receptor antagonist (human coronary artery endothelial: 48.8+/-15.6%; human coronary aortic endothelial: 59.5+/-9.5%; human coronary artery smooth muscle: 59.8+/-9.8% of control; P<0.05). Progesterone-induced HLA-G expression was not protective against hypoxia/reoxygenation injury. CONCLUSIONS: HLA-G is not expressed at baseline in vascular endothelial and smooth muscle cells but can be induced by exposure to progesterone. Although tightly regulated, induction of HLA-G expression in these cells may represent a promising and novel therapeutic strategy to protect against rejection and cardiac allograft vasculopathy after heart transplantation.

Predictors of acute renal dysfunction after ventricular assist device placement.

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.

The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients.

BACKGROUND: Trough- or 2-h post-dose (C2) blood cyclosporine (CsA) concentrations are used for prediction of efficacy and toxicity of CsA in transplant recipients concomitantly treated with antiproliferative agents, but information on utility of blood CsA levels in patients treated with proliferation signal inhibitors (PSIs), such as everolimus, is sparse. Because of the inhibitory effect of PSIs on the P-glycoprotein drug efflux pump present in lymphocytes, we hypothesized that CsA pharmacokinetics in blood and lymphocytes were dissociated in patients concomitantly treated with everolimus. METHODS: Twelve-hour pharmacokinetic studies of whole-blood and intralymphocytic CsA concentrations were conducted in long-term heart-transplant recipients treated with mycophenolate mofetil (MMF) + CsA (n = 8) and everolimus + CsA (n = 9). RESULTS: There was a highly significant correlation between blood CsA C2 levels and blood CsA AUC(0-12) in groups of patients treated with MMF or everolimus (R(2) 0.93 and 0.96, respectively; P < 0.001 for both). Whereas blood CsA C2 levels were closely associated with lymphocyte CsA AUC(0-12) in patients treated with MMF (R(2) = 0.98), there was poor correlation between whole-blood C2 and lymphocyte AUC(0-12) in patients treated with everolimus (R(2) = 0.24). CONCLUSION: Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus.

10-Year Experience with HLA-G in Heart Transplantation.

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.