Growth Differentiation Factor-15 as a Predictor of Functional Capacity, Frailty, and Ventricular Dysfunction in Patients With Aortic Stenosis and Preserved Left Ventricular Ejection Fraction.

In aortic stenosis (AS), left ventricular (LV) remodeling often occurs before symptom onset, and early intervention may be beneficial. Risk stratification remains challenging and identification of biomarkers may be useful. We evaluated the association between growth differentiation factor-15 (GDF-15) and soluble suppression of tumorigenicity 2 (sST2) and known markers of poor prognosis in AS. Baseline plasma GDF-15 and sST2 levels were measured in 70 patients with moderate-severe AS (aortic valve area <1.5 cm2) and preserved LV ejection fraction (>45%). Patients were categorized into "low GDF-15" versus "high GDF-15" and "low sST2" versus "high sST2" groups. Groups were compared for differences in cardiovascular risk factors, 6-minute walk test, 5 m gait speed, cognitive function (Montreal Cognitive Assessment), and echocardiographic parameters. Overall, 44% of patients were deemed asymptomatic by New York Heart Association class, 61% had severe AS (aortic valve area <1 cm2) and all patients had preserved LV ejection fraction. GDF-15 levels were not predictive of AS severity. However, high GDF-15 (>1,050 pg/ml) was associated with LV dysfunction as shown by lower indexed stroke volume (p <0.01), worse LV global longitudinal strain (p = 0.04), greater mean E/e' (p = 0.02) and indexed left atrial volume (p <0.01). It was also associated with decreased functional capacity with shorter 6-minute walk test (p = 0.01) and slower 5 m gait speed (p = 0.02). Associations between sST2 levels and markers of poor prognosis were less compelling. In this study of patients with moderate to severe AS, elevated GDF-15 levels are associated with impaired functional capacity, poorer performance on fragility testing, and LV dysfunction. In conclusion, GDF-15 may integrate these markers of adverse outcomes into a single biomarker of poor prognosis.

Neutrophils and Circulating Inflammatory Biomarkers in Diabetes Mellitus and Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is characterized by low-grade chronic inflammation, which could be exacerbated by type 2 diabetes mellitus (DM). We hypothesized that neutrophils in patients with DM and patients with HFpEF with/without DM contribute to low-grade inflammation through the release of pro-inflammatory cytokines. Venous blood was withdrawn from patients with DM (n = 22), HFpEF (n = 15), HFpEF with DM (n = 13), and healthy controls (CTL) (n = 21). Levels of circulating cytokines and in vitro cytokines released by isolated neutrophils were assessed by enzyme-linked immunosorbent assay. Compared with CTL, there was a significant decrease in circulating nitric oxide in patients with DM (p ≤0.001), HFpEF (p ≤0.05), and HFpEF with DM (p ≤0.001) up to 44%. Circulating soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels increased (up to 2.5-fold and 1.9-fold, respectively; p ≤0.001) in patients with HFpEF and patients with HFpEF and DM, whereas soluble E-selectin only increased in patients with HFpEF and DM (1.4-fold, p ≤0.001). Circulating vascular endothelial growth factor levels were similar in CTL and patients with DM but were decreased in patients with HFpEF with/without DM (up to 94%; p ≤0.001). Circulating C-reactive protein, interleukin (IL)-8, IL-6, and IL-receptor antagonist increased in all patient groups with a maximum of 3.3-fold, 4.7-fold, 4.8-fold, and 1.6-fold, respectively, in patients with HFpEF and patients with DM. In vitro, lipopolysaccharide increased neutrophils IL-6 release from HFpEF with DM (3.7-fold; p ≤0.001), and IL-8 release from DM and HFpEF with DM versus CTL (2.8-fold and 10.1-fold, respectively; p ≤0.001). IL-1 receptor antagonist and vascular endothelial growth factor release from HFpEF neutrophils significantly decreased up to 87.0% and 92.2%, respectively, versus CTL. Neutrophils from patients with DM and HFpEF release more cytokines than CTL. This increase in pro-inflammatory status may explain the greater event rate in patients with HFpEF and DM.

Right ventricular function and its coupling to pulmonary circulation predicts exercise tolerance in systolic heart failure.

AIMS: Right ventricular (RV) dysfunction, pulmonary hypertension, and exercise intolerance have prognostic values, but their interrelation is not fully understood. We investigated how RV function alone and its coupling with pulmonary circulation (RV-PA) predict cardio-respiratory fitness in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: The Evaluation of Resynchronization Therapy for Heart Failure (EARTH) study included 205 HFrEF patients with narrow (n = 85) and prolonged (n = 120) QRS duration undergoing implantable cardioverter defibrillator implantation. All patients underwent a comprehensive evaluation with exercise tolerance tests and echocardiography. We investigated the correlations at baseline between RV parameters {size, function [tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RV-FAC), and RV myocardial performance index (RV-MPI)], pulmonary artery systolic pressure (PASP), and tricuspid regurgitation}; left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume index (LVEDVi), and left atrial volume index (LAVi); and cardiopulmonary exercise test (CPET) [peak VO2 , minute ventilation/carbon dioxide production (VE/VCO2 ), 6 min walk distance (6MWD), and submaximal exercise duration (SED)]. We also studied the relationship between RV-PA coupling (TAPSE/PASP ratio) and echocardiographic parameters in patients with both data available. Univariate and multivariate linear regression models were used. Patients enrolled in EARTH (overall population) were mostly male (73.2%), mean age 61.0 ± 9.8 years, New York Heart Association class II-III (87.8%), mean LVEF of 26.6 ± 7.7%, and reduced peak VO2 (15.1 ± 4.6 mL/kg/min). Of these, 100 had both TAPSE and PASP available (TAPSE/PASP population): they exhibited higher BNP, wider QRS duration, larger LVEDVi, with more having tricuspid regurgitation compared with the 105 patients for whom these values were not available (all P < 0.05). RV-FAC (ß = 7.5), LAVi (ß = -0.1), and sex (female, ß = -1.9) predicted peak VO2 in the overall population (all P = 0.01). When available, TAPSE/PASP ratio was the only echocardiographic parameter associated with peak VO2 (ß = 6.8; P < 0.01), a threshold ≤0.45 predicting a peak VO2  ≤ 14 mL/kg/min (0.39 for VO2  ≤ 12). RV-MPI was the only echocardiographic parameter associated with ventilatory inefficiency (VE/VCO2 ) and 6MWD (ß = 21.9 and ß = -69.3, respectively, both P ≤ 0.01) in the overall population. In presence of TAPSE/PASP, it became an important predictor for those two CPET (ß = -18.0 and ß = 72.4, respectively, both P < 0.01), together with RV-MPI (ß = 18.5, P < 0.01) for VE/VCO2 . Tricuspid regurgitation predicted SED (ß = -3.2, P = 0.03). CONCLUSIONS: Right ventricular function assessed by echocardiography (RV-MPI and RV-FAC) is closely associated with exercise tolerance in patients with HFrEF. When the TAPSE/PASP ratio is available, this marker of RV-PA coupling becomes the stronger echocardiographic predictor of exercise capacity in this population, highlighting its potential role as a screening tool to identify patients with reduced exercise capacity and potentially triage them to formal peak VO2 and/or evaluation for advanced HF therapies.

Neutrophils pro-inflammatory and anti-inflammatory cytokine release in patients with heart failure and reduced ejection fraction.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is characterized by sub-clinical inflammation. Changes in selected biomarkers of inflammation concomitant with the release of pro-inflammatory and anti-inflammatory cytokines by neutrophils have not been investigated in patients with HFrEF. METHODS AND RESULTS: Fifty-two patients, aged 68.8 ± 1.7 years, with HFrEF and left ventricular ejection fraction 28.7 ± 1.0%, and 21 healthy controls (CTL) were recruited. Twenty-five HF patients had type 2 diabetes. Venous blood samples from HF and CTL were collected once. Neutrophil-derived pro-inflammatory and anti-inflammatory cytokine levels were assessed in plasma by ELISA. Plasma biomarkers assessed included: C-reactive protein (CRP), vascular endothelial growth factor (VEGF), interleukins (IL)-6, -8, -1 receptor antagonist (-1RA), nitric oxide (NO), soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1) and E-Selectin (sE-Sel). Neutrophils were isolated and stimulated with various agonists to promote VEGF, IL-6, IL-8, and IL-1RA release. Compared with CTL, HFrEF patients showed a marked decrease in circulating VEGF [178.0 (interquartile range; IQR 99.6; 239.2) vs. 16.2 (IQR 9.3; 20.2) pg/mL, P ≤ 0.001] and NO [45.2 (IQR 42.1; 57.6) vs. 40.6 (IQR 30.4; 47.1) pg/mL, P = 0.0234]. All other circulating biomarkers were significantly elevated. Neutrophils isolated from patients with HFrEF exhibited a greater IL-8 release in response to LPS [1.2 ± 0.1 (CTL); 10.4 ± 1.6 ng/mL (HFrEF) and 12.4 ± 1.6 ng/mL (HFrEF and DM), P ≤ 0.001]. IL-6 release in response to LPS was not changed in HFrEF patients without diabetes, whereas it was significantly increased in patients with HFrEF and diabetes [46.7 ± 3.9 (CTL) vs. 165.8 ± 48.0 pg/mL (HFrEF), P = 0.1713 and vs. 397.7 ± 67.4 pg/mL (HFrEF and DM), P ≤ 0.001]. In contrast, the release of VEGF and IL-1RA was significantly reduced in HFrEF (VEGF; TNF-α: 38.6 ± 3.1 and LPS: 25.3 ± 2.6 pg/mL; IL1RA; TNF-α: 0.6 ± 0.04 and LPS: 0.3 ± 0.02 ng/mL) compared with CTL (VEGF; TNF-α: 60.0 ± 9.4 and LPS: 41.2 ± 5.9 pg/mL; IL1RA; TNF-α: 3.3 ± 0.2 and LPS: 2.3 ± 0.1 ng/mL). CONCLUSIONS: Patients with HFrEF exhibit a significant decrease in circulating VEGF. The release of VEGF and both pro-inflammatory and anti-inflammatory cytokines from the stimulated neutrophils is markedly altered in these patients. The clinical significance of these findings deserves further investigation.

Palpitations Revealing a Primary Pulmonary Artery Sarcoma.

Primary pulmonary artery sarcoma is an exceedingly rare and aggressive malignancy that carries poor prognosis. Clinical manifestations are nonspecific and include chest pain, dyspnea, syncope, palpitations, and asthenia, among others. Delay to diagnosis is common and compromises the prognosis. Here, we report an interesting case of primary pulmonary artery sarcoma presenting with frequent monomorphic premature ventricular contractions arising from the right/left ventricle outflow tract. Cardiac imaging is key in the evaluation of patients with frequent premature ventricular contractions to rule out rare pathologies such as tumour compression.

Le sarcome primaire de l'artère pulmonaire est une tumeur maligne extrêmement rare et agressive de mauvais pronostic. Les manifestations cliniques sont non spécifiques et peuvent inclure de la douleur thoracique, de la dyspnée, des syncopes, des palpitations et de l'asthénie. Le retard diagnostic est fréquent et compromet le pronostic. Nous rapportons ici un cas intéressant de sarcome primaire de l'artère pulmonaire pour lequel le patient présentait des extrasystoles ventriculaires prématurées monomorphes qui provenaient des chambres de chasse des ventricules gauche et droit. L'imagerie est essentielle à l'évaluation des patients présentant de fréquentes extrasystoles ventriculaires afin d'écarter des pathologies rares comme la compression tumorale d'une chambre cardiaque.

Association of Bronchopulmonary Dysplasia and Right Ventricular Systolic Function in Young Adults Born Preterm.

BACKGROUND: Adults born preterm are at a higher risk of cardiopulmonary disease and premature death. Preterm birth is associated with abnormalities in right ventricular (RV) structure and function, but the impact of bronchopulmonary dysplasia (BPD), a common complication of extremely preterm birth, on these parameters remains unknown. RESEARCH QUESTION: Are preterm birth and BPD associated with alterations in RV structure and function in early adulthood? STUDY DESIGN AND METHODS: Echocardiographic and spirometry data were obtained from the Health of Adults Born Preterm Investigation (HAPI). RV structure and performance were evaluated by using echocardiography, and respiratory function was assessed by using spirometry. RESULTS: The study comprised 86 young adults born preterm before 30 weeks of gestation, including 28 with moderate to severe BPD, and 85 adults of the same age born full term. Individuals were assessed at a mean age of 23 years. RV systolic function was altered in the preterm group, with lower tricuspid annular plane systolic excursion and lower RV s' and RV outflow tract velocity time integral values, especially in those born preterm with BPD. Nine (36%) participants born preterm with BPD, six (13%) participants born preterm without BPD, and six (8%) participants born full term had a tricuspid annular plane systolic excursion value < 16 mm, a marker of RV systolic dysfunction (P value for the comparison between preterm no BPD and BPD, .032). No difference was found in RV diastolic function or estimates of pulmonary artery pressure between groups. Although respiratory function was altered in those born preterm, and more so in the case of BPD, no association was observed between spirometry indices of respiratory function and RV systolic function. INTERPRETATION: Preterm birth is associated in adulthood with alterations in RV systolic function, which are more pronounced in the case of BPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03261609; URL: www.clinicaltrials.gov.

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

AIMS: Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups. METHODS AND RESULTS: We performed a case-control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub-types. We also performed an exploratory genome-wide study. We included 799 patients with HF and 1529 controls. After adjusting for age, sex, and genetic ancestry, we found that the C allele of rs2234962 in BAG3 was associated with a decreased risk of idiopathic dilated cardiomyopathy (odds ratio 0.42, 95% confidence interval 0.25-0.68, P = 0.0005), consistent with a previous report. No association for the other primary variants or exploratory genome-wide study was found. CONCLUSIONS: Our findings provide independent replication for the association between a common coding variant (rs2234962) in BAG3 and the risk of idiopathic dilated cardiomyopathy.

HEARTBiT: A Transcriptomic Signature for Excluding Acute Cellular Rejection in Adult Heart Allograft Patients.

BACKGROUND: Nine mRNA transcripts associated with acute cellular rejection (ACR) in previous microarray studies were ported to the clinically amenable NanoString nCounter platform. Here we report the diagnostic performance of the resulting blood test to exclude ACR in heart allograft recipients: HEARTBiT. METHODS: Blood samples for transcriptomic profiling were collected during routine post-transplantation monitoring in 8 Canadian transplant centres participating in the Biomarkers in Transplantation initiative, a large (n = 1622) prospective observational study conducted between 2009 and 2014. All adult cardiac transplant patients were invited to participate (median age = 56 [17 to 71]). The reference standard for rejection status was histopathology grading of tissue from endomyocardial biopsy (EMB). All locally graded ISHLT ≥ 2R rejection samples were selected for analysis (n = 36). ISHLT 1R (n = 38) and 0R (n = 86) samples were randomly selected to create a cohort approximately matched for site, age, sex, and days post-transplantation, with a focus on early time points (median days post-transplant = 42 [7 to 506]). RESULTS: ISHLT ≥ 2R rejection was confirmed by EMB in 18 and excluded in 92 samples in the test set. HEARTBiT achieved 47% specificity (95% confidence interval [CI], 36%-57%) given ≥ 90% sensitivity, with a corresponding area under the receiver operating characteristic curve of 0.69 (95% CI, 0.56-0.81). CONCLUSIONS: HEARTBiT's diagnostic performance compares favourably to the only currently approved minimally invasive diagnostic test to rule out ACR, AlloMap (CareDx, Brisbane, CA) and may be used to inform care decisions in the first 2 months post-transplantation, when AlloMap is not approved, and most ACR episodes occur.

Beta-Blocker Type Effect on Substrate Oxidation during HIIE in Heart Failure Patients: Pilot Data / Efeito do Tipo Betabloqueador na Oxidação de Substratos durante HIIE em Pacientes com Insuficiência Cardíaca: Dados Piloto

Abstract The effect of third and second-generation type of beta-blocker on substrate oxidation especially during high-intensity exercises are scarce. The objective of the study is to explore differences of beta-blocker regimens (vasodilating vs. non-vasodilating beta-blockers) for substrate oxidation during in high-intensity intermittent exercise (HIIE) in chronic heart failure and reduced ejection fraction (HFrEF). Eighteen CHF males (58.8 ± 9 years), 8 under use of β1 specific beta-blockers+alfa 1-blocker and 10 using β1 non-specific beta-blockers, were randomly assigned to 4 different HIIE, in a cross-over design. The 4 protocols were: 30 seconds (A and B) or 90 seconds (C and D) at 100% peak power output, with passive (A and C) or active recovery (50% of PPO; B and D). Energy expenditure (EE; kcal/min), quantitative carbohydrate (CHO) and lipid oxidation (g/min) and qualitative (%) contribution were calculated. Two-way ANOVA and Bonferroni post-hoc test were used (p-value ≤ 0.05) to compare CHO and lipid oxidation at rest and at 10min. Total exercise time or EE did not show differences for beta-blocker use. The type of beta-blocker use showed impact in CHO (%) and lipid (g/min and %) for rest and 10 min, but absolute contribution of CHO (g/min) was different just at 10min (Interaction p = 0.029). Higher CHO oxidation was found in vasodilating beta-blockers when comparing to non-vasodilating. According to our pilot data, there is an effect of beta-blocker type on substrate oxidation during HIIE, but no influence on EE or exercise total time in HFrEF patients.

Resumo Os dados sobre efeito do tipo de betabloqueador de terceira e segunda geração na oxidação do substrato, especialmente durante exercícios de alta intensidade, são escassos. O objetivo do estudo é explorar as diferenças de tratamentos com betabloqueadores (betabloqueadores vasodilatadores vs. não-vasodilatadores) na oxidação de substratos durante exercícios intermitentes de alta intensidade (HIIE) na insuficiência cardíaca crônica e fração de ejeção do ventrículo esquerdo reduzida (ICFEr). Dezoito pacientes do sexo masculino com ICC (58,8 ± 9 anos), 8 em uso de betabloqueadores β1 específicos + bloqueador α-1 e 10 utilizando betabloqueadores β1 não-específicos, foram aleatoriamente designados para 4 diferentes HIIE, em um desenho cruzado. Os 4 protocolos foram: 30 segundos (A e B) ou 90 segundos (C e D) a 100% da potência de pico de saída (PPO), com recuperação passiva (A e C) ou ativa (50% de PPO; B e D). O gasto energético (GE; kcal/min), a ingestão de carboidratos quantitativos (CHO) e oxidação lipídica (g/min) e qualitativa (%) foram calculados. Anova de dois fatores e teste post-hoc de Bonferroni foram usados (p-valor ≤ 0,05) para comparar a oxidação de CHO e lipídios em repouso e aos 10 minutos. O tempo total de exercício ou GE não mostraram diferenças de acordo com o uso de betabloqueadores. O tipo de betabloqueador mostrou impacto em CHO (%) e lípides (g/min e %) para repouso e aos 10 min, mas a contribuição absoluta de CHO (g/min) foi diferente apenas aos 10 minutos (Interação p = 0,029). Foram encontradas maiores oxidações de CHO com betabloqueadores vasodilatadores quando comparados com os não-vasodilatadores. De acordo com nossos dados piloto, há um efeito do tipo do betabloqueador na oxidação do substrato durante o HIIE, mas nenhuma influência no GE ou no tempo total de exercício nos pacientes com ICFEr.

Alterations in Portal Vein Flow and Intrarenal Venous Flow Are Associated With Acute Kidney Injury After Cardiac Surgery: A Prospective Observational Cohort Study.

Background Acute kidney injury ( AKI ) after cardiac surgery is associated with adverse outcomes. Venous congestion can impair kidney function, but few tools are available to assess its impact at the bedside. The objective of this study was to determine whether portal flow pulsatility and alterations in intrarenal venous flow assessed by Point-Of-Care ultrasound are associated with AKI after cardiac surgery. Methods and Results This single-center prospective cohort study recruited patients undergoing cardiac surgery with cardiopulmonary bypass. Hepatic and renal Doppler ultrasound assessments were performed before surgery, at the intensive care unit admission, and daily for 3 days after surgery. The primary statistical analysis was performed using proportional hazards model for time-dependent variables. Among the 145 patients included, 49 patients (33.8%) developed AKI after cardiac surgery. The detection of portal flow pulsatility was associated with an increased risk of AKI (hazard ratio: 2.09, confidence interval, 1.11-3.94, P=0.02), as were severe alterations of intrarenal venous flow (hazard ratio: 2.81, confidence interval, 1.42-5.56, P=0.003). These associations remained significant in multivariable models. The addition of these markers to preoperative risk factors and central venous pressure measurement at intensive care unit admission improved the prediction of AKI . (Continuous net reclassification improvement: 0.364, confidence interval, 0.081-0.652 for portal Doppler and net reclassification improvement: 0.343, confidence interval, 0.081-0.628 for intrarenal Doppler) Conclusions Portal flow pulsatility and intrarenal flow alterations are markers of venous congestion and are independently associated with AKI after cardiac surgery. These tools might offer valuable information to develop strategies aimed at treating or preventing congestive cardiorenal syndrome after cardiac surgery. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02831907.

Cardiopulmonary, biomarkers, and vascular responses to acute hypoxia following cardiac transplantation.

Previous studies have suggested good adaptation of cardiac transplant (CTx) recipients to exposure to a high altitude. No studies have investigated the cardiopulmonary and biomarker responses to acute hypoxic challenges following CTx. Thirty-six CTx recipients and 17 age-matched healthy controls (HC) were recruited. Sixteen (16) patients (42%) had cardiac allograft vasculopathy (CAV). Cardiopulmonary responses to maximal and submaximal exercise at 21% O2 , 20-minutes hypoxia (11.5% O2 ), and following a 10-minute exposure to 11.5% O2 using 30% of peak power output were completed. Vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), suppression of tumorigenicity 2 (ST2) were measured at baseline and at peak stress. Endothelial peripheral function was assessed using near-infrared spectroscopy. Compared with HC, CTx presented a lesser O2 desaturation both at rest (-19.4 ± 6.8 [CTx] vs -24.2 ± 6.0% O2 [HC], P < 0.05) and following exercise (-23.2 ± 4.9 [CTx] vs -26.2 ± 4.7% O2 [HC], P < 0.05). CTx patients exhibited a significant decrease in peak oxygen uptake. IL-6 and VEGF levels were significantly higher in CTx recipients in basal conditions but did not change in response to acute stress. CTx patients exhibit a favorable ventilatory and overall response to hypoxic stress. These data provide further insights on the good adaptability of CTx to exposure to high altitude.

Experience with the SynCardia total artificial heart in a Canadian centre.

BACKGROUND: The SynCardia total artificial heart (TAH) provides complete circulatory support by replacing both native ventricles. Accepted indications include bridge to transplantation and destination therapy. We review our experience with TAH implantation during a period when axial flow pump became available. METHODS: We retrospectively analyzed the demographics, clinical characteristics and survival of all patients receiving the TAH. RESULTS: From September 2004 to November 2016, 13 patients (12 men, mean age 45 ± 13 yr) received the TAH for refractory cardiogenic shock secondary to idiopathic (56%) or ischemic (17%) cardiomyopathy and to other various causes (33%). Before implantation, mean ejection fraction was 14% ± 4%, 7 (54%) patients had previous cardiac surgery, 4 (31%) were on mechanical ventilation, and 3 (23%) patients were on dialysis. The mean duration of TAH support was 46 ± 40 days. Three (23%) patients died while on support after a mean of 15 days. Actuarial survival on support was 77% ± 12% at 30 days after implantation. Complications on support included stroke (n = 1, 8%), acute respiratory distress syndrome requiring prolonged intubation (n = 5, 38%) and acute renal failure requiring temporary dialysis (n = 5, 38%). Ten (77%) patients survived to be transplanted after a mean of 52 ± 42 days of support. Actuarial survival rates after transplant were 67% ± 16% at 1 month and 56% ± 17% at 1 year after transplantation. CONCLUSION: The TAH provides an alternative with low incidence of neurologic events in extremely fragile and complex patients waiting for heart transplantation. Complex and unusual anatomic conditions explained the current use of TAH.

CONTEXTE: Le cœur artificiel total (CAT) SynCardia offre un soutien circulatoire complet en remplaçant les 2 ventricules naturels. Parmi ses indications acceptées, mentionnons la transition pré-greffe et l'assistance permanente. Nous passons ici en revue notre expérience en matière d'implantation de CAT à partir de l'avènement des pompes à flux axial. MÉTHODES: Nous avons analysé de manière rétrospective les caractéristiques démographiques et cliniques et la survie de tous les patients ayant reçu un CAT. RÉSULTATS: De septembre 2004 à novembre 2016, 13 patients (12 hommes, âge moyen 45 ± 13 ans) ont reçu le CAT pour un choc cardiogénique réfractaire dû à la cardiomyopathie idiopathique (50 %) ou ischémique (17 %) ou à d'autres causes (33 %). Avant l'implantation, la fraction d'éjection était en moyenne de 14 % ± 4 %, 7 patients (54 %) avaient déjà subi une chirurgie cardiaque, 4 (31 %) étaient sous ventilation mécanique et 3 (23 %) étaient dialysés. La durée moyenne du soutien par CAT a été de 46 ± 40 jours. Trois patients (23 %) sont décédés malgré l'implantation du dispositif après une moyenne d'utilisation de 15 jours. La survie actuarielle pendant l'utilisation du dispositif a été de 77 % ± 12 % 30 jours suivant l'implantation. Les complications ont inclus : accident vasculaire cérébral (n = 1, 8 %), syndrome de détresse respiratoire aigüe nécessitant une intubation prolongée (n = 5, 38 %) et insuffisance rénale aigüe nécessitant une dialyse temporaire (n = 5, 38 %). Dix patients (77 %) ont survécu jusqu'à leur greffe après une moyenne d'utilisation de 52 ± 42 jours. Les taux de survie actuarielle après la greffe ont été de 67 % ± 16 % après 1 mois et de 56 % ± 17 % après 1 an suivant la greffe. CONCLUSION: Le CAT est une solution de rechange qui s'accompagne d'une incidence faible de complications neurologiques chez des patients à l'état extrêmement fragile et complexe en attente d'une greffe cardiaque. Des complications anatomiques inhabituelles ont expliqué l'utilisation du CAT.

Changes in patient characteristics following cardiac transplantation: the Montreal Heart Institute experience.

BACKGROUND: Heart transplantation is no longer considered an experimental operation, but rather a standard treatment; nevertheless the context has changed substantially in recent years owing to donor shortage. The aim of this study was to review the heart transplant experience focusing on very long-term survival (≥ 20 years) and to compare the initial results with the current era. METHODS: From April 1983 through April 1995, 156 consecutive patients underwent heart transplantation. Patients who survived 20 years or longer (group 1) were compared with patients who died within 20 years after surgery (group 2). To compare patient characteristics with the current era, we evaluated our recent 5-year experience (group 3; patients who underwent transplantation between 2010 and 2015), focusing on differences in terms of donor and recipient characteristics. RESULTS: Group 1 (n = 46, 30%) included younger patients (38 ± 11 v. 48 ± 8 yr, p = 0.001), a higher proportion of female recipients (28% v. 8%, p = 0.001) and a lower prevalence of ischemic heart disease (42% v. 65%, p = 0.001) than group 2 (n = 110, 70%). Patients in group 3 (n = 54) were older (52 ± 12 v. 38 ± 11 yr, p = 0.001), sicker (rate of hospital admission at transplantation 48% v. 20%, p = 0.001) and transplanted with organs from older donors (42 ± 15 v. 29 ± 11 yr, p = 0.001) than those in group 1. CONCLUSION: Very long-term survival ( ≥ 20 yr) was observed in 30% of patients transplanted during the first decade of our experience. This outcome will be difficult to duplicate in the current era considering our present population of older and sicker patients transplanted with organs from older donors.

CONTEXTE: De nos jours, la transplantation cardiaque n'est plus considérée comme une intervention expérimentale, mais bien comme une opération standard; mais le contexte a substantiellement changé ces dernières années en raison d'une pénurie de donneurs. Cette étude avait pour but de faire le point sur la situation de la greffe cardiaque, et plus particulièrement sur la survie à très long terme (≥ 20 ans), et de la comparer aux résultats initiaux. MÉTHODES: Entre avril 1983 et avril 1995, 156 patients consécutifs ont subi une greffe cardiaque. Les patients qui ont survécu 20 ans ou plus (groupe 1) ont été comparés aux patients décédés moins de 20 ans après l'intervention (groupe 2). Pour comparer les caractéristiques des premiers patients à celles des cas plus récents, nous avons fait un bilan des 5 années allant de 2010 à 2015 (groupe 3), en portant attention aux différences quant aux caractéristiques des donneurs et des receveurs. RÉSULTATS: Le groupe 1 (n = 46, 30 %) incluait des patients plus jeunes (38 ± 11 ans c. 48 ± 8 ans, p = 0,001), une proportion plus élevée de femmes (28 % c. 8 %, p = 0,001) et la prévalence de maladie cardiaque ischémique y était moindre (42 % c. 65 %, p = 0,001) comparativement au groupe 2 (n = 110, 70 %). Les patients du groupe 3 (n = 54) étaient plus âgés (52 ± 12 ans c. 38 ± 11 ans, p = 0,001), plus malades (taux d'hospitalisation au moment de la transplantation 48 % c. 20 %, p = 0,001) et ont reçu le cœur de donneurs plus âgés (42 ± 15 ans c. 29 ± 11 ans, p = 0,001) que ceux du groupe 1. CONCLUSION: Une survie à très long terme (≥ 20 ans) a été observée chez 30 % des patients ayant reçu leur greffe au cours de la première décennie de notre expérience. Ce résultat sera difficile à reproduire de nos jours étant donné que notre population actuelle est constituée de receveurs plus âgés et plus malades, qui reçoivent le cœur de donneurs plus âgés.

Risk of Heart Failure and Death After Prolonged Smoking Cessation: Role of Amount and Duration of Prior Smoking.

BACKGROUND: According to the 2004 Surgeon General's Report on Health Consequences of Smoking, after >15 years of abstinence, the cardiovascular risk of former smokers becomes similar to that of never-smokers. Whether this health benefit of smoking cessation varies by amount and duration of prior smoking remains unclear. METHODS AND RESULTS: Of the 4482 adults ≥65 years without prevalent heart failure (HF) in the Cardiovascular Health Study, 2556 were never-smokers, 629 current smokers, and 1297 former smokers with >15 years of cessation, of whom 312 were heavy smokers (highest quartile; ≥32 pack-years). Age-sex-race-adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for centrally adjudicated incident HF and mortality during 13 years of follow-up were estimated using Cox regression models. Compared with never-smokers, former smokers as a group had similar risk for incident HF (aHR, 0.99; 95% CI, 0.85-1.16) and all-cause mortality (aHR, 1.08; 95% CI, 0.96-1.20), but former heavy smokers had higher risk for both HF (aHR, 1.45; 95% CI, 1.15-1.83) and mortality (aHR, 1.38; 95% CI, 1.17-1.64). However, when compared with current smokers, former heavy smokers had lower risk of death (aHR, 0.64; 95% CI, 0.53-0.77), but not of HF (aHR, 0.97; 95% CI, 0.74-1.28). CONCLUSIONS: After >15 years of smoking cessation, the risk of HF and death for most former smokers becomes similar to that of never-smokers. Although this benefit of smoking cessation is not extended to those with ≥32 pack-years of prior smoking, they have lower risk of death relative to current smokers.

Decreased circulating and neutrophil mediated VEGF-A165 release in stable long-term cardiac transplant recipients.

BACKGROUND: Vascular endothelial growth factor (VEGF) may play a role on the allograft remodelling following cardiac transplantation (CTx). We measured the circulating levels of VEGF-A165 concomitantly with the proinflammatory (Interleukin-8; IL-8), anti-inflammatory (IL-1 receptor antagonist; IL-1RA) and their release from neutrophils of CTx recipients. METHODS: Eighteen CTx recipients aged 49.6 ± 3.1 years, being transplanted for 145 ± 20 months were age-matched to 35 healthy control (HC) subjects. Concomitantly to plasma assessment, circulating neutrophils were isolated, purified and stimulated by vehicle (PBS), N-formyl-Met-Leu-Phe (fMLP, 10(-7) M), bacterial lipopolysaccharide (LPS, 1 µg/mL), or tumour necrosis factor alpha (TNF-α, 10 ng/mL). RESULTS: Compared with HC, CTx recipients exhibited a decrease (-80%) in plasmatic levels of VEGF-A165 (225 ± 42 (HC) vs 44 ± 10 pg/mL (CTx); (p < 0.001). There were no differences in the levels of IL-8 and IL-1RA. Under basal or stimulated conditions, neutrophils from CTx patients exhibited a marked decrease ranging from -30 to -88% on their capacity to release VEGF-A165, IL-8 and IL-1RA upon stimulation. CONCLUSIONS: Long-term CTx recipients exhibit a marked reduction in the circulating levels of VEGF-A165, as well as neutrophil-mediated release of VEGF-A165, IL-1RA and IL-8 compared to healthy volunteers. The mechanisms and physiological impacts of these findings deserve additional investigations.

Effect of everolimus on the immunomodulation of the human neutrophil inflammatory response and activation.

The primary cause of mortality at 5 years following a cardiac transplantation is the development of atherosclerosis, termed coronary allograft vasculopathy (CAV). This pathology is characterized by diffused intimal hyperplasia and emanates from coronary arterial injuries caused by immune inflammatory cells. Neutrophils play an important role in this inflammatory process; however, their potential participation in the pathogenesis of CAV is poorly understood. Despite their essential contribution to the prevention of graft rejection, immunosuppressive drugs could have detrimental effects owing to their pro-inflammatory activities. Thus, we investigated the impact of different immunosuppressive drugs on the inflammatory response of neutrophils isolated from the blood of healthy volunteers. Under basal conditions, mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) had the most potent anti-inflammatory effect, decreasing both IL-8 release (≈-80%) and vascular endothelial growth factor (VEGF) release (≈-65%) and preserving the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA). In TNF-α-treated neutrophils, pre-incubation with everolimus provided the most potent effect, simultaneously reducing the release of both VEGF and IL-8 while doubling the release of IL-1RA. This latter effect of everolimus was maintained even when administered in combination with other immunosuppressive drugs. Sirolimus and everolimus decreased the tumor necrosis factor (TNF)-α-induced adhesion of neutrophils to human endothelial cells and human extracellular matrix. This effect was largely dependent on the ability of these compounds to alter ß2-integrin/CD18 activation. Our results suggest a potential mechanism for the beneficial effect of everolimus in the prevention of CAV in heart transplant recipients.

The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications.

The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Update provides discussion on the management recommendations on 3 focused areas: (1) anemia; (2) biomarkers, especially natriuretic peptides; and (3) clinical trials that might change practice in the management of patients with heart failure. First, all patients with heart failure and anemia should be investigated for reversible causes of anemia. Second, patients with chronic stable heart failure should undergo natriuretic peptide testing. Third, considerations should be given to treat selected patients with heart failure and preserved systolic function with a mineralocorticoid receptor antagonist and to treat patients with heart failure and reduced ejection fraction with an angiotensin receptor/neprilysin inhibitor, when the drug is approved. As with updates in previous years, the topics were chosen in response to stakeholder feedback. The 2014 Update includes recommendations, values and preferences, and practical tips to assist the clinicians and health care workers to best manage patients with heart failure.

Myocyte growth, repair, and oxidative stress following pediatric heart transplantation.

Cardiac remodeling is associated with plasma biomarkers of fibrinogenesis, inflammation, and oxidative stress, and upregulation of mitogenic, pro-fibrotic, and apoptotic signaling pathways. Our primary objective was to evaluate biomarker and subcellular myocardial changes in pediatric heart transplant recipients. Fifty-two-week prospective, randomized (tacrolimus, Tac, vs. cyclosporine, CsA), open-label, parallel group study. Serial myocardial biopsies were probed for mitogenic and pro-inflammatory proteins. Plasma biomarkers of oxidative stress (F2α isoprostanes, nitrotyrosine), and inflammation and oxidation (hsCRP and cystatin-C) were measured. Nine of 11 randomized patients completed the study (four Tac, five CsA). Mean levels of F2α isoprostanes, hsCRP, and cystatin-C were maximal at Week 2. Peak activation of all MAP kinases in myocardial tissue was maximal at Week 10; no association was seen with rejection. Cardiac Bax/Bcl-2 levels (index of apoptosis) correlated negatively with F2α isoprostanes at Week 2 (r = -0.88) and with hsCRP at Week 52 (r = -0.67). At Week 52, hsCRP levels correlated positively with molecular indices of cardiac cell growth. We found evidence of systemic and myocardial oxidative damage and inflammation early posttransplant, which may be related to the remodeling process. Further study is needed to better understand the cardiac and systemic repair processes following pediatric heart transplantation.

Long-term evolution, secular trends, and risk factors of renal dysfunction following cardiac transplantation.

Recent reports suggest that individuals who underwent heart transplantation in the last decade have improved post-transplant kidney function. The objectives of this retrospective study were to describe the incidence and to identify fixed and time-dependent predictors of renal dysfunction in cardiac recipients transplanted over a 25-year period (1983-2008). To illustrate temporal trends, patients (n = 306) were divided into five groups based on year of transplantation. The primary endpoint was the estimated glomerular filtration rate (eGFR) at year 1. Secondary endpoints were time to moderate (eGFR <60 ml/min/1.73 m(2) ) and severe renal dysfunction (eGFR <30 ml/min/1.73 m(2) ). Risk factor analyses relied on multivariable regression models. Kidney function was mildly impaired before transplant (median eGFR=61.0 ml/min/1.73 m(2) ), improved at discharge (eGFR=72.3 ml/min/1.73 m(2) ; P < 0.001), decreased considerably in the first year (eGFR = 54.7 ml/min/1.73 m(2) ; P < 0.001), and deteriorated less rapidly thereafter. At year 1, 2004-2008 recipients exhibited a higher eGFR compared with all other patients (P < 0.001). Factors independently associated with eGFR at year 1 and with moderate and severe renal dysfunction included age, gender, pretransplant eGFR, blood pressure, glycemia, and use of prednisone (P < 0.05). In summary, kidney function worsens constantly up to two decades after cardiac transplantation, with the greatest decline occurring in the first year. Corticosteroid minimization and treatment of modifiable risk factors (hypertension, diabetes) may minimize renal deterioration.