Inflammation in heart failure: pathophysiology and therapeutic strategies.

A role for inflammation in the development and progression of heart failure (HF) has been proposed for decades. Multiple studies have demonstrated the potential involvement of several groups of cytokines and chemokines in acute and chronic HF, though targeting these pathways in early therapeutic trials have produced mixed results. These studies served to highlight the complexity and nuances of how pro-inflammatory pathways contribute to the pathogenesis of HF. More recent investigations have highlighted how inflammation may play distinct roles based on HF syndrome phenotypes, findings that may guide the development of novel therapies. In this review, we propose a contemporary update on the role of inflammation mediated by the innate and adaptive immune systems with HF, highlighting differences that exist across the ejection fraction spectrum. This will specifically be looked at through the lens of established and novel biomarkers of inflammation. Subsequently, we review how improvements in inflammatory pathways may mediate clinical benefits of existing guideline-directed medical therapies for HF, as well as future therapies in the pipeline targeting HF and inflammation.

Low-Density Neutrophils Contribute to Subclinical Inflammation in Patients with Type 2 Diabetes.

Type 2 diabetes (T2D) is characterized by low-grade inflammation. Low-density neutrophils (LDNs) represent normally less than 2% of total neutrophils but increase in multiple pathologies, releasing inflammatory cytokines and neutrophil extracellular traps (NETs). We assessed the count and role of high-density neutrophils (HDNs), LDNs, and NET-related activities in patients with T2D. HDNs and LDNs were purified by fluorescence-activated cell sorting (FACS) and counted by flow cytometry. Circulating inflammatory and NETs biomarkers were measured by ELISA (Enzyme Linked Immunosorbent Assay). NET formation was quantified by confocal microscopy. Neutrophil adhesion onto a human extracellular matrix (hECM) was assessed by optical microscopy. We recruited 22 healthy volunteers (HVs) and 18 patients with T2D. LDN counts in patients with diabetes were significantly higher (160%), along with circulating NETs biomarkers (citrullinated H3 histone (H3Cit), myeloperoxidase (MPO), and MPO-DNA (137%, 175%, and 69%, respectively) versus HV. Circulating interleukins (IL-6 and IL-8) and C-Reactive Protein (CRP) were significantly increased by 117%, 171%, and 79%, respectively, in patients compared to HVs. Isolated LDNs from patients expressed more H3Cit, MPO, and NETs, formed more NETs, and adhered more on hECM compared to LDNs from HVs. Patients with T2D present higher levels of circulating LDN- and NET-related biomarkers and associated pro-inflammatory activities.

COVID-19 Bereavement in Ten Latin American Countries: Measurement Invariance of the Pandemic Grief Scale and Its Relation to Suicidal Ideation.

The present study aimed to evaluate the cross-cultural measurement invariance of the Pandemic Grief Scale (PGS) in ten Latin American countries. A total of 2,321 people who had lost a family member or other loved one due to COVID-19 participated, with a mean age of 34.22 years old (SD = 11.99). In addition to the PGS, a single item of suicidal ideation was applied. The unidimensional model of the PGS had adequate fit in most countries and good reliability estimates. There was evidence of measurement invariance by country and gender. Also, a one-point increase in the PGS was associated with an almost twofold increase in the odds of suicidal ideation. Scores greater than or equal to 4 on the PGS are proposed as a cut off to identify individuals with suicidal ideation. Strong evidence of the cross-cultural validity of the PGS is provided.

Cross-cultural validation of the new version of the Coronavirus Anxiety Scale in twelve Latin American countries.

The Coronavirus Anxiety Scale (CAS) was recently developed to assess dysfunctional anxiety related to COVID-19. Although different studies reported that the CAS is psychometrically sound, it is unclear whether it is invariant across countries. Therefore, the present study aimed to examine the measurement invariance of the CAS in twelve Latin American countries (Argentina, Bolivia, Chile, Colombia, Cuba, Ecuador, El Salvador, Guatemala, Mexico, Paraguay, Peru, and Uruguay). A total of 5196 people participated, with a mean age of 34.06 (SD = 26.54). Multigroup confirmatory factor analysis (CFA) was used to examine the measurement invariance of the CAS across countries and gender. Additionally, the graded response model (GRM) was used to provide a global representation of the representativeness of the scale with respect to the COVID-19 dysfunctional anxiety construct. The unidimensional structure of the five-item CAS was not confirmed in all countries. Therefore, it was suggested that a four-item model of the CAS (CAS-4) provides a better fit across the twelve countries and reliable scores. Multigroup CFA showed that the CAS-4 exhibits scalar invariance across all twelve countries and all genders. In addition, the CAS-4 items are more informative at average and high levels of COVID-19 dysfunctional anxiety than at lower levels. According to the results, the CAS-4 is an instrument with strong cross-cultural validity and is suitable for cross-cultural comparisons of COVID-19 dysfunctional anxiety symptoms in the general population of the twelve Latin American countries evaluated. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12144-021-02563-0.

Angiopoietin 1 release from human neutrophils is independent from neutrophil extracellular traps (NETs).

BACKGROUND: Neutrophils induce the synthesis and release of angiopoietin 1 (Ang1), a cytosolic growth factor involved in angiogenesis and capable of inducing several pro-inflammatory activities in neutrophils. Neutrophils also synthesize and release neutrophil extracellular traps (NETs), comprised from decondensed nuclear DNA filaments carrying proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), proteinase 3 (PR3) and calprotectin (S100A8/S100A9), which together, contribute to the innate immune response against pathogens (e.g., bacteria). NETs are involved in various pathological conditions through pro-inflammatory, pro-thrombotic and endothelial dysfunction effects and have recently been found in heart failure (HF) and type 2 diabetes (T2DM) patients. The aim of the present study was to investigate the role of NETs on the synthesis and release of Ang1 by the neutrophils in patients with T2DM and HF with preserved ejection fraction (HFpEF) (stable or acute decompensated; ADHFpEF) with or without T2DM. RESULTS: Our data show that at basal level (PBS) and upon treatment with LPS, levels of NETs are slightly increased in patients suffering from T2DM, HFpEF ± T2DM and ADHF without (w/o) T2DM, whereas this increase was significant in ADHFpEF + T2DM patients compared to healthy control (HC) volunteers and ADHFpEF w/o T2DM. We also observed that treatments with PMA or A23187 increase the synthesis of Ang1 (from 150 to 250%) in HC and this effect is amplified in T2DM and in all cohorts of HF patients. Ang1 is completely released (100%) by neutrophils of all groups and does not bind to NETs as opposed to calprotectin. CONCLUSIONS: Our study suggests that severely ill patients with HFpEF and diabetes synthesize and release a greater abundance of NETs while Ang1 exocytosis is independent of NETs synthesis.

Care processes and structures associated with higher medication adherence in adolescent and young adult transplant recipients.

BACKGROUND: We aimed to identify care processes and structures that were independently associated with higher medication adherence among young transplant recipients. METHODS: We conducted a prospective, observational cohort study of 270 prevalent kidney, liver, and heart transplant recipients 14-25 years old. Patients were ≥3 months post-transplant, ≥2 months post-discharge, and followed in one of 14 pediatric or 14 adult transplant programs in Canada. Patients were enrolled between June 2015 and March 2018 and followed for 6 months. Adherence was assessed at baseline, 3, and 6 months using the BAASIS© self-report tool. Patients were classified as adherent if no doses were missed in the prior 4 weeks. Transplant program directors and nurses completed questionnaires regarding care organization and processes. RESULTS: Of the 270 participants, 99 were followed in pediatric programs and 171 in adult programs. Median age was 20.3 years, and median time since transplant was 5 years. At baseline, 71.5% were adherent. Multivariable mixed effects logistic regression models with program as a random effect identified two program-level factors as independently associated with better adherence: minimum number of prescribed blood draws per year for those >3 years post-transplant (per 1 additional) (OR 1.12 [95% CI 1.00, 1.26]; p = .047), and average time nurses spend with patients in clinic (per 5 additional minutes) (OR 1.15 [1.03, 1.29]; p = .017). CONCLUSION: Program-level factors including protocols with a greater frequency of routine blood testing and more nurse time with patients were associated with better medication adherence. This suggests that interventions at the program level may support better adherence.

Synthesis of Human Neutrophil Extracellular Traps Contributes to Angiopoietin-Mediated In Vitro Proinflammatory and Proangiogenic Activities.

Neutrophil extracellular traps (NETs) are composed of nuclear DNA in a web-like structure extruded from neutrophils in response to either bacterial infection or inflammation. We previously reported the expression of angiopoietin Tie2 receptor on human neutrophils and the capacity of both angiopoietins (Ang1 and Ang2) to induce proinflammatory activities, such as synthesis and release of platelet-activating factor, upregulation of ß2 integrin complex (CD11/CD18), and neutrophil chemotaxis. In contrast, only Ang1 but not Ang2 is capable of promoting translational and transcriptional activities in neutrophils. In this article, we addressed whether Ang1 and/or Ang2 could modulate the release of NETs and if they contribute to angiopoietin-mediated proinflammatory activities. We observed that Ang1 and Ang2, alone or combined (10 nM, 3 h), increase NET synthesis and release by ≈2.5-fold as compared with PBS-treated neutrophils. The release of NETs is Tie2 dependent and requires downstream intracellular participation of PI3K, p38, and p42/44 MAPK pathways; reactive oxygen species production; intracellular calcium store depletion; and protein arginine deiminase 4 activation. These isolated NETs induced neutrophil and endothelial cell activation, leading to neutrophil adhesion onto human extracellular matrix and HUVEC and in vitro formation of capillary-like tubes by endothelial cells. Our study reports the capacity of Ang1 and Ang2 to promote the release of NETs and that these NETs contribute to angiopoietin-mediated in vitro proinflammatory and proangiogenic activities.

Is there a potential association between spironolactone and the risk of new-onset diabetes in a cohort of older patients with heart failure?

PURPOSE: Some evidence suggests that spironolactone may have a deleterious effect on glucose homeostasis. The objective of this study was to assess whether spironolactone use is associated with a higher risk of developing diabetes in a large cohort of patients with heart failure (HF). METHODS: Two Quebec government administrative databases were used to identify a cohort of hospitalized patients discharged between January 1995 and December 2009 with a primary discharge diagnosis of HF and without secondary discharge diagnosis of diabetes. Patients were categorized as new users of spironolactone and non-users. The primary outcome was defined as new-onset diabetes (NOD) during 5 years of follow-up and was ascertained using ICD codes for diabetes or use of hypoglycemic agents. RESULTS: Among the 2974 patients that were included in the cohort analysis, 769 were given a new prescription of spironolactone. The incidence rate of NOD was similar among spironolactone users (5.0 per 100 person-years) and non-users (4.9 per 100 person-years). There was no significant association between the use of spironolactone and NOD in the crude, unadjusted model (hazard ratio (HR) 1.01; 95% confidence interval (CI) 0.80-1.28; p = 0.9217), and it remained unchanged in the adjusted Cox proportional hazard model (HR = 0.92; 95% CI = 0.72-1.18; p = 0.5227). The results were consistent with those observed in sensitivity analyses of a 1:3 propensity score-matched cohort (HR = 0.97; CI = 0.76-1.25; p = 0.8169). CONCLUSION: We found no evidence supporting the claim that use of spironolactone is associated with a higher risk of diabetes among patients hospitalized for HF.

A comparison of the effects of selective and non-selective mineralocorticoid antagonism on glucose homeostasis of heart failure patients with glucose intolerance or type II diabetes: A randomized controlled double-blind trial.

Mineralocorticoid receptor antagonists (MRAs) decrease morbidity and mortality in patients with heart failure (HF). However, spironolactone, a non-selective MRA, has been shown to exert a harmful effect on glucose homeostasis. The objective of this multicenter, randomized, controlled, double-blind trial was to compare the effects of spironolactone to those of the selective MRA eplerenone on glucose homeostasis among 62 HF patients with glucose intolerance or type II diabetes. Trial registration number:NCT01586442.

A genotype-directed comparative effectiveness trial of Bucindolol and metoprolol succinate for prevention of symptomatic atrial fibrillation/atrial flutter in patients with heart failure: Rationale and design of the GENETIC-AF trial.

BACKGROUND: Few therapies are available for the safe and effective treatment of atrial fibrillation (AF) in patients with heart failure. Bucindolol is a non-selective beta-blocker with mild vasodilator activity previously found to have accentuated antiarrhythmic effects and increased efficacy for preventing heart failure events in patients homozygous for the major allele of the ADRB1 Arg389Gly polymorphism (ADRB1 Arg389Arg genotype). The safety and efficacy of bucindolol for the prevention of AF or atrial flutter (AFL) in these patients has not been proven in randomized trials. METHODS/DESIGN: The Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure (GENETIC-AF) trial is a multicenter, randomized, double-blinded "seamless" phase 2B/3 trial of bucindolol hydrochloride versus metoprolol succinate, for the prevention of symptomatic AF/AFL in patients with reduced ejection fraction heart failure (HFrEF). Patients with pre-existing HFrEF and recent history of symptomatic AF are eligible for enrollment and genotype screening, and if they are ADRB1 Arg389Arg, eligible for randomization. A total of approximately 200 patients will comprise the phase 2B component and if pre-trial assumptions are met, 620 patients will be randomized at approximately 135 sites to form the Phase 3 population. The primary endpoint is the time to recurrence of symptomatic AF/AFL or mortality over a 24-week follow-up period, and the trial will continue until 330 primary endpoints have occurred. CONCLUSIONS: GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype. (ClinicalTrials.govNCT01970501).

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.

Pregnancy after heart transplantation: a well-thought-out decision? The Quebec provincial experience - a multi-centre cohort study.

Despite reports of successful pregnancies in heart transplant (HTx) recipients, many centers recommend their patients against maternity. We reviewed our provincial experience of pregnancy in HTx recipients by performing charts review of all known gestations following HTx in the province of Quebec (Canada), stratified between planned and unplanned pregnancies. Long-term survival was compared to HTx recipient women of childbearing age who did not become pregnant. Eighteen pregnancies, 56% unplanned, occurred in eight patients, 10.1 (2.6-27.0) years after HTx. Immunosuppression was CNI-based, with a mean dose increase of 48.3% (tacrolimus) and 26.5% (cyclosporine), without rejection. Cardiometabolic complications were high compared to the general Canadian population, including preeclampsia (15.4% vs. 5.5%), hypertension (38.5% vs. 4.6%), and diabetes (15.4% vs. 5.6%). Mean gestational age was 35.1 (23.4-39.6) weeks (72.2% live births; 53.8% prematurity). Mean birthweight was 2418 (660-3612) g. Serum creatinine increased during pregnancy, becoming significant after delivery (P = 0.0239), and returning to preconception level in all but three patients within a year. After 4.6 (1.2-17.2) years of follow-up, two rejection episodes occurred in one patient. Long-term mortality was similar to overall HTx women (Kaplan-Meier; P = 0.8071). Pregnancy in HTx carries high cardiometabolic complications and decreased kidney function, but is feasible with acceptable outcomes and no impact on mother's survival.

Older adults with heart failure treated with carvedilol, bisoprolol, or metoprolol tartrate: risk of mortality.

PURPOSE: The long-term use of ß-blockers has been shown to improve clinical outcomes among patients with heart failure (HF). However, a lack of data persists in assessing whether carvedilol or bisoprolol are superior to metoprolol tartrate in clinical practice. We endeavored to compare the effectiveness of ß-blockers among older adults following a primary hospital admission for HF. METHODS: We conducted a cohort study using Quebec administrative databases to identify patients who were using ß-blockers, carvedilol, bisoprolol, or metoprolol tartrate after the diagnosis of HF. We characterized the patients by the type of ß-blocker prescribed at discharge of their first HF hospitalization. An adjusted multivariate Cox proportional hazards model was used to compare the primary outcome of all-cause mortality. We also conducted analyses by matching for a propensity score for initiation of ß-blocker therapy and assessed the effect on primary outcome. RESULTS: Among 3197 patients with HF with a median follow-up of 2.8 years, the crude annual mortality rates (per 100 person-years) were at 16, 14.9, and 17.7 for metoprolol tartrate, carvedilol, and bisoprolol, respectively. Adjusted hazard ratios of carvedilol (hazard ratio 0.92; 0.78-1.09) and bisoprolol (hazard ratio 1.04; 0.93-1.16) were not significantly different from that of metoprolol tartrate in improving survival. After matching for propensity score, carvedilol and bisoprolol showed no additional benefit with respect to all-cause mortality compared with metoprolol tartrate. CONCLUSIONS: Our evidence suggests no differential effect of ß-blockers on all-cause mortality among older adults with HF. Copyright © 2016 John Wiley & Sons, Ltd.

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.

Blood Pressure and Atrial Fibrillation: A Combined AF-CHF and AFFIRM Analysis.

BACKGROUND: Hypertension is an established risk factor for new-onset atrial fibrillation (AF). However, the relationship between blood pressure and recurrent AF is less well understood. METHODS AND RESULTS: A pooled analysis of patient-level data from AFFIRM and AF-CHF trials was conducted on all 2,715 patients with paroxysmal or persistent AF, 68 ± 8 years, 66% male, randomized to rhythm control and followed for 40.6 ± 16.5 months. We assessed the impact of a baseline systolic blood pressure (SBP; <120 mmHg [N = 1,008], 120-140 mmHg [N = 930], >140 mmHg [N = 777]) on recurrent AF and proportion of time spent in AF. In patients with LVEF >40% (N = 1,719), SBP was not associated with recurrent AF in multivariate regression analyses (P = 0.752). In contrast, in patients with LVEF ≤40% (N = 996), the AF recurrence rate was higher in those with an SBP >140 mmHg compared to 120-140 mmHg (hazard ratio 1.47; 95% CI [1.12-1.93], P = 0.005). The rate of recurrent AF was similar in patients with SBP <120 mmHg compared to 120-140 mmHg (hazard ratio 1.15; 95% CI [0.92-1.43], P = 0.225). Consistently, the proportion of time spent in AF was not influenced by SBP in patients with LVEF >40% (P = 0.645). However, in patients with LVEF ≤40%, the adjusted mean proportion of time spent in AF was 17.2% if SBP was <120 mmHg, 15.4% for SBP 120-140 mmHg, and 24.0% for SBP >140 mmHg (P = 0.025). CONCLUSION: Systolic blood pressure is an important determinant of recurrent AF and overall AF burden in patients with left ventricular dysfunction (LVEF≤40%) but not in those with preserved ventricular function.

Cardiac resynchronization therapy in patients with heart failure and a QRS complex <120 milliseconds: the Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial.

BACKGROUND: Although the benefits of cardiac resynchronization therapy are well established in selected patients with heart failure and a prolonged QRS duration, salutary effects in patients with narrow QRS complexes remain to be demonstrated. METHODS AND RESULTS: The Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial is a randomized, double-blind, 12-center study that was designed to compare the effects of active and inactive cardiac resynchronization therapy in patients with severe left ventricular dysfunction and a QRS duration <120 milliseconds. The trial was interrupted prematurely by the Data Safety and Monitoring Board because of futility and safety concerns after 85 patients were randomized. Changes in exercise duration after 12 months were no different in patients with and without active cardiac resynchronization therapy (-0.7 minutes [95% confidence interval (CI), -2.9 to 1.5] versus 0.8 minutes [95% CI, -1.2 to 2.9]; P=0.31]. Similarly, no significant differences were observed in left ventricular end-systolic volumes (-6.4 mL [95% CI, -18.8 to 5.9] versus 3.1 mL [95% CI, -9.2 to 15.5]; P=0.28) and ejection fraction (3.3% [95% CI, 0.7-6.0] versus 2.1% [95% CI, -0.5 to 4.8]; P=0.52). Moreover, cardiac resynchronization therapy was associated with a significant reduction in the 6-minute walk distance (-11.3 m [95% CI, -31.7 to 9.7] versus 25.3 m [95% CI, 6.1-44.5]; P=0.01), an increase in QRS duration (40.2 milliseconds [95% CI, 34.2-46.2] versus 3.4 milliseconds [95% CI, 0.6-6.2]; P<0.0001), and a nonsignificant trend toward an increase in heart failure-related hospitalizations (15 hospitalizations in 5 patients versus 4 hospitalizations in 4 patients). CONCLUSIONS: In patients with a left ventricular ejection fraction ≤35%, symptoms of heart failure, and a QRS duration <120 milliseconds, cardiac resynchronization therapy did not improve clinical outcomes or left ventricular remodeling and was associated with potential harm. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00900549.

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.

Sirolimus Immunoprophylaxis and Renal Histological Changes in Long-Term Cardiac Transplant Recipients: A Pilot Study.

BACKGROUND: The effects of sirolimus (SIR), as a substitution for calcineurin inhibitor (CNI) immunoprophylaxis, on renal function in very-long-term cardiac transplant recipients have been a matter of controversy. OBJECTIVE: To assess the impacts of SIR as a substitution for CNI on renal function up to 24 months in long-term cardiac recipients as well as the renal histological changes in patients with suspected CNI-induced nephrotoxicity. METHODS: A total of 23 cardiac transplant recipients aged 57.7 ± 11.2 years, 91 months post-cardiac transplantation were recruited; 15 patients were randomized to CNI-free immune suppression with SIR, and 8 patients were allocated to continue their CNI regimens. Serum creatinine and calculated serum creatinine clearance were measured at prespecified time points up to 24 months. Renal structure and function were assessed by renal biopsies, renal ultrasound, and magnetic resonance imaging at baseline. RESULTS: There were no significant changes in creatinine clearance during the course of the study in patients treated with SIR. However, SIR-treated patients exhibited a significant decrease in 24-hours and nighttime systolic and diastolic blood pressures. Typical findings of significant hypertensive renal disease were detected in 9 of the 11 (82%) patients. Features of chronic CNI toxicity were detected in 6 (55%) patients. CONCLUSIONS: There is a very high rate of hypertensive renal disease concomitantly with some degree of CNI toxicity in long-term cardiac transplant recipients with renal dysfunction. This very high rate of hypertension-related disease may limit the impact of SIR on improving renal function long term following cardiac transplantation.