Induction therapy in heart transplantation: A systematic review and network meta-analysis for developing evidence-based recommendations.

INTRODUCTION: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA). METHODS: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework. RESULTS: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab. CONCLUSION: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients.

Use of induction therapy post-heart transplantation: Clinical practice recommendations based on systematic review and network meta-analysis of evidence.

BACKGROUND: The use of induction therapy (IT) agents in the early post-heart transplant period remains controversial. The following recommendations aim to provide guidance on the use of IT agents, including Basiliximab and Thymoglobulin, as part of routine care in heart transplantation (HTx). METHODS: We recruited an international, multidisciplinary panel of 15 stakeholders, including patient partners, transplant cardiologists and surgeons, nurse practitioners, pharmacists, and methodologists. We commissioned a systematic review on benefits and harms of IT on patient-important outcomes, and another on patients' values and preferences to inform our recommendations. We used the GRADE framework to summarize our findings, rate certainty in the evidence, and develop recommendations. The panel considered the balance between benefits and harms, certainty in the evidence, and patient's values and preferences, to make recommendations for or against the routine post-operative use of Thymoglobulin or Basiliximab. RESULTS: The panel made recommendations on three major clinical problems in HTx: (1) We suggest against the routine post-operative use of Basiliximab compared to no IT, (2) we suggest against the routine use of Thymoglobulin compared to no IT, and (3) for those patients for whom IT is deemed desirable, we suggest for the use of Thymoglobulin as compared to Basiliximab. CONCLUSION: This report highlights gaps in current knowledge and provides directions for clinical research in the future to better understand the clinical utility of IT agents in the early post heart transplant period, leading to improved management and care.

Drug levels after sirolimus initiation and short-term outcomes in ambulatory heart transplantation recipients.

INTRODUCTION: We evaluated the effect of relative changes in combined tacrolimus and sirolimus (drug) levels, following sirolimus initiation, on outcomes in ambulatory heart transplantation (HTx) recipients. METHODS: We performed a retrospective analysis of HTx recipients who received tacrolimus, followed by sirolimus initiation, any time after HTx. We calculated the relative change in combined drug levels 1-month post-sirolimus initiation, relative to tacrolimus levels pre-initiation, and categorized patients into decreased (≥15% decrease), stable (<15% decrease to <15% increase), or increased (≥15% increase) groups. We compared, across the three groups, changes in post-initiation estimated glomerular filtration rate (eGFR) and left ventricular ejection fraction (LVEF) using one-way ANOVA and Sidák's post-hoc analysis, as well as the individual and composite outcomes of new donor specific antibodies (DSA), acute cellular rejection (ACR), and all-cause mortality using Fisher's exact test. RESULTS: Amongst 99 HTx recipients included, the median age was 53 years, time to sirolimus initiation was 1.5 years post-HTx, and pre-sirolimus eGFR was 52 mL/min/1.73 m2 . Nine patients had decreased, 15 stable, and 75 increased, relative combined drug levels. Relative change in eGFR was significantly higher in patients with decreased levels compared to patients with increased levels at 6 months post-initiation (P < .05), but this was not sustained at 12 months. There were no differences in LVEF change or in individual and composite risks for developing DSA, ACR, and all-cause mortality at 12 months across the groups. CONCLUSION: Post-sirolimus initiation, a relative decrease in combined drug levels, compared to increased levels, was associated with temporarily improved renal function.

The design of studies testing the effectiveness of risk-guided care has many challenges: a scoping review addressing key considerations.

OBJECTIVES: Studies evaluating the effectiveness of care based on patients' risk of adverse outcomes (risk-guided care) use a variety of study designs. In this scoping review, using examples, we review characteristics of relevant studies and present key design features to optimize the trustworthiness of results. STUDY DESIGN AND SETTING: We searched five online databases for studies evaluating the effect of risk-guided care among adults on clinical outcomes, process, or cost. Pairs of reviewers independently performed screening and data abstraction. We descriptively summarized the study design and characteristics. RESULTS: Among 14,561 hits, we identified 116 eligible studies. Study designs included randomized controlled trials (RCTs), post hoc analysis of RCTs, and retrospective or prospective cohort studies. Challenges and sources of bias in the design included limited performance of predictive models, contamination, inadequacy to address the credibility of subgroup effects, absence of differences in care across risk strata, reporting only process measures as opposed to clinical outcomes, and failure to report benefits and harms. CONCLUSION: To assess the benefit of risk-guided care, RCTs provide the most trustworthy evidence. Observational studies offer an alternative but are hampered by confounding and other limitations. Reaching valid conclusions when testing risk-guided care requires addressing the challenges identified in our review.

Increased Mortality in Patients With Acutely Decompensated Heart Failure During the COVID-19 Pandemic in Toronto, Canada.

Background: Coronavirus disease 2019 (COVID-19) has resulted in a reduction in patients seeking timely consultation for illnesses that are not related to COVID-19. Previously, we reported a decline in the number of emergency department (ED) visits and hospitalizations for acute decompensated heart failure (ADHF) during the 2020 COVID-19 pandemic vs that in 2019. We aimed to determine the consequences of these early trends on ADHF-patient morbidity and mortality. Methods: We compared consecutive patients presenting with ADHF to 3 academic medical centres in Toronto, Canada from March 1-September 28, 2020, vs those from the same time period in 2019. We used multivariate logistic regression models to evaluate whether the odds of hospitalization after presenting to the ED, recurrent ED visits or readmission within 30 days, and in-hospital all-cause mortality differed by timeframe. Results: We observed that, during the COVID-19 pandemic, a lower total number of patients presented to the hospital with ADHF, vs that in 2019. Despite this difference, the probability of being admitted to the hospital did not differ for patients seen in 2020 vs 2019. Among ADHF patients admitted to the hospital, however, we observed a significantly higher proportion being admitted to the intensive care unit, and a relative 66% increase in in-hospital mortality during the 2020 COVID-19 era, compared to that in 2019. Conclusions: Our findings suggest that improved messaging may be needed for patients living with chronic health conditions, including HF, during the pandemic, to educate and encourage them to present to hospital services when in need.

Contexte: La maladie à coronavirus 2019 (COVID-19) s'est traduite par une diminution du nombre de patients demandant des consultations médicales pour des états de santé sans lien avec la COVID-19. Nous avons précédemment décrit une diminution du nombre de consultations aux urgences et d'hospitalisations en raison d'une insuffisance cardiaque aiguë décompensée (ICAD) au cours de la pandémie de COVID-19 en 2020, par rapport à 2019. Nous avons voulu déterminer les conséquences de ces tendances précoces sur la morbidité et la mortalité chez les patients atteints d'ICAD. Méthodologie: Nous avons comparé les données pour les patients consécutifs atteints d'ICAD de trois centres médicaux hospitaliers de Toronto (Canada) traités entre le 1er mars et le 28 septembre 2020 et durant la même période en 2019. À l'aide de modèles de régression logistique multivariée, nous avons évalué les différences entre les probabilités d'hospitalisation après une consultation aux urgences, de consultations récurrentes aux urgences ou de réadmission dans les 30 jours suivant la visite initiale, ainsi que de mortalité hospitalière toutes causes confondues pour les patients vus durant ces deux périodes. Résultats: Durant la pandémie de COVID-19, le nombre total de patients atteints d'ICAD s'étant présentés à l'hôpital a été plus faible que celui relevé pour l'année 2019. Malgré cet écart, la probabilité d'admission à l'hôpital ne différait pas pour les patients vus en 2020 et en 2019. Parmi les patients atteints d'ICAD admis à l'hôpital, nous avons toutefois observé une proportion significativement plus élevée de séjours aux soins intensifs et une hausse relative de 66 % du taux de mortalité hospitalière, en comparant les données de 2020 (pandémie de COVID-19) et celles de 2019. Conclusions: Nos observations indiquent qu'il pourrait être nécessaire d'améliorer la communication avec les patients atteints de problèmes de santé chroniques (y compris l'IC) en situation de pandémie de façon à mieux les informer et à les encourager à consulter les services hospitaliers lorsque nécessaire.

Cardiac Sarcoidosis: A Clinical Overview.

Cardiac sarcoidosis (CS) with clinical manifestation occurs in about 5-8% of patients with sarcoidosis. CS may be clinically suspected by the presence of ventricular arrhythmia, conduction abnormalities, and heart failure (HF). However, 20%-25% of patients may present with silent CS, having asymptomatic cardiac involvement. The diagnosis of CS is based on findings from nuclear studies, cardiac magnetic resonance, and extra-cardiac tissue biopsy. Due to the inflammatory nature of the disease, immunosuppressive medications are a cornerstone of therapy. The treatment also includes recommended HF medical therapies. Since CS patients are at risk of sudden cardiac death resulting from progression of cardiac dysfunction or the presence of scar originating from fatal arrhythmias, implantable cardioverter-defibrillators should be considered, with special indication beyond accepted recommendations in HF. In CS, the extent of left ventricular dysfunction is the most important mortality predictor. Heart transplant or mechanical circulatory support may represent life saving strategies in selective CS patients.

A 2020 Environmental Scan of Heart Failure Clinics in Ontario.

BACKGROUND: Multidisciplinary heart failure (HF) clinics decrease hospital admission rates and healthcare use, while improving patient outcomes. To understand the contemporary availability of HF clinics in Ontario, Canada, and the services provided, we performed an environmental scan of physician-led and nurse practitioner (NP)-led HF clinics. METHODS: Between November, 2019 and February 2020, we identified Ontario HF clinics led by physicians or NPs. Following an invitation, we conducted a semi-structured interview to evaluate the services offered and qualitatively compared our findings to the results of the 2010 Ontario provincial survey. RESULTS: The number of HF clinics (36 vs 34 in 2010) and physicians (157 vs 143 in 2010) have not changed since the 2010 survey. Of the 36 clinics we identified, 30 participated in our interview (22 physician-led and 8 NP-led). Twenty-five clinics (83%) were hospital-based, of which 9 (30%) were part of an academic institution. Comparisons of our findings to the 2010 study on 30 clinics show an approximately 3-fold increase (P <0.001) in both median annual and new patient visits. As previously reported, the clinics varied in services offered, but trended toward an increased availability of onsite echocardiography, exercise-stress testing, and nuclear cardiology. CONCLUSIONS: Compared to the survey performed a decade ago, the number of HF clinics and physicians have not changed, and the services provided remain heterogenous. However, the increased number of patients served suggests a greater demand for these clinics. Improving the accessibility of these clinics and standardizing the service model are critical to improving patient outcomes.

CONTEXTE: Les cliniques multidisciplinaires d'insuffisance cardiaque (IC) diminuent les taux d'hospitalisations et l'utilisation des soins de santé, tout en améliorant les résultats pour les patients. Pour connaître l'offre actuelle de cliniques d'IC en Ontario, au Canada, et les services qui y sont dispensés, nous avons effectué une analyse contextuelle des cliniques d'IC dirigées par des médecins ou par des infirmières praticiennes. MÉTHODOLOGIE: Entre novembre 2019 et février 2020, nous avons recensé des cliniques d'IC dirigées par des médecins ou des infirmières praticiennes en Ontario. Après avoir fait parvenir une invitation à ces professionnels de la santé, nous avons mené des entrevues semi-structurées afin d'évaluer les services offerts et avons, de façon qualitative, comparé nos résultats à ceux de l'enquête provinciale menée en 2010 en Ontario. RÉSULTATS: Le nombre de cliniques d'IC (36 contre 34 en 2010) et de médecins (157 contre 143 en 2010) n'a pas changé depuis l'enquête de 2010. Parmi les 36 cliniques recensées, 30 ont participé à nos entrevues (22 dirigées par des médecins et huit dirigées par des infirmières praticiennes). Vingt-cinq (83 %) des cliniques étaient situées en milieu hospitalier, dont neuf (30 %) qui faisaient partie d'un établissement d'enseignement. Les comparaisons de nos résultats à ceux de l'étude de 2010 sur 30 cliniques montrent que le nombre annuel médian de visites et le nombre de visites par de nouveaux patients ont tous deux triplé (p < 0,001). Comme il a déjà été mentionné, les services offerts étaient différents d'une clinique à l'autre, mais la tendance allait vers une augmentation des services d'échocardiographie, d'épreuves à l'effort et de cardiologie nucléaire offerts sur place. CONCLUSIONS: Par rapport aux résultats de l'enquête réalisée il y a 10 ans, le nombre de cliniques d'IC et de médecins n'a pas changé, et les services fournis demeurent hétérogènes. Toutefois, la hausse du nombre de patients desservis semble indiquer une hausse de la demande pour ces cliniques. Une meilleure accessibilité à ces cliniques et une uniformisation du modèle de services sont essentielles à l'amélioration des résultats pour les patients.

Targeted delivery of genes to endothelial cells and cell- and gene-based therapy in pulmonary vascular diseases.

Pulmonary arterial hypertension (PAH) is a devastating disease that, despite significant advances in medical therapies over the last several decades, continues to have an extremely poor prognosis. Gene therapy is a method to deliver therapeutic genes to replace defective or mutant genes or supplement existing cellular processes to modify disease. Over the last few decades, several viral and nonviral methods of gene therapy have been developed for preclinical PAH studies with varying degrees of efficacy. However, these gene delivery methods face challenges of immunogenicity, low transduction rates, and nonspecific targeting which have limited their translation to clinical studies. More recently, the emergence of regenerative approaches using stem and progenitor cells such as endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) have offered a new approach to gene therapy. Cell-based gene therapy is an approach that augments the therapeutic potential of EPCs and MSCs and may deliver on the promise of reversal of established PAH. These new regenerative approaches have shown tremendous potential in preclinical studies; however, large, rigorously designed clinical studies will be necessary to evaluate clinical efficacy and safety.

The angiopietin-1-Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice.

The role of the angiopoietin-1 (Ang1)-Tie2 pathway in the pathogenesis of pulmonary arterial hypertension (PAH) is controversial. Although Ang1 is well known to prevent endothelial activation and injury in systemic vascular beds, this pathway has been suggested to mediate pulmonary vascular remodeling in PAH. Therefore, we used transgenic models to determine the effect of increased or decreased Tie2 activity on the development of PAH. We now report modest spontaneous elevation in right ventricular systolic pressure in Tie2-deficient mice (Tie2(+/-)) compared with wild-type (WT) littermate controls, which was exacerbated upon chronic exposure to the clinically relevant PAH triggers, serotonin (5-HT) or interleukin-6 (IL-6). Moreover, overexpression of Ang1 in transgenic mice had no deleterious effect on pulmonary hemodynamics and, if anything, blunted the response to 5-HT. Exposure to 5-HT or IL-6 also decreased lung Ang1 expression, further reducing Tie2 activity and inducing pulmonary apoptosis in the Tie2(+/-) group only. Similarly, cultured pulmonary artery endothelial cells subjected to Tie2 silencing demonstrated increased susceptibility to apoptosis after 5-HT treatment. Finally, treatment of Tie2-deficient mice with Z-VAD, a pan-caspase inhibitor, prevented the pulmonary hypertensive response to 5-HT. Thus, these findings firmly establish that endothelial survival signaling via the Ang1-Tie2 pathway is protective in PAH.

Fluorescent microangiography (FMA): an improved tool to visualize the pulmonary microvasculature.

Visualization of the complex lung microvasculature and resolution of its three-dimensional architecture remains a difficult experimental challenge. We present a novel fluorescent microscopy technique to visualize both the normal and diseased pulmonary microvasculature. Physiologically relevant pulmonary perfusion conditions were applied using a low-viscosity perfusate infused under continuous airway ventilation. Intensely fluorescent polystyrene microspheres, confined to the vascular space, were imaged through confocal optical sectioning of 200 microm-thick lung sections. We applied this technique to rat lungs and the markedly enhanced depth of field in projected images allowed us to follow vascular branching patterns in both normal lungs and lungs from animals with experimentally induced pulmonary arterial hypertension. In addition, this method allowed complementary immunostaining and identification of cellular components surrounding the blood vessels. Fluorescent microangiography is a widely applicable and quantitative tool for the study of vascular changes in animal models of pulmonary disease.

Role of angiopoietin-1 in experimental and human pulmonary arterial hypertension.

INTRODUCTION: The pulmonary microvasculature, consisting mainly of an endothelial cell (EC) monolayer and scant matrix support, is incompletely muscularized. Thus, the distal pulmonary arterioles may be predisposed to regression on exposure to environmental stresses (ie, hypoxia) and may be dependent on EC survival factors, like angiopoietin (Ang) 1, to attenuate the development of pulmonary arterial hypertension (PAH). In order to clarify the link between Ang1 expression and the development of PAH in patients, we also studied messenger RNA and protein expression in lung samples from healthy control subjects and patients with idiopathic PAH (IPAH) or PAH associated with other diseases (APAH). METHODS: Ang/Tie2 gene expression was assessed in rats that had been exposed to hypoxia (ie, 10% O2) for 1, 3, or 7 days. In a separate experiment, the cell-based gene transfer of Ang1/Ang2 was performed, and the effects were evaluated in rats with hypoxia-induced PAH. RESULTS: Hypoxia induced significant early increases in right ventricular systolic pressure (RVSP) and right ventricle/left ventricle-plus-septum mass ratio (RV/[LV + S]), with a significant decrease in Tie2 expression. Hypoxic rats receiving Ang1 demonstrated significant improvements in RVSP and RV/(LV + S), with a partial normalization in Tie2 protein levels. Robust Ang1 expression was observed in healthy human lungs. Furthermore, there were no significant changes in the levels of Ang1 or Ang2 in IPAH or APAH samples vs those in control subjects. CONCLUSIONS: Decreased activity of the Tie2 pathway with hypoxia may contribute to PAH, possibly by loss of EC survival signaling, which can be overcome by Ang1 gene transfer.

Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease.

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance caused by narrowing and loss of pulmonary microvasculature, which in its late stages becomes refractory to traditional therapies. We hypothesized that bone marrow-derived endothelial progenitor cells (EPCs), which normally function to repair and regenerate blood vessels, would restore pulmonary hemodynamics and increase microvascular perfusion in the rat monocrotaline (MCT) model of PAH. Mononuclear cells were isolated from the bone marrow of syngeneic Fisher-344 rats by Ficoll gradient centrifugation and cultured for 7 to 10 days in endothelial growth medium. Fluorescently labeled endothelial-like progenitor cells (ELPCs) engrafted at the level of the distal pulmonary arterioles and incorporated into the endothelial lining in the MCT-injured lung. The administration of ELPCs 3 days after MCT nearly completely prevented the increase in right ventricular systolic pressure seen at 3 weeks with MCT alone (31.5+/-0.95 versus 48+/-3 mm Hg, respectively; P<0.001), whereas injection of skin fibroblasts had no protective effect (50.9+/-5.4 mm Hg). Delayed administration of progenitor cells 3 weeks after MCT prevented the further progression of PAH 2 weeks later (ie, 5 weeks after MCT), whereas only animals receiving ELPCs transduced with human endothelial NO-synthase (eNOS) exhibited significant reversal of established disease at day 35 (31+/-2 mm Hg, P<0.005) compared with day 21 (50+/-3 mm Hg). Fluorescent microangiography revealed widespread occlusion of pulmonary precapillary arterioles 3 weeks after MCT, whereas arteriolar-capillary continuity and microvascular architecture was preserved with the administration of syngeneic ELPCs. Moreover, the delivery of ELPCs to rats with established PAH resulted in marked improvement in survival, which was greatest in the group receiving eNOS-transduced cells. We conclude that bone marrow-derived ELPCs can engraft and repair the MCT-damaged lung, restoring microvasculature structure and function. Therefore, the regeneration of lung vascular endothelium by injection of progenitor cells may represent a novel treatment paradigm for patients with PAH.

A novel model for post-transplant obliterative airway disease reveals angiogenesis from the pulmonary circulation.

We present a novel animal model for post-transplant obliterative airway disease in which the donor trachea is implanted into the recipient's lung parenchyma. Although this procedure is technically more challenging than the heterotopic model of implantation into a subcutaneous pouch, it has several important advantages some of which are the appropriate local environment and the possibility of local immunosuppressive therapy after transtracheal gene, cell or drug delivery. This model has revealed new insights into angiogenic potential of the pulmonary circulation.