Biomarkers to assess right heart pressures in recipients of a heart transplant: a proof-of-concept study

Background: This proof-of-concept study investigated the feasibility of using biomarkers to monitor right heart pressures (RHP) in heart transplanted (HTx) patients. Methods: In 298 patients, we measured 7.6 years post-HTx mean pressures in the right atrium (mRAP) and pulmonary artery (mPAP) and capillaries (mPCWP) along with plasma high-sensitivity troponin T (hsTnT), a marker of cardiomyocyte injury, and the multidimensional urinary classifiers HF1 and HF2, mainly consisting of dysregulated collagen fragments. Results: In multivariable models, mRAP and mPAP increased with hsTnT (per 1-SD, +0.91 and +1.26 mm Hg; P < 0.0001) and with HF2 (+0.42 and +0.62 mm Hg; P ≤ 0.035), but not with HF1. mPCWP increased with hsTnT (+1.16 mm Hg; P < 0.0001), but not with HF1 or HF2. The adjusted odds ratios for having elevated RHP (mRAP, mPAP or mPCWP ≥10, ≥24, ≥17 mm Hg, respectively) were 1.99 for hsTnT and 1.56 for HF2 (P ≤ 0.005). In detecting elevated RHPs, areas under the curve were similar for hsTnT and HF2 (0.63 vs 0.65; P = 0.66). Adding hsTnT continuous or per threshold or HF2 continuous to a basic model including all covariables did not increase diagnostic accuracy (P ≥ 0.11), whereas adding HF2 per optimized threshold increased both the integrated discrimination (+1.92%; P = 0.023) and net reclassification (+30.3%; P = 0.010) improvement. Conclusions: Correlating RHPs with noninvasive biomarkers in HTx patients is feasible. However, further refinement and validation of such biomarkers is required before their clinical application can be considered

Planar hypohamiltonian oriented graphs

In 1978 Thomassen asked whether planar hypohamiltonian oriented graphs exist. Infinite families of such graphs have since been described but for infinitely many it remained an open question whether planar hypohamiltonian oriented graphs of order exist. In this paper we develop new methods for constructing hypohamiltonian digraphs, which, combined with efficient graph generation algorithms, enable us to fully characterise the orders for which planar hypohamiltonian oriented graphs exist. Our novel methods also led us to discover the planar hypohamiltonian oriented graph of smallest order and size, as well as infinitely many hypohamiltonian orientations of maximal planar graphs. Furthermore, we answer a question related to a problem of Schiermeyer on vertex degrees in hypohamiltonian oriented graphs, and characterise all the orders for which planar hypotraceable oriented graphs exist.Research Foundation Flanders; VSC(Flemish Supercomputer Center);DST‐NRF Centre of Excellence in Mathematical and Statistical Sciences.http://wileyonlinelibrary.com/journal/jgthj2023Mathematics and Applied Mathematic

Dietary cholesterol withdrawal reduces vascular inflammation and induces coronary plaque stabilization in miniature pigs

Objective: To study the effect of dietary cholesterol withdrawal on size and composition of LDL-hypercholesterolemia-induced coronary plaques in miniature pigs. Methods: Pigs were on normal chow (control group), on a cholesterol-rich diet for 37 weeks (hypercholesterolemic group) or on a cholesterol-rich diet followed by normal chow for 26 weeks (cholesterol withdrawal group). Endothelial function was assessed with quantitative angiography after intracoronary infusion of acetylcholine, plaque load with intra-coronary ultrasound and plaque composition with image analysis of cross-sections. The effect of porcine serum on coronary smooth muscle cell (SMC) function was studied in vitro. Results: Cholesterol-rich diet caused LDL-hypercholesterolemia, increased plasma levels of oxidized LDL (ox-LDL) and C-reactive protein (CRP), and induced endothelial dysfunction and coronary atherosclerosis. Dietary cholesterol withdrawal lowered LDL, ox-LDL and CRP. It restored endothelial function, did not affect plaque size but decreased lipid, ox-LDL and macrophage content. Smooth muscle cells and collagen accumulated within the plaque. Increased smoothelin-to-α-smooth muscle actin ratio indicated a more differentiated SMC phenotype. Cholesterol lowering reduced proliferation and apoptosis. In vitro, hypercholesterolemic serum increased SMC apoptosis and decreased SMC migration compared to non-hypercholesterolemic serum. Conclusions: Cholesterol lowering induced coronary plaque stabilization as evidenced by a decrease in lipids, ox-LDL, macrophages, apoptosis and cell proliferation, and an increase in differentiated SMC and collagen. Increased migration and decreased apoptosis of SMC may contribute to the disappearance of the a-cellular core after lipid lowerin

The role of transesophageal echocardiography in guiding heart donation after circulatory death.

peer reviewedHeart donation after circulatory death (DCD) can significantly expand the heart donor pool, helping to overcome the problem of organ shortage and the increase in waiting list mortality and morbidity. To improve the outcome of DCD heart transplantation, thoraco-abdominal normothermic regional perfusion (TA-NRP) can be performed by selectively restoring circulation followed by in vivo functional heart assessment. Here, we report on the use of periprocedural transoesophageal echocardiography (TOE) as a minimally invasive cardiac assessment tool during different stages of a DCD heart procurement procedure using TA-NRP. We conclude that TOE is a valuable method to assess the donor heart for transplantation eligibility before and after withdrawal of life-sustaining therapy and during subsequent TA-NRP

Heart re-transplantation in Eurotransplant

Internationally 3% of the donor hearts are distributed to re-transplant patients. In Eurotransplant, only patients with a primary graft dysfunction (PGD) within 1 week after heart transplantation (HTX) are indicated for high urgency listing. The aim of this study is to provide evidence for the discussion on whether these patients should still be allocated with priority. All consecutive HTX performed in the period 1981-2015 were included. Multivariate Cox' model was built including: donor and recipient age and gender, ischaemia time, recipient diagnose, urgency status and era. The study population included 18 490 HTX, of these 463 (2.6%) were repeat transplants. The major indications for re-HTX were cardiac allograft vasculopathy (CAV) (50%), PGD (26%) and acute rejection (21%). In a multivariate model, compared with first HTX hazards ratio and 95% confidence interval for repeat HTX were 2.27 (1.83-2.82) for PGD, 2.24 (1.76-2.85) for acute rejection and 1.22 (1.00-1.48) for CAV (P < 0.0001). Outcome after cardiac re-HTX strongly depends on the indication for re-HTX with acceptable outcomes for CAV. In contrast, just 47.5% of all hearts transplanted in patients who were re-transplanted for PGD still functioned at 1-month post-transplant. Alternative options like VA-ECMO should be first offered before opting for acute re-transplantation

FDG-PET/CT in Heart Transplant

Heart transplantation remains the best treatment option for patients with end-stage heart failure to improve quality of life and survival despite significant improvements in both medical therapies and mechanical circulatory support devices. Nevertheless, given the shortage of donor hearts and increased waiting time, more patients need mechanical circulatory support as a bridge to transplant or even as destination therapy with an inherent risk of infectious complications. Furthermore, heart transplant recipients are at risk for developing several mild to potentially life-threatening complications, thereby impairing their outcome. These complications vary according to the time after transplant surgery and can be divided into graft-related (early graft failure, allograft rejection, and cardiac allograft vasculopathy) and non–graft-related disorders such as infections and malignancies. Positron emission tomography combined with computed tomography using 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET/CT) is an established tool in oncology and has become the reference standard to noninvasively assess infectious and inflammatory processes with high accuracy. This chapter provides a brief overview on the current state of heart transplantation and complications during the posttransplant period. Secondly, a concise update is given on the diagnostic value of FDG-PET/CT in ventricular assist device infections in the pretransplant setting. Then, graft-related complications are discussed focusing on the potential role of FDG-PET/CT to detect allograft rejection. The last part summarizes the current evidence on the use of FDG-PET/CT in the workup of infectious complications and lymphoproliferative disorders after heart transplantation

Outcomes according to the International Society for Heart and Lung Tansplantation angiographic grading scale Reply

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Symptom experience associated with maintenance immunosuppression after heart transplantation: patients' appraisal of side effects

OBJECTIVE: To evaluate symptom experience related to side effects of immunosuppressive therapy in heart transplant recipients. METHODS: This descriptive, cross-sectional study included 105 heart transplant recipients (90 men; 15 women) with a median age of 56 years. Maintenance immunosuppression consisted of triple therapy (cyclosporine, corticosteroids, azathioprine). Symptom frequency and symptom distress were assessed by an adapted version of the Transplant Symptom Frequency and Symptom Distress Scale, which includes 27 symptoms associated with side effects of immunosuppressive therapy. RESULTS: The most frequent symptom for both sexes was increased hair growth. Impotence and painful menstruation were experienced as the most distressing symptoms for men and women, respectively. Women reported a significantly higher level of symptom experience. The majority of the most frequent and most distressing symptoms were corticosteroid associated. CONCLUSIONS: Patients' perception of side effects completes the symptomatologic profile of immunosuppressive therapy. A gender-specific evaluation is indicated because symptom experience differs between the sexes.status: publishe

Endothelium-enriched microRNAs as diagnostic biomarkers for cardiac allograft vasculopathy

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a limiting factor for the long-term survival of heart transplant recipients. Clinical decisions and care may be improved by the development of prediction models based on circulating biomarkers. The endothelium may play a central pathogenetic role in the development of CAV. We evaluated the hypothesis that endothelium-enriched microRNAs (miRNAs) discriminate between patients with and without CAV. METHODS: This cross-sectional study recruited 52 patients undergoing coronary angiography between 5 and 15 years after heart transplantation. Circulating levels of endothelium-enriched miRNAs (miR-21-5p, miR-92a-3p, miR-92a-1-5p, miR-126-3p, and miR-126-5p) were quantified by real-time reverse transcription polymerase chain reaction. The discriminative ability of logistic regression models was evaluated using the concordance (C) statistic. RESULTS: Median plasma levels of miR-210-5p, miR-92a-3p, miR-126-3p, and miR-126-5p were 1.82-fold (p = not significant), 1.87-fold (p < 0.05), 1.94-fold (p = 0.074), and 1.59-fold (p = 0.060) higher in patients with CAV than in patients without CAV. Recipient age (C statistic = 0.689; 95% confidence interval [CI], 0.537-0.842), and levels of serum creatinine (C statistic = 0.703; 95% CI, 0.552-0.854), miR-92a-3p (C statistic = 0.682; 95% CI, 0.533-0.831), and miR-126-5p (C statistic = 0.655; 95% CI, 0.502-0.807) predicted CAV status in univariable models. In multivariable logistic regression models with recipient age and creatinine as covariates, miR-126-5p (chi-square = 4.37(1), p = 0.037), miR-92a-3p (chi-square = 6.01(1), p = 0.014), and the combination of miR-126-5p and miR-92a-3p (chi-square = 8.16(2), p = 0.017) added significant information. The model with age, creatinine, miR-126-5p, and miR-92a-3p as covariables conferred good discrimination between patients without and with CAV (C statistic = 0.800; 95% CI, 0.674-0.926). CONCLUSIONS: Endothelium-enriched miRNAs have diagnostic ability for CAV beyond clinical predictors.publisher: Elsevier articletitle: Endothelium-enriched microRNAs as diagnostic biomarkers for cardiac allograft vasculopathy journaltitle: The Journal of Heart and Lung Transplantation articlelink: http://dx.doi.org/10.1016/j.healun.2015.06.008 content_type: article copyright: Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.status: publishe