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Adv Healthc Mater. 2022 Dec 26:e2202699. doi: 10.1002/adhm.202202699. Online ahead of print.

ABSTRACT

Cardiovascular diseases have been the leading cause of death worldwide during the past several decades. Cell loss is the main problem that resulted in cardiac dysfunction and further mortality. Cell therapy aiming to replenish the lost cells is proposed to treat cardiovascular diseases especially ischemic heart diseases which lead to a big portion of cell loss. Due to the direct injection's low cell retention and survival ratio, cell therapy using biomaterials as cell carriers attracts more and more attention because of their promotion of cell delivery and maintenance at the aiming sites. In this review, we systematically summarized the three main factors involved in cell therapy for myocardial tissue regeneration: cell sources (somatic cells, stem cells and engineered cells), chemical components of cell carriers (natural materials, synthetic materials and electroactive materials), and categories of cell delivery materials (patches, microspheres, injectable hydrogels, nanofiber and microneedles, etc.). An introduction of the methods including magnetic resonance/radionuclide/photoacoustic and fluorescence imaging for tracking the behavior of transplanted cells in vivo is also included. Current challenges of biomaterials-based cell therapy and their future directions are provided to give both beginners and professionals a clear view of the development and future trends in this area. This article is protected by copyright. All rights reserved.

PMID:36572412 | DOI:10.1002/adhm.202202699

APL Bioeng. 2022 Dec 20;6(4):046108. doi: 10.1063/5.0108914. eCollection 2022 Dec.

ABSTRACT

The myocardium is a mechanically active tissue typified by anisotropy of the resident cells [cardiomyocytes (CMs) and cardiac fibroblasts (cFBs)] and the extracellular matrix (ECM). Upon ischemic injury, the anisotropic tissue is replaced by disorganized scar tissue, resulting in loss of coordinated contraction. Efforts to re-establish tissue anisotropy in the injured myocardium are hampered by a lack of understanding of how CM and/or cFB structural organization is affected by the two major physical cues inherent in the myocardium: ECM organization and cyclic mechanical strain. Herein, we investigate the singular and combined effect of ECM (dis)organization and cyclic strain in a two-dimensional human in vitro co-culture model of the myocardial microenvironment. We show that (an)isotropic ECM protein patterning can guide the orientation of CMs and cFBs, both in mono- and co-culture. Subsequent application of uniaxial cyclic strain-mimicking the local anisotropic deformation of beating myocardium-causes no effect when applied parallel to the anisotropic ECM. However, when cultured on isotropic substrates, cFBs, but not CMs, orient away from the direction of cyclic uniaxial strain (strain avoidance). In contrast, CMs show strain avoidance via active remodeling of their sarcomeres only when co-cultured with at least 30% cFBs. Paracrine signaling or N-cadherin-mediated communication between CMs and cFBs was no contributing factor. Our findings suggest that the mechanoresponsive cFBs provide structural guidance for CM orientation and elongation. Our study, therefore, highlights a synergistic mechanobiological interplay between CMs and cFBs in shaping tissue organization, which is of relevance for regenerating functionally organized myocardium.

PMID:36567768 | PMC:PMC9771596 | DOI:10.1063/5.0108914

Adv Healthc Mater. 2022 Dec 26:e2202699. doi: 10.1002/adhm.202202699. Online ahead of print.

ABSTRACT

Cardiovascular diseases have been the leading cause of death worldwide during the past several decades. Cell loss is the main problem that resulted in cardiac dysfunction and further mortality. Cell therapy aiming to replenish the lost cells is proposed to treat cardiovascular diseases especially ischemic heart diseases which lead to a big portion of cell loss. Due to the direct injection's low cell retention and survival ratio, cell therapy using biomaterials as cell carriers attracts more and more attention because of their promotion of cell delivery and maintenance at the aiming sites. In this review, we systematically summarized the three main factors involved in cell therapy for myocardial tissue regeneration: cell sources (somatic cells, stem cells and engineered cells), chemical components of cell carriers (natural materials, synthetic materials and electroactive materials), and categories of cell delivery materials (patches, microspheres, injectable hydrogels, nanofiber and microneedles, etc.). An introduction of the methods including magnetic resonance/radionuclide/photoacoustic and fluorescence imaging for tracking the behavior of transplanted cells in vivo is also included. Current challenges of biomaterials-based cell therapy and their future directions are provided to give both beginners and professionals a clear view of the development and future trends in this area. This article is protected by copyright. All rights reserved.

PMID:36572412 | DOI:10.1002/adhm.202202699

Exp Ther Med. 2022 Nov 29;25(1):35. doi: 10.3892/etm.2022.11734. eCollection 2023 Jan.

ABSTRACT

Ginsenoside Rh2 (GRh2) is a monomer isolated from red ginseng that has extensive pharmacological effects. However, whether GRh2 has a protective effect on ischaemia/reperfusion (I/R) in the myocardium has yet to be elucidated. The present study aimed to identify the anti-inflammatory and antioxidant effects of GRh2 on I/R in the myocardium and its underlying mechanism. A rat model of myocardial I/R injury was constructed by ligating the left anterior descending coronary artery, which was subsequently treated with GRh2. A total of 40 male Sprague-Dawley rats were divided into the following four groups: The sham group, the I/R group, the I/R+GRh2 (10 mg/kg) group and the I/R+GRh2 (20 mg/kg) group. Neonatal rat cardiomyocytes were also used to evaluate the protective effect of GRh2 on hypoxia/reoxygenation (H/R)-induced myocardial injury in vitro. The GRh2 pre-treatment reduced the I/R- or H/R-induced release of myocardial enzymes and the production of IL-1β, IL-18 and TNF-α. GRh2 reduced the area of myocardial infarction and the histological changes in the myocardium and improved cardiac functions. In addition, GRh2 reduced the expression levels of NOD-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein, caspase-1, malondialdehyde and reactive oxygen species and increased the expression levels of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), glutathione peroxidase and superoxide dismutase. In conclusion, the present study confirmed that GRh2 could reduce oxidative stress and inflammation in cardiomyocytes after reperfusion, and its mechanism of action may be related to its regulation of the Nrf2/HO-1/NLRP3 signalling pathway.

PMID:36569435 | PMC:PMC9764046 | DOI:10.3892/etm.2022.11734

Front Pharmacol. 2022 Dec 8;13:1057918. doi: 10.3389/fphar.2022.1057918. eCollection 2022.

ABSTRACT

Cardiovascular diseases (CVD) are a group of cardiac and vascular disorders including myocardial ischemia, congenital heart disease, heart failure, hypertension, atherosclerosis, peripheral artery disease, rheumatic heart disease, and cardiomyopathies. Despite considerable progress in prophylaxis and treatment options, CVDs remain a leading cause of morbidity and mortality and impose an extremely high socioeconomic burden. Oxidative stress (OS) caused by disequilibrium in the generation of reactive oxygen species plays a crucial role in the pathophysiology of CVDs. Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor of endogenous antioxidant defense systems against OS, is considered an ideal therapeutic target for management of CVDs. Increasingly, natural products have emerged as a potential source of Nrf2 activators with cardioprotective properties and may therefore provide a novel therapeutic tool for CVD. Here, we present an updated comprehensive summary of naturally occurring products with cardioprotective properties that exert their effects by suppression of OS through activation of Nrf2 signaling, with the aim of providing useful insights for the development of therapeutic strategies exploiting natural products.

PMID:36569290 | PMC:PMC9772885 | DOI:10.3389/fphar.2022.1057918

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2022 Nov;34(11):1138-1143. doi: 10.3760/cma.j.cn121430-20220627-00604.

ABSTRACT

OBJECTIVE: To study the antioxidant protective effects of different low-dose of insulin glargine on organs of burned rats with delayed resuscitation.

METHODS: Forty male Sprague-Dawley (SD) rats were randomly divided into sham group, delayed resuscitation control group, and insulin glargine 0.5, 1.0, and 2.0 U groups, with 8 rats in each group. The rats were immersed in hot water (95.0±0.5) centigrade for 15 s to establish the third-degree scald model with 30% total body surface area. The rats in the sham group were immersed in a 37 centigrade water bath for 15 s. Insulin glargine (0.5, 1.0, 2.0 U×kg-1×d-1) was injected subcutaneously in corresponding insulin glargine group 2 hours after injury, and the same amount of normal saline was injected intraperitoneally in the delayed resuscitation control group. Intraperitoneal injection of normal saline 40 mL/kg simulated delayed resuscitation 6 hours after injury in all groups. Abdominal aortic blood samples, heart and kidney tissue were collected immediately after simulating burn in the sham group, and 24 hours after burn in other four groups. The blood glucose, myocardial enzymes [lactate dehydrogenase (LDH), creatine kinase (CK), α-hydroxybutyrate dehydrogenase (α-HBDH), and aspartate aminotransferase (AST)] and renal function indexes [blood urea nitrogen (BUN) and serum creatinine (SCr)] were measured by spectrophotometry, and the isoenzyme MB of creatine kinase (CK-MB) level was determined by immunosuppression method to evaluate the effects of different low-dose insulin glargine intervention on blood glucose, cardiac and renal functions in scalded rats with delayed resuscitation. The oxidative and antioxidant indices [xanthine oxidase (XOD), myeloperoxidase (MPO), copper-zinc superoxide dismutase (CuZn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC)] from the heart and kidney tissues of rats were detected by spectrophotometry to analyze the antioxidant effects of different low-dose insulin glargine interventions.

RESULTS: Compared with the sham group, the blood glucose of the rats in the delayed resuscitation control group was significantly increased, the heart and kidney functions were significantly reduced, the oxidation capacity was enhanced, and the antioxidant indicators were significantly reduced. After the intervention of insulin glargine, with the increase of insulin glargine dose, the blood glucose, myocardial enzyme and renal function indicators of rats showed a gradual downward trend, the oxidation indicators continued to decrease, and the antioxidant indicators showed a gradual upward trend. When the dose was 2.0 U×kg-1×d-1, the blood glucose, LDH, CK, CK-MB, α-HBDH, AST, BUN, SCr, XOD and MPO were significantly lower than those in the delayed resuscitation control group [blood glucose (mmol/L): 5.91±0.25 vs. 11.76±0.36, LDH (U/L): 3 332.12±51.61 vs. 5 008.94±490.12, CK (kU/L): 0.49±0.03 vs. 0.85±0.04, CK-MB (U/L): 125.40±12.19 vs. 267.52±11.63, α-HBDH (U/L): 122.99±5.37 vs. 240.85±13.99, AST (U/L): 11.95±1.81 vs. 17.87±1.57, BUN (mmol/L): 4.72±0.15 vs. 7.16±0.34, SCr (μmol/L): 87.11±6.51 vs. 137.50±11.36, XOD (U/g): 166.29±3.27 vs. 204.90±4.82 in heart tissue, 63.51±1.46 vs. 79.69±1.75 in kidney tissue, MPO (U/g): 1.05±0.02 vs. 1.55±0.06 in heart tissue, 1.04±0.04 vs. 1.87±0.01 in kidney tissue, all P < 0.05], and CuZn-SOD, CAT, GSH-Px and T-AOC were significantly higher than those in the delayed resuscitation control group [CuZn-SOD (kU/g): 82.95±2.69 vs. 56.52±2.26 in heart tissue, 94.50±2.73 vs. 62.02±1.66 in kidney tissue, CAT (U/g): 36.07±2.01 vs. 15.15±2.22 in heart tissue, 184.49±4.53 vs. 156.02±3.96 in kidney tissue, GSH-Px (kU/g): 231.93±8.03 vs. 179.48±3.15 in heart tissue, 239.63±7.30 vs. 172.20±2.09 in kidney tissue, T-AOC (kU/g): 4.85±0.23 vs. 2.71±0.11 in heart tissue, 5.51±0.08 vs. 3.50±0.07 in kidney tissue, all P < 0.05].

CONCLUSIONS: Different low-dose of insulin glargine (≤ 2.0 U×kg-1×d-1) could exert antioxidant protection on the heart and kidney of rats with delayed resuscitation after burns, with a dose-dependent manner.

PMID:36567555 | DOI:10.3760/cma.j.cn121430-20220627-00604

Eur J Prev Cardiol. 2022 Dec 26:zwac308. doi: 10.1093/eurjpc/zwac308. Online ahead of print.

ABSTRACT

AIMS: The 2021 European Society of Cardiology (ESC) guidelines recommend that patients with type 2 diabetes (T2D) with a very high cardiovascular disease (CVD) risk receive cardiovascular (CV)-protective glucose-lowering medication (glucagon-like peptide-1 receptor agonists or sodium-glucose co-transporter-2 inhibitors). This analysis compared previous prescribing practices with the ESC recommendations.

METHODS AND RESULTS: Patients in the Swedish National Diabetes Register (NDR) with T2D, aged 18-90 years, not receiving CV-protective glucose-lowering medication in 2017 were identified, and the ESC criteria for very high CVD risk was applied. The composite outcome of major adverse CV events (MACE; defined as CV death, non-fatal stroke or non-fatal myocardial infarction) during 2017 was calculated and the number of MACE avoided with semaglutide, an example of a CV-protective glucose-lowering medication, was estimated for patients within a certain CV risk score.Of the 320,028 patients in the NDR with T2D who were not receiving CV-protective glucose-lowering medication, 129,512 patients had a very high CVD risk. Patients with a very high CVD risk had a high incidence of MACE (75.4 events/1000 person-years), which was higher in those with atherosclerotic CVD (ASCVD) with and without elevated glycated haemoglobin (>9%; 136.5 and 90.8 events/1000 person-years, respectively). If patients with a very high CVD risk, according to the ESC, and ASCVD received semaglutide, 803 MACE may have been avoided in 2017.

CONCLUSIONS: This analysis highlights differences between previous prescribing practices in Sweden and the 2021 ESC guidelines, and offers strategies to prioritize CV-protective glucose-lowering medication for patients who would benefit most.

PMID:36567502 | DOI:10.1093/eurjpc/zwac308

Clin Endocrinol (Oxf). 2022 Dec 25. doi: 10.1111/cen.14872. Online ahead of print.

ABSTRACT

CONTEXT: Patients with chronic hypoparathyroidism (cHypoPT) are prone to intracranial-calcification, cataract, and nephrocalcinosis. In this study, we systematically investigated the possibility of increased coronary-artery calcification (CAC) and coronary-artery disease (CAD) in them.

DESIGN: Cross-sectional PATIENTS AND METHODS: 94 non-surgical cHypoPT (M:F=50:44; age=45±15years) with 18.6±9.3 years of illness were assessed. Those with dyspnea, angina, syncope, abnormal electrocardiogram, echocardiography, or significant CAC underwent coronary-angiography or myocardial-perfusion-stress imaging. Their lipid parameters and hsCRP were compared with age-matched healthy controls (Group A, n =101). The prevalence of CAC in cHypoPT was compared with that of subjects referred from cardiology-clinics (Group B, n=148, age=52±11 years).

RESULTS: One of 94 cHypoPT had known CAD. On screening, 17 cHypoPT required evaluation for CAD. Two of 17 had severe coronary-stenosis and 12 showed subclinical-CAD. CAC and aortic-valve calcification occurred in 21.5% and 11.8%. Clinical and subclinical CAD, CAC, and aortic-valve calcification in cHypoPT ≥50 years of age was 8.1%, 27.0%, 52.8%, and 27.8%, respectively. Frequency of age-adjusted CAC was comparable between cHypoPT and control-group B (30.2% vs. 30.7%, P=0.93). Elevated hsCRP was higher in cHypoPT than in controls-A (52% vs. 32%, P<0.01). Factors associated with CAD in cHypoPT were CAC and hypertension. However, CAD and CAC showed no association with long-term calcemic or phosphatemic control and intracranial-calcification in cHypoPT.

CONCLUSIONS: Clinical and subclinical CAD was observed in 3.2% and 12.8% of cHypoPT patients. The increased prevalence of CAD, CAC and aortic-valve calcification in cHypoPT above 50 years of age suggested their careful cardiac evaluation during follow-up. This article is protected by copyright. All rights reserved.

PMID:36567495 | DOI:10.1111/cen.14872

Eur Heart J Acute Cardiovasc Care. 2022 Dec 26:zuac161. doi: 10.1093/ehjacc/zuac161. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Experimental studies demonstrate protective effects of doxycycline on myocardial ischemia-reperfusion injury. The trial investigated whether doxycycline administered prior to reperfusion in patients presenting with ST-elevation myocardial infarction (STEMI) reduces infarct size (IS) and ameliorates adverse left ventricular (LV) remodeling.

METHODS: In this randomized, double-blind, placebo-controlled trial, patients presenting with STEMI undergoing primary percutaneous coronary intervention (PPCI) were randomized to either intravenous doxycycline or placebo prior to reperfusion followed by 7-days of oral doxycycline or placebo. The primary outcome was final IS adjusted for area-at-risk (fIS/AAR) measured on two cardiac magnetic resonance scans ∼6 months apart.

RESULTS: Of 103 participants, 50 were randomized to doxycycline and 53 to placebo and were matched for age (59 ± 12 vs. 60 ± 10 years), male sex (92% vs. 79%), diabetes mellitus (26% vs. 11%) and left anterior descending artery occlusion (50% vs. 49%), all p > 0.05. Patients treated with doxycycline had a trend for larger fIS/AAR (0.79 [0.5-0.9] vs. 0.61 [0.47-0.76], p = 0.06), larger fIS at 6 months (18.8% [12-26] vs. 13.6% [11-21], p = 0.08), but similar acute IS (21.7% [17-34] vs. 19.4% [14-27], p = 0.19) and AAR (26% [20-36] vs. 24.7% [16-31], p = 0.22) compared to placebo. Doxycycline did not ameliorate adverse LV remodeling (%Δend-diastolic volume index, 1.1% [-3.8-8.4] vs. -1.34% [-6.1-5.8], p = 0.42) and was independently associated with larger fIS (regression coefficient = 0.175, p = 0.03).

CONCLUSION: Doxycycline prior to PPCI neither reduced IS acutely or at 6 months nor attenuated adverse LV remodeling. These data raise safety concerns regarding doxycycline use in STEMI for infarct modulation and healing.

PMID:36567466 | DOI:10.1093/ehjacc/zuac161

Qual Life Res. 2022 Dec 26. doi: 10.1007/s11136-022-03331-8. Online ahead of print.

ABSTRACT

PURPOSE: Little is known about the impact of co-morbidities on health-related quality of life (HRQoL) for people with idiopathic pulmonary fibrosis (IPF). We aimed to investigate the relative contribution of co-morbidities to HRQoL of people with IPF.

METHODS: N = 157 participants were recruited from the Australian IPF Registry (AIPFR). Health state utilities (HSUs), and the super-dimensions of physical and psychosocial scores were measured using the Assessment of Quality of Life-8-Dimensions (AQoL-8D). The impact of co-morbidities on HRQoL was investigated using linear regression and general dominance analyses.

RESULTS: A higher number of co-morbidities was associated with lower HSUs (p trend = 0.002). Co-morbidities explained 9.1% of the variance of HSUs, 16.0% of physical super-dimensional scores, and 4.2% of psychosocial super-dimensional scores. Arthritis was associated with a significant reduction on HSUs (β = - 0.09, 95% confidence interval [CI] - 0.16 to - 0.02), largely driven by reduced scores on the physical super-dimension (β = - 0.13, 95% CI - 0.20 to - 0.06). Heart diseases were associated with a significant reduction on HSUs (β = - 0.09, 95% CI - 0.16 to - 0.02), driven by reduced scores on physical (β = - 0.09, 95% CI - 0.16 to - 0.02) and psychosocial (β = -0.10, 95% CI - 0.17 to - 0.02) super-dimensions.

CONCLUSIONS: Co-morbidities significantly impact HRQoL of people with IPF, with markedly negative impacts on their HSUs and physical health. A more holistic approach to the care of people with IPF is important as better management of these co-morbidities could lead to improved HRQoL in people with IPF.

PMID:36572788 | DOI:10.1007/s11136-022-03331-8

Br J Haematol. 2022 Dec 26. doi: 10.1111/bjh.18613. Online ahead of print.

ABSTRACT

Since the early 1970s, the treatment of acute myeloid leukaemia (AML) has undergone a major transformation. Initially based on only two drugs, an anthracycline and cytosine arabinoside, the aim of therapy was to achieve a haematological response allowing patients to recover and go home. Back in those early days, cure was not a realistic expectation. Treatment was analogous to a heart attack; upon recovery and a short respite, recurrence and death inevitably followed. Over the subsequent decades, slow but remarkable progress was made such that a subgroup of young adults could become long-term survivors. This astonishing feat was achieved initially without the use of new drugs. Supportive care played a major role with the widespread availability of platelet transfusions and improved antimicrobial therapy, particularly antifungal. No less important was the better use of existing drugs and the development of allogeneic haematopoietic cell transplantation. While initially the focus was on maximal tolerated therapy, an understanding of the immunologic role of allogeneic transplantation, better genetic characterization of the biology of the disease, advanced tools for detection of minimal disease as well as the recent development of new drugs changed the focus to a more refined approach targeting patients who are more likely to respond. Clearly, the historical paradigm where the term AML was generic and applicable to all patients requires a rethinking from the traditional therapeutic demarcations of therapy into phases of induction, consolidation and maintenance. These evolving new concepts and paradigm will be herein considered.

PMID:36572392 | DOI:10.1111/bjh.18613

Aliment Pharmacol Ther. 2022 Dec 26. doi: 10.1111/apt.17368. Online ahead of print.

ABSTRACT

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and its management in cirrhosis can be challenging due to the altered hepatic metabolism of medications and increased risk of bleeding.

AIMS: To provide a comprehensive overview of the diagnosis, pathophysiology and management of AF in patients with cirrhosis from both a cardiology and a hepatology perspective.

METHODS: An extensive literature search was performed using the terms 'atrial fibrillation' and 'cirrhosis'. Guideline documents and consensus statements were explored.

RESULTS: The prevalence of AF in patients with cirrhosis ranges between 6.6% and 14.2%, while the incidence of new-onset AF in the post-operative period after liver transplant ranged between 6.8% and 10.2%. AF in patients with cirrhosis is associated with adverse outcomes in both pre-transplant and post-transplant settings, including an increased risk of stroke when compared to the general population. We review the pathogenesis of AF in general and in cirrhosis. This review also provides guidance on the management of AF, including the use of anticoagulation and rate versus rhythm control. In the absence of strict contraindications, all patients with cirrhosis and AF should be anticoagulated. The use of DOACs is preferred over vitamin K antagonists. In patients with a high bleeding risk, a DOAC with an approved antidote may be preferred.

CONCLUSIONS: Atrial fibrillation is increased in patients with cirrhosis. AF management requires careful consideration of treatment options. Since patients with cirrhosis were excluded from all major randomised clinical trials, dedicated research on the pathophysiology and management of AF in cirrhosis is needed.

PMID:36571829 | DOI:10.1111/apt.17368

Eur Radiol. 2022 Dec 26. doi: 10.1007/s00330-022-09358-2. Online ahead of print.

ABSTRACT

OBJECTIVES: To describe the dynamic changes in cardiac deformation and tissue characteristics using cardiac magnetic resonance (CMR) in asymptomatic patients during 12 months after heart transplantation (HT).

METHODS: From April 2020 to January 2021, 21 consecutive HT patients without clinical symptoms were included in this prospective study. Multiparametric CMR was performed at 3, 6, and 12 months after HT. Twenty-five healthy volunteers served as controls.

RESULTS: During follow-up, a decline in left ventricular (LV) global radial strain (GRS) (p = 0.020) and right ventricular (RV) global longitudinal strain (GLS) (p < 0.001) and an increase in post-contrast T1 (p = 0.024) and T2 (p < 0.001) in asymptomatic HT patients occurred at 3 months, which normalized at 6 months postoperatively, compared with those in healthy controls. A decline in LVGLS (p < 0.001) and LV global circumferential strain (GCS) (p < 0.001) and an increase in native T1 (p < 0.001), T2 (p < 0.001), and extracellular volume (ECV) (p < 0.001) occurred at 3 months. Although most parameters improved gradually, LVGLS, native T1, and ECV remained abnormal compared with those in healthy controls at 12 months; only T2 and LVGCS were normalized at 6 months and 12 months, respectively. ECV was significantly correlated with LVGLS, LVGCS, and LVGRS.

CONCLUSION: Cardiac deformation and tissue characteristics were abnormal early after HT, although the patients were clinically asymptomatic. The dynamic changes in CMR characteristics demonstrate a gradual recovery of myocardial injury associated with transplantation during the first 12 months after HT.

KEY POINTS: • Multiparametric CMR can detect the dynamic changes of transplantation-associated myocardial injury. • Post-contrast T1, T2, LVGRS, and RVGLS values are normalized at 6 months after HT. • Native T1, ECV, and LVGLS values remain abnormal compared with those in healthy controls at 12 months after HT.

PMID:36571606 | DOI:10.1007/s00330-022-09358-2

Cancer. 2022 Dec 26. doi: 10.1002/cncr.34600. Online ahead of print.

ABSTRACT

BACKGROUND: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available.

METHODS: A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data.

RESULTS: Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease.

CONCLUSIONS: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies.

PLAIN LANGUAGE SUMMARY: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.

PMID:36571557 | DOI:10.1002/cncr.34600

World J Transplant. 2022 Dec 18;12(12):394-404. doi: 10.5500/wjt.v12.i12.394.

ABSTRACT

Significant scarcity of a donor pool exists for heart transplantation (HT) as the prevalence of patients with end-stage refractory heart failure is increasing exceptionally. With the discovery of effective direct-acting antiviral and favorable short-term outcomes following HT, the hearts from hepatitis C virus (HCV) patient are being utilized to increase the donor pool. Short-term outcomes with regards to graft function, coronary artery vasculopathy, and kidney and liver disease is comparable in HCV-negative recipients undergoing HT from HCV-positive donors compared to HCV-negative donors. A significant high incidence of donor-derived HCV transmission was observed with great success of achieving sustained viral response with the use of direct-acting antivirals. By accepting HCV-positive organs, the donor pool has expanded with younger donors, a shorter waitlist time, and a reduction in waitlist mortality. However, the long-term outcomes and impact of specific HCV genotypes remains to be seen. We reviewed the current literature on HT from HCV-positive donors.

PMID:36570408 | PMC:PMC9782687 | DOI:10.5500/wjt.v12.i12.394

World J Transplant. 2022 Dec 18;12(12):388-393. doi: 10.5500/wjt.v12.i12.388.

ABSTRACT

Despite organ transplantation being the most successful treatment for end-stage organ dysfunction, the number of annual solid organ transplantations is much lower than that required to satisfy the demand of patients on waiting lists. The explanation for this phenomenon is the relative scarcity of non-living organ donors due to several factors, such as: (1) Late arrival of patients with a neurocritical condition to an emergency service; (2) lack of detection of those patients as possible organ donors by health professionals dedicated to pro curement or by clinicians at emergency and intensive care units, for instance; (3) late transfer of the patient to an intensive care unit to try to recover their health and to provide hemodynamic, ventilatory, and metabolic support; (4) lack of confirmation of the physiological status of the possible donor; (5) late or incorrect positive diagnosis of the subject's death, either due to brain or cardiac death; (6) difficulty in obtaining legal authorization, either by direct relatives or by the authority, for the extraction of organs; and (7) deficient retrieval surgery of the organs actually donated. The recent reports of relatively successful xenotransplants from genetically modified pigs open the possibility to fix this mismatch between supply and demand, but some technical (organ rejection and opp ortunistic infections), and economic issues, still remain before accepting a progressive replacement of the organ sources for transplantation. An approximate economic cost analysis suggests that the hypothetical acquisition cost of any genetically modified pig derived organ is high and would not even satisfy the solid organ demand of the wealthiest countries.

PMID:36570406 | PMC:PMC9782685 | DOI:10.5500/wjt.v12.i12.388

Front Immunol. 2022 Dec 8;13:1060576. doi: 10.3389/fimmu.2022.1060576. eCollection 2022.

ABSTRACT

INTRODUCTION: In de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model.

METHODS: Naïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period.

RESULTS AND DISCUSSION: Administering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L-/- recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically.

PMID:36569922 | PMC:PMC9773869 | DOI:10.3389/fimmu.2022.1060576

Front Cell Dev Biol. 2022 Dec 8;10:1065536. doi: 10.3389/fcell.2022.1065536. eCollection 2022.

ABSTRACT

The only curative therapy for many endstage diseases is allograft organ transplantation. Due to the limited supply of donor organs, relatively few patients are recipients of a transplanted organ. Therefore, new strategies are warranted to address this unmet need. Using gene editing technologies, somatic cell nuclear transfer and human induced pluripotent stem cell technologies, interspecies chimeric organs have been pursued with promising results. In this review, we highlight the overall technical strategy, the successful early results and the hurdles that need to be addressed in order for these approaches to produce a successful organ that could be transplanted in patients with endstage diseases.

PMID:36568986 | PMC:PMC9773398 | DOI:10.3389/fcell.2022.1065536

Transplant Direct. 2022 Dec 16;9(1):e1424. doi: 10.1097/TXD.0000000000001424. eCollection 2023 Jan.

ABSTRACT

Cardiorenal syndrome (CRS) contributes significantly to morbidity and mortality in patients requiring mechanical circulatory support and transplantation. There are no validated markers to predict major adverse kidney events (MAKEs), for which simultaneous heart-kidney transplant (SHKT) could offer improved survival. We evaluate renal histology in predicting MAKEs in transplant-listed patients.

METHODS: We identified 18 patients with renal histology consistent with CRS from 655 consecutive heart transplant-listed patients between 2010 and 2019. Biopsies were analyzed for glomerular, tubular, interstitial, and arteriolar changes tallied to give a biopsy chronicity score. The primary outcome, MAKE, was a composite of death, need for renal replacement therapy (RRT), or estimated glomerular filtration rate decline >50%. These were evaluated at 2 time points: before and following the transplant. Secondary outcomes included the individual components of the composite outcomes and the need for short-term RRT following the transplant.

RESULTS: The mean age was 52.3 y, 22% were female. Five patients did not survive to transplant. One patient underwent successful SHKT. MAKE occurred in 8 of 18 before the transplant and in 8 of 13 following the transplant. Neither outcome was predicted by baseline biochemistry. The biopsy chronicity score was significantly higher in patients with MAKE before transplant (4.3 versus 1.7, P = 0.024) and numerically higher in patients requiring short-term RRT following transplant (3.2 versus 0.7, P = 0.075). Contrary to limited previous literature, interstitial fibrosis did not predict any outcome, whereas tubular atrophy and arteriosclerosis were associated with MAKE before transplant.

CONCLUSIONS: A higher biopsy chronicity score was associated with adverse kidney endpoints, raising its potential utility over standard biochemistry in considering SHKT referral.

PMID:36568725 | PMC:PMC9760601 | DOI:10.1097/TXD.0000000000001424

Crit Care Explor. 2022 Dec 22;4(12):e0812. doi: 10.1097/CCE.0000000000000812. eCollection 2022 Dec.

ABSTRACT

To describe the clinical characteristics and organ donation rate of patients supported by extracorporeal membrane oxygenation (ECMO) at the time of death.

DESIGN: Retrospective observational study. Pearson chi-square and Fisher exact tests were used in statistical analyses.

SETTING: One hundred twenty-seven acute care hospitals in New Jersey, Pennsylvania, and Delaware.

PATIENTS: Adult and pediatric patients who were on ECMO at the time of referral to a large organ procurement organization (OPO) between 2016 and 2020.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Nineteen thousand nine hundred thirty patients were referred to the OPO between November 2016 and September 2020, of which 5,034 were medically suitable potential donors. Of this cohort, 143 patients were supported on ECMO at the time of OPO referral and 141 were included in analyses (median age 47 yr, 60% male). Thirty-three percent (46/141, median age 48 yr, 52% male) donated organs, compared with 50% of non-ECMO patients (p ≤ 0.0005). ECMO and non-ECMO patients had organs recovered but not transplanted at similar rates (11% vs 10%, p = 0.8). There were no significant differences in sex (p = 0.16) or ethnicity (p = 0.50) between organ donor and nondonor groups. Fifty-one percent (21/41) of organ donors donated after circulatory death and 49% (20/41) after brain death. Patients declared dead by neurologic criteria were more likely to donate (51%) than those declared dead by circulatory criteria (21%, p < 0.001). Frequency of cardiac arrest prior to ECMO was similar between donors and nondonors (p = 0.68). Thirty-nine percent (16/41) of donors had an out-of-hospital cardiac arrest (OHCA) and 51% (21/41) were cannulated via extracorporeal cardiopulmonary resuscitation (ECPR). The most common reason patients were not donors was that family declined (57%).

CONCLUSIONS: One-third of patients referred to the OPO on ECMO at the time of death donated organs. While donation occurred less frequently after ECMO, ECMO and non-ECMO patients had organs used rather than discarded at a similar rate. Patients successfully donated following OHCA and/or ECPR. Clinicians should not consider ECMO a barrier to organ donation.

PMID:36567782 | PMC:PMC9760628 | DOI:10.1097/CCE.0000000000000812