Nonalcoholic Fatty Liver Disease and the Heart: JACC State-of-the-Art Review

Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) are both manifestations of end-organ damage of the metabolic syndrome. Through multiple pathophysiological mechanisms, CVD and NAFLD are associated with each other. Systemic inflammation, endothelial dysfunction, hepatic insulin resistance, oxidative stress, and altered lipid metabolism are some of the mechanisms by which NAFLD increases the risk of CVD. Patients with NAFLD develop increased atherosclerosis, cardiomyopathy, and arrhythmia, which clinically result in cardiovascular morbidity and mortality. Defining the mechanisms linking these 2 diseases offers the opportunity to further develop targeted therapies. The aim of this comprehensive review is to examine the association between CVD and NAFLD and discuss the overlapping management approaches.     

Legg‐Calvé‐Perthes Disease Produces Chronic Hip Synovitis and Elevation of Interleukin‐6 in the Synovial Fluid

Legg‐Calvé‐Perthes disease (LCPD) is a childhood hip disorder of ischemic osteonecrosis of the femoral head. Hip joint synovitis is a common feature of LCPD, but the nature and pathophysiology of the synovitis remain unknown. The purpose of this study was to determine the chronicity of the synovitis and the inflammatory cytokines present in the synovial fluid at an active stage of LCPD. Serial MRI was performed on 28 patients. T2‐weighted and gadolinium‐enhanced MR images were used to assess synovial effusion and synovial enhancement (hyperemia) over time. A multiple‐cytokine assay was used to determine the levels of 27 inflammatory cytokines and related factors present in the synovial fluid from 13 patients. MRI analysis showed fold increases of 5.0 ± 3.3 and 3.1 ± 2.1 in the synovial fluid volume in the affected hip compared to the unaffected hip at the initial and the last follow‐up MRI, respectively. The mean duration between the initial and the last MRI was 17.7 ± 8.3 months. The volume of enhanced synovium on the contrast MRI was increased 16.5 ± 8.5 fold and 6.3 ± 5.6 fold in the affected hip compared to the unaffected hip at the initial MRI and the last follow‐up MRI, respectively. In the synovial fluid of the affected hips, IL‐6 protein levels were significantly increased (LCPD: 509 ± 519 pg/mL, non‐LCPD: 19 ± 22 pg/mL; p = 0.0005) on the multi‐cytokine assay. Interestingly, IL‐1β and TNF‐α levels were not elevated. In the active stage of LCPD, chronic hip synovitis and significant elevation of IL‐6 are produced in the synovial fluid. Further studies are warranted to investigate the role of IL‐6 on the pathophysiology of synovitis in LCPD and how it affects bone healing. © 2015 American Society for Bone and Mineral Research     

A Biomechanical Comparison of Fiberglass Casts and 3-Dimensional–Printed,Open-Latticed,Ventilated Casts

Background: The aim of this study was to quantify the stabilizing properties of a 3-dimensional (3D)-printed short-arm cast and compare those properties with traditional fiberglass casts in a cadaveric subacute distal radius fracture model. Methods: A cadaveric subacute fracture model was created in 8 pairs of forearms. The specimens were equally allocated to a fiberglass cast or 3D-printed cast group. All specimens were subjected to 3 biomechanical testing modalities simulating daily life use: flexion and extension of digits, pronation and supination of the hand, and 3-point bending. Between each loading modality, radiological evaluation of the specimens was performed to evaluate possible interval displacement. Interfragmentary motion was quantified using a 3D motion-tracking system. Results: Radiographic assessment did not reveal statistically significant differences in radiographic parameters between the 2 groups before and after biomechanical testing. A statistically significant difference in interfragmentary motion was calculated with the 3-point bending test, with a mean difference of 0.44 (±0.48) mm of motion. Conclusions: A statistically significant difference in interfragmentary motion between the 2 casting groups was only identified in 3-point bending. However, the clinical relevance of this motion remains unclear as the absolute motion is less than 1 mm. The results of this study show noninferiority of the 3D-printed casts compared with the traditional fiberglass casts in immobilizing a subacute distal radius fracture model. These results support the execution of a prospective randomized clinical trial comparing both casting techniques.     

Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction

For over a century, there has been intense debate as to the reason why some cardiac stresses are pathological and others are physiological. One long-standing theory is that physiological overloads such as exercise are intermittent, while pathological overloads such as hypertension are chronic. In this study, we hypothesized that the nature of the stress on the heart, rather than its duration, is the key determinant of the maladaptive phenotype. To test this, we applied intermittent pressure overload on the hearts of mice and tested the roles of duration and nature of the stress on the development of cardiac failure. Despite a mild hypertrophic response, preserved systolic function, and a favorable fetal gene expression profile, hearts exposed to intermittent pressure overload displayed pathological features. Importantly, intermittent pressure overload caused diastolic dysfunction, altered beta-adrenergic receptor (betaAR) function, and vascular rarefaction before the development of cardiac hypertrophy, which were largely normalized by preventing the recruitment of PI3K by betaAR kinase 1 to ligand-activated receptors. Thus stress-induced activation of pathogenic signaling pathways, not the duration of stress or the hypertrophic growth per se, is the molecular trigger of cardiac dysfunction.     

Innate immunity alone is not sufficient for chronic rejection but predisposes healed allografts to T cell-mediated pathology

BackgroundAcute allograft rejection is dependent on adaptive immunity, but it is unclear whether the same is true for chronic rejection. Here we asked whether innate immunity alone is sufficient for causing chronic rejection of mouse cardiac allografts.MethodsWe transplanted primarily vascularized cardiac grafts to recombinase activating gene-knockout (RAG^?/?) mice that lack T and B cells but have an intact innate immune system. Recipients were left unmanipulated, received adjuvants that stimulate innate immunity, or were reconstituted with B-1 lymphocytes to generate natural IgM antibodies. In a second model, we transplanted cardiac allografts to mice that lack secondary lymphoid tissues (splenectomized aly/aly recipients) and studied the effect of NK cell inactivation on T cell-mediated chronic rejection.ResultsAcute cardiac allograft rejection was not observed in any of the recipients. Histological analysis of allografts harvested 50 to 90 days after transplantation to RAG^?/? mice failed to identify chronic vascular or parenchymal changes beyond those observed in control syngeneic grafts. Chronic rejection of cardiac allografts parked in splenectomized aly/aly mice was observed only after the transfer of exogenously activated T cells. NK inactivation throughout the experiment, or during the parking period alone, reduced the severity of T cell-dependent chronic rejection.ConclusionsThe innate immune system alone is not sufficient for causing chronic rejection. NK cells predispose healed allografts to T cell-dependent chronic rejection and may contribute to chronic allograft pathology.     

Endoscopic Therapy with 2-Octyl-cyanoacrylate for the Treatment of Gastric Varices

Background

Gastric variceal bleeding is associated with significant morbidity and mortality and limited endoscopic therapeutic options.

Aim

The aim of this study was to evaluate the short- and long-term efficacy and safety of endoscopic therapy with 2-octyl-cyanoacrylate in patients with gastric variceal bleeding.

Methods

A single-center retrospective review of patients receiving endoscopic therapy for gastric variceal hemorrhage. Patient demographics, laboratory, and procedural data were collected. Patients were followed to death, liver transplantation, or last follow-up. Success rates were defined as immediate control of bleeding; early re-bleeding (1–7 days), short-term re-bleeding (1–12 weeks), overall survival, and serious procedure complications.

Results

A total of 41 patients (39 with cirrhosis) underwent 54 cyanoacrylate injections during study period. Mean age was 57 and 73 % were males. Twenty-four (58.5 %) patients had failed or were deemed ineligible for transjugular intra-hepatic portosystemic shunt, and 5 % were done for primary prophylaxis. Immediate hemostasis was achieved in five active bleeders. During a median survival time of 117 days, early re-bleeding was seen in 1 (2.4 %), short-term re-bleeding in five patients (12 %), and varices were eradicated in 15 (46.8 %) patients on follow-up. Mean MELD score at the time of the first injection was 17.1 ± 7.8. Mean volume injected was 3.4 cc and median number of varices injected per session was one. Eight patients died during the long-term follow-up: metastatic cancer (2), infections (3), liver failure (1), and re-bleeding (2). There were no serious procedure-related complications.

Conclusions

Endoscopic cyanoacrylate therapy appears effective and safe for treatment of patients with bleeding from gastric varices or high-risk stigmata.     

Sirtuin‐6 deficiency exacerbates diabetes‐induced impairment of wound healing

Delayed wound healing is one of the major complications in diabetes and is characterized by chronic proinflammatory response, and abnormalities in angiogenesis and collagen deposition. Sirtuin family proteins regulate numerous pathophysiological processes, including those involved in promotion of longevity, DNA repair, glycolysis and inflammation. However, the role of sirtuin 6 (SIRT6), a NAD+‐dependent nuclear deacetylase, in wound healing specifically under diabetic condition remains unclear. To analyse the role of SIRT6 in cutaneous wound healing, paired 6‐mm stented wound was created in diabetic db/db mice and injected siRNA against SIRT6 in the wound margins (transfection agent alone and nonsense siRNA served as controls). Wound time to closure was assessed by digital planimetry, and wounds were harvested for histology, immunohistochemistry and Western blotting. SIRT6‐siRNA‐treated diabetic wound showed impaired healing, which was associated with reduced capillary density (CD31‐staining vessels) when compared to control treatment. Interestingly, SIRT6 deficiency decreased vascular endothelial growth factor expression and proliferation markers in the wounds. Furthermore, SIRT6 ablation in diabetic wound promotes nuclear factor‐κB (NF‐κB) activation resulting in increased expression of proinflammatory markers (intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, tumor necrosis factor‐α and interleukin‐1β) and increased oxidative stress. Collectively, our findings demonstrate that loss of SIRT6 in cutaneous wound aggravates proinflammatory response by increasing NF‐κB activation, oxidative stress and decrease in angiogenesis in the diabetic mice. Based on these findings, we speculate that the activation of SIRT6 signalling might be a potential therapeutic approach for promoting wound healing in diabetics.