Inhibition of the NLRP3/IL-1ß axis protects against sepsis-induced cardiomyopathy.

BACKGROUND: Septic cardiomyopathy worsens the prognosis of critically ill patients. Clinical data suggest that interleukin-1ß (IL-1ß), activated by the NLRP3 inflammasome, compromises cardiac function. Whether or not deleting Nlrp3 would prevent cardiac atrophy and improve diastolic cardiac function in sepsis was unclear. Here, we investigated the role of NLRP3/IL-1ß in sepsis-induced cardiomyopathy and cardiac atrophy. METHODS: Male Nlrp3 knockout (KO) and wild-type (WT) mice were exposed to polymicrobial sepsis by caecal ligation and puncture (CLP) surgery (KO, n = 27; WT, n = 33) to induce septic cardiomyopathy. Sham-treated mice served as controls (KO, n = 11; WT, n = 16). Heart weights and morphology, echocardiography and analyses of gene and protein expression were used to evaluate septic cardiomyopathy and cardiac atrophy. IL-1ß effects on primary and immortalized cardiomyocytes were investigated by morphological and molecular analyses. IonOptix and real-time deformability cytometry (RT-DC) analysis were used to investigate functional and mechanical effects of IL-1ß on cardiomyocytes. RESULTS: Heart morphology and echocardiography revealed preserved systolic (stroke volume: WT sham vs. WT CLP: 33.1 ± 7.2 µL vs. 24.6 ± 8.7 µL, P < 0.05; KO sham vs. KO CLP: 28.3 ± 8.1 µL vs. 29.9 ± 9.9 µL, n.s.; P < 0.05 vs. WT CLP) and diastolic (peak E wave velocity: WT sham vs. WT CLP: 750 ± 132 vs. 522 ± 200 mm/s, P < 0.001; KO sham vs. KO CLP: 709 ± 152 vs. 639 ± 165 mm/s, n.s.; P < 0.05 vs. WT CLP) cardiac function and attenuated cardiac (heart weight-tibia length ratio: WT CLP vs. WT sham: -26.6%, P < 0.05; KO CLP vs. KO sham: -3.3%, n.s.; P < 0.05 vs. WT CLP) and cardiomyocyte atrophy in KO mice during sepsis. IonOptix measurements showed that IL-1ß decreased contractility (cell shortening: IL-1ß: -15.4 ± 2.3%, P < 0.001 vs. vehicle, IL-1RA: -6.1 ± 3.3%, P < 0.05 vs. IL-1ß) and relaxation of adult rat ventricular cardiomyocytes (time-to-50% relengthening: IL-1ß: 2071 ± 225 ms, P < 0.001 vs. vehicle, IL-1RA: 564 ± 247 ms, P < 0.001 vs. IL-1ß), which was attenuated by an IL-1 receptor antagonist (IL-1RA). RT-DC analysis indicated that IL-1ß reduced cardiomyocyte size (P < 0.001) and deformation (P < 0.05). RNA sequencing showed that genes involved in NF-κB signalling, autophagy and lysosomal protein degradation were enriched in hearts of septic WT but not in septic KO mice. Western blotting and qPCR disclosed that IL-1ß activated NF-κB and its target genes, caused atrophy and decreased myosin protein in myocytes, which was accompanied by an increased autophagy gene expression. These effects were attenuated by IL-1RA. CONCLUSIONS: IL-1ß causes atrophy, impairs contractility and relaxation and decreases deformation of cardiomyocytes. Because NLRP3/IL-1ß pathway inhibition attenuates cardiac atrophy and cardiomyopathy in sepsis, it could be useful to prevent septic cardiomyopathy.

High risk of non-alcoholic liver disease mortality in patients with chronic hepatitis C with illicit substance use disorder.

Aims: Hepatitis C virus (HCV) is a slowly progressive disease, often transmitted among people who inject drugs (PWID). Mortality in PWID is high, with an overrepresentation of drug-related causes. This study investigated the risk of death in patients with chronic hepatitis C virus (HCV) infection with or without illicit substance use disorder (ISUD).Methods: Patients with HCV were identified using the Swedish National Patient Registry according to the International Classification of Diseases-10 (ICD-10) code B18.2, with ≤5 matched comparators from the general population. Patients with ≥2 physician visits with ICD-10 codes F11, F12, F14, F15, F16, or F19 were considered to have ISUD. The underlying cause of death was analyzed for alcoholic liver disease, non-alcoholic liver disease, liver cancer, drug-related and external causes, non-liver cancers, or other causes. Mortality risks were assessed using the standardized mortality ratio (SMR) with 95% CIs and Cox regression analyses for cause-specific hazard ratios.Results: In total, 38,186 patients with HCV were included, with 31% meeting the ISUD definition. Non-alcoholic liver disease SMRs in patients with and without ISUD were 123.2 (95% CI, 103.7-145.2) and 69.4 (95% CI, 63.8-75.3), respectively. The significant independent factors associated with non-alcoholic liver disease mortality were older age, being unmarried, male sex, and having ISUD.Conclusions: The relative risks for non-alcoholic liver disease mortality were elevated for patients with ISUD. Having ISUD was a significant independent factor for non-alcoholic liver disease. Thus, patients with HCV with ISUD should be given HCV treatment to reduce the risk for liver disease.

Frequent loss to follow-up after diagnosis of hepatitis C virus infection: A barrier towards the elimination of hepatitis C virus.

BACKGROUND: Previous studies on hepatitis C cascade of care have been mainly focused on diagnosis and treatment rate, while less attention has been given to patients lost to follow-up (LTFU) after diagnosis. Analyses of this latter issue on population level are missing. AIMS: In this nationwide study of people with HCV, we aimed to estimate the proportion LTFU after HCV diagnosis, characterize them, and analyze their other healthcare contacts. METHODS: Patients diagnosed with chronic HCV in the Swedish National Patient Register during 2001-2011 and still alive December 31, 2013, were included. The number of cured patients without need of follow-up was estimated. Visits to HCV specialist care during 2012-2013 were analysed. For those LTFU, other specialist care contacts were studied. RESULTS: In total 29 217 patients were included, with 24 733 with need of HCV care. 61% (n = 15 007) of them were LTFU from HCV care in 2012-2013 and 58% did not attend HCV care during the second year after HCV diagnosis. The departments of surgery/orthopaedic or psychiatry/dependency were the most common other non-primary healthcare contacts. Predictors for LTFU were young age, male sex, low education, presence of psychiatric/dependency diagnosis, unmarried and longer duration since diagnosis of HCV. CONCLUSIONS: This study showed that almost two-thirds of patients were LTFU after HCV diagnosis, with frequent occurrence early after diagnosis. Efforts to link patients back to HCV care, in combination with early and easy access to HCV treatment and harm reduction, are necessary to reach the HCV elimination goal.

Ninjurin1 regulates striated muscle growth and differentiation.

Chronic pressure overload due to aortic valve stenosis leads to pathological cardiac hypertrophy and heart failure. Hypertrophy is accompanied by an increase in myocyte surface area, which requires a proportional increase in the number of cell-cell and cell-matrix contacts to withstand enhanced workload. In a proteomic analysis we identified nerve injury-induced protein 1 (Ninjurin1), a 16kDa transmembrane cell-surface protein involved in cell adhesion and nerve repair, to be increased in hypertrophic hearts from patients with aortic stenosis. We hypothesised that Ninjurin1 is involved in myocyte hypertrophy. We analyzed cardiac biopsies from aortic-stenosis patients and control patients undergoing elective heart surgery. We studied cardiac hypertrophy in mice after transverse aortic constriction and angiotensin II infusions, and performed mechanistic analyses in cultured myocytes. We assessed the physiological role of ninjurin1 in zebrafish during heart and skeletal muscle development. Ninjurin1 was increased in hearts of aortic stenosis patients, compared to controls, as well as in hearts from mice with cardiac hypertrophy. Besides the 16kDa Ninjurin1 (Ninjurin1-16) we detected a 24kDa variant of Ninjurin1 (Ninjurin1-24), which was predominantly expressed during myocyte hypertrophy. We disclosed that the higher molecular weight of Ninjurin1-24 was caused by N-glycosylation. Ninjurin1-16 was contained in the cytoplasm of myocytes where it colocalized with stress-fibers. In contrast, Ninjurin1-24 was localized at myocyte membranes. Gain and loss-of-function experiments showed that Ninjurin1-24 plays a role in myocyte hypertrophy and myogenic differentiation in vitro. Reduced levels of ninjurin1 impaired cardiac and skeletal muscle development in zebrafish. We conclude that Ninjurin1 contributes to myocyte growth and differentiation, and that these effects are mainly mediated by N-glycosylated Ninjurin1-24.

Higher risk of renal disease in chronic hepatitis C patients: Antiviral therapy survival benefit in patients on hemodialysis.

BACKGROUND & AIMS: Several studies have shown that chronic hepatitis C (CHC) infection has a negative impact on kidney function, as well as survival, in patients with chronic kidney disease (CKD) or on hemodialysis. The aim of this nationwide registry study was to describe renal disease in Swedish patients with CHC. METHODS: In the present study, patients were identified for CHC (B18.2) and CKD (N18) according to the International Classification of Diseases (ICD)-10 in the nationwide Swedish inpatient care day surgery (1997-2013) and non-primary outpatient care (2001-2013) patient registries. Hemodialysis was defined using the procedure code in the non-primary outpatient care. For each patient, up to five non-CHC diagnosed age/sex/place of residency-matched comparators were drawn from the general population at the time of diagnosis. Follow-up started at the date of CHC diagnosis and patients accrued person-time until, whichever came first, death, emigration or December 31st, 2013. RESULTS: Between 2001 and 2013, 42,522 patients received a CHC diagnosis. Of these patients, 2.5% (1,077/45,222) were diagnosed with CKD during 280,123 person-years, compared with 0.7% (1,454/202,694) in the matched general population comparators (1,504,765 person-years), resulting in a standardized incidence ratio (SIR) of 4.0. There was a 3.3-7.0-fold risk of patients with CHC requiring hemodialysis. Overall, 17% of patients with CHC receiving hemodialysis were treated for CHC; 24% in the treated cohort died compared with 56% of the untreated cohort (p <0.0001), with antiviral treatment improving survival with an odds ratio of 3.901 (p = 0.001). CONCLUSIONS: The results from this nationwide registry study showed that patients with CHC are at a higher risk of developing CKD. Furthermore, hepatitis C treatment seemed to improve survival for patients with CHC on hemodialysis compared with untreated patients. LAY SUMMARY: Hepatitis C is an infectious disease that mainly infects the liver, but has also been shown to have negative effects on other organs. This nationwide study demonstrates an increased risk of hepatitis C patients developing reduced kidney function and the need for dialysis. The study also showed improved survival in dialysis patients who received antiviral treatment.

Deletion of Nlrp3 protects from inflammation-induced skeletal muscle atrophy.

BACKGROUND: Critically ill patients develop atrophic muscle failure, which increases morbidity and mortality. Interleukin-1ß (IL-1ß) is activated early in sepsis. Whether IL-1ß acts directly on muscle cells and whether its inhibition prevents atrophy is unknown. We aimed to investigate if IL-1ß activation via the Nlrp3 inflammasome is involved in inflammation-induced atrophy. METHODS: We performed an experimental study and prospective animal trial. The effect of IL-1ß on differentiated C2C12 muscle cells was investigated by analyzing gene-and-protein expression, and atrophy response. Polymicrobial sepsis was induced by cecum ligation and puncture surgery in Nlrp3 knockout and wild type mice. Skeletal muscle morphology, gene and protein expression, and atrophy markers were used to analyze the atrophy response. Immunostaining and reporter-gene assays showed that IL-1ß signaling is contained and active in myocytes. RESULTS: Immunostaining and reporter gene assays showed that IL-1ß signaling is contained and active in myocytes. IL-1ß increased Il6 and atrogene gene expression resulting in myocyte atrophy. Nlrp3 knockout mice showed reduced IL-1ß serum levels in sepsis. As determined by muscle morphology, organ weights, gene expression, and protein content, muscle atrophy was attenuated in septic Nlrp3 knockout mice, compared to septic wild-type mice 96 h after surgery. CONCLUSIONS: IL-1ß directly acts on myocytes to cause atrophy in sepsis. Inhibition of IL-1ß activation by targeting Nlrp3 could be useful to prevent inflammation-induced muscle failure in critically ill patients.

Prevalence and comorbidities of chronic hepatitis C: a nationwide population-based register study in Sweden.

PURPOSE: The aim of this study was to estimate the prevalence of physician-diagnosed and registered chronic hepatitis C (CHC), and to estimate the reported frequencies of Charlson comorbidities compared with matched comparators from the general population. MATERIALS AND METHODS: Patients were identified according to ICD codes for CHC in the Swedish National Patient Register (1997-2013). Prevalence was estimated according to different patient identification algorithms and for different subgroups. Charlson comorbidities were ascertained from the same register and compared with age/sex/county of residence matched general population comparators. RESULTS: A total of 34,633 individuals with physician-diagnosed CHC were alive in Sweden in 2013 (mean age, 49 years; 64% men), corresponding to a physician-diagnosed prevalence of 0.36%. The prevalence varied by case definition (0.22%-0.36%). The estimate dropped to 0.14% for monitored CHC disease (defined as ≥1 CHC-related visit in 2013). Overall, 41.3% of the CHC patients had ≥1 physician-registered Charlson comorbidity; the most common was liver diseases (22.1%). Compared with matched comparators from the general population (n = 171,338), patients with CHC had more physician-diagnosed and registered diseases such as chronic pulmonary disease (10.2% vs. 4.0%), diabetes (10.6% vs. 5.5%) and liver-related cancer (1.3% vs. 0.2%; all p < .01). No information on behavioural factors, such as smoking, alcohol consumption or on-going illicit drug use, was available. CONCLUSION: The physician-diagnosed prevalence of CHC was slightly lower than previously reported estimates, and varied by case definition. The additional comorbidities observed in the CHC group should be taken into consideration, as these comorbidities add to the disease burden.

Sick leave and disability pension in inflammatory bowel disease: a systematic review.

BACKGROUND & AIMS: Inflammatory bowel disease has considerable effects on work-related outcomes and leads to high societal costs due to sick leave and disability pension. The aims of this study were to systematically review evidence on work-related outcomes that are relevant to productivity losses and to evaluate whether medical or surgical interventions have a positive impact on patients' work ability. METHODS: A systematic literature search in PubMed was conducted in June 2013. Abstracts were screened by two independent reviewers, and full-text articles describing the frequency of work-related outcomes were retrieved. Two independent reviewers extracted data according to the PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses. Findings were organized by study design (non-interventional/interventional). Non-interventional studies were structured according to whether they presented data in comparison to control groups or not and interventional studies were summarized according to type of intervention. RESULTS: This review included 30 non-interventional (15 with comparison groups and 15 without comparison group) and 17 interventional studies (9 surgical and 8 medical). The majority of the studies reported a high burden of work-related outcomes among inflammatory bowel disease patients regardless of the methodology used. While biologic agents showed positive effect on work absenteeism and presenteeism in randomized clinical trials, the impact of surgical interventions needs further evaluation. CONCLUSIONS: Inflammatory bowel disease patients experience a high burden in work-related outcomes. Additional data on productivity losses and the long-term impact of interventions is needed to help inform decision-makers about treatment options and their benefits in reducing productivity losses in inflammatory bowel disease patients.