Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease.

Background & Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. Methods: Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n = 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. Results: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocyte/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis, we demonstrate that recruitment of MdMs precedes Kupffer cell loss and liver damage. Electron microscopy of isolated macrophages revealed increased lipid accumulation in MdMs, and ex vivo lipid transfer experiments suggested that MdMs may serve a distinct role in lipid uptake during MAFLD. Conclusions: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD. Impact and implications: Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD.

Distinct Inflammatory Milieu in Patients With Right Heart Failure.

BACKGROUND: Right heart failure (RHF) is associated with worse clinical outcomes. In addition to hemodynamic perturbations, the syndrome of RHF involves liver congestion and dysfunction. The mechanisms that underlie heart-liver interactions are poorly understood and may involve secreted factors. As a first step to understand the cardiohepatic axis, we sought to elucidate the circulating inflammatory milieu in patients with RHF. METHODS: Blood samples were collected from the inferior vena cava and hepatic veins during right heart catheterization from 3 groups of patients: (1) controls with normal cardiac function, (2) patients with heart failure who did not meet all criteria of RHF, and (3) patients who met prespecified criteria for RHF defined by hemodynamic and echocardiographic parameters. We performed a multiplex protein assay to survey levels of several circulating markers and analyzed their association with mortality and the need for a left ventricular assist device or heart transplant. Finally, we leveraged publicly available single-cell RNA sequencing data and performed tissue imaging to evaluate the expression of these factors in the liver. RESULTS: In this study, RHF was associated with elevated levels of a subset of cytokines/chemokines/growth factors compared with controls. In particular, soluble CD163 (cluster of differentiation 163) and CXCL12 (chemokine [C-X-C motif] ligand 12) were higher in RHF and predicted left ventricular assist device/transplant-free survival in an independent validation cohort. Furthermore, single-cell RNA sequencing and immunohistochemistry of human liver biopsies suggest that these factors are expressed by Kupffer cells and may be liver derived. CONCLUSIONS: RHF is associated with a distinct circulating inflammatory profile. Soluble CD163 and CXCL12 are novel biomarkers that can prognosticate patient outcomes. Future studies to define how these molecules influence heart failure phenotypes and disease progression may lead to new approaches to the management of patients with RHF.

A Distinct Inflammatory Milieu in Patients with Right Heart Failure.

Background: Right heart failure (RHF) is associated with worse clinical outcomes. In addition to hemodynamic perturbations, the syndrome of RHF involves liver congestion and dysfunction. The mechanisms that underlie heart-liver interactions are poorly understood and may involve secreted factors. As a first step to understand the cardiohepatic axis, we sought to elucidate the circulating inflammatory milieu in patients with RHF. Methods: Blood samples were collected from the IVC and hepatic veins during right heart catheterization from 3 groups of patients: 1) controls with normal cardiac function, 2) patients with heart failure (HF) who did not meet all criteria of RHF, and 3) patients who met prespecified criteria for RHF defined by hemodynamic and echocardiographic parameters. We performed multiplex protein assay to survey levels of several circulating markers and analyzed their association with mortality and need for left ventricular assist device or heart transplant. Finally, we leveraged publicly available single cell RNA sequencing (scRNAseq) data and performed tissue imaging to evaluate expression of these factors in the liver. Results: In this study of 43 patients, RHF was associated with elevated levels of a subset of cytokines/chemokines/growth factors compared to controls. In particular, soluble CD163 (sCD163) and CXCL12 were higher in RHF and predicted survival in an independent validation cohort. Furthermore, scRNAseq and immunohistochemistry of human liver biopsies suggest that these factors are expressed by Kupffer cells and may be liver derived. Conclusions: RHF is associated with a distinct circulating inflammatory profile. sCD163 and CXCL12 are novel biomarkers that can prognosticate patient outcomes. Future studies to define how these molecules influence HF phenotypes and disease progression may lead to new approaches to management of patients with RHF.

Established Clinical Prediction Rules for Bleeding Had Mediocre Discrimination in Left Ventricular Assist Device Recipients.

Left ventricular assist devices (LVAD) reduce mortality in patients with end-stage heart failure, but LVAD management is frequently complicated by bleeding. Bleeding prediction post-LVAD implantation is challenging as prediction rules for hemorrhage have not been rigorously studied in this population. We aimed to validate clinical prediction rules for bleeding, derived in the atrial fibrillation and venous thromboembolism populations, in an LVAD cohort. This was a retrospective cohort study of LVAD recipients at an academic center. The primary end-point was time to gastrointestinal bleed or intracranial hemorrhage after implant; the secondary end-point was time to any major hemorrhage after hospital discharge. Four hundred and eighteen patients received an LVAD (135 HeartMate II, 125 HeartMate 3, 158 HVAD) between November 2009 and January 2019. The primary end-point occurred in 169 (40.4%) patients with C -statistics ranging 0.55-0.58 (standard deviation [SD] 0.02 for all models). The secondary end-point occurred in 167 (40.0%) patients with C -statistics ranging 0.53-0.58 (SD 0.02 for all models). Modifying the age and liver function thresholds increased the C -statistic range to 0.56-0.60 for the primary and secondary end-points. In a sensitivity analysis of HeartMate 3 patients, prediction rules performed similarly. Existing prediction rules for major bleeding had mediocre discrimination in an LVAD cohort.

COVID-19 in orthotopic heart transplant recipients and association with donor specific antibodies.

De novo donor-specific antibodies (DSAs) are associated with increased risk of antibody-mediated rejection and worse clinical outcomes after orthotopic heart transplant (OHT). No study has reported the production of DSAs after infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in an OHT population. In this retrospective study, we described coronavirus disease 2019 (COVID-19) incidence and clinical course in a large, contemporary OHT cohort. We showed that the case-fatality rate has significantly decreased since the early days of the pandemic, although remains higher than that of the general population. In addition, we found that 10% of OHT recipients developed de novo DSAs or experienced an increase in pre-existing DSAs after COVID-19, with the majority occurring in unvaccinated patients (15% vs 2%). Further studies are necessary to substantiate our findings in an external cohort.

Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.

Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress.

Impact of New UNOS Allocation Criteria on Heart Transplant Practices and Outcomes.

BACKGROUND: In October 2018, a new heart allocation policy was implemented with intent of prioritizing the sickest patients and decreasing waitlist time. We examined the effects of the new policy on transplant practices and outcomes 1 year before and 1 year after the change. METHODS: Transplant recipients from October 2017 to September 2019 at our institution were identified and divided into 2 cohorts, a preallocation and postallocation criteria change. Patient demographics, clinical data, and bridging strategy were assessed. Early outcomes including ischemic time, severe primary graft dysfunction, need for renal replacement therapy, and duration of hospital stay were investigated. RESULTS: In the 12 months before the change, 38 patients were transplanted as compared to 33 patients in the 12 months after the change. The average wait-time to transplant decreased after the allocation change (49 versus 313 d, P = 0.02). Patients were more likely to be bridged with an intra-aortic balloon pump (45% versus 3%) and less likely to be supported with a durable left ventricular assist device (LVAD) after the change (24% versus 82%). There was an increase in total ischemic time after the change (177 versus 117 min, P ≤ 0.01). There were no significant differences in other early posttransplant outcomes. CONCLUSIONS: Implementation of the new allocation system for heart transplantation resulted in dramatic changes in the bridging strategy utilized at our institution. Temporary mechanical support usage increased following the change and the number of recipients supported with durable LVADs decreased. Early posttransplant outcomes appear similar.

Human Monocytic Ehrlichiosis Associated With Myocarditis and Hemophagocytic Lymphohistiocytosis.

We present 3 cases at a single institution of human monocytic ehrlichiosis resulting in myocarditis and hemophagocytic lymphohistiocytosis. Contrary to previously published studies in which case fatalities were only as high as 1%, 2 of the 3 patients we discuss experienced a fulminant course resulting in death despite appropriate doxycycline treatment. Human monocytic ehrlichiosis is rarely a cause of myocarditis and hemophagocytic lymphohistiocytosis, but a high degree of suspicion is important because early empirical therapy may decrease morbidity and mortality. (Level of Difficulty: Intermediate.).

Racial differences in patients referred for right heart catheterization and risk of pulmonary hypertension.

African Americans (AA) have a higher incidence of pulmonary hypertension (PH) risk factors. Few studies have examined the racial differences in the prevalence and etiology of PH and direct comparison of invasive hemodynamics between AAs and Caucasians has rarely been reported. In this study, we examined whether racial differences exist in patients referred for right heart catheterization (RHC) and hypothesized that AA race is an independent risk factor for PH and is associated with increased adjusted mortality. We extracted data for AA and Caucasian patients who underwent RHC at Vanderbilt between 1998 and 2014. Clinical information was obtained from Vanderbilt's Synthetic Derivative, a de-identified mirror of our Electronic Medical Record. A total of 4576 patients were analyzed, including 586 (13%) AAs and 3990 (87%) Caucasians. AAs were younger than Caucasians by an average of eight years, but had more prevalent heart failure, features of metabolic syndrome, and higher creatinine. AAs also had higher mean pulmonary artery pressure and pulmonary vascular resistance. After adjusting for relevant co-morbidities, the AA race is associated with 41% increased risk of PH (odds ratio [OR] = 1.41, 95% confidence interval [CI] = 1.12-1.79). Among patients with PH, AA race is associated with 24% increased adjusted mortality (hazard ratio [HR] = 1.24, 95% CI = 1.09-1.45). AAs were younger but had more prevalent cardiometabolic and renal disease and worse pulmonary hemodynamics. The AA race is an independent risk factor for PH. Among patients with PH, the AA race is associated with increased adjusted mortality. Future studies should focus on delineating whether genetic or environmental factors contribute to PH risk in AAs.