Project description:Liver disease resulting from heart failure (HF) has generally been referred as "cardiac hepatopathy". One of its main forms is congestive hepatopathy (CH), which results from passive venous congestion in the setting of chronic right-sided HF. The current spectrum of CH differs from earlier reports with HF, due to ischemic cardiomyopathy and congenital heart disease having surpassed rheumatic valvular disease. The chronic passive congestion leads to sinusoidal hypertension, centrilobular fibrosis, and ultimately, cirrhosis ("cardiac cirrhosis") and hepatocellular carcinoma after several decades of ongoing injury. Contrary to primary liver diseases, in CH, inflammation seems to play no role in the progression of liver fibrosis, bridging fibrosis occurs between central veins to produce a "reversed lobulation" pattern and the performance of non-invasive diagnostic tests of liver fibrosis is poor. Although the clinical picture and prognosis is usually dominated by the underlying heart condition, the improved long-term survival of cardiac patients due to advances in medical and surgical treatments are responsible for the increased number of liver complications in this setting. Eventually, liver disease could become as clinically relevant as cardiac disease and further complicate its management.
Project description:Congestive hepatopathy (CH) with chronic passive congestion is characterized by the progression of liver fibrosis without prominent inflammation and hepatocellular damage. Currently, the lack of reliable biomarkers for liver fibrosis in CH often precludes the clinical management of patients with CH. To explore fibrosis biomarkers, we performed proteome analysis on serum exosomes isolated from patients with CH after the Fontan procedure. Exosomal cluster of differentiation (CD)44 levels were increased in patients with CH compared to healthy volunteers and was accompanied by increases in serum levels of soluble CD44 and CD44 expression in the liver. To address the roles of CD44 in CH, we established a mouse model of chronic liver congestion by partial inferior vena cava ligation (pIVCL) that mimics CH by fibrosis progression with less inflammation and cellular damage. In the pIVCL mice, enhanced CD44 expression in hepatic stellate cells (HSCs) and deposition of its ligand hyaluronan were observed in the liver. Blood levels of soluble CD44 were correlated with liver fibrosis. The blockade of CD44 with specific antibody inhibited liver fibrosis in pIVCL mice and was accompanied by a reduction in S100 calcium-binding protein A4 expression following activation of HSCs. Conclusion: Chronic liver congestion promotes fibrosis through CD44. This identifies CD44 as a novel biomarker and therapeutic target of liver fibrosis in patients with CH.
Project description:Background: We aimed to review the indications and outcomes of adults undergoing combined heart-liver transplantation (CHLT) in the US using national registry data. Methods: Adult (≥18 years) CHLT recipients in the United Network for Organ Sharing database were included (09/1987-09/2020; era 1 = 1989-2000, era 2 = 2001-2010, era 3 = 2011-2020). Survival analysis was conducted by means of Kaplan-Meier method, log-rank test, and Cox regression. Results: We identified 369 adults receiving CHLT between 12/1989-08/2020. The number of adult CHLT recipients (R2 = 0.75, p < 0.001) and centers performing CHLT (R2 = 0.80, p < 0.001) have increased over the study period. The most common cardiac diagnosis in the first two eras was restrictive/infiltrative cardiomyopathy, while the most common in era 3 was congenital heart disease (p = 0.03). The 1-, 3-, and 5-years patient survival was 86.8, 80.1, and 77.9%, respectively. In multivariable analysis, recipient diabetes [adjusted hazard ratio (aHR) = 2.35, 95% CI: 1.23-4.48], CHLT between 1989-2000 compared with 2011-2020 (aHR = 5.00, 95% CI: 1.13-22.26), and sequential-liver first CHLT compared with sequential-heart first CHLT (aHR = 2.44, 95% CI: 1.15-5.18) were associated with increased risk of mortality. Higher left ventricular ejection fraction was associated with decreased risk of mortality (aHR = 0.96, 95% CI: 0.92-0.99). Conclusion: CHLT is being increasingly performed with evolving indications. Excellent outcomes can be achieved with multidisciplinary patient and donor selection and surgical planning.
Project description:We evaluated whether combined heart and liver transplant (H+LTx) can protect the heart graft from the development of cardiac allograft vasculopathy using coronary three-dimensional (3D) volumetric intravascular ultrasound (IVUS).From 2004 to 2009, we identified 24 isolated heart transplant (HTx) and 10 H+LTx recipients in whom two coronary 3D IVUS studies were performed 1 year apart. Baseline 3D IVUS was performed at 0.22 (0.17-1.16) years after transplantation, with follow-up 3D IVUS exams performed after baseline exam (0.96 [0.83-1.08]).Rate of plaque volume and plaque index (plaque volume/vessel volume) progression was attenuated in the H+LTx group (0.3±1.1 vs. 1.5±2.9 mm/mm; P=0.08 and 0.01±0.03 vs. 0.1±0.1; P=0.004, respectively). Rejection burden was much lower in the H+LTx patients. Outcome analysis in 66 consecutive patients (56 HTx and 10 H+LTx) was performed irrespective of performance of second coronary IVUS. H+LTx was associated with reduced rate of cardiac events (P=0.04), which remained significant when adjusted for the difference in the primary etiology for heart disease (P=0.05).Our preliminary serial 3D coronary IVUS data show that H+LTx attenuates cardiac allograft vasculopathy by decreasing the rate of plaque volume and plaque index progression and improves coronary-related outcomes. Because of the small numbers and the differences in etiology of heart disease, our data should be interpreted cautiously, and larger clinical trials would be required to recommend H+LTx for improved coronary remodeling.
Project description:Heart failure and liver disease often coexist because of systemic disorders and diseases that affect both organs as well as complex cardio-hepatic interactions. Heart failure can cause acute or chronic liver injury due to ischaemia and passive venous congestion, respectively. Congestive hepatopathy is frequently observed in patients with congenital heart disease and after the Fontan procedure, but also in older patients with chronic heart failure. As congestive hepatopathy can evolve into cirrhosis and hepatocellular carcinoma, screening for liver injury should be performed in patients with chronic cardiac diseases and after Fontan surgery. Fibrosis starts in the centro-lobular zone and will extend progressively to the portal area. Chronic liver injury can be reversible if heart function improves. However, in the case of terminal heart failure, uncontrolled by medical resources or by assistive device support, the combination of heart and liver transplants must be discussed in patients with chronic advanced liver fibrosis. In this review of the literature, we will focus on congestive hepatopathy and its complications, such as liver fibrosis and hepatocellular carcinoma, with the aim of improving the management and surveillance of patients experiencing these complications.
Project description:Advances in autologous hematopoietic cell transplantation (HCT) strategies have resulted in a growing number of long-term survivors. However, these survivors are at increased risk of developing cardiovascular complications due to pre-HCT therapeutic exposures and conditioning and post-HCT comorbidities. We examined the incidence and predictors of congestive heart failure (CHF) in 1244 patients undergoing autologous HCT for a hematologic malignancy between 1988 and 2002. The cumulative incidence of CHF was 4.8% at 5 years and increased to 9.1% at 15 years after transplantation; the CI for female lymphoma survivors was 14.5% at 15 years. The cohort was at a 4.5-fold increased risk of CHF (standardized incidence ratio = 4.5), compared with the general population. The risk of CHF increased substantially for patients receiving ≥ 250 mg/m(2) of cumulative anthracycline exposure (odds ratio [OR]: 9.9, P < .01), creating a new and lower threshold for cardiac surveillance after HCT. The presence of hypertension among recipients of high-dose anthracycline (≥ 250 mg/m(2)) resulted in a 35-fold risk (OR: 35.3, P < .01) of CHF; the risk was nearly 27-fold (OR: 26.8, P < .01) for high-dose anthracycline recipients with diabetes, providing evidence that hypertension and diabetes may be critical modifiers of anthracycline-related myocardial injury after HCT and creating targeted populations for aggressive intervention.
Project description:Right ventricular (RV) function is an important predictor of prognosis in patients with heart failure. However, the relationship of the RV free wall longitudinal strain (RV FWS) and the degree of hepatic dysfunction during the acute worsening of heart failure (AWHF) is unknown. We sought to determine associations of RV FWS with laboratory liver function tests and parameters of RV function including tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RV FAC), maximal tricuspid jet velocity (TR Vmax), RV S' velocity, and estimated RV systolic pressure (RVSP). A total of 42 AWHF patients from the CATSTAT-HF study were stratified in two groups by the RV FWS median (-16.5%). Patients < RV FWS median had significantly prolonged international normalized ratio (INR; p = 0.002), increased total bilirubin (p < 0.001) and alkaline phosphatase (ALP; p = 0.020), and decreased albumin (p = 0.005) and thrombocytes (p = 0.017) compared to patients > RV FWS median. RV FWS independently correlated to total bilirubin (β = 0.457, p = 0.004), ALP (β = 0.556, p = 0.002), INR (β = 0.392, p = 0.022), albumin (β = -0.437, p = 0.013), and thrombocytes (β = -404, p = 0.038). Similarly, TAPSE, RV FAC, and RV S' significantly correlated with RV FWS. In conclusion, RV impairment, reflected in reduced RV FWS, is independently associated with a higher degree of hepatic dysfunction among patients with AWHF (CATSTAT-HF ClinicalTrials gov number, NCT03389386).
Project description:Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case-control study design was used. Cases (post-HCT CHF) were identified from 2950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived ?1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females [Odds Ratio (OR) = 2·9, P < 0·01], individuals with pre-HCT chest radiation (OR = 4·7, P = 0·05), hypertension (OR = 2·9, P = 0·01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T?A; OR = 2·8, P < 0·01), HFE (rs1799945, 63C?G; OR = 2·5, P = 0·05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G?A; OR = 4·3, P < 0·01). A combined (clinical and genetic) CHF predictive model performed better [area under the curve (AUC), 0·79] than the genetic (AUC = 0·67) or the clinical (AUC = 0·69) models alone.
Project description:10 biopsies from one patient undergoing a auxiliary liver and combined kidney transplantation, where one liver lobe is replaced by an auxiliary liver lobe. Thereafter the kidney is transplanted. Keywords: Time course study 10 samples, no replicates.