Abstract
ObjectivesEffects of liver disease on portal venous (PV), hepatic arterial (HA), total liver blood flow (TLBF), and cardiac function are poorly understood. Terlipressin modulates PV flow but effects on HA, TLBF, and sepsis/acute-on-chronic liver failure (ACLF)-induced haemodynamic changes are poorly characterised. In this study, we investigated the effects of terlipressin and sepsis/ACLF on hepatic haemodynamics and cardiac function in a rodent cirrhosis model using caval subtraction phase-contrast (PC) MRI and cardiac cine MRI.MethodsSprague-Dawley rats (n = 18 bile duct–ligated (BDL), n = 16 sham surgery controls) underwent caval subtraction PCMRI to estimate TLBF and HA flow and short-axis cardiac cine MRI for systolic function at baseline, following terlipressin and lipopolysaccharide (LPS) infusion, to model ACLF.ResultsAll baseline hepatic haemodynamic/cardiac systolic function parameters (except heart rate and LV mass) were significantly different in BDL rats. Following terlipressin, baseline PV flow (sham 181.4 ± 12.1 ml/min/100 g; BDL 68.5 ± 10.1 ml/min/100 g) reduced (sham − 90.3 ± 11.1 ml/min/100 g, p < 0.0001; BDL − 31.0 ± 8.0 ml/min/100 g, p = 0.02), sham baseline HA flow (33.0 ± 11.3 ml/min/100 g) increased (+ 92.8 ± 21.3 ml/min/100 g, p = 0.0003), but BDL baseline HA flow (83.8 ml/min/100 g) decreased (− 34.4 ± 7.5 ml/min/100 g, p = 0.11). Sham baseline TLBF (214.3 ± 16.7 ml/min/100 g) was maintained (+ 2.5 ± 14.0 ml/min/100 g, p > 0.99) but BDL baseline TLBF (152.3 ± 18.7 ml/min/100 g) declined (− 65.5 ± 8.5 ml/min/100 g, p = 0.0004). Following LPS, there were significant differences between cohort and change in HA fraction (p = 0.03) and TLBF (p = 0.01) with BDL baseline HA fraction (46.2 ± 4.6%) reducing (− 20.9 ± 7.5%, p = 0.03) but sham baseline HA fraction (38.2 ± 2.0%) remaining unchanged (+ 2.9 ± 6.1%, p > 0.99). Animal cohort and change in systolic function interactions were significant only for heart rate (p = 0.01) and end-diastolic volume (p = 0.03).ConclusionsCaval subtraction PCMRI and cardiac MRI in a rodent model of cirrhosis demonstrate significant baseline hepatic haemodynamic/cardiac differences, failure of the HA buffer response post-terlipressin and an altered HA fraction response in sepsis, informing potential translation to ACLF patients.Key PointsCaval subtraction phase-contrast and cardiac MRI demonstrate:• Significant differences between cirrhotic/non-cirrhotic rodent hepatic blood flow and cardiac systolic function at baseline.• Failure of the hepatic arterial buffer response in cirrhotic rodents in response to terlipressin.• Reductions in hepatic arterial flow fraction in the setting of acute-on-chronic liver failure.
Highlights
Complications of liver cirrhosis such as portal hypertension are underpinned by major changes in the dual portal venous (PV) and hepatic arterial (HA) blood supply to the liver[1]
Baseline mean PV flow and total liver blood flow (TLBF) were significantly lower in BDL compared with shamoperated animals
We observed reduced PV flow and TLBF, despite elevated HA flow/fraction at baseline in BDL rats. This suggests longstanding PV flow reductions are buffered by rises in HA flow, but that this response is inadequate in cirrhosis, with TLBF reduced overall
Summary
Complications of liver cirrhosis such as portal hypertension are underpinned by major changes in the dual portal venous (PV) and hepatic arterial (HA) blood supply to the liver[1]. Total liver blood flow (TLBF) is regulated closely so that reduction of PV flow triggers increased HA flow—the hepatic arterial buffer response [2]. This response is thought to be impaired in liver disease, but remains poorly understood because references tests are invasive and are confounded by vessel instrumentation, so that they are unfeasible in disease or impractical in smaller animal models [3]. Vasoactive drugs may be used to manage vascular complications of liver disease but are controversial. Compensatory increases in HA flow have been demonstrated in naïve porcine studies [8], but the effects of terlipressin on TLBF and HA flow in the context of chronic liver disease have not been reported previously
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