Quantification of paravalvular leaks associated with TAVI implants using 4D MRI in an aortic root phantom made possible by the use of 3D printing

IntroductionTranscatheter aortic valve implantation (TAVI) has become an alternative to surgical replacement of the aortic valve elderly patients. However, TAVI patients may suffer from paravalvular leaks (PVL). Detecting and grading is usually done by echocardiography, but is limited by resolution, 2D visualization and operator dependency. 4D flow magnetic resonance imaging (MRI) is a promising alternative, which did not reach clinical application in TAVI patients. The aim of this study was applying 3D printing technologies in order to evaluate flow patterns and hemodynamics of PVLs following TAVI, exploiting 4D flow MRI and standard ultrasound. Materials and methodsAn MR-compatible, anatomically left ventricle, aortic root, and ascending aorta model was fabricated by combining 3D-printed parts and various soft silicone materials to match physiological characteristics. An Abbott Portico (TM) valve was used in continuous antegrade flow (12-22 l/min), retrograde flow with varying transvalvular pressures (60-110 mmHg), and physiological pulsatile hemodynamics (aortic pressure: 120/80 mmHg, cardiac output: 5 l/min) Time-resolved MR measurements were performed above and below the TAVI stent and compared with color Doppler ultrasound measurements in exactly the same setup. ResultsThe continuous antegrade flow measurements from MRI largely agreed with the flowmeter measurements, and a maximum error of only 7% was observed. In the retrograde configuration, visualization of the paravalvular leaks was possible from the MR measurements, but flow was overestimated by up to 33%. The 4D MRI measurement in the pulsatile setup revealed a single main PVL, which was also confirmed by the color Doppler measurements, and velocities were similar (2.0 m/s vs. 1.7 m/s). Discussion4D MRI techniques were used to qualitatively assess flow in a patient-specific, MR-compatible and flexible model, which only became possible through the use of 3D printing techniques. Flow patterns in the ascending aorta, identification and quantification of PVLs was possible and the location and extent of PVLs were confirmed by ultrasound measurements. The 4D MRI flow technique allowed evaluation of flow patterns in the ascending aorta and the left ventricle below the TAVI stent with good results in identifying PVLs, demonstrating its capabilities over ultrasound by providing the ability to visualize the paravalvular jets in three dimensions at however, additional expenditure of time and money

Splenectomy ameliorates portal pressure and anemia in animal models of cirrhotic and non-cirrhotic portal hypertension

PURPOSE: Portal hypertension (PH)-associated splenomegaly is caused by portal venous congestion and splanchnic hyperemia. This can trigger hypersplenism, which favors the development of cytopenia. We investigated the time-dependent impact of splenectomy on portal pressure and blood cell counts in animal models of non-cirrhotic and cirrhotic PH. MATERIALS AND METHODS: Ninety-six rats underwent either partial portal vein ligation (PPVL), bile duct ligation (BDL), or sham operation (SO), with subgroups undergoing additional splenectomy. Portal pressure, mean arterial pressure, heart rate, blood cell counts and hemoglobin concentrations were evaluated throughout 5 weeks following surgery. RESULTS: Following PPVL or BDL surgery, the animals presented a progressive rise in portal pressure, paralleled by decreased mean arterial pressure and accelerated heart rate. Splenectomy curbed the development of PH in both models (PPVL: 16.25 vs. 17.93 ​mmHg, p ​= ​0.083; BDL: 13.55 vs. 15.23 ​mmHg, p ​= ​0.028), increased mean arterial pressure (PPVL: +7%; BDL: +9%), and reduced heart rate (PPVL: −10%; BDL: −13%). Accordingly, splenectomized rats had lower von Willebrand factor plasma levels (PPVL: −22%; BDL: −25%). Splenectomy resulted in higher hemoglobin levels in PPVL (14.15 vs. 13.08 ​g/dL, p ​< ​0.001) and BDL (13.20 vs. 12.39 ​g/dL, p ​= ​0.097) animals, and significantly increased mean corpuscular hemoglobin concentrations (PPVL: +9%; BDL: +15%). Thrombocytopenia only developed in the PPVL model and was alleviated in the splenectomized subgroup. Conversely, BDL rats presented with thrombocytosis, which was not affected by splenectomy. CONCLUSIONS: Splenectomy improves both cirrhotic and non-cirrhotic PH, and ameliorates the hyperdynamic circulation. Hypersplenism related anemia and thrombocytopenia were only significantly improved in the non-cirrhotic PH model

The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of &minus;41% (10 mg/kg) and &minus;69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (&minus;41%), expression of col1a1 (&minus;37%) and pdgfr-&beta; (&minus;36%), as well as desmin area (&minus;42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 &plusmn; 2.1 vs. 8.9 &plusmn; 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (&minus;28%) but also mean arterial pressure (&minus;25%) and heart rate (&minus;37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion

The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats

In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signaling. Soluble guanylate cyclase (sGC) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pulmonary hypertension but has not been studied in liver cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic (bile duct ligation, BDL) and toxic (carbon-tetrachloride, CCl4) rat models. In cirrhotic livers sGC expression was upregulated. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In an early BDL disease stage, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibited angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less pronounced and confined to an early disease stage. Similarly, in patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. We also found an improvement of transaminases in patients with pulmonary hypertension receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.(VLID)464158