Marvin J. Slepian

In recent years, the treatment of aortic stenosis with TAVR has rapidly expanded to younger and lower-risk patients. However, persistent thrombotic events such as stroke and valve thrombosis expose recipients to severe clinical complications that hamper TAVR’s rapid advance. We presented a novel methodology for establishing a link between commonly acceptable mild paravalvular leak (PVL) levels through the device and increased thrombogenic risk. It utilizes in vitro patient-specific TAVR 3D-printed replicas evaluated for hydrodynamic performance. High-resolution µCT scans are used to reconstruct in silico FSI models of these replicas, in which multiple platelet trajectories are studied through the PVL channels to quantify thrombogenicity, showing that those are highly dependent on patient-specific flow conditions within the PVL channels. It demonstrates that platelets have the potential to enter the PVL channels multiple times over successive cardiac cycles, increasing the thrombogenic risk. This cannot be reliably approximated by standard hemodynamic parameters. It highlights the shortcomings of subjectively ranked PVL commonly used in clinical practice by indicating an increased thrombogenic risk in patient cases otherwise classified as mild PVL. It reiterates the need for more rigorous clinical evaluation for properly diagnosing thrombogenic risk in TAVR patients.

Background The Impella® microaxial blood pumps utilize purge fluid containing heparin to prevent biofouling of internal surfaces. Purge fluid interfaces with blood or blood components at two notable internal locations: (1) 5–8 μm radial gap (“Radial Gap” or “Gap 1”) between the motor shaft and bearing, a site accessible by blood proteins or small molecules; and (2) 100 μm axial gap (“Axial Gap” or “Gap 2”) between the impeller rotor and bearing, the site of mixing with larger circulating blood components. Despite its efficacy, heparin in the purge fluid complicates overall patient anticoagulation management. Here, we investigate sodium bicarbonate as an alternative to heparin in the purge fluid in a simulated purge gap micro‐environment. Methods To assess protein stability simulated at Gap 1, human serum albumin (HSA; 40 mg/ml) species were quantified utilizing size exclusion liquid chromatography (SEC‐HPLC) after stirring with purge fluid (5% dextrose in water (D5W) with heparin (25 U/ml) or sodium bicarbonate (25 or 50 mEq/L)) over a 24‐h period. pH measurements were taken immediately prior to stirring. Mixing between blood and purge fluid at Gap 2 was mimicked in vitro utilizing a 60:40 blood: purge fluid ratio. Purge fluid consisted of D5W with or without sodium bicarbonate (25 or 50 mEq/L). Human citrated blood samples were freshly collected with or without the addition of heparin (5 U/ml). Coagulability was determined via thromboelastography (TEG). pH measurements of blood mixtures were taken immediately before and after TEG analysis. Results Sodium bicarbonate alone or synergistically with heparin was effective in increasing protein stability, increasing pH, and reducing coagulability. In the Gap 1 model, sodium bicarbonate led to preservation of HSA monomer after 24 h mixing, with monomer composing 88.3 ± 2.3% and 88.6 ± 0.9% of total HSA species for 25 or 50 mEq/L sodium bicarbonate, respectively. Only 60.4 ± 4.3% monomer was observed with D5W alone ( p < 0.005). HSA aggregates and fragments were evident in heparin and D5W purge mixtures, but absent in sodium bicarbonate (25 and 50 mEq/L). pH of HSA mixtures significantly increased in the presence of sodium bicarbonate. In the Gap 2 model, combined heparin (5 U/ml) and sodium bicarbonate prolonged clotting time (TEG‐ACT), leading to an average increase of 795 ± 275 s ( p = 0.04) and 846 243 s ( p = 0.03). This trend of reduced coagulability was similarly observed in clot initiation time (R time), clot formation time (K time), and clotting rate ( α angle). Blood mixture pH measurements increased with addition of sodium bicarbonate in both heparinized and non‐heparinized blood samples. Conclusion Sodium bicarbonate in the purge fluid has the potential to significantly increase protein stability and reduce protein denaturation at the Impella® radial gap (Gap 1), while reducing blood coagulation at the Impella® axial gap (Gap 2). The influence of sodium bicarbonate on the biochemical environment of the purge fluid may ensure stable purge flow resistance and play a synergistic or supportive role in the purge gap micro‐environment when used with systemic anticoagulation.