Surgically repaired tetralogy of Fallot in the 7th decade: a late presentation of severe pulmonic regurgitation.

BACKGROUND: Surgically repaired tetralogy of Fallot (TOF) is a congenital heart disease with a cumulative survival rate of 72% in the 4th decade of life in longitudinal single-cohort studies. Debate surrounds conservative versus surgical management in adults with TOF once pulmonary regurgitation occurs. CASE PRESENTATION: A 73-year-old male with surgically corrected TOF presented with heart failure symptoms. He underwent ToF repair with a classic right Blalock-Taussig shunt at 2 years of age with transannular patching at 18 years of age. Echocardiography revealed elevated right ventricular systolic pressures, severe right ventricular dilatation, and pulmonary regurgitation. Our patient's new-onset right-sided heart failure was managed medically with diuresis. He received a new pulmonic valve via percutaneous approach on a later planned hospitalization with resolution of symptoms and improved tricuspid regurgitation. CONCLUSION: It is a class I recommendation for pulmonic valve intervention once greater than moderate PR occurs; however, medical optimization should take place first. Following adequate RV load optimization, our patient underwent successful transcatheter pulmonic valve implantation with resolution of symptoms and cessation of diuretic.

Viral SERPINS-A Family of Highly Potent Immune-Modulating Therapeutic Proteins.

Serine protease inhibitors, SERPINS, are a highly conserved family of proteins that regulate serine proteases in the central coagulation and immune pathways, representing 2-10% of circulating proteins in the blood. Serine proteases form cascades of sequentially activated enzymes that direct thrombosis (clot formation) and thrombolysis (clot dissolution), complement activation in immune responses and also programmed cell death (apoptosis). Virus-derived serpins have co-evolved with mammalian proteases and serpins, developing into highly effective inhibitors of mammalian proteolytic pathways. Through interacting with extracellular and intracellular serine and cysteine proteases, viral serpins provide a new class of highly active virus-derived coagulation-, immune-, and apoptosis-modulating drug candidates. Viral serpins have unique characteristics: (1) function at micrograms per kilogram doses; (2) selectivity in targeting sites of protease activation; (3) minimal side effects at active concentrations; and (4) the demonstrated capacity to be modified, or fine-tuned, for altered protease targeting. To date, the virus-derived serpin class of biologics has proven effective in a wide range of animal models and in one clinical trial in patients with unstable coronary disease. Here, we outline the known viral serpins and review prior studies with viral serpins, considering their potential for application as new sources for immune-, coagulation-, and apoptosis-modulating therapeutics.

The feasibility of transcatheter arterial chemoembolization following radiation therapy for hepatocellular carcinoma.

BACKGROUND: Technological developments have led to an increased usage of external-body radiotherapy (RT) for the treatment of hepatocellular carcinoma (HCC). Transcatheter arterial chemoembolization (TACE) may be required later in patients treated with RT because of the high recurrence rate and multinodular presentation of HCC. However, despite the risk of liver function impairment, the cumulative liver damage correlated with TACE following a hepatic RT has not been adequately assessed. PURPOSE: To evaluate the feasibility of TACE following RT for HCC. MATERIALS AND METHODS: Sixty-seven patients with HCC who underwent TACE after RT were retrospectively evaluated between 2012 and 2018. We assessed increases in Child-Turcotte-Pugh (CTP) by ≥2 points at 1 month, the incidence of major complications, survival duration, and short-term mortality within 6 months after TACE. Furthermore, we evaluated the predictive factors for liver function impairment and short-term mortality. RESULTS: Eight patients experienced a CTP increase ≥2 points at 1 month. There were no cases of liver abscesses or bilomas. Nine patients died within 6 months following TACE. The mean liver dose (MLD) was a significant predictor of liver function impairment at 1 month (p = 0.042). Low liver functional reserve, distant metastasis (p = 0.037), MLD (p = 0.046), TACE type (p = 0.025), and TACE within 3 months following RT (p = 0.007) were significant predictors of short-term mortality. CONCLUSIONS: Despite the feasibility of TACE following RT, clinicians should pay attention to impaired pretreatment liver function, following high dose RT, and the short duration between RT and TACE.

Stepwise Reversion of Multiply Mutated Recombinant Antitrypsin Reveals a Selective Inhibitor of Coagulation Factor XIa as Active as the M358R Variant.

Alpha-1 antitrypsin (AAT, also known as alpha-1 proteinase inhibitor or SERPINA1) is the most abundant member of the serpin superfamily found in human plasma. The naturally occurring variant AAT M358R, altered at the P1 position of the critical reactive center loop (RCL), is re-directed away from inhibition of AAT's chief natural target, neutrophil elastase, and toward accelerated inhibition of thrombin (FIIa), kallikrein (Kal), and other proteases such as factor XIa (FXIa). FXIa is an emerging target for the development of antithrombotic agents, since patients with FXI deficiency are protected from thromboembolic disease and do not exhibit a strong bleeding tendency. Previously, we used phage display, bacterial lysate screening, and combinatorial mutagenesis to identify AAT-RC, an engineered AAT M358R with additional changes between RCL positions P7-P3', CLEVEPR-STE [with changes bolded and the P1-P1' (R358-S359) reactive center shown as R-S]. AAT-RC was 279- and 16-fold more selective for FXIa/IIa or FXIa/Kal than AAT M358R; the increased selectivity came at a cost of a 2.3-fold decrease in the rate of FXIa inhibition and a 3.3-fold increase in the stoichiometry of inhibition (SI). Here, we asked which alterations in AAT-RC were most important for the observed increases in selectivity for FXIa inhibition. We back-mutated AAT-RC to AAT-RC-1 (P7-P3' FLEVEPRSTE), AAT-RC-2 (P7-P3' FLEAEPRSTE), and AAT RC-3 (P7-P3' FLEAIPR-STE). Proteins were expressed as cleavable, hexahistidine-tagged glutathione sulfotransferase fusion proteins in E. coli and purified by proteolytic elution from glutathione agarose, with polishing on nickel chelate agarose. Selectivity for FXIa over Kal of AAT-RC-1, -2, and -3 was 14, 21, and 2.3, respectively. AAT-RC-2 inhibited FXIa 31% more rapidly than AAT M358R, with the same SI, and enhanced selectivity for FXIa over Kal, FXa, FXIIa, activated protein C, and FIIa of 25-, 130-, 420-, 440-, and 470-fold, respectively. Structural modeling of the AAT-RC-2/FXIa encounter complex suggested that both E (Glu) substitutions at P3 and P3' may promote FXIa binding via hydrogen bonding to K192 in FXIa. AAT-RC-2 is the most selective and active AAT variant reported to date for FXIa inhibition and will be tested in animal models of thrombosis and bleeding.

Identification of an alpha-1 antitrypsin variant with enhanced specificity for factor XIa by phage display, bacterial expression, and combinatorial mutagenesis.

Coagulation Factor XIa (FXIa) is an emerging target for antithrombotic agent development. The M358R variant of the serpin alpha-1 antitrypsin (AAT) inhibits both FXIa and other proteases. Our aim was to enhance the specificity of AAT M358R for FXIa. We randomized two AAT M358R phage display libraries at reactive centre loop positions P13-P8 and P7-P3 and biopanned them with FXIa. A bacterial expression library randomized at P2'-P3' was also probed. Resulting novel variants were expressed as recombinant proteins in E. coli and their kinetics of FXIa inhibition determined. The most potent FXIa-inhibitory motifs were: P13-P8, HASTGQ; P7-P3, CLEVE; and P2-P3', PRSTE (respectively, novel residues bolded). Selectivity for FXIa over thrombin was increased up to 34-fold versus AAT M358R for these single motif variants. Combining CLEVE and PRSTE motifs in AAT-RC increased FXIa selectivity for thrombin, factors XIIa, Xa, activated protein C, and kallikrein by 279-, 143-, 63-, 58-, and 36-fold, respectively, versus AAT M358R. AAT-RC lengthened human plasma clotting times less than AAT M358R. AAT-RC rapidly and selectively inhibits FXIa and is worthy of testing in vivo. AAT specificity can be focused on one target protease by selection in phage and bacterial systems coupled with combinatorial mutagenesis.

Atypical Type 2 Endoleak from an Artery Supplying the Psoas Major Muscle Following Endovascular Repair in a Case of Isolated Common Iliac Artery Aneurysm.

In this report, we present a rare case of type 2 endoleak (T2EL) from an artery supplying the psoas major muscle, following an endovascular repair of a common iliac artery aneurysm (CIAA). A 79-year-old male underwent endovascular aneurysm repair (EVAR) for the right isolated CIAA using stent graft, with embolization of the ipsilateral internal iliac artery. The aneurysm was stable for 2 years, after which a follow-up CT revealed a 5 mm increase in the CIAA diameter and an endoleak of unknown origin. Conventional and CT angiographies revealed the source to be a branch from the ipsilateral deep circumflex iliac artery supplying the psoas major muscle that had developed an anastomosis at its terminal end with the vasa vasorum at the CIAA. Transarterial embolization of T2EL using glue was performed successfully, following which the T2EL disappeared.

The utility of transarterial embolization and computed tomography for life-threatening spontaneous retroperitoneal hemorrhage.

PURPOSE: To assess the safety and efficacy of transarterial embolization (TAE) and to evaluate the utility of contrast-enhanced computed tomography (CE-CT) for life-threatening spontaneous retroperitoneal hemorrhage (SRH). METHODS: Nineteen patients underwent TAE following CE-CT for life-threatening SRH. CE-CT and angiographic findings, technical successes, and clinical successes were evaluated. The diagnostic performance of CE-CT for the detection of active bleeding arteries was also assessed by two independent readers. RESULTS: Active extravasation of contrast material was accurately observed in 78.9‒84.2% of the patients on CE-CT. Angiograms revealed active extravasation in 37 arteries of 15 patients (78.9%), and 4 patients showed no sign of active bleeding. Sensitivity, positive predictive value, and accuracy rate of CE-CT for the detection of active bleeding vessels was 59.5%, 62.9‒71.0% and 55.6‒60.0% respectively. The successful embolization of 48 intended arteries was achieved in all the patients, including empirical TAE in four patients. Hemodynamic stabilization was achieved in 17 patients (89.5%) with a significant decrease in transfusion (p < 0.001). CONCLUSION: TAE is a technically safe and clinically effective treatment method for life-threatening SRH. CE-CT has moderate capability for accurate identification of active bleeding arteries. TAE including arteries that potentially distribute anatomic territory of the hematoma is essential.