Early Experience With a Novel Dissection-Specific Stent-Graft to Prevent Distal Stent-Graft-Induced New Entry Tears After Thoracic Endovascular Repair of Chronic Type B Aortic Dissections.

BACKGROUND: The aim was to report short and mid-term outcomes of a novel, investigational, dissection-specific stent-graft (DSSG), specifically designed to address the features of chronic type B aortic dissection (CTBAD) and reduce the risk of distal stent-graft-induced new entry tears (dSINE). MATERIALS AND METHODS: A retrospective single center cohort study of all patients undergoing TEVAR with the DSSG for CTBAD from January 1, 2017 to January 31, 2020. The DSSG, which is a modified stent-graft based on the Cook Zenith Alpha Thoracic platform, has no proximal barbs, and a customized longer body length with substantial taper. The second and third distal Z-stents are sited internally to avoid any contact of the metal skeleton with the dissection membrane and have reduced radial force, while the most distal stent was removed creating a distal 30 mm unsupported Dacron graft. RESULTS: Sixteen patients (13 males, 3 females) with a median age of 66 years (range 31-79 years) underwent elective TEVAR of CTBAD using the DSSG. Six patients (38%) had an underlying connective tissue disorder. The median tapering was 10 mm (range 4 mm-21 mm) and median length 270 mm (range 210-380 mm). Technical success was achieved in all but one case (96%). One patient died within 30 days, due to retrograde type A dissection with cardiac tamponade. The 30-day rate of stroke, spinal cord ischemia, and re-interventions was 0%. After median imaging follow-up time of 17 months (range 1-31 months), one patient developed a dSINE 4 months after the index procedure. After median survival follow-up of 23 months (range 2-35 months), one late death occurred due to traumatic brain injury, while no aortic-related death occurred during follow-up. Complete false lumen (FL) thrombosis was achieved in 9 patients while the remaining 6 showed partial FL thrombosis. No instances of diameter increase at the level oftreated aortic segment were noted with serial measurements showing either stable (n = 7) or decreased (n = 8) maximal transverse diameter. CONCLUSIONS: Use of a novel DSSG with low radial force for TEVAR in the setting of CTBAD is safe and feasible. This early real-world experience shows promising mid-term effectiveness with low rates of dSINE or unplanned re-interventions and satisfactory aortic remodeling during follow-up. Longer follow-up is needed, however, before any firm conclusions can be drawn.

Branched Endovascular Aortic Plug in Patients With Infrarenal Aortic Graft Infection and Hostile Anatomy.

Purpose: To present a novel 4-branched endovascular aortic plug (BEVAP) for treatment of patients with infrarenal aortic graft infection. Case Reports: Two polymorbid male patients with aortic graft infections and an unsuturable diseased paravisceral aorta were treated under compassionate use with a custom-made stent-graft. The BEVAP is a factory-modified Zenith t-Branch thoracoabdominal endovascular graft with the distal tubular main graft portion removed, creating an aortic plug that excludes the abdominal aorta while maintaining perfusion to the visceral organs. The BEVAP device is deployed using a femoral approach, and the branches are accessed through an axillary approach. A standard axillobifemoral bypass is created to perfuse the lower body. One to 2 days later, the infected infrarenal graft is resected without the need of aortic clamping or closure of the aortic stump. The BEVAP device in these 2 cases resulted in thrombosis of the abdominal aorta and the infected graft prior to explantation. Conclusion: Using the BEVAP enables radical treatment of selected patients with hostile anatomy and infrarenal aortic graft infections who have an aneurysmal paravisceral aortic segment that prevents traditional radical surgical treatment with in situ reconstruction or extra-anatomical bypass.

Candy-Plug Generation II for False Lumen Occlusion in Chronic Aortic Dissection: Feasibility and Early Results.

Purpose: To present the early results of false lumen (FL) occlusion in chronic aortic dissection using the Candy-Plug generation II (CP II), which has a self-closing fabric channel that obviates the need for separate occlusion of its center. Materials and Methods: Fourteen consecutive patients (mean age 60±11 years; 10 men) with persistent FL backflow and aneurysm formation at the thoracic segment in chronic aortic dissection underwent thoracic endovascular aortic repair (TEVAR) with FL occlusion using the refined CP II. Primary endpoints were technical success (successful deployment) and clinical success (no FL backflow at the CP II level). Secondary endpoints included 30-day mortality and morbidity and aortic remodeling during follow-up. Results: Technical success was 100%. One patient required additional intraprocedural FL embolization at the CP II level due to persistent FL backflow on final angiography (clinical success 93%), though there was no flow through the CP II center. There were no intraprocedural complications. Immediate complete FL occlusion was achieved in 12 patients; the other 2 required reintervention. One had contrast enhancement in the distal FL proximal to the CP II and was treated with coil embolization. The other patient had persistent type I endoleak at the level of the left subclavian artery (LSA) and underwent left carotid-LSA bypass and proximal stent-graft extension. One patient died due to retrograde type A aortic dissection that was not related to CP II placement. Over a mean 8-month follow-up (range 3-12), 9 patients had computed tomography angiography; 8 patients had evidence of aortic remodeling, while 1 aneurysm sac was stable. Conclusion: The CP II reduces the number of procedural steps and offers good seal, with minimal morbidity and mortality and a high rate of aortic remodeling.

False Lumen Occlusion in Chronic Aortic Dissection: The New Generation Candy-Plug II.

BACKGROUND: To introduce the new generation Candy-Plug II with a self-closing channel construction inside the plug. METHODS: The technique of the Candy-Plug II was demonstrated in a 50-year-old patient with residual chronic aortic dissection and thoracic false lumen aneurysm with false lumen backflow after open surgical repair of the ascending aorta for acute type A aortic dissection. The Candy-Plug Technique was applied in addition to a branched arch procedure using a new generation Candy-Plug II for false lumen occlusion. The Candy-Plug II is a short tubular stent graft with a small open channel inside the graft to accommodate the central cannula and allow retrieval of the dilator tip, which closes itself as soon as the dilator tip is removed. The channel inside the graft is unsupported and will collapse and thereby close. This new design obviates additional placement of a plug to occlude the midsection of the first-generation Candy-Plug. After deployment of the Candy-Plug, distal false lumen occlusion was confirmed on final angiogram and postoperative computed tomography scans without any leakage through the Candy-Plug. CONCLUSIONS: The new generation Candy-Plug II is a useful refinement of the previously available model. It reduces the procedural steps and provides a longer sealing segment.

Air Embolism During TEVAR: An Additional Flush Port on the Delivery System Pusher Significantly Reduces the Amount of Air Released During Deployment of a Thoracic Stent-Graft in an Experimental Setting.

PURPOSE: To investigate the influence of (1) an additional side port for flushing the hollow pusher in Zenith thoracic stent-graft delivery systems and (2) additional carbon dioxide flushing on the amount of air released during stent-graft deployment. METHODS: Twenty thoracic stent-grafts with an additional flush port to fill the hollow pusher were separated into 2 equal groups (C and D). Both groups were flushed with 20 mL of normal saline through the extra side port connected to the pusher and with 60 mL of saline through the regular flushing port. One group of grafts (group D) was additionally flushed with carbon dioxide through the regular flushing port prior to saline. All grafts were deployed into a curved plastic pipe attached to the bottom of a water-filled container. The released gas was recorded and measured using a calibrated setup. To evaluate the influence of the extra side port irrespective of the carbon dioxide flushing technique, group C was compared with a previously published reference group A without an extra side port that was flushed with the standard 60 mL of saline. RESULTS: Volumes of gas were released in various amounts from the stent-grafts during deployment. The average amount of released gas was 0.51 mL in group C and 0.07 mL in group D (p<0.001). The mean amount of gas from group C samples (0.51 mL) was also significantly lower (p=0.002) compared with the reference group (0.79 mL). CONCLUSION: Thoracic endografts release air during deployment. Reducing the air-filled space inside the pusher of the catheter assembly using an additional side port can significantly reduce the amount of released air. Using the extra side port in combination with the carbon dioxide flushing technique reduces gas release further to small volumes. In a clinical setting this could be a promising approach to lower the risk of air embolism and stroke during thoracic endovascular aortic repair.

Transapical Access for Antegrade Catheterization of the Inner Branches of an Arch Stent-Graft Deployed Distal to an Ascending Arch Stent-Graft.

Propose: To describe a technique for antegrade cannulation and bridging of the supra-aortic branches through a transapical access in the treatment of an arch aneurysm using combined ascending and branched arch stent-grafts. TECHNIQUE: An 81-year-old man with a past history of open infrarenal aortic repair, emergent endovascular aortic repair for thoracic aortic rupture, and later perivisceral 4-vessel branched endovascular repair of type I thoracoabdominal aneurysm presented for repair of a concomitant 7.5-cm arch aneurysm. Because of a 44-mm ascending aorta, a tapered 50/44-mm ascending stent-graft was delivered through a transapical access to establish an adequate landing zone before implantation of a 46-mm inner branched arch device via a transfemoral route. Innominate and left subclavian arteries were antegradely cannulated and bridged through the existing transapical path. CONCLUSION: Our case demonstrates the feasibility of transapical access for cannulation of an arch branched device, while introducing the theoretical possibility of completing the entire procedure through a transapical access.

Identification and synthesis of a novel selective partial PPARdelta agonist with full efficacy on lipid metabolism in vitro and in vivo.

The aim was to identify a novel selective PPARdelta agonist with full efficacy on free fatty acid (FFA) oxidation in vitro and plasma lipid correction in vivo. Using the triple PPARalpha,gamma,delta agonist 1 as the structural starting point, we wanted to investigate the possibility of obtaining selective PPARdelta agonists by modifying only the acidic part of 1, while holding the lipophilic half of the molecule constant. The structure-activity relationship was guided by in vitro transactivation data using the human PPAR receptors, FFA oxidation efficacy performed in the rat muscle L6 cell line, and in vivo rat pharmacokinetic properties. Compound 7 ([4-[3,3-bis-(4-bromo-phenyl)-allylthio]-2-chloro-phenoxy]-acetic acid) was identified as a selective, partial agonist with good oral pharmacokinetic properties in rat. Chronic treatment of high fat fed ApoB100/CETP-Tgn mice with 7 corrected the plasma lipid parameters and improved insulin sensitivity. These data suggest that selective PPARdelta agonists have the potential to become a novel treatment of dyslipidemia.

Selective PPAR agonists for the treatment of type 2 diabetes.

Type 2 diabetes is a metabolic disease characterized by increased plasma glucose and insulin as well as dyslipidemia. If left untreated, chronic diseases will develop that are associated with neuropathic damage and higher mortality risk. Using a rational drug design, novel compounds have been developed that selectively activate the human PPAR receptors, leading to lessening of hyperglycemia and hyperinsulinemia as well as reduction of lipid levels in conjunction with an increase of the beneficial HDL-cholesterol. These PPAR agonists showed increased potency and efficacy compared to previously marketed insulin sensitizers. Lead compounds with desirable pharmacokinetic properties were chosen for further testing in several animal models. The in vivo activity of some synthetic ligands, capable of activating two or all three members of peroxisome proliferator-activated receptors (PPAR) family of receptors, suggested that they may have improved efficacy in type 2 diabetes therapy. Here, we briefly summarize the development of some novel PPAR agonists identified by our group in recent years.

Large dimeric ligands with favorable pharmacokinetic properties and peroxisome proliferator-activated receptor agonist activity in vitro and in vivo.

Two potent nonselective, but PPARalpha-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.

Arylcyanoguanidines as activators of Kir6.2/SUR1K ATP channels and inhibitors of insulin release.

Phenylcyanoguanidines substituted with lipophilic electron-withdrawing functional groups, e.g. N-cyano-N'-[3,5-bis-(trifluoromethyl)phenyl]-N' '-(cyclopentyl)guanidine (10) and N-cyano-N'-(3,5-dichlorophenyl)-N' '-(3-methylbutyl)guanidine (12) were synthesized and investigated for their ability to inhibit insulin release from beta cells, to repolarize beta cell membrane potential, and to relax precontracted rat aorta rings. Structural modifications gave compounds, which selectively inhibit insulin release from betaTC6 cells (e.g. compound 10: IC(50) = 5.45 +/- 1.9 microM) and which repolarize betaTC3 beta cells (10: IC(50) = 4.7 +/- 0.5 microM) without relaxation of precontracted aorta rings (10: IC(50) > 300 microM). Inhibition of insulin release from rat islets was observed in the same concentration level as for betaTC6 cells (10: IC(50) = 1.24 +/- 0.1 microM, 12: IC(50) = 3.8 +/- 0.4 microM). Compound 10 (10 microM) inhibits calcium outflow and insulin release from perifused rat pancreatic islets. The mechanisms of action of 10 and 12 were further investigated. The compounds depolarize mitochondrial membrane from smooth muscle cells and beta cell and stimulate glucose utilization and mitochondrial respiration in isolated liver cells. Furthermore, 10 was studied in a patch clamp experiment and was found to activate Kir6.2/SUR1 and inhibit Kir6.2/SUR2B type of K(ATP) channels. These studies indicate that the observed effects of the compounds on beta cells result from activation of K(ATP) channels of the cell membrane in combination with a depolarization of mitochondrial membranes. It also highlights that small structural changes can dramatically shift the efficacy of the cyanoguanidine type of selective activators of Kir6.2/SUR2 potassium channels.

6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives potently and selectively activate ATP sensitive potassium channels of pancreatic beta-cells.

6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives were synthesized and characterized as activators of adenosine 5'-triphosphate (ATP) sensitive potassium (K(ATP)) channels in the beta-cells by measuring effects on membrane potential and insulin release in vitro. The effects on vascular tissue in vitro were measured on rat aorta and small mesenteric vessels. Selected compounds were characterized as competitive inhibitors of [(3)H]glibenclamide binding to membranes of HEK293 cells expressing human SUR1/Kir6.2 and as potent inhibitors of insulin release in isolated rat islets. 6-Chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (54) was found to bind and activate the SUR1/Kir6.2 K(ATP) channels in the low nanomolar range and to be at least 1000 times more potent than the reference compound diazoxide with respect to inhibition of insulin release from rat islets. Several compounds, e.g., 3-propylamino- (30), 3-isopropylamino- (34), 3-(S)-sec-butylamino- (37), and 3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (53), which were found to be potent and beta-cell selective activators of K(ATP) channels in vitro, were found to inhibit insulin secretion in rats with minimal effects on blood pressure and to exhibit good oral pharmacokinetic properties.

Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity.

Synthesis and structure-activity relationships of tricyclic alpha-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARalpha and PPARgamma transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARalpha (EC(50) = 0.36 microM) and PPARgamma (EC(50) = 0.17 microM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARgamma activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARalpha activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.

Novel selective PPARdelta agonists: optimization of activity by modification of alkynylallylic moiety.

Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPARdelta activators. The alkynylallylic moiety was synthesized from alkyn-1-ols by hydroalumination followed by a cross-coupling reaction. Series of active compounds 6 were obtained by stepwise changing the structure of the known PPARpan agonist 5 into Y-shaped compounds. The most active and selective compound, 6f, had a PPARdelta potency of 0.13 microM, which is 50-fold more potent than compound 5.

Design of a partial PPARdelta agonist.

Structure based ligand design was used in order to design a partial agonist for the PPARdelta receptor. The maximum activation in the transactivation assay was reduced from 87% to 39%. The crystal structure of the ligand binding domain of the PPARdelta receptor in complex with compound 2 was determined in order to understand the structural changes which gave rise to the decrease in maximum activation.

Design of potent PPARalpha agonists.

Computational analysis of the ligand binding pocket of the three PPAR receptor subtypes was utilized in the design of potent PPARalpha agonists. Optimum PPARalpha potency and selectivity were obtained with substituents having van der Waals volume around 260. Compound 6 had a PPARalpha potency of 0.002 microM and a selectivity ratio to PPARgamma and PPARdelta of 410 and 2000, respectively.

Structure-activity relationships of dimeric PPAR agonists.

A series of dimeric PPAR agonists were designed and tested for PPAR activity in vitro. The SAR showed that dimeric ligands with a common group or full dimeric ligands had retained or even increased PPARgamma potency. The dimeric agonist concept can be used to fine tune the subtype selectivity of PPAR agonists. The PPARgamma potency could, at least partly, be explained using molecular modeling.

Prediction of PPAR-alpha ligand-mediated physiological changes using gene expression profiles.

Peroxisome proliferator-activated receptor (PPAR)-alpha controls the transcription of a variety of genes involved in lipid metabolism and is the target receptor for the hypolipidemic drug class of fibrates. In the present study, the molecular and physiological effects of seven different PPAR-activating drugs have been examined in a rodent model of dyslipidemia. The drugs examined were selected to display varying potencies and efficacies toward PPAR-alpha. To help elucidate the link between the gene regulation elicited by PPAR-alpha ligands and the concomitant physiological changes, we have used cDNA microarray analysis to identify smaller gene sets that are predictive of the function of these ligands. A number of genes showed strong correlations to the relative PPAR-alpha efficacy of the drugs. Furthermore, using multivariate analysis, a strong relationship between the drug-induced triglyceride lowering and the transcriptional profiles of the different drugs could be found.

Synthesis and biological activity of 3,3-diamino-sulfonylacrylonitriles as novel inhibitors of glucose induced insulin secretion from beta cells.

Pinacidil analogues, for example, N-cyano-N'-(3,5-dichlorophenyl)-N"-(3-methylbutyl)guanidine, 1, have previously been described as potassium channel openers on beta cells and smooth muscle cells. In the present study 3,3-diamino-sulfonylacrylonitrile, a new bioisostere of the cyanoguanidine group, was investigated. 3,3-Diamino-sulfonylacrylonitriles were prepared in a two step synthesis from the corresponding isothiocyanates and sulfonylacetonitriles. Single crystal X-ray crystallography and NMR spectroscopy were used to establish the structure of 2-(4-chlorophenylsulfonyl)-3-cyclobutylamino-3-(3,5-dichlorophenylamino)acrylonitrile 3i. The analysis confirmed that 3i assumes a staggered conformation considered as the energetically most favourable. The compounds synthesised have been identified as potent inhibitors of glucose stimulated insulin secretion from beta cell lines and rat pancreatic islets with minimal effects on vascular smooth muscle.

Design and synthesis of novel PPARalpha/gamma/delta triple activators using a known PPARalpha/gamma dual activator as structural template.

Using a known dual PPARalpha/gamma activator (5) as a structural template, SAR evaluations led to the identification of triple PPARalpha/gamma/delta activators (18-20) with equal potency and efficacy on all three receptors. These compounds could become useful tools for studying the combined biological effects of PPARalpha/gamma/delta activation.