Clinical Characteristics and Current Practice of Endovascular Revascularization in Aorto-Iliac, Femoropopliteal and Infra-Popliteal Lower Extremity Artery Disease-Insights from the RECCORD Registry.

BACKGROUND: Endovascular revascularization (EVR) is a pillar of therapeutic management in patients with symptomatic lower extremity artery disease (LEAD). Due to lack of scientific evidence, the approach of EVR type and the devices used at the different anatomic vascular segments of the lower limbs vary substantially between operators and centers. We analyzed data from the RECcording COurses of vasculaR Diseases (RECCORD) registry to assess the current real-world EVR treatment patterns in relation to anatomic vascular segments in symptomatic LEAD patients in Germany. PATIENTS AND METHODS: RECCORD is an ongoing, prospective, multicenter, all-comers and entirely web-based registry platform. Baseline demographic and periprocedural data of patients undergoing EVR for symptomatic LEAD were assessed and performed EVRs were grouped according to the intervened anatomic vascular segment. We analyzed four EVR groups comprising either the aorto-iliac, femoropopliteal, or infrapopliteal segments (all these EVRs with or without a further intervention in another anatomic segment) or the infrapopliteal segment alone. RESULTS: A total of 2210 EVR segments (in 1639 patients) were analyzed. Of those 616 (27.9%) were aorto-iliacal, 1346 (60.9%) femoropopliteal, 248 (11.2%) infrapopliteal and 104 (4.7%) only infrapopliteal segments. Aorto-iliac EVR was associated with younger age, smoking, claudication and simple lesions, while the distal infrapopliteal EVRs were related to advanced age, diabetes, multiple comorbidities, limb threatening ischemia and complex lesions. The use of different EVR devices at the aorto-iliac, femoropopliteal, infrapopliteal and only infrapopliteal segments were: only ballon-angioplasty: 8.3%, 12.9%, 58.1% and 63.5%; stenting: 82.3%, 45.3%, 16.9% and 12.5%; drug-coated balloon: 11.2%, 55.0%, 19.4% and 19.2%. CONCLUSION: The RECCORD registry data demonstrate that in LEAD clinical and lesion characteristics are related to anatomic vascular segments. Despite the clear relationship between vascular segments and the current use of device types, prospective, segment-specific clinical studies are warranted to establish a consistent, evidence-based path for EVR in LEAD.

Access Site Related Vascular Complications following Percutaneous Cardiovascular Procedures.

Vascular access site complications (ASC) are among the most frequent complications of percutaneous cardiovascular procedures (PCP) and are associated with adverse outcome and high resources utilization. In this prospective study, we investigated patients with postprocedural clinical suspicion of ASC evaluated by duplex ultrasound (DUS) for the presence of ASC. We assessed the incidence, in-hospital outcome, treatment of complications and predictors for ASC. Overall, 12,901 patients underwent PCP during a 40 months period. Of those, 2890 (22.4%) patients had postprocedural clinical symptoms of ASC and were evaluated using DUS. An ASC was found in 206 of the DUS examined patients (corresponding to 7.1% of the 2890 DUS examined patients). In 6.7% of all valvular/TAVI procedures, an ASC was documented, while coronary, electrophysiological and peripheral PCP had a comparable and low rate of complications (1.2-1.5%). Pseudoaneurysm (PSA) was the most frequent ASC (67.5%), followed by arteriovenous fistula (13.1%), hematoma (7.8%) and others (11.7%). Of all PSA, 84 (60.4%) were treated surgically, 44 (31.6%) by manual compression and 11 (7.9%) conservatively. Three (0.02%) patients died due to hemorrhagic shock. In conclusion, femoral ASC are rare in the current era of PCP with PSA being the leading type of ASC. Nonetheless, patients with predisposing risk factors and postprocedural suspicious clinical findings should undergo a DUS to early detect and mitigate ASC-associated outcome.

Feasibility and impact of carbon dioxide angiography on acute kidney injury following endovascular interventions in patients with peripheral artery disease and renal impairment.

BACKGROUND: Post-contrast acute kidney injury (AKI) is a dreaded complication of endovascular revascularization using iodinated contrast medium in patients with peripheral artery disease and concomitant chronic kidney disease (CKD). This study sought to evaluate the incidence of AKI in patients with peripheral artery disease and CKD undergoing endovascular revascularization and using carbon dioxide (CO2) as contrast medium. METHODS AND RESULTS: From 04/2015 to 07/2018, all consecutive peripheral artery disease patients with CKD stage ≥ 3 referred for endovascular revascularization of symptomatic peripheral artery disease were prospectively included. During endovascular revascularization, CO2 as contrast medium was manually injected and iodinated contrast medium was additionally used when needed. The reference group consisted of 211 cardiovascular risk factor-matched patients undergoing endovascular revascularization with iodinated contrast medium only. CO2-guided endovascular revascularization was performed in 102 patients, thereof 16 (15.7%) patients exclusively with CO2. Baseline CKD stage ≥ 4 and iodinated contrast medium volume > 50 ml were disproportionally associated with post-procedural post-contrast AKI. At CKD stage 4 the odds ratio for post-contrast AKI was 13.2 (95% CI 1.489-117.004; p = 0.02) for iodinated contrast medium volume 51-100 ml and 37.7 (95% CI 3.927-362.234; p = 0.002) for iodinated contrast medium volume > 100 ml. The corresponding values at CKD stage 5 were 23.7 (95% CI 2.666-210.583; p = 0.005) and 28.3 (95% CI 3.289-243.252; p = 0.002), respectively. Radiation (dose area product) was significantly higher in the CO2-endovascular revascularization group (6.025 ± 6.926 cGy*cm2 vs. 4.281 ± 4.722 cGy*cm2, p = 0.009). CONCLUSION: CO2 is an applicable and safe alternative to iodinated contrast medium for endovascular revascularization in peripheral artery disease patients with concomitant CKD. Patients with CKD stage 4 or 5, being at highest risk for post-contrast AKI, should primarily be treated by CO2-guided endovascular revascularization.

[Medication-based secondary prevention in patients with peripheral arterial occlusive disease : An analysis based on secondary data]. / Medikamentöse Sekundärprävention bei Patienten mit peripherer arterieller Verschlusskrankheit : Eine sekundärdatenbasierte Analyse.

BACKGROUND: Peripheral arterial occlusive disease (PAOD) is an atherosclerotic vascular disease with high morbidity and mortality. A consistent medication-based secondary prevention is part of the essential and evidence-based treatment of PAOD. The aim of this study was to ascertain the status quo of medicinal secondary prevention based on submitted prescriptions. METHODS: In the time period from 2014 to 2017 patients with a confirmed PAOD coding (I70.2-/I73.9-) were identified based on secondary data of the Association of Statutory Health Insurance Physicians Westphalia-Lippe (KVWL). The prescriptions submitted with respect to platelet inhibitors, oral anticoagulants, lipid lowering therapy (LLT) and angiotensin-converting enzyme (ACE) inhibitors in the fourth quarter year after diagnosis coding were collated. RESULTS: In the diagnosis period 2014/2015 a total of 238,397 patients had PAOD in the catchment area of the KVWL. The proportion of submitted prescriptions in the fourth quarter year after diagnosis was 25.9% for LLT, 13.6% for acetylsalicylic acid, 4.5% for clopidogrel, 5.5% for vitamin K antagonists (VKA), 3.5% for non-vitamin K­dependent oral anticoagulants (NOAC) and 26.8% for ACE inhibitors. Over the course of the 3 years (n = 241,375 patients with PAOD 2016/2017) the proportion of submitted prescriptions for all substances except VKA increased (p < 0.001), whereby the largest relative increase was noted for NOAC (relative increase of 81.7%). CONCLUSION: The guideline-conform medicinal secondary prevention in patients with PAOD in Germany is still in need of improvement. A consistent implementation of evidence-based medicinal secondary prevention harbors a great potential for improvement of the overall prognosis in patients with PAOD.

Outcome of patients with chronic limb-threatening ischemia with and without revascularization.

Background: Patients with chronic critical limb-threatening ischemia (CLTI) are at high risk of amputation and death. Despite the general recommendation for revascularization in CTLI in the guidelines, the underlying evidence for such a recommendation is limited. The aim of our study was to assess the outcome of patients with CLTI depending on the use of revascularization in a retrospective real-world cohort. Patients and methods: Administrative data of the largest German Health insurance (BARMER GEK) were provided for all patients that were hospitalized for the treatment of CLTI Rutherford category (RF) 5 and 6 between 2009 and 2011. Patients were followed-up until December 31st, 2012 for limb amputation and death in relation to whether patients did (Rx +) or did not have (Rx -) revascularization during index-hospitalization. Results: We identified 15,314 patients with CLTI at RF5 (n = 6,908 (45.1%)) and RF6 (n = 8,406 (54.9%)), thereof 7,651 (50.0%) underwent revascularization (Rx +) and 7,663 (50.0%) were treated conservatively (Rx -). During follow-up (mean 647 days; 95% CI 640-654 days) limb amputation (46.5% Rx- vs. 40.6% Rx+, P < 0.001) and overall mortality (48.2% Rx- vs. 42.6% Rx+, P < 0.001) were significantly lower in the subgroup Rx+. Conclusions: In a real-world setting, only half of CLTI were revascularized during the in-hospital treatment. Though, revascularization was associated with significantly better observed short- and long-term outcome. These data do not allow causal conclusion due to lack of data on the underlying reason for applied or withheld revascularization and therefore may involve a relevant selection bias.

Overburden soil and marine dredging sludge utilization for production of new composites as highly efficient environmental management.

The main objectives of this study were to develop new composites only from industrial wastes: overburden soil (40-60 wt%), dredging sludge from marine port sediments (20-40%) and lime production waste as a binder (15-30%). The axial resistance strength of the developed materials, on the 365th day, was 18.9 MPa and the values of apparent density and dilatation coefficient ranged from 2.69 to 3.14 g/cm³ and from 0.14 to 1.56%, respectively. Water absorption values after 90 days of cure varied between 8.9 and 15.1% and water resistance coefficient reached 1.17. They can be used for the production of construction materials such as tiles, bricks, and blocks, as road base and airfield runways, dam cores, industrial and municipal waste dumps bases, building foundations. The studies of the developed material, by the methods of XRD, AAS, SEM, EDS, DTA - DTG, tomographic mapping of the chemical elements and isotopic composition (LAMMA), demonstrated the synthesis of new formations, mainly amorphous, with small inclusions of crystalline structures. Results of leaching and solubility tests by the AAS method showed the full ecological compatibility of the developed materials with the environmental standards of Brazil.

Evaluation of Therapeutic Oligonucleotides for Familial Amyloid Polyneuropathy in Patient-Derived Hepatocyte-Like Cells.

Familial amyloid polyneuropathy (FAP) is caused by mutations of the transthyretin (TTR) gene, predominantly expressed in the liver. Two compounds that knockdown TTR, comprising a small interfering RNA (siRNA; ALN-TTR-02) and an antisense oligonucleotide (ASO; IONIS-TTRRx), are currently being evaluated in clinical trials. Since primary hepatocytes from FAP patients are rarely available for molecular analysis and commercial tissue culture cells or animal models lack the patient-specific genetic background, this study uses primary cells derived from urine of FAP patients. Urine-derived cells were reprogrammed to induced pluripotent stem cells (iPSCs) with high efficiency. Hepatocyte-like cells (HLCs) showing typical hepatic marker expression were obtained from iPSCs of the FAP patients. TTR mRNA expression of FAP HLCs almost reached levels measured in human hepatocytes. To assess TTR knockdown, siTTR1 and TTR-ASO were introduced to HLCs. A significant downregulation (>80%) of TTR mRNA was induced in the HLCs by both oligonucleotides. TTR protein present in the cell culture supernatant of HLCs was similarly downregulated. Gene expression of other hepatic markers was not affected by the therapeutic oligonucleotides. Our data indicate that urine cells (UCs) after reprogramming and hepatic differentiation represent excellent primary human target cells to assess the efficacy and specificity of novel compounds.

Effects of Different Variants in the ENPP1 Gene on the Functional Properties of Ectonucleotide Pyrophosphatase/Phosphodiesterase Family Member 1.

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (E-NPP1), encoded by ENPP1, is a plasma membrane protein that generates inorganic pyrophosphate (PPi ), a physiologic inhibitor of hydroxyapatite formation. In humans, variants in ENPP1 are associated with generalized arterial calcification of infancy, an autosomal-recessive condition causing premature onset of arterial calcification and intimal proliferation resulting in stenoses. ENPP1 variants also cause pseudoxanthoma elasticum characterized by ectopic calcification of soft connective tissues. To determine the functional impact of ENPP1 missense variants, we analyzed 13 putative pathogenic variants in vitro regarding their functional properties, that is, activity, localization, and PPi generation. Transfection of eight of the 13 variants led to complete loss of NPP activity, whereas four mutants (c.1412A > G, p.Tyr471Cys; c.1510A > C, p.Ser504Arg; c.1976A > G, p.Tyr659Cys; c.2330A > G, p.His777Arg) showed residual activity compared with wild-type E-NPP1. One putative pathologic variant (c.2462 G > A, p.Arg821His) showed normal activity. The five mutants with normal or residual E-NPP1 enzyme activity were still able to generate PPi and localized in the plasma membrane. In this study, we identified a functional ENPP1 polymorphism, which was expected to be pathogenic till now. Furthermore, we identified four mutants (p.Tyr471Cys, p.Ser504Arg, p.Tyr659Cys, p.His777Arg) with residual E-NPP1 function, which would be potential therapeutical targets for conformational-stabilizing agents.

Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.

Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.