EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis.

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.

Long-term durability and clinical outcome of a prospective randomized trial comparing carotid endarterectomy with ACUSEAL polytetrafluoroethylene patching versus pericardial patching.

BACKGROUND: Several studies have shown the superiority of carotid endarterectomy (CEA) with patch closure over primary closure. However, no definite study has shown any significant differences in clinical outcome between various types of patches. Because more vascular surgeons have used pericardial patching recently, this study will analyze the late clinical outcome (≥10 years) of our previously reported prospective randomized trial comparing CEA with ACUSEAL (polytetrafluoroethylene) vs pericardial patching. METHODS: A total of 200 CEAs were randomized (1:1) to either Vascu-Guard pericardial patching or ACUSEAL patching. All patients had immediate duplex ultrasound imaging, which was repeated at 6 months and annually thereafter. Kaplan-Meier analysis was used to estimate rates of freedom from stroke, stroke-free survival, and rates of freedom from ≥50% and ≥80% restenosis. RESULTS: Overall demographic and clinical characteristics were somewhat similar with a mean follow-up of 80 months (range: 0-149 months). The rates of freedom from stroke were 97, 97, 97, 96, 93 for ACUSEAL vs 99, 98, 97, 97, 92 for pericardial patching (P = .1112) at 1, 2, 3, 5, and 10 years, respectively. Similarly, the rates of freedom from stroke/death were 94, 93, 90, 76, 50 for ACUSEAL vs 99, 96, 91, 78, 47 for pericardial patching (P = .8591). The rates of freedom from ≥50% restenosis were 98, 98, 96, 89, 79 for ACUSEAL vs 87, 83, 83, 81, 71 for pericardial patching (P = .0489). The rates of freedom from ≥80% restenosis were 99, 99, 99, 96, 85 for ACUSEAL vs 96, 96, 96, 93, 93 for pericardial patching (P = .9407). The overall survival rates were 95, 94, 91, 77, 51 for ACUSEAL vs 100, 98, 93, 79, 50 for pericardial patching (P = .9123). Other patch complications (eg, rupture, aneurysmal dilation, infection, etc) were similar. CONCLUSIONS: Both CEA with ACUSEAL (polytetrafluoroethylene) and pericardial patching are durable and have similar clinical outcomes at 10 years except that ACUSEAL patching has significantly better rates of freedom from ≥50% restenosis.

A single-center experience of 30-day perioperative and one year clinical outcomes of transcarotid artery revascularization in 100 consecutive patients.

BACKGROUND: Transcarotid Artery Revascularization (TCAR) using the ENROUTE system (Silk Road) has been proposed as a safe and effective alternative to both carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TF-CAS). Two large registries (ROADSTER 1 and ROADSTER 2) have shown that TCAR has acceptable/low rates of perioperative stroke/death. This study will analyze the 30-day perioperative and 1-year clinical outcomes from a single-center. PATIENT POPULATION AND METHODS: This is a retrospective analysis of prospectively collected data from SVS/VQI TCAR surveillance project (TSP) of 100 consecutive patients (102 TCAR procedures) done in our institution. These procedures were done for high-risk patients for CEA, which included anatomical (previous CEA, high cervical lesion, neck radiation, stoma, arch type, etc.), physiological (CHF, severe coronary artery disease, COPD on O2 therapy, etc.) and combined anatomical/physiological reasons. These procedures were done by vascular surgeons after receiving the appropriate training. The perioperative stroke, death, and MI rates were analyzed. Kaplan Meyer analysis was used to estimate rate of freedom from stroke/death and the incidence of ≥50% and ≥80% in-stent restenosis at 1 year. RESULTS: 100 consecutive high-risk patients for CEA included: 38% anatomical, 44% physiological, and 18% combined anatomical and physiological reasons. The mean age was 72.5 years (range 52-90 years). Indications for TCAR were 34% for symptomatic lesions (TIA/stroke) and 66% for asymptomatic lesions. Mean ipsilateral treated stenosis was 80.4%. Contralateral ≥50% stenosis/occlusion was present in 31% of patients. Technical success rate was 100%. 92% had pre-stenting PTA and 26% had post-stenting PTA. The mean flow reversal time was 8.5 min (range 3-26 min). The 30-day perioperative stroke rate was 2.9% (1/67, 1.5% for asymptomatic patients), the stroke/death rate was 2.9%, and stroke/death and MI rate was 3.9% (4/102). Other perioperative complications included cranial nerve injury 3/102 (2.9%), carotid artery dissection (2%), and major hematoma (necessitated operation evacuation) (5.9%). Freedom from stroke rates and stroke/death rates at 1 year were: 90% and 89%. Freedom from ≥50% and ≥80% in-stent restenosis rates at 1 year were 82% and 90%, respectively. None of these restenosis were symptomatic except two (2/13). Freedom from reintervention rate at 1 year was 98%. CONCLUSION: Although the perioperative events were somewhat higher than what has been reported in previous registries, TCAR for patients who are high-risk for CEA has a low perioperative stroke and stroke/death rates with satisfactory outcome at 1 year. Further long-term data is probably needed to verify long-term outcome.

Predictors and timeline of spontaneous conversion to normal sinus rhythm: A single center retrospective cohort study of patients with symptomatic atrial fibrillation.

INTRODUCTION: Annual healthcare expenditures associated with atrial fibrillation (AF) in the United States (US) continue to grow as more symptomatic patients present to emergency departments (ED). Predictors of spontaneous conversion to normal sinus rhythm (ScNSR) remain poorly understood, as well as the timeline of ScNSR remains unclear. We sought to 1) to assess the association of key demographics, anthropometric, and clinical factors to ScNSR and 2) to evaluate the timeline of ScNSR, and 3) determine clinical predictors of ScNSR. METHODS: This single center, retrospective cohort study analyzed patients aged ≥18 years with symptomatic AF as diagnosed and evaluated through the ED of a rural tertiary care center in West Virginia from September 2015 to December 2018. RESULTS: Our cohort consisted of 375 AF patients (mean age 65 years, 54% male). A total of 177 patients attained ScNSR either in the ED or after hospital admission with a mean conversion time of 14.7 h (±12). Onset of symptoms <24 hrs has strong positive association to ScNSR 3.97 (95% CI: 2.24-7.05; p < 0.0001). Male gender 0.55 (95% CI: 0.35-0.85; p = 0.007) and hypertension 0.48 (95% CI: 0.31-0.76; p = 0.002), showed a strong negative association to ScNSR. Of the patients that converted spontaneously (177), the majority, 136 (76.8%) achieved ScNSR within 24 h of ED triage without use of electrical or chemical cardioversion. CONCLUSION: Most patients with AF in the ED converted spontaneously to sinus rhythm within the first 24 h which underscores the importance of earlier watchful waiting over interventions to achieve normal sinus rhythm (NSR).

Critical analysis of vertebral artery flow patterns/subclavian steal detected by cerebrovascular duplex ultrasound examinations and its clinical implications.

BACKGROUND: The prevalence of subclavian steal (defined as retrograde/bidirectional vertebral artery flow) in the general population and in patients undergoing cerebrovascular duplex ultrasound (CDUS) examinations is variable. This is the largest study to date to analyze the incidence of duplex-suggested subclavian steal in 5615 CDUS examinations over a 1-year period and to examine its clinical implications. PATIENT POPULATION AND METHODS: All consecutive CDUS examinations performed over a 1-year period were analyzed for the presence of subclavian steal. Indications of testing, presence of posterior cerebral circulation/subclavian steal symptoms, and any interventions for subclavian steal were analyzed. RESULTS: A total of 171 of 5615 (3.1%) CDUS examinations were found to have subclavian steal (duplex-suggested). One hundred seventeen (2.1%) had retrograde flow and 54 (1%) had bidirectional flow. Of 171, 104 (60.8%) were left sided. Indications for CDUS were post-carotid endarterectomy/carotid artery stenting surveillance in 39 patients (22.8%), surveillance for progression of carotid stenosis in 76 patients (44.4%), transient ischemic attack/stroke in 26 patients (15%), asymptomatic screening/carotid bruit in 18 patients (10.5%), and isolated posterior cerebral circulation symptoms in 12 patients (7%). A total of 63% patients had associated >50% carotid stenosis. The mean arm Doppler pressure gradient was 32.2 mm Hg for asymptomatic patients vs 37 mm Hg for patients with posterior circulation symptoms (P = .3254). There were significant differences between the mean systolic arm pressure for patients with retrograde vs antegrade vs bidirectional flow (105 mm Hg vs 146 mm Hg vs 134 mm Hg, respectively, P < .0001). All patients with retrograde flow had >50% subclavian stenosis or occlusion (100 of 117 had subtotal/total occlusion) except for one patient. Meanwhile, 52 of 54 patients with bidirectional flow had >50% subclavian stenosis (6 of 54 with subtotal/total occlusion), whereas two patients were normal/<50% stenosis (P < .0001). Overall, 26 of 171 patients (15.2%) had interventions for disabling symptoms. Eleven of 26 of all interventions were for disabling arm claudication, and only 10 of 171 patients (5.8%) were intervened for disabling posterior circulation symptoms with complete resolution of symptoms in all except one. At a late follow-up with a mean of 18 months (range: 1-37 months), there was no late major stroke with only two lacunar infarcts (not subclavian steal related). There were also seven late deaths, none stroke related. CONCLUSIONS: The incidence of subclavian steal in patients who undergo CDUS is relatively rare. Most of these patients are asymptomatic and can be treated conservatively, and only a few may need intervention for disabling symptoms with good symptom resolution.

Rates of progression of carotid in-stent stenosis and clinical outcomes.

BACKGROUND: We previously reported the incidence of ≥50% and ≥80% carotid in-stent stenosis. In the present study, we analyzed the rate of progression of in-stent stenosis and clinical outcomes with longer follow-up. METHODS: We performed a retrospective analysis of prospectively collected data for 450 patients who had undergone transfemoral carotid artery stenting with longer follow-up (mean, 70 months). The progression of in-stent stenosis was defined as stenosis advancing to a higher severity of disease (ie, from <50% to ≥50% and from ≥50% to ≥80%). Kaplan-Meier analysis was used to estimate the rate of progression from <50% to ≥50% and ≥50% to ≥80%, the overall rates of ≥50% and ≥80% in-stent stenosis, and survival at 1, 3, 5, and 10 years. RESULTS: At a mean follow-up of 70.3 months (range, 1-222 months), 121 of 446 patients (27%) had had progression to ≥50% and 39 (8.7%) to ≥80% in-stent stenosis. Of the 406 patients whose first duplex ultrasound findings were normal or showed in-stent stenosis of <50%, 82 had had progression from normal or <50% to ≥50% in-stent stenosis at a mean of 51.7 months (range, 1-213 months). Of the 121 patients with ≥50% stenosis, 14 (11.6%) had experienced progression to ≥80% at a mean of 33.6 months (range, 6-89 months). Of the 82 patients with progression from <50 to ≥50%, 10 (12%) had experienced a neurologic event (eight transient ischemic attacks [TIAs] and two strokes). Of the 14 with progression from ≥50% to ≥80%, 2 (14.3%) had experienced a TIA, and the remaining patients were asymptomatic. Of the 39 patients with ≥80% in-stent stenosis, 9 (23%) had experienced a neurologic event (eight TIAs and one contralateral stroke). Overall, 13 of the 121 patients with late ≥50% restenosis (10.7%) had experienced a neurologic event (10 ipsilateral TIA, 2 ipsilateral stroke, and 1 contralateral stroke. Thus, 12 of 446 patients (2.7%) had experienced an ipsilateral TIA or stroke at a mean follow-up of 70 months. The rates of freedom from <50% to ≥50% in-stent stenosis progression were 93%, 85%, 78%, and 66% at 1, 3, 5, and 10 years. The rates of freedom from progression from ≥50% to ≥80% in-stent stenosis were 89%, 81%, and 77% at 1, 3, and 5 years, respectively. The overall rates of freedom from ≥50% in-stent stenosis and ≥80% in-stent stenosis were 86%, 77%, 71%, and 59% and 96%, 93%, 91%, and 84% at 1, 3, 5, and 10 years, respectively. Finally, the stroke survival rates were 95%, 80%, 63%, and 31% at 1, 3, 5, and 10 years, respectively. CONCLUSIONS: The rate of progression of carotid in-stent stenosis was modest, with a low incidence of stroke events. Therefore, the use of duplex ultrasound surveillance after carotid artery stenting should be selective and its benefits and utility perhaps reevaluated.

Clinical Outcome of Drug-Eluted Stenting (Zilver PTX) in Patients With Femoropopliteal Occlusive Disease a Single Center Experience.

BACKGROUND: Few industry sponsored trials reported satisfactory outcomes in the use of drug-eluting stents (DES) for treatment of femoropopliteal arterial disease. This study analyzed the early/late clinical outcome from a real world single center. PATIENT POPULATIONS/METHODS: A total of 115 limbs treated with Zilver PTX were analyzed for: major adverse limb event (MALE: above ankle limb amputation/major intervention at 1 year), major adverse events (MAEs; death, amputation, and target lesion thrombosis/reintervention), primary patency (based on duplex ultrasound ± ankle brachial indexes), limb salvage, and amputation free survival rates (AFS) at 1 and 2 years. RESULTS: Indications included claudication in 32% and critical limb threatening ischemia (CLTI) in 68%. Lesions treated included: superficial femoral artery (SFA) 66%, both SFA and popliteal artery (PA) 19% and PA 15%. Mean lesion length was 21 cm and 68% had total occlusion. 45% were Trans-Atlantic Inter-Society Consensus (TASC) TASC II D lesions and 55% A-C lesions. Mean follow-up was 18.4 months (1-76 months). Perioperative major morbidity rate was 8.7% with 0% mortality. MALE rate at 1 year was 17% (13.5% for claudication vs 19.2% for CLTI, p=0.4499). MAE rate was 30% for claudication versus 52% for CLTI (p=0.0392). Overall primary patency rates at 1 and 2 years were 75% and 54% (86% and 71% for claudication vs 70% and 46% for CLTI, respectively, p=0.0213). Primary patency rates at 1 and 2 years were 94% and 88% for TASC A-C lesions versus 50% and 16% for TASC D lesions (p<0.0001). Overall freedom from MALE rate at 1 and 2 years were 85% and 79% (86% and 86% for claudication vs 84% and 74% for CLTI, p=0.2391). These rates were 96% and 93% for TASC A-C lesions versus 70% and 50% for D lesions, respectively (p<0.0001). Limb salvage rates at 1 and 2 years were 93% and 86% (100% and 100% for claudication vs 89% and 78% for CLTI, p=0.012). Overall AFS rates at 1 and 2 years were 79% and 71% (93% and 82% for TASC A-C vs 59% and 59% for D lesions, p=0.001). CONCLUSION: Clinical outcomes after DES (Zilver PTX) in femoropopliteal arterial lesions were satisfactory for TASC A-C lesions but inferior/unsatisfactory for TASC D lesions.

Elastin calcification in in vitro models and its prevention by MGP's N-terminal peptide.

Medial calcification has been associated with diabetes, chronic kidney disease, and genetic disorders like pseudoxanthoma elasticum. Recently, we showed that genetic reduction of arterial elastin content reduces the severity of medial calcification in matrix Gla protein (MGP)-deficient and Eln haploinsufficient Mgp-/-;Eln+/- mice. This study suggests that there might be a direct effect of elastin amount on medial calcification. We studied this using novel in vitro systems, which are based on elastin or elastin-like polypeptides. We first examined the mineral deposition properties of a transfected pigmented epithelial cell line that expresses elastin and other elastic lamina proteins. When grown in inorganic phosphate-supplemented medium, these cells deposited calcium phosphate minerals, which could be prevented by an N'-terminal peptide of MGP (m3pS) carrying phosphorylated serine residues. We next confirmed these findings using a cell-free elastin-like polypeptide (ELP3) scaffold, where the peptide prevented mineral maturation. Overall, this work describes a novel cell culture model for elastocalcinosis and examines the inhibition of mineral deposition by the m3pS peptide in this and a cell-free elastin-based scaffold. Our study provides strong evidence suggesting the critical functional roles of MGP's phosphorylated serine residues in the prevention of elastin calcification and proposes a possible mechanism of their action.

Safety and durability of concomitant carotid endarterectomy with carotid-subclavian bypass grafting.

BACKGROUND: Concomitant carotid endarterectomy (CEA; for severe internal carotid artery stenosis) with carotid-subclavian bypass grafting (CSBG; for proximal common carotid artery or subclavian artery occlusion) is rarely used. Only a few studies have been reported. This report analyzed early and late clinical outcomes of the largest study to date of the combined procedures in our institution. METHODS: Electronic medical records of patients who had concomitant CEA with CSBG during three decades were analyzed. Indications for surgery were arm ischemia, neurologic events, and clinical subclavian steal. Early (30 days) perioperative complications (stroke, death, and others) and late complications (stroke, death) were recorded. Kaplan-Meier analysis was used to estimate late graft/CEA primary patency, freedom from stroke, and stroke-free survival rates. Graft patency was determined clinically and confirmed using duplex ultrasound. Outcomes were compared with previously published data on isolated CSBG by the same group. RESULTS: There were 37 combined procedures analyzed. Mean age was 64 years (range, 45-81 years). Indications for surgery were arm ischemia in 12 (32%), hemispheric transient ischemic attack or stroke in 15 (41%), vertebrobasilar insufficiency in 4 (11%), symptomatic subclavian steal in 10 (27%), and asymptomatic common carotid artery occlusion with severe internal carotid artery stenosis in 6 (16%). The 30-day perioperative (stroke and death) rate was 5.4% (one stroke and one death). Immediate symptom relief was noted in 100%, with 2.7% (transient ischemic attack) symptom recurrence. The crude patency rate of both CEA and CSBG was 92%. At 1 year, 2 years, 3 years, 4 years, and 5 years, respectively, primary patency rates were 100%, 96%, 96%, 96%, and 85%; freedom from stroke rates were 97%, 97%, 97%, 97%, and 97%; and stroke-free survival rates were 94%, 94%, 87%, 82%, and 78%. When these outcomes were compared with the isolated CSBG group alone (28 patients), there was no difference in perioperative stroke (2.7% for concomitant CEA/CSBG vs 0% for isolated CSBG), perioperative death (2.7% vs 2.8%), or late patency rates (92% vs 96%). CONCLUSIONS: Concomitant CEA/CSBG is safe and durable. There was no significant difference in perioperative stroke/death or late patency rates compared with isolated CSBG.

Use of drug-eluting stents in patients with critical limb ischemia and infrapopliteal arterial disease: a real-world single-center experience.

BACKGROUND: Although no drug-eluting stent (DES) has been approved by the Food and Drug Administration to treat infrapopliteal arterial disease, several industry-sponsored trials have reported the outcomes with the use of paclitaxel or sirolimus DESs. To the best of our knowledge, only one study to date has reported on the use of everolimus DESs for infrapopliteal arterial disease. In the present study, we analyzed the clinical outcomes with everolimus DESs in our real-world, single-center experience. METHODS: A total of 107 limbs with critical limb threatening ischemia (98 patients; 118 lesions) treated with DESs (Xience; Abbott Vascular, Santa Clara, Calif) were analyzed. The postoperative early outcomes, major adverse limb events (above the ankle limb amputation or major intervention at 1 year), and major adverse events (death, amputation, target lesion thrombosis or reintervention) were analyzed. Kaplan-Meier analysis was used to estimate the primary patency rates (using duplex ultrasound), amputation-free rates, and amputation-free survival rates. RESULTS: Of the 118 lesions treated, 33% were in the anterior tibial artery, 28% were in the tibioperoneal (TP) artery, 21% were in the posterior tibial artery, 8% were in the peroneal artery, 5% were in the TP/posterior tibial artery, 4% were in the TP artery/PA, and 1% were in the TP/anterior tibial artery. The mean lesion length was 41 mm, and 59% were totally occluded (41% stenotic). The mean follow-up was 18.5 months (range, 1-70 months). The overall postoperative complication rate was 11% (2% major amputations), with 2% mortality. Late symptom improvement of one or more Rutherford category was obtained in 71%. The major adverse events rate at 30 days and 1 year was 12% and 45%, respectively. The major adverse limb events rate at 1 year was 15%. The overall primary patency rate was 42%. The primary patency rate at 1, 2, and 3 years was 57%, 45%, and 33%, respectively. The major amputation-free and overall amputation-free survival rates were 87%, 80%, and 77% and 76%, 65%, and 61% at 1, 2, and 3 years, respectively. CONCLUSIONS: The clinical outcomes after DES (Xience; Abbott Vascular) for infrapopliteal lesions were somewhat satisfactory at 1 year but inferior to the previously reported outcomes, especially at 3 years. Further data with long-term follow-up are needed.

Home-based physiology labs in the time of COVID-19 prove popular with medical students.

The COVID-19 pandemic and the resulting "lockdown" have forced many medical schools to shift from traditional "face-to-face" teaching methodologies and embrace full online delivery. Although lectures and tutorials are readily communicated by this approach, the execution of laboratory exercises is much more difficult. To overcome these challenges, face-to-face laboratory sessions were replaced by a blended learning approach in which students were provided instructional material online and then required to conduct the laboratory exercises at home. These laboratory exercises made use of easily accessible household materials and mobile applications. A self-report survey was designed to assess students' perception of their learning experience and attitudes to the home-based laboratory exercises. The survey consisted of 16 questions that students had to respond to using a 5-point Likert scale. Students were also allowed to provide open responses to select questions. Overall, the 80% of students that completed the survey expressed strong satisfaction with their learning experience and were enthusiastic toward home-based laboratory exercises. However, concerns about not being able to complete particular face-to-face exercises that required specialized equipment were expressed. Several students proposed a combined approach going forward. Our results show that home-based laboratory exercises offer a multimodal option that enriches the learning curriculum by engaging students in "hands-on" bespoke practicals using inexpensive household materials.

Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans.

RATIONALE: Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms; however, the precise molecular mechanism has not been elucidated. OBJECTIVE: The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy. METHODS AND RESULTS: We used a mouse model of postnatal ascending aortic aneurysms ( Fbln4SMKO; termed SMKO [SMC-specific knockout]), in which deletion of Fbln4 (fibulin-4) leads to disruption of the elastin-contractile units caused by a loss of elastic lamina-SMC connections. In this mouse, upregulation of Egr1 (early growth response 1) and angiotensin-converting enzyme leads to activation of Ang II (angiotensin II) signaling. Here, we showed that the matricellular protein, Thbs1 (thrombospondin-1), was highly upregulated in SMKO ascending aortas and in human thoracic aortic aneurysms. Thbs1 was induced by mechanical stretch and Ang II in SMCs, for which Egr1 was required, and reduction of Fbln4 sensitized the cells to these stimuli and led to higher expression of Egr1 and Thbs1. Deletion of Thbs1 in SMKO mice prevented the aneurysm formation in ≈80% of DKO (SMKO;Thbs1 knockout) animals and suppressed Ssh1 (slingshot-1) and cofilin dephosphorylation, leading to the formation of normal actin filaments. Furthermore, elastic lamina-SMC connections were restored in DKO aortas, and mechanical testing showed that structural and material properties of DKO aortas were markedly improved. CONCLUSIONS: Thbs1 is a critical component of mechanotransduction, as well as a modulator of elastic fiber organization. Maladaptive upregulation of Thbs1 results in disruption of elastin-contractile units and dysregulation of actin cytoskeletal remodeling, contributing to the development of ascending aortic aneurysms in vivo. Thbs1 may serve as a potential therapeutic target for treating thoracic aortic aneurysms.

The incidence of carotid in-stent stenosis is underestimated ≥50% or ≥80% and its clinical implications.

BACKGROUND: The incidence of carotid in-stent stenosis has been reported to vary between 1% and 30%. Most published studies have short follow-up, which may lead to underestimation of the incidence of in-stent stenosis. This study analyzed the incidence of ≥50% and ≥80% in-stent stenosis using validated duplex ultrasound criteria and its clinical implications. METHODS: This is a retrospective analysis of prospectively collected data of 450 carotid artery stenting (CAS) procedures (February 6, 2001-December 19, 2016). All patients had postoperative carotid duplex ultrasound examination, which was repeated at 1 month, 6 months, and every 6 to 12 months thereafter. A Kaplan-Meier analysis was used to estimate rates of freedom from ≥50% in-stent stenosis (internal carotid artery peak systolic velocity of ≥224 cm/s) and ≥80% in-stent stenosis (internal carotid artery peak systolic velocity of ≥325 cm/s), freedom from reintervention, and survival. RESULTS: The mean age was 68.3 years, with a mean follow-up of 40.3 months. A total of 201 patients (45% [201/450]) had CAS for symptomatic disease. Primary CAS was done in 291 patients (65%); in the remaining 35%, CAS was done for postcarotid endarterectomy (CEA) stenosis. A total of 101 patients (23%) had ≥50% late carotid in-stent stenosis, and of these, 33 (7.4%) had ≥80% in-stent stenosis. Nineteen patients (4.3%) developed late transient ischemic attack and three (0.7%) late stroke. Twenty-three (5.2%) patients had late reintervention. Rates of freedom from ≥50% in-stent stenosis in the whole series were 85%, 79%, 75%, 72%, and 70% at 1 year, 2 years, 3 years, 4 years, and 5 years, respectively. The rates of freedom from ≥50% in-stent stenosis for primary CAS and CAS for post-CEA stenosis were not statistically significant (P = .540). The rates of freedom from ≥80% in-stent stenosis for the whole series were 96%, 95%, 93%, 90%, and 89% at 1 year, 2 years, 3 years, 4 years, and 5 years, respectively. The rates of freedom from ≥80% in-stent stenosis for primary CAS and CAS for post-CEA stenosis were also not statistically significant (P = .516). Rates of freedom from reintervention were 98%, 96%, 93%, 93%, and 91% at 1 year, 2 years, 3 years, 4 years, and 5 years, respectively, and there were no significant differences between primary CAS and CAS for post-CEA stenosis (P = .939). The overall late survival rates were 99%, 97%, 96%, 94%, and 91% at 1 year, 2 years, 3 years, 4 years, and 5 years. CONCLUSIONS: The incidence of ≥50% in-stent stenosis is relatively high; however, the rates of ≥80% stenosis and late neurologic events are low. Longer follow-up of patients with ≥50% carotid in-stent stenosis may yield higher incidence of ≥80% stenosis.

Clinical outcome of drug-coated balloon angioplasty in patients with femoropopliteal disease: A real-world single-center experience.

BACKGROUND: Several multicenter industry-sponsored clinical trials reported satisfactory results in the use of drug-coated balloons (DCBs) for treatment of femoropopliteal occlusive disease. However, few single-center studies have been published to verify the outcome from real-world experience. METHODS: In this study, 228 patients treated with DCB angioplasty (Lutonix 0.35; Bard, Tempe, Arizona) were analyzed. Perioperative major adverse events (death, amputation, target lesion thrombosis or reintervention) were calculated. Kaplan-Meier analysis was used to estimate primary patency rates (based on duplex ultrasound with or without ankle-brachial index) and limb salvage rates. RESULTS: Lesions treated were primarily TransAtlantic Inter-Society Consensus (TASC) type C and D lesions. Indications included claudication (Rutherford classes 2 and 3) in 40% and critical limb ischemia (CLI; Rutherford classes 4 and 5) in 60%. Lesions treated included 61% in the superficial femoral artery, 15% in the popliteal artery, and 24% in both superficial femoral artery and popliteal artery. Mean follow-up was 12.2 months (range, 1-42 months). Overall perioperative morbidity and mortality rates were 13% and 1%. The perioperative major adverse event rate was 3%. Symptom relief (improvement of one Rutherford category or more) was obtained in 64%. Primary patency rates were 56% and 39% at 1 year and 2 years, respectively. Limb salvage rates were 92% and 83% at 1 year and 2 years. Patients with claudication had a lower rate of early perioperative complications (4% vs 19%; P = .001). Symptom improvement was 76% for claudication vs 49% for CLI (P < .001). Overall, major amputation rate was 0% for claudication vs 13% for CLI (P < .001). The primary patency rates at 1 year and 2 years were 59% and 41% for claudication vs 54% and 37% for CLI (P = .307). The assisted primary patency rates at 1 year and 2 years were 72% and 52% for claudication vs 64% and 46% for CLI (P = .223). Primary patency rates at 1 year and 2 years were 82% and 71% for TASC A to C lesions vs 29% and 14% for TASC D lesions (P < .001). Limb salvage rates at 1 year and 2 years were 100% and 100% for claudication vs 85% and 74% for CLI (P < .001). CONCLUSIONS: Clinical outcomes after DCB angioplasty in femoropopliteal lesions were inferior to what has been reported in previous studies, particularly for TASC D lesions. Further investigation from real-world experience with long-term follow-up is needed to confirm these results.

Loss of Smooth Muscle α-Actin Leads to NF-κB-Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement.

RATIONALE: Mutations in ACTA2, encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. OBJECTIVE: We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. METHODS AND RESULTS: Acta2-/- mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2-/- aortas or kidneys. Aortic tissue and explanted smooth muscle cells from Acta2-/- aortas show increased production of reactive oxygen species and increased basal nuclear factor κB signaling, leading to an increase in the expression of the AngII receptor type I a and activation of signaling at 100-fold lower levels of AngII in the mutant compared with wild-type cells. Furthermore, disruption of smooth muscle α-actin filaments in wild-type smooth muscle cells by various mechanisms activates nuclear factor κB signaling and increases expression of AngII receptor type I a. CONCLUSIONS: These findings reveal that disruption of smooth muscle α-actin filaments in smooth muscle cells increases reactive oxygen species levels, activates nuclear factor κB signaling, and increases AngII receptor type I a expression, thus potentiating AngII signaling in vascular smooth muscle cells without an increase in the exogenous levels of AngII.

Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma.

In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor ß (TGF-ß). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-ß antagonism. These results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.

Results of Telehealth Electronic Monitoring for Post Discharge Complications and Surgical Site Infections following Arterial Revascularization with Groin Incision.

BACKGROUND: Post-surgical discharge complications result in increased hospital readmissions, cost, and patient dissatisfaction. Telehealth technology to monitor patients, especially those in geographically isolated areas, may reduce post-operative complications and improve health and financial outcomes. The primary objective of this study was to compare outcomes between patients who received TeleHealth Electronic Monitoring (THEM) and those with routine discharge instructions and no monitoring, Standard Of Care (SOC). METHODS: This is a prospective randomized study of vascular surgery patients with infrainguinal incisions. THEM patients received a tablet and home monitoring devices that transmitted information to care managers. Monitoring tools included image capture, weight scales, blood pressure cuffs, thermometers, and oxygen saturation monitors. Care managers used the TeleMed 2020 Enform™ platform to review alerts, real-time patient data, and dialogue with the care team. RESULTS: Eighty patients were screened and 30 enrolled, of which 16 (53.3%) were randomized to the THEM group and 14 (46.7%) to the control group. Average age and body mass index for THEM and control patients were similar (62.5 ± 7.2 vs. 65.7 ± 7.3, P = 0.234; and 27.7 ± 4.3 vs. 29.1 7.1, P = 0.487), respectively. There was a similar number of male participants in each group (THEM 62.5% vs. SOC 42.9%, P = 0.464). There were no significant differences in wound or 30-day readmissions (THEM 6.3% vs. SOC 7.1%, P = 1.000). Interestingly, 30-day infection rates indicated that care managers identified marginally more superficial wound problems in the THEM group (31.3% vs. 7.1%, P = 0.175). Both groups reported an increase in short-form-8 physical summary scores, but was more pronounced in THEM patients (P = 0.076). THEM patients reported a significantly greater improvement in quality of life on 3 of the short-form-8 quality subscales (physical function, role-physical, and role-emotional; THEM delta 7.5 versus Control delta 1.1; THEM delta 8.7 versus Control delta 1.1; and THEM delta 6.3 versus Control delta -0.5; all P < 0.05). THEM patients reported trends for higher satisfaction in terms of general satisfaction, technical quality, and accessibility for Patient Satisfaction Questionnaire-18 survey questions (4.2 vs. 3.7, P = 0.072; 4.5 vs. 4.1, P = 0.081; and 4.2 vs. 3.8, P = 0.063), respectively. CONCLUSIONS: THEM was technically feasible and provided some benefit to patients in geographically disparate areas. THEM was associated with increased patient satisfaction. Additional findings suggested that THEM patients embraced telehealth technology and took advantage of increased access to healthcare professionals. Telehealth successfully merged remotely generated information with care manager interaction. Presently, a larger study, preferably multi-center, is warranted and under consideration.

Effect of diode laser and topical fluoride applications on white-spot lesions in bovine enamel.

This study evaluated the effectiveness of diode laser irradiation combined with topical fluoride application for increasing the hardness of demineralized bovine enamel and esthetically improving white-spot lesions (WSLs). In addition, the study evaluated intrapulpal temperature changes during laser irradiation. One hundred twenty bovine incisors with 4 × 4-mm artificial WSLs were randomly assigned to 8 groups (n = 15): untreated control; fluoride only; LF1, LF2, and LF3, fluoride plus 2-W laser for 15, 30, and 60 seconds, respectively; and LF4, LF5, and LF6, fluoride plus 5-W laser for 15, 30, and 60 seconds, respectively. The Vickers hardness number, CIE L*a*b color space values, and visual analog scale ratings for color improvement were recorded at baseline, after demineralization to create the WSLs, and after treatment. The intrapulpal temperature changes were recorded at completion of irradiation for 30 bovine teeth that were assigned to 6 groups (n = 5) to receive doses of irradiation equivalent to the treatment of the corresponding laser groups described previously. Statistical analysis included 1-way analysis of variance and Tukey multiple comparison tests (α = 0.05) The mean Vickers hardness numbers were significantly greater for the laser groups, and mean visual analog scale scores were significantly greater for all the treatment groups (P < 0.05). The fluoride group had a significantly lower mean color change (ΔE*) value (P < 0.05). The mean intrapulpal temperature changes in the 5-W laser groups were significantly greater than those in the 2-W groups (P < 0.05). Diode laser irradiation combined with topical fluoride application significantly increased the hardness and improved the esthetic appearance of WSLs compared to no treatment (control) and fluoride treatment alone. Intrapulpal temperature changes indicated that diode laser irradiation is safer at a 2-W setting than a 5-W setting.

Loss of tooth structure associated with preparation for two monolithic CAD-CAM complete coverage restorations.

STATEMENT OF PROBLEM: Different techniques are used to fabricate complete coverage restorations. Each fabrication technique requires a specific preparation design that may violate a principle of tooth preparation, that is, conservation of tooth structure. PURPOSE: The purpose of this in vitro study was to compare the volume of loss of mandibular first molar structure associated with a preparation for computer-aided design and computer-aided manufacturing (CAD-CAM) versus conventionally fabricated complete coverage restorations. MATERIALS AND METHODS: Fifty artificial mandibular right first molars were weighed before and after preparation for complete coverage restorations of the following types: complete cast, monolithic zirconia, monolithic pressed lithium disilicate, monolithic milled lithium disilicate, and metal-ceramic crowns (n=10 per method). Tooth mass loss was measured by subtracting the mass after preparation from the mass before the preparation, and tooth volume loss was calculated by dividing the mass by the density of the material. A robust analysis of variance (ANOVA), followed by a post hoc test, was used to compare the volume of tooth loss (α=.01). RESULTS: Mean tooth volume losses were 255.6 mm3, 270.0 mm3, 312.7 mm3, 331.7 mm3, and 309.9 mm3 for complete cast, monolithic zirconia, monolithic pressed lithium disilicate, monolithic milled lithium disilicate, and metal-ceramic crowns, respectively. Teeth prepared for monolithic CAD-CAM zirconia and lithium disilicate crowns did not exhibit a significantly lower (P>.01) decrease in volume loss than with complete cast and monolithic pressed lithium crowns. CONCLUSIONS: Preparation of teeth for monolithic CAD-CAM complete coverage restorations is not associated with a significantly higher volume of tooth loss than their conventionally fabricated counterpart preparations.

Latent transforming growth factor binding protein 4 regulates transforming growth factor beta receptor stability.

Mutations in the gene for the latent transforming growth factor beta binding protein 4 (LTBP4) cause autosomal recessive cutis laxa type 1C. To understand the molecular disease mechanisms of this disease, we investigated the impact of LTBP4 loss on transforming growth factor beta (TGFß) signaling. Despite elevated extracellular TGFß activity, downstream signaling molecules of the TGFß pathway, including pSMAD2 and pERK, were down-regulated in LTBP4 mutant human dermal fibroblasts. In addition, TGFß receptors 1 and 2 (TGFBR1 and TGFBR2) were reduced at the protein but not at the ribonucleic acid level. Treatment with exogenous TGFß1 led to an initially rapid increase in SMAD2 phosphorylation followed by a sustained depression of phosphorylation and receptor abundance. In mutant cells TGFBR1 was co-localized with lysosomes. Treatment with a TGFBR1 kinase inhibitor, endocytosis inhibitors or a lysosome inhibitor, normalized the levels of TGFBR1 and TGFBR2. Co-immunoprecipitation demonstrated a molecular interaction between LTBP4 and TGFBR2. Knockdown of LTBP4 reduced TGFß receptor abundance and signaling in normal cells and supplementation of recombinant LTBP4 enhanced these measures in mutant cells. In a mouse model of Ltbp4 deficiency, reduced TGFß signaling and receptor levels were normalized upon TGFBR1 kinase inhibitor treatment. Our results show that LTBP4 interacts with TGFBR2 and stabilizes TGFß receptors by preventing their endocytosis and lysosomal degradation in a ligand-dependent and receptor kinase activity-dependent manner. These findings identify LTBP4 as a key molecule required for the stability of the TGFß receptor complex, and a new mechanism by which the extracellular matrix regulates cytokine receptor signaling.