The correlation between platelet responsiveness to clopidogrel and CYP2C19 polymorphism in patients with peripheral vascular disease.

OBJECTIVE: Several patients undergoing endovascular intervention and bypass surgery present with high platelet reactivity following clopidogrel treatment. We aimed to determine the frequency of the genetic polymorphism of CYP2C19*2 and the contribution of this polymorphism along with other clinical parameters to clopidogrel response in an Egyptian population. PATIENTS AND METHODS: A total of 50 patients receiving clopidogrel at a maintenance dose of 75 mg daily post vascular intervention from January 1, 2019, to May 30, 2020, were enrolled in this study. Clopidogrel resistance was determined through platelet aggregation analysis using Chrono-Log® platelet aggregometer. Single-nucleotide polymorphism (SNP) genotyping was performed using quantitative real-time polymerase chain reaction (QRT-PCR). RESULTS: The incidence of clopidogrel resistance among this Egyptian population is about 22%. Univariate analysis demonstrated that CYP2C19*2 genotype (p = 0.001), high body mass index (BMI; p = 0.025), diabetes (p = 0.037),  high fasting blood glucose (FBG) level (p = 0.037), and high glycosylated hemoglobin (HbA1c) level (p = 0.004) were significantly associated with clopidogrel resistance. Multivariate analysis showed that CYP2C19*2 genotype (odds ratio (OR), 927.71; 95% confidence interval (CI), 1.915-449496.2; p = 0.030) and high BMI (OR, 1.789; 95% CI, 1.044-3.064; p = 0.034) were the most powerful predictors of clopidogrel resistance. CONCLUSIONS: Clopidogrel resistance in patients with peripheral vascular disease is associated with the presence of CYP2C19*2 allele, obesity, and diabetes; these factors should be considered prior to clopidogrel administration.

Successful Catheter-Directed Thrombolysis for Acute Lower Limb Ischemia Secondary to COVID-19 Infection.

A 49-year-old man was admitted to his local hospital with left leg pain and breathing difficulties. He had negative nasopharyngeal polymerase chain reaction tests for severe acute respiratory syndrome coronavirus 2. Chest X-ray and Computed tomography pulmonary angiogram displayed typical coronavirus disease 2019 (COVID-19) radiological features as ground-glass opacities and bronchovascular thickening. His respiratory symptoms resolved after four days of supportive treatment, whereas his left leg became more painful and discolored. He was referred to our center with acute left leg ischemia. computed tomography angiogram revealed eccentric mural thrombus at the aortic bifurcation, extending into left common iliac and an abrupt occlusion of left popliteal, tibioperoneal, and posterior tibial arteries. He was treated with catheter-directed thrombolysis for 48-hours that achieved successful revascularization of the ischemic limb with no intervention-related complications. At six-week follow-up, he showed full recovery. Our case demonstrates that catheter-directed thrombolysis is a successful and safe treatment option in a COVID-19 patient with acute arterial occlusion.

Digital Ischemia in COVID-19 Patients: Case Report.

As coronavirus 2019 (COVID-19) continues to cause an immense burden on the global health care systems, it is crucial to understand the breadth of this disease process. Recent reports identified hypercoagulability in a subset of critically ill patients and extremity ischemia in an even smaller cohort. Because abnormal coagulation parameters and extremity ischemia have been shown to correlate with poor disease prognosis, understanding how to treat these patients is crucial. To better describe the identification and management of this phenomenon, we present 2 cases of critically ill patients with COVID-19 who developed fingertip ischemia while in the intensive care unit.

Botulinum Toxin A Salvage of Ischemic Hand Trauma.

Posttraumatic hand injuries from crush injury, infusion, or iatrogenic vascular cannulation can cause ischemic finger damage that can progress to necrosis and digital amputation. Botulinum toxin type A (Botox) improves blood flow in chronic vasospastic disorders of the hand. Botox's efficacy in salvaging ischemic loss in digits in acute traumatic and iatrogenic injury has not been previously reported. From February of 2015 to December of 2016, 11 patients at a Level I trauma center (West Virginia University) presented to the hand surgery service with early ischemic injury and vascular compromise to hand and fingers as a result of crush, direct drug injection, or proximal arterial injury from drug injection or catheterization. Before 2015, all patients with vascular compromise were treated with standard protocol. After January of 2016, patients were treated with additional injection of 80 to 100 U of Botox into the palm and wrist. Before administration of Botox, six patients with vascular compromise of one or more fingers were treated with a conservative protocol and 83 percent had amputation of necrotic digits. After January of 2016, five patients with ischemia were treated with Botox into the palm and proximal arteries. All Botox-treated digits were preserved (100 percent salvage). Pain scores were lower in Botox-treated fingers. We conclude that (1) in the acute traumatic vascular hand injury, early Botox injection markedly increases digital salvage; (2) direct nerve effects after Botox injections improve postinjury pain scores; and (3) early use of Botox in finger injuries is our standard approach to impending ischemia in the hand.

The History of Testosterone and the Evolution of its Therapeutic Potential.

INTRODUCTION: Testosterone therapy has been controversial since its synthesis in the 1930s to the present day. Testosterone's history provides depth and context for current controversies. AIM: To review the history of testosterone therapy from its initial synthesis in the 1930s to the modern day. METHODS: Expert review of the literature. MAIN OUTCOME MEASURES: Impactful events in the history of testosterone. RESULTS: By the 1940s there was already a fascinating literature that described the many symptomatic benefits of testosterone therapy that are recognized today. Numerous early reports suggested testosterone therapy improved angina pectoris and peripheral vascular disease. The assertion by Huggins and Hodges (Cancer Res 1941;1:293-297) in 1941 that testosterone activated prostate cancer (PCa) cast a pall for the next 70 years. The introduction of the radioimmunoassay in the 1970s shifted the diagnosis of testosterone deficiency from signs and symptoms to an undue emphasis on blood test results. The fear of PCa was the primary obstacle to the adoption of testosterone therapy for decades. Prescription rates increased as accumulated evidence showed testosterone therapy was not associated with increased PCa risks. The observation that androgenic stimulation of PCa reaches a maximum at relatively low testosterone concentrations-the saturation model-provided the theoretical framework for understanding the relation between androgens and PCa and led to multiple case series documenting reassuring results of testosterone therapy in men with PCa. Recent concerns regarding cardiovascular risks also have diminished because new evidence suggests testosterone therapy might actually be cardioprotective. In 2016 the Testosterone Trials provided high-quality evidence of multiple benefits of testosterone therapy, nearly all of which had been recognized by clinicians by 1940. CONCLUSIONS: If the past has any lessons for the future, it is likely that research will continue to demonstrate health benefits of testosterone therapy, while it remains one of the most controversial topics in medicine. Morgentaler A, Traish A. The History of Testosterone and the Evolution of its Therapeutic Potential. Sex Med Rev 2020;8:286-296.

Effects of simultaneous pancreas-kidney transplantation and kidney transplantation alone on the outcome of peripheral vascular diseases.

BACKGROUND: The effects of Simultaneous Pancreas Kidney Transplantation (SPKT) on Peripheral Vascular Disease (PVD) warrants additional study and more target focus, since little is known about the mid- and long-term effects on the progression of PVD after transplantation. METHODS: 101 SPKT and 26 Kidney Transplantation Alone (KTA) recipients with insulin-dependent diabetes mellitus (IDDM) were retrospectively evaluated with regard to graft and metabolic outcome. Special subgroup analysis was directed towards the development and progression of peripheral vascular complications (PVC) (amputation, ischemic ulceration, lower extremity angioplasty/ bypass surgery) after transplantation. RESULTS: The 10-year patient survival was significantly higher in the SPKT group (SPKT: 82% versus KTA 40%; P < 0.001). KTA recipients had a higher prevalence of atherosclerotic risk factors, including coronary artery disease (P < 0.001), higher serum triglyceride levels (P = 0.049), higher systolic (P = 0.03) and diastolic (P = 0.02) blood pressure levels. The incidence of PVD before transplantation was comparable between both groups (P = 0.114). Risk factor adjusted multivariate analysis revealed that patients with SPKT had a significant lower amount (32%) of PVCs (32 PVCs in 21 out of 101 SPKT; P < 0.001) when compared to the KTA patients who developed a significant increase in PVCs to 69% of cases (18 PVCs in 11 out of 26 KTA; P < 0.001). In line mean values of HbA1c (P < 0.01) and serum triglycerides (P < 0.01) were significantly lower in patients with SPKT > 8 years after transplantation. CONCLUSION: SPKT favorably slows down development and progression of PVD by maintaining a superior metabolic vascular risk profile in patients with IDDM1.

Ecklonia Cava Extract Attenuates Endothelial Cell Dysfunction by Modulation of Inflammation and Brown Adipocyte Function in Perivascular Fat Tissue.

It is well known that perivascular fat tissue (PVAT) dysfunction can induce endothelial cell (EC) dysfunction, an event which is related with various cardiovascular diseases. In this study, we evaluated whether Ecklonia cava extract (ECE) and pyrogallol-phloroglucinol-6,6-bieckol (PPB), one component of ECE, could attenuate EC dysfunction by modulating diet-induced PVAT dysfunction mediated by inflammation and ER stress. A high fat diet (HFD) led to an increase in the number and size of white adipocytes in PVAT; PPB and ECE attenuated those increases. Additionally, ECE and PPB attenuated: (i) an increase in the number of M1 macrophages and the expression level of monocyte chemoattractant protein-1 (MCP-1), both of which are related to increases in macrophage infiltration and induction of inflammation in PVAT, and (ii) the expression of pro-inflammatory cytokines (e.g., tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, chemerin) in PVAT which led to vasoconstriction. Furthermore, ECE and PPB: (i) enhanced the expression of adiponectin and IL-10 which had anti-inflammatory and vasodilator effects, (ii) decreased HFD-induced endoplasmic reticulum (ER) stress and (iii) attenuated the ER stress mediated reduction in sirtuin type 1 (Sirt1) and peroxisome proliferator-activated receptor γ (PPARγ) expression. Protective effects against decreased Sirt1 and PPARγ expression led to the restoration of uncoupling protein -1 (UCP-1) expression and the browning process in PVAT. PPB or ECE attenuated endothelial dysfunction by enhancing the pAMPK-PI3K-peNOS pathway and reducing the expression of endothelin-1 (ET-1). In conclusion, PPB and ECE attenuated PVAT dysfunction and subsequent endothelial dysfunction by: (i) decreasing inflammation and ER stress, and (ii) modulating brown adipocyte function.

Five-year real-world outcomes of anti-vascular endothelial growth factor monotherapy versus combination therapy for polypoidal choroidal vasculopathy in a Chinese population: a retrospective study.

BACKGROUND: To evaluate 5-year outcomes of anti-vascular endothelial growth factor (VEGF) monotherapy and combination therapy of anti-VEGF agents and photodynamic therapy (PDT) for polypoidal choroidal vasculopathy (PCV) in a real-world Chinese population. METHODS: Retrospective study. Fifty-three eyes of 46 patients with subtype 1 and 2 PCV followed up for at least 60 months were grouped into three regimens: anti-VEGF monotherapy, PDT combining with anti-VEGF therapy initially, and PDT combining with deferred anti-VEGF therapy. Main outcome measure was best-corrected visual acuity (BCVA) using logarithm of minimal angle of resolution (logMAR). RESULTS: The mean BCVA of eyes with subtype 1 PCV (n = 28) deteriorated from 0.69 logMAR at baseline to 1.25 logMAR at months 60 (P = 0.001), while the mean BCVA of eyes with subtype 2 PCV (n = 25) sustained stable from 0.62 logMAR at baseline to 0.57 at months 60 (P = 0.654). No significant differences of visual outcomes were found between the 3 treatment regimens for subtype 1 PCV. Anti-VEGF monotherapy and initial combination treatment had better visual outcomes in eyes with subtype 2 PCV than deferred combination group during part of follow-up significantly. Initial combination group needed a less number of PDT than deferred combination group (P < 0.001). CONCLUSIONS: Compared with subtype 1 PCV, subtype 2 PCV has a more favorable visual outcome in real world. All the regimens presented unfavorable visual outcomes for subtype 1 PCV. Anti-VEGF monotherapy and initial combination therapy should be superior to deferred combination therapy in the long-term management of subtype 2 PCV. Prospective randomized studies of larger size are needed to determine the long-term efficacy and safety of various treatment for PCV in real world.

Somatosensory predictors of response to pregabalin in painful chemotherapy-induced peripheral neuropathy: a randomized, placebo-controlled, crossover study.

Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and treatment-resistant sequela of many chemotherapeutic medications. Ligands of α2δ subunits of voltage-gated Ca channels, such as pregabalin, have shown efficacy in reducing mechanical sensitivity in animal models of neuropathic pain. In addition, some data suggest that pregabalin may be more efficacious in relieving neuropathic pain in subjects with increased sensitivity to pinprick. We hypothesized that greater mechanical sensitivity, as quantified by decreased mechanical pain threshold at the feet, would be predictive of a greater reduction in average daily pain in response to pregabalin vs placebo. In a prospective, randomized, double-blinded study, 26 patients with painful CIPN from oxaliplatin, docetaxel, or paclitaxel received 28-day treatment with pregabalin (titrated to maximum dose 600 mg per day) and placebo in crossover design. Twenty-three participants were eligible for efficacy analysis. Mechanical pain threshold was not significantly correlated with reduction in average pain (P = 0.97) or worst pain (P = 0.60) in response to pregabalin. There was no significant difference between pregabalin and placebo in reducing average daily pain (22.5% vs 10.7%, P = 0.23) or worst pain (29.2% vs 16.0%, P = 0.13) from baseline. Post hoc analysis of patients with CIPN caused by oxaliplatin (n = 18) demonstrated a larger reduction in worst pain with pregabalin than with placebo (35.4% vs 14.6%, P = 0.04). In summary, baseline mechanical pain threshold tested on dorsal feet did not meaningfully predict the analgesic response to pregabalin in painful CIPN.

Function-first ligandomics for ocular vascular research and drug target discovery.

Human eyes may develop different vascular diseases with neovascularization and/or leakage, including wet age-related macular degeneration (AMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), retinopathy of prematurity, corneal neovascularization and intraocular tumors. A breakthrough in therapy is the advent and approval of vascular endothelial growth factor (VEGF) inhibitors. However, anti-VEGF drugs not only have limited efficacy to treat AMD, DME and PDR but also are not approved for other ocular indications. The key to addressing these unmet clinical needs is to develop novel therapies against VEGF-independent angiogenic factors or signaling pathways for alternative or combination therapy. We recently developed the first paradigm of ligandomics for global mapping of cell-wide ligands as well as disease-selective ligands. Therapies targeting disease-selective angiogenic or vascular leakage factors likely have high efficacy, minimal side effects, wide therapeutic windows and relatively low drug attrition rates. A critical challenge is how to distinguish between genuine drug targets and spurious hits identified by high-throughput ligandomics. Here we exploited the unique advantages of the eye and extracellular ligands by combining ligandomics with "function-first" and/or "therapy-first" analyses to efficiently characterize functional activity, disease selectivity, pathogenic role and therapeutic potential of identified ligands. The innovative function- or therapy-first ligandomics will systematically and reliably delineate disease-selective angiogenic or vascular leakage factors and markedly facilitate ocular vascular research and ligand-guided targeted anti-angiogenic therapy.

Peroneal artery entrapment syndrome (PRAES): a rare cause of ischaemic toes.

A 75-year-old man presenting with intermittent discolouration of his left toes was referred to vascular surgery with suspicion of embolic vascular disease. A contrast-enhanced MR angiogram was performed which revealed bilateral dominant peroneal arteries (PRAs). There was evidence of short atherosclerotic stenosis directly at the point where the left PRA passes through the tibiofibular interosseous membrane which we postulate to be the source of the emboli. We present what is believed to be the first reported case of PRA entrapment complicated by distal toe emboli.

[Effect of actovegin and solcoseryl on microcirculation in experimental critical lower limb ischaemia]. / Vliianie aktovegina i solkoserila na mikrotsirkuliatsiiu pri kriticheskoi ishemii nizhnikh konechnostei v éksperimente.

The authors examined the effect of actovegin and solcoseryl on microcirculation parameters in treatment of experimental critical lower limb ischaemia. The study included a total of 130 male Wistar albino rats divided into four groups: intact, control, first and second study groups. The intact group consisted of 10 animals used for assessment of the normal indices of microcirculation, with the remaining three groups comprising 40 rats each. All animals, except the intact ones, were subjected to modelled critical ischaemia of a hind limb. The control group animals received no treatment, with the rats of the first and second study groups given intraperitoneal actovegin and solcoseryl, respectively, at a dose of 50 µg/kg first injected 3 hours after the operation and then once daily for five days. The level of microcirculation in the murine crural muscles was assessed by means of laser Doppler flowmetry on postoperative days 5, 10, 21 and 28. At the same time intervals, we performed histological examination of the ischaemized muscles, determining the level of microcirculation, the level of arteriovenular shunting, the area of necrosis and capillary network density. It was determined that actovegin and solcoseryl exerted a positive effect on formation of new capillaries in the ischaemized muscles, increasing density of the capillary network, decreasing arteriovenular shunting, increasing the level of microcirculation, decreasing the specific area of muscular tissue necrosis. The obtained findings showed advantages of actovegin over solcoseryl by the dynamics of the parameters of microcirculation, arteriovenular shunting, and capillary network density.

Impacto de la medicina regenerativa en angiología. Experiencia cubana / Impact of the regenerative medicine in Angiology. Cuban experience

Introducción: La medicina regenerativa se apoya fundamentalmente en la terapia celular, en la administración de factores bioactivos, en la ingeniería de tejidos y en la terapia génica, integra todos estos procederes destinados a la promoción de la regeneración celular. Objetivo: Comunicar los principales resultados de la aplicación de la medicina regenerativa en Cuba en la especialidad de angiología. Métodos: Para la implantación celular se emplearon células mononucleares de la médula ósea y también las movilizadas con Filgrastim a la sangre periférica. Las plaquetas se usaron en forma de plasma rico en plaquetas o de lisado plaquetario. Se incluyeron los pacientes con diferentes enfermedades vasculares atendidos en instituciones del país en el período 2004-2015. Resultados: Con la terapia celular se obtuvo resultados favorables en pacientes con isquemia crítica de miembros inferiores, claudicación intermitente, tromboangeítis obliterante, pie diabético, síndrome posflebítico y linfedema de miembros inferiores. Con el uso de las plaquetas se obtuvieron resultados prometedores en pacientes claudicantes, con pie diabético y úlceras posflebíticas. Conclusiones: El balance realizado al finalizar el 2015 demuestra que el uso de la medicina regenerativa ha sido introducida en 14 de las 15 provincias cubanas. Se han beneficiados con la terapia celular 9 124 pacientes, de ellos 3 741 (41 por ciento) de la especialidad de angiología. Esta terapia resulta de menor costo que los procedimientos convencionales empleados en el tratamiento de las enfermedades vasculares periféricas; evita la amputación y el impacto social que esto representa se cuenta entre sus resultados más importantes

Introduction: Regenerative medicine is fundamentally based on cell therapy, administration of bioactive factors, tissue engineering and gene therapy and integrates all these procedures intended to promote cell regeneration. Objective: To present the main results of application of regenerative medicine in angiology in our country. Method: For cell implantation, mononuclear cells from the bone marrow and also those released with Filgrastim into the peripheral blood were used. Platelets were then used as platelet-rich plasma or platelet lysate. Patients with different vascular disorders, who had been treated in the 2004-2015 period in various domestic institutions, were included in this study. Results: The cell therapy yielded positive results in patients with critical lower limb ischemia, intermittent claudication, thromboangiitis obliterans, diabetic foot, postphlebitic syndrome, and lower limb lymphedema. The use of platelets showed promising results in patients with intermittent claudication, diabetic foot, and postphlebitic ulcers. Conclusions: The assessment made at the end of 2015 shows that regenerative medicine is implemented in 14 of the 15 Cuban provinces. A total number of 9 124 patients, 3 741 (41 percent) of whom are treated by the angiology specialty have benefited from cell therapy. This type of therapy is less costly than the conventional methods used in the treatment of peripheral vascular diseases, and avoidance of amputation and its social impact are the most significant outcomes of this therapy(AU)

Cystic adventitial disease of the common femoral vein.

We present the case of a 46-year-old commercial pilot with a history of unilateral leg swelling following a flight to Geneva. Although initial clinical examination suggested a deep vein thrombosis, the swelling only partially resolved with anticoagulation and further imaging suggested the presence of adventitial cystic disease (ACD). The patient underwent initial anticoagulation to allow any thrombus to be lysed, followed by excision of the ACD from the venous wall and venous reconstruction. Following the excision of the ACD, providing the patient remains asymptomatic and further imaging finds normal venous anatomy, we hope the patient will discontinue anticoagulation and return to flying.

Aspirin, Plavix, and Other Antiplatelet Medications: What the Oral and Maxillofacial Surgeon Needs to Know.

Most patients with coronary artery disease and peripheral vascular disease are on long-term antiplatelet therapy and dual therapy. Achieving a balance between ischemic and bleeding risk remains an important factor in managing patients on antiplatelet therapy. For most outpatient surgical procedures, maintenance and continuation of this therapy are recommended. Consultation with the patient's cardiologist, physician, and/or vascular surgeon is always recommended before interrupting or withholding this treatment modality.

Photodynamic therapy: current role in the treatment of chorioretinal conditions.

Verteporfin photodynamic therapy (vPDT) is a selective vaso-occlusive treatment that targets choroidal vascular abnormalities. It was initially developed to treat neovascular age-related macular degeneration using the 'standard' vPDT protocol (verteporfin 6 mg/m(2), vPDT laser fluence 50 J/cm(2)). vPDT therapy has subsequently evolved as an important treatment modality for a range of other chorioretinal conditions including choroidal haemangioma, central serous chorioretinopathy, polypoidal choroidal vasculopathy, and peripapillary choroidal neovascularisation. Various 'safety-enhanced' vPDT protocols have been devised to optimise treatment outcomes, typically using reduced dose verteporfin (verteporfin 3 mg/m(2)) or reduced fluence vPDT (vPDT laser fluence 25 J/cm(2)). This paper reviews the current role of vPDT therapy in the treatment of chorioretinal conditions.

Drug-coated balloons: what is the evidence?

Having evolved at a rapid pace, the therapy options for percutaneous treatment of peripheral arterial disease in the lower limbs, especially percutaneous transluminal angioplasty in combination with stent-technology, are able to deliver a rate where at least 80% of the treated patients remain free from reintervention after the first years under ideal study conditions, meaning that defined and often restrict in- and exclusion criteria were fulfilled and mid-term dual platelet therapy is warranted. This is somewhat a huge leap when compared to the 50-60% in the 1980s and 1990s, but we now face an era of an increasingly demanding clientele, where the industry also strives to cover this final 20% with newer technologies. As recent studies with drug-eluting stents (DES) suggests, nowadays it is possible to achieve up to 90% patency in the short- and mid-term, but this comes accompanied by remarkably increased therapy costs, making it almost impossible to most centers to implant it as the standard therapy option. Trying to fill this gap between the low-patency of the plain old balloon angioplasty and the higher costs of the DES, drug-coated balloon technology has found its niche, knowing that reimbursement shows a broad variation across the countries and continents.

Drug coated balloons below-the-knee: just too early?

Patients with infrapopliteal arterial disease are generally considered challenging due to the usual presence of multivessel atherosclerotic disease. Several treatment options have been used by different authors but none of them can be considered ideal. In the last few years drug coated balloons have gained popularity especially due to the extraordinary results in the femoro-popliteal region. Following the great success, physicians started to use this promising device also in the below-the-knee (BTK) region. The initial enthusiasm correlated to some studies is not confirmed by the largest randomized trial, IN.PACT Deep, comparing In.Pact DCB to standard PTA. This trial failed completely to show the superiority of drug coated balloon (DCB). The negative outcome was mainly correlated to safety issues with an amputation rate higher for the drug coated balloon when compared to the conventional balloon (8.8% DCB vs.3.6% PTA, P=0.08). A thorough evaluation has been performed to justify these negative outcomes, given the good results reported by other studies. But nowadays it is still difficult to find a clear explanation. Especially for this negative outcome and for the big difference, in term of results, between the different studies in the BTK region and also between the above and below the knee regions more trials are mandatory.