Leg Ischemia Research Articles

下肢虚血で発症した無痛性急性A型大動脈解離の1例(Painless acute type A aortic dissection presenting as isolated lower leg ischemia: a case report)

急性大動脈解離（AAD）の典型的な発症時症状である胸背部痛を伴わない無痛性AADに関するこれまでの報告は，意識障害・失神や対麻痺などの神経学的徴候を有するものが多い。今回，AADを示唆する身体所見がなく下肢虚血症状単独で発症した無痛性A型AAD症例を経験したので報告する。症例は74歳の男性，左下肢痛で発症し急性動脈閉塞が疑われ救急搬送された。左下肢所見は，大腿動脈以下で拍動触知不能，下腿部以下で皮膚の冷感・色調蒼白と知覚障害，足趾の運動障害を認め，急性下肢虚血（ALI）のRutherford臨床分類で即時の血行再建術を要する重症度IIb（危機的即時型）に該当した。ALI精査目的の造影CT検査でAAD解離偽腔圧排による左総腸骨動脈分岐部閉塞を認め，A型AADによるALIと診断，一時的腋窩動脈­大腿動脈バイパスによる左下肢血行再建後に上行大動脈置換術を実施し良好な結果を得た。発症時に典型的な疼痛や神経学的徴候を伴わずALI単独で発症する無痛性A型AADの報告例は少なく，見落としのない迅速で的確な診断を下し早急に適切な治療を開始するためには，ALIの鑑別診断に無痛性AADを念頭に置き，胸部を含む造影CT検査を実施することが重要である。 Aortic dissection typically presents with severe chest, back, or abdominal pain. We describe rare, atypical, and painless acute type A aortic dissection presenting as isolated left lower extremity ischemia in a 74–year–old male. He developed left lower limb pain and was transported by ambulance with suspected acute arterial obstruction. Computed tomography revealed dissection from the aortic root to the right common iliac artery, narrowing at the bifurcation, and eventual occlusion of the left common iliac artery, indicating a diagnosis of acute limb ischemia due to type A aortic dissection. Because the patient had a persistent sensory disturbance of the lower limb after admission, we created a temporary axillo–femoral bypass for the earliest possible relief of limb ischemia, followed by ascending aorta replacement and a femoral–femoral artery bypass. The outcome was satisfactory. With painless AAD, in which there are no complaints of pain at the time of onset, diagnosis is exceedingly difficult. Clinicians should consider painless AAD as a differential diagnosis of acute limb ischemia, and establish the correct diagnosis before applying potentially harmful interventions such as anticoagulation. 胸部や腰背部の疼痛を伴って発症する急性大動脈解離（AAD）の典型例では，直ちに胸腹部造影CT検査を実施することで診断は比較的容易である。一方，疼痛を伴わない解離の多彩な合併症による症状で発症する無痛性AAD（painless AAD: PLAAD）が6.4～17%の頻度で存在する 1, 2。PLAADは解離の結果引き起こされた合併病変の症状が主訴となるため，来院時当初にAADと確定診断することは困難であることが多い。 今回，AADを示唆する身体所見がなく左下肢痛単独で発症し救急隊員からの第一報が急性下肢動脈閉塞であったStanford A型PLAADの1例を経験したので報告する。 なお，本症例報告の論文掲載について患者本人より同意を得ている。 患 者：74歳の男性 主 訴：左下肢痛 既往歴：高血圧 家族歴：特記事項なし 現病歴：観光中，かがんで立ち上がった際に左下肢痛が突然出現し歩行困難となった（18時30分）。同伴者により救急要請，現着した救急隊員が急性下肢動脈閉塞と判断し当院へ受け入れ要請（19時10分），40分後救急搬入された。 来院時現症：身長180cm，体重93kg。血圧161/78mmHg，脈拍73/分・整，左右差なし。右大腿動脈は触知良好，左下肢動脈は鼠径部以下で触知およびドプラー血流計での血流音聴取が不能であった。左下腿部以下で皮膚の冷感・色調蒼白と知覚障害を認め，左足趾は屈曲・進展ともに不能であった。救急隊員からの第一報である急性下肢動脈閉塞と診断，原因精査と治療方針決定のため実施した造影CT検査でStanford A型AADが判明し当直医（循環器内科）から当科コンサルトとなった。 胸部単純X線写真：上縦隔陰影の拡大，左第1弓の突出を認めた。 造影CT所見：上行大動脈基部から右総腸骨動脈に至る解離腔を認めた。上行大動脈の径は46mmと拡大，偽腔（径21mm）は腕頭動脈直下まで血栓閉塞していた（Fig. 1A）。近位弓部から末梢側への偽腔は開存，腹腔動脈，上腸間膜動脈，下腸間膜動脈などの腹腔内分枝は偽腔から分岐していた。左総腸骨動脈は偽腔による圧排のため分岐部で狭小化後に閉塞（Fig. 1B），外腸骨動脈は全域で描出されなかった。左下肢動脈は，側副血行路より内腸骨動脈を介し総大腿動脈と大腿深動脈が造影されたが，浅大腿動脈は大腿上部で先細り後に途絶，これより末梢側の動脈は描出されなかった（Fig. 1C）。 Preoperative computed tomography findings. Preoperative contrast–enhanced images show type A acute aortic dissection with thrombus in the false lumen of the ascending aorta (A), dissection flap in the right common iliac artery, and eventual occlusion of the left common iliac artery (B). Multi–detecter row computed tomography volume rendered image shows occlusion of the left common and external iliac arteries. The internal iliac and left common femoral arteries appeared via collateral circulation, and the left superficial femoral artery has disappeared at the distal portion (C). 血液検査所見：血小板数10.7×104/μL，FDP 66.5μg/mL，Dダイマー 16.7μg/mL，LDH 227IU/L。他の血液検査項目に異常を認めなかった。 心臓エコー所見：左室駆出率は60%で左室壁運動は正常であった。大動脈弁逆流，心嚢液貯留はなく，観察範囲の上行大動脈にフラップを認めなかった。 以上の所見より，Stanford A型AADの解離偽腔による圧迫で左総腸骨動脈の血流障害が起こり，急性下肢虚血（acute limb ischemia: ALI）を発症したと診断した。左下肢虚血は，ALIのRutherford臨床分類 3で即時の血行再建術により救肢可能とされる重症度IIbに該当し，緊急血行再建術の適応であった。またAADに対しては，偽腔血腫の径が高危険群とされる11mm以上の21mmであったため，致命的な合併症の回避を目的として，同時に上行大動脈置換術を実施する方針とした。 手 術：23時入室。全身麻酔下での胸骨正中切開による開胸操作と並行し右腋窩動脈と両側大腿動脈を露出した。全身ヘパリン化後，リング付き8mm人工血管（Gelsoft：Vascutek–Terumo社，Glasgow）で右腋窩動脈と左大腿動脈間に一時的バイパス（temporary bypass: TB）を作製し左下肢灌流を開始した（発症から216分，手術開始から48分，Fig. 2A）。人工心肺（cardiopulmonary bypass: CPB）を右大腿動脈送血，上・下大静脈脱血で開始，離断したTB人工血管とCPB送血回路分枝を接続し右腋窩動脈と左大腿動脈への送血を確保した（Fig. 2B）。中心冷却を進め膀胱温25℃で選択的順行性脳灌流下に体循環停止とし，腕頭動脈直下の小弯側に認めたエントリーを切除，1分枝付き28mm人工血管（J Graft：日本ライフライン社，千葉）を用いopen aortic anastomosis法で上行大動脈置換術を実施した。CPB離脱後，大腿動脈の拍動を確認したが微弱で明らかな左右差があり，送血で用いた人工血管をあらかじめ作製しておいた下腹部皮下トンネル内を右鼠径部へと誘導し右総大腿動脈と吻合することで大腿動脈­大腿動脈交叉バイパスによる左下肢血行再建術を追加し手術を終了，左下肢色調は改善し足背動脈と後脛骨動脈の血流音聴取が可能となった。手術時間514分，CPB時間221分，循環停止時間101分，術中尿量4,100mLであった。 A) Left lower limb perfusion using a temporary axillo–femoral bypass before CPB. B) CPB was initiated with right femoral artery arterial cannulation. The artificial graft was divided into two, and both grafts were cannulated using a bifurcated arterial tubing. Then, axillary and femoral perfusion via divided graft were added. CPB: cardiopulmonary bypass 術後経過：CPB離脱時から開始した低用量（0.05μg/kg/時）カルペリチド持続投与を継続し，尿量を維持した。帰室時CPK，AST，LDHは，17,281IU/L，351IU/L，1,206IU/Lで，帰室9時間後（下肢血流再開18時間後）に最高値35,510IU/L，426IU/L，1,312IU/Lまで上昇した。乳酸値は帰室時の71mg/dLが最高値で帰室16時間後には正常値まで低下した。BUNは術後4日目に最高値40.3mg/dLまで上昇，クレアチニンは術前0.68mg/dLから術後帰室時0.88mg/dL，帰室35時間後1.04mg/dLと次第に上昇を認め急性腎障害を発症した。さらに術後4日目に最髙値1.35mg/dLまで上昇したが，フロセミド持続投与（5mg/時）追加により尿量増加が得られ，術後14日目に腎機能は正常化した。下肢虚血再灌流による急性肺障害のため術後8日目に抜管，翌日から離床開始，同50日目に間欠性跛行や下肢神経障害なく独歩自宅退院となった。 ALIは，「原因を問わず肢切断に至る可能性がある下肢の血流の急激な減少である」と定義され 4，下肢のみならず生命予後も不良で大切断率12.7～20%，死亡率9.3～13.3%と報告 5, 6されている。ALIの原因は様々であるが，原因の大部分を占める塞栓症，血栓症とともに大動脈解離は鑑別疾患の一つとして重要である。 大動脈解離に合併するALIは，偽腔内圧上昇の結果生じる真腔圧排による動脈血流障害が主原因である場合が多く，本症例も偽腔圧排による左総大腿動脈の血流障害が原因と考えられる。わが国におけるA型AADに伴うALI合併頻度は，これまでの欧米からの報告と同程度で6.8～13.3% 7, 8である。近年になりA型AADの手術治療成績は向上してきているが，ALI合併例における手術成績は依然不良でALIの合併は独立した術後院内死亡の危険因子である 7, 9。その理由として，ALI合併例では他の臓器虚血を合併することが多いこと，致死的な合併症の発生を回避するためA型AAD治療の原則である胸部大動脈手術が優先されることが多く，下肢虚血時間の延長が再灌流後の横紋筋融解症や筋腎代謝症候群の発症リスクを高めることなどがあげられる。 一方，本症例のように下肢虚血のみであっても危機的即時型IIbの症例では，血流再開後の虚血再灌流障害によるコンパートメント症候群，横紋筋融解症による急性腎障害，筋腎代謝症候群への重症化対策が手術成績を左右するため，組織が非可逆的変化に陥るとされる6時間という時間的制約を念頭に治療戦略を立てることが重要である。本症例では手術室入室時，既に発症から270分が経過した時間的猶予がない状況であり下肢血行再建を先行したが，症例ごとに診断確定から胸部大動脈手術先行による下肢血流再開までに要する時間を考慮し，ALI発症から下肢血流再開まで6時間以内を目指した治療方針を検討する必要がある。また血行再建は，短時間での確実・十分な下肢血流確保が可能で生体侵襲の少ない方法を選択することが重要であると考え，本症例では短時間での下肢血流再開が期待できる一方で侵襲が大きくなるCPBを用いた下肢送血による血流再開ではなく，AADによる致死的合併症発生時にも対応可能な一時的バイパス術による血行再建を選択した。周術期管理においては，横紋筋融解症とCPB侵襲による急性腎障害への対応のため尿量維持が最も重要となる。当科では適正な循環動態下での薬物療法にもかかわらず尿量が減少し，体液量増加によるうっ血性心不全・肺水腫・体幹部浮腫などの回復遅延・増強や血清カリウム値上昇（≥6mEq/L）を認めた場合には，持続的血液浄化療法を開始する方針としているが，本症例では実施することなく回復した。 本症例は，これまでのA型PLAAD報告例に多く含まれている発症時の意識障害や失神発作のため疼痛を自覚したり訴えたりすることが困難であったPLAAD症例とは異なり，意識障害・失神や局所神経徴候を伴わず，さらにAADを示唆する身体所見や症状がなくALIが唯一の症状として発症したA型PLAAD症例である。著者の文献検索により捕捉し得た同様の症例は4例（Table 1）10, 11, 12, 13であり，まれな病態であると考えられる。これまでの報告で注目すべきは4例中2例（Case 3とCase 4）で，AADの鑑別診断前にヘパリンが投与され，重篤な合併症が発生している点である。わが国の治療ガイドライン 14においても，「ALIと診断された患者には，速やかにヘパリンを投与し，治療法を決定する」という事項がクラスIとして推奨されている。ALIの診断は下肢所見のみから可能であり，身体所見や問診で併存疾患が否定された時点でガイドラインに従いヘパリンが投与されるケースは少なくないと思われる。ALIの救急診療の際には，AADを示唆する典型的な症状がなく問診での鑑別が困難である本症例のようなPLAADの存在を念頭に置き，胸部を含む造影CT検査後の抗凝固療法実施を徹底することがALIの鑑別診断として明記されているAADの見落としをなくすために重要であると考える。 典型的な症状である胸背部痛を伴わず左下肢痛単独で発症したA型PLAADの1例を経験した。ALI症状を有する患者の救急診療において推奨される抗凝固剤投与が誤った初期治療となることを回避するため，本症例のような意識障害や局所神経徴候のないPLAADを鑑別診断として常に念頭に置くことが重要である。 著者に利益相反はない。

RF91 USE OF NIRS AND REFLECTANCE PULSE OXIMETRY AS A MONITORING IN DISTAL PERFUSION OF THE LIMB DURING PERIPHERAL ECMO.

Background and aim: One of the biggest complications in patients treated with venoarterial ECMO is lower extremity ischemia, site of the peripheral cannulation. The ELSO database reports a 5% incidence of ischemic leg complications in patients with peripheral va-ECMO, leading to leg amputation in 1% of cases. The objective of the study is to optimize the perfusion of the cannulated limb for the reduction of the incidence of ischemia, pacing a distal perfusion catheter (8 Fr) in the superficial femoral artery, before the insertion of the deep femoral artery and monitoring of tissue oxygen saturation by NIRS and reflectance pulse oxymetry. Methods: Our study includes the analysis of the experience on a group of 9 patients in which tissue saturation was monitored by NIRS (group A) and another group that includes patients on whom the distal flow of the limb has been periodically detected by Eco Doppler SD2, without monitoring of tissue saturation (group B). Results: In the experience of group B a late diagnosis of ischemia of the cannulated limb was found despite the distal perfusion. In group A NIRS monitoring allowed to readily diagnose a hypoperfusion, detected with a variation of saturation > 10% with respect to the tissue saturation of the contralateral limb and the basal value, resolving it with the immediate repositioning distal perfusion cannula. Conclusions: We conclude that transcutaneous NIRS and reflectance pulse oximetry may be an effective non-invasive method for continuous monitoring of leg perfusion in patients treated with peripheral ECMO and distal limb reperfusion.

Stroke increases ischemia-related decreases in motor unit discharge rates.

Following stroke, hyperexcitable sensory pathways, such as the group III/IV afferents that are sensitive to ischemia, may inhibit paretic motor neurons during exercise. We quantified the effects of whole leg ischemia on paretic vastus lateralis motor unit firing rates during submaximal isometric contractions. Ten chronic stroke survivors (>1 yr poststroke) and 10 controls participated. During conditions of whole leg occlusion, the discharge timings of motor units were identified from decomposition of high-density surface electromyography signals during repeated submaximal knee extensor contractions. Quadriceps resting twitch responses and near-infrared spectroscopy measurements of oxygen saturation as an indirect measure of blood flow were made. There was a greater decrease in paretic motor unit discharge rates during the occlusion compared with the controls (average decrease for stroke and controls, 12.3 ± 10.0% and 0.1 ± 12.4%, respectively; P < 0.001). The motor unit recruitment thresholds did not change with the occlusion (stroke: without occlusion, 11.68 ± 5.83%MVC vs. with occlusion, 11.11 ± 5.26%MVC; control: 11.87 ± 5.63 vs. 11.28 ± 5.29%MVC). Resting twitch amplitudes declined similarly for both groups in response to whole leg occlusion (stroke: 29.16 ± 6.88 vs. 25.75 ± 6.78 Nm; control: 38.80 ± 13.23 vs 30.14 ± 9.64 Nm). Controls had a greater exponential decline (lower time constant) in oxygen saturation compared with the stroke group (stroke time constant, 22.90 ± 10.26 min vs. control time constant, 5.46 ± 4.09 min; P < 0.001). Ischemia of the muscle resulted in greater neural inhibition of paretic motor units compared with controls and may contribute to deficient muscle activation poststroke. NEW & NOTEWORTHY Hyperexcitable inhibitory sensory pathways sensitive to ischemia may play a role in deficient motor unit activation post stroke. Using high-density surface electromyography recordings to detect motor unit firing instances, we show that ischemia of the exercising muscle results in greater inhibition of paretic motor unit firing rates compared with controls. These findings are impactful to neurophysiologists and clinicians because they implicate a novel mechanism of force-generating impairment poststroke that likely exacerbates baseline weakness.

Dynamics of below-the-knee arterial blood flow after endovascular revascularisation of peripheral arteries as a potential predictor of clinical outcomes during one-year follow-up.

Patients with advanced lower limb ischaemia are, at present, mainly treated using revascularisation. The aim of the study was to investigate whether the dynamics of blood flow in below-the-knee (BTK) arteries assessed by angiography correlate with clinical outcomes after a 12-month follow-up in patients with severe leg ischaemia treated per-cutaneously. The current study enrolled 287 consecutive patients who underwent 302 endovascular procedures on the infrain-guinal arteries. The mean age of the included participants was 67.4 ± 10.4 years. After the procedure, blood flow in all patent BTK arteries was assessed using frame count (FC). Patients were then evaluated after one, three, six, and 12 months. During the follow-up visits, clinical condition was evaluated based on the Rutherford scale, ankle-brachial index, and the need for reintervention or amputation. Clinical improvement at the end of the follow-up period was observed in 242 (80.1%) cases and no improvement or worsening in was seen in 42 (13.0%) patients. In total, 66 (21.8%) reinterventions and 18 (6%) amputations during the follow-up period were recorded. Patients with higher FC in the tibial anterior artery experienced significantly better clinical improvement within the 12-month follow-up period (p = 0.02). Lower FC predisposed to worse clinical outcomes after an-gioplasty. Similar tendencies were found for the tibial posterior and fibular arteries but without statistical significance. The results suggest a negative relationship between FC observed on the final angiogram and clinical outcomes in patients undergoing endovascular treatment of the peripheral arteries.

A Challenging Diagnosis of Leg Ulcer.

Ischaemic ulcers of the lower limb can have several aethiopathological mechanisms. For instance, the uncommon Martorell hypertensive leg ulcer is an infrequent complication of long-term uncontrolled arterial hypertension and is largely ignored and underdiagnosed. The typical ulcer is on the lower leg, is extremely painful and presents in female patients over 60 years of age with cardiovascular risk factors, mainly severe arterial hypertension. The diagnosis is histological, with obliteration of the arterioles by arteriolosclerosis. In these cases, antihypertensive medication is the standard treatment. We describe the case of an African-American female patient with long-term hypertension who presented with a very painful leg ulcer. The diagnosis was complicated by the coexistence of more common causes of ulcer. Despite analgesic medicines, pain relief was only obtained with control of hypertension. A definite diagnosis was made following biopsy.In describing this diagnosis of an ischaemic leg ulcer, we highlight the need to consider the skin as a target organ of arterial hypertension.LEARNING POINTSMartorell hypertensive leg ulcer is an underdiagnosed cutaneous lesion arising from long-term uncontrolled hypertension.The diagnosis is confirmed by histopathology.Standard treatment is adequate control of blood pressure.

Objective Performance Goals for Surgical Treatment of Critical Limb Ischemia

Based on prospective vein bypass trials for lower leg ischemia, objective performance goals (OPG) were established by the Society for Vascular Surgery (SVS) and are used as a benchmark tool for open and endovascular treatments. This study aims to analyze OPG of all patients with critical limb ischemia (CLI) treated by open revascularization techniques at a tertiary care facility in routine practice. From January 2005 to March 2013, 315 patients (mean age 72years) with CLI were retrospectively included in this study. Inclusion criteria were patients with Fontaine stage III and IV, realized revascularization with open surgical procedures (bypass grafting or endarterectomy), or hybrid method (open+endovascular). Exclusion criteria were primary major amputations, patients with revascularization treatments of the index leg within the last 3months, and missing aftercare. Primary end point was "amputation-free survival" (AFS), and secondary end point was "freedom from major adverse limb event+perioperative death (30days)" (MALE+POD) according to the SVS. The technical end point was primary patency. Mean follow-up was 34months. The following variables were studied: clinical stage (Fontaine), previous interventions, bypass material used, and site of the distal anastomosis. The statistical evaluation and preparation was carried out using the Kaplan-Meier estimator and the log-rank test. A multivariate analysis was performed using the Cox proportional hazards model. A P value ≤0.05 was considered to be statistically significant. A total of 128 patients (31%) fulfilling the adjusted SVS OPG criteria showed significantly better results for AFS, MALE+POD, and primary patency (P=0.013, P=0.015, P=0.002, respectively). Regarding the AFS (1year: 74%), multivariate analysis displayed significant worse results for patients with end-stage renal disease (hazard ratio [HR] 2.90, 95% confidence interval [CI] 1.83-4.60, P<0.001) and Fontaine stage IV (HR 1.69, 95% CI 1.11-2.57, P=0.015). Regarding MALE+POD (1year: 64%), male patients (HR 0.64, 95% CI 0.46-0.90, P=0.011) showed a significantly better outcome and patients without previous interventions of the index leg (HR 1.51, 95% CI 1.09-2.09, P=0.013) showed a significantly worse outcome. In this study, we were able to show that it is possible to reach the efficacy of OPGs set by SVS in a surgically treated all-comers cohort of CLI patients. Nevertheless, patients who did not fulfill the SVS OPG criteria showed significantly worse results for AFS and MALE+POD.

Multimodality Intraoperative Neurophysiological Monitoring (IONM) in Anterior Hip Arthroscopic Repair Surgeries.

Arthroscopic hip surgery is performed routinely for the treatment of various hip disorders. Leg traction during labral tear repair, femoroplasty, and acetabuloplasty for hip stabilization can stretch the peripheral nerves. This may cause temporary or permanent nerve injury. This study illustrates the benefit of utilizing multimodality Intraoperative Neurophysiological Monitoring (IONM) during hip surgical procedures.We performed a retrospective review of 10 arthroscopic hip surgeries with neurophysiological monitoring at one medical center. The patients consisted of six females and four males (mean age: 48.9 years). The procedures were equally divided into left and right-sided procedures. IONM setup included posterior tibial, peroneal, and femoral or saphenous nerve somatosensory evoked potentials (SSEPs), transcranial electrical motor evoked potentials (TCeMEP), train of four (TOF), and electromyography (EMG) from the lower extremities.All patients exhibited changes in IONM data during the surgical procedure. Changes in the latency and amplitude or loss of the lower SSEPs on the surgical side occurred in 36% of the monitorable SSEPs. The surgeon instructed the team to reduce the leg lengthening by removing traction when changes were observed. The SSEPs exhibited a full recovery in 75% of the affected lower extremity SSEPs. In the two instances of nonrecovery, the SSEP responses remained increased in latency or decreased in amplitude at closing, but the waveform was intact. There were five instances of complete loss of the waveform (four in the ipsilateral leg, and one in the contralateral leg) with recovery after traction was reduced. TCeMEP changes occurred in 53% of the ipsilateral lower muscles monitored. Many of the TCeMEP changes were attributed to ischemia of the feet and could not be resolved intraoperatively.Multimodality IONM can be a beneficial and protective tool during surgical procedures involving hip and acetabular areas. Early identification of changes in evoked potentials during hip arthroscopy surgeries can minimize post-operative neurological deficits due to peripheral nerve injury and leg ischemia.

The effects of different remote ischemic conditioning on ischemia-induced failure of microvascular circulation in humans.

Intermittent ischemia in remote tissues can be applied before ischemic injury, during ischemic injury or at the beginning of reperfusion of an index organ ischemia. The aim of this study was to investigate the effect of Remote Ischemic Conditioning (RIC) of the leg on changes in ischemia-induced the microvascular functions of the arm. Ischemic microvascular injury was induced by arm ischemia (20 min) and reperfusion in healthy, nonsmoker, male volunteers (ischemia group-ISC, n: 9). In another group of volunteers, to investigate the effects of remote organ ischemic conditioning 5 cycles of reperfusion followed by leg ischemia (each lasting 60 seconds) were applied either before (preRIC, n:11), or during (perRIC, n:12) or immediately after (postRIC, n:9) 20 minutes of arm ischemia. The microvascular flow of arm was assessed before and after ischemia using iontophoresis of the endothelium-derived nitric oxide (NO) releaser acetylcholine (ACh) and the endothelium-independent NO donor sodium nitroprusside (SNP). Changes in microvascular blood flow were measured using Laser Doppler imaging. The plasma level of biomarkers related to endothelial function such as nitric oxide (NO), asymmetric dimethylarginine (ADMA), total antioxidant capacity (TAC) and hydrogen sulphide (H2S) were measured. No difference was determined between the groups in terms of age, BMI or blood biochemicals reflecting cardiovascular status. ACh caused a rise in microvascular blood flow in a charge dependent manner. The ACh-induced flow increase was not significantly depressed by ischemia and not affected by any of the types of RIC in the study subjects. The increase in SNP-induced microvascular flow was significantly decreased in the ISC, perRIC and postRIC groups, but not in the preRIC group. Plasma levels of NO, ADMA, TAC and H2S were not changed by ischemia and RIC. These results suggested that microvascular perfusion of human forearm skin was elevated by either endothelium or drug-derived NO. The effect of ischemia and RIC on NO-induced flow increase was affected differently by different applications in the healthy young individuals. These complicated results are taken into consideration in experimental and therapeutic interventions.

Cutaneous Arteriolosclerosis Is Not Specific to Ischemic Hypertensive Leg Ulcers

Background: The histological characteristic of hypertensive leg ulcers (HLU) is the presence of “arteriolosclerosis.” The pertinence of performing a skin biopsy to diagnose HLU is questionable, as cutaneous arteriolosclerosis may be related to patient comorbidities. The objective here was to evaluate the frequency of arteriolosclerosis in skin leg biopsies performed in patients without ulcer and in control patients with HLU. Methods: We performed a retrospective study between January 2013 and July 2014. Patients were included if they had undergone a deep skin biopsy on the lower limbs, in the absence of any leg ulcer. Controls were patients with typical HLU. Results: Fifty-eight patients and 6 controls were included. Hypertension was present in 25 patients (43%). Arteriolosclerosis, defined as fibrous endarteritis, was present in 35 out of 58 patients (60%) and in all of the controls. No hyalinosis or hyperplastic proliferative arteriolosclerosis was observed in the patients or controls. Only age was an independent factor associated with the presence of cutaneous arteriolosclerosis (p &x#3c; 0.0001). Conclusion: Cutaneous arteriolosclerosis is significantly and independently associated with age. Thus, skin biopsy seems not to be necessary for the diagnosis of HLU but only for a differential diagnosis.

Arterial Recanalization for Access for Arterial Intervention in Children: Techniques and Outcomes

PurposeTo assess technical success of arterial recanalization in children requiring repeated arterial access and intervention. Materials and MethodsOver 14 years, 41 attempts to cross 30 arterial occlusions were made in 22 patients (13 male, 9 female). Median patient age was 12 months (15 days–14 years), and weight was 7.6 kg (3.0–77.3 kg). Techniques and outcomes were recorded. ResultsTwenty-five of 41 (61%) attempts at crossing an arterial occlusion were successful. Nineteen of 30 (63%) first attempts to cross occlusions were successful, and 6 of 11 (55%) repeat attempts were successful. The occluded segments were combinations of common femoral artery (n = 4), external iliac artery (n = 36), common iliac artery (n = 11), and aorta (n = 1). Complications occurred in 5 of 41(12%) attempts: 3 minor complications (hematoma, extravasation, and transient leg ischemia) and 2 major complications (rupture and thrombosis). ConclusionsArterial access by recanalization of occluded segments is technically feasible in children, with a low complication rate.

Near infrared spectroscopy-guided exercise training for claudication in peripheral arterial disease.

Supervised treadmill exercise for claudication in peripheral arterial disease is effective but poorly tolerated because of ischemic leg pain. Near infrared spectroscopy allows non-invasive detection of muscle ischemia during exercise, allowing for characterization of tissue perfusion and oxygen utilization during training. We evaluated walking time, muscle blood flow, and muscle mitochondrial capacity in patients with peripheral artery disease after a traditional pain-based walking program and after a muscle oxygen-guided walking program. Patients with peripheral artery disease trained thrice weekly in 40-minute-long sessions for 12 weeks, randomized to oxygen-guided training ( n = 8, age 72 ± 9.7 years, 25% female) versus traditional pain-based training ( n = 10, age 71.6 ± 8.8 years, 20% female). Oxygen-guided training intensity was determined by maintaining a 15% reduction in skeletal muscle oxygenation by near infrared spectroscopy rather than relying on symptoms of pain to determine exercise effort. Pain free and maximal walking times were measured with a 12-minute Gardner treadmill test. Gastrocnemius mitochondrial capacity and blood flow were measured using near infrared spectroscopy. Baseline pain-free walking time was similar on a Gardner treadmill test (2.5 ± 0.9 vs. 3.6 ± 1.0 min, p = 0.5). After training, oxygen-guided cohorts improved similar to pain-guided cohorts (pain-free walking time 6.7 ± 0.9 vs. 6.9 ± 1.1 min, p < 0.01 for change from baseline and p = 0.97 between cohorts). Mitochondrial capacity improved in both groups but more so in the pain-guided cohort than in the oxygen-guided cohort (38.8 ± 8.3 vs. 14.0 ± 9.3, p = 0.018). Resting muscle blood flow did not improve significantly in either group with training. Oxygen-guided exercise training improves claudication comparable to pain-based training regimens. Adaptations in mitochondrial function rather than increases in limb perfusion may account for functional improvement. Increases in mitochondrial oxidative capacity may be proportional to the degree of tissue hypoxia during exercise.

Trends of the treatment of Critical Limb Ischemia during the last two decades.

In this review 14 studies were identified reporting the treatment strategy in 4891 patients with Critical Limb Ischemia (CLI) with the aim to investigate if the strategy of treatment of the first episode of CLI has changed during the last 15-20 years. A computer research has been performed on PubMed and Scopus databases on November 2016. The used terms for the investigation about studies evaluating the strategy of treatment of CLI at the first-time presentation, have been "critical leg ischemia", "critical limb ischemia", "critical lower limb ischemia" along with the terms "placebo", "medical treatment" and/or "conservative" revascularisation, surgical revascularisation, endovascular revascularisation, hybrid revascularisation and primary amputation. Studies were included if they were either retrospective or prospective and reporting the rate of patients who underwent to any form of revascularization, conservative treatment and primary amputation. The one-year limb and life survival rates have been reported as major outcomes. The pooled rate of revascularization was 72.5% (95% CI 80-64.96) of which 54.5%, surgical, 38.3% endovascular and 7.1% hybrid. The bivariate regression of revascularisation procedures has been with not significant increase, from 68% in 1993 to 88% in 2015. The endovascular procedures have shown a significant increase of the trend, from 2% to more the 50% (p 0.007), while surgical and hybrid procedures have not. The pooled rate of conservative treatment was 18% (95% CI 11.6-24.5%) with a not significant increasing trend and primary amputation pooled rate was 8.7% (95% CI 12.0-5,4) with a significant decreasing trend (p 0.009). The one-year limb survival rate was 75,4% (95% CI 81.5-69.3%) and the life survival was 76%. (95% CI 85.4-66.1%) both with a not significant increasing trend. In conclusion, this review highlights how the treatment strategy of the first CLI manifestation has changed over the last 15-20 years. It has shown an increase of the rate of revascularization procedures, particularly for endovascular and a significant reduction of the rate of primary amputations. The rate of patients treated conservatively appears to be unchanged and maybe influencing the rate of limb and life survival, that have remained unchanged.

MicroRNA-30c-5p modulates neuropathic pain in rodents.

Neuropathic pain is a debilitating chronic syndrome that is often refractory to currently available analgesics. Aberrant expression of several microRNAs (miRNAs) in nociception-related neural structures is associated with neuropathic pain in rodent models. We have exploited the antiallodynic phenotype of mice lacking the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a transforming growth factor-β (TGF-β) pseudoreceptor. We used these mice to identify new miRNAs that might be useful for diagnosing, treating, or predicting neuropathic pain. We show that, after sciatic nerve injury in rats, miR-30c-5p was up-regulated in the spinal cord, dorsal root ganglia, cerebrospinal fluid (CSF) and plasma and that the expression of miR-30c-5p positively correlated with the severity of allodynia. The administration of a miR-30c-5p inhibitor into the cisterna magna of the brain delayed neuropathic pain development and reversed fully established allodynia in rodents. The mechanism was mediated by TGF-β and involved the endogenous opioid system. In patients with neuropathic pain associated with leg ischemia, the expression of miR-30c-5p was increased in plasma and CSF compared to control patients without pain. Logistic regression analysis in our cohort of patients showed that the expression of miR-30c-5p in plasma and CSF, in combination with other clinical variables, might be useful to help to predict neuropathic pain occurrence in patients with chronic peripheral ischemia.

Leg ulcers (ulcus cruris): The frequent macrovascular causes

Leg ulcers (ulcus cruris): The frequent macrovascular causes Abstract. Four pathologies make up the macrovascular etiologies of leg uclers: Venous leg ulcers (50 %), mixed venous-arterial leg ulcers (20 %), arterial leg ulcers (5 %), and Martorell hypertensive ischemic leg ulcer (5 %). The remaining 20 % concern a large array of other etiologies. Every leg ulcer requires vascular (arterial and venous) work-up, that can be completed with microbiology, biopsy, and more in-depth internal diagnostics, as indicated. Venous leg ulcers are treated with compression therapy. Incompetent saphenous veins and tributaries are abolished if the deep venous system is patent. Occluded iliac veins are recanalised and stented, as possible. Refractory venous leg ulcers are grafted with split skin or punch grafts, depending on their surface. Extensive dermatolipofasciosclerosis may be tangentially removed by shave therapy or fasciectomy, that can be combined with negative pressure wound treatment (NPWT). Skin equivalents are an alternative to treat superficial venous leg ulcers that fail to epithelialise. Their indication in the treatment of more complex leg ulcers still needs to be better investigated and understood. The use of dermal matrices leads to more stable scars. Mixed venous-arterial leg ulcers heal slower and recur more frequently. Compression needs to be reduced. Refractory cases require arterial revascularisation, to transform the mixed venous-arterial into a venous leg ulcer. Arterial leg ulcers require arterial revascularization and split skin graft. Martorell hypertensive ischemic leg ulcer is still underrecognised and often confounded with with pyoderma gangrenosum, which leads therapy into a wrong direction. Necrosectomy, antibiotic treatment in the presence of relevant bacterial superinfection, and repeated split skin grafts eventually heal the vast majority of these extremely painful and potentially mortal wounds.

The association between nutritional and functional status in patients undergoing endovascular intervention due to chronic lower limbs ischemia

Background: The nutritional status and functional status of patients are important prognostic factors. The aim of the study was to assess the relationships between patients’ nutritional status and the outcome of endovascular intervention in patients with chronic lower limb ischemia during one-year follow-up. Materials and methods: In 79 consecutive patients subjected to endovascular intervention due to chronic leg ischemia following examinations were performed before and after 3 and 12 month after surgery: physical examination, Minimal Nutritional Assessment (MNA) score, Nutritional Risk Screening 2002 score (NRS2002), Barthel, ADL, IADL scale, ankle-brachial index (ABI), claudication distance on the treadmill and handgrip strength. Results: More than half of patients were initially overweight or obese. Following 3 months after the surgery, improvement in lower limb symptoms was observed, together with significant increase in ABI, claudication distance, total MNA score and IADL scale. The risk associated with malnutrition (MNA questionnaire), Barthel score and hand grip strength showed a statistically significant relationship with the subjective feeling of improvement after surgery. Its absence was more frequent in patients characterized by higher risk of malnutrition, with less muscular strength and poorer fitness. Conclusions: Endovascular treatment of lower limbs ischemia improved not only symptoms of leg ischemia but also the general functional status of patients. The initial nutritional status, functional status and hand grip strength of patients with chronic lower limb ischemia were associated with a better clinical outcome of endovascular intervention.

Clinical ultrasound stimulating angiogenesis following drug-release from polymersomes on the ischemic zone for peripheral arterial occlusive disease

Peripheral Arterial Occlusive Disease (PAOD) is an aging disease that affects the quality of life of many people by its intermittent claudication and critical limb ischemia presentations. Traditional treatment and management of PAOD are asking patients to make a life change and medication with antiplatelet, statins and cilostazol, which decrease the possibility of clot formation. Our strategy has employed a magnetic Fe3O4-PLGA polymersome to carry the cilostazol into the ischemic area by magnetic attraction following remote-control drug release through low-energy ultrasound exposure. In the animal studies, the cilostazol-loaded Fe3O4-PLGA polymersomes were injected and accumulated at ischemic leg through magnetic attraction. Then, using a clinical-use ultrasound machine the leg was irradiated to forward cilostazol release from the accumulated polymersomes. Dramatically, we found an observable result of bloody flux recovery in the leg after 7 days compared to the non-treated leg that showed no evidence of the blood recovery.

Clinical factors that influence the cellular responses of saphenous veins used for arterial bypass

ObjectiveWhen an autogenous vein is harvested and used for arterial bypass, it suffers physical and biologic injuries that may set in motion the cellular processes that lead to wall thickening, fibrosis, stenosis, and ultimately graft failure. Whereas the injurious effects of surgical preparation of the vein conduit have been extensively studied, little is known about the influence of the clinical environment of the donor leg from which the vein is obtained. MethodsWe studied the cellular responses of fresh saphenous vein samples obtained before implantation in 46 patients undergoing elective lower extremity bypass surgery. Using an ex vivo model of response to injury, we quantified the outgrowth of cells from explants of the adventitial and medial layers of the vein. We correlated this cellular outgrowth with the clinical characteristics of the patients, including the Wound, Ischemia, and foot Infection classification of the donor leg for ischemia, wounds, and infection as well as smoking and diabetes. ResultsCellular outgrowth was significantly faster and more robust from the adventitial layer than from the medial layer. The factors of leg ischemia (P < .001), smoking (P = .042), and leg infection (P = .045) were associated with impaired overall outgrowth from the adventitial tissue on multivariable analysis. Only ischemia (P = .046) was associated with impaired outgrowth of smooth muscle cells (SMCs) from the medial tissue. Co-culture of adventitial cells and SMCs propagated from vein explants revealed that adventitial cells significantly inhibited the growth of SMCs, whereas SMCs promoted the growth of adventitial cells. The AA genotype of the −838C>A p27 polymorphism (previously associated with superior graft patency) enhanced these effects, whereas the factor of smoking attenuated adventitial cell inhibition of SMC growth. Comparing gene expression, the cells cultured from the media overexpress Kyoto Encyclopedia of Genes and Genomes pathways associated with inflammation and infection, whereas those from the adventitia overexpress gene families associated with development and stem/progenitor cell maintenance. ConclusionsThe adverse clinical environment of the leg may influence the biologic behavior of the cells in the vein wall, especially the adventitial cells. Chronic ischemia was the most significant factor that retards adventitial cell outgrowth. The cells arising from the vein adventitia may be key players in determining a healthy adaptive or a pathologic response to the injuries associated with vein grafting.

ImmunoPET of CD146 in a Murine Hindlimb Ischemia Model.

Peripheral arterial disease (PAD) consists of a persistent obstruction of lower-extremity arteries further from the aortic bifurcation attributable to atherosclerosis. PAD is correlated with an elevated risk of morbidity and mortality as well as of deterioration of the quality of life with claudication and chronic leg ischemia being the most frequent complications. Therapeutic angiogenesis is a promising therapeutic strategy that aims to restore the blood flow to the ischemic limb. In this context, assessing the efficacy of pro-angiogenic treatment using a reliable noninvasive imaging technique would greatly benefit the implementation of this therapeutic approach. Herein, we describe the angiogenesis and perfusion recovery characteristics of a mouse model of PAD via in vivo positron emission tomography (PET) imaging of CD146 expression. For that, ischemia was generated by ligation and excision of the right femoral artery of Balb/C mice and confirmed through laser Doppler imaging. The angiogenic process, induced by ischemia, was noninvasively monitored and quantified through PET imaging of CD146 expression in the injured leg using a 64Cu-labeled anti-CD146 monoclonal antibody, 64Cu-NOTA-YY146, at post-operative days 3, 10, and 17. The CD146-specific character of 64Cu-NOTA-YY146 was verified via a blocking study performed in another cohort at day 10 after surgery. Tracer uptake was correlated with in situ CD146 expression by histological analysis. PET scan results indicated that 64Cu-NOTA-YY146 uptake in the injured leg was significantly higher, with the highest uptake with a value of 14.1 ± 2.0 %ID/g at post-operative day 3, compared to the normal contralateral hindlimb, at all time points (maximum uptake of 2.2 ± 0.2 %ID/g). The pre-injection of a blocking dose resulted in a significantly lower tracer uptake in the ischemic hindlimb on day 10 after surgery, confirming tracer specificity. CD146/CD31 immunofluorescent co-staining showed an excellent correlation between the high uptake of the tracer with in situ CD146 expression levels and a marked co-localization of CD146 and CD31 signals. In conclusion, persistent and CD146-specific tracer accumulation in the ischemic hindlimb was observed, confirming the feasibility of 64Cu-NOTA-YY146 to be used as an imaging agent to monitor the progression of angiogenesis and recovery in future PAD research.

Acute type A aortic dissection repair in an octogenarian with achondroplasia: a case report

BackgroundAchondroplasia is an inherited disorder and the most common type of short-limbed dwarfism in human beings, affecting more than 250,000 individuals worldwide. To the best of our knowledge, no study has reported a correlation between achondroplasia and aortic dissection. Here, we report a rare case of acute type A aortic dissection repair in a patient with achondroplasia.Case presentationAn 82-year-old Japanese female with achondroplasia was admitted to our hospital because of acute-onset severe chest pain migration to her back accompanied by numbness and pain in the right lower limb. A computed tomography scan revealed acute type A aortic dissection with right leg ischemia because of an occlusion of the right common iliac artery. We successfully performed hemiarch repair.ConclusionsThis report presents the first case of a patient at such an advanced age with dwarfism and cardiac surgery and the second case to illustrate successful acute aortic dissection repair in achondroplasia. Of note, all procedures were performed without specialized equipment. Overall, this report adds to the experience of successful cardiac surgery in this unique patient population.

A case of chronic ulcer due to subcutaneous arteriolosclerosis in an obese patient mimicking pyoderma gangrenosum.

The differential diagnosis of chronic ulcers covers a wide range of diseases and poses a diagnostic challenge. Subcutaneous ischemic arteriolosclerosis can lead to local ischaemia and ulceration as a result of arteriolar narrowing and reduction of tissue perfusion. This pathophysiological feature can be seen in eutrophication (nonuremic calciphylaxis) in morbid obesity, hypertensive ischemic leg ulcer (Martorell ulcer) and calciphylaxis in chronic renal insufficiency. All of the ulcers happened in this way can be wrongly diagnosed as pyoderma gangrenosum because of clinical similarity and inadequate biopsies. We report a case of chronic ulcer due to subcutaneous arteriolosclerosis in morbid obesity, wrongly diagnosed as pyoderma gangrenosum. It can be detrimental to misdiagnose the ulcers due to subcutaneous arteriolosclerosis as pyoderma gangrenosum since they need a diametrically different approach.