Apostolos K. Tassiopoulos

Definition of venous reflux in lower-extremity veins

PURPOSEnThis prospective study was designed to determine the upper limits of normal for duration and maximum velocity of retrograde flow (RF) in lower extremity veins.nnnMETHODSnEighty limbs in 40 healthy subjects and 60 limbs in 45 patients with chronic venous disease were examined with duplex scanning in the standing and supine positions. Each limb was assessed for reflux at 16 venous sites, including the common femoral, deep femoral, and proximal and distal femoral veins; proximal and distal popliteal veins; gastrocnemial vein; anterior and posterior tibial veins; peroneal vein; greater saphenous vein, at the saphenofemoral junction, thigh, upper calf, and lower calf; and lesser saphenous vein, at the saphenopopliteal junction and mid-calf. Perforator veins along the course of these veins were also assessed. In the healthy volunteers, 1553 vein segments were assessed, including 480 superficial vein segments, 800 deep vein segments, and 273 perforator vein segments; and in the patients, 1272 vein segments were assessed, including 360 superficial vein segments, 600 deep vein segments, and 312 perforator vein segments. Detection and measurement of reflux were performed at duplex scanning. Standard pneumatic cuff compression pressure was used to elicit reflux. Duration of RF and peak vein velocity were measured immediately after release of compression.nnnRESULTSnDuration of RF in the superficial veins ranged from 0 to 2400 ms (mean, 210 ms), and was less than 500 ms in 96.7% of these veins. In the perforator veins, regardless of location, outward flow ranged from 0 to 760 ms (mean, 170 ms), and was less than 350 ms in 97% of these veins. In the deep veins, RF ranged from 0 to 2600 ms. Mean RF in the deep femoral veins and calf veins was 190 ms, and was less than 500 ms in 97.6% of these veins. In the femoropopliteal veins, mean RF was 390 ms, and ranged from 510 to 2600 ms in 21 of 400 segments; however, RF was less than 990 ms in 99% of these veins. Duration of RF was significantly longer in all three veins systems in patients (P <.0001 for all comparisons). With a cutoff value of more than 1000 ms rather than more than 500 ms, prevalence of abnormal RF in the femoropopliteal veins was significantly reduced, from 29% to 18% (P =.002). Thirty-seven vein segments (2.4%) had RF greater than 500 ms in the supine position, compared with less than 500 ms in 22 of these vein segments (59%) in the standing position. Of the 48 vein segments (3.1%) with RF greater than 500 ms in the standing position, RF was less than 500 ms in 6 of these vein segments (13%) in the supine position. Similar observations were noted in patient veins. There was no association between RF and peak vein velocity. Peak vein velocity had no significance in determining reflux.nnnCONCLUSIONSnThe cutoff value for reflux in the superficial and deep calf veins is greater than 500 ms. However, the reflux cutoff value for the femoropopliteal veins should be greater than 1000 ms. Outward flow in the perforating veins should be considered abnormal at greater than 350 ms. Reflux testing should be performed with the patient standing.

Patient-Based Abdominal Aortic Aneurysm Rupture Risk Prediction with Fluid Structure Interaction Modeling

Elective repair of abdominal aortic aneurysm (AAA) is warranted when the risk of rupture exceeds that of surgery, and is mostly based on the AAA size as a crude rupture predictor. A methodology based on biomechanical considerations for a reliable patient-specific prediction of AAA risk of rupture is presented. Fluid–structure interaction (FSI) simulations conducted in models reconstructed from CT scans of patients who had contained ruptured AAA (rAAA) predicted the rupture location based on mapping of the stresses developing within the aneurysmal wall, additionally showing that a smaller rAAA presented a higher rupture risk. By providing refined means to estimate the risk of rupture, the methodology may have a major impact on diagnostics and treatment of AAA patients.

Management of true aneurysms of hemodialysis access fistulas

OBJECTIVESnThis study was designed to determine the clinical presentation, characteristics, and management of true aneurysms in dialysis access fistulas.nnnMETHODSnPatients presenting with symptoms or functional arteriovenous fistula (AVF) problems and aneurysmal enlargement of the outflow vein were evaluated with duplex ultrasound scans. Dilatation to more than three times the native vessel diameter was considered aneurysmal. Pseudoaneurysms were excluded from the study. Patients demographics, aneurysm characteristics (diameter, location, thrombus, association with stenosis, and outflow obstruction), symptoms, type of treatment, and follow-up were recorded.nnnRESULTSnTwenty-three patients with a mean age of 55 years were found to have 29 upper extremity aneurysms of the outflow vein on duplex ultrasound scan. Nine patients (39%) had radiocephalic, 11 patients (48%) had brachiocephalic, 2 patients (9%) had brachiobasilic, and 1 patient (4%) had radiobasilic arteriovenous fistula. The average aneurysm size was 3.3 cm and the mean time from fistula placement to treatment was 47.1 months. Four patients (17%) were asymptomatic and were repaired due to technical and mechanical problems with AVFs, including stenosis and lack of normal vein for cannulation, compromising continued use. Nineteen patients (83%) presented with symptoms, including pain (48%), skin changes (30%), venous hypertension (22%), steal syndrome (22%), and high output failure (9%). Four patients (17%) were found to have outflow vein stenosis, 2 patients (9%) had central venous stenosis, and 2 patients (9%) had central venous occlusion. In 13 patients (56%) who had a functioning kidney transplant, the fistula was ligated with or without aneurysm excision. Three of the 13 patients developed superficial phlebitis with 1 patient requiring surgical evacuation of a clot; the other 2 patients were managed conservatively. Two of the 13 patients required creation of new access due to renal transplant failure. In the remaining 10 patients, the aneurysm was treated and the fistula salvaged due to a persistent need for hemodialysis. The median follow-up of these patients was 19 months ranging from 8 to 25 months. Seven patients (30%) underwent excision and repair with the great saphenous vein and 3 patients (13%) had excision and repair with prosthetic material, 2 of which underwent central venous angioplasty and stenting. Two patients developed thrombosis of their repair requiring new access in the contralateral arm. Three patients needed secondary percutaneous interventions for anastomotic stenosis.nnnCONCLUSIONnAlthough true aneurysms in patients with dialysis access are uncommon, significant complications may occur as a consequence of their presence. These complications can be treated and the fistulas can usually be salvaged.

Role of nitric oxide and tumor necrosis factor on lung injury caused by ischemia/reperfusion of the lower extremities

PURPOSEnAcute aortic occlusion with subsequent ischemia/reperfusion (I/R) of the lower extremities is known to predispose to lung injury. The pathophysiologic mechanisms of this injury are not clear. In the present study, we studied the role of tumor necrosis factor (TNF) and nitric oxide (NO) in lung injury caused by lower extremity I/R.nnnMETHODSnA rat model in which the infrarenal aorta was cross-clamped for 3 hours followed by 1 hour of reperfusion was used. The rats were randomized into five groups: group 1, aorta exposed but not clamped; group 2, aorta clamped for 3 hours, followed by 1 hour of reperfusion; group 3, 1 mg/kg dexamethasone administered before the aorta was clamped; group 4, 25 mg aminoguanidine, a specific inducible NO synthase (iNOS) inhibitor, administered before the aorta was clamped; and group 5, 2 mg/kg TNFbp, a PEG-ylated dimeric form of the high-affinity p55 TNF receptor I (RI), administered before the aorta was clamped. NO concentration in the exhaled gas (ENO) was measured, as an index of NO production by the lung, in 30 minute intervals during I/R. Serial arterial blood samples for TNF assay were obtained during the course of the experiment. At the end of the experiment, the lungs were removed and histologically examined for evidence of injury.nnnRESULTSnENO in group 2 increased from 0.7 +/- 0.3 ppb at baseline to 54.3 +/- 7.5 ppb at the end of ischemia and remained stable during reperfusion (54.6 +/- 8.5 ppb at the end of reperfusion). ENO production was blocked by aminoguanidine, by dexamethasone, and by TNFbp given before aortic occlusion. Serum TNF in groups 2, 3 and 4 increased rapidly during early ischemia, reaching its peak value 60 minutes after occlusion of the aorta, then gradually declined to baseline levels at the end of ischemia, and remained low during reperfusion. TNFbp decreased serum TNF concentration significantly when it was given before aortic occlusion. Histologic examination of the lungs at the end of the experiment revealed that aminoguanidine, dexamethasone, and TNFbp had a protective effect on the lungs.nnnCONCLUSIONSnSerum TNF increases rapidly during lower extremity ischemia and causes increased production of NO from the lung by upregulating iNOS. Increased NO is associated with more severe lung injury, and iNOS blockade has beneficial effects on the lung. TNF blockade before ischemia decreases NO production by the lung and attenuates lung injury. ENO can be used as an early marker of lung injury caused by lower extremity I/R.

Angiogenic mechanisms of endothelialization of cardiovascular implants: a review of recent investigative strategies

Both cardiovascular implants and therapeutic interventions on native arteries fail due to biologic responses occurring at the blood/prosthesis/arterial wall and tissue/prosthesis/arterial wall interfaces, resulting in the failure modes of thrombosis and myointimal hyperplasia. Systemic pharmacologic approaches including use of anti-coagulant and anti-platelet agents have significant untoward side effects and have not resulted in a dramatic impact on failure modes in many applications, including small diameter vascular grafts. Local delivery of therapeutic agents via surface attachment with defined release kinetics may alter thrombogenicity and/or myointimal hyperplasia. Therapeutic agents may include a spectrum of biologic agents from peptides to endothelial cells. Efficient attachment and release of these agents in biologically active form is dependent upon improved methods of surface modification. The intended action of the biologic agent may similarly be impacted by the surface and bulk characteristics of the underlying biomaterial. It is often assumed, without concrete data, that surface re-endothelialization may have a beneficial impact on both thrombogenicity and myointimal hyperplasia. New clinical data on endothelial cell seeding has been supportive. Spontaneous re-endothelialization may be stimulated via an induced directed angiogenesis resulting in trans-interstitial capillarization and surface endothelialization. Recent advances in therapeutic angiogenesis have suggested the power of angiogenic factors to induce neovascularization of ischemic tissue beds. These concepts have been used to surface modify prosthetic devices with either VEGF or FGF and both in vitro and animal data suggest a potent stimulation of surface re-endothelialization. Neither of these growth factors is likely to be ideal. VEGF is relatively endothelial cell specific but is a relatively weak endothelial cell mitogen. FGF-1 and FGF-2 are more potent mitogens but are less cell specific. Recent work has led to the generation of mutant growth factors via site-induced mutagenesis and results of several such FGF mutants on endothelial cell and smooth muscle cell proliferative response have been studied. The use of designer growth factors on cardiovascular implants and on manipulated native vessels may have a significant positive impact on re-endothelialization and thereby on the failure modes of thrombosis and myointimal hyperplasia.

Treatment of septic shock in rats with nitric oxide synthase inhibitors and inhaled nitric oxide.

OBJECTIVEnTo evaluate the effect of treatment with a combination of nitric oxide synthase inhibitors and inhaled nitric oxide on systemic hypotension during sepsis.nnnDESIGNnProspective, randomized, controlled study on anesthetized animals.nnnSETTINGnA cardiopulmonary research laboratory.nnnSUBJECTSnForty-seven male adult Sprague-Dawley rats.nnnINTERVENTIONSnAnimals were anesthetized, mechanically ventilated with room air, and randomized into six groups: a) the control group (C, n=6) received normal saline infusion; b) the endotoxin-treated group received 100 mg/kg i.v. of Escherichia coli lipopolysaccharide (LPS, n=9); c) the third group received LPS, and 1 hr later the animals were treated with 100 mg/kg i.v. Nw-nitro-L-arginine (LNA, n=9); d) the fourth group received LPS, and after 1 hr, the animals were treated with 100 mg/kg i.v. aminoguanidine (AG, n=9); e) the fifth group received LPS and 1 hr later was treated with LNA plus 1 ppm inhaled nitric oxide (LNA+NO, n=7); f) the sixth group received LPS and 1 hr later was treated with aminoguanidine plus inhaled NO (AG+NO, n=7). Inhaled NO was administered continuously until the end of the experiment.nnnMEASUREMENTS AND MAIN RESULTSnSystemic mean blood pressure (MAP) was monitored through a catheter in the carotid artery. Mean exhaled NO (ENO) was measured before LPS (T0) and every 30 mins thereafter for 5 hrs. Arterial blood gases and pH were measured every 30 mins for the first 2 hrs and then every hour. No attempt was made to regulate the animal body temperature. All the rats became equally hypothermic (28.9+/-1.2 degrees C [SEM]) at the end of the experiment. In the control group, blood pressure and pH remained stable for the duration of the experiment, however, ENO increased gradually from 1.3+/-0.7 to 17.6+/-3.1 ppb after 5 hrs (p< .05). In the LPS treated rats, MAP decreased in the first 30 mins and then remained stable for 5 hrs. The decrease in MAP was associated with a gradual increase in ENO, which was significant after 180 mins (58.9+/-16.6 ppb) and reached 95.3+/-27.5 ppb after 5 hrs (p< .05). LNA and AG prevented the increase in ENO after LPS to the level in the control group. AG caused a partial reversal of systemic hypotension, which lasted for the duration of the experiment. LNA reversed systemic hypotension almost completely but only transiently for 1 hr, and caused severe metabolic acidosis in all animals. The co-administration of NO with AG had no added benefits on MAP and pH. In contrast, NO inhalation increased the duration of the reversal in MAP after LNA, alleviated the degree of acidosis, and decreased the mortality rate (from 55% to 29%).nnnCONCLUSIONSnIn this animal model, LPS-induced hypotension was alleviated slightly and durably after AG, but only transiently after LNA. Furthermore, co-administration of NO with AG had no added benefits but alleviated the severity of metabolic acidosis and mortality after LNA. We conclude that nitric oxide synthase (NOS) inhibitors, given as a single large bolus in the early phase of sepsis, can exhibit some beneficial effects. Administration of inhaled NO with NOS inhibitors provided more benefits in some conditions and therefore may be a useful therapeutic combination in sepsis. NO production in sepsis does not seem to be a primary cause of systemic hypotension. Other factors are likely to have a major role.

The distribution and significance of varicosities in the saphenous trunks

OBJECTIVEnThe purpose of this study was to determine the prevalence, distribution, and extent of varicosities and focal dilatations in the saphenous trunks, their association with the sites of reflux, and their correlation with CEAP classes.nnnMETHODSnThis prospective study included patients belonging to different CEAP classes (2-6) and a control group of age- and gender-matched healthy volunteers (group C). Color-flow duplex scan imaging was used to evaluate the entire venous system from groin to ankle for reflux and obstruction. Varicose segments and focal dilatations of the great and small saphenous veins (GSV and SSV) were recorded, and the diameters throughout the length of the saphenous trunks were measured. The presence of varicosities in the tributaries and accessory veins were documented.nnnRESULTSnFrom the 739 consecutive patients, 239 were excluded due to superficial venous thrombosis (SVT), deep venous thrombosis (DVT), both SVT and DVT, previous interventions, or C3-C6 presentation with no chronic venous disease (CVD). The included 500 patients (681 limbs) were divided into two groups based on CEAP class: group A (C2 + C3) and group B (C4-6). Group A had significantly more women than group B and a younger mean age (48 vs 56 years). Overall, GSV reflux (86%) was more prevalent than SSV reflux (17%), P < .0001. Saphenous trunk diameters, saphenofemoral junction (SFJ) and saphenopopliteal junction (SPJ) involvement were greater in group B, (P < .01). Group C had smaller saphenous diameters compared to group A in all locations (P < .05) but the malleoli. The prevalence of the saphenous varicose segments in both groups was small with the GSV in group B being the highest (4.3%) and the SSV in group A being the smallest (1.2%). Focal dilatations were significantly more prevalent than varicosities in the saphenous trunks (P < .0001). Varicosities of tributaries and accessory veins were more prevalent than those of saphenous trunks (P < .0001). The mean length of varicose segments in the saphenous trunks was short (3.8 cm, range, 2.1-6.4 for group A vs 4.1 cm, range, 2.3-8.3 for group B, P = .09).nnnCONCLUSIONnA novel definition for varicosities in the saphenous trunks was established. Using this definition, it was determined that focal dilatations are far more common than varicosities. Because both of these entities are more prevalent in the accessory saphenous veins and tributaries, and CEAP class correlates positively with the extent of reflux and saphenous trunk diameter, studies on earlier interventions are warranted to prevent CVD progression.

Increased risk of breast cancer in splenectomized patients undergoing radiation therapy for Hodgkin's disease

PURPOSEnSecond malignancies have been reported among patients who were treated by radiation therapy or chemotherapy alone or in combination. Studies have implied an increased risk of breast cancer in women who received radiotherapy as part of their treatment for Hodgkins disease. This review was performed to determine if there is an association between splenectomy and subsequent breast cancer.nnnMETHODS AND MATERIALSnOne hundred and thirty-six female patients with histologically proven Hodgkins disease were seen in the Division of Radiation Oncology between 1962 and 1985. All patients received mantle or mediastinal irradiation as part of their therapy. The risk of breast cancer was assessed and multiple linear regression analysis was performed on the following variables: patient age, stage, dose and extent of radiation field, time after completing radiation therapy, splenectomy, and chemotherapy.nnnRESULTSnBreast cancer was observed in 11 of 74 splenectomized patients and in none of 62 patients not splenectomized. The mean follow-up was 13 years in splenectomized patients and 16 years, 7 months in nonsplenectomized patients. Nine patients developed invasive breast cancer and two developed ductal carcinoma in situ. Splenectomy was the only variable independently associated with an increased risk of breast cancer (p < 0.005) in multiple linear regression analysis; age, latency, and splenectomy considered together were also associated with an increased risk of breast cancer (p < 0.01).nnnCONCLUSIONnOur data show an increased risk of breast cancer in splenectomized patients who had treatment for Hodgkins disease. A multiinstitutional survey may better define the influence of splenectomy relative to developing breast cancer in patients treated for Hodgkins disease. The risk of breast cancer should be considered when recommending staging laparotomy, and we recommend close follow-up examination including routine mammograms for female patients successfully treated for Hodgkins disease.

Patterns of Venous Reflux and Obstruction in Patients With Skin Damage Due to Chronic Venous Disease

Identified were characteristics of individuals with skin damage related to chronic venous disease. Patients with chronic venous disease (n = 164) were evaluated with duplex ultrasound imaging and were placed in classes 4, 5, and 6 according to the CEAP classification. Their findings were compared with 100 class 2 controls. The prevalence of deep venous thrombosis was higher in the study group (23.7%) versus controls (5.1%; P < .0001), as was the prevalence of deep, perforator, and combined patterns of disease (P < .0001, P < .0007, and P < .0001). The mean duration of disease in controls 2 was shorter compared with the study group (P = .0019). The prevalence of reflux and obstruction within the study group was higher than in controls (P = .0021). Skin changes accurately reflect severity of chronic venous disease. Superficial and perforator vein reflux is the major cause of disease.

Recurrent deep vein thrombosis: long-term incidence and natural history.

Objective:To determine the long-term incidence, risk factors, and associated morbidity and mortality of recurrent deep vein thrombosis (DVT). Summary Background Data:Few studies have examined the long-term natural history and impact of recurrent DVT. Methods:We conducted a prospective observational study that followed 153 consecutive patients with an acute first episode of DVT. Clinical examination and ultrasound were performed serially for at least 5 years. Location and extent of the initial DVT, recurrence, pulmonary embolism, cause of mortality, signs and symptoms of post thrombotic syndrome (PTS), and the risk factors were recorded. Results:The incidence of recurrence at 5 years was 26.1%. Patients with both proximal and distal DVT had a higher recurrence rate than proximal (17/48 35% vs. 12/49, 24%, P = 0.27) or calf alone (11/56, 20%, P = 0.08). Unprovoked DVT and age >65 years were associated with higher recurrence rates (P < 0.001; relative risk [RR]: 2.9, 95% confidence interval [CI]: 1.5–5.7) and (P = 0.025; RR: 1.5, 95% CI: 1–2.3), respectively. Thrombophilia was not associated with increased risk of recurrence (P = 0.21). Patients with DVT due to surgery or trauma had a lower recurrence (P < 0.001). Ipsilateral recurrence was associated with increased severity of PTS (P < 0.001; RR: 1.6, 95% CI: 1.4–2.2). PE occurred 47 times, 12 (25%) of which were fatal events. Conclusions:Factors associated with a higher rate of recurrence included unprovoked DVT and age >65. Elevated thrombus burden had a trend towards higher risk. Patients with surgery and trauma had low recurrence rates. Ipsilateral recurrence was strongly associated with PTS. PE occurred frequently and was a common cause of death.