Vascular Behçet's syndrome: an update.

Behçet's syndrome (BS) is a complex vasculitis, characterised by peculiar histological, pathogenetic and clinical features. Superficial venous thrombosis (SVT) and deep vein thrombosis (DVT) are the most frequent vascular involvements, affecting altogether 15-40% of BS patients. Atypical thrombosis is also an important clinical feature of BS, involving the vascular districts of the inferior and superior vena cava, suprahepatic veins with Budd-Chiari syndrome, portal vein, cerebral sinuses and right ventricle. On the other hand, arterial involvement, although affecting only 3-5% of patients, represents a unique feature of BS, with aneurysms potentially affecting peripheral, visceral and pulmonary arteries. Vascular events in BS are promoted by inflammation, with neutrophils playing a key role in the pathogenesis of thrombotic events; in turn, coagulative components such as fibrinogen, thrombin, factor Xa and factor VIIa amplify the inflammatory cascade. Understanding the contribution of inflammatory and coagulation components in the pathogenesis of BS vascular events is crucial to define the most effective therapeutic strategy. Control of vascular thrombosis is achieved with immunosuppressants drugs rather than anticoagulants. In particular, use of azathioprine and cyclosporine in association with low-dose corticosteroids should be considered in DVT and SVT cases, while treatment with cyclophosphamide together with anti-TNF-α agents can be effectively used in arterial involvement. More recently, the anti-TNF-α drugs have also been reported as a valid alternative for the treatment also of venous events, especially DVT. An exception to the use of anticoagulant in BS could be represented by cerebral veins thrombosis. In this review, we will depict the main characteristics of the vascular involvement in BS, briefly describing histological and pathogenetic features, while focusing on the clinical and therapeutical approaches of the vascular manifestations of BS.

Chlorhexidine-coated peripherally inserted central catheters reduce fibroblastic sleeve formation in an in vivo ovine model.

PURPOSE:: This study compared an antimicrobial and anti-thrombogenic peripherally inserted central catheter treated with a chlorhexidine-based technology, a peripherally inserted central catheter with bulk distributed fluoro-oligomers, and a poly 2-methoxyethyl acrylate-based peripherally inserted central catheter to an untreated peripherally inserted central catheter (control) in an ovine model at 14 and 30 days post-implant. METHODS:: One of four types of peripherally inserted central catheters was surgically implanted into the left jugular vein of each of 18 sheep for 14 or 30 days. Blood analysis consisted of complete blood counts, serum chemistries, and coagulation (fibrinogen, prothrombin time, and partial thromboplastin time) profiles. Sheep were sacrificed to examine the vein and thorax. Histological analysis was performed on serial catheter sections using standard microscopy on hematoxylin and eosin-stained tissues. RESULTS:: All catheters developed fibroblastic sleeves at both 14 and 30 days. The chlorhexidine-peripherally inserted central catheter showed a 64% lower mean fibroblastic sleeve weight and a 66% shorter mean fibroblastic sleeve length compared to the untreated control at 14 days. By 30 days, compared to untreated control, the chlorhexidine-peripherally inserted central catheter showed 81% lower mean fibroblastic sleeve weight with 75% shorter mean fibroblastic sleeve length, the fluoro-oligomer-peripherally inserted central catheter showed 54% lower mean sheath weight with 40% shorter mean fibroblastic sleeve length, and the poly 2-methoxyethyl acrylate-peripherally inserted central catheter had 41% lower mean fibroblastic sleeve weight with 57% lower fibroblastic sleeve length. CONCLUSION:: Among the three anti-thrombogenic peripherally inserted central catheter technologies, the chlorhexidine-peripherally inserted central catheter had the smallest fibroblastic sleeves, followed by the fluoro-oligomer-peripherally inserted central catheter, poly 2-methoxyethyl acrylate-peripherally inserted central catheter, and control peripherally inserted central catheter.

ß-Adrenergic stimulation induces pro-arrhythmic activity in the caval vein myocardial tissue.

Electrical activity of the right superior vena cava (SVC) is considered as a source of the atrial fibrillation. We have shown that bioelectrical properties of the SVC myocardium differ from those of the working atrial myocardium. Electrically evoked action potential duration in SVC is significantly shorter, the resting membrane potential in both stimulated and quiescent SVC preparations is significantly more positive than in atria. Activation of ß-adrenoreceptors in SVC myocardium leads to a series of action potentials, and this process depends on protein kinase A. Probably, ß-adrenergic stimulation enhances SVC arrhythmogenesis in vivo.

Peculiarities of Blood Flow Changes in Venae Cavae during Experimental Pulmonary Embolism.

The model of acute pulmonary embolism in rabbits demonstrated reduced pulmonary blood flow, cardiac output, left atrial pressure, and blood flow in venae cavae against the background of elevated left pulmonary artery pressure and increased pulmonary vascular resistance. Simultaneously, the blood flow in the superior vena cava decreased to a lesser extent than that in the inferior vena cava, which was a characteristic feature of the model of pulmonary pathology. In contrast, when histamine was infused into the left jugular vein to equally elevate pressure in pulmonary artery as in the above model, the blood flow in the superior vena cava decreased to a greater extent than that in inferior vena cava. During stenosis of inferior vena cava that decreased the cardiac output to the level observed during modeled pulmonary embolism, the blood flows in both venae cavae dropped equally.

Simvastatin ameliorates deep vein thrombosis in rabbits by regulating the fibrinolytic system.

The study aimed to observe the therapeutic effect of simvastatin in a deep vein thrombosis (DVT) animal model and conduct a preliminary study into its mechanism. A total of 72 New Zealand white rabbits were randomly divided into control group (n = 18), low molecular weight heparin (LMWH) group (n = 18), simvastatin group (n = 18), and simvastatin + LMWH group (n = 18). A posterior vena cava thrombus model was established and interventions were administered according to the group procedures. Blood plasma was sampled before and 3, 7, and 14 days after the intervention when the vena cava (including thrombus) specimen was collected. Specimens were weighed, histopathologically examined, and monitored for changes in venous wall inflammation. Concentrations of P-selectin, plasminogen activator inhibitor (PAI-1), and the urokinase plasminogen activator (u-PA) activity were measured with enzyme-linked immunosorbent assay. P-selectin expression in the venous wall was measured with immunohistochemistry, and quantitative PCR detected the changes of local PAI-1/u-PA expression. Simvastatin and LMWH reduced the weight of the thrombus and promoted thrombus dissolution. Simvastatin significantly inhibited the systemic and local expression of P-selectin, whereas LMWH was inhibitory only at the late stage of the acute phase. Plasma active concentration and local gene expression of PAI-1 was inhibited by simvastatin, whereas for u-PA; it was promoted at the early stage of the acute phase, but inhibited in the late stage. Simvastatin inhibited the expression of inflammatory mediators, reduced the DVT inflammatory response, alleviated inflammatory injury and reduced thrombus formation. Simvastatin may provide a beneficial adjuvant therapy for DVT.

Randomized, Placebo-Controlled Trial of Dobutamine for Low Superior Vena Cava Flow in Infants.

OBJECTIVE: To gather information for a future confirmatory trial of dobutamine (DB) for circulatory impairment (ie, low superior vena cava [SVC] flow). STUDY DESIGN: A total of 127 infants born at < 31 weeks gestational age were serially scanned from birth to 96 hours after birth. The infants were randomly assigned to 2 groups and were treated with DB (stepwise dose increase, 5-10-15-20 µg/kg/min) or placebo if they had an SVC flow < 41 mL/kg/min within the first 24 hours after birth. The primary outcome measures were the achievement and maintenance of an SVC flow ≥ 41 mL/kg/min. Secondary outcome measures were the short-term evolution of clinical and biochemical variables, near-infrared spectroscopy, cranial Doppler ultrasound, and clinical outcomes. RESULTS: SVC flow increased throughout the first 96 hours for the entire cohort. All of the randomized infants (n = 28) except 2 achieved and maintained an SVC flow ≥ 41 mL/kg/min after intervention; however, the infants treated with DB (n = 16) showed a higher heart rate and improved base excess compared with those treated with placebo (n = 12). Low SVC flow was associated with low gestational age (P = .02) and poor condition at birth (P = .02). Low SVC flow significantly increased the risk of severe ischemic events (OR, 13; 95% CI, 2.4-69.2; P < .01). CONCLUSION: This exploratory trial demonstrates a tendency toward improved short-term clinical and biochemical perfusion variable outcomes in infants with low SVC flow treated with DB. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01605279) and the European Clinical Trials Database (EurodraCT 2009-010901-35).

[Tactics of the patients management in continuing acute thrombosis of deep veins].

Experience of active tactics of treatment application in 18 patients, suffering an acute thrombosis in system of lower vena cava, is presented. Possibilities were estimated and efficacy of active surgical tactics proved in continuing deep vein thrombosis on early stage were estimated. Active tactics, using catheter--governed thrombolysis, permits to escape pulmonary thromboembolism and to reduce a severity of further chronic venous insufficiency.

[Hemodynamic mechanisms of the superior and inferior vena cava flow changes following experimental myocardial ischemia].

In acute experiments in anesthetized cats myocardial left ventricular ischemia caused the decreasing of the arterial pressure, cardiac output, superior and inferior vena cava flow and venous return. The diminishing of the superior vena cava flow was caused by the decreasing of the cardiac output, increasing of the vascular resistance and decreasing of the blood flow in the region of the brachiocephalica artery. The inferior vena cava flow decreased following the diminishing of the cardiac output and abdominal aorta blood flow, while vascular resistance in this region did not change. In acute experiments in anesthetized rabbits following myocardial ischemia after the blockade of N-cholinoreceptors the superior and inferior vena cava flow decreased in the same level as in control animals. Following myocardial ischemia after the blockade of α-adrenoreceptors the superior and inferior vena cava flow decreased more significant, than in control animals.

Clinical impact of adenosine triphosphate injection on arrhythmogenic superior vena cava in the context of atrial fibrillation ablation.

BACKGROUND: Superior vena cava (SVC) is an infrequent yet an important source of atrial fibrillation. The clinical impact of ATP injection on arrhythmogenic SVC has not been evaluated. METHODS AND RESULTS: A total of 43 patients (59±11 years; men, 32) who underwent ATP test for arrhythmogenic SVC after the electric isolation at either initial procedure or repeat procedure were included. Pulmonary vein antrum isolation was performed at index procedure in all patients. SVC was isolated after identifying the arrhythmogenicity at index and repeat atrial fibrillation ablation procedure in 34 (79.1%) and 9 (20.9%) patients, respectively. Atrial fibrillation originated from the SVC spontaneously and under isoproterenol infusion in 30 (75.0%) patients, and immediately after ATP injection in 10 (25.0%) patients. Tachycardia persistently confined to SVC was recorded after electric isolation in 13 (30.2%) patients. SVC reconnection was provoked by ATP test in 7 of 36 (19.4%) patients at acute phase. At median 4.0 (2.25-7.5) months after SVC isolation, reconnection was observed in 12 of 15 (80.0%) patients at repeat procedure. Among 12 patients with reconnection at baseline, SVC reconnection was provoked by ATP test after reisolation in 1 (8.3%) patient. Among 3 patients without SVC reconnection at baseline, reconnection was provoked by ATP test at chronic phase in 1 patient. CONCLUSIONS: Dormant conduction between an arrhythmogenic SVC and the right atrium can be exposed by ATP administration both immediately and late after isolation, potentially facilitating detection and ablation for isolation.

Electrophysiological characteristics of canine superior vena cava sleeve preparations: effect of ranolazine.

BACKGROUND: In addition to extrasystoles of pulmonary vein (PV) origin, those arising from the superior vena cava (SVC) can precipitate atrial fibrillation (AF). The present study evaluates the electrophysiological properties of canine SVC sleeve preparations and the effect of ranolazine on late phase 3 early and delayed afterdepolarization (EAD and DAD)-induced triggered activity in SVC sleeves and compares SVC and PV sleeve electrophysiological properties. METHODS AND RESULTS: Action potentials (APs) were recorded from superfused SVC and PV sleeves using microelectrode techniques. Acetylcholine (1 µmol/L), isoproterenol (1 µmol/L), high calcium ([Ca(2+)](o)=5.4 mmol/L), or a combination were used to induce EADs, DADs, and triggered activity. A marked diversity of action potential characteristics was observed in the SVC sleeve, including action potentials with short and long APs, with and without phase 4 depolarization. Rapid pacing induced hyperpolarization, accentuating the slope of phase 4 depolarization. Phase 4 depolarization and rapid pacing-induced hyperpolarization were reduced or eliminated after atropine (10 µmol/L) or ranolazine (10 µmol/L). APs displaying phase 4 depolarization (n=19) had longer APDs, smaller amplitude and V(max), and a more positive take-off potential than APs lacking phase 4 depolarization (n=15). Ranolazine (5-10 µmol/L) eliminated late phase 3 EAD- and DAD-induced triggered activity as well as isoproterenol-induced automaticity elicited in SVC sleeves. Compared with PV, SVC sleeves display phase 4 depolarization, smaller V(max), and longer APs. CONCLUSIONS: Autonomic influences promote spontaneous automaticity and triggered activity in SVC sleeves, thus generating extrasystolic activity capable of initiating atrial arrhythmias. Ranolazine can effectively suppress these triggers.

Left superior vena cava conduction to the left atrium unmasked by adenosine in a patient with paroxysmal atrial fibrillation during pulmonary vein isolation.

The use of adenosine in unmasking potential 'trigger' activity in a patient with paroxysmal atrial fibrillation (AF) and persistent left superior vena cava (LSVC) has never been reported. In a 75-year-old woman with paroxysmal AF and LSVC anomaly, pulmonary vein isolation (PVI) procedure was performed. After successful PVI, repeated bolus adenosine infusions were given. Adenosine response originating from the LSVC was observed: it was reproducible, brief, and exhibited decremental atrial-to-LSVC conduction properties until cessation. Pacing from the LSVC resulted in atrial capture (confirming vein-to-atrium conduction). Disconnection of the LSVC from the coronary sinus (CS) was obtained by successfully ablating within the distal CS. Adenosine challenge may be important to identify AF triggers in non-PVI foci.

Impact of topical cooling solution and prediction of pulmonary graft viability from non-heart-beating donors.

BACKGROUND: Functional assessment of the potentially damaged graft from a non-heart-beating donor (NHBD) is mandatory for successful outcome after transplantation. We investigated the impact of the topical cooling solution on graft preservation and whether inflammatory markers in bronchoalveolar lavage (BAL) can predict pulmonary graft viability in a pig ex vivo lung perfusion model. METHODS: Pigs were euthanized and left untouched for 1 (SAL-1, PER-1) or 3 (SAL-3, PER-3) hours. Topical cooling was done with saline or low-potassium dextran solution (Perfadex) for 1 or 3 hours. In the heart-beating donor control group, the lungs were flushed, explanted and stored for 4 hours. BAL samples were taken from right lungs after explantation and assessed for nitrite, interleukin-8 (IL-8) and protein levels. Left lungs were prepared for ex vivo evaluation. Hemodynamic and oxygenation parameters were measured. RESULTS: Pulmonary vascular resistance (PVR), oxygenation index and Pao(2)/Fio(2) ratio differed significantly between the SAL-3 (42.2 +/- 6.0, 15.9 +/- 3.2 and 148 +/- 14.6 Wood units, respectively) and PER-3 (23.9 +/- 2.7, 6.4 +/- 0.8 and 221.7 +/- 15.06 Wood units, respectively) groups (p < 0.05). BAL IL-8 levels were higher in the SAL-3 group compared with the PER-3 group. BAL nitrite and protein levels were statistically higher in the SAL-3 group (0.98 +/- 0.17 micromol/liter, 728.3 +/- 75.7 microg/ml) than in the PER-3 (0.22 +/- 0.09 micromol/liter, 393.3 +/- 51.1 microg/ml) group (p < 0.05) and correlated with an increase in PVR (r = 0.623, p = 0.001; r = 0.530, p = 0.006, respectively). CONCLUSIONS: After 3 hours of warm ischemia topical cooling with Perfadex resulted in better graft function. Nitrite and protein levels in BAL correlated well with PVR and may therefore be used as a non-invasive marker to predict graft function for NHBDs.

Refractoriness of the sheep superior vena cava myocardial sleeve.

The cardiomyocytes in the superior vena cava (SVC) myocardial sleeve have distinct action potentials and ionic current profiles, but the refractoriness of these cells has not been reported. Using standard intracellular microelectrode techniques, we demonstrated in sheep that the effective refractory period (ERP) of the cardiomyocytes in the SVC (114.7 +/- 6.5 ms) is shorter than that in the inferior vena cava (IVC) (166.7 +/- 6.2 ms), right atrial free wall (RAFW) (201.0 +/- 6.0 ms) and right atrial appendage (RAA) (203.1 +/- 5.8 ms) (P < 0.05). The right atrial cardiomyocyte ERP was heterogeneously shortened by acetylcholine, a muscarinic type 2 receptor (M(2)R) agonist. After perfusion with 15 microM acetylcholine, the shortest ERP occurred in the SVC (the ERP in the SVC, IVC, RAFW and RAA was 53.6 +/- 2.7, 98.9 +/- 2.2, 121.8 +/- 6.0 and 109.7 +/- 5.1 ms, respectively; P < 0.05). Carbachol (1 microM), another M(2)R agonist, produced a similar effect as acetylcholine. Furthermore, we used methoctramine, a M(2)R blocker, 4-DAMP, a muscarinic type 3 receptor (M(3)R) blocker, and tropicamide, a muscarinic type 4 receptor (M(4)R) blocker to inhibit the acetylcholine-induced ERP shortening of SVC cardiomyocytes, and found that the 50% inhibitory concentration for methoctramine, 4-DAMP and tropicamide was 5.91, 45.72 and 80.34 nM, respectively. Therefore, we conclude that the sheep SVC myocardial sleeve is a unique electrophysiological region of the right atrium with the shortest ERP both under physiological condition and under cholinergic agonist stimulation. M(2)R might play a major role in the response of the SVC myocardial sleeve to parasympathetic nerve tone. The association between the distinct refractoriness in SVC and atrial fibrillation originating from the region deserves further investigation.

Pharmacological endothelin receptor interaction does not occur in veins from ET(B) receptor deficient rats.

Heterodimerization of G-protein coupled receptors can alter receptor pharmacology. ET A and ET B receptors heterodimerize when co-expressed in heterologous expression lines. We hypothesized that ET A and ET B receptors heterodimerize and pharmacologically interact in vena cava from wild-type (WT) but not ET B receptor deficient (sl/sl) rats. Pharmacological endothelin receptor interaction was assessed by comparing ET-1-induced contraction in rings of rat thoracic aorta and thoracic vena cava from male Sprague Dawley rats under control conditions, ET A receptor blockade (atrasentan, 10 nM), ET B receptor blockade (BQ-788, 100 nM) or ET B receptor desensitization (Sarafotoxin 6c, 100 nM) and ET A plus ET B receptor blockade or ET A receptor blockade plus ET B receptor desensitization. In addition, similar pharmacological ET receptor antagonism experiments were performed in rat thoracic aorta and vena cava from WT and sl/sl rats. ET A but not ET B receptor blockade or ET B receptor desensitization inhibited aortic and venous ET-1-induced contraction. In vena cava but not aorta, when ET B receptors were blocked (BQ-788, 100 nM) or desensitized (S6c, 100 nM), atrasentan caused a greater inhibition of ET-1-induced contraction. Vena cava from WT but not sl/sl rats exhibited similar pharmacological ET receptor interaction. Immunocytochemistry was performed on freshly dissociated aortic and venous vascular smooth muscle cells to determine localization of ET A and ET B receptors. ET A and ET B receptors qualitatively co-localized more strongly to the plasma membrane of aortic compared to venous vascular smooth muscle cells. Our data suggest that pharmacological ET A and ET B receptor interaction may be dependent on the presence of functional ET B receptors and independent of receptor location.

Low superior vena cava flow and effect of inotropes on neurodevelopment to 3 years in preterm infants.

OBJECTIVE: The goal was to report the 1- and 3-year outcomes of preterm infants with low systemic blood flow in the first day and the effect of dobutamine versus dopamine for treatment of low systemic blood flow. METHODS: A cohort of 128 infants born at <30 weeks of gestation underwent echocardiographic measurement of superior vena cava flow at 3, 10, and 24 hours of age. Forty-two infants with low superior vena cava flow (<41 mL/kg per minute) were assigned randomly to dobutamine or dopamine. Surviving infants underwent blinded neurodevelopmental assessments at corrected ages of 1 and 3 years. RESULTS: Seventy-six of 87 surviving infants were seen at 1 year and 67 at 3 years. Forty-four infants had low superior vena cava flow. At 3 years, with adjustment for perinatal risk factors, death was predicted by low superior vena cava flow, lower gestational age, and low 5-minute Apgar score. Substantial reductions in the Griffiths General Quotient were associated with low superior vena cava flow and birth weight of <10th percentile. Infants with low flow had significant reductions in personal-social, hearing and speech, and performance subscales. Death or disability at 3 years was predicted by low superior vena cava flow and lower gestational age. For infants treated with inotropes, no significant differences were found in clinical outcomes, except for reduced rates of late severe periventricular/intraventricular hemorrhage in the dobutamine group. At 3 years, infants in the dopamine group had significantly more disability and a lower Griffiths General Quotient. At the latest time measured, however, combined rates of death or disability were similar. CONCLUSIONS: Early low superior vena cava flow was associated with substantial rates of death, morbidity, and developmental impairments. No difference was found in combined rates of death and disability for infants assigned randomly to dopamine or dobutamine.

Effects of verapamil on superior vena cava electrical remodeling induced by short-term pacing from right atrium and superior vena cava in human.

BACKGROUND: Although the superior vena cava (SVC) may be involved in the triggering or maintenance of atrial fibrillation (AF), the electrophysiological properties of SVC in human are ill-defined. METHODS: The baseline effective refractory periods (ERPs) of high right atrium (HRA), SVC and the conduction time (CT) between HRA and SVC were measured at pacing cycle lengths (PCL) of 600 and 400 ms respectively in 20 patients (12 females, age 46+/-13 years) with paroxysmal supraventricular tachycardia. Immediately after acute electrical remodeling (ER) induced by constant HRA or SVC pacing at PCL of 400 ms for 5 min, ERPs of HRA, SVC and the CT between HRA and SVC were determined. After verapamil was administered, the same protocols for determining ERPs of HRA, SVC and the CT between HRA and SVC were repeated. RESULTS: The baseline ERP of SVC was significantly longer than that of HRA. The CT from SVC to HRA was significantly longer than that from HRA to SVC. After acute ER, both the ERPs of HRA and SVC were significantly shortened. However, no significant changes of the CT between HRA and SVC could be demonstrated. After verapamil infusion, significant shortening of the ERP of HRA and SVC still occurred following acute ER and the ERP of SVC was still longer than that of HRA. CONCLUSIONS: In human, ER can occur both in HRA and SVC after a short and moderately rapid heart rate pacing either from HRA or SVC. Verapamil cannot prevent such ER from occurring.