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Joseph D Raffetto
European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery 07/2012; 44(4):451. · 2.92 Impact Factor
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ABSTRACT: Infected aortic aneurysms (IAAs) are rare but can have devastating outcomes, particularly if diagnosis and treatment are delayed. The incidence of IAA is between 0.65% and 2% of all aortic aneurysms. The disease has a poor prognosis because these aneurysms have an increased tendency to grow rapidly and to rupture, and patients often have severe comorbidities and coexisting sepsis. Typical microorganisms associated with IAA are Salmonella, Streptococci, and Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus (MRSA) continues to emerge as a cause of serious infections, but its association with IAA is extremely rare. We present a rare case of infected abdominal aortic aneurysm caused by hospital-acquired (HA) MRSA. This case adds another presentation to the clinical spectrum of HA MRSA infections, and it highlights the problems encountered in the choice of the therapy of serious HA or health care-acquired infections in an era of increasing MRSA infections. We will discuss the clinical spectrum of HA MRSA infections as well as the problems encountered in the management of IAA, and will review the relevant literature.
Annals of Vascular Surgery 07/2012; 26(5):732.e1-6. · 1.03 Impact Factor
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ABSTRACT: The vascular endothelium plays a major role in the control of arterial tone; however, its role in venous tissues is less clear. The purpose of this study was to determine the role of endothelium in the control of venous function and the relaxation pathways involved.
Circular segments of inferior vena cava (IVC) from male Sprague-Dawley rats were suspended between two wires and isometric contraction to phenylephrine (Phe; 10(-5)M) and 96 mM KCl was measured. Acetylcholine (Ach; 10(-10) to 10(-5)M) was added and the percentage of venous relaxation was measured. To determine the role of nitric oxide (NO) and prostacyclin (PGI(2)), vein relaxation was measured in the presence of the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME; 3 × 10(-4) M) and the cyclooxygenase inhibitor indomethacin (10(-5) M). To measure the role of hyperpolarization, vein relaxation was measured in the presence of K(+) channel activator cromakalim (10(-11) to 10(-6) M), and the nonselective K(+) channel blocker tetraethylammonium (TEA; 10(-3) M). To test for the contribution of a specific K(+) channel, the effects of K(+) channel blockers: glibenclamide (adenosine triphosphate [ATP]-sensitive K(ATP), 10(-5) M), 4-aminopyridine (4-AP; voltage-dependent K(v), 10(-3) M), apamin (small conductance Ca(2+)-dependent SK(Ca), 10(-7) M), and iberiotoxin (large conductance Ca(2+)-dependent BK(Ca), 10(-8) M) on Ach-induced relaxation were tested.
Ach caused concentration-dependent relaxation of Phe contraction (maximum 49.9 ± 4.9%). Removal of endothelium abolished Ach-induced relaxation. IVC treatment with L-NAME partially reduced Ach relaxation (32.8 ± 4.9%). In IVC treated with L-NAME plus indomethacin, significant Ach-induced relaxation (33.6 ± 3.2%) could still be observed, suggesting a role of endothelium-derived hyperpolarizing factor (EDHF). In IVC treated with L-NAME, indomethacin and TEA, Ach relaxation was abolished, supporting a role of EDHF. In veins stimulated with high KCl, Ach caused relaxation (maximum 59.5 ± 3.5%) that was abolished in the presence of L-NAME and indomethacin suggesting that any Ach-induced EDHF is blocked in the presence of high KCl depolarizing solution, which does not favor outward movement of K(+) ion and membrane hyperpolarization. Cromakalim, an activator of K(ATP), caused significant IVC relaxation when applied alone or on top of maximal Ach-induced relaxation, suggesting that the Ach response may not involve K(ATP). Ach-induced relaxation was not inhibited by glibenclamide, 4-AP, or apamin, suggesting little role of K(ATP), K(v) or SK(Ca), respectively. In contrast, iberiotoxin significantly inhibited Ach-induced relaxation, suggesting a role of BK(Ca).
Thus, endothelium-dependent venous relaxation plays a major role in the control of venous function. In addition to NO, an EDHF pathway involving BK(Ca) may play a role in endothelium-dependent venous relaxation.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 12/2011; 55(6):1716-25. · 3.52 Impact Factor
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ABSTRACT: An isolated external iliac artery chronic total occlusion is currently treated either with subintimal percutaneous transluminal angioplasty and stent or with a bypass. This article describes a new application of an old technique, endarterectomy and patch angioplasty, performed on the external iliac artery through a single flank incision. This novel approach can provide lasting patency with a low risk of complications. We present four cases and a review of the literature on the other available treatment options. This minimally invasive technique may provide a viable alternative that can be used alone or in combination with other open or endovascular techniques and can be applied in cases of groin sepsis.
Annals of Vascular Surgery 11/2011; 25(8):1165-9. · 1.03 Impact Factor
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Luminita H Pojoga,
Jonathan S Williams,
Tham M Yao,
Abhinav Kumar, Joseph D Raffetto,
Graciliano R A do Nascimento,
Ossama M Reslan,
Gail K Adler,
Gordon H Williams,
Yujiang Shi,
Raouf A Khalil
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ABSTRACT: Histone methylation, a determinant of chromatin structure and gene transcription, was thought to be irreversible, but recent evidence suggests that lysine-specific demethylase-1 (LSD1, Kdm1a) induces demethylation of histone H3 lysine 4 (H3K4) or H3K9 and thereby alters gene transcription. We previously demonstrated a human LSD1 phenotype associated with salt-sensitive hypertension. To test the hypothesis that LSD1 plays a role in the regulation of blood pressure (BP) via vascular mechanisms and gene transcription, we measured BP and examined vascular function and endothelial nitric oxide (NO) synthase (eNOS) expression in thoracic aorta of male wild-type (WT) and heterozygous LSD1 knockout mice (LSD1(+/-)) fed either a liberal salt (HS; 4% NaCl) or restricted salt diet (LS; 0.08% NaCl). BP was higher in LSD1(+/-) than WT mice on the HS diet but not different between LSD1(+/-) and WT mice on the LS diet. Further examination of the mechanisms of this salt-sensitive hypertension in LSD1(+/-) mice on the HS diet demonstrated that plasma renin activity and plasma levels and urinary excretion of aldosterone were less in LSD1(+/-) than WT, suggesting suppressed renin-angiotensin-aldosterone system. In contrast, phenylephrine (Phe)-induced aortic contraction was greater in LSD1(+/-) than WT mice on the HS diet. Treatment of aortic rings with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a blocker of guanylate cyclase) enhanced Phe contraction in LSD1(+/-) compared with WT mice on the HS diet. Acetylcholine (Ach)-induced relaxation was less in LSD1(+/-) than WT mice on the HS diet. Endothelium removal or pretreatment with N(ω)-nitro-L-arginine methyl ester (blocker of NOS) or ODQ abolished Ach-induced relaxation in aorta of WT but had minimal effect in LSD1(+/-). Vascular relaxation to sodium nitroprusside, an exogenous NO donor and guanylate cyclase activator, was decreased in LSD1(+/-) vs. WT mice on the HS diet. RT-PCR and Western blots revealed decreased eNOS mRNA expression and eNOS and guanylate cyclase protein in the heart and aorta of LSD1(+/-) compared with WT mice on HS diet. Thus, during the HS diet, LSD1 deficiency is associated with hypertension, enhanced vascular contraction, and reduced relaxation via NO-cGMP pathway. The data support a role for LSD1-mediated histone demethylation in the regulation of NOS/guanylate cyclase gene expression, vascular function, and BP during the HS diet.
AJP Heart and Circulatory Physiology 08/2011; 301(5):H1862-71. · 3.71 Impact Factor
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ABSTRACT: Saponosides (horse chestnut seed extract, escin) and flavonoids (diosmin, Daflon 500, Servier, France) exhibit venotonic properties that have been utilized in treatment of varicose veins. However, the cellular mechanisms underlying the venotonic properties of escin and diosmin are unclear. Because Ca(2+) is a major regulator of venous smooth muscle (VSM) function, we tested the hypothesis that escin and diosmin promote Ca(2+)-dependent venous contraction.
Rings of inferior vena cava (IVC) from male rats were suspended in a tissue bath for measurement of isometric contraction. Following control contraction to 96 mM KCl, the effects of escin and diosmin (10(-10) to 10(-4) M) on vein contraction were measured. To test the role of intracellular Ca(2+) release, the vein response to escin and diosmin was measured in Ca(2+)-free (2mM EGTA) Krebs. To test for Ca(2+)-dependent effects, IVC segments were pretreated with escin or diosmin (10(-4) M) in 0 Ca(2+) Krebs, then extracellular CaCl(2) (0.1, 0.3, 0.6, 1, 2.5 mM) was added and the [Ca(2+)](e)-contraction relationship was constructed. To test for synergistic effects of diosmin, IVC segments were pretreated with diosmin (10(-4) M), then stimulated with KCl (16-96 mM) or escin (10(-10) to 10(-4) M) and vein contraction was measured. Contraction data were presented as mg/mg tissue (means ± SEM).
In IVC segments incubated in normal Krebs (2.5 mM Ca(2+)), escin caused concentration-dependent contraction (max 104.3 ± 19.6 at 10(-4) M). Escin-induced contraction was not a rigor state, because after washing with Krebs, the veins returned to a relaxed state. In Ca(2+)-free Krebs, there was essentially no contraction to escin. In escin-treated veins incubated in 0 Ca(2+) Krebs, stepwise addition of extracellular CaCl(2) caused corresponding increases in contraction (max 80.0 ± 11.1 at 2.5 mM). In the absence of escin, the α-adrenergic agonist phenylephrine (PHE, 10(-5) M), angiotensin II (AngII, 10(-6) M), and membrane depolarization by KCl (96 mM) caused significant contraction (122.5 ± 45.1, 114.2 ± 12.2 and 221.7 ± 35.4, respectively). In IVC segments pretreated with escin (10(-4) M), the contractile response to PHE (9.7 ± 2.6), AngII (36.0 ± 9.1), and KCl (82.3 ± 10.2) was significantly reduced. Diosmin (10(-4) M) caused small contractions in normal Krebs (11.7 ± 1.9) and Ca(2+)-free Krebs (4.2 ± 2.2). In diosmin-treated veins incubated in 0 Ca(2+) Krebs, addition of extracellular CaCl(2) caused minimal contraction. Diosmin did not enhance the IVC contraction to PHE, AngII, or escin, but enhanced the contractile response to KCl (24-51 mM).
In rat IVC, escin induces extracellular Ca(2+)-dependent contraction, but disrupts α-adrenergic and AT(1)R receptor-mediated pathways and depolarization-induced contraction. The initial venotonic benefits of escin may be offset by disruption of vein response to endogenous venoconstrictors, limiting its long-term therapeutic benefits in varicose veins. Diosmin does not cause venous contraction or potentiate the venotonic effects of endogenous venoconstrictors or escin ex vivo, and its use as venotonic may need to be further evaluated.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 04/2011; 54(2):489-96. · 3.52 Impact Factor
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ABSTRACT: Decreased venous tone and vein wall dilation may contribute to varicose vein formation. We have shown that prolonged vein wall stretch is associated with upregulation of matrix metalloproteases (MMPs) and decreased contraction. Because hypoxia-inducible factors (HIFs) expression also increases with mechanical stretch, this study tested whether upregulation of HIFs is an intermediary mechanism linking prolonged vein wall stretch to the changes in MMP expression and venous contraction.
Segments of rat inferior vena cava (IVC) were suspended in tissue bath under 0.5-g basal tension for 1 hour, and a control contraction to phenylephrine (PHE, 10(-5)M) and KCl (96 mM) was elicited. The veins were then exposed to prolonged 18 hours of tension at 0.5 g, 2 g, 2 g plus HIF inhibitor U0126 (10(-5)M), 17-[2-(dimethylamino)ethyl] amino-17-desmethoxygeldanamycin (17-DMAG, 10(-5)M), or echinomycin (10(-6)M), or 2 g plus dimethyloxallyl glycine (DMOG; 10(-4)M), a prolyl-hydroxylase inhibitor that stabilizes HIF. The fold-change in PHE and KCl contraction was compared with the control contraction at 0.5-g tension for 1 hour. Vein tissue homogenates were analyzed for HIF-1α, HIF-2α, MMP-2, and MMP-9 messenger RNA (mRNA) and protein amount using real-time reverse transcription polymerase chain reaction and Western blots.
Compared with control IVC contraction at 0.5-g tension for 1 hour, the PHE and KCl contraction after prolonged 0.5-g tension was 2.0 ± 0.35 and 1.1 ± 0.06, respectively. Vein contraction to PHE and KCl after prolonged 2-g tension was significantly reduced (0.87 ± 0.13 and 0.72 ± 0.05, respectively). PHE-induced contraction was restored in IVC exposed to prolonged 2-g tension plus the HIF inhibitor U0126 (1.38 ± 0.15) or echinomycin (1.99 ± 0.40). U0126 and echinomycin also restored KCl-induced contraction in IVC exposed to prolonged 2-g tension (1.14 ± 0.05 and 1.11 ± 0.15, respectively). Treatment with DMOG further reduced PHE- and KCl-induced contraction in veins subjected to prolonged 2-g tension (0.47 ± 0.06 and 0.57 ± 0.01, respectively). HIF-1α and HIF-2α mRNA were overexpressed in IVC exposed to prolonged 2-g tension, and the overexpression was reversed by U0126. The overexpression of HIF-1α and HIF-2α in stretched IVC was associated with increased MMP-2 and MMP-9 mRNA. The protein amount of HIF-1α, HIF-2α, MMP-2, and MMP-9 was also increased in IVC exposed to prolonged 2-g wall tension.
Prolonged increases in vein wall tension are associated with overexpression of HIF-1α and HIF-2α, increased MMP-2 and MMP-9 expression, and reduced venous contraction in rat IVC. Together with our report that MMP-2 and MMP-9 inhibit IVC contraction, the data suggest that increased vein wall tension induces HIF overexpression and causes an increase in MMP expression and reduction of venous contraction, leading to progressive venous dilation and varicose vein formation.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 03/2011; 53(3):764-73. · 3.52 Impact Factor
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ABSTRACT: The pathophysiology of venous dermal abnormality in chronic venous ulcers is reflective of a complex interplay that involves sustained venous hypertension, inflammation, changes in the microcirculation, cytokine and matrix metalloproteinase activation, and altered cellular function. Red blood cells and macromolecules extravasate into the interstitium and activate endothelial cells. Endothelial expression of specific adhesion molecules recruits leukocytes and causes diapedesis of these cells into the dermal microvasculature, promoting an inflammatory response with activation of cytokines and proteinases. Altered cell function enhances a state of vulnerability in the surrounding tissues, initiating specific changes associated with venous disease. Ultimately, the persistent inflammatory-proteinase activity leads to advanced chronic venous insufficiency and ulcer formation. The mainstay of therapy in venous ulcer abnormality is correction of the underlying venous hypertension through compression therapy and/or surgery. Understanding the science involved in the pathophysiology of venous ulcer formation has led to the development of adjunctive treatment directed at the dysregulated molecular pathways. Randomized clinical trials are critical for determining the most effective evidence-based treatments for venous ulcer, and this review discusses important trials that have had a significant impact on venous ulcer healing. In addition, the authors have included subsections referred to as "Translational Implications for Therapy" in the basic science sections of the review to help bridge the basic science knowledge with clinical applications that may help to modulate the molecular abnormalities in the pathophysiologic cascade leading to venous ulcers.
Plastic and reconstructive surgery 01/2011; 127 Suppl 1:279S-288S. · 2.74 Impact Factor
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ABSTRACT: Sarcomas of the large vessels usually present centrally in the aorta, pulmonary artery, and inferior vena cava. Peripheral arterial sarcomas are exceptionally rare. They have been reported in the iliac and common or profunda femoral arteries, and are frequently undifferentiated. In this study, we describe a differentiated intimal sarcoma of the superficial femoral artery with abundant osteosarcoma within the specimen. Before knowing the diagnosis, treatment was for a presumed pseudoaneurysm using excision and bypass. Postoperatively, the patient received palliative radiation therapy. The tumor's location and histopathology are unique. A differentiated intimal sarcoma has never been reported in the superficial femoral artery, and it represents the second peripheral arterial intimal sarcoma reported with osteosarcomatous differentiation.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 01/2011; 53(5):1394-7. · 3.52 Impact Factor
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ABSTRACT: Aneurysms of the extracranial carotid arteries are rare and account for 0.4-1% of all arterial aneurysms and about 4% of all peripheral arterial aneurysms. Causes include atherosclerosis, fibromuscular dysplasia, trauma (penetrating and blunt cervical trauma and hyperextension of the neck), iatrogenic lesions, infection, congenital defects, and irradiation arteritis. Atherosclerosis is responsible for 46-70% of all carotid artery aneurysms. The most frequent site of carotid artery aneurysms is the common carotid artery, particularly at its bifurcation and proximal internal carotid artery (ICA). The middle and distal portions of the ICA are the next most common sites. Aneurysms at the point of bifurcation are usually fusiform, whereas those located in the middle and distal portions of the ICA are usually saccular. This uncommon but interesting vascular disorder usually presents as a parapharyngeal pulsatile mass. It can be partially or completely thrombosed and thereby cause embolization or compression of neurovascular structures, with ruptures and ischemic events as other complications. Surgical treatment of extracranial carotid aneurysms is required in most cases, to avert disastrous consequences. Conservative management of extracranial ICA aneurysms has resulted in a mortality rate of nearly 71%. Nonoperative treatment is generally indicated in young patients who have nonpenetrating traumatic and spontaneously dissecting aneurysms. However, when anticoagulation therapy fails or when persistent neurologic symptoms or progressive expansion of the aneurysm occurs, surgical repair is indicated.
Annals of Vascular Surgery 07/2010; 24(5):691.e11-6. · 1.03 Impact Factor
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ABSTRACT: Varicose veins (VarVs) are a common disorder of venous dilation and tortuosity with unclear mechanism. The functional integrity and the ability of various regions of the VarVs to constrict is unclear. This study tested the hypothesis that the different degrees of venodilation in different VarV regions reflect segmental differences in the responsiveness to receptor-dependent vasoconstrictive stimuli and/or in the postreceptor signaling mechanisms of vasoconstriction.
Varix segments and adjacent proximal and distal segments were obtained from patients undergoing VarV stripping. Control great saphenous vein specimens were obtained from patients undergoing lower extremity arterial bypass and coronary artery bypass grafting. Circular vein segments were equilibrated under 2 g of tension in a tissue bath, and changes in isometric constriction in response to angiotensin II (AngII, 10(-11)-10(-7) M), phenylephrine (PHE, 10(-9)-10(-4) M), and KCl (96 mM) were recorded. The amount of angiotensin type 1 receptor (AT(1)R) was measured in vein tissue homogenate.
AngII caused concentration-dependent constriction in control vein (max 35.3 +/- 9.6 mg/mg tissue, pED(50) 8.48 +/- 0.34). AngII caused less contraction and was less potent in proximal (max 7.9 +/- 2.5, pED(50) 6.85 +/- 0.61), distal (max 5.7 +/- 1.2, pED(50) 6.74 +/- 0.68), and varix segments of VarV (max 7.2 +/- 2.0, pED(50) 7.11 +/- 0.50), suggesting reduced AT(1)R-mediated contractile mechanisms. VarVs and control veins had similar amounts of AT(1)R. alpha-adrenergic receptor stimulation with PHE caused concentration-dependent constriction in control veins (max 73.0 +/- 13.9 mg/mg tissue, pED(50) 5.48 +/- 0.12) exceeding that of AngII. PHE produced similar constriction and was equally potent in varix and distal segments but produced less constriction and was less potent in proximal segments of VarVs (max 32.1 +/- 6.4 mg/mg tissue, pED(50) 4.89 +/- 0.13) vs control veins. Membrane depolarization by 96 mM KCl, a receptor-independent Ca(2+)-dependent response, produced significant constriction in control veins and similar contractile response in proximal, distal, and varix VarV segments, indicating tissue viability and intact Ca(2+)-dependent contraction mechanisms.
Compared with control veins, different regions of VarV display reduced AngII-mediated venoconstriction, which may be involved in the progressive dilation in VarVs. Postreceptor Ca(2+)-dependent contraction mechanisms remain functional in VarVs. The maintained alpha-adrenergic responses in distal and varix segments, and the reduced constriction in the upstream proximal segments, may represent a compensatory adaptation of human venous smooth muscle to facilitate venous return from the dilated varix segments of VarV.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 04/2010; 51(4):962-71. · 3.52 Impact Factor
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ABSTRACT: A greater incidence of varicose veins has been reported in premenopausal women than in men. We hypothesized that the sex differences in venous function reflect reduced constriction and enhanced venous dilation in women due to direct venous relaxation effects of estrogen on specific estrogen receptors (ER).
Circular segments of inferior vena cava (IVC) from male and female Sprague-Dawley rats were suspended between two wires, and isometric contraction (in mg/mg tissue) to phenylephrine, angiotensin II (AngII), and 96 mM KCl was measured. To investigate sex differences in venous smooth muscle, Ca(2+) release from the intracellular stores, and Ca(2+) entry from the extracellular space, the transient phenylephrine contraction in 0 Ca(2+) Krebs was measured. Extracellular CaCl(2) (0.1, 0.3, 0.6, 1, 2.5 mM) was added, and the [Ca(2+)](e)-dependent contraction was measured. To investigate sex differences in venous endothelial function, acetylcholine-induced relaxation was measured. To test the role of specific ERs, the amount of venous tissue ERs was measured using Western blots, and the venous relaxation in response to 17beta-estradiol (E2, activator of most ERs), 4,4,'4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT; ERalpha agonist), 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; ERbeta agonist), and ICI 182,780 (ERalpha/ERbeta antagonist, and G protein-coupled receptor 30 [GPR30] agonist) was measured in IVC segments nontreated or treated with the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME).
Phenylephrine caused concentration-dependent contraction that was less in female (max 104.2 +/- 16.2) than male IVC (172.4 +/- 20.4). AngII (10(-6))-induced contraction was also less in female (81.0 +/- 11.1) than male IVC (122.5 +/- 15.0). Phenylephrine contraction in 0 Ca(2+) Krebs was insignificantly less in female (4.8 +/- 1.8) than male IVC (7.2 +/- 1.7), suggesting little difference in the intracellular Ca(2+) release mechanism. In contrast, the [Ca(2+)](e)-dependent contraction was significantly reduced in female than male IVC. Also, contraction to membrane depolarization by 96 mM KCl, which stimulates Ca(2+) influx, was less in female (129.7 +/- 16.7) than male IVC (319.7 +/- 30.4), supporting sex differences in Ca(2+) entry. Acetylcholine relaxation was greater in female (max 80.6% +/- 4.1%) than male IVC (max 48.0% +/- 6.1%), suggesting sex differences in the endothelium-dependent relaxation pathway. Western blots revealed greater amounts of ERalpha, ERbeta, and GPR30 in female than male IVC. ER agonists caused concentration-dependent relaxation of phenylephrine contraction in female IVC. E2-induced relaxation (max 76.5% +/- 3.4%) was more than DPN (74.8% +/- 9.1%), PPT (71.4% +/- 12.5%), and ICI 182,780 (67.4% +/- 7.8%), and was similar in L-NAME-treated and nontreated IVC.
The reduced alpha-adrenergic, AngII, depolarization-induced, and [Ca(2+)](e)-dependent venous contraction in female rats is consistent with sex differences in the Ca(2+) entry mechanisms, possibly due to enhanced endothelium-dependent vasodilation and increased ER expression/activity in female rats. E2/ER-mediated venous relaxation in female rats is not prevented by NOS blockade, suggesting activation of an NO-independent relaxation pathway. The decreased venous contraction and enhanced E2/ER-mediated venous relaxation would lead to more distensible veins in female rats.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 04/2010; 51(4):972-81. · 3.52 Impact Factor
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ABSTRACT: A significant portion of patients undergoing lower extremity bypass surgery (LEB) for peripheral arterial disease (PAD) will have cardiovascular or graft-related events. It has been previously demonstrated that systemic inflammation is associated with PAD and its clinical outcomes. We hypothesized that serum biomarkers of insulin resistance and inflammation would identify a subgroup at elevated risk for graft failure, limb loss, and mortality.
This was a prospective longitudinal study of patients (n = 225) undergoing LEB using autogenous vein. Baseline blood samples were obtained prior to surgery in the fasting state. High-sensitivity C-reactive protein (hsCRP) and the adipokines resistin and high-molecular weight adiponectin (HMWA) were measured by enzyme-linked immunosorbent assay (ELISA). Median follow-up was 893 days. The major endpoints of primary patency (PP) and amputation-free survival (AFS) were examined using multivariable methods. Endpoints were screened against biomarkers and patient characteristics for univariate associations. Promising explanatory variables (P < .1) were included in multivariable Cox proportional hazard models.
The mean age of subjects was 67.6 years; 71.6% were male and 87.1% were Caucasian. One hundred thirty-three (59.1%) subjects underwent bypass for critical limb ischemia (CLI) and 73 (32.4%) had tissue loss. Patients with CLI and diabetes demonstrated elevated resistin and hsCRP levels. HMWA levels correlated with CLI and with a measure of insulin resistance (HOMA-IR) but not with clinical diabetes. Baseline biomarkers were higher in those presenting with tissue loss and in patients with postoperative events (mortality, limb loss). After multivariable analysis (including CLI, diabetes, age, estimated glomerular filtration rate [eGFR], adiponectin, resistin, and CRP), resistin (hazard ratio [HR] 1.75, 95% confidence interval [CI], 1.07-2.85; P = .025) and CRP (HR 2.39, 95% CI, 1.30-4.39; P = .005) were independently predictive of reduced AFS. However, only resistin maintained its significance when restricted to the diabetic cohort (HR 2.10, 95% CI, 1.10-3.99; P = .025). Higher levels of HMWA were found to be associated with primary graft patency (HR 0.73 for graft failure; 95% CI, 0.55 to 0.97; P = .031) in a multivariable model adjusting for diabetes, CRP, African-American race, CLI, high-risk conduits, and redo bypass procedures.
These findings suggest that serum biomarkers of insulin resistance and inflammation may be predictive of clinical outcomes following LEB. Improving the systemic milieu of insulin resistance and inflammation in these high-risk patients may lead to reduced morbidity and mortality.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 03/2010; 51(5):1152-9. · 3.52 Impact Factor
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New England Journal of Medicine 01/2010; 362(1):66. · 53.30 Impact Factor
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Joseph D Raffetto
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ABSTRACT: The pathophysiology of venous dermal pathology in chronic venous disease (CVD) is reflective of a complex interplay that involves sustained venous hypertension, inflammation, cytokine and matrix metalloproteinase (MMP) activation, and altered cellular function. Endothelial expression of specific adhesion molecules recruits leukocytes, and diapedesis of these cells into the dermal microvasculature promotes an inflammatory response with activation of cytokines and proteinases. Altered cell function enhances a state of vulnerability in the surrounding tissues initiating specific changes associated with venous disease. Ultimately, the persistent inflammatory-proteinase activity leads to advanced chronic venous insufficiency (CVI) and ulcer formation.
Thrombosis Research 01/2009; 123 Suppl 4:S66-71. · 2.44 Impact Factor
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ABSTRACT: Hybrid procedures combine endovascular and open surgical techniques. We examined utilization rates and ways of performing them more efficiently.
Hybrids were selected using codes for femoral endarterectomy, infrainguinal, or aorto-iliac-femoral bypass and angioplasty from Nationwide Inpatient Sample (NIS) data, then categorized as staged, or performed on the same day. Outcomes included utilization rates, total hospital charges, and length of stay (LOS). Confounders of charges and LOS were identified and excluded from final comparisons.
Utilization increased 7% from 2000 to 2004. Univariate associations linked staging to variables included in linear regressions for hospital charges and LOS. Excluding identified confounders from the final subgroup analysis still showed large differences in charges (same-day = $34,206, staged = $60,087) and LOS (same-day = 3 days, staged = 7 days).
Utilization of hybrids is increasing. Performing hybrids on the same day, if possible, greatly reduces hospital charges and LOS, emphasizing preadmission planning and simultaneous coordination of both portions.
American journal of surgery 12/2008; 196(5):634-40. · 2.36 Impact Factor
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ABSTRACT: Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of varicose veins. We have shown that MMP-2 causes relaxation of venous segments and suggested a role of venous smooth muscle (VSM) hyperpolarization; however, the downstream mechanisms are unclear. We tested whether MMP-2 induced venous relaxation involves inhibition of the Ca(2+) mobilization mechanisms of VSM contraction due to generation of Arg-Gly-Asp (RGD)-containing peptides.
Circular segments of inferior vena cava (IVC) were isolated from male Sprague-Dawley rats, suspended between two wires in a tissue bath, and isometric contraction was measured. Contraction data in mg/mg tissue were presented as means +/- SEM.
In IVC incubated in normal Krebs (2.5 mM Ca(2+)), the alpha-adrenergic agonist phenylephrine (Phe, 10(-5) M) caused initial peak (133.2 +/- 17.5) followed by a maintained contraction (73.4 +/- 11.6), that was inhibited by MMP-2 (1 microg/mL) to 32.4 +/- 12.8 in 30 min. The inhibitory effects of MMP-2 were reversible by washing the tissue with Krebs or in the presence of the MMP inhibitors TIMP-1 (1 microg/mL), Ro 28-2653, and BB-94 (10(-6) M), and were not associated with changes in IVC structure, demonstrating specificity. Angiotensin II (AngII, 10(-6) M) caused a monophasic contraction (114.2 +/- 12.2), that was also inhibited by MMP-2 (66.0 +/- 7.4), suggesting a post-receptor effect on the downstream mechanisms of VSM contraction. To test the role of Ca(2+) release from the sarcoplasmic reticulum, IVC was incubated in Ca(2+)-free 2 mM ethylene glycol-bis(2-aminoethyl ether-N,N,N',N'-tetra-acetic acid (EGTA) Krebs with or without MMP-2. In Ca(2+)-free Krebs, caffeine did not cause contraction, suggesting a limited role of the Ca(2+)-induced Ca(2+)-release mechanism, and Phe and AngII caused a small contraction (7.2 +/- 1.7 and 14.9 +/- 2.8) that was slightly increased by MMP-2 (10.4 +/- 3.0 and 33.8 +/- 10.0), suggesting little effect on IP(3)-induced Ca(2+) release. To test the role of Ca(2+) entry through membrane channels, after eliciting a transient Phe contraction in nominally 0 Ca(2+) Krebs, increasing concentrations of CaCl(2) (0.1, 0.3, 0.6, 1, 2.5 mM) were added and the extracellular Ca(2+) concentration [Ca(2+)](e)-contraction relationship was constructed. The [Ca(2+)](e)-contraction relation was reduced in MMP-2 treated IVC, suggesting inhibition of Ca(2+) entry. In IVC treated with MMP-2, the Ca(2+) channel blocker diltiazem (10(-5)M) did not cause any further inhibition of Phe contraction, suggesting that Ca(2+) entry is already inhibited by MMP-2. To test whether MMP-2 actions involve generation of RGD and modulation of integrin receptors, experiments where repeated in IVC segments saturated with RGD (10(-5) M), or pretreated with the alpha(v)beta(3) integrin blocker cyclo(Ala-Arg-Gly-Asp-3-aminomethylbenzoyl) (cyclo-RGD). RGD-peptide caused only small relaxation of Phe contracted IVC (6.4 +/- 3.4%), and addition of MMP-2 to RGD-treated IVC caused further relaxation (69.7 +/- 3.0%). Pretreatment of IVC with cyclo-RGD did not significantly affect MMP-2 induced relaxation (55.0 +/- 5.0%).
In rat IVC, MMP-2 attenuates [Ca(2+)](e)-dependent VSM contraction without affecting Ca(2+) release from intracellular Ca(2+) stores. MMP-2 induced VSM relaxation may not involve RGD generation or activation of alpha(v)beta(3) integrin receptor. MMP-2 induced inhibition of the Ca(2+) entry mechanism of VSM contraction may play a role in the venous dilation associated with varicose vein formation.
Journal of Surgical Research 11/2008; 159(2):755-64. · 2.25 Impact Factor
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ABSTRACT: Increased venous hydrostatic pressure plays a role in the pathogenesis of varicose veins. Increased expression of matrix metalloproteinases (MMPs) has been identified in varicose veins. Also, we have shown that MMP-2 inhibits venous contraction. However, the relation between venous pressure, MMP expression, and venous dysfunction is unclear. The purpose of this study was to test the hypothesis that prolonged increases in venous wall tension cause overexpression of MMPs and decreased contractility, which in turn promote venous dilation.
Circular segments of inferior vena cava (IVC) were isolated from male Sprague-Dawley rats and suspended between two wires in Krebs solution. Preliminary vein wall tension-contraction relation showed maximal potassium chloride (KCl) (96 mmol/L) contraction at 0.5 g basal tension, which remained steady with increases in tension up to 2 g. Vein segments were subjected to either control (0.5 g) or high (2 g) basal tension for short (1 hour) or long duration (24 hours). Isometric contraction in response to phenylephrine (Phe, 10(-5) mol/L), angiotensin II (AngII, 10(-6) mol/L), and KCl was measured. The veins were frozen to determine the expression and localization of MMPs using immunoblots and immunohistochemistry.
In IVC segments subjected to 0.5 g tension for 1 hour, Phe and AngII produced significant contraction. At higher 2 g basal tension for 24 hours, both Phe and AngII contractions were significantly reduced. Reduction in KCl contraction was also observed at high 2 g basal tension for 24 hours, suggesting that the reduction in vein contraction is not specific to a particular receptor, and likely involves inhibition of a post-receptor contraction mechanism. In vein segments under 2 g tension for 24 hours and treated with TIMP-1, Phe, AngII, and KCl contractions were partially restored, suggesting the involvement of MMPs. IVC immunoblot analysis demonstrated prominent bands corresponding to MMP-2 and MMP-9 protein. High 2 g wall tension for 24 hours was associated with marked increase in the amount of MMP-2 and -9 relative to the housekeeping protein actin. There was a correlation between MMP expression and decreased vein contraction. Also, significant increases in MMP-2 and -9 immunostaining were observed in IVC segments subjected to high 2 g tension for 24 hours. Both MMP-2 and MMP-9 caused significant inhibition of Phe contraction in IVC segments.
In rat IVC, increases in magnitude and duration of wall tension is associated with reduced contraction and overexpression of MMP-2 and -9. In light of our findings that MMP-2 and -9 promote IVC relaxation, the data suggest that protracted increases in venous pressure and wall tension increase MMPs expression, which in turn reduce venous contraction and lead to progressive venous dilation.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 09/2008; 48(2):447-56. · 3.52 Impact Factor
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ABSTRACT: Matrix metalloproteinases (MMPs) play a major role in extracellular matrix (ECM) turnover under both physiological and pathological conditions. Studies on venous tissues from experimental animals and humans identified several MMP subtypes, and showed significant changes in the expression and activity of specific MMPs during vein wall remodeling. Also, significant research has focused on the role of MMPs in chronic venous disease (CVD) and varicose vein formation in the lower extremities and their progression to thrombophlebitis and venous leg ulcer. Several hypotheses have been forwarded regarding the pathophysiological mechanisms underlying the relation between MMPs and the formation, progression and complications of varicose veins. The effects of MMPs on ECM degradation could result in significant venous tissue remodeling and degenerative and structural changes in the vein wall, leading to venous dilation and valve dysfunction. MMPs may also induce early changes in the endothelium and venous smooth muscle function in the absence of significant ECM degradation or structural changes in the vein wall. In addition, evidence suggests increased activity of MMPs in the advanced stages of chronic venous insufficiency (CVI) associated with skin changes and leg ulceration as well as in the wound fluid environment. Several pharmacological therapies and surgical strategies are being utilized in the management of varicose veins, with variable success and recurrence rates. Inhibition of MMPs may represent a novel therapeutic intervention to limit the progression of varicose veins to CVI and leg ulceration.
Current Vascular Pharmacology 08/2008; 6(3):158-72. · 2.90 Impact Factor
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ABSTRACT: Venous ulcer fibroblasts (w-fb) have attenuated growth compared to normal fibroblasts (n-fb). The MAPKp38 pathway mediates stress-responses in various diseases. We hypothesize that p38 pathway is altered in w-fb.
W-fb were isolated from venous ulcers and n-fb from the ipsilateral thigh. Fibroblasts were analyzed for phosphorylated p38 using immunoblot. The relation between p38 and w-fb proliferation was assessed with SB203580 (p38 inhibitor). Fibroblasts were treated with bFGF, TNF-a, and IL-1 and p38 expression analyzed.
Phosphorylated p38 expression was increased in w-fb (AU%=233.5+/-59.7, P=0.039) compared to n-fb (AU%=99.9+/-14.6). W-fb treated with SB203580 demonstrated increased growth compared to untreated w-fb. W-fb treated with bFGF demonstrated decreased p38. TNF-alpha and IL-1beta significantly increase p38 expression.
MAPK p38 is up-regulated in w-fb. Regulation of w-fb proliferation is influenced by p38. Altering the p38 pathway in vivo with growth factors or cytokine inhibition may improve fibroblast proliferation and venous ulcer healing.
Vascular and Endovascular Surgery 07/2008; 42(4):367-74. · 0.99 Impact Factor
