Percutaneous coronary intervention in octogenarians with refractory angina.
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Aged↗
Biomedical subjects
K M Channon
Publications and source records attributed to K M Channon.
Traumatic innominate artery transection.
Blunt innominate artery injury is a rare but often lethal complication of severe deceleration trauma. We report the case of a 38-year-old man with such an injury who was successfully operated on an emergency basis. In cases of brachiocephalic vessel trauma, a high index of suspicion in chest deceleration injuries may lead to a proper investigative process and an accurate diagnosis. Clinical signs as blood pressure gradient between the arms and widening of the mediastinum on chest X-ray is highly suggestive of trauma of the thoracic aorta and its great vessels. A chest CT scan may contribute to the diagnosis and can rule out major trauma of the aorta, but the procedure of choice for the definite diagnosis is usually the angiography. Subsequent early repair is favorable to avoid complications and fatal events. Cardiopulmonary bypass use in selected cases favors the outcome.
Accidents, Traffic↗
Nitric oxide synthase (nNOS) gene transfer modifies venous bypass graft remodeling: effects on vascular smooth muscle cell differentiation and superoxide production.
BACKGROUND: Pathological vascular remodeling in venous bypass grafts (VGs) results in smooth muscle cell (SMC) intimal hyperplasia and provides the substrate for progressive atherosclerosis, the principal cause of late VG failure. Nitric oxide (NO) bioactivity is reduced in VGs, in association with increased vascular superoxide production, but how these features relate to pathological VG remodeling remains unclear. We used gene transfer of the neuronal isoform of nitric oxide synthase (nNOS) to investigate how increased NO production modulates vascular remodeling in VGs and determined the effects on late VG phenotype. METHODS AND RESULTS: New Zealand White rabbits (n=60) underwent jugular-carotid interposition bypass graft surgery with intraoperative adenoviral gene transfer of nNOS or beta-galactosidase. Vessels were analyzed after 3 days (early, to investigate acute injury/inflammation) or 28 days (late, to investigate SMC intimal hyperplasia). In early VGs, nNOS gene transfer significantly increased NOS activity and substantially reduced adhesion molecule expression and inflammatory cell infiltration. In late VGs, recombinant nNOS protein was no longer evident, but there were sustained effects on VG remodeling, resulting in a striking reduction in SMC intimal hyperplasia, a more differentiated intimal SMC phenotype, and reduced vascular superoxide production. CONCLUSIONS: Intraoperative nNOS gene transfer has sustained favorable effects on VG remodeling and on the vascular phenotype of mature VGs. These findings suggest that early, transient modification of the response to vascular injury is a powerful approach to modulate VG biology and highlight the potential utility of NOS gene transfer as a therapeutic strategy in VGs.
Adenoviridae↗
Relationship between the G894T polymorphism (Glu298Asp variant) in endothelial nitric oxide synthase and nitric oxide-mediated endothelial function in human atherosclerosis.
Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), plays important roles in normal vascular homeostasis, and reduced endothelial NO bioactivity is an important feature of vascular disease states. The Glu298Asp (G894T) polymorphic variant of eNOS has been associated with vascular disease, but functional data are lacking. Accordingly, we examined the relationships between NO-mediated endothelial function, the presence of the eNOS Glu298Asp variant, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations to different agonists were determined in human saphenous veins obtained from patients with coronary artery disease and identified risk factors (n = 104). Patients were genotyped for the eNOS G894T polymorphism. Nitric oxide-mediated endothelial vasorelaxations were highly variable between patients. Reduced vasorelaxations were associated with increased number of clinical risk factors for atherosclerosis (r = - 0.54, P < 0.001), whereas the Glu298Asp variant was not associated with any differences in contractions to phenylephrine, NO-mediated vasorelaxations to acetylcholine, bradykinin or calcium ionophore, or relaxations to the NO donor sodium nitroprusside. Increased atherosclerotic risk factors, but not the presence of the eNOS Glu298Asp variant, are associated with impaired nitric oxide-mediated endothelial vasomotor function, suggesting that this polymorphism does not have a major direct functional effect on vascular eNOS activity in human atherosclerosis.
Aged↗
Minimally invasive saphenous vein harvesting: effects on endothelial and smooth muscle function.
BACKGROUND: The long saphenous vein remains the commonest conduit used in coronary artery bypass grafting procedures. Surgical trauma during vein harvesting can cause endothelial and smooth muscle injury that has important implications for vein graft longevity. Minimally invasive vein harvesting is advocated to reduce wound morbidity. However, the functional consequences of increased handling and traction, with potentially detrimental effects, remain unknown. METHODS: Forty patients were prospectively randomized into either a minimally invasive (minimal) or traditional (open) saphenous vein harvest group. Smooth muscle contractile function was assessed by responses to potassium chloride and phenylephrine. Endothelial cell function was assessed by responses to serial escalations in concentration of acetylcholine, bradykinin, calcium ionophore, sodium nitroprusside, and N-nitro-L-arginine using isometric tension studies. RESULTS: Harvest times were similar for both groups. The total incision length in the minimal group was significantly shorter than in the open group. There were no differences in smooth muscle contractions to either receptor-independent or receptor-mediated agonists between the two groups. Similarly, vasorelaxation in response to both endothelium-dependent and endothelium-independent agonists were similar in both groups. CONCLUSIONS: Minimally invasive saphenous vein harvesting is associated with similar medial smooth muscle and endothelial function as open harvesting. These findings suggest that minimally invasive harvesting techniques can be used without major detrimental effects on vascular integrity.
Aged↗
A simplified approach to temporary DDD pacing using a single lead, balloon-tipped catheter with overlapping biphasic impulse stimulation.
Temporary DDD pacing offers significant hemodynamic benefits in emergency management of bradyarrhythmias but is underused because of its complexity (two leads) and unreliability. Single lead VDD pacing with atrial sensing via a floating dipole is feasible, but atrial pacing is limited by high thresholds and phrenic nerve stimulation (PNS). Overlapping biphasic impulse (OLBI) stimulation may avoid these problems. The authors designed a single lead balloon-tipped catheter for temporary transvenous DDD pacing, incorporating noncontact atrial dipoles for OLBI stimulation. This catheter was deployed using fluoroscopic guidance in 74 patients (43 men, 31 women) with mean age 56.9 +/- 17.0 years. Pacing parameters were assessed at implantation and follow-up. The median procedural time was 6.6 (range 1.2-25.0) minutes and fluoroscopy time 1.9 (range 0.2-7.8) minutes. Stable VDD pacing was achieved in all cases. Atrial capture was achieved in 73 of 74 cases with both modes at maximum output but was restricted by PNS at outputs below atrial capture threshold in 3 of 74 cases with OLBI and 10 of 74 cases with standard bipolar mode (P = 0.04). At outputs > or = 1.0 V above atrial threshold, reliable DDD pacing without PNS was achieved and maintained in 67 (91%) of 74 patients in OLBI compared to 53 (72%) of 74 patients in bipolar mode (P = 0.003). Pacing parameters were stable during follow-up (median 53 hours, range 6-168 hours). In conclusion, the single lead catheter with OLBI stimulation allows temporary VDD and DDD pacing without PNS to be achieved in > 90% of patients. This rapid and convenient approach should facilitate DDD pacing in emergency settings.
Cardiac Pacing, Artificial↗
Endothelial cell protection against ischemia/reperfusion injury by lecithinized superoxide dismutase.
BACKGROUND: Organs used for transplantation may experience long periods of cold ischemic preservation and consequently oxygen free radical-mediated damage following reperfusion. Lecithinized superoxide dismutase (lec-SOD) is a novel free radical scavenger that has been shown to bind with high affinity to cell membranes. The aim of this study was to determine whether lec-SOD bound to endothelial cells under organ preservation conditions to mediate direct antioxidant activity at the endothelial cell surface and thus offer protection against the harmful effects of ischemia/reperfusion injury. METHODS: An in vitro study was performed on large vessel endothelial cells (HUVEC) and a human microvascular endothelial cell line HMEC-1, to investigate the potential therapeutic benefits of incorporating lec-SOD into organ preservation solution. A cold hypoxia/reoxygenation system was developed to examine lec-SOD binding affinity to endothelial cells, protection against hypoxia/reoxygenation-induced cell death, and neutrophil adhesion. RESULTS: Lec-SOD bound to endothelial cells with higher affinity than unmodified recombinant human superoxide dismutase (rhSOD) and significantly protected both HUVEC and HMEC-1 from cell death following 27 hours of cold hypoxia (P < 0.01). Furthermore, neutrophil adhesion to the endothelium stimulated by hypoxia and reoxygenation was significantly inhibited by treatment with lec-SOD but not by lecithin or rhSOD (P < 0.01). Analysis by flow cytometry demonstrated that E-selectin and ICAM-1 were up-regulated by hypoxia/reoxygenation that was inhibited in part by lec-SOD. CONCLUSIONS: The results from this study suggest that incorporation of lec-SOD into organ preservation solutions provides effective protection to endothelial cells against cold ischemia and reperfusion injury following transplantation.
Antioxidants↗
Reactive oxygen species mediate endothelium-dependent relaxations in tetrahydrobiopterin-deficient mice.
(6R)-5,6,7,8-Tetrahydro-biopterin (H(4)B) is essential for the catalytic activity of all NO synthases. The hyperphenylalaninemic mouse mutant (hph-1) displays 90% deficiency of the GTP cyclohydrolase I, the rate-limiting enzyme in H(4)B synthesis. A relative shortage of H(4)B may shift the balance between endothelial NO synthase (eNOS)-catalyzed generation of NO and reactive oxygen species. Therefore, the hph-1 mouse represents a unique model to assess the effect of chronic H(4)B deficiency on endothelial function. Aortas from 8-week-old hph-1 and wild-type mice (C57BLxCBA) were compared. H(4)B levels were determined by high-performance liquid chromatography and NO synthase activity by [(3)H]citrulline assay in homogenized tissue. Superoxide production by the chemiluminescence method was measured. Isometric tension was continuously recorded. The intracellular levels of H(4)B as well as constitutive NO synthase activity were significantly lower in hph-1 compared with wild-type mice. Systolic blood pressure was increased in hph-1 mice. However, endothelium-dependent relaxations to acetylcholine were present in both groups and abolished by inhibition of NO synthase with N(G)-nitro-L-arginine methyl ester as well. Only in hph-1 mice were the relaxations inhibited by catalase and enhanced by superoxide dismutase. After incubation with exogenous H(4)B, the differences between the 2 groups disappeared. Our findings demonstrate that H(4)B deficiency leads to eNOS dysfunction with the formation of reactive oxygen species, which become mediators of endothelium-dependent relaxations. A decreased availability of H(4)B may favor an impaired activity of eNOS and thus contribute to the development of vascular diseases.
Acetylcholine↗
Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis.
BACKGROUND: Increased superoxide anion production increases oxidative stress and reduces nitric oxide bioactivity in vascular disease states. NAD(P)H oxidase is an important source of superoxide in human blood vessels, and some studies suggest a possible association between polymorphisms in the NAD(P)H oxidase CYBA gene and atherosclerosis; however, no functional data address this hypothesis. We examined the relationships between the CYBA C242T polymorphism and direct measurements of superoxide production in human blood vessels. METHODS AND RESULTS: Vascular NAD(P)H oxidase activity was determined in human saphenous veins obtained from 110 patients with coronary artery disease and identified risk factors. Immunoblotting, reverse-transcription polymerase chain reaction, and DNA sequencing showed that p22phox protein, mRNA, and 242C/T allelic variants are expressed in human blood vessels. Vascular superoxide production, both basal and NADH-stimulated, was highly variable between patients, but the presence of the CYBA 242T allele was associated with significantly reduced vascular NAD(P)H oxidase activity, independent of other clinical risk factors for atherosclerosis. CONCLUSIONS: Association of the CYBA 242T allele with reduced NAD(P)H oxidase activity in human blood vessels suggests that genetic variation in NAD(P)H oxidase components may play a significant role in modulating superoxide production in human atherosclerosis.
Aged↗
Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors.
Superoxide anion plays important roles in vascular disease states. Increased superoxide production contributes to reduced nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of vascular disease. We measured superoxide production by NAD(P)H oxidase in human blood vessels and examined the relationships between NAD(P)H oxidase activity, NO-mediated endothelial function, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations and direct measurements of vascular superoxide production were determined in human saphenous veins obtained from 133 patients with coronary artery disease and identified risk factors. The predominant source of vascular superoxide production was an NAD(P)H-dependent oxidase. Increased vascular NAD(P)H oxidase activity was associated with reduced NO-mediated vasorelaxation. Furthermore, reduced endothelial vasorelaxations and increased vascular NAD(P)H oxidase activity were both associated with increased clinical risk factors for atherosclerosis. Diabetes and hypercholesterolemia were independently associated with increased NADH-dependent superoxide production. The association of increased vascular NAD(P)H oxidase activity with endothelial dysfunction and with clinical risk factors suggests an important role for NAD(P)H oxidase-mediated superoxide production in human atherosclerosis. The full text of this article is available at http://www.circresaha.org.
Acetylcholine↗
Antithrombotic strategies in gene therapy.
Advances in the field of molecular medicine are making gene therapy a viable treatment strategy for the next millennium. Indeed, over the past 10 years, a number of improvements have occurred that have resulted in an increased interest in gene therapy for the treatment of diseases in cardiovascular medicine. Because antithrombotic and anticoagulation therapy generally involves the systemic administration of agents that target a small region of the vasculature, localized and controlled delivery of specific genes could offer enormous potential to treat a number of life-threatening diseases. In addition, gene therapy may allow sustained antithrombotic or anticoagulant treatment when prolonged systemic administration is undesirable. Gene therapy for antithrombotic strategies can involve a number of different approaches. This could include inhibition of coagulation factors, over-expression of anticoagulant factors, or modulation of endothelial biology to make thrombus formation or propagation unfavorable. Preclinical data regarding these different strategies are reviewed and their potential limitations discussed.
Animals↗
Images in cardiology. Emergency DDD pacing using a single lead, balloon tip catheter.
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Aged↗
Nitric oxide synthase in atherosclerosis and vascular injury: insights from experimental gene therapy.
Gene therapy aims to intervene in a disease process by transfer and expression of specific genes in a target tissue or organ. Cardiovascular gene therapy in humans remains in its infancy, but in the last decade, experimental gene transfer has emerged as a powerful biological tool to investigate the function of specific genes in vascular disease pathobiology. Nitric oxide synthases, the enzymes that produce nitric oxide, have received considerable attention as potential candidates for vascular gene therapy because nitric oxide has pleiotropic antiatherogenic actions in the vessel wall, and abnormalities in nitric oxide biology are apparent very early in the atherogenic process. In this article, we review the use of nitric oxide synthases in experimental vascular gene therapy and assess the utility of these approaches for investigating the role of nitric oxide in atherosclerosis and their potential for human gene therapy.
Animals↗
Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits.
BACKGROUND: Hypercholesterolemia reduces nitric oxide bioavailability, manifested by reduced endothelium-dependent vascular relaxation, and also induces vascular adhesion molecule expression and inflammatory cell infiltration. We have previously shown that gene therapy with NO synthase in hypercholesterolemic rabbits substantially reverses the deficit in vascular relaxation. In the present study, we show that NO synthase gene therapy rapidly and substantially reduces vascular adhesion molecule expression, lipid deposition, and inflammatory cell infiltration. METHODS AND RESULTS: Thirty male New Zealand White rabbits were maintained on a 1% cholesterol diet for 11 to 13 weeks, then underwent carotid artery gene transfer with Ad.nNOS or Ad.betaGal (recombinant adenoviruses expressing neuronal NO synthase or beta-galactosidase, respectively), or received medium alone in a sham procedure. Arteries were harvested at 1 and 3 days after gene transfer, and the following parameters were determined by immunohistochemical and image-analysis techniques: intercellular adhesion molecule-1, vascular cell adhesion molecule-1, lipid deposition by oil red O staining, lymphocyte infiltration (CD43-positive cells), and monocyte infiltration (RAM-11-positive cells). In Ad.nNOS-treated arteries, all markers were significantly decreased relative to Ad. betaGal or sham-treated arteries within 3 days after gene transfer. Ad.nNOS had a particularly striking impact on monocyte infiltration; as early as 24 hours after gene transfer, Ad.nNOS-treated arteries had >3-fold fewer monocytes than Ad.betaGal- or sham-treated arteries. CONCLUSIONS: NO synthase gene therapy rapidly ameliorates several markers of atherosclerosis in the cholesterol-fed rabbit.
Animals↗
Echocardiography in stroke and thromboembolism: transoesophageal imaging for all?
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Echocardiography, Transesophageal↗
Giant coronary artery aneurysm presenting as a mediastinal mass.
An asymptomatic mediastinal mass in a 72-year-old man was imaged by computer tomography, magnetic resonance imaging, and coronary arteriography, revealing a giant atheromatous aneurysm of the right coronary artery.
Aged↗
In vivo gene transfer of nitric oxide synthase enhances vasomotor function in carotid arteries from normal and cholesterol-Fed rabbits.
BACKGROUND: The vascular endothelium is anatomically intact but functionally abnormal in preatherosclerotic states, and an early deficit in the bioavailability of nitric oxide (NO) or related molecules has been described in both humans and animal models. We hypothesized that the targeted gene transfer of NO synthase (NOS) isoforms might ameliorate or reverse the deficit. METHODS AND RESULTS: We constructed a recombinant adenovirus, Ad.nNOS, that expresses the neuronal isoform of NOS (nNOS) and used it for in vivo endovascular gene transfer to carotid arteries (CA) from normal and cholesterol-fed rabbits. Vessels were harvested 3 days after gene transfer. In CA from normal rabbits, Ad.nNOS generated high levels of functional nNOS protein predominantly in endothelial cells and increased vascular NOS activity by 3.4-fold relative to sham-infected control CA. Ad.nNOS gene transfer also significantly enhanced endothelium-dependent vascular relaxation to acetylcholine; at 3 micromol/L acetylcholine, Ad.nNOS-treated arteries showed an 86+/-4% reduction in precontracted tension, whereas control CA showed a 47+/-6% reduction in tension. Contraction in response to phenylephrine and relaxation in response to nitroprusside were unaffected in both control and Ad.nNOS-treated CA. To determine the effect of Ad.nNOS in atherosclerotic arteries, 10 male New Zealand White rabbits maintained on a 1% cholesterol diet for 10 to 12 weeks underwent gene transfer according to the same protocol used in normal rabbits. Ad.nNOS-treated arteries showed a 2-fold increase in NADPH-diaphorase staining intensity relative to sham-infected and Ad. betaGal-treated arteries. The CA from cholesterol-fed rabbits showed impaired acetylcholine-induced relaxation, but this abnormality was almost entirely corrected by Ad.nNOS gene transfer. CONCLUSIONS: In vivo adenovirus-mediated endovascular delivery of nNOS markedly enhances vascular NOS activity and can favorably influence endothelial physiology in the intact and atherosclerotic vessel wall.
Animals↗
Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2.
Angiogenesis is required for tumor growth and metastasis, and inhibition of angiogenesis is a promising approach for anticancer therapy. Tie2 (a.k.a Tek) is an endothelium-specific receptor tyrosine kinase known to play a role in tumor angiogenesis. To explore the therapeutic potential of blocking the Tie2 pathway, an adenoviral vector was constructed to deliver a recombinant, soluble Tie2 receptor (AdExTek) capable of blocking Tie2 activation. Two days after i.v. injection of AdExTek, the plasma concentration of ExTek exceeded 1 mg/ml and was maintained for about 8 days. Administration of AdExTek to mice with two different well established primary tumors, a murine mammary carcinoma (4T1) or a murine melanoma (B16F10.9), significantly inhibited the growth rate of both tumors (64% and 47%, respectively). To study the effect of ExTek on tumor metastasis, both tumor cell lines were coinjected i.v. with either AdExTek or a control virus. Mice coinjected with control virus developed numerous large, well vascularized lung metastases. In contrast, mice coinjected with AdExTek virus developed few, if any, grossly apparent metastases, and histologic examination revealed only small avascular clusters of tumor cells. Administration of AdExTek also inhibited tumor metastasis when delivered at the time of surgical excision of primary tumors in a clinically relevant model of tumor metastasis. This study demonstrates the potential utility of gene therapy for systemic delivery of an antiangiogenic agent targeting an endothelium-specific receptor, Tie2.
Adenoviridae↗