90 results on '"Selwyn AP"'
Search Results
2. Effect of intensive lipid lowering, with or without antioxidant vitamins, compared with moderate lipid lowering on myocardial ischemia in patients with stable coronary artery disease: the Vascular Basis for the Treatment of Myocardial Ischemia Study.
- Author
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Stone PH, Lloyd-Jones DM, Kinlay S, Frei B, Carlson W, Rubenstein J, Andrews TC, Johnstone M, Sopko G, Cole H, Orav J, Selwyn AP, Creager MA, Vascular Basis Study Group, and Burke GL
- Published
- 2005
Catalog
3. Equalization of right- and left-sided intracardiac pressures: is it constriction?
- Author
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Campbell P, Leopold JA, Selwyn AP, and Sisto D
- Subjects
- Aged, Blood Pressure, Heart Failure therapy, Humans, Male, Heart Failure physiopathology, Heart Ventricles physiopathology
- Published
- 2011
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4. Endothelin-1 is a key mediator of coronary vasoconstriction in patients with transplant coronary arteriosclerosis.
- Author
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Larose E, Behrendt D, Kinlay S, Selwyn AP, Ganz P, and Fang JC
- Subjects
- Adult, Aged, Blood Flow Velocity, Case-Control Studies, Coronary Artery Disease etiology, Coronary Artery Disease physiopathology, Coronary Circulation, Endothelin A Receptor Antagonists, Female, Humans, Infusions, Intravenous, Male, Microcirculation, Middle Aged, Peptides, Cyclic administration & dosage, Receptor, Endothelin A metabolism, Severity of Illness Index, Time Factors, Vascular Resistance, Vasodilator Agents administration & dosage, Coronary Artery Disease metabolism, Endothelin-1 metabolism, Heart Transplantation adverse effects, Vasoconstriction drug effects
- Abstract
Background: Transplant coronary arteriosclerosis (TCA) is the principal long-term complication in cardiac transplant recipients. The mediators responsible for vascular proliferation and vasoconstriction typical of TCA remain largely unknown. We tested whether endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, contributes to the pathogenesis and manifestations of TCA., Methods and Results: BQ-123, an ET-1 receptor-A antagonist, was infused into a coronary artery (40 nmol/min for 60 minutes) of 18 subjects, 6 + or - 4 years after transplantation. Vasomotor responses were measured in the infused artery and in a noninfused control artery in patients with (n=10) and without (n=8) advanced TCA (108 total coronary segments). Changes in diameters were compared at 15-minute intervals up to 60 minutes. Contribution of ET-1 to coronary constrictor tone was assessed by comparing vasodilation from BQ-123 with that of the maximal vasodilator nitroglycerin (200-microg intracoronary bolus). BQ-123 dilated coronary arteries of transplanted patients (8.4% at 60 minutes versus -0.4% in noninfused arteries, P<0.001). Dilation was greater for arteries with advanced TCA defined as diameter stenosis > or = 15% (dilation 15.2% with versus 0.6% without advanced TCA, P=0.004). Judged against the response to nitroglycerin, ET-1 accounted for 53.2% of coronary tone in advanced TCA but only 12.9% without advanced TCA., Conclusions: This study shows for the first time in humans that ET-1 is an important mediator of coronary vasoconstriction in TCA and accounts for >50% of the increased vasomotor tone. Therapeutic targeting of ET-1 may retard the development of TCA. more...
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- 2009
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5. Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.
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Soejima K, Stevenson WG, Sapp JL, Selwyn AP, Couper G, and Epstein LM
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- Adult, Aged, Aged, 80 and over, Cardiomyopathy, Dilated physiopathology, Cicatrix etiology, Cicatrix physiopathology, Female, Humans, Male, Middle Aged, Tachycardia, Ventricular diagnosis, Tachycardia, Ventricular etiology, Treatment Outcome, Body Surface Potential Mapping methods, Cardiomyopathy, Dilated complications, Catheter Ablation methods, Tachycardia, Ventricular therapy
- Abstract
Objectives: The purpose of this study was to evaluate the occurrence, locations, and relationship of ventricular tachycardia (VT) to low-voltage areas in dilated cardiomyopathy (DCM)., Background: The substrate causing monomorphic VT after infarction is characterized by regions of low-voltage (<1.5 mV) scar on electroanatomic maps. The substrate causing VT associated with DCM is less well defined., Methods: A total of 28 patients were studied with endocardial (26 patients) and epicardial (8 patients) electroanatomic mapping. The VT circuits were defined by entrainment or pace mapping., Results: Ventricular tachycardia was due to focal VT in 5, bundle-branch re-entry in 2, and myocardial re-entry in 22 patients (both focal and re-entry VTs in 1 patient). All patients with myocardial re-entry had endocardial (20 of 20 patients) and/or epicardial (7 of 7 patients mapped) scar. Most (63%) endocardial scars were adjacent to a valve annulus. Of the 19 VT circuit isthmuses identified, 12 were associated with an endocardial scar and 7 with an epicardial scar. All myocardial re-entrant VTs were abolished in 12 of 22 patients, and inducible VT was modified in 4 patients. During follow-up of 334 +/- 280 days, 54% of patients with myocardial re-entry were free of VT despite frequent episodes before ablation., Conclusions: The VTs in DCM are most commonly the result of myocardial re-entry associated with scar. Scars are often adjacent to a valve annulus, deep in the endocardium, and can be greater in extent on the epicardium than on the endocardium. The use of epicardial mapping and radiofrequency is likely to improve success. more...
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- 2004
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6. Increased Th1 activity in patients with coronary artery disease.
- Author
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Fernandes JL, Mamoni RL, Orford JL, Garcia C, Selwyn AP, Coelho OR, and Blotta MH
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- Adult, Aged, Aged, 80 and over, Angina Pectoris metabolism, Female, Humans, In Vitro Techniques, Interferon-gamma blood, Interleukin-12 blood, Male, Middle Aged, Receptors, CXCR3, Receptors, Chemokine metabolism, Coronary Artery Disease immunology, Th1 Cells immunology
- Abstract
Background: Atherosclerotic lesions are mainly composed of macrophages and T lymphocytes. Specific T helper type 1 (Th1) cytokines and interferon gamma (IFN-gamma) inducible chemokines have been shown to be present in these lesions, modulating the local immunologic response. To explore whether this increase in Th1 activity could also be detected in circulating cells indicating a systemic activation, we studied the peripheral expression of Th1 cytokines and chemokines in patients with coronary artery disease and controls., Methods and Results: Fifty patients with coronary artery disease (25 with unstable angina and 25 with stable angina) and 10 controls were studied. Serum interleukin (IL)-12 and IFN-gamma and the expression of IFN-gamma inducible chemokines IP-10, Mig and their receptor CXCR3 in peripheral cells were analyzed. Serum IL-12 and intracellular expression of IFN-gamma were significantly elevated in patients with unstable angina. An enhanced expression of IFN-gamma chemokines IP-10, Mig and CXCR3 in patients with stable angina was also observed., Conclusions: This study demonstrates an increased systemic inflammatory activity in patients with coronary heart disease with a predominant Th1 response, particularly in patients with unstable angina, suggesting an important role played by this polarization in plaque formation and rupture., (Copyright 2004 Elsevier Ltd.) more...
- Published
- 2004
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7. Long-term effect of combined vitamins E and C on coronary and peripheral endothelial function.
- Author
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Kinlay S, Behrendt D, Fang JC, Delagrange D, Morrow J, Witztum JL, Rifai N, Selwyn AP, Creager MA, and Ganz P
- Subjects
- Antioxidants administration & dosage, Ascorbic Acid administration & dosage, Brachial Artery drug effects, Coronary Disease physiopathology, Coronary Vessels drug effects, Double-Blind Method, Drug Therapy, Combination, Endothelium, Vascular physiology, Female, Humans, Male, Middle Aged, Oxidative Stress drug effects, Time Factors, Vasodilation physiology, Vitamin E administration & dosage, Antioxidants therapeutic use, Ascorbic Acid therapeutic use, Coronary Disease drug therapy, Endothelium, Vascular drug effects, Vitamin E therapeutic use
- Abstract
Objectives: We tested whether long-term administration of antioxidant vitamins C and E improves coronary and brachial artery endothelial function in patients with coronary artery disease (CAD)., Background: Endothelial function is a sensitive indicator of vascular health. Oxidant stress and oxidized low-density lipoprotein (LDL) impair endothelial function by reducing nitric oxide bioavailability in the artery wall., Methods: We randomly assigned 30 subjects with CAD to combined vitamin E (800 IU per day) and C (1000 mg per day) or to placebos in a double-blind trial. Coronary artery endothelial function was measured as the change in coronary artery diameter to acetylcholine infusions (n = 18 patients), and brachial artery endothelial function was assessed by flow-mediated dilation (n = 25 patients) at baseline and six months. Plasma markers of oxidant stress (oxidized LDL and autoantibodies) were also measured., Results: Plasma alpha-tocopherol (p < 0.001) and ascorbic acid (p < 0.02) increased with active therapy. Compared to placebo, there was no improvement in coronary and brachial endothelial vasomotor function over six months. Although vitamins C and E tended to reduce F2-isoprostanes (p = 0.065), they failed to alter oxidized LDL or autoantibodies to oxidized LDL., Conclusions: Long-term oral vitamins C and E do not improve key mechanisms in the biology of atherosclerosis or endothelial dysfunction, or reduce LDL oxidation in vivo. more...
- Published
- 2004
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8. Circulating autoantibodies to oxidized LDL correlate with impaired coronary endothelial function after cardiac transplantation.
- Author
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Fang JC, Kinlay S, Behrendt D, Hikita H, Witztum JL, Selwyn AP, and Ganz P
- Subjects
- Acetylcholine antagonists & inhibitors, Acetylcholine pharmacology, Adult, Coronary Artery Disease blood, Coronary Artery Disease etiology, Coronary Vessels drug effects, Coronary Vessels immunology, Endothelium, Vascular drug effects, Endothelium, Vascular immunology, Female, Humans, Immunoglobulin G blood, Linear Models, Lipids blood, Lipoproteins, LDL blood, Lipoproteins, LDL metabolism, Living Donors, Macrophages metabolism, Male, Middle Aged, Multivariate Analysis, Nitroglycerin antagonists & inhibitors, Nitroglycerin pharmacology, Vasomotor System drug effects, Vasomotor System immunology, Autoantibodies blood, Coronary Vessels physiopathology, Endothelium, Vascular physiopathology, Heart Transplantation adverse effects, Lipoproteins, LDL immunology
- Abstract
Objective: The oxidative modification of low density lipoprotein (LDL) may play a role in the pathogenesis of transplant-associated arteriosclerosis. Oxidized LDL (OxLDL) is immunogenic as well as atherogenic, and the level of autoantibodies to OxLDL has been taken as an index of the oxidant state of LDL. Because endothelial dysfunction is key in the initiation of transplant-associated arteriosclerosis, we postulated that the level of OxLDL autoantibody is associated with the degree of impairment of coronary endothelial function., Methods and Results: Coronary endothelium-dependent dilation was assessed by using intracoronary acetylcholine and endothelium-independent dilation by nitroglycerin in 36 cardiac transplant recipients within 1 year of transplantation. The coronary responses to acetylcholine ranged from -37% (vasoconstriction) to 31% (vasodilation), and the responses to nitroglycerin ranged from 0% to 42% (vasodilation). The coronary vasomotor response to acetylcholine was significantly and inversely related to OxLDL autoantibody levels (r=-0.43, P<0.01) but not LDL levels (r=-0.04, P=0.83) or circulating OxLDL levels detected by monoclonal antibody EO6 (r=-0.27, P=0.11). The coronary artery response to nitroglycerin was not related to levels of OxLDL autoantibodies, LDL, or EO6 (all P=NS)., Conclusions: Autoantibodies to OxLDL are increased in patients with coronary endothelial dysfunction in the first year after cardiac transplantation. The oxidative modification of LDL by inducing endothelial dysfunction in cardiac transplant recipients may be a critical step in the atherogenic effects of LDL and may provide a potential target for therapy. more...
- Published
- 2002
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9. Coronary flow velocity and disturbed flow predict adverse clinical outcome after coronary angioplasty.
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Kinlay S, Grewal J, Manuelin D, Fang JC, Selwyn AP, Bittl JA, and Ganz P
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- Coronary Stenosis pathology, Coronary Stenosis physiopathology, Follow-Up Studies, Humans, Prospective Studies, Treatment Outcome, Angioplasty, Balloon, Laser-Assisted, Blood Flow Velocity physiology, Coronary Artery Disease etiology, Coronary Circulation physiology, Coronary Restenosis etiology, Coronary Stenosis surgery, Postoperative Complications pathology, Postoperative Complications physiopathology
- Abstract
Objective: Laminar flow becomes disturbed at high velocities, reducing shear stress and augmenting vascular inflammation and proliferation, processes that are pivotal in restenosis and atherogenesis. We hypothesized that disturbed blood flow after coronary angioplasty is associated with adverse long-term clinical outcome., Methods and Results: The cineangiograms from 97 patients undergoing laser-assisted coronary angioplasty were analyzed. Coronary blood flow velocity, the residual lesion dimensions, and the Reynolds number (an index of disturbed flow) were measured by using a frame-counting technique and quantitative coronary angiography. Cox proportional hazards were used to assess the relative risk of adverse events (target-vessel revascularization, myocardial infarction, or death) over a mean 2.5 years after the index procedure. There were 41 adverse events during 245 patient years of follow-up (17% per year of follow-up). The risk of an adverse event was increased for patients with a high flow velocity (>250 mm/s; relative risk 2.5, 95% CI 1.3 to 4.7) or a high Reynolds number (>200) at the stenosis inlet (relative risk 2.1, 95% CI 1.1 to 4.1) at the end of the procedure. Adjustment for other factors did not alter these results., Conclusions: High Reynolds numbers, indicating disturbed blood flow after coronary angioplasty, increase the risk of adverse clinical events, potentially through shear-stress-related molecular mechanisms that promote restenosis and atherogenesis. more...
- Published
- 2002
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10. Rescue percutaneous coronary intervention following coronary artery bypass graft--a descriptive analysis of the changing interface between interventional cardiologist and cardiac surgeon.
- Author
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Adams MR, Orford JL, Blake GJ, Wainstein MV, Byrne JG, and Selwyn AP
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- Aged, Aged, 80 and over, Coronary Artery Disease epidemiology, Coronary Artery Disease therapy, Female, Follow-Up Studies, Hospital Mortality, Humans, Incidence, Male, Massachusetts, Middle Aged, Multivariate Analysis, Predictive Value of Tests, Reoperation, Severity of Illness Index, Time Factors, Treatment Outcome, Angioplasty, Balloon, Coronary, Cardiology, Coronary Artery Bypass, Thoracic Surgery
- Abstract
Background: Despite decreasing rates of acute and subacute complications of percutaneous coronary intervention (PCI), these procedures are generally only performed in centers where it is possible for failed PCI to be treated by rescue coronary artery bypass graft (CABG). Case reports and case series have documented successful PCI following failed CABG. We sought to confirm this decrease in the need for rescue CABG following failed PCI and to examine trends in the utilization of rescue PCI following failed CABG., Hypothesis: The interface between interventional cardiologist and cardiac surgeon is characterized by changing practice patterns and resource utilization., Methods: We examined the medical records of all patients admitted to the Brigham and Women's Hospital over a 7-year period and identified 169 patients who required both PCI and CABG during the same hospital admission. We describe and compare three predetermined groups of patients defined by the sequence of, and indication for, the relevant myocardial revascularization procedures., Results: In all, 100 patients required CABG for failed PCI, 46 patients had planned hybrid procedures involving both CABG and PCI, and 23 patients required PCI following failed CABG. There was a decrease in the need for rescue CABG following failed PCI, both in total numbers and as a percentage of total cases (2.5% in 1994 and 0.22% in 1999). There was a simultaneous increase in the utilization of rescue PCI following failed CABG (0% in 1994 and 1.6% in 2000). Hybrid procedures were identified as a source of innovative solutions to a variety of challenging clinical problems., Conclusions: Changing patterns of resource utilization should be considered when planning hospital facilities and patient triage, and these patients undergoing percutaneous or surgical revascularization may benefit from close cooperation between the cardiac surgeon and the interventional cardiologist. more...
- Published
- 2002
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11. Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo.
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Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, and Ganz P
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- Adult, Anatomy, Cross-Sectional, Blood Pressure drug effects, Brachial Artery anatomy & histology, Brachial Artery physiology, Cardiovascular Diseases etiology, Compliance drug effects, Elasticity drug effects, Enzyme Inhibitors pharmacology, Humans, Male, Nitric Oxide Donors pharmacology, Nitroglycerin pharmacology, Risk Factors, Stress, Mechanical, omega-N-Methylarginine pharmacology, Arteries physiology, Endothelium, Vascular metabolism, Nitric Oxide physiology
- Abstract
Arterial elasticity is determined by structural characteristics of the artery wall and by vascular smooth muscle tone. The identity of endogenous vasoactive substances that regulate elasticity has not been defined in humans. We hypothesized that NO, a vasodilator released constitutively by the endothelium, augments arterial elasticity. Seven healthy young men were studied. A 20-MHz intravascular ultrasound catheter was introduced through an arterial sheath to measure brachial artery cross-sectional area, wall thickness, and intra-arterial pressure. After control was established, indices of elasticity (pressure-area relationship, instantaneous compliance, and stress-strain, pressure-incremental elastic modulus (E(inc)), and pressure-pulse wave velocity relationships) were examined over 0 to 100 mm Hg transmural pressure obtained by inflation of an external cuff. Thereafter, the basal production of endothelium-derived NO was inhibited by N(G)-monomethyl-L-arginine (L-NMMA) (4 and 8 mg/min). Finally, nitroglycerin (2.5 and 12.5 microgram/min), an exogenous donor of NO, was given to relax the vascular smooth muscle. Elasticity was measured under all of these conditions. L-NMMA (8 mg/min) decreased brachial artery area (P=0.016) and compliance (P<0.0001) and increased E(inc) (P<0.01) and pulse wave velocity (P<0.0001). Nitroglycerin (12.5 microgram/min) increased brachial artery area (P<0.001) and compliance (P<0.001) and decreased pulse wave velocity (P=0.02). NO, an endothelium-derived vasodilator, augments arterial elasticity in the human brachial artery. Loss of constitutively released NO associated with cardiovascular risk factors may adversely affect arterial elasticity in humans. more...
- Published
- 2001
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12. Vigabatrin directed against kindled seizures following cortical insult: impact on epileptogenesis and somatosensory recovery.
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Montañez S, Kline AE, Selwyn AP, Suozzi JC, Butler SE, and Hernandez TD
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- Animals, Cerebral Cortex pathology, Dose-Response Relationship, Drug, Electric Stimulation, Electrodes, Implanted, Evoked Potentials, Somatosensory drug effects, Functional Laterality physiology, Male, Physical Stimulation, Rats, Rats, Long-Evans, Seizures etiology, Seizures physiopathology, Sensation drug effects, Anticonvulsants therapeutic use, Cerebral Cortex injuries, Kindling, Neurologic physiology, Seizures drug therapy, Sensation physiology, Vigabatrin therapeutic use
- Abstract
The anticonvulsant drug vigabatrin has not been found to be detrimental to the recovery process when administered following focal cortical insult. This finding is in contrast to the negative postinjury consequences of other anticonvulsant drugs (e.g., phenobarbital and diazepam) with more direct activation of the GABA/benzodiazepine receptor complex. Moreover, phenobarbital directed against kindled seizures affects functional recovery more adversely than either the drug or subconvulsive seizures alone. The purpose of the present study was to determine whether vigabatrin (150, 200, and 250 mg/kg) directed against kindled seizures would impact recovery from lesion-induced somatosensory deficits. Vigabatrin was coupled with daily electrical kindling of the amygdala during the first week after a unilateral anteromedial cortex (AMC) lesion. Somatosensory recovery was assessed using bilateral tactile stimulation tests. Animals receiving the highest dose of vigabatrin prior to electrical kindling (250 mg/kg vigabatrin/kindled) remained significantly impaired even after two months of testing relative to vehicle/kindled, kindled/250 mg/kg vigabatrin, which received vigabatrin after electrical kindling, and the 150, 200, and 250 mg/kg vigabatrin/nonkindled groups (p < 0.0001). In contrast, neither vigabatrin (at any of the doses tested) nor subconvulsive kindled seizures impacted the recovery process (p > 0.05) when administered alone (i.e., without the drug + seizure interaction). These data add to the accumulating experimental and clinical evidence suggesting that the neurobehavioral consequences of the interaction between anticonvulsant drugs and subclinical seizures after brain insult are detrimental to functional recovery. more...
- Published
- 2001
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13. Role of endothelin-1 in the active constriction of human atherosclerotic coronary arteries.
- Author
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Kinlay S, Behrendt D, Wainstein M, Beltrame J, Fang JC, Creager MA, Selwyn AP, and Ganz P
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- Coronary Circulation drug effects, Coronary Vessels drug effects, Coronary Vessels pathology, Endothelin Receptor Antagonists, Humans, Middle Aged, Multivariate Analysis, Nitroglycerin pharmacology, Peptides, Cyclic pharmacology, Receptor, Endothelin A, Vasoconstriction drug effects, Vasodilator Agents pharmacology, Coronary Artery Disease physiopathology, Coronary Vessels physiopathology, Endothelin-1 physiology, Vasoconstriction physiology
- Abstract
Background: Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries., Methods and Results: In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ET(A) receptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 microgram). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes, P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes, P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes, P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01)., Conclusions: ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia. more...
- Published
- 2001
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14. Lack of compensatory enlargement at sites of coronary vasospasm: identification by ultrasound and successful treatment with stenting.
- Author
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Kinlay S, Selwyn AP, Ganz P, and O'Gara PT
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- Adult, Angioplasty, Balloon, Coronary, Cardiac Catheterization, Coronary Angiography, Coronary Vasospasm diagnostic imaging, Electrocardiography, Exercise Test, Follow-Up Studies, Humans, Male, Time Factors, Coronary Vasospasm diagnosis, Coronary Vasospasm therapy, Stents, Ultrasonography, Interventional
- Abstract
The case of a young man with spontaneous vasospasm at two sites in his left anterior descending coronary artery is described. Intravascular ultrasound demonstrated mild eccentric atherosclerosis with smaller total artery cross-sectional area (defined as the external elastic membrane) compared with reference segments. Impaired compensatory enlargement (remodeling) in response to mild atherosclerosis may derive from one or more biologic mechanisms that are also responsible for vasospasm. This characteristic is easily identified by intravascular ultrasound. In this case, coronary stenting of the vasospastic sites led to excellent long-term control of symptoms more than 1 year after intervention. more...
- Published
- 2000
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15. Plasma alpha-tocopherol and coronary endothelium-dependent vasodilator function.
- Author
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Kinlay S, Fang JC, Hikita H, Ho I, Delagrange DM, Frei B, Suh JH, Gerhard M, Creager MA, Selwyn AP, and Ganz P
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- Acetylcholine, Cholesterol blood, Coronary Artery Disease blood, Coronary Vessels drug effects, Endothelium, Vascular physiology, Female, Humans, Male, Middle Aged, Nitroglycerin, Triglycerides blood, Vasomotor System drug effects, Coronary Artery Disease physiopathology, Coronary Vessels physiology, Vasomotor System physiology, Vitamin E blood
- Abstract
Background: In the presence of atherosclerosis, the coronary endothelial vasomotor response to acetylcholine is frequently abnormal but is variable between patients. We tested the hypothesis that the plasma concentration of alpha-tocopherol is associated with the preservation of nitric oxide-mediated endothelium-dependent vasomotion., Methods and Results: We studied 15 men and 6 women (mean age 61+/-10 years) at coronary angiography who were not taking vitamin supplements. Coronary endothelium-dependent and -independent vasomotion was assessed by intracoronary infusions of acetylcholine and nitroglycerin. The vasomotor responses were compared with the plasma concentration of alpha-tocopherol and the plasma alpha-tocopherol concentration relative to total lipid (total cholesterol plus triglycerides). The mean plasma alpha-tocopherol was 25.6+/-6.1 micromol/L, total cholesterol 193+/-27 mg/dL, triglycerides 115+/-66 mg/dL, and alpha-tocopherol to total lipid 4. 2+/-0.9 micromol. L(-1). (mmol/L)(-1). The mean vasomotor response to acetylcholine was -1% (range -33% to 28%) and to nitroglycerin 22% (range 0% to 54%). Plasma alpha-tocopherol was significantly correlated with the acetylcholine response (r=0.49, P<0.05) but not the nitroglycerin response (r=0.13, P>0.05). The acetylcholine response remained significant after adjustment for other potential sources of oxidant stress (total cholesterol, diabetes mellitus, smoking, angina class) (P<0.01). The relative concentration of alpha-tocopherol to total lipid was not related to endothelial function (r=0.24, P=0.3, n=20)., Conclusions: alpha-Tocopherol may preserve endothelial vasomotor function in patients with coronary atherosclerosis. This effect may be related primarily to the action of alpha-tocopherol in the vascular wall. Further studies that assess the impact of alpha-tocopherol supplementation as therapy of endothelial dysfunction are justified. more...
- Published
- 1999
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16. Inflammation, the endothelium, and the acute coronary syndromes.
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Kinlay S, Selwyn AP, Libby P, and Ganz P
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- Acute Disease, Cell Adhesion Molecules biosynthesis, Coronary Disease metabolism, Endothelium, Vascular metabolism, Humans, Syndrome, Coronary Disease pathology, Endothelium, Vascular pathology
- Abstract
Disruption of atherosclerotic plaques with associated thrombus is responsible for the majority of the acute coronary syndromes. Plaque instability is related closely to the degree of inflammation. Inflammatory cells within the plaque produce cytokines that inhibit collagen production by vascular smooth muscle cells and increase the production of metalloproteinases, which degrade the extracellular matrix in the fibrous cap. The recruitment of inflammatory cells into the vessel wall occurs in a coordinated sequence of events involving the expression of cellular adhesion molecules on the surface of activated endothelial cells and the production of chemoattractants, and occurs in part in response to oxidation of low-density lipoprotein within the vessel wall. The cellular adhesion molecules are shed into the circulating blood in several disease states, including clinically evident atherosclerosis. The acute-phase reactants C-reactive protein and interleukin-6, and markers of the fibrinolytic state (plasminogen activator inhibitor-1 and tissue plasminogen activator), are also elevated in the acute coronary syndromes and in healthy individuals at increased risk for developing coronary artery disease. These markers may reflect vascular inflammation and thereby the stability of atherosclerotic plaques. Their measurement may pinpoint the mechanisms of benefit of cholesterol-lowering therapy and other interventions designed to reduce coronary risk, and potentially could offer a new method for monitoring coronary risk factor reduction in patients. more...
- Published
- 1998
17. Hemostatic/fibrinolytic predictors of allograft coronary artery disease after cardiac transplantation.
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Meckel CR, Anderson TJ, Mudge GH, Mitchell RN, Yeung AC, Selwyn AP, Ganz P, and Simon DI
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- Adult, Arteriosclerosis etiology, Biomarkers, Coronary Angiography, Coronary Disease blood, Coronary Disease diagnosis, Female, Fibrinogen metabolism, Humans, Male, Middle Aged, Risk Factors, Thrombosis etiology, Coronary Disease etiology, Fibrinolysis, Heart Transplantation adverse effects, Heart Transplantation physiology, Hemostasis
- Abstract
Allograft coronary artery disease (CAD) remains the leading cause of morbidity and mortality affecting the long-term survival of patients after cardiac transplantation. Because there is increasing evidence that imbalances in hemostatic and fibrinolytic pathways are associated with graft failure, we hypothesized that atherothrombotic risk factors may contribute to allograft CAD. This study sought to determine if plasma hemostatic and fibrinolytic parameters are associated with the severity of allograft CAD. The extent of allograft CAD was investigated by angiography and intravascular ultrasound (IVUS) in 16 cardiac transplant recipients. Intimal thickening was quantified using IVUS by measuring the intimal index (li = intimal area/[intimal area + luminal area]) in two to five segments of the left anterior descending (LAD) coronary artery. The maximal li per patient was calculated and index to the time post-transplant (Mxli/Yr). Plasma fibrinogen (FGN), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), lipoprotein(a) (Lp(a)), and net fibrinolytic activity of plasma were assayed 6-24 months after transplant as indicators of the fibrinolytic system and then correlated with the IVUS measurements. The FGN level correlated with the severity of intimal thickening, Mxli/Yr (r2 = 0.41, p = 0.008), and was inversely correlated with angiographic tertiary vessel filling (r2 = 0.25, p = 0.051). In patients with lower plasma fibrinolytic activity (lytic zone less than 100 mm2), Mxli/Yr was increased eightfold (0.218 +/- 0.137 versus 0.025 +/- 0.021, p = 0.001). t-PA (r2 = 0.0004, p = 0.94), PAI-1 (r2 = 0.008, p = 0.75) and Lp(a) levels (r2 = 0.11, p = 0.21) did not predict Mxli/Yr. Thus, we demonstrate that plasma FGN and net fibrinolytic activity correlate with the degree of intimal thickening measured by IVUS after cardiac transplantation. These data suggest that fibrin deposition may play a role in allograft CAD after cardiac transplantation. more...
- Published
- 1997
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18. Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease.
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Andrews TC, Raby K, Barry J, Naimi CL, Allred E, Ganz P, and Selwyn AP
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- Aged, Anticholesteremic Agents therapeutic use, Cholesterol, LDL blood, Diet, Electrocardiography, Female, Humans, Lovastatin therapeutic use, Male, Middle Aged, Myocardial Ischemia drug therapy, Cholesterol blood, Coronary Disease complications, Myocardial Ischemia blood, Myocardial Ischemia complications
- Abstract
Background: Cholesterol lowering is associated with a reduction in cardiovascular morbidity and mortality. This study sought to determine whether cholesterol lowering also results in a reduction of myocardial ischemia during daily life., Methods and Results: We enrolled 40 patients with proven coronary artery disease, total serum cholesterol between 191 and 327 mg/dL, and at least one episode of ST-segment depression on ambulatory ECG monitoring. Twenty patients were randomized to an American Heart Association Step 1 diet plus placebo (placebo group) and 20 to the same diet plus lovastatin (treatment group). Serum cholesterol and LDL cholesterol levels and ambulatory monitoring were repeated after 4 to 6 months of therapy. The two groups were comparable with respect to baseline characteristics, number of episodes of ST-segment depression, and baseline serum cholesterol levels. The treatment group had lower mean total and LDL cholesterol levels at study end and experienced a significant reduction in the number of episodes of ST-segment depression compared with the placebo group. ST-segment depression was completely resolved in 13 of 20 patients (65%) in the treatment group versus 2 of 20 (10%) in the placebo group. The treatment group exhibited a highly significant reduction in ischemia (P < .001). By logistic regression, treatment with diet and lovastatin was an independent predictor of ischemia resolution., Conclusions: Cholesterol lowering with lovastatin appears to be effective in eliminating myocardial ischemia during daily life in a significant proportion of patients. more...
- Published
- 1997
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19. Atherogenic lipids, vascular dysfunction, and clinical signs of ischemic heart disease.
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Selwyn AP, Kinlay S, Libby P, and Ganz P
- Subjects
- Humans, Hypercholesterolemia therapy, Myocardial Ischemia etiology, Vasodilation, Cholesterol, LDL physiology, Endothelium, Vascular physiopathology, Hypercholesterolemia physiopathology
- Abstract
LDL is oxidized in vascular endothelial cells to a highly injurious product that results in characteristic cell dysfunction(s) in large arteries and resistance vessels. The characteristic dysfunctions (ie, loss of dilation, constriction, thrombosis, and inflammation) operate before and throughout the development of atherosclerosis and particularly during plaque rupture. Although oxidized LDL appears to induce these cell/vessel wall dysfunctions in a time- and concentration-dependent manner, Tamai and colleagues have shown that this interaction can be dynamic in that a reduction in lipids restores endothelium-dependent vasomotor function almost immediately. The same intervention (ie, lipid lowering) also appears to stabilize atheroma in the long term, improves endothelium-dependent vasomotion over months, and results in a reduction in clinical signs of risk in coronary heart disease (ie, ischemia and the need for revascularization). The above leads us to some important but unanswered questions. Can we rely on clinical measures of arterial vasomotor dysfunction to represent the other important cell dysfunctions (eg, inflammation, abnormal growth) while monitoring the response to therapeutic interventions? How can we effectively inhibit oxidation of LDL in the arterial wall, and is this useful in reversing the many cell dysfunctions and clinical sequelae of coronary atherosclerosis? What is the time course for restoration of endothelial dysfunction in the atherosclerotic epicardial coronary arteries in patients with effective lipid-lowering therapy? The intracellular responses to oxidized LDL are so numerous (loss of vasodilation, loss of anticoagulant mechanisms, abnormal inflammation, and growth) that targeting therapies to specific pathways may prove difficult. Parallel efforts in basic physiological and clinical research have resulted in remarkable progress that has improved outcomes in patients with coronary heart disease. We expect that many of the characteristic cell/vessel wall dysfunctions that result from adverse interactions with risk factors are dynamic and can be manipulated in a relatively short time frame. Treatment of atherogenic lipids with other risk factors must be further refined and may well become the cornerstone for effective management of angina, unstable syndromes, and ischemia in addition to the control of important outcomes such as myocardial infarction and coronary death. more...
- Published
- 1997
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20. Nitroglycerin-induced coronary vasodilation is not enhanced in patients with impaired endothelium-dependent dilation.
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Anderson TJ, Meredith IT, Charbonneau F, Yeung AC, Dyce M, Selwyn AP, and Ganz P
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- Acetylcholine pharmacology, Coronary Angiography, Coronary Circulation drug effects, Coronary Disease physiopathology, Coronary Vessels drug effects, Endothelium, Vascular drug effects, Female, Humans, Male, Middle Aged, Vasoconstriction drug effects, Coronary Vessels physiopathology, Endothelium, Vascular physiopathology, Nitroglycerin pharmacology, Vasodilation drug effects, Vasodilator Agents pharmacology
- Abstract
Objectives: This study was designed to determine whether enhanced sensitivity to exogenous nitrovasodilators is present in the coronary arteries of patients with impaired endothelium-dependent dilation., Background: Animal studies have demonstrated that the dilator response to exogenous nitrovasodilators is exaggerated in the setting of endothelial dysfunction (diminished nitric oxide activity). Whether such relative hyperresponsiveness to exogenous nitrates occurs and is important in humans is unknown., Methods: We assessed coronary vasomotion in 110 patients (mean [+/- SD] age 56 +/- 10 years) by serial intracoronary infusions of acetylcholine (10(-8) to 10(-6) mol/liter) to test endogenous nitric oxide and nitroglycerin (40 micrograms) to test responses to exogenous nitrovasodilators., Results: The vasomotor response to 10(-6) mol/liter of acetylcholine differed between patients with (n = 95) and those without (n = 15) normal endothelial dysfunction (-21 +/- 14% vs. 12 +/- 8%, respectively, p < 0.001). However, neither the dilator response to nitroglycerin (21 +/- 14% vs. 18 +/- 13%) nor the baseline diameter differed between those with endothelial dysfunction and normal function, respectively. There was no correlation between the magnitude of the dilator response to nitroglycerin and acetylcholine. The response to nitroglycerin was decreased with increasing age (r = -0.21, p = 0.03) but was not related to any other demographic factors or to the angiographic appearance of the vessel., Conclusions: The coronary vasodilator response to nitroglycerin is not significantly enhanced in patients with impaired endothelium-dependent dilation but decreases with increasing age. This finding provides indirect evidence that basal coronary tone is not increased in patients with endothelial dysfunction and that supersensitivity to exogenous nitrates is not clinically important in humans. more...
- Published
- 1996
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21. Endothelium-dependent coronary vasomotion relates to the susceptibility of LDL to oxidation in humans.
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Anderson TJ, Meredith IT, Charbonneau F, Yeung AC, Frei B, Selwyn AP, and Ganz P
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- Acetylcholine pharmacology, Aged, Anticholesteremic Agents therapeutic use, Humans, Hypercholesterolemia drug therapy, Hypercholesterolemia physiopathology, Middle Aged, Oxidation-Reduction, Vasoconstriction drug effects, Vasodilation drug effects, Coronary Vessels physiopathology, Endothelium, Vascular physiopathology, Hypercholesterolemia metabolism, Lipoproteins, LDL metabolism
- Abstract
Background: Oxidatively modified LDL has been shown to markedly impair endothelium-dependent dilation in experimental studies. The aim of the present study was to determine the relationship between the coronary vasomotor response to the endothelium-dependent agonist acetylcholine and the in vitro susceptibility of LDL to oxidation in patients., Methods and Results: Endothelium-dependent coronary vasomotion in response to acetylcholine (10(-8) to 10(-6) mol/L) was assessed in 23 patients with hypercholesterolemia (mean age, 56 +/- 9 years) after 1 year of therapy with either an American Heart Association Step 1 diet (seven patients), lovastatin and cholestyramine (seven patients), or lovastatin and probucol (nine patients). The susceptibility of LDL to oxidation was determined by measuring the lag phase of conjugated diene formation induced by Cu2+. Patients treated with lovastatin and probucol had prolongation of the lag phase (263 +/- 64 minutes) compared with diet- (91 +/- 22 minutes) or lovastatin and cholestyramine-(118 +/- 57 minutes) treated patients (P<.0001). By univariate analysis, the coronary vasomotor response to acetylcholine was significantly related to the lag phase of conjugated diene formation (P=.002), cholesterol-lowering therapy (P=.002), and serum cholesterol (P=.02). By multivariate analysis, the lag phase remained a significant predictor of the acetylcholine vasomotor response, independent of the effect of cholesterol-lowering treatment., Conclusions: In patients treated with lipid-lowering agents, the vasodilator response to acetylcholine is related to the susceptibility of LDL to oxidation. These findings suggest that oxidative stress is an important determinant of the coronary endothelial dysfunction observed in patients with atherosclerosis and hypercholesterolemia. more...
- Published
- 1996
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22. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year posttransplant.
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Davis SF, Yeung AC, Meredith IT, Charbonneau F, Ganz P, Selwyn AP, and Anderson TJ
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- Acetylcholine, Coronary Angiography, Coronary Vessels drug effects, Coronary Vessels pathology, Endothelium, Vascular drug effects, Female, Follow-Up Studies, Humans, Male, Middle Aged, Postoperative Complications diagnosis, Prognosis, Transplantation, Homologous, Ultrasonography, Interventional, Vasomotor System drug effects, Coronary Artery Disease diagnosis, Coronary Vessels physiology, Endothelium, Vascular physiology, Heart Transplantation, Vasomotor System physiology
- Abstract
Background: Accelerated coronary arteriosclerosis is the major obstacle to long-term survival after cardiac transplantation. Endothelial dysfunction is common early posttransplant. The relationship between early endothelial dysfunction and the development of allograft arteriosclerosis has not been analyzed serially with intravascular ultrasound in the same patients. We hypothesized that an early constrictor response to acetylcholine, indicative of endothelial dysfunction, may predict the development of transplant coronary arteriosclerosis., Methods and Results: Endothelium-dependent vasomotion was assessed early posttransplant in 20 patients by serial intracoronary acetylcholine infusion, and the percent change in diameter was measured by quantitative angiography. The development of arteriosclerosis was studied by use of intravascular ultrasound in the same 20 patients by quantifying the changes in intimal index (delta Ii) and maximal intimal thickness [delta Mt] of 46 matched coronary segments between initial and 1-year follow-up studies. Coronary segments with endothelial dysfunction (constriction > or = 5%; n = 23) demonstrated a significantly greater increase in mean Ii and Mt by 1 year posttransplant compared with segments with normal endothelial function (n = 23) (delta Ii = 7 +/- 2% versus 2 +/- 1% [P < .05] and delta Mt = 140 +/- 40 versus 50 +/- 20 microns [P < .05]). No other parameters examined predicted the development of allograft arteriosclerosis in the initial year posttransplant., Conclusions: Paired studies that used intravascular ultrasound showed that early endothelial dysfunction predicts the development of allograft arteriosclerosis during the initial year posttransplant. This early pathophysiological feature is likely an important marker that could be useful in therapeutic trials. more...
- Published
- 1996
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23. Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans.
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Cooper CJ, Landzberg MJ, Anderson TJ, Charbonneau F, Creager MA, Ganz P, and Selwyn AP
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- Acetylcholine pharmacology, Adult, Aged, Arginine analogs & derivatives, Arginine pharmacology, Female, Humans, Male, Middle Aged, Vasodilation, omega-N-Methylarginine, Nitric Oxide physiology, Pulmonary Circulation, Vascular Resistance
- Abstract
Background: Endothelium-derived nitric oxide (NO) may be an important mediator of vascular resistance in the pulmonary circulation. We tested the hypotheses that in conscious adults the endothelium, through NO production, is important in maintaining basal pulmonary vascular resistance and that it can increase NO production further in response to receptor-mediated stimulation, leading to further vasodilation., Methods and Results: Pulmonary arterial resistance vessel function was studied within the distribution of a segmental lower lobe pulmonary artery in eight conscious adults 37 to 76 years old who were undergoing cardiac catheterization. Segmental blood flow was determined with use of a Doppler-tip guide wire and quantitative angiography. Drugs were administered locally within the segmental artery through an infusion catheter. NG-Monomethyl-L-arginine (L-NMMA) was used as a specific inhibitor of NO production, whereas acetylcholine (ACh) was used to test receptor-mediated vasodilation. To demonstrate that vasodilation to ACh was NO dependent, ACh response was tested alone, in the presence of L-NMMA, and in the presence of a control constrictor phenylephrine. Basal pulmonary vascular resistance was NO dependent because L-NMMA infusion resulted in a dose-dependent decrease in local flow velocity (P < .005), with flow decreasing 33% at the highest dose of L-NMMA. ACh infusion resulted in a dose-dependent increase in flow velocity (P = .001). The ACh response was at least in part NO dependent because it was diminished by the presence of L-NMMA (P < .05). The effect of L-NMMA on the ACh response was not due to nonspecific preconstriction because L-NMMA diminished the ACh response significantly more than did the endothelium-independent constrictor phenylephrine (P < .05) despite comparable preconstriction., Conclusions: In healthy conscious adults, (1) normal basal pulmonary resistance is maintained in part by continuous local production of NO and (2) the local NO production is responsive to receptor-mediated stimulation, leading to further vasodilation, and can be tested with ACh. more...
- Published
- 1996
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24. Identification of anomalous coronary arteries and their anatomic course by magnetic resonance coronary angiography.
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McConnell MV, Ganz P, Selwyn AP, Li W, Edelman RR, and Manning WJ
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- Adult, Aged, Aged, 80 and over, Coronary Angiography, Coronary Vessel Anomalies diagnostic imaging, Female, Humans, Magnetic Resonance Angiography methods, Male, Middle Aged, Coronary Vessel Anomalies diagnosis
- Abstract
Background: Anomalous coronary arteries are a rare but recognized cause of myocardial ischemia and sudden death. Identification currently requires x-ray angiography, which may have difficulty defining the three-dimensional course of the anomalous vessel. Magnetic resonance coronary angiography (MRCA) has been shown to image coronary artery anatomy noninvasively. We hypothesize that MRCA may be useful in the identification of anomalous coronary arteries and their anatomic course., Methods and Results: Sixteen patients (9 men, 7 women, age 44 to 81 years) with anomalous aortic origins of the coronary arteries by conventional x-ray angiography underwent MRCA. Multiple images of the major epicardial coronary arteries were obtained by use of a breathhold, fat-suppressed, segmented-k space, gradient-echo technique by investigators blinded to all patient data. Anomalous coronary artery pathology, by x-ray angiography, included right-sided left main coronary artery (n = 3), right-sided left circumflex artery (n = 6), separate left-sided left anterior descending and left circumflex arteries (n = 2), left-sided right coronary artery (n = 4), and an anteriorly displaced right coronary artery (n = 1). MRCA correctly identified the anomalous coronary vessel(s) in 14 of 15 patients. In 1 patient, the anomalous vessel was incorrectly identified, and in 2 patients the course of the anomalous vessel was not clearly seen; one of these was a nondominant, anomalous right coronary artery., Conclusions: MRCA is a useful technique for the noninvasive identification of anomalous coronary arteries and their anatomic course. more...
- Published
- 1995
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25. Nitric oxide and nitrovasodilators: similarities, differences and potential interactions.
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Anderson TJ, Meredith IT, Ganz P, Selwyn AP, and Yeung AC
- Subjects
- Animals, Blood Platelets drug effects, Blood Platelets physiology, Endothelium, Vascular drug effects, Endothelium, Vascular physiopathology, Humans, Nitrates chemistry, Nitrates metabolism, Nitroglycerin pharmacology, Vasodilator Agents chemistry, Vasodilator Agents metabolism, Endothelium, Vascular physiology, Nitrates pharmacology, Nitric Oxide physiology, Vasodilator Agents pharmacology
- Abstract
Many similarities exist between the exogenous nitrates and endothelium-derived relaxing factor, which is nitric oxide or a thiol derivative. Both act by way of guanylate cyclase, which increases intracellular concentrations of cyclic guanosine monophosphate, resulting in smooth muscle cell relaxation and antiplatelet effects. Thiols may be important in the biotransformation of exogenous nitrates and other intracellular processes involving nitric oxide. As such, important interactions might be expected between nitrates and endothelium-dependent processes that involve nitric oxide. This review explores the mechanisms of action, biologic effects and potential interactions between nitrates and endothelium-derived relaxing factor. more...
- Published
- 1994
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26. Accuracy of electronic digital calipers compared with quantitative angiography in measuring coronary arterial diameter.
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Uehata A, Matsuguchi T, Bittl JA, Orav J, Meredith IT, Anderson TJ, Selwyn AP, Ganz P, and Yeung AC
- Subjects
- Coronary Disease epidemiology, Heart Transplantation diagnostic imaging, Humans, Models, Cardiovascular, Models, Structural, Observer Variation, Coronary Angiography methods, Coronary Disease diagnostic imaging, Coronary Vessels pathology, Image Processing, Computer-Assisted instrumentation
- Abstract
Background: Quantitative angiography is the accepted method for measuring coronary luminal diameter. Electronic digital calipers have been used to assess arterial diameters in vasomotor function studies and after interventional procedures. However, careful validation of calipers against quantitative angiography has not been described., Methods and Results: We used digital calipers and quantitative angiography to measure 517 arterial diameters (88 nonstenotic segments) in 24 transplant patients undergoing vasomotor function studies with acetylcholine and nitroglycerin, 20 stenoses in 14 patients with coronary artery disease, and 15 stenoses in 15 patients before and after excimer laser-facilitated coronary angioplasty and at 6 months' follow-up. In nonstenotic arterial segments ranging in size from 0.6 to 3.5 mm, calipers overestimated diameters measured by quantitative angiography by 0.29 +/- 0.21 mm (mean +/- SD) (limits of agreement, -0.13 to 0.71 mm). However, when the vasomotor responses were expressed as percent diameter change, the two methods did not differ significantly (-1 +/- 10%; limits of agreement, -21% to 19%). In the 35 stenoses measured before intervention and 30 stenoses measured after intervention, calipers and quantitative angiography differed by 3 +/- 9% (limits of agreement, -15% to 21%) across a range of stenosis severity (11% to 80%). Repeat caliper measurements by the same observer of the percent diameter change in the transplant patients and the percent stenosis in the coronary artery disease patients led to standard deviations of the differences of 9.3% and 7.6%, respectively. Two different observers recorded percent diameter change and percent stenosis that differed with standard deviations of 9.6% and 7.8%, respectively., Conclusions: Quantitative angiography and electronic digital calipers produce similar relative changes in arterial diameters and percent stenosis in a broad range of severities. Digital calipers thus are a rapid and convenient alternative to computerized quantitative angiography in certain research studies and clinical practice of assessing stenosis severity. more...
- Published
- 1993
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27. Functional significance of intimal thickening as detected by intravascular ultrasound early and late after cardiac transplantation.
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Anderson TJ, Meredith IT, Uehata A, Mudge GH, Selwyn AP, Ganz P, and Yeung AC
- Subjects
- Acetylcholine, Coronary Disease epidemiology, Coronary Disease etiology, Coronary Vessels physiopathology, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Multivariate Analysis, Time Factors, Ultrasonography methods, Coronary Disease diagnostic imaging, Coronary Vessels diagnostic imaging, Heart Transplantation adverse effects, Tunica Intima diagnostic imaging
- Abstract
Background: Detection of transplant coronary disease remains difficult. Both intravascular ultrasound (IVUS) imaging and functional coronary vasomotion studies have been used to evaluate this process. However, the time course of intimal thickening as assessed by IVUS and the relation between structure and function have not been explored., Methods and Results: In 40 patients 1 to 8 years after transplantation, 108 coronary artery segments were analyzed by IVUS. Intimal index [% intimal area (lumen+intimal area)] and maximal thickness were used to quantify intimal thickening. Abnormal IVUS was present in 53 of 108 segments (49%) (mean intimal index of diseased segments, 23 +/- 2%; maximal thickness, 530 +/- 47 microns). For those patients with intimal thickening in all segments of the analyzed artery, more time had elapsed since transplantation (4.3 +/- 0.6 years) than for those whose arteries contained some normal (2.6 +/- 0.3 years) or all normal segments (2.2 +/- 0.6 years, P < .05). Both the proportion of segments with intimal thickening and the degree of thickening increased as a function of time after transplantation (P < .5). By multivariate analysis, the independent predictors of intimal thickening were increasing time after transplantation and pretransplantation hypercholesterolemia (P = .02). Within the cohort of 40 patients, endothelium-dependent vasomotor function was evaluated in 26 matched segments from 11 patients studied 1 year after transplantation and in 15 matched segments from 8 patients studied > or = 5 years after transplantation by serial infusions of acetylcholine (10(-8) to 10(-6) mol/L). Of the 26 segments assessed for structure/function correlation at 1 year after transplantation, 22 had no intimal thickening by IVUS. However, endothelial dysfunction was present in 13 of these normal segments (mean diameter constriction, 18.8 +/- 2.3%). Of the 15 segments studied > or = 5 years after transplantation, 11 had intimal thickening. Nine of these 11 segments had preserved endothelial function (mean diameter dilation, 8.6 +/- 2.9%). There was no relation between the degree of intimal thickening and the magnitude of the endothelium-dependent response to acetylcholine., Conclusions: This study has shown that intimal thickening after transplantation begins as a heterogeneous process and increases in extent and magnitude over time. Also, endothelial dysfunction occurs early before the intimal thickening; yet in those patients surviving > or = 5 years, endothelial function may recover even in the presence of moderate intimal pathology. The variable relation between intimal pathology and endothelial function is probably a result of the episodic nature of immune injury. more...
- Published
- 1993
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28. Myocardial revascularization before repair of an aortic aneurysm.
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Anderson TJ, Meredith IT, Selwyn AP, and Raby KE
- Subjects
- Angioplasty, Balloon, Coronary, Aortic Aneurysm mortality, Humans, Postoperative Complications mortality, Risk Factors, Aortic Aneurysm surgery, Coronary Artery Bypass mortality
- Published
- 1993
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29. Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels.
- Author
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Treasure CB, Klein JL, Vita JA, Manoukian SV, Renwick GH, Selwyn AP, Ganz P, and Alexander RW
- Subjects
- Acetylcholine pharmacology, Adenosine pharmacology, Adult, Coronary Circulation drug effects, Female, Hemodynamics, Humans, Male, Microcirculation drug effects, Middle Aged, Coronary Vessels physiopathology, Endothelium, Vascular physiopathology, Hypertension physiopathology, Hypertrophy, Left Ventricular physiopathology, Vascular Resistance, Vasodilation
- Abstract
Background: Patients with hypertension and myocardial hypertrophy may have signs and symptoms of myocardial ischemia in the absence of obstructive coronary disease. Prior investigations have demonstrated impaired coronary flow reserve and have led to speculation that microvascular dysfunction might contribute to ischemia in these patients. Experimental studies have shown that the endothelium, an important regulator of microvascular tone, can be damaged by hypertension and is dysfunctional in cardiomyopathy. We hypothesized that endothelium-dependent vasodilation is impaired in the coronary microvasculature of patients with hypertension and ventricular hypertrophy., Methods and Results: We studied coronary microvascular responses in 10 patients with left ventricular hypertrophy secondary to essential hypertension (HTN) (mean arterial pressure at catheterization, 151/94 mm Hg; mean posterior wall thickness, 1.4 +/- 0.1 cm) and nine normal control subjects with no history of hypertension (mean arterial pressure at catheterization, 128/75 mm Hg; mean posterior wall thickness, 1.0 +/- 0.02 cm) using the intracoronary Doppler catheter and quantitative angiography to assess changes in coronary blood flow (CBF). All patients had normal left ventricular systolic function. To assess microvascular endothelial function, we infused the endothelium-dependent vasodilator acetylcholine (10(-8)-10(-6) M) and the endothelium-independent vasodilator adenosine (10(-6)-10(-4) M) into the left anterior descending coronary artery. In response to acetylcholine, CBF increased only 32 +/- 25% in HTN patients, whereas CBF increased 192 +/- 39% in normal control subjects (p = 0.003). CBF increased 465 +/- 93% in HTN patients and 439 +/- 41% in normal control subjects in response to adenosine (p = NS). The proportion of coronary flow reserve attributable to endothelium-dependent dilation (obtained from peak acetylcholine/peak adenosine flow response) was 48 +/- 9% in normal control subjects but only 7 +/- 8% in HTN patients (p = 0.008)., Conclusions: Endothelium-dependent vasodilation is markedly impaired in the coronary microvessels of patients with hypertension and ventricular hypertrophy. Loss of this vasodilator mechanism may contribute to disordered coronary flow regulation and the ischemic manifestations of hypertensive heart disease. more...
- Published
- 1993
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30. Epicardial coronary artery responses to acetylcholine are impaired in hypertensive patients.
- Author
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Treasure CB, Manoukian SV, Klein JL, Vita JA, Nabel EG, Renwick GH, Selwyn AP, Alexander RW, and Ganz P
- Subjects
- Acetylcholine administration & dosage, Adult, Coronary Angiography, Coronary Disease etiology, Coronary Vessels physiopathology, Endothelium, Vascular drug effects, Endothelium, Vascular physiopathology, Female, Humans, Infusions, Parenteral, Male, Middle Aged, Nitroglycerin administration & dosage, Nitroglycerin pharmacology, Acetylcholine pharmacology, Coronary Vessels drug effects, Hypertension physiopathology
- Abstract
Hypertension is a risk factor for coronary atherosclerosis possibly via an adverse effect on the vascular endothelium. Endothelium-mediated relaxation is impaired in animal models of hypertension. However, the effects of hypertension on human coronary artery endothelial cell function are unknown. To test whether endothelium-mediated relaxation is impaired in the coronary arteries of patients with hypertension, we studied 14 patients with essential hypertension requiring therapy and 15 nonhypertensive control patients undergoing cardiac catheterization. All had angiographically normal, smooth-appearing coronary arteries. Patients were matched for age and other coronary atherosclerosis risk factors. To assess endothelial cell function, the endothelium-dependent vasodilator acetylcholine (ACh, 0.01, 0.1, and 1.0 microM) and the endothelium-independent vasodilator nitroglycerin (40 micrograms) were selectively infused into the left anterior descending or circumflex coronary artery. Diameter change (expressed as percent) was assessed using quantitative angiography. There was a marked vasoconstrictor response to serial doses of ACh in hypertensive patients (-7%, -21%, and -27%) compared with control patients (-4%, -5%, and -7%) (p less than 0.02). The vasodilator response to nitroglycerin was preserved in hypertensive patients (+29%) and control patients (+25%) (p = NS), suggesting that endothelial cell dysfunction accounted for the differences in response to ACh. Thus, patients with hypertension have an accentuated coronary vasoconstrictor response to ACh, suggesting that endothelium-mediated regulation of coronary vascular tone is impaired by essential hypertension. This may reflect more generalized coronary endothelial changes contributing to the pathogenesis of atherosclerosis as well as hypertension. more...
- Published
- 1992
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31. Loss of the coronary microvascular response to acetylcholine in cardiac transplant patients.
- Author
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Treasure CB, Vita JA, Ganz P, Ryan TJ Jr, Schoen FJ, Vekshtein VI, Yeung AC, Mudge GH, Alexander RW, and Selwyn AP
- Subjects
- Adenosine pharmacology, Adult, Endothelium, Vascular physiology, Female, Forecasting, Hemodynamics drug effects, Humans, Male, Microcirculation drug effects, Middle Aged, Pericardium, Postoperative Period, Acetylcholine pharmacology, Coronary Circulation drug effects, Heart Transplantation
- Abstract
Background: The coronary arteries of transplanted hearts frequently develop accelerated diffuse arteriosclerosis. The effects of this disease on resistance vessel function are unknown., Methods and Results: To investigate the integrity of endothelium-dependent small-vessel vasodilation in transplanted hearts, coronary blood flow (CBF) responses to the endothelium-dependent dilator acetylcholine (10(-8) to 10(-6) M) and the essentially endothelium-independent dilator adenosine (10(-6) to 10(-4) M) were assessed in 40 studies of 29 transplant patients 1-3 years after transplantation and in seven nontransplanted controls. CBF was measured at constant arterial pressure with a Doppler catheter in the left anterior descending coronary artery. Controls, year 1 transplant patients, and year 2 transplant patients had similar increases in CBF in response to acetylcholine (232 +/- 40%, 200 +/- 41%, and 201 +/- 54%, respectively; p = NS), whereas year 3 transplant patients had increased CBF of only 100 +/- 39% (p less than 0.05 versus controls). An index of the proportion of CBF reserve attributable to endothelium-dependent dilation was obtained by normalizing each patient's peak acetylcholine flow response by the peak adenosine flow response. In patients receiving both acetylcholine and adenosine, endothelium-dependent flow responses declined over time [57 +/- 9% in controls, 56 +/- 10% for year 1, 47 +/- 12% for year 2, and 29 +/- 9% for year 3 (p less than 0.05 versus controls)]. An increased mean cyclosporine level (range, 99-261 ng/ml) (r = 0.67, p = 0.004) and increased transplant recipient age (range, 20-63 years) (r = 0.51, p = 0.004) predicted a preserved endothelium-dependent microvascular response., Conclusions: Thus, microvascular endothelium-dependent dilation deteriorates over time in the transplanted heart, which may reflect underlying graft arteriosclerosis and contribute to ischemic damage of the myocardium. more...
- Published
- 1992
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32. Patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion demonstrate marked increase in sensitivity to constrictor effects of catecholamines.
- Author
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Vita JA, Treasure CB, Yeung AC, Vekshtein VI, Fantasia GM, Fish RD, Ganz P, and Selwyn AP
- Subjects
- Cardiac Catheterization, Coronary Angiography, Coronary Artery Disease physiopathology, Coronary Vessels drug effects, Endothelium, Vascular drug effects, Female, Humans, Male, Middle Aged, Vasoconstriction drug effects, Vasoconstriction physiology, Acetylcholine, Coronary Artery Disease diagnosis, Coronary Vessels physiopathology, Endothelium, Vascular physiology, Phenylephrine
- Abstract
Background: Studies in patients undergoing cardiac catheterization have demonstrated that normal coronary arteries dilate and atherosclerotic arteries constrict in response to exercise and the cold pressor test, but the mechanisms are unknown. These vasomotor responses are mirrored by the vasomotor response to the endothelium-dependent agent acetylcholine. Exercise and the cold pressor test are associated with adrenergic stimulation and increased circulating catecholamines. The present study tested the hypothesis that coronary arteries with intact endothelial function are relatively resistant to the constrictor effects of catecholamines, whereas arteries with loss of endothelial function have increased sensitivity to catecholamine-induced constriction., Methods and Results: The vasomotor function of the coronary endothelium was assessed by serial acetylcholine infusions (final concentration, 10(-8) to 10(-6) M) in 30 segments in 15 patients with minimal or no evidence of coronary atherosclerosis. The acetylcholine responses were related to the vasomotor response to intracoronary phenylephrine infusion (final concentration, 10(-9) to 10(-6) M) in the same segments. In the group of 18 segments that constricted to acetylcholine, there was a constrictor response to phenylephrine at an approximately 100-fold lower concentration than the group of 12 segments that did not constrict to acetylcholine., Conclusions: These results suggest that the endothelial dysfunction that characterizes early and late atherosclerosis is associated with a marked increase in sensitivity to the constrictor effects of catecholamines. This finding may explain the constrictor responses of atherosclerotic coronary arteries to exercise and the cold pressor test. In stenotic coronary arteries this mechanism may play a role in the production of myocardial ischemia. more...
- Published
- 1992
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33. The role of endothelial dysfunction to predict the development of allograft coronary artery disease following cardiac transplantation.
- Author
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Mudge GH Jr, Yeung A, Selwyn AP, and Ganz P
- Subjects
- Arteriosclerosis etiology, Endothelium, Vascular physiopathology, Humans, Coronary Disease etiology, Heart Transplantation adverse effects
- Published
- 1992
34. Psychosocial factors impair vascular responses of coronary arteries.
- Author
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Williams JK, Vita JA, Manuck SB, Selwyn AP, and Kaplan JR
- Subjects
- Animals, Cholesterol, Dietary administration & dosage, Coronary Angiography, Coronary Vasospasm physiopathology, Diet, Atherogenic, Endothelium, Vascular physiology, Lipids blood, Macaca fascicularis, Male, Social Environment, Vasodilation physiology, Coronary Artery Disease physiopathology, Coronary Vasospasm psychology, Coronary Vessels physiopathology, Stress, Psychological physiopathology
- Abstract
Background: Four sets of monkeys were used to examine the effect of chronic psychosocial disruption and diet on dilator responses of coronary arteries., Methods and Results: One set consisted of monkeys consuming monkey chow and living in a stable social setting (nonatherosclerotic controls, n = 6). Three sets consumed an atherogenic diet for 14 months followed by one of three treatments for the next 16 months: 1) a high-cholesterol diet and housed in unstable social groups (n = 9); 2) a low-cholesterol diet and housed in unstable (n = 8); or 3) stable groups (n = 10). Quantitative coronary angiography revealed that intracoronary infusion of acetylcholine resulted in a change of diameter (versus infusion of 5% dextrose in water) of +4 +/- 1% in control monkeys and -11 +/- 4% in unstable monkeys consuming a high-cholesterol diet (p less than 0.05). In monkeys consuming the cholesterol-lowering diet, the change in artery diameter was +2 +/- 4% in stable and -10 +/- 4% in unstable social conditions (p less than 0.05) despite a similar plaque size (0.4 +/- 0.2 and 0.5 +/- 0.1 mm2) and total plasma cholesterol concentrations (179 +/- 9 and 172 +/- 6 mg/dl), respectively. The arterial response to nitroglycerin was similar among all groups of monkeys., Conclusions: We conclude that chronic social disruption is associated with relative arterial constriction in response to acetylcholine in atherosclerotic monkeys consuming a cholesterol-lowering diet. more...
- Published
- 1991
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35. Loss of flow-mediated endothelium-dependent dilation occurs early in the development of atherosclerosis.
- Author
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McLenachan JM, Williams JK, Fish RD, Ganz P, and Selwyn AP
- Subjects
- Acetylcholine pharmacology, Animals, Arteriosclerosis diagnostic imaging, Cholesterol, Dietary administration & dosage, Iliac Artery diagnostic imaging, Iliac Artery physiology, Macaca fascicularis, Radiography, Regional Blood Flow physiology, Time Factors, Vasodilation drug effects, Arteriosclerosis physiopathology, Endothelium, Vascular physiology, Vasodilation physiology
- Abstract
Background: Healthy arteries exhibit endothelium-dependent dilation in response to both local acetylcholine and increased blood flow. In humans, clinically overt coronary artery disease is characterized by loss of dilation to both acetylcholine and blood flow. The temporal relation, however, between functional abnormalities of the endothelium and the development of atherosclerosis has not been established., Methods and Results: We examined endothelial vasodilator function in vivo at an early stage of the development of atherosclerosis. Two groups of seven Macaca fascicularis monkeys were studied; one group was fed a high cholesterol diet (0.73-1.0 mg cholesterol per calorie) for 11 months. Cholesterol feeding was associated with increased plasma cholesterol levels and with intimal thickening of the iliac arteries but with no reduction in luminal diameter. Endothelium-dependent vasomotor responses of the iliac arteries were then examined in vivo by quantitative contrast angiography. Acetylcholine produced significant dilation in the controls but paradoxical constriction in the group with early atherosclerosis (+9.0 +/- 3.2% versus -5.3 +/- 5.4%, p less than 0.05). In response to a twofold increase in blood flow achieved by administering adenosine distal to the arterial segment under examination, the controls again dilated, whereas the atherosclerotic group failed to dilate (+ 11.6 +/- 2.1% versus + 0.5 +/- 2.4%, p less than 0.05). Both groups, however, were able to dilate, and dilated equally, to the nonendothelium-dependent agent nitroglycerin (+ 13.7 +/- 4.8% versus + 19.1 +/- 4.3%, NS)., Conclusions: Endothelium-dependent vasodilation in response to both acetylcholine and increased blood flow may be lost early in the course of developing atherosclerosis before the appearance of stenosing and occlusive disease. more...
- Published
- 1991
- Full Text
- View/download PDF
36. Effects of asymptomatic ischemia on long-term prognosis in chronic stable coronary disease.
- Author
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Yeung AC, Barry J, Orav J, Bonassin E, Raby KE, and Selwyn AP
- Subjects
- Actuarial Analysis, Adult, Aged, Aged, 80 and over, Chronic Disease, Coronary Disease mortality, Electrocardiography, Ambulatory, Exercise Test, Female, Humans, Male, Middle Aged, Prognosis, Regression Analysis, Survival Analysis, Time Factors, Coronary Disease physiopathology
- Abstract
Background: Ischemia on ambulatory electrocardiographic monitoring has been shown to adversely affect short-term prognoses in patients with unstable angina, after myocardial infarction, and with chronic stable angina., Methods and Results: In this long-term study, we followed 138 patients (mean age, 59 +/- 9 years) with chronic stable angina and positive exercise tests for cardiac events (e.g. death, myocardial infarction, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft surgery). In 105 patients, ambulatory electrocardiographic monitoring was performed after all antianginal medication was withheld for 48 hours. In 26 patients, the diagnostic tests were repeated while on their usual medication. In addition to the 105 patients, 33 patients had their monitoring performed only while on their usual medication. During 37 +/- 17 months of follow-up, there were nine deaths, nine myocardial infarctions, and 35 revascularization procedures. In patients monitored off medication, Cox survival analysis showed that the occurrence of ischemia on electrocardiographic monitoring was the most significant predictor of death and myocardial infarction in the subsequent 2 years (p = 0.02) and all adverse events for 5 years (p = 0.009). Patients who were monitored on medication and did not have ischemia (n = 18) appeared to have more adverse events than patients who had no ischemia while being monitored off medication (n = 43)., Conclusions: Asymptomatic ischemia on ambulatory electrocardiographic monitoring in patients with stable angina predicts death and myocardial infarction for 2 years and all adverse events for 5 years. Monitoring performed while on medication may show no ischemia; however, this may not indicate low risk of future coronary events. more...
- Published
- 1991
- Full Text
- View/download PDF
37. Relations between heart rate, ischemia, and drug therapy during daily life in patients with coronary artery disease.
- Author
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McLenachan JM, Weidinger FF, Barry J, Yeung A, Nabel EG, Rocco MB, and Selwyn AP
- Subjects
- Administration, Cutaneous, Coronary Disease physiopathology, Double-Blind Method, Exercise Test methods, Female, Humans, Male, Middle Aged, Time Factors, Activities of Daily Living, Coronary Disease drug therapy, Electrocardiography, Ambulatory, Heart Rate physiology, Nitroglycerin therapeutic use, Propranolol therapeutic use
- Abstract
Background: Previous studies have shown that little if any increase in heart rate occurs 1 minute before the onset of ischemia in ambulant patients with coronary artery disease. This study tested the hypothesis that there are characteristic relations between heart rate and ischemia in ambulant patients with coronary artery disease., Methods and Results: Twenty-one patients with proven coronary disease demonstrated 212 episodes of ischemia during 504 hours of continuous monitoring of the electrocardiogram. An important increase in heart rate (from 74 +/- 11 to 90 +/- 14 beats/min, p less than 0.001) occurred between 5 and 30 minutes (not 1 minute) before the onset of ischemia. A significantly higher heart rate at onset of ischemia was seen during Bruce protocol exercise testing than during daily life (117 +/- 12 versus 95 +/- 15 beats/min, p less than 0.01). However, when a less-strenuous, but more prolonged, exercise protocol was used in a subgroup of patients (n = 12), ischemia occurred at a heart rate that was significantly lower than during the Bruce protocol (88 +/- 14 versus 103 +/- 15 beats/min, p less than 0.05) and was not significantly different from the threshold heart rate at onset of ischemia during daily life (88 +/- 14 versus 84 +/- 12 beats/min, p = NS). As part of two placebo-controlled trials, treatment with both propranolol and nitroglycerin altered the distribution of ischemic events by heart rate but in opposite directions. Although propranolol largely eliminated events occurring at high (greater than 100 beats/min) and moderate (80-100 beats/min) heart rates, the number of events at low (less than 80 beats/min) heart rates was increased. In contrast, nitroglycerin reduced episodes at low and moderate heart rates only., Conclusions: Important increases in heart rate occur before the onset of ischemia during daily life, but this increase occurs much earlier than has been reported. Duration of heart rate increase appears to influence the heart rate threshold for ischemia, and this may contribute to the occurrence of ischemia at lower heart rates during daily life than during standard exercise testing. Last, different classes of drugs appear to have characteristic effects on ischemia occurring at different heart rates that may be useful in planning therapy. more...
- Published
- 1991
- Full Text
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38. Diurnal rhythms and clinical events in coronary artery disease.
- Author
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Selwyn AP, Raby K, Vita JA, Ganz P, and Yeung A
- Subjects
- Catecholamines blood, Coronary Disease blood, Coronary Disease drug therapy, Endothelium, Vascular physiopathology, Humans, Sympathetic Nervous System physiopathology, Cardiovascular System physiopathology, Circadian Rhythm, Coronary Disease physiopathology
- Abstract
Patients with coronary atherosclerosis present with angina, myocardial infarction and sudden death, most often caused by atherosclerotic stenosis complicated by spasm and/or occlusive thrombosis. All of these events have been shown to exhibit similar diurnal rhythms, with a peak incidence in the morning after waking and rising. Other cardiovascular parameters also show a similar diurnal rhythm associated with increased sympathetic outflow and circulating catecholamines, producing increases in heart rate, blood pressure, myocardial contractility and oxygen demand soon after waking and rising. Experimental and clinical research has recently pointed to several possible mechanisms that might be responsible for these events. In patients with atherosclerosis, dysfunction of the endothelium in the epicardial coronary arteries results in a failure to limit the constrictor response to catecholamines. Catecholamines can also alter the procoagulant nature of vascular surfaces. We speculate that the interaction between increased sympathetic activity and the procoagulant and vasoconstrictor states of atherosclerotic coronary stenoses may lead to a lower threshold to ischaemia in the waking hours, with a corresponding increase in angina, myocardial infarction and sudden death. These factors may be important considerations for the selection of suitable therapies and for future research. more...
- Published
- 1991
39. Coronary atherosclerosis is associated with left ventricular dysfunction and dilatation in aortic stenosis.
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Vekshtein VI, Alexander RW, Yeung AC, Plappert T, Sutton MG, Ganz P, Selwyn AP, and Bittl JA
- Subjects
- Aged, Aortic Valve Stenosis physiopathology, Coronary Artery Disease physiopathology, Electrocardiography, Female, Heart Ventricles, Humans, Male, Middle Aged, Multivariate Analysis, Aortic Valve Stenosis complications, Coronary Artery Disease complications, Heart physiopathology, Vasodilation
- Abstract
Patients with aortic stenosis develop widely variable patterns of left ventricular hypertrophy and dysfunction. We postulated that coronary atherosclerosis (CAD) may be associated with impaired left ventricular function and chamber dilatation in patients with aortic stenosis. Left ventricular mass and volumes were quantified from two-dimensional echocardiography and correlated with coronary angiography in 78 patients with severe aortic stenosis and no previous myocardial infarction or regional wall motion abnormalities. Eighteen patients (group 1) had smooth coronary arteries, 25 patients had irregular coronary arteries with 50% or less stenosis (group 2), and 35 patients had obstructive CAD (group 3). Even though the calculated valve area was similar in all three study groups, group 1 patients had higher values for ejection fraction (65 +/- 9%, 51 +/- 17%, and 48 +/- 13%; p = 0.0002), systolic mass-to-volume ratio (9.2 +/- 3.9, 5.6 +/- 2.8, and 5.2 +/- 2.2; p = 0.0001), and cardiac index (2.9 +/- 0.7, 2.5 +/- 0.7, and 2.3 +/- 0.6 l/min.min2; p = 0.015) than patients in groups 2 and 3, respectively (mean +/- SD). Mean circumferential wall stress was inversely related to severity of CAD. Multivariate analysis showed that CAD is an independent predictor of ejection fraction and mass-to-volume ratio in this group of patients. Thus, in an elderly population with severe aortic stenosis, patients with both obstructive and nonobstructive CAD have an increased incidence of left ventricular enlargement and systolic dysfunction. more...
- Published
- 1990
- Full Text
- View/download PDF
40. Early evidence of endothelial vasodilator dysfunction at coronary branch points.
- Author
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McLenachan JM, Vita J, Fish DR, Treasure CB, Cox DA, Ganz P, and Selwyn AP
- Subjects
- Acetylcholine pharmacology, Adolescent, Adult, Angiography, Coronary Angiography, Coronary Artery Disease etiology, Coronary Artery Disease physiopathology, Coronary Vessels drug effects, Disease Susceptibility, Endothelium, Vascular diagnostic imaging, Female, Humans, Male, Middle Aged, Coronary Vessels physiopathology, Endothelium, Vascular physiopathology, Vasodilation
- Abstract
Intracoronary acetylcholine produces endothelium-dependent dilation of normal coronary arteries and paradoxical constriction of atherosclerotic vessels. Regional differences in endothelium-dependent vasomotion, however, have not been studied in relation to the nonuniform development of atherosclerosis. We compared the vasomotor response to increasing doses of acetylcholine of angiographically smooth coronary artery segments prone to atherosclerosis (coronary branch points) with segments remote from branch points (straight segments). In patients with entirely smooth coronary arteries and a dilator response to acetylcholine (group 1, n = 7), branch points and straight segments demonstrated equal and significant dose-dependent dilation to acetylcholine (14.7 +/- 8.9% and 12.3 +/- 12.7%, respectively; p identical to NS). In patients with early atherosclerosis as manifest by luminal coronary irregularities, the lowest dose of acetylcholine (10(-8) M) produced constriction at branch points and slight dilation at straight segments (-6.3 +/- 7.4% vs. +2.2 +/- 7.3%, p less than 0.05). At higher doses of acetylcholine, both branch point and straight segments constricted, but constriction remained more pronounced at branch points. Both branch point and straight segments, however, retained the ability to dilate to the non-endothelium-dependent agent, nitroglycerin. In a third group of patients with angiographically entirely smooth coronary arteries but without dilation to acetylcholine, constriction to acetylcholine again occurred first at branch points. Thus, coronary branch points demonstrate increased sensitivity to acetylcholine-induced constriction in patients with angiographic evidence of early coronary atherosclerosis and in middle-aged patients with smooth coronary arteries. These segments, however, retain the ability to dilate to nitroglycerin. Whether this early evidence of defective endothelium-dependent vasodilation predicts the later development of occlusive atherosclerosis is not yet known. more...
- Published
- 1990
- Full Text
- View/download PDF
41. Silent ischemia after myocardial infarction. Prognosis, mechanism, and intervention.
- Author
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Yeung AC, Barry J, and Selwyn AP
- Subjects
- Biomechanical Phenomena, Coronary Disease physiopathology, Coronary Disease therapy, Humans, Myocardial Infarction mortality, Prognosis, Risk Factors, Survival Analysis, Coronary Disease complications, Myocardial Infarction complications
- Abstract
Asymptomatic ischemia after myocardial infarction is a common clinical problem. As much as 50% of the postinfarction patient population who have ischemia on exercise testing may have no symptoms at all. In these patients, ischemia detected by either exercise testing or ambulatory electrocardiographic monitoring, with or without symptoms, confers a worse prognosis. The mechanism of silent ischemia in this group of patients may be due to the deprivation of afferent innervations created by critically placed infarctions. The management of these postinfarction patients must be centered on the treatment of ischemia, regardless of symptoms. more...
- Published
- 1990
42. Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis.
- Author
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Nabel EG, Selwyn AP, and Ganz P
- Subjects
- Acetylcholine pharmacology, Adult, Coronary Angiography, Coronary Artery Disease diagnostic imaging, Coronary Circulation drug effects, Coronary Vessels drug effects, Endothelium, Vascular drug effects, Female, Humans, Male, Middle Aged, Nitroglycerin pharmacology, Papaverine pharmacology, Ultrasonography, Vasodilation drug effects, Vasodilation physiology, Coronary Artery Disease physiopathology, Coronary Circulation physiology, Coronary Vessels physiopathology, Endothelium, Vascular physiopathology
- Abstract
Changes in blood flow can alter vasomotion of conduit arteries. This study examined vasomotor responses to incremental blood flow induced by papaverine in the epicardial arteries of 10 patients with angiographically normal coronary arteries (group 1) and in 14 patients with arterial irregularities (group 2) using quantitative angiography and Doppler ultrasound flow velocity measurements. An increase in coronary blood flow of 384.3 +/- 32.8% (p less than 0.001) in group 1 patients was associated with dilation of the proximal coronary artery segment and a 23.2 +/- 4.6% increase in cross-sectional area (p less than 0.001). In contrast, in group 2 patients a similar increase in coronary blood flow of 339.3 +/- 18.7% (p less than 0.001) was associated with mixed responses and a modest net constriction in cross-sectional area of -7.4 +/- 2.8% (p less than 0.05). The dilation response to nitroglycerin was intact in group 1 (31.7 +/- 4.2%, p less than 0.001) and in group 2 (26.4 +/- 3.2%, p less than 0.001). In five patients from group 1 acetylcholine, an endothelium-dependent dilator, produced an increase in cross-sectional area of 20.7 +/- 4.6% (p less than 0.05) that paralleled the response to an increase in flow in the same segment (a 24.3 +/- 6.1% increase in cross-sectional area, p less than 0.05). Five group 2 patients demonstrated a vasoconstrictor response to acetylcholine (a -22.8 +/- 3.4% decrease in cross-sectional area, p less than 0.05) together with an impaired dilation response to incremental flow (a -6.4 +/- 3.2% decrease in cross-sectional area).(ABSTRACT TRUNCATED AT 250 WORDS) more...
- Published
- 1990
- Full Text
- View/download PDF
43. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy.
- Author
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Treasure CB, Vita JA, Cox DA, Fish RD, Gordon JB, Mudge GH, Colucci WS, Sutton MG, Selwyn AP, and Alexander RW
- Subjects
- Acetylcholine, Adenosine, Humans, Male, Microcirculation physiopathology, Middle Aged, Nitric Oxide physiology, Vascular Resistance physiology, Vasodilation drug effects, Cardiomyopathy, Dilated physiopathology, Coronary Circulation physiology, Coronary Vessels physiopathology, Endothelium, Vascular physiology, Vasodilation physiology
- Abstract
Dilator reserve of the coronary microvasculature is diminished in patients with dilated cardiomyopathy. Although increased extravascular compressive forces, tachycardia, and increased myocardial mass can explain some impairment, recent evidence suggests the possibility of intrinsic microvascular disease. We tested the hypothesis that impairment of endothelium-dependent dilation of the microvasculature could be a contributing mechanism. We infused the endothelium-dependent dilator acetylcholine (Ach) (10(-8) to 10(-6) M) and the smooth muscle vasodilator adenosine (AD) (10(-6) to 10(-4) M) into the left anterior descending coronary artery in eight patients with dilated cardiomyopathy (mean ejection fraction, 28%) and seven controls (atypical chest pain). Small vessel resistance was assessed by measuring coronary blood flow (CBF) at constant arterial pressure with a Doppler velocity catheter (corrected for cross-sectional area by angiography). With Ach, control patients increased CBF 232 +/- 40% (mean +/- SEM), whereas CBF did not significantly change in cardiomyopathy patients (41 +/- 24%) (p less than 0.0001, control vs. cardiomyopathy). With AD, control patients increased CBF 422 +/- 56% and cardiomyopathy patients increased CBF 268 +/- 43% (p = 0.13). An index of the proportion of coronary flow reserve attributable to endothelium-dependent vasodilation was obtained by standardizing each patient's Ach dose response to his maximal AD flow response. In seven control patients receiving both Ach and AD, 56 +/- 9% of the maximal AD flow response was attained with the endothelium-dependent vasodilator Ach, whereas in seven cardiomyopathy patients receiving both Ach and AD, only 23 +/- 14% of the maximal AD response was attained (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) more...
- Published
- 1990
- Full Text
- View/download PDF
44. Paradoxical narrowing of atherosclerotic coronary arteries induced by increases in heart rate.
- Author
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Nabel EG, Selwyn AP, and Ganz P
- Subjects
- Aged, Angiography, Blood Flow Velocity physiology, Cardiac Catheterization, Cardiac Pacing, Artificial, Coronary Angiography, Coronary Artery Disease diagnosis, Coronary Circulation physiology, Coronary Disease etiology, Female, Humans, Male, Middle Aged, Tachycardia physiopathology, Vasomotor System physiopathology, Coronary Artery Disease physiopathology, Coronary Vessels physiopathology, Heart Rate physiology
- Abstract
Vasodilation in normal and vasoconstriction in atherosclerotic coronary arteries have been observed in response to complex stimuli such as exercise and the cold pressor test. To study a single parameter that changes during these activities, and to better understand the pathophysiology of ischemia associated with increases in heart rate, we studied coronary vasomotion and blood flow response to increasing heart rate alone, produced by atrial pacing, with quantitative angiographic and Doppler flow-velocity measurements in 15 patients. In five patients with angiographically smooth coronary arteries (group 1), tachycardia produced progressive dilation of the epicardial artery with increases in cross-sectional area (CSA) of +15.5 +/- 3.4%, +22.4 +/- 2.1%, +28.5 +/- 3.3%, and +30.6 +/- 2.2% at 90, 110, 130, and 150 beats/min, respectively. In contrast, in five patients with mild angiographic narrowings (group 2), coronary segments failed to dilate with progressive tachycardia (-6.3 +/- 2.0%, -8.3 +/- 2.0%, -12.5 +/- 2.0%, and -11.4% at 90, 110, 130, and 150 beats/min, respectively), and progressive loss of luminal area was observed in five patients with severe angiographic narrowings (group 3) (-34.4 +/- 3.4%, -49.6 +/- 2.2%, -59.2%, and -72.8% at 90, 110, 130, and 150 beats/min, respectively). Coronary blood flow increased significantly with tachycardia in group 1 (+44.5 +/- 10.2%, +86.0 +/- 24.6%, +105.8 +/- 29.3%, and +137.5 +/- 46.0%), increased slightly in group 2 (+7.8 +/- 3.2%, +9.4 +/- 4.4%, +8.4 +/- 3.9%, and +10.0%), and decreased significantly in group 3 (-31.8 +/- 6%, -42.6 +/- 10.7%, -61.0%, and -70.0%). We conclude that an isolated increase in heart rate in patients with normal coronary arteries results in a modest increase in flow and vasodilation. In early atherosclerosis, the flow increase is blunted and dilation is replaced with paradoxical loss in luminal size. In patients with stenoses, further loss in luminal size occurs accompanied by a decrease in coronary blood flow. Thus, increasing heart rate alone in the setting of coronary stenoses could produce myocardial ischemia by a reduction in coronary supply, as well as by an increase in oxygen demand. more...
- Published
- 1990
- Full Text
- View/download PDF
45. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.
- Author
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Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish RD, Yeung AC, Vekshtein VI, Selwyn AP, and Ganz P
- Subjects
- Adult, Angiography, Cholesterol blood, Coronary Angiography, Endothelium, Vascular drug effects, Female, Humans, Male, Nitroglycerin pharmacology, Risk Factors, Sex Factors, Vasoconstriction drug effects, Vasodilation drug effects, Acetylcholine pharmacology, Coronary Disease diagnosis, Coronary Vessels drug effects
- Abstract
In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunction. In patients with angiographically smooth coronary arteries, acetylcholine has been reported to produce both vasodilation and constriction. To test the hypothesis that the acetylcholine response relates to risk factors for coronary artery disease, acetylcholine 10(-8) to 10(-6) M was infused into the left anterior descending or circumflex coronary artery, and diameter changes were assessed with quantitative angiography in 34 patients with angiographically smooth coronary arteries. The acetylcholine response ranged from +37% (dilation) to -53% (constriction) at the peak acetylcholine dose. All coronary arteries dilated in response to nitroglycerin (26 +/- 17%), suggesting an abnormality of endothelial function in the patients with a constrictor response to acetylcholine. By multiple stepwise regression analysis, serum cholesterol (p less than 0.01), male gender (p less than 0.001), family history (p less than 0.05), age (p less than 0.05), cholesterol level (p less than 0.01), and total number of risk factors (p less than 0.0001) were independently associated with the acetylcholine response. Thus, coronary risk factors are associated with loss of endothelium-dependent vasodilation. The development of vasoconstriction is likely to be an abnormality of endothelial function that precedes atherosclerosis or an early marker of atherosclerosis not detectable by angiography. more...
- Published
- 1990
- Full Text
- View/download PDF
46. The interpretation of thallium-201 cardiac scintigrams. Studies in experimental ischemic heart disease in dogs.
- Author
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Selwyn AP, Welman E, Pratt TA, Clark J, McArthur C, and Lavender JP
- Subjects
- Animals, Coronary Vessels diagnostic imaging, Dogs, Electrocardiography, Krypton, Radionuclide Imaging, Coronary Disease diagnostic imaging, Radioisotopes, Thallium
- Published
- 1978
- Full Text
- View/download PDF
47. Thrombolytic therapy of acute pulmonary embolism: current status and future potential.
- Author
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Goldhaber SZ, Meyerovitz MF, Markis JE, Kim D, Kessler CM, Sharma GV, Vaughan DE, Selwyn AP, Dawley DL, and Loscalzo J
- Subjects
- Acute Disease, Clinical Trials as Topic, Fibrinolytic Agents adverse effects, Humans, Pulmonary Artery diagnostic imaging, Pulmonary Embolism diagnostic imaging, Radiography, Recombinant Proteins adverse effects, Recombinant Proteins therapeutic use, Time Factors, Tissue Plasminogen Activator adverse effects, Tissue Plasminogen Activator therapeutic use, Urokinase-Type Plasminogen Activator therapeutic use, Fibrinolytic Agents therapeutic use, Pulmonary Embolism drug therapy
- Abstract
Recombinant human tissue-type plasminogen activator (rt-PA), a relatively clot-specific fibrinolytic agent, represents a novel and promising approach to thrombolytic therapy of pulmonary embolism. Therefore, the efficacy and safety of peripheral intravenous rt-PA therapy were assessed in 47 patients with angiographically documented pulmonary embolism. The drug regimen was 50 mg over 2 hours followed by repeat angiography and, if necessary, an additional 40 mg over 4 hours. By 6 hours, 44 of the 47 patients had angiographic evidence of clot lysis that was slight (n = 5), moderate (n = 12) or marked (n = 27). Among the 34 patients with pulmonary hypertension before treatment (mean pulmonary artery pressure exceeding 17 mm Hg), the pressure decreased from 43/17 (mean 27) to 31/13 (mean 19) mm Hg (p less than 0.0001). Fibrinogen decreased 33% from baseline at 2 hours and 42% from baseline at 6 hours. There were two major complications that required surgical control of bleeding: hemorrhage from a pelvic tumor and mediastinal tamponade in a patient 8 days after coronary artery bypass surgery. The initial results demonstrate that, among selected patients, peripheral intravenous rt-PA can rapidly and, for the most part, safely lyse pulmonary embolism within 6 hours. more...
- Published
- 1987
- Full Text
- View/download PDF
48. The effects of propranolol on myocardial perfusion and metabolism during acute regional ischaemia.
- Author
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Fox KM, Selwyn AP, and Welman E
- Subjects
- Animals, Creatine Kinase, Dogs, Krypton, Radioisotopes, Coronary Disease metabolism, Heart drug effects, Myocardial Infarction metabolism, Propranolol pharmacology
- Abstract
The unique physical properties of the short-lived inert and freely diffusing isotope 81mkrypton allow a continuous observation to be made of regional myocardial perfusion. Eighteen dogs were anaesthetised and a reversible snare placed on the left anterior descending coronary artery (LAD). 81mKrypton was used to study regional myocardial perfusion, and myocardial metabolism was assessed using the epicardial ECG and release of creatine kinase activity (CK). Six dogs did not undergo LAD occlusion ("sham operated"); in six other dogs the LAD was occluded (controls), and another six dogs were given propranolol, 0.5 mg/kg, 20 min after LAD occlusion. All the parameters were measured before and for 5 h after LAD occlusion. When compared to controls, dogs treated with propranolol showed significant improvement (p less than 0.01) in regional myocardial perfusion; smaller loss of electrically active myocardium for any given degree of early ST-segment elevation; and a delay in the release of CK activity from a local coronary vein. These results suggest that propranolol exerts a beneficial effect following the development of acute myocardial infarction. more...
- Published
- 1980
- Full Text
- View/download PDF
49. Projection of electrocardiographic signs in praecordial maps after exercise in patients with ischaemic heart disease.
- Author
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Fox KM, Selwyn AP, and Shillingford JP
- Subjects
- Adult, Aged, Coronary Disease physiopathology, Exercise Test methods, Heart physiopathology, Humans, Male, Middle Aged, Coronary Disease diagnosis, Electrocardiography methods
- Abstract
Praecordial surface maps of the electrocardiogram were recorded before and after exercise using 16 electrodes covering the left hemithorax. The ST segment and R and S wave changes were measured in the praecordial maps from 20 individuals with no detectable cardiovascular disease. These showed no significant alteration in ST segments of R/S. In contrast in 40 patients with angiocardiographically proven coronary artery disease it was possible clearly to outline the distribution, severity, and time course of praecordial areas of ST segment depression (36 patients) and ST segment elevation (10 patients). In addition these praecordial areas of ST segment changes were accompanied by a regional and significant fall in the R/S. The praecordial electrocardiogram with exercise complements the anatomical information obtained from the coronary arteriogram by clearly outlining electrocardiographic projections of regional myocardial ischaemia or cell death. more...
- Published
- 1979
- Full Text
- View/download PDF
50. Features of the exercise test that reflect the activity of ischemic heart disease out of hospital.
- Author
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Campbell S, Barry J, Rocco MB, Nabel EG, Mead-Walters K, Rebecca GS, and Selwyn AP
- Subjects
- Activities of Daily Living, Adult, Aged, Ambulatory Care, Angiography, Coronary Disease diagnostic imaging, Electrocardiography, Female, Heart Rate, Humans, Male, Middle Aged, Monitoring, Physiologic, Prognosis, Risk, Time Factors, Coronary Disease physiopathology, Exercise Test
- Abstract
To better understand the relationship between the transient myocardial ischemia seen during an exercise test and ischemic activity out of hospital, 39 patients with well-documented coronary artery disease underwent standard treadmill exercise testing (Bruce protocol) and 24 to 48 hr of continuous ambulatory electrocardiographic monitoring during normal daily activities. A total of 245 episodes of transient ischemia were recorded in 21 of 32 patients with positive exercise electrocardiograms (group I), whereas seven patients with negative test results (group II) had no episodes of transient ischemia, during monitoring out of hospital (p less than .01). Certain measures in the exercise test were related to the severity of ischemia out of hospital: there were more episodes and a greater total duration of transient ischemia per 24 hr of ambulatory monitoring in patients who developed ischemic electrocardiographic changes before 6 min of exercise (p less than or equal to .021) or at a heart rate of less than 150 beats/min (p = .005) and in those in whom these ST segment changes persisted for more than 5 min after exercise (p less than or equal to .016). In contrast, there was no relationship between transient ischemia out of hospital and the commonly quoted exercise variables: chest pain, total exercise duration, and the maximum levels of heart rate, systolic blood pressure, and double product. Thus, patients with coronary artery disease and negative exercise electrocardiograms are most unlikely to experience active ischemia during normal daily life.(ABSTRACT TRUNCATED AT 250 WORDS) more...
- Published
- 1986
- Full Text
- View/download PDF
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