Biomedical subjects

Andrew P Selwyn

Publications and source records attributed to Andrew P Selwyn.

15 recordsLinked to original sources

PubMed2006

Impact of coronary endothelial function on the progression of cardiac transplant-associated arteriosclerosis: effect of anti-oxidant vitamins C and E.

BACKGROUND: Excessive vascular oxidant stress has been implicated in cardiac transplant-associated arteriosclerosis (TxAA). In a recent placebo-controlled study of 40 cardiac transplant recipients, vitamin C 500 mg twice a day and vitamin E 400 IU twice a day for 1 year retarded the progression of TxAA, as assessed by intravascular ultrasound (IVUS). Endothelial dysfunction is a key feature of TxAA and reflects oxidant stress. We hypothesized that coronary endothelial dysfunction portends greater TxAA progression and a larger therapeutic response to anti-oxidant vitamins. METHODS: In this pre-specified analysis, the 40 cardiac transplant recipients were categorized according to normal or abnormal coronary endothelial vasomotor function at baseline, as assessed by acetylcholine (10(-8) to 10(-6) mol/liter). The effect of anti-oxidant vitamins within these two groups of patients was assessed by the change in intimal index over 1 year using IVUS. RESULTS: With placebo (n = 21), the increase in intimal index was greater in the presence vs absence of endothelial dysfunction (11 +/- 3% vs 5 +/- 1%, p < 0.05). Among patients with endothelial dysfunction (n = 21), the intimal index increased 11 +/- 3% with placebo, but decreased -1 +/- 2% with vitamins (p = 0.002). Among patients with normal endothelial function (n = 14), the intimal index increased 5 +/- 1% with placebo and 1 +/- 1% with vitamins (p < 0.05). CONCLUSIONS: Endothelial dysfunction indicates rapid TxAA progression, even in the statin era. Although anti-oxidant vitamins reduce disease progression in patients with normal or abnormal endothelial function, the magnitude of benefit is larger in patients with endothelial dysfunction.

Antioxidants↗

PubMed2005

Characterization of human atherosclerotic plaques by intravascular magnetic resonance imaging.

BACKGROUND: Development and validation of novel imaging modalities to assess the composition of human atherosclerotic plaques will improve the understanding of atheroma evolution and could facilitate evaluation of therapeutic strategies for plaque modification. Surface MRI can characterize tissue content of carotid but not deeper arteries. This study evaluated the usefulness of intravascular MRI (IVMRI) to discern the composition of human iliac arteries in vivo. METHODS AND RESULTS: Initial studies validated IVMRI against histopathology of human atherosclerotic arteries ex vivo. A 0.030-inch-diameter IVMRI detector coil was advanced into isolated human aortoiliac arteries and coupled to a 1.5-T scanner. Information from combined T1-, moderate T2-, and proton-density-weighted images differentiated lipid, fibrous, and calcified components with favorable sensitivity and specificity and allowed accurate quantification of plaque size. The validated approach was then applied to image iliac arteries of 25 human subjects in vivo, and results were compared with those of intravascular ultrasound (IVUS). IVMRI readily visualized inner and outer plaque boundaries in all arteries, even those with extensive calcification that precluded IVUS interpretation. It also revealed the expected heterogeneity of atherosclerotic plaque content that was noted during ex vivo validation. Again, IVUS did not disclose this heterogeneity. The level of interobserver and intraobserver agreement in the interpretation of plaque composition was high for IVMRI but poor for IVUS. CONCLUSIONS: IVMRI can reliably identify plaque composition and size in arteries deep within the body. Identification of plaque components by IVMRI in vivo has important implications for the understanding and modification of human atherosclerosis.

Adult↗

PubMed2005

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.

BACKGROUND: Lipid lowering with statins prevents adverse cardiac events. Both lipid-lowering and antioxidant therapies may favorably affect vasomotor function and thereby improve ischemia. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial, 300 patients with stable coronary disease, a positive exercise treadmill test, 48-hour ambulatory ECG with > or =1 episode of ischemia, and fasting total cholesterol of 180 to 250 mg/dL were assigned to 1-year treatment with intensive atorvastatin to reduce LDL to <80 mg/dL (n=96), intensive atorvastatin to reduce LDL to <80 mg/dL plus antioxidant vitamins C (1000 mg/d) and E (800 mg/d) (n=101), or diet and low-dose lovastatin, if needed, to reduce LDL to <130 mg/dL (n=103; control group). Ischemia end points, including ambulatory ECG monitoring and exercise treadmill testing, and endothelial assessment using brachial artery flow-mediated dilation were obtained at baseline and at 6 and 12 months. Baseline characteristics were similar in all groups. LDL decreased from approximately 153 mg/dL at baseline in the 2 atorvastatin groups to approximately 83 mg/dL at 12 months (each P<0.0001) and from 147 to 120 mg/dL in the control group (P<0.0001). During ambulatory ECG monitoring, mean number of ischemic episodes per 48 hours decreased 31% to 61% in each group (each P<0.001; P=0.15 across groups), without a change in daily heart rate activity. Mean duration of ischemia for 48 hours decreased 26% to 62% in each group (each P<0.001; P=0.06 across groups). Mean exercise duration to 1-mm ST-segment depression significantly increased in each group, but total exercise duration and mean sum of maximum ST depression were unchanged. Angina frequency decreased in each group. There was no incremental effect of supplemental vitamins C and E on any ischemia outcome. Flow-mediated dilation studies indicated no meaningful changes. CONCLUSIONS: Intensive lipid lowering with atorvastatin to an LDL level of 80 mg/dL, with or without antioxidant vitamins, does not provide any further benefits in ambulatory ischemia, exercise time to onset of ischemia, and angina frequency than moderate lipid lowering with diet and low-dose lovastatin to an LDL level of <120 mg/dL.

Angina Pectoris↗

PubMed2004

Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.

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.

Adult↗

PubMed2004

Increased Th1 activity in patients with coronary artery disease.

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.

Adult↗

PubMed2004

Long-term effect of combined vitamins E and C on coronary and peripheral endothelial function.

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.

Antioxidants↗

PubMed2004

Vascular basis for the treatment of myocardial ischemia study: trial design and baseline characteristics.

BACKGROUND: Increased low-density lipoprotein (LDL) and oxidized LDL cholesterol levels adversely affect endothelial function in patients with stable coronary artery disease (CAD). Statin drugs are efficacious in primary and secondary prevention of clinical CAD events, but they have not been extensively studied as a treatment for ischemia during routine daily activities or during exercise, indicators of high-risk in patients with stable CAD. The purpose of the Vascular Basis for the Treatment of Myocardial Ischemia study is to determine whether aggressive lowering of LDL cholesterol level with atorvastatin, with or without supplemental antioxidant vitamins C and E, can improve endothelial function and ischemia during ambulatory electrocardiogram (AECG) monitoring and exercise treadmill testing (ETT). METHODS: Patients are eligible when they have ischemia during an ETT and AECG monitoring and when their fasting total cholesterol level is < or =250 mg/dL. Eligible patients are randomized to receive 1 of 3 treatments: intensive atorvastatin to reduce LDL cholesterol level to < or =80 mg/dL, intensive atorvastatin to reduce LDL cholesterol level to < or =80 mg/dL plus antioxidant vitamins C and E, and control of diet and low-dose lovastatin, when needed, to reduce LDL cholesterol level < or = to 130 mg/dL. Patients undergo endothelial function testing, 48-hour AECG monitoring, and ETT at randomization and at 6 and 12 months. RESULTS: A total of 300 patients have been randomized: 101 to receive atorvastatin alone, 103 to receive atorvastatin plus antioxidant vitamins, and 96 to receive placebo. Baseline characteristics are similar across treatment groups. CONCLUSIONS: The Vascular Basis study will provide important insight on the effects of aggressive management of dyslipidemia with statin drugs and antioxidant vitamins in patients with stable but high-risk CAD.

Adult↗

PubMed2003

Endothelial function, inflammation, and prognosis in cardiovascular disease.

The vascular endothelium is an active, dynamic tissue that controls many important functions, including regulation of vascular tone and maintenance of blood circulation, fluidity, coagulation, and inflammatory responses. Cardiovascular risk factors affect many of the normal functions of the endothelium. In particular, oxidized low-density lipoprotein cholesterol initiates a series of events that begin with cell activation, endothelial dysfunction, local inflammation, and a procoagulant vascular surface. These conspire to result in plaque formation and ultimately plaque rupture and cardiovascular events. Endothelial dysfunction may be evaluated by means of invasive techniques, such as coronary artery reactivity to acetylcholine, or noninvasive techniques, such as brachial artery ultrasonography. Loss of endothelium-dependent vasodilation is a characteristic feature throughout the development of atherosclerosis, and it is independently related to future adverse cardiovascular risk. Therefore, measurement of endothelial function can possibly be used to determine risk, to triage management, and to improve outcomes. At the same time, inflammation is a crucial factor in the atherosclerotic disease process. To identify and monitor the ongoing inflammatory process, markers of inflammation such as C-reactive protein (CRP) have been studied. Scientific evidence shows that elevated plasma CRP values add to the predictive ability of other established risk factors; moreover, elevated values appear to augment the Framingham Coronary Risk Score in identifying individuals who should be considered for cardioprotective treatment programs. Interestingly, thiazolidinediones (TZDs), peroxisome proliferator-activated receptor-gamma agonists that are effective in the treatment of type 2 diabetes mellitus, not only increase insulin sensitivity but can benefit endothelial function because they exhibit anti-inflammatory effects. For many individuals, including those with the metabolic syndrome and/or type 2 diabetes, endothelial dysfunction and elevated plasma CRP levels indicate increased risk of cardiovascular disease. Notably, the TZDs have been shown to reduce CRP levels and may improve endothelial function.

Cardiovascular Diseases↗

PubMed2003

Prothrombotic and antithrombotic pathways in acute coronary syndromes.

The acute coronary syndromes arise from procoagulant changes in complex plaques, which trigger both platelet activation and coagulation pathways. These 2 pathways intersect at a number of points that form positive-feedback loops to sustain and accelerate thrombus formation. In normal hemostasis and with a healthy endothelium, intravascular thrombosis is prevented, and vascular patency is protected by the fibrinolytic system and a number of antithrombotic factors, such as antithrombin, thrombomodulin, and tissue factor pathway inhibitor. However, atherosclerosis is characterized by a hypercoagulable state, and the fibrinolytic balance is skewed toward occlusive thrombus formation at critical sites on vulnerable plaques. This review focuses on cellular and humoral mechanisms and the antithrombotic strategies that are important during the acute phase of an ischemic coronary syndrome, both in patients managed conservatively and in patients scheduled for an interventional procedure. These strategies include fibrinolytic therapy, antiplatelet therapies (aspirin, clopidogrel, glycoprotein IIb/IIIa receptor inhibitors), and low-molecular-weight heparin.

Acute Disease↗

PubMed2003

Effects of statins on inflammation in patients with acute and chronic coronary syndromes.

Inflammation plays a crucial role in the cell biology of atherosclerosis. Coronary risk factors, and particularly low-density lipoprotein (LDL) cholesterol, injure the endothelium and decrease the bioavailability of nitric oxide to promote the expression of proinflammatory genes, cellular adhesion molecules, cytokines, chemokines, and growth factors. For example, the expression of CD40/CD40 ligand increases cell-mediated immune responses to activate a number of inflammatory cells and destabilize atherosclerosis. As part of this response, soluble markers of inflammation that are released into the blood offer insights into the cell biology of inflammation in atherosclerosis. In groups of patients, these markers have provided a means to study inflammatory mechanisms and have supported the value of many of our interventions that prevent cardiovascular disease. Statins have potent effects to reduce LDL cholesterol in the plasma and the artery wall and also appear to have a number of nonlipid effects that decrease inflammatory stimuli. Because statins also reduce some soluble markers of inflammation, it is likely that at least part of their benefit reflects a reduction in vascular inflammation in stable and unstable coronary syndromes. Although these inflammatory markers are valuable tools for studying the mechanisms of atherosclerosis, their use in clinical practice to stratify cardiovascular risk or assess treatment in individual patients requires further evaluation.

Acute Disease↗

PubMed2002

Circulating autoantibodies to oxidized LDL correlate with impaired coronary endothelial function after cardiac transplantation.

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.

Acetylcholine↗

PubMed2002

Coronary flow velocity and disturbed flow predict adverse clinical outcome after coronary angioplasty.

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.

Angioplasty, Balloon, Laser-Assisted↗

PubMed2002

Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial.

BACKGROUND: Cardiac transplantation is associated with oxidant stress, which may contribute to the development of accelerated coronary arteriosclerosis. We postulated that treatment with antioxidant vitamins C and E would retard the progression of transplant-associated arteriosclerosis. METHODS: In a double-blind prospective study, 40 patients (0-2 years after cardiac transplantation) were randomly assigned vitamin C 500 mg plus vitamin E 400 IU, each twice daily (n=19), or placebo (n=21) for 1 year. The primary endpoint was the change in average intimal index (plaque area divided by vessel area) measured by intravascular ultrasonography (IVUS). Coronary endothelium-dependent vasoreactivity was assessed with intracoronary acetylcholine infusions. IVUS, coronary vasoreactivity, and vitamin C and E plasma concentrations were assessed at baseline and at 1 year follow-up. All patients received pravastatin. Analyses were by intention to treat. FINDINGS: Vitamin C and E concentrations increased in the vitamin group (vitamin C 43 [SD 21] to 103 [43] mmol/L; vitamin E 24 [14] to 65 [27] mmol/L) but did not change in the placebo group (vitamin C 45 [15] vs 43 [16] mmol/L; vitamin E 27 [14] vs 27 [9] mmol/L; p<0.0001 for difference between groups). During 1 year of treatment, the intimal index increased in the placebo group by 8% (SE 2) but did not change significantly in the treatment group (0.8% [1]; p=0.008). Coronary endothelial function remained stable in both groups. INTERPRETATION: Supplementation with antioxidant vitamins C and E retards the early progression of transplant-associated coronary arteriosclerosis.

Antioxidants↗

PubMed2002

Rescue percutaneous coronary intervention following coronary artery bypass graft--a descriptive analysis of the changing interface between interventional cardiologist and cardiac surgeon.

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.

Aged↗

PubMed2002

Clopidogrel inhibits shear-induced platelet function.

We enrolled 17 healthy adult volunteers and measured platelet hemostasis time (PHT) and collagen-induced thrombus formation (CITF) before and after the oral administration of 300 mg of clopidogrel utilizing the Xylum Clot Signature Analyzer. We documented a statistically significant 30% prolongation of the PHT from 291+/-13 (SE) seconds to 376+/-31 (SE) s (P=0.037). There was a 7% prolongation of the CITF from 347+/-10 to 371+/-17 (SE) s (P=0.245). This study suggests that the Xylum Clot Signature Analyzer can measure changes in platelet function in response to a modest platelet inhibitor, and may be a useful clinical tool for the monitoring of antiplatelet therapies in patients.

Adult↗