E L Alderman

Stanford University, Palo Alto, California, United States

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Publications (222)2231.32 Total impact

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    ABSTRACT: Coronary artery disease (CAD) is the major cause of death in patients with type 2 diabetes mellitus. Although demographic and clinical factors associated with extent of CAD in patients with diabetes mellitus have been described, genetic factors have not. We hypothesized that genetic variation in peroxisome proliferator-activated receptor (PPAR) pathway genes, important in diabetes mellitus and atherosclerosis, would be associated with extent of CAD in patients with diabetes mellitus. We genotyped 1043 patients (702 white, 175 blacks) from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) genetic cohort for 3351 variants in 223 PPAR pathway genes using a custom targeted-genotyping array. Angiographic end points were determined by a core laboratory. In whites, a single variant (rs1503298) in TLL1 was significantly (P=5.5 × 10(-6)) associated with extent of CAD, defined as number of lesions with percent diameter stenosis ≥20%, after stringent Bonferroni correction for all 3351 single nucleotide polymorphisms. This association was validated in the diabetic subgroups of 2 independent cohorts, the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) post-myocardial infarction registry and the prospective Family Heart Study (FHS) of individuals at risk for CAD. TLL1rs1503298 was also significantly associated with extent of severe CAD (≥70% diameter stenosis; P=3.7 × 10(-2)) and myocardial jeopardy index (P=8.7 × 10(-4)). In general linear regression modeling, TLL1rs1503298 explained more variance of extent of CAD than the previously determined clinical factors. We identified a variant in a single PPAR pathway gene, TLL1, that is associated with the extent of CAD independently of clinical predictors, specifically in patients with type 2 diabetes mellitus and CAD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.
    Circulation 09/2011; 124(13):1426-34. DOI:10.1161/CIRCULATIONAHA.111.029173 · 14.95 Impact Factor
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    ABSTRACT: We evaluated demographic, clinical, and angiographic factors influencing the selection of coronary artery bypass graft (CABG) surgery versus percutaneous coronary intervention (PCI) in diabetic patients with multivessel coronary artery disease (CAD) in the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) trial. Factors guiding selection of mode of revascularization for patients with diabetes mellitus and multivessel CAD are not clearly defined. In the BARI 2D trial, the selected revascularization strategy, CABG or PCI, was based on physician discretion, declared independent of randomization to either immediate or deferred revascularization if clinically warranted. We analyzed factors favoring selection of CABG versus PCI in 1,593 diabetic patients with multivessel CAD enrolled between 2001 and 2005. Selection of CABG over PCI was declared in 44% of patients and was driven by angiographic factors including triple vessel disease (odds ratio [OR]: 4.43), left anterior descending stenosis >or=70% (OR: 2.86), proximal left anterior descending stenosis >or=50% (OR: 1.78), total occlusion (OR: 2.35), and multiple class C lesions (OR: 2.06) (all p < 0.005). Nonangiographic predictors of CABG included age >or=65 years (OR: 1.43, p = 0.011) and non-U.S. region (OR: 2.89, p = 0.017). Absence of prior PCI (OR: 0.45, p < 0.001) and the availability of drug-eluting stents conferred a lower probability of choosing CABG (OR: 0.60, p = 0.003). The majority of diabetic patients with multivessel disease were selected for PCI rather than CABG. Preference for CABG over PCI was largely based on angiographic features related to the extent, location, and nature of CAD, as well as geographic, demographic, and clinical factors. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI 2D]; NCT00006305).
    JACC. Cardiovascular Interventions 05/2009; 2(5):384-92. DOI:10.1016/j.jcin.2009.01.009 · 7.44 Impact Factor
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    ABSTRACT: This report describes the baseline angiographic findings in the Bypass Angioplasty Revascularization Investigation (BARI) 2 Diabetes (BARI 2D) trial, a randomized study that was initiated after the original BARI trial (BARI 1). Unlike BARI 1, which compared coronary artery bypass graft surgery with coronary angioplasty (percutaneous coronary intervention) in patients with and without diabetes, BARI 2D is investigating early versus deferred revascularization as needed in selected patients with type 2 diabetes mellitus and significant stable coronary artery disease (CAD). This analysis included 1,773 patients without previous procedures. The intended mode of revascularization, percutaneous coronary intervention or coronary artery bypass graft surgery, was specified before randomization. Angiographic findings in those randomized to revascularization versus medical treatment were similar. Overall, the mean number of lesions >or=20% diameter stenosis was 4.6 +/- 2.3, and the myocardial jeopardy index was 46 +/- 24%. Patients selected for the coronary artery bypass graft stratum had a higher mean number of lesions >or=20% diameter stenosis (5.7 vs 4.0, p <0.0001) and a higher myocardial jeopardy index (61% vs 38%, p <0.0001) than those selected for the percutaneous coronary intervention stratum. Female gender, black race, and higher body mass index were associated with less extensive CAD, whereas a history of hypertension, age at entry, low-density lipoprotein cholesterol, and ankle-brachial index <or=0.9 were associated with more extensive CAD. In conclusion, BARI 2D patients, who by design have mild or no symptoms, demonstrate considerable variation in the extent of CAD and amount of jeopardized myocardium. Coronary arteriographic findings are consistent with the intent of the design of BARI 2D. Certain baseline and clinical features were associated with the extent of disease and myocardial jeopardy.
    The American journal of cardiology 04/2009; 103(5):632-8. DOI:10.1016/j.amjcard.2008.11.024 · 3.43 Impact Factor
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    ABSTRACT: Patients sustaining acute myocardial infarction (AMI) often require urgent percutaneous revascularization within the first 24 h from onset of the infarction due to continuous ischemia and hemodynamic instability. Upon arrival to the cardiac catheterization, the electrocardiogram of AMI patients may exhibit acute ST-elevation (STEMI) with or without accompanying Q-wave or depression of the ST segment (non-STEMI or non-Q-wave infarction). Data comparing acute outcome of device application in patients presenting for urgent revascularization with established Q-wave myocardial infarction (QWMI) versus those with non-STEMI (NQMI) are sparse. Excimer laser is a revascularization modality applied for debulking of atherosclerotic plaque and vaporization of associated thrombus in the setting of AMI. One hundred fifty-one AMI patients with continuous chest pain and ischemia who enrolled into a multicenter study and underwent urgent revascularization were divided for the purpose of a retrospective analysis into two groups. One group presented with established electrocardiographic Q-wave, whereas the other had ST-depression (NQMI). In comparison with the NQMI group, the QWMI patients had a higher incidence of failed thrombolytic therapy (17% vs 3, p = 0.006), cardiogenic shock (20 vs 6%, p = 0.01), left anterior descending as a culprit infarct-related vessel (46 vs 14%, p < 0.0001), a higher incidence of TIMI 0 flow (48 vs 24%, p = 0.04), a heavier thrombus burden (grade 4 TIMI thrombus, 58 vs 23%; p = 0.0001), and higher CPK (1272 +/- 2180 vs 404 +/- 577, p = 0.001) and troponin levels (62 +/- 95 vs 14 +/- 48, p = 0.0003). Both groups underwent laser angioplasty and stenting for relief of continuous chest pain and ischemia within 24 h of infarction onset. Quantitative coronary arteriography in an independent core laboratory measured similar improvement in baseline minimal luminal diameter and percent diameter stenosis by application of laser energy in both groups. Among the QWMI patients, a significantly higher acute gain was recorded with the laser treatment in lesions containing a large/extensive thrombus burden as compared with lesions containing only a small clot burden (1.2 +/- 0.7 vs 0.8 +/- 0.5, p = 0.01). Such a phenomenon was not detected among the NQMI patients (1.0 +/- 0.5 vs 0.8 +/- 0.6, p=ns). Baseline TIMI flow grade (0.9 +/- 1.0 for QWMI vs 1.5 +/- 1.2 for NQMI, p = 0.0001) increased with laser emission to 2.8 +/- 0.5 and subsequently reached a final level of TIMI 3 in both groups. In comparison with the QWMI patients, there was a trend toward a reduced rate of major adverse coronary events among the NQMI patients (12% QWMI vs 4% NQMI, p = 0.09). Significant differences in baseline clinical characteristics, extent of myocardial damage, location of infarct related vessel, thrombus burden, and TIMI flow exist between QWMI and NQMI patients who require urgent intervention. However, application of excimer laser results in similar high procedural success and low complication rates in both groups. Maximal acute laser gain is achieved among QWMI patients whose lesions are laden with a heavy thrombus burden.
    Lasers in Medical Science 01/2008; 23(1):1-10. DOI:10.1007/s10103-007-0444-z · 2.42 Impact Factor
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    ABSTRACT: The PAS-Port device (Cardica, Redwood City, CA) allows the rapid deployment of a clampless proximal anastomosis between a vein graft and the aorta. Fifty-four patients awaiting elective coronary artery bypass graft surgery were enrolled. Outcome variables were intraoperative device performance, early and 6- month angiographic graft patency, and 12-month clinical follow-up. Sixty-three PAS-Port devices were deployed in 54 patients. Two deployments were unsuccessful. There were no reoperations for bleeding. Two patients died of causes unrelated to the device. Patency evaluation at discharge was performed by angiogram on 49 implants and computed tomography in 2 implants (86% follow-up). At discharge, all evaluated grafts were patent (100%) and rated Fitzgibbon A. At 6-month follow-up, there was no additional mortality; 47 implants (88% follow-up) were evaluated by angiography (Fitzgibbon O [n = 1], Fitzgibbon B [n = 1], and Fitzgibbon A [n = 45]) and 5 by computed tomography. All grafts but 1 were patent (98.1%). At 12 months, 2 additional patients died of causes unrelated to the PAS-Port implant. Forty-six of 50 alive patients (95.8%) were followed up without any reports of device-related major adverse cardiac events. Discharge (100%) and 6-month patency (98%) are excellent; patency and 12 months' clinical follow-up compares favorably with data from historical hand-sewn controls. The PAS-Port system safely allows the clampless creation of a proximal anastomosis.
    The Annals of thoracic surgery 02/2006; 81(1):90-6. DOI:10.1016/j.athoracsur.2005.06.035 · 3.65 Impact Factor
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    ABSTRACT: The C-Port System (Cardica, Inc, Redwood City, Calif) integrates in one tool all functions necessary to enable rapid automated distal coronary anastomoses. The goal of this prospective, nonrandomized, and multicenter study is to determine the safety and efficacy of this novel anastomotic system. Five centers enrolled 133 patients awaiting elective coronary artery bypass grafting surgery. Outcome variables were intraoperative device performance, incidence of device-related adverse events, predischarge and 6-month angiographic graft patency, and 12-month clinical outcome. Independent core laboratories performed qualitative and quantitative angiographic and computed tomographic assessments. The C-Port was used to perform a vein-to-coronary anastomosis in 130 patients. Intraoperative conversion to a hand-sewn anastomosis was necessary in 11 patients because of inadequate target site preparation, inappropriate target vessel selection, or both. Inadequate blood flow related to poor runoff required conversion in 3 additional patients. Three patients died before discharge of causes unrelated to the device. At discharge, 113 patients had a C-Port implant in place, and 104 C-Port anastomoses were studied by means of angiography, resulting in 100 FitzGibbon A, 3 FitzGibbon B, and 1 FitzGibbon 0 classifications. At 6 months, one additional patient died of a device-unrelated cause, and 98 patients were evaluated by means of angiography (n = 89). Overall patency (FitzGibbon A) was 92.1%. Three C-Port anastomoses were rated FitzGibbon B, and 4 were rated FitzGibbon 0. At 12 months, 107 (98.2%) of 109 alive patients were followed up, without any reports of device-related major adverse cardiac events. The C-Port System allows for a rapid, reliable, and compliant distal anastomosis and yields favorable 6-month angiographic and 12-month clinical results when compared with published studies.
    The Journal of thoracic and cardiovascular surgery 01/2006; 130(6):1645-52. DOI:10.1016/j.jtcvs.2005.08.033 · 3.99 Impact Factor
  • The Thoracic and Cardiovascular Surgeon 01/2005; 53(S 01). DOI:10.1055/s-2005-861903 · 1.08 Impact Factor
  • E. Alderman · K. Kip · P. Whitlow · T. Bashore
    ACC Current Journal Review 11/2004; 13(11):65–66. DOI:10.1016/j.accreview.2004.10.076
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    ABSTRACT: Coronary angiograms obtained five years following revascularization were examined to assess the extent of compromise in myocardial perfusion due to failure of revascularization versus progression of native disease. The Bypass Angioplasty Revascularization Investigation (BARI) randomized revascularization candidates between bypass surgery and angioplasty. Entry and five-year angiograms from 407 of 519 (78%) patients at four centers were analyzed. Analysis of the distribution of coronary vessels and stenoses provided a measure of myocardial jeopardy that correlates with presence of angina. The extent to which initial benefits of revascularization were undone by failed revascularization versus native disease progression was assessed. Myocardial jeopardy fell following initial revascularization, from 60% to 17% for percutaneous coronary intervention (PCI)-treated patients compared with 60% to 7% for coronary artery bypass graft (CABG) surgery patients (p < 0.001), rebounding at five years to 25% for PCI and 20% for surgery patients (p = 0.01). Correspondingly, angina prevalence was higher at five years in PCI-treated patients than in surgery-treated patients (28% vs. 18%; p = 0.03). However, myocardial jeopardy at five years, and not initial treatment (PCI vs. surgery), was independently associated with late angina. Increased myocardial jeopardy from entry to five-year angiogram occurred in 42% of PCI-treated patients and 51% of CABG-treated patients (p = 0.06). Among the increases in myocardial jeopardy, two-thirds occurred in previously untreated arteries. Native coronary disease progression occurred more often than failed revascularization in both PCI- and CABG-treated patients as a cause of jeopardized myocardium and angina recurrence. These results support intensive postrevascularization risk-factor modification.
    Journal of the American College of Cardiology 08/2004; 44(4):766-74. DOI:10.1016/j.jacc.2004.05.041 · 15.34 Impact Factor
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    ABSTRACT: Abnormal glucose tolerance (AGT; diabetes or impaired glucose tolerance) is associated with increased risk of cardiovascular disease, especially in women. Cardiovascular disease rates in women increase after menopause. The Women's Health Initiative found that postmenopausal hormone therapy (PHT) increased the risk of cardiovascular disease and that effects in diabetic women did not differ from those in women without diabetes. In this study, we hypothesized that PHT would have a worse effect on disease among women with AGT. We randomly assigned 423 postmenopausal women with angiographically defined atherosclerosis (321 women had exit angiograms) with (n=140) or without (n=181) AGT to receive estrogen, estrogen plus progestin, or a placebo for 2.8+/-0.9 years. LDL was lower and HDL and triglycerides were higher after PHT in non-AGT and AGT women, but more adverse changes occurred in C-reactive protein and fibrinogen in women with AGT (P=0.11 and P=0.02 for interactions). PHT had no effect on fasting glucose or insulin concentrations in women without AGT, but in women with AGT, fasting glucose levels, insulin concentration, and insulin resistance as assessed by the HOMA (homeostasis model) calculation decreased slightly (P=0.28, P=0.25, P=0.14 for interaction, respectively). Atherosclerotic progression was greater in women with AGT. Atherosclerotic progression in previously nondiseased segments was enhanced by PHT to a greater extent in women with AGT (P=0.11 for interaction). PHT is associated with a worsening of coronary atherosclerosis and exacerbation of the profile of inflammatory markers in women with AGT. Therefore, PHT is not warranted for use in diabetic women. Further study is needed to explore the improvement in insulin resistance and glycemia that appears to occur with PHT in women with AGT.
    Circulation 08/2004; 110(2):201-6. DOI:10.1161/01.CIR.0000134955.93951.D5 · 14.95 Impact Factor
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    ABSTRACT: Patients who develop acute myocardial infarction due to occlusion in a saphenous vein graft (SVG) constitute a revascularization challenge. Excimer laser angioplasty may have a potential advantage in the treatment of SVGs, since its 308 nanometer wavelength is avidly absorbed by both atherosclerotic plaque and thrombus. The data presented herein support the notion that excimer laser angioplasty is a technology that has a potential role in achieving adequate revascularization outcomes in this selected, high-risk patient population.
    The Journal of invasive cardiology 05/2004; 16(4):177-80. · 0.82 Impact Factor
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    ABSTRACT: Patients with acute myocardial infarction (AMI) with thrombus-laden lesions constitute a revascularization challenge. Thrombus and atherosclerotic plaque absorb laser energy; thus, we studied the safety and efficacy of excimer laser in AMI. In a multicenter trial, 151 patients with AMI underwent excimer laser angioplasty. Baseline left ventricular ejection fraction was 44 +/- 13%, and 13% of patients were in cardiogenic shock. A saphenous vein graft was the target vessel in 21%. Quantitative coronary angiography and statistical analysis were performed by independent core laboratories. A 95% device success, 97% angiographic success, and 91% overall procedural success rate were recorded. Maximal laser gain was achieved in lesions with extensive thrombus burden (p <0.03 vs small burden). Thrombolysis In Myocardial Infarction (TIMI) trial flow increased significantly by laser: 1.2 +/- 1.1 to 2.8 +/- 0.5 (p <0.001), reaching a final 3.0 +/- 0.2 (p <0.001 vs baseline). Minimal luminal diameter increased by laser from 0.5 +/- 0.5 to 1.6 +/- 0.5 mm (mean +/- SD, p <0.001), followed by 2.7 +/- 0.6 mm after stenting (p <0.001 vs baseline and vs after laser). Laser decreased target stenosis from 83 +/- 17% to 52 +/- 15% (mean +/- SD, p <0.001 vs baseline), followed by 20 +/- 16% after stenting (p <0.001 vs baseline and vs after laser). Six patients (4%) died, each presented with cardiogenic shock. Complications included perforation (0.6%), dissection (5% major, 3% minor), acute closure (0.6%), distal embolization (2%), and bleeding (3%). In a multivariant regression model, absence of cardiogenic shock was a significant factor affecting procedural success. Thus, in the setting of AMI, gaining maximal thrombus dissolution in lesions with extensive thrombus burden, combined with a considerable increase in minimal luminal diameter and restoration of anterograde TIMI flow, support successful debulking by excimer laser. The presence of thrombus does not adversely affect procedural success; however, cardiogenic shock remains a predictor of major adverse events during hospitalization.
    The American Journal of Cardiology 04/2004; 93(6):694-701. DOI:10.1016/j.amjcard.2003.11.050 · 3.43 Impact Factor
  • D. Waters · E. Alderman · J. Hsia · B. Howard · F. Cobb · W. Rogers · Ana Espínola
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    ABSTRACT: Objetivo Evaluar el efecto de dosis altas de vitamina E y C, solas o en combinación con tratamiento hormonal sustitutivo (THS), en mujeres posmenopáusicas con enfermedad coronaria (EC) establecida. Diseño Ensayo clínico aleatorizado doble ciego de 4,5 años de seguimiento, con diseño 2 × 2. Emplazamiento Siete clínicas de Estados Unidos y Canadá. Población de estudio Selección de 423 mujeres posmenopáusicas, afectadas de coronariopatía, con una o más estenosis coronarias entre el 15 y el 75% en una arteria diagnosticada mediante coronariografía, no tributarias de tratamiento quirúrgico. Se excluyó a los pacientes con infarto de miocardio reciente, THS previo y enfermedad grave. Intervención Las pacientes incluidas fueron aleatorizadas en 4 grupos similares, que recibían vitamina C 500 mg y vitamina E 400 U, o placebo con o sin THS (0,625 mg de estrógenos conjugados equinos más 2,5 mg de medroxiprogesterona si no estaban histerectomizadas): grupo asignado a placebo THS y placebo vitaminas (n = 108), grupo asignado a THS y placebo vitaminas (n = 103), grupo asignado a placebo THS y vitaminas (n = 105) y grupo asignado a THS y vitaminas (n = 107). Medición de resultados Cambios en la media del mínimo diámetro de la luz (MDL) de todas las lesiones coronarias mediante angiografía. Las pacientes con infarto de miocardio intercurrente o muerte se asignaron al peor rango angiográfico. Resultados Se evaluaron 1.328 lesiones de 320 mujeres. El descenso de la media del MDL fue mayor en los tres grupos de tratamiento activo comparado con el doble placebo, pero sin llegar a la significación estadística. Cuando se compararon los grupos con intervención específica, el grupo de THS mostró un empeoramiento de MDL (0,047 frente a 0,024; p = 0,17), así como el grupo de tratamiento con vitaminas (0,044 frente a 0,028; p = 0,32). Cuando los resultados se analizaron incluyendo a las mujeres con infarto de miocardio intercurrente o muerte, ambos grupos tuvieron un incremento de riesgo (grupo THS, p = 0,45; grupo vitaminas, p = 0,09). La mortalidad fue menor en el grupo que recibía doble placebo (2), mayor en el grupo que recibía los dos tratamientos (10) e intermedia en los otros grupos (placebo TSH y vitaminas 6, y THS y placebo vitaminas 4). La mortalidad total fue mayor en el grupo asignado a THS (14 frente a 8; riesgo relativo [RR], 1,8; IC del 95%, 0,75-4,3; p = 0,20) y a antioxidantes (16 frente a 6; RR, 2,8; IC del 95%, 1,1-7,2; p = 0,047). No hubo diferencias en los diferentes subgrupos (diabetes, fumadores, raza, histerectomía). Conclusiones En mujeres posmenopáusicas con EC, el suplemento con vitaminas antioxidantes o el THS no proporcionan ningún beneficio, e incluso pueden aumentar la mortalidad, por lo que no se aconseja su utilización en este grupo.
    FMC - Formación Médica Continuada en Atención Primaria 12/2003; 10(3):219. DOI:10.1016/S1134-2072(03)75873-3
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    ABSTRACT: To evaluate the safety and effectiveness of a self-closing surgical clip with an interrupted technique in left internal thoracic artery to left anterior descending artery bypass grafting. Eighty-two patients were enrolled and treated (February 2000 through August 2001) in a prospective, nonrandomized, multicenter trial. Left internal thoracic artery to left anterior descending artery anastomoses were performed in 60 off-pump coronary artery bypasses (73%), 12 conventional coronary artery bypass grafting (15%), and 10 minimally invasive direct coronary artery bypass (12%) procedures. Angiograms (64 to 383 days, mean 200 days) were obtained on 63 patients (77%). Qualitative and quantitative angiographic assessment was performed by an independent core laboratory. The self-closing surgical clip was used for 82 left internal thoracic artery to left anterior descending artery interrupted anastomoses without the requirement for knot tying or primary suture management. Minimum left internal thoracic artery to left anterior descending artery anastomosis time was 3 minutes. There was one perioperative and one late death (both not heart related) and one reexploration for bleeding unrelated to the anastomotic site. FitzGibbon grades were as follows: A (n = 60, 95.2%), B (n = 3, 4.8%) including one kinked left internal thoracic artery, and O (n = 0, 0%). Quantitative analysis (n = 57) showed mean lumen diameters of left internal thoracic artery proximal to the anastomosis of 2.1 mm, at anastomosis of 2.0 mm, and in the left anterior descending artery distal to the anastomosis of 1.9 mm. The average ratio of the anastomosis to the left anterior descending artery diameter was 1.14 (0.45 to 1.93). Anastomotic stenosis as a percentage of average left internal thoracic artery to left anterior descending artery diameter was -2.3%, comparing favorably with results (23% to 24%) reported from the Patency, Outcomes, Economics, Minimally invasive direct coronary artery (POEM) bypass study. The interrupted technique, facilitated by a self-closing anastomotic clip, yields favorable 6-month angiographic results when compared with other published studies.
    Journal of Thoracic and Cardiovascular Surgery 08/2003; 126(1):168-77; discussion 177-8. DOI:10.1016/S0022-5223(03)00234-4 · 3.99 Impact Factor
  • D.D. Waters · E.L. Alderman · J. Hsia
    ACC Current Journal Review 03/2003; 12(2):42. DOI:10.1016/S1062-1458(03)00044-8
  • L. Schwartz · K.E. Kip · R.L. Frye · E.L. Alderman · H.V. Schaff · K.M. Detre
    ACC Current Journal Review 03/2003; 12(2):96. DOI:10.1016/S1062-1458(03)00097-7
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    Obstetrical and Gynecological Survey 02/2003; 58(3):189-190. DOI:10.1097/01.OGX.0000055762.75837.F8 · 2.36 Impact Factor
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    ABSTRACT: LDLs include particle subclasses that have different mobilities on polyacrylamide gradient gels: LDL-I (27.2 to 28.5 nm), LDL-IIa (26.5 to 27.2 nm), LDL-IIb (25.6 to 26.5 nm), LDL-IIIa (24.7 to 25.6 nm), LDL-IIIb (24.2 to 24.7 nm), LDL-IVa (23.3 to 24.2 nm), and LDL-IVb (22.0 to 23.3 nm in diameter). We hypothesized that the association between smaller LDL particles and coronary artery disease (CAD) risk might involve specific LDL subclasses. Average 4-year onstudy lipoprotein measurements were compared with annualized rates of stenosis change from baseline to 4 years in 117 men with CAD. The percentages of total LDL and HDL occurring within individual subclasses were measured by gradient gel electrophoresis. Annual rate of stenosis change was related concordantly to onstudy averages of total cholesterol (P=0.04), triglycerides (P=0.05), VLDL mass (P=0.03), total/HDL cholesterol ratio (P=0.04), LDL-IVb (P=0.01), and HDL(3a) (P=0.02) and inversely to HDL(2)-mass (P=0.02) and HDL(2b) (P=0.03). The average annual rate in stenosis change was 6-fold more rapid in the fourth quartile of LDL-IVb (>or=5.2%) than in the first quartile (<2.5%, P=0.03). Stepwise multiple regression analysis showed that LDL-IVb was the single best predictor of stenosis change. LDL-IVb was the single best lipoprotein predictor of increased stenosis, an unexpected result, given that LDL-IVb represents only a minor fraction of total LDL.
    Arteriosclerosis Thrombosis and Vascular Biology 02/2003; 23(2):314-21. DOI:10.1161/01.ATV.0000053385.64132.2D · 5.53 Impact Factor
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    ABSTRACT: Context Hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease, but no clinical trials have demonstrated benefit to support their use.Objective To determine whether HRT or antioxidant vitamin supplements, alone or in combination, influence the progression of coronary artery disease in postmenopausal women, as measured by serial quantitative coronary angiography.Design, Setting, and Patients The Women's Angiographic Vitamin and Estrogen (WAVE) Trial, a randomized, double-blind trial of 423 postmenopausal women with at least one 15% to 75% coronary stenosis at baseline coronary angiography. The trial was conducted from July 1997 to January 2002 in 7 clinical centers in the United States and Canada.Interventions Patients were randomly assigned in a 2 × 2 factorial design to receive either 0.625 mg/d of conjugated equine estrogen (plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy), or matching placebo, and 400 IU of vitamin E twice daily plus 500 mg of vitamin C twice daily, or placebo.Main Outcome Measure Annualized mean (SD) change in minimum lumen diameter (MLD) from baseline to concluding angiogram of all qualifying coronary lesions averaged for each patient. Patients with intercurrent death or myocardial infarction (MI) were imputed the worst rank of angiographic outcome.Results The mean (SD) interval between angiograms was 2.8 (0.9) years. Coronary progression, measured in mean (SD) change, worsened with HRT by 0.047 (0.15) mm/y and by 0.024 (0.15) mm/y with HRT placebo (P = .17); and for antioxidant vitamins by 0.044 (0.15) mm/y and with vitamin placebo by 0.028 (0.15) mm/y (P = .32). When patients with intercurrent death or MI were included, the primary outcome showed an increased risk for women in the active HRT group (P = .045), and suggested an increased risk in the active vitamin group (P = .09). Fourteen patients died in the HRT group and 8 in the HRT placebo group (hazard ratio [HR], 1.8; 95% confidence interval [CI], 0.75-4.3), and 16 in the vitamin group and 6 in the vitamin placebo group (HR, 2.8; 95% CI, 1.1-7.2). Death, nonfatal MI, or stroke occurred in 26 HRT patients vs 15 HRT controls (HR, 1.9; 95% CI, 0.97-3.6) and in 26 vitamin patients and 18 vitamin controls (HR, 1.5; 95% CI, 0.80-2.9). There was no interaction between the 2 treatment interventions.Conclusion In postmenopausal women with coronary disease, neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential for harm was suggested with each treatment. Figures in this Article In numerous observational studies over the past 30 years, postmenopausal estrogen replacement therapy, with or without a progestin, has been consistently associated with a reduced risk of coronary events, both in women with and without evidence of coronary disease.1- 5 Estrogen exerts beneficial effects on blood lipids, low-density lipoprotein (LDL) oxidation, vascular function, and on some aspects of the coagulation system.6 Yet hormone replacement therapy (HRT) was not shown to be beneficial in the only 2 randomized, placebo-controlled trials of postmenopausal women with coronary disease.7- 9 Furthermore, the only large primary prevention trial of HRT reported to date, the Women's Health Initiative, was stopped prematurely because overall risk exceeded benefit, including an increased risk of nonfatal myocardial infarction (MI) and coronary death, which was the study's primary outcome.10 As a result of this discrepancy between clinical trial results and other evidence, guidelines do not offer consistent, explicit recommendations for the use of this therapy in postmenopausal women.11 Like HRT, antioxidant consumption, either dietary or in the form of vitamin supplements, has been associated with a reduced risk of coronary disease in epidemiological studies.12- 16 In a coronary angiographic trial, participants who took supplemental vitamin E (not as part of the trial) demonstrated less lesion progression.17 Theoretically, antioxidants inhibit a key component of atherogenesis (oxidation of LDL cholesterol within the vessel wall), and other mechanisms have been demonstrated in animal experiments, including preservation of nitric oxide activity, inhibition of leukocyte adhesion, reduction of cellular oxidative injury, and inhibition of platelet adhesion.18 Five randomized, placebo-controlled trials of vitamin E in patients with or at risk for coronary disease have been completed,19- 23 and all but the smallest and shortest20 reported no benefit. Although the antioxidant effects of vitamins E and C may be synergistic, vitamin C was combined with vitamin E in only 1 of these trials.23 In addition to inhibiting LDL oxidation through a variety of mechanisms, vitamin C also exhibits other anti-atherosclerotic effects in animal models.24 To study possible benefits left unexplored by previous studies, the Women's Angiographic Vitamin and Estrogen (WAVE) Trial tested the combination of relatively high doses of vitamins E and C. Patients were randomized to HRT and/or antioxidant vitamins in a placebo-controlled 2 × 2 factorial design. The study population consisted of postmenopausal women with documented coronary disease, and the end point was the change in minimum lumen diameter (MLD) of qualifying coronary lesions.
    JAMA The Journal of the American Medical Association 01/2003; 288(19):2432-2440. DOI:10.1001/jama.288.19.2432 · 30.39 Impact Factor
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    ABSTRACT: The Women's Angiographic Vitamin and Estrogen trial was a randomized, double-blind, placebo-controlled study designed to test the efficacy of estrogen replacement and antioxidant vitamins for preventing angiographic progression of coronary artery disease. Postmenopausal women with one or more angiographically documented coronary stenoses of 15-75% at baseline were assigned in a 2 x 2 factorial randomization to active hormone replacement therapy (conjugated estrogens for women who had had a hysterectomy or conjugated estrogens with medroxyprogesterone for women with intact uteri) or placebo and to active vitamins E and C or their placebos. Seven clinical centers, five in the United States and two in Canada, randomized 423 women between July 1997 and July 1999. Quantitative coronary angiography was performed at baseline and repeated after projected mean follow-up of 3 years.
    Controlled Clinical Trials 01/2003; 23(6):708-27. DOI:10.1016/S0197-2456(02)00237-4

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Institutions

  • 1971–2011
    • Stanford University
      • • Division of Cardiovascular Medicine
      • • Falk Cardiovascular Research Center
      • • Department of Medicine
      • • Division of Pediatric Cardiology
      Palo Alto, California, United States
  • 1970–1999
    • Stanford Medicine
      • • Division of Cardiovascular Medicine
      • • Division of Vascular and Endovascular Surgery
      • • Department of Medicine
      Stanford, California, United States
  • 1996–1998
    • University of Pittsburgh
      • Department of Epidemiology
      Pittsburgh, Pennsylvania, United States
  • 1989–1994
    • University of Washington Seattle
      • Division of Cardiology
      Seattle, Washington, United States
  • 1989–1990
    • Palo Alto Medical Foundation
      • Research Institute
      Palo Alto, California, United States
  • 1988
    • Università di Pisa
      Pisa, Tuscany, Italy
  • 1983
    • National Heart, Lung, and Blood Institute
      베서스다, Maryland, United States