Coronary Artery Disease: Creager MA

King SB, Aversano T, Ballard WL, Beekman RH, Cowley MJ, Ellis SG, Faxon DP, Hannan EL, Hirshfeld JW, Jacobs AK, Kellett MA, Kimmel SE, Landzberg JS, McKeever LS, Moscucci M, Pomerantz RM, Smith KM, Vetrovec GW, Creager MA, Hirshfeld JW, Holmes DR, Newby LK, Weitz HH, Merli G, Piña I, Rodgers GP, Tracy CM, Anonymous00143, Anonymous00144, Anonymous00145. · No affiliation provided · J Am Coll Cardiol. · Pubmed #17601554 No free full text.

This publication has no abstract.

Anonymous00180, King SB, Aversano T, Ballard WL, Beekman RH, Cowley MJ, Ellis SG, Faxon DP, Hannan EL, Hirshfeld JW, Jacobs AK, Kellett MA, Kimmel SE, Landzberg JS, McKeever LS, Moscucci M, Pomerantz RM, Smith KM, Vetrovec GW, Creager MA, Holmes DR, Newby LK, Weitz HH, Merli G, Piña I, Rodgers GP, Tracy CM. · No affiliation provided · Circulation. · Pubmed #17592076 links to  free full text

This publication has no abstract.

Goldin A, Beckman JA, Schmidt AM, Creager MA. · Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA. · Circulation. · Pubmed #16894049 links to  free full text

Abstract: Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to sugars. AGEs are prevalent in the diabetic vasculature and contribute to the development of atherosclerosis. The presence and accumulation of AGEs in many different cell types affect extracellular and intracellular structure and function. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Activation of RAGE by AGEs causes upregulation of the transcription factor nuclear factor-kappaB and its target genes. Soluble AGEs activate monocytes, and AGEs in the basement membrane inhibit monocyte migration. AGE-bound RAGE increases endothelial permeability to macromolecules. AGEs block nitric oxide activity in the endothelium and cause the production of reactive oxygen species. Because of the emerging evidence about the adverse effects of AGEs on the vasculature of patients with diabetes, a number of different therapies to inhibit AGEs are under investigation.

Lu JT, Creager MA. · Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Rev Cardiovasc Med. · Pubmed #15580157 No free full text.

Abstract: Cigarette smoking is one of the most important risk factors for peripheral arterial disease (PAD). Smoking increases the risk of PAD by several fold and is a more influential risk factor for PAD than for coronary artery disease. Multiple pathophysiologic mechanisms may account for the prevalence of atherosclerosis in cigarette smokers. These include abnormalities of endothelial function, lipoprotein metabolism, coagulation, and platelet function. Smoking cessation decreases the risk of cardiovascular morbidity and mortality, and may improve functional capacity in patients with PAD. Therapies to promote smoking cessation include counseling, nicotine replacement, and bupropion. Healthcare providers must enhance their efforts and target smoking cessation as a modifiable risk factor in patients with PAD and other manifestations of atherosclerosis.

Gornik HL, Creager MA. · Vascular Medicine Section, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. · J Nutr. · Pubmed #15465805 links to  free full text

Abstract: The vascular endothelium is a crucial regulator of vascular function and homeostasis. Nitric oxide (NO) is an important paracrine substance released by the endothelium to regulate vasomotor tone. Risk factors for atherosclerosis, as well as atherosclerosis per se, are associated with endothelial dysfunction and decreased bioavailablilty of NO. Indeed, endothelial dysfunction is integral to the pathogenesis of atherosclerosis and other cardiovascular diseases. Moreover, endothelial dysfunction relates to an increased risk of adverse cardiovascular outcomes. L-Arginine is an essential amino acid required by the constitutive enzyme, endothelial NO oxide synthase (eNOS), to produce NO. Administration of L-arginine improves endothelial function in animal models and in humans with hypercholesterolemia and with atherosclerosis. Clinical trials to date support potential clinical applications of L-arginine in the treatment of coronary artery disease and peripheral arterial disease, as well as in the prevention of in-stent restenosis. The mechanism of benefit of L-arginine on endothelial function is unclear, because intracellular concentrations of L-arginine far exceed that required by eNOS. One potential explanation of this "arginine paradox" is that L-arginine restores endothelial function in atherosclerotic patients, in whom there are elevated levels of asymmetric dimethylarginine, an endogenous inhibitor of eNOS. Given the promising findings of early studies of L-arginine as a potential therapy for cardiovascular disorders, large-scale clinical trials are warranted.

Lüscher TF, Creager MA, Beckman JA, Cosentino F. · Cardiology, CardioVascular Center, University Hospital and Cardiovascular Research, Institute of Physiology, University Zürich, Switzerland. · Circulation. · Pubmed #14517152 links to  free full text

This publication has no abstract.

Garasic JM, Creager MA. · Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA. · Rev Cardiovasc Med. · Pubmed #12439376 No free full text.

Abstract: Patients with peripheral arterial disease frequently develop symptoms of claudication that interfere with ambulation and adversely affect quality of life, and some develop critical limb ischemia. Many of these patients have coexisting coronary artery disease, and surgical revascularization poses risks of perioperative myocardial infarction and cardiovascular death. Peripheral catheter-based interventions are a feasible alternative. Percutaneous treatment can preserve the surgical option and is often used as an adjunct to surgery by addressing inflow stenoses and limiting the extent of surgical reconstruction that is necessary. Iliac artery balloon angioplasty has been shown to have a high rate of initial procedural success and long-term patency, and the use of stents is promising, especially in cases complicated by flow-limiting dissection or significant residual stenosis. Percutaneous revascularization of the femoropopliteal arteries has shown high restenosis rates and stents should be confined, at present, to flow-limiting dissections or inadequate results from balloon angioplasty alone. The indication for percutaneous revascularization below the knee is typically limited to those patients with critical limb ischemia who are at high risk for surgical reconstruction; short-term results with modern equipment have been promising and can salvage ischemic limbs.

Beckman JA, Creager MA, Libby P. · Leducq Center for Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. · JAMA. · Pubmed #12020339 links to  free full text

Abstract: CONTEXT: Complications of atherosclerosis cause most morbidity and mortality in patients with diabetes mellitus. Despite the frequency and severity of disease, proven medical therapy remains incompletely understood and underused. OBJECTIVE: To review the epidemiology, pathophysiology, and medical and invasive treatment of atherosclerosis in patients with diabetes mellitus. DATA SOURCES: Using the index terms diabetes mellitus, myocardial infarction, peripheral vascular diseases, cerebrovascular accident, endothelium, vascular smooth muscle, platelets, thrombosis, cholesterol, hypertension, hyperglycemia, insulin, angioplasty, and coronary artery bypass, we searched the MEDLINE and EMBASE databases from 1976 to 2001. Additional data sources included bibliographies of identified articles and preliminary data presented at recent cardiology conferences. STUDY SELECTION: We selected original investigations and reviews of the epidemiology, pathophysiology, and therapy of atherosclerosis in diabetes. We selected randomized, double-blind, controlled studies, when available, to support therapeutic recommendations. Criteria for data inclusion (168 of 396) included publication in a peer-reviewed journal or presentation at a national cardiovascular society-sponsored meeting. DATA EXTRACTION: Data quality was determined by publication in peer-reviewed literature. Data extraction was performed by one of the authors. DATA SYNTHESIS: Diabetes mellitus markedly increases the risk of myocardial infarction, stroke, amputation, and death. The metabolic abnormalities caused by diabetes induce vascular dysfunction that predisposes this patient population to atherosclerosis. Blood pressure control, lipid-lowering therapy, angiotensin-converting enzyme inhibition, and antiplatelet drugs significantly reduce the risk of cardiovascular events. Although diabetic patients undergo revascularization procedures because of acute coronary syndromes or critical limb ischemia, the outcomes are less favorable than in nondiabetic cohorts. CONCLUSIONS: Since most patients with diabetes die from complications of atherosclerosis, they should receive intensive preventive interventions proven to reduce their cardiovascular risk.

Sperling RT, Creager MA. · Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. · Coron Artery Dis. · Pubmed #10421967 No free full text.

Abstract: The constitutive release of NO by the endothelium plays a key role in maintaining normal low basal pulmonary vascular tone and countering hypoxic vasoconstrictive tone in many mammals and in humans. Many, but not all, studies have suggested that reduced availability of NO contributes to the increased pulmonary vascular resistance that occurs in experimental models and in humans with pulmonary hypertension. Potential mechanisms limiting the activity of NO include L-arginine deficiency and a reduction in eNOS expression or message stability. Inhaled NO therapy may overcome some of these abnormalities, improving oxygenation and reducing pulmonary artery pressure in patients with primary and secondary forms of pulmonary hypertension.

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, Anonymous00317. · Cardiovascular Division, Brigham & Women's Hospital, Boston, Mass 02115, USA. · Circulation. · Pubmed #15809368 links to  free full text

Abstract: 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.

Kinlay S, Behrendt D, Fang JC, Delagrange D, Morrow J, Witztum JL, Rifai N, Selwyn AP, Creager MA, Ganz P. · Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. · J Am Coll Cardiol. · Pubmed #14975474 No free full text.

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.

Kinlay S, Fang JC, Hikita H, Ho I, Delagrange DM, Frei B, Suh JH, Gerhard M, Creager MA, Selwyn AP, Ganz P. · Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Circulation. · Pubmed #10411842 links to  free full text

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.

Cacoub PP, Abola MT, Baumgartner I, Bhatt DL, Creager MA, Liau CS, Goto S, Röther J, Steg PG, Hirsch AT, Anonymous00101. · Pierre and Marie Curie University-Paris 6, and AP HP, Hospital La Pitié-Salpêtrière, Paris, France. · Atherosclerosis. · Pubmed #19054514 No free full text.

Abstract: OBJECTIVES: To examine differences in risk factor (RF) management between peripheral artery disease (PAD) and coronary artery (CAD) or cerebrovascular disease (CVD), as well as the impact of RF control on major 1-year cardiovascular (CV) event rates. METHODS: The REACH Registry recruited >68000 outpatients aged >or=45 years with established atherothrombotic disease or >or=3 RFs for atherothrombosis. The predictors of RF control that were evaluated included: (1) patient demographics, (2) mode of PAD diagnosis, and (3) concomitant CAD and/or CVD. RESULTS: RF control was less frequent in patients with PAD (n=8322), compared with those with CAD or CVD (but no PAD, n=47492) [blood pressure; glycemia; total cholesterol; smoking cessation (each P<0.001)]. Factors independently associated with optimal RF control in patients with PAD were male gender (OR=1.9); residence in North America (OR=3.5), Japan (OR=2.5) or Latin America (OR=1.5); previous coronary revascularization (OR=1.3); and statin use (OR=1.4); whereas prior leg amputation was a negative predictor (OR=0.7) (P<0.001). Optimal RF control was associated with fewer 1-year CV ischemic symptoms or events. CONCLUSIONS: Patients with PAD do not achieve RF control as frequently as individuals with CAD or CVD. Improved RF control is associated with a positive impact on 1-year CV event rates.

Baumgartner I, Hirsch AT, Abola MT, Cacoub PP, Poldermans D, Steg PG, Creager MA, Bhatt DL, Anonymous00053. · Department of Clinical and Interventional Angiology, Swiss Cardiovascular Centre, Angiology Division, University Hospital, Bern, Switzerland. · J Vasc Surg. · Pubmed #18639426 No free full text.

Abstract: OBJECTIVE: Datasets regarding patients with abdominal aortic aneurysm (AAA) have almost universally been restricted to single geographic regions. We aimed to obtain data on the risk factor profile and cardiovascular (CV) co-morbidity among multi-ethnic patients with known AAA in the global REACH (REduction of Atherothrombosis for Continued Health) Registry. METHODS: The REACH Registry is an international, prospective, observational out-patient registry enrolling out-patients >/=45 years of age with established coronary artery disease (CAD), cerebrovascular disease (CVD) or peripheral arterial disease (PAD) or with at least three atherothrombotic risk factors. This report includes observations pertaining to 68,236 out-patients enrolled in 44 countries. MAIN OUTCOME MEASURES: Gender, ethnic origin, CV risk factors, established atherosclerotic disease (CAD, CVD and PAD) at baseline, and CV outcome events at 1-year were compared in patients with and without AAA. RESULTS: An AAA was reported in 1722 (2.5%) of 68,236 out-patients enrolled in the REACH Registry. Older age (73 +/- 8 vs 68 +/- 10, P < .0001), male gender (81% vs 63%, P < .0001), White ethnicity (79% vs 67%, P < .0001) and a history of smoking (81% vs 55%, P < .0001) were independently related to the diagnosis of AAA. There was a weaker association with hypertension or hypercholesterolemia, and an inverse relation with diabetes. Fatal and non-fatal coronary and cerebrovascular event rates were not different between the AAA and non-AAA cohorts, but individuals with AAA suffered increased rates of other cardiovascular deaths (1.39% vs 0.94%, P = .0135), hospitalizations for atherothrombotic events (14.1% vs 9.3%, P < .0001) due to increased rates of revascularization procedures, and new or worsening PAD (3.7% vs 1.3%, P < .0001) at 1-year follow-up. CONCLUSION: This study, the largest published to date, presents the CV risk profile and outcome of patients with an established diagnosis of AAA from a cohort of patients with either overt manifestations of CV disease or multiple risk factors, and further defines these patients in a multi-ethnic, global context.

Pradhan AD, Shrivastava S, Cook NR, Rifai N, Creager MA, Ridker PM. · Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital and Harvard Medical School, 900 Commonwealth Ave E, Boston, MA 02215-1204, USA. · Circulation. · Pubmed #18227386 links to  free full text

Abstract: BACKGROUND: Most investigations of novel biomarkers for prediction of cardiovascular disease pertain to coronary artery disease. Few large-scale prospective studies have critically assessed plasma-based factors as predictors of peripheral arterial disease (PAD), and comparative data between individual biomarkers and lipid levels are sparse, especially among women. METHODS AND RESULTS: We evaluated the relationship between baseline levels of several novel biomarkers and confirmed incident symptomatic PAD (n=100) in a prospective cohort study (median follow-up, 12.3 years) involving 27,935 US female health professionals > or = 45 years of age without diagnosed vascular disease at baseline. Biomarkers assessed were high-sensitivity C-reactive protein, fibrinogen, soluble intercellular adhesion molecule-1 (sICAM-1), homocysteine, lipoprotein(a), hemoglobin A1c, creatinine, and conventional lipid levels. In univariate analyses, levels of high-sensitivity C-reactive protein, fibrinogen, sICAM-1, homocysteine, lipoprotein(a), creatinine clearance, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and the ratio of total cholesterol to HDL-C (TC:HDL-C) were significantly related to PAD (all P<0.05). However, after multivariable adjustment, risk associations were significant only for high-sensitivity C-reactive protein (adjusted hazard ratio [HR] extreme tertiles, 2.1; 95% confidence interval, 1.2 to 3.7), sICAM-1 (adjusted HR, 4.0; 95% confidence interval, 1.9 to 8.6), HDL-C (adjusted HR, 0.4; 95% confidence interval, 0.3 to 0.8), and TC:HDL-C (adjusted HR, 2.2; 95% confidence interval, 1.2 to 3.9). In a model simultaneously controlling for traditional risk factors plus these significant biomarkers, sICAM-1 remained independently predictive of PAD (adjusted HR in each tertile, 1.0 [reference], 2.3, and 3.5). CONCLUSIONS: Among a broad range of biomarkers of cardiovascular risk, only 4 factors, sICAM-1, high-sensitivity C-reactive protein, HDL-C, and TC:HDL-C, were significantly associated with incident symptomatic PAD in women. Findings pertaining to novel biomarkers provide clinical confirmation of a prominent role of endothelial activation and leukocyte recruitment in lower-extremity arterial disease.

Nohria A, Grunert ME, Rikitake Y, Noma K, Prsic A, Ganz P, Liao JK, Creager MA. · Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA. · Circ Res. · Pubmed #17095725 links to  free full text

Abstract: Investigations from basic biology suggest that activation of the Rho/Rho kinase pathway reduces the bioavailability of nitric oxide (NO) and thereby promotes atherosclerosis and its clinical complications. Yet, little information is available about the relationship of the Rho/Rho kinase pathway to NO bioavailability in humans with atherosclerosis. Accordingly, we determined whether inhibition of Rho kinase augments NO bioavailability and improves endothelial function in human subjects with coronary artery disease (CAD). Thirteen CAD subjects and 16 age- and sex-matched healthy controls were randomly assigned to receive the Rho kinase inhibitor, fasudil, or placebo for 1 month each in a double-blind crossover trial. Flow-mediated, endothelium-dependent and nitroglycerin-induced, endothelium-independent vasodilation were assessed by brachial artery ultrasonography. Rho kinase activity was measured in peripheral leukocytes. Fasudil increased endothelium-dependent vasodilation in CAD subjects from 9.4+/-1.9% to 13.4+/-1.9% (P=0.001) but not in healthy controls (from 11.3+/-1.4% to 7.7+/-1.1%; P=0.07). Endothelium-independent vasodilation was not affected by fasudil in either CAD or healthy subjects. Fasudil reduced Rho kinase activity by 59+/-18% in CAD subjects (P=0.001) but not in healthy subjects (by 3+/-6%; P=0.60). The change in endothelium-dependent vasodilation achieved with fasudil relative to placebo was inversely proportional to Rho kinase inhibition (ie, greater Rho kinase inhibition was associated with larger improvement in endothelium-dependent vasodilation) (r=-0.48; P=0.01). These findings suggest that Rho/Rho kinase activation promotes endothelial dysfunction in humans with atherosclerosis. Inhibition of the Rho/Rho kinase pathway should provide a useful strategy to restore NO bioavailability in humans with atherosclerosis.

Hamburg NM, Charbonneau F, Gerhard-Herman M, Ganz P, Creager MA. · Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, 75 Francis Street, Boston, MA 02115, USA. · Am J Cardiol. · Pubmed #15374789 No free full text.

Abstract: Endothelial function was evaluated in 34 young men and women with a family history of premature coronary artery disease (CAD) and 28 control subjects. Men with a family history of CAD had significantly impaired flow-mediated, endothelium-dependent vasodilation of the brachial artery compared with controls; however, in women, there was no difference in flow-mediated vasodilation between subjects with a family history and controls.

Beckman JA, Ganz J, Creager MA, Ganz P, Kinlay S. · Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Arterioscler Thromb Vasc Biol. · Pubmed #11597935 links to  free full text

Abstract: Coronary artery calcification is increased in the presence of atherosclerosis. However, there is great variability in the calcification of individual coronary stenoses, and the clinical significance of this finding remains unknown. We tested the hypothesis that culprit lesions associated with myocardial infarction or unstable angina are less calcified than are stenoses associated with stable angina. The study consisted of 78 patients who underwent intravascular ultrasound imaging of culprit stenoses after the placement of a stent. Seventeen patients presented with stable angina; 43, with unstable angina; and 18, with myocardial infarction. The extent of coronary calcification was measured by the angle of its arc and was quantified with a computer-based protractor. The arc of calcium was measured in the stented area at the point of maximal calcification and also as an average of the calcification found at proximal, middle, and distal stent segments. The maximal arc of calcium decreased progressively from patients with stable angina (91+/-10 degrees ) to those with unstable angina (59+/-8 degrees ) and to those with myocardial infarction (49+/-11 degrees, P=0.014). Similarly, the average arc of calcium was greatest (32+/-7 degrees ) in patients with stable angina, less (15+/-4 degrees ) in patients with unstable angina, and least (10+/-5 degrees ) in patients with acute myocardial infarction (P=0.014). These associations remained significant after adjustment for other factors that potentially affect arterial calcification. Acute coronary syndromes are associated with a relative lack of calcium in the culprit stenoses compared with stenoses of patients with stable angina. These findings have implications for the understanding of the biology of acute coronary syndromes as well as for the identification of coronary stenoses by methods that rely solely on the presence of calcium.

Kinlay S, Behrendt D, Wainstein M, Beltrame J, Fang JC, Creager MA, Selwyn AP, Ganz P. · Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Circulation. · Pubmed #11535565 links to  free full text

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.