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Biomedical subjects

M A Creager

Publications and source records attributed to M A Creager.

At least 73 records · Page 4Linked to original sources
PubMed1995

Systemic nature of endothelial dysfunction in atherosclerosis.

Vascular endothelium plays a pivotal role in the maintenance of vasodilation and the inhibition of platelet aggregation and smooth muscle cell proliferation through the release of nitric oxide and other factors. Extensive data have demonstrated abnormalities in coronary endothelial function in the epicardial coronary arteries in patients with atherosclerosis or risk factors for atherosclerosis. This dysfunction leads to abnormal vasoconstriction and platelet aggregation, which likely play a role in producing ischemia in patients with coronary artery disease. Invasive techniques have been available to assess endothelium-dependent vasodilator responses in the coronary arteries. However, until recently little has been known about endothelial responses in the peripheral vasculature, as methods to assess this have not been readily available. The hypothesis that endothelial dysfunction is a systemic process is explored, and new noninvasive methods of assessing endothelial function are discussed.

Arteriosclerosis↗
PubMed1995

Utility of leg ultrasonography in suspected symptomatic isolated calf deep venous thrombosis.

PURPOSE: To evaluate the utility of duplex ultrasonography in patients with suspected symptomatic, isolated calf deep venous thrombosis. PATIENTS AND METHODS: Thirty patients with clinically suspected isolated calf deep venous thrombosis were examined with both duplex ultrasonography and contrast venography and the results were compared. RESULTS: Venography detected 7 cases of isolated calf deep venous thrombosis, all of which were also detected by ultrasonography. Ultrasound identified an additional 3 cases of soleal vein thrombosis, but venography did not visualize these veins. Of the 20 negative ultrasound studies, 11 were technically inadequate; however, no false-negative ultrasound studies were noted. CONCLUSIONS: Compression ultrasonography may be reliable for the evaluation of patients with suspected symptomatic infrapopliteal deep venous thrombosis. Its apparent superiority to contrast venography in visualizing muscular calf veins warrants further study; however, the high rate of technical inadequacy in ultrasound studies observed here, if confirmed in larger studies, may limit the usefulness of ultrasound in this setting.

Adult↗
PubMed1995

Effect of nitric oxide synthase inhibition on bleeding time in humans.

Endothelium-derived nitric oxide (NO) is a potent in vitro inhibitor of platelet adhesion and aggregation, but its role in regulating platelet reactivity in vivo and in humans in particular is undefined. Our primary objective was to determine whether the in vivo inhibition of NO production shortens template bleeding time (BT). The hemodynamic and platelet effects of NG-mono-methyl-L-arginine (L-NMMA), an NO synthase inhibitor, were studied in 12 normal volunteers. Forearm template BT was determined before and 15 min after the intravenous (i.v.) infusion of 4.3 mg/kg L-NMMA. L-NMMA infusion increased mean arterial pressure from 88 +/- 4 to 99 +/- 3 mm Hg (p = 0.0001). Plasma NO levels, determined by chemiluminescence, decreased 65 +/- 10% from basal values (p < 0.05), confirming inhibition of endogenous NO production. Intravenous L-NMMA shortened BT from 5.5 +/- 0.9 to 4.0 +/- 0.6 min (p = 0.026), or by 24 +/- 8% (p = 0.008). L-NMMA infusion did not significantly change ex vivo platelet aggregation. To determine whether vasoconstriction affected BT, we investigated forearm blood flow (FBF; determined by venous occlusion plethymography), and template BT in 3 subjects after the local infusion of L-NMMA (2-4 mg/min intraarterially, i.a.). Intraarterial administration of L-NMMA caused a 39 +/- 3% (p = 0.006) reduction in FBF in the infused arm but did not change BT. These data show that systemic inhibition of NO production shortens BT in humans. However, the precise mechanism by which L-NMMA shortens BT is not completely defined.

Adult↗
PubMed1994

Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women.

OBJECTIVE: To assess the effect of estrogen replacement therapy on endothelium-dependent vasodilation in postmenopausal women. DESIGN: Double-blind, placebo-controlled, crossover trial. SETTING: University medical center. PATIENTS: 13 postmenopausal women aged 44 to 69 years (average age, 55 +/- 7 years). INTERVENTION: Patients were randomly assigned to receive placebo, oral estradiol at a dose of 1 mg/d, and oral estradiol at a dose of 2 mg/d. Each treatment phase lasted 9 weeks. MEASUREMENTS: High-resolution ultrasonography was used to measure vascular reactivity in a peripheral conduit vessel, the brachial artery. Endothelium-dependent vasodilation was determined by measuring the change in brachial artery diameter during increases in flow induced by reactive hyperemia. Endothelium-independent vasodilation was measured after sublingual nitroglycerin was administered. RESULTS: Flow-mediated, endothelium-dependent vasodilation of the brachial artery was greater when patients received estradiol (13.5% and 11.6% for 1-mg and 2-mg doses, respectively) than when patients received placebo (6.8%; P < 0.05 for each dose compared with placebo). In contrast, estrogen administration had no effect on endothelium-independent vasodilation as assessed by sublingual nitroglycerin. CONCLUSION: Short-term estrogen replacement therapy improves flow-mediated endothelium-dependent vasodilation in postmenopausal women. This improvement may be mediated by a direct effect of estrogen on vascular function or may be induced through modification of lipoprotein metabolism.

Administration, Oral↗
PubMed1994

Carotid arterial compliance in patients with congestive heart failure secondary to idiopathic dilated cardiomyopathy.

Conduit artery distensibility affects the pulsatile component of afterload and may contribute to impaired left ventricular function in patients with congestive heart failure (CHF). The objectives of this study were to (1) determine whether arterial distensibility is reduced in patients with CHF, and (2) determine whether decreased arterial compliance is related to an abnormality in vascular wall structure (i.e., wall thickness or excessive levels of circulating neurohumoral vasoconstrictors, or both). The study participants included 40 patients with CHF secondary to idiopathic dilated cardiomyopathy and 33 age-matched healthy volunteers. High-resolution ultrasonography was performed to directly visualize the common carotid artery and measure its diameter and wall thickness. Its elastic properties were determined by relating changes in arterial diameter to changes in pressure generated with each heart beat. Carotid artery distensibility was less (14.1 +/- 1.1 vs 25.3 +/- 1.6 10(-6).N-1.m2, p < 0.001) and Young's modulus of elasticity was greater (3.99 +/- 0.51 vs 2.29 +/- 0.23 10(5).N.m-2, p < 0.005) in patients with CHF than in normal subjects. Also, carotid artery wall thickness was increased in patients with CHF. When the entire population was considered, age, wall thickness, and plasma norepinephrine and aldosterone concentrations correlated inversely with distensibility, whereas age and plasma norepinephrine concentration correlated directly with elasticity. Among normal subjects, only age correlated inversely with distensibility; among patients with CHF, only plasma norepinephrine concentration correlated with elasticity. It is concluded that carotid artery distensibility is reduced in patients with CHF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Efficacy and safety of repeated boluses of urokinase in the treatment of deep venous thrombosis.

The only Food and Drug Administration-approved thrombolytic regimen for treatment of deep venous thrombosis (DVT) is a 24- to 72-hour continuous infusion of intravenous streptokinase. This approach to DVT thrombolysis is not entirely satisfactory because of the bleeding complications that may accompany this therapy. In the current study, we treated 27 patients with DVT with a novel dosing regimen of urokinase: 1,000,000 U administered as a 10-minute bolus, with a total of 3 boluses given over approximately 24 hours. Patients were given heparin overnight between bolus urokinase doses. Efficacy was assessed by comparing baseline and prehospital discharge vascular imaging studies, which constituted either venous ultrasound or contrast venography. A vascular-imaging panel of physicians, unaware of the sequence of paired studies, found that 14 patients (52%) had clot lysis (6 slight, 6 moderate and 2 marked), 9 (33%) had no change, and 4 (15%) had more extensive thrombosis after treatment (1 slight, 2 moderate and 1 marked). There were no bleeding complications. At 48 hours after starting urokinase, mean plasma fibrinogen levels had decreased 61% from baseline, and the mean bleeding time had increased 28% from baseline (but remained within the normal range). Because of the promising efficacy and safety that were found in this case series, it is concluded that further testing of bolus urokinase is warranted against anticoagulation alone.

Adult↗
PubMed1994

Arterial baroreflex regulation of blood pressure in patients with congestive heart failure.

OBJECTIVES: This study was designed to determine whether arterial baroreflex control of blood pressure is altered in patients with congestive heart failure. BACKGROUND: Arterial baroreceptor reflexes normally contribute to cardiovascular homeostasis by preserving blood pressure during changes in volume and posture. METHODS: Arterial baroreceptor reflex function was studied in 18 patients with congestive heart failure and 18 age-matched healthy subjects. The arterial baroreceptor-blood pressure reflex was assessed by measuring the blood pressure response to perturbations in carotid sinus pressure. Carotid baroreceptors were stimulated by applying negative pressure to a custom neck chamber (-10, -20 and -30 mm Hg) and were unloaded by applying neck positive pressure (+10, +20 and +30 mm Hg). RESULTS: Peak carotid baroreceptor-blood pressure reflex sensitivity was lower in patients with heart failure than in normal subjects (0.19 +/- 0.02 vs. 0.30 +/- 0.03 mm Hg/mm Hg, p < 0.05). During neck positive pressure, blood pressure increased less in the heart failure group than in the normal group. During neck suction, however, the decrease in blood pressure was similar in the two groups. CONCLUSIONS: Patients with heart failure are less able than normal subjects to increase blood pressure during arterial baroreceptor unloading, but they can reduce blood pressure appropriately during baroreceptor stimulation. These observations suggest that the resting blood pressure position on the arterial baroreceptor stimulus-response curve, the operational point, is closer to the baroreceptor threshold in patients with heart failure than in normal subjects. As a result, reduced inhibitory signals from arterial baroreceptors most likely contribute to a heightened state of sympathetic activity and vasoconstriction in patients with congestive heart failure.

Baroreflex↗
PubMed1994

Fixed low-dose versus adjusted higher-dose warfarin following orthopedic surgery. A randomized prospective trial.

Orthopedic patients are at a high risk for developing venous thromboembolism, yet only a fraction of eligible patients receive anticoagulation prophylaxis after hospital discharge. This pilot study compared the efficacy of a fixed 2 mg/d dose of warfarin versus an adjusted higher dose of warfarin for 1 month after discharge to prevent the development of proximal leg deep venous thrombosis among recently discharged orthopedic patients. After standard inhospital treatment with adjusted higher-dose warfarin and a predischarge leg ultrasound to exclude deep venous thrombosis, 96 orthopedic patients were randomized just prior to discharge to either fixed low-dose (n = 49) or adjusted higher-dose warfarin (n = 47). At the 6-week follow-up evaluation, ultrasonographically confirmed, asymptomatic, proximal leg deep venous thrombosis occurred in two patients (4%). Both patients were randomized to the fixed low-dose group, although one remained on adjusted higher-dose warfarin throughout the trial. No patient in either group developed major bleeding complications. Further studies should be undertaken to further test fixed low-dose warfarin for venous thromboembolic prevention in high-risk orthopedic patients.

Female↗
PubMed1994

Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans.

BACKGROUND: The endothelium synthesizes and releases a relaxing factor with the physiochemical properties of nitric oxide (NO). However, the role of endothelium-derived NO in the basal regulation of systemic and pulmonary vascular resistance in humans is not known. Our primary objectives were to determine the effects of inhibiting NO synthesis on blood pressure and systemic vascular resistance and to establish the role of endothelium-derived NO in the regulation of normoxic pulmonary vascular tone. METHODS AND RESULTS: We studied the systemic and pulmonary hemodynamic effects of NG-monomethyl-L-arginine (L-NMMA, 0.03 to 1.0 mg.kg-1.min-1 IV), an NO synthase inhibitor, in 11 healthy volunteers, aged 33 +/- 2 years. An arterial cannula and a pulmonary artery catheter were placed in each subject to measure blood pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure. Cardiac output was determined by the Fick technique, and systemic and pulmonary vascular resistances were calculated. Serum NO levels (free and protein bound) were measured by chemiluminescence in 5 subjects. Six of the subjects also received phenylephrine (25 to 100 micrograms/min IV) to compare the cardiac hemodynamic effects of L-NMMA with those of a direct-acting vasoconstrictor. L-NMMA caused dose-dependent increases in both blood pressure and systemic vascular resistance. At the highest dose of L-NMMA, there was a 15.5 +/- 1.3% increase in mean blood pressure and a 63.4 +/- 8.2% increase in systemic vascular resistance (each P < .01). Pulmonary vascular resistance increased 39.8 +/- 9.4% (P < .01), whereas mean pulmonary artery pressure did not change. Administration of L-NMMA also reduced cardiac output by 27.8 +/- 2.9% and stroke volume by 15.4 +/- 3.5% (each P < .01). Serum NO levels decreased 65 +/- 10% from basal values (P < .05), confirming inhibition of endogenous NO production. Phenylephrine increased blood pressure to a level comparable to that observed with L-NMMA. The decline in stroke volume was greater with L-NMMA than with phenylephrine (P < .01). CONCLUSIONS: This study demonstrates that basal release of endothelium-derived NO is directly involved in the determination of systemic vascular resistance and, therefore, blood pressure in healthy humans. In addition, NO regulates basal normoxic pulmonary vascular tone. The complex hemodynamic effects of NO are composite properties of its actions on systemic and pulmonary vascular resistance and cardiac function.

Adult↗
PubMed1994

Effect of captopril and enalapril on endothelial function in hypertensive patients.

Endothelium-dependent vasodilation is impaired in patients with essential hypertension. The objective of this study was to determine whether long-term treatment with angiotensin-converting enzyme inhibitors improves endothelium-dependent vasodilation in forearm resistance vessels of patients with hypertension. Furthermore, since tissue thiols may be relevant to nitric oxide-mediated vasodilation, we queried whether an angiotensin-converting enzyme inhibitor with a sulfhydryl group preferentially augments endothelium-dependent vasodilation in these individuals. The study included 24 patients with essential hypertension (mean age, 45 +/- 2 years) and 20 normotensive subjects (mean age, 47 +/- 1 years). Methacholine chloride (0.3 to 10 micrograms/min) was infused via the brachial artery to assess endothelium-dependent vasodilation in forearm resistance vessels. Nitroglycerin (1 to 30 micrograms/min) was administered to evaluate endothelium-independent vasodilation. Forearm blood flow was determined by venous occlusion strain-gauge plethysmography. Forearm vascular function studies were performed in hypertensive patients before and 7 to 8 weeks after randomization to either captopril or enalapril, angiotensin-converting enzyme inhibitors with and without a sulfhydryl moiety, respectively. Normotensive subjects were studied on only one occasion. Before treatment, the forearm vasodilative response to methacholine was attenuated in hypertensive compared with normotensive subjects (P < .01). The effects of nitroglycerin on forearm blood flow did not differ significantly between the two groups. Both captopril and enalapril reduced mean blood pressure in the hypertensive subjects (12 +/- 2 versus 15 +/- 3 mm Hg, respectively; P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Recommendations for training in vascular medicine. American College of Cardiology Peripheral Vascular Disease Committee.

Each trainee in vascular medicine must be eligible for the board certification examination of the American Board of Internal Medicine or its equivalent. Training faculty, preferably at least two members, should meet the qualifications and training requirements described in this report. They must be dedicated, effective teachers and should spend most of their time in research, education and patient care related to peripheral vascular diseases. A curriculum of training should be established. Faculty experts in related specialties and in the related basic sciences should be available for teaching. The institution should have a fully equipped noninvasive vascular laboratory and areas where catheter revascularization techniques and vascular surgery are performed. The period of training should not be less than 1 year, preferably continuous.

Cardiology↗
PubMed1993

Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study.

OBJECTIVES: The aim of this study was to assess the efficacy of flosequinan in chronic heart failure. BACKGROUND: Flosequinan is a new vasodilator drug that acts by interfering with the inositol-triphosphate/protein kinase C pathway, an important mechanism of vasoconstriction. The drug dilates both peripheral arteries and veins, is orally active and has a long duration of action that permits once-daily dosing. Previous studies have shown that flosequinan produces sustained hemodynamic benefits in heart failure, but large scale studies evaluating its clinical efficacy have not been reported. METHODS: One hundred ninety-three patients with chronic heart failure (New York Heart Association functional class II or III and left ventricular ejection fraction < 40%) receiving digoxin and diuretic drugs were randomly assigned (double-blind) to the addition of flosequinan (100 mg once daily, n = 93) or placebo (n = 100) for 3 months. The clinical status and exercise tolerance of each patient was evaluated at the start of the study and every 2 to 4 weeks during the trial while background therapy remained constant. RESULTS: After 12 weeks, maximal treadmill exercise time increased by 96 s in the flosequinan group but by only 47 s in the placebo group (p = 0.022 for the difference between groups). Maximal oxygen consumption increased by 1.7 ml/kg per min in the flosequinan group (n = 17) but by only 0.6 ml/kg per min in the placebo group (n = 23), p = 0.05 between the groups. Symptomatically, 55% of patients receiving flosequinan but only 36% of patients receiving placebo benefited from treatment (p = 0.018). In addition, fewer patients treated with flosequinan had sufficiently severe worsening of heart failure to require a change in medication or withdrawal from the study (p = 0.07). By intention to treat, seven patients in the flosequinan group and two patients in the placebo group died. CONCLUSIONS: These findings indicate that flosequinan is an effective drug for patients with chronic heart failure who remain symptomatic despite treatment with digoxin and diuretic drugs. The effect of the drug on survival remains to be determined.

Chronic Disease↗
PubMed1993

Relationship of arterial compliance to baroreflex function in hypertensive patients.

The objectives of this study were to determine whether carotid arterial compliance is reduced in patients with hypertension and to assess whether reduced arterial compliance is related to abnormal arterial baroreflex function. Accordingly, concurrent measurements of carotid arterial diameter (via computerized high resolution B-mode ultrasonography) and blood pressure were made to determine carotid arterial compliance in 23 normotensive and 16 age-matched hypertensive patients. In addition, arterial baroreflex function was assessed in 12 of the normal subjects and nine of the hypertensive patients by measuring the infusions of nitroprusside and phenylephrine. Compared with the normotensive subjects, the patients with hypertension had reduced compliance (5.9 +/- 0.7 vs. 16.6 +/- 1.8 10(-7) m2/kPa, mean +/- SE, P < 0.001). The baroreflex slope relating the change in R-R interval to the change in systolic blood pressure during the drug infusions was less in the hypertensive than normotensive subjects (12.3 +/- 2 vs. 18.9 +/- 2 ms/mmHg, P < 0.05). Consequently, when both normotensive and hypertensive subjects were considered, there was a significant correlation between the baroreflex slope and compliance (r = 0.53, P < 0.05). However, there was no correlation between the baroreflex slope and compliance within either the normotensive group (r = 0.04, P = NS) or the hypertensive group (r = 0.43, P = NS) when analyzed separately. There was a significant correlation between age and compliance (r = -0.48, P < 0.01) but not between age and baroreflex function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Contribution of vasopressin to blood pressure regulation during hypovolemic hypotension in humans.

In animals subjected to hemorrhage, plasma arginine vasopressin concentrations increase to levels sufficient to cause vasoconstriction, thus attenuating the hypotensive response. The purpose of this study was to examine the contribution of vasopressin to blood pressure regulation during hypotension in humans. Hypotension was induced in twelve normal subjects by lower body negative pressure (LBNP) before and after intravenous administration of vasopressin V1 receptor antagonist. Before drug administration, LBNP reduced systolic blood pressure from 125 +/- 4 to 78 +/- 12 mmHg (P < 0.01) as vasopressin concentration increased from 2.9 +/- 0.6 to 17 +/- 6 pg/ml (P < 0.05). After administration of the vasopressin antagonist, LBNP reduced systolic blood pressure from 128 +/- 3 to 89 +/- 11 mmHg (P < 0.01). The hypotensive response to LBNP was not potentiated by inhibiting vasopressin's vasoconstrictive effects (P = NS). Thus hypotension causes marked increases in plasma vasopressin concentration. In contrast to findings in animal studies, however, vasopressin does not contribute to the maintenance of blood pressure during hypotension in humans.

Adult↗
PubMed1993

Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.

BACKGROUND: Endothelium-dependent vasodilation is abnormal in experimental models of diabetes mellitus. We postulated that abnormalities of endothelial function are also present in patients with insulin-dependent diabetes mellitus and may contribute to the pathogenesis of vascular disease in these individuals. METHODS AND RESULTS: Vascular reactivity was measured in the forearm resistance vessels of 15 patients with insulin-dependent diabetes mellitus and 16 age-matched normal subjects. No patient had hypertension or dyslipidemia. Each subject was pretreated with aspirin to inhibit endogenous production of prostanoids. Methacholine chloride (0.3 to 10 micrograms/min) was administered via the brachial artery to assess endothelium-dependent vasodilation. Sodium nitroprusside (0.3 to 10 micrograms/min) and verapamil (10 to 300 micrograms/min) were infused intra-arterially to assess endothelium-independent vasodilation; phenylephrine (0.3 to 3 micrograms/min) was administered to examine vasoconstrictor responsiveness. Forearm blood flow was determined by venous occlusion plethysmography, and dose-response curves were generated for each drug. Basal forearm blood flow in diabetic and normal subjects was comparable (2.6 +/- 0.2 versus 2.1 +/- 0.3 mL x 100 mL-1 x min-1, respectively; P = NS). The forearm vasodilative response to methacholine was less in diabetic than in normal subjects. At the highest dose of methacholine, the forearm blood flow increased 9.5 +/- 1.1 mL x 100 mL-1 x min-1 in diabetic subjects and 15.3 +/- 1.4 mL.100 mL-1 x min-1 in normal subjects (P < .01). The forearm blood flow responses to nitroprusside and verapamil and the forearm vasoconstrictor responses to phenylephrine were similar in diabetic and healthy subjects. In diabetic subjects, endothelium-dependent vasodilation correlated inversely with serum insulin concentration but not with glucose concentration, glycosylated hemoglobin, or duration of diabetes. CONCLUSIONS: Endothelium-dependent vasodilation is abnormal in forearm resistance vessels of patients with insulin-dependent diabetes mellitus. This abnormality may be relevant to the high prevalence of vascular disease that occurs in these individuals.

Adult↗
PubMed1992

Detection and significance of intraoperative and postoperative myocardial ischemia in peripheral vascular surgery.

OBJECTIVE: To determine the incidence and significance of intraoperative and postoperative myocardial ischemia and their relationship to preoperative ischemia and postoperative cardiac events in patients undergoing peripheral arterial surgery. DESIGN: Prospective cohort trial. PATIENTS: One hundred fifteen patients undergoing elective vascular surgery who met predefined eligibility criteria and were thought to have acceptable cardiac risk as assessed by independent cardiologists. INTERVENTIONS: Ambulatory electrocardiographic monitoring preoperatively, intraoperatively, and up to 72 hours postoperatively. MEASUREMENTS: Preoperative clinical characteristics and laboratory data were collected. Predefined adverse cardiac events were identified by an investigator who was "blinded" to monitoring results. Monitor recordings were interpreted for ST-segment depression by investigators blinded to patient information. MAIN RESULTS: Intraoperative ischemia was present in 21 patients (18%), and postoperative ischemia was present in 35 (30%). There were 16 postoperative cardiac events. The relative risk of suffering a cardiac event was 2.7 in patients with intraoperative ischemia and was 16 in patients with postoperative ischemia. Preoperative ischemia closely correlated with intraoperative and postoperative ischemia. Preoperative and postoperative ischemia preceded cardiac events in 14 of 16 patients. CONCLUSIONS: Preoperative ischemia appears to identify high-risk patients, and subsequent perioperative monitoring detects silent ischemia that commonly precedes clinical events and that may be treatable with anti-ischemia therapy.

Adult↗