Rita Mincemoyer

Prognostic Value of Coronary Vascular Endothelial Dysfunction

Background—Whether patients at increased risk can be identified from a relatively low-risk population by coronary vascular function testing remains unknown. We investigated the relationship between coronary endothelial function and the occurrence of acute unpredictable cardiovascular events (cardiovascular death, myocardial infarction, stroke, and unstable angina) in patients with and without coronary atherosclerosis (CAD). Methods and Results—We measured the change in coronary vascular resistance (&Dgr;CVR) and epicardial diameter with intracoronary acetylcholine (ACh, 15 &mgr;g/min) to test endothelium-dependent function and sodium nitroprusside (20 &mgr;g/min) and adenosine (2.2 mg/min) to test endothelium-independent vascular function in 308 patients undergoing cardiac catheterization (132 with and 176 without CAD). Patients underwent clinical follow-up for a mean of 46±3 months. Acute vascular events occurred in 35 patients. After multivariate analysis that included CAD and conventional risk factors for atherosclerosis, &Dgr;CVR with ACh (P =0.02) and epicardial constriction with ACh (P =0.003), together with increasing age, CAD, and body mass index, were independent predictors of adverse events. Thus, patients in the tertile with the best microvascular responses with ACh and those with epicardial dilation with ACh had improved survival by Kaplan-Meier analyses in the total population, as did those in the subset without CAD. Similar improvement in survival was also observed when all adverse events, including revascularization, were considered. Endothelium-independent responses were not predictive of outcome. Conclusions—Epicardial and microvascular coronary endothelial dysfunction independently predict acute cardiovascular events in patients with and without CAD, providing both functional and prognostic information that complements angiographic and risk factor assessment.

Imipramine in patients with chest pain despite normal coronary angiograms

BACKGROUND Ten to 30 percent of patients undergoing cardiac catheterization because of chest pain are found to have normal coronary angiograms. Because these patients may have a visceral pain syndrome unrelated to myocardial ischemia, we investigated whether drugs that are useful in chronic pain syndromes might also be beneficial in such patients. METHODS Sixty consecutive patients underwent cardiac, esophageal, psychiatric, and pain-sensitivity testing and then participated in a randomized, double-blind, placebo-controlled three-week trial of clonidine at a dose of 0.1 mg twice daily (20 patients), imipramine at a dose of 50 mg nightly with a morning placebo (20 patients), or placebo twice daily (20 patients); this treatment phase was compared with an identical period of twice-daily placebo for all patients (placebo phase). RESULTS Thirteen (22 percent) of the 60 patients had ischemic-appearing electrocardiographic responses to exercise, 22 of the 54 tested (41 percent) had abnormal esophageal motility, 38 of 60 (63 percent) had one or more psychiatric disorders, and 52 of 60 (87 percent) had their characteristic chest pain provoked by right ventricular electrical stimulation or intracoronary infusion of adenosine. During the treatment phase, the imipramine group had a mean (+/- SD) reduction of 52 +/- 25 percent in episodes of chest pain, the clonidine group had a reduction of 39 +/- 51 percent, and the placebo group a reduction of 1 +/- 86 percent, all as compared with the placebo phase of the trial. Only the improvement with imipramine was statistically significant (P = 0.03). Repeat assessment of sensitivity to cardiac pain while the patients were receiving treatment showed significant improvement only in the imipramine group (P = 0.01). The response to imipramine did not depend on the results of cardiac, esophageal, or psychiatric testing at base line, or on the change in the psychiatric profile during the course of the study, which generally improved in all three study groups. CONCLUSIONS Imipramine improved the symptoms of patients with chest pain and normal coronary angiograms, possibly through a visceral analgesic effect.

Effects of Hormone-Replacement Therapy on Fibrinolysis in Postmenopausal Women

Background Plasma levels of plasminogen-activator inhibitor type 1 (PAI-1), an essential inhibitor of fibrinolysis in humans, increase in women after menopause, and this may contribute to the risk of cardiovascular disease. We studied the effects of hormone-replacement therapy on PAI-1 levels. Methods In a randomized, crossover study, we investigated the effects of oral conjugated estrogen (0.625 mg per day) in 30 postmenopausal women and transdermal estradiol (0.1 mg per day) in 20 postmenopausal women, either alone or in combination with medroxyprogesterone acetate (2.5 mg daily) for one month, on plasma PAI-1 antigen levels. Degradation products of cross-linked fibrin (D-dimer) were measured in serum as an index of fibrinolysis. Results PAI-1 levels were inversely associated with D-dimer levels at base line (r = -0.540, P = 0.002). Conjugated estrogen, both alone and in combination with medroxyprogesterone acetate, reduced mean (±SD) plasma levels of PAI-1 from 32±34 ng per milliliter to 14±10 ng per m...

Acute and Chronic Angiotensin-1 Receptor Antagonism Reverses Endothelial Dysfunction in Atherosclerosis

BACKGROUND The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The present study was performed to determine whether angiotensin-1 (AT(1)) receptor inhibition improves endothelial dysfunction. METHODS AND RESULTS In the femoral circulation of 19 patients with atherosclerosis and of 9 control subjects, we studied microvascular responses to reactive hyperemia, angiotensin II, acetylcholine, and sodium nitroprusside before and after the administration of intra-arterial losartan (10 mg). Femoral artery flow velocity was measured with a Doppler flow wire, and the femoral vascular resistance index (FVRI) was calculated as mean arterial pressure divided by flow velocity. Losartan induced a minor (5.9+/-2%, P=0. 02) reduction in FVRI and inhibited angiotensin II-mediated vasoconstriction in both patient groups (P<0.01). After the administration of losartan, acetylcholine-mediated vasodilation was augmented in patients (44+/-5% to 58+/-4% reduction in FVRI with infusion at a rate of 150 microgram/min, P<0.001) but not control subjects. Vasodilation during reactive hyperemia was also greater after AT(1) receptor inhibition (P=0.03) in patients, but the response to sodium nitroprusside remained unchanged. In a separate group of 31 patients with atherosclerosis, we investigated the effect of 8 weeks of oral losartan therapy on brachial artery flow-mediated vasodilation with the use of high-resolution ultrasound. Oral losartan therapy improved flow-mediated brachial artery dilation (1.4+/-0.9% to 3.2+/-0.8%, P=0.03) but had no effect on the nitroglycerin response. Serum nitrogen oxide levels increased from 21.6+/-1.7 to 26.7+/-2.4 micromol/L (P=0.008). CONCLUSIONS The results of the present study indicate that inhibition of the AT(1) receptor in patients with atherosclerosis reverses endothelial dysfunction by improving NO availability and therefore may have long-term therapeutic benefits.

Oral l-Arginine in Patients With Coronary Artery Disease on Medical Management

BACKGROUND Vascular nitric oxide (NO) bioavailability is reduced in patients with coronary artery disease (CAD). We investigated whether oral L-arginine, the substrate for NO synthesis, improves homeostatic functions of the vascular endothelium in patients maintained on appropriate medical therapy and thus might be useful as adjunctive therapy. METHODS AND RESULTS Thirty CAD patients (29 men; age, 67+/-8 years) on appropriate medical management were randomly assigned to L-arginine (9 g) or placebo daily for 1 month, with crossover to the alternate therapy after 1 month off therapy, in a double-blind study. Nitrogen oxides in serum (as an index of endothelial NO release), flow-mediated brachial artery dilation (as an index of vascular NO bioactivity), and serum cell adhesion molecules (as an index of NO-regulated markers of inflammation) were measured at the end of each treatment period. L-Arginine significantly increased arginine levels in plasma (130+/-53 versus 70+/-17 micromol/L, P<0.001) compared with placebo. However, there was no effect of L-arginine on nitrogen oxides (19.3+/-7.9 versus 18. 6+/-6.7 micromol/L, P=0.546), on flow-mediated dilation of the brachial artery (11.9+/-6.3% versus 11.4+/-7.9%, P=0.742), or on the cell adhesion molecules E-selectin (47.8+/-15.2 versus 47.2+/-14.4 ng/mL, P=0.601), intercellular adhesion molecule-1 (250+/-57 versus 249+/-57 ng/mL, P=0.862), and vascular cell adhesion molecule-1 (567+/-124 versus 574+/-135 ng/mL, P=0.473). CONCLUSIONS Oral L-arginine therapy does not improve NO bioavailability in CAD patients on appropriate medical management and thus may not benefit this group of patients.

Vascular Effects of Estrogen and Vitamin E Therapies in Postmenopausal Women

BACKGROUND Estrogen and vitamin E therapies have been suggested to reduce cardiovascular risk, but comparison of the vascular effects of these therapies to determine mechanisms of potential benefit has not been performed in postmenopausal women. METHODS AND RESULTS In a double-blind, 3-period crossover study, we randomly assigned 28 healthy postmenopausal women to conjugated equine estrogens (CE) 0. 625 mg/d, vitamin E 800 IU/d, and their combination, with measurements made before and after each 6-week treatment period. The ratio of LDL to HDL cholesterol and lipoprotein(a) decreased on therapies including CE but increased on vitamin E alone (P<0.001 and P=0.002, respectively, by ANOVA). Brachial artery flow-mediated dilation improved on all therapies (all P<0.001 versus pretreatment values) and to a similar degree (P=0.267 by ANOVA). No therapy improved the dilator response to nitroglycerin. CE lowered serum levels of cell adhesion molecules E-selectin, ICAM-1, and VCAM-1 (all P<0.05 versus pretreatment values). Vitamin E had no significant effect on levels of these markers of inflammation (P<0. 001 by ANOVA for E-selectin). CE alone or combined with vitamin E but not vitamin E alone lowered or showed a trend for lowering plasma levels of plasminogen activator inhibitor type-1 (P=0.069 by ANOVA). CONCLUSIONS Estrogen and vitamin E therapies similarly improved arterial endothelium-dependent vasodilator responsiveness consistent with increased nitric oxide in healthy postmenopausal women, despite divergent effects on atherogenic lipoproteins. However, only estrogen reduced markers of vascular disease.

Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women.

To investigate the effect of estrogen with antioxidant potential on soluble markers of chronic vascular inflammation, we administered either transdermal 17beta-estradiol 0.1 mg/day (9 women) or 17beta-estradiol 0.1 mg and medroxyprogesterone acetate 2.5 mg/day (11 women) for 1-month treatment in a randomized design, with measurement of cell adhesion molecules. Hormone therapy significantly lowered intercellular adhesion molecules-1 levels by 8% (p = 0.009) and tended to lower E-selectin levels (by 6%, p = 0.096), and VCAM-1 levels (by 4%, p = 0.084).

Relationship of the C242T p22phox gene polymorphism to angiographic coronary artery disease and endothelial function

Patients with coronary artery disease (CAD) have impaired endothelial function in part due to an increase in vascular oxidant stress. p22phox, an essential component of the NADPH oxidase, is thought to play a critical role in the generation of superoxide anions in the vessel wall. The C242T polymorphism, located in the potential heme-binding site of the p22phox gene, has recently been reported to confer a protective effect on CAD risk in a Japanese study population. In a U.S. population of 252 patients (83% Caucasian) undergoing angiography for diagnosis of CAD, we investigated whether the C242T polymorphism was associated with the presence of CAD. In a subset of 142 patients, we studied whether the polymorphism manifests its potential protective effects through alteration of vascular endothelial function by measuring coronary epicardial and microvascular responses to intracoronary acetylcholine and sodium nitroprusside. Prevalence of the C242T allele was not different in 149 patients with CAD compared to 103 patients with angiographically normal coronary arteries (65.1% vs. 54.4%, P = 0.11). The C242T allele frequency in our population was nearly fourfold higher than reported previously in a Japanese population. There were also no significant differences in coronary epicardial or microvascular responses to acetylcholine or sodium nitroprusside between groups of patients with or without the C242T allele. In a U.S. population, the C242T polymorphism does not appear to confer protection from endothelial dysfunction or CAD. Am. J. Med. Genet. 86:57-61, 1999. Published 1999 Wiley-Liss, Inc.

Three year anatomic, functional and clinical follow-up after successful percutaneous transluminal coronary angioplasty.

Because the long-term anatomic effects of percutaneous transluminal coronary angioplasty are unknown, follow-up evaluations including coronary angiography, treadmill exercise testing and rest and bicycle exercise radionuclide angiography were performed in 46 patients 6.3 +/- 2.0 and 37.6 +/- 3.6 (mean +/- SD) months after they had undergone successful single lesion angioplasty. The severity of the coronary stenosis decreased significantly at each evaluation; the mean diameter stenosis was 66 +/- 13% before angioplasty, 30 +/- 13% immediately after and 26 +/- 16% and 19 +/- 13% at 6 months and 3 years, respectively. Exercise time increased from 9.8 +/- 4.4 minutes before angioplasty to 18.3 +/- 4.5 minutes immediately after the procedure and remained at that level at 6 months (20.3 +/- 4.6 minutes) and 3 years (18.2 +/- 4.5 minutes). Left ventricular ejection fraction during exercise decreased 4 +/- 6% compared with rest before angioplasty, but increased 7 +/- 7% immediately after angioplasty and this increase was maintained at 6 months (+/- 6 +/- 7%) and 3 years (+/- 4 +/- 6%). Before angioplasty, 1 patient was in Canadian Heart Association functional class 0, 15 were in class II, 24 in class III and 6 in class IV. Three years later, 25 were in class 0, 10 in class I, 7 in class II and 4 in class III. These results indicate that the short-term anatomic and functional success of coronary angioplasty is maintained for at least 3 years.

Effects of oral L-arginine on endothelium-dependent vasodilation and markers of inflammation in healthy postmenopausal women

OBJECTIVES We examined whether oral administration of L-arginine, the substrate for nitric oxide (NO) synthesis, increases NO bioactivity in healthy postmenopausal women. BACKGROUND Nitric oxide may protect arteries against atherosclerosis, as suggested by experimental studies in animals. Estrogen therapy, which has been shown to increase NO bioactivity in the vasculature of healthy postmenopausal women, is not acceptable for long-term use by many women. METHODS In a randomized, double-blind, crossover study, 10 postmenopausal women without additional risk factors for atherosclerosis received L-arginine 9 g or placebo daily for one month, with treatment periods separated by one month. Nitric oxide levels in serum (as an index of endothelial NO release), brachial artery endothelium-dependent dilator responses to hyperemia by ultrasonography (as an index of vascular NO bioactivity) and markers of inflammation in blood that are inhibited by NO in cell culture experiments were measured at the end of each treatment period. RESULTS L-arginine levels in plasma were increased in all women during L-arginine treatment compared with placebo (136.8 +/- 63.1 vs. 75.2 +/- 16.2 micromol/liter, p = 0.009). However, there was no change in serum nitrogen oxide levels (42.1 +/- 24.5 vs. 39.1 +/- 16.6 micromol/liter, p = 0.61), nor was there an effect of L-arginine on flow-mediated dilation during hyperemia (3.8 +/- 3.0% vs. 4.9 +/- 4.8%, p = 0.53) compared with placebo. Our study had sufficient power (beta = 0.80) to detect a true absolute treatment difference in flow-mediated brachial artery dilation of 1.7% or larger as statistically significant at alpha = 0.05. There was no effect of L-arginine on serum levels of soluble cell adhesion molecules compared with placebo: E-selectin (50.6 +/- 14.8 vs. 52.1 +/- 17.0 ng/ml, p = 0.45), intercellular adhesion molecule-1 (230 +/- 51 vs. 230 +/- 52 ng/ml, p = 0.97) and vascular cell adhesion molecule-1 (456 +/- 62 vs. 469 +/- 91 ng/ml, p = 0.53). CONCLUSIONS Oral administration of L-arginine may not augment endothelial NO synthesis and release in postmenopausal women and is thus unlikely to be of general benefit to healthy postmenopausal women in protection from the development of atherosclerosis.