Richard W. Harper

Contribution of Vasodilator Prostanoids and Nitric Oxide to Resting Flow, Metabolic Vasodilation, and Flow-Mediated Dilation in Human Coronary Circulation

BACKGROUND Endothelial dysfunction is associated with atherosclerosis and may contribute to ischemic syndromes. We assessed the contribution of endothelium-derived nitric oxide (NO) and vasodilator prostanoids to resting blood flow, metabolic vasodilation, and flow reserve in the human coronary circulation. METHODS AND RESULTS Coronary hemodynamics were assessed before and after inhibition of vasodilator prostanoids and NO with intracoronary aspirin (acetylsalicylic acid [ASA]) and N(G)-monomethyl-L-arginine (L-NMMA), respectively. Angiographically smooth or mildly irregular vessels, with normal adenosine-induced coronary flow reserve, were studied in 25 patients undergoing clinically indicated procedures. Coronary blood velocity was measured by Doppler flow wire, and coronary blood flow (CBF) was calculated. ASA reduced resting conduit vessel diameter by 11% (P = 0.003) and CBF by 27% (P = 0.008) and increased coronary vascular resistance (CVR) by 24% (P<0.0001). ASA attenuated pacing-induced hyperemia by 28% (45.0+/-4.6 versus 32.6+/-3.4 mL/min, P = 0.005) and increased minimum CVR by 39% (2.8+/-0.3 versus 3.9+/-0.5 mm Hg x mL(-1) x min(-1), P = 0.007). L-NMMA reduced resting conduit vessel diameter by 9% (P = 0.05) and CBF by 20% (P = 0.08) and increased CVR by 19% (P = 0.03). L-NMMA attenuated pacing-induced hyperemia by 20% (42.4+/-5.1 versus 34.1+/-3.4 mL/min, P = 0.04) and increased minimum CVR by 33% (2.9+/-0.4 versus 3.8+/-0.5 mm Hg x mL(-1) x min(-1), P = 0.02). ASA (7.7+/-2.3% versus -1.6+/-3.2%, P = 0.06) and L-NMMA (12.1+/-3.9% versus 0.0+/-2.9%, P = 0.02) abolished pacing-induced conduit vessel flow-mediated dilation. Conclusions-Tonic release of vasodilator prostanoids and NO contributes to resting conduit and resistance vessel tone and to peak functional hyperemia and flow-mediated dilation after metabolic stimulation. This underscores the importance of normal endothelial function for metabolic vasodilation and suggests that it may be a key mechanism for preventing myocardial ischemia in coronary artery disease.

Long-term estrogen therapy improves vascular function in male to female transsexuals.

OBJECTIVES This study sought to examine the effects of long-term estrogen therapy on vascular function in male to female transsexuals and to compare the findings with those observed in men and premenopausal women. BACKGROUND Gender differences in coronary artery disease have largely been attributed to the beneficial effects of estrogen on vascular function and plasma lipids in women. However, the effects of estrogen on the male vasculature have not been widely studied. METHODS We compared the effects of estrogen on vascular function in 14 male to female transsexuals, 14 age-matched men and 15 premenopausal women. Flow-mediated vasodilation and response to nitroglycerin were assessed in the brachial artery using noninvasive ultrasound. RESULTS Flow-mediated vasodilation was similar in transsexuals and women but greater than that in men ([mean +/- SE] 11.5 +/- 1.3% and 9.4 +/- 1.1% vs. 5.2 +/- 1.0% respectively, p < 0.005). Responses to nitroglycerin were also greater in transsexuals and women than in men (21.6 +/- 1.7% and 21.0 +/- 0.9% vs. 14.5 +/- 1.2%, respectively, p = 0.0005). These differences persisted even after adjusting for vessel size. Despite similar total cholesterol levels, transsexuals had high density lipoprotein cholesterol levels similar to those in women and greater than those observed in men (1.76 +/- 0.12 and 1.82 +/- 0.11 mmol/liter vs. 1.35 +/- 0.07 mmol/liter, respectively, p < 0.005). Moreover, triglyceride levels were greater in transsexuals than in men and women, and low density lipoprotein cholesterol (LDL-C) particle size was smaller (25.7 +/- 0.2 nm vs. 26.2 +/- 0.1 and 26.6 +/- 0.1 nm, respectively, p = 0.0001). Serum testosterone (an index of estrogen therapy in transsexuals) was markedly suppressed in transsexuals and similar to that in women. Univariate analysis revealed that there was a strong inverse correlation between serum testosterone and flow-mediated vasodilation (r(s) = -0.48, p < 0.005). Multivariate analysis revealed that the best combination of predictors of flow-mediated vasodilation was serum testosterone, vessel size and LDL-C (R2 = 0.3, p < 0.005). CONCLUSIONS Long-term estrogen therapy appears to improve vascular function in male to female transsexuals and occurs despite higher triglyceride levels and the presence of small, dense LDL-C. The beneficial effects of estrogen are not gender specific or solely mediated through endothelium-derived nitric oxide.

Closure of secundum atrial septal defects with the Amplatzer septal occluder device: Techniques and problems

Percutaneous transvenous closure of atrial septal defects (ASDs) has become feasible in recent years, as later‐generation devices have largely overcome initial difficulties in device deployment and complication rates. The Amplatzer septal occluder (ASO) is one such device that we have used extensively and is, in our opinion, the most versatile and practical to use. It is capable of closing defects up to 40 mm in diameter via a relatively low‐profile delivery sheath. More importantly, the ASO may be easily withdrawn into the sheath after deployment but prior to release, which is essential in safely closing difficult defects where successful positioning on the initial deployment is not guaranteed. In this article based on our experience, review of the literature, and communications with other operators, we describe the various problems encountered in closing atrial septal defects and make suggestions as to the best way of overcoming these difficulties. Cathet Cardiovasc Intervent 2002;57:508–524.

Combined CT coronary angiography and stress myocardial perfusion imaging for hemodynamically significant stenoses in patients with suspected coronary artery disease: a comparison with fractional flow reserve

OBJECTIVES We sought to determine the accuracy of combined coronary computed tomography angiography (CTA) and computed tomography stress myocardial perfusion imaging (CTP) in the detection of hemodynamically significant stenoses using fractional flow reserve (FFR) as a reference standard in patients with suspected coronary artery disease. BACKGROUND CTP can be qualitatively assessed by visual interpretation or quantified by the transmural perfusion ratio determined as the ratio of subendocardial to subepicardial contrast attenuation. The incremental value of each technique in addition to coronary CTA to detect hemodynamically significant stenoses is not known. METHODS Forty symptomatic patients underwent FFR and 320-detector computed tomography assessment including coronary CTA and CTP. Myocardial perfusion was assessed using the transmural perfusion ratio and visual perfusion assessment. Computed tomography images were assessed by consensus of 2 observers. Transmural perfusion ratio <0.99 was used as the threshold for abnormal perfusion. FFR ≤0.8 indicated hemodynamically significant stenoses. RESULTS Coronary CTA detected FFR-significant stenoses with 95% sensitivity and 78% specificity. The additional use of visual perfusion assessment and the transmural perfusion ratio both increased the specificity to 95%, with sensitivity of 87% and 71%, respectively. The area under the receiver-operating characteristic curve for coronary CTA + visual perfusion assessment was significantly higher than both coronary CTA (0.93 vs. 0.85, p = 0.0003) and coronary CTA + the transmural perfusion ratio (0.93 vs. 0.79, p = 0.0003). Per-vessel and per-patient accuracy for coronary CTA, coronary CTA + the transmural perfusion ratio, and coronary CTA + visual perfusion assessment was 83% and 83%, 87% and 92%, and 92% and 95%, respectively. CONCLUSIONS In suspected coronary artery disease, combined coronary CTA + CTP identifies patients with hemodynamically significant stenoses with >90% accuracy compared with FFR. When interpreted with coronary CTA, visual perfusion assessment provided superior incremental value in the detection of FFR-significant stenoses compared with the quantitative transmural perfusion ratio assessment.

Determinants of Increased Regional Left Atrial Coagulation Activity in Patients With Mitral Stenosis

BACKGROUND Recent evidence suggests that regional left atrial coagulation activity may be increased in mitral stenosis and perhaps contribute to the pathophysiology of left atrial thrombus. However, the relation of left atrial coagulation activity to factors that predispose to left atrial thrombus formation is unknown, and the relation between left atrial and systemic coagulation activities is unresolved. METHODS AND RESULTS Left atrial and peripheral venous levels of the coagulation marker prothrombin fragment 1 + 2 (F1 + 2) were measured in 32 patients with mitral stenosis with normal clotting times and no left atrial thrombus who were undergoing percutaneous balloon mitral valvuloplasty. Baseline peripheral venous F1 + 2 levels, measured at the beginning of the valvuloplasty procedure, did not differ from those of 30 age-matched control patients. Prevalvuloplasty left atrial F1 + 2 levels, obtained immediately after transseptal puncture, were similar to femoral venous levels in patients without left atrial spontaneous echo contrast (LASEC) (0.81 +/- 0.32 versus 0.81 +/- 0.27 nmol/L, n = 7) but greater than femoral venous levels in patients with LASEC and either sinus rhythm (1.57 +/- 0.86 versus 0.99 +/- 0.38 nmol/L, n = 16, P < .001) or atrial fibrillation (1.52 +/- 0.69 versus 0.85 +/- 0.33 nmol/L, n = 9, P < .003). Furthermore, LASEC emerged as the only significant predictor of increased regional left atrial coagulation activity (P = .005) on stepwise multivariate logistic regression analysis. CONCLUSIONS Increased regional left atrial coagulation activity in mitral stenosis occurs in the presence of LASEC, is evident in either sinus rhythm or atrial fibrillation, and is associated with normal systemic coagulation activity.

Continuous release of vasodilator prostanoids contributes to regulation of resting forearm blood flow in humans.

Continuous release of nitric oxide contributes to the maintenance of resting tone in the human forearm and coronary circulations; however, evidence for a similar role of vasodilator prostanoids such as prostacyclin is lacking. We examined whether continuous release of prostacyclin contributes to basal forearm blood flow. Flow was measured using venous occlusion plethysmography in 38 healthy volunteers [mean age 21.3 ± 2.5 yr (±SD); 13 female, 25 male] at rest, after administration of three incremental intra-arterial infusions of either the cyclooxygenase inhibitor aspirin or placebo, and before and after administration of the endothelium-dependent and -independent dilators acetylcholine (30 μg/min) and nitroprusside (1 μg/min). To assess the effect of aspirin on the production of prostacyclin, plasma 6-keto prostaglandin F1α(6-keto-PGF1α; the stable metabolite of prostacyclin) was measured by simultaneous arterial and venous sampling. Aspirin produced a time- and dose-dependent reduction in forearm blood flow, resulting in a 32% decrease at the highest dose. The effect was maximal after 10 min. Flow at rest and after aspirin doses of 1, 3, and 10 mg/min was 2.6 ± 0.2, 2.3 ± 0.2, 2.1 ± 0.2, and 1.8 ± 0.2 ml ⋅ 100 ml forearm tissue-1 ⋅ min-1, respectively (means ± SE, P< 0.001). Commensurate with these data, the net forearm production of 6-keto-PGF1α was 52.9 ± 16.4, 11.7 ± 8.6, 18.7 ± 8.5, and 12.0 ± 12.5 pg ⋅ 100 ml forearm tissue-1 ⋅ min-1 for the respective doses ( P = 0.04). No time-dependent reduction in flow was seen in subjects with vehicle infusion. Aspirin did not affect the responses to acetylcholine or nitroprusside. These data suggest that continuous release of prostacyclin plays a role in the maintenance of resting forearm blood flow. There appears to be a direct link between the reduction in flow with aspirin and inhibition of prostacyclin production.

Chiari network entanglement and herniation into the left atrium by an atrial septal defect occluder device.

The Chiari network is a fenestrated membrane consisting of threads and strands in the right atrium. First described in 1897 by anatomist Hans Chiari, it is a congenital remnant of embryonic development resulting from incomplete resorption of the right valve of the sinus venosus. Found in 2% to 3% of the population, it is generally not of clinical importance. Rarely, however, the network may be associated with serious complications such as thrombus formation, embolus entrapment, arrhythmia, tumor development, and catheter entrapment. We report the entanglement of an Amplatzer septal occluder device catheter in a prominent Chiari network that was herniated into the left atrium. Transesophageal echocardiographic recognition of this before deployment and guidance during disentanglement is described below.

Long-term oestrogen therapy is associated with improved endothelium-dependent vasodilation in the forearm resistance circulation of biological males.

1. The aim of the present study was to determine the effects of long‐term oestrogen on resistance vessel reactivity in biological males.

Effect of anti-oxidant treatment and cholesterol lowering on resting arterial tone, metabolic vasodilation and endothelial function in the human forearm: a randomized, placebo-controlled study.

1. The aim of the present study was to determine whether anti‐oxidant therapy with vitamin E and/or cholesterol‐lowering therapy with simvastatin would augment resting forearm blood flow (FBF) and metabolic vasodilation in response to exercise and improve endothelial function in young patients with hypercholesterolaemia.

Captopril potentiates the effects of nitroglycerin in the coronary vascular bed

OBJECTIVES This study was designed to examine the effects of captopril on the coronary vascular responses to nitroglycerin. BACKGROUND The vasodilator effects of nitroglycerin are mediated by sulfhydryl-dependent bioconversion and influenced by local and systemic neural and hormonal counter-regulatory factors. METHODS In patients with angina pectoris, the effects of 10 days of treatment with the sulfhydryl-containing angiotensin-converting enzyme inhibitor captopril on the coronary vasodilator responses to intracoronary nitroglycerin (1- to 20-micrograms doses) were examined utilizing a double-blind, placebo-controlled, randomized design. The effects of captopril on the induction of nitroglycerin tolerance were also examined after a 20-h intravenous infusion of nitroglycerin. RESULTS Captopril reduced mean arterial pressure at rest by 8 mm Hg compared with 3 mm Hg in the placebo group (p = NS) and did not affect baseline coronary blood flow (168 vs. 144 ml/min in the placebo group, standard error of the differences of means (SED) 26) or coronary vascular resistance (53 vs. 57 dynes.s.cm-5, SED 9). Intracoronary nitroglycerin increased coronary blood flow in a dose-dependent fashion in both the captopril and placebo groups (p < 0.001). However, captopril potentiated the effects of all doses of nitroglycerin and shifted the dose-response relationship to the left (p < 0.001). At the maximal dose of 20 micrograms, intracoronary nitroglycerin increased the coronary blood flow by a further 60% in the captopril group compared with placebo. After 20 h of intravenous nitroglycerin (24 +/- 3 micrograms/min), the coronary vasodilator responses to intracoronary nitroglycerin were attenuated (p < 0.02) in the placebo group. However, the responses to intracoronary nitroglycerin in the captopril group, remained similar to the responses observed before intravenous nitroglycerin exposure. CONCLUSIONS Captopril potentiates the coronary vasodilator responses of nitroglycerin in both the absence and the presence of nitroglycerin tolerance. The mechanisms and therapeutic implications of this interaction require further exploration.