Narbeh Melikian

Effects of Neuronal Nitric Oxide Synthase on Human Coronary Artery Diameter and Blood Flow In Vivo

Background— Nitric oxide (NO)-mediated local regulation of vascular tone is considered to involve endothelial NO synthase (eNOS). However, we recently reported that human forearm basal microvascular tone in vivo is tonically regulated by neuronal NO synthase (nNOS), in contrast to an acetylcholine-stimulated reduction in tone, which is eNOS dependent. Here, we investigated the in vivo effects of an nNOS-selective inhibitor, S-methyl-l-thiocitrulline (SMTC), on the human coronary circulation and on flow-mediated dilatation in the forearm. Methods and Results— In patients with angiographically normal coronary arteries, intracoronary infusion of SMTC (0.625 &mgr;mol/min) reduced basal coronary blood flow by 34.1±5.2% (n=10; P<0.01) and epicardial coronary diameter by 3.6±1.2% (P=0.02) but had no effect on increases in flow evoked by intracoronary substance P (20 pmol/min). The nonselective NOS inhibitor NG-monomethyl-l-arginine (25 &mgr;mol/min) also reduced basal coronary flow (by 22.3±5.3%; n=8; P<0.01) but, in contrast to SMTC, inhibited substance P-induced increases in flow (P<0.01). In healthy volunteers, local infusion of SMTC (0.2 &mgr;mol/min) reduced radial artery blood flow by 36.0±6.4% (n=10; P=0.03) but did not affect flow-mediated dilatation (P=0.55). In contrast, NG-monomethyl-l-arginine (2 &mgr;mol/min) infusion reduced radial blood flow to a similar degree (by 39.7±11.8%; P=0.02) but also inhibited flow-mediated dilatation by ≈80% (P<0.01). Conclusions— These data indicate that local nNOS-derived NO regulates basal blood flow in the human coronary vascular bed, whereas substance P-stimulated vasodilatation is eNOS mediated. Thus, nNOS and eNOS have distinct local roles in the physiological regulation of human coronary vascular tone in vivo.

Neuronal Nitric Oxide Synthase and Human Vascular Regulation

Vascular blood flow and its distribution among different vascular beds are regulated by changes in microvascular tone. Nitric oxide (NO) plays a key role in the local paracrine regulation of vessel tone both under resting conditions and when blood flow increases in response to agonist stimulation or increased shear stress. The conventional notion that endothelial NO synthase (eNOS)-derived NO is largely responsible for both effects has been challenged by first-in-human studies with a selective inhibitor of neuronal NOS (nNOS), S-methyl-l-thiocitrulline (SMTC). These studies reveal that SMTC causes a reduction in basal blood flow in the normal human forearm and coronary circulations (that is reversed by l-arginine), without affecting the eNOS-mediated vasodilatation elicited by acetylcholine, substance P, or increased shear stress. S-methyl-l-thiocitrulline also inhibits mental stress-induced vasodilatation. These results are consistent with a significant body of experimental studies suggesting that nNOS plays an important role in the local regulation of vessel tone in other species, independent of the effects of nNOS-derived NO in the central nervous system. These emerging data suggest that eNOS and nNOS have distinct roles in the physiologic local regulation of human microvascular tone in vivo and pave the way for further detailed investigation of the relative contribution of nNOS and eNOS in vascular regulation in human disease.

Interference of Drug-Eluting Stents With Endothelium-Dependent Coronary Vasomotion Evidence for Device-Specific Responses

Background—There is evidence that endothelial coverage of drug-eluting stents might be delayed or absent, a risk factor for late thrombotic events. We studied the effects of different drug-polymer-device iterations on endothelium-dependent coronary vasomotion. Systemic markers of endothelial inflammation were correlated with coronary vasomotor changes. Methods and Results—Patients with paclitaxel-eluting stents (n=11), sirolimus-eluting stents (n=21), biolimus A9-eluting stents (n=28), zotarolimus-eluting stents (n=10), and bare-metal stents (n=13) were studied 10, 9, 9, 9, and 12 months after implantation, respectively. Endothelium-dependent coronary vasomotion was tested proximally and distally to the stent and at a reference vessel segment during atrial pacing at increasing heart rates by quantitative coronary angiography. Indexes of platelet-monocyte binding and other biomarkers were studied in a subgroup of 19 patients. The baseline characteristics and hemodynamics of the patients in the different stent groups were comparable. Significant differences were observed across the 5 stent groups, concerning the vasomotion of segments proximal (P=0.006) and distal (P=0.003) to the stent. Normal vasomotion (vasodilatation) was maintained in the biolimus A9-eluting stent, zotarolimus-eluting stent, and bare-metal stent groups, whereas vasoconstriction was observed in the sirolimus-eluting stent and paclitaxel-eluting stent groups. Platelet-monocyte binding in whole blood showed a significant inverse correlation with vasomotion in reference but not in segments adjacent to the stent (r=−0.57; P=0.01). Conclusions—Paclitaxel-eluting stents and sirolimus-eluting stents seem to cause endothelial dysfunction of the implanted vessel, whereas biolimus A9-eluting stents and zotarolimus-eluting stents behave more closely to bare-metal stents, with preserved endothelial vasomotor response. Coronary vasoconstriction was not associated with detectable systemic endothelial activation.

Direct stenting for stable angina pectoris is associated with reduced periprocedural microcirculatory injury compared with stenting after pre-dilation.

OBJECTIVES We conducted a randomized study to compare the effect of direct stenting (DS) and conventional stenting (CS) on post-procedural index of microcirculatory resistance (IMR) values. BACKGROUND Direct stenting has been suggested to reduce periprocedural microcirculatory injury compared with stenting that follows pre-dilation (CS). The index of microcirculatory resistance is a sensitive invasive marker of coronary microvascular resistance. METHODS Fifty patients admitted for elective percutaneous coronary intervention (PCI) were included. All patients had stable angina (Canadian Cardiovascular Society class <IV) related to a lesion suitable for DS and were randomized to DS (n = 25) or CS (n = 25). Baseline demographics and clinical and procedural data were comparable in both groups. An intracoronary pressure/temperature sensor-tipped guide wire was used. Thermodilution curves were obtained at baseline and during maximal hyperemia achieved by infusion of intravenous adenosine. The index of microcirculatory resistance was calculated from the ratio of the mean distal coronary pressure at maximal hyperemia to the inverse of mean hyperemic transit time. RESULTS After otherwise-uneventful PCI, patients treated with CS had significantly greater IMR (DS 13 +/- 3, CS 24 +/- 14; p < 0.01) and tended to have greater post-PCI troponin T values (DS 0.035 +/- 0.04, CS 0.17 +/- 0.02; p = 0.07). In the whole sample, 20% of patients had post-PCI troponin release (troponin T >0.03 ng/ml). Patients with troponin elevation had significantly greater post-PCI IMR values than patients without troponin elevation: 24.7 +/- 13.2 versus 16.9 +/- 10.2; p = 0.04. CONCLUSIONS In patients undergoing successful coronary stenting for stable angina, DS is associated with reduced microvascular dysfunction induced by PCI as compared with CS.

Quantitative assessment of coronary microvascular function in patients with and without epicardial atherosclerosis

AIMS: The influence of atherosclerosis and its risk factors on coronary microvascular function remain unclear as current methods of assessing microvascular function do not specifically test the microcirculation in isolation. We examined the influence of epicardial vessel atherosclerosis on coronary microvascular function using the index of myocardial resistance (IMR). METHODS AND RESULTS: IMR (a measure of microvascular function) and fractional flow reserve (FFR, a measure of the epicardial compartment) were measured in 143 coronary arteries (116 patients). Fifteen patients (22 arteries, mean age 48+/-16 years) had no clinical evidence of atherosclerosis (control group). One hundred and one patients (121 arteries, mean age 63+/-11 years) had established atherosclerosis and multiple cardiovascular risk factors (atheroma group). Mean IMR in the control group (19+/-5, range 8-28) was significantly lower than in the atheroma group (25+/-13, range 6-75) (P

Interference of Drug-Eluting Stents With Endothelium-Dependent Coronary VasomotionCLINICAL PERSPECTIVE

Background—There is evidence that endothelial coverage of drug-eluting stents might be delayed or absent, a risk factor for late thrombotic events. We studied the effects of different drug-polymer-device iterations on endothelium-dependent coronary vasomotion. Systemic markers of endothelial inflammation were correlated with coronary vasomotor changes. Methods and Results—Patients with paclitaxel-eluting stents (n=11), sirolimus-eluting stents (n=21), biolimus A9-eluting stents (n=28), zotarolimus-eluting stents (n=10), and bare-metal stents (n=13) were studied 10, 9, 9, 9, and 12 months after implantation, respectively. Endothelium-dependent coronary vasomotion was tested proximally and distally to the stent and at a reference vessel segment during atrial pacing at increasing heart rates by quantitative coronary angiography. Indexes of platelet-monocyte binding and other biomarkers were studied in a subgroup of 19 patients. The baseline characteristics and hemodynamics of the patients in the different stent groups were comparable. Significant differences were observed across the 5 stent groups, concerning the vasomotion of segments proximal (P=0.006) and distal (P=0.003) to the stent. Normal vasomotion (vasodilatation) was maintained in the biolimus A9-eluting stent, zotarolimus-eluting stent, and bare-metal stent groups, whereas vasoconstriction was observed in the sirolimus-eluting stent and paclitaxel-eluting stent groups. Platelet-monocyte binding in whole blood showed a significant inverse correlation with vasomotion in reference but not in segments adjacent to the stent (r=−0.57; P=0.01). Conclusions—Paclitaxel-eluting stents and sirolimus-eluting stents seem to cause endothelial dysfunction of the implanted vessel, whereas biolimus A9-eluting stents and zotarolimus-eluting stents behave more closely to bare-metal stents, with preserved endothelial vasomotor response. Coronary vasoconstriction was not associated with detectable systemic endothelial activation.

Asymmetric Dimethylarginine and Reduced Nitric Oxide Bioavailability in Young Black African Men

Black Africans have a higher incidence of cardiovascular disease than white Europeans. We explored potential mechanisms of this excess risk by assessing endothelium function, inflammatory status (C-reactive protein), oxidative stress (isoprostane-F2&agr;), and plasma asymmetrical dimethyl arginine (ADMA; an endogenous competitive inhibitor of NO synthase) in each ethnic group. Thirty healthy black Africans and 28 well-matched white European male subjects were studied (mean age±SE: 32.2±0.9 and 29.2±1.2 years, respectively; P=0.07). High-resolution ultrasound was used to assess vascular function in the brachial artery by measuring flow mediated dilatation ([percentage of change]; endothelium-dependent function) and glyceryltrinitrate dilatation ([percentage of change]; endothelium-independent function). Blood pressure, fasting lipids, glucose, and estimated glomerular filtration rate levels were similar in both groups. There was no difference in C-reactive protein (black Africans: 0.8±0.1 mg/L; white Europeans: 0.6±0.1 mg/L; P=0.22), isoprostane-F2&agr; (black Africans: 42.9±1.5 pg/mL; white Europeans: 39.2±1.5 pg/mL; P=0.23), and leptin (black Africans: 64.1±10.2 ng/mL; white Europeans: 47.8±9.8 ng/mL; P=0.37) levels between the 2 ethnic groups. However, compared with white Europeans, plasma ADMA levels were significantly higher in black Africans (0.34±0.02 &mgr;mol/L and 0.25±0.03 &mgr;mol/L; P=0.03). There was no difference in the percentage of glyceryltrinitrate dilatation (P=0.7), but the percentage of flow-mediated dilatation was significantly lower in black Africans (black Africans: 5.2±0.3; white Europeans: 6.3±0.4; P=0.02). In a stepwise multiple regression model, ADMA level was the only independent determinant of flow-mediated dilatation (P=0.02). In turn, race was the only independent determinant of ADMA levels (P=0.03). Our findings indicate that circulating ADMA levels are significantly higher in healthy black African males than in white European males. This may contribute to the lower NO bioavailability and higher incidence of cardiovascular disease seen in black Africans.

In vitro and in vivo studies on thermistor-based intracoronary temperature measurements: Effect of pressure and flow†

Intracoronary thermography has been proposed to detect vulnerable plaques. We hypothesized that changes in coronary pressure and flow in the coronarytree may interfere with the temperature measurements obtained with thermistors.

Pulmonary function, CT and echocardiographic abnormalities in sickle cell disease

Objectives To test the hypothesis that vascular abnormalities on high-resolution CT (HRCT) would be associated with echocardiographic changes and lung function abnormalities in patients with sickle cell disease (SCD) and the decline in lung function seen in SCD patients. Methods HRCT, echocardiography and lung function assessments were made in 35 adults, 20 of whom had previously been assessed a median of 6.6 years prior to this study. The pulmonary arterial dimensions on HRCT were quantified as the mean segmental pulmonary artery/bronchus (A/B) ratio and the summated cross-sectional area of all pulmonary vessels <5 mm in diameter (cross-sectional area (CSA)<5 mm%). Results The segmental A/B ratio was negatively correlated with FEV1, vital capacity (VC), forced expiratory flow between 25% and 75% of VC (FEF25/75) and arterial oxygen saturation (SpO2) and positively with the residual volume: total lung capacity ratio (RV:TLC) and respiratory system resistance (Rrs). CSA<5 mm% was negatively correlated with FEV1, FEF25/75 and SpO2 and positively with RV, RV:TLC and respiratory system resistance (Rrs). There were significant correlations between cardiac output assessed by echocardiography and the segmental A/B ratio and CSA<5 mm%. Lung function (FEV1 p=0.0004, VC p=0.0347, FEF25/75 p=0.0033) and the segmental A/B ratio (p=0.0347) and CSA<5 mm% (p<0.0001) significantly deteriorated over the follow-up period. Conclusions Abnormalities in pulmonary vascular volumes may explain some of the lung function abnormalities and the decline in lung function seen in adults with SCD.

Sympathetic activation increases NO release from eNOS but neither eNOS nor nNOS play an essential role in exercise hyperemia in the human forearm

Nitric oxide (NO) release from endothelial NO synthase (eNOS) and/or neuronal NO synthase (nNOS) could be modulated by sympathetic nerve activity and contribute to increased blood flow after exercise. We examined the effects of brachial-arterial infusion of the nNOS selective inhibitor S-methyl-l-thiocitrulline (SMTC) and the nonselective NOS inhibitor N(G)-monomethyl-l-arginine (l-NMMA) on forearm arm blood flow at rest, during sympathetic activation by lower body negative pressure, and during lower body negative pressure immediately after handgrip exercise. Reduction in forearm blood flow by lower body negative pressure during infusion of SMTC was not significantly different from that during vehicle (-28.5 ± 4.02 vs. -34.1 ± 2.96%, respectively; P = 0.32; n = 8). However, l-NMMA augmented the reduction in forearm blood flow by lower body negative pressure (-44.2 ± 3.53 vs. -23.4 ± 5.71%; n = 8; P < 0.01). When lower body negative pressure was continued after handgrip exercise, there was no significant effect of either l-NMMA or SMTC on forearm blood flow immediately after low-intensity exercise (P = 0.91 and P = 0.44 for l-NMMA vs. saline and SMTC vs. saline, respectively; each n = 10) or high-intensity exercise (P = 0.46 and P = 0.68 for l-NMMA vs. saline and SMTC vs. saline, respectively; each n = 10). These results suggest that sympathetic activation increases NO release from eNOS, attenuating vasoconstriction. Dysfunction of eNOS could augment vasoconstrictor and blood pressure responses to sympathetic activation. However, neither eNOS nor nNOS plays an essential role in postexercise hyperaemia, even in the presence of increased sympathetic activation.