Coronary ß2-adrenoreceptors mediate endothelium-dependent vasoreactivity in humans: novel insights from an in vivo intravascular ultrasound study.

AIMS: The interaction between coronary ß(2)-adrenoreceptors and segmental plaque burden is complex and poorly understood in humans. We aimed to validate intracoronary (IC) salbutamol as a novel endothelium-dependent vasodilator utilizing intravascular ultrasound (IVUS), and thus assess relationships between coronary ß(2)-adrenoreceptors, regional plaque burden and segmental endothelial function. METHODS AND RESULTS: In 29 patients with near-normal coronary angiograms, IVUS-upon-Doppler Flowire imaging protocols were performed. Protocol 1: incremental IC salbutamol (0.15, 0.30, 0.60 µg/min) infusions (15 patients, 103 segments); protocol 2: salbutamol (0.30 µg/min) infusion before and after IC administration of N(G)-monomethyl-L-arginine (L-NMMA) (10 patients, 82 segments). Vehicle infusions (IC dextrose) were performed in 4 patients (21 segments). Macrovascular response [% change segmental lumen volume (ΔSLV)] and plaque burden [per cent atheroma volume (PAV)] were studied in 5-mm coronary segments. Microvascular response [per cent change in coronary blood flow (ΔCBF)] was calculated following each infusion. Intracoronary salbutamol demonstrated significant dose-response ΔSLV and ΔCBF from baseline, respectively (0.15 µg/min: 3.5 ± 1.3%, 28 ± 14%, P = 0.04, P = NS; 0.30 µg/min: 5.5 ± 1.4%, 54 ± 17%, P = 0.001, P < 0.0001; 0.60 µg/min: 4.8 ± 1.6%, 66 ± 15%, P = 0.02, P < 0.0001), with ΔSLV responses further exemplified in low vs. high plaque burden groups. Salbutamol vasomotor responses were suppressed by l-NMMA, supporting nitric oxide-dependent mechanisms. Vehicle infusions resulted in no significant ΔSLV or ΔCBF. Multivariate analysis including conventional cardiovascular risk factors, PAV, segmental remodelling and plaque eccentricity indices identified PAV as the only significant predictor of a ΔSLV to IC salbutamol (coefficient -0.18, 95% CI -0.32 to -0.044, P = 0.015). Conclusions Intracoronary salbutamol is a novel endothelium-dependent epicardial and microvascular coronary vasodilator. Intravascular ultrasound-derived regional plaque burden is a major determinant of segmental coronary endothelial function.

Coronary artery wall shear stress is associated with endothelial dysfunction and expansive arterial remodelling in patients with coronary artery disease.

AIMS: To investigate in vivo relationships between segmental wall shear stress (WSS), endothelium-dependent vasoreactivity and arterial remodelling. METHODS AND RESULTS: Twenty-four patients with minor angiographic coronary arterial disease (≤30% stenosis severity) underwent intracoronary (IC) salbutamol provocation during intravascular ultrasound (IVUS)-upon-Doppler guidewire imaging. Macrovascular response (change in segmental lumen volume [SLV] at baseline and following IC salbutamol), plaque burden (percent atheroma volume [PAV]), remodelling indices (RI), eccentricity indices (EI) and WSS were evaluated in 179 consecutive 5 mm coronary segments. Baseline WSS was directly related to endothelium-dependent epicardial coronary vasomotion (% change SLV, coefficient 17.2, p=0.004), and inversely related to RI (coefficient -0.23, p=0.02) and EI (coefficient -10.0, p=0.001). Baseline WSS was lower in segments displaying endothelial dysfunction (defined as any change in SLV ≤0) compared with preserved function (0.66±0.33 vs. 0.71±0.22 N/m2, p=0.046). Independent of plaque burden, segments with the lowest tertile of WSS displayed less vasodilatation, or vasoconstriction, than segments with the highest tertile of WSS. Higher plaque burden segments harbouring the lowest tertiles of WSS displayed vasoconstriction, expansive arterial remodelling and greater plaque eccentricity. CONCLUSIONS: In patients with stable coronary syndromes and minor angiographic coronary disease, coronary segments with lower in vivo WSS values display functional and morphological features of plaque vulnerability.

Coronary atheroma composition and its association with segmental endothelial dysfunction in non-ST segment elevation myocardial infarction: novel insights with radiofrequency (iMAP) intravascular ultrasonography.

Little is known of the relationship between coronary atheroma composition and corresponding endothelial dysfunction. We tested the hypothesis that segmental epicardial vasoreactivity relates to atheroma composition in patients with non-ST segment elevation myocardial infarction (NSTEMI) in vivo. In 23 NSTEMI patients referred for coronary angiography, a non-culprit vessel underwent intracoronary salbutamol (0.30 µg/min) provocation during automated IVUS pullback. A 40 MHz rotational IVUS catheter delivered radiofrequency signals at constant 67 µm intervals via a custom-built IVUS console (iMAP, iLAB, Boston Scientific). Macrovascular response [change in segmental lumen volume (SLV) at baseline and following salbutamol], percent atheroma volume (PAV) and tissue composition was evaluated in 187 contiguous non-overlapping 5 mm coronary segments. Compared with segments that dilated, constrictive segments showed similar SLV, but greater vessel volumes and PAV at baseline. The extent of necrotic and lipidic plaque was significantly greater in constrictive segments, whereas fibrotic plaque content was significantly greater in segments that dilated. Calcific plaque content did not relate to endothelium-dependent vasoreactivity. The change in SLV correlated inversely with the amount of lipidic and necrotic plaque (both r = -0.23, p = 0.002), and directly with fibrotic plaque content (r = 0.23, p = 0.002). In a multivariable model, the extent of both lipidic and necrotic plaque independently associated with segmental vasoconstriction (ß = 1.2, p = 0.023; ß = 0.66, p = 0.027). Following NSTEMI, both lipidic and necrotic plaque content each associate with segmental endothelial dysfunction. The link between plaque composition and vessel reactivity provides a mechanistic basis of the pathogenesis associated with vulnerable plaque in humans in vivo.

Left main coronary arterial endothelial function and heterogenous segmental epicardial vasomotor reactivity in vivo: novel insights with intravascular ultrasonography.

AIMS: While the relationship between epicardial coronary vasomotor reactivity and cardiovascular events is well established, this observation has yet to be evaluated within the left main coronary artery (LMCA) in humans in vivo. Our aims were to test the endothelium-dependent vasomotor properties of the LMCA, and to compare these responses to downstream epicardial segments. METHODS AND RESULTS: Thirty patients referred for coronary angiography underwent intracoronary (IC) salbutamol provocation during intravascular ultrasound imaging within a non-critically diseased, left-sided conduit vessel. Macrovascular vasomotor response [change in average lumen area (LA) at baseline and following 5 min of 0.30 µg/min IC salbutamol] and percent atheroma volume (PAV) were evaluated in 30 LMCA, 42 proximal, 109 mid, and 132 distal epicardial coronary segments. In comparison with all other segments, the LMCA had the greatest lumen and vessel areas (P < 0.001), yet the proximal epicardial segments contained the greatest PAV (P < 0.02). The mid and distal epicardial segments displayed significant endothelium-dependent vasodilatation from baseline (P = 0.017 and <0.001, respectively); however, the proximal epicardial and LMCA segments did not (P = 0.45 and 0.16, respectively). Significant segmental vasomotor heterogeneity was noted in all 30 patients, with opposing vasomotor responses between adjacent LMCA and epicardial segments. Across all segments, baseline LA inversely correlated with the % change in LA (r = -0.16, P = 0.0005). CONCLUSION: Endothelium-dependent vasomotor reactivity is heterogenous within the conduit coronary system. Vascular dynamic responses were less prominent in the larger calibre LMCA and proximal epicardial segments. This may, in part, relate to higher shear stress in smaller, distal segments and yet also may explain the propensity for culprit plaques to cluster proximally.

Coronary endothelium-dependent vasoreactivity and atheroma volume in subjects with stable, minimal angiographic disease versus non-ST-segment-elevation myocardial infarction: an intravascular ultrasound study.

BACKGROUND: Epicardial plaque burden and endothelial function are recognized predictors of coronary events. We aimed to investigate mechanistic relationships between atheroma volume and endothelial function in patients with non-ST-segment-elevation myocardial infarction (NSTEMI) using intravascular ultrasound. METHODS AND RESULTS: In coronary vessels of patients with near-normal or minimal angiographic disease (n=23) and NSTEMI (n=24), intravascular ultrasound-derived measures (percent atheroma volume), arterial remodeling index, and segmental lumen volumes were performed in contiguous 5-mm epicardial segments. Repeat intravascular ultrasound imaging was performed after consecutive 5-minute intracoronary infusions (vehicle solution, 0.30 µg/min and 0.60 µg/min intracoronary salbutamol) to measure changes in segmental lumen volume (endothelium-dependent function). Male sex, diabetes mellitus, smoking, higher triglycerides, and lower high-density lipoprotein cholesterol were more prevalent in the NSTEMI group. Patients with NSTEMI demonstrated greater segmental percent atheroma volume (40.4 ± 12 versus 27.5 ± 14%, P<0.001), remodeling index (1.2 [1.0-1.5] versus 1.0 [0.9-1.0], P<0.001), and displayed less endothelium-dependent vasomotion (% change segmental lumen volume: 2.1 ± 0.89 versus 5.1 ± 0.89%, P=0.02) compared to patients with minimal angiographic disease. No significant difference in endothelial function between both groups was observed when controlling for plaque burden. Multivariate analysis for change in segmental lumen volume identified percent atheroma volume (ß=-0.18, P=0.0004), high-sensitivity C-reactive protein >2 mg/L (ß=-3.1, P=0.03), diabetes mellitus (ß=-6.9, P<0.0001), low-density lipoprotein cholesterol levels (ß=-0.04, P=0.01), and smoking (ß=-3.2, P=0.01) as independent associates. CONCLUSIONS: Although coronary endothelial vasoreactivity is blunted in the setting of NSTEMI, this is a reflection of the greater volume of atherosclerosis and cardiovascular risk factors. Thus, the relationship between coronary endothelium-dependent vasomotor reactivity and atheroma volume remains constant irrespective of the nature of the clinical presentation.