Human Epicardial Coronary Arteries Research Articles

Refining Our Understanding of the Flow Through Coronary Artery Branches; Revisiting Murray's Law in Human Epicardial Coronary Arteries.

Background: Quantification of coronary blood flow is used to evaluate coronary artery disease, but our understanding of flow through branched systems is poor. Murray’s law defines coronary morphometric scaling, the relationship between flow (Q) and vessel diameter (D) and is the basis for minimum lumen area targets when intervening on bifurcation lesions. Murray’s original law (Q α DP) dictates that the exponent (P) is 3.0, whilst constant blood velocity throughout the system would suggest an exponent of 2.0. In human coronary arteries, the value of Murray’s exponent remains unknown. Aim: To establish the exponent in Murray’s power law relationship that best reproduces coronary blood flows (Q) and microvascular resistances (Rmicro) in a bifurcating coronary tree. Methods and Results: We screened 48 cases, and were able to evaluate inlet Q and Rmicro in 27 branched coronary arteries, taken from 20 patients, using a novel computational fluid dynamics (CFD) model which reconstructs 3D coronary anatomy from angiography and uses pressure-wire measurements to compute Q and Rmicro distribution in the main- and side-branches. Outputs were validated against invasive measurements using a Rayflow™ catheter. A Murray’s power law exponent of 2.15 produced the strongest correlation and closest agreement with inlet Q (zero bias, r = 0.47, p = 0.006) and an exponent of 2.38 produced the strongest correlation and closest agreement with Rmicro (zero bias, r = 0.66, p = 0.0001). Conclusions: The optimal power law exponents for Q and Rmicro were not 3.0, as dictated by Murray’s Law, but 2.15 and 2.38 respectively. These data will be useful in assessing patient-specific coronary physiology and tailoring revascularisation decisions.

P5631The impact of plaque type on strut embedment/protrusion and shear stress distribution in bioresorbable scaffold

Abstract Background and aim Scaffold design and plaque characteristics influence implantation outcomes and local flow dynamics in treated coronary segments. Our aim is to assess the impact of strut embedment/protrusion of bioresorbable scaffold on local shear stress distribution in different atherosclerotic plaque types. Method Fifteen Absorb everolimus-eluting Bioresorbable Vascular Scaffolds were implanted in human epicardial coronary arteries. Optical coherence tomography (OCT) was performed post-scaffold implantation and strut embedment/protrusion were analyzed using a dedicated software. OCT data was fused with angiography to reconstruct three-dimensional coronary anatomy. Blood flow simulation was performed and wall shear stress (WSS) was estimated in each scaffolded surface and the relationship between strut embedment/protrusion and WSS was evaluated. Results There were 9083 struts analysed. Ninety-seven percent of the struts (n=8840) were well apposed and 243 (3%) were malapposed. At cross-section level (n=1289), strut embedment was significantly increased in fibroatheromatous plaques (76±48μm) and decreased in fibro-calcific plaques (35±52 μm). Compatible with strut embedment, WSS was significantly higher in lipid-rich fibroatheromatous plaques (1.50±0.81Pa), whereas significantly decreased in fibro-calcified plaques (1.05±0.91Pa). After categorization of WSS as low (<1.0 Pa) and normal/high WSS (≥1.0 Pa), the percent of low-WSS in the plaque subgroups were 30.1%, 31.1%, 25.4% and 36.2% for non-diseased vessel wall, fibrous plaque, fibro-atheromatous plaque and fibro-calcific plaque, respectively (p-overall<0.001). Table 1. Cross-section level Embedment/Protrusion and WSS according to the plaque type Plaque type Embedment depth (μm) Protrusion distance (μm) WSS (Pa) Non-atherosclerotic intimal thickening/normal vessel wall (n=2275) 47±34*Δ¥ 123±34¶Ξπ 1.44±0.9解 Fibrous (n=4191) 53±40*#& 118±38¶Ψ‡ 1.24±0.78αθ∞ Fibroatheromatous (n=2027) 76±48#ΦΔ 94.6±46Ω†Ψπ 1.50±0.81Σ§α Fibro-calcific (n=590) 35±52&Φ¥ 139±50‡†Ξ 1.05±0.91∞£Σ For embedment: *p=0.09, #p<0.001, &p<0.001, Φp<0.0001, Δp<0.0001, ¥p<0.0001. For protrusion: ¶p=0.74, Ξp<0.0001, πp<0.0001, Ψp<0.0001, ‡p<0.0001, †p<0.0001. For WSS: θp<0.001, §p=0.06, £p<0.0001, αp<0.0001, ∞p<0.0001, Ωp<0.0001. n=total strut number in each plaque type, p-values come from mixed-effects regression analysis. Conclusion The composition of the underlying plaque influences strut embedment which seems to have effect on WSS. The struts deeply embedded in lipid-rich fibroatheromas plaques resulted in higher WSS compared to the other plaque types.

The impact of plaque type on strut embedment/protrusion and shear stress distribution in bioresorbable scaffold.

Scaffold design and plaque characteristics influence implantation outcomes and local flow dynamics in treated coronary segments. Our aim is to assess the impact of strut embedment/protrusion of bioresorbable scaffold on local shear stress distribution in different atherosclerotic plaque types. Fifteen Absorb everolimus-eluting Bioresorbable Vascular Scaffolds were implanted in human epicardial coronary arteries. Optical coherence tomography (OCT) was performed post-scaffold implantation and strut embedment/protrusion were analysed using a dedicated software. OCT data were fused with angiography to reconstruct 3D coronary anatomy. Blood flow simulation was performed and wall shear stress (WSS) was estimated in each scaffolded surface and the relationship between strut embedment/protrusion and WSS was evaluated. There were 9083 struts analysed. Ninety-seven percent of the struts (n = 8840) were well-apposed and 243 (3%) were malapposed. At cross-section level (n = 1289), strut embedment was significantly increased in fibroatheromatous plaques (76 ± 48 µm) and decreased in fibrocalcific plaques (35 ± 52 µm). Compatible with strut embedment, WSS was significantly higher in lipid-rich fibroatheromatous plaques (1.50 ± 0.81 Pa), whereas significantly decreased in fibrocalcified plaques (1.05 ± 0.91 Pa). After categorization of WSS as low (<1.0 Pa) and normal/high WSS (≥1.0 Pa), the percent of low WSS in the plaque subgroups were 30.1%, 31.1%, 25.4%, and 36.2% for non-diseased vessel wall, fibrous plaque, fibroatheromatous plaque, and fibrocalcific plaque, respectively (P-overall < 0.001). The composition of the underlying plaque influences strut embedment which seems to have effect on WSS. The struts deeply embedded in lipid-rich fibroatheromas plaques resulted in higher WSS compared with the other plaque types.

3273Expression of lectin-like oxidized low-density lipoprotein receptor-1 in human epicardial and intramyocardial coronary arteries of male patients undergoing coronary artery bypass grafting

3273Expression of lectin-like oxidized low-density lipoprotein receptor-1 in human epicardial and intramyocardial coronary arteries of male patients undergoing coronary artery bypass grafting

Expression of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 in Human Epicardial and Intramyocardial Coronary Arteries of Male Patients Undergoing Coronary Artery Bypass Grafting

Objectives: Atherosclerosis is almost absent in intramyocardial coronary arteries, while epicardial coronary arteries may show extensive occlusive disease. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression has been implicated in atherogenesis. We aimed to investigate differences in arterial wall LOX-1 expression between human epicardial and intramyocardial coronary arteries. Methods: Epicardial and intramyocardial total artery wall specimens were obtained from 13 male patients (aged 61.9 ± 10.3 years) undergoing coronary artery bypass graft surgery due to 3-vessel coronary artery disease. LOX-1 expression was examined by reverse transcription-polymerase chain reaction. Results: LOX-1 expression was significantly higher in the arterial wall of epicardial coronary arteries compared to intramyocardial coronary arteries. The LOX-1/GAPDH ratio was 0.48 ± 0.07 vs. 0.35 ± 0.03 (p < 0.001). Conclusions: Our findings may partially explain the atheroprotective effect of the intramyocardial course since arterial wall LOX-1 expression was lower in intramyocardial arteries and higher in epicardial coronary arteries.

Cranioselectivity of Sumatriptan Revisited: Pronounced Contractions to Sumatriptan in Small Human Isolated Coronary Artery

Initial concerns about the coronary side-effect potential of the anti-migraine drug sumatriptan and second-generation triptans initiated cranioselectivity studies using proximal human coronary arteries. However, myocardial ischaemia may originate from both large and small human coronary arteries. We investigated the contractions to sumatriptan in proximal (internal diameter 2-3mm), distal (internal diameter 1,000-1,500μm) and small (internal diameter 500-1,000μm) human epicardial coronary arteries and compared these with contractions in the human middle meningeal artery. Concentration response curves to sumatriptan in human coronary arteries were constructed in the absence or presence of the 5-hydroxytryptamine1B (5-HT1B) receptor antagonist SB224289 and the 5-HT1D receptor antagonist BRL15572. The effect of sumatriptan on increased cyclic adenosine monophosphate (cAMP) levels induced by forskolin in proximal and distal coronary artery segments was investigated using a biochemical assay. Western blotting was used to analyse the 5-HT1B receptor density in the human arteries. Contractions in the proximal human coronary artery were significantly smaller than those in the human meningeal artery, as we showed previously. In contrast, contractions to sumatriptan in distal and small human coronary arteries were not different from those in the human meningeal artery. The 5-HT1B receptor antagonist SB224289, but not the 5-HT1D receptor antagonist BRL15572, inhibited the contraction induced by sumatriptan in the coronary arteries. Moreover, in distal, but not in proximal, coronary arteries, sumatriptan inhibited the increase in cAMP levels induced by forskolin. Contrary to our expectations, the 5-HT1B receptor expression was more pronounced in the proximal human coronary artery than in the distal and small human coronary artery. Based on functional experiments in distal and small human coronary arteries, contractions to sumatriptan are not as cranioselective as previously assumed. However, the vast clinical experience with sumatriptan and other triptans has proven that these drugs are cardiovascularly safe when contraindications are taken into account.

Functional alpha-1B adrenergic receptors on human epicardial coronary artery endothelial cells

Alpha-1-adrenergic receptors (α1-ARs) regulate coronary arterial blood flow by binding catecholamines, norepinephrine (NE), and epinephrine (EPI), causing vasoconstriction when the endothelium is disrupted. Among the three α1-AR subtypes (α1A, α1B, and α1D), the α1D subtype predominates in human epicardial coronary arteries and is functional in human coronary smooth muscle cells (SMCs). However, the presence or function of α1-ARs on human coronary endothelial cells (ECs) is unknown. Here we tested the hypothesis that human epicardial coronary ECs express functional α1-ARs. Cultured human epicardial coronary artery ECs were studied using quantitative real-time reverse transcription polymerase chain reaction, radioligand binding, immunoblot, and 3H-thymidine incorporation. The α1B-subtype messenger ribonucleic acid (mRNA) was predominant in cultured human epicardial coronary ECs (90–95% of total α1-AR mRNA), and total α1-AR binding density in ECs was twice that in coronary SMCs. Functionally, NE and EPI through the α1B subtype activated extracellular signal-regulated kinase (ERK) in ECs, stimulated phosphorylation of EC endothelial nitric oxide synthase (eNOS), and increased deoxyribonucleic acid (DNA) synthesis. These results are the first to demonstrate α1-ARs on human coronary ECs and indicate that the α1B subtype is predominant. Our findings provide another potential mechanism for adverse cardiac effects of drug antagonists that nonselectively inhibit all three α1-AR subtypes.

The Alpha-1D Is the Predominant Alpha-1-Adrenergic Receptor Subtype in Human Epicardial Coronary Arteries

The goal was to identify alpha-1-adrenergic receptor (AR) subtypes in human coronary arteries. The alpha1-ARs regulate human coronary blood flow. The alpha1-ARs exist as 3 molecular subtypes, alpha1A, alpha1B, and alpha1D, and the alpha1D subtype mediates coronary vasoconstriction in the mouse. However, the alpha1A is thought to be the only subtype in human coronary arteries. We obtained human epicardial coronary arteries and left ventricular (LV) myocardium from 19 transplant recipients and 6 unused donors (age 19 to 70 years; 68% male; 32% with coronary artery disease). We cultured coronary rings and human coronary smooth muscle cells. We assayed alpha1- and beta-AR subtype messenger ribonucleic acid (mRNA) by quantitative real-time reverse transcription polymerase chain reaction and subtype proteins by radioligand binding and extracellular signal-regulated kinase (ERK) activation. The alpha1D subtype was 85% of total coronary alpha1-AR mRNA and 75% of total alpha1-AR protein, and alpha1D stimulation activated ERK. In contrast, the alpha1D was low in LV myocardium. Total coronary alpha1-AR levels were one-third of beta-ARs, which were 99% the beta2 subtype. The alpha1D subtype is predominant and functional in human epicardial coronary arteries, whereas the alpha1A and alpha1B are present at very low levels. This distribution is similar to the mouse, where myocardial alpha1A- and alpha1B-ARs mediate beneficial functional responses and coronary alpha1Ds mediate vasoconstriction. Thus, alpha1D-selective antagonists might mediate coronary vasodilation, without the negative cardiac effects of nonselective alpha1-AR antagonists in current use. Furthermore, it could be possible to selectively activate beneficial myocardial alpha1A- and/or alpha1B-AR signaling without causing coronary vasoconstriction.

Influence of Ageing on Vasomotor Responses of Human Epicardial Coronary Arteries

Vasomotor responses to various agonists were studied on isolated circular segments of human epicardial coronary arteries from three different age groups; 23–38 years, 40–58 years and 63–86 years. Noradrenaline had no or only weak contractile effect on coronary arteries from younger patients but induced contraction of all artery segments from older patients. The Emax value was significantly (P<0.0001) higher in arteries from the oldest group compared to each of the two younger age groups, whereas the potency was similar in all three groups. Linear regression analysis of noradrenaline-induced contraction in individual patients revealed a significantly positive age-correlation (correlation coefficient 0.67, P<0.0001). Contraction induced by endothelin-1 and relaxation induced by substance P, calcitonin gene-related peptide and vasoactive intestinal peptide on arteries precontracted with U46619 showed no significant differences in maximum responses and potencies between the three age groups, and no significant linear age-correlation. These data demonstrate a large variability in contractile responses to noradrenaline with contractions seen mostly in coronary arteries from older patients. It thus seems that sympathetic activation could contribute to coronary ischaemia in some patients.

Mechanisms of Disease: L-arginine in coronary atherosclerosis—a clinical perspective

L-arginine is the substrate of endothelial nitric oxide synthase and the main precursor of nitric oxide in the vascular endothelium, thus its effects are mediated largely by increases in nitric oxide production. L-arginine has antioxidant and antiapoptotic properties, increases smooth muscle relaxation, inhibits the expression of adhesion molecules and chemotactic peptides, decreases endothelin-1 expression, and inhibits platelet aggregation. This amino acid also improves endothelial function in patients with coronary artery disease and dilates human epicardial atheromatous coronary arteries. Despite the positive results from small case-control studies, it is still unclear whether chronic administration of L-arginine has any effect on clinical outcome in patients with coronary artery disease. In addition, other indirect strategies, such as the inhibition of arginase, could prove more effective at improving intracellular L-arginine bioavailability than exogenous L-arginine administration. The potential clinical usefulness of L-arginine, therefore, needs further evaluation in large, prospective clinical trials. Here, we present a critique of the existing literature about the role of L-arginine in the prevention of atherosclerosis.

17β-estradiol effects on human coronaries and grafts employed in myocardial revascularization: a preliminary study

BackgroundThis study was undertaken to compare the in vitro effects of 17β-estradiol on human epicardial coronary arteries, resistance coronary arteries and on arterial vessels usually employed as grafts in surgical myocardial revascularization.MethodsCoronary artery rings (descending coronary artery, right coronary artery, circumflex coronary artery, first septal branch) and arterial graft rings (internal thoracic artery, gastro-epiploic artery) obtained from human heart donors with heart not suitable to cardiac transplantation were connected to force transducer for isometric force recording. Precontracted specimens with and without endothelium were exposed to increasing concentration of 17β-estradiol (3–30–300–3000 nmol/l) and to vehicle (0.1% v/v ethanol). We also evaluated the effects of 17β-estradiol on vessels before and 20 minutes after exposure to L-monomethyl-arginine and indomethacin.Results17β-estradiol induced a significant relaxation in all precontracted vessels (mean maximum effect: 78,6% ± 8,5). This effect was not different among the different rings and was not related to the presence of endothelium. N-monomethyl-L-arginine and indomethacin did not modify 17β-estradiol relaxant effect.ConclusionThe vasodilator action of the 17β-estradiol is similar on coronary arteries, resistance coronary arteries and arterial vessels usually employed as grafts in myocardial revascularization.

Activation of telomerase and expression of human telomerase reverse transcriptase in coronary atherosclerosis

Introduction Considerable research on telomerase on human neoplastic and normal long-lived proliferative tissues has emerged. We explored the expression of telomerase in atherosclerotic human epicardial coronary arteries. Methods Forty discrete human coronary arterial segments obtained from 19 heart transplant recipients were classified into nonatherosclerotic and atherosclerotic groups based on coronary angiography and histological examination. PCR-ELISA-based telomeric repeat amplification protocol (TRAP), and immunohistochemical analyses were conducted to determine the functional activity and cell-specific expression of telomerase. Results Seventy percent of atherosclerotic coronary arteries exhibited positive telomerase activity, and the reactivation incidence reached fourfold higher than that of controls ( P=.007). The telomerase catalytic protein, human telomerase reverse transcriptase (hTERT), was expressed in 88% of atherosclerotic tissues, a fivefold higher frequency compared with that of the controls. There was also a correlation of hTERT expression with the level of telomerase bioactivity ( P=.017) and with the severity of atherosclerotic grade ( P<.001). In comparison with the immunostaining of mitotic antigen, Ki-67, we found an association of hTERT expression with actively cycling cells in early lesions but with quiescent cells in late advanced atherosclerotic stages. Conclusions The up-regulation of telomerase and its catalytic hTERT protein during stages of atherosclerotic evolution may implicate a role of telomerase in vascular remodeling underlying atherogenesis.

Counterpoint: Flow-mediated dilation does not reflect nitric oxide-mediated endothelial function

The phenomenon of flow-mediated dilation (FMD) relevant to this debate describes the vasodilation in a conduit vessel in response to elevations in flow-associated shear stress. Nitric oxide (NO) is thought to play a key role in vascular health due to its established vasoprotective characteristics (

Expression, localisation and function of ACE and chymase in normal and atherosclerotic human coronary arteries

The expression, localisation and function of enzymes responsible for the local formation of angiotensin II in atherosclerotic and non-atherosclerotic human coronary arteries were studied. Human epicardial coronary arteries expressed mRNA for both ACE and chymase. Immunohistochemical studies revealed that ACE was localised to the vascular endothelium, and to a lesser extent the medial smooth muscle cells, in both large and small arteries. Chymase was detected in both types of vessel but was shown to be associated with mast cells. The contractions to angiotensin I in large arteries were inhibited only by a combination of quinaprilat and soyabean trypsin inhibitor. In the intramyocardial arteries the response to angiotensin I was markedly inhibited in the presence of chymostatin. These findings demonstrate that a dual pathway for the synthesis of angiotensin II is active in diseased and non-diseased coronary arteries.

Noninvasive assessment of coronary vasodilation using magnetic resonance angiography

The purpose of this study was to investigate the use of coronary magnetic resonance angiography (MRA) for assessing human epicardial coronary artery vasodilation. Coronary vasodilation plays a vital role in the human coronary circulation. Previous studies of epicardial coronary vasodilation have used invasive coronary angiography. Coronary MRA may provide an alternative noninvasive method to directly assess changes in coronary size. Thirty-two subjects were studied: 12 patients (age 55 +/- 18 years) and 20 healthy subjects (age 34 +/- 4 years). High-resolution multi-slice spiral coronary MRA (in-plane resolution of 0.52 to 0.75 mm) was performed before and after sublingual nitroglycerin (NTG). Quantitative analysis of coronary vasodilation was performed on cross-sectional images of the right coronary artery (RCA). A time-course analysis of coronary vasodilation was performed in a subset of eight subjects for 30 min after NTG. Signal-to-noise ratio was also measured on the in-plane RCA images. Coronary MRA demonstrated a 23% increase in cross-sectional area after NTG (16.9 +/- 7.8 mm2 to 20.8 +/- 8.9 mm2, p <0.0001), with significant vasodilation between 3 and 15 min after NTG on time-course analysis. The MRA measurements had low interobserver variability (< or =5%) and good correlation with X-ray angiography (r=0.98). The magnitude of vasodilation correlated with baseline cross-sectional area (r=0.52, p=0.03) and age (r=0.40, p=0.019). Post-NTG images also demonstrated a 31% improvement in coronary signal-to-noise ratio (p = 0.002). Nitroglycerin-enhanced coronary MRA can noninvasively measure coronary artery vasodilation and is a promising noninvasive technique to study coronary vasomotor function.

Identical α-chain T-cell receptor transcripts are present on T cells infiltrating coronary arteries of human cardiac allografts with chronic rejection

Chronic cardiac allograft rejection is characterized by graft arteriopathy and is a major obstacle of graft survival. We investigated T-cell receptor (TCR) α-chain transcripts of T cells infiltrating human epicardial coronary arteries from cardiac allografts with chronic rejection. The non-palindromic adaptor-polymerase chain reaction (NPA-PCR) was used to specifically amplify TCR α-chain transcripts from five explanted cardiac allografts with chronic rejection. The amplified products were cloned and sequenced to obtain the entire VαJα region. Immuno-histochemistry was used to identify the mononuclear cell infiltrates in the coronary arteries. All the five coronary artery specimens exhibited large populations of infiltrating mononuclear cells, which were primarily comprised of T cells and macrophages. In three specimens, high proportions (∼80%) of identical α-chain TCR transcripts were detected. In peripheral blood mononuclear cells from a healthy individual, α-chain TCR transcripts were unique when compared to each other. Endomyocardial biopsies collected from one patient six months before the allograft was explanted, contained identical α-chain TCR transcripts to those found to be clonally expanded in the coronary arteries from this patient. These results indicate that T cells infiltrating the epicardial arteries of cardiac allografts with chronic rejection undergo proliferation and clonal expansion in response to a specific antigen, which very likely is an (allo)antigen(s).

Different contribution of endothelial nitric oxide in the relaxation of human coronary arteries of ischemic and dilated cardiomyopathic hearts.

Coronary artery disease and congestive heart failure (CHF) have been associated with a reduction in nitric oxide (NO) release or bioavailability from the vascular endothelium. The objectives of this study were to compare the role of NO in human coronary vessels isolated from nonischemic dilated (DCM) (n = 10) and ischemic (ICM) (n = 12) cardiomyopathic hearts. Segments were mounted on a wire myograph to record changes in isometric tension. All experiments were performed in the presence of indomethacin (10 microM). Contractions induced by angiotensin II (0.1 microM) or a depolarizing physiologic solution containing 40 mM KCl, were of similar amplitude in DCM and ICM. In vessels precontracted with angiotensin II, acetylcholine (1 microM) caused an endothelium-dependent relaxation of rings from DCM but a paradoxical contraction of rings from ICM; NO synthase inhibition with Nomega-nitro-L-arginine (L-NNA, 100 microM) did not affect acetylcholine-induced relaxation or contraction of DCM or ICM vessels, respectively. By contrast, substance P (0.1 microM) induced an endothelium-dependent relaxation in both groups of vessels; this relaxation was prevented (p < 0.05) by L-NNA in vessels from ICM hearts but only reduced (p < 0.05) by L-NNA in vessels from DCM hearts. In depolarized conditions, acetylcholine contracted (p < 0.05) whereas substance P induced a complete relaxation (p < 0.05) of vessels from both groups: substance P-induced relaxation was abolished (p < 0.05) by L-NNA. Our data suggest that in the presence of indomethacin, NO does not contribute to acetylcholine-induced relaxation of human epicardial coronary arteries isolated from DCM hearts. Furthermore, whereas NO and a secondary endothelium-derived relaxing factor sensitive to high K+ contribute to substance P-induced relaxation of rings from DCM hearts, only NO is involved in ICM hearts.

Influence of ageing on vasomotor responses of human epicardial coronary arteries.

Vasomotor responses to various agonists were studied on isolated circular segments of human epicardial coronary arteries from three different age groups; 23-38 years, 40-58 years and 63-86 years. Noradrenaline had no or only weak contractile effect on coronary arteries from younger patients but induced contraction of all artery segments from older patients. The Emax value was significantly (P<0.0001) higher in arteries from the oldest group compared to each of the two younger age groups, whereas the potency was similar in all three groups. Linear regression analysis of noradrenaline-induced contraction in individual patients revealed a significantly positive age-correlation (correlation coefficient 0.67, P<0.0001). Contraction induced by endothelin-1 and relaxation induced by substance P, calcitonin gene-related peptide and vasoactive intestinal peptide on arteries precontracted with U46619 showed no significant differences in maximum responses and potencies between the three age groups, and no significant linear age-correlation. These data demonstrate a large variability in contractile responses to noradrenaline with contractions seen mostly in coronary arteries from older patients. It thus seems that sympathetic activation could contribute to coronary ischaemia in some patients.

Inhibition of nitric oxide synthesis in human epicardial coronary arteries and stenoses in relation to serum lipid level

Administration of N G-monomethyl- l-arginine (LNMMA), an inhibitor of nitric oxide synthase, causes a reduction in epicardial coronary artery and stenosis diameter in patients with coronary artery disease, indicating that these diseased vessels produce nitric oxide. Elevations of low density lipoprotein cholesterol impair human endothelium-dependent relaxation. The relationship between serum lipid level and nitric oxide production by normal and atheromatous human epicardial coronary arteries in vivo is unknown. The effects of an intracoronary infusion of LNMMA (8 and 16 μmol/min) followed by intracoronary administration of 250 mcg nitroglycerin on non-stenotic proximal and distal coronary segments and coronary stenoses were studied in 11 patients with coronary artery disease and in 19 patients with ‘normal arteriograms’. Coronary luminal diameter was measured by computerized quantitative angiography. In patients with cholesterol level⩾220 mg/dl, no significant response to LNMMA was observed in the proximal segments in either those with ‘normal angiograms’ or those with coronary disease. In patients with cholesterol <220 mg/dl significant constriction ( P<0.01) was observed in the proximal segments of patients with ‘normal coronary angiograms’ at both 8 and 16 μmol doses, but occurred only at the 16 μmol/min dose ( P<0.01) in those with coronary disease. In conclusion the difference in vasomotor response to LNMMA in relation to cholesterol level is localised to the proximal coronary segments, and the response does not correlate with cholesterol or triglyceride level. This is therefore more likely to be an indirect effect of elevated cholesterol, e.g. undetected atheroma, than a direct effect on nitric oxide synthesis.

Differential leukotriene constrictor responses in human atherosclerotic coronary arteries.

Leukotrienes are a class of biologically active lipids that have potent effects on the heart. To assess their role in coronary artery disease, we compared the contractile responses of leukotriene C4 (LTC4) and leukotriene D4 (LTD4) and their binding activity in both atherosclerotic and nonatherosclerotic human coronary arteries. We also studied expression of the enzymes that control their formation to understand how the 5-lipoxygenase (5-LO) pathway is activated in the coronary arteries. The capacity of leukotrienes to affect coronary vessel tone and the influence of atherosclerosis was tested in organ baths. Leukotriene receptors were examined by autoradiography, and antibody binding to the various enzymes responsible for their formation was assessed by use of immunocytochemistry. Nonatherosclerotic coronary artery ring segments were unresponsive to LTC4 and LTD4. In contrast, LTC4 and LTD4 induced concentration-dependent contractions in atherosclerotic coronary arteries. Specific [3H]-LTC4 but not LTD4 binding to atherosclerotic coronary artery was evident, with no evidence of specific binding of [3H]-leukotrienes to nonatherosclerotic coronary artery. High-resolution autoradiography identified specific [3H]-LTC4 binding sites to smooth muscle cell and to regions of intimal proliferation and plaque. Cells showing positive antibody binding to 5-LO, FLAP (5-lipoxygenase activating protein), and leukotriene A4 hydrolase were also present in the coronary arteries and had a similar distribution to macrophages. Atherosclerosis is associated with a specific leukotriene receptor(s) capable of inducing hyperreactivity of human epicardial coronary arteries in response to LTC4 and LTD4.