Cholesterol-lowering treatment is associated with improvement in coronary vascular remodeling and endothelial function in patients with normal or mildly diseased coronary arteries

Coronary vascular remodeling and altered endothelial function have been described in the early stages of native atherosclerosis. The purpose of this study was to evaluate the association between cholesterol-lowering therapy and coronary vascular remodeling and endothelial function in patients with normal or mildly diseases coronary arteries. Patients (N=101) with normal or mildly diseased coronary arteries by coronary angiography underwent intravascular ultrasound examination of the left anterior descending coronary artery. Vessel and lumen area, atherosclerotic plaque area, and plaque morphology were evaluated. Vascular reactivity was examined with the use of intracoronary adenosine, acetylcholine, and nitroglycerin. Patients were divided into 3 groups based on the total cholesterol levels: group 1 (n=25), patients with a history of hypercholesterolemia adequately treated (total cholesterol <240 mg/dL); group 2 (n=26), patients with hypercholesterolemia not adequately controlled (total cholesterol >/=240 mg/dL); and group 3 (n=50), patients without hypercholesterolemia. Vessel area and lumen area were significantly greater in groups 1 and 3 than in group 2 (for respective values in groups 1, 2, and 3: vessel area 11.9+/-0.5, 10.6+/-0.4, and 11.8+/-0.4 mm(2), both P<0.05; lumen area 8.3+/-0.4, 6.9+/-0.3, and 8.9+/-0.3 mm(2), both P<0.01). However, plaque areas in groups 1 and 2 were similar. Furthermore, acetylcholine-induced percent increases in coronary blood flow were significantly greater in groups 1 and 3 than in group 2 (for respective values in groups 1, 2, and 3: 70.5+/-20.1%, 22.8+/-13.7%, and 68.6+/-14.8%, both P<0. 05). Cholesterol-lowering treatment is associated with an improvement in coronary lumen area that results not from a decrease in plaque area but from an increase in vessel area, reflecting vascular remodeling. Additionally, this adaptive process may occur in association with an improvement of endothelium-dependent vasodilation of the resistance coronary artery.     

Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries

OBJECTIVES: This study evaluates the impact of obesity on coronary endothelial function in patients with normal or mild coronary artery disease. BACKGROUND: The American Heart Association (AHA) has recently classified obesity as a modifiable risk factor for coronary heart disease. METHODS: A total of 397 consecutive patients with normal or mildly diseased coronary arteries at angiography underwent coronary vascular reactivity evaluation using intracoronary adenosine, acetylcholine and nitroglycerin. Patients were divided into three groups based on the body mass index (BMI): Group 1, patients with a BMI <25 (n = 117, normal weight); Group 2, patients with a BMI 25-30 (n = 149, overweight) and Group 3, patients with a BMI >30 (n = 131, obese). RESULTS: There were no significant differences among the groups in regard to other cardiovascular risk factors, except that overweight but not obese patients were significantly older than normal-weight patients (47 +/- 1 years in Group 1, 53 +/- 1 years in Group 2 and 50 +/- 1 years in Group 3, p < 0.001). The percent change of coronary blood flow to acetylcholine (%delta CBF Ach) was significantly lower in the obese patients than in the normal-weight group (85.2 +/- 12.0% in Group 1, 63.7 +/- 10.0% in Group 2 and 38.1 +/- 9.6% in Group 3, p = 0.009). By multivariate analysis, overweight (odds ratio, 1.55; 95% confidence interval, 1.2-2.0) and obesity (odds ratio, 2.41; 95% confidence interval, 1.5-4.0) status were independently associated with impaired coronary endothelial function. CONCLUSIONS: The study demonstrates that obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries.     

Comparison of effect between nitrates and calcium channel antagonist on vascular function in patients with normal or mildly diseased coronary arteries

The comparative long-term antianginal efficacy of long-acting nitrates versus calcium channel antagonists remains unclear. The goal of the present study was to compare the coronary endothelial cell function and coronary artery vasoconstriction between patients with normal or mildly diseased coronary arteries treated with long-acting nitrates or calcium channel antagonists. Forty-two patients suspected to have angina pectoris and with normal or mildly diseased coronary arteries underwent Doppler flow study of the left anterior descending coronary artery. All patients were suspected to have angina pectoris and were receiving either long-acting nitrates (n = 18; Nitrates group) or calcium channel antagonists (n = 24; Ca-antagonists group) for at least 1 year. Vascular reactivity was assessed by intracoronary administration of papaverine, acetylcholine (Ach), and nitroglycerin using a Doppler guidewire. Segments that showed the greatest constrictive response to Ach were used for assessment of vasoconstriction. The percent increase in coronary blood flow (CBF) and coronary artery diameter (CAD) induced by Ach was significantly smaller in the Nitrates group than in the Ca-antagonists group (33% ± 74% vs 83% ± 77%, P < 0.05; −3% ± 16% vs 11% ± 12%, P < 0.01, respectively). The percent diameter reduction in the region of greatest constrictive response to Ach was significantly greater in the Nitrates group than in the Caantagonists group (44% ± 39% vs 15% ± 32%, P < 0.02). Long-term treatment with long-acting nitrates may produce less favorable effects on coronary endothelial function and the constrictive response to Ach when compared with long-acting calcium channel antagonists in patients with normal or mildly diseased coronary arteries. These authors contributed equally to this study.     

Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome

OBJECTIVE: To study the role of coronary flow reserve for the prediction of long-term cardiovascular event rate. DESIGN: Observational, longitudinal. SETTING: Single-center, coronary vasomotor testing at university hospital. PARTICIPANTS: One hundred and twenty patients with angiographically normal or minimally diseased coronary vessel. METHODS: Coronary flow reserve was assessed by intracoronary Doppler and quantitative coronary angiography. Cardiovascular events during follow-up (6.5+/-3 years, range 14-125 months) were defined as sudden death, myocardial infarction, unstable angina, ischemic stroke or the need for revascularization by percutaneous transluminal coronary angioplasty or coronary as well as peripheral bypass surgery. RESULTS: Reduced coronary flow reserve was significantly associated with a poor long-term outcome: cardiovascular events occurred in seven (18%) patients in the lowest tertile of coronary flow reserve compared with four patients in the middle tertile (10%) and two patients in the upper tertile (5%) (P=0.019 by Kaplan-Meier analysis). The multivariate Cox proportional hazard model revealed coronary flow reserve as an independent predictor of prognosis (P=0.017) in addition to angiographic evidence of atherosclerosis (P=0.047) and arterial hypertension (P=0.013). CONCLUSIONS: Coronary flow reserve in normal to mildly diseased arteries is an independent predictor of long-term prognosis of atherosclerosis within the next decade.     

Evidence of partially preserved endothelial dilator function in diseased coronary arteries

OBJECTIVE—To examine the effects of substance P (endothelium dependent vasodilator) and glyceryl trinitrate (endothelium independent vasodilator) on epicardial coronary arteries in patients with normal coronary angiograms and patients with coronary artery disease.
DESIGN—Intracoronary infusions of normal saline, the receptor mediated nitric oxide stimulant substance P (5.6 and 27.8 pmol/min each for five minutes), and glyceryl trinitrate (250 µg bolus) were given in 24 patients with coronary artery disease and stable angina, and in nine patients with normal angiograms. The diameter of proximal and distal coronary segments was measured by computerised quantitative angiography
RESULTS—Proximal segments of patients with coronary artery disease dilated less than those of patients with normal angiograms in response to 27.8 pmol/min substance P (mean (SEM): 7.9 (1.3)% v 15 (2.3)% respectively, p < 0.01). The proximal segments of diseased arteries also dilated less than those of "normal" arteries in response to glyceryl trinitrate (10.2 (1.6)% v 18.4 (2.9)%, respectively, p < 0.01). The responses of distal segments to substance P and glyceryl trinitrate were similar in the two patient groups. There were correlations (all p < 0.001) between the coronary diameter after substance P and after glyceryl trinitrate in normal proximal segments (r = 0.94) and normal distal segments (r = 0.64), in diseased proximal segments (r = 0.95) and diseased distal segments (r = 0.89), and for coronary stenoses (r = 0.93).
CONCLUSIONS—Proximal segments of patients with coronary disease dilated less than the proximal segments of "normal" patients in response to substance P and glyceryl trinitrate. The response to substance P is substantial and closely correlated with the response to glyceryl trinitrate in both "normal" patients and those with coronary disease. This suggests that although the proximal segments of diseased coronary arteries have a reduced capacity to dilate in response to direct stimulation of smooth muscle cell relaxation, they retain much of their endothelium dependent vasodilator function.


Keywords: endothelium; nitric oxide; coronary artery disease; glyceryl trinitrate     

Improvement of endothelial function in patients with hypercholesterolemia and normal coronary arteries with lipid-lowering therapy]

INTRODUCTION AND AIMS: In patients with coronary risk factors the presence of endothelial dysfunction in epicardial arteries has been documented. The purpose of this study was to determine whether endothelial dysfunction, documented hypercholesterolemic patients and angiographically normal coronary arteries, improves by reduction and normalization of lipid levels. PATIENTS AND METHOD: In 10 patients with hypercholesterolemia and normal coronary angiography, the endothelium-dependent coronary vasomotion was studied by intracoronary infusion of acetylcholine into the left anterior descending coronary artery. Vasomotion changes in response to acetylcholine were analyzed by quantitative angiography. Five patients without coronary risk factors and normal coronary arteries formed the control group. Patients with hypercholesterolemia were treated with lipid-lowering therapy (diet and lovastatin) and endothelial function was reevaluated after 24 +/- 4 months. RESULTS: In the initial study, hypercholesterolemic patients compared with the control group showed a vasoconstrictor response to serial doses of acetylcholine(10(-6) M, 10(-5) M, 10(-4)M) indicative of endothelial dysfunction (study group: -0.3 +/- 10%, -6 +/- 4%, -18 +/- 10% vs control group: -0.6 +/- 6%, -2 +/- 6%, 3+/-6%; p < 0.01 to 10(-4) M acetylcholine dose. During follow-up hypercholesterolemic patients who a significant reduction in total cholesterol levels and LDL. Compared to first study, at follow-up, there was an improvement in the response to acetylcholine (-0.4 +/- 4%, -3 +/- 6%, -3 +/- 10%; p<0.001 vs basal values at 10(-4) M acetylcholine concentration). Reduction in total cholesterol during follow-up was related to the improvement in the vasoconstrictor response to acetylcholine (r=0.53; p< 0.05). CONCLUSION: In patients with hypercholesterolemia and angiographycally normal coronary arteries with documented endothelial dysfunction, the reduction and normalization of lipid levels during follow-up may improve endothelium-dependent coronary vasomotion.     

Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior

Although the entire coronary tree is exposed to the atherogenic effect of the systemic risk factors, atherosclerotic lesions form at specific arterial regions, where low and oscillatory endothelial shear stress (ESS) occur. Low ESS modulates endothelial gene expression through complex mechanoreception and mechanotransduction processes, inducing an atherogenic endothelial phenotype and formation of an early atherosclerotic plaque. Each early plaque exhibits an individual natural history of progression, regression, or stabilization, which is dependent not only on the formation and progression of atherosclerosis but also on the vascular remodeling response. Although the pathophysiologic mechanisms involved in the remodeling of the atherosclerotic wall are incompletely understood, the dynamic interplay between local hemodynamic milieu, low ESS in particular, and the biology of the wall is likely to be important. In this review, we explore the molecular, cellular, and vascular processes supporting the role of low ESS in the natural history of coronary atherosclerosis and vascular remodeling and indicate likely mechanisms concerning the different natural history trajectories of individual coronary lesions. Atherosclerotic plaques associated with excessive expansive remodeling evolve to high-risk plaques, because low ESS conditions persist, thereby promoting continued local lipid accumulation, inflammation, oxidative stress, matrix breakdown, and eventually further plaque progression and excessive expansive remodeling. An enhanced understanding of the pathobiologic processes responsible for atherosclerosis and vascular remodeling might allow for early identification of a high-risk coronary plaque and thereby provide a rationale for innovative diagnostic and/or therapeutic strategies for the management of coronary patients and prevention of acute coronary syndromes.     

Cigarette smoking induced oxidative stress may impair endothelial function and coronary blood flow in angiographically normal coronary arteries.

BACKGROUND: Smoking contributes to the progression of atherosclerotic heart disease by causing endothelial dysfunction. In the present study the effect of smoking on endothelial functions and coronary flow was investigated, as well as the relationship of these factors with oxidative stress parameters, in subjects with normal coronary arteries. MATERIALS AND RESULTS: The study group comprised 87 patients with angiographically normal coronary arteries (36 smokers, 51 nonsmokers). Coronary flow patterns were determined by the Thrombolysis In Myocardial Infarction (TIMI) frame count method. Endothelial function was evaluated by high-frequency ultrasound imaging of the brachial artery. Superoxide dismutase (SOD) and reduced glutathione (GSH) and reduction of oxidative material in the body and the endproduct of lipid peroxidation, malondialdehyde (MDA), were measured as oxidative stress markers. Mean TIMI frame count was significantly higher in smokers than nonsmokers (42.2 +/- 16 vs 29.5 +/- 9.5, p = 0.0001). Endothelium-dependent flow-mediated dilatation was 6.81+/-1.95% in nonsmokers and 5.7 +/- 2.2% in smokers (p = 0.0001). The smokers had dramatically higher levels of SOD and MDA and lower levels of GSH than the nonsmoker group. CONCLUSION: Smoking induced oxidative stress deteriorates coronary blood flow by disturbing endothelial function.     

Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior.

Although the entire coronary tree is exposed to the atherogenic effect of the systemic risk factors, atherosclerotic lesions form at specific arterial regions, where low and oscillatory endothelial shear stress (ESS) occur. Low ESS modulates endothelial gene expression through complex mechanoreception and mechanotransduction processes, inducing an atherogenic endothelial phenotype and formation of an early atherosclerotic plaque. Each early plaque exhibits an individual natural history of progression, regression, or stabilization, which is dependent not only on the formation and progression of atherosclerosis but also on the vascular remodeling response. Although the pathophysiologic mechanisms involved in the remodeling of the atherosclerotic wall are incompletely understood, the dynamic interplay between local hemodynamic milieu, low ESS in particular, and the biology of the wall is likely to be important. In this review, we explore the molecular, cellular, and vascular processes supporting the role of low ESS in the natural history of coronary atherosclerosis and vascular remodeling and indicate likely mechanisms concerning the different natural history trajectories of individual coronary lesions. Atherosclerotic plaques associated with excessive expansive remodeling evolve to high-risk plaques, because low ESS conditions persist, thereby promoting continued local lipid accumulation, inflammation, oxidative stress, matrix breakdown, and eventually further plaque progression and excessive expansive remodeling. An enhanced understanding of the pathobiologic processes responsible for atherosclerosis and vascular remodeling might allow for early identification of a high-risk coronary plaque and thereby provide a rationale for innovative diagnostic and/or therapeutic strategies for the management of coronary patients and prevention of acute coronary syndromes.     

Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease

Acetylcholine causes endothelium-dependent dilation of normal arteries in most animal species. The effect of acetylcholine on normal human coronary arteries is controversial. Pathologic studies and epicardial echocardiography have shown that diffuse atherosclerosis is often present despite angiographic evidence of discrete coronary artery disease (CAD). Therefore, we postulated that acetylcholine would cause vasoconstriction of coronary arteries that are angiographically normal in patients with CAD. Coronary artery diameter, measured by automated quantification of digitized cineangiograms, was determined before and after the intracoronary infusion of 0.2 mM acetylcholine at 0.8-1.6 ml/min. The diameter of stenotic or irregular segments of six atherosclerotic coronary arteries decreased from 1.80 +/- 0.42 mm before acetylcholine to 1.26 +/- 0.46 mm after acetylcholine (p = 0.0025). Acetylcholine had a significantly different effect on the diameter of two groups of coronary arteries that are angiographically normal. Acetylcholine caused a 0.16 +/- 0.09-mm increase in the diameter of 14 normal coronary arteries in patients without CAD, whereas it caused a 0.26 +/- 0.12-mm decrease in the diameter of 14 normal coronary arteries in patients with CAD (p less than 0.01). Thus, the normal response to intracoronary acetylcholine is vasodilation, suggesting that endothelium-derived relaxing factor is released from normal human coronary endothelium. The vasoconstrictive effect of acetylcholine in the angiographically normal coronary arteries of patients with CAD suggests the presence of a diffuse abnormality of endothelial function.     

Dipyridamole echocardiography test in patients with normal or near normal coronary arteries.

We read with great interest the paper by Sicari et al.¹dealing with the prognostic value of dipyridamole echocardiographytest in patients with chest pain syndrome     

Acute coronary syndromes in patients with angiographically normal or near normal (non-obstructive) coronary arteries

Patients with acute coronary syndrome (ACS) with normal or near-normal (non-obstructive) coronary arteries (ACSNNOCA) constitute an important, albeit heterogeneous, patient subset of younger patients, more commonly females, who may have lower risk of cardiovascular events compared to patients with obstructive coronary artery disease; however this risk remains substantial, hence needing further investigation to identify the underlying cause and devise a proper therapeutic strategy. A diagnostic algorithm starts during coronary angiography with some essential additional diagnostic steps, such as a left ventricular angiogram that may readily identify the underlying cause, e.g. Takotsubo syndrome, while intravascular imaging and vascular reactivity testing may need to be considered for assessing other diagnostic possibilities (e.g. occult atherosclerotic plaque rupture, spontaneous coronary dissection or microvascular dysfunction). Nevertheless, pursuing further investigation with less risky noninvasive tests, such as echocardiography and cardiac magnetic resonance imaging, may effectively identify the cause of ACSNNOCA (e.g. myocarditis or Takotsubo syndrome), and guide management.     

血管内皮生长因子与慢性支气管炎合并肺气肿大鼠早期肺动脉重构关系的研究

目的研究血管内皮生长因子（VEGF）在慢性支气管炎合并肺气肿早期（非低氧血症期）肺动脉重构中的作用及N-乙酰半胱氨酸（NAC）的抗氧化作用对其的影响。方法24只健康雄性Wistar大鼠随机分为4组,每组6只：假吸烟组（A组）、慢性支气管炎合并肺气肿组（B组）、NAC预防组（C组）、NAC治疗组（D组）,B、C及D组采用两次气管内注入脂多糖（LPS）及烟熏4周法制备慢性支气管炎合并肺气肿大鼠模型,C组在烟熏及气管内注入LPS前每天给予NAC（50mg／只）灌胃,D组在第15～28天烟熏前每天给子NAC（50mg／只）灌胃。各组作血气分析、对肺组织进行苏木精-伊红染色、维多利亚蓝＋VG（Van—Gieson）染色观察气道炎症、肺泡面积改变、肺血管改变及采用免疫组化法观察VEGF的表达情况。结果与A组比较,B组各大鼠小气道出现组织细胞损伤、管壁炎症细胞浸润及平均肺泡面积增大（P〈0.05）,符合慢性支气管炎合并肺气肿的病理改变;B组动脉氧分压、氧饱和度及二氧化碳均在正常范围。与A组比较,B组肺血管管壁增厚、管腔缩小（P〈0．01）,且肌化动脉、部分肌化动脉比率增加（P〈0．01）,VEGF在肺动脉周围表达增多（P〈0.01）。而C组及D组经NAC抗氧化干预后肺血管管壁增厚及管腔缩小减轻（P〈0．05）,并且肌化动脉、部分肌化动脉比率减少（P〈0．01）,肺动脉周围VEGF表达比B组减少（P〈0．01）。结论由吸烟及LPS诱导的大鼠慢性支气管炎合并肺气肿早期（非低氧皿症期）VEGF表达增多参与了肺动脉重构,NAC可抑制肺动脉重构与其通过抗氧化作用降低VEGF表达有关。     

Association between plasma lipoprotein(a) and endothelial dysfunction in normocholesterolemic and non-diabetic patients with angiographically normal coronary arteries.

The present study was designed to examine whether elevated levels of lipoprotein(a) (Lp(a)) are related to the impairment of the endothelium-dependent vasoresponse to acetylcholine (ACh) in normocholesterolemic and non-diabetic human normal coronary arteries. ACh (30 microg) was injected into the left main coronary artery of 31 patients (serum low-density cholesterol <160mg/dl and fasting plasma glucose <126mg/dl) with angiographically normal coronary arteries, and the relation between diameter change and lipid levels was analyzed. The mean diameter change of all coronary segments examined (segments 6, 8, 11 and 13) was reduced by 14.6+/-26.5% in response to ACh, but increased by 23.3+/-6.0% in response to nitroglycerin, suggesting endothelial dysfunction in those arteries. The mean diameter change of the left anterior descending artery or left circumflex artery in each patient was negatively correlated only with the level of Lp(a). Stepwise multiple regression analysis also revealed that only Lp(a) among the lipids showed significant correlation with impaired vasodilation (p=0.033). These findings suggest that elevated levels of plasma Lp(a) might be a strong predictor of endothelial dysfunction in normocholesterolemic and non-diabetic subjects.     

血管内皮功能和同型半胱氨酸对老年冠心病患者发病的相关性探讨

目的探讨血管内皮功能和同型半胱氨酸(Hcy)在老年冠心病患者中的作用机制。方法选取老年冠心病患者150例,根据诊断分为陈旧性心肌梗死组56例,稳定性心绞痛组51例,急性冠状动脉综合征组43例。对比各组患者Hcy水平、高血压、吸烟史、TC、及LDL-C等,分析Hcy水平及内皮依赖型血管舒张率与冠心病严重程度的相关性。结果急性冠状动脉综合征组Hcy水平升高比例显著高于稳定性心绞痛组和陈旧性心肌梗死组(79.1%vs 14.3%,29.4%,P=0.000)。3组间Hcy水平正常及升高比例比较差异有统计学意义(P=0.000)。急性冠状动脉综合征组Hcy水平显著高于稳定性心绞痛组及陈旧性心肌梗死组[(19.8±7.2)μmol/L vs(11.0±4.5)μmol/L,(12.3±6.1)μmol/L,P<0.01],但内皮依赖型舒张率显著低于稳定性心绞痛组及陈旧性心肌梗死组[(4.1±2.8)%vs(7.5±5.1)%,(6.5±3.2)%,P<0.01]。相关分析显示,Hcy水平与冠心病严重程度呈正相关(r=6.332,P=0.038),而内皮依赖型血管舒张率与冠心病严重程度呈负相关(r=-7.254,P=0.038)。结论血管内皮功能及Hcy水平与老年冠心病患者的病情联系紧密,临床治疗时可对其进行监测,值得重视。