Advancing age is associated with diminished vascular remodeling and impaired vasodilation in resistance coronary arteries

BACKGROUND: Compensatory enlargement of the coronary arterial wall has been described in the early stages of native atherosclerosis. However, little is known about the specific effect of aging on this adaptive process in atherosclerosis. The purpose of the current study was to characterize the effects of advancing age on vascular remodeling and endothelium-dependent and -independent coronary vasodilation in patients without coronary artery disease risk factors. METHODS: Twenty-six patients without coronary risk factors and with normal and mildly diseased coronary arteries were studied. Vessel, lumen and atherosclerotic plaque areas were evaluated by intravascular ultrasound and coronary flow response was assessed using papaverine and acetylcholine in the left anterior descending coronary artery. RESULTS: There was a weak but significant correlation between plaque area and age (r = 0.29, P<0.01). Vessel area was also weakly but significantly correlated with age (r = 0.22, P<0.05). However, lumen area had no correlation with age. Vessel area in the younger group (<50 years) and the older group (> or =50 years) increased 1.64 and 0.55 mm2 for every 1 mm2 increase in plaque area (r = 0.62, P<0.0001 and r = 0.39, P<0.05, respectively). With regard to vascular reactivity, there was an inverse correlation between the percentage increases in coronary blood flow (CBF) evoked by acetylcholine and aging (r = -0.49, P<0.05). The percentage increases in CBF evoked by papaverine also inversely correlated with aging (r=-0.53, P<0.01). However, the percentage changes in coronary artery diameter evoked with acetylcholine did not correlate with aging. CONCLUSION: This study suggests that endothelium-dependent and -independent vasodilation of the resistance coronary artery are impaired with advancing age, which may be in association with attenuated coronary vascular remodeling with aging.     

Coronary flow regulation in patients with ischemic heart disease: release of purines and prostacyclin and the effect of inhibitors of prostaglandin formation

The present investigation was undertaken to study cardiac release of adenosine and prostacyclin (prostaglandin [PG] I2) in patients with ischemic heart disease (IHD), and to assess coronary vascular resistance before and after inhibition of synthesis in such patients. In 48 patients with IHD, arterial and coronary sinus blood samples were taken at rest, during atrial pacing to angina, and after pacing. Levels of purines were determined by high-performance liquid chromatography and the PGI2 metabolite 6-keto-PGF1 alpha was measured with radioimmunoassay. Coronary sinus blood flow was determined with retrograde continuous thermodilution before and after oral administration of indomethacin, aspirin, naproxen, or ibuprofen. Atrial pacing induced myocardial ischemia, as evidenced by typical chest pain and arrested lactate extraction. Adenosine was extracted at rest, but during ischemia there was a significant release of its metabolite hypoxanthine, indicating increased myocardial breakdown of high-energy adenine nucleotides. Arterial and coronary sinus concentrations of 6-keto-PGF1 alpha were low and no significant differences between them were found. After administration of the PG-synthesis inhibitor indomethacin, coronary vascular resistance was elevated, as was the cardiac oxygen extraction. The three other PG-synthesis inhibitors (aspirin, naproxen, and ibuprofen) did not, however, induce any change in coronary vascular resistance or in the cardiac extraction of oxygen. On the basis of these data we suggest that in patients with IHD cardiac ischemia results in increased myocardial production and release of purines, cardiac ischemia does not elicit any detectable increase in coronary production of prostacyclin, and the increased coronary resistance induced by indomethacin does not reflect the involvement of locally formed PG in the maintenance of coronary flow, but is rather a direct effect of the drug.     

Functional consequences and intracoronary localization of alpha-adrenergic stimulation of the canine coronary circulation

Although alpha-adrenergic stimulation can increase coronary vascular resistance, it remains unknown whether the vasoconstriction can override intrinsic coronary regulatory influences to produce ischemia. Methoxamine, 2 to 4 mg, was infused into the circumflex coronary artery of 23 chloralose-anesthetized open chest dogs, and resulted in a 68% increase in coronary vascular resistance. The functional consequence of this increased coronary vascular resistance was assessed by gated radionuclide ventriculography and ST-T wave changes on the electrocardiogram. In six dogs (Group I), aortic pressure changed trivially (less than 5 mm Hg) to allow distinction between direct effects of the flow reduction and indirect effects of increased aortic pressure. In this group, coronary blood flow decreased 33% from a control value of 44 +/- 10 ml/min (p less than 0.001) and left ventricular ejection fraction decreased from 0.54 +/- 0.12 to 0.46 +/- 0.10 (p less than 0.025). In eight dogs (Group II) in which aortic pressure increased by more than 5 mm Hg, left ventricular ejection fraction decreased from 0.46 +/- 0.07 to 0.39 +/- 0.09 (p less than 0.002). Pressure gradients were measured between the aorta and a distal coronary artery branch to calculate small and large vessel resistances separately in four other dogs (Group III). The resistance of small coronary arteries accounted for 92% of the total increase in coronary vascular resistance produced by methoxamine. In five other dogs (Group IV), intracoronary methoxamine, 2 mg, produced ST-T wave changes suggestive of ischemia as it increased coronary vascular resistance by 33%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of brief myocardial ischemia on sympathetic coronary vasoconstriction.

The purpose of the present study was to determine whether sympathetic coronary vasoconstrictor responses are altered after brief ischemia and reperfusion. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate, arterial pressure, left ventricular pressure, left ventricular dP/dt, anterior myocardial wall thickening, and left circumflex coronary artery (LCX) and left anterior descending coronary artery (LAD) blood flow velocities. Changes in coronary vascular resistance were recorded during intravenous bolus doses of norepinephrine and bilateral electrical stimulation of the stellate ganglia. After beta-adrenergic blockade and bilateral vagotomy, electrical stimulation of the stellate ganglia increased coronary vascular resistance in the LAD and LCX beds by 38 +/- 5% and 39 +/- 5%, respectively. After a 15-minute LAD occlusion, repeat electrical stimulation produced increases in coronary resistance of 16 +/- 3% and 45 +/- 8%, respectively (p less than 0.05 for the LAD before versus after the occlusion). The peak increase in coronary vascular resistance to two doses of norepinephrine was unchanged. After a shorter period of myocardial ischemia (7 minutes), similar increase in coronary resistance to stellate stimulation were observed before (27 +/- 4%) and after (26 +/- 6%) myocardial ischemia. The mechanism of this impaired sympathetic coronary vasoconstriction was further tested by examining the responses to bretylium and tyramine. Brief ischemia did not alter the coronary constrictor responses to either bretylium or tyramine, suggesting that mechanisms governing prejunctional release of norepinephrine are intact in the postischemic coronary arterial bed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impact of smoking on coronary atherosclerosis and remodeling as determined by intravascular ultrasonic imaging

Using preintervention intravascular ultrasound among patients with coronary artery disease, the current study indicates that patients who smoked had a similar degree of reference and lesion site arterial area, plaque burden, lumen compromise, attenuated adaptive vascular remodeling response, and less lesion site calcification as nonsmokers.     

Prolonged duration of myocardial ischemia in patients with coronary heart disease and impaired cardiopulmonary baroreceptor sensitivity

To investigate the potential contribution of cardiopulmonary reflexes in myocardial ischemia, the coronary vascular response to cardiopulmonary baroreceptor unloading and the number and the duration of spontaneous episodes of symptomatic and asymptomatic myocardial ischemia were evaluated in 23 patients with coronary heart disease. Lower-body negative pressure at -10 mm Hg, which causes selective deactivation of cardiopulmonary receptors, reduced left ventricular filling pressure in all patients, but calculated coronary vascular resistance increased in only 14 patients (from 0.846 +/- 0.1 to 1.07 +/- 0.1 mm Hg/ml/min, p less than 0.01) (group 1). In the remaining nine patients, coronary resistance did not change during cardiopulmonary receptor unloading (group 2). A 60-mm Hg increase in neck tissue pressure, which induces arterial baroreflex-mediated sympathetic activation, caused comparable coronary vasoconstriction in the two groups. Clinical characteristics of the two groups were similar, except that a lower ejection fraction was measured in group 1 (45 +/- 2% vs. 56 +/- 1%, p less than 0.01). In the 14 patients in group 1, 24-hour electrocardiographic monitoring showed 151 episodes of myocardial ischemia (average individual value, 10.8 +/- 1), 137 of which were asymptomatic, with an individual daily ischemic period of 62 +/- 6 minutes. In contrast, the nine patients in group 2 had only symptomatic episodes of myocardial ischemia, and the daily ischemic period in these patients was longer than in patients of group 1 (104 +/- 10 minutes, p less than 0.01). After a 3-day treatment with digitalis, the patients of group 2 showed 38 asymptomatic episodes of myocardial ischemia and a shorter daily ischemic period (85 +/- 6 minutes, p less than 0.01 vs. control conditions). In contrast, no change in number and duration of the ischemic episodes was detected in group 1. The effects of acute administration of digitalis (Lanatoside-C 0.02 mg/kg body wt e.v.) on the coronary vascular response to cardiopulmonary receptor unloading were assessed in a separate group of patients with ischemic heart disease. Digitalis treatment did not significantly modify the magnitude of the coronary vascular response induced by -10 mm Hg lower-body negative pressure in the patients showing in control conditions an increase of coronary vascular resistance greater than 20% of the basal value during cardiopulmonary receptor unloading. On the contrary, digitalis potentiated the coronary reflex response to -10 mm Hg lower-body negative pressure in the patients with impaired cardiopulmonary responsiveness (delta percent increase in coronary vascular resistance: 1 +/- 1% in control conditions; 23 +/- 3.9% after digitalis, p less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Correlation of functional and structural alterations of the coronary arterioles during development of type II diabetes mellitus in rats

OBJECTIVE: Cardiac complications in diabetes mellitus (DM) are frequently ascribed to microangiopathy. Therefore, we sought to directly correlate the serial changes in coronary arterial function with the extent of coronary arteriolar remodeling in a model spontaneously developing type II DM. METHODS: Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats were used. At 5, 15 and 30 weeks of age, ten rats in each group were subjected to systemic and coronary hemodynamic measurements using the colored microsphere technique before and during maximal coronary hyperemia and histological assessment with Azan-Mallory stain of the coronary arterioles. RESULTS: As early as 15 weeks of age, at which time fasting plasma glucose concentration remained normal, OLETF rats exhibited a lower coronary flow reserve and a greater coronary vascular resistance during hyperemia than did LETO rats. On histomorphometry, OLETF rats exhibited a greater wall-to-lumen ratio and a greater degree of perivascular fibrosis of arterioles at 15 weeks of age and thereafter, both of which exhibited a significant correlation with the minimal coronary vascular resistance. CONCLUSIONS: The degree of functional deterioration in coronary circulation was directly correlated with the severity of coronary arteriolar structural remodeling during the development of microangiopathy in early stage of DM.     

Cardiac and coronary vascular effects of chronically administered estrogen in the dog

The acute administration of cunjugated equine estrogen (CEE) to dogs significantly attenuated the severity and incidence of ventricular arrhythmias during ischemia and reperfusion. We hypothesized that one of the cardioprotective mechanisms of estrogen might be the ability to maintain electrical stability of the heart during ischemia. The current study was conducted to determine the effect of chronic administration of estrogen, simulating hormone replacement therapy, on the ventricular arrhythmias of ischemia and reperfusion, Chronically-treated (100 μg/kg/week CEE, or vehicle) male beagles were anesthetized and subjected to regional ischemia (20 min) and reperfusion. Although there was a trend towards a lower incidence of arrhythmias during ischemia in estrogen-treated dogs, values did not achieve significance at P<0.05. Baseline coronary vascular resistance was significantly higher in estrogen-treated dogs (2.3 vs 1.5 mmHg/ml/min/100 g, P<0.05) indicating an increase in vasomotor tone. There was also an increase in the time it took hyperemic coronary blood flow to reach a peak value upon reperfusion (71 sec in estrogen-treated dogs vs 12 sec in vehicle-treated dogs, P<0.05). This slower reflow is consistent with increased coronary vascular resistance upon reflow in estrogen-treated dogs. We conclude that the chronic administration of CEE to male dogs increased coronary vascular tone, and impaired the rate of reperfusion, but did not decrease the incidence of ventricular arrhythmias caused by ischemia. Received: 31 July 1997, Returned for revision: 18 September 1997, Revision received: 19 October 1997, Accepted: 4 November 1997     

过氧化物酶体增殖剂活化受体与心肌重塑

过氧化物酶体增殖剂活化受体是一类核转录因子 ,具有多种有益的生理作用 :参与心脏能量代谢 ,增加胰岛素敏感性 ,阻断过度激活的肾素 血管紧张素系统和胰岛素抵抗形成的恶性循环 ,抑制炎症反应 ,改善心功能 ,提高血管顺应性、降低后负荷 ,对抗心肌重塑。缺血 /再灌注时过氧化物酶体增殖剂活化受体激动剂抑制心肌组织炎症细胞浸润 ,减轻心肌缺血 /再灌注损伤而保护心脏。     

Effect of cocaine on the coronary circulation and systemic hemodynamics in dogs

This study investigated the effect of intravenous cocaine (0.5 to 2 mg/kg body weight) on the coronary circulation and systemic hemodynamics in closed chest sedated dogs. The role of alpha- and beta-adrenoceptor stimulation in mediating these effects was also investigated. Cocaine produced dose-dependent increases in mean arterial pressure and rate-pressure product. Although the lower doses of cocaine had no significant effect on the coronary circulation, the 2 mg/kg dose produced a 55 +/- 14% increase in coronary vascular resistance (p less than 0.05 versus baseline) and a 19 +/- 3% reduction in diameter of the left anterior descending coronary artery (p less than 0.05 versus baseline). Despite these potentially deleterious effects on the coronary circulation (occurring at a time of markedly increased myocardial oxygen demand), the electrocardiogram did not demonstrate ischemic changes and there was no myocardial lactate production. Cocaine-induced coronary vasoconstriction was abolished by pretreatment with the alpha-adrenoceptor antagonist phentolamine, but not by pretreatment with the beta-adrenoceptor antagonist propranolol. The findings that cocaine did not change systemic vascular resistance in dogs without adrenergic blockade, reduced systemic vascular resistance in dogs after alpha-blockade (p less than 0.05) and increased systemic vascular resistance in dogs after beta-blockade (p = 0.06) suggest that epinephrine (rather than norepinephrine) is primarily responsible for the peripheral vascular actions of cocaine. Thus, in this canine preparation with normal coronary arteries, cocaine produced vasoconstriction of both epicardial and coronary resistance vessels that was not associated with evidence of myocardial ischemia. The pharmacologic mechanism for the effect of cocaine on the coronary circulation is alpha-adrenoceptor stimulation, whereas systemic hemodynamic effects are mediated by combined alpha- and beta-adrenoceptor stimulation.     

Review: Clinical Aspects of Vascular Remodeling

Vascular remodeling represents a spectrum of structural changes whereby the vascular wall responds to changes in its hemodynamic environment. Such changes may be classified as vessel enlargement (outward remodeling), diminution (inward remodeling), alternatively as adaptive (compensatory, appropriate to the hemodynamic stimulus), or maladaptive (dysfunctional, inappropriate). The direction and scale of remodeling are coordinated by endothelial production of growth factors, proteases, and cellular adhesion molecules in response to sensed changes in blood flow. In early atherosclerosis, outward remodeling preserves lumen size. Although protective in the long-term, the matrix degradation involved in this process may predispose atherosclerotic plaques to rupture, hence increasing the risks of acute coronary syndromes. Inward remodeling also occurs in advanced atherosclerotic lesions, whereby the vessel shrinks rather than enlarging, exacerbating rather than ameliorating stenosis. In transplant coronary artery disease, early inward remodeling may be a more important component of vessel stenosis than intimal thickening, while inappropriate inward remodeling appears to be as least as important as excessive intimal growth in the development of restenosis after angioplasty. Increased awareness of vascular remodeling, and in particular its malaptive forms, may provide new therapeutic insights for the future.     

Neuronal control of coronary blood flow

Controversies on acetylcholine-induced increases or decreases in coronary blood flow arise from obvious species differences, the role of endothelium in mediating vascular smooth muscle responses, and the marked negative chronotropic and inotropic effects of acetylcholine. In man, there appears to be a predominant dilation of intact epicardial coronary arteries and a constriction of artherosclerotic segments. However, at present there is no evidence for a vagal initiation of myocardial ischemia. Coronary vascular β-adrenergic receptors mediate dilation, but appear to be functionally insignificant during sympathetic activation. The β-adrenergic mechanism contributing to myocardial ischemia are indirect, mediated by a tachycardia-related redistribution of blood flow away from the ischemic myocardium. α-Adrenergic receptors mediating epicardial coronary artery constriction in experimental studies appear not to be responsible for the initiation of ischemia in patients with angina at rest. However, α-adrenergic constriction of coronary resistance vessels resulting in the precipitation of poststenotic myocardial ischemia was demonstrated in experimental studies and recently confirmed in patients with effort angina. Non-adrenergic, non-cholinergic neurotransmitters exist; however, their role in regulating coronary blood flow remains entirely unclear.     

Effect of 8-bromo-cyclic guanosine monophosphate (cGMP) on coronary artery constriction in isolated rabbit hearts

The vasodilator 8-bromo-guanosine 3':5'-monophosphate (8-bromo-cGMP) effectively counteracts vasopressin-induced coronary artery constriction in a supported perfused working rabbit heart. In this preparation, the coronary arteries remain in contact with the beating heart. The obtuse marginal artery and portions of the left anterior descending coronary artery were deprived of endothelium. Perfusion was carried out with Krebs-Henseleit solution, oxygenated with a disposable infant oxygenator. The internal diameter of large coronary arteries was determined by color arteriography (injection of patent blue dye and gated photography). The effect of vasopressin with and without the addition of 8-bromo-cGMP on cardiac performance (cardiac output, left ventricular systolic pressure, left ventricular end-diastolic pressure, maximal rate of rise in left ventricular pressure [dP/dtmax], mean aortic pressure) and large coronary vessel and total coronary vascular resistance was determined in nine experiments. In addition, changes in coronary sinus partial pressure of carbon dioxide (PCO2) and pH were observed. Vasopressin alone caused a significant decline in coronary flow, myocardial oxygen consumption and coronary sinus pH. Cardiac performance declined, probably because of myocardial ischemia. Large coronary vessel and total coronary vascular resistance rose. The vasodilator 8-bromo-cGMP strongly inhibited the vasoconstrictor action of vasopressin, counteracted the increase in large and total coronary vascular resistance, prevented the fall in myocardial oxygen consumption and eliminated changes in pH or PCO2 of coronary sinus effluent. Because of the elimination of myocardial ischemia by 8-bromo-cGMP, cardiac performance was normalized.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional coronary microvascular injury evident as increased permeability due to brief ischemia and reperfusion

Although morphological studies suggest that coronary vascular injury is a result of prolonged ischemia and subsequent reperfusion, whether functional coronary microvascular injury develops during brief in vivo ischemia is unclear. In other organs, permeability is a sensitive indicator of functional vascular injury. Therefore, a new double-indicator method of assessing vascular protein permeability, a method that is both sensitive and specific for vascular injury, was used to investigate the effects of ischemia of graded duration followed by reperfusion on coronary microvascular function. To help confirm functional coronary vascular injury, endothelium-dependent vasodilation of isolated coronary vascular rings also was examined. Microvascular permeability was quantitatively assessed as a protein leak index by measuring the rate of extravascular accumulation of radiolabeled protein (indium 113m transferrin) normalized for vascular surface area (technetium 99m erythrocytes). Anesthetized dogs underwent 0 (control), 15, 30, or 60 minutes of left anterior descending coronary artery occlusion followed by 60 minutes of reperfusion. Even 15 minutes of ischemia increased the protein leak index by 50% (3.16 +/- 0.30 ischemic vs. 2.09 +/- 0.11 control). Longer periods of ischemia increased the protein leak index in proportion to the duration of ischemia. The protein leak index increased threefold (6.51 +/- 0.60) after 60 minutes of ischemia. At each duration of ischemia, there was significant regional variation in the protein leak index that correlated with the severity of ischemic blood flow to that region measured with microspheres. Endothelial injury also was evident after 15 and 30 minutes of ischemia as impaired vasodilation of isolated coronary rings in response to the endothelium-dependent vasodilators acetylcholine and the calcium ionophore A23187. Electron microscopy and in vitro direct immunofluorescence revealed evidence of vascular injury after 60 minutes but not after 15 minutes of ischemia. We conclude that even brief ischemia and reperfusion cause functional coronary vascular injury evident as increased microvascular permeability and impaired endothelium-dependent vasodilation and that regional differences in the degree of microvascular injury correlate with differences in the severity of ischemia.     

Molecular mechanisms of increased intrahepatic resistance in portal hypertension

Portal hypertension is associated with changes in the intrahepatic, systemic, and portosystemic collateral circulation. Alterations in vasoreactivity (vasodilation and vasoconstriction) play a central role in the pathogenesis of portal hypertension by contributing to increased intrahepatic resistance, hyperdynamic circulation, and expansion of the collateral circulation. Portal hypertension is also importantly characterized by changes in vascular structure; termed vascular remodeling, which is an adaptive response of the vessel wall that occurs in response to chronic changes in the environment such as shear stress. These complementary processes of vasoreactivity and vascular remodeling contribute importantly to increased intrahepatic resistance and represent important targets in the treatment of portal hypertension. This review will focus on these processes within the intrahepatic circulation, a circulatory bed whose study, that Dr Roberto Groszmann has pioneered.     

Effects of cardiovascular risk factors on coronary artery remodeling in patients with mild atherosclerosis

BACKGROUND: Vascular remodeling counteracts luminal encroachment during the progression of coronary artery disease (CAD) and modulates the manifestation of hemodynamically significant lesions. However, the role of cardiovascular risk factors for coronary remodeling has not been fully clarified. METHODS: Therefore, we investigated the role of local plaque burden and systemic risk factors on coronary vascular remodeling in 25 patients (49 segments) with angiographically normal or minimally diseased coronary arteries by intravascular ultrasound. In an additional 12 patients without coronary atherosclerosis, physiological vessel tapering was determined and used to calculate the extent of remodeling in diseased segments. RESULTS: An increase in local plaque burden was directly correlated with positive vascular remodeling (r = 0.54, P<0.001). However, cardiovascular risk factors like hypertension (P<0.001) and hypercholesterolemia (P = 0.03) were associated with reduced positive or even negative remodeling. Moreover, the total number of classical cardiovascular risk factors was a strong predictor for reduced positive remodeling (P for trend <0.001). In contrast, coronary flow reserve, a measure of shear stress imposed on the vessel wall, positively correlated with compensatory enlargement (r = 0.44, P = 0.002). By multivariate analysis, plaque burden (P = 0.001), hypertension (P = 0.001) and coronary flow reserve (P = 0.018) proved to be independent determinants of vascular remodeling of epicardial coronary arteries. CONCLUSIONS: Cardiovascular risk factors impair compensatory arterial enlargement and even predispose to shrinkage of epicardial arteries during the initial stage of atherosclerosis. Reduced positive vascular remodeling might contribute to the clinical manifestation of CAD by facilitating the development of flow-limiting stenoses in patients at risk.     

Role of inflammation in the regulation of coronary blood flow in ischemia and reperfusion: mechanisms and therapeutic implications

A multitude of factors, including increased coronary vascular resistance and dysregulated coronary microcirculatory function, contribute to the impairment of coronary blood flow (CBF) regulation and the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. CBF is primarily determined by coronary vascular resistance, which is affected by the balance between various vasodilators and vasoconstrictors. Myocardial I/R causes reduced production of endogenous vasodilators, such as nitric oxide (NO), leaving unopposed vasoconstriction that is caused mainly by continued presence of endothelin-1 (ET-1) and serotonin (5-HT); this imbalance in turn enhances vascular tone, triggers inflammatory response, decreases CBF and exacerbates reperfusion injury. Various inflammatory cytokines participate in the regulation of coronary vasomotor function by affecting the balance between vasodilators and vasoconstrictors. In addition to the enhanced coronary vasoconstriction, coronary microembolization, inflammatory cell infiltration and post-ischemic hyperpermeability contribute to the impairment of coronary microcirculatory function and myocardial perfusion during I/R. Ongoing research examining the role of inflammation in the regulation of CBF and coronary microcirculatory function in myocardial I/R is expected to yield new insights that will lead to therapies for ameliorating the vascular inflammatory response in coronary artery diseases (CADs) in the clinical setting. This article is part of a Special Issue entitled "Coronary Blood Flow".     

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.     

Understanding the coronary circulation through studies at the microvascular level

Studies of the coronary circulation have divided vascular resistances into three large components: large vessels, small resistance vessels, and veins. Studies of the epicardial microcirculation in the beating heart using stroboscopic illumination have suggested that resistance is more precisely controlled in different segments of the circulation. Measurements of coronary pressure in different sized arteries and arterioles have indicated that under normal conditions, 45-50% of total coronary vascular resistance resides in vessels larger than 100 microns. This distribution of vascular resistance can be altered in a nonuniform manner by a variety of physiological (autoregulation, increases in myocardial oxygen consumption, sympathetic stimulation) and pharmacological stimuli (norepinephrine, papaverine, dipyridamole, serotonin, vasopressin, nitroglycerin, adenosine, and endothelin). Studies of exchange of macromolecules in the microcirculation using fluorescent-labeled dextrans have also identified the size of the small pore (35-50 A) in coronary microvessels that can be altered by myocardial ischemia. Studies of the coronary microcirculation have demonstrated that the control of vascular resistance is extremely complex, and mechanisms responsible for these heterogeneous responses need further examination.