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Background: Transplant coronary arteriosclerosis (TCA) is the principal long-term complication in cardiac transplant recipients. The mediators responsible for vascular proliferation and vasoconstriction typical of TCA remain largely unknown. We tested whether endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, contributes to the pathogenesis and manifestations of TCA., Methods and Results: BQ-123, an ET-1 receptor-A antagonist, was infused into a coronary artery (40 nmol/min for 60 minutes) of 18 subjects, 6 + or - 4 years after transplantation. Vasomotor responses were measured in the infused artery and in a noninfused control artery in patients with (n=10) and without (n=8) advanced TCA (108 total coronary segments). Changes in diameters were compared at 15-minute intervals up to 60 minutes. Contribution of ET-1 to coronary constrictor tone was assessed by comparing vasodilation from BQ-123 with that of the maximal vasodilator nitroglycerin (200-microg intracoronary bolus). BQ-123 dilated coronary arteries of transplanted patients (8.4% at 60 minutes versus -0.4% in noninfused arteries, P<0.001). Dilation was greater for arteries with advanced TCA defined as diameter stenosis > or = 15% (dilation 15.2% with versus 0.6% without advanced TCA, P=0.004). Judged against the response to nitroglycerin, ET-1 accounted for 53.2% of coronary tone in advanced TCA but only 12.9% without advanced TCA., Conclusions: This study shows for the first time in humans that ET-1 is an important mediator of coronary vasoconstriction in TCA and accounts for >50% of the increased vasomotor tone. Therapeutic targeting of ET-1 may retard the development of TCA.

Objectives: To determine whether gadolinium-DTPA (Gd-DTPA) facilitates discrimination of fibrous, lipid or calcified constituents during intravascular magnetic resonance imaging (IVMRI) of human atherosclerotic arteries., Background: Atherosclerotic plaques that cause fatal thrombosis due to rupture have high content of lipid relative to fibrous tissue. We recently demonstrated that IVMRI identifies lipid, fibrous, and calcified components within atherosclerotic human arteries with favorable sensitivity and specificity. Gd-DTPA, a T1-shortening agent, selectively amplifies the signal from fibrous tissue on T1 weighted (T1w) surface MRI., Methods: A 0.030 in. diameter receiver coil coupled to a 1.5T MR scanner was positioned in iliac arteries of nine subjects with atherosclerosis. Previously validated multi-parametric analysis of T1w and moderate T2w images identified 137 fibrous, lipid and calcified regions of interest within 37 arterial segments. T1w imaging was repeated following 0.1 mmol/kg IV Gd-DTPA infusion., Results: Computer-derived mean gray value in fibrous regions increased by 34.2% with Gd-DTPA (95% CI 24.3-43.5%, p=0.0001) while lipid and calcified regions showed only a non-significant increase of 4.3% (95% CI -0.6 to 9.2%, p=0.0825) and 3.8% (95% CI -1.1 to 7.7%, p=0.103), respectively. The increase in mean gray value with Gd-DTPA was greater for fibrous than for lipid or calcified regions (p=0.0001)., Conclusions: Gd-DTPA selectively enhances signal intensity of fibrous constituents during IVMRI of human atherosclerotic arteries and thus identifies key tissue characteristics associated with plaque stability. These findings have important implications for the assessment of plaque-stabilizing therapies and ultimately for reducing cardiovascular events.

Background: Excessive vascular oxidant stress has been implicated in cardiac transplant-associated arteriosclerosis (TxAA). In a recent placebo-controlled study of 40 cardiac transplant recipients, vitamin C 500 mg twice a day and vitamin E 400 IU twice a day for 1 year retarded the progression of TxAA, as assessed by intravascular ultrasound (IVUS). Endothelial dysfunction is a key feature of TxAA and reflects oxidant stress. We hypothesized that coronary endothelial dysfunction portends greater TxAA progression and a larger therapeutic response to anti-oxidant vitamins., Methods: In this pre-specified analysis, the 40 cardiac transplant recipients were categorized according to normal or abnormal coronary endothelial vasomotor function at baseline, as assessed by acetylcholine (10(-8) to 10(-6) mol/liter). The effect of anti-oxidant vitamins within these two groups of patients was assessed by the change in intimal index over 1 year using IVUS., Results: With placebo (n = 21), the increase in intimal index was greater in the presence vs absence of endothelial dysfunction (11 +/- 3% vs 5 +/- 1%, p < 0.05). Among patients with endothelial dysfunction (n = 21), the intimal index increased 11 +/- 3% with placebo, but decreased -1 +/- 2% with vitamins (p = 0.002). Among patients with normal endothelial function (n = 14), the intimal index increased 5 +/- 1% with placebo and 1 +/- 1% with vitamins (p < 0.05)., Conclusions: Endothelial dysfunction indicates rapid TxAA progression, even in the statin era. Although anti-oxidant vitamins reduce disease progression in patients with normal or abnormal endothelial function, the magnitude of benefit is larger in patients with endothelial dysfunction.

Background: Development and validation of novel imaging modalities to assess the composition of human atherosclerotic plaques will improve the understanding of atheroma evolution and could facilitate evaluation of therapeutic strategies for plaque modification. Surface MRI can characterize tissue content of carotid but not deeper arteries. This study evaluated the usefulness of intravascular MRI (IVMRI) to discern the composition of human iliac arteries in vivo., Methods and Results: Initial studies validated IVMRI against histopathology of human atherosclerotic arteries ex vivo. A 0.030-inch-diameter IVMRI detector coil was advanced into isolated human aortoiliac arteries and coupled to a 1.5-T scanner. Information from combined T1-, moderate T2-, and proton-density-weighted images differentiated lipid, fibrous, and calcified components with favorable sensitivity and specificity and allowed accurate quantification of plaque size. The validated approach was then applied to image iliac arteries of 25 human subjects in vivo, and results were compared with those of intravascular ultrasound (IVUS). IVMRI readily visualized inner and outer plaque boundaries in all arteries, even those with extensive calcification that precluded IVUS interpretation. It also revealed the expected heterogeneity of atherosclerotic plaque content that was noted during ex vivo validation. Again, IVUS did not disclose this heterogeneity. The level of interobserver and intraobserver agreement in the interpretation of plaque composition was high for IVMRI but poor for IVUS., Conclusions: IVMRI can reliably identify plaque composition and size in arteries deep within the body. Identification of plaque components by IVMRI in vivo has important implications for the understanding and modification of human atherosclerosis.

Background: Atherosclerotic lesions are mainly composed of macrophages and T lymphocytes. Specific T helper type 1 (Th1) cytokines and interferon gamma (IFN-gamma) inducible chemokines have been shown to be present in these lesions, modulating the local immunologic response. To explore whether this increase in Th1 activity could also be detected in circulating cells indicating a systemic activation, we studied the peripheral expression of Th1 cytokines and chemokines in patients with coronary artery disease and controls., Methods and Results: Fifty patients with coronary artery disease (25 with unstable angina and 25 with stable angina) and 10 controls were studied. Serum interleukin (IL)-12 and IFN-gamma and the expression of IFN-gamma inducible chemokines IP-10, Mig and their receptor CXCR3 in peripheral cells were analyzed. Serum IL-12 and intracellular expression of IFN-gamma were significantly elevated in patients with unstable angina. An enhanced expression of IFN-gamma chemokines IP-10, Mig and CXCR3 in patients with stable angina was also observed., Conclusions: This study demonstrates an increased systemic inflammatory activity in patients with coronary heart disease with a predominant Th1 response, particularly in patients with unstable angina, suggesting an important role played by this polarization in plaque formation and rupture., (Copyright 2004 Elsevier Ltd.)

Objective: Laminar flow becomes disturbed at high velocities, reducing shear stress and augmenting vascular inflammation and proliferation, processes that are pivotal in restenosis and atherogenesis. We hypothesized that disturbed blood flow after coronary angioplasty is associated with adverse long-term clinical outcome., Methods and Results: The cineangiograms from 97 patients undergoing laser-assisted coronary angioplasty were analyzed. Coronary blood flow velocity, the residual lesion dimensions, and the Reynolds number (an index of disturbed flow) were measured by using a frame-counting technique and quantitative coronary angiography. Cox proportional hazards were used to assess the relative risk of adverse events (target-vessel revascularization, myocardial infarction, or death) over a mean 2.5 years after the index procedure. There were 41 adverse events during 245 patient years of follow-up (17% per year of follow-up). The risk of an adverse event was increased for patients with a high flow velocity (>250 mm/s; relative risk 2.5, 95% CI 1.3 to 4.7) or a high Reynolds number (>200) at the stenosis inlet (relative risk 2.1, 95% CI 1.1 to 4.1) at the end of the procedure. Adjustment for other factors did not alter these results., Conclusions: High Reynolds numbers, indicating disturbed blood flow after coronary angioplasty, increase the risk of adverse clinical events, potentially through shear-stress-related molecular mechanisms that promote restenosis and atherogenesis.

Background: Cardiac transplantation is associated with oxidant stress, which may contribute to the development of accelerated coronary arteriosclerosis. We postulated that treatment with antioxidant vitamins C and E would retard the progression of transplant-associated arteriosclerosis., Methods: In a double-blind prospective study, 40 patients (0-2 years after cardiac transplantation) were randomly assigned vitamin C 500 mg plus vitamin E 400 IU, each twice daily (n=19), or placebo (n=21) for 1 year. The primary endpoint was the change in average intimal index (plaque area divided by vessel area) measured by intravascular ultrasonography (IVUS). Coronary endothelium-dependent vasoreactivity was assessed with intracoronary acetylcholine infusions. IVUS, coronary vasoreactivity, and vitamin C and E plasma concentrations were assessed at baseline and at 1 year follow-up. All patients received pravastatin. Analyses were by intention to treat., Findings: Vitamin C and E concentrations increased in the vitamin group (vitamin C 43 [SD 21] to 103 [43] mmol/L; vitamin E 24 [14] to 65 [27] mmol/L) but did not change in the placebo group (vitamin C 45 [15] vs 43 [16] mmol/L; vitamin E 27 [14] vs 27 [9] mmol/L; p<0.0001 for difference between groups). During 1 year of treatment, the intimal index increased in the placebo group by 8% (SE 2) but did not change significantly in the treatment group (0.8% [1]; p=0.008). Coronary endothelial function remained stable in both groups., Interpretation: Supplementation with antioxidant vitamins C and E retards the early progression of transplant-associated coronary arteriosclerosis.

Background: Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries., Methods and Results: In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ET(A) receptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 microgram). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes, P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes, P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes, P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01)., Conclusions: ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia.

Percutaneous coronary interventions (PCIs) play an increasingly important role in the management of patients with coronary artery disease. However, these important procedures are complicated by restenosis in a sizeable number of patients. The pathobiology of atherosclerosis comprises a complex interaction among lipids, the endothelium, circulating and tissue inflammatory cells, platelets, and vascular smooth muscle cells. The superimposition of the mechanical and cellular consequences of PCIs on the abnormal substrate of atherosclerosis leads to a characteristic and distinct pathobiology that initiates and perpetuates restenosis. A clear understanding of the significant differences between atherosclerosis and restenosis will provide a rational basis for developing treatment plans that always address both problems. This article reviews and contrasts the pathobiology of atherosclerosis and restenosis and compares the mechanisms and time-course of these distinct entities.

Atherosclerosis is often asymptomatic, unrecognized, and undertreated. Lumen irregularities are important angiographic findings that should be addressed aggressively through risk factor modification, medical therapy, and coronary revascularization. Both angiographic and clinical benefits have been demonstrated with lipid reduction therapy in randomized clinical trials. Coronary revascularization is indicated for symptom relief and improvement in quality of life in patients with acute coronary syndromes at "intermediate" and "high" risk of subsequent death or myocardial infarction. In patients following percutaneous coronary intervention (PCI), future cardiac events may be related to lumen renarrowing or to progression of atherosclerotic disease at sites remote from the site of coronary revascularization. The time course of restenosis is relatively self-limiting, generally occurring within 6-12 months after the procedure. Clinical events occurring > 1 year after PCI generally relate to new lesions or progression of existing atherosclerotic disease. Patients with diabetes mellitus may be at higher risk for late coronary events than nondiabetic patients. In post-coronary artery bypass surgery (CABG) patients, the majority of late events relate to degeneration of saphenous vein grafts. Lipid lowering therapy after coronary revascularization has been shown to prevent clinical events related to plaque instability and inhibit progression of saphenous vein graft disease. Thus, there are 2 goals in management of patients with symptomatic coronary artery disease: (1) to relieve the flow-limiting stenosis, and (2) to prevent future clinical events with aggressive lipid lowering and modification of other risk factors. Patients, specialists, and primary care physicians each need to take accountability for this risk-factor modification.

Obstructive coronary artery disease is the most common cause of morbidity and mortality in the developed world. Our understanding of the pathobiology of coronary atherosclerosis provides us with new opportunities to reduce myocardial ischemia by interventions that address these mechanisms directly. These interventions include lipid-lowering therapies that improve local coronary vasomotion, inflammation, and the procoagulant state. These interventions have also been shown to result in important reductions in clinical events, including angina pectoris, myocardial ischemia and infarction, and death. Ambulatory electrocardiography provides a versatile and quantifiable measure of regional myocardial ischemia. Reductions in ischemia, as quantified by this diagnostic modality, are associated with improved clinical outcomes that may reflect improvements in the cellular pathophysiology of coronary atherosclerosis. This review discusses new information regarding the interactions between low-density lipoprotein cholesterol, the cell biology of atherosclerosis, and the activity of ischemia in patients with coronary artery disease.

Background: In the presence of atherosclerosis, the coronary endothelial vasomotor response to acetylcholine is frequently abnormal but is variable between patients. We tested the hypothesis that the plasma concentration of alpha-tocopherol is associated with the preservation of nitric oxide-mediated endothelium-dependent vasomotion., Methods and Results: We studied 15 men and 6 women (mean age 61+/-10 years) at coronary angiography who were not taking vitamin supplements. Coronary endothelium-dependent and -independent vasomotion was assessed by intracoronary infusions of acetylcholine and nitroglycerin. The vasomotor responses were compared with the plasma concentration of alpha-tocopherol and the plasma alpha-tocopherol concentration relative to total lipid (total cholesterol plus triglycerides). The mean plasma alpha-tocopherol was 25.6+/-6.1 micromol/L, total cholesterol 193+/-27 mg/dL, triglycerides 115+/-66 mg/dL, and alpha-tocopherol to total lipid 4. 2+/-0.9 micromol. L(-1). (mmol/L)(-1). The mean vasomotor response to acetylcholine was -1% (range -33% to 28%) and to nitroglycerin 22% (range 0% to 54%). Plasma alpha-tocopherol was significantly correlated with the acetylcholine response (r=0.49, P<0.05) but not the nitroglycerin response (r=0.13, P>0.05). The acetylcholine response remained significant after adjustment for other potential sources of oxidant stress (total cholesterol, diabetes mellitus, smoking, angina class) (P<0.01). The relative concentration of alpha-tocopherol to total lipid was not related to endothelial function (r=0.24, P=0.3, n=20)., Conclusions: alpha-Tocopherol may preserve endothelial vasomotor function in patients with coronary atherosclerosis. This effect may be related primarily to the action of alpha-tocopherol in the vascular wall. Further studies that assess the impact of alpha-tocopherol supplementation as therapy of endothelial dysfunction are justified.

Emerging evidence is redefining traditional concepts of coronary atherosclerosis. Recent data indicate that severe stenoses, the traditional focus of attention, do not cause most coronary events. Rather, interest has increased in the often less stenotic but more vulnerable lesions that are characterized by thin fibrous caps, large lipid accumulations, large numbers of macrophages, and depletion of smooth muscle cells. Such lesions appear prone to rupture, which allows the blood to come into contact with the highly thrombogenic material in the lipid core of the plaque, thereby precipitating thrombosis. The fibrous cap may become weakened through decreased synthesis of the extracellular matrix or increased degradation of the matrix. The cytokine interferon-gamma, produced by T-lymphocytes, inhibits the ability of smooth muscle cells to synthesize collagen, a structurally important component of the fibrous cap. A family of enzymes known as matrix metalloproteinases can degrade all major constituents of the vascular extracellular matrix: collagen, elastin, and proteoglycans. Additional studies on the biochemical mechanisms of atherosclerosis may provide a fuller understanding of the ways in which lipid-lowering therapy can confer clinical benefit.

Background: Accelerated coronary arteriosclerosis is the major obstacle to long-term survival after cardiac transplantation. Endothelial dysfunction is common early posttransplant. The relationship between early endothelial dysfunction and the development of allograft arteriosclerosis has not been analyzed serially with intravascular ultrasound in the same patients. We hypothesized that an early constrictor response to acetylcholine, indicative of endothelial dysfunction, may predict the development of transplant coronary arteriosclerosis., Methods and Results: Endothelium-dependent vasomotion was assessed early posttransplant in 20 patients by serial intracoronary acetylcholine infusion, and the percent change in diameter was measured by quantitative angiography. The development of arteriosclerosis was studied by use of intravascular ultrasound in the same 20 patients by quantifying the changes in intimal index (delta Ii) and maximal intimal thickness [delta Mt] of 46 matched coronary segments between initial and 1-year follow-up studies. Coronary segments with endothelial dysfunction (constriction > or = 5%; n = 23) demonstrated a significantly greater increase in mean Ii and Mt by 1 year posttransplant compared with segments with normal endothelial function (n = 23) (delta Ii = 7 +/- 2% versus 2 +/- 1% [P < .05] and delta Mt = 140 +/- 40 versus 50 +/- 20 microns [P < .05]). No other parameters examined predicted the development of allograft arteriosclerosis in the initial year posttransplant., Conclusions: Paired studies that used intravascular ultrasound showed that early endothelial dysfunction predicts the development of allograft arteriosclerosis during the initial year posttransplant. This early pathophysiological feature is likely an important marker that could be useful in therapeutic trials.

Background: Patients with coronary artery disease and abnormalities of serum lipids often have endothelial vasodilator dysfunction, which may contribute to ischemic cardiac events. Whether cholesterol-lowering or antioxidant therapy can restore endothelium-dependent coronary vasodilation is unknown., Methods: We randomly assigned 49 patients (mean serum cholesterol level, 209 +/- 33 mg per deciliter [5.40 +/- 0.85 mmol per liter]) to receive one of three treatments: an American Heart Association Step 1 diet (the diet group, 11 patients); lovastatin and cholestyramine (the low-density lipoprotein [LDL]-lowering group, 21 patients); or lovastatin and probucol (the LDL-lowering-antioxidant group, 17 patients). Endothelium-dependent coronary-artery vasomotion in response to an intracoronary infusion of acetylcholine (10(-8) to 10(-6) M) was assessed at base line and after one year of therapy. Vasoconstrictor responses to these doses of acetylcholine are considered to be abnormal., Results: Treatment resulted in significant reductions in LDL cholesterol levels of 41 +/- 22 percent in the LDL-lowering-antioxidant group and 38 +/- 20 percent in the LDL-lowering group (P < 0.001 vs. the diet group). The maximal changes in coronary-artery diameter with acetylcholine at base line and at follow-up were -19 and -2 percent, respectively, in the LDL-lowering-antioxidant group, -15 and -6 percent in the LDL-lowering group, and -14 and -19 percent in the diet group (P < 0.01 for the LDL-lowering-antioxidant group vs. the diet group; P = 0.08 for the LDL-lowering group vs. the diet group). (The negative numbers indicate vasoconstriction). Thus, the greatest improvement in the vasoconstrictor response was seen in the LDL-lowering-antioxidant group., Conclusions: The improvement in endothelium-dependent vasomotion with cholesterol-lowering and antioxidant therapy may have important implications for the activity of myocardial ischemia and may explain in part the reduced incidence of adverse coronary events that is known to result from cholesterol-lowering therapy.

Coronary vasomotion is influenced by a variety of factors, including atherosclerosis and diurnal variations in alpha-adrenergic tone. The effect of such factors on the coronary response to vasodilator drugs is unknown. To determine whether there is a diurnal variation to the response of coronary arteries to nifedipine, and whether this response is altered by atherosclerosis, we studied 11 patients with smooth coronary arteries, six in the morning and five in the afternoon, and 12 patients with irregular coronary arteries, six in the morning and six in the afternoon. Changes in coronary blood flow and the vasomotor response of an epicardial coronary artery were measured before and after a 2 mg intracoronary infusion of nifedipine. There were no appreciable differences in epicardial vessel dilator response or coronary blood flow in the morning and afternoon among patients with smooth coronary arteries. By contrast, patients with irregular coronary arteries had a significantly diminished dilator response in the afternoon, without an appreciable change in coronary blood flow. We postulate that normal coronary arteries maintain basal tone throughout the day. By contrast, atherosclerotic coronary arteries cannot do the same, increasing tone in the morning in response to catecholamines. When catecholamine levels drop in the afternoon, basal tone decreases in atherosclerotic vessels, and the dilator response to nifedipine is blunted. This observation may have an important impact on the expected benefits and timing of vasodilator therapy in patients with coronary artery disease.

Background: Studies in patients undergoing cardiac catheterization have demonstrated that normal coronary arteries dilate and atherosclerotic arteries constrict in response to exercise and the cold pressor test, but the mechanisms are unknown. These vasomotor responses are mirrored by the vasomotor response to the endothelium-dependent agent acetylcholine. Exercise and the cold pressor test are associated with adrenergic stimulation and increased circulating catecholamines. The present study tested the hypothesis that coronary arteries with intact endothelial function are relatively resistant to the constrictor effects of catecholamines, whereas arteries with loss of endothelial function have increased sensitivity to catecholamine-induced constriction., Methods and Results: The vasomotor function of the coronary endothelium was assessed by serial acetylcholine infusions (final concentration, 10(-8) to 10(-6) M) in 30 segments in 15 patients with minimal or no evidence of coronary atherosclerosis. The acetylcholine responses were related to the vasomotor response to intracoronary phenylephrine infusion (final concentration, 10(-9) to 10(-6) M) in the same segments. In the group of 18 segments that constricted to acetylcholine, there was a constrictor response to phenylephrine at an approximately 100-fold lower concentration than the group of 12 segments that did not constrict to acetylcholine., Conclusions: These results suggest that the endothelial dysfunction that characterizes early and late atherosclerosis is associated with a marked increase in sensitivity to the constrictor effects of catecholamines. This finding may explain the constrictor responses of atherosclerotic coronary arteries to exercise and the cold pressor test. In stenotic coronary arteries this mechanism may play a role in the production of myocardial ischemia.

Background: Mental stress can cause angina in patients with coronary artery disease, but its effects on coronary vasomotion and blood flow are poorly understood. Because atherosclerosis affects the reactivity of coronary arteries to various stimuli, such as exercise, we postulated that atherosclerosis might also influence the vasomotor response of coronary arteries to mental stress., Methods: We studied 26 patients who performed mental arithmetic under stressful conditions during cardiac catheterization. (An additional four patients who did not perform the mental arithmetic served as controls.) Coronary segments were classified on the basis of angiographic findings as smooth, irregular, or stenosed. In 15 of the patients without focal stenoses in the left anterior descending artery, acetylcholine (10(-8) to 10(-6) mol per liter) was infused into the artery to test endothelium-dependent vasodilation. Changes in coronary blood flow were measured with an intracoronary Doppler catheter in these 15 patients., Results: The response of the coronary arteries to mental stress varied from 38 percent constriction to 29 percent dilation, whereas the change in coronary blood flow varied from a decrease of 48 percent to an increase of 42 percent. The direction and magnitude of the change in the coronary diameter were not predicted by the changes in the heart rate, blood pressure, or plasma norepinephrine level. Segments with stenoses (n = 7) were constricted by a mean (+/- SE) of 24 +/- 4 percent, and irregular segments (n = 20) by 9 +/- 3 percent, whereas smooth segments (n = 25) did not change significantly (dilation, 3 +/- 3 percent; P less than 0.0002). Coronary blood flow increased by 10 +/- 10 percent in smooth vessels, whereas the flow in irregular vessels decreased by 27 +/- 5 percent. The degree of constriction or dilation during mental stress correlated with the response to the infusions of acetylcholine (P less than 0.0003, r = 0.58)., Conclusions: Atherosclerosis disturbs the normal vasomotor response (no change or dilation) of large coronary arteries to mental stress; in patients with atherosclerosis paradoxical constriction occurs during mental stress, particularly at points of stenosis. This vasomotor response correlates with the extent of atherosclerosis in the artery and with the endothelium-dependent response to an infusion of acetylcholine. These data suggest that in atherosclerosis unopposed constriction caused by a local failure of endothelium-dependent dilation causes the coronary arteries to respond abnormally to mental stress.

Background: Four sets of monkeys were used to examine the effect of chronic psychosocial disruption and diet on dilator responses of coronary arteries., Methods and Results: One set consisted of monkeys consuming monkey chow and living in a stable social setting (nonatherosclerotic controls, n = 6). Three sets consumed an atherogenic diet for 14 months followed by one of three treatments for the next 16 months: 1) a high-cholesterol diet and housed in unstable social groups (n = 9); 2) a low-cholesterol diet and housed in unstable (n = 8); or 3) stable groups (n = 10). Quantitative coronary angiography revealed that intracoronary infusion of acetylcholine resulted in a change of diameter (versus infusion of 5% dextrose in water) of +4 +/- 1% in control monkeys and -11 +/- 4% in unstable monkeys consuming a high-cholesterol diet (p less than 0.05). In monkeys consuming the cholesterol-lowering diet, the change in artery diameter was +2 +/- 4% in stable and -10 +/- 4% in unstable social conditions (p less than 0.05) despite a similar plaque size (0.4 +/- 0.2 and 0.5 +/- 0.1 mm2) and total plasma cholesterol concentrations (179 +/- 9 and 172 +/- 6 mg/dl), respectively. The arterial response to nitroglycerin was similar among all groups of monkeys., Conclusions: We conclude that chronic social disruption is associated with relative arterial constriction in response to acetylcholine in atherosclerotic monkeys consuming a cholesterol-lowering diet.

Patients with aortic stenosis develop widely variable patterns of left ventricular hypertrophy and dysfunction. We postulated that coronary atherosclerosis (CAD) may be associated with impaired left ventricular function and chamber dilatation in patients with aortic stenosis. Left ventricular mass and volumes were quantified from two-dimensional echocardiography and correlated with coronary angiography in 78 patients with severe aortic stenosis and no previous myocardial infarction or regional wall motion abnormalities. Eighteen patients (group 1) had smooth coronary arteries, 25 patients had irregular coronary arteries with 50% or less stenosis (group 2), and 35 patients had obstructive CAD (group 3). Even though the calculated valve area was similar in all three study groups, group 1 patients had higher values for ejection fraction (65 +/- 9%, 51 +/- 17%, and 48 +/- 13%; p = 0.0002), systolic mass-to-volume ratio (9.2 +/- 3.9, 5.6 +/- 2.8, and 5.2 +/- 2.2; p = 0.0001), and cardiac index (2.9 +/- 0.7, 2.5 +/- 0.7, and 2.3 +/- 0.6 l/min.min2; p = 0.015) than patients in groups 2 and 3, respectively (mean +/- SD). Mean circumferential wall stress was inversely related to severity of CAD. Multivariate analysis showed that CAD is an independent predictor of ejection fraction and mass-to-volume ratio in this group of patients. Thus, in an elderly population with severe aortic stenosis, patients with both obstructive and nonobstructive CAD have an increased incidence of left ventricular enlargement and systolic dysfunction.

Changes in blood flow can alter vasomotion of conduit arteries. This study examined vasomotor responses to incremental blood flow induced by papaverine in the epicardial arteries of 10 patients with angiographically normal coronary arteries (group 1) and in 14 patients with arterial irregularities (group 2) using quantitative angiography and Doppler ultrasound flow velocity measurements. An increase in coronary blood flow of 384.3 +/- 32.8% (p less than 0.001) in group 1 patients was associated with dilation of the proximal coronary artery segment and a 23.2 +/- 4.6% increase in cross-sectional area (p less than 0.001). In contrast, in group 2 patients a similar increase in coronary blood flow of 339.3 +/- 18.7% (p less than 0.001) was associated with mixed responses and a modest net constriction in cross-sectional area of -7.4 +/- 2.8% (p less than 0.05). The dilation response to nitroglycerin was intact in group 1 (31.7 +/- 4.2%, p less than 0.001) and in group 2 (26.4 +/- 3.2%, p less than 0.001). In five patients from group 1 acetylcholine, an endothelium-dependent dilator, produced an increase in cross-sectional area of 20.7 +/- 4.6% (p less than 0.05) that paralleled the response to an increase in flow in the same segment (a 24.3 +/- 6.1% increase in cross-sectional area, p less than 0.05). Five group 2 patients demonstrated a vasoconstrictor response to acetylcholine (a -22.8 +/- 3.4% decrease in cross-sectional area, p less than 0.05) together with an impaired dilation response to incremental flow (a -6.4 +/- 3.2% decrease in cross-sectional area).(ABSTRACT TRUNCATED AT 250 WORDS)

Vasodilation in normal and vasoconstriction in atherosclerotic coronary arteries have been observed in response to complex stimuli such as exercise and the cold pressor test. To study a single parameter that changes during these activities, and to better understand the pathophysiology of ischemia associated with increases in heart rate, we studied coronary vasomotion and blood flow response to increasing heart rate alone, produced by atrial pacing, with quantitative angiographic and Doppler flow-velocity measurements in 15 patients. In five patients with angiographically smooth coronary arteries (group 1), tachycardia produced progressive dilation of the epicardial artery with increases in cross-sectional area (CSA) of +15.5 +/- 3.4%, +22.4 +/- 2.1%, +28.5 +/- 3.3%, and +30.6 +/- 2.2% at 90, 110, 130, and 150 beats/min, respectively. In contrast, in five patients with mild angiographic narrowings (group 2), coronary segments failed to dilate with progressive tachycardia (-6.3 +/- 2.0%, -8.3 +/- 2.0%, -12.5 +/- 2.0%, and -11.4% at 90, 110, 130, and 150 beats/min, respectively), and progressive loss of luminal area was observed in five patients with severe angiographic narrowings (group 3) (-34.4 +/- 3.4%, -49.6 +/- 2.2%, -59.2%, and -72.8% at 90, 110, 130, and 150 beats/min, respectively). Coronary blood flow increased significantly with tachycardia in group 1 (+44.5 +/- 10.2%, +86.0 +/- 24.6%, +105.8 +/- 29.3%, and +137.5 +/- 46.0%), increased slightly in group 2 (+7.8 +/- 3.2%, +9.4 +/- 4.4%, +8.4 +/- 3.9%, and +10.0%), and decreased significantly in group 3 (-31.8 +/- 6%, -42.6 +/- 10.7%, -61.0%, and -70.0%). We conclude that an isolated increase in heart rate in patients with normal coronary arteries results in a modest increase in flow and vasodilation. In early atherosclerosis, the flow increase is blunted and dilation is replaced with paradoxical loss in luminal size. In patients with stenoses, further loss in luminal size occurs accompanied by a decrease in coronary blood flow. Thus, increasing heart rate alone in the setting of coronary stenoses could produce myocardial ischemia by a reduction in coronary supply, as well as by an increase in oxygen demand.

Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, acetylcholine constricts blood vessels. We tested the hypothesis that muscarinic cholinergic vasodilation is impaired in coronary atherosclerosis. Graded concentrations of acetylcholine and, for comparison, the nonendothelial-dependent vasodilator nitroglycerin were infused into the left anterior descending artery of eight patients with advanced coronary stenoses (greater than 50 percent narrowing), four subjects with angiographically normal coronary arteries, and six patients with mild coronary atherosclerosis (less than 20 percent narrowing). Vascular responses were evaluated by quantitative angiography. In several segments each of four normal coronary arteries, acetylcholine caused a dose-dependent dilation from a control diameter of 1.94 +/- 0.16 mm to 2.16 +/- 0.15 mm with the maximal acetylcholine dose (P less than 0.01). In contrast, all eight of the arteries with advanced stenoses showed dose-dependent constriction, from 1.05 +/- 0.05 to 0.32 +/- 0.16 mm at the highest concentration of acetylcholine (P less than 0.01), with temporary occlusion in five. Five of six vessels with minimal disease also constricted in response to acetylcholine. All vessels dilated in response to nitroglycerin, however. We conclude that paradoxical vasoconstriction induced by acetylcholine occurs early as well as late in the course of coronary atherosclerosis. Our preliminary findings suggest that the abnormal vascular response to acetylcholine may represent a defect in endothelial vasodilator function, and may be important in the pathogenesis of coronary vasospasm.

Increased vascular constriction has been observed at the site of atherosclerotic lesions, suggesting an association between atherosclerosis and altered vascular tone. While atherosclerosis may increase sensitivity to exogenous vasoconstrictors, little is known about the response of normal and atherosclerotic coronary arteries to an exogenous stimulus that excites the sympathetic nervous system. Therefore, we studied the response to cold pressor test (CPT) using quantitative angiography and Doppler flow velocity measurements in eight patients with angiographically normal coronary arteries (group I), nine patients with mild coronary atherosclerosis (less than 50% diameter narrowing) (group II), and 13 patients with advanced coronary stenoses (greater than 50% diameter narrowing) (group III). In 31 segments of angiographically smooth arteries in group I, the CPT produced vasodilation from a control mean diameter of 2.68 +/- 0.09 (mean +/- SE) to 2.99 +/- 0.09 mm at peak CPT (p less than 0.001), a 12 +/- 1% increase in diameter. In group II, 27 irregular segments constricted to peak CPT from a mean control diameter of 1.82 +/- 0.12 to 1.66 +/- 0.12 mm (p less than .001), a 9 +/- 1% decrease, while 10 smooth segments dilated from a mean control diameter of 1.98 +/- 0.11 mm to 2.34 +/- 0.15 mm (p less than .01), a 19 +/- 2% increase in diameter. Likewise, in group III, the 17 stenotic segments constricted from 1.16 +/- 0.09 to 0.89 +/- 0.09 mm (p less than .001), a 24 +/- 6% decrease; the irregular segments also constricted from 2.44 +/- 0.11 to 2.22 +/- 0.12 mm (p = .002), a 10 +/- 2% decrease. In contrast, two smooth segments dilated from 2.98 to 3.23 mm (mean), an 8% increase in diameter. Coronary blood flow increased 65 +/- 4% (mean) during CPT in group I, it increased 15 +/- 6% in group II, and it decreased 39 +/- 8% in group III. The vasodilator response in four normal patients was partly inhibited by the administration of intracoronary propranolol (17 +/- 3% increase during control, 10 +/- 2% increase after propranolol, 41% less dilation; p = .002). We conclude that the response of normal coronary arteries to the CPT test is dilation, in part related to beta-adrenoreceptor stimulation and possibly flow-mediated endothelial dilation or alpha 2-adrenergic activity. The paradoxical vasoconstrictor response induced by atherosclerosis may represent altered catecholamine sensitivity and/or a defect in endothelial vasodilator function. The presence of atherosclerosis impairs vasodilator responses and thus may contribute to the pathogenesis of myocardial ischemia.

Studies in animals have suggested that increases in blood flow result in dilation of large arteries by an endothelium-dependent mechanism. Atherosclerosis can impair endothelium-dependent vasodilation to vasoactive agents. The purpose of this study was to determine whether or not large coronary arteries in humans exhibit dilation with increases in blood flow and to test the hypothesis that this response is impaired in the presence of atherosclerosis. Graded concentrations of adenosine were infused into the distal left anterior descending (LAD) coronary artery to test the dilator response of the proximal LAD to increases in blood flow. The proximal LAD was thereby exposed to changes in blood flow, but not directly to adenosine. Ten patients with angiographically smooth proximal LAD segments (group 1) and seven patients with irregularities in the proximal LAD consistent with mild atherosclerosis (group 2) were studied. Infusions of adenosine throughout the range of 0.022 to 2.2 mg/min into the LAD produced a dose-dependent increase in estimated coronary blood flow and a mean increase of 305 +/- 27% at 2.2 mg/min adenosine. At 2.2 mg/min adenosine, a striking difference (p less than 0.001) occurred between the significant flow-mediated dilation of the proximal LAD observed in group 1 (+13.2 +/- 1.3% from 2.63 +/- 0.16 mm, p less than 0.001), and the lack of dilation in group 2 (+1.8 +/- 1.5% from 3.20 +/- 0.17 mm, p = NS), despite a greater increase in coronary blood flow in group 2 (+387 +/- 29%) than in group 1 (+230 +/- 36%).(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the vasomotion of epicardial coronary arteries during exercise and tested the hypotheses that abnormal vasoconstriction is related to the presence of atherosclerosis and may be related to endothelial dilator dysfunction. During cardiac catheterization quantitative coronary angiography was performed in 21 patients during supine bicycle exercise. 21 of 28 smooth, angiographically normal vessel segments dilated (14.0 +/- 1.8%) during exercise; four smooth segments did not change whereas only three constricted. In contrast, 15 of 16 vessel segments with irregularities constricted in response to exercise (17.0 +/- 0.1%) with only one segment dilating. All 10 stenotic segments constricted to exercise (23 +/- 4%). Six patients also received intracoronary acetylcholine before exercise to test endothelium-dependent dilator function. In five of six patients all nine vessel segments showed the same directional response to acetylcholine and exercise. Three irregular and two stenotic segments constricted with acetylcholine (51 +/- 21%) and exercise (9.0 +/- 0.6%). In contrast, four smooth segments dilated to acetylcholine (19 +/- 6%) and exercise (9 +/- 1%). Both exercise and acetylcholine generally dilated smooth but constricted irregular and stenosed coronary segments. It appears likely that atherosclerosis plays an important role in the abnormal vasomotion of diseased coronary arteries during exercise and the pattern of abnormality suggests impairment of vasodilator function.

Altered arterial wall shear stress may adversely affect vascular endothelium and contribute to atherogenesis. This study examined the hypothesis that, in humans, dilation of normal coronary arteries with increased flow limits increases in shear stress and that loss of flow-mediated dilation in atherosclerosis results in failure to control shear stress. Coronary blood flow was increased by infusing adenosine (0.022 to 2.2 mg/min) through a 2.5F Doppler flow catheter positioned in the middle segment of the left anterior descending coronary artery in 8 patients with mild atherosclerosis but no flow-limiting stenosis and in 10 patients with entirely smooth coronary arteries. Quantitative angiography and coronary flow velocity were used to estimate shear stress in a proximal segment of the left anterior descending artery exposed to increased flow, but not to adenosine. The peak increase in blood flow was the same in smooth (371 +/- 65%) and irregular (377 +/- 50%) arteries. However, at peak flow, dilation was greater in smooth segments (16.3 +/- 2.7%) than in irregular segments (2.0 +/- 1.5%) (p less than 0.001). In each patient, smooth segments dilated with increasing shear stress (slope 7.4 +/- 0.9%), whereas irregular segments dilated less (slope 0.9 +/- 0.6%) and showed greater increases in shear stress (p less than 0.01). The peak increase in shear stress was less in smooth (189 +/- 23%) than in irregular (365 +/- 52%) segments (p less than 0.01). These results suggest a control mechanism in normal coronary arteries whereby increases in shear stress stimulate vasodilation and thus limit further increases in this force at the endothelial surface.(ABSTRACT TRUNCATED AT 250 WORDS)