Biomedical subjects

A M Zeiher

Publications and source records attributed to A M Zeiher.

At least 127 records · Page 7Linked to original sources

PubMed1994

Coronary atherosclerotic wall thickening and vascular reactivity in humans. Elevated high-density lipoprotein levels ameliorate abnormal vasoconstriction in early atherosclerosis.

BACKGROUND: Abnormal vascular reactivity represents a fundamental disturbance in vascular biology with the development of atherosclerosis. Because endothelial vasodilator function plays a pivotal role in controlling vasomotor tone, we hypothesized that atherosclerotic wall thickening might directly interfere with deficient endothelium-mediated dilation and thereby contribute to the abnormal reactivity of atherosclerotic arteries in vivo. METHODS AND RESULTS: In 26 patients without focal stenoses in the left anterior descending coronary artery, acetylcholine (0.036 to 3.6 micrograms/mL) was infused into the artery to evaluate endothelium-mediated vasodilation. Segmental vasomotor responses to acetylcholine were correlated with the local extent of atherosclerotic wall thickening quantitated by intracoronary ultrasound examination. Seventeen of the patients also underwent cold pressor testing to assess the vasoreactivity to sympathetic activation. The response of coronary artery segments to acetylcholine varied from 35% dilation to 52% constriction and demonstrated a segmental pattern, with dilation and constriction observed in different segments of the same artery. The vasomotor response to acetylcholine was closely correlated with the extent of local atherosclerotic wall thickening (r = -.82, P < .0001). Over the entire range of atherosclerotic wall thickening, segments from patients with elevated high-density lipoprotein (HDL) cholesterol serum levels (> 75th percentile) demonstrated a significantly blunted constrictor response to acetylcholine (P < .01 at the maximal acetylcholine concentration) compared with segments from patients with HDL cholesterol < 75th percentile. The degree of constriction or dilation in response to the acetylcholine infusion correlated with the response to cold pressor testing (r = .75, P < .0001). Again, the cold pressor test-induced constrictor response was significantly (P < .05) blunted in segments from patients with elevated HDL cholesterol serum levels compared with those from patients with HDL cholesterol < 75th percentile despite equal degrees of atherosclerotic wall thickening. CONCLUSIONS: Coronary vasomotor responses to the endothelium-dependent dilator acetylcholine and to sympathetic stimulation by cold pressor test correlate with local atherosclerotic wall thickening. Thus, the degree of abnormal local vascular reactivity is closely related to the extent of atherosclerotic "plaque load" in human epicardial arteries in vivo. Elevated HDL cholesterol serum levels ameliorate abnormal vasoconstriction at any given extent of atherosclerotic wall thickening, suggesting that HDL cholesterol exerts a beneficial effect on abnormal vascular reactivity, a fundamental functional disturbance associated with coronary atherosclerosis.

Acetylcholine↗

PubMed1994

Digital angiographic assessment of the physiological changes to the regional microcirculation induced by successful coronary angioplasty.

BACKGROUND: Impulse response analysis of digital coronary angiographic images calculates a parameter known as the mean transit time of the microcirculation (Tmicro). This has been shown to accurately assess the regional microcirculatory response to proximal stenosis in relation to flow. Our goal was to apply impulse response analysis to patients undergoing successful angioplasty and to quantify the induced physiological changes with respect to quantitative angiographic measurements of stenosis dimensions. METHODS AND RESULTS: We studied 24 patients before and after successful single-vessel percutaneous transluminal coronary angioplasty (PTCA). Minimal luminal stenosis area was increased from 0.9 +/- 0.6 before PTCA to 4.1 +/- 1.3 mm2 after PTCA (P < .0001). In all patients this was accompanied by an increase in the inverse of Tmicro (Tmicro-1), from 8.5 +/- 3.0 to 26.5 +/- 9.0 min-1 (P < .0001) with a linear correlation between Tmicro-1 and minimal luminal stenosis area (r = .73; SEE = 7.74). Stenosis flow reserve, estimated by integration of stenosis dimensions, increased in all patients from 1.8 +/- 1.0 to 4.5 +/- 0.4 after PTCA (P < .01). A comparison of Tmicro-1 with stenosis flow reserve revealed a nonlinear relation. In 16 patients undergoing PTCA of the left anterior descending or circumflex artery, contrast injections into the left main stem allowed simultaneous measurements of Tmicro-1 in the adjacent, nonstenotic artery. Adjacent artery Tmicro-1 did not change after PTCA (25.8 +/- 6.2 compared with 25.6 +/- 6.8 min-1 before PTCA; P = NS); moreover, Tmicro-1 of the dilated artery measured after PTCA was equivalent to the nonstenotic adjacent artery, indicating normalization of microcirculatory responses. CONCLUSIONS: These data suggest that Tmicro-1 determined by digital angiographic impulse response analysis of a single contrast injection under resting flow conditions may be a practical method to assess the regional microcirculatory response to changes in stenosis severity effected by coronary angioplasty.

Adult↗

PubMed1994

Adjunctive intracoronary infusion of antithrombin III during percutaneous transluminal coronary angioplasty. Results of a prospective, randomized trial.

BACKGROUND: Heparin needs the plasma protein antithrombin III to function as an inhibitor of thrombin, and local antithrombin III deficiency might therefore limit the antithrombotic effectiveness of heparin during percutaneous transluminal coronary angioplasty. METHODS AND RESULTS: In the present double-blind study, 615 consecutive patients undergoing percutaneous transluminal coronary angioplasty (PTCA), of a total of 713 stenoses, were prospectively randomized to receive a bolus injection of 15,000 U heparin followed by a continuous intracoronary infusion via the guiding catheter of either 250 U heparin per minute or 250 U heparin plus 25 U antithrombin III per minute during the procedure. Four clinical variables, 19 lesion-specific characteristics, and 16 procedure-related variables were evaluated. Procedural success was assessed by quantitative angiography; procedure-related ischemic complications were analyzed during in-hospital follow-up. Procedural success rates (< 50% final diameter stenosis and no major ischemic complication) were similar, with 85% in the heparin group (n = 324 patients) and 83% in the heparin+antithrombin III group (n = 291 patients). Percent diameter stenosis after PTCA was 39 +/- 18% in the heparin group and 40 +/- 20% in the heparin+antithrombin III group (NS). There were no differences between the two groups with respect to PTCA-related acute vessel occlusion, angiographic evidence of intracoronary thrombus formation, post-procedure creatine kinase increase, Q-wave myocardial infarction, or emergency coronary artery bypass surgery. High-risk subgroup analysis revealed no beneficial effect of adjunctive intracoronary antithrombin III in any of the analyzed subgroups. In addition, although risk stratification according to the criteria of the American College of Cardiology/American Heart Association Task Force classification proved to be very useful for the entire study population, no beneficial effect of intracoronary antithrombin III infusion was observed in any of the different risk groups. CONCLUSIONS: Compared with heparin alone, adjunctive intracoronary antithrombin III therapy does not appear to have any beneficial effect on procedural outcome as well as type and frequency of acute complications during PTCA even in subgroups of patients with a high risk for thrombotic complications. Thus, a local deficiency of antithrombin III does not play a major role for the failure of heparin to abolish thrombotic complications during PTCA.

Aged↗

PubMed1994

Coronary endothelial vasodilator dysfunction: clinical relevance and therapeutic implications.

Endothelial function of epicardial arteries and coronary resistance vessels, as well as endothelial dysfunction and clinical symptoms of coronary artery disease and their therapeutic implications are reviewed including the presentation of the author's own results. Coronary endothelial vasodilator dysfunction represents a fundamental functional disturbance in vascular biology with the development of atherosclerosis. This functional alteration in coronary vascular reactivity appears to play an important integral part in the clinical presentation of coronary artery disease. Humoral and neuronal factors in favour of vasoconstrictor influences affect the balance between myocardial oxygen supply and demand, thus, facilitating the manifestation of myocardial ischemia. In order to identify more selective therapies the potential mechanisms underlying an impaired release or activity of EDRF/NO must be considered. Dysfunction of the endothelial L-arginine/NO pathway may involve decreased activity of NO synthase, increased inactivation of NO formed from its precursor L-arginine, impaired signal transduction mechanisms and reduced intracellular availability of L-arginine. Currently, initial therapeutic strategies include the supplementation of L-arginine, the use of antioxidants, as well as ACE-inhibitors. ACE-inhibitors have been shown not only to reduce vascular tone (and hypertrophy) by inhibition of angiotensin II formation, but also by increasing the endothelial production of NO and prostacyclin most likely due to the local accumulation of endothelium-derived bradykinin. Thus, ACE-inhibition appears to provide the potential to improve endothelial NO synthesis. Indeed, study results demonstrate that chronic ACE-inhibition is associated with an increased coronary blood flow response to acetylcholine suggesting an improvement in endothelial vasodilator functioning of coronary resistance vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Endothelial modulation of coronary vasomotor tone in humans. Effects of atherosclerosis and risk factors for coronary artery disease.

Tests in patients with atherosclerosis or running the risk to get coronary heart diseases have been reported, the objective of which was to detect the importance the physiologic and pathophysiologic regulatory mechanisms of coronary blood flow have in early diagnosis. The reaction of coronary vessels after the infusion of acetylcholine compared to this they showed after the infusion of papaverine was tested, this is to say the responsiveness of coronary vessels to pharmacologic influences caused by the endothelium and aiming directly at the striatal muscles. Both, quantitative coronary angiography and intracoronary sonography served as measuring instruments. The results revealed that progressive endothelial dysfunction in the coronary vessels of risk patients can be detected by the help of pharmacologically differentiated active substances. In patients with increased cholesterin levels, the function of the endothelium is impaired, although a constriction of the lumen has not been observed. Some gradually more distinct dysfunctions have been found in patients with structural symptoms of coronary atherosclerosis and above all in patients with angiographically provable lumen alterations.

Arteriosclerosis↗

PubMed1993

Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension.

The effects of age, atherosclerosis, hypertension, and hypercholesterolemia on vascular function of the coronary circulation were studied by subselective intracoronary infusions of acetylcholine, which releases endothelium-derived relaxing factor, and papaverine, which directly relaxes vascular smooth muscle, in normal patients (n = 18; no risk factors for coronary artery disease), in patients with evidence of early atherosclerosis but normal cholesterol levels and normal blood pressure (n = 12), in patients with hypertension without left ventricular hypertrophy (n = 12), and in patients with hypercholesterolemia (n = 20). Papaverine-induced maximal increases in coronary blood flow were significantly greater in normals, but no differences were noted between the groups of patients with early atherosclerosis, with hypertension, and with hypercholesterolemia. The capacity of the coronary system to increase blood flow in response to acetylcholine was similar in normal and normocholesterolemic patients with epicardial atherosclerosis and/or hypertension but was significantly impaired in patients with hypercholesterolemia, irrespective of evidence of epicardial atherosclerotic lesions. Age (r = -0.62, P < 0.0001) and total serum cholesterol levels (r = -0.70; P < 0.0001) were the only significant independent predictors of a blunted coronary blood flow response to acetylcholine. Thus, hypercholesterolemia and advanced age selectively impair endothelium-mediated relaxation of the coronary microvasculature in response to acetylcholine, whereas endothelial dysfunction is restricted to epicardial arteries in age-matched normocholesterolemic patients with evidence of coronary atherosclerosis and/or hypertension.

Acetylcholine↗

PubMed1993

[Incidence, predisposing factors, acute complications and prognostic significance of intracoronary thrombus formation during PTCA].

UNLABELLED: Besides coronary artery dissection, intracoronary thrombus formation is known to be an important mechanism for acute coronary occlusion in the course of percutaneous transluminal coronary angioplasty (PTCA). Therefore, we analyzed 210 consecutive patients (217 dilated stenoses) to define the incidence and potential predisposing clinical and morphological factors of intracoronary thrombus formation. Intracoronary thrombus formation was angiographically detectable in 11% of the cases, a dissection in 21%. Acute PTCA-related coronary occlusion (incidence = 5.5%) was significantly associated with intracoronary thrombus formation (p < 0.001) but less so with dissection (p = 0.074). Acute redilatation after an initially successful PTCA was almost exclusively necessary in patients with intracoronary thrombus formation (p < 0.001). Univariate analysis demonstrated the following factors to be significantly associated with intracoronary thrombus formation: Irregular lumen of stenosis (p = 0.006), stenosis at branch point (p = 0.012) and unstable angina pectoris (p = 0.001). Patients with intracoronary thrombus formation did not show a worse long-term prognosis regarding clinical events compared with a matched group (average follow-up of 20 months). CONCLUSION: Luminal irregularities within the stenosis to be dilated and the clinical syndrome of unstable angina pectoris are predisposing factors for PTCA-induced intracoronary thrombus formation, suggesting that preexisting local activation of the coagulation system plays an independent role for intracoronary thrombus formation during PTCA. Although intracoronary thrombus formation increases the risk for acute complications during PTCA, the long-term result is not adversely affected.

Adult↗

PubMed1992

Arterial dilatory reserve in congestive heart failure.

AIM: The purpose of this study was to determine whether there are abnormalities in flow-mediated large vessel relaxation in patients with congestive heart failure (CHF). METHODS: The radial arterial diameter and flow responses upon the release of 10 min of forearm arterial occlusion (reactive hyperemia) were measured with ultrasound and Doppler devices. RESULTS: In patients with CHF there was a 26% reduction in peak blood flow (P = 0.09) compared to age-matched controls. However, the increase in arterial diameter that followed the peak blood flow was reduced by 49% in CHF (P < 0.01). CONCLUSIONS: The causes of the abnormal flow-mediated large artery relaxation in CHF are unclear; both structural and endothelial abnormalities may contribute.

Blood Flow Velocity↗

PubMed1991

Assessment of coronary vasomotor tone in humans.

The assessment of endothelium-mediated modulation of coronary vasomotor tone in the intact human circulation under physiologic conditions requires very precise determination of both epicardial artery diameters, reflecting effects within the conduit vessels, as well as coronary blood flow, reflecting effects within the resistance vasculature during cardiac catheterization. In the present report, the accuracy and limitations of quantitative approaches to assess arterial dimensions from coronary angiograms are discussed. Using state-of-the-art image-processing techniques and x-ray imaging, epicardial artery diameter changes within the range of 8-10% can be reliably detected by quantitative coronary angiography. In addition, advances in interventional techniques do provide a means to selectively assess intracoronary blood-flow velocities using intracoronary Doppler catheters. Combining epicardial artery diameter measurements and intracoronary blood-flow velocity parameters allows for a reasonably accurate instantaneous estimate of coronary arterial blood flow. The advantages and limitations of the intracoronary Doppler technique compared to other techniques are discussed.

Coronary Angiography↗

PubMed1991

Coronary hemodynamic determinants of epicardial artery vasomotor responses during sympathetic stimulation in humans.

Sympathetic stimulation by cold-pressor testing induces a complex interplay between adrenergic receptor stimulation, humoral and local metabolic factors, and alterations in coronary perfusion pressure. Since the endothelium importantly modulates the effect of neurohumoral stimulation, we evaluated the coronary hemodynamic determinants of epicardial artery vasomotor responses to cold-pressor testing in 12 normal patients with intact endothelial function, and in 20 patients with early atherosclerosis, demonstrating a dysfunctional endothelium. Endothelial function was assessed by intracoronary infusion of the endothelium-dependent dilator acetylcholine. Vasomotor responses were examined by quantitative coronary angiography and continuous intracoronary flow velocity measurements using a Doppler catheter. All coronary artery segments demonstrating a dilator response to intracoronary acetylcholine also vasodilated in response to cold-pressor testing by 19.7 +/- 8.2% (mean +/- 1 SD). In contrast, all arteries with evidence of atherosclerosis demonstrated a vasoconstrictor response during cold pressor testing with an area reduction by 18.4 +/- 7.5%. The systemic hemodynamic variables heart rate and mean aortic pressure increased by comparable amounts in both groups of patients during cold pressor testing, indicating comparable increases in myocardial workloads. There was a significant positive relation between increases in blood flow and changes in arterial luminal area. Increases in blood flow were closely related to increases in mean aortic pressure in normal epicardial vessels, but this relation was blunted in vessels with a dysfunctional endothelium. Estimated shear stress changes within the epicardial conductance vessels were significantly lower in normal compared to atherosclerotic arteries. Thus, the increase in coronary blood flow is an important hemodynamic determinant of epicardial artery dilation in normal arteries during cold pressor testing. On the other hand, the vasodilator response limits increases in shear stress for a given increase in blood flow. In contrast, the failure of atherosclerotic arteries to dilate, despite increased myocardial demands, exaggerates increases in local shear stress in relation to changes in flow.

Acetylcholine↗

PubMed1991

Progression of coronary endothelial dysfunction in man and its potential clinical significance.

Endothelial injury represents an important factor in the initiation of atherosclerosis and is associated with abnormal vasomotor responses (= dysfunctional endothelium) to a variety of stimuli. Therefore, the evaluation of endothelial function may provide a means to detect early vascular alteration preceding overt atherosclerotic lesions. To test this clinically important hypothesis, we studied the coronary vasomotor responses to three different endothelium-dependent stimuli in patients with different early stages of coronary artery disease: first, increasing doses of intracoronary infusion of acetylcholine (ACH) (10(-8), 10(-7), 10(-6) M); second, transient increases in coronary flow causing flow-dependent dilation by injection of papaverine into the midportion of the left descending artery (exposing the proximal segment of this vessel to increased flow, but not to papaverine); and third, sympathetic stimulation by cold pressor test. Coronary diameters were assessed by repeated coronary angiography and quantitative angiography, blood flow velocity (and subsequent calculation of blood flow) was obtained by intracoronary Doppler. In normal individuals, all three stimuli elicited epicardial artery dilation. In patients with smooth coronary arteries, but hypercholesterolemia, a substantial vasoconstriction was observed in response to ACH, whereas the response to cold pressor test and increases in flow was normal, that is, vasodilation occurred. In patients with angiographically visible atherosclerosis, acetylcholine and cold pressor test exerted coronary vasoconstriction. Moreover, flow-dependent, endothelium-mediated dilation was attenuated in those patients demonstrating visible luminal irregularities in the vessel under study. In patients with hypercholesterolemia, substantial endothelial dysfunction (as assessed by attenuated blood-flow increase in response to acetylcholine) was demonstrated in the coronary microcirculation. Thus, progression of endothelial dysfunction occurs during the early course of development of coronary atherosclerosis. Utilizing quantitative coronary angiography and the intracoronary Doppler technique, these early functional alterations can be identified safely at a stage when atherosclerotic lesions are not detectable by angiography. This may be useful in designing early effective interventions which restore endothelial function and prevent the occurrence of overt atherosclerosis.

Coronary Artery Disease↗

PubMed1991

Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis.

The endothelium plays a critical role in the control of vasomotor tone by the release of vasoactive substances. Because endothelial injury or dysfunction is considered important very early in atherogenesis, we hypothesized that abnormal endothelial function precedes the angiographic detection of coronary atherosclerosis in the human coronary circulation. The coronary vasomotor responses to three different endothelium-mediated stimuli (intracoronary infusion of acetylcholine 10(-8) to 10(-6) M, increase in blood flow to induce flow-dependent dilation, and sympathetic stimulation by cold pressor testing) were assessed by quantitative angiography and subselective intracoronary Doppler flow velocity measurements within the left anterior descending coronary artery in 38 patients. All three stimuli elicited epicardial artery dilation in all 11 patients with smooth coronary arteries and absence of risk factors for coronary artery disease (group 1). All nine patients with smooth coronary arteries but with hypercholesterolemia (group 2) demonstrated a selective impairment in endothelial function with vasoconstriction (35 +/- 12.7% decrease in mean luminal area) in response to acetylcholine but showed a preserved flow-dependent dilation (15.5 +/- 4.4% increase in mean luminal area) and vasodilation in response to cold pressor testing (14.2 +/- 4.6% increase in mean luminal area). In all nine patients with an angiographically defined smooth coronary artery segment but with evidence of atherosclerosis elsewhere in the coronary system (group 3), both acetylcholine and cold pressor testing induced vasoconstriction (26.2 +/- 8.7% and 18.7 +/- 7.9% decrease in mean luminal area, respectively), whereas flow-dependent dilation was preserved (20.4 +/- 8.7% increase in mean luminal area). In the nine patients with angiographic evidence of wall irregularities (group 4), flow-dependent dilation was also abolished and vasoconstriction occurred in response to acetylcholine and cold pressor testing (34.5 +/- 10.7% and 19.9 +/- 6.3% decrease in mean luminal area, respectively). All coronary artery segments dilated in response to nitroglycerin, suggesting preserved function of vascular smooth muscle. Despite similar reductions in coronary vascular resistance in response to the smooth muscle relaxant papaverin, patients with hypercholesterolemia demonstrated a selective impairment of vasodilation of the resistance vasculature in response to acetylcholine (p less than 0.05 versus groups 1, 3, and 4). Thus, there is a progressive impairment of endothelial vasoactive functioning in coronary arteries of patients with different early stages of atherosclerosis, beginning with a selective endothelial dysfunction in angiographically defined normal arteries in patients with hypercholesterolemia and progressively worsening to a complete loss of endothelium-mediated vasodilation in angiographically defined atherosclerotic coronary arteries.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗

PubMed1991

Intracoronary thrombus formation causes focal vasoconstriction of epicardial arteries in patients with coronary artery disease.

BACKGROUND: Experimental studies have demonstrated that intracoronary platelet aggregation and thrombus formation may induce marked vasoconstriction of epicardial arteries with endothelial injury. METHODS AND RESULTS: To examine the effects of intracoronary thrombus formation on coronary vasomotor tone of human epicardial arteries in vivo, we studied 15 patients who developed intracoronary thrombi adherent to the guide wire during balloon dilatation. Epicardial artery luminal area was evaluated by quantitative coronary angiography proximal and distal to the site of intracoronary thrombus formation and in a reference vessel before and after thrombus formation as well as after intracoronary injection of 0.2-0.3 mg nitroglycerin. All artery segments distal to the site of thrombus formation showed vasoconstriction with a luminal area reduction of -27.4 +/- 17.1% (p less than 0.001), whereas proximal vessel segments and reference vessels not manipulated during percutaneous transluminal coronary angioplasty did not demonstrate any significant luminal area changes during thrombus formation. Angiographic measurements after advancing the guide wire with the adherent thrombus (performed in six of the 15 patients) revealed in all patients that vasoconstriction did develop at a new site distal to the thrombus persistence of the initial vasoconstriction now residing proximal to the thrombus. Thus, there was a sequential association between thrombus formation and subsequent distal vasoconstriction. Intracoronary injection of nitroglycerin abolished the thrombus-induced vasoconstriction. No significant luminal area changes were observed in 20 patients without angiographic evidence of intracoronary thrombus formation. CONCLUSIONS: Intracoronary thrombus formation during percutaneous transluminal coronary angioplasty causes focal vasoconstriction of epicardial arteries in patients with coronary artery disease. Although caution must be advised in the extrapolation of this phenomenon, which was observed in a manipulated artery during coronary angioplasty, the vasoconstrictor response to intracoronary thrombus formation in vivo may play an important role in the dynamic mechanisms of acute coronary heart disease syndromes.

Angiography↗

PubMed1991

Endothelial dysfunction of the coronary microvasculature is associated with coronary blood flow regulation in patients with early atherosclerosis.

BACKGROUND: The vascular endothelium is capable of regulating tissue perfusion by the release of endothelium-derived relaxing factor to modulate vasomotor tone of the resistance vasculature. METHODS AND RESULTS: To test whether atherosclerosis is associated with a functional abnormality of endothelium-mediated microvascular relaxation affecting coronary blood flow regulation, we compared coronary blood flow responses with cold pressor testing with the response of the coronary vasculature to acetylcholine (an endothelium-dependent vasodilator) and to papaverin (a direct dilator of vascular smooth muscle) in 12 normal control patients and in 19 patients with non-flow-limiting epicardial atherosclerosis (CAD). The drugs were subselectively infused into the left anterior descending coronary artery via a Doppler catheter, and the response in coronary blood flow was assessed by measuring intracoronary blood flow velocity and cross-sectional arterial area (quantitative angiography). Coronary vascular resistance decreased in all normal control patients by -24.1 +/- 5.5% (mean +/- SD) during the cold pressor test, whereas the CAD patients demonstrated a variable coronary vascular resistance response to cold pressor testing despite comparable changes in the rate-pressure product. The slopes of the acetylcholine dose-blood flow response (percent change in coronary blood flow/dosage of acetylcholine) were significantly reduced in the CAD patients with 38.5 +/- 24.8 compared with the normal patients (80.8 +/- 28.1; p less than 0.001). Although coronary blood flow responses to papaverin were slightly but significantly (p less than 0.05) reduced in the CAD patients, the response to the endothelium-dependent dilator acetylcholine was considerably out of proportion to the papaverin response in these patients compared with the normal patients. The capacity of the coronary system to increase blood flow in response to acetylcholine expressed as relative proportion of the maximal papaverin response was 52.5 +/- 18.2% in the normal control patients but only 33.6 +/- 23.6% in the CAD patients (p less than 0.025 versus normals). There was a significant negative correlation (r = -0.69; p less than 0.0001) between cold pressor test-induced changes in coronary vascular resistance and the capacity of the coronary system to increase blood flow in response to acetylcholine. CONCLUSIONS: Early stages of epicardial atherosclerosis are associated with an impairment in endothelium-dependent dilation of the coronary microvasculature, indicating that the pathophysiological consequences of atherosclerosis may extend into the human coronary microcirculation. The correlation between cold pressor test-induced coronary vascular resistance changes and the extent of endothelial dysfunction suggests a relation between endothelial function of the microvasculature and coronary blood flow regulation during sympathetic stimulation associated with increased myocardial work.

Acetylcholine↗

PubMed1991

Endothelial function in human coronary arteries in vivo. Focus on hypercholesterolemia.

To examine whether and to what extent hypercholesterolemia may affect the vasoactive role of the endothelium before the onset of angiographically visible atherosclerosis in the coronary circulation, we studied normal subjects (group 1, n = 11), individuals with elevated low density lipoprotein plasma values but angiographically smooth coronary arteries (group 2, n = 8), and patients with hypercholesterolemia and minimal disease of the vessel under study (group 3, n = 8). Coronary vasomotor function was evaluated by three interventions: subselective intracoronary infusion of acetylcholine (0.036, 0.36, and 3.6 micrograms/min) with a 3F Doppler catheter in the left anterior descending artery, 0.3 mg intracoronary nitroglycerin ("endothelium-independent"), and increase in blood flow (assessment of flow-dependent, endothelium-mediated coronary dilation). In group 1, all interventions caused coronary dilation of the left anterior descending artery as assessed by automatic quantification of digitized cineframes. However, in group 2, acetylcholine elicited substantial coronary vasoconstriction, and the vasodilator response to nitroglycerin and to increases in flow (flow-dependent dilation) was preserved. In group 3, the acetylcholine-induced coronary vasoconstriction was even more pronounced, and the flow-dependent dilation was impaired (+5.1 +/- 1% versus +10.5 +/- 1.1% [group 1], p less than 0.05). The coronary flow reserve (derived from Doppler flow velocity measurements) in response to papaverine was not significantly different in normal and hypercholesterolemic individuals (groups 2 and 3). However, the increase in coronary flow exerted by acetylcholine was substantially depressed in patients with hypercholesterolemia (groups 2 and 3) as compared with normal individuals (+48 +/- 8.3% and +49 +/- 25% versus +220 +/- 28.5%, respectively, p less than 0.01). Thus, hypercholesterolemia elicits endothelial dysfunction in coronary conduit and resistance vessels in humans that precedes angiographically visible atherosclerotic lesions in large coronary arteries. Conceivably, these vascular alterations contribute to increased coronary vasomotor tone within the coronary circulation and may predispose these patients to myocardial ischemia.

Acetylcholine↗

PubMed1990

[Effect of atrial natriuretic factor on coronary vascular tone].

To test whether atrial natriuretic factor (ANF) may be involved in the modulation of coronary vasomotor tone, ANF was injected into angiographically normal left coronary arteries. Measurement of epicardial diameters of the circumflex (Cx) and left anterior descending artery (LAD) were made from biplane angiograms by an automatic contour-detection system. Bolus injection of ANF (0.07 micrograms/kg, diluted in 1 ml 0.9% NaCl, n = 7) increased diameter of proximal segments of LAD (11 +/- 4%) and Cx (10 +/- 4%) (p less than 0.02 each vs control) without altering heart rate and mean arterial pressure (MAP). Intracoronary nitroglycerin (NTG, 0.3 mg) increased diameters of identical LAD and Cx segments by 18 +/- 3% and 20 +/- 4%. Intracoronary ANF infusion (0.02 micrograms/kg/min over 5 min, followed by 0.1 micrograms/kg/min, n = 10) exerted dose-dependent increases in diameters of LAD and Cx (low dose: + 5 +/- 2%, p less than 0.05 vs control; high dose: + 13 +/- 3%, p less than 0.01 vs control). ANF-infusion increased arterial plasma ANF levels from 280 +/- 80 pg/ml during control to 894 +/- 82 pg/ml (low dose; + 614 pg/ml vs control) and to 2290 +/- 228 pg/ml (high dose). Severe ischemia in four patients undergoing angioplasty exerted substantial increase in arterial ANF levels (160 +/- 60 to 608 +/- 111 pg/ml; + 448 pg/ml vs control), similar to the increase elicited by low dose ANF infusion in man.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Factor↗

PubMed1989

Coronary vasomotion in response to sympathetic stimulation in humans: importance of the functional integrity of the endothelium.

The coronary vasomotor response to the cold pressor test was studied with use of quantitative coronary angiography in 32 patients without evidence of coronary artery disease and 55 patients with such disease; in a subset of 22 patients (9 with normal coronary arteries and 13 with coronary artery disease), the effects of the cold pressor test were compared with the effects of the endothelium-dependent vasodilator acetylcholine with simultaneous intracoronary Doppler flow velocity measurements to assess the influence of endothelial dysfunction. The cold pressor test induced vasodilation of 8.9 +/- 5.7% in all 77 analyzed vessel segments of the group with normal arteries (p less than 0.01). In contrast, in patients with coronary artery disease, the 52 analyzed stenotic segments were constricted by -12.1 +/- 9.5% (p less than 0.01), the 57 analyzed vessel segments with luminal irregularities were constricted by -8.9 +/- 5.2% (p less 0.01) and 40 (85%) of 47 angiographically normal segments also were constricted by -7.0 +/- 4.9% (p less than 0.05). Preserved vasodilating capability was demonstrated by intracoronary nitroglycerin in all analyzed segments. In nine patients with normal coronary arteries, the analyzed vessel segments were dilated in response to both the cold pressor test and intracoronary acetylcholine by 10.9 +/- 5.4% and 13.4 +/- 4.7%, respectively. In contrast, in all 13 patients with coronary artery disease, vasoconstriction of identical vessel segments by -9.1 +/- 3.7% and -23 +/- 10.4%, respectively, was observed after both the cold pressor test and intracoronary acetylcholine. Intracoronary propranolol did not significantly affect either the vasodilative response in 11 normal coronary arteries (11.3 +/- 4.4% before and 8.6 +/- 4.3% after beta-blockade) or the vasoconstrictor response in 8 atherosclerotic coronary arteries (-11.4 +/- 4.6% before and -14.6 +/- 5.3% after beta-blockade). The dilation of normal and the constriction of atherosclerotic coronary arteries with cold pressor testing exactly mirror the response to the endothelium-dependent dilator acetylcholine. Endothelial dysfunction in coronary atherosclerosis resulted in a loss of normal dilator function and permitted vasoconstrictor responses to sympathetic stimulation. Thus, coronary vasomotion of large epicardial arteries in response to sympathetic stimulation by the cold pressor test in humans is intimately related to the integrity of endothelial function.

Acetylcholine↗

PubMed1989

Validation of a digital angiographic model to quantitate autoregulatory vasodilation of the coronary system.

Compensatory vasodilation of the distal coronary vascular bed is the major autoregulatory mechanism in response to coronary stenosis. Using impulse response analysis (IRA) of digital angiographic time-density curves, myocardial contrast-transit was modelled as two-compartment system to obtain total coronary transit times (T) and microcirculation transit times (Tmicro) as parameters of flow (Q) divided by distribution volume (V) of the corresponding compartments. IRA parameters were compared with electromagnetic Q in eight dogs. At rest, Vmicro/V increased (P less than 0.02) from 0.69 +/- 0.08 in normal arteries (n = 25) to 0.86 +/- 0.06 in stenotic arteries (n = 24). With maximal vasodilation during hyperaemia, Vmicro/V was similar for normal (0.89 +/- 0.05; n = 19) and stenotic arteries (0.9 +/- 0.05; n = 18). There was a close linear (r = 0.88) correlation between 1/Tmicro and Q during hyperaemia. However, at rest with intact vasomotor tone, 1/Tmicro and Q were linearly related (r = 0.94; n = 12) only when Q was reduced below normal by tight stenosis; but the relationship became curvilinear in non-Q-limiting stenosed and normal arteries due to progressive decrease in Vmicro. Instead, resting 1/Tmicro demonstrated a very close linear correlation with coronary flow reserve (r = 0.95). We conclude that two-compartmental modelling of coronary contrast transit reflects stenosis-mediated autoregulatory vasodilation of the coronary microcirculation by a single measurement at rest.

Animals↗