H. Wollschläger

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)

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 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 subselectivelyinfused 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 < 0.001). Although coronary blood flow responses to papaverin were slightly but significantly (p < 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 < 0.025 versus normals). There was a significant negative correlation (r= −0.69; p< 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 pathophys-iological 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.

Flow-dependent coronary artery dilatation in humans.

To determine the role of endothelium-mediated flow-dependent coronary dilatation in humans, we studied the coronary dilatation exerted by maximal pharmacologic increase of coronary flow in 14 patients with normal coronary arteries. Biplane views of the circumflex (Cx) and left anterior descending (LAD) coronary arteries were obtained before and 80 seconds after inducing a maximal increase in flow selectively in the Cx by injecting 7 mg papaverine through a 2F infusion catheter in the midportion of the Cx (n = 10). The diameter of the proximal Cx segment (exposed to increased flow but not to papaverine directly) increased with papaverine by 11.1 +/- 4% (range, 5.2-16.4%, p less than 0.001 vs. control), whereas the LAD diameter did not change. LAD and Cx diameters increased by 18.3% and 21.2% after nitroglycerin given into the left main artery, which showed the preserved capability of the LAD to dilate. In four patients with normal coronary arteries and six patients with coronary artery disease (CAD, non-flow-limiting stenosis), a similar protocol was applied with the LAD for the assessment of flow-dependent dilatation. Simultaneously, intracoronary blood flow velocity was measured by an intracoronary Doppler catheter. Papaverine-induced coronary flow reserve (peak/resting velocity ratio) in the LAD was 4 +/- 0.7 (range, 3.5-5) in normal arteries and was 3.5 +/- 0.6 (range, 2.7-4.4) in CAD.(ABSTRACT TRUNCATED AT 250 WORDS)

Contrasting peripheral short-term and long-term effects of converting enzyme inhibition in patients with congestive heart failure. A double-blind, placebo-controlled trial.

To discover the underlying mechanisms involved in the beneficial long-term effects of angiotensin converting enzyme (ACE) inhibitors, we investigated the systemic and peripheral effects of short- and long-term ACE inhibition in patients with chronic heart failure. After assessing the short-term effects and dose titration with cilazapril, a new long-acting ACE inhibitor, 21 patients were randomized to receive either placebo or the ACE inhibitor. Seventeen patients completed the 3-month treatment. Central hemodynamic output, femoral blood flow (measured by thermodilution), oxygen saturation, and lactate and norepinephrine levels were determined simultaneously in the femoral vein and radial artery during treatment and after a 3-month rest and during symptom-limited bicycle exercise. Short-term ACE inhibition improved rest and exercise hemodynamic output, but it did not alter peak femoral blood flow, calculated leg oxygen consumption, or systemic oxygen uptake during exercise, despite significant reduction in femoral norepinephrine extraction and arterial angiotensin levels during exercise. In contrast, long-term ACE inhibition further improved exercise cardiac output and increased leg blood flow (from 2.3 to 2.9 l/min, p less than 0.05), leg oxygen consumption (from 277 to 403 ml/min, p less than 0.05), and systemic oxygen uptake (from 1,133 to 1,453 ml/min, p less than 0.05), whereas these variables remained unchanged with placebo treatment (p less than 0.02 between groups). Moreover, a moderate but significant increase in femoral oxygen extraction occurred after long-term therapy (ACE inhibitor: from 76% to 83%, p less than 0.05; placebo: from 75% to 74%, NS; p less than 0.01 between groups). We conclude that long-term ACE inhibition is clinically beneficial in that it improves blood flow to skeletal muscle during exercise over time. The long-term effects of ACE inhibition are, in part, probably related to peripheral (vascular) mechanisms, for example, by reversing the inability of peripheral vessels to dilate and by improving oxygen utilization.

Transesophageal echocardiography device

In a device for transoesophagal echocardiography, an ultrasound transformer (1) is used to make a sequence of layer images for a plurality of parallel sectional planes with the aid of an ultrasonic diagnostic device (8). The layer images made during one cardiac cycle with the image repetition rate of the ultrasonic diagnostic device (8) are stored in a buffer store (34) and transferred to a main store (48) with the aid of a selection stage (49) to generate three-dimensional sets of images only when a locating device (13), and ECG device (24) and a respiration detector (54) generate release signals which are allocated to a constant spatial probe position, a constant R--R interval distance and a constant respiratory state. The content of the main store (48) is evaluated with the aid of an image processing system (56), whereby sectional images may be calculated, especially for any sectional plane, and displayed on a monitor (31).

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

BackgroundExperimental studies have demonstrated that intracoronary platelet aggregation and thrombus formation may induce marked vasoconstriction of epicardial arteries with endothelial injury. Methods and ResultsTo 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 < 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 with 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. ConclusionsIntracoronary 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.

Safety of low-density lipoprotein cholesterol reduction with atorvastatin versus simvastatin in a coronary heart disease population (the TARGET TANGIBLE Trial)

Reduction in plasma lipids has been recognized as one of the primary cardiovascular risk reduction strategies in the secondary prevention of coronary heart disease (CHD). The primary end points of TARGET TANGIBLE were the safety (adverse events and laboratory measurements) and efficacy (responder rates) of therapy with atorvastatin versus simvastatin with the aim of achieving low-density lipoprotein (LDL) cholesterol lowering to < or =100 mg/dl (2.6 mmol/L). A total of 3,748 CHD patients with LDL cholesterol levels > or =130 mg/dl (3.4 mmol/L) entered a run-in diet phase of 6 weeks without any lipid-lowering drug therapy. At the end of the diet phase, 2,856 patients met the lipid criteria and were randomized to active treatment for 14 weeks. Patients received 10 to 40 mg of either drug in an optional titration design at 2:1 randomization for atorvastatin versus simvastatin. Adverse event rates were statistically equivalent (p<0.01) for simvastatin (35.7%) and for atorvastatin patients (36.3%). Both drugs were well tolerated; <5% of patients in both groups were withdrawn due to adverse events. In all, 37 atorvastatin patients (2%) and 27 simvastatin patients (3%) had serious adverse events. Drug-related side effects (elevations in creatine kinase, liver enzymes) occurred in both groups at similar rates with 10 atorvastatin patients (0.5%) and 5 simvastatin patients (0.5%) presenting confirmed transaminase elevations >3 x the upper limit of the normal range. Significantly fewer patients in the atorvastatin group (n = 724) required titration to 40 mg compared with the simvastatin group (n = 514) (38% vs. 54%, respectively; p<0.001). Atorvastatin resulted in a significantly greater number of patients reaching the LDL cholesterol goal than those treated with simvastatin, with 67% of atorvastatin patients and 53% of simvastatin patients reaching the target LDL cholesterol level of < or =100 mg/dl (2.6 mmol/L) (p<0.001). Both atorvastatin and simvastatin are safe for use by patients in the secondary prevention of CHD, with patients in both drug groups having similar adverse event rates. Despite the use of concomitant medications there was no drug-induced rhabdomyolysis with either atorvastatin or simvastatin.

Coronary thrombolysis during acute myocardial infarction by intravenous BRL 26921, a new anisoylated plasminogen-streptokinase activator complex

The safety and fibrinolytic efficacy of a new anisoylated plasminogen-streptokinase activator complex (APSAC) was tested in 50 patients with acute myocardial infarction (AMI) less than 4 hours in duration. APSAC (30 mg) was given intravenously as a bolus injection 151 +/- 47 minutes after clinical symptoms. Coronary angiography was then performed to assess coronary artery patency: 28 patients had an inferior AMI and 22 an anterior AMI. A patent infarct-related artery was found in 32 patients (64%) on first coronary angiography 66 +/- 21 minutes after administration of APSAC. Subsequent reperfusion was observed in 10 patients after 74 +/- 16 minutes (84%). Bleeding complications or hematomas were observed in 18 patients, of whom 3 required blood transfusions. Marked hypofibrinogenemia was observed within 24 hours in most patients. A control coronary angiogram was recorded in 37 patients (74%) after 25 +/- 19 days and showed reocclusion in 5 patients.

Effect of stenotic geometry on flow behaviour across stenotic models

In the study the influence of the geometry of stenoses on poststenotic flow characteristics such as faminar flow, separation, flow instabilities and local turbulences were assessed. Stenoses were represented by 12 rigid-walled models. The different geometric characteristics were length, percentage lumen area reduction, exit angle and eccentric location of the residual lumen. The flow characteristics were investigated by visualising the flow pattern with a birefringent solution and by measuring the flow and the pressure drop along the stenoses. All data were obtained under steady flow conditions for Reynolds numbers varying from approximately 1 to 500. In stenoses with short and concentric shapes local turbulence develops at Reynolds numbers well below the corresponding Reynolds numbers obtained in stenoses with the same percent lumen area reduction but with a long and eccentric shape. The results indicate that the photoelastic technique is a suitable method of obtaining a picture of the overall flow field downstream of a constriction.

Computed Triple Orthogonal Projections for Optimal Radiological Imaging with Biplane Isocentric Multidirectional X-ray Systems

One of the major objectives in angiocardiography is the visualization of anatomical details with projections perpendicular to the long axis of the anatomical structure. In addition, ‘one of the most basic rules in radiology . . . is the need for at least two views of the object with the projections being perpendicular to each other’ [1]. Thus, most useful informations can be derived from a radiological study if the concept of ‘triple orthogonality’ is applied: two projections perpendicular to the long axis of the anatomical object and perpendicular to each other.