Delayed response of myocardial flow reserve to lipid-lowering therapy with fluvastatin.

BACKGROUND: Lipid-lowering therapy can improve endothelial function in patients with coronary artery disease (CAD) and hypercholesterolemia. Little is known about induced changes in myocardial microcirculation. This study prospectively investigated the temporal effects of lipid-lowering therapy with fluvastatin on coronary flow and flow reserve (CFR) in patients with CAD assessed by PET. METHODS AND RESULTS: In an open clinical trial, CFR was studied in 15 patients with angiographically documented multivessel CAD and hypercholesterolemia (LDL >160 mg/dL). Dynamic 13N-labeled ammonia PET imaging in conjunction with adenosine was used to assess regional and global CFR at baseline as well as at 2 and 6 months during treatment with fluvastatin (60 to 80 mg/d). Despite a rapid decrease in total cholesterol (29+/-6%) and LDL (37+/-9%), myocardial blood flow at rest and during stress was unchanged after 2 months of treatment (2.7+/-0.9 versus 2.5+/-0.6 mL x g-1 x min-1). At 6 months, stress blood flow as well as CFR increased significantly (3.4+/-1.0 mL x g-1 x min-1). No change in hemodynamic parameters was noted during the entire study. Nine of 15 patients increased CFR by >20%. All responders demonstrated improvement in anginal symptoms, whereas nonresponders stated no change (n=4) or worsening of symptoms (n=2). The improvement in CFR was not related to the amount of lipid lowering and was independent of the severity of stenoses. CONCLUSIONS: Improvement in stress blood flow and CFR is delayed compared with the lipid-lowering effect of fluvastatin, suggesting a slow recovery of the vasodilatory response to adenosine.

Photodynamic therapy of vascular stenosis: results from cell culture studies on human endothelial cells.

BACKGROUND: Experimental results from human cell culture studies have shown that smooth muscle cells derived from human atherosclerotic plaques react more sensitively to photoactivated dihematoporphyrin-ester and -ether (DHE) than smooth muscle cells from human nonatherosclerotic arteries. A therapeutic concept of photodynamic therapy of vascular stenosis appears, therefore, to be promising. The prerequisite for an intravascular application is a relatively harmless application of the photosensitizing agent to the luminal lining of endothelial cells. METHODS: The effect of DHE with and without photoactivation was examined on endothelial cell cultures from human saphenous veins. The cellular uptake of DHE in relation to the serum content of the culture medium was evaluated, as well as its effect on proliferative activity, cell size, cell volume, and cellular viability. RESULTS: Intracellular uptake of DHE decreased significantly when higher serum concentrations were present in the culture medium. Incubation of cells with the photosensitizer for 9 days in the dark without light activation resulted in a significant decrease of endothelial cell proliferation only at concentrations higher than 2.5 micrograms/mL (= 2.5 mg/kg body weight for systemic application in vivo). Additional photoactivation caused no reduction of cell viability at DHE concentrations of 1 microgram/mL, but at 2.5 micrograms/mL and 5 micrograms/mL, a reduction of viable cells within 24 hours was observed in relation to the energy densities used for irradiation. CONCLUSIONS: Because smooth muscle cells from atherosclerotic plaques are, however, much more sensitive to photodynamic treatment, the concept of a photodynamic therapy of vascular stenosis may provide a good tool in the reduction of restenosis rates after recanalization of severely stenosed or even occluded arteries.

[Spatial fluorescence imaging of atherosclerotic plaque: contrast enhancement by 2 wavelength laser stimulation, digital image processing and dye marking]. / Räumliche Fluoreszenzdarstellung atherosklerotischer Plaques: Kontrastverstärkung durch Zwei-Wellenlängen-Laseranregung, digitale Bildverarbeitung und Farbstoffmarkierung.

A new video-enhanced fluorescence imaging technique has been used for the first time for in vitro differentiation of human atherosclerotic plaques vs normal arterial wall. Laser-induced superficial tissue fluorescence of specimens from human aorta was documented after alternating excitation with violet (405 nm +/- 5 nm) and blue (470 nm +/- 10 nm) krypton-ion laser light. Subsequent digital subtraction of the corresponding fluorescence images allowed to differentiate areas of atherosclerosis from normal intima. Fluorescence intensity was correlated with the morphological aspect of samples and histology of the plaque. Dihematoporphyrin-ether/ester (DHE) incubation enhanced fluorescence contrast of plaques in comparison to normal artery vessel wall. Depending on the concentration of the incubation solution (10, 20, and 40 micrograms DHE/ml NaCl solution), fluorescence increased. Fluorescence intensity was highest in fatty plaque areas, while calcific lesions showed no substantial DHE uptake.

[The effect of intravenous nifedipine administration on coronary occlusion during coronary angioplasty on ischemia tolerance and collateral function]. / Die Wirkung der intravenösen Nifedipingabe bei koronarer Okklusion während Koronarangioplastie auf Ischämietoleranz und Kollateralfunktion.

In 29 consecutive patients (pts) coronary wedge pressure (CWP) was determined as an indicator of coronary collateral function during coronary angioplasty. Collaterals to the target vessel were angiographically detectable in 21 pts. CPW, aortic pressure (AOP), pulmonary wedge pressure (PCP), intervals to appearance of angina pectoris, surface and intracoronary ECG-changes were registered during two (n = 10) or three (n = 19) consecutive balloon dilatations. A total of 21 pts received 0.8-1.0 mg nifedipine intravenously before a second or third dilatation was performed; a control group (n = 8) received placebo. Hemodynamic parameters were reproducible for all dilatations without nifedipine. After administration of nifedipine significant changes occurred: decreases of CPW (from 34 to 29 mm Hg), AOP (from 121 to 110 mmHg), and PCP (from 12.4 to 9.4 mm Hg), and increase of ischemic tolerance time (angina pectoris) (from 35 to 56 s) (p less than 0.01). Changes in CWP and AOP showed a statistical tendency to correlate (p = 10). Thus, intravenous administration of nifedipine can improve ischemic tolerance during coronary angioplasty. Simultaneous measurement of coronary wedge pressure could not prove enhancement of collateral function as being responsible for these antiischemic effects.

Laser balloon angioplasty: technical realization and vascular tissue effects of a modified concept.

A modified concept using a movable fiber with radial light dispersion was developed for combining mechanical balloon dilatation and intraluminal circumferential Nd-Yag laser irradiation of the arterial wall. The aims of the study were the technical feasibility and the acute and chronic vascular tissue effects of laser-assisted balloon dilatation. The carotid arteries (n = 9 dogs) and femoral arteries (n = 5 dogs) of dogs were mechanically dilated and simultaneously circumferentially irradiated through the balloon by 1,064 nm Nd-Yag laser (20-25 W). Temperature at the adventitial surface was kept constant at 50 degrees C, 60 degrees C, 70 degrees C, or 80 degrees C for either 8 or 15 seconds by a computerized feedback system for temperature control. Angiographic and histological results were available acutely, subacutely (2 days), and at 3 months. Angiographically, stable and smooth enlargement of the lumen was demonstrated acutely. At 3 months, occlusions, probably thrombotic in origin, had occurred in 5 of the carotid arteries and none of the femoral arteries. Histologically, laser-induced coagulation of the arterial wall with loss of cellular elements was demonstrated. Collagen and elastic fibers remained relatively intact. In two carotid arteries intimal proliferation was observed at the treated site. Thus, this technique appears to be technically feasible, yet further study is needed to assess its potential to reduce or repair acute vascular complications (dissections) and to reduce restenoses after percutaneous transluminal coronary angioplasty (PTCA). However, the clinical value of this technique appears to be limited in view of the thromboses and reactive proliferations observed in this preliminary study.

Effects of Nd: YAG laser coagulation of myocardium on coronary vessels.

Laser coagulation of arrhythmogenic myocardium proved to be an effective surgical therapy for refractory arrhythmias. To determine the influence of Nd: YAG laser coagulation of myocardium on coronary vessels, a total of 48 transcatheter laser impacts (10 W, 10 sec, 7 W mm2) were directed to the left ventricular free wall via endocardial (24 lesions in 2 dogs) or epicardial (24 lesions in 2 dogs) approach. In 8 of 24 endomyocardial lesions (2 and 6 months old) coronary vessels with a diameter of greater than 50 microns were found within the coagulation zones. The volume of these lesions was significantly (P less than 0.01) smaller (139 +/- 43 mm3) than those (n = 16) with coronary vessels measuring less than 50 microns (311 +/- 87 mm3). Volumes of epimyocardial lesions (1-2 hours old) produced by transcoronary irradiation with normal coronary blood flow were significantly (P less than 0.01) smaller (31 +/- 17 mm3) than with reduced (73 +/- 22) or interrupted (119 +/- 34 mm3) blood flow (n = 8, each). Both directly irradiated coronary vessels and those found within the coagulation zones and scars appeared histologically normal through all layers with an intact intima without fibrosis or thrombosis. The ultrastructure of irradiated arteries, even with total interruption of blood flow, was no different from that of non-irradiated controls. Thus, coronary artery blood flow significantly reduces the volume of coagulated myocardium, whereas the vessels themselves appear to remain undamaged by laser irradiation as used for myocardial coagulation.

[Use of the thermal laser effect of laser irradiation for cardiovascular applications exemplified by the Nd:YAG laser]. / Die Nutzung der thermischen Wirkung von Laserstrahlung für kardiovaskuläre Anwendungen am Beispiel des Nd:YAG-Lasers.

Techniques of percutaneous transluminal application of laser energy for vessel recanalization have been used clinically since 1983. The commonly used Nd:YAG and argon lasers achieve ablation of atherosclerotic plaques by thermal action (vaporization). In order to reduce undesirable thermal damage in the neighborhood of the target tissue and to avoid vessel perforation, optimal irradiation parameters, modified (atraumatic) fiber tips (hot tips, sapphires), and steerable catheter systems needed to be implemented. Favorable results from peripheral application have encouraged use in the coronary circulation. More recently, coagulative tissue effects of circumferential irradiation of the vessel wall during balloon dilatation have been used for stabilization of acute and late results after mechanical balloon angioplasty. Enhancement of the differential light absorption of atherosclerotic plaque by use of biological dyes may further improve selective intravascular laser application. Intraoperative ECG-guided laser coagulation of arrhythmogenic areas of myocardium is a method for treatment of malignant arrhythmias. Transluminal non-operative application of myocardial laser photocoagulation has now been tested experimentally and shown to be safe and effective. There was no arrhythmogenicity or thermal damage of coronary arteries associated with this method. Innovative techniques such as nanosecond pulsed excimer lasers (athermal action) and development of "intelligent" lasers--which are equipped with spectroscopy-guided feedback systems for plaque recognition--have opened new perspectives and will further improve safety and efficacy of clinical laser application. However, according to current experience, the thermally acting Nd:YAG laser is an effective and versatile mode of laser therapy for selected cardiovascular indications.