Background-Ultrasound can cause microbubble destruction. If microbubbles are administered as a continuous infusion, then their destruction within the myocardium and measurement of their myocardial reappearance rate at steady state will provide a measure of mean myocardial microbubble velocity. Conversely, measurement of their myocardial concentration at steady state will provide an assessment of microvascular cross-sectional area. Myocardial blood flow (MBF) can then be calculated from the product of the two. Methods and Results-Ex vivo and in vitro experiments were performed in which either flow was held constant and pulsing interval (interval between microbubble destruction and replenishment) was altered, or vice versa. In vivo experiments were performed in 21 dogs. In group 1 dogs (nϭ7), MBF was mechanically altered in a model in which coronary blood volume was constant. In group 2 dogs (nϭ5), MBF was altered by direct coronary infusions of vasodilators. In group 3 dogs (nϭ9), non-flow-limiting coronary stenoses were created, and MBF was measured before and after the venous administration of a coronary vasodilator. In all experiments, microbubbles were delivered as a constant infusion, and myocardial contrast echocardiography was performed using different pulsing intervals. The myocardial video intensity versus pulsing interval plots were fitted to an exponential function: yϭA(1Ϫe Ϫ␤t ), where A is the plateau video intensity reflecting the microvascular cross-sectional area, and ␤ reflects the rate of rise of video intensity and, hence, microbubble velocity. Excellent correlations were found between flow and ␤, as well as flow and the product of A and ␤. Conclusions-MBF can be quantified with myocardial contrast echocardiography during a venous infusion of microbubbles.This novel approach has potential for measuring tissue perfusion in any organ accessible to ultrasound. (Circulation. 1998;97:473-483.)

Background-Our aim was to observe ultrasound-induced intravascular microbubble destruction in vivo and to characterize any resultant bioeffects. Methods and Results-Intravital microscopy was used to visualize the spinotrapezius muscle in 15 rats during ultrasound delivery. Microbubble destruction during ultrasound exposure caused rupture of Յ7-m microvessels (mostly capillaries) and the production of nonviable cells in adjacent tissue. The number of microvessels ruptured and cells damaged correlated linearly (PϽ0.001) with the amount of ultrasound energy delivered. Conclusions-Microbubbles can be destroyed by ultrasound, resulting in a bioeffect that could be used for local drug delivery, angiogenesis, and vascular remodeling, or for tumor destruction. (Circulation. 1998;98:290-293.)

Pulmonary hypertension during exercise is common in severe chronic obstructive pulmonary disease (COPD). It was hypothesised that the use of the endothelin-receptor antagonist bosentan can improve cardiopulmonary haemodynamics during exercise, thus increasing exercise tolerance in patients with severe COPD.In the present double-blind, placebo-controlled study, 30 patients with severe or very severe COPD were randomly assigned in a 2:1 ratio to receive either bosentan or placebo for 12 weeks. The primary end-point was change in the 6-min walking distance. Secondary end-points included changes in health-related quality of life, lung function, cardiac haemodynamics, maximal oxygen uptake and pulmonary perfusion patterns.Compared with placebo, patients treated with bosentan during 12 weeks showed no significant improvement in exercise capacity as measured by the 6-min walking distance (mean¡SD 331¡123 versus 329¡94 m). There was no change in lung function, pulmonary arterial pressure, maximal oxygen uptake or regional pulmonary perfusion pattern. In contrast, arterial oxygen pressure dropped, the alveolar-arterial gradient increased and quality of life deteriorated significantly in patients assigned bosentan.The oral administration of the endothelin receptor antagonist bosentan not only failed to improve exercise capacity but also deteriorated hypoxaemia and functional status in severe chronic obstructive pulmonary disease patients without severe pulmonary hypertension at rest. KEYWORDS: Endothelin-receptor antagonist, exercise capacity, pulmonary hypertension, treatment P ulmonary hypertension (PH) at rest and during exercise is a very frequent complication in the natural history of chronic obstructive pulmonary disease (COPD) [1,2]. Correspondingly, this condition has been reported in 20-91% of patients with severe COPD and/or emphysema [3,4]. The presence of PH is commonly associated with more frequent use of healthcare resources and worse clinical outcome [5]. Remarkably, pulmonary artery pressure has been suggested to be the single best predictor of mortality in COPD [6].In COPD, PH is generally of moderate severity, but the range of mean pulmonary artery pressures varies substantially [7]. Moderate and severe PH are present in 9.8 and 3.7%, respectively, of the patients undergoing right heart catheterisation before lung volume reduction surgery [7]. Despite many uncertainties, studies indicate that 35% of all patients with severe COPD have pulmonary artery pressures of .20 mmHg at rest [8]. In addition, pulmonary pressures during exercise are greater than predicted by the pulmonary vascular resistance (PVR) equation in COPD, suggesting active pulmonary vasoconstriction on exertion [9]. Hence, of those patients without PH at rest, a further 52% are estimated to develop PH during exercise [5].There are many pathological similarities between idiopathic pulmonary arterial hypertension (PAH) and PH related to COPD. Like idiopathic PAH, pulmonary arteries in patients with COPD show evidence of fibromuscula...

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