Direct and indirect assessment of skeletal muscle blood flow in chronic congestive heart failure.

In patients with chronic congestive heart failure (CHF), skeletal muscle blood flow can be measured directly by the continuous thermodilution technique and by the xenon133 clearance method. The continuous thermodilution technique requires retrograde catheterization of the femoral vein and, thus, cannot be repeated conveniently in patients during evaluation of pharmacologic interventions. The xenon133 clearance, which requires only an intramuscular injection, allows repeated determination of skeletal muscle blood flow. In patients with severe CHF, a fixed capacity of the skeletal muscle vasculature to dilate appears to limit maximal exercise performance. Moreover, the changes in peak skeletal muscle blood flow noted during long-term administration of captopril, an angiotensin-converting enzyme inhibitor, appears to correlate with the changes in aerobic capacity. In patients with CHF, resting supine deep femoral vein oxygen content can be used as an indirect measurement of resting skeletal muscle blood flow. The absence of a steady state complicates the determination of peak skeletal muscle blood flow reached during graded bicycle or treadmill exercise in patients with chronic CHF. Indirect assessments of skeletal muscle blood flow and metabolism during exercise performed at submaximal work loads are currently developed in patients with chronic CHF.

Effects of phosphodiesterase inhibition on skeletal muscle vasculature.

The pathophysiology of the syndrome of congestive heart failure (CHF) includes 2 major components that closely interact. The first one is a reduction in ventricular performance, which is manifested initially during exercise and is later present at rest. The second one involves abnormalities of the peripheral circulation and organs, which become gradually more prominent and lead ultimately to symptoms. The exercise capacity of patients with chronic CHF is limited not only by an inadequate increase in cardiac output and an excessive increase in ventricular filling pressure, but also by a fixed vasodilatory response to exercise. Although the role of increased activity of the sympathetic and renin-angiotensin-aldosterone systems in the derangements of the peripheral circulation has been extensively investigated, the structural abnormalities of the arterial wall have received little emphasis in patients with CHF. Chronic reduction of the cardiac output may lead to endothelium-dependent reduction in arterial diameter and vasomotor response, which may in turn increase systemic vascular resistance and further reduce cardiac output. Therapeutic agents should be characterized by their acute and chronic effects not only on ventricular performance, but also on the peripheral circulation. More specifically, when one is concerned with the effect of a therapeutic intervention on exercise capacity, evaluation of its direct and indirect effects on the skeletal muscle vasculature is particularly important. Accordingly, the effects of phosphodiesterase inhibition on vascular smooth muscle tone and skeletal muscle vasculature are reviewed. In addition, the potential of phosphodiesterase inhibition to reverse structural abnormalities of the arterial wall is discussed.

Coronary restenosis: evaluation of a restenosis injury index in a swine model.

To investigate the mechanisms of restenosis and detect useful interventions to prevent it, reliable quantitative measurements must be evaluated. Coronary arteries of domestic and minipigs (n = 18) were mechanically injured by balloon overstretching and killed at different intervals (2 to 25 weeks) after quantitative angiographic analysis. Morphometric measurements evaluated intimal hyperplasia at 0.59 +/- 0.42 mm without relation to artery size or balloon/artery ratio. Intimal hyperplasia, expressed as the ratio of neointimal area to total wall area (A), is directly related to the injury, assessed by the ratio of internal elastic lamina (IEL) fracture length to IEL circumference (B), r = 0.84, p = 0.002. Restenosis injury index, defined as A/B, provides a useful tool for the quantitative assessment of future angioplasty-related restenosis interventions.

Local Delivery of TGF-b Antibodies to Prevent Neointima Formation after Balloon Injury in a Pig Coronary Artery Model.

BACKGROUND: The formation of neointima after vessel injury results from smooth muscle cell proliferation and extracellular matrix secretion. This process is activated by multiple growth factor release. Among these, Transforming Growth Factor-b (TGF-b) has been shown to play an important role. We hypothesized that local delivery of TGF-b antibodies could reduce neointima formation after balloon angioplasty. METHODS AND RESULTS: Using autoperfusion double-balloon catheters (Baxter, Irvine, California), we infused polyclonal TGF-b antibodies in 30 minutes, immediately after oversized balloon angioplasty in pig coronary arteries. Eleven coronary arteries received 100 m anti-TGF-b and thirteen served as controls. Animals were sacrificed 10 weeks later; coronary segments were harvested and processed for histologic quantitative assessment of the neointima. The extent of injury was similar in treated versus control vessels (39% +/- 5% vs. 30% +/- 4%) and there was no difference in intimal thickening (0.63 +/- 0.19 mm for treated vs. 0.52 +/- 0.12 mm for controls). A previously validated restenosis injury index (ratio of neointimal area to total wall area over extent of injury) was also similar in both groups, 1.46 +/- 0.15 for treated versus 1.55 +/- 0.14 for controls. CONCLUSION: Local delivery of a single dose of TGF-b antibodies failed to demonstrate a benefit on neointima formation in a pig coronary artery model.