Delivery strategies to target therapies to inflammatory tissue.

BACKGROUND: Inflammation plays a key role in many chronic disease processes as well as an acute role in injury and wound healing. Various cell types are recruited from the bloodstream to the inflamed site through adhesion molecules, cytokines, chemokines and others. OBJECTIVES: This review examines many drug-targeting strategies that make use of these molecules or signaling pathways, and seeks to describe certain commonalities irrespective of the disease process or agent to be delivered. METHODS: A survey of the literature, primarily within the last year, was performed. Search words included 'drug targeting' and 'inflammation' and of those, the scope was refined to include those studies that specifically sought to modify or ameliorate an aspect of the inflammatory process in the treatment of a disease. RESULTS/CONCLUSION: Inflammation plays a key role in many diseases, and many similar targets (such as adhesion molecules) are the focus of the treatment of those diseases.

Age-related changes in the aortic valve affect leaflet stress distributions: implications for aortic valve degeneration.

BACKGROUND AND AIM OF THE STUDY: The degeneration of aortic valve leaflets occurs primarily due to high mechanical stresses in zones of leaflet flexion. Aging, which has been identified as a risk factor for degenerative aortic stenosis, is associated with reductions in stretch and in compliance, and an increase in tissue thickness of the leaflet and root. The study aim was to investigate the effects of age-related tissue changes on valve opening dynamics and leaflet stress patterns, and its implications for valve degeneration. METHODS: A three-dimensional finite element model of the aortic valve and root was developed in Ansys. A transient, non-linear analysis was carried out of the valve opening phase. Three age groups were identified based on leaflet and root tissue properties: group I age <35 years; group II aged 33-55 years; and group III aged >55 years. The valve opening dynamics was studied and von Mises stresses in various regions of the leaflet were computed. RESULTS: Maximum leaflet stresses occurred along the leaflet-root attachment, analogous to the spatial distribution of calcific deposits in the aortic valve. With increasing age, the rate of valve opening decreased, and the magnitude of leaflet tip displacement in both radial and axial directions reduced progressively. At the leaflet-root attachment, groups II and III showed 19% and 32.7% increases in average stress over group I, respectively. At the free edge, the stresses in group III increased 2.7% over group I; however, the average stress at the free edge in group II decreased 3.5% over group I. In the leaflet belly, groups II and III showed 27.6% and 60.9% increases in stresses over group I, respectively. CONCLUSION: Changes in leaflet and root tissue properties lead to altered leaflet dynamics and increased stresses. This not only emphasizes the role of aging on the development and progression of degenerative aortic valve disease, but also has implications in the design of bioprosthetic heart valves.

Prediction of pressure recovery location in aortic valve stenosis: an in-vitro validation study.

BACKGROUND AND AIM OF THE STUDY: Pressure recovery is a source of discrepancy between Doppler-derived and catheter aortic valve pressure drops. Pressure recovery occurs where the stenotic jet reattaches to the aortic wall. An equation to predict the jet reattachment location has been developed based on the density and viscosity of blood, the velocity in the stenotic jet, and the aortic root and valve areas. The study aim was to define the conditions where this equation is valid and could be accurately applied to Doppler echocardiographic data. METHODS: In a pulse duplicator, mean flow rates were varied between 2 and 5 l/min, and anatomic orifice areas between 0.32 and 2.85 cm2, to produce values of the ratio of anatomic valve area to the aortic root area (E) of 0.04 to 0.36. For each hemodynamic state, continuous-wave, pulsed-wave Doppler and color Doppler flow maps were recorded. Instantaneous flow rates and pressures proximal and distal to the valve were recorded. Calculated reattachment lengths were compared to measurements from color Doppler echocardiography. RESULTS: Except for the smallest E value, there was a correlation between the predicted and measured jet reattachment lengths. The equation was good for predicted attachment lengths of less than 5 cm. Overestimation was seen for the smallest E value, representing a critically stenotic valve. CONCLUSION: Except for the most severe stenoses, pressure drops for aortic valves are best measured with the aortic sensor placed approximately 5 cm above the aortic valve. For moderate stenoses, where pressure recovery is relevant, the site of fully recovered pressure can be predicted.

Effects of aging on the diagnostic assessment of valvular heart disease.

The diagnostic assessment of the severity of valvular heart disease in the older population is impacted by the anatomic and physiologic changes that accompany normal aging and by the interposition of diseases prevalent in the elderly. In this paper, the impact of those changes on the assessment of valvular heart disease will be reviewed. Special attention will be paid to the effects of age and disease on the measurement of the pressure drop and orifice area.

Age-related changes in hemodynamics affecting valve performance.

Degenerative processes result in changes in both the aortic and mitral valves. For example, degenerative changes may lead to significant aortic stenosis or myxomatous mitral valves. Flows through each valve are determined not only by the properties of the valve itself, but also by the properties of proximal and distal chambers, which also undergo changes with age and diseases associated with the elderly, such as hypertension and coronary artery disease. Assessment of valvular performance should consider the effects of atrial-ventricular coupling (for the mitral valve) or ventricular-arterial coupling (for the aortic valve). Design of therapy or intervention should accordingly consider effects on the system as a whole.

Development of markers of valve stiffness for prediction of hemodynamic progression of aortic stenosis.

Degenerative aortic valve stenosis is a progressive disease with an unpredictable rate of progression. Early changes in the degenerative process include thickening and stiffening of the leaflets, reflected in altered rates of opening and closing. Methods have been proposed to measure this in vivo and relate it to the rate of disease progression. In this in vitro study, we tested the hypothesis that changes in ambient hemodynamics that might contribute to the wear and tear process that mediates the degenerative process affect valve mechanics, and that this is reflected in the rates of valve opening and closing. Evidence supporting this hypothesis is presented and an alternative method to account for these effects is proposed.

Pathophysiology of Hypertension in the Elderly.

The onset and progression of hypertension is associated with alterations in structure, function, and hemodynamics of the heart, vascular system, and other major organs. An understanding of the structural and functional changes in the cardiovascular system associated with this process would allow for early detection and the development of treatment strategies. In this paper, we focus on the anatomic alterations that accompany vascular aging and the resulting cardiovascular dynamics. Techniques to measure changes in cardiovascular dynamics and left ventricular performance are reviewed. The impact of therapeutic strategies on cardiovascular dynamics and left ventricular function are also discussed. (c)2000 by CVRR, Inc.