Blood flow dynamics of one cardiac cycle and relationship to mechanotransduction and trabeculation during heart looping.

Analyses of form-function relationships during heart looping are directly related to technological advances. Recent advances in four-dimensional optical coherence tomography (OCT) permit observations of cardiac dynamics at high-speed acquisition rates and high resolution. Real-time observation of the avian stage 13 looping heart reveals that interactions between the endocardial and myocardial compartments are more complex than previously depicted. Here we applied four-dimensional OCT to elucidate the relationships of the endocardium, myocardium, and cardiac jelly compartments in a single cardiac cycle during looping. Six cardiac levels along the longitudinal heart tube were each analyzed at 15 time points from diastole to systole. Using image analyses, the organization of mechanotransducing molecules, fibronectin, tenascin C, α-tubulin, and nonmuscle myosin II was correlated with specific cardiac regions defined by OCT data. Optical coherence microscopy helped to visualize details of cardiac architectural development in the embryonic mouse heart. Throughout the cardiac cycle, the endocardium was consistently oriented between the midline of the ventral floor of the foregut and the outer curvature of the myocardial wall, with multiple endocardial folds allowing high-volume capacities during filling. The cardiac area fractional shortening is much higher than previously published. The in vivo profile captured by OCT revealed an interaction of the looping heart with the extra-embryonic splanchnopleural membrane providing outside-in information. In summary, the combined dynamic and imaging data show the developing structural capacity to accommodate increasing flow and the mechanotransducing networks that organize to effectively facilitate formation of the trabeculated four-chambered heart.

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.

Immuno-targeting of nonionic surfactant vesicles to inflammation.

Niosomes composed of sorbitan monostearate (Span 60), polyoxyethylene sorbitan monostearate (Tween 61), cholesterol, and dicetyl phosphate were conjugated with a purified monoclonal antibody to CD44 (IM7) through a cyanuric chloride (CC) linkage on the polyoxyethylene group of the Tween 61 molecule. Inclusion of small amounts of Tween 61 within the surfactant component of niosomes formed using thin film hydration techniques and sonication did not hamper vesicle stability as compared to Span 60 niosomes. Conjugation was verified by UV absorbance of fluorescently tagged IM7 in non-fluorescing niosomes and fluorescent micrographs. The immuno-niosomes were incubated with synovial lining cells expressing CD44. Attachment of niosomes was evident and showed selectivity and specificity compared to controls. These findings suggest that the resulting immuno-niosomes may provide an effective method for targeted drug delivery.

A role for the cytoskeleton in heart looping.

Over the past 10 years, key genes involved in specification of left-right laterality pathways in the embryo have been defined. The read-out for misexpression of laterality genes is usually the direction of heart looping. The question of how dextral looping direction occurred mechanistically and how the heart tube bends remains unknown. It is becoming clear from our experiments and those of others that left-right differences in cell proliferation in the second heart field (anterior heart field) drives the dextral direction. Evidence is accumulating that the cytoskeleton is at the center of laterality, and the bending and rotational forces associated with heart looping. If laterality pathways are modulated upstream, the cytoskeleton, including nonmuscle myosin II (NMHC-II), is altered downstream within the cardiomyocytes, leading to looping abnormalities. The cytoskeleton is associated with important mechanosensing and signaling pathways in cell biology and development. The initiation of blood flow during the looping period and the inherent stresses associated with increasing volumes of blood flowing into the heart may help to potentiate the process. In recent years, the steps involved in this central and complex process of heart development that is the basis of numerous congenital heart defects are being unraveled.

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.

Ultrasound enhancement of drug release across non ionic surfactant vesicle membranes.

Nonionic surfactant vesicles (niosomes) have potential applications in targeted drug delivery and imaging because of their ability to encapsulate therapeutic agents and their enhanced uptake by physiological membranes. Ultrasound may be used to mediate delivery non-invasively by altering the niosome membrane structure. Niosomes composed of polyoxyethylene sorbitan monostearate (Tween 61), cholesterol, and dicetyl phosphate were synthesized via a thin film hydration technique. A fluorescing dye, carboxyfluorescein (CF), was encapsulated and used as a drug model. The amount of dye in the niosomes, the concentration of the vesicles, and their mean particle size after each 5 minute incremental exposure to ultrasound were monitored. Dye concentration encapsulated by the niosomes in the samples decreased while the population and size distribution of the niosome remained largely unchanged. Our conclusion is that ultrasound enhances the rate of dye diffusion across the niosome membrane non-destructively.

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.

Effect of three-dimensional valve shape on the hemodynamics of aortic stenosis: three-dimensional echocardiographic stereolithography and patient studies.

OBJECTIVES: This study tested the hypothesis that the impact of a stenotic aortic valve depends not only on the cross-sectional area of its limiting orifice but also on three-dimensional (3D) valve geometry. BACKGROUND: Valve shape can potentially affect the hemodynamic impact of aortic stenosis by altering the ratio of effective to anatomic orifice area (the coefficient of orifice contraction [Cc]). For a given flow rate and anatomic area, a lower Cc increases velocity and pressure gradient. This effect has been recognized in mitral stenosis but assumed to be absent in aortic stenosis (constant Cc of 1 in the Gorlin equation). METHODS: In order to study this effect with actual valve shapes in patients, 3D echocardiography was used to reconstruct a typical spectrum of stenotic aortic valve geometrics from doming to flat. Three different shapes were reproduced as actual models by stereolithography (computerized laser polymerization) with orifice areas of 0.5, 0.75, and 1.0 cm(2) (total of nine valves) and studied with physiologic flows. To determine whether valve shape actually influences hemodynamics in the clinical setting, we also related Cc (= continuity/planimeter areas) to stenotic aortic valve shape in 35 patients with high-quality echocardiograms. RESULTS: In the patient-derived 3D models, Cc varied prominently with valve shape, and was largest for long, tapered domes that allow more gradual flow convergence compared with more steeply converging flat valves (0.85 to 0.90 vs. 0.71 to 0.76). These variations translated into differences of up to 40% in pressure drop for the same anatomic area and flow rate, with corresponding variations in Gorlin (effective) area relative to anatomic values. In patients, Cc was significantly lower for flat versus doming bicuspid valves (0.73 +/- 0.14 vs. 0.94 +/- 0.14, p < 0.0001) with 40 +/- 5% higher gradients (p < 0.0001). CONCLUSIONS: Three-dimensional valve shape is an important determinant of pressure loss in patients with aortic stenosis, with smaller effective areas and higher pressure gradients for flatter valves. This effect can translate into clinically important differences between planimeter and effective valve areas (continuity or Gorlin). Therefore, valve shape provides additional information beyond the planimeter orifice area in determining the impact of valvular aortic stenosis on patient hemodynamics.

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.