The formation of an anti-restenotic/anti-thrombotic surface by immobilization of nitric oxide synthase on a metallic carrier.

Coronary stenosis due to atherosclerosis, the primary cause of coronary artery disease, is generally treated by balloon dilatation and stent implantation, which can result in damage to the endothelial lining of blood vessels. This leads to the restenosis of the lumen as a consequence of migration and proliferation of smooth muscle cells (SMCs). Nitric oxide (NO), which is produced and secreted by vascular endothelial cells (ECs), is a central anti-inflammatory and anti-atherogenic player in the vasculature. The goal of the present study was to develop an enzymatically active surface capable of converting the prodrug l-arginine, to the active drug, NO, thus providing a targeted drug delivery interface. NO synthase (NOS) was chemically immobilized on the surface of a stainless steel carrier with preservation of its activity. The ability of this functionalized NO-producing surface to prevent or delay processes involved in restenosis and thrombus formation was tested. This surface was found to significantly promote EC adhesion and proliferation while inhibiting that of SMCs. Furthermore, platelet adherence to this surface was markedly inhibited. Beyond the application considered here, this approach can be implemented for the local conversion of any systemically administered prodrug to the active drug, using catalysts attached to the surface of the implant.

Tunable nonlinear viscoelastic "focusing" in a microfluidic device.

In this Letter we describe a novel method for tunable viscoelastic focusing of particles flowing in a microchannel. It is proposed that some elasticity, inherently present in dilute polymer solutions, may be responsible for highly nonuniform spatial distribution of flowing particles across the channel cross section, yielding their "focusing" in the midplane of the channel. A theory based on scaling arguments is presented to explain the lateral migration and is found to be in a very good agreement with the experimental observations. It was found that, in agreement with the theoretical prediction, the particles would have different spatial distribution depending on their size and rheology of the suspending medium. We demonstrate how the viscoelastic focusing can be precisely controlled by proper rheological design of the carrier solution.

Pattern analysis of temporal changes in the carotid artery diameter under normal and pathological conditions.

Age-related and temporal cyclic changes in the left and right common carotid arteries (CCA) diameters were studied in two groups of subjects: (i) 11 healthy normotensive subjects (ages 19-72 years), and (ii) eight hypertensive subjects (ages 59-85 years), with various degrees of stenosis in their ICA. Cross-sectional images of the left and right CCA were acquired via an ultrasonic system. Images were digitized, and the contour of the arterial wall for each frame was manually traced. Assuming a circular geometry, the arterial diameter was calculated. Averaging four to six consecutive heart beats yielded the typical patterns of temporal diameter changes for both the left and right CCA. For the group of normal subjects, a typical pattern of the temporal diameter changes with a consistent left vs right peak diameter delay (LRPDD), with the right CCA preceding the left, was observed. Plotting the normalized left vs right CCA diameters yielded a typical loop (DDloop) which changed in the counter-clockwise direction from systole to diastole. For the group of hypertensive subjects, the LRPDD decreased or became negative with the left CCA preceding the right if the stenosis degree exceeded 50% (p < 0.01). The DDloop changed from a counterclockwise to a clockwise direction. For the group of normal subjects, end diastolic, end systolic diameters and the elastic index of the CCA increased with age while the relative systolic change in diameter decreased with age. For the group of hypertensive subjects, the relative systolic change in diameter was smaller, compared to normals (7.8 +/- 1.2% vs 10.7 +/- 3.1%, respectively; p < 0.05). The elastic index for this group was significantly higher compared to the normal subjects (1.4 +/- 0.3 vs 0.6 +/- 0.2 x 10(5) dynes/cm2, respectively; p < 0.001). These findings imply that patterns of CCA temporal diameter changes can indicate the existence of a pathological state.

The relations between microvascular structure and oxygen supply.

The current theories of microcirculatory control require a higher command center to maintain tissue homeostasis. The theory of arteriolar vasodilation generates conflicting results by increasing the flow and the capillary hydrostatic pressures. A new theory, recently suggested to account for local tissue flow control, applies a blinking mechanism of open capillaries, whereby alternating circulatory modes increase flow to specific tissue regions, without inducing a higher control center. The mechanism is evaluated here mathematically by examining the oxygen demand, supply and local tissue concentration of oxygen. It is shown that this theory explains how periods of oxygen debts are compensated by increased flow with changes in the operation mode. The results show that there is a direct relation between the tissue microvascular complexity and the capability of the specific tissue to withstand periods of oxygen deficit.

Analysis of coronary circulation under ischaemic conditions.

Coronary flow patterns and pressure/flow relationships in coronary vessels with arterial stenoses are examined by using a model that combines the flow in the epicardial arterial tree with the intramyocardial perfusion. By using appropriate resistive elements, the model allows for the autoregulation of the vascular bed and for the development of coronary collaterals. Arterial flow predictions are compared to canine data. Coronary stenosis is simulated by a local pressure drop caused by a combination of viscous and inertial forces; stenosis with a constant cross-sectional area is compared to a dynamic stenosis in which the cross-sectional area is a function of the instantaneous transmural pressure. Simulation results predict that the normal phasic flow patterns in the epicardial arteries are unaffected up to 73% reduction in cross-sectional area, while the average flow remains unchanged up to 90% area reduction. At the critical level of 90% rigid stenosis, the autoregulation is saturated and the phasic nature of the arterial flow is severely damped. Dynamic stenoses demonstrate hysteresis loops of the instantaneous pressure/flow relationship. Theoretical predictions of local and global values are in excellent agreement with experimental measurements, indicating that the proposed approach can be used to realistically describe the coronary flow in the ischemic heart.

Analysis of flow in coronary epicardial arterial tree and intramyocardial circulation.

A mathematical model combining the coronary flow in the epicardial arterial tree and the intramyocardial circulation is presented. The epicardial arterial tree is represented by a resistive capacitive network based on its realistic anatomy. The intramyocardial flow is affected by the pump action of the contracting myocardium through the extravascular compressive pressure (ECP), which, in turn, affects the dynamic resistance and compliance changes based on the relationship between the transmural pressure and the cross-sectional area of a vessel. The model accounts for the autoregulatory mechanism of the intramyocardial compartments (arteriolar, microvascular and venular) and is structured according to the epicardial coronary anatomy. Realistic coronary epicardial arterial flow patterns are obtained, which compare well to experimentally measured data in six dogs under basal conditions and during reactive hyperemic response. Simulations of the average transmural flow in the three intramyocardial vascular compartments show that the flow in the arterial side is predominantly diastolic, with a systolic retrograde component, and is dominantly systolic antegrade flow in the venular side, consistent with experimental data. Interestingly, the transmurally average microcirculatory flow is continuous, with very small change throughout the cardiac cycle, and is practically insensitive to changes in the model parameters. The model presents a quantitative tool that describes the dynamic patterns of coronary flow in relationship to muscular and extravascular parameters.

Metabolic and mechanical control of the microcirculation.

Existing models of the microcirculatory control usually assume a single mechanical parameter which in an unspecified way relates to the oxygen levels or to the metabolic demand. This parameter changes the mechanical properties of the microvascular bed upstream of where the change is needed, and in most cases affect a very wide region of the myocardium, rather than a number of cells at a specific location. The model presented here suggests a control mechanism which relates to the metabolic demand of a single cell, or a small number of cells. The analysis shows that each specific structure has a potential for a different change, and that these changes can occur with a minimal change in the energy demand. The model shows that these specific changes can affect a 300-500% change in rate of flow. This range of change is consistent with experimental evidence which is hitherto unexplained by current existing models.

Role of the diaphragm in chest wall mechanics.

We analyzed three different assumptions about diaphragm function that determine the thoracoabdominal interaction. In the simplest case, the diaphragm is assumed to be a completely flaccid membrane serving only to partition the thorax and the abdominal cavity. In the second case, it is assumed to have a finite tension but to maintain a relatively flat surface at the base of the rib cage (i.e., a negligible zone of apposition). In the general case, it is assumed that the diaphragm has finite tension and its position may vary (i.e., permitting a zone of apposition). These possible modes of behavior are incorporated into a mathematical model of ventilatory system mechanics that distinguishes the diaphragm, lung, abdomen, and rib cage. The significance of these modes is examined with respect to data from human experiments in which gas or liquid is introduced into the pleural or abdominal spaces, causing a volume change (Vep). We show that the Vep effect on the thoracic and abdominal volumes is sensitive to diaphragm mechanics and depends on the nature of the Vep: gastric distension (with water or air) or pneumothorax. Only the behavior of the general model is consistent with physiological observations, especially the distribution of Vep. Our general mathematical model can quantitatively predict this behavior.

Low positive end expiratory pressures improve the left ventricular workload versus coronary blood flow relationship.

Positive end expiratory pressure (PEEP) has desirable effects on blood oxygenation. Nonetheless, PEEP ventilation has an adverse cardiovascular response which limits its utilization. We have studied the effect of PEEP ventilation on the relationship between coronary flow (CBF) to left ventricular workload. In the closed chest of surgically instrumented dogs, increasing PEEP caused a significant decrease in aortic, left ventricular pressures and aortic flow. The coronary blood flow decreased by 5% for PEEP values of 4 cm of H2O and by 25% for 14 cm of H2O of PEEP. The left ventricular (dP/dt)max was markedly decreased. Following the application of 16 cm H2O of PEEP, the predicted myocardial oxygen consumption using Kreb's equation decreased by 42% of base line values, p less than 0.001. The ratio of CBF to predicted oxygen consumption increased with higher PEEP values, a 84% increment at 16 cm H2O of PEEP relative to zero PEEP (p less than 0.001). Our results suggest that PEEP may have beneficial effects on the relationship between CBF and the predicted myocardial oxygen consumption, and therefore may minimize hypoxic myocardial situations. Further studies that will directly measure the myocardial oxygen consumption are essential before clinical conclusions can be drawn from our results.

Experimental analysis of pulsatile flow through elastic collapsible tubes: application to cardiac assist device.

This study presents a simulated analysis of Phased Compression Cardiac Assist Device (PCCAD) and evaluation of its applicability as a non-invasive temporary assist for a failing heart. The new technique is based on the chest pump mechanism for blood flow augmentation during external massage by phased compression of the abdominal and thoracic cavities. A semi-closed hydraulic system to simulate the systemic circulation was constructed; the system includes a left ventricle which functions according to the Starling principle and a pneumatic system which controls the pressures applied to the thoracic and abdominal cavities, in complete synchronization with the beating normal or failing heart. The possibility of manipulating the three pumps in series (venous, heart, and arterial) has been checked, and the principal parameters which effect the efficiency of the PCCAD were evaluated. This in vitro analysis shows the high potential of a non-invasive temporary cardiac assist device. It points to the necessary measures one has to take in order to achieve good synchronization and to interfere externally with the augmentation of cardiac output or with the augmentation of root aortic pressure.

Manipulation of external pressure as a method to assist the failing heart.

The development and state of the art in circulatory assistance using external pressure variations is reviewed. All of these techniques use the principle that by cyclic external pressure waves properly timed to the cardiac cycle, hemodynamic energy can be noninvasively transmitted to assist the circulation. Cyclic pressure waves to the lower body require that the high pressure phase occurs in diastole in order to augment cardiac output or coronary flow. In contrast, pressure waves to the chest would optimally augment cardiac output if they begin at the onset of ventricular systole. Manipulation of lung pressure by synchronized ventilation may be also utilized to augment cardiac output. The above methods are discussed in detail in the manuscript with special emphasis on the pathophysiology and mechanisms of cardiac assistance.

Pressures generated by rib cage and abdominal compressions during cardiopulmonary resuscitation.

When the rib cage and abdomen are compressed during cardiopulmonary resuscitation (CPR), the effect on intrathoracic pressure, and therefore on haemodynamics, cannot be quantitatively predicted without a physiologically based mathematical model of chest wall dynamics. Using such a model, we compared model simulations of pleural Ppl and abdominal Pab pressures with those from dog experiments in which the compression of the rib cage was delayed from 0 to 500 ms after compression of the abdomen. Integrals of Ppl and transdiaphragmatic pressure, Pdi = Pab-ppl, over their positive and negative values during a cycle were chosen as indices of driving pressures for cardiac output. Both from the model output and experimental data, we found that the positive ppl integral PPI tends to increase with a longer delay between rib cage and abdominal compressions. The negative ppl integral NPI, however, tends to decrease according to the model predictions and data. Furthermore, the positive and negative integrals of Pdi also tend to change with delay time in the opposite way, as shown by both the model simulations and the experiments. Our results show that chest wall tissues modify the externally applied pressures, thereby not allowing us to use the externally applied pressure sources directly as the driving pressure of the cardiovascular system under study. The optimal conditions for haemodynamics during CPR require a compromise between the positive and negative integral indices. Prediction of the optimal haemodynamics from externally applied pressures requires the coupling of appropriate physiological models of chest wall dynamics and haemodynamics.

Effect of vest cardiopulmonary resuscitation rate on cardiac output and coronary blood flow.

We studied the effect of CPR rate on the hemodynamic indices of surgically instrumented canine experimental models. Using pneumatic vest CPR, we applied simultaneous rib cage and abdominal compressions at rates of 1 to 12 Hz. CPR with 2-Hz frequency yielded the highest aortic and coronary flows (252 +/- 14 and 6.8 +/- 1.1 ml/min vs. 178 + 12 and 0.96 +/- 0.08 ml/min at 1 Hz, respectively; p less than .005). The validity of the present American Heart Association recommendation for 1-Hz CPR rate would benefit from further studies.

Quantitative characterization and sorting of three-dimensional geometries: application to left ventricles in vivo.

A procedure for automatic sorting of three-dimensional (3-D) shapes is proposed. The procedure is applied to sort into normal and abnormal categories, human left ventricles (LV) using in vivo data from 19 subjects (ten normal and nine abnormal LV's) studied by ultrafast tomography (Cine-CT). The procedure starts by utilizing a vector in a helical coordinate system to describe the spatial geometry of each individual LV cavity. This individual vector is then anatomically aligned and normalized to eliminate effects due to size, yielding a dimensionless vector, denoted as "geometrical cardiogram" (GCG). The GCG characterizes the instantaneous 3-D geometrical information of the individual LV. For the group of healthy subjects, the Karhunen-Loeve Transform (KLT) is then applied to compress the geometric information contained in their individuals' GCG vectors, at end diastole (ED) and end systole (ES), and yield a unique set of basis vectors. The "normal shape domain" is next defined as a truncated set of the KLT basis vectors from which a normal GCG can be reconstructed with a mean squared error (MSE) smaller than a defined threshold. The calculated MSE of any individual GCG reconstructed in this domain is then used as a criterion for sorting the 3-D shapes. Hearts which yield MSE greater than the threshold are considered abnormal. When applied to the study group of 19 subjects a significant difference (p less than 0.0001) between the MSE values obtained for the normal LV's, and those obtained for the abnormal LV's was detected, thus leading to a successful sorting of all the studied LV's. Finally, the KLT is applied to yield a compact representation of the 3-D geometry of any LV (normal or abnormal).

The effect of positive end-expiratory pressure on the coronary blood flow.

Positive end-expiratory pressure (PEEP) is used liberally whenever a ventilated patient shows signs of increased pulmonary venous shunting. Clinicians using PEEP to improve blood oxygenation may face the cardiovascular side effects which limit utilization of the desired respiratory effects of PEEP. We measured the pressure flow characteristics of the cardiovascular system and the coronary arterial system as a function of PEEP, using closed-chest surgically instrumented dogs, in order to assess its effects on myocardial blood flow with respect to the left ventricular energy demands. The aortic left ventricular blood pressure as well as the aortic blood flow decreased with increasing PEEP values. The coronary blood flow decreased by 5% for PEEP values of 4 cm H2O, and by 25% for 14 cm H2O of PEEP. PEEP values under 10 cm H2O reduced the left ventricular end-diastolic pressure (LVEDP), while higher PEEP values caused an increase in LVEDP. The relation between the alterations of coronary and aortic blood flows changed with PEEP values. Low PEEP values (less than 10 cm H2O) had a tendency for higher relative reduction of aortic blood flow, whereas higher PEEP values (higher than 10 cm H2O) reduced the coronary blood flow more than the reduction occurring in the aortic blood flow. Our results suggest that low PEEP values may have beneficial effects on the relation between aortic blood flow and coronary blood flow, therefore low PEEP application may minimize hypoxic myocardial alterations. Further studies that will measure left ventricular workload or another metabolic index for estimating myocardial perfusion relative to its metabolic demand are essential before clinical conclusions can be drawn from our results.

Augmentation of cardiac output and carotid blood flow by chest and abdomen phased compression cardiopulmonary resuscitation.

Phased compression cardiopulmonary resuscitation, whereby the chest and abdomen are compressed sequentially, is a new approach to the classical cardiopulmonary resuscitation technique, which is based on the compression of the chest alone. Six dogs with cardiac arrest were treated by external chest and abdominal compression using a rigid plexiglas suit lined with flexible perithoracic and periabdominal bladders. Fast inflation and deflation of the two independent bladders, together with forced ventilation of the lung, generated phased pressure pulses. The physiological variables monitored throughout the experiment included central venous, left ventricular, and central arterial pressures, carotid blood flow, cardiac output, and acid base balance. The phased compression technique was performed with phased time lags of 0, 150, 300, 400, 600, 700, and 850 ms between the abdominal and thoracic pressure pulses. A random sequence of the different phased compression modes, each lasting for 3-10 minutes, was applied during the prolonged resuscitation procedure that lasted for up to 70 minutes. By starting the abdominal compression 300-400 ms before the thoracic compression the carotid flow index improved by 77% (from 13% with simultaneous compression to 23% with phased compression) and the cardiac output index increased by 65% (from 7.8% with simultaneous compression to 12.5%). The results provide insight into the chest pump concept and the role of intrathoracic and intra-abdominal pressures in generating improved blood circulation during cardiopulmonary resuscitation, and show the advantages of phased compression over chest compression alone and simultaneous chest and abdominal compression.