Method of deflection corrected tonometry with phantom vessel experiments.

BACKGROUND: The Continuous Non-Invasive measurement of arterial Blood Pressure [CNIBP] is possible via the method of arterial tonometry and the arterial volume clamp methods. Arterial tonometry successfully measures continuous arterial pressure but requires large vessel deformation and a highly miniaturized pressure sensor to obtain a direct calibration of pressure. A properly designed tonometer is capable of achieving pressure accuracy of less than 5% error at the radial artery. The volume clamp method achieves comparable errors but is generally restricted to the very peripheral arteries. Since the brachial or radial arteries are preferable sites to record blood pressure, tonometry is generally preferred. However, due to its strict operating requirements, tonometry requires a highly skilled operator. The greatest source of measurement error results from slight deviation from the artery wall applanation position. In this study, a method for correcting tonometry deflection error is introduced and evaluated using preliminary experiments. METHODS-MODELING: In prior analysis it has been shown that arterial wall flattening causes contact stress to become uniform and equal to the arterial pressure. In this article, we derive the contact stress for deflections other than the ideal applanation position and to allow variable vessel deflection. This analysis permits the contact stress to be corrected for tonometer positions that are not exact so that pressure accuracy is maintained in spite of less than ideal positioning. This will alleviate the necessity for highly skilled users and allow rapid determination of the pulse pressure. METHODS-EXPERIMENTAL: Experiments were performed to evaluate applied model corrections for tonometer accuracy versus vessel deflection. Two experiments were performed to evaluate tonometer accuracy when deflection is varied. The first experiment used no deflection correction and the second experiment applied model derived deflection correction. A force sensor was used to deflect a phantom latex vessel of known internal pressure. The corrected contact pressure was then compared with known pressures to evaluate the pressure accuracy. RESULTS-MODELING: a geometric model was derived for vessel contact area versus deflection. This resulted in a formula that provides contact area continuously for any amount of deflection. Once the contact area is known the average tonometer contact pressure was obtained that corresponds with the vessel internal pressure. RESULTS - EXPERIMENTAL: A latex tubing phantom vessel was pressurized to a known amount and was deflected in increments over its full diameter while measuring contact force at each position. The model-derived formula was then used to calculate pressure at each position. The calculated pressure was then compared with known internal pressure to evaluate pressure accuracy for all the phantom pressure and deflection points. CONCLUSIONS: A modeling method for tonometer deflection correction was derived and evaluated using a phantom vessel. Average error was significantly reduced over the non-corrected data. The variability of error was also reduced for all data points collected. The experiments reveal that blood pressure measurement error can be reduced to levels obtained in near ideal tonometry conditions without the need for precise position control. The relaxed user precision is anticipated to simplify the use and design requirements for arterial tonometry in practice.

Characteristic dysfunction of stunned myocardium induced by 2,3-butanedione monoxime without ischaemia.

1. In the present study, we tested the hypothesis that, even in the absence of prior ischaemia, 2,3-butanedione monoxime (BDM), an inhibitor of contraction at the actin-myosin level, could produce the postischaemic dysfunction characteristic of stunned myocardium. 2,3-Butanedione monoxime was injected directly into the left anterior descending coronary artery (LAD) before and again after myocardial stunning produced by 15 min occlusion of the LAD followed by 30 min reperfusion. 2. Regional myocardial force, segment shortening and regional work were measured in both the LAD-perfused area and the area perfused by the circumflex coronary artery, which served as a control area. Regional dysfunction produced by BDM injection or ischaemia-reperfusion was assessed quantitatively by five parameters: end-diastolic length (EDL), shortening onset delay (delay), systolic bulge (bulge), end-shortening time delay (EST) and tail work ratio (TWR). 3. It was found that injection of BDM into the LAD caused dyskinesis similar to that caused by occlusion-reperfusion. Both displayed elevated EDL and marked increases in delay, bulge, EST and TWR; these parameters were significantly higher in the dyskinesis caused by BDM injection. Despite dysfunctional fibre shortening, intracoronary BDM injection did not reduce regional force. 4. Thus, BDM can elicit changes similar to those characteristic of postischaemic dysfunction. Because contractility was not impaired, dysfunction was apparently caused by disrupting the association between contractile force and muscle motion.

Elongation as a new shape index for the left ventricle.

OBJECTIVES: This study was done to quantify the shape of the left ventricle (LV). It was proposed that the shape of the LV is intimately related to its performance and that its elongation (ELO) is a sensitive measure of this performance. The performance was tested against classical cardiovascular parameters. METHODS: Using echocardiography and Simpson's rule, the endocardial surface area of the LV was calculated noninvasively with a simple experimental-mathematical model at enddiastole and endsystole. ELO as shape index was derived from the endocardial surface area of the LV with a simple formula. The endocardial surface area of the LV and ELO were determined in volunteers, in patients with mild heart failure and in patients with severe heart failure. RESULTS: The normal value of endocardial surface area of LV at enddiastole is 138.3 cm2 while the normal value at endsystole is 99 cm2. The endocardial surface area of the LV is significantly bigger in patients with mild heart failure than in volunteers (p < 0.01) while the parameters ELO, ejection fraction and Doppler measurements are similar. The normal values of ELO at diastole and systole are 12 and 25 respectively. The value of ELO at endsystole is lower only in patients with severe heart failure. This means a more spherical shape and poor systolic function of the LV. CONCLUSION: ELO is usefull as quantitative and qualitative index of left ventricular shape. ELO could be integrated and applied with new diagnostic tools such three-dimensional and contrast echocardiography.

Hypervolaemia improves global and local function and efficiency in postischaemic myocardium.

1. In the present study, we investigated the effects of blood volume on postischaemic function and efficiency. In 14 anaesthetized dogs, following recovery from a period of 15 min occlusion of the left anterior descending coronary artery, the effects of hypervolaemia (HYPER; 15% increased volume produced by fast infusion of Hespan; B Braun Medical, Irvine, CA, USA), normovolaemia (NORMO) and hypovolaemia (HYPO) were studied. 2. Although myocardial O2 consumption was not significantly increased by volume (6.37+/-0.94 vs 6.89+/-1.1 mL/min per 100 g for HYPO and HYPER, respectively), local work of the stunned myocardium was markedly elevated (8.8+/-1.7 vs 22.5+/-3.5 g.mm/ beat, for HYPO and HYPER, respectively; P < 0.05). External work of the heart was also significantly improved (71.8+/-12.7 vs 139.5+/-16.2 mmHg.L/min for HYPO and HYPER, respectively). These data indicate markedly improved efficiency produced by volume, because work was increased with no change in myocardial O2 consumption. 3. Local dysfunction was characterized by several parameters, including systolic bulge, end-diastolic length, delay to onset of shortening, end shortening time delay (EST) and tail work ratio. Hypervolaemia reduced EST compared with hypovolaemia (98.6+/-18.3 vs 110.7+/-14.9 msec, respectively; P < 0.05) and improved tail work ratio (28.0+/-7.0 vs 36.0+/-7.0%, respectively; P < 0.05), with no effects on systolic bulge, end-diastolic length and delay to onset of shortening. 4. Thus, even in the postischaemic myocardium, increasing work by volume is energetically efficient and is accompanied by partial improvement of local dysfunction.

Noninvasive measurement of the human brachial artery pressure-area relation in collapse and hypertension.

A noninvasive method to obtain pressure-lumen area (P-A) measurements of the human brachial artery is introduced. The data obtained from this method are analyzed using a mathematical model of the relationship between vessel pressure and lumen area including vessel collapse and hypertension. An occlusive arm cuff is applied to the brachial artery of ten normal subjects. The cuff compliance is determined continuously by means of a known external volume calibration pump. This permits the computation of the P-A curve of the brachial artery under the cuff. A model is applied to analyze the P-A relation of each subject. The results show that the lumen area varies considerably between subjects. The in vivo resting P-A curve of the brachial artery possesses features similar to that of in vitro measurements. A primary difference is that the buckling pressure is higher in vivo, presumably due to axial tension, as opposed to in vitro where it is near zero or negative. It is found that hypertension causes a shift in the P-A curve towards larger lumen areas. Also, the compliance-pressure curve is shown to shift towards higher transmural pressures. Increased lumen area provides an adaptive mechanism by which compliance can be maintained constant in the face of elevated blood pressure, in spite of diminished distensibility.

Beta-adrenergic stimulation of reperfused myocardium after 2-hour ischemia.

Postischemic myocardium possesses considerable contractile and metabolic reserves, but their mobilization could result in increased cell death. We tested the hypothesis that beta-adrenergic stimulation of reperfused myocardium would increase segment work more than O2 consumption, thereby improving efficiency without increased cell death. In 16 open-chest anesthetized dogs, the left anterior descending coronary artery (LAD) was ligated for 2 h; during the reperfusion period, isoproterenol (ISO; 0.1 microg/kg/min, i.v.) was administered to nine of the animals. Regional myocardial segment length and force were measured in the anterior (LAD) and posterior circumflex coronary artery (CFX) regions of the left ventricular myocardium. Work was calculated as the integrated products of force and shortening for each region. Regional myocardial O2 consumption was obtained from LAD flow and arterial and local venous O2 saturations. Infarct size (tetrazolium) was measured in the treated and untreated hearts at the end of the experiment. In untreated hearts, the first derivative of left ventricular pressure, cardiac output, and external work were significantly depressed during reperfusion; ISO restored all values to preocclusion levels. Regional myocardial work in both LAD and CFX regions was significantly increased by ISO (from 564 +/- 207 to 1,635 +/- 543 g/mm/min in LAD, and from 753 +/- 90 to 1,426 +/- 245 g/mm/min in CFX). Efficiency (work/oxygen consumption) of the reperfused region was similarly increased. LAD flow was significantly increased by ISO, and O2 extraction was unchanged. Infarct size was 28.2 +/- 4.7% in untreated hearts and 29.0 +/- 3.5% in ISO hearts. Thus isoproterenol stimulation significantly improved both regional and global function without subsequent evidence of increased cell death.

Vessel growth and collapsible pressure-area relationship.

The role that the pattern of vessel wall growth plays in determining pressure-lumen area (P-A) and pressure-compliance curves was examined. A P-A vessel model was developed that encompasses the complete range of pressure, including negative values, and accounts for size given the fixed length, nonlinear elastic wall properties, constant wall area, and collapse. Data were obtained from excised canine carotid and femoral arteries, jugular veins, and elastic tubing. The mean error of estimate was 8 mmHg for all vessels studied and 2 mmHg for blood vessels. The P-A model was employed to examine two patterns of arterial wall thickening, outward growth and remodeling (constant wall area), under the assumption of constant wall properties. The model predicted that only outward wall growth resets compliance such that it increases at a given arterial pressure, explaining previously contradictory data. In addition, it was found that outward wall growth increases the lumen area between normal and high pressures. Remodeling resulted in lumen narrowing and a decrease in compliance for positive pressures.

Novel design of a regional myocardial force transducer.

A novel force transducer was designed to measure the circumferential regional force developed in the ventricular myocardium in vivo. The transducer is composed of a frame, a carrier bar, and a cantilever spring. Two resistance strain gauges embedded on the spring serve as force-sensing elements. The output of a Wheatstone-bridge circuit, containing these two gauges and a temperature compensation resistor, is connected to a preamplifier. The main advantages of this prototype include the initial stretch-adjustment ability (physiologic 0) low temperature drift, high linearity (r = 0.99) with loads ranging from 0 to 100 g, and moderate sensitivity of 0.232 mV/V/g at room temperature. The transducer was validated with in-vivo canine experiments. The experimental results showed that this transducer can be used to reliably measure the myocardial force development during altered cardiac conditions, such as myocardial stunning and myocardial ischemia.

Modeling of mechanical dysfunction in regional stunned myocardium of the left ventricle.

Reversible mechanical dysfunction of the myocardium after a single or multiple episode(s) of coronary artery occlusion has been observed in previous studies and is termed myocardial stunning. The hypothesis that stunning could be represented by a decrease in maximum available muscle force in the stunned region was examined by means of a mathematical model that incorporates series viscoelastic elements. A canine experimental model was also employed to demonstrate depressed contractility and a consistent delay of shortening in the stunned region. The mechanical model of the left ventricle was designed to include a normal and stunned region, for which the stunned region was allowed to have variable size. Each region consisted of a volume and time dependent force generator in parallel with a passive elastic force element. The passive elastic element was placed in series with a constant viscosity component and a series elastic component. The model was solved by means of a computer. Passive and active properties of each region could be altered independently. The typical regional measures of muscle performance such as percent shortening, percent bulge, percent thickening, delay of shortening, percent increase in end-diastolic length and other hemodynamic measures were computed. These results were similar to those observed in animal models of stunning. In addition, a nearly linear relationship with end-diastolic length and delay of shortening was predicted by the model. It was concluded that a decrease in the peak isovolumic elastance and augmentation of viscosity effect of creep during stunning can explain mechanical abnormalities of stunned myocardium.

Analysis of effect of two concurrent ischaemic zones on left ventricular function.

Left ventricular (LV) function due to two concurrent ischaemic zones (IZs) is investigated using a cardiovascular system model. The model comprises a three-compartment LV, the venous return and the arterial system. Haemodynamic responses of the LV to changes in the IZ size and myocardial contraction timings are explored. Results show that the greater the degree of asynschonisation is between the normal zone and the IZ, and the larger the ischaemic size, the more severe the LV dysfunction. Pre-load augmentation improves LV function. Model-predicted features are consistent with reported observations associated with myocardial ischaemia. The extent of the usefulness and limitations of this model is also discussed.

Amyloid beta-mediated oxidative and metabolic stress in rat cortical neurons: no direct evidence for a role for H2O2 generation.

H2O2 and free radical-mediated oxidative stresses have been implicated in mediating amyloid beta (1-40) [A beta (1-40)] neurotoxicity to cultured neurons. In this study, we confirm that addition of the H2O2-scavenging enzyme catalase protects neurons in culture against A beta-mediated toxicity; however, it does so by a mechanism that does not involve its ability to scavenge H2O2. A beta-mediated elevation in intracellular H2O2 production is suppressed by addition of a potent H2O2 scavenger without any significant neuroprotection. Three intracellular biochemical markers of H2O2-mediated oxidative stress were unchanged by A beta treatment: (a) glyceraldehyde-3-phosphate dehydrogenase activity, (b) hexose monophosphate shunt activity, and (c) glucose oxidation via the tricarboxylic acid cycle. lonspray mass spectra of A beta in the incubation medium indicated that A beta itself is an unlikely source of reactive oxygen species. In this study we demonstrate that intracellular ATP concentration is compromised during the first 24-h exposure of neurons to A beta. Our results challenge a pivotal role for H2O2 generation in mediating A beta toxicity, and we suggest that impairment of energy homeostasis may be a more significant early factor in the neurodegenerative process.

Computer modeling of non-adjacent regional ischemic zones on ventricular function.

Multiple regional myocardial ischemia that leads to depressed left ventricular (LV) function is commonplace. Quantitative analysis of the hemodynamic consequences, however, has been limited. We investigated this aspect using a novel computer model of the cardiovascular system. The model consists of an LV with two ischemic zones (IZs) and a normal zone (NZ), the preload, and the arterial system afterload. The IZ size and activation timing could be altered. Results show that the greater the size and activation asynchronization between NZ and IZ, the more severe the LV dysfunction. Increased preload during ischemia improved LV function. This computer model predicts features that agree well with reported experimental observations and is particularly useful for myocardial ischemic function analysis.

Linear hydraulic pressure-pulse actuator (LHPA): a versatile instrument that produces a simulated blood pressure pulse wave for small sized vessels.

An instrument is presented which produces a simulated circulatory pulsatile pressure wave for small sized vessels. The linear hydraulic pressure-pulse actuator (LHPA) is designed to be extremely versatile, that is, a blood pressure wave source of any shape, amplitude, offset and frequency can be simulated. In addition, the LHPA can reproduce accurately a real pulse pressure wave by simply imputting an actual data record of a circulatory pressure pulse. The design is accomplished by incorporating the use of a linear force solenoid driven with a voltage-to-current source power amplifier. Testing of the device is presented here, as well as pressure pulse results from a recorded pulsatile pressure input to the LHPA. The device is simple to implement in that its response is linear, for volume changes upto +/- 5 mL, without the need for feedback compensation.

Impairment of integrin-mediated cell-matrix adhesion in oxidant-stressed PC12 cells.

Oxidants are believed to play an important and complex role in neuronal injury and death in the aging process and various neurode generative diseases. We studied the effect of oxidative stress on integrin-mediated cell-extracellular matrix (ECM) interactions using the PC12 neuronal cell line. In assays in which attachment was measured between 30 and 90 min, addition of hydrogen peroxide (H2O2) to the attachment medium resulted in a dose-dependent inhibition of initial cell attachment to collagen. Addition of H2O2 also caused previously attached cells to detach from collagen. The inhibition by H2O2 was specific for integrin-mediated adhesion, since attachment to substrata coated with non-ECM molecules was much less affected. Exposure of cells to H2O2 resulted in a rapid and profound reduction of intracellular ATP, accompanied by only a slight increase in intracellular free Ca2+ concentration ([Ca2+]i). Treatment of cells with the microfilament-disrupting agent, cytochalasin B, like that with H2O2, inhibited cell adhesion to collagen. We propose that integrin-mediated cell adhesion, which requires interactions between cytoplasmic portions of integrin subunits and cytoskeletal microfilaments, is impaired by oxidative stress as a result of the depletion of intracellular ATP and that such depletion is an early event in the process of oxidant-induced neuronal injury.

Human cortical neuronal (HCN) cell lines: a model for amyloid beta neurotoxicity.

Human cortical neuronal cell lines HCN-1A and HCN-2 are killed for following exposure of the differentiated cells to amyloid beta-peptide(1-40), a component of senile plaques and other amyloid deposits in brains from Alzheimer's patients. We present a model of A beta toxicity uncomplicated by the presence of other cell types that can be used to address the mechanism of A beta neurotoxicity. This model will be useful in the evaluation of neuroprotective compounds which may attenuate cortical neuronal loss in Alzheimer's disease.

Theory of the oscillometric maximum and the systolic and diastolic detection ratios.

It is proposed that the maximum in cuff pressure oscillations during oscillometry is due to the buckling of the brachial artery under a cuff. This theory is investigated by means of a mathematical model of oscillatometry that includes the mechanics of the occlusive arm cuff, the arterial pressure pulse waveform, and the mechanics of the brachial artery. A numerical solution is provided for the oscillations in cuff pressure for one cycle of cuff inflation and deflation. The buckling pressure is determined from actual arterial data and the von Mises buckling criteria. The buckling of an artery under a cuff occurs near -2 to 0 mm Hg transmural pressure. This effect corresponds with a maximum arterial compliance and maximum cuff pressure oscillations when cuff pressure is nearly equal to mean arterial pressure (MAP), in support of the suggested theory. The model was also found to demonstrate the basic characteristics of experimental oscillometry, such as an increasing and decreasing amplitude in oscillations as cuff pressure decreases, the oscillations that occur when cuff pressure is above systolic pressure, maximum oscillation amplitudes in the range of 1 to 4 mm Hg, and an oscillatory maximum at cuff pressure equal to MAP. These findings support the case that the model is representative of oscillometry. Finally, the model predicted values for the systolic and diastolic detection ratios of 0.593 and 0.717, respectively, similar to those found empirically. These ratios alter with blood pressure, but the tightness of the cuff wrap did not change their value.

Real-time left ventricular volume of the canine heart from ultrasonic dimension data.

A real-time (instantaneous) system is presented to measure the dynamic volume of the left ventricle. This system uses the invasive measurement of long axis diameter, short axis diameter, and wall thickness of the cardiac left ventricle. Three pairs of pulse-transit ultrasonic dimension transducers are used to obtain these measurements. The dynamic volume was then found by applying these measurements to an ellipsoidal shell model of the left ventricle. It is possible to obtain on-site, real-time, continuous measurements of the left ventricular volume (LVV) by employing an electronic device which implements a corrected volume equation for the ellipsoidal shell model. The device's output is a calibrated estimation for the LVV. The function of the device is shown to compare well with other accepted measurements for the LVV.

Mechanics of the occlusive arm cuff and its application as a volume sensor.

Although a common medical instrument, the mechanical function of an occlusive arm cuff has not been fully described in an engineering sense. The occlusive arm cuff is examined here using a mathematical mechanics model and experimental measurements. Cuff stretch was modeled by a nonlinear pressure-volume function. Air compression was represented by Boyle's law. An apparatus was developed to measure pressure due to the air volume pumped into the cuff for fixed arm volume. Data were obtained for two different cuff designs, and reveal a nonlinear cuff pressure-volume relationship that could be represented accurately by the mathematical model. Calibration constants are provided for the two types of occlusive cuff. Thus, the cuff pressure was found to consist of a balance between that produced by stretch of the elastic cuff bladder and that of the compression of the air contained within the bladder. The use of the gas law alone was found to be inadequate to represent the cuff mechanics. When applying the cuff to measure change in arm volume, such as during plethysmography or oscillometry, it cannot be assumed that the cuff sensitivity is constant. More precisely, it was found that the occlusive cuff is a transducer with a volume sensitivity that increases with cuff pressure and volume until it becomes nearly constant at high levels of cuff pressure (150 mmHg). A hypothetical case of a linear elastic artery with constant pulse pressure was used as input to the cuff model to illustrate the change in cuff pressure oscillations that occurs while cuff pressure is released.(ABSTRACT TRUNCATED AT 250 WORDS)

Ascorbic acid-enhanced antiproliferative effect of flavonoids on squamous cell carcinoma in vitro.

We examined the effects of flavone and two polyhydroxylated plant flavonoids (quercetin and fisetin), either singly or in combination with ascorbic acid, on the growth of a human squamous cell carcinoma cell line (HTB 43) in vitro. Fisetin and quercetin significantly impaired cell growth in the presence of ascorbic acid. Exposure of cells to ascorbic acid (2 micrograms/ml) and 2 micrograms/ml of either fisetin or quercetin resulted in 61 and 45% inhibition of cell growth, respectively, in 72 h, while treatment with ascorbic acid alone had no effect on cellular proliferation. Flavone and ascorbic acid, either as single agents or in combination, exhibited no significant inhibition at any of the concentrations tested. The enhancement of the antiproliferative effect of the above flavonoids by ascorbic acid may be due to its ability to protect these compounds against oxidative degradation.

Peripheral vascular effects on auscultatory blood pressure measurement.

Experiments were conducted to examine the accuracy of the conventional auscultatory method of blood pressure measurement. The influence of the physiologic state of the vascular system in the forearm distal to the site of Korotkoff sound recording and its impact on the precision of the measured blood pressure is discussed. The peripheral resistance in the arm distal to the cuff was changed noninvasively by heating and cooling effects and by induction of reactive hyperemia. All interventions were preceded by an investigation of their effect on central blood pressure to distinguish local effects from changes in central blood pressure. These interventions were sufficiently moderate to make their effect on central blood pressure, recorded in the other arm, statistically insignificant (i.e., changes in systolic [p < 0.3] and diastolic [p < 0.02]). Nevertheless, such alterations were found to modify the amplitude of the Korotkoff sound, which can manifest itself as an apparent change in arterial blood pressure that is readily discerned by the human ear. The increase in diastolic pressure for the cooling experiments was statistically significant (p < 0.001). Moreover, both measured systolic (p < 0.004) and diastolic (p < 0.001) pressure decreases during the reactive hyperemia experiments were statistically significant. The findings demonstrate that alteration in vascular state generates perplexing changes in blood pressure, hence confirming experimental observations by earlier investigators as well as predictions by our model studies.