Dynamic myocardial contractile parameters from left ventricular pressure-volume measurements.

A new dynamic model of left ventricular (LV) pressure-volume relationships in beating heart was developed by mathematically linking chamber pressure-volume dynamics with cardiac muscle force-length dynamics. The dynamic LV model accounted for >80% of the measured variation in pressure caused by small-amplitude volume perturbation in an otherwise isovolumically beating, isolated rat heart. The dynamic LV model produced good fits to pressure responses to volume perturbations, but there existed some systematic features in the residual errors of the fits. The issue was whether these residual errors would be damaging to an application where the dynamic LV model was used with LV pressure and volume measurements to estimate myocardial contractile parameters. Good agreement among myocardial parameters responsible for response magnitude was found between those derived by geometric transformations of parameters of the dynamic LV model estimated in beating heart and those found by direct measurement in constantly activated, isolated muscle fibers. Good agreement was also found among myocardial kinetic parameters estimated in each of the two preparations. Thus the small systematic residual errors from fitting the LV model to the dynamic pressure-volume measurements do not interfere with use of the dynamic LV model to estimate contractile parameters of myocardium. Dynamic contractile behavior of cardiac muscle can now be obtained from a beating heart by judicious application of the dynamic LV model to information-rich pressure and volume signals. This provides for the first time a bridge between the dynamics of cardiac muscle function and the dynamics of heart function and allows a beating heart to be used in studies where the relevance of myofilament contractile behavior to cardiovascular system function may be investigated.

Smooth muscle relaxation and local hydraulic impedance properties of the aorta.

Smooth muscle relaxation is expected to yield beneficial effects on hydraulic impedance properties of large vessels. We investigated the effects of intravenous diltiazem infusion on aortic wall stiffness and local hydraulic impedance properties. In seven anesthetized, closed-chest dogs, instantaneous cross-sectional area and pressure of the descending thoracic aorta were measured using transesophageal echocardiography combined with acoustic quantification and a micromanometer, respectively. Data were acquired during a vena caval balloon inflation, both at the control condition and with diltiazem infusion. At the operating point, diltiazem reduced blood pressure in all dogs but did not alter aortic dimensions or wall stiffness. Over the observed pressure range, aortic area-pressure relationships were linear. Whereas diltiazem affected the slope of this relationship variably (no change in 3 dogs, increase in 1 dog, decrease in 3 dogs), the zero-pressure area intercept was significantly increased in every case such that higher area was observed at any given pressure. When comparisons were made at a common level of wall stress, wall stiffness was either increased or unchanged during diltiazem infusion. In contrast, diltiazem decreased wall stiffness in every case when comparisons were made at a common level of aortic midwall radius. Aortic characteristic impedance and pulse wave velocity, components of left ventricular hydraulic load that are determined by aortic elastic and geometric properties, were affected variably. A comparison of wall stiffness at matched wall stress appears inappropriate for assessing changes in smooth muscle tone. Because of the competing effects of changes in vessel diameter and wall stiffness, smooth muscle relaxation is not necessarily accompanied by the expected beneficial changes in local aortic hydraulic impedance. These results can be reconciled by recognizing that components other than vascular smooth muscle (e.g., elastin, collagen) contribute to aortic wall stiffness.

Accuracy of echocardiographic estimates of left ventricular mass in mice.

Genetically modified mice have created the need for accurate noninvasive left ventricular mass (LVM) measurements. Recent technical advances provide two-dimensional images adequate for LVM calculation using the area-length method, which in humans is more accurate than M-mode methods. We compared the standard M-mode and area-length methods in mice over a wide range of LV sizes and weights (62-210 mg). Ninety-one CD-1 mice (38 normal, 44 aortic banded, and 9 inherited dilated cardiomyopathy) were imaged transthoracically (15 MHz linear transducer, 120 Hz). Compared with necropsy weights, area-length measurements showed higher correlation than the M-mode method (r = 0.92 vs. 0.81), increased accuracy (bias +/- SD: 1.4 +/- 27.1% vs. 36.7 +/- 51.6%), and improved reproducibility. There was no significant difference between end-systolic and end-diastolic estimates. The truncated ellipsoid estimation produced results similar in accuracy to the area-length method. Whereas current echocardiographic technology can accurately and reproducibly estimate LVM with the two-dimensional, area-length formula in a variety of mouse models, additional technological improvements, rather than refinement of geometric models, will likely improve the accuracy of this methodology.

The left ventricular stress-velocity relation in transgenic mice expressing a dominant negative CREB transgene in the heart.

OBJECTIVE: CREB(A133) transgenic mice that express a dominant negative CREB transcription factor in cardiomyocytes develop a dilated cardiomyopathy that is anatomically, physiologically, and clinically similar to human idiopathic dilated cardiomyopathy. The goals of this study were to quantitate left ventricular (LV) contractility and measure cardiac reserve in CREB(A133) mice by using the relation of end-systolic wall stress to the velocity of fiber shortening. METHODS: A total of 37 adult CD-1 mice (including both nontransgenic and CREB(A133) transgenic mice) were studied with simultaneously acquired high-fidelity instantaneous aortic pressures and 2-dimensionally targeted M-mode echocardiograms. RESULTS: CREB(A133) mice displayed significantly lower values of LV fiber shortening velocities over a wide range of afterloads, and they displayed smaller dobutamine-induced shifts from baseline contractility relations. Counterbalancing effects of differences in LV geometry and aortic pressures resulted in comparable levels of LV wall stress during ejection in both groups. CONCLUSION: These results demonstrate directly that CREB(A133) mice display reduced LV contractility at baseline and decreased cardiac reserve.

Disparate effects of three types of extracellular acidosis on left ventricular function.

Effects of acidosis on muscle contractile function have been studied extensively. However, the relative effects of different types of extracellular acidosis on left ventricular (LV) contractile function, especially the temporal features of contraction, have not been investigated in a single model. We constituted perfusion buffers of identical ionic composition, including Ca2+ concentration ([Ca2+]), to mimic physiological control condition (pH 7.40) and three types of acidosis with pH of 7.03: inorganic (IA), respiratory (RA), and lactic (LA). Isolated rabbit hearts (n = 9) were perfused with acidotic buffers chosen at random, each preceded by the control buffer. Under steady-state conditions, instantaneous LV pressure (Pv) and volume (Vv) were recorded for a range of Vv. The results were as follows. 1) LV passive (end-diastolic) elastance increased with IA and RA. However, this increase may not be a direct effect of acidosis; it can be explained on the basis of myocardial turgor. 2) Although LV inotropic state (peak active Pv and elastance) was depressed by all three acidotic buffers, the magnitude of inotropic depression was significantly less for LA. 3) Temporal features of Pv were altered differently. Whereas IA and RA reduced time to peak Pv (tmax) and hastened isovolumic relaxation at a common level of LV wall stress, LA significantly increased tmax and retarded relaxation. These results and a model-based interpretation suggest that cooperative feedback (i.e., force-activation interaction) plays an important role in acidosis-induced changes in LV contractile function. Furthermore, it is proposed that LA-induced responses comprise two components, one due to intracellular acidosis and the other due to pH-independent effects of lactate ions.

Serial assessment of the cardiovascular system in normal pregnancy. Role of arterial compliance and pulsatile arterial load.

BACKGROUND: Temporal changes in systemic arterial compliance and wave propagation properties (pulsatile arterial load) and their role in ventricular-systemic arterial coupling during gestation have not been explored. Noninvasive methods combined with recently developed mathematical modeling techniques were used to characterize vascular and left ventricular (LV) mechanical adaptations during normal gestation. METHODS AND RESULTS: Fourteen healthy women were studied at each trimester of pregnancy and again postpartum. Experimental measurements included instantaneous aortic pressure (subclavian pulse tracings) and flow (aortic Doppler velocities) and echocardiographic imaging of the LV. A small increase in LV muscle mass and end-diastolic chamber dimension occurred by late gestation, with no significant alterations in myocardial contractility. Cardiac output increased and the steady component of arterial load (total vascular resistance) decreased during pregnancy. Several changes in pulsatile arterial load were noted: Global arterial compliance increased (approximately 30%) during the first trimester and remained elevated thereafter. The magnitude of peripheral wave reflections at the aorta was reduced. The mathematical model-based analysis revealed that peripheral wave reflections at the aorta were delayed and that both conduit and peripheral vessels contributed to the increased arterial compliance. Finally, coordinated changes in the pulsatile arterial load and LV properties were responsible for maintaining the efficiency of LV-to-arterial system energy transfer. CONCLUSIONS: The rapid time course of compliance changes and the involvement of both conduit and peripheral vessels are consistent with reduced vascular tone as being the main underlying mechanism. The pulsatile arterial load alterations during normal pregnancy are adaptive in that they help to accommodate the increased intravascular volume while maintaining the efficiency of ventricular-arterial coupling and diastolic perfusion pressure.

Detachment of low-force bridges contributes to the rapid tension transients of skinned rabbit skeletal muscle fibres.

1. To probe the cross-bridge cycle and to learn more about the cardioplegic agent BDM (2,3-butanedione monoxime), its effects on the force-velocity properties and tension transients of skinned rabbit muscle fibres were studied at 1-2 degrees C and pH 7.0. 2. Three millimolar BDM decreased isometric force by 50%, velocity by 29%, maximum power by 73%, and stiffness by 25%, so that the relative stiffness (stiffness/force ratio) increased by 50% compared with reference conditions in the absence of BDM. 3. Tension transients obtained under the reference condition (0 BDM) could be represented by three components whose instantaneous stiffness accounted for the initial (Phase 1) force deviation and whose exponential recoveries caused the rapid, partial (Phase 2) force recovery following the step. The fastest component had non-linear extension-force properties that accounted for about half the isometric stiffness and it recovered fully. The two slower components had linear extension-force properties that together accounted for the other half of the sarcomere stiffness. These components recovered only partially following the step, producing the intermediate (T2) level which the force approached during Phase 2. 4. Matching the force transients obtained under test conditions (3 mM BDM) required three alterations: (1) reducing the amplitude of the two slower components by 50%, in proportion to isometric force, (2) adding a non-relaxing component and (3) decreasing the amplitude of the rapidly recovering component by 12.5% so that its relative amplitude (amplitude/isometric force) was increased by 75%. The non-recovering component and the increase in relative amplitude of the rapid component were responsible for the increase in relative stiffness of the fibres produced by BDM. The rapidly recovering component had the same time constant and step-size-dependent recovery rates as the fastest of the three mono-exponential components isolated from the tension transient response under the reference condition. BDM therefore appeared to augment the fastest component of the tension transient under the reference condition. 5. The results suggest that BDM detains cross-bridges in low-force, attached states. Since these bridges are attached, they contribute to sarcomere stiffness. Since they are detained, relaxation or reversal of their immediate responses is probably due to bridge detachment rather than to their undergoing the power stroke. The observation that a portion of the test response matched the fastest component of the reference response when the amplitude of the fastest component was increased suggests that a part of the normal rapid, transient tension recovery following a release step is due to detachment of low-force bridges moved to negative-force positions by the step.

Doppler echocardiographic reference values for healthy rhesus monkeys under ketamine hydrochloride sedation.

Cardiac ultrasound is a noninvasive technique that is commonly used to serially evaluate cardiac structure and function. Recent advances in Doppler-Echocardiography enable the ultrasonographer to perform a sophisticated noninvasive assessment of cardiovascular physiology. The Rhesus monkey is a frequently used non-human primate animal model of human cardiovascular disease because this species closely models human anatomy and physiology. However, while this species is frequently used in cardiovascular research, standardized echocardiographic values generated from large numbers of normal Rhesus are not available. In the present study, we performed cardiac ultrasound imaging on 28 healthy Rhesus monkeys to obtain normal reference values of cardiovascular structure and function in this species. Nomograms were generated from these data by plotting parameters of cardiovascular geometry and function with body weight. These normal reference data were compared to previously reported values obtained from prior studies that used noninvasive, invasive, and morphometric techniques.

Evaluation of ventricular and arterial hemodynamics in anesthetized closed-chest mice.

Transgenic and knock-out mice with cardiovascular phenotypes have created the need for methods to measure murine arterial and ventricular mechanics. The aims of this study were (1) to develop a method for the assessment of wall stress (sigma es)-rate corrected velocity of fiber shortening (Vcfc) relation and (2) to assess the feasibility of quantifying global arterial function in normal mice. This method can thus serve as a reference for future studies in genetically altered mice by establishing normal values for comparison. Ten anesthetized closed-chest mice were studied with targeted M-mode echocardiography of the left ventricle recorded simultaneously with high-fidelity aortic pressures. Data were acquired at baseline and during infusions of methoxamine and isoproterenol. Tracings were digitized to obtain end-systolic wall stress (sigma es) and rate-corrected velocity of fiber shortening (Vcfc) relationships and plots of systolic meridional wall stress. Instantaneous aortic pressures and continuous wave aortic Doppler velocities were digitized to study arterial hemodynamics. The Vcfc-sigma es relationship was inverse and linear in all mice studied with a median value of r2 = 0.94. Isoproterenol resulted in an upward shift from the baseline contractility line obtained with methoxamine (mean shift = 2.0 +/- 0.3 circ/sec). Relative to baseline the integral of wall stress decreased with isoproterenol and increased with methoxamine. Methoxamine increased mean arterial pressure and total vascular resistance and decreased heart rate, cardiac output, and arterial compliance. Isoproterenol decreased total vascular resistance and increased cardiac output. Stress-shortening relationships, systolic wall stress, and evaluation of vascular function can be obtained in a closed-chest mouse model.

Ejection has both positive and negative effects on left ventricular isovolumic relaxation.

In isovolumically beating hearts, the speed of left ventricular (LV) relaxation is uniquely determined by peak active stress (sigma max). In contrast, such a succinct description of relaxation is lacking for the ejection beats, although ejection is generally thought to hasten relaxation. We set out to determine how ejection modifies the relaxation-sigma max relationship obtained in the isovolumically beating hearts. Experiments were performed on five isolated rabbit hearts subjected to various loading conditions. Instantaneous LV pressure and volume were recorded and converted to active stress, from which isovolumic relaxation time (Tr) was defined as the time for stress to fall from 75 to 25% of sigma max (isovolumic beats) or its end-ejection value (ejection beats). Steady-state and transient isovolumic beat and steady-state ejection beat data were used to develop a multiple regression model. This model identified stress, current beat ejection, and previous beat ejection history as independent predictor variables of Tr and fit the data well in all hearts (r2 > 0.98). Furthermore, this model could predict relaxation in transient ejection beats (r2 = 0.30 for all hearts). Whereas the coefficient for the current beat ejection was negative (i.e., negative effect or hastening relaxation), the ejection history coefficient was positive (i.e., positive effect or slowing relaxation). The sum of these two coefficients was negative, corresponding to the commonly observed net negative effect of ejection on relaxation. The expected positive inotropic effect of ejection was also observed. The dissipations of both positive inotropic and relaxation effects were slow, suggesting a nonmechanical underlying mechanism(s). We postulate that these two effects are linked and caused by ejection-mediated changes in myofilament Ca2+ sensitivity.

Echocardiographic contrast agents and left ventricular contractility: evaluation using an isolated rabbit heart model.

The effects of Albunex (Molecular Biosystems, Inc., San Diego, Calif.) and a second generation contrast agent, FS069, on left ventricular (LV) contractility were evaluated using an isolated rabbit heart model under constant loading conditions and heart rate. Contrast injections (2 ml total volume) were performed in two separate protocols (N1 = 6, N2 = 6). In protocol 1, various doses of Albunex (0.1 to 2.0 ml in saline solution) were used, and paired control injections of a matched dose of 5% solution of human albumin in saline solution were administered. In protocol 2, LV contractility was assessed during injections of the following solutions: (1) 1:250 suspension of FS069 in saline solution, which caused optimal myocardial contrast enhancement; (2) a 1:25 suspension of FS069; (3) a 1:25 suspension of FS069 prefiltered using an 8 microns pore filter; and (4) 2 ml saline solution as a control. Instantaneous LV pressure was analyzed for variations in peak systolic pressure (peak P) and maximum pressure derivative (peak P'), both indices of LV contractility under conditions of fixed heart rate and chamber volume. Albumin alone caused a transient, dose-dependent depression of LV contractility, reflected by decreases in both peak P and peak P' values. These decreases presumably were caused by the decreasing availability of ionized calcium as a result of calcium binding. No further decrease in contractility was noted when Albunex microspheres were present in the solution. Saline injections caused a transient minor increase in LV contractility, reflected by increases of 4.5% +/- 1.1% and 10.6% +/- 3.8% in peak P and peak P' values, respectively. These levels returned to baseline levels within 2 minutes. A similar response was observed when a 1:250 suspension of FS069 was used. The 1:25 suspension of FS069 caused a bimodal response, with initial rises in peak P and peak P' levels (5.2% +/- 3.6% and 12.8% +/- 6.5%, respectively), followed by minor reductions in contractility (2.0% +/- 2.4% and 1.7% +/- 2.1%, respectively). The latter decrease in contractility caused by the 1:25 suspension of FS069 was eliminated by filtering. The isolated rabbit heart model is a highly sensitive tool that allows accurate and direct assessment of possible adverse effects of intravascular contrast agents on LV contractility. Using this model, we showed that neither Albunex microspheres nor FS069 microspheres impaired myocardial contractility.

Aortic elastic properties with transesophageal echocardiography with automated border detection: validation according to regional differences between proximal and distal descending thoracic aorta.

We have previously described the use of transesophageal echocardiography with automated border detection to quantify regional aortic elastic properties. The purpose of this study was to validate this technique further by measuring regional variations of aortic elastic properties and comparing them with previously published data acquired by invasive methods. In nine anesthetized, closed-chest dogs, aortic pressure and lumenal area (transesophageal echocardiography with automated border detection) signals were recorded simultaneously at two aortic sites: just distal to the branching site of the left subclavian artery (proximal) and at the level of the diaphragm (distal). Instantaneous wall thickness was estimated by combining M-mode measurement of aortic end-diastolic thickness with instantaneous lumenal area. Data were acquired over a wide range of loading conditions, generated by inferior vena caval balloon occlusion. Aortic compliance per unit length, midwall radius, midwall stress, and incremental elastic modulus were computed. Aortic midwall radius and incremental elastic modulus values for proximal and distal aortic sites were compared at a common level of midwall stress. Compliance per unit length was higher in the proximal compared with the distal descending thoracic aorta (0.013 +/- 0.003 versus 0.008 +/- 0.003 cm2/mm Hg; mean +/- SD; p = 0.0011). Midwall radius was larger at the proximal location (0.76 +/- 0.07 cm versus 0.64 +/- 0.07 cm; p = 0.0001), whereas incremental elastic modulus was greater distally (0.799 +/- 0.052 dynes x 10(6)/cm2 versus 0.912 +/- 0.130 dynes x 10(6)/cm2; p = 0.02). Lower compliance values at the distal site of the descending thoracic aorta resulted from greater wall stiffness and a smaller radius. Transesophageal echocardiography with automated border detection provides reliable measurements of instantaneous aortic areas necessary for quantifying regional elastic properties.

Wave propagation in coupled left ventricle-arterial system. Implications for aortic pressure.

The objective of this study was to examine the effects of wave propagation properties (global reflection coefficient gamma IG; pulse wave velocity, c(ph); and characteristic impedance zeta(o) on the mechanical performance of the coupled left ventricle-arterial system. Specifically, we sought to quantify effects on aortic pressure (P(ao)) and flow Q(ao) while keeping constant other determinants of P(ao) and Q(ao) (left ventricular end-diastolic volume, V(ed), and contractility, heart rate, and peripheral resistance, R(s)). Isolated rabbit hearts were subjected to real-time, computer-controlled physiological loading. The arterial circulation was modeled with a lossless tube terminating in a complex load. The loading system allowed for precise and independent control of all arterial properties as evidenced by accurate reproduction of desired input impedances and computed left ventricular volume changes. While propagation phenomena affected P(ao) and Q(ao) morphologies as expected, their effects on absolute P(ao) values were often contrary to the current understanding. Diastolic (Pd) and mean (Pm) P(ao) and stroke volume decrease monotonically with increases in gamma G, c(ph), or zeta(o) over wide ranges. In contrast, these increase had variable effects on peak systolic P(ao) (Ps): decreasing with gamma G, biphasic with c(ph), and increasing with zeta(o). There was an interaction between gamma G and c(ph) such that gamma G effects on P(m) and P(d) were augmented a higher C(ph) and vice versa. Despite large changes in system parameters, effects on Pm and Ps were modest ( < 10% and < 5%, respectively); effects on Pd were always two to four times greater. Similar results were obtained when the single-tube model of the arterial system was replaced by an asymmetrical T-tube configuration. Our data do not support the prevailing hypothesis that P(s) (and therefore ventricular load) can be selectively and significantly altered by manipulating gamma G, c(ph), and/or zeta o.

Fit to diastolic arterial pressure by third-order lumped model yields unreliable estimates of arterial compliance.

The pressure pulse contour analysis method uses a third-order lumped model to evaluate the elastic properties of the arterial system and their modifications with adaptive responses or disease. A fundamental assumption underlying this method is that the estimates of model parameters (two compliances, an inertance, and a peripheral resistance) obtained from a measurement of cardiac output, and a simultaneous measurement of an arterial pressure, are independent of the pressure measurement site. If true, this hypothesis would provide a minimally invasive method for estimation of arterial compliance. The aim of the present study was to test the validity of this assumption and the ability of the method to assess changes of compliance in response to vasoactive drug administration. In five anaesthetised, open-chest dogs we measured pulsatile pressure and flow in the ascending aorta and pulsatile pressure in the terminal aorta, under basal, vasoconstricted (methoxamine), and vasodilated (sodium nitroprusside) conditions. Model peripheral resistance was assumed equal to the ratio of mean pressure to cardiac output. Estimates of inertance and compliances, and the associated estimation errors, were determined by fitting the model output to either the diastolic portions of ascending aortic pressure, P(adt), or terminal aortic pressure, Ptd(t). Results showed that the assumption of independency of model parameter estimates on the arterial pressure measurement site was not verified. Different images of the vasoactive drug-induced changes in vascular compliance were obtained from fits to P(adt) and Ptd(t). Model parameter estimates were associated with high estimation errors and were very sensitive to the choice of the period of diastolic pressure to be fitted. Model predicted aortic pressure, over the entire heart cycle, did not compare well with experimental ascending aortic pressure. Our results question the reliability of the pressure pulse contour analysis method for evaluating arterial compliance.

Contrast echocardiographic quantification of regional myocardial perfusion: validation with an isolated rabbit heart model.

Quantification of regional myocardial tissue blood flow (RMBF) based on contrast echocardiography has yet to be achieved. This study validated our recently proposed algorithm for quantification of RMBF with colored microspheres. Experiments were carried out in an isolated rabbit heart preparation (n = 11). Aortic root injections of perfluoropropane-filled albumin microsphere solution (FS069) and colored microspheres were performed at five levels of coronary flow achieved by altering perfusion pressure. During each injection of contrast material, consecutive end-diastolic images of the heart and an extracardiac reference chamber were acquired with a 7.5 MHz transducer and digitized. Time-intensity curves from the reference chamber and myocardial regions of interest, corresponding to the anatomic segments used for colored microsphere analysis, were analyzed for RMBF. Blood flow was calculated as the intravascular volume fraction (ratio of areas under myocardial and reference curves) divided by mean transit time (deconvolution of impulse response) and compared with those obtained with colored microspheres. Injections of FS069 resulted in highly reproducible enhancement of myocardial contrast. Analysis of time-intensity curves provided consistent measurements of RMBF (r = 0.91), which correlated highly with microsphere data (r = 0.84). The use of this new algorithm allows accurate quantification of RMBF in the isolated heart model. Further validation of this approach in an animal model with peripheral intravenous injections of contrast material will allow noninvasive clinical measurements of RMBF.

Dynamic micromechanical properties of cultured rat atrial myocytes measured by atomic force microscopy.

The atomic force microscope (AFM) was used to quantify micromechanical properties (i.e., localized to an area of approximately 0.015 microns 2) of cultured rat atrial myocytes. Quiescent cells in calcium-free solution were quite compressible over the nuclear region, e.g., a force of 3-4 nN produced 180-225 nm cell indentation. Transverse stiffness of quiescent cells increased by approximately 2-fold after an increase in extracellular calcium from 0 to 5 mM and by approximately 16-fold after fixation with Formalin. There was five- to eightfold variation in stiffness of quiescent cells over the cell surface, such that stiffness was lowest over the nuclear region, and it increased toward the cell periphery. These regional variations correlated with the cytoskeletal heterogeneity as revealed by the AFM and fluorescence imaging. Localized contractile activity of beating cells could be monitored in terms of the surface deformation with high transverse spatial (approximately 1-3 nm) and temporal (60-100 microseconds) resolutions. Alterations in cell contractile activity with physiological perturbations and dynamic changes in cell stiffness during a single contraction could be observed. These results demonstrate the feasibility of AFM-based characterization of highly localized cellular micromechanical properties. Relationships among localized cell mechanical behavior and the underlying biochemical and/or structural environment, a crucial aspect in understanding cellular (dys)function, can now be directly examined.

Physiological relevance of T-tube model parameters with emphasis on arterial compliances.

The T-tube model of systemic arterial circulation was examined with respect to the physiological relevance of model parameters. root aortic pressure [Pao(t)] and flow [Qao(t)] and descending aortic flow [Qb(t)] were measured in anesthetized, open-chest dogs under control conditions, during inflation of a balloon positioned in the left external iliac artery (n = 5), and during infusion of vasoactive drugs nitroprusside (NTP, n = 4) and phenylephrine (PHL, n = 5). With Pao(t) as the input, the model accurately predicted both Qao(t) and Qb(t) under all conditions (r2 > 0.96). The balloon inflation data established the ability of the model to discriminate between proximal and distal arterial mechanical properties. Furthermore, proximal properties (i.e., tube characteristic impedances and transit times) were independent of distal properties such as terminal compliances and resistances (or equivalently, wave reflections). The effects of NTP and PHL were pharmacologically consistent and served to further validate this model. NTP primarily affected distal (load) properties, whereas PHL altered both load and tube parameters. Physiological interpretation of model parameters, particularly compliance, is also discussed. The ability of the model to correctly discriminate between proximal and distal arterial properties is relevant because these properties may affect cardiovascular function differently.

Alterations in systemic arterial mechanical properties during septic shock: role of fluid resuscitation.

The effects of septic shock (endotoxin; EDTX) on arterial mechanical properties were studied in anesthetized rabbits, both in the absence (EDTX alone) and presence (EDTX + fluids) of fluid resuscitation. Aortic pressure-flow (n = 20) and pressure-diameter (n = 10) measurements were used to calculate systemic arterial and regional aortic mechanical properties. At 3 h of EDTX shock, EDTX-alone rabbits had elevated total peripheral resistance (TPR, + 30%, P < 0.05), reduced cardiac output (CO, -40%, P < 0.05), and increased aortic characteristic impedance (Zc, +78%, P < 0.05). In contrast, the EDTX + fluids group responded with decreased TPR (-30%, P < 0.05), a tendency to increase CO (+23%), and elevated Zc (+46%, P < 0.05). A reduction in aortic diameter (-20%, P < 0.05) and an increase in elastic modulus (+50%, P < 0.05) and water content (+23%, P < 0.02) of the aortic wall were observed following endotoxemia. Thus following EDTX 1) "hyperdynamic" septic shock profile (i.e., low TPR, high CO) was observed only when concomitant fluid replacement was provided, 2) aortic wall stiffening was present due to both increased smooth muscle tone and vessel wall edema, and 3) fluid resuscitation resulted in discordant changes in TPR and Zc, suggesting differential flow-induced vasodilation between arteriolar and aortic smooth muscle.

Differential effects of chronic oral antihypertensive therapies on systemic arterial circulation and ventricular energetics in African-American patients.

BACKGROUND: A comprehensive evaluation of arterial load characteristics and left ventricular energetics in systemic hypertension has been limited by the need for invasive techniques to access instantaneous aortic pressure and flow. As a consequence of this methodological limitation, no data exist on the effects of long-term antihypertensive therapy on global arterial impedance properties and indexes of myocardial oxygen consumption (MVO2). Using recently validated noninvasive techniques, we compared in hypertensive patients the effects of chronic oral treatment with ramipril, nifedipine, and atenolol on arterial impedance and mechanical power dissipation as well as indexes of MVO2. METHODS AND RESULTS: Sixteen African-American subjects with systemic hypertension were studied with a randomized, double-blind, crossover protocol. Instantaneous central aortic pressure and flow, from which arterial load characteristics can be derived, were estimated from calibrated subclavian pulse tracings (SPTs) and continuous-wave aortic Doppler velocity in conjunction with two-dimensional (2D) echocardiographic measurements of the aortic annulus, respectively. To derive ventricular wall stress and indexes of MVO2, left ventricular short- (M-mode) and long-axis (2D echo) images were acquired simultaneously with SPTs. Data were collected at the end of a 2-week washout period (predrug control) and after 6 weeks of treatment with each agent. Although all three agents reduced diastolic blood pressure to the same extent, different effects on mean and systolic pressures and vascular impedance properties were noted. Nifedipine reduced total peripheral resistance (TPR; 1744 +/- 398 versus 1290 +/- 215 dyne-s/cm5) and increased arterial compliance (ACL; 1.234 +/- 0.253 versus 1.776 +/- 0.415 mL/mm Hg). This improvement in arterial compliance was not entirely accounted for by the reduction in distending pressure. Ramipril also decreased TPR (1740 +/- 292 versus 1437 +/- 290 dyne-s/cm5) and increased ACL (1.214 +/- 0.190 versus 1.569 +/- 0.424 mL/mm Hg), but with this agent, the change in arterial compliance was explained solely on the basis of a reduction in distending pressure. Atenolol, in contrast, did not affect either TPR or ACL. In agreement with the compliance results, nifedipine and ramipril significantly lowered the first two harmonics of the impedance spectrum, but atenolol did not. None of these agents resulted in a significant change in characteristic impedance or in the relative amplitude of the reflected pressure wave. Total vascular mechanical power and percent of oscillatory power remained unaltered with all antihypertensive treatments. Only ramipril and nifedipine reduced the integral of both meridional and circumferential systolic wall stresses, indicating that MVO2 per beat was reduced with these agents. Stress-time index, a measure of MVO2 per unit time, decreased significantly with ramipril but not with nifedipine because of an increase in heart rate noted in 10 of 16 patients (mean increase, 10 beats per minute). Thus, a reduction in MVO2 coupled with unchanged total vascular mechanical power suggests improved efficiency of ventriculoarterial coupling with ramipril and with nifedipine in the subset of patients in whom heart rate remained unchanged. In contrast, there was no evidence of a reduction in wall stress, stress integral, or stress-time index with atenolol. CONCLUSIONS: The noninvasive methodology used in this study constitutes a new tool for serial and simultaneous evaluation of arterial hemodynamics and left ventricular energetics in systemic hypertension. In this study, we demonstrate the differential effects of chronic antihypertensive therapies on systemic arterial circulation and indexes of MVO2 in African-American subjects. Consideration of drug-induced differential responses of arterial load and indexes of MVO2 with each drug may provide a more physiological approach to the treatment of systemic hypertension in indivi

Effects of left ventricular pressure on sonicated albumin microbubbles: evaluation using an isolated rabbit heart model.

OBJECTIVES: We used an isolated, crystalloid-perfused rabbit heart model to test the hypothesis that the phasic changes in left ventricular contrast are due to bubble compression and decompression during systole and diastole, respectively. BACKGROUND: Contrast enhancement of the left ventricular cavity has been shown to decrease during ventricular systole. This phenomenon has been attributed to pressure-induced microbubble destruction. Such destruction, if confirmed, would severely confound the quantitative interpretation of contrast echocardiographic data. METHODS: A fixed volume of contrast solution (5% human albumin and Albunex, approximately 400:1 ratio) was introduced into a latex balloon placed within the left ventricular cavity of an isolated paced rabbit heart preparation (n = 12). Instantaneous left ventricular pressure was measured using a high fidelity microtip catheter and digitized on-line. The beating heart was placed in a water tank, and ultrasound images were obtained using a 7.5-MHz transducer and were recorded and digitized off-line at 12 frames/s. Simultaneously, the pacing signal was used for gated on-line acquisition of end-diastolic frames. A simple theoretic model based on surface tension physical principles was used to predict changes in bubble size and, consequently, the reflection intensity in response to the measured changes in left ventricular pressure. RESULTS: We found that under peak left ventricular systolic pressures ranging from 89 to 155 mm Hg, 1) end-diastolic videointensity decreased by 8 +/- 6% (mean +/- SD) over 25 consecutive heart beats; and 2) intracyclic variations in measured videointensity were in close agreement with the theoretic calculations: 80.1 +/- 2.9% versus 80.2 +/- 4.6% of diastolic videointensity at systole. CONCLUSIONS: The major cause of systolic decrease in contrast enhancement is periodic bubble compression (as opposed to bubble destruction) induced by high systolic pressures. The minor progressive decrease in end-diastolic videointensity reflects the degree of instability of Albunex microbubbles under left ventricular pressures. However, the clinical impact of these destructive effects is likely to be only minor because of the rapid transit of microbubbles through the left heart chambers and myocardial microcirculation.