Clarence C. Wu

Relationship between left ventricular wall thickness and left atrial size: Comparison with other measures of diastolic function

We postulated that in patients with essential hypertension and normal left ventricular (LV) systolic function, left atrial (LA) size correlates with LV wall thickness by better reflecting the chronicity and duration of LA hypertension than the commonly used hemodynamic and Doppler measures of LV diastolic function. Accordingly, hemodynamic, Doppler, and two-dimensional echocardiographic measurements were performed in 30 subjects with no cardiovascular abnormalities other than essential hypertension (mean systolic blood pressure of 150 +/- 29 mm Hg). The mean LV wall thickness was 0.57 +/- 0.14 cm/m2 and the mean LV ejection fraction was 0.62 +/- 0.12. Hemodynamic and Doppler measures including pulmonary capillary wedge and LV end-diastolic pressures, isovolumic LV pressure relaxation, LV chamber elastic stiffness, and E/A ratio (E and A waves on the pulsed Doppler signal of the mitral valve) correlated poorly (r = 0.01 to -0.52) with LV wall thickness. Both E/A ratio and isovolumic LV pressure relaxation correlated better (p = 0.05) with patient age than with LV wall thickness. In contrast, LA area (in the apical four-chamber view) had a good correlation (r = 0.77 for LA area in atrial diastole and r = 0.86 for LA area in atrial systole) with LV wall thickness. Multiple regression analysis revealed LA area in atrial systole to be the best correlate of LV wall thickness. We conclude that because the left atrium is a thin-walled structure, its size may increase with an increase in LA pressure. In the absence of mitral valve disease and atrial fibrillation, LA size may reflect the chronicity and duration and thus the history of LA hypertension. LA size in the apical four-chamber view may, therefore, provide a simple noninvasive assessment of the degree of LV diastolic dysfunction.

Intracoronary angiotensin-converting enzyme inhibition improves diastolic function in patients with hypertensive left ventricular hypertrophy.

BACKGROUND There is increasing recognition of myocardial angiotensin-converting enzyme, which is induced with the development of left ventricular hypertrophy (LVH). The potential physiological significance of subsequent increased angiotensin I to II conversion in the presence of LVH is unclear but has been postulated to cause abnormal Ca2+ handling and secondary diastolic dysfunction. Accordingly, we hypothesized that acute angiotensin-converting enzyme inhibition would result in decreased production of angiotensin II and improved active (Ca(2+)-dependent) relaxation in patients with hypertensive LVH. METHODS AND RESULTS Intracoronary (IC) enalaprilat was administered to 25 patients with and without LVH secondary to essential hypertension. Indexes of diastolic and systolic LV function were determined from pressure (micromanometer)-volume (conductance) analysis at steady state and with occlusion of the inferior vena cava. Patients were divided into those receiving high- (5.0 mg, n = 15) and low-dose (1.5 mg, n = 10) IC enalaprilat during a 30-minute infusion at 1 mL/min. The high-dose patients were further divided along the median normalized LV wall thickness of 0.671 cm/m2. The time constant of isovolumic relaxation (TauL) was prolonged at baseline in patients receiving high-dose enalaprilat with wall thickness > 0.671 cm/m2 (TauL, 56 +/- 2 versus 44 +/- 2 and 45 +/- 2 milliseconds, respectively, P < .01 by ANOVA) and shortened only in this patient group (TauL, 49 +/- 3 versus 46 +/- 2 and 43 +/- 2 milliseconds, respectively, P < .01 versus baseline and other groups by ANOVA). The improvement in TauL was directly proportional to the degree of LVH (r = .92, P < .001). Although there was a decrease in LV end-diastolic pressure (23 +/- 2 to 15 +/- 1 mm Hg, P < .01) and volume (86 +/- 8 to 67 +/- 9 mL/m2, P < .05) in those patients with a reduction in TauL, this is due to movement down a similar diastolic pressure-volume relation with no change in chamber elastic stiffness (0.023 +/- 0.002 to 0.025 +/- 0.004 mL-1, P = NS). CONCLUSIONS Intracoronary enalaprilat resulted in an improvement in active (Ca(2+)-dependent) relaxation in those patients with more severe hypertensive LVH. The improvement in active relaxation was directly proportional to the severity of LVH. These results support the hypothesis that the cardiac renin-angiotensin system is an important determinant of active diastolic function in hypertensive LVH.

Acute Cardiovascular Effects of OPC-18790 in Patients With Congestive Heart Failure Time- and Dose-Dependence Analysis Based on Pressure-Volume Relations

BACKGROUND OPC-18790 is a water-soluble quinolinone derivative that shares the pharmacological properties of vesnarinone and that may be useful for treating heart failure. We studied the contribution and relative dose sensitivities of the inotropic, lusitropic, and vascular effects of OPC-18790 in patients with dilated cardiomyopathy. METHODS AND RESULTS Pressure-volume (PV) analysis was performed in 17 patients who received either 5 micrograms.kg-1.min-1 (low dose, n = 10) or 10 micrograms.kg-1.min-1 (high dose, n = 7) OPC-18790 by 1-hour IV infusion. Right heart pressures and flow and left heart PV relations (conductance catheter) were measured at baseline and every 15 minutes during infusion. Transient inferior vena caval obstruction was used to determine PV relations. Both doses produced venodilation reflected by a 10% decline in left ventricular end-diastolic volume and a 30% fall in atrial and pulmonary artery pressures. Arterial dilation was four times greater at the high dose, with an approximately 40% fall in effective arterial elastance and systemic resistance. Contractility rose by 25% to 100% (depending on PV index) with both doses. Ventricular-arterial coupling (ratio of ventricular end-systolic to arterial elastances) was approximately 0.25 at baseline and doubled (or tripled) at low (or high) dose, correlating with improved efficiency. Isovolumetric relaxation shortened, whereas the diastolic PV relation was generally unchanged. Heart rate was unaltered. CONCLUSIONS OPC-18790 has potent venous and arterial vasodilator effects and moderate inotropic and lusitropic effects without a change in heart rate. These combined actions suggest a unique potential of OPC-18790 for heart failure treatment.

Myocardial Contrast Echocardiography Can Be Used to Quantify Intramyocardial Blood Volume New Insights Into Structural Mechanisms of Coronary Autoregulation

BACKGROUND Changes in intramyocardial blood volume (IBV) mediate autoregulatory adaptations to coronary stenosis. This study investigated whether (1) myocardial contrast echocardiography (MCE) can quantify changes in IBV during coronary stenosis and (2) the relation between coronary resistance- and MCE-derived IBV could yield insight into structural mechanisms of IBV change. METHODS AND RESULTS A circulating in vitro model with constant flow and varying volume was used to determine whether indicator dilution theory could be applied to MCE. Contrast echo was performed with albumin microbubbles, and time-intensity data were fit to a gamma-variate function. With six different volumes, bubble transit time was linearly related to volume (r=.91). To determine whether changes in IBV could be quantified in vivo, the left anterior descending coronary artery in 12 dogs was instrumented with a flow probe, occluder, and intracoronary pressure catheter, and non-flow-limiting stenoses were created. IBV was derived by use of coronary resistance measurements applied to models that assumed autoregulation to occur via vasodilatation or microvascular recruitment. MCE-IBV was calculated from microbubble transit rates. At constant flow, MCE and resistance IBV increased with stenosis. Although MCE and resistance IBV were linearly related, MCE overestimated IBV derived from the vasodilatation model and underestimated IBV calculated from the recruitment model. CONCLUSIONS MCE can quantify autoregulatory increases in IBV that maintain resting myocardial perfusion. These data suggest that both microvessel vasodilatation and recruitment are dual mechanisms of IBV change. MCE thus may be a clinically useful technique for the detection and quantification of coronary artery disease at rest.

Accuracy of the conductance catheter for measurement of ventricular volumes seen clinically: effects of electric field homogeneity and parallel conductance

The conductance-volume method is an important clinical tool which allows the assessment of left ventricular function in vivo. However, the accuracy of this method is limited by the homogeneity of electric field the conductance catheter produces and the parallel conductance of surrounding structures. This paper examines these sources of error in volumes seen clinically, The characteristics of electric field within a chamber were examined using computer simulation. Nonconductive and conductive models were constructed and experimental measurements obtained using both single-field (SF) and dual-field (DF) excitation. Results from computer simulations and in vitro measurements were compared to validate the proposed theoretical model of conductance-volume method. The effects of field homogeneity and significance of parallel conductance in volume measurement were then determined. The results of this study show that DF provide a more accurate measure of intraventricular volume than SF, especially at larger volumes. However, both significantly underestimate true volume at larger volumes. In addition, the parallel conductance due to the chamber wall is significant at small volumes, but diminishes at larger volumes. Furthermore, the effect of parallel conductance beyond the chamber wall may be negligible. This study demonstrates the limitations in applying current conductance technology to patients with dilated hearts.

Fabrication of microstructures using aluminum anodization techniques

A promising technique for the fabrication of high-aspect-ratio microstructures, presented by Tan et. al. at MEMS-95, takes advantage of the highly ordered pore structure of anodic metal oxides. In this work, we have extended and simplified this method. This process is capable of producing high-aspect-ratio microstructures oriented normal to a nonplanar substrate. Unlike the original process in which the aluminum substrate was anodized to the desired depth, masked and subsequently etched, the modified process involves performing the masking lithography prior to anodization. Patterned areas of an aluminum substrate are masked with a 0.6/spl mu/m layer of sputtered silicon dioxide. The SiO/sub 2/ layer prevents anodization in masked areas while the oxide grows in unmasked areas. In this paper, we present preliminary results using this local anodization process on aluminum substrates and discuss the use of the process for fabricating structures on nonplanar substrates.

Direct myocardial effects of OPC-18790 in human heart failure: Beneficial effects on contractile and diastolic function demonstrated by intracoronary infusion with pressure-volume analysis

OBJECTIVES We sought to determine the precise myocardial effects of OPC-18790 as demonstrated by intracoronary administration. BACKGROUND Although previous studies have determined the cardiovascular effects of a novel intravenous inotrope, OPC-18790, the observed benefits on contractile and diastolic function may have been confounded by the marked changes in peripheral loading associated with this drug when given intravenously. METHODS Eight heart failure patients received intracoronary OPC-18790 at 31.25 microg/min for 20 min, and then at 62.5 microg/min for another 20 min. Hemodynamic variables and pressure-volume indexes using the conductance catheter method were determined at baseline and then after the two doses. RESULTS There were no significant effects on heart rate, cardiac output or loading conditions, including afterload as determined by systemic vascular resistance and arterial elastance (Ea) and preload as determined by end-diastolic volume (EDV). There were significant increases in end-systolic elastance (Ees) from 0.74+/-0.11 to 0.90+/-0.16 mm Hg/ml at 31.25 microg/min and to 137+/-0.33 mm Hg/ml at 62.5 microg/min (p < 0.05 by analysis of variance [ANOVA]). Diastolic function improved, as determined by the time constant for isovolumetric relaxation tau, which decreased significantly from baseline to 31.25 microg/min (94+/-9 to 79+/-9 ms, p < 0.05), and did not shorten further at 62.5 microg/min (78+/-8 ms, p=NS). There were significant decreases in right atrial pressure (9+/-1 to 7+/-1 mm Hg, p < 0.01 by ANOVA) and mean pulmonary artery wedge pressure (21+/-3 to 16+/-2 mm Hg, p < 0.05 by ANOVA). This fall in filling pressures was not accompanied by any change in EDV. Inspection of the diastolic portion of the pressure-volume curve confirmed a downward shift consistent with pericardial release in five of the eight patients. CONCLUSIONS Intracoronary administration of OPC-18790 demonstrates that the direct myocardial effects of this agent include a modest increase in inotropy and improvement in diastolic function, both of which occur without increases in heart rate, indicating that this agent may be beneficial for the intravenous treatment of congestive heart failure.

Microfabricated device for arterial wall and atherosclerotic plaque penetration

Percutaneous coronary intervention is currently used to treat coronary atherosclerosis but is plagued by restenosis. The atherosclerotic plaque acts as a barrier, preventing the delivery of drugs or gene therapy to prevent restenosis. The authors hypothesize that microfabricated probes, manufactured using silicon fabrication technology, can penetrate through atherosclerotic plaque, creating paths for therapeutic delivery. Two sets of microfabricated probes (65/spl plusmn/15 and 140/spl plusmn/20 /spl mu/m) were deployed in normal and atherosclerotic rabbit iliac artery segments (n=5 each) under distention pressures of 100, 200, 300, and 500 mmHg, to simulate deployed stents. The tissues were fixed while the probes remained in place and analyzed using standard SEM, TEM and light microscopy techniques to evaluate the extent and nature of vessel penetration. In healthy tissue, microprobes are able to pierce the internal elastic lamina and penetrate the media, with the highest probes nearly reaching the media/adventitia boundary. Atherosclerotic plaque is pierced by microprobes at all intraluminal pressures examined. These results indicate that microprobes may serve as a technique to penetrate the atherosclerotic plaque for the purpose of delivering therapeutics beyond the plaque.

Use of the conductance cathieter to determine left ventricular volume: current leakage beyond the left ventricular cavity

The conductance catheter offers the only method for the determination of left ventricular volume on a continuous basis in patients. Two potential limitations of this technique include inhomogeneity of the electric field and current leakage into adjacent structures. The objectives of this study were to determine the extent of current leakage into adjacent structures and the source of additional volume detected when the electric field is made more homogeneous. Both nonconductive and conductive cylinders over the range of left ventricular volumes seen clinically were constructed. The conductance catheter was radially centered in the models and a signal conditioner-processor was used to generate the electric field and calculate the corresponding volume. The conductive models were surrounded by saline to simulate surrounding structures. We demonstrate that electric current does not extend beyond the model wall, implying that adjacent structures such as the right ventricle are unlikely to affect the conductive volume measurements in vivo. Second, rhe increased homogeneity of the electric field detects more chamber but not more wall volume. INTRODUCTION The conductance volume measurement method employs a multi-electrode catheter to generate an electric field in the left ventricle and measure instantaneous segmental resistance from which cardiac volumes are determined. It is the only instrument for the determination of left ventricular volume on a continuous basis in patients during studies of left ventricular function [l]. There are two potential limitations in equating conductance volume with chamber volume. The first involves the inhomogeneity of the electric field. Baan et af introduced a new method called dual field excitation. Analytical analysis has shown that a more homogeneous electric field is generated using this new excitation technique [ 2 ] . As a result, more volume is detected using dual field excitation. A second limitation involves the possibility of current leakage into adjacent structures, and has been termed parallel conductance. The objectives of this study were to determine: 1) the extent of current leakage beyond the left ventricular chamber and 2) the source of additional volume detected by dual field excitation. METHODS Nine nonconductive Plexiglas cylinders with volumes ranging from 6 to 340 ml were constructed. Ten conductive carbon black-polypropylene cylinders were cast with volumes ranging from 19 to 340 ml. The resistivity, rho, of the carbon black polypropylene was determined to be 24*5 ohm-cm (n=7). The inner cavity of the cylinders were filled with a sodium chloride solution of resistivity 11 ohmcm in order to approximately simulate the 1 :2 resistivity ratio of blood to myocardium [3]. A signal conditioner processor was used to generate the electric field and calculate the corresponding volume. Experiments were conducted using three different excitation modes of the conductance catheter: single field (SF), dual field 0.25 (DF-.25), and dual field 0.30 (DF-.30). The 0.25 and 0.30 modes of dual field excitation represent the current ratios of the correcting field to the original field [ 2 ] . Wall volume detected by the conductance catheter was determined by subtracting the volume signal of the nonconductive models from the volume signal of the conductive models. Volumes from the conductive models were measured with the cylinders surrounded first by air and then by sodium chloride solutions of two different resistivities (rho = 11, rho = 22 ohm-cm) in order to simulate surrounding blood and cardiac tissues, respectively . RESULTS The conductance catheter estimation of the Plexiglas cylinder volumes was found to be accurate in volumes less than 125 ml (Figure 1). However, in volumes seen clinically ( > 125 ml), the conductance catheter underestimated true volume in a nonlinear fashion. Dual field excitation increased the total volume detected, but did not enable the conductance catheter to detect the true chamber volume of the larger models. In the smaller conductive cylinders (<200 ml), the conductance catheter overestimated the true chamber volume, but did not exceed the chamber plus conductive wail volume (Figure 2) . However, in the larger conductive cylinders (> 200 ml), the conductance catheter 0-780313771/93

Method and apparatus for drug and gene delivery

3.00 631993 IEEE 903 underestimated true chamber volume. In both the nonconductive and the conductive models, the addition of dual field excitation increased the total volume detecled at larger total volumes (> 125 ml), but not at smaller total volumes (<50 ml). In addition, the use o f dual field excitation did not significantly increase the detection of conductive wall volume (Figure 3). The submergence of the conductive cylinders in sodium chloride solutions (rho = 1 I , rho = 22 ohm-cm) to simulate adjacent blood volumes and cardiac tissues, respectively, did not change the volume detected by the conductance catheter (Figure 4). = E 3 5 0