Howard L. Haber

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.

Specific factor Xa inhibition reduces restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits.

BACKGROUND Balloon angioplasty of atherosclerotic arteries results in activation of the coagulation cascade. Several coagulation factors, including factor Xa and thrombin, are mitogenic for vascular smooth muscle cells in vitro and thus may play a role in restenosis after balloon angioplasty. Specific inhibition of factor Xa can be achieved with recombinant antistasin (rATS) or tick anticoagulant peptide (rTAP). We hypothesized that inhibition of Xa would limit restenosis after balloon angioplasty in an atherosclerotic rabbit model. METHODS AND RESULTS Focal femoral atherosclerosis was induced by air desiccation injury and a high-cholesterol diet in 38 New Zealand White rabbits. Recombinant antistasin (n = 20 arteries) or rTAP (n = 14 arteries) was administered by intravenous bolus at the time of balloon angioplasty and followed by a 2-hour infusion; controls (n = 21 arteries) received bolus heparin alone (150 U/kg). Therapeutic prolongation of the activated partial thromboplastin time occurred, and antithrombotic drug levels were achieved in all animals. Luminal diameter in millimeters by quantitative angiography did not differ between treatment groups before (1.1 +/- 0.2 for controls, 1.1 +/- 0.2 for rATS, and 1.1 +/- 0.3 for rTAP) or after balloon angioplasty (1.5 +/- 0.3 for controls, 1.4 +/- 0.2 for rATS, and 1.4 +/- 0.2 for rTAP). At 28 days, treatment with factor Xa inhibitors tended to result in arteries with larger luminal diameter than controls (1.2 +/- 0.3 for rATS, 1.2 +/- 0.3 for rTAP versus 1.0 +/- 0.3 for control, P = .09 by one-way ANOVA). Restenosis, defined as reduction in angiographic luminal diameter (in mm) from 2 hours after angioplasty to 28 days after angioplasty was less in the rATS group than in controls (-0.2 +/- 0.1 versus -0.5 +/- 0.4, P < .001) and tended to be less in the rTAP group (-0.3 +/- 0.2 versus -0.5 +/- 0.4, P = .07). Quantitative histopathological analysis showed less percent cross-sectional area narrowing by plaque in both rATS- and rTAP-treated arteries compared with controls (42 +/- 21%, 47 +/- 18%, and 63 +/- 14%, respectively; P < .01 by one-way ANOVA). CONCLUSIONS We conclude that a 2-hour infusion of rATS or rTAP reduced angiographic restenosis and resulted in less luminal cross-sectional narrowing by plaque compared with controls.

Why do patients with congestive heart failure tolerate the initiation of beta-blocker therapy?

BACKGROUND Despite its negative inotropic effects, the initiation of beta-adrenergic blockade is tolerated by patients with congestive heart failure (CHF). Accordingly, we examined the acute hemodynamic effects of beta-adrenergic blockade on systolic and diastolic left ventricular (LV) function and ventriculo-arterial coupling. In addition, isolated myocardium from patients with CHF shows selective beta 1-receptor downregulation, implying a greater role for the beta 2-receptor in maintaining in vivo LV contractility. As a secondary aim, we hypothesized that nonselective beta-adrenergic blockade would have greater negative inotropic effect than beta 1-blockade in patients with CHF. METHODS AND RESULTS Patients with clinical CHF (n = 24) and control patients without CHF (n = 24) were given either the nonselective beta-blocker propranolol or the beta 1-selective blocker metoprolol. LV pressure-volume relations were obtained before and after the administration of intravenous beta-blocker, and measures of LV systolic and diastolic function were examined. Patients with CHF had a deterioration in LV systolic function with a fall in LV systolic pressure (139 +/- 6 to 125 +/- 6 mm Hg), cardiac index (2.56 +/- 0.11 to 2.20 +/- 0.11 mL.min-1 x M-1), dP/dtmax (1173 +/- 63 to 897 +/- 50 mm Hg/s), and end-systolic elastance (0.88 +/- 0.10 to 0.64 +/- 0.10 mm Hg/mL), P < .05 for all. Although there was deterioration of active LV relaxation (isovolumetric relaxation 63 +/- 2 to 73 +/- 3 milliseconds, peak filling rate 543 +/- 33 to 464 +/- 28 mL/s, P < .05 for both), there was no change in passive LV diastolic function (pulmonary capillary wedge, 24 +/- 2 to 24 +/- 1 mm Hg; chamber stiffness, 0.0154 +/- 0.0005 to 0.0163 +/- 0.0005 mL-1, P = NS for both), and a decrease in afterload (arterial elastance 3.85 +/- 0.31 to 3.38 +/- 0.24 mm Hg/mL, P < .05). Control patients had no change in these parameters other than a prolongation of isovolumetric relaxation (48 +/- 1 to 55 +/- 2 milliseconds, P < .05). The effects of propranolol (n = 12) versus metoprolol (n = 12) on these parameters in patients with CHF were similar. CONCLUSIONS These data do not support a greater in vivo physiological role of the myocardial beta 2-receptor in CHF. The preservation of passive diastolic function and ventriculo-arterial coupling provide possible explanations of why beta-adrenergic blockade is tolerated by patients with CHF.

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.

Ventricular systolic assessment in patients with dilated cardiomyopathy by preload-adjusted maximal power. Validation and noninvasive application.

BACKGROUND Noninvasive cardiac-specific analysis of contractile function in patients with dilated heart failure remains problematic. This study tests whether maximal power divided by the square of end-diastolic volume (PWRmx/EDV2, or preload-adjusted PWRmx) can provide such assessment. METHODS AND RESULTS To validate the load insensitivity of the PWRmx index and determine its response to contractile change, 24 subjects with chronic dilated cardiomyopathy underwent invasive pressure-volume catheterization study using the conductance catheter technique. Preload was transiently reduced by 30% using balloon occlusion of the inferior vena cava, and afterload impedance was lowered by 50%, induced by a bolus injection of nitroglycerin. Contractile state was varied by intravenous dobutamine, verapamil, or esmolol. PWRmx was calculated from the simultaneous product of ventricular pressure and rate of volume change (dV/dt), the latter derived from the volume catheter signal. PWRmx varied directly with preload but was minimally influenced by afterload. However, PWRmx/EDV2 was not significantly altered by either loading change. PWRmx/EDV2 did vary with contractility, correlating closely with changes in the end-systolic pressure-volume relation (r = .91, P < .001). To test the noninvasive application of this index, 12 additional patients were studied, with PWRmx/EDV2 derived from nuclear ventriculography combined with a novel method to measure central arterial pressures. Subjects received intravenous nitroprusside or dobutamine in random order. Ejection fraction increased similarly with both agents (+42.9 +/- 8.9% for dobutamine and +29.4 +/- 5.3% for nitroprusside, both P < .01). In contrast, PWRmx/EDV2 did not significantly change with nitroprusside but increased by 126 +/- 16.1% with dobutamine (P < .01). CONCLUSIONS Preload-adjusted PWRmx is a steady-state index of ventricular systolic function that is sensitive to inotropic state and minimally influenced by physiological changes in afterload impedance or volume load. It appears useful for noninvasive cardiac-specific analysis of acute drug effects.

Effect of chronic subcutaneous or intramural administration of heparin on femoral artery restenosis after balloon angioplasty in hypercholesterolemic rabbits. A quantitative angiographic and histopathological study.

BackgroundHeparin is known to have antithrombotic, anticoagulant, and antiproliferative effects. We hypothesized that chronic subcutaneous and/or direct intramural administration of heparin would reduce restenosis and inhibit plaque growth after balloon angioplasty. Methods and ResultsFocal atherosclerosis was induced bilaterally in the femoral arteries of 59 rabbits by air desiccation intimal injury and a 2% cholesterol diet. After angioplasty, the rabbits were assigned to one of four treatment groups. Control arteries (n =21) received no additional heparin. A second group of 20 arteries was treated with a porous balloon that delivered heparin (1,500 units) directly into the arterial wall. A third group (n=29) received subcutaneous heparin (350 units. kg−1·day−1) for 28 days, and a fourth group (n=23) was treated with subcutaneous and intramural heparin. Quantitative angiography showed a modest reduction in restenosis (defined as the change in minimal luminal diameter from immediately after angioplasty to 28 days) with subcutaneous heparin compared with control arteries (032±0.18 versus 0.58±0.34 mm, p<0.01); however, luminal diameter was not improved at 28 days compared with before angioplasty. Intramural delivery of heparin by the porous balloon catheter was confirmed by use of fluoresceinated heparin in one animal. Angiographic restenosis was not reduced in arteries treated with intramural heparin versus controls (0.61±0.54 versus 0.58±034 mm, p=NS). Blinded planimetric analysis of histological sections showed no differences in luminal cross-sectional area narrowing by atherosclerotic plaque, in plaque area, or in plaquelmedia ratio at 28 days among the four treatment groups. ConclusionsChronic subcutaneous heparin after balloon angioplasty results in a modest reduction in angiographic restenosis in this model; however, the absolute luminal diameter is not improved compared with before angioplasty, and plaque area and percent luminal narrowing by plaque were not different among the four treatment groups. Heparin can be delivered into an atherosclerotic plaque by a porous balloon, but this treatment does not reduce restenosis after angioplasty in this model.

Bolus intravenous nitroglycerin predominantly reduces afterload in patients with excessive arterial elastance.

OBJECTIVES We hypothesized that bolus intravenous nitroglycerin would be an afterload-reducing agent in patients with excessive initial afterload for their level of left ventricular systolic function. Conversely, bolus intravenous nitroglycerin should be a preload-reducing agent in patients without excessive initial afterload. BACKGROUND Although nitroglycerin has both preload- and afterload-reducing actions, methods to predict its predominant site of action in an individual patient have not been previously described. METHODS Left ventricular pressure-volume relations were recorded with micromanometer and conductance catheters during bolus injection of intravenous nitroglycerin in 27 patients with both normal left ventricular systolic function and varying degrees of congestive heart failure. Preload was determined by end-diastolic volume, afterload by effective arterial elastance, left ventricular systolic function by end-systolic elastance and coupling of afterload and ventricular function by the ratio of effective arterial elastance to end-systolic elastance (Ea/Ees ratio). An Ea/Ees ratio > 1 was defined as excessive afterload for the level of ventricular function. RESULTS Patients with an initial Ea/Ees ratio < 1 (Group 1) constituted a group of normotensive patients with intact ventricular function who exhibited a predominant reduction in preload in response to intravenous nitroglycerin. Those with an initial Ea/Ees ratio > 1 and normal or mildly depressed ventricular function (Group 2a) constituted a group of patients, most of whom were hypertensive, who exhibited a predominant afterload reduction. Finally, those with an initial Ea/Ees ratio > 1 and abnormal ventricular function (Group 2b) constituted a group of patients with clinical congestive heart failure who exhibited both preload and afterload reduction but a predominant afterload reduction because stroke volume increased. CONCLUSIONS Patients with normal arterial elastance and ventricular function respond to nitroglycerin with a predominant preload reduction, whereas patients with either excessive arterial elastance or abnormal ventricular function respond with a predominant afterload reduction.

Exercise thallium-201 scintigraphy after thrombolytic therapy with or without angioplasty for acute myocardial infarction

Scant data are available concerning the application and results of exercise thallium-201 (Tl-201) scintigraphy after acute myocardial infarction (AMI) treated with thrombolytic therapy. The goals of this study were to determine the ability of exercise Tl-201 scintigraphy to detect inducible ischemia and to identify multivessel coronary artery disease (CAD) in 88 consecutive postinfarction patients who received thrombolytic therapy and underwent both predischarge noninvasive testing and coronary angiography. Exercise-induced Tl-201 redistribution on quantitative scintigraphy was significantly more prevalent than exercise ST-segment depression (48 vs 14%, p < 0.001). Sensitivity and specificity of exercise ST depression alone for identification of multivessel disease was 29 and 96%, respectively. Sensitivity of a remote Tl-201 defect for multivessel CAD detection was 35 and 87%, respectively--not significantly different from values for ST depression alone. When considered as a single variable, the presence of either ST depression or a remote Tl-201 defect was associated with a 58% sensitivity (p < 0.05, compared with either ST depression or Tl-201 redistribution alone), but a somewhat diminished specificity of 78%. There was no difference in extent or severity of angiographic CAD in patients with multivessel CAD with or without inducible ischemia. In conclusion, this study shows that exercise Tl-201 imaging is more sensitive than exercise Tl-201 imaging is more sensitive than exercise ST depression for detection of residual ischemia during submaximal exercise in patients who received thrombolytic therapy for AMI. The combination of the presence of either Tl-201 redistribution or ischemic ST depression was better than either variable alone for identifying patients with multivessel CAD.

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.

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