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Circulation. 1995;92:371-379

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(Circulation. 1995;92:371-379.)
© 1995 American Heart Association, Inc.

Articles

Mechanism of Adenosine-Induced Elevation of Pulmonary Capillary Wedge Pressure in Humans

Presented in part at the 66th Scientific Sessions of the American Heart Association.

Amit Nussbacher, MD; Sigemituzo Ariê, MD; Roberto Kalil, MD; Pedro Horta, MD; Marc D. Feldman, MD; Giovanni Bellotti, MD; Fulvio Pileggi, MD; Mark Ellis, BS; William H. Johnson, RN; Gustavo B. Camarano, MD; David A. Kass, MD

From Instituto do Coraçao (A.N., S.A., R.K., P.H., G.B., F.P.), University of Sáo Paulo, Brazil; Division of Cardiology (M.D.F., M.E., W.H.J., G.B.C.), University of Virginia (Charlottesville); and Department of Medicine (D.A.K.), Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Md.

Correspondence to David A. Kass, MD, Halsted 500, Division of Cardiology, The Johns Hopkins Medical Institutions, 600 N Wolfe St, Baltimore, MD 21287.


*    Abstract
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 *Abstract
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down arrowResults
down arrowDiscussion
down arrowConclusions
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Background Continuous intravenous administration of adenosine to humans often results in a paradoxical rise in pulmonary capillary wedge pressure (PCWP), whereas arterial resistance is lowered and cardiac output and heart rate increase. This is believed to be due to diastolic stiffening of the ventricle or to a negative inotropic effect. In the present study, we tested these and other mechanisms by using pressure–volume (PV) analysis and echocardiography.

Methods and Results Fifteen patients with normal rest left ventricular function underwent cardiac catheterization and received adenosine at a rate of 140 µg/kg per minute IV for 6 to 10 minutes. PV relations were measured in 9 patients (without coronary artery disease) using the conductance catheter method. In 6 additional patients with coronary artery disease, echocardiograms were used to assess wall thickness and function, and aortic and coronary sinus blood, lactate, oxygen, and adenosine levels were measured. Adenosine increased PCWP by 19% (+2.6 mm Hg) in both patient groups while lowering arterial load by 30% and increasing cardiac output by 45% (all P<.001). There was no significant effect of adenosine on mean linear chamber compliance or monoexponential elastic stiffness, as the diastolic PV relation was unchanged in most patients. Diastolic wall thickness also was unaltered. Thus, the PCWP rise did not appear to be due to diastolic stiffening. Adenosine induced a rightward shift of the end-systolic PV relation (ESPVR) (+12.7±3.7 mL) without a slope change. This shift likely reflected effects of afterload reduction, as other indexes (stroke work–end-diastolic volume relation and dP/dtmax at matched preload) were either unchanged or increased. Furthermore, this modest shift in ESPVR was more than compensated for by vasodilation and tachycardia, so reduced systolic function could not explain the increase in PCWP. There also was no net lactate production to suggest ischemia. Rather than arising from direct myocardial effects, PCWP elevation was most easily explained by a change in vascular loading, as both left ventricular end-diastolic volume and right atrial pressure increased (P<.05). This suggests that adenosine induced a redistribution of blood volume toward the central thorax.

Conclusions PCWP elevation in response to adenosine primarily results from changes in vascular loading rather than from direct effects on cardiac diastolic or systolic function.


Key Words: adenosine • hemodynamics • diastole • contractility • pressure–volume relations


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowConclusions
down arrowReferences
 
Intravenous administration of adenosine to humans induces potent electrophysiological and cardiovascular responses. When delivered as a rapid bolus, adenosine slows sinus rate and delays atrioventricular nodal conduction.1 Both of these actions have proved to be useful for the treatment of supraventricular tachyarrhythmias.2 Continuous administration yields a very different response, marked by sinus tachycardia and coronary and peripheral vasodilation.3 4 5 6 7 8 9 10 11 This latter mode of delivery has also proved to be clinically useful, particularly when combined with radioscintigraphy, to assess myocardial perfusion abnormalities.9 12

Although many of the hemodynamic responses to continuous intravenous adenosine are well understood, one effect that remains puzzling is an increase in pulmonary capillary wedge pressure (PCWP).13 The exact magnitude of PCWP rise varies among studies from 3 mm Hg to as much as 12 mm Hg, but frequently some increase is reported.4 9 10 11 This response is quite different from that of most commonly used vasodilators.14 15 16 17 PCWP elevation in response to adenosine has dampened enthusiasm for the use of this agent in patients with heart failure.5 10 It also may raise concerns about flow scintigraphy data. Specifically, if the PCWP rise reflected substantial alterations in underlying left ventricular (LV) function, these changes might influence the flow results.

In a recent editorial, Verani13 proposed several mechanisms to explain the adenosine effect on PCWP. The leading hypothesis was that adenosine altered LV function by inducing sufficient vasodilation to engorge the coronary vasculature and lower chamber compliance through an erectile effect. Support for this mechanism was provided by data reported from a study in isolated rabbit hearts.18 Alternatively, adenosine might have a cardiodepressant effect from either direct stimulation of A1 receptors or ischemia due to "coronary steal."13 19 20 The latter appeared less likely given that substantial PCWP elevation was reported in patients with normal epicardial vessels, in whom ischemic ECG and wall motion abnormalities were absent.9 According to a third mechanism, adenosine had negative lusitropic effects that delayed relaxation and thereby elevated diastolic pressures. Last, the PCWP elevation might result from an increase in ventricular volumes due to altered vascular loading. Such volume changes could lead to even greater pressure increases in the presence of an intact pericardium.

The present study was designed to test each of these potential mechanisms of adenosine-induced PCWP elevation in humans. In one group of patients, we used continuous high-fidelity pressure–volume (PV) analysis with conductance catheters. This method provides beat-to-beat quantification of ventricular systolic and diastolic function and therefore is well suited for studying a rapidly acting substance anticipated to simultaneously influence multiple components of cardiovascular function. In a second group of patients, we evaluated the influence of adenosine infusion on regional wall thickness and wall motion, coronary sinus oximetry, lactate, and adenosine concentration.


*    Methods
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 *Methods
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Study Population
The present study was performed in two patient groups. Group 1 studies (n=9) were conducted at The Heart Institute, University of Sáo Paulo Medical School, Brazil. These patients were evaluated with catheter-based PV analysis21 22 23 to examine cardiac mechanics and vascular loading responses to intravenous adenosine. Group 2 studies (n=6) were conducted at the University of Virginia at Charlottesville. These patients were studied with transthoracic echocardiography to measure ventricular wall thickness changes during adenosine administration. In addition, aortic and coronary sinus blood levels of adenosine, lactate, and oxygen saturation were determined. Group 1 subjects were referred for atypical chest pain syndrome, and all had angiographically normal coronary arteries and left ventriculography. However, coronary spasm and syndrome X were not explicitly ruled out. All group 2 patients, on the other hand, had significant coronary artery disease (two had one-vessel disease and four had multivessel disease). No patient in either group had a prior myocardial infarction or displayed baseline wall motion abnormalities. In addition, group 2 patients did not have ischemic ECG changes or echocardiographic wall motion abnormalities before or during adenosine infusion. Informed consent was obtained from all patients. The clinical protocols were approved by the Committee of Clinical Investigation, The Heart Institute, University of Sáo Paulo Medical School or the Human Investigation Committee, University of Virginia. There were no complications from the study.

Group 1: PV Study
Procedures
All patients first underwent routine left and right heart catheterization. A balloon-tipped flotation right heart catheter was introduced via a femoral vein to measure right atrial pressure (RAP) and PCWP. Cardiac output was measured by a thermodilution technique using the average of at least three separate determinations. After routine left heart catheterization, special catheters were placed for PV analysis. Details of this procedure have been reported.21 22 23 Briefly, an 8F multielectrode conductance (volume) catheter (Webster Labs) was advanced from the femoral artery to the LV apex. A micromanometer-tipped catheter (SPC-320, Millar) was advanced through the entire length of the conductance catheter to measure LV cavity pressure. The volume catheter was used with a stimulator/processor (Sigma V, CardioDynamics) that applied a dual-field,24 low-amperage alternating current to electrodes at the apex and aortic root and measured segmental voltages at intervening electrodes. These signals were converted to total chamber volume.

PV relations were measured during transient preload reduction induced by balloon obstruction of inferior vena caval (IVC) inflow.21 A 7F balloon occlusion catheter (SP-9168, Cordis) was introduced through a femoral vein and positioned in the right atrium. The balloon was inflated with 10 to 15 mL of CO2 and simultaneously withdrawn toward the IVC to rapidly reduce venous inflow. Additional inflation with 10 mL CO2 was used as needed to maintain preload reduction. The time required for each inflation-deflation sequence generally was 10 to 15 seconds. Several inflation attempts initially were made in each patient to determine the best balloon placement and method for achieving maximal preload reduction. Thereafter, single inflations were performed at the selected protocol time point. PV loops were monitored continuously during the protocol with the use of custom-designed data acquisition and display software.

Protocol
After the catheters were placed, baseline data were recorded at steady state and during transient preload reduction. Computer-digitized data were sampled every 5 milliseconds, and the results were stored onto disk. Adenosine then was infused at a rate of 140 µg/kg per minute for just more than 6 minutes. This is the dosage usually used for myocardial perfusion scintigraphy studies.9 12 Steady-state data were measured at each minute during adenosine infusion and at 10 minutes after infusion. End-systolic and end-diastolic PV relations (ESPVR and EDPVR, respectively) acquired during transient preload reduction were assessed at baseline, after 6 minutes of adenosine infusion, and after a 10-minute recovery.

Data Analysis
The conductance catheter signal is proportional to LV blood volume with a nonzero offset and nonunity slope. The offset results from conductive properties of the LV muscle wall and surrounding structures, and the slope results from nonuniform current density. Two-point calibration of the signal was performed based on thermodilution-derived stroke volume (SVtd) and ejection fraction (EF), which were measured by contrast ventriculography. End-diastolic and end-systolic volumes (EDV and ESV, respectively) were calculated from these values, as follows: EDV=SVtd/EF and ESV=EDV-SVtd. Corresponding volumes obtained from the raw catheter signal were set equal to these true values for calibration.

Steady-state ventricular parameters were derived from signal-averaged data using approximately five consecutive cardiac cycles at end expiration. End-diastolic pressure (EDP) was the pressure measured at the lower right corner of the PV loop, as determined by an automated algorithm.23 End-systolic pressure (ESP) was measured at the point of maximal elastance (maximal P/[V-Vo]), where Vo is the volume axis intercept of the ESPVR.21 EDV and ESV were determined by averaging volumes centered about mean LV pressure during isovolumic contraction and relaxation, respectively. SV was the mean width of the PV loop, and stroke work (SW) was the integrated area within the loop. The time constant of isovolumic relaxation ({tau}) was determined from pressures extending from -dP/dtmax to pressure at the onset of filling. The inverse slope of the linear regression of dP/dt versus P(t) yielded {tau}. Arterial load was assessed by the effective arterial elastance25 26 (Ea =ESP/SV), measured from steady-state PV loops. Ea combines mean resistive and pulsatile components of the arterial load into a single parameter and has been previously validated in humans by comparisons with aortic input impedance data.26

Systolic and diastolic chamber functions were assessed with the use of PV relations derived from the multiple cardiac cycles measured during transient IVC occlusion.21 Three methods were used to assess systolic function. One was the ESPVR, determined from the set of points of maximal P/(V-Vo), with Vo derived by an iterative method.21 The ESPVR slope (end-systolic elastance [Ees]) was obtained by perpendicular regression.21 The volume axis placement of each ESPVR was assessed by the ESV at an ESP of 130 mm Hg (ESV130), determined from this regression. This ESP was chosen as it lay within or very near the measured data range for all patients. The second systolic index was the SW-EDV relation derived from the same set of cardiac cycles.27 The slope of this relation (MSW) provided another relatively load-insensitive measure of systolic pump function. As with the ESPVR, the horizontal placement (ie, along the EDV axis) of SW-EDV relations was assessed within the measured data range by calculating the EDV at a common SW level of 10 000 mm Hg · mL (V10 000). The third systolic index was the maximal derivative of pressure (dP/dtmax) measured at a matched EDV. This method minimized the preload sensitivity of dP/dtmax.28 PV loops were selected from among those measured before or during IVC occlusion so that dP/dtmax could be compared at the highest EDV common to each experimental time point.

Diastolic PV relations were derived from the same set of multiple cardiac beats measured during transient IVC occlusion.21 22 23 To quantify chamber diastolic distensibility, we generated EDPVRs using data points from the latter third of cardiac filling (two points per beat). These data were fit to both linear23 (V=CdiaP+Co) and monoexponential22 (P=Po+a [e(bV)-1]) models to determine chamber compliance (Cdia) and elastic stiffness (b), respectively.

Group 2: Wall Thickening and Coronary Sinus Blood Analysis
Procedures
Transthoracic echocardiographic views of the LV were obtained in a left parasternal short-axis and/or subcostal view with the use of a 3.5-MHz phased-array transducer (RT5000, General Electric Medical Systems). Images were recorded on VHS tape and underwent subsequent blinded review by two independent observers. Fractional shortening and end-diastolic wall thickness were determined from M-mode images, and wall motion abnormalities were determined from two-dimensional images. Interobserver variability (weighted {kappa} statistic) has been previously reported29 from this laboratory to be .85, where a value >.8 signifies excellent agreement.

Adenosine content in coronary sinus blood was measured with a specially designed catheter that mixed blood with a solution to arrest adenosine metabolism at the catheter tip. Details of the catheter stop solution have been described and validated.30 31 Immediately after collection, coronary sinus blood was centrifuged at 4800g for 2 minutes. The supernatant was filtered through a 0.2-µm filter (Acrodisc, Gelman Sciences), and adenosine concentration was determined by radioimmunoassay (RIA). Anti-immune antibodies were produced in rabbits immunized with N6-carboxymethyladenosine conjugated to methyl albumin. A synthetic high-specificity, high-affinity ligand (125I-N6-aminobenzyladenosine) was used in the RIA, which can detect 6.25 nm (312.5 fmol) of underivatized adenosine and cross-reacts at <0.002% with adenine nucleotides and guanosine and not at all with 1 nmol inosine. RIA sensitivity was increased to a detection limit of 0.125 nm (6.25 fmol) by derivatizing samples with benzyl bromide to form N6-benzyladenosine. The assay was adapted to an automated RIA procedure.30

Blood oxygen saturation was determined with the use of an electromechanical fuel-cell method (Co-oximeter, Corning Medical). Blood lactate levels were determined by a modification of the Marbach and Weil method,32 which uses the oxidation of lactate to pyruvate (Automatic Clinical Analyzer, du Pont). Lactate extraction was defined as (aortic lactate minus coronary sinus lactate) divided by aortic lactate.

Protocol
All medications were discontinued 24 hours before cardiac catheterization. As with group 1 patients, 30 minutes were provided between the routine diagnostic catheterization and the research protocol to minimize the hemodynamic effects of the radiocontrast. A dual-lumen 8F adenosine catheter was passed from the right internal jugular vein into the coronary sinus, with the tip positioned at least 3.0 cm into the sinus. A 7F Swan-Ganz catheter was positioned in the pulmonary artery, and a 7F Judkins right catheter was positioned in the ascending aorta. Baseline hemodynamic measurements included heart rate, mean PCWP, systemic resistance, cardiac output, and echocardiographic measures of LV septal and free wall thicknesses and percent thickening. Baseline measurements also were made of aortic and coronary sinus adenosine, lactate, and oxygen saturation levels. Adenosine then was infused at a rate of 140 µg/kg per minute (same rate as for group 1 patients) for 10 minutes. Measurements were repeated after a 7- to 10-minute adenosine infusion.

Statistical Analysis
All data are reported as mean±SD, with statistical significance accepted if P<.05. Group 1 data were analyzed with repeated-measures ANOVA, using Dunnett's test for multiple comparisons and dummy variables to code for between-patient variation. Data for group 2 patients were in the form of a single paired comparison. Therefore, the effect of adenosine on each parameter was assessed by two-tailed Student's paired t test.


*    Results
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*Results
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Group 1: Hemodynamic Response
Table 1Down provides group data for systemic and cardiac hemodynamic responses to adenosine. Heart rate, cardiac output, and EF all rose significantly, whereas arterial load (Ea) declined. These responses are consistent with those reported previously.4 5 9 10 11 PCWP rose by nearly 20%. This change was somewhat less than that reported by Ogilby et al9 but within a range observed by other investigators.4 10 11 LV EDP also increased by a similar amount, indicating that PCWP elevation was not due to an isolated effect on the pulmonary vasculature. Virtually all hemodynamic parameters returned to baseline after a 10-minute recovery (Table 1Down) with the exception of Ea, which remained above control levels.


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  		Table 1. Hemodynamic Effects of Adenosine

Fig 1Down displays PV data at baseline and after a 6-minute adenosine infusion for a representative patient. The PV loops became shorter and wider in response to adenosine, reflecting arterial vasodilation. This is depicted in the figure by a diagonal line connecting the end-systolic PV point to a point at (EDV,0). The negative slope of this line is Ea.26 In addition to vasodilation, both LV EDV and EDP increased. Similar changes in EDV were observed in seven of the nine patients and were statistically significant overall (Table 1Up). In three patients, this change in EDV was associated with a disproportionate rise in pressure, shifting the diastolic PV curve upward as well. RAP also increased (Table 1Up), suggesting enhanced right as well as left heart filling.



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  		Figure 1. Representative pressure–volume loop at baseline (solid line) and after 6 minutes of intravenous adenosine infusion (dashed line). Major effects were a decline in systolic pressure and volume, an increase in stroke volume, and a slight increase in end-diastolic volume and pressure. Arterial vasodilation is quantified by Ea (effective arterial elastance), shown as the diagonal line connecting the end-systolic pressure–volume point and (EDV, 0). LV indicates left ventricular; and EDV, end-diastolic volume.

Systolic PV Relations
Fig 2Down displays PV loops and relations measured during transient IVC obstruction for two representative patients. Baseline ESPVRs and EDPVRs (far left) are reproduced in each subsequent panel to assist in comparison (dashed lines). The PV loop at the onset of left heart preload decline is indicated in bold. In the top example (Fig 2aDown through 2c), adenosine shifted the ESPVR rightward with minimal slope change. The shift was mostly reversed after 10 minutes of recovery. This type of response was observed in six patients, whereas in the remaining three, ESPVRs were minimally altered by adenosine. In the bottom example (Fig 2dDown through 2f) is the latter response. Fig 3Down displays the corresponding SW-EDV relations for the same two representative patients. In contrast to the rightward ESPVR shifts, the SW-EDV relations were not significantly altered by adenosine.



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  		Figure 2. Two representative examples of pressure–volume loops and relations measured at baseline, after 6 minutes of adenosine infusion, and at 10 minutes of recovery. Loops a through c and loops d through f represent data from two different patients, respectively. Baseline end-systolic and end-diastolic pressure–volume relations are reproduced on each subsequent panel for comparison. The initial pressure–volume loop at the onset of preload reduction is indicated in bold. In most patients, adenosine shifted the end-systolic pressure–volume relation rightward with no change in slope, as demonstrated in the top example. This was reversed on recovery. In a few patients, there was no change or even a small leftward shift of the end-systolic pressure–volume relation. The bottom example displays this response.



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  		Figure 3. Plots of stroke work (SW)–end-diastolic volume (EDV) relations for the same two patients whose pressure–volume loop data are given in Fig 2Up. Despite parallel shifts in end-systolic pressure–volume relations, the SW-EDV relations were not altered by adenosine in either slope or position. Open diamond indicates baseline; filled circle, adenosine; and open triangle, recovery.

Group results for ESPVR and SW-EDV relations are provided in Table 2Down. Mean Ees (ESPVR slope) was not significantly changed by adenosine, but there was a slight rightward shift of the relation. As noted in "Methods," this was quantified by the {Delta}ESV measured at a common ESP of 130 mm Hg ({Delta}ESV130=+12.7±3.7 mL; P<.01). In contrast, neither the slope (MSW) nor position (V10 000) of the SW-EDV relations was altered by adenosine. Table 2Down also reports dP/dtmax measured at a common EDV. Interestingly, this parameter of systolic function actually rose by 24.9±17.8% (P<.01), perhaps reflecting its greater sensitivity to heart rate.28


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  		Table 2. Systolic Function Before, During, and After Adenosine as Measured by Pressure-Volume Relations

Diastolic PV Relations
To test whether adenosine stiffened the left ventricle, we examined EDPVRs from the same PV data as displayed in Fig 2Up. The results before and after adenosine were nearly superimposible in most patients. Fig 4Down displays four examples of diastolic PV relations on an expanded pressure scale. Data are displayed for baseline and after 6 minutes of adenosine infusion. EDPVRs fell along a single relation in many patients, indicating that the drug did not alter chamber compliance. As noted earlier, adenosine shifted the EDPVR upward in three patients (eg, Fig 4dDown), suggesting a possible change in chamber distensibility. Patients with this latter response had similar increases in PCWP and RAP as those who did not have this response.



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  		Figure 4. Plots of end-diastolic pressure–volume relations (EDPVRs) for four representative patients. Open diamond indicates baseline. Filled circles indicate 6 min adenosine. In the majority of subjects, the EDPVRs were virtually superimposible, with the rise in end-diastolic pressure accompanied by a small increase in end-diastolic volume. In several patients (ie, b), adenosine shifted the EDPVR rightward and upward, increasing pressures disproportionately to the change in volume. On average (see Table 3Up), adenosine had no effect on chamber compliance or elastic stiffness.

Table 3Down provides the group data for diastolic chamber compliance and elastic stiffness. Neither parameter was significantly altered by adenosine. There also was no effect of adenosine on the isovolumic relaxation time constant.


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  		Table 3. Left Ventricular Diastolic Compliance and Isovolumic Relaxation

Group 2: Impact of Adenosine on Coronary Flow and LV Diastolic Wall Thickness
One correlate of the hypothesis that adenosine raised PCWP by stiffening the heart from an erectile effect was that myocardial diastolic wall thickness should increase. The lack of mean compliance and stiffness changes found in group 1 patients suggested that this might not be the case. To directly probe this issue, a second group of patients were studied with echocardiography. Summary data at baseline and after adenosine infusion are provided in Table 4Down. Adenosine elevated PCWP, reduced arterial load, and increased cardiac output in group 2 patients by amounts similar to those observed in group 1 patients. Despite the rise in PCWP, neither septal nor posterolateral free wall end-diastolic thickness was altered. Adenosine increased fractional thickening in both regions, consistent with the reduced arterial load.


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  		Table 4. Hemodynamic, Echocardiographic, and Metabolic Data for Group 2 Patients

Adenosine concentration in aortic blood increased nearly sixfold during the infusion, from 8.6±3.4 pmol/mL at baseline to 45.8±24.4 pmol/mL with adenosine (P<.001). Furthermore, there was little difference between arterial and coronary sinus concentrations, indicating negligible myocardial adenosine production. As noted in "Methods," none of the patients displayed negative lactate extraction (ie, myocardial lactate production) either at baseline or with adenosine. Lactate extraction did decline during adenosine infusion, but this could have reflected a rise in coronary flow (ie, analogous to the rise in coronary sinus oxygen content). There was no evidence for ischemia based on regional wall motion abnormalities or ECG changes.


*    Discussion
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 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowConclusions
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Elevation of PCWP during continuous intravenous infusion of adenosine has been observed in patients with normal or diseased coronary vasculatures and in those with or without myocardial disease.4 9 10 11 Of four proposed mechanisms for this response, three depended on adenosine altering either ventricular diastolic or systolic function. First, adenosine might engorge the coronary vasculature with sufficient blood volume to increase ventricular stiffness by an erectile effect. Second, adenosine could lower contractility, triggering a compensatory rise in cardiac preload. Third, the molecule could prolong the relaxation process, delaying filling and resulting in elevated diastolic pressures. Only the fourth mechanism did not require a change in ventricular properties but rather was related to peripheral vascular loading effects of adenosine that might shift intravascular volume toward the central thorax.

The present study is the first to directly test each of these hypotheses. The results failed to support a mechanistic link between PCWP elevation and direct effects of adenosine on either LV diastolic or systolic function. Rather, they suggested that the most common explanation for a rise in PCWP was an increase in left heart (EDV and EDP) and right heart (RAP) filling. We speculate that this rise resulted from an adenosine-induced redistribution of blood volume from the periphery to the central thorax (fourth mechanism).

LV Diastolic PV Relation and Compliance
In isolated rabbit hearts, Vogel et al18 reported that adenosine induced sufficient coronary vasodilation to engorge the ventricular walls, reducing chamber compliance and shifting the diastolic PV curve leftward. These data helped support the notion that PCWP elevation in humans to whom adenosine was administered also resulted from diastolic stiffening.9 13 However, the present study found that in general the EDPVRs were similar before and during adenosine infusion and that chamber stiffness, compliance, and diastolic wall thickness were not significantly changed. Even in the few patients in whom the EDPVR moved upward, this shift occurred in the setting of increased EDV and RAP and appeared more as a parallel shift (eg, Figs 2eUp and 4dUp). This could reflect extrinsic loading effects.

One potential explanation for this discrepancy is that the adenosine dosage and/or the particular patients studied did not achieve sufficiently high coronary flows. Patients with coronary artery disease (eg, group 2) can have diminished flow reserve.33 This also applies to patients with syndrome X,34 which was not ruled out in group 1 subjects. However, we did observe that coronary sinus oxygen saturation more than doubled in group 2 patients, indicating substantial flow increases. Furthermore, wall thickness measured in the regions perfused by diseased and nondiseased vessels displayed a similar lack of change with adenosine. Although oximetry was not performed in group 1 patients, flow increases of more than 200% from identical adenosine dosages have been reported in patients with normal coronary arteries.8 Other studies have found that PCWP elevation in patients with coronary artery disease, who, again, are most likely to have reduced flow reserve, exceeds that observed in healthy subjects.9 Thus, although we still cannot rule out the possibility that greater flow increases may have induced more substantial diastolic changes, the present data do indicate that PCWP elevation can be observed without corresponding changes in diastolic stiffness, even at the flow levels that were achieved.

A second potential cause for a disparity between isolated heart and intact human data relates to the state of coronary vascular integrity and autoregulation. Isolated heart preparations (crystalloid or red blood cell suspension perfused) typically display a greater sensitivity of myocardial flow35 and developed pressure36 to changes in cardiac perfusion pressure compared with intact hearts.37 This primarily reflects a decline in coronary regulatory controls. Under these conditions, primary increases in flow are more likely to elevate intramyocardial fluid volumes and chamber stiffness.38

Contractile Effects of Adenosine
Cardiodepression sufficient to reduce cardiac output and mean arterial pressure is often compensated for by a rise in LV filling and, thus, PCWP. Adenosine has been shown to reduce contractility in isolated hearts as a result of A1 receptor stimulation with consequent antiadrenergic action mediated by inhibitory G protein.39 40 41 Similar effects in vivo could explain a PCWP rise. However, in the intact circulation, direct effects of adenosine on contractility are combined with sympathetic stimulation due to chemoreceptor activation by the drug42 and baroreflex activation. Assessment of even the net result is further complicated by the presence of altered peripheral loading.

The present study was the first to use PV relations to more specifically assess contractile changes during continuous adenosine infusion in humans. Even with the use of multiple "load-insensitive" measures of contractile function, the results were somewhat ambiguous. Although the slopes of both the ESPVR and SW-EDV relations were unchanged by adenosine, the ESPVR shifted rightward, whereas the SW-EDV relation did not. Furthermore, dP/dtmax at a matched EDV actually rose with adenosine, suggesting increased inotropy.

The lack of concordance among these contractile assessments most likely reflected their relative sensitivities to inotropic change, loading, and heart rate.43 In particular, parallel ESPVR shifts have been reported with altered arterial loading and ascribed to an afterload-history dependence of the relation. Freeman et al44 45 demonstrated that vasopressors such as angiotensin II as well as balloon inflation in the aorta shifted the ESPVR leftward, whereas vasodilation from nitroprusside shifted it rightward.44 Under these same conditions, the SW-EDV relation was minimally changed,44 much as we observed in the present study.

One might argue that a rightward shift of the ESPVR, regardless of mechanism, represents a decline in systolic pump function. However, adenosine also induced pronounced peripheral vasodilation, which offset this shift, leading to a net rise in cardiac output and EF. Thus, there would be little stimulus for a compensatory rise in cardiac preload. As noted, rightward ESPVR shifts from afterload reduction are not restricted to adenosine, although a PCWP rise is fairly unique. Last, the present data do not rule out direct cardiodepressant effects of adenosine in humans that may have been countered by reflex sympathetic stimulation. However, they do not support a link between cardiodepression and PCWP elevation, since this would require that the net result be a significant decline in systolic pump function.

Ischemia
In addition to direct myocardial effects, adenosine is believed to potentiate myocardial ischemia by adversely altering the regional distribution of coronary flow, particularly in patients with coronary stenoses.12 20 However, as noted by Verani,13 this does not appear to be a major mechanism for PCWP elevation since prior studies have found (albeit slightly less) PCWP elevation in subjects with normal hearts and coronary vasculatures similar to that in those with coronary artery disease.9 Also, regional wall motion abnormalities rarely develop during adenosine infusion, even in patients with coronary artery disease.9 The results from the present study further support these findings. Group 1 (without coronary artery disease) and group 2 (with coronary artery disease) patients had similar elevations in PCWP, and there were no wall motion abnormalities in group 2 subjects. Furthermore, we observed no net myocardial lactate production or increase in coronary sinus adenosine concentration in group 2 patients. Lactate extraction did decline; however, some decrease is expected based on a rise in coronary flow, just as one observes a fall in arteriovenous oxygen difference. Admittedly, coronary sinus sampling has limitations since blood draining from normally perfused regions can dilute any changes. Thus, although these data do not rule out an ischemic mechanism, they cannot be used to support it.

Preload Effects
Unlike some studies,9 we found that EDV rose significantly during adenosine infusion. This disparity may be due to methodological differences in volume measurement. Contrast and radionuclide ventriculography techniques used in prior studies require boundary detection algorithms and geometric models to generate volumes. This can make them vulnerable to calculation errors that obscure small but real volume changes. The conductance catheter signal, on the other hand, depends on the physics of a current field distributed throughout the blood and surrounding tissues. As long as wall mass and hematocrit are unchanged and the catheter position remains stable, the signal is very reproducible. This facilitates detection of small but real relative changes in LV volume.

The exact mechanism for the EDV increase from adenosine remains speculative. Vasodilators such as nitrates or angiotensin-converting enzyme inhibitors dilate both arterial and venous beds, increasing venous capacitance46 and reducing central venous pressures.14 15 16 17 Even hydralazine, which acts primarily on the arterial vasculature, also typically lowers PCWP in humans.15 In contrast, adenosine raises right heart filling pressures while lowering arterial resistance. Although the magnitude of RAP increase was small, it could still reflect a substantial volume change given the high compliance of the right heart–pulmonary system. These results, however, are consistent with several reported pharmacological properties of adenosine. For example, although adenosine has been shown to dilate peripheral veins,47 this response is much weaker than in the arterial system.3 47 48 Furthermore, adenosine induces both direct42 and indirect baroreflex-mediated sympathetic stimulation, as manifest by tachycardia, skin flushing, and chest pain, and this could reduce venous capacitance.49 The combination of minimal direct venodilation along with sympathetic activation might be sufficient to increase cardiac filling. This hypothesis will certainly require future direct testing with measurements of unstressed venous capacitance.46


*    Conclusions
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 up arrowIntroduction
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up arrowResults
up arrowDiscussion
*Conclusions
down arrowReferences
 
We tested several mechanisms for elevated PCWP during continuous infusion of adenosine in humans and found that it was most often related to altered vascular loading associated with increased cardiac filling. We propose that differential sensitivities of venous and arterial vessels to adenosine coupled with sympathetic stimulation result in a shift of intravascular volume to the central thorax. Diastolic chamber compliance, elastic stiffness, and wall thickness were not significantly altered by adenosine, raising doubts that an erectile effect plays a prominent role in PCWP elevation. Furthermore, contractile state and active relaxation were minimally altered and could not explain the rise in PCWP. These data should provide a useful perspective for clinicians and investigators when administering adenosine as an intravenous infusion, particularly to patients with coexisting myocardial dysfunction.


*    Acknowledgments
 
This work was supported by US Public Health Service grant HL-47511. Dr Kass is an Established Investigator of the American Heart Association.

Received September 16, 1994; revision received January 3, 1995; accepted January 17, 1995.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
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*References
 

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