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(Circulation. 1996;94:3190-3197.)
© 1996 American Heart Association, Inc.

Articles

Right Ventricular Performance and Contractile Reserve in Patients With Severe Heart Failure

Assessment by Pressure-Area Relations and Association With Outcome

John Gorcsan, III, MD; Srinivas Murali, MD; Peter J. Counihan, MD; William A. Mandarino, MS; Robert L. Kormos, MD

the Divisions of Cardiology (J.G., S.M., P.J.C.) and Cardiothoracic Surgery (W.A.M., R.L.K.), University of Pittsburgh Medical Center, Pittsburgh, Pa.

Correspondence to John Gorcsan III, MD, Division of Cardiology, University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213-2582. E-mail gorcsan@a1.isd.upmc.edu.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Right ventricular (RV) performance appears to be important in patients with severe heart failure. Although clinical assessments of RV function previously have been limited to load-dependent ejection phase indices, a new method has been developed using the relatively load-insensitive concepts of pressure-volume relations with automated echocardiographic measures of RV cross-sectional area as a surrogate for volume.

Methods and Results Sixteen patients with New York Heart Association functional class IV heart failure and group mean left ventricular ejection fraction of 20±5% were studied. RV pressure-area loops were recorded on-line from echocardiographic measures of RV area and high-fidelity pressure during transient inferior vena caval balloon occlusions. RV contractile reserve was assessed as its functional response to an increase in dobutamine from 5.7±4.1 to 13.1±4.7 µg/kg per minute. Complete data sets were available in 13 patients. Group mean RV end-systolic elastance (E'es) and maximal elastance (E'max) increased with augmented dobutamine infusion (2.9±1.5 to 5.5±3.3 mm Hg/cm² and 3.3±1.6 to 6.4±3.9 mm Hg/cm², respectively; P<.01 versus baseline), although individual responses were variable. During a 30-day follow-up, 9 patients remained unstable, requiring continuous intravenous inotropic therapy; 6 of these had profound deterioration requiring mechanical circulatory support. The remaining 4 patients had a comparatively good short-term outcome with clinical stability. A 100% increase in RV E'es or E'max was associated with a good short-term outcome (P<.05).

Conclusions RV performance can be assessed by pressure-area relations in patients with heart failure. RV contractile reserve in response to increases in dobutamine was associated with a good short-term outcome and may be of prognostic value in patients with severe heart failure.

Key Words: echocardiography • pressure • heart failure • catheterization

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Although the RV may contribute to some degree to global cardiac performance in individuals with preserved LV function, RV function appears to be especially important to patients with severe left heart failure.^{1 2 3 4 5 6} Recent studies in patients with advanced heart failure have suggested that RV function may determine exercise capacity and that the RV ejection fraction response to exercise has prognostic significance.⁶ However, many of these patients cannot perform exercise for the determination of exercise RV ejection fraction, and methodological difficulties have existed with the clinical assessment of RV function because of its complex geometric shape and the load dependence of ejection phase indices. Pressure-volume relations have been established as an important means to assess ventricular performance because of their relative load insensitivity but have only rarely been used to assess RV function in clinical settings because on-line volume acquisition has not been available.^{7 8 9 10 11 12} We have recently validated a method to assess RV performance in an animal model using cross-sectional area by echocardiographic automated border detection as a surrogate for RV volume to assess end-systolic relations in a manner similar to pressure-volume relations.¹³ This new method provides an opportunity to potentially evaluate RV performance in patients with congestive heart failure that has not been possible previously. The objectives of this study were (1) to determine the feasibility of assessing RV performance in patients with severe heart failure by on-line pressure-area relations, (2) to assess RV contractile reserve in these patients by evaluating its response to inotropic modulation with the ß₁-agonist dobutamine, and (3) to determine if RV performance and contractile reserve may be associated with short-term outcome in these patients.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
The study group consisted of 16 patients with New York Heart Association functional class IV heart failure who were awaiting cardiac transplantation and who were hospitalized for an exacerbation of congestive heart failure. The protocol was approved by the Institutional Review Board on Biomedical Research, and all patients gave written informed consent. Patients were 50±9 years of age (range, 36 to 64); there were 13 men and 3 women. The group mean LV ejection fraction was 20±5% by two-dimensional echocardiography. The etiology of heart failure was ischemic in 6 patients and nonischemic dilated cardiomyopathy in 10 patients. All patients were studied previously by coronary angiography, and significant reversible ischemia was excluded by thallium scintigraphy. All patients were receiving digoxin, loop diuretics, and maximal tolerable doses of ACE inhibitors. Ten patients required dobutamine infusion, with a group mean dose of 5.7±4.1 µg/kg per minute for severe congestive heart failure at the time of study (Table 1). This dose was determined before the study with the use of clinical criteria as the minimal dose required to control symptoms of congestive heart failure and maintain renal, hepatic, and cerebral functions.¹⁴

View this table: [in this window] [in a new window]   Table 1. Hemodynamic Parameters

All patients were studied in the cardiac catheterization laboratory. A thermodilution pulmonary artery catheter (Baxter-Edwards) was inserted through a right internal jugular vein to record pressures and cardiac output. This catheter was then replaced with a 4F high-fidelity fiberoptic pressure catheter (Camino Laboratories, model 110-4) that was advanced into the RV. An IVC balloon occluder ranging from 20- to 40-mm diameter when inflated with saline was then inserted via a right femoral vein through an 8F vascular sheath as previously described.¹⁵ Transthoracic imaging was performed with the use of a 2.5-MHz transducer from the apical 4-chamber view using an automated border detection ultrasound system (Sonos 1500 model 77035A, Hewlett-Packard).¹⁶ LV volumes and ejection fractions were calculated with the use of a modified Simpson's rule.¹⁷ Automated measures of RV cross-sectional area from the body of the RV were then acquired as an index of volume (Fig 1). The mid ventricular plane with the maximal length from the apex through the atria was used. This plane was selected because technically adequate images were available from the apical windows in all patients who were supine in the catheterization laboratory and because changes in cross-sectional area from the body of the RV have been shown to vary linearly with changes in RV volume.¹³ The threshold for discriminating blood from tissue backscatter characteristics was directly influenced by manual gain settings adjusted as previously described.^{16 17 18 19} Time gain compensation controls were increased in the right atrial cavity adjacent to the tricuspid valve plane to maximize automated tracking of the RV blood area throughout the cardiac cycle.¹⁷ A region of interest was then manually drawn beyond the RV endocardial border and tricuspid valve plane so that the RV cavity area remained within this region during trial transient vena caval occlusion maneuvers. The analog RV area signal was directly recorded on a computer workstation (Apollo Computer Inc, model A1421) through a customized hardware and software interface as we have previously described.^{17 18 19} Briefly, ECG (lead II) and simultaneous RV pressure and area signals were continuously digitized at 150 Hz (model RTS-132, SignifiCat). RV pressure and area signals were plotted to display pressure-area loops in real time. Maximal area values were aligned with the point preceding the onset of isovolumic contraction from the RV pressure for each run to allow for the variable delay (46±48 ms) in the area signal output.

View larger version (84K): [in this window] [in a new window]   Figure 1. An example of an echocardiographic image from a patient with severe heart failure. Automated border detection outlines the blood-tissue interface, and the region of interest is drawn around the RV cavity. On-line measures of RV area appear at the bottom.

Protocol
Routine hemodynamic and cardiac output measurements were assessed by thermodilution pulmonary artery catheter. Simultaneous pressure and area waveform and loop data were recorded before and during transient IVC balloon occlusion maneuvers (Fig 2) with patients suspending respirations at end expiration to minimize cardiopulmonary interactions.²⁰ RV contractile reserve was then assessed by evaluating its functional response to 5 to 7 µg/kg per minute of dobutamine infusion in the patients who were not initially receiving intravenous inotropic support or increasing the dose of dobutamine approximately twofold in patients with existing dobutamine therapy (Table 1). IVC occlusion maneuvers were then repeated after 10 minutes of the new dobutamine infusion dosage and were performed in triplicate for each portion of the protocol. The high-fidelity RV catheter was then immediately replaced with the routine fluid-filled catheter to reassess hemodynamics.

View larger version (44K): [in this window] [in a new window]   Figure 2. An example of simultaneous RV pressure and cross-sectional area waveform during IVC occlusion and release from a patient with severe heart failure in this study. Data were acquired with the patient holding his breath at end expiration.

Data Analysis
All physiological signals were transferred into a customized program written in ASYST software (ASYST Software Technologies, Inc). A low-pass filter with a cutoff frequency of 50 Hz was used to eliminate high-frequency noise. This filter has been shown not to alter the physiological signal spectrum while suppressing electromagnetic interference.^{17 18 19} Data sets were divided into cardiac cycles from the R wave of the electrocardiogram, allowing the user to eliminate ectopic beats. The first IVC occlusion run in chronological order with enough beats to perform the analysis described below was chosen for each condition for each patient. RV function was assessed by pressure-area loops before IVC occlusions by fractional area change (FAC)=[(end-diastolic area-end-systolic area)/end-diastolic area]x100% and stroke work (SW')=fpressure d area. RV performance at baseline and in response to increased dobutamine infusion was then evaluated by applying the relatively load-insensitive indices that have been validated for pressure-volume and pressure-area relations in the LV.^{18 19} E'es was determined as the slope of end-systolic points (maximal pressure/area) for each loop with the use of an automated iterative linear regression technique.^{7 8 9 10 11} Elastance using pressure-area data was designated E' to distinguish it from the standard symbol E using pressure-volume data. Time-varying elastance, E'(t), was derived every 7 ms from linear regression of the isochronous pressure-volume points of differently loaded beats beginning with end diastole and continuing past end systole using the equation E'(t)=P(t)/[A(t)-Ao(t)], where E'(t)=time-varying elastance, P=pressure, A=area, t=time, and Ao=area-axis intercept. The maximal value of E'(t) was defined as maximal elastance^{7 8 9 10 11} (Fig 3). PRSW' was the slope of the linear regression equation obtained from the stroke work versus end-diastolic area relationship.^{12 21} Right ventricular/arterial coupling was assessed by calculation of E'a as the ratio of end-systolic pressure to the difference between end-diastolic area and end-systolic area from the RV pressure-area loops, as previously described.²²

View larger version (28K): [in this window] [in a new window]   Figure 3. An example of the calculation of time-varying elastance from RV pressure-area loops. Left, Isochronous pressure-area points at representative times from the onset of systole, with time (t) shown in milliseconds from the QRS complex. Right, Plots of elastance throughout systole with the maximal value (E'max) at baseline (solid line) and during increased dobutamine infusion (dashed line).

Patient Follow-up
All patients were followed for a minimum of 30 days from the time of study to assess short-term outcome. The clinical requirement for continuous intravenous inotropic support, intra-aortic balloon pump placement, mechanical circulatory assist device placement, or patient death was defined as a poor outcome. The ability to be weaned from intravenous inotropic support and discharged from the hospital was considered a good short-term outcome.

Statistical Analysis
All data appear as mean±SD. Potential changes in RV function with increasing doses of dobutamine were determined with the use of ANOVA for repeated measures. Potential differences in RV performance or contractile reserve between groups of patients with differing dosage and duration of dobutamine, and between patients grouped by outcome, were determined with the use of Newman-Keuls two-way ANOVA. A Fisher's exact test was used to determine a potential association of RV contractile reserve with patient outcome.²³ Significance corresponds to P<.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Hemodynamic and clinical data for 15 patients at baseline and after dobutamine intervention are shown in Table 1. One patient who had angina with increased dobutamine infusion was eliminated from the study. A predicted significant increase in group mean cardiac output occurred with the increase in dobutamine dose. No significant changes in heart rate, pulmonary artery, or wedge pressures were observed. Ejection phase indices of steady-state RV and LV function from pressure-area loops before IVC are shown in Table 2. RV pressure-area loops with IVC occlusion were available from 13 patients, and examples are shown in Fig 4 with calculated data in Table 3. Two patients were excluded from pressure-area relations analysis because occlusion was unsuccessful in 1 patient with a severely dilated IVC, and 1 patient had frequent premature ventricular contractions with attempted caval occlusion. Group mean RV FAC, E'es, and E'max statistically increased with increased dobutamine infusion, consistent with the expected physiological response to inotropic modulation, although significant changes in PRSW' or E'a were not observed in the group as a whole because of variable individual responses.

View this table: [in this window] [in a new window]   Table 2. Echocardiographic Data

View larger version (45K): [in this window] [in a new window]   Figure 4. Representative examples of RV pressure-area relations with slope of E'es at baseline and with increasing dosage of dobutamine. Patient A, who had no significant increase in RV contractility with augmented dobutamine, had subsequent clinical deterioration. Patient B, who demonstrated an increase in RV contractility in response to dobutamine, had subsequent short-term clinical stability.

View this table: [in this window] [in a new window]   Table 3. Right Ventricular Pressure-Area Relations

Patient Outcome
Over the subsequent 30 days, 10 patients continued to decompensate, requiring continuous intravenous inotropic support because of worsening congestive heart failure, 3 of whom received intra-aortic balloon pump placement. Six of these patients demonstrated the most profound clinical deterioration requiring mechanical circulatory support: 3 with an LV assist device, 2 with biventricular mechanical assist devices, and 1 with a total artificial heart. None of these patients died during this period. The 4 remaining patients achieved clinical stability within the next 14 days from the time of study and were discharged from the hospital. These patients remained stable for a minimum of 2 months, although 2 subsequently decompensated and received heart transplantation at 2 and 4 months, respectively. Two patients remained stable at home.

Association of Ventricular Performance With Patient Outcome
Neither the routine hemodynamic measurements nor the baseline measures of LV ejection fraction or RV performance from pressure-area relations were statistically associated with patient outcome. The ability to augment RV performance in response to increased dobutamine infusion, however, was associated with a favorable short-term clinical outcome. A 100% increase in RV FAC, E'es, or E'max or a 75% increase in RV PRSW' was independently associated with a relatively good short-term outcome (P<.05) (Fig 5). Only 1 patient who increased RV FAC, E'es, and E'max by 100% remained hospitalized and dependent on inotropes. This patient outlier had a severely elevated pulmonary artery pressure to 85 mm Hg with a pulmonary vascular resistance of 5.1 Wood units and subsequently underwent heterotopic heart transplantation.

View larger version (15K): [in this window] [in a new window]   Figure 5. Plot of percent change (%) with increasing dobutamine infusion of RV E'es, E'max, and PRSW' from baseline. Dashed line represents respective % values associated with good versus poor short-term outcome. Open circle is patient outlier with severe pulmonary hypertension.

The 6 patients who went on to require implantation of a mechanical circulatory assist device represented the patient subgroup who demonstrated the most severe clinical deterioration during the follow-up period. Accordingly, indices of RV performance, RV ventriculo-arterial coupling, and LV ejection in patients who did not require mechanical circulatory assistance were compared to these 6 patients who did. Significant increases in RV E'es, RV E'max, RV PRSW', and LV ejection fraction were observed with augmented dobutamine infusion along with an improvement in RV ventriculo-arterial coupling in the patient group who did not go on to mechanical circulatory assistance (Fig 6A through 6C). In contrast, the patient group who subsequently required mechanical circulatory assistance failed to demonstrate a response to increased dobutamine infusion. These data further suggest that patients with severe heart failure who are unable to augment ventricular function in response to an increase in dobutamine infusion are at risk for further clinical deterioration and the need for mechanical support.

View larger version (77K): [in this window] [in a new window]   Figure 6. Plots of RV pressure-area relations, biventricular ejection indices, and RV ventriculo-arterial coupling at baseline and in response to increasing dosage of dobutamine infusion, with patients grouped by subsequent outcome. Patients with the most severe clinical deterioration requiring mechanical circulatory support appear in the plots on the right. Individual and mean±SD values are shown (*P<.05 vs baseline and mechanical circulatory support). A, RV E'es, E'max, and PRSW'. B, RV fractional area change and LV ejection fraction. C, RV E'a.

Effects of Existing Dobutamine Therapy
The patients in this study were heterogeneous with respect to their existing dosage and duration of dobutamine therapy, which may potentially affect study results. Although the baseline dose of dobutamine differed among patients, all baseline hemodynamics, biventricular ejection indices, and RV pressure-area relations were similar in subgroups of patients receiving a low dose (<5 µg/kg per minute) or a higher dose (5 µg/kg per minute) of dobutamine. Furthermore, all of these baseline indices were similar in patients who were receiving dobutamine for 14 days versus >14 days. However, the 7 patients who received dobutamine infusion for 14 days demonstrated increases in RV E'es and E'max with augmented dobutamine infusion (2.59±1.09 to 5.89±3.43 and 2.88±1.24 to 7.46±4.74 mm Hg/cm², respectively; P<.05), whereas the patients receiving dobutamine for >14 days did not. Increases in RV PRSW' in response to augmented dobutamine infusion were similar despite initial dosage and duration of dobutamine therapy. These data demonstrate that a tolerance to dobutamine therapy may affect RV contractile reserve E'es and E'max results. RV PRSW' data, however, were unaffected by existing dosage or duration of dobutamine infusion.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This study demonstrates the feasibility of assessment of RV performance and contractile reserve through the use of pressure-area relations in patients with severe heart failure. Physiologically predicted increases in RV contractility occurred with augmented dobutamine infusion in the patient group as a whole, but variable responses were observed. An ability to significantly augment RV function in response to increased dobutamine infusion was associated with a good short-term outcome, and alternatively all patients who could not significantly augment RV function remained inotrope dependent and hospitalized. Furthermore, the 6 patients with the most profound subsequent deterioration requiring mechanical circulatory assistance failed to demonstrate improvements in RV performance or ventriculo-arterial coupling with augmented dobutamine infusion in contrast to the remaining patients who had significant improvements when analyzed separately.

These data in patients with severe heart failure may support the importance of the functional ability of the RV to respond to stress through the use of the sympathomimetic agent dobutamine as a surrogate for stress. An altered response to dobutamine in patients with heart failure has been described previously by Bristow et al,^{24 25} who have demonstrated a significant reduction in myocardial ß-receptor density and decrease in isoproterenol-mediated adenylyl cyclase stimulation and muscle contraction from RV endomyocardial biopsies. These investigators have also shown a selective downregulation of ß₁-receptor subtypes and a relationship between degree of ß-receptor downregulation in patients with heart failure and the contractile response to intravenous dobutamine, a relatively selective ß₁-agonist.²⁶ These data from this present clinical study assessing RV contractile reserve by dobutamine infusion support the hypothesis that the degree of ß-receptor–G protein–adenylyl cyclase complex dysfunction may be a marker for more advanced cardiac disease and thus associated with a poorer short-term outcome.

Right Ventricular Pressure-Area Relations
The model of ventricular performance using pressure-volume relations as described originally by Suga and Sagawa⁷ has become an established standard because of its relative insensitivity to loading conditions. RV mechanical function has previously been described in a similar fashion as the LV with load-independent parameters such as the E'es and PRSW' relations.^{8 9 10 11 12 13} Complex RV geometry has hindered the on-line determination of volume in situ and accordingly pressure-volume assessments of RV function are difficult clinically. Previously reported methods to estimate RV volume including angiography, routine echocardiography, radionuclide ventriculography, and multiple markers techniques require substantial off-line digitization.^{27 28 29 30} Although the conductance catheter may provide continuous on-line volume data, its use with the RV has not been validated fully in humans.^{31 32 33} Although a pressure-sensing catheter and IVC balloon occluder are still required for RV pressure-area relations described in this present study, transthoracic echocardiography eliminates the need for invasive volume determination.

Right Ventricular Function and Patient Outcome
Although many advances are being made with medical therapy, severe congestive heart failure continues to have a poor overall prognosis.^{34 35} The most definitive therapeutic option for many patients with this syndrome is heart transplantation. Unfortunately, the waiting list continues to grow with decreasing donor availability, and a mechanism does not exist to confidently predict short-term outcome in these patients.³⁶ Previous investigators have suggested the importance of various indices, including LV ejection fraction, LV end-diastolic volume index, LV stroke work index, and maximal exercise oxygen consumption, in predicting outcome in patients with heart failure.^{36 37 38 39 40 41} Neurohumoral mediators, such as plasma norepinephrine, renin activity, atrial natriuretic peptide, and cytokine levels also have been suggested as prognostic indicators of heart failure.^{41 42} Many of these studies have evaluated heterogeneous groups with variable degrees of heart failure, and predicting short-term prognosis in severe heart failure patients who are at the greatest risk for morbid events and death remains difficult. Furthermore, clinical trials may begin in the near future to evaluate the implantable artificial heart, not as a bridge, but as an alternative to transplantation, and only patients with a poor short-term prognosis should be considered as candidates for transplantation or device implantation. A recent exercise radionuclide ventriculographic study by DiSalvo et al⁶ demonstrated that RV ejection fraction 35% with exercise was the only independent predictor of event-free survival in patients with severe heart failure by a multivariate proportional hazards model. Although their findings support the importance of RV function in these patients, a limitation of their study was that RV ejection fraction is a load-dependent measure, and a complex interaction of RV ejection with pulmonary vascular changes may exist with exercise. Accordingly, it may be advantageous to evaluate RV performance using the relatively load-independent concepts of pressure-volume relations in patients with severe heart failure.

Study Limitations
An important limitation of two-dimensional echocardiography, like all other tomographic imaging methods, is the use of cross-sectional area to reflect three-dimensional volume of the anatomically complex RV. The method of pressure-area relations does not attempt to determine absolute RV volume but uses changes in cross-sectional area as a surrogate for changes in RV volume, which have been shown to be linearly related in an animal model.¹³ The linearity of the RV area-volume relationship has been shown to be relatively unaffected by changes in LV volume or by isovolumic deformational changes in the RV. A potential limitation of this technique may be in its application to patients with RV pressure or volume overload where geometry is distorted. However, the RV end-systolic elastance, time-varying elastance, and preload recruitable stroke work models applied to pressure-area relations in the present study in patients with severe cardiac disease demonstrated significant linear relationships and the physiologically predicted response to inotropic modulation. Furthermore, impaired RV contractile reserve assessed by pressure-area relations with dobutamine infusion identified patients who appeared to have more advanced disease associated with a poor outcome. Further studies testing the RV area-volume relationship in patients with RV disease may be needed to describe conclusively this association.

Another potential limitation of this technique is the placement and orientation of the echocardiographic transducer to obtain a reproducible tomographic imaging plane. Variability was minimized by marking probe placement on the patient's chest wall with a skin marker and using internal anatomic landmarks including the RV apex, tricuspid annulus, and left ventricular papillary muscles to align transducer angulation as previously described.^{17 18 19} No patient in the present study was excluded because of inadequate echocardiographic images for automated border detection. This high yield may be related to ventricular dilation in these patients, resulting in the RV being closer to the chest wall, improving the ultrasound interface. Although automated border detection data are highly sensitive to operator gain settings, reproducibility and accuracy have been demonstrated by several investigators and our group when adequate echocardiographic images are available.^{16 17 18 19}

The ability of RV performance and contractile reserve to confidently predict outcome in patients with severe heart failure is potentially limited because of the small number of patients in this initial study, their heterogeneity to existing dosage and duration of dobutamine therapy, and the determination of predictive contractile reserve values with a post hoc analysis. These concepts must be further tested prospectively in a larger series of heart failure patients to confidently conclude that RV contractile reserve is of predictive value. However, the findings of this present study support and extend the findings of others who have demonstrated the importance of RV function in the syndrome of congestive heart failure.

	Selected Abbreviations and Acronyms

 

E'a = effective arterial elastance E'es = end-systolic elastance E'max = maximal elastance IVC = inferior vena cava LV = left ventricle PRSW' = preload recruitable stroke work RV = right ventricle

	Acknowledgments

 
The authors are grateful to Marc D. Feldman, MD, for his expertise and valuable suggestions in the preparation of the manuscript, and Karen Janosko, RN, for her diligent patient data collection.

Received March 11, 1996; revision received July 24, 1996; accepted July 30, 1996.

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