Author + information
- Received April 10, 2000
- Revision received August 3, 2000
- Accepted September 20, 2000
- Published online January 1, 2001.
- Stefano Ghio, MD, FESC∗,* (, )
- Antonello Gavazzi, MD, FESC∗,
- Carlo Campana, MD∗,
- Corinna Inserra, MD∗,
- Catherine Klersy, MD†,
- Roberta Sebastiani, MD∗,
- Eloisa Arbustini, MD‡,
- Franco Recusani, MD∗ and
- Luigi Tavazzi, MD, FESC, FACC∗
- ↵*Reprint requests and correspondence: Dr. Stefano Ghio, Dipartimento di Cardiologia, Policlinico S. Matteo, Piazza Golgi 1, 27100 Pavia, Italy
We sought a better understanding of the coupling between right ventricular ejection fraction (RVEF) and pulmonary artery pressure (PAP), as it might improve the accuracy of the prognostic stratification of patients with heart failure.
Despite the long-standing view that systolic function of the right ventricle (RV) is almost exclusively dependent on the afterload that this cardiac chamber must confront, recent studies claim that RV function is an independent prognostic factor in patients with chronic heart failure.
Right heart catheterization was performed in 377 consecutive patients with heart failure.
During a median follow-up period of 17 ± 9 months, 105 patients died and 35 underwent urgent heart transplantation. Pulmonary artery pressure and thermodilution-derived RVEF were inversely related (r = 0.66, p < 0.001). However, on Cox multivariate survival analysis, no interaction between such variables was found, and both turned out to be independent prognostic predictors (p < 0.001). It was found that RVEF was preserved in some patients with pulmonary hypertension, and that the prognosis of these patients was similar to that of the patients with normal PAP. In contrast, when PAP was normal, reduced RV function did not carry an additional risk.
These observations emphasize the necessity of combining the right heart hemodynamic variables with a functional evaluation of the RV when trying to define the individual risk of patients with heart failure.
In patients with primary dilated cardiomyopathy or ischemic heart disease, left ventricular (LV) dysfunction is the original physiologic disorder leading to the clinical syndrome of chronic heart failure. In fact, a reduced ejection fraction of the LV is a powerful predictor of death in a general population of patients with heart failure; however, its prognostic value loses strength when applied to patients with advanced heart failure, so that it may not be used to select the proper time for heart transplantation (1). The identification of patients with heart failure at higher risk of death has become an area of active investigation over the last two decades. Recently, a number of studies have provided evidence that right ventricular ejection fraction (RVEF), either directly measured (by radionuclide angiography or rapid response thermodilution) or indirectly estimated (by echocardiography), is an independent prognostic factor in patients with moderate to severe heart failure (2–6). In addition, in patients with advanced disease, thermodilution-derived RVEF proved to be the single most important determinant of short-term prognosis among all of the hemodynamic variables obtained during right heart catheterization (4).
Uncertainty about clinical acceptance of these data stems from the long-standing view maintaining that the systolic function of the right ventricle (RV) is almost exclusively dependent on the afterload that this cardiac chamber must confront (7–12). Pulmonary hypertension frequently complicates heart failure and is generally considered “per se” an indicator of poor prognosis (13,14).
We therefore designed a study aimed at evaluating whether a better understanding of the coupling between RV function and pulmonary artery pressure (PAP) could improve the prognostic stratification of patients with chronic heart failure.
The study enrolled 379 consecutive outpatients referred to the Cardiology Department of the S. Matteo Hospital, Pavia, Italy, between January 1992 and December 1998 for heart failure management and/or heart transplantation evaluation who met the inclusion criteria: 1) moderate to severe chronic heart failure; 2) significant LV systolic dysfunction (left ventricular ejection fraction [LVEF] <35%); and 3) etiology of either primary dilated cardiomyopathy or ischemic heart disease. Idiopathic dilated cardiomyopathy was defined as LV dysfunction in the absence of significant coronary artery disease on coronary angiography and in the absence of specific heart muscle disease or active myocarditis on the endomyocardial biopsy. Ischemic heart disease was diagnosed on the basis of documented previous myocardial infarction or significant coronary artery disease on coronary arteriography. We excluded from this series patients with end-stage valvular heart disease, cardiac amyloidosis, hypertrophic cardiomyopathy, active alcoholism, chronic obstructive pulmonary disease, recent acute myocardial infarction (<6 months) or unstable angina. Patients receiving infusion therapy with dopamine, dobutamine or phosphodiesterase inhibitors at presentation were also excluded.
All patients underwent right heart catheterization as part of the diagnostic protocol for heart transplantation eligibility. Medical therapy was individually adjusted according to a standardized treatment regimen, as previously reported (4). The clinical characteristics of the patients are shown in Table 1.
Right heart catheterization
After the patient had given informed consent, a modified Swan-Ganz thermodilution catheter mounted with a rapid-response thermistor (93A-431H-7F, American Edwards Laboratories, Irvine, California) was inserted transcutaneously through the right internal jugular vein and advanced until its tip was into the pulmonary artery. The thermistor was connected to a dedicated computer (REF-1 Ejection Fraction/Cardiac Output Computer, American Edwards Laboratories) to display on-line the cardiac output and RVEF (15,16). The protocol has been previously described in detail (4). The following hemodynamic variables were measured or derived: systemic blood pressure (arm-cuff sphygmomanometer), right atrial pressure, PAP, pulmonary wedge pressure, thermodilution RVEF, cardiac output, cardiac index, systemic vascular resistance and pulmonary vascular resistance. Thermodilution measurements were obtained in triplicate.
A mean PAP value >20 mm Hg was taken as the cut-off for pulmonary hypertension. A RVEF value <35% was taken as the cut-off for RV systolic dysfunction; this value was chosen as the median value of RVEF in our patients with normal PAP. Based on the values of PAP and RVEF, the study group was classified into four subgroups: normal PAP/preserved RVEF, high PAP/low RVEF, high PAP/preserved RVEF and normal PAP/low RVEF. Two patients were lost to follow-up and were therefore excluded.
Standard M-mode, two-dimensional and Doppler echocardiographic studies were performed using either Toshiba SSA 270A (Toshiba Corporation, Tokyo, Japan) or Esaote SIM 7000 Challenge (Esaote, Florence, Italy) ultrasound equipment. Left ventricular dimensions were measured according to the recommendations of the American Society of Echocardiography; end-diastolic and end-systolic LV volumes were calculated according to the single-plane, area–length method.
Data are shown as the mean value ± SD for continuous variables and absolute or relative frequencies for categorical variables. Correlations between mean PAP and other hemodynamic variables were assessed using linear regression analysis. Survival analysis was performed according to the Cox regression method. The end points of survival analysis were cardiac death or urgent heart transplantation (status 1 according to the UNOS criteria) (1). Elective heart transplantation was considered as a censored observation with the patients withdrawn from the analysis at the time of transplantation. Cumulative survival was compared in the four subgroups of patients obtained according to the presence or absence of pulmonary hypertension and RV dysfunction. A p value <0.05 was considered statistically significant. The statistical package Stata 6.0 (Stata Corporation, College Station, Texas) was used for computations.
Spectrum of PAP in the entire study group
A mean PAP value >20 mm Hg was found in 236 of 379 patients. As compared with the 143 patients with normal PAP, the patients with pulmonary hypertension were more frequently in New York Heart Association (NYHA) functional class III or IV (83% vs. 46%, p < 0.000), had a lower cardiac index (2 ± 0.6 vs. 2.6 ± 0.6 liters/min per m2, p < 0.000), a lower RVEF (19 ± 11% vs. 34 ± 8%, p < 0.000) and a higher right atrial pressure (7.6 ± 5 vs. 1.2 ± 3 mm Hg, p < 0.000). Mean PAP and pulmonary capillary wedge pressure were found to be strongly related (r = 0.85, p < 0.000) (Fig. 1).
Relation between PAP and RV function
A significant inverse relation, in a context of a wide scattering of the data, was found between mean PAP and RVEF (r = −0.66; p = 0.000). This relation was similar between patients with dilated cardiomyopathy and those with ischemic heart disease (Fig. 2).
Prognostic independence of PAP and RV function
On univariate analysis, several variables were found to be significantly (p < 0.05) related to survival (NYHA class III or IV, LV end-systolic diameter index, LVEF, mean PAP, pulmonary capillary wedge pressure, right atrial pressure, cardiac index, pulmonary vascular resistance, systemic vascular resistance and RVEF). All these variables were included in the multivariate model, with the exception of pulmonary vascular resistance, which was co-linear with systemic vascular resistance, and pulmonary capillary wedge pressure, which was co-linear with mean PAP. No interaction was found between mean PAP and RVEF. Cox multivariate analysis identified four independent prognostic predictors of mortality or urgent transplantation: NYHA class III or IV, RVEF, mean PAP and LV end-systolic diameter index (Table 2).
Prognostic stratification according to the coupling between PAP and RV function
Table 3summarizes the clinical, echocardiographic and hemodynamic characteristics of the four subgroups of patients, obtained according to the presence or absence of pulmonary hypertension and RV dysfunction. During a median follow-up period of 17.2 months, 105 patients (28%) died and 35 patients (9.2%) underwent urgent heart transplantation. Of the 105 observed deaths, 39 were attributed to sudden death and 66 to progressive heart failure. The median time to death was 11.2 months, and the median time to urgent heart transplantation was 7.6 months. The median survival of the entire study group was 33.9 months.
During the follow-up period, 86 patients died and 29 underwent urgent transplantation in the high PAP/low RVEF group (n = 215); five patients died and one underwent urgent transplantation in the high PAP/preserved RVEF group (n = 21); nine patients died in the normal PAP/preserved RVEF group (n = 73); and five patients died and five underwent urgent transplantation in the normal PAP/low RVEF group (n = 68). On Cox survival analysis, the patients in the high PAP/low RVEF group had the worst prognosis: their hazards ratio was seven times higher than that of the patients in the normal PAP/preserved RVEF group (95% confidence interval [CI] 3.6 to 14.1, p = 0.000), 4.3 times higher than that of the patients in the high PAP/preserved RVEF group (95% CI 2.2 to 8.2, p = 0.000) and 3.3 times higher than that of the patients in the normal PAP/low RVEF group (n = 68) (95% CI 1.5 to 7.2, p < 0.002). The prognoses of the patients in the normal PAP/preserved RVEF group, in the normal PAP/low RVEF group and in the high PAP/preserved RVEF group were not statistically different (Fig. 3).
The results of this study are likely to have a significant impact on the management of patients assessed for heart transplantation. As a general rule, increased PAP is coupled with reduced systolic function of the RV and is clinically associated with a poor prognosis. However, exceptions to this rule may occur frequently in clinical practice, so that a refinement of the prognostic stratification of the patients with chronic heart failure requires the knowledge of both PAP and RV function.
Coupling between RV function and PAP
The finding of an inverse relation between RV systolic function and PAP is in accordance with most previous pathophysiologic studies (7–12,17). Interestingly, this relation was similar between patients with dilated cardiomyopathy and those with ischemic heart disease, supporting the concept that in patients with heart failure due to primary dilated cardiomyopathy or to ischemic heart disease, the major determinant of the impairment in systolic function of the RV is afterload mismatch. Our data demonstrate that exceptions to the physiologic relation between mean PAP and RVEF may be observed frequently in clinical practice. First, RV function may be preserved despite elevated PAP. A possible explanation for this finding is that the development of RV dysfunction in response to an increase in afterload is time-dependent. This is impossible to prove without defining, in each patient, the duration of pulmonary hypertension; however, liver function tests were found to be abnormal only in patients with pulmonary hypertension and RV dysfunction, reflecting either the greater hemodynamic derangement or, possibly, a longer duration of the RV overload (18,19). An alternative hypothesis is that more favorable RV remodeling could determine better function in some patients. This seems unlikely because the ultrasound exploration did not show evidence of RV hypertrophy in any of these patients; furthermore, to our knowledge, no pathologic or clinical study has ever described RV hypertrophy in patients with heart failure due to ischemic heart disease or primary dilated cardiomyopathy. Second, RV dysfunction may be observed even in patients with normal PAP. Unexpectedly, this group of patients was fairly large (68 of 379 patients). There are several possible explanations for this finding: in patients with advanced disease, a low cardiac output state could determine normal PAP associated with reduced RV function; however, given the good prognosis of this group as a whole, it is unlikely that more than a few patients were in such a condition. A primary reduction in contractility could be responsible for the compromised RV function (17). The data, however, do not support such a hypothesis. In fact, there was a slightly greater prevalence of patients with dilated cardiomyopathy in the normal PAP/low RVEF group (p = NS). Overtreatment with diuretic drugs is another likely explanation, although in this group, the daily dose of frusemide was significantly lower than that of the patients in the high PAP/low RVEF group and similar to that of the other groups. Finally, a high prevalence of atrial fibrillation was observed in patients with normal PAP and low RVEF, leading to the hypothesis that the absence of active atrial contraction could play a major role in the pathogenesis of RV dysfunction.
Prognosis of patients with heart failure according to RV function and PAP
The demonstration that exceptions can be found to the general rule that inversely relates PAP and RV function is not only a matter of physiologic speculation but also of great clinical value in the prognostic stratification of patients with advanced heart failure. The clinical implications of these findings are twofold. First, in patients with heart failure and normal PAP, the assessment of RV function does not seem to improve the prognostic stratification. In contrast, when PAP is high at rest despite optimized medical therapy, the prognosis of the patients is strongly related to RV performance. For example, reduced RVEF is a harbinger of high risk of death or urgent transplantation, whereas preserved RVEF implies a prognosis that is very similar to that of patients with normal PAP.
The complex geometry of the RV makes it difficult to assess the systolic function of this cardiac chamber. No technique is exempt from potential criticism. Thermodilution-derived RVEF may be inaccurate in patients with high and irregular heart rates and in patients with severe tricuspid regurgitation; given these limitations, this technique has been well validated and has proved to be useful in several clinical conditions (4,15,16). Cardiopulmonary exercise testing would have helped to better stratify the risk of these patients and to verify whether the association between reduced RVEF and normal PAP, though not negatively affecting the prognosis, could be responsible for a lower exercise tolerance. Finally, in humans, there is considerable variability in the extent of increased PAP in response to pulmonary venous hypertension. Because this was not an objective of the present study, the results do not help to clarify why pulmonary hypertension develops in patients with heart failure due to ischemic heart disease or primary dilated cardiomyopathy. These issues might be the subject of future investigations.
These observations emphasize the necessity of combining the right heart hemodynamic variables with a functional evaluation of the RV when trying to define the individual risk of patients with chronic heart failure. Although we obtained all of the data during right heart catheterization (using a rapid-response thermodilution catheter to measure RVEF), such an integrated evaluation should also be easily performed with other techniques—in particularly, by means of the ultrasound evaluation, which allows a noninvasive estimate of both PAP and RV function.
☆ This study was supported in part by grant 080RFM92/02 from the Italian Health Ministry to IRCCS Policlinico S. Matteo.
- left ventricle or ventricular
- left ventricular ejection fraction
- New York Heart Association
- pulmonary artery pressure
- right ventricle or ventricular
- right ventricular ejection fraction
- Received April 10, 2000.
- Revision received August 3, 2000.
- Accepted September 20, 2000.
- American College of Cardiology
- Mudge G.H,
- Goldstein S,
- Addonizio L.J,
- et al.
- Polak J.F,
- Holman L,
- Wynne J,
- Colucci W.S
- Di Salvo T.G,
- Mathier M,
- Semigran M.J,
- Dec W.G
- De Groote P,
- Millaire A,
- Foucher-Hossein C,
- et al.
- Brown K.A,
- Okada R.D,
- Boucher C.A,
- Strauss H.W,
- Pohost G.M
- Oldershaw P
- Batin P,
- Wickens M,
- McEntegart D,
- Fullwood L,
- Cowley A.J