Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure

Patients

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.

Echocardiography

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.

Statistical analysis

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).

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Figure 1

Relation between mean pulmonary artery pressure (PAP) and pulmonary capillary wedge pressure (PCWP).

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).

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Figure 2

Relation between mean pulmonary artery pressure (PAP) and right ventricular ejection fraction (RVEF) in patients with dilated cardiomyopathy (DCM = continuous line, open squares) and in patients with ischemic heart disease (IHD = dotted line, open triangles).

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).

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Figure 3

Survival rates without urgent heart transplantation in patients grouped according to the coupling between mean pulmonary artery pressure (PAP) and right ventricular ejection fraction (RVEF). Group 1 = normal PAP/preserved RVEF (n = 73); group 2 = normal PAP/low RVEF (n = 68); group 3 = high PAP/preserved RVEF (n = 21); and group 4 = high PAP/low RVEF (n = 215).

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.

Study limitations

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.

Conclusions

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.