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CLINICAL STUDIES

Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure

Marco Metra, MD^*, Pompilio Faggiano, MD, Antonio D’Aloia, MD^*, Savina Nodari, MD^*, Anna Gualeni, MD^*, Domenica Raccagni, MD^* and Livio Dei Cas, MD^*

^* Cattedra di Cardiologia, Universitá di Brescia, Brescia, Italy
Divisione di Cardiologia, Ospedale Fatebenefratelli, Brescia, Italy

Manuscript received October 9, 1997; revised manuscript received October 23, 1998, accepted December 11, 1998.

Reprint requests and correspondence: Dr. Marco Metra, Cattedra di Cardiologia, Università di Brescia, c/o Spedali Civili, P.zza Spedali Civili 25100 Brescia, Italy.
deicas{at}master.cci.unibs.it

	Abstract

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OBJECTIVES

We studied whether direct assessment of the hemodynamic response to exercise could improve the prognostic evaluation of patients with heart failure (HF) and identify those in whom the main cause of the reduced functional capacity is related to extracardiac factors.

BACKGROUND

Peak exercise oxygen consumption (VO₂) is one of the main prognostic variables in patients with HF, but it is influenced also by many extracardiac factors.

METHODS

Bicycle cardiopulmonary exercise testing with hemodynamic monitoring was performed, in addition to clinical evaluation and radionuclide ventriculography, in 219 consecutive patients with chronic HF (left ventricular ejection fraction, 22 ± 7%; peak VO₂, 14.2 ± 4.4 ml/kg/min).

RESULTS

During a follow-up of 19 ± 25 months, 32 patients died and 6 underwent urgent transplantation with a 71% cumulative major event-free 2-year survival. Peak exercise stroke work index (SWI) was the most powerful prognostic variable selected by Cox multivariate analysis, followed by serum sodium and left ventricular ejection fraction, for one-year survival, and peak VO₂ and serum sodium for two-year survival. Two-year survival was 54% in the patients with peak exercise SWI 30 g·m/m² versus 91% in those with a SWI >30 g·m/m² (p < 0.0001). A significant percentage of patients (41%) had a normal cardiac output response to exercise with an excellent two-year survival (87% vs. 58% in the others) despite a relatively low peak VO₂ (15.1 ± 4.7 ml/kg/min).

CONCLUSIONS

Direct assessment of exercise hemodynamics in patients with HF provides additive independent prognostic information, compared to traditional noninvasive data.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   CO = cardiac output   HF = heart failure   LVEF = left ventricular ejection fraction   PWP = pulmonary wedge pressure   SWI = stroke work index   VO2 = oxygen consumption

Peak VO₂ is highly dependent on the hemodynamic response to exercise (4,12–14) and, therefore, measures the cardiovascular reserve of the patient. However, it may also be influenced by other factors. It has been observed that, in a significant proportion of patients with heart failure (HF), the main cause of functional limitation may reside in an abnormality of skeletal muscle metabolism with earlier lactic acidosis despite a normal peripheral blood flow (15,16). However, as these patients may present a significant impairment of resting left ventricular function and functional capacity, they should be identified through an additional procedure. Accordingly, some studies have suggested that the direct assessment of the hemodynamic response to exercise may improve the prognostic evaluation of patients with HF (17–19), but these data have not been confirmed by other investigators (20,21).

In our study, we assessed the prognostic value of the hemodynamic variables measured at peak exercise, compared with the resting hemodynamic data and variables obtained by noninvasive exams, in a large group of ambulatory patients with chronic HF.

	Methods

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Patients.   The study group included 219 consecutive ambulatory patients with chronic symptomatic HF caused by significant left ventricular systolic dysfunction (ejection fraction 35%) selected among 324 patients referred to our Institute, between January 1992 and January 1996, for an evaluation for heart transplantation or for persistent symptoms despite therapy with optimal doses of diuretics and angiotensin-converting enzyme (ACE) inhibitors. Among the 324 referred patients, 45 were excluded for a left ventricular ejection fraction (LVEF) >35%, at equilibrium radionuclide ventriculography, because these patients are known to have a good prognosis (1,3,9,11). The others were excluded as their main cause of functional limitation was not related to myocardial dysfunction or because they were in unstable conditions. Namely, we excluded the patients unable to exercise because of noncardiac limitations, with reduced exercise tolerance caused by myocardial ischemia or major ventricular arrhythmias, with valvular or congenital heart diseases, with a recent (3 months) myocardial infarction, unstable angina or acute myocarditis, candidates for myocardial revascularization and patients requiring intravenous inotropic agents or mechanical circulatory support. Last, we excluded patients treated with calcium antagonists, beta-adrenergic blocking agents or antiarrhythmics, other than mexiletine or amiodarone, because of the possible influence of these drugs on the prognosis of HF. As we administered beta-blockers to most of our patients since January 1996, we have limited to this date our recruitment for this study.

All patients had a history of chronic HF of >6 months duration and were studied in clinically stable conditions, with no change in their drug regimen, in the previous week. Almost all patients were receiving digoxin (94%, mean dose 0.16 ± 0.06 mg/day, range 0.0625 to 0.25), furosemide (98%; mean dose 73 ± 61 mg, range 25 to 500) and an ACE inhibitor (either captopril, 51%, mean dose 78 ± 47 mg/day, range 18.75 to 150 mg, or enalapril, 48%, mean dose 19.8 ± 10.6 mg/day, range 5 to 40 mg). Oral nitrates were taken by 57%, hydralazine by 6%, oral anticoagulants by 64%, mexiletine by 8% and amiodarone (mean dose 208 ± 63 mg/day) by 37% of the studied patients. In the weeks before the study, doses of diuretics were adjusted with the aim of eliminating clinical signs of congestion; doses of captopril or enalapril were titrated up to 150 mg/day or 40 mg/day, respectively, or to the appearance of hypotension (systolic blood pressure 80 mm Hg) or marked renal insufficiency. This protocol has been shown to improve the clinical course of a significant proportion of patients with advanced HF (8,11,22).

All patients were followed up for a minimum of 6 months (range 6 months to 4.5 years) or until heart transplantation or death. Each patient underwent repeated clinical evaluations every one to six months. Follow-up information was obtained in all patients by repeated clinical examinations or telephone calls in August 1996.

Procedures and variables.   All patients underwent a clinical evaluation, equilibrium radionuclide ventriculography and cardiopulmonary exercise testing with simultaneous hemodynamic monitoring.

Exercise testing was performed after an overnight fast without withholding oral medications. A triple lumen Swan-Ganz catheter was inserted percutaneously through the right internal jugular vein and positioned in the pulmonary artery to obtain hemodynamic measurements. Cardiac output (CO) was measured using the thermodilution method. Derived hemodynamic variables were calculated using standard formulas (23).

Bicycle exercise testing was performed with the patient in the sitting position with simultaneous expiratory gas exchange and hemodynamic monitoring. Exercise was started at a work load of 0 W, with further increments of 20 W every 2 min, at the velocity of 50 rpm, up to the appearance of limiting dyspnea or fatigue. Electrocardiographic and respiratory variables were continuously monitored. Hemodynamic measurements were obtained at rest, during the last minute of each work load increment and at peak exercise. Peak VO₂ was obtained averaging the final 30 s of exercise. The anaerobic threshold was determined by standard criteria (10,12,14,24). All patients had performed at least one preliminary exercise test to be familiar with the procedure.

Hemodynamic measurements were obtained after a resting equilibration period of about 20 min, at rest, both in the supine and sitting positions, and then at each workload and at peak exercise during the test. When the patient was seated, the transducer was positioned at the level of the fourth intercostal space in the midaxillary line. The CO response to exercise was defined as normal or reduced according to the equation of Higginbotham et al. (19,20,25). According to this equation, a normal CO at peak exercise should be 5 x VO₂ (liters/min) + 3 liters/min.

Statistical analysis.   All data are expressed as mean ± SD. Differences between groups were assessed using unpaired t test, analysis of variance or chi-square analysis, and correlations were assessed by linear regression analysis, Spearman rank order analysis and multivariate stepwise regression analysis, as appropriate. Cumulative survival estimates were calculated using the Kaplan–Meier method with differences between the survival curves assessed by the Mantel–Cox method. A p value <0.05 was considered statistically significant. To identify the independent predictors of survival, multivariate analysis was performed using the Cox proportional hazards model using the variables significant at a p <0.1 level at univariate analysis.

Outcome events were death and urgent transplantation (UNOS status 1) (11). Death was defined as sudden when it occurred outside the hospital without symptomatic worsening in the previous 24 h or as caused by progressive heart failure when it was preceded by progressive clinical deterioration. Elective transplantation was considered as a censored observation with the patient withdrawn from analysis at the time of transplantation. Results of the hemodynamic study did not influence the incidence of the subsequent major events. Namely, all the patients were discharged after the hemodynamic study and urgent transplantation was always performed for a new hospital admission caused by worsening of HF symptoms.

	Results

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Cumulative major event-free survival was 93% at 6 months, 84% at 12 months and 71% at 2 years. Thirty-two patients died and six underwent urgent transplantation (status 1). The cause of death was progressive HF in 18 patients (56%) and sudden death in the remaining 14 (44%). Twenty-two patients (10%) underwent elective heart transplantation.

Univariate and multivariate predictors of survival.   Compared with survivors, nonsurvivors had significantly lower values of serum sodium, LVEF, peak VO₂ and VO₂ at the anaerobic threshold (Table 1). Most of the resting and exercise hemodynamic variables were significantly different between the two groups (Table 2). Cumulative survival curves of the patients subdivided on the basis of the median values of serum sodium, peak VO₂, LVEF, resting pulmonary wedge pressure (PWP) and peak exercise stroke work index (SWI) are shown in Figure 1.

View larger version (28K): [in this window] [in a new window]   Figure 1 Cumulative survival curves for the patients dichotomized on the basis of the median values of serum sodium (Na+) concentration, peak oxygen consumption (VO2), left ventricular ejection fraction (LVEF), resting supine pulmonary wedge pressure (PWP) and peak exercise left ventricular stroke work index (SWI).

View larger version (31K): [in this window] [in a new window]   Figure 2 Cumulative survival curves for patients dichotomized by median values of both peak exercise left ventricular stroke work index (ex SWI) and serum sodium (Na+) (top) and both peak exercise left ventricular stroke work index (ex SWI) and peak oxygen consumption (pVO2) (bottom).

Analysis of patients with a normal hemodynamic response to exercise.   Despite its high correlation with peak exercise hemodynamic variables, peak VO₂ had a lower prognostic value compared with them. This may be explained by the presence of a significant proportion of patients who had only a mild impairment of the CO response to exercise despite a reduced functional capacity. Ninety-one patients (41%) had a normal CO response to exercise, as defined by Higginbotham et al. (25), whereas it was reduced in the remaining 128.

Patients with a normal CO response to exercise had, compared with those with an impairment of exercise CO, higher resting LVEF (25 ± 7 vs. 20 ± 7%; p < 0.001), peak VO₂ (15.1 ± 4.7 vs. 13.5 ± 4.1 ml/kg/min; p < 0.01), peak exercise systolic blood pressure (155 ± 26 vs. 141 ± 32 mm Hg; p < 0.01) and resting and peak exercise cardiac index (2.7 ± 0.5 vs. 2.3 ± 0.5 and 5.8 ± 1.6 vs. 3.5 ± 1.0 liters·m·m^–2, respectively; p < 0.001 in both cases) with lower resting and peak exercise PWP (19 ± 8 vs. 26 ± 10 and 34 ± 12 vs. 40 ± 10 mm Hg, respectively; p < 0.001 in both cases). Despite these differences, a significant percentage of them had a reduced functional capacity and impaired resting hemodynamics. Namely, a peak VO₂ 14 ml/kg/min was present in 43 (47%), a LVEF 20% in 26 (29%) and a resting PWP 20 mm Hg in 31 (34%) of the patients with a normal CO response to exercise. These patients had, however, an excellent two-year survival (Fig. 3).

View larger version (17K): [in this window] [in a new window]   Figure 3 Cumulative survival curves for patients with a normal and reduced cardiac output response to exercise (ex).

	Discussion

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It would be, therefore, useful to utilize additional variables that allow a further stratification of the patients with a low peak VO₂ into high and low risk categories. The measurement of peak VO₂ as the percentage of its maximal predicted values, rather than as an absolute value, may remove the effect of age, gender, and body surface area (29,31–33). Second, the direct assessment of the exercise hemodynamics might identify the patients whose functional limitation is caused mainly by skeletal muscle deconditioning and/or poor motivation, rather than by cardiovascular factors (15,16). However, the usefulness of this method is still controversial (19–21).

The results of our study show that the direct evaluation of the exercise hemodynamics yields additional prognostic information compared with standard noninvasive variables. Peak exercise SWI was the most powerful independent prognostic factor, followed by serum sodium and LVEF, for one-year mortality or urgent transplantation, and by peak VO₂ and serum sodium for two-year events. Previous studies also found peak exercise SWI to be the most powerful independent prognostic variable (17–20). These investigations, however, were performed using relatively small sample sizes which, with only one exception (18), included only patients referred for cardiac transplantation.

The prognostic value of exercise hemodynamics may be explained by the significant percentage of patients (41%) with a normal, or only slightly impaired, CO response to exercise in our study group. Even if many variables were significantly different between these patients and the others, a significant proportion of them had either a high resting PWP, a low LVEF or a low peak VO₂ (34%, 29% and 47%, respectively). Therefore, they might have been considered candidates for heart transplantation (11) despite their excellent long-term survival (Fig. 3). Thus, direct measurement of the hemodynamic response to exercise allows the identification of the patients with a normal or only slightly impaired CO response to exercise who have a good prognosis despite a low functional capacity. Alternative methods, like the repetition of a noninvasive cardiopulmonary exercise test after three to six months, may also be used to identify them (10,26).

Comparison with previous studies.   In our study, similarly to previous ones (4,8,12–14), peak exercise hemodynamics and, namely, peak exercise CO, were significantly related to peak VO₂. Furthermore, our equation of the correlation between CO and VO₂ was very similar to the one found by Higginbotham et al. (25) and Mancini et al. (20). However, despite this correlation, direct assessment of the exercise hemodynamics allowed a better prognostic evaluation than peak VO₂ and other noninvasive variables. Our results are similar to those of Chomsky et al. (19). In their investigation, direct assessment of the exercise hemodynamics identified a group of patients with a normal CO response to exercise who had an excellent prognosis despite a low peak VO₂. Similarly to our results, these patients were 45% of the whole study group (19). In contrast, in the study by Mancini et al. (20), assessment of the exercise hemodynamics was not useful, and only 6% of the patients had a normal CO response to exercise, with most of the hemodynamic variables, including CO and resting PWP, not significantly different between survivors and nonsurvivors.

These discrepancies may be explained by the characteristics of the patient populations. Mancini et al. studied 65 patients referred for transplantation during a time interval of 18 months. Thus, their study population was probably more accurately selected, with the exclusion of patients with poor motivation to perform an exercise test or with skeletal muscle deconditioning (20). In contrast, our study population included 219 patients, recruited during 4 years, referred both for persistent symptoms or heart transplantation. These patients were, therefore, less selected and, probably, more similar to the general population of patients with HF of moderate severity; for example, elderly patients or patients with skeletal muscle wasting were included. It must, however, be noted that to have a homogeneous patient group, we studied only the patients with a LVEF 35% and treated with optimal doses of diuretics and ACE inhibitors. Accordingly, their clinical features and mortality were similar to those of previous investigations (1,3,6,9,18–22). Our results, however, cannot be extrapolated to other categories of HF patients, like those with prevalent diastolic dysfunction or with associated myocardial ischemia or malignant tachyarrhythmias. The accurate exclusion of patients with exercise-induced myocardial ischemia also explains why the percentage of patients with idiopathic dilated cardiomyopathy was greater in our study than in the general HF population.

Prognostic value of other variables.   The prognostic value of serum sodium also has been pointed out in other studies (7,8,22,34,35), and it is explained by its high correlation with neurohumoral activation (34,35). The relatively low prognostic value of LVEF, in our study, is explained by our selection of only patients with a LVEF 35%; this variable has its greatest prognostic value when assessed in study groups with a wider range of cardiac dysfunction (9,23,34). Resting PWP did not yield independent information at multivariate analysis. However, this variable was highly significant at univariate analysis (Table 3), with a relation with survival similar to previous results (Fig. 1) (8,11,21). It lost significance at multivariate analysis because of its high correlation with peak exercise SWI (r = –0.56; p < 0.001; using Spearman rank order correlation analysis). Our study, therefore, points out the importance of the hemodynamic variables for the prognostic assessment of patients with HF, with a further improvement when they are also evaluated during maximal exercise.

Conclusions.   Our results show that the direct assessment of the hemodynamic response to exercise allows the identification of powerful independent prognostic indexes which, in addition to serum sodium, LVEF and peak VO₂, allow a further stratification of patients with chronic HF and reduced functional capacity into high and low risk subgroups. The usefulness of the direct assessment of the exercise hemodynamics is explained by the presence of a significant percentage of patients with only a mild impairment of the hemodynamic response to exercise who still retain an excellent prognosis despite a low peak VO₂ and/or a low LVEF, and/or high resting PWP.

	Footnotes

 
This study was partially supported with a fund from the target project FATMA (protocol n.91.00137.41) of the National Council of Research, Rome, Italy and with a fund from the CARIPLO foundation of the "Centro per lo studio del trattamento dello scompenso cardiaco."

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