Decreased exercise capacity is the main symptom in patients with heart failure (HF). We assessed the association among noninvasively determined maximal cardiac output at exercise, systolic and diastolic cardiac functions at rest, and peak oxygen uptake (pV o 2 ) exercise capacity in patients with congestive HF. We studied 102 patients 62 ± 11 years of age with New York Heart Association class II to IV stable HF and left ventricular (LV) ejection fraction <45%. All patients underwent echocardiography and a treadmill cardiopulmonary exercise test for evaluation of pV o 2 corrected for fat-free mass. During the cardiopulmonary exercise test, cardiac output was estimated noninvasively and continuously using Nexfin HD. Fat-free mass–corrected pV o 2 was associated in an univariate linear regression analysis with peak exercise cardiac index (CI) (beta 0.511, p <0.001), LV end-diastolic pressure estimates (peak early diastolic filling velocity/early diastolic tissue velocity [E/e′], beta −0.363, p = 0.001), and right ventricular function (tricuspid annular plane systolic excursion, beta 0.393, p <0.001). In multivariate analysis peak exercise CI (beta 0.380, p = 0.001), but not cardiac output or LV ejection fraction at rest, was an independent predictor of pV o 2 . Other independent predictors of pV o 2 were E/e′ (beta −0.276, p = 0.009) and tricuspid annular plane systolic excursion (beta 0.392, p <0.001), also when adjusted for age and gender. In conclusion, peak CI is an independent predictor of fat-free mass–corrected pV o 2 in patients with systolic HF. Of all echocardiographic parameters at rest, right ventricular function and E/e′ were independently and significantly associated with pV o 2 , whereas LV ejection fraction at rest was not.
The cardiac mechanisms responsible for limited exercise capacity in patients with heart failure (HF) are not well understood, possibly because most hemodynamic functional variables are measured at rest. Previous studies have suggested that left ventricular (LV) ejection fraction at rest is a poor predictor of maximal exercise capacity. In contrast, echocardiographic LV filling pressures, LV diastolic function, and left atrial function have been shown to correlate weakly with functional status. Currently, the association between noninvasively measured cardiac output and peak oxygen uptake (pV o 2 ) during exercise has not been studied in patients with HF. Pulmonary artery catheter measurements using thermodilution are considered the golden standard for measuring cardiac output. They are invasive and carry a degree of risk. Recently, several methods to noninvasively determine cardiac output have become available. The Nexfin HD, a newly developed monitoring device that measures hemodynamics including cardiac output noninvasively and continuously, has recently been validated in patients after cardiac surgery and with HF compared to noninvasive echocardiographic and invasive thermodilution. In this study we evaluated the association between noninvasively measured Nexfin cardiac output and cardiac index (CI) during exercise and systolic and diastolic echocardiographic function measurements, and exercise capacity in patients with HF.
Methods
The study population consisted of 102 consecutive patients included in the BENEFICIAL trial. BENEFICIAL was a prospective, randomized, double-blinded, placebo-controlled, phase II study evaluating the efficacy and safety of alagebrium (ALT-711, an advanced glycation end-product cross-link breaker) in patients with systolic HF. The rationale and complete design of the BENEFICIAL trial has been previously published by Willemsen et al. All patients had New York Heart Association II to IV stable HF for ≥3 months and LV ejection fraction ≤45%. The study was approved by the medical ethical committee of the University Medical Center in Groningen and all patients gave written informed consent. The European Union Drug Regulating Authorities Clinical Trials (EudraCT) number of this study is 2007-000319-27.
A treadmill cardiopulmonary exercise test was performed in all patients using the modified Bruce protocol. The first stage was performed at 1.7 miles/hour and 0% grade, the second stage at 1.7 miles/hour and 5% grade, and the third stage corresponded to the first stage of the Bruce protocol. Each stage lasted approximately 3 minutes. Each exercise test started with an acclimatization period of 2 minutes standing on the treadmill. A standard 12-lead electrocardiogram was recorded continuously during the exercise test. Intermittent blood pressure was recorded at regular intervals of approximately 2 minutes using a manual upper arm cuff sphygmomanometer. Subjects wore a tightly fitting face mask to which was connected a capnograph and a sample tube enabling online ventilation and metabolic gas exchange measurements. V o 2 , carbon dioxide production, and minute ventilation were measured by breath-by-breath gas analysis. The minute ventilation/carbon dioxide production slope was calculated by a technician performing the test through linear regression by analyzing breath-by-breath values obtained throughout the full test from all data points. Respiratory exchange ratio was computed as carbon dioxide production/V o 2 and a respiratory exchange ratio ≥1.0 was taken to indicate maximal effort. pV o 2 was calculated as the average V o 2 for the 2 highest measurements at peak exercise; it was corrected for fat-free mass and expressed as milliliter per minute per kilogram of fat-free mass. Reasons for terminating the treadmill cardiopulmonary exercise test were subject fatigue or exercise-limiting breathlessness. However, patients were actively encouraged to achieve a respiratory exchange ratio >1.0 if possible.
During the cardiopulmonary exercise test, cardiac output and CI were measured beat to beat using the Nexfin HD (BMEYE BV, Amsterdam, Netherlands). A finger cuff of appropriate size was wrapped around the middle phalanx of the middle, index, or ring finger of the right hand and the heart reference system, a hydrostatic height correction system, was positioned at heart level. The 2 hands were used by the patients to maintain a stable position on the treadmill. CI was determined by Nexfin for each heart beat by dividing cardiac output by body surface area. Cardiac output and CI at rest were computed by averaging over the last minute before the start of the exercise protocol. Peak CI and cardiac output were calculated as average CI and cardiac output for the last 30 seconds of exercise, similar to the pV o 2 calculations.
Two-dimensional echocardiography was performed on the same day as the exercise testing protocol in all 102 patients by a single experienced sonographer (Y.M.H.) using a VIVID 7 system (General Electric, Horton, Norway) with a 2.5- to 3.5-mHz probe. All measurements were performed according to European Society of Echocardiography guidelines. Systolic dysfunction was determined by the Simpson LV ejection fraction, where possible, and defined as an LV ejection fraction ≤45%. To assess LV diastolic filling dynamics pulse-wave Doppler was performed on mitral inflow in the apical 4-chamber view. Peak early diastolic (E) and late diastolic filling velocities, isovolumetric relaxation time, and deceleration time of E were obtained. Tissue Doppler imaging was used to derive early (e′) and late diastolic tissue velocities and systolic tissue velocities on the 4 basal mitral annular sites (lateral, septal, anterior, and inferior), mean tissue velocities were calculated from septal and lateral annular velocities, and mean values for the 4 annular sites was calculated. Estimation of LV filling pressure was done by dividing E by e′ (mean of septal and lateral, E/e′). Right ventricular function was assessed by tricuspid annular plane systolic excursion.
Kolmogorov-Smirnov test was used to verify the normality of distribution of continuous variables. Continuous variables were expressed as mean ± SD when normally distributed or median (interquartile range) when distribution was skewed. Categorical parameters were expressed as frequency and percentage. Differences in characteristics between patient groups were analyzed using t test when the parameter was normally distributed or Mann–Whitney U test when normality was not met. Chi-square test was used for comparison of categorized variables. To determine the association between variables and exercise capacity, univariate linear regression analysis was performed. In multivariate analysis we evaluated independent predictors of pV o 2 . We constructed a model using peak CI, introducing different echocardiographic parameters of diastolic LV function. Interaction analysis was conducted between multivariate associated variables and association with pV o 2 . To visualize the independent effect of CI and diastolic function (E/e′) on pV o 2 , we categorized CI (above/below mean) and E/e′ (above/below median) and assessed the difference between groups of different combination of high and low CI and E/e′. All models were adjusted for age and gender. A 2-sided p value <0.05 was considered statistically significant. All analyses were performed using SPSS 16.0.2 (SPSS, Inc., Chicago, Illinois).
Results
Demographic and clinical characteristics of the study population are presented in Table 1 . In total 102 patients were included in this analysis, 80 men and 22 women, with a mean age of 62 ± 11 years. Results of echocardiography and exercise test at rest are presented in Table 1 .
| Variable | |
|---|---|
| Age (years) | 60 ± 11 |
| Men | 80 (78%) |
| Cause of heart failure | |
| Ischemic | 70 (69%) |
| Nonischemic | 32 (31%) |
| Hypertension (by history) | 32 (31%) |
| Diabetes mellitus | 17 (17%) |
| New York Heart Association functional class | |
| II | 66 (65%) |
| III | 33 (32%) |
| IV | 3 (3%) |
| Systolic blood pressure (mm Hg) | 114.9 ± 15.2 |
| Diastolic blood pressure (mm Hg) | 72.1 ± 9.2 |
| Heart rate (beats/min) | 69.5 ± 14.3 |
| Body mass index (kg/m 2 ) | 27.8 ± 4.1 |
| Serum creatinine (μmol/L) | 86.5 (78.0–101.3) |
| N-terminal pro–brain natriuretic peptides (ng/L) | 403 (154–851) |
| Medication use | |
| Angiotensin-converting enzyme inhibitors | 79 (78%) |
| Angiotensin receptor blocker | 19 (19%) |
| β Blockers | 95 (93%) |
| Diuretics | 56 (55%) |
| Aldosterone antagonists | 29 (28%) |
| Echocardiography at rest | |
| Left ventricular ejection fraction (%) | 32 ± 10 |
| Mean systolic tissue velocity (cm/s) | 4.21 ± 1.32 |
| Early/late diastolic mitral valve inflow ratio | 0.89 (0.69–1.17) |
| Mean early diastolic tissue velocity (cm/s) | 5.16 ± 1.90 |
| Mean late diastolic tissue velocity (cm/s) | 5.40 ± 1.96 |
| Early diastolic mitral valve inflow/early diastolic tissue velocity ratio | 12.7 (10.0–18.3) |
| Tricuspid annular plane systolic excursion (mm) | 24 ± 5 |
| Cardiac output during exercise | |
| Baseline cardiac output (L/min) | 4.8 ± 1.3 |
| Peak cardiac output (L/min) | 10.7 ± 3.3 |
| Baseline cardiac index (L/min/m 2 ) | 1.9 ± 1.1 |
| Peak cardiac index (L/min/m 2 ) | 5.3 ± 1.5 |
| Peak oxygen uptake during exercise | |
| Baseline peak oxygen uptake (ml/min) | 355 ± 81 |
| Peak oxygen uptake (ml/min) | 1,870 ± 606 |
| Peak oxygen uptake corrected for body weight (ml/min/kg) | 21.7 ± 5.9 |
| Percent predicted peak oxygen uptake | 84 ± 24 |
| Peak oxygen uptake corrected for fat-free mass (ml/min/kg) | 32.1 ± 8.4 |
Noninvasive cardiac output and CI at maximal exercise were available in only 65 patients mainly because of severe artifacts on 38 recordings caused from the hand with the Nexfin finger cuff on it to maintain stability during the exercise protocol by gripping the handle bar.
Results of linear regression analysis on prediction outcome of pV o 2 (corrected for fat-free mass) are presented in Table 2 . In univariate analysis, older age and urea and creatinine were significantly associated with lower pV o 2 . Of all echocardiographic measurements of systolic LV function, LV ejection fraction and mean systolic tissue velocities showed a significant association with pV o 2 . Of all measurements of diastolic function, E/e′ had the strongest association with pV o 2 ( Figure 1 ). Furthermore, as a marker of right ventricular function, higher tricuspid annular plane systolic excursion was significantly associated with higher pV o 2 ( Figure 2 ). Peak exercise cardiac output and peak exercise CI were significantly associated with pV o 2 ( Figure 3 ). Using pV o 2 corrected for body weight instead of fat-free mass produced similar results.
| Variable | Univariate Linear Regression | |
|---|---|---|
| Beta (standardized) | p Value | |
| Age (years) | −0.389 | <0.001 |
| Men | 0.087 | 0.385 |
| Diastolic blood pressure (mm Hg) | 0.182 | 0.069 |
| Heart rate (beats/min) | −0.028 | 0.781 |
| Diabetes mellitus | −0.095 | 0.347 |
| Hemoglobin (mmol/L) | 0.109 | 0.279 |
| Serum urea (mmol/L) | −0.217 | 0.030 |
| Log creatinine | −0.268 | 0.007 |
| Log N-terminal pro–brain natriuretic peptides (ng/L) | −0.511 | <0.001 |
| Left ventricular ejection fraction (%) | 0.334 | 0.001 |
| Mean systolic tissue velocity (cm/s) | 0.278 | 0.006 |
| Early diastolic mitral valve inflow velocity (m/s) | −0.139 | 0.171 |
| Log early/late diastolic mitral valve inflow ratio | −0.136 | 0.205 |
| Mean early diastolic tissue velocity (cm/s) (total) | 0.233 | 0.020 |
| Mean early diastolic tissue velocity (septal/lateral) | 0.260 | 0.009 |
| Mean late diastolic tissue velocity (cm/s) | 0.254 | 0.015 |
| Early diastolic mitral valve inflow/early diastolic tissue velocity ratio | −0.363 | 0.001 |
| Tricuspid annular plane systolic excursion (mm) | 0.393 | <0.001 |
| Cardiac index at rest (L/min/m 2 ) | 0.300 | 0.002 |
| Peak cardiac index (L/min/m 2 ) | 0.511 | <0.001 |
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