Research ArticleOriginal Research

Evaluation of Right Ventricular Function in Patients With COPD

Yosuke Tanaka, Mitsunori Hino, Kyoichi Mizuno and Akihiko Gemma
Respiratory Care May 2013, 58 (5) 816-823; DOI: https://doi.org/10.4187/respcare.01856

Abstract

BACKGROUND: Pulmonary hypertension is an independent risk factor for death in patients with COPD. Current prognostic models of COPD do not include sufficient indicators of right ventricular (RV) function to enable accurate assessment of changes in RV function over time. The aim of the present study was to test the hypothesis that it would be useful to include noninvasive markers of RV function in the routine assessment and prognostic models of early stage COPD with or without pulmonary hypertension.

METHODS: We reviewed the clinical records of 49 male subjects who had COPD but no other conditions that might affect physical status or prognosis, who underwent cardiac ultrasonography. Various echocardiographic parameters of pulmonary circulation and RV function were compared with indices of physical status and prognosis.

RESULTS: The Medical Research Council dyspnea score was higher in subjects with echocardiographic findings suggestive of pulmonary hypertension than those without (mean ± SD 3.17 ± 1.23 vs 2.26 ± 0.81, P = .02). RV ejection time, RV isovolumetric relaxation time, RV isovolumetric contraction time + RV isovolumetric relaxation time, and RV total ejection isovolume index differed significantly between subjects with echocardiographic findings suggestive of pulmonary hypertension and those without. The RV total ejection isovolume index was strongly correlated with the MRC score (P < .001), and was significantly correlated with the overall survival rate (hazard ratio 5.31, 95% CI 1.91–14.77) and hospital-free survival rate (hazard ratio 3.26, 95% CI 1.48–7.16).

CONCLUSIONS: It may be valuable to add assessment of RV function to the routine evaluation of physical status in patients with COPD.

Introduction

COPD is well known to cause systemic effects. Discrepancies are often observed between the physical status of COPD patients and the results of routine tests such as pre and post exercise blood gas analysis and pulmonary function tests.1 Classification of the severity of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) classification is based on the degree of air-flow obstruction (percent-of-predicted FEV1). This classification is limited, as it does not include other important factors such as exercise tolerance, comorbidities, and complications.1 Physical status is affected by various factors, including impairment of ventilation and gas exchange, hypoxia, and impairment of pulmonary circulation.1 For this reason, assessment of the severity of COPD often uses a combination of assessment tools, such as the BODE index (body mass index, air-flow obstruction, dyspnea, and exercise capacity), the St George's Respiratory Questionnaire (SGRQ), and the 36-item Medical Outcomes Study Short Form questionnaire (SF-36).2,3 None of these indices include an assessment of pulmonary artery pressure or right ventricular (RV) load. However, some studies have reported that pulmonary hypertension (PH) is an independent risk factor for death in patients with COPD.4,5 Early changes in RV function have been reported in clinically stable COPD patients with no evidence of PH.6 If a noninvasive and easily available marker of RV function is included in prognostic models of COPD, RV overload may be detected even in patients with mild or absent elevation of pulmonary artery pressure.

Some studies have reported the assessment of RV function and pulmonary artery pressure by Doppler echocardiography.7–15 These studies recommended using the total ejection isovolume (TEI) index as a noninvasive method to assess RV function in patients with PH.7,8 Several studies have reported on the use of the TEI index to assess RV function, but these studies included only patients with severe pulmonary arterial hypertension, old tuberculosis, or connective tissue disease.7,9,11 The TEI index has not been used as a marker of RV function in prognostic models of COPD.

At our institution, echocardiography with a focus on pulmonary artery pressure and the TEI index is performed routinely on COPD patients, to check for PH and to detect any other cardiac conditions that may affect activities of daily living (ADLs).

Based on the assumption that COPD leads to reduced RV compliance and changes in RV function before pulmonary artery pressure begins to rise, we hypothesized that it would be useful to include markers of RV function in the routine assessment and prognostic models of early stage COPD, with or without PH. Such a marker of RV function should be clinically feasible and noninvasive. We used the data available at our institution to retrospectively compare the TEI index with the physical status and prognosis of COPD patients.

QUICK LOOK

Current knowledge

Pulmonary hypertension is an independent risk factor for death in patients with COPD. The available prognostic models for COPD do not include indicators of right ventricular (RV) function for assessing RV function over time.

What this paper contributes to our knowledge

There were strong correlations between COPD-associated RV dysfunction and prognosis, and difficulty with activities of daily living. COPD may cause RV dysfunction in the absence of pulmonary hypertension. COPD assessment guidelines should include assessment of pulmonary hypertension and RV function.

Methods

The clinical records of all male patients with COPD who were admitted to our hospital from April 2000 to March 2005 were reviewed to identify those who underwent routine echocardiography during this time period and did not require any change in their treatment regimen for at least 3 months before and 3 months after echocardiography. The diagnosis of COPD was in accordance with the criteria established by the American Thoracic Society. We included only men in this study because the assessment of physical status is affected by symptoms such as respiratory distress, which may be affected by hormonal changes in women.16–26 Patients were excluded from the analysis if any condition other than COPD that might affect ADLs, such as arrhythmia, changes in left ventricular (LV) function, or intervertebral disc herniation, was observed from the time of echocardiography until the end of the analysis period in March 2011. Patients were also excluded if they required psychotropic medication, a change in medication dose for more than 4 weeks, or a change in any medication that may affect hemodynamic function, such as theophylline, steroids, diuretics, digitalis, or antihypertensive agents, as these could affect assessment of the progression of COPD. An increase in diuretic medication was allowed if it was required to treat congestion resulting from worsening PH. These selection criteria were set because this study aimed to evaluate the usefulness of additional assessment of RV function, compared with the usual assessments undertaken in patients with COPD.

At our institution, all patients with COPD routinely underwent echocardiography in addition to standard chest x-ray and pulmonary function tests, unless they explicitly refused. All echocardiography measurements were performed at rest, and were performed by the same staff using the same equipment throughout the study period. Subjects were evaluated for respiratory failure, physical status, hospital-free survival, and overall survival. Physical status was assessed using the Medical Research Council (MRC) dyspnea scale.27 Treatment of COPD was limited to that recommended by the American Thoracic Society guidelines for COPD,1 ensuring that arterial oxygen saturation did not fall below 90% during ADLs. This study was approved by the medical ethics committee of Nippon Medical School.

Echocardiographic Examination

Complete 2-dimensional, pulsed-wave, color-flow echocardiography was performed using an ultrasound machine (Sonos 1000, Hewlett-Packard, Palo Alto, California), as previously described.7,9–11,14,28–33

The right heart circulation was assessed as follows. Color Doppler flow imaging was used to detect and semi-quantify pulmonary and tricuspid valve regurgitation. The tricuspid in-flow velocity was recorded from the apical 4-chamber view with the pulsed-wave Doppler sample volume positioned at the tip of the tricuspid leaflets during diastole. The RV out-flow tract velocity was recorded from the parasternal short-axis view with the pulsed-wave Doppler sample volume positioned just below the pulmonary valve.

Doppler Measurements

All measurements for the assessment of RV function were performed according to the methods previously reported7,9–11 (Fig. 1). Mean values were obtained by averaging at least 5 beats. RV out-flow acceleration time and tricuspid regurgitation velocity were measured to determine if there was any evidence of PH. Results were considered to be suggestive of PH when the tricuspid regurgitation velocity was > 2.8 m/s without pulmonary valve stenosis,8,34 when PA acceleration time was < 90 ms, or when PA acceleration time/PA ejection time was < 0.3.14,15,35 All measurements were made at end-expiration.

Fig. 1.
Fig. 1.

Schema of color Doppler echocardiographic measurements. A: Interval between the cessation of tricuspid in-flow and the start of the next tricuspid in-flow. B: Interval between the R wave and the cessation of right ventricular (RV) out-flow. C: Interval between the R wave and the start of tricuspid in-flow. RV out-flow acceleration time (AcT) is the interval between the start of RV out-flow and peak velocity. Ejection time (ET) is the interval of RV out-flow, measured from the start to the end of the RV out-flow Doppler velocity profile below the baseline. Tricuspid closing to opening time is the interval between the end and start of the tricuspid in-flow Doppler velocity profile above the baseline, shown as A. Mean values were obtained by averaging at least 5 beats. Interval A from the cessation to the start of tricuspid forward flow was calculated as the sum of isovolumetric contraction time (ICT, calculated as A – ET – IRT), ET, and isovolumetric relaxation time (IRT, calulated as C – B). The interval measured by subtracting ET from A was calculated as ICT + IRT. The total ejection isovolume (TEI) index, which is a systolic and diastolic myocardial performance index, was calculated as (A – ET)/ET. The other parameters (IRT, ICT, and ICT/ET) were determined according to the method of Tei et al.9

Statistical Analysis

Values are expressed as mean ± standard deviation. All comparisons between groups were performed using the Mann-Whitney U test. Correlations were investigated using Spearman rank correlation test. Survival analysis was performed using the Cox proportional hazards model. In all analyses, P < .05 was considered significant. All statistical analyses were performed using statistics software (JMP 6.03, SAS Institute, Cary, North Carolina).

Results

Of the 241 COPD patients who attended our hospital from April 2000 to March 2005, 53 met the inclusion criteria for this study. Patients were excluded for the following reasons: 33 had cardiac disease that affected ADLs, such as LV dysfunction, 26 had unstable COPD, 11 had dementia, 18 had cerebral disease that impaired ADLs, 24 had arrhythmia including atrial fibrillation, 15 had other conditions with affected ADLs such as intervertebral disc herniation, 23 had pulmonary disease other than COPD, 5 were taking psychotropic medication, and 9 could not attend the hospital on a regular basis. Twenty-four of these patients met at least 2 exclusion criteria. Four additional patients were excluded later because they developed cardiac disease that might have resulted in LV dysfunction on effort during the analysis period (the time from echocardiography to March 2011). None of the remaining 49 patients had conditions other than COPD that might have affected ADLs.

Table 1 shows the clinical characteristics of the study population. There were no significant differences in age, height, body weight, or pulmonary function indices between subjects with findings suggestive of PH and those without. Physical status assessed by the MRC dyspnea score was significantly worse in subjects with findings suggestive of PH (P = .02).

View this table:
Table 1.

Clinical Characteristics of the Study Population

Table 2 shows the Doppler echocardiographic parameters in subjects with and without findings suggestive of PH. Except for isovolumetric contraction time, these parameters were all significantly different between the 2 groups. Even though physical status assessed by the MRC dyspnea score and several color Doppler echocardiographic parameters differed significantly between the groups, there was overlap between groups in all of these indices. These findings differ from the data reported in previous studies of subjects with severe PH.9–11 As a result, none of the indices could be used to distinguish the 2 groups of subjects in this study, indicating that RV functional disorder may occur even in the absence of PH.

View this table:
Table 2.

Color Doppler Echocardiographic Results

Figure 2 shows a significant correlation between the TEI index and the MRC dyspnea score. The results presented in Table 1 and Figure 2 indicate that the pulmonary circulation affects the physical status of COPD subjects, especially the limitation of ADLs. No other parameters were significantly correlated with the MRC dyspnea score. Figure 3 and Table 3 show hospital-free and overall survival analyzed by the Cox proportional hazards model. Backward stepwise selection, including age, height, weight, total lung capacity (TLC), FEV1/FVC, percent-of-predicted FEV1, and TEI index, showed that percent-of-predicted FEV1, FEV1/FVC, TEI index, and height were correlated with hospital-free survival. As the correlation coefficient between FEV1/FVC and percent-of-predicted FEV1 was high, correlation was assessed separately among age, height, weight, TLC, FEV1/FVC, and TEI index, and among age, height, weight, TLC, percent-of-predicted FEV1, and TEI index. TEI index and height were shown to be independently correlated with hospital-free survival. Backward stepwise selection, including age, height, weight, TLC, percent-of-predicted FEV1, FEV1/FVC, and TEI index, showed that TEI index and height were correlated with overall survival. Analyses using body mass index instead of height and weight showed that body mass index was not correlated with hospital-free or overall survival. Further analysis showed that TEI index and height were independently correlated with overall survival. The TEI index showed an especially high correlation with both hospital-free survival (P = .003) and overall survival (P < .001). These results indicate that the TEI index may be a useful marker of RV function to include in prognostic models of COPD. RV dysfunction as determined by the TEI index may provide an indication of disease progression and clarify the effects of COPD on ADLs.

Fig. 2.
Fig. 2.

Correlation between total ejection isovolume (TEI) index and MRC dyspnea score in subjects with COPD (Spearman rank correlation test). The correlation is significant.

Fig. 3.
Fig. 3.

Cumulative survival versus (A) hospital-free survival days and (B) overall survival days (via Cox proportional hazards model) in 49 subjects. For hospital-free survival days (A), backward stepwise selection included age, height, weight, percent-of-predicted FEV1, FEV1/FVC, total lung capacity (TLC), and total ejection isovolume (TEI) index. Only TEI index (P = .003) and height (P = .03) were correlated with hospital-free survival days. For overall survival days (B), backward stepwise selection included age, height, weight, percent-of-predicted FEV1, FEV1/FVC, TLC, and TEI index. Only TEI index (P < .001) and height (P < .03) were related to overall survival. TEI index and height were independently correlated with hospital-free and overall survival. The other factors were were not correlated with hospital-free or overall survival. Analysis using body mass index instead of height and weight showed that body mass index was not associated with hospital-free or overall survival.

View this table:
Table 3.

Survival Versus Total Ejection Isovolume Index Category*

Discussion

In 2005 it was reported that severe PH was associated with reduced survival of COPD patients.4,5 However, no studies have included assessment of RV function in the evaluation of the physical status of COPD patients with absent or very early PH. The present study found that MRC dyspnea scores were significantly correlated with the TEI index and several echocardiographic parameters, but not with pulmonary function indices. The TEI index was also significantly correlated with overall and hospital-free survival. These data strongly suggest that assessment of RV function using the TEI index is very useful for assessing the physical status and prognosis of patients with COPD.

We evaluated exertional dyspnea using the MRC dyspnea score. In patients with COPD, exercise capacity is limited by PH, muscular fatigue of the lower extremities, and pulmonary dysfunction. Exercise test results do not correlate well with the results of pulmonary circulation or function tests. Some reports have indicated that the anaerobic threshold can be noninvasively determined by analysis of expiratory gas.36,37 This is difficult in patients with COPD, however, because the responses that increase ventilatory volume at the anaerobic threshold are limited, the increase in carbon dioxide production is delayed because the PaCO2 tends to increase during exercise, and the respiratory pattern is disturbed.36,37 The characteristic ventilatory responses at the anaerobic threshold and maximum oxygen uptake are therefore difficult to measure.

Various methods are currently used to evaluate the physical status of COPD patients, including the 6-min walk test, New York Heart Association functional class, SF-36, BODE index, and SGRQ.2,3 We could not use these methods in the present analysis because of the retrospective nature of the study. The GOLD classification may not be an ideal method for evaluation of the physical status of COPD patients because it is mostly based on the degree of air-flow limitation,1 and does not account for the effects of other systemic conditions. However, the MRC dyspnea score has been reported to be as useful as the SGRQ or Chronic Respiratory Questionnaire as a measure of disability in patients with COPD.27 The MRC dyspnea score was therefore used in this study to evaluate the physical status of COPD patients, and more detailed evaluation of the physical status was not possible.

Nevertheless, the TEI index showed good correlation with the MRC dyspnea score, suggesting that if a more detailed physical status score was used, an even stronger correlation may have been found between physical status and the TEI index. The severity of dyspnea and the effect of dyspnea on ADLs depend on factors such as musculoskeletal build, heart rate, and cardiac disease causing LV dysfunction at rest or on effort. Patients with LV dysfunction on effort associated with cor pulmonale8,16,37 were included because this condition results from RV dysfunction.38–41 Other underlying conditions that may have resulted in LV diastolic dysfunction were excluded. It should be noted that the TEI index is not affected by heart rate.9 Our results confirmed that the arterial oxygen saturation did not fall below 90% in any patients during ADLs.

The strict exclusion criteria of this study resulted in inclusion of < 25% of the COPD patients treated at our institution. The present data suggest that RV dysfunction associated with COPD, as assessed by the TEI index, markedly affected ADLs, with or without findings suggestive of PH. The TEI index was highly correlated with the MRC dyspnea score and the prognosis of COPD patients.

Our results showed that the TEI index was an independent prognostic factor in COPD. Height was also correlated with prognosis in patients with COPD, whereas age, weight, FEV1/FVC, percent-of-predicted FEV1, and TLC were not. Failure to detect any association between age, weight, FEV1/FVC, percent-of-predicted FEV1, and TLC and the prognosis of COPD patients may be partly explained by the highly homogeneous study population. Some of these factors might have shown correlations with prognosis if the exclusion criteria had been relaxed. However, relaxation of the exclusion criteria was not possible in this study, for the reasons described above.

This study has a number of limitations. Many of the subjects had a good overall physical status, because they were all out-patients in a stable condition. All hemodynamic parameters were assessed by echocardiography only, which has limited accuracy, compared with invasive methods such as catheterization. The prevalence of echocardiography findings suggestive of PH in this study was higher than the reported prevalence of PH on invasive hemodynamic assessment in patients with severe emphysema requiring lung-volume-reduction surgery.42 This may reflect aspects of this cohort that are not generalizable, and reinforces the need for our observations to be repeated and validated. Even though echocardiography has a relatively poor ability to accurately diagnose PH in individual cases,34 the MRC dyspnea score was significantly different between the groups with and without findings suggestive of PH. The percent-of-predicted diffusing capacity of the lung for carbon monoxide was slightly higher in the group with findings suggestive of PH than the group without, but this difference was not significant. This may be due to the method of assessing PH in this study, as well as the nature of percent-of-predicted DLCO, which, unlike FEV1/FVC or percent-of-predicted FEV1, is substantially affected by the subject's breathing effort.

Another limitation was the small sample size, this being a single-center study including only male subjects, the majority of whom were elderly. Subject numbers were limited by the inclusion of only those who were in a stable condition requiring no changes in their treatment regimens within 3 months of echocardiography, and the exclusion of patients with any condition other than COPD that might have affected their ADLs. The study showed that the MRC dyspnea score was correlated with PH, and the RV TEI index was correlated with the MRC dyspnea score. To our knowledge, this is the first study demonstrating that the TEI index is correlated with survival independently of factors such as the severity of COPD, TLC, and age.

We also compared the clinical characteristics between subjects with a TEI index < 0.28 and those with a TEI index ≥ 0.28; the score of 0.28 was selected as the cutoff because the normal RV TEI index is 0.28 ± 0.04.7,9 In this analysis the difference in MRC dyspnea score between the 2 groups was significant (P = .04). By contrast, the other parameters listed in Table 4, including percent-of-predicted FEV1, DLCO, and percent-of-predicted DLCO, were not significantly different. However, because there were fewer subjects with a TEI index < 0.28 than subjects with a TEI index ≥ 0.28, this cutoff value may be too low for subjects with COPD in routine clinical settings, which likely biased the results. When we repeated the analysis by classifying subjects according to RV TEI index < 0.40 or ≥ 0.40, there were significant differences between the 2 groups for MRC dyspnea score, FEV1/FVC, and percent-of-predicted FEV1. These findings may be inevitable when evaluating RV function in subjects with COPD. Considering these findings, the RV TEI index is a highly sensitive marker for RV function in prognostic models of COPD, because a strong correlation was observed only with the TEI index in analyses of specific indices including MRC dyspnea score, hospital-free survival, and overall survival.

View this table:
Table 4.

Clinical Characteristics Versus Total Ejection Isovolume Index Category

These results indicate that further large-scale studies using a more accurate assessment method for PH are warranted, to achieve a more detailed assessment of the RV dysfunction associated with COPD, to further investigate whether RV dysfunction mirrors the early decline in pulmonary function or occurs later secondary to pulmonary failure, and to determine whether echocardiography can provide additional useful measurements.

Conclusions

The results of this study demonstrate a strong correlation between RV dysfunction associated with COPD and ADLs and prognosis of COPD patients, as expected. However, no marker of RV function that can be used in daily clinical practice is currently available. Our results may lead to further studies, and hopefully to inclusion of an assessment of both PH and RV function in the guidelines for COPD assessment. In the present study there was an overlap in all parameters between patients with findings suggestive of PH and those without, unlike data from previous studies of patients with severe PH.8–10 This indicates that COPD may result in RV dysfunction without apparent PH.

Acknowledgments

We thank Professor Chuwa Tei, Department of Cardiovascular, Respiratory, and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan; Peter D Wagner MD, Division of Pulmonary and Critical Care Medicine, University of California, San Diego; and Richard L ZuWallack MD, Pulmonary Diseases, Saint Francis Hospital and Medical Center, Hartford, Connecticut, for their helpful advice.

Footnotes

  • Correspondence: Yosuke Tanaka MD PhD, Department of Respiratory Medicine, Chiba-Hokusoh Hospital, Nippon Medical School, 1715 Kamagari, Inzai, Chiba 270-1694, Japan.

  • The authors have disclosed no conflicts of interest.

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