Abstract
Cardiovascular disease (CVD) is one of the main causes of morbidity and mortality in chronic obstructive pulmonary disease (COPD) patients however data regarding left ventricle (LV) function in COPD is limited. We, in this study, aimed to evaluate the LV systolic function and its relation to BODE index in COPD patients with the utility of two-dimensional speckle tracking echocardiography (2D-STE). The study involved 125 COPD patients and 30 control subjects. All patients underwent 2D-echocardiography, pulmonary function tests and -minute walk tests. The patients were divided into four quartiles according to BODE index score. COPD patients had lower mitral annulus systolic velocity (Sm), average global longitudinal strain (GLS), average global longitudinal strain rate systolic (GLSRs), average GLSR early diastolic (GLSRe), average GLSR late diastolic (GLSRa), tricuspid annular plane systolic excursion (TAPSE) and peak systolic myocardial velocity (Sm-RV) (p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001 and p = 0.002 respectively) than control subjects. There were significant differences between BODE index quartiles in terms of Sm, average GLS and average GLSRs. Patients were divided into two groups according to median value of GLS (> –18.6 and ≤ –18.6). BODE index quartiles were found to be independent predictors of decreased GLS in multivariate logistic regression analysis (p = 0.030). Increased BODE index was associated with impaired LV mechanics in patients with COPD.
Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation (Citation1). In addition, COPD presents significant extra-pulmonary effects and is associated with important co-morbidities (Citation1). The main causes of morbidity and mortality among COPD patients are, cardiovascular disease (CVD) lung cancer, and osteoporosis (Citation2).
The significance of the right ventricular (RV) performance is recognized as one of the factors determining the clinical course and prognosis in COPD, however, the potential role of the left ventricle (LV) is less studied (Citation3) and usually conventional echocardiographic methods are used. Two-dimensional speckle tracking echocardiography (2D-STE) is a novel technique used for the measurement of cardiac mechanics. It assesses myocardial deformation and the myocardial deformation rate and can be used to evaluate both global and regional myocardial strain and strain rate without being limited by Doppler beam angle, tethering effect and load dependency (Citation4, Citation5). Previous studies have reported that subclinical changes in LV systolic function that cannot be detected by conventional LV ejection fraction (EF), can be identified by quantification of myocardial strain (Citation6) and is a superior predictor of outcomes to EF (Citation7).
Recently, the BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, a multidimensional grading system, has been validated as a tool for measuring COPD severity (Citation8), predicting the risk of death from any cause and from respiratory causes among patients with COPD (Citation9), measuring the impact of COPD exacerbations, and has been shown to be a better predictor of COPD hospitalizations than the staging system defined by the global initiative for chronic obstructive lung disease (GOLD) (Citation8).
We, in this study, aimed to evaluate LV systolic function and its relationship with BODE index, by means of 2D-STE in patients with COPD and no evidence of CVD. To our knowledge, this is the first study evaluating this relationship.
Methods
Study design
From December 2011 to August 2013, we conducted a single-center cross-sectional study including 125 consecutive COPD patients who were followed-up by the Department of Respiratory Medicine. The diagnosis of COPD was based on a history of cigarette smoking of at least 10 pack-years, symptoms and radiographic findings suggestive of COPD and spirometric findings with a post-bronchodilator FEV1 / Forced vital capacity (FVC) < 70% of predicted and FEV1 < 80% of predicted (Citation10). At the time of enrollment, all study patients were free of exacerbations of COPD for at least 6 months. The control group consisted of 30 non-COPD subjects who were evaluated by expert pulmonologists in terms of smoking status, clinical characteristics, and spirometric and radiographic findings. Exclusion criteria are shown in Supplement 1.
Informed consent was obtained from the patients and local ethics committee approved the study protocol. Baseline clinical and demographic information were obtained from all patients. Hypertension was identified on the basis of prior receiving antihypertensive treatment or whether BP exceeded 140/90 mmHg in at least three measurements. Diabetes was defined as prior receiving oral antidiabetic medications or insulin, or having fasting glucose levels above 126 mg/dl. Smoking behavior was defined as current or ex-smoker and pack-years of smoking was recorded. Estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease (MDRD) Study equation (Citation11).
All patients were evaluated by spirometric study, arterial blood gas analysis and echocardiography. The COPD patients also underwent the 6-minute walk distance (6-MWD) test.
Pulmonary function tests
Pulmonary function tests were performed, as previously reported (Citation12) FEV1 and FVC were measured with a clinical spirometer (ZAN 100, Morgan Strumenti Scientifici, Italy).
Arterial blood gas analysis
Blood was drawn via the radial or brachial artery. Arterial oxygen pressure (PaO2), arterial carbon dioxide pressure (PaCO2) and arterial oxygen saturation (SO2) were calculated.
BODE index
The BODE index was calculated by summation of each scores obtained from BMI, modified medical research council (MMRC) dyspnea scale (Citation13), spirometric measurements and 6-MWD. The 6-MWD test was performed twice at least 30-minutes apart and the longest walk distance was used for scoring (Citation14). The BODE index ranged from 0 to 10 points and the patients were divided into four quartiles according to the BODE index score. Quartile-1 (Q1): 0–2 points; Quartile-2 (Q2): 3-4 points; Quartile-3 (Q3): 5-6 points; Quartile-4 (Q4): 7-10 points (Citation9). The method of echocardiography is shown in Supplement 2, and Two-dimensional Speckle Tracking Analysis is shown in Supplement 3.
Statistical analysis
SPSS 17.0 statistical software (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Continuous variables are expressed as mean ± standard deviation (SD) and categorical variables are expressed as percentage. The Kolmogorov–Smirnov test was used to test the normality of distribution of continuous variables. Group means for continuous variables were compared with the use of Student's t-test, the Mann–Whitney U-test, ANOVA or Kruskal–Wallis test, as appropriate.
Categorical variables were compared with the use of chi-square test. Tukey's honestly significant difference test was used for post hoc analysis. Pearson or Spearman correlation analysis was used to assess correlation between GLS and continuous variables depending on Gaussian distributions. COPD patients were divided into two groups according to the median value of GLS (>-18.6 and £-18.6). Multivariate logistic regression analysis was performed to find independent associates of impaired GLS (£-18.6). Inter-observer agreement of echocardiographic parameters obtained from 2D-STE data was calculated using Bland-Altman analysis and intra-class correlation coefficient was used to assess intra-observer agreement. A two-tailed p < 0.05 was considered statistically significant.
Results
The study population consisted of 125 COPD patients and 30 control non-COPD subjects. The baseline characteristics of COPD patients and control subjects are shown in Table . Echocardiographic study revealed that the COPD patients had higher E/Em ratio, PAPs (<0.001, <0.001; respectively) and lower Sm, average GLS, average GLSRs, average GLSRe, average GLSRa, TAPSE and Sm-RV than control subjects (p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001 and p = 0.002 respectively).
Table 1. Baseline characteristics of the study population
Patients were classified with respect to BODE index quartiles and multiple comparisons were performed among quartiles and control group (see Table ). There was significant difference between Q1-Q4 regarding BMI (p = 0.049). Although FEV1 and FEV1/FVC values were significantly different between BODE quartiles and also with control subjects, FEV1/FVC values were similar between Q1-Q2 (p = 0.948) and Q2-Q3 (p = 0.154). The control group had lower pack-years of smoking history than BODE index quartiles (p < 0.001), which did not differ among quartiles. Q3 and Q4 subjects had higher PCO2 values than controls (p < 0.001 and p < 0.001).
Table 2. Comparison of echocardiographic parameters between among BODE index quartiles and control group
The other clinic and laboratory parameters were similar between BODE index quartiles and control group. Of echocardiographic parameters Sm, average GLS and average GLSRs values were higher in control subjects, compared to BODE index quartiles (p < 0.001, p < 0.001, and p < 0.001, respectively). Sm, average GLS and average GLSRs values were different between BODE index quartiles except between Q1 - Q2 (p = 1.00, p = 0.99 and p = 0.98) and Q3 - Q4 (p = 0.23, p = 0.55 and p = 0.06). In addition, E /Em ratio and PAPs values were lower in control subjects than BODE index quartiles (p < 0.001, p < 0.001 and p < 0.001, respectively) and significantly different between BODE index quartiles except Q1-Q2 (p = 0.643) and Q3 - Q4 (p = 0.964). TAPSE values were significantly different between Q3 - Q4 (p = 0.03), Q1- Q4 (p < 0.001) and Q2- Q4 (p = 0.01). However there was not significant difference between quartiles and also control group in terms of Sm-RV values (p = 0.188).
Correlates of decreased GLS
Patients with COPD were divided into two groups according to median GLS value (>-18.6 and £-18.6). The characteristics of COPD patients according to GLS values are shown in Supplement 4. GLS was compared with nominal components of BODE index. The patients with GLS £ -18.6 was older than those with GLS ³18.6 (p = 0.024). Also GLS£ -18.6 group had lower FEV1 (% predicted) and SO2 values (p = 0.028 and p = 0.011). MMRC (3-4) were significantly higher and 6-MWD was lower in GLS £ -18.6 group (p < 0.001 and p < 0.001). Of echocardiographic parameters, LV end-diastolic dimension and Sm were lower, and E/Em ratio and PAPs values were higher in GLS £ -18.6 group than GLS ³ 18.6 group (p = 0.002, p = 0.002 and p: 0.011, p = 0.009). To find independent predictors of decreased GLS (£-18.6), multivariate logistic regression analysis was performed. Independent variables such as age, BODE index quartiles, E/Em ratio, Sm, LV end-diastolic dimension, PAPs, SO2 and PCO2 were entered into the model. BODE index quartiles were found to be independently correlated with decreased GLS (p = 0.030) (Table ).
Table 3. The predictors of GLS (≤-18.6) in logistic regression analysis
In univariate correlation analysis, SO2 was found to be negatively correlated with GLS (r = -0.286, p = 0.01). Reproducibility is shown in Supplement 5.
Discussion
This study demonstrated that patients with COPD had impaired LV systolic function than healthy controls. With the utility of 2D-STE derived GLS, we, for the first time, showed that BODE index was independently associated with impaired LV systolic functions. BODE 0-1 (Q1) group even had impaired LV systolic functions than healthy controls. This shows that cardiac complications may develop early in the course of lung disease.
Accumulating evidence suggests that multiple factors can be associated with mortality in COPD and a composite index may provide a more comprehensive evaluation of patients with COPD (Citation8, Citation15). Celli et al. identified 4 easily measured variables that predicted an elevated risk for death: BMI (B), degree of airflow obstruction (O) as measured by FEV1, dyspnea as measured by the MRC dyspnea scale (D), and exercise capacity (E) as measured by the 6-MWD test. These variables were incorporated into a multidimensional scale, the BODE index, that ranged from 0 (least risk) to 10 (highest risk).
Heart failure (HF) is prevalent in more than 20% of the patients with COPD. Moreover, the risk ratio of developing HF among COPD patients is 4.5 times higher than that of control individuals without the disease. In addition, the presence of ventricular dysfunction in patients with COPD tend to increase the risk of mortality (Citation16). Early detection of subclinical LV systolic dysfunction is of high importance, because timely medical treatment could prevent or delay the subsequent development of HF (Citation17). Systolic dysfunction might be initially apparent in the longitudinal direction, because subendocardial fibers, which are the ones more vulnerable to myocardial ischemia and fibrosis, are longitudinally oriented (Citation18). It has been shown that, GLS correlates well with EF measured by echocardiography (Citation19).
However, they measure different aspects of myocardial function, with EF measuring radial and partly longitudinal function, whereas GLS measures longitudinal function. LV systolic functions could be impaired despite normal EF values and 2D-STE allows precise and quantitative measurement of myocardial function and can therefore detect subclinical changes (Citation20). There is considerable inter-observer variability among experienced cardiologists during 2D-STE evaluation. On the other hand, LV-EF could be measured with different conventional echocardiographic methods, including the Simpson method, which we used, and although they seem apparently easy, there is also considerable inter-observer variability in terms of LV-EF measurement.
Schoos et al. evaluated the echocardiographic predictors of mortality in COPD (Citation21). The severity of COPD was staged by GOLD classification. In univariable survival analysis, 6-MWD, FEV1/FVC and GLS correlated with mortality; however, in multivariate analyses mortality was only predicted by GLS and not by functional capacity, COPD severity or RV structure and function. In addition, increasing GOLD classes was not found to be associated with increasing mortality. Our results shows that the BODE index is an independent predictor for GLS. In clinical practice the BODE index could provide information about COPD severity and also subclinical LV systolic functions. If our results are confirmed, in future studies it may represent a useful screening tool for submitting patients to 2D-STE, even if LV-EF is normal.
Liu et al. investigated the predictive value of combined serum C-reactive protein (CRP) and BODE index for mortality in COPD patients (Citation22) and they suggested that serum CRP concentrations and BODE index score were independent prognostic variables for mortality in patients with stable COPD. In our study, we found that there was a decreasing trend for GLS with increasing BODE index quartiles, but consistent with the findings from the study of Liu et al. (Citation22), we did not find a statistically significant difference between Q1-Q2 and Q3-Q4 groups.
One of the causes of LV systolic dysfunction in COPD patients is due to RV dysfunction. Increased RV end-diastolic pressure may lead to a decrease in the filling pressure of the LV because of a leftward shift of the interventricular septum. In current study, RV functions were not evaluated by STE but TAPSE and RV-Sm were studied instead. There was no significant difference between BODE index quartiles in terms of Sm-RV, and TAPSE was found to be decreased only in Q4 group. When the patients were divided into two groups according to median GLS value, TAPSE and Sm-RV were not different between the groups. This shows that LV systolic dysfunction is independent of RV functions. In a previous study, a relationship was observed between BODE index quartiles and subclinical RV dysfunction assessed with STE (Citation23). In this study LV-EF was not different between the groups. These findings demonstrate that subclinical LV and RV dysfunction, which is related to BODE quartiles, develops due to other causes rather than ventricular interdependence.
Another potential cause of LV systolic dysfunction in COPD includes increased arterial stiffness, which has been shown to be increased in patients with COPD even in mild severity airway obstruction (Citation24, Citation25). Arterial stiffness is independently related to abnormal segmental relaxation and global longitudinal systolic deformation in patients with normal EF (Citation26). Angiotensin converting enzyme is present in high concentrations in the lungs, and chronic hypoxia can activate renin angiotensin system, which has proinflammatory and profibrotic effects.
This might have a role in the pathogenesis of LV dysfunction in COPD (Citation27). It was shown that hypoxemia was associated with endothelial dysfunction, which could be one of the underlying mechanisms of LV dysfunction (Citation28). Consistent with the findings from previous studies (Citation21), our results showed significant inverse correlation between SO2 and GLS. Presence of systemic inflammation may be another potential mechanism underlying LV dysfunction (Citation29). Although we did not evaluate inflammatory markers in this study, there is strong evidence that persistent low-grade systemic inflammation is present in COPD (Citation29) and it seems to be the key determinant for the development of pulmonary and systemic endothelial dysfunction (Citation30, Citation31). In our study, patients with lower GLS value had higher incidence of MMRC 3-4 compared to patients with higher GLS value. MMRC dyspnea scale reflects patient's perception of symptoms that is related to skeletal muscle atrophy and loss of muscle mass as a consequence of systemic manifestation of COPD (Citation9, Citation32). Increased MMRC dyspnea scale and lower GLS may contribute to common presentations that reflect increased systemic inflammation.
Previously it was shown that patients with COPD had a high prevalence of LV diastolic dysfunction (Citation1). But we, for the first time, demonstrated that LV diastolic function, assessed by E/Em ratio, was more impaired with higher BODE quartiles. LV diastolic dysfunction in patients with COPD may be due to abnormalities in LV-preload and/or afterload. Barr et al. (Citation33) showed that greater extent of emphysema on computed tomography scanning and more severe airflow obstruction were linearly related to impaired LV filling, reduced stroke volume, and lower cardiac output without changes in the EF. This interpretation is supported by the inverse relationship between pulmonary diffusion capacity (Kco) and LV isovolumic relaxation time (IVRT). However, previously it was shown that increased values of IVRT in COPD patients was only predicted by aortic stiffness (Citation4). The earlier return of the reflected arterial wave augments aortic systolic pressure increasing LV afterload, while the concomitant reduction of aortic diastolic blood pressure may reduce coronary perfusion leading to sub-endocardial ischemia (Citation4). Thus, our patients are likely to have ventricular-arterial stiffening with impaired systolic and diastolic function in the absence of CV disease.
Recently, it was suggested that therapy for COPD with existing medications targeting the lung may not be enough to improve outcomes (Citation27). We consider that early preventive therapeutic interventions for adverse cardiac remodeling may decrease mortality and morbidity in patients with COPD.
Limitations
The sample size of subjects was relatively small to generalize our findings. Although magnetic resonance imaging (MRI) is the gold standard for myocardial strain imaging, 2D-STE correlates well with MRI. PAPs were estimated simply based on tricuspid regurgitation measurements and right ventricular catheterization and Swan-Ganz catheter was not performed. However, this widely used Doppler-derived pressure estimation is well recognized and has been documented to have a good correlation with simultaneously obtained catheter-derived measurements. The fact that RV functions were not evaluated with STE was also a limitation. The patients’ BODE index quartiles could vary in the course of time. Our study did not inform about the impact of BODE index quartile interchange on LV function, necessitating further studies.
Conclusion
Our study revealed that assessment of BODE index could provide information about LV function and increasing BODE index quartiles was associated with impaired LV function. Especially, patients with high BODE index should be examined with 2D-STE for assessment of LV systolic dysfunction. Future studies are needed to explore positive effects of preventive therapeutic interventions for adverse cardiac remodeling on cardiovascular outcomes in COPD patients.
Declaration of Interest Statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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