Chronic obstructive pulmonary disease (COPD) is a progressive life-limiting condition and a major cause of mortality worldwide.1 COPD affects about 328 million people worldwide, and it is the third leading cause of death, accounting for 3.2 million deaths each year.2 Many of these deaths are related to cardiovascular morbidity, especially in patients with mild-to-moderate COPD.3 Pathophysiological links between COPD and cardiovascular disease include lung hyperinflation, hypoxemia, pulmonary hypertension, systemic inflammation and oxidative stress, exacerbations, shared risk factors and shared genetics, as well as COPD phenotype.4

Dynamic hyperinflation (DH) is a frequent pathophysiological disorder experienced by many COPD patients that is a main determinant of symptom perception,5 exercise tolerance6 and daily physical activity.7 Although the association between lung hyperinflation and reduced cardiac function has received much attention in recent years,8–10 the effect of DH on cardiac response to exercise remains less known. Most of the available information comes from classical studies on the effect of exercise and voluntary hyperventilation on cardiac function as well as the extrapolation of studies conducted in patients with mechanical ventilation.11,12 However, the demonstration of a potential effect of DH on the cardiac response to exercise could establish a link between COPD and cardiovascular morbidity, mainly in the early stages of the disease, when there is still no developed cardiac structural damage.

To our knowledge, only one study to date has simultaneously evaluated the DH and cardiac response to exercise of COPD patients, although using surrogated outcomes. In 45 COPD patients, Tzani et al.13 analyzed the relationship between end-expiratory lung volume (EELV) increase and cardiac response, assessed by oxygen pulse and the product of systolic blood pressure and heart rate (DP reserve), reporting that the increase in EELV maintained a negative relationship with both parameters. Although interpretation must be done cautiously because there are indirect measures, the lower response of oxygen pulse in patients with DH could be attributed to a lower preload due to a diastolic filling defect of the left ventricle (LV), whereas the lower response of the DP reserve might suggest impaired LV contractility.13 This is particularly interesting since DH promotes low-grade systemic inflammation in stable COPD patients.14 Moreover, it is known that subcellular low-grade inflammation in the heart induces subcellular component abnormalities, such as oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress and impaired calcium handling, leading to impaired myocardial contractility.15

Therefore, our objective was to compare the response of stroke volume (SV) and cardiac output (CO) to exercise between COPD patients with or without DH and control subjects. Moreover, we have tried to evaluate the main determinants of this response, primarily considering lung parenchymal damage, left ventricular systolic and diastolic function, and biomarkers of systemic inflammation and oxidative stress, heart tissue damage and airway inflammation.

Table 1 presents the main characteristics of COPD patients and control subjects. Both groups were homogeneous in anthropometric characteristics and smoking habit, showing obvious differences in lung function and exercise tolerance. The comorbidity burden and dyspnea level of COPD patients was relatively mild, reflecting the predominance of patients with moderate airflow limitation (67%). In fact, although COPD patients had a worse SGRQ score than control subjects (40.2±16.8 vs. 15.2±8.6, P<0.001), the percentage of subjects with a moderate-high level of daily physical activity was identical in the two groups (82%). Tables S2–S4 present the comparisons between COPD patients and control subjects for the attenuation densities of the lung parenchyma, levels of systemic and airway biomarkers, and echocardiographic parameters.

COPD patients showed a lower ΔSV/ΔVO2 slope than control subjects (7.91±8.66 vs. 12.55±8.54, P=0.035) (Fig. 1A). However, there were no differences between the two study groups in the exercise response of cardiac output (ΔCO/ΔVO2) or cardiac index (ΔIC/ΔVO2) (0.66±0.97 vs. 0.94±0.58, P=0.179; and 0.35±0.50 vs. 0.53±0.38, P=0.149, respectively). This discrepancy reflects the development of a compensatory mechanism at the expense of a greater increase in heart rate (HR), as demonstrated by the higher HR slope of COPD patients than control subjects (9.1±5.5 vs. 7.0±1.8 1/mL/kg, P=0.043).

Fig. 1.

Comparison of the stroke volume response to exercise (SV/VO2) between COPD patients and control subjects (A) and between COPD patients with or without dynamic hyperinflation (DH) (B).

(0.18MB).

Specifically, 38 COPD patients developed DH, with a mean EELV increase of 0.62±0.59L. The comparison of COPD patients with or without DH did not identify differences in anthropometric characteristics, smoking, comorbidity, dyspnea level, GOLD risk group, BODE and ADO indices or current treatment (Table 2). The only difference was that COPD patients who presented DH had a worse CAT score than those without DH (16±9 vs. 11±7, P=0.024). Regarding exercise tolerance (Table 3) and lung parenchyma attenuation (Table S5), no significant differences were detected between COPD patients with or without DH. However, COPD patients who developed DH had a smaller LV end-diastolic diameter and volume, a lower early diastolic mitral wave, and a higher E/e′ ratio (Table 4), reflecting some impact on diastolic function. In fact, while diastolic function was normal in all COPD patients without DH, 23% of patients with DH had diastolic dysfunction grade I and 20% grade II (P=0.005). Furthermore, the left ventricle filling pressure was only elevated in one patient without DH compared to 17 with DH (P=0.006). In turn, the presence of DH was also accompanied by greater inflammatory tone (both systemic and in the airways), increased oxidative stress (reflected by a higher plasma concentration of 8-isoprostane), as well as increased plasma concentration of high-sensitivity cardiac troponin T (Table 5).

In COPD patients, the EELV increase was related to the inspiratory-expiratory difference of the P15 (r=−0.458, P=0.001), early diastolic mitral wave (r=0.339, P=0.015), E/e′ ratio (r=0.339, P=0.015), right atrial area (r=−0.394, P=0.042) and pulmonary artery systolic pressure (r=0.422, P=0.008), as well as plasma concentrations of IL-1β (r=0.320, P=0.016), 8-isoprostane (r=0.323, P=0.021) and hs-ctnT (r=0.468, P=0.001) and with EBC concentrations of IL-6 (r=0.328, P=0.015) and IL-8 (r=0.301, P=0.027) (Figs. S1–S4).

In presence of dynamic hyperinflation, COPD patients experienced a decrease in the cardiac response to exercise, with lower values of ΔSV/ΔVO2 (4.14±2.36 vs. 14.19±11.49, P=0.005) (Fig. 1B)-, ΔCO/ΔVO2 (0.36±0.48 vs. 1.18±1.39, P=0.035) and ΔCI/ΔVO2 (0.20±0.24 vs. 0.65±0.72, P=0.029) than COPD patients without DH. Overall, the increase in EELV was inversely related to SV, CO and CI response to exercise (Fig. 2). In addition, the ΔSV/ΔVO2 of COPD patients was also directly related to their LVEDD (r=0.345, P=0.037) and inversely related to plasma levels of IL-1β (r=−0.443, P=0.004), IL-8 (r=−0.373, P=0.025), hs-ctnT (r=−0.426, P=0.009) and 8-isoprostane (r=−0.379, P=0.023), as well as EBC concentrations of IL-6 (r=−0.403, P=0.011) and IL-8 (r=−0.319, P=0.048) (Fig. 3 and S5).

Fig. 2.

Relationship between the change in end-expiratory lung volume (EELV) and the response to exercise of stroke volume (A), cardiac output (B) and cardiac index (C) in COPD patients.

(0.17MB).

Fig. 3.

Relationship between plasma levels of interleukin (IL)-1β (A) and high-sensitivity cardiac troponin T (hs-ctnT) with stroke volume response to exercise (ΔSV/ΔVO2) in COPD patients.

(0.11MB).

Table 6 shows the multiple linear regression models of the selected parameters as independent predictors of ΔSV/ΔVO2 in COPD patients. When all the variables significantly related to ΔSV/ΔVO2 were included, the only independent predictor was the EELV increase, reflecting the major contribution of DH to impairment of cardiac response to exercise in COPD patients. However, when this parameter was excluded (model 2), plasma levels of IL-1β and hs-ctnT were retained as independent predictors of the SV response to exercise (Fig. 3), which demonstrates a relevant contribution of systemic inflammation and the existence of a certain degree of myocardial damage.

Our results show that patients with COPD experience a smaller increase in SV during exercise than control subjects, and that this reduction in cardiac response to exercise is fundamentally associated with the development of DH.

While patients with COPD demonstrated a lower increase in SV during exercise compared to control subjects, we identified no differences between the two groups in the response of CO or CI. This suggests the existence of a compensatory effect on heart rate that, as previously described in classic hemodynamic studies,12,28 increases more notably in patients with COPD than in control subjects. In any case, our results do not rule out a reduction in CO response at maximum exercise, since the determinations were done at lower load intensities. In fact, other authors have described that, in patients with COPD, CO increases up to a load corresponding to 50% of peak work capacity, while at higher intensities its increase in relation to VO2 is attenuated.29

Regarding patients with COPD, our results demonstrate that those who develop DH have a marked reduction in cardiac response to exercise, both in terms of SV and CO. Previously, it had been suggested that dynamic hyperinflation could compromise cardiac response to exercise in patients with COPD, through indirect indicators such as oxygen pulse.13 However, to our knowledge, our results are the first using specific measurements, instead of estimating from surrogate parameters, to confirm the depressant effect of DH on the increase in SV and CO during exercise in patients with COPD. Unlike other authors, in our case, we have not identified a relationship between the severity of airflow limitation or static hyperinflation and cardiac response to exercise. In eight COPD patients with no known cardiopathy in whom CO was measured by thoracic electrical bioimpedance, those with severe or very severe airflow limitation were reported to have a slower CO response to exercise than patients with mild-moderate involvement.30 It is possible that the difference in the degree of airflow limitation with respect to our patients justifies this apparent discrepancy. In turn, Vassaux et al.10 have reported that severe static hyperinflation is associated with a lower peak and baseline oxygen pulse, a circumstance that is also not confirmed in our patients using objective cardiac function measurements. In any case, it should also be taken into account that the prevalence of severe static hyperinflation in our sample has been relatively low (14%).

From a theoretical point of view, the potential deleterious effect of DH on the LV response to exercise has been mainly attributed to a decrease in preload, due to the reduction of filling pressure and LV compliance, compression of the cardiac fossa and increased compliance of the extra-alveolar vessels.31 However, our results do not demonstrate the existence of a relationship between the SV response to exercise and the size of the cardiac chambers or the baseline diastolic function of patients with COPD. These findings concur with a simulation study of DH in healthy subjects subjected to expiratory loads,32 which found that the reduction of SV only seems to be due to a decrease in diastolic filling of the LV when DH is very mild, while at a greater intensity of DH the reduction in SV seems to be due to a mechanism of direct ventricular interaction.32 In this context, it is very attractive to pose whether DH could have a direct effect on the cardiac chambers, either by direct compression or mediated by other intermediate pathways. As already mentioned, the first evidence of the impact of DH on myocardial contractility was provided by Tzani et al.,13 who demonstrated that the increase in EELV of patients with COPD is related to a lower increase in the oxygen pulse but also with a lower DP reserve. It is important to consider that the DP reserve is an indicator of the maximum performance of the LV, which reflects the myocardial oxygen consumption during exercise, depending on the contractile state of the heart.33 In fact, classical studies have shown that the consumption of oxygen by the myocardium during exercise can be reliably estimated based on the DP value.34 Therefore, the lower cardiac response to exercise seen in patients who develop DH could also be a consequence of impaired intrinsic LV contractility.

Thus, it is very interesting that when the EELV is eliminated from the multiple linear regression models, which nullifies the effect of all the parameters related to DH, the baseline levels of IL-1β and high-sensitivity cardiac troponin T are independent predictors of SV response to exercise, reflecting a potential contribution of systemic inflammation and myocardial damage. In fact, IL-1β may be an essential mediator in the pathogenesis of heart failure by suppressing cardiac contractility, promoting myocardial hypertrophy and inducing cardiomyocyte apoptosis.35 Several in vivo and in vitro studies reinforce the potential effect of IL-1β on LV contractility. In in vitro models, prolonged exposure to IL-1β induces a reversible alteration in the excitation-contraction coupling of cultured cardiomyocytes.36 Significant murine models have shown that the administration of IL-1β induces reversible LV contractile dysfunction,37 while its blockage improves LV function and restores contractility.38 Thus, IL-1β has been found to depress cardiac function through the NO-dependent35 and NO-independent pathways and inhibit β-adrenergic agonist-mediated increase in cardiac myocyte contractility and cAMP accumulation.39 Moreover, IL-1β, alone or in combination with IFN-γ and TNF-α, induces cardiomyocyte apoptosis, associated with the activation of Bak and Bcl-xL through pathways involving nitric oxide (NO).40 Although the significance of IL-1β mediated suppression of function in most cardiac pathologic conditions remains poorly defined, evidence suggests that IL-1β is an essential mediator in some clinical situations, such as sepsis-induced contractile dysfunction.35

As for hs-cTnT, its increase has been described in many cardiac and extracardiac conditions other than ischemic cardiomyopathy.41 Given that our patients presented no evidence of sepsis, heart failure, tachyarrhythmia, hypo or hypertension, stroke, respiratory failure, renal failure, severe anemia, pulmonary embolism, seizures or aortic stenosis, it is plausible that the increased levels of hs-cTnT are related with a low-grade inflammatory state,41 as reflected in the relationship between serum concentrations of IL-1β and hs-cTnT recently described in patients with heart failure.42 In this case, the identification of higher hs-cTnT values in COPD patients who develop DH and its relationship with the SV response to exercise constitutes another finding that could suggest a certain degree of myocardial stress. In fact, in previous studies conducted both in patients with stable chronic heart failure as with newly diagnosed hypertension, serum hs-cTnT concentrations were related to LV ejection fraction43–45 and it is generally accepted that hs-cTnT elevation is a reliable biomarker of cardiomyocyte microinjury and hemodynamic stress.46

In our opinion, the main strengths of the present study lie in the strict selection and characterization of patients with COPD without previous evidence of cardiac involvement and in the specific measurement of SV and CO. Likewise, we also recognize several limitations. First, this is a single-center study conducted with a limited number of subjects, although sufficient to detect differences in cardiac response to exercise according to the previously estimated sample size. Second, the characteristics and duration of the rebreathing procedure make it difficult to obtain consistent SV and CO determinations at peak exercise, so we only assess the cardiac response at submaximal exercise. Third, it was not possible to simultaneously measure SV and CO with stress echocardiography, so there is no evaluation of the diastolic function of LV during exercise. Fourth, the spectrum of patients evaluated corresponds mainly to patients with moderate airflow limitation, so the results may not be extrapolated to very severe forms of disease.

In conclusion, our study demonstrates that, in COPD patients with no known heart disease, DH is associated with a lower increase in SV and CO during exercise. This depression of the cardiac response to exercise is unrelated to LV diastolic dysfunction yet does maintain an independent association with biomarkers of systemic inflammation and myocardial stress. Therefore, it could be speculated that DH also has an effect on LV contractility mediated by inflammation.

This study was supported by grants fromInstituto de Salud Carlos III-Fondos FEDERPI10-02089 and PI16/00201 to F. García-Río.

None declared.