The main original findings of the present investigation involving patients with HF, COPD and coexisting HF + COPD are as follows: 1) the prevalence of HF + COPD overlap was 20% in the studied population. 2) patients with HF + COPD had the greatest impairment with cardiorespiratory fitness, expressed by lower values in key CPET variables; 3) when groups were contrasted at different distinct exercise time points, the HF group has better responses compared to the other two groups, including WR, peak V̇O2; 4) correlations in the overall group suggest that components of pulmonary function and anthropometric characteristics can influence CPET variables; 5) after the follow-up period of both groups, no differences were found in the occurrence of cardiopulmonary events and deaths.
The aging population is a worldwide phenomenon; due to the health issues associated with aging, a higher proportion of the global population are at risk for chronic disease and diagnoses as well as comorbidity23. A coexistance of HF and COPD (overlap syndrome) has been associated with increased morbidity and decreased quality of life as well as a greater use of health resources; the literature indicates a HF + COPD prevalence between 10–30%8,24,25. Age, sex and anthropometric characteristics have been shown to influence cardiorespiratory fitness26. In our study, these factors were different between groups, being that the COPD and HF + COPD groups were older than the HF group (p < 0.05), moreover body composition was different between HF and COPD groups. These findings may indicate an advantage for this group, although the groups are in an age range between 60–70 years on average. These differences may explain the slightly more favorable exercise response in the HF group.
Left ventricular EF has been an important survival marker in patients with cardiopulmonary diseases. It has been shown that age has an influence on systolic function, and although differences in EF were not found between HF and HF + COPD, the mean age of the overlap group was higher. Shah et al. assessed 18,398 subjects with reduced EF and found that the mean survival of patients aged 65–69 was 4 years27,28. In relation to pulmonary function, no differences were found between the two groups with COPD in spirometric values. Nevertheless, static lung values demonstrated that the COPD group presented with compatible volumes with greater air trapping, as expected, and a worse DLCO. In general, inflammation and structural changes in the airways resulting from COPD increase expiratory flow limitations and worsens with advancing disease severity. This pathophysiologic manifestation is known related to the degree of limitations in performing activities of daily life and participation in leisure time physical activities29.
The association of comorbidities in individuals with cardiopulmonary diseases increases the risk of clinical events and mortality30. We found significant differences for the main evaluated comorbidities, specifically the HF group had higher mean values of comorbidities when compared to the COPD group. These comorbidities are risk factors for the development of cardiopulmonary disease and can often be the initial trigger or the aggravating etiological factor of the disease31.
It is already well known that patients with HF and COPD have reduced exercise performance, due to impaired ventilatory function and systemic manifestations that affect the muscular and cardiopulmonary system, increasing the limitation to exertion32,33. CPET allows a rigorous evaluation of the interaction between respiratory deficiencies caused by diseases and reduced exercise capacity in individuals under physiological stress, being possible to verify which is the main limiting factor to physical exercise34. Thus, in the present study, the HF + COPD group had a lower WR when compared to the HF group. The association between advanced age, intrapulmonary conditions, impaired cardiovascular function and loss of muscle strength and endurance in these patients leads to impaired performance during exercise, and intolerance to high workloads35,36. Peak V̇O2 is the main marker of aerobic capacity. In our study, we only found differences in absolute values; no differences were found for the relative values. A combination of factors leads to a reduction in peak V̇O2 of patients with HF + COPD: ventilatory abnormalities that generate inefficiency in capitation, changes in the heart pump that lead to impaired delivery, and changes in muscle cell composition that contribute to reduced oxygen utilization37, 38.
A comprehensive assessment of several measures obtained from CPET provide for a more comprehensive cardiorespiratory fitness evaluation39. The O2 pulse is a strong predictor of disease severity and adverse events40. Mathematically, the O2 pulse is determined by the product of the stroke volume and arteriovenous oxygen difference, and changes in O2 pulse during exercise suggested alterations in the stroke volume41. In the current study, we observes that the HF group, when compared to the COPD group, have higher O2 pulse values. The RPP was significantly lower in the HF + COPD group when compared with the COPD group, indicating poorer cardiac function, as expected in this comorbidity group. The influence of HF in the group with overlap syndrome can increase myocardial oxygen consumption, leading to exhaustion of coronary blood flow reserve and impaired myocardial perfusion42. Another important variable that reflects central and peripheral components of cardiac work is CP. Our HF + COPD group presented with worse CP values, this can be explained by the fact that the association of the two diseases leads to reduced cardiac function, which during high-intensity exercise can lead to pulmonary congestion, and that, associated with higher pulmonary arterial pressure and pulmonary vascular resistance, increases ventilation–perfusion incompatibility, producing ventilatory inefficiency and contributing to low CP values43.
In recent years, more complex variables derived from CPET have proved to be strong prognostic variables, capable of providing complementary and superior information compared to the isolated use of peak V̇O2 44. In our study, no differences were found for the V̇E/VCO2 slope, although all groups demonstrated a mean value above the normal threshold (i.e., > 30), thus observing a worse prognosis for these patients. Guazzi et al followed 213 cardiac patients and found that V̇E/V̇CO2 slope values ≥ 34 associated with V̇O2 peak ≤ 14 ml.kg − 1.min − 1 were strong predictors of hospitalization and mortality45.
The V̇E/V̇CO2 intercept is a new parameter, and in patients with lung diseases it increases with the severity of disease46. Surprisingly, only the COPD group had higher values of V̇E/V̇CO2 intercept, suggesting an increased dead space on exercise, something that was not seen in our overlap group. Nevertheless, HF + COPD presented reduced VP in comparison with HF group (p < 0.05). The VP has been studied as a prognostic marker in cardiopulmonary diseases47,48. This variable reflects peak cardiac output, alveolar perfusion, peripheral perfusion and the chemo-afferent reflexes of the skeletal muscle, with values below 3.5 mmHg indicating worsening survival21.
Pulmonary and systemic cardiocirculatory maladjustments occur in both HF and COPD and in individuals with overlap, these effects are more prominent. Muscle weakness is the most common systemic effect, as it occurs in chronic processes such as what occurs in both diseases. The systemic effects of these diseases directly affect the ventilatory function, which manifest a pronounced intolerance to exercise, worse health status and higher mortality49,50. In the current study, the HF + COPD group had worse perception of symptoms, when compared to the HF group; the perception of dyspnea was higher, and when compared to the COPD group, fatigue values were higher (p < 0.05).
The HF group presented with better responses to incremental exercise when contrasted with the COPD and HF + COPD groups (Fig. 3). We believe that the fact that the HF group is composed of the majority of patients with mild staging reflected better physiological adjustments to exercise, furthermore, the association between advanced age, intrapulmonary conditions, impaired cardiovascular function (that even in COPD is present) and loss of muscle strength and endurance in COPD and HF + COPD patients leads to further deterioration cardiorespiratory fitness, making these patients not tolerate high workloads and present with a poorer exercise performance51,36.
Important correlations between clinical variables, body composition and CPET variables were found in this study. It is important to note that lean mass moderately influenced peak V̇O2, OUES and O2 pulse responses in the patients studied. An adequate interaction between the ventilatory, cardiovascular and muscular systems is a determining factor for appropriate oxygen metabolism during incremental exercise. Cardiopulmonary disease initially leads to a compromise of the pulmonary and cardiovascular systems, however, with disease progression, lean mass alterations occur in these populations affecting muscle performance during exercise. These changes occur due factors such as hypoxia, oxidative stress, disuse, nutritional depletion, systemic inflammation and changes in muscle morphology, fiber type distribution and metabolism52. Other important findings correlate DLCO, and FEV1 with peak V̇O2, WR and VP. Impaired lung function due to air flow limitations, increased intrathoracic pressures, increased intrathoracic blood volume and chronic pulmonary congestion and accumulation of extravascular lung water has a direct effect on the cardiopulmonary response to exercise, leading to increased pulmonary ventilation, ventilatory inefficiency and, consequently, low peak V̇O2 and WR8,53.
Surprisingly, we found no differences between the outcomes assessed in the follow-up of patients in both groups. Although the HF + COPD group has a greater impairment of cardiorespiratory fitness, it is possible to note that the HF and COPD groups also present values of key cardiopulmonary variables for the studied populations compatible with a worse prognosis and high risk of adverse events in the period from 1 to 4 years of follow-up54. Furthermore, advances in the clinical treatment of both diseases together with greater access to cardiopulmonary rehabilitation have favored better control of the progress of these diseases55.
This study has some limitations which are inherent to its nature that consider the screening of patients at two ambulatory clinics (pneumology and cardiology) diagnosed with at least one of the diseases and aged over 50 years. As the purpose of the present study was to evaluate the coexistence of one condition in the other, it would be expected that some clinical variables would be different. In this context, the absence of female individuals in the HF + COPD group and the difference of age between groups can influence the CPET response. However, to mitigate this bias, knowing that some variables could be influenced by age and sex, we performed a linear regression analysis to verify the influence on CPET variables that differed. We verified that age and sex had weak but significant influence on WR (R2:0.22 p: 0.000), absolute peak V̇O2 (R2:0.25 p: 0.000), O2 pulse (R2:0.20 p: 0.000) and CP (R2:0.09 p: 0.02).