This is a prospective, consecutive, and single-center study performed in a third-level teaching center in Spain. From November 2020 to February 2024, 161 patients with ambulatory symptomatic HF from the HF Unit of the institution accepted to participate. HF was defined as a clinical syndrome characterized by symptoms and signs resulting from an abnormality of cardiac structure or function [11,12]. All patients included were diagnosed by cardiologists, including measurement of natriuretic peptides and echocardiographic assessment revealing cardiac structural or functional abnormalities according to clinical guidelines [11,12]. Patients with worsening HF requiring parenteral administration of diuretics (n=5) or inability to perform plethysmography (n=5) were excluded. Additionally, 6 patients were excluded because of a nonreliable assessment of plethysmography, leaving a final study sample of 144 patients. Demographic, clinical, electrocardiographic, echocardiographic, laboratory data, and medical treatment were recorded in pre-established electronic questionnaires.

COPD diagnosis was previously established according to GOLD criteria, defined by postbronchodilator FEV1/FVC<0.70. COPD status and treatment were recorded at study entry. Among patients with COPD (n=46), 42 were receiving inhaled maintenance therapy (dual or triple inhaled therapy).

Patients were clinically stable and on optimized HF therapy for at least 4 weeks before study assessment. Loop diuretics (furosemide or torsemide) were recorded under “diuretics.” Sequential nephron blockade was defined as the combination of loop diuretics with thiazide or thiazide-like agents. SGLT2 inhibitors were analyzed separately. Short-acting bronchodilators were withheld before testing according to ERS/ATS recommendations. Long-acting inhaled therapies were not routinely discontinued.

The investigation conforms with the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all participating subjects. The institution's ethics committee approved the study.

Pulmonary function testing and lung volume measurements were performed according to American Thoracic Society (ATS) and European Respiratory Society (ERS) standards by experienced personnel [13]. Predicted values were calculated using the Global Lung Function Initiative (GLI) reference equations. Two-dimensional echocardiographic assessment followed contemporary guideline recommendations.

Spirometry confirmed the COPD diagnosis with a postbronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio of less than 0.70. The severity of COPD was assessed according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [14].

IC was defined as the maximum volume of air that can be inhaled from the end of a normal tidal exhalation. It is calculated as the sum of tidal volume (TV) and inspiratory reserve volume (IRV). IC reflects the capacity of the lungs to accommodate additional air during deep inspiration and serves as a measure of lung compliance and respiratory reserve. IC/TLC ratio is the proportion of the lung total capacity available for inspiratory expansion. This ratio provides an indicator of lung hyperinflation and the degree of ventilatory restriction, particularly in patients with obstructive pulmonary diseases such as COPD. A lower IC/TLC ratio typically indicates increased lung hyperinflation, where the IC is reduced relative to the TLC, limiting the patient's ability to take deep breaths. This parameter is particularly valuable in assessing disease severity and its impact on functional capacity [15]. Diffusing capacity for carbon monoxide (DLCO) was measured according to ATS/ERS standards, and percent predicted values were derived from GLI reference equations.

Transthoracic echocardiography was performed using a phased-array transducer (2–5MHz) to evaluate left and right ventricular function, valvular abnormalities, and overall cardiac structure. Left ventricular ejection fraction (LVEF) was measured using the Simpson biplane method, in accordance with contemporary echocardiographic recommendations [16]. Diastolic function was assessed by Doppler analysis of mitral inflow (E/A ratio), tissue Doppler imaging (e′ velocity), and estimation of left atrial pressure. Right ventricular function was evaluated using tricuspid annular plane systolic excursion (TAPSE). Additional parameters such as pulmonary artery systolic pressure (PASP) were also recorded when feasible. All measurements were performed by trained operators on the same day as pulmonary tests.

A systematic echographic evaluation was performed to determine congestion parameters, including measurement of the inferior vena cava (IVC), pulmonary congestion, and systemic venous congestion on the same day as pulmonary tests.

Lung ultrasound was performed by scanning 8 pulmonary zones in B mode. Pulmonary congestion was defined by the presence of B-lines (>3 B-lines per intercostal space in at least 2 pulmonary zones), indicative of interstitial edema [18].

IVC assessment was performed using transthoracic echocardiography in the subxiphoid view. The maximum diastolic IVC diameter was measured in 2-dimensional (B-mode) imaging at 1–2cm from the junction with the right atrium.

Renal venous flow was evaluated using pulsed Doppler to assess the presence of continuous or discontinuous flow patterns in the renal veins. Renal venous congestion was defined by a discontinuous flow pattern [19]. Renal venous Doppler was assessed in 128 patients (88.9% of the sample) because of technical limitations.

A blood sample was obtained 24–48h before the patient examination. Sample collection included analyses for blood cell count, hemoglobin, hematocrit, basic biochemistry, NT-proBNP, and CA125. All samples were processed and analyzed in certified laboratories using standardized techniques to ensure the accuracy and reliability of the results.

The 6MWT was conducted according to standard guidelines in a controlled environment and performed by trained personnel following plethysmography.

Continuous variables were expressed as mean (standard deviation [SD]) for normally distributed data or median (interquartile range [IQR]) for nonnormally distributed data, as determined by the Kolmogorov–Smirnov test. Categorical variables were expressed as frequencies and percentages. Differences in baseline characteristics across IC/TLC quartiles were tested by calculating P values for trend. Multivariable logistic or linear regression analyses assessed the association among proxies of FO and distance walked in 6min (dependent variables) and the exposure (IC/TLC). IC/TLC was modeled both categorically and continuously to capture potential heterogeneity. Nonlinear associations were explored using fractional polynomial regression to avoid imposing linear assumptions. We also evaluated the relationship between these parameters considering the RV/TLC ratio as the exposure variable. Covariates tested in all multivariable models were based on biological knowledge (variables associated with more advanced HF disease and FO) and included age, sex, body mass index, New York Heart Association (NYHA) class, time from HF diagnosis, systolic blood pressure, heart rate, atrial fibrillation, estimated glomerular filtration rate (eGFR), hemoglobin, NT-proBNP, left ventricular ejection fraction, tricuspid annular plane systolic excursion (TAPSE), mitral regurgitation grade III/IV, tricuspid regurgitation grade III/IV, left atrial area, and diuretic and inhaled treatments. COPD status was included as a covariate in multivariable models to account for potential confounding.

The final covariates in each multivariable model are presented in the respective figure legend. All analyses were performed with STATA 18.1 (STATA Statistical Software, StataCorp LP, College Station, TX, USA).

The mean age of the sample was 72.8±9.7 years, 108 (75%) were men, and the median (p25%–p75%) time from HF diagnosis was 36 months (7–96). Most patients (86.8%) were in stable NYHA class II at enrollment. Ischemic etiology and atrial fibrillation were present in 35.4% and 58.3% of patients, respectively. Regarding LVEF, 49 (34%), 24 (16.7%), and 71 (49.3%) patients displayed HF with reduced, mildly reduced, and preserved ejection fraction, respectively. The median (p25%–p75%) eGFR and hemoglobin were 55.5mL/min/1.73m2 (40.5–68.1) and 14.6g/dL (13–15.6), respectively. Most patients were receiving loop diuretics. A total of 46 patients (30.9%) had COPD (10, 26, and 10 GOLD grades 1, 2, and 3, respectively), and 42 were receiving double or triple inhalation therapy.

In the whole sample, the mean±SD of IC/TLC was 0.37±0.11, being lower in COPD patients (0.31±0.10 vs 0.39±0.10; P<.001).

A detailed description of baseline characteristics across IC/TLC quartiles is presented in Table 1 and Supplementary Table 1. Overall, subjects with lower IC/TLC showed epidemiological, clinical, echocardiographic, and laboratory findings of more advanced HF. Likewise, lower IC/TLC quartiles identified subjects with lower FEV1/FVC, FEV1, and diffusing capacity for carbon monoxide (DLCO) (Table 1).

The presence of peripheral edema was the most frequent proxy of FO finding (28.5%), followed by IVC diameter>21mm (26.4%), jugular engorgement (17.4%), renal venous congestion (16.4%), and orthopnea (16.0%). The median (p25–p75%) NT-proBNP and CA125 were 1272pg/mL (779–2322) and 17U/mL (11–33), respectively. A description of FO parameters across IC/TLC quartiles is presented in Table 2.

The impact of hyperinflation on hemodynamics has been previously studied in COPD patients [1–4]; however, to our knowledge, this is the first study aiming to quantify the potential deleterious effects of lung hyperinflation in patients with chronic HF. These findings underscore the role of hyperinflation as a key component of heart–lung interactions. Dynamic lung hyperinflation in COPD leads to increased end-expiratory lung volumes caused by airflow limitation and loss of elastic recoil. As the lung parenchyma loses elasticity, lung recoil diminishes, resulting in a compensatory rise in functional residual capacity (FRC) and a subsequent reduction in IC [4,20,21]. This progression reflects worsening static lung hyperinflation, marked by a declining IC/TLC ratio. In COPD, the IC/TLC ratio is a strong predictor of mortality and correlates with reduced exercise capacity and quality of life [15,22–25] by impairing lung function (reduced inspiratory capacity, diaphragmatic function, and ventilatory efficiency) [4,20,21].

In the present study, we did not observe significant heterogeneity according to COPD diagnosis, suggesting that the effects associated with COPD and those related to static hyperinflation should not be considered interchangeable. COPD is a clinical entity defined by persistent airflow limitation, typically identified by spirometric criteria. In contrast, the IC/TLC ratio reflects a physiological indicator of lung hyperinflation, representing a shift of tidal breathing toward higher lung volumes. Importantly, this mechanical alteration may arise from multiple mechanisms beyond COPD, including age-related changes in lung mechanics, diaphragmatic dysfunction, and cardiopulmonary interactions associated with HF and pulmonary congestion. Therefore, reduced IC/TLC in our cohort likely reflects alterations in respiratory mechanics that are not exclusively attributable to obstructive lung disease. Accordingly, IC/TLC should be interpreted as a physiological surrogate of altered ventilatory mechanics rather than a direct mechanistic driver of congestion.

In a recent study, Leahy et al. reported that patients with HF with preserved ejection fraction who developed hyperinflation during exercise exhibited higher pulmonary capillary wedge pressures, suggesting that dysfunctional ventilatory mechanics and the resulting increase in intrathoracic pressure may contribute to this hemodynamic impairment [29].

In COPD, hyperinflation causes elevated intrathoracic pressures, which impair cardiac hemodynamics through multiple mechanisms [1,2,4,26]. These include reduced venous return and limited cardiac compliance, leading to decreased cardiac preload [1,2,4,26]. Additionally, air trapping may increase right ventricular afterload [4–6]. All these mechanisms may be associated with reduced cardiac output and increased venous pressure and volume overload [1,2,4]. In rats, severe hyperinflation leads to cardiorespiratory failure, characterized by arterial hypotension and myocardial injury, particularly in the right ventricle [28]. In COPD patients, hyperinflation-induced cardiac filling impairment due to mechanical constraints on the heart likely explains the smaller cardiac size reported with more severe air trapping [8,9,29,30]. These heart–lung interactions seem especially relevant in HF, where even minor preload and afterload perturbations may aggravate cardiac hemodynamics.

Consistent with these findings, our results show a consistent association between lower IC/TLC ratios and proxies of systemic congestion, including jugular venous distension and renal venous congestion. Moreover, we found a strong association between lung hyperinflation and higher circulating levels of CA125, an emerging biomarker of FO (mainly tissue congestion) [31,32]. Interestingly, the association between lower IC/TLC and FO was observed for highly specific parameters (jugular engorgement and ultrasound kidney congestion) and not for parameters with lower specificity, such as pedal edema [33].

No significant relationship was found between IC/TLC and markers of pulmonary congestion. This discrepancy between the effects of air trapping on left- and right-sided hemodynamics may stem from hyperinflation predominantly compressing systemic veins and right-sided structures rather than affecting left ventricular filling, which operates under significantly higher pressures. This could also explain the lack of association between hyperinflation and NT-proBNP levels, as elevated NT-proBNP is primarily linked to higher left ventricular end-diastolic and pulmonary venous pressures rather than right-sided HF [34].

Lastly, IC/TLC was significantly associated with reduced submaximal functional capacity, as measured by the 6MWT. In adjusted analyses, a 0.1 decrease in IC/TLC corresponded to a 22-m reduction in 6MWT. This magnitude is consistent with, or approaches, the lower range of MCID estimates for 6MWD reported in HF and COPD populations (∼15–30m), although thresholds vary according to population characteristics and methodological approach [35,36].

This relationship remained significant after multivariable adjustment, emphasizing the clinical relevance of hyperinflation in limiting exercise tolerance. In agreement with these findings, Chiari et al. reported that dynamic pulmonary hyperinflation during exercise correlated with reduced peak oxygen uptake in chronic HF [37]. In addition to the strong relationship with FO, hyperinflation imposes a greater workload on the respiratory muscles and reduces cardiac preload during inspiration, which may explain the observed functional impairment. This aligns with previous findings showing that a reduced IC/TLC ratio is associated with dyspnea and exercise limitations in patients with COPD and HF [19,25]. Additionally, the IC/TLC ratio affects the cardiac oxygen pulse, a marker of global cardiac function during exercise, underscoring the impact of hyperinflation on cardiac performance [38].

All these findings reinforce the notion that hyperinflation is not merely a pulmonary finding but also a potential contributor to systemic fluid imbalance, neurohormonal activation, and functional intolerance in HF patients.

The current findings highlight the potential utility of recognizing lung hyperinflation as a contributor to HF progression, particularly in patients with concomitant COPD. Hyperinflation also emerges as a potential therapeutic target since current triple inhalation therapy reduces air trapping and cardiovascular events in COPD patients [39]. Additionally, amelioration of air trapping may underlie the suggested benefit observed with inspiratory muscle training in patients with HF with preserved ejection fraction [40]. Further dedicated studies should address the clinical benefit of treating hyperinflation in patients with HF.