Background
Heart failure (HF) is a common clinical disorder carrying significant morbidity and mortality [
1,
2]. Ventilatory impairment is known to occur in patients with HF, and is ascribed to factors such as heart enlargement, pulmonary stiffness due to chronic interstitial edema, and respiratory muscle dysfunction [
3‐
7]. The coexistence of chronic airflow obstruction may add to ventilatory dysfunction, and is believed to have a negative prognostic impact in patients with chronic HF [
8].
As of now, most of the studies on the prognostic impact of respiratory dysfunction in HF focused on simple spirometry [
9‐
14], with only a few exploring the exchange of gases across the alveolar-capillary membrane [
15,
16].
Alveolar volume (V
A) is the volume of air in the lung available for gas exchange, and is currently measured by the dilution of an inert gas during a single breath-hold maneuver [
17]. Due to the single-breath approach, such measurement is sensitive to ventilatory disturbances. In healthy subjects, V
A equals total lung capacity (TLC) measured by multiple-breath helium dilution. In subjects with ventilatory impairment, V
A is often much lower than TLC because of the insufficient mixing of gas in alveolar spaces [
18].
We conducted a prospective, observational study aimed at establishing the prognostic value of VA, as % of the predicted value, in 260 consecutive patients with systolic HF. The outcome measure was all-cause mortality over a median follow-up time of about three years.
Discussion
The present study was designed to establish whether VA, as percent of the predicted value, is a prognostic indicator in systolic HF. Our results can be summarized thus: (a) the cumulative incidence of death is significantly higher in patients with VA < 80% predicted than in those with VA ≥ 80%; (b) the estimated HR of death is about two-fold greater among the patients in the lower VA category, and remains significantly higher after adjusting for relevant confounding variables; (c) as indicated by Laplace regression, reduced VA is strongly associated with early deaths.
We found a significant, inverse correlation between V
A and cardiothoracic ratio. This suggests that heart enlargement is a major determinant of reduced V
A in chronic HF. Generalized stiffness of the lung parenchyma may also contribute to diminish V
A. Such reduced lung distensibility is due to chronic interstitial edema, and pulmonary vascular remodeling that are known to occur in long-standing HF [
25].
We also observed that V
A is significantly correlated with the circulating levels of NT-proBNP, an established prognostic biomarker of HF [
2]. After adjusting for NT-proBNP, the HR of death associated with reduced V
A remains statistically significant so indicating that V
A is an independent predictor of survival.
A number of studies investigated on simple spirometry as a potential indicator of future cardiovascular events. In the setting of the Framingham Study, Kannel et al. observed that FVC is a significant, independent predictor of cardiovascular morbidity and mortality in allegedly healthy subjects [
9]. Later, Kannel et al. reported that FVC is a predictor of subsequent cardiac failure in individuals with coronary artery disease and left ventricular hypertrophy [
10].
In recent years, there has been increasing interest in evaluating the prognostic impact of COPD comorbidity in patients with chronic HF. Mascarenhas et al. [
11] conducted a retrospective study in 186 patients with systolic HF, and found no significant association between having COPD and all-cause mortality (HR 1.40, 95% CI 0.88 to 2.44). Only severe airflow obstruction (FEV
1 < 50% of predicted value) appeared to be a predictor of reduced survival (HR 2.10, 95% CI 1.05 to 4.22) [
11]. In 527 patients with a clinical diagnosis of HF, Iversen et al. reported that FEV
1 has independent prognostic value (HR 0.86 per 10% change with respect to the predicted value, p < 0.001) [
12]. By contrast, Macchia et al. estimated an adjusted HR of death of 0.77 (95% CI, 0.37 to 1.58) in patients with systolic HF and concomitant chronic airway obstruction, suggesting that COPD has no significant bearing on survival [
13]. The three studies differ substantially for proportion of severe airflow obstruction, NYHA class III-IV, and duration of follow-up, and this may explain the inconsistent results obtained as regards the prognostic impact of COPD in HF.
Recently, Miniati et al. reported that a reduction of FEV
1 – be it due to airflow obstruction or ventilatory restriction – is a significant, independent predictor of reduced survival in 439 patients with systolic HF [
14]. In that study, the adjusted HR of death was 1.8-fold higher in patients with FEV
1 <80% predicted as compared with those having FEV
1 ≥80% [
14].
As of now, limited data is available on the prognostic relevance of lung function tests other than spirometry. It is well established that chronic HF brings about extensive remodeling of the pulmonary intra-alveolar vessels and interstitium [
26], which may hamper the exchange of gases across the alveolar-capillary barrier [
15]. In 106 patients with systolic HF, Guazzi and coworkers reported that alveolar-capillary membrane conductance of less than 24.7 mL/min/mmHg is significantly and independently associated with a worse outcome [
16]. Partitioning of lung diffusing capacity into its membrane and capillary blood volume components requires the determination of DL
CO at two different concentrations of oxygen in the inspired test bolus [
15,
16]. This technique is seldom used in routine clinical practice.
V
A represents an estimate of the lung gas volume into which CO is distributed and, therefore, is critical in the measurement of DL
CO with the single-breath approach [
17]. In the presence of uneven distribution of ventilation, due to altered lung distensibility or airflow obstruction, V
A primarily reflects the volume of the airspaces into which the tracer gas rapidly equilibrates during the breath-hold time [
17]. The estimated volume can, therefore, be regarded as reflecting the size of the well-ventilated lung regions. As shown in Table
2, spirometrically determined ventilatory restriction, was present in only 53 (39%) of 135 patients with V
A <80% predicted. So, we believe that measuring V
A may add valuable information as regards lung function assessment in patients with systolic HF.
Undoubtedly, factors other than V
A affect the lung diffusing capacity, including the physical properties of the alveolar membrane, the density of alveolar capillaries, and the hemoglobin concentration [
17]. Thus, in multivariate analysis, we incorporated DL
CO among the potential confounding variables. After adjustment, the HR of death associated with the lower V
A category remained statistically significant.
Study limitations
First, we only studied patients with systolic HF, so our findings may not apply to patients with isolated diastolic heart dysfunction. Second, our data originated from a single referral center, and included a relatively small number of cases. Broader multicenter prospective studies are needed to firmly establish the prognostic value of VA in HF. Third, we obtained a single determination of VA. So, it would of interest to evaluate the effect of cardiovascular and pulmonary medications on VA size over time, and to test whether improvement in VA is associated with a better oucome in patients with chronic HF.
Competing interests
The authors declare that they have no competing interests.
Authors’ contribution
Study design (MM). Data collection (CP, ME, RP, IP). Data analysis (MM, SM, MB). Drafting the manuscript (MM). Approval of the final version of the manuscript (all authors).