Prognostic Value of Alveolar Volume in Systolic Heart Failure

Discussion

The present study was designed to establish whether V_A, 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 V_A < 80% predicted than in those with V_A ≥ 80%; (b) the estimated HR of death is about two-fold greater among the patients in the lower V_A category, and remains significantly higher after adjusting for relevant confounding variables; (c) as indicated by Laplace regression, reduced V_A 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.

We also observed that V_A is significantly correlated with the circulating levels of NT-proBNP, an established prognostic biomarker of HF. 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. Later, Kannel et al. reported that FVC is a predictor of subsequent cardiac failure in individuals with coronary artery disease and left ventricular hypertrophy.

In recent years, there has been increasing interest in evaluating the prognostic impact of COPD comorbidity in patients with chronic HF. Mascarenhas et al. 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 (FEV₁ < 50% of predicted value) appeared to be a predictor of reduced survival (HR 2.10, 95% CI 1.05 to 4.22). In 527 patients with a clinical diagnosis of HF, Iversen et al. reported that FEV₁ has independent prognostic value (HR 0.86 per 10% change with respect to the predicted value, p < 0.001). 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. 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 FEV₁ – be it due to airflow obstruction or ventilatory restriction – is a significant, independent predictor of reduced survival in 439 patients with systolic HF. In that study, the adjusted HR of death was 1.8-fold higher in patients with FEV₁ <80% predicted as compared with those having FEV₁ ≥80%.

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, which may hamper the exchange of gases across the alveolar-capillary barrier. 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. 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. 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. 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. 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. 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 V_A in HF. Third, we obtained a single determination of V_A. So, it would of interest to evaluate the effect of cardiovascular and pulmonary medications on V_A size over time, and to test whether improvement in V_A is associated with a better oucome in patients with chronic HF.