Low D LCO predicts all-cause hospital admissions in patients with reduced left ventricular ejection fraction or diastolic dysfunction.

A low D LCO should be valued as a predictor of all-cause hospital admissions in patients with reduced LVEF or isolated diastolic dysfunction. The severity of the impairment seen on D LCO testing also appears to affect the risk of hospitalisation. https://bit.ly/3e4r8bH.

To the Editor:

The diffusing capacity of the lung for carbon monoxide (DLCO) can be decreased in many disease states, including COPD and interstitial lung disease [1, 2]. Low DLCO can also be seen in those with clinically relevant congestive heart failure (CHF) due to its deleterious consequences on lung volumes, perfusion and gas exchange efficiency [3, 4]. Pulmonary function testing results are frequently available in patients with CHF. DLCO measurements have previously been shown to impact exercise capacity in CHF patients with either reduced or preserved left ventricular ejection fraction (LVEF) [5-7]. Impaired DLCO has also been suggested as a potential predictor of negative clinical outcomes in CHF [8]. We, therefore, aimed to determine if patients with reduced LVEF or isolated diastolic dysfunction on echocardiography and a low DLCO are at a higher risk of hospital admissions than their counterparts with a preserved DLCO. Confirmation of this hypothesis would support the need for closer monitoring of CHF patients who also present with a reduced DLCO.

We performed a retrospective review at Montfort Hospital (Ottawa, ON, Canada), a large urban academic centre, to identify all patients who underwent echocardiography (1 January 2016 to 30 June 2017) and pulmonary function testing, including DLCO measurements by single-breath carbon monoxide uptake. We charted all-cause hospital admissions between 1 January 2016 and 31 December 2018 for all subjects. LVEF was determined by the biplane Simpson method and the American Society of Echocardiography guidelines were used for the evaluation of left ventricular diastolic function [9]. DLCO % predicted results were determined for each patient using the 2017 Global Lung Function Initiative reference values [10]. A reduced DLCO was defined as a result below the lower limit of normal.

A total of 363 individuals underwent both echocardiography and DLCO measurements; 128 (35.3%) had at least one admission to the hospital. 131 patients had evidence of cardiac dysfunction (40% with a decreased LVEF versus 60% with isolated diastolic dysfunction). 66 of these subjects (50.4%) had a reduced DLCO (33 from both the reduced LVEF and isolated diastolic dysfunction groups). Cigarette smoking status was similar in those with a low or preserved DLCO, with 26% and 29%, respectively, reporting being lifelong nonsmokers. ANOVA revealed that DLCO had an independent relationship with all-cause hospital admissions (p<0.01). Indeed, patients with cardiac dysfunction and a low DLCO were admitted to the hospital more frequently than those with a preserved DLCO (mean of 1.29 versus 0.45 admissions, p<0.01). Subjects with a moderate or severe decrease of DLCO (≤60% predicted) were at an even higher risk of hospitalisation (mean of 1.64 admissions, p<0.01) compared with those with only a mild decrease (mean of 0.87 admissions) (table 1). No significant difference was seen amongst patients with a low DLCO when comparing individuals with a reduced LVEF versus isolated diastolic dysfunction (p=0.25). The mean±sd predicted DLCO in these two groups was 54±15% and 55±15%, respectively.

TABLE 1

All-cause hospital admissions in patients with reduced left ventricular ejection fraction or diastolic dysfunction (n=131) dependent on diffusing capacity of the lung for carbon monoxide (DLCO) measurements

DLCO	Patients n (%)	Mean all-cause hospital admissions (95% CI)
≥LLN	65 (49.6)	0.45 (0.18–0.71)
<LLN	66 (50.4)	1.29 (0.89–1.68)
≤60% predicted	36 (27.5)	1.64 (1.00–2.28)

LLN: lower limit of normal.

We also sought to investigate whether these findings would remain significant taking into consideration the % predicted forced expiratory volume in 1 s (FEV1) and the presence of airflow limitation, given the potential confounding effects from pulmonary disease on DLCO. As expected, the mean FEV1 was lower in the group with a reduced DLCO (73% versus 93% predicted, respectively). Patients with a decreased DLCO also had evidence of airflow limitation on spirometry more often (55% versus 28%). Of note, FEV1 did not have a meaningful effect on all-cause hospital admissions (p=0.08). A reduced DLCO was also a predictor of hospitalisations in individuals (25 out of 79 patients) with cardiac dysfunction and a FEV1 ≥80% predicted (mean of 0.84 versus 0.30 admissions, p=0.01). In keeping with these results, DLCO remained an independent predictor of hospitalisations after adjustment for FEV1 (p=0.02). In the subgroup of patients with cardiac dysfunction but no airflow limitation present (n=77), subjects with a low DLCO (n=30) still had an increased risk of admission (mean of 1.10 versus 0.36 admissions, p<0.01).

Our analysis revealed that a low DLCO predicts all-cause hospital admissions in patients with reduced LVEF or isolated diastolic dysfunction. There was a nearly threefold increase in mean hospitalisations in those with a reduced DLCO. The severity of the impairment seen on DLCO testing also appeared to affect the risk of hospitalisation. It is interesting to note that no significant relationship with all-cause hospital admissions was found when using FEV1. Thus, impairment in gas exchange efficiency seems more relevant than the severity of airflow limitation in predicting this negative outcome in these patients.

Low DLCO could reflect worse pulmonary perfusion secondary to impaired cardiac output and endothelial dysfunction in the lung capillaries [3, 4]. Repeated episodes of pulmonary oedema, increased interstitial fluid and alveolar–capillary membrane thickening might play a role. Increased ventilation–perfusion mismatch is an important determinant of a low DLCO. The association of poor pulmonary perfusion with ventilation distribution abnormalities could have also influenced our results [11-14]. Regardless of the underlying mechanisms, these abnormalities are expected to worsen as the extracardiac manifestations of impaired ventricular function become more relevant. A reduced DLCO may reflect the potentiating effects of negative cardiopulmonary interactions on chronic breathlessness, thereby increasing the likelihood of the patient being admitted to hospital [15].

What are the implications of our results? First and foremost, our data provide novel support to the notion that patients with impaired systolic and/or diastolic function and a reduced DLCO should be flagged as being at a higher risk of admission to the hospital. Secondly, they set the stage for prospective studies looking at changes in DLCO as the treatment of the underlying cardiac dysfunction is optimised. If so, it is conceivable that a higher DLCO over time could be associated with a lower risk of hospitalisation, particularly when there is a direct cause–effect relationship between ventricular function and a low DLCO. Thirdly, the advent of reliable point-of-care DLCO measurement systems raises the perspective that easily accessible results could play an unexplored role in the longitudinal follow-up of these patients. Finally, the added value of the diffusion coefficient (KCO=DLCO/alveolar volume) in those with preserved DLCO also merits investigation since a low KCO but normal DLCO indicates impaired gas exchange efficiency, which might be related to abnormal pulmonary perfusion due to cardiovascular disease [15].

Our analysis does have some inherent limitations given that it is a retrospective review from objective testing results. Despite the fact that a reduced DLCO remained a strong predictor of hospitalisations even when removing subjects with airflow limitation or a FEV1 <80% predicted, we cannot rule out that a low DLCO may have been negatively influenced by other concomitant pathologies, including pulmonary disease. The relatively small number of events also precluded further investigating the potential effects of worsening ventricular function on our main outcome. The confounding effects of anaemia should also be considered as well as the deleterious effects of recent smoking.

In conclusion, DLCO measurements provide meaningful clinical information to help predict hospital admissions in patients with CHF. As pulmonary function testing is frequently available in these patients, our data indicate that those with a reduced DLCO should be monitored more closely in an attempt to reduce the burden of repeated hospital admissions.