Lung Function and Aortic Calcification–Hardening the Evidence or Inflaming the Need for Further Research?

Keywords::

• aortic calcification
• arterial stiffness
• COPD
• lung function

Large elastic arteries such as the aorta not only provide a conduit for blood flow but also fulfill a dynamic role in buffering the large intermittent pressure changes due to ventricular ejection in order to minimise end organ and microvascular damage and allow a more constant blood flow through smaller vessels. However, this buffering capacity is lost during the ageing process and in disease states associated with premature vascular ageing.

It has been known for some time that impaired lung function (1) and lung function decline (2) are risk factors that predict cardiovascular (CV) death and morbidity over and above the traditional risk factors. Furthermore, chronic respiratory disease states, such as chronic obstructive pulmonary disease (COPD) are also associated with greater CV risk (3) as well as with other traditional risk factors such as diabetes mellitus (4), insulin resistance (5) and a systemic inflammatory state (6). Despite this, lung function is not routinely assessed in CV clinics, nor are CV measurements made in respiratory clinics.

Aortic stiffness, as assessed by carotid femoral PWV (CF-PWV) has established itself as a non invasive predictor of CV disease in both the general population and in at-risk groups such as hypertension and renal failure (7,8). This has focused intense research interest into the possible pathophysiological mechanisms responsible for large artery stiffening (9). The recognition that conventional risk factors such as diabetes and hypercholesterolaemia play little part in determining CF-PWV (10), suggests that other, as yet, poorly understood pathophysiological mechanisms may be more involved. Furthermore, recent evidence suggests the fascinating possibility that regional aortic PWV may be influenced by differential pathophysiological processes. Recently, impaired lung function was an independent variable of CF-PWV in 800 men in the Caerphilly Prospective study (11). In parallel, increased aortic stiffness has been reported in patients with chronic respiratory disease such as COPD (12,13) and COPD related to alpha 1 antitrypsin deficiency (14), thus supporting the inclusion of assessment of arterial stiffness in the modern management of patients with chronic respiratory disease.

In this issue of The Journal, McAllister and colleagues (15) measure aortic calcification in subjects from the Multi-ethnic Study of Atherosclerosis (MESA) lung study and relate this to impaired lung function. In addition, they explore regional assessment of proximal aortic distensibility using magnetic resonance (MR) analysis. Of 6,814 subjects without clinical CV disease in the main MESA study; the MESA lung study recruited 3,965. The results of those with acceptable traces of normal or obstructed spirometry who had either aortic calcification (n = 1,312) or proximal aortic distensibility (n = 1,917) measured, were included in this manuscript.

Importantly, the presence of aortic calcification in itself is a prognostic factor (16) and over 2/3 of the subjects had evidence of distal abdominal aortic calcification; with an association between the degree of calcification in those who had calcification and impaired lung function. This remained evident even after adjustment for other important confounders. However, there was no such association of lung function with calcification in the thoracic aorta. Here though, the “presence of calcification” depended on different plaque criteria and additionally, there are accepted technical issues that challenge quantifying calcification in this area. The authors’ report a greater distal aortic calcification in subjects according to the spirometric criteria of moderate and severe airflow obstruction compared to subjects with normal spirometry and without asthma, yet the 95% confidence intervals are wide, which may be partly attributable to the low numbers of subjects with more severe airflow obstruction.

The authors quite rightly suggest inflammation as a potential mechanism driving aortic calcification and increased arterial stiffness (17). This is supported by recent animal (18) and human (19) data. However, as yet it remains unclear whether inflammation increases elastin breakdown and fragmentation providing the substrate for calcification or whether calcified elastin promotes inflammation. In subjects with COPD, different factors may also influence deposition of aortic calcification in specific areas such as vascular inflammation (20, 21) or systemic factors such as low bone mineral density (22, 23). Recent animal data suggests that inflammation promotes both vascular calcification and osteoporosis (24), both associated with COPD.

A recent paper in this journal reported thoracic calcification and its association with emphysema index (25) in 240 current and former smokers participating in the National Lung Screening trial (NLST), 2/3 having airflow obstruction. In their MESA population including a large proportion of never smokers, McAllister et al. (15) reported no such association of emphysema index with distal calcification and did not report the relationship with thoracic calcification, though further nuances in methodology of both emphysema index and thoracic calcification score make direct comparison of the 2 papers not feasible. Aortic calcification has been related to aortic stiffness in several disease states such as renal disease and isolated systolic hypertension (26, 27).

Although aortic stiffness, as assessed by CF-PWV is the currently accepted gold standard for the prediction of future cardiovascular events (7, 8), this technique fails to measure regional PWV in the aorta, and therefore assumes that any change to CF-PWV is global in nature, affecting the entire aorta. This is a simplistic view given the profound differences in pulse pressure, function and wall content of the aorta along its path. In addition, the CF-PWV does not measure the very proximal aortic stiffness. Advances in MRI now allow such regional assessments that have previously only been possible using invasive techniques (28).

However, differing methodologies, such as aortic distensibility and PWV of aortic stiffness have been conflicting (29–31), with a recent cross-sectional analysis, in more substantial sized population from previous, reporting age related regional aortic PWV are more evident in the distal aorta (30). McAllister et al reported no association of lung function or emphysema index with proximal aortic distensibilty (15), but this does not prevent abnormal haemodynamics further down the aortic path due to different insults. Further, there may be compensatory changes in the proximal aorta to compensate for more distal stiffness (15, 30).

The study by McAllister et al. is important, as it focuses attention on the association between lung function, arterial haemodynamics, vascular calcification and CV outcome. However, like any good research, it poses even more questions than it answers. These need to be addressed further with a better understanding of the potential pathophysiological mechanisms in order to develop “hard evidence” and thus allow therapeutic interventions designed to decrease CV death and morbidity in subjects with COPD. This will require data from large longitudinal studies that will follow subjects with COPD after a comprehensive baseline assessment including haemodynamic variables such as aortic stiffness and vascular imaging. In the meantime, the extrapulmonary consequences of COPD cannot be neglected, and we encourage Respiratory physicians to consider non-invasive assessment of haemodynamics in patients with impaired lung function and COPD and our Cardiology colleagues to assess lung function as part of their CV risk evaluations.

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.