Background
Bronchiectasis is a chronic airway disease characterized by recurrent infection and chronic inflammation. The prevalence of bronchiectasis has been increasing over the past decade and led to substantial morbidity and mortality worldwide [
1‐
3]. Recent studies have demonstrated that patients with bronchiectasis have increased risks of developing cardiovascular disease (CVD), and that concomitant CVD might pose a negative impact on survival [
4‐
7]. The underlying mechanisms of elevated cardiovascular risk are still unclear, but increased systemic inflammation and frequent exacerbations due to chest infections might play a crucial role [
5,
8].
Arterial stiffness reflects the decreased capability of an artery to dilate and contract in response to pressure changes. A multitude of non-invasive methods have been developed to assess arterial stiffness [
9,
10]. Of these, pulse-wave velocity (PWV) is the most widely used and validated technique [
10]. The carotid-femoral PWV (cfPWV) is the gold standard for assessing arterial stiffness [
9,
11], but requires patients’ persistent lateral rotation of the neck and exposure of inguinal region [
12]. However, brachial-ankle PWV (baPWV) has been extensively applied for assessment in East Asian countries (including China), presumably due to the greater ease and convenience over a longer arterial length, and recent evidence has shown similar usefulness of baPWV in CVD risk stratification compared with cfPWV [
13].
Previous studies suggested that individuals with chronic respiratory diseases have increased arterial stiffness compared with age- and sex-matched control subjects [
14‐
16]. This has led us to postulate that similar conclusions apply to bronchiectasis patients because they share some common biological pathways for developing CVD (i.e. hypoxia and systemic inflammation) [
8,
17]. In a small, single-center study (20 patients versus 20 controls), Gale and colleagues [
18] have shown that bronchiectasis patients had greater arterial stiffness, but they defined arterial stiffness by measuring aortic PWV.
Bronchiectasis Severity Index (BSI) and FACED score have been widely used to categorize the severity of bronchiectasis [
19,
20]. However, their relationship with arterial stiffness remained unclear. In addition, bronchiectasis exacerbations are common and important events related to exaggerated airway infection and systemic inflammation [
21,
22], which might accelerate the process of impairment of the cardiovascular system.
Therefore, we aimed to: (1) assess arterial stiffness in bronchiectasis patients by measuring baPWV as compared with age- and sex-matched healthy controls; (2) elucidate the relationship between disease severity and arterial stiffness; and (3) determine the factors influencing on arterial stiffness in patients with bronchiectasis.
Discussion
Our study found that bronchiectasis patients have increased baPWV compared with healthy controls, which was validated in subgroup analysis excluding individuals with concomitant hypertension or coronary heart disease or diabetes. BaPWV correlated with disease severity assessed with both BSI and FACED scores. Aging, PA colonization, SBP, BMI and exacerbation frequency in the previous year, but not systemic inflammatory markers, were independent factors affecting the baPWV in patient with bronchiectasis.
Recent studies have demonstrated that bronchiectasis might be an independent risk factor for CVD, which was unrelated to smoking--traditional cardiovascular risk factors or comorbidities associated with the etiology of bronchiectasis. This highlighted the importance of preventing from further development of CVD in bronchiectasis [
3‐
5,
7]. Thus, identifying the early changes of cardiovascular system before the occurrence of major clinical events (i.e. stroke and myocardial infarction), have additional implications for CVD prevention at individual levels, such as early-stage targeted prevention and intervention for high-risk patients. Arterial stiffness has a strong predictive value for cardiovascular events beyond traditional cardiovascular risk factors in healthy populations [
9], as well as in patients with chronic lung diseases, and is the most suited parameter for routine clinical practice. Prior to our study, only one case-control study has reported that patient with bronchiectasis (
n = 20) had increased arterial stiffness, measured by aortic PWV, compared with matched controls [
18]. Similar results were also validated in our study despite using different indicators of arterial stiffness. We have, for the first time, demonstrated that baPWV correlated positively with the disease severity which was assessed with both the BSI and FACED scores, the two-validated composite disease severity metrics, suggesting that arterial stiffness developed early in bronchiectasis and aggravates along with greater disease severity or disease progression. A meta-analysis has shown that an increase in baPWV by 1 m/s corresponded to an increase of 12 and 13% in the total cardiovascular events and cardiovascular mortality, respectively [
27]. The elevation in baPWV between bronchiectasis patients and control subjects in our cohort was 1.62 m/s, which might result in an estimated increase of 19 and 21% in total cardiovascular events and cardiovascular mortality, respectively. In this regard, this difference should be sufficient to elicit adverse outcomes in patients with bronchiectasis.
Global assessments of bronchiectasis severity with both BSI and FACED scores showed positive correlation with baPWV. This was further confirmed in our multivariate analysis that aging, PA colonization and the number of exacerbation within one year (all crucial components of the BSI) were independent factors influencing on baPWV in bronchiectasis. Recently, Evans et al. [
5] have reported that bronchiectasis severity was independently associated with vascular disease, which was also consistent with our findings. Interestingly, the average age of bronchiectasis patients in our cohort was 51 years, which was significantly lower than that in European and US cohorts (70 years and 64 years, respectively) [
28,
29]. Since the fact that age was the strongest predictive factor of baPWV in our cohort, age-related changes in baPWV would be more prominent in European and US bronchiectasis cohorts, which merits further validations. Meanwhile, we found that PA colonization and the number of exacerbation within one year were significantly associated with arterial stiffness. The median difference of baPWV in patients with PA colonization compared to those without was 3.13 m/s (unadjusted analysis), which corresponded to a 38% increase in excess risks of cardiovascular events [
27]. Arterial stiffness was reportedly increased in cystic fibrosis children colonized with PA compared with uninfected children [
30], which was consistent with our findings. PA colonization may represent a distinct clinical phenotype of bronchiectasis with poorer quality-of-life, frequent exacerbation and poorer long-term outcomes [
31‐
33]. Our findings have extended the rationale to optimize management of patients with PA colonization, by integrating the concept of reduction in cardiovascular events. The association between exacerbation frequency and cardiovascular risk has been reported in COPD, and that chronic low-grade systemic inflammation might be one of the possible mechanisms linking frequent exacerbations to increased arterial stiffness [
34]. However, the lack of association between systemic inflammatory markers and arterial stiffness in our study indicated that this assumption cannot be extrapolated to bronchiectasis patients. Nevertheless, further studies are merited to investigate the links between chronic bacterial infection, exacerbation, systemic inflammation and increased arterial stiffness by inclusion of greater sample sizes and longer follow-up duration.
Systemic inflammation has been proposed to accelerate and stimulate vascular extracellular matrix remodeling process of elastin fragmentation and collagen deposition, resulting in increased arterial stiffness [
35]. However, data for the causal link between low-grade systemic inflammation and a higher incidence of cardiovascular disease in bronchiectasis are lacking [
5]. In this study, although we found an association between baPWV and plasma fibrinogen, but not IL-6, IL-8 and CRP in univariate regression models, the results could not be further confirmed in multivariate model. Furthermore, systemic inflammatory markers did not correlate with bronchiectasis severity as assessed with BSI. However, we could not preclude the possibility that other known or unidentified inflammatory markers (i.e. intercellular adhesion molecule-1, vascular cell adhesion molecule, and E-selectin) might be related to arterial stiffness. Saleh et al. [
36] recently shows that bronchiectasis patients presented with significantly heterogeneous levels of systemic inflammatory proteins, which could not be adequately accounted for by the differences in disease aetiology or severity. This indicated that persistent systemic inflammation may affect only some bronchiectasis patients as evidenced in COPD [
37]. To further answer this question, it would be helpful to investigate exclusively in this specific subgroup of patients whether the correlation between inflammatory markers and increased arterial stiffness exists.
In addition, changes of arterial stiffness in bronchiectasis patients could not be explained by traditional cardiovascular risk factors, such as plasma lipids [
38], diabetes [
39], smoking history [
40] and FEV
1 [
41], all powerful risk factors for predicting arterial stiffening. This might be because of a lack of effect of these risk factors per se, or because arterial stiffness was not driven by an atherosclerotic process at least in its early stages but rather by an alternative pathologic factor in which blood pressure plays a role [
42]. It is well recognized that arterial stiffness depends on mechanical stretch of the arterial wall and, hence, on blood pressure at the time of the measurement [
43]. Stretch is thought to transfer loading to stiffer elements within the wall that are of greater tensile strength (i.e. from elastin to collagen) and, therefore results in an overall stiffening of the wall. Accordingly, systolic blood pressure was independently associated with greater arterial stiffness in our study.
A major strength is that we have conducted the reproducibility of baPWV measurement and, for the first time, systematically investigated arterial stiffness in bronchiectasis patients. However, several limitations merit interpretation. First, the study design was cross-sectional, and clinical follow-up data were not available, which precluded the causality inference between bronchiectasis, bacterial colonization, systemic inflammation, arterial stiffness and CVD, and the direct comparison of predictive value of baPWV and cardiovascular risk scores for future cardiovascular events, which merits further investigation. Second, the inclusion of patients and controls subjects with CHD, diabetes and hypertension might be criticized, although subgroup analysis with exclusion of these patients did not alter the findings. Thirdly, there are still some debates regarding whether COPD and asthma should be viewed as aetiologies of bronchiectasis [
44], and abundant evidence of elevated arterial stiffness has been reported in COPD [
14,
15]. We therefore conducted an exploratory subgroup analysis by removing patients with COPD or asthma in order to determine whether inclusion of these patients might have biased our findings. Reassuringly, baPWV remained significantly greater in bronchiectasis patients than those healthy controls (median; 1488 cm/s versus 1352 cm/s,
P = 0.004). Finally, left ventricular morphology and function were not assessed, which have been reportedly associated with arterial stiffness [
45].