High prevalence of peripheral and carotid artery disease in patients with interstitial lung diseases
Abstract
Summary:Background: Interstitial lung diseases (ILD) are a heterogenous group of diseases, which have pulmonary fibrosis, restrictive lung disease, and decreased diffusion capacity as a common final path. Premature death frequently results not from ILD itself but from comorbidities. Peripheral artery disease (PAD) is a common comorbid disease in different chronic lung diseases. The focus of the present study is to clarify the prevalence of PAD in ILD. Patients and methods: A total of 97 patients with ILD and 30 controls were included in the study. Patients with ILD were subdivided into two groups according to the progression of pulmonary fibrosis: progressive fibrosing and non-progressive fibrosing ILD (PF-ILD and nPF-ILD, respectively). All participants underwent standard angiological and pneumological diagnostic procedures including six-minute walking test, measurement of ankle-brachial-index, and colour-coded duplex sonography. Results: We observed no relevant differences in the baseline characteristics except age. Both, PF-ILD and nPF-ILD patients, presented with a highly increased incidence of atherosclerotic lesions compared to the control group (p<0.001). PAD was present in all patients with PF-ILD and in 73% of patients with nPF-ILD. These results were confirmed by age-adjusted regression analyses. Conclusions: The present results indicate that ILD is an independent risk factor for atherosclerosis. Patients with PF-ILD are more severely affected than nPF-ILD patients with age as a confounding variable. Atherogenesis in ILD may be mediated by increased cardiovascular risk, systemic inflammation and chronic hypoxemia.
Introduction
Interstitial lung diseases (ILD) are a highly heterogenous group of diseases encompassing more than 200 different entities [1]. Due to this variety, information on prevalence and incidence of ILD is still vague. The prevalence is estimated to be between 6.3 and 97.9 per 100,000 persons in Europe [2, 3]. Most common entities of ILD are idiopathic pulmonary fibrosis (IPF), stage IV sarcoidosis, and ILD that is associated with connective tissue diseases (CTD-ILD) such as systemic sclerosis or rheumatoid arthritis. Although the diseases that lead to ILD are mostly rare and have their own individual classification and course, they share a common final path leading to pulmonary fibrosis. This is accompanied by restrictive lung disease and decreased diffusion capacity as well as reduced quality of life and premature death [4]. However, frequently not ILD itself but its comorbidities increase the mortality rate [5].
Comorbidities in ILD and IPF, in particular, have been the subject of several research articles, reviews, and register analyses during the last decade [6]. In particular, coronary artery disease (CAD) and myocardial infarction have proven to be independently associated with ILD [7]. Accordingly, patients with IPF suffer from an increased risk of developing myocardial infarction and ischaemic heart disease. Peripheral arterial disease (PAD) is another entity of atherosclerosis and, surprisingly, is estimated to have a much lower prevalence, between 3.6 and 20.0%, amongst patients with ILD [6, 8, 9]. However, most of the underlying studies are limited either by their retrospective design or, in case of register analyses, their dependence on international classification of the diseases (ICD) -codes. This is crucial, as the ICD-codes for CAD or PAD depend on clinical scores such as Fontaine’s classification describing walking distance until the occurrence of intermittent claudication. These clinical signs, however, may be absent or masked in patients with ILD, because they often are limited by persistent and severe dyspnoea.
In other lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), obstructive sleep apnoea (OSA) and advanced stages of sarcoidosis, an increased risk of comorbid atherosclerosis or preatherosclerotic changes have been observed. Here, it is likely that this increased risk is caused by systemic inflammation and/or intermittent hypoxia [10, 11].
Therefore, prevalence of cardiovascular diseases and particularly PAD in ILD has likely been underestimated. Subsequently, the main intention of this study was to prospectively investigate the prevalence of atherosclerosis in patients with ILD. Furthermore, this study aimed to evaluate whether or not progressive-fibrosing ILD is a risk factor for PAD.
Patients and methods
This prospective observational study was conducted according to the principles of the Declaration of Helsinki for Human Research and has been approved by the local ethics committee of the University Hospital in Bonn (application number: 006/19). Written informed consent of all participants was obtained prior to examination.
Patients and controls
From January 2019 to December 2020, a total of 104 consecutive patients diagnosed with ILD were enrolled in the study. Seven patients were excluded because they declined (or were unable) to undergo angiological examinations. Based on the results of lung-function testing, the patients were divided into two groups: progressive-fibrosing ILD (PF-ILD, n=49) and non-progressive fibrosing ILD (nPF-ILD, n=48). PF-ILD was defined according to the INBUILD-criteria [12]: a relative decline in forced vital capacity (FVC) of ≥10% of the predicted value, a relative decline in FVC of 5% to less than 10% of the predicted value accompanied by worsening of respiratory symptoms or progression of pulmonary fibrosis as assessed via high-resolution computed tomography (HR-CT) accompanied by worsening of respiratory symptoms over the course of two years [4, 12]. Patients with ILD who did not match PF-ILD criteria were assigned to the nPF-ILD group. Thirty patients without known pulmonary or vascular disease were recruited as controls.
Pneumological assessment
All patients and controls underwent bodyplethysmography (Bodyplethysmograph JAEGER), to test the diffusion capacity in single breath mode (Alveo-Diffusionstest Jaeger) and a six-minute walk test with blood gas analysis before and after. All parameters were assessed as a standard value and percentage of the predicted value. The latter were calculated by on-board software using reference values provided by the Global Lung Initiative [13]. The corresponding abbreviations are labelled with “%”. The following parameters were derived from body plethysmography for further analysis: total lung capacity (TLC, TLC%), forced vital capacity (FVC, FVC%), forced expiratory volume (FEV1, FEV1%), Tiffeneau index (FEV1/FVC), carbon monoxide (CO) diffusion capacity (DLCO%) and CO diffusion coefficient (KCO%). A Six-minute walk test (6MWT) was performed and the following parameters were assessed: distance, oxygen and carbon monoxide partial pressure (pO2, pCO2) before and after walking, and Borg-dyspnoea score to determine subjective feeling of dyspnoea [14].
Blood testing
Blood tests were performed including blood count, triglycerides, total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), lipoprotein a, C-reactive protein (CRP), interleukin-6 (IL-6) and HBA1C. These parameters have been proven to accelerate atherogenesis and arterial stiffness [15].
Angiological assessment
Standard angiological diagnostics
All patients and controls underwent standard angiological diagnostic procedures. This included measurement of ankle-brachial-index (ABI) using a Vasolab 320 (ELCAT) and colour-coded duplex sonography (CCDS) performed with a PHILIPS EPIQ 7 ultrasonic platform equipped with a L12-3 linear array scanner. CCDS was applied on lower-limb arteries and cervical arteries. The presence of any atherosclerotic plaque was documented in B-mode and CCDS and resulted in the diagnosis of PAD. Plaque of the cervical arteries was defined by the meeting of two out of three criteria: 1) intima-media thickness >1.5 mm; 2) protrusion into the lumen; 3) abnormal wall texture [16]. Plaque of the lower extremity arteries was defined as abnormal protrusion into the lumen and/or abnormal wall texture. Depending on the affected vascular territory, presence of PAD was subdivided into PAD of lower-limb (peripheral) arteries (pPAD) and PAD of cervical arteries (cPAD). Clinically, participants were subclassified via the Fontaine classification of PAD [17] (Electronic supplementary material [ESM] 1). The onset of claudication was assessed during 6MWT.
Statistical analysis
All variables are described as the mean value±standard deviation or as numbers with percentages, as appropriate. Differences between the baseline characteristics of the groups were calculated via Pearson’s Chi-Square and Cramer’s V test for categorical variables and analysis of variance (ANOVA) for continuous variables.
Additionally, the PF-ILD, nPF-ILD and control groups were compared with regard to PAD and its subclasses, pPAD and cPAD, and Fontaine’s classification. Binary outcome variables (PAD, pPAD, cPAD) were analysed via logistic regression models. For the Fontaine classification, ordinal regression analysis was performed. Since only six patients were classified on Fontaine stages IIb and III, classification was simplified to Fontaine stages 0, I, and ≥II for regression analysis. The latter thereby encompassed Fontaine stages IIa, IIb, III and IV. Results are presented as odds ratios (OR) with confidence intervals (CI) for logistic and ordinal regression models. Regression models were adjusted for age, since age differed significantly between the three groups and is an independent predictor of atherosclerosis.
As four outcome variables were examined p-values <0.01 were considered significant (according to Bonferroni correction for multiple testing).
Statistical analyses were conducted using IBM® SPSS® Statistics (version 26) and R (version 4.0.3).
Results
Baseline characteristics, medication, and blood testing
Baseline characteristics
Baseline characteristics are presented in Table I. With a mean age of 68.9±10.9 years, patients with PF-ILD were significantly older compared to controls (60.6±11.5 years; p<0.001) and nPF-ILD patients (59.0±14.3 years; p<0.001). Significantly more patients with PF-ILD (14.3%) also suffered from chronic obstructive pulmonary disease (COPD) in comparison to nPF-ILD patients (2.1%; p<0.05) and controls (0%; p<0.05). No further significant differences were found between the groups, including relevant risk factors for atherogenesis, such as number of packyears, body mass index (BMI), arterial hypertension, hypercholesterolemia, or diabetes.
Medication
Information about the medications taken by the study participants is presented in ESM 2. Administration of oral anticoagulants, encompassing vitamin-K-antagonists and new oral anticoagulants was significantly more frequent in patients with PF-ILD compared to control (p<0.01) and nPF-ILD (p<0.05) patients. Statins (p<0.001), diuretics (p<0.01), long-acting-beta-agonists (LABA, p<0.01) and oral corticosteroids (p<0.001) were found to be more frequent in patients with ILD compared to controls; yet there was no significant difference between PF-ILD and nPF-ILD patients. Notably, two controls reported the intake of LAMA and/or LABA. Of those, one patient was diagnosed with mild allergic asthma, the other reported unspecific dyspnoea, without any signs of COPD or asthma. Both took their medication as needed.
Blood testing
Blood tests revealed largely normal cell counts apart from leucocytes, which were elevated in patients with PF-ILD (9.36±3.13 G/l) and nPF-ILD (8.42±2.80 G/l) compared to the control group (5.36±0.35 G/l; p<0.001). As for risk factors of atherosclerosis, total cholesterol was lower in patients with PF-ILD (180.47±39.76 mg/dl) in contrast to nPF-ILD (203.37±47.90 mg/dl; p<0.05) and controls (203.10±31.39 mg/dl; p<0.05), and HbA1c was higher in both patients with PF-ILD (5.97±0.88%) and nPF-ILD (5.81±0.94%) compared to controls (5.36±0.35%; p<0.05). However, all mean HbA1c values were within reference range (<6%). No significant differences occurred for HDL and LDL. The level of inflammation, as shown by CRP and IL-6 levels, was upregulated in ILD patients. CRP was significantly higher in patients with PF-ILD (11.07±13.79 mg/l) compared with nPF-ILD (6.16±9.44 mg/l; p<0.05) and controls (2.58±3.59 mg/l; p<0.01). Differences in IL-6 were even more distinct. Here too, patients with PF-ILD presented with the highest values (8.61±7.23 pg/ml) in contrast to nPF-ILD (4.52±3.77 pg/ml: p<0.001) and controls (2.53±1.54 pg/ml; p<0.001) patients. The complete results of the blood tests are available in ESM 3.
Lung-function testing, CO-diffusion analysis and six minute walk test
The results of these tests are illustrated in ESM 4. Patients with ILD, especially PF-ILD patients, presented with significantly reduced lung volumes as well as reduced CO-diffusion capacity and coefficient. O2 support was necessary in 12 patients with PF-ILD and two patients with nPF-ILD (p<0.001). PF-ILD was accompanied by a significantly reduced maximum distance during the 6MWT (275±178 m) compared to control (506±97 m; p<0.001) and nPF-ILD patients (434±94 m; p<0.001).
Prevalence of PAD, pPAD, cPAD and vascular strain analysis
Standard angiological diagnostics
Frequencies of cPAD (80.4% vs. 26.7%, p<0.001), pPAD (83.5% vs. 23.3%, p<0.001) and PAD in general (86.6% vs. 33.3%, p<0.001) were significantly higher in patients with ILD compared to controls. After subdivision of the entire ILD collective into PF-ILD and nPF-ILD patients, the following results were obtained:
Table II shows the prevalence of PAD, pPAD, cPAP and their distribution over Fontaine stages without adjustment for age. PAD in general was present in all patients with PF-ILD (100%) and 73% of patients with nPF-ILD (p<0.001). cPAD and pPAD were significantly more frequent in PF-ILD compared to nPF-ILD (both with p<0.001) and controls (both with p<0.001) (Figure 1).
By performing an adjustment for age via regression analysis, the three groups showed significant differences in the prevalence of pPAD (p<0.001) with the odds of developing pPAD increasing by a factor of 71.22 (12.55–404.11) in PF-ILD compared to controls and by a factor of 14.86 (4.17–53.00) in nPF-ILD compared to controls. The prevalence of cPAD was also significantly different between the groups with p<0.001 and an OR of 38.69 (8.33–179.81) when comparing PF-ILD patients with the control group and an OR of 10.32 (3.02–35.27) between nPF-ILD patients and the control group. Subsequently, these results were mirrored by the simplified Fontaine classification (as described in chapter 2.5.). As for PAD in general, an adjusted regression analysis could not be performed since all PF-ILD patients were affected. Despite a numerical higher prevalence of PAD, pPAD, and cPAD as well as mean Fontaine classes in PF-ILD, the patients showed no significant difference between PF-ILD and nPF-ILD after adjusting for age. The adjusted regression analyses for pPAD, cPAD and simplified Fontaine classification are presented in Tables III, IV and V.
Discussion
In the general population, the prevalence of PAD is estimated to be 3–10% of people. With over 70 years of age, the prevalence is increasing to 15–20% [18, 19]. The prevalence of PAD in patients with ILD has been considered to be between 3.6 and 20.0% [6, 8, 9] up to now and, therefore, within the expected frequency of PAD in the general population. These current results indicate, however, that this estimate may need to be revised. Our study revealed a remarkably high atherosclerotic burden in patients with ILD, especially in patients with PF-ILD. Amongst these, every participant presented with atherosclerotic lesions in either carotid or lower-limb arteries. Although age was found to be a confounding factor that was able to explain the more severe affection of PF-ILD compared to nPF-ILD patients, these results are striking and put ILD close to other pulmonary diseases with high rates of comorbid atherosclerosis, such as COPD [11] or obstructive sleep apnoea [10]. According to present data, ILD is an independent risk factor for the presence of atherosclerotic lesions documented via CCDS. It is to discuss that most patients with ILD presented with asymptomatic, subclinical PAD. However, subclinical PAD has also proven to elevate the cardiovascular risk substantially [20]. Moreover, most patients with ILD, PF-ILD in particular, are suffering from severe dyspnoea which primarily limits their walking distance (cf. ESM 3). During 6MWT exertional dyspnoea limited the walking especially of those patients depending on oxygen support. Therefore, the number of symptomatic patients may be underestimated.
Atherosclerosis is a multifactorial disease that is initiated by LDL accumulation in the arterial wall and sustained and mediated by various drivers, such as smoking habits, diabetes, hypertension, sex, age and systemic inflammation [21, 22]. Eventually, atherosclerosis arises from a mismatch between pro- and contra-atherogenic factors. To interpret the findings of this study, the present results need to be put in the context of atherogenesis and its main drivers: classic cardiovascular risk factors on the one hand and systemic inflammation on the other.
Cardiovascular risk factors in ILD have already been described in detail: According to Schwarzkopf et al. (2018), ILD is accompanied by a relevant burden of cardiovascular risk factors, such as arterial hypertension with and without complications (66.2%), chronic pulmonary diseases (55.9%) and diabetes, with and without complications (31.2%) [5]. Raghu et al. (2015) reported a prevalence of diabetes in patients with IPF between 10% and 32.7%. The prevalence of arterial hypertension ranged from 14% to 71%, and the frequency of hypercholesterolemia varied from 6% to 53% [6]. Both meta-analyses reported higher numbers for males and for advanced age. These data were mirrored in present sample by all groups without significant intergroup difference, except for age, representing a high-risk collective of developing atherosclerosis. Amongst high-risk patients increased prevalence of PAD, up to 40%, can be expected [23]. This expectation was met by the control group in our sample; however, it still is greatly below the prevalence rate of PAD in ILD patients from this study. Therefore, the cardiovascular risk profile alone of patients with ILD does not provide a sufficient explanation for their high atherosclerotic burden.
In this study, patients with ILD presented with significantly elevated levels of CRP and IL-6, both signs of systemic inflammation. The concentration of IL-6 was also significantly higher in patients with PF-ILD compared to nPF-ILD as well as control patients. This study has not been designed to explain atherogenesis in ILD. However, an analogy to other pulmonary diseases with high atherosclerotic burden can be discussed. Here, an association with atherosclerosis due to activated inflammatory pathways is well-known and has been the subject of several investigations. For example, COPD is accompanied by an elevated cardiovascular risk [24]. This is mediated not only by smoking, which is a common risk factor for both diseases, but systemic inflammation. Although the pathology is still not completely understood, current knowledge suggests that cigarette smoke induces an upregulation of IL-6 and tumour necrosis factor alpha (TNFα), resulting in self-sustaining systemic inflammation and a proatherogenic environment [25, 26]. Patients with OSA seem to be even more severely affected [10]. Here too, the pathogenesis remains under study. Most likely, nightly intermittent hypoxemia (IH) and reoxygenation induce several proatherogenic pathways: Locally, increasing levels of reactive oxygen species (ROS) promote oxidative stress and endothelial dysfunction. Systemically, intermittent hypoxemia leads to higher levels of IL-6 and, consecutively, TNFα, CRP, hypoxia-inducible-factor (HIF) 1, and activation of nuclear factor kappaB pathway (NF-κB) [26, 27, 28]. Therefore, systemic inflammation seems to play a pivotal role in comorbid atherogenesis in pulmonary diseases.
In summary, the pathogenesis of atherosclerosis in ILD is still not fully understood. Most likely, the combination of a high cardiovascular risk profile and systemic inflammatory processes, similar to those in patients with OSA or COPD, may be responsible for atherogenesis in ILD.
PAD still is associated with a high five-year mortality of up to 25% and is considered to be a more severe manifestation of atherosclerosis compared to CAD alone. This increased risk is attributed to higher levels of systemic inflammation and higher burden of cardiovascular risk factors [29]. In this context, the common presence of PAD in patients with ILD, surely is one explanation for the high mortality rate of ILD patients and an indicator of systemic inflammation induced by pulmonary fibrosis.
Limitations
This study is mostly limited by its sample size. Distribution of ILD-causing diseases, especially IPF, differed significantly throughout ILD groups, therefore the results with regard to PF-ILD possibly are biased by IPF patients. Although there were no significant differences with regard to the baseline characteristics (except for age), distribution of packyears, prevalence of diabetes and/or prevalence of COPD may have influenced the present results, as they all are connected to atherogenesis. This study was further limited by the methods, as CCDS was used to verify the presence of atherosclerotic lesions, whereas data on prevalence of PAD in the general population mostly relies on ABI. The number of symptomatic patients may have been underestimated due to reduced walking speed due to exertional dyspnoea.
Larger studies or register analyses, including angiological surveillance, are needed to confirm the present results.
Conclusions
This study provides the first evidence that ILD is an independent risk factor for PAD. PAD seems to be generally present in ILD patients and is associated with increased five-year mortality. Therefore, the high mortality rate of ILD patients may also be attributed to PAD. Patients should be screened for PAD when diagnosed with ILD, and PF-ILD in particular. Secondary prevention, lipid-lowering therapy, and regular re-examinations should be recommended in this context.
Electronic supplementary material
The electronic supplementary material (ESM) is available with the online version of the article at https://doi.org/10.1024/0301-1526/a001068
We sincerely thank Meghan Lucas (scientific coordinator, University Hospital Bonn, Medical Department II, Cardiology, Pneumology, Angiology, Bonn, Germany) for proofreading the manuscript. Furthermore, we would like to express our gratitude to all patients and controls for participating in this study as well as to the medical staff for their support.
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