Cardiovascular risk in Idiopathic Pulmonary Fibrosis-Juniper publishers
JUNIPER PUBLISHERS-OPEN ACCESS INTERNATIONAL JOURNAL OF PULMONARY & RESPIRATORY SCIENCES
Opinion
Idiopathic Pulmonary Fibrosis (IPF) is a progressive
interstitial lung disease with a median survival of 3-5 years following
diagnosis [1]. Patients most commonly present with cough or dyspnea, and
the disease is characterized by a chronic, progressive parenchymal
fibrosis with a Usual Interstitial Pneumonia (UIP) histological pattern.
On CT scanning this is defined as basal predominant reticulation,
traction bronchiectasis, and in some cases, honeycombing. At time of
biopsy, UIP is histologically defined as paraseptal fibrosis with
architectural distortion and fibroblastic foci. The natural course of
the disease is one which leads to progressive respiratory failure and
death [1]. Until recently, treatment consisted of regular surveillance,
symptom relief, pulmonary rehabilitation, managing of comorbidities
(e.g. gastro-oesophageal reflux) and ultimately palliative care or
referral for lung transplantation [2]. Following the 2014 publications
of the ASCEND [3] and IMPULSIS [4] trials, two new antifibrotic
treatments (Pirfenidone and Nintedanib) have become widely available for
IPF patients who meet certain criteria. These criteria are determined
differently by different healthcare bodies around the world e.g. in the
United Kingdom patients must have had a multi-disciplinary team
diagnosis of IPF and a forced vital capacity (FVC) between 50 and 80% to
be eligible for treatment with an antifibrotic medication. Both of
these medications have been shown to slow the progression of the disease
and therefore delay functional decline [3,4].
However, the mortality and morbidity burden in IPF
is not only related to the disease process itself, but also due to a
number of co-morbid conditions, which can be partly explained by the
disease being more prevalent in the elderly, with median age of onset at
66 years [2,5,6]. Co-morbidities can be either pulmonary or
extra-pulmonary. Pulmonary conditions include pulmonary hypertension
(3-86%), obstructive sleep apnea (5.9-91%), lung cancer (3-23%), and
chronic obstructive pulmonary disease (COPD) (6-67%) [6].
Extra-pulmonary conditions
include gastro-oesophageal reflux (0-94%) diabetes mellitus (10-42%) as
well as depression and anxiety (21-49%) [6].
One important co-morbidity is Cardiovascular Disease
(CVD) which is a serious but potentially modifiable association that
affects patients with IPF [7]. CVD manifestations include pulmonary
hypertension, heart failure, Coronary Artery Disease (CAD) cardiac
arrhythmias and stroke [8].Atherosclerosis and pulmonary fibrosis have
some similar pathophysiological changes, with both developing from
excessive inflammation and fibrosis, driven by elevated cytokine and
chemokine expression [9]. In pulmonary hypertension, chronic hypoxia
causes cardiac ischemia and the combination of chronic inflammation and
elevated pulmonary pressures also increase the risk for developing
cardiac arrhythmias [8].
Population studies have identified a specific
increased risk of CVD in patients with IPF.Primary health care data from
the Health Improvement Network in the United Kingdom showed an
increased risk of Acute Coronary Syndrome (ACS) (OR 1.53; 95% CI
1.15-2.03), angina (OR 1.84; 95% CI 1.48-2.29) and DVT (OR 1.98; 95% CI,
1.13-3.48) prior to the diagnosis of IPF. This is independent of
confounding factors such as smoking, age or gender [10]. Post diagnosis
population studies reveal an increased risk of ACS (RR 3.14; 95% CI
2.02-4.87) and DVT (RR 3.39; 95% CI 1.57-7.28) [10]. A subsequent
multivariate analysis in IPF using data taken from the Korean Heart
Study showed that IPF was an independent risk factor for CAD following
adjustments for age, hypertension, diabetes and hypercholesterolemia
[11]. Data from patients with IPF undergoing lung transplant assessment
(where part of the work up included coronary angiography) revealed that
68% of patients had CAD [12]. This is supported by a cross-sectional
study of 630 patients also referred for lung transplant. Here, they
demonstrated an increased prevalence of CAD in patients with fibrotic
lung disease compared to non-fibrotic lung disease (OR 2.18; 95% CI
1.17-4.06) [9]. Further analysis of lung transplant data reveals that
the incidence of CAD seems higher than in other chronic lung diseases
such as COPD [13]. Importantly, IPF patients with significant CAD had
worse outcomes than those with none or non-significant disease [13].One
interesting additional argument for the increasing burden of CVD is the
concept that with the management of a complex disease such as IPF, there
may be less awareness and emphasis on standard medical complaints (such
as CVD) resulting in a reduced use of statins and antihypertensive
medication [10].
Early recognition and treatment of CVD in this
already high-risk population is important.Current methods include
coronary angiography, detection of coronary calcifications on HRCT,
systemic blood pressure measurement, monitoring serum cholesterol and
use of validated risk calculators such as the Framingham and the QRISK-2
scores [1]. The QRISK-2 scoring system uses a number of parameters to
calculate both the percentage risk of having a heart attack or stroke
within the next 10 years, as well as a relative risk compared to an
adult of the same age, sex, and ethnicity in the general population
[14]. Preliminary data where this tool has been applied in IPF
identified a cohort of patients where two thirds were deemed to be at
‘high’ cardiovascular risk[15]. This suggests a role for improved
screening at diagnosis to allow for appropriate cardiovascular
intervention. Once screening has picked up patients at high
cardiovascular risk, the responsibility for managing this needs to be
clearly delineated to either the pulmonary physician treating the IPF or
to the patient’s general practitioner. Given the high burden of disease
and the significantly worse outcomes of patients with IPF and CVD
compared to IPF alone, further studies are needed to validate this
finding and identify other ways in which cardiovascular risk can be
reduced in patients with IPF.
Conflicts of Interest
ED reports no conflicts of interest. MT has received travel support and consultancy fees from Roche and Boehringer Ingelheim.
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