Cardiovascular implications of idiopathic pulmonary fibrosis: A way forward together?

Abstract

Cardiovascular disease has an increased prevalence among patients with idiopathic pulmonary fibrosis (IPF). Cardiovascular disease and IPF share similar symptoms with overlapping demographics and risk factors for disease development. Common cellular mediators leading to disease development and progression have been identified in both the cardiovascular and pulmonary organ systems. In this context, discovery of new therapeutic targets and medical therapies could be mutually beneficial across cardiopulmonary diseases. Here we present (1) a clinical review of IPF for the cardiovascular clinician and (2) common cellular mechanisms responsible for fibrosis in the heart and lungs and (3) highlight future research considerations and the potential role of novel therapeutic agents which may be mutually beneficial in cardiac and pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, almost universally fatal pulmonary disease with a median survival following diagnosis of 2–5 years.^1,2 Patients with IPF have a high burden of comorbidities including cardiovascular disease (CVD) and share risk factors in common with CVD: male gender, history of cigarette smoking, and age greater than 60 years. CVD has an increased prevalence in IPF, independent of these common risk factors.^3,4 Given these common risk factors, patients undergoing evaluation for dyspnea are often initially misdiagnosed with heart failure (HF), leading to at times a 2-year lag in diagnosis of IPF.^5,6 Delayed access to care has been shown to be associated with increase mortality independent of disease severity.⁷ An increased awareness of IPF among cardiology clinicians is important to reduce misdiagnosis and expedite time to diagnosis of IPF.⁸ Whereas prior reviews have focused on the overlap of chronic obstructive pulmonary disease (COPD) and HF, concise reviews on IPF in CVD are fairly limited.⁹ Here we present (1) a clinical review of IPF for the cardiovascular clinician and (2) common cellular mechanisms responsible for fibrosis in the heart and lungs and (3) highlight future research considerations and the potential role of novel therapeutic agents which may be mutually beneficial in cardiac and pulmonary fibrosis.

Clinical presentation

IPF is an interstitial lung disease with an unknown cause, most commonly affecting men in the sixth and seventh decades of life.¹⁰ It is a relatively rare disease with an estimated incidence of 3–9 cases per 100,000 per year.¹¹ The early symptoms of IPF, shortness of breath on exertion, cough, and decreased exercise tolerance, are similar to HF.¹² In a patient with IPF, bibasilar rales that can be heard during lung auscultation may be mistaken for HF. Subtle physical examination findings can help distinguish between IPF and HF. Bibasilar rales, although present in both conditions, characteristically sound like “velcro crackles” in IPF, and finger clubbing may also be present, neither of which would be expected in HF.¹²

Diagnosis

When IPF is suspected, further clinical history and high-resolution chest tomography (HRCT) is the required next step. The diagnosis requires the exclusion of other known causes of interstitial lung disease and either a definitive pattern of usual interstitial pneumonia (UIP) on HRCT or a combination of HRCT and histopathology consistent with UIP¹³ (Figure 1). A UIP pattern on HRCT is characterized by basilar, subpleural predominant, reticular opacities with or without peripheral bronchio-lectasis and, most importantly, the presence of honey-combing.¹³ Surgical lung biopsy can be considered in cases with a probable or indeterminate pattern on HRCT.¹³ Multidisciplinary discussion involving expertise from pulmonary, radiology, and pathology is recommended by guidelines to improve diagnostic accuracy.^13,14.

Figure 1.

Diagnosis of IPF: diagnostic algorithm for a suspected diagnosis of IPF.

Manifestations of CVD in IPF

Coronary artery disease

Patients with IPF are at increased risk of developing coronary artery disease (CAD) independent of common confounding risk factors.^3,15 Izbicki et al found that CAD was present in approximately 29% of patients with pulmonary fibrosis compared to approximately 10% with emphysema. This association was not fully explained by smoking status because it was more common in emphysema group (98%) compared to the pulmonary fibrosis group (31%).¹⁶ In a comparison between IPF and COPD patients referred for lung transplant, Nathan et al found that the prevalence of CAD in the IPF versus COPD groups was approximately 66% versus 46%, respectively (P < .028).¹⁵

A mechanistic explanation for this observed association has not been clearly delineated. Finger clubbing commonly found in advanced IPF involves neovascularization and smooth muscle proliferation which are also present in atherosclerosis.^17–21 It has been hypothesized that increased atherogenesis is an extrapulmonary manifestation of fibroproliferative processes seen in the lung.²² Alternatively, patients with IPF may be on suboptimal cardiovascular medical therapy as a consequence of preferential attention to pulmonary disease. This is supported by a study which found that patients with IPF were less likely to receive statin and β-blockers compared to the general population.³

The role of statins for the treatment of IPF is unclear. Prior post hoc analysis and observational data have demonstrated benefits in statin users compared to nonusers, suggesting a potential for improved outcomes in IPF.^{23, 24} However, this has not been rigorously investigated with a randomized placebo-controlled trial.

Pulmonary hypertension and right HF

Pulmonary hypertension (PH) in patients with IPF is classified as group 3 disease secondary to lung disease. The data on the incidence of PH in IPF are limited considering transthoracic echocardiogram has been shown to perform poorly for measuring right ventricular systolic pressure in patients with advanced lung disease and right heart catheterization is not routinely performed in most patients. In a study of patients with advanced lung disease who were diagnosed with PH by echocardiogram, only 37% had a diagnosis of PH confirmed following evaluation with right heart catheterization.²⁵ Retrospective studies examining the prevalence of PH in IPF patients undergoing evaluation for lung transplant range between 22% and 32%.^{26, 27} On the contrary, the ARTEMIS-IPF trial which excluded severe disease (forced vital capacity b 50%) showed that only 10% of the study population had PH. In this cohort, follow-up through nearly 1 year showed an additional 5% of the remaining study population developed PH. This suggests that PH progresses slowly in mild, clinically stable IPF patients.²⁸

Mechanisms contributing to the development of PH in patients with IPF are complex. In advanced disease, hypoxia is known to cause smooth muscle hypertrophy and collagen deposition in pulmonary arteries. Furthermore, pulmonary vasculature can be either destroyed or obstructed by the progression of pulmonary fibrosis. On a cellular level, fibroblast growth factor and platelet-derived growth factor (PDGF) contribute to vascular remodeling present in the development of PH.²⁹

IPF treatment guidelines recommend against treating PH in IPF with ambrisentan, macitentan, bosentan, or sildenafil due to an association of either no benefit or, in some cases, harm.³⁰ This is felt to be due to inhibition of compensatory hypoxic vasoconstriction resulting in reduced gas exchange due to worse ventilation and perfusion mismatch.¹² Currently, there is no drug therapy which demonstrates safety and efficacy for the treatment of group 3 PH in IPF.

Pathologic fibrosis in heart and lungs

Fibrosis is an innate immune response, essential in wound healing and scar formation.³¹ In chronic fibrosis, a maladaptive injury response occurs leading to the development of continuous, progressive scar formation, resulting in organ dysfunction. Myocardial infarction, HF, and IPF each involve abnormal injury response mechanisms resulting in chronic fibrosis.

Myocardial infarction

Following myocardial infarction resulting in cardiac myocyte death, the heart adapts and remodels at the cellular level to meet physiological demands given the lack of consistent regeneration capacity. These adaptations result in myocardial fibrosis which occurs in 3 distinct phases: inflammatory, proliferation, and maturation phases. The proliferation phase is characterized by the release of fibroblasts and myofibroblasts which deposit extracellular matrix (ECM) proteins in attempt to preserve tissue integrity through scar formation.³²

Heart failure

Through a series of initially adaptive responses, cardiac fibrosis secondary to myocardial infarction ultimately progresses to HF.³³ HF with a reduced ejection fraction is, in part, related to the consequence of increased ventricular stiffness secondary to increased collagen deposition as a response to myocyte damage.³⁴ HF with preserved ejection fraction is secondary to impairments of passive ventricular wall properties secondary to abnormal ECM composition and changes in the myocyte cytoskeleton.³⁵

Idiopathic pulmonary fibrosis

The pathogenesis of IPF is complex and not well understood. It is hypothesized to occur secondary to repeated alveolar epithelium injury complicated by a dysregulated injury-repair response process affecting parenchymal lung tissue between the capillaries and alveolar spaces.³⁶ The injury response is highly dysregulated, resulting in excessive accumulation of fibroblasts and ECM proteins leading to scar formation. Exacerbations of IPF lead to abrupt, often irreversible declines in lung function secondary to inter- and intra-alveolar accumulation of fibroblasts and ECM in previously normal lung tissue.³⁷

Fibrogenic mediators

There are numerous fibrogenic mediators that the heart and lungs have in common. Fibroblasts are a key feature in cardiac and pulmonary fibrosis. They accumulate near the injury site, either at a cardiac myocyte infarct or at epithelial alveolar injury in the lung, leading to the deposition and overproduction of ECM proteins resulting in scar formation.³⁸ The origin of fibroblasts in the heart and lung remains incompletely understood. In cardiac tissue, they originate locally within the heart or from circulating precursor cells from the bone marrow.³⁹ In addition to these proposed origins in the heart, lung fibroblasts are proposed to originate via transdifferentiation from either epithelial mesenchymal or pleural mesothelial cells.⁴⁰

Transforming growth factor-β (TGF-β) promotes fibroblast migration, proliferation, and activation in the heart and lungs.⁴¹ In cardiac tissue following an infarct, TGF-β is responsible for myofibroblast differentiation which activates signaling leading to ECM production.³² In the lungs, TGF-β is responsible for epithethial-mesenchymal transdifferentiation and maturation of myofibroblasts and inhibits fibroblast apoptosis resulting in excessive scar formation.^42–44 Therapeutically targeting TGF-β is not practical given its critical role in immunity and tissue healing.

PDGF, similar to TGF-β, has a role in fibroblast migration, activation, and proliferation.⁴¹ In the heart, the downstream effects of PDGF are mediated primarily through interactions with PDGF receptors α and β. Activation of PDGFR-α and -β results in increased cardiac fibrosis through collagen deposition, leading to myocardial hypertrophy and vascular maturation, respectively,^45,46 whereas inhibition of PDGFR-α reduces the amount of collagen deposited at the site of infarct injury.⁴⁵ In pulmonary fibrosis, PDGF expression is increased in epithelium, macrophages, and fibroblasts of fibrotic lung tissue.⁴²

The renin-angiotensin system (RAS) is a well-known regulator of cardiac fibrosis through angiotensin II which increases fibroblast activation leading to collagen production, resulting in cardiac hypertrophy.⁴⁷ Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been shown to improve cardiac function in patients with hypertension and/or HF.⁴⁸ The role of the RAS system in IPF is less well understood. Experimental models of pulmonary fibrosis have shown attenuation of fibrosis through inhibition of the RAS system.⁴⁹ However, the effect in human subjects has been less clear, with studies limited by small sample size and retrospective design.^50,51 The RAS and TGF-β pathways work in a reciprocal manner. Angiotensinogen is stimulated by TGF-β, and angiotensin II upregulates TGF-β expression.⁵² Therefore, at least conceptually, this could be an attractive target pathway for further investigation and intervention.

The extracellular matrix is significantly increased in size in fibrosis due to an accumulation of collagens I and III.⁵³ Two modulators of ECM are matrix metalloproteinases and their inhibitors (TIMPs). Of the 26 matrix metalloproteinases identified, 8 have been identified as contributing to both cardiac fibrosis and IPF.^54,55 Less is understood about the role of TIMPs in fibrosis. Initial studies implicated them in the accumulation of fibrosis in IPF.⁵⁶ Similarly, in cardiac fibrosis, an adenovirus-mediated response leading to myofibroblast differentiation has been reported secondary to overexpression of TIMP-1, −2, −3, and −4.⁵⁷

Clinical perspectives

Medical therapy

Most patients with IPF will die from respiratory failure, whereas 20% will die from a nonpulmonary cause, most commonly CVD or lung cancer.^1,58 In 2014, pirfenidone and nintedanib were the first approved medical therapies for the treatment of IPF. Termed antifibrotics, these drugs, although not curative, have each demonstrated a significant reduction in the annual rate of lung function decline.³⁰ Furthermore, through combined pooled analysis, nintedanib has shown a significant reduction in the risk for exacerbation, and pirfenidone has suggested a possible benefit in mortality.^59,60 Pirfenidone works by inhibiting TGF-β–related collagen synthesis, decreases ECM, and blocks fibroblast proliferation.⁶¹ Nintedanib acts by inhibiting multiple tyrosine kinase inhibitors which block downstream production of fibrogenic growth factors.⁶² Initiation of antifibrotic therapy is recommended in patients with mild to moderate IPF.

Cardiotoxicity

Adverse cardiac events were similar between the nintedanib and placebo groups; however, there were a higher number of myocardial infarctions observed in the nintedanib arm compared to placebo.⁶³ The reason for this is not well understood. Furthermore, through its interactions with P-glycoprotein and CYP3A4, nintedanib may increase risk for bleeding; therefore, caution should be taken when using in combination with anticoagulation. By comparison, a long-term study of pirfenidone showed no associated cardiac adverse effects.⁶⁴

Translational outlook

Medical therapy for HF is more advanced compared to the therapeutic options in IPF considering the diverse array of medication classes with proven efficacy in the former. However, with that being said, currently, there are no approved therapies which target cardiac fibrosis directly. Fortunately, early preclinical studies have shown promise toward this important next frontier. In animal models, pirfenidone has suggested a beneficial effect on myocardial infarction, dysrhythmias, and diabetic cardiomyopathy.^65–67 The proposed mechanism for benefit is through a reduction in myocardial fibrosis and through stimulation of L-type voltage-gated calcium channels which are essential in systolic function.⁶⁷ Pirfenidone is currently under investigation in a phase II clinical trial, PIROUETTE. This trial is evaluating the safety and efficacy of pirfenidone for the treatment of HF with preserved ejection fraction over 52 weeks.⁶⁸ The drug pipeline carries potential beyond repurposing existing antifibrotic agents. Aghajanian et al demonstrated in mice that, following treatment with engineered T cells, injured myocardium could undergo a reduction in cardiac fibrosis and restoration of function.⁶⁹ These investigations into the use of antifibrotics and immunotherapy targeting cardiac fibrosis directly are promising future therapeutic avenues. These examples highlight how advancements in therapies which target fibrosis could have a broad range of therapeutic targets including IPF and HF.

Future research agenda

Despite IPF being a rare disease, IPF registries have become increasingly more common with at least 20 registries now established worldwide.⁷⁰ Similar to registries in CVD, these registries serve a complimentary role to clinical trials. As opposed to clinical trials, registries have the following advantages: (1) enrollment of a more heterogeneous population in terms of severity and comorbidities, (2) longer longitudinal follow-up, and (3) biospecimen banking.⁷⁰ The incidence of IPF is likely to only increase as (1) the population ages and (2) disease-related IPF survival improves. Thus, CVD-related outcomes in IPF will become increasingly more important to overall outcomes and specifically CVD outcomes as they relate to new therapeutic agents. With this in mind, it will be important for IPF registries to continue to capture comorbidities and assess CVD-related disease events at follow-up. Furthermore, considering the overlap between fibrotic mediators responsible for the development of CVD and IPF, biobanked specimens could be a promising opportunity for future research and drug development in cardiopulmonary fibrosis. Biobanked specimens in combination with longitudinal clinical data could be leveraged to identify biomarkers associated with disease progression, prognosis, and therapeutic response.

Conclusion

Cardiovascular clinicians are well positioned to en-counter undiagnosed IPF considering the prevalence of CVD in this population and common risk factors. Once suspected, early referral to an interstitial lung disease specialist for diagnosis and treatment could improve survival. Cardiac and pulmonary fibrosis share many common cellular pathways. Thus, it will be important for disease registries to consider the potential magnitude of collaboration across disease specialties. Currently, we are in the infancy of the antifibrotic era; with further development of registries in combination with novel immunotherapy research, we stand to make great progress toward improving outcomes in fibrosis-related cardiopulmonary disease.