REVIEW Treatment Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond Alberto Aimo ,1,2 Giosafat Spitaleri ,3 Dario Nieri,4 Laura Maria Tavanti,4 Claudia Meschi,5 Giorgia Panichella,1 Josep Lupón ,3,6,7 Francesco Pistelli ,4 Laura Carrozzi,4,5 Antoni Bayes-Genis 3,6 and Michele Emdin 1,2 1. Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy; 2. Fondazione Toscana Gabriele Monasterio, Pisa, Italy; 3. Heart Failure Clinic and Cardiology Service, University Hospital Germans Trias i Pujol, Badalona, Spain; 4. Pulmonary Unit, Cardiothoracic and Vascular Department, Pisa University Hospital, Pisa, Italy; 5. Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy; 6. Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; 7. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain Abstract Pirfenidone (PFD) slows the progression of idiopathic pulmonary fibrosis (IPF) by inhibiting the exaggerated fibrotic response and possibly through additional mechanisms, such as anti-inflammatory effects. PFD has also been evaluated in other fibrosing lung diseases. Myocardial fibrosis is a common feature of several heart diseases and the progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. No primarily antifibrotic medications are used to treat patients with heart failure. There is some evidence that PFD has antifibrotic actions in various animal models of cardiac disease and a phase II trial on patients with heart failure and preserved ejection fraction has yielded positive results. This review summarises the evidence about the possible mechanisms of IPF and modulation by PFD, the main results about IPF or non-IPF interstitial pneumonias and also data about PFD as a potential protective cardiac drug. Keywords Pirfenidone, idiopathic pulmonary fibrosis, lung, heart, animal models, clinical trials Disclosure: The authors have no conflicts of interest to declare. Received: 28 October 2021 Accepted: 15 February 2022 Citation: Cardiac Failure Review 2022;8:e12. DOI: https://doi.org/10.15420/cfr.2021.30 Correspondence: Alberto Aimo, Scuola Superiore Sant’Anna and Fondazione Toscana Gabriele Monasterio, Piazza Martiri della Libertà 33, 56124, Pisa, Italy. E: a.aimo@santannapisa.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly. Pirfenidone (PFD) is an oral drug with antifibrotic properties.1 Its modes of with transforming growth factor-β (TGF-β) signalling and other growth action are not completely understood.2 The first results from studies using factors, such as platelet-derived growth factor (PDGF) and basic fibroblast animal models support to the use of PFD in lung diseases primarily growth factor.12,13 PFD also upregulates several matrix metalloproteinases characterised by progressive fibrosis, and PFD is currently one of the two (MMPs) that attenuate extracellular matrix (ECM) accumulation.14 PFD also conditionally recommended drugs for the treatment of idiopathic modulates acute inflammation by reducing the expression of inflammatory pulmonary fibrosis (IPF).3,4 IPF is the most common and by far the most cytokines, most notably tumour necrosis factor (TNF)-α, interleukin (IL)-4 aggressive type of the idiopathic interstitial pneumonias, being associated and IL-13, and by inhibiting the formation of the nucleotide-binding with a severe prognosis with a median survival of 2–5 years for patients oligomerisation domain (NOD)-like receptor pyrin domain containing 3 not receiving antifibrotic drugs.5,6 PFD has been recently evaluated in (NLRP3) inflammasome, a protein complex responsible for the recognition fibrosing lung diseases other than IPF, such as unclassifiable progressive of stress signals and involved in the onset and maintenance of fibrosing interstitial lung disease, and is under investigation for other inflammatory responses.10,15 Finally, PFD may modulate the activity and interstitial pneumonias.7–9 It has also been regarded with interest as a proliferation of both T and B lymphocytes.10 possible treatment for cardiac disorders where fibrosis plays an important pathogenetic role, such as heart failure with preserved ejection fraction Idiopathic Pulmonary Fibrosis: (HFpEF). This review provides an update on current and possible novel Possible Disease Mechanisms applications of pirfenidone. The exact pathogenesis of IPF is still unknown, but its histopathological hallmarks have been well identified. This condition is characterised by Pharmacokynetics and Pharmacodynamics areas of fibrosis alternating with relatively spared zones, honeycombing, PFD is a small synthetic molecule rapidly absorbed in the gastrointestinal and architectural distortion.16 Repeated microinjuries combined with an tract, with a half-life of about 3 hours.10,11 It is metabolised in the liver, inability of alveolar epithelium to effectively repair wounds and epigenetic mainly by cytochrome P450, and mostly excreted as the metabolite alterations lead to an aberrant activation of alveolar endothelial cells, 5-carboxy-pirfenidone, either through the urine (80%) or in faeces (20%). which produce many profibrotic growth factors, chemokines, MMPs and PFD inhibits fibroblast proliferation and collagen synthesis by interfering procoagulant factors (such as tissue factor, activated factor VII, factor X © RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com Pirfenidone for Lung and Cardiac Disorders and thrombin), all inducing the proliferation of fibroblasts and their sensitisation with an allergen.21,31,32 Another study has demonstrated that differentiation into myofibroblasts. These last cells play a key role in the PFD could reduce the production of proinflammatory cytokines by abnormal wound healing process, causing an exaggerated production of inhibiting p38 MAPK in B lymphocytes, thus representing a novel potential ECM, tissue scarring and irreversible lung fibrosis.17,18 mechanism of action of PFD in lung fibrosis, since the inflammatory milieu induced by B-cell-derived cytokines can cause the activation and TGF-β is probably the most important factor in IPF as it stimulates alveolar migration of fibroblasts.33 endothelial cells and fibroblasts, also through several microRNAs (miRNAs).19 Moreover, extracellular vesicles (small vesicles released by Clinical Trials on Pirfenidone for the Treatment virtually all eukaryotic cells upon different stimuli and which can transport of Idiopathic Pulmonary Fibrosis miRNAs), play an active role in intercellular communication, promoting the In 1999, Raghu et al. conducted the first open-label study to evaluate the fibrotic response.20 Finally, some cells belonging to both innate and efficacy and safety of PFD for patients with IPF.34 An open-label treatment adaptive immune systems, such as dendritic cells, monocytes/ was administered in terminally ill patients who had failed or not tolerated macrophages, T and B lymphocytes, with their associated cytokines, can conventional therapy. The mortality observed was 22% at 1 year and 37% still play a role in IPF pathogenesis.21 at 2 years, and PFD arrested the further decline of lung function in most patients. The drug was well tolerated with minimal side-effects that Pirfenidone in the Treatment of Idiopathic disappeared after it was discontinued or its dosage was decreased.34 Pulmonary Fibrosis: Possible Mechanisms Antifibrotic Effects A second open-label study was conducted in 2002 in patients with Iyer et al. reported a protective effect of oral PFD towards bleomycin- advanced IPF.35 Over 1 year of treatment, the deterioration in terms of induced lung fibrosis.1 Although bleomycin-induced fibrosis does not chest radiographic scores, pulmonary function and arterial blood oxygen represent an accurate model of IPF, this was the first demonstration of partial pressure (PaO2) appeared to stabilise, but survival was not potential antifibrotic activity of PFD in vivo. PFD was shown to effectively significantly prolonged, probably because of the short treatment duration. inhibit fibronectin and the production of α-smooth muscle actin (α-SMA) As in the previous study, PFD was well tolerated.35 which is an important factor in fibroblast-to-myofibroblast transition, by human lung fibroblasts, when incubated with TGF-β. PFD also suppressed In 2005 a double-blind, placebo-controlled, randomised, phase II trial fibrotic changes, mediated by TGF-β, in human fetal lung fibroblasts.22,23 tested the efficacy of PFD at a maximum dose of 1,800 mg/day in 107 Another study confirmed that PFD reduced TGF-β-mediated α-SMA patients with IPF.36 The primary endpoint – the change in the lowest production by primary human lung fibroblasts and it effectively impaired oxygen desaturation (SpO2) during a 6-minute walking test (6MWT) – did phosphorylation of SMAD3 and phospho-p38 mitogen-activated protein not reach statistical significance (p=0.072), but PFD treatment kinase (p38 MAPK), two key effectors in the downstream of TGF-β demonstrated its efficacy in a few secondary endpoints, showing a signalling, thus providing a possible explanation for PFD antifibrotic significantly smaller decline in vital capacity (VC) (p=0.037) and preventing effects in IPF.24 PFD can also act on heat shock proteins (HSP) and collagen acute exacerbation of IPF at 9 months (p=0.003). The trial was prematurely overproduction. Indeed, PFD significantly inhibited HSP-47 and collagen I stopped due to an excess of acute IPF exacerbations in the placebo mRNA expression in a human type II alveolar epithelial cell line stimulated group. Treatment with PFD was associated with more adverse events, not by TGF-β; moreover, cellular expression of fibronectin was reduced after affecting the adherence to treatment. pre-treatment with PFD.25 PFD has also been shown to be able to inhibit collagen fibril formation and assembly as well as inhibiting both PDGF and In 2010, a phase III trial evaluated high doses (1,800 mg/day) and low basic fibroblast growth factor, thus influencing myofibroblast differentiation doses (1,200 mg/day) of PFD in 275 patients with IPF.37 This trial or collagen I overproduction.26–28 demonstrated the efficacy of high-dose PFD treatment in slowing down VC deterioration (−90 ml versus −160 ml; p=0.042) and increasing the Overall, these data show some potentially relevant mechanisms for the progression-free survival time (p=0.028) over 1 year. A lower but significant antifibrotic action of PFD, mainly focused on the inhibition of the TGF-β difference in VC decline was also seen in the PFD low-dose group pathway. (p=0.039). No statistically significant difference was detected in the mean change of the lowest SpO2 during a 6MWT. The incidence of adverse Anti-inflammatory Effects events was higher in the PFD treatment groups, without differences in In a study using an orthotopic mouse lung transplant model, PFD treatment treatment discontinuation. suppressed the activation of dendritic cells (DCs), which present antigens to T-cells, by several mechanisms including a PFD-mediated reduced Two Phase III international randomised double-blind placebo trials response to Toll-like receptors agonists, PFD significantly reduced the (CAPACITY 004 and CAPACITY 006), involving 779 patients with IPF, were production of several cytokines and chemokines, such as CCL2, TNF-α, performed in North America, Europe and Australia.38 The primary endpoint CCL12 and IL-10, from stimulated DCs in vitro.29 In another study, PFD of both studies was the change in percentage predicted forced vital blunted T-cell proliferation and production of inflammatory cytokines.30 capacity (FVC%pred) from baseline to week 72. The CAPACITY 004 study PFD has been shown to reduce the polarisation of alveolar macrophages included 435 patients treated with high-dose PFD (2,403 mg/day), low- (AMs) towards the M2 phenotype in rats; since M2-type AMs have dose PFD (1,197 mg/day) or placebo while the CAPACITY 006 study profibrotic properties, mainly by secreting cytokines able to promote included 344 patients treated with exclusively high-dose PFD or placebo. fibroblast proliferation, these findings could support a possible alternative mode of action for PFD. The CAPACITY 004 trial showed a significant difference in FVC%pred from baseline over 72 weeks between high-dose PFD and the placebo arm In another murine model, PFD reduced airway responsiveness, (−8% versus −12.4%; p=0.001). In the low-dose PFD group the mean inflammatory cytokines and cells in the bronchoalveolar fluid after pre- change in FVC%pred was intermediate to that in the high-dose PFD and CARDIAC FAILURE REVIEW www.CFRjournal.com Pirfenidone for Lung and Cardiac Disorders placebo groups. The high-dose PFD group also showed a positive result such as rheumatoid arthritis associated with ILD and systemic sclerosis against placebo in terms of prolongation of progression-free survival. associated with ILD (SSc-ILD), as well as in unclassifiable fibrosing ILDs. Instead, the CAPACITY 006 study recorded a significant difference in reduction in FVC%pred rate of decline up to week 48 in PFD group In 2016, the LOTUSS study evaluated the safety profile of PFD in patients (p=0.005), but this difference was not maintained to week 72 (p=0.501). with SSc-ILD, demonstrating an acceptable tolerability profile that No significant effect was reported on progression-free survival, but high- improved as titration time increased.46 In 2020, Acharya et al. published a dose PFD significantly reduced decline in 6MWT distance at week 72. The double-blind, randomised, placebo-controlled pilot study, where 34 adverse effects, mainly gastrointestinal and skin-related events, were subjects with SSc-ILD and an FVC%pred of 50–80% were randomised 1:1 generally mild to moderate in severity, without any significant clinical to receive PFD (2,400 mg/day) or placebo for 6 months. Stabilisation/ consequence or reduction in therapy adherence. improvement in FVC was observed in 94% and 77% subjects in the PFD and placebo groups, respectively (p=0.33). The changes in FVC%pred, Since the CAPACITY 006 study failed to meet its primary endpoint, another 6MWD, dyspnoea scores, modified Rodnan skin score (MRSS), and TNF-α randomised, double-blind, placebo-controlled Phase III trial was and TGF-β levels did not differ significantly.47 requested by US regulatory authorities, which was performed in 2014 to support the approval of PFD for IPF treatment.39 In the ASCEND trial, 555 Among chronic fibrosing ILDs, chronic hypersensitivity pneumonitis may patients with IPF were randomly assigned to receive PFD (2,403 mg/day) represent a diagnostic challenge with respect to IPF and its incidence is or placebo over 1 year. The PFD group showed a 50% reduction compared probably underestimated.48 An open-label study evaluated the efficacy with the placebo group (17% versus 32%, respectively) in primary endpoint, and safety of PFD associated with prednisone and azathioprine with 22 which was a decline of at least 10% of the FVC%pred or death at week 52 people with chronic hypersensitivity pneumonitis enrolled and divided compared to baseline. Furthermore, the proportion of patients with no into two groups: 9 patients received only prednisone and azathioprine decline in FVC increased by 133% in the PFD group (p<0.001). PFD-treated and the remaining 13 received combining PFD with prednisone and patients also displayed a relative reduction of 28% (p=0.04) in the decline azathioprine. After 1 year of treatment, patients in the PFD arm did not of the 6MWT distance and a 43% longer progression-free survival show a significant improvement in FVC but they did have an improved (p<0.001). Gastrointestinal and skin-related side-effects were more quality of life with an acceptable safety profile.49 common in the PFD group, but rarely caused discontinuation.39 PFD has also been proposed in the treatment of COVID-19, both for the In a pre-specified analysis of the pooled population of CAPACITY and acute phase and the fibrotic sequelae.50 Four clinical trials on PFD and ASCEND trials (1,247 patients), PFD significantly reduced the relative risk COVID-19 are currently recruiting new patients (NCT04653831, of all-cause mortality at 1 year by 48% (p<0.01) and the risk of IPF-related NCT04607928, NCT04856111 and NCT04282902). mortality at 1 year by 68% (p=0.006).40 Similarly, treatment with PFD at 2,403 mg/day reduced the proportion of patients with a decline of 10 Fibrosis in Cardiac Disease percentage points or more in the FVC%pred or death by 44% and Myocardial fibrosis is a common pathophysiological process in most heart increased the proportion of patients with no lung function decline by 59%. diseases, defined as an excess of ECM deposition by cardiac fibroblasts.51 PFD efficacy seemed to be independent of baseline disease severity.40,41 The activation of profibrotic pathways is a compensatory mechanism in response to myocardial damage and necrosis. Nonetheless, excessive Even if the inclusion criteria for clinical trials do not necessarily reflect ECM deposition may trigger a vicious cycle eventually leading to heart real-world patients and practices, emerging real-world data has shown failure (HF).52 Fibrosis can be divided into two distinct forms: reparative or that the tolerability and the overall efficacy of PFD on reducing FVC replacement fibrosis and reactive or interstitial fibrosis.53 While the first is decline in patients with IPF were consistent with findings from the clinical generally observed in the development of an organised fibrotic scar after trials.42–44 MI, the latter is a typically perivascular or interstitial fibrosis, as part of progressive pathological cardiac remodelling.53 Although the Pirfenidone and Progressive Fibrosing pathophysiological mechanisms leading to fibrotic remodelling differ Interstitial Lung Diseases according to the underlying disease, the cellular effectors are shared. Diffuse interstitial lung diseases (ILDs) represent a large heterogeneous Cardiomyocyte death or injurious stimuli, such as inflammation, often group of rare pulmonary disorders. ILDs arise from a large spectrum of trigger fibrosis.54 distinctive aetiologies. They can be a pulmonary complication of connective tissue disease, such as rheumatoid arthritis, systemic sclerosis Activation and conversion of fibroblasts into myofibroblasts are crucial and polymyositis, or result from the exposure to environmental antigens, points. The ECM proteins produced by myofibroblasts, such as collagens, such as chronic hypersensitivity pneumonitis, or through occupational glycoproteins and proteoglycans, offer local mechanical support to the exposure, such as asbestosis, or due to unknown cause, such as idiopathic failing heart in a multi-step process involving the degradation of damaged interstitial pneumonia and sarcoidosis.5 A variable proportion of patients existing ECM, and the production, secretion and maturation of new ECM.53 with ILDs may have clinical features similar to IPF characterised by the Monocytes, macrophages, lymphocytes, mast cells, vascular cells and decline of lung function, worsening of respiratory symptoms and health- cardiomyocytes may also contribute to the fibrotic response by secreting related quality of life and higher mortality. In this case, they are termed profibrotic factors, such as inflammatory cytokines and chemokines, progressive fibrosing ILDs or fibrosing ILDs with a progressive reactive oxygen species, proteases, endothelin-1, the renin–angiotensin– phenotype.45 aldosterone system (RAAS), and matrix proteins, such as TGF-β and PDGF.54 Pharmacological studies with antifibrotic drugs have been conducted in patients with progressive fibrosing ILDs; both PFD and nintedanib have Following MI, the necrosis of cardiomyocytes triggers an inflammatory been used in fibrosing diseases secondary to connective tissue diseases, reaction, ultimately leading to replacement of dead myocardium with a CARDIAC FAILURE REVIEW www.CFRjournal.com Pirfenidone for Lung and Cardiac Disorders Figure 1: Cardiac Protective Effects of Pirfenidone Pirfenidone N O Inflammation Myocardial fibrosis Oxidative stress Pressure overload Diabetes Anthracyclines Atrial fibrillation Duchenne muscular dystrophy ↑ NLRP3 inflammasome ↑ TGF-β ↑ Lipid peroxidation ↑ TGF-β Myocyte degeneration formation ↑ Fibronectin ↑ Hydroxyproline production ↑ TNF-α ↑ TGF-β ↑ Vascular permeability ↑ Perivascular and interstitial Disorganisation of myofibrils ↑ MMP-9 ↑ Deposition of collagenous ↑ Probiotic factors (TGF-β) collagen deposition and vacuolistion of the ↓ LTCC expression extracellular matrix myofibers LTCC = L-type calcium channel; MMP-9 = matrix metalloproteinase 9; NLRP3 = NLR family pyrin domain containing 3; TGF-β = transforming growth factor-β; TNF-α = tumour necrosis factor-α. reparative fibrotic scar.54,55 Ageing is associated with progressive fibrosis proliferation and fibrotic tissue deposition in pressure-overloaded rats.64 that may contribute to the development of increased wall stress, and Additionally, inflammatory cells are found in the perivascular spaces of diastolic and systolic ventricular dysfunction.56,57 Pressure overload- hypertensive hearts, suggesting that pressure overload might trigger an related fibrosis, caused by hypertension or aortic stenosis, is progressively inflammatory response through inflammatory chemokines, such as associated with increased stiffness, diastolic dysfunction, ventricular monocyte chemoattractant protein-1, followed by reactive fibrosis.62 dilation and HF.58 Volume overload due to valvular regurgitant lesions may also result in cardiac fibrosis.54 Chronic mitral regurgitation can result in Multiple studies have shown that PFD might reduce vascular permeability left atrial enlargement and atrial fibrotic remodelling, which is one of the in the acute phase and reduce the development of chronic fibrosis in fundamental causes of persistent AF.59 pressure-overloaded hearts.15,65–67 Wang et al. investigated PFD in a mouse model of hypertensive left ventricular (LV) remodelling induced by Pirfenidone as a Possible Cardiac Protective Drug transverse aortic constriction.15 They demonstrated that PFD attenuated As myocardial fibrosis is a key mechanism in the development of structural myocardial fibrosis by inhibiting inflammation and fibrosis caused by and functional cardiac alterations, therapeutic strategies targeting this NLRP3, a protein induced by pressure overload and involved in NLRP3 process are becoming increasingly important. The heart diseases that will inflammasome formation. Furthermore, mice treated with PFD showed a benefit most from anti-fibrotic therapies are the same where fibrosis plays higher survival rate compared with the control group.15 a major pathogenic role, such as MI, AF and HF. A notable example is HFpEF. Following the systematic failure of trials on neurohormonal PFD was also studied in a rat model of hypertensive cardiomyopathy antagonists, researchers’ attention has shifted to the phenotypic induced by unilateral nephrectomy followed by administration of salt and heterogeneity of HFpEF, with the ultimate goal of developing therapies deoxycorticosterone acetate. Treatment with PFD for 2 weeks prevented tailored on individual patient phenotypes.60 The new HFpEF paradigm cardiac remodelling by attenuating LV hypertrophy and reducing diastolic states that coronary microvascular inflammation and myocardial fibrosis stiffness without lowering systolic blood pressure or reversing the can be considered the central theme in the HFpEF conundrum, and increased vascular responses to norepinephrine.65 antifibrotic drugs, such as PFD, may be effective tools in blocking this pathological mechanism.61 Similarly, PFD administration in a mouse model of cardiac hypertrophy induced by angiotensin II infusion reduced LV hypertrophy and inhibited The following section summarises evidence about PFD’s antifibrotic perivascular and interstitial tissue fibrosis.67 PFD reduced the expression activity in various animal models of cardiac disease, including pressure of atrial and B-type natriuretic peptides, which are closely related to overload, diabetes and anthracycline-induced cardiomyopathies, MI, AF cardiac hypertrophy, and the levels of TGF-β1 and monocyte and Duchenne muscular dystrophy (DMD; Figure 1). chemoattractant protein-1. Furthermore, PFD inhibited the expression of mineralocorticoid receptors, which implies it may prevent cardiac Cardiac Protection in Animal Models remodelling also by inhibiting the aldosterone signalling pathways.67 Pressure Overload Myocyte hypertrophy and myocardial fibrosis are two key mechanisms of Another study investigated the effects of PFD on cardiac fibrosis in a hypertensive cardiomyopathy. The increased deposition of collagen type pressure-overloaded HF mouse model, achieved by transverse aortic I and III by cardiac fibroblasts in hypertensive hearts allows the force constriction.66 PFD reduced TGFβ-induced collagen 1 expression and generated by hypertrophied myocytes to be transmitted to the entire increased the expression of claudin 5, a tight junction protein that ventricle.62 However, the excessive deposition of fibrotic tissue causes regulates vascular permeability. These effects resulted in reduced fibrosis increased myocardial stiffness and diastolic dysfunction.63 and reduced serum albumin leakage into the interstitial space. TGF-β plays a crucial role because its increased expression is associated The role of PFD in models of right ventricular (RV) pressure overload is with an increased synthesis of collagen type I and III. The administration controversial. PFD reduced RV fibrosis in a Sugen-hypoxia model of of an anti-TGF-β monoclonal antibody was reported to reduce fibroblast pulmonary hypertension.68 Conversely, Andersen et al. found that PFD did CARDIAC FAILURE REVIEW www.CFRjournal.com Pirfenidone for Lung and Cardiac Disorders Table 1: Results from Preclinical Studies Involving Pirfenidone for Lung and Cardiac Disorders Study Model Intervention Findings Miric et al. 200172 Rat model of STZ-induced diabetic PFD (200 mg/day) from week 4 to week 8 • PFD attenuated LV perivascular and interstitial collagen cardiomyopathy after STZ treatment deposition and diastolic stiffness increase induced by STZ • PFD did not normalise cardiac contractility Mirkovic et al. 200265 Rat model of hypertensive DOCA-salt or no further treatment for • PFD attenuated LV hypertrophy and reduced collagen deposition cardiomyopathy by single kidney 2 weeks and diastolic stiffness removal PFD (0.4% in powdered rat food) for further 2 weeks Giri et al. 200474 DXR-induced rat model of cardiac Saline + regular diet; DXR + regular diet; • PFD suppressed DXR-induced increases in hydroxyproline and renal toxicity saline + the same diet mixed with 0.6% PFD; content in the heart and kidney, lipid peroxidation of the kidney DXR + the same diet mixed with 0.6% PFD for and plasma and protein content of the urine 25 days • PFD minimised the DXR-induced histopathological changes of heart and kidney Lee et al. 200681 Dog model of congestive heart failure PFD (800 mg 3 times per day) for 3 weeks • PFD attenuated arrhythmogenic left atrial remodelling, left atrial fibrosis, AF duration • PFD reduced TGF-β, TNF-α and metalloproteinase-9 and increased TIMP-4 levels Van Erp et al. 200686 Dystrophin-deficient mdx mouse PFD for 7 months • PFD improved cardiac contractility and decreased TGF-β model of Duchenne muscular expression but did not reduce extracellular matrix deposition dystrophy Yamazaki et al. 201267 Mouse model of angiotensin PFD (300 mg/kg/day) for 2 weeks • PFD inhibited angiotensin II-induce LV hypertrophy, decreased II-induced cardiac hypertrophy heart weight, attenuated mRNA expression of ANP, BNP, TGF-β1 and mineralocorticoid receptors Wang et al. 201315 Mouse model of TAC-induced LV PFD (200 mg/kg) every 2 days from day 10 • PDF increased survival rate and reduced fibroblast proliferation hypertrophy after surgery and the expression of TGF-β1 and hydroxyproline • PFD attenuated myocardial inflammation by regulating the NLRP3 inflammasome-mediated IL-1β signalling pathway Yamagami et al. 201566 Mouse model of TAC-induced LV PFD (400 mg/kg) twice daily from week 4 to • PFD improved systolic function and suppressed LV dilation and hypertrophy week 8 after surgery fibrotic progression induced by pressure overload • PFD inhibited changes in the collagen 1 and CLDN5 expression levels resulting in reduced fibrosis and vascular permeability Andersen et al. 201969 Rat model of pressure overload RV PFD (700 mg/kg/day) for 6 weeks • PFD did not reduce RV fibrosis or improve RV haemodynamics failure by pulmonary trunk banding Poble et al. 201968 Sugen/hypoxia rat model of severe PFD (30 mg/kg/day) three times a day for • PFD reduced proliferation of pulmonary artery smooth cells and pulmonary hypertension 3 weeks extracellular matrix deposition in lungs and RV ANP = atrial natriuretic peptide; BNP = B-type natriuretic peptide; CLDN5 = claudin 5; DOCA = deoxycorticosterone acetate; DXR = doxorubicin; LV = left ventricle; PFD = pirfenidone; TAC = transverse aortic constriction; TGF-β = transforming growth factor-β; TNF-α = tumour necrosis factor-α; RV = right ventricle; STZ = stretpozocin. not reduce fibrosis or improve RV haemodynamics when the RV pressure and fibrosis.73 Giri et al. investigated the protective role of PFD in a rat overload was induced by pulmonary artery banding in a rat model.69 model of anthracycline-induced toxicity.74 PFD therapy attenuated the doxorubicin-induced increase in hydroxyproline content and the Diabetic and Anthracycline- histopathological changes in the heart characterised by disorganisation induced Cardiomyopathies and vacuolisation of cardiac myofibrils.74 Diabetic cardiomyopathy is characterised by structural and functional abnormalities, including systolic and diastolic dysfunction and LV MI hypertrophy.70 In this setting, cardiac fibrosis is partially due to increased Cardiac fibrosis is a primary event following MI, which impairs cardiac expression of TGF-β1 caused by RAAS activation, oxidative stress, function eventually leading to HF and may also act as a substrate for advanced glycation end-products, hyperglycaemia and hyperinsulinaemia, ventricular tachyarrhythmias.10,75,76 PFD therapy has shown to reduce although the specific mechanisms remain elusive.71 In a rat model of fibrosis in a rat model of post-MI remodelling.66 Treatment was started diabetic cardiomyopathy, streptozotocin administration promoted 1 week after ischaemia-reperfusion injury and continued for 4 weeks. interstitial collagen deposition in the kidney and the aorta, increased LV PFD-treated rats showed smaller infarct scars compared with controls, fibrosis and diastolic stiffness and reduced the maximum positive inotropic less total LV fibrosis, a reduced decline in LV ejection fraction (LVEF) and responses to norepinephrine and a calcium sensitiser in papillary lower rates of ventricular tachycardia inducibility.77 muscles.72 PFD treatment reversed cardiac and renal fibrosis and improved diastolic function but did not normalise cardiac contractility or In another rat model of MI, PFD administration by gavage for 4 weeks renal function.72 after permanent ligation of the left anterior descending artery reduced cardiac fibrosis and infarct size.75 The cardioprotective effects may be Cardiotoxicity is a well-recognised side-effect of several cancer therapies, due, in large part, to an inhibition of the angiotensin II type 1 receptor especially anthracyclines, which are associated with myocardial oedema (AT1R)/p38 MAPK/RAS axis through the activation of liver X receptor-α CARDIAC FAILURE REVIEW www.CFRjournal.com Pirfenidone for Lung and Cardiac Disorders (LXR-α).75 Similarly, in two different in vivo mice models of acute myocardial Evidence of Cardiac Protection injury (induced by diphtheria toxin and closed-chest ischaemia-reperfusion Two clinical studies have retrospectively examined the effects of PFD on injury), PFD attenuated LV remodelling and improved survival rates.78 echocardiographic parameters of LV function. In the first, PFD treatment Treatment with PFD had no effect on diphtheria toxin-induced did not improve parameters of LV structure, diastolic function, systolic cardiomyocyte cell death and the infiltration of neutrophils, monocytes or function and global longitudinal strain.87 In the second, PFD was macrophages, but decreased CD19+ lymphocytes. B-cell depletion associated with decreased indexed LV end diastolic and end systolic abrogated the beneficial effects of PFD. In vitro studies demonstrated that volumes, although no significant changes in LV diastolic, systolic function stimulation with lipopolysaccharide and extracts from necrotic cells and strain were observed.88 However, both studies included only IPF activated B lymphocytes and PFD blunted this activation; therefore, PFD patients and were limited by their small size and retrospective design. may also exert cardioprotective effects by modulating cardiac B lymphocytes.78 To date, only one randomised, double-blind, placebo-controlled trial included patients with a cardiac condition. The PIROUETTE phase 2 trial AF evaluated the safety and efficacy of a 52-week treatment with PFD in 94 Atrial interstitial fibrosis is a crucial element of structural and electrical patients with HFpEF (LVEF ≥45%) and myocardial fibrosis (defined as an remodelling, which plays a crucial role in the onset and perpetuation of ECM volume ≥27% measured by cardiac MRI [CMR]).89 At 52 weeks, the AF.79,80 Indeed, fibrosis prolongs conduction times, leading to the creation extracellular volume displayed an absolute decrease by 0.7% in the PFD of macro-reentrant circuits that increase susceptibility to AF and maintains group and an increase by 0.5% in the placebo group, with a between- AF.79 In a canine model of HF, PFD treatment reduced TGFβ, TNF-α and group difference that was very small (also considering the variability in MMP-9 levels and increased the levels of an endogenous cardio-specific extracellular volume measurements by CMR), but still achieved statistical inhibitor of MMP, tissue inhibitor of MMP 4 (TIMP-4).81 These changes significance (between-group difference −1.21%; 95% CI [−2.12 to −0.31]; reduced atrial remodelling and AF development.70 PFD could also prevent p=0.009). A limited but significant reduction in N-terminal pro-B-type AF by modulating the electrical properties of atrial tissue. Indeed, chronic natriuretic peptide values was also found. Conversely, no significant treatment with PFD increased the expression of L-type calcium channels differences in measures of diastolic function, 6MWT nor Kansas City in adult rat cardiomyocytes. These channels are typically downregulated Cardiomyopathy Questionnaire summary score values were observed.79 in AF; their increased expression by PFD prolongs both the action potential These findings suggested that PFD may be beneficial but further trials are duration and the refractory period, thus lowering the susceptibility to AF.82 needed to determine the clinical effectiveness and safety in a broader population. Duchenne Muscular Dystrophy DMD is a severe, progressive, muscle-wasting disease caused by Conclusion mutations in the DMD gene that abolish the expression of dystrophin in PFD is an antifibrotic drug mostly studied in lung models. Solid evidence the skeletal muscle. Patients with DMD often develop systolic and diastolic based on clinical trials and real-life studies shows that PFD improves the dysfunction and myocardial fibrosis, often progressing to clinical HF.83,84 outcomes of IPF, slowing down or blocking the decline of respiratory Indeed, dystrophin deficiency also causes cardiomyocyte degeneration function and improving survival. The therapeutic role of PFD in fibrosing and an increased deposition of ECM resulting in a progressive impairment ILDs, including SARS-CoV-2, is being evaluated. Furthermore, the of cardiac function.85 antifibrotic and anti-inflammatory activities of PFD provide a rationale for the evaluation of PFD for the treatment of chronic cardiovascular or renal Van Erp et al. randomised 36 dystrophin-deficient mice to PFD or placebo diseases where fibrosis plays a crucial role. Following some promising for 7 months. PFD reduced TGF-β expression and improved cardiac results in animal models of several disorders, a phase II trial has recently contractility, but did not cause a significant reduction in myocardial reported a beneficial effect of PFD in patients with HFpEF, though limited fibrosis.86 The beneficial effects of PFD in this setting might then derive to small changes in extracellular volume on repeated CMR scans.10 PFD from a reduced synthesis of inflammatory cytokines and less oxidative was well tolerated, confirming the good safety profile emerging from stress more than an antifibrotic effect. 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