Categories
Biomedical Research

Pirfenidone: Using Lung Medicine to Treat Heart Failure

Recent research on the use of pirfenidone suggests it may be suitable for treatment in patients with heart failure. The drug is already approved for treating idiopathic pulmonary fibrosis and has shown some promising results in the reduction of myocardial fibrosis in patients with a preserved left ventricular ejection fraction, potentially providing a new approach to treating heart failure.

By Adaora Belonwu

Published 8:22 EST, Tues October 19th, 2021

INTRO

Dilated cardiomyopathy refers to a disease of the heart muscle where heart ventricles (usually starting in the left ventricle) become enlarged and can no longer pump blood efficiently. This can have a knock-on effect on the valves’ ability to close, increasing the risk of backflow and exacerbating the poor blood flow, ultimately leading to heart failure. Currently, more than 900,000 people in the UK are living with heart failure.

Prior to 2013, the risk stratification of patients with non-ischemic dilated cardiomyopathy was primarily based on left ventricular ejection fraction (LV EF). However, during that year, researchers from JAMA reported that myocardial fibrosis (MF, defined as a myocardial extracellular volume of 27% or greater) detected by late gadolinium enhancement cardiovascular MRI is an independent and incremental predictor of mortality and sudden cardiac death in patients with cardiomyopathy. They prospectively studied 472 patients with dilated cardiomyopathy and looked at all-cause mortality as well as many secondary endpoints. Their findings were that midwall fibrosis was an important prognosticator. The presence of fibrosis and the extent were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation. The addition of fibrosis to ejection fraction significantly improved risk reclassification for all-cause mortality and sudden cardiac death. Thus assessment of mid-wall fibrosis by late gadolinium enhancement cardiac MRI provided independent prognostic information beyond ejection fraction in patients with non-ischemic cardiomyopathy, allowing better risk stratification of heart failure. 

PIRFENIDONE’S BACKGROUND IN ANTIFIBROTIC THERAPY

Pirfenidone is an approved oral antifibrotic therapy that is used to slow disease progression in patients suffering from idiopathic pulmonary fibrosis (IPF). IPF is known to be linked to increased fibroblast proliferation, excess collagen synthesis, inflammation, and increased concentration of reactive oxygen species. These all contribute to the scarring of lung tissue and the progression of IPF. Pirfenidone has anti-fibrogenic, anti-inflammatory, and anti-oxidative properties as a result of limiting the production of TGF-beta, IL-6 cytokines and TNF-alpha, whilst also eliminating hydroxyl radicals. The property that is most important in pirfenidone’s ability to be used to reduce myocardial fibrosis is its ability to inhibit the synthesis and secretion of fibrogenic molecules such as TGF-beta and TNF-alpha. This thus prevents the proliferation of fibroblasts and collagen, demonstrated through various in vitro and rodent models. 

ANALYSIS OF RESEARCH AND STUDY

The PIROUETTE trial was headed by Chris Miller MD a cardiologist at Manchester University NHS Foundation and clinical research scientist based in Manchester University. The phase 2 double-blind trial selected a group of heart failure patients with an ejection fraction of at least 45% and elevated natriuretic peptides. Subsequently, they received cardiac MRIs, and those who provided evidence of myocardial fibrosis were randomly assigned a 52-week course of either pirfenidone or placebo. At the end of the 52 weeks, the second round of cardiac MRIs showed a statistically significant mean reduction in myocardial extracellular volume by 1.21%. However, investigations into a possible association between the regression of fibrosis and improvements in quality-of-life and 6-minute walk distance were not statistically significant. 

According to Miller, the phase 2 trial was the “first study to show the efficacy of an antifibrotic intervention in heart failure and the reduction in natriuretic peptide levels. The latter was shown with pirfenidone which provides support for myocardial fibrosis having a causal role in heart failure and being an efficacious therapeutic target.”

Figure 1: an infographic summarising some physiological effects of natriuretic peptides. Natriuretic peptides are hormones mainly secreted from the heart that cause the excretion of an excessively large amount of sodium in the urine. High levels of natriuretic peptides are usually in response to heart failure

Adverse effects of prolonged pirfenidone use include gastrointestinal problems ( e.g nausea, dyspepsia, and vomiting), rashes, and hepatic toxicity. Thus further research may be necessary to find TGF-beta pathway targets that are safer for MF reduction.

CONCLUSION 

Heart failure with preserved ejection fraction accounts for up to half of all heart failure cases. Observational data suggests that myocardial fibrosis is an important disease process for heart failure prognosis, and preclinical studies have indicated that the extracellular matrix may have a primary role in the development of heart failure. Thus pirfenidone’s ability to target TGF-beta and therefore the extracellular matrix marks a novel approach to treating heart failure, potentially bettering the lives of nearly millions worldwide.

Adaora Belonwu, Youth Medical Journal 2021

REFERENCES

Díez, Javier, et al. “Myocardial Interstitial Fibrosis in Nonischemic Heart Disease, Part 3/4.” Journal of the American College of Cardiology, vol. 75, no. 17, 2020, pp. 2204–2218., doi:10.1016/j.jacc.2020.03.019.

“Facts and Figures.” BHF, http://www.bhf.org.uk/what-we-do/news-from-the-bhf/contact-the-press-office/facts-and-figures.

Gomer, Richard, et al. “Pirfenidone Treatment of Idiopathic Pulmonary Fibrosis.” Therapeutics and Clinical Risk Management, 2011, p. 39., doi:10.2147/tcrm.s12209.

Gondek, Agata, et al. “Relevance of the Assessment of Natriuretic Peptide Plasma Concentrations in Hypertensive Pregnant Women.” Biomarkers, vol. 25, no. 6, 2020, pp. 449–457., doi:10.1080/1354750x.2020.1795264.

González, Arantxa, et al. “The Complex Dynamics of Myocardial Interstitial Fibrosis in Heart Failure. Focus on Collagen Cross-Linking.” Biochimica Et Biophysica Acta (BBA) – Molecular Cell Research, vol. 1866, no. 9, 2019, pp. 1421–1432., doi:10.1016/j.bbamcr.2019.06.001.

Graziani, Francesca, et al. “Rationale for the Use of Pirfenidone in Heart Failure With Preserved Ejection Fraction.” Frontiers in Cardiovascular Medicine, vol. 8, 2021, doi:10.3389/fcvm.2021.678530.

Hilberg, Ole, et al. “Pirfenidone: Significant Treatment Effects in Idiopathic Pulmonary Fibrosis.” The Clinical Respiratory Journal, vol. 6, no. 3, 2012, pp. 131–143., doi:10.1111/j.1752-699x.2012.00302.x.

Hilberg, Ole, et al. “Pirfenidone: Significant Treatment Effects in Idiopathic Pulmonary Fibrosis.” The Clinical Respiratory Journal, vol. 6, no. 3, 2012, pp. 131–143., doi:10.1111/j.1752-699x.2012.00302.x.

Hughes, Sue. “New Approach to Heart Failure Targets Myocardial Fibrosis.” Medscape, Medscape, 21 May 2021, http://www.medscape.com/viewarticle/951627.“Medical Definition of Natriuretic Peptide.” MedicineNet, MedicineNet, 29 Mar. 2021, http://www.medicinenet.com/natriuretic_peptide/definition.htm#:~:text=Natriuretic peptide: One of the,myocardium in response to dilatation.

By Adaora Belonwu

Adaora Belonwu is a student at St Michael's Catholic Grammar School in London. Currently she is interested in the fields of embryology, immunology and regenerative medicine.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s