Study of IPF, Cardiovascular Disease Suggests Complex Interplay

A new analysis attempting to find causal links between idiopathic pulmonary fibrosis (IPF) and cardiovascular disease has turned up limited direct connections, but a complex relationship.¹

The study, which was published in the Annals of Human Genetics, found that large artery atherosclerosis stroke has an apparent negative influence on the risk of IPF. However, the study found no other significant associations, suggesting the relationship between cardiovascular disease and IPF is “more complex” than previously thought.

The study may pave the way for further studies into the “intricate relationship” between IPF and cardiovascular disease, according to the authors. | Image credit: Vitalii Vodolazskyi - stock.adobe.com

Yongtong Cao, PhD, of the China-Japan Friendship Hospital, in China, wrote along with colleagues that decades of research has suggested people with IPF face a significant risk of certain cardiovascular diseases. A 1990 study, for instance, showed people with IPF had higher rates of death from ischemic heart disease.² A 2004 study found coronary artery disease is more common in people with fibrotic lung diseases.³ And a 2008 study suggested people with IPF had an increased risk of vascular disease.⁴ Yet, Cao and colleagues said the story told by such studies is incomplete.¹

“All the results demonstrated the link between IPF and CVD (cardiovascular disease), but the mechanism of the link isn’t clear,” they wrote.

Some investigators have posited that the links are due to the 2 disease categories having similar pathological features, Cao and colleagues said, while others have suggested the link is the result of the promotion of atherosclerosis by IPF.

The investigators decided to turn to Mendelian randomization, a method that uses genetic analysis to evaluate potential causation. They said the technique has not yet been used to study links between IPF and cardiovascular disease.

The authors took publicly available genome-wide association study data for more than 27,000 people, of whom 4561 had had IPF; the rest were controls. They then compared that data with datasets for patients with a number of cardiovascular diseases, including atrial fibrillation, coronary artery disease, and heart failure, among others. Those data were analyzed using the inverse variance-weighted, weighted median, and Mendelian randomization-Egger methods.

Those analyses identified limited connections.

The inverse variance-weighted analysis suggested that large artery atherosclerosis stroke had a negative impact on IPF risk, suggesting that IPF might have a protective role in stroke incidence. The weighted median analysis supported that inverse relationship.

Cao and colleagues said there is relatively little research into the association between IPF and large artery atherosclerosis stroke, but they said the available research suggests that “the reason may be the differences in inflammatory responses between IPF and large artery atherosclerosis stroke.”

They noted that people with IPF have higher levels of regulatory T cells, which can exert immune tolerance through direct and side-by-side inhibition.

“Although coronary atherosclerosis has inflammatory responses, it is mostly affected by local inflammation, and abnormalities in lipid metabolism are a major risk factor for coronary atherosclerosis, which may decipher the reason why there is no relationship between IPF and coronary atherosclerosis,” they wrote.

The authors said their study was based on data mostly collected in Europe, which may limit the generalizability of their findings. They added that additional research is necessary to validate the findings and potentially further elucidate the reasons behind the links.

In the meantime, they said their study “paves the way” for further studies into the “intricate relationship” between IPF and cardiovascular disease.

“Integrating more phenotype data and genetic data from different populations to research will help better understand the relationship and common pathological mechanism of these two diseases,” they concluded.

References

1. Hu L, Liu R, Yang L, Xu M, Zhou Y, Cao Y. Bidirectional Mendelian randomization study: unraveling the link between idiopathic pulmonary fibrosis and cardiovascular disease. Ann Hum Genet. Published online July 4, 2025. doi:10.1111/ahg.12605

2. Panos RJ, Mortenson RL, Niccoli SA, King TE Jr. Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment. Am J Med. 1990;88(4):396-404. doi:10.1016/0002-9343(90)90495-y

3. Kizer JR, Zisman DA, Blumenthal NP, et al. Association between pulmonary fibrosis and coronary artery disease. Arch Intern Med. 2004;164(5):551-556. doi:10.1001/archinte.164.5.551

4. Hubbard RB, Smith C, Le Jeune I, Gribbin J, Fogarty AW. The association between idiopathic pulmonary fibrosis and vascular disease: a population-based study. Am J Respir Crit Care Med. 2008;178(12):1257-1261. doi:10.1164/rccm.200805-725OC