Q: How would you summarize your study for a lay audience?

In short: We found that the defense protein “Resistin like molecule gamma” (Relmy), produced by neutrophils, punches holes into heart cells after a heart attack. This promotes dangerous, fast, and irregular heart rhythm and cell death in the heart.

The longer version: The most lethal complications of coronary artery disease are myocardial infarction (MI) and sudden cardiac death.

In MI, the blockage of a heart artery leads to insufficient oxygen supply to heart muscle cells (cardiomyocytes). This compromises their ability to maintain a stable rhythm and can give rise to a dangerous, unstable heart rhythms (arrhythmia) called ventricular tachycardia (VT) and ventricular fibrillation (VF).

VT and VF are both serious arrhythmias that can lead to sudden cardiac arrest and death within minutes. In VT, the heart beats very rapidly, but in a coordinated rhythm. In VF, the rhythm is chaotic and uncoordinated.

Most arrhythmias occur within 48 hours after MI and coincide with massive immune cell infiltration into the heart tissue. We were interested in how these immune cells may promote arrhythmia.

We found neutrophils that get recruited into the infarct (the area of dead tissue resulting from the cutoff of oxygen supply) in large numbers upregulate the gene “Retnlg,” coding the protein resistin like molecule gamma (RELMy). We also found a comparable gene, “RETN,” in human infarcted heart tissue. When we removed this protein from neutrophils in mice, the arrhythmia burden after MI was reduced 12-fold.

Q: What question were you investigating?

We were investigating the question of how neutrophils, a specific kind of immune cell, promote ventricular arrhythmia (a dangerous fast irregular heartbeat) after heart attacks. Cardiomyocytes as the main actors in arrhythmia are very well studied, but if and how immune cells can promote arrythmia is less clear. This work is important because ventricular arrhythmia is the most lethal complication after myocardial infarction. We need to understand better what promotes arrythmia to help us develop new antiarrhythmic drugs.

Q: What methods or approach did you use?

We used a plethora of methods to figure this out. For an initial understanding about which proteins in neutrophils might be important, we used deposited data on gene expression generated by single cell and spatial RNA-sequencing from mice that underwent myocardial infarction. But we also used data from human studies to find similarities in human tissue.

We also relied on confocal and super-high resolution microscopy in isolated mouse heart muscle cells that were treated with the labeled protein. Further, we deployed in vitro assays such as a liposome model and cell culture techniques to investigate the mouse and the human version of the protein to find out if they work similar.

Q: What did you find?

We found that after MI in mouse models, neutrophils upregulatethe expression of “Retnlg,” the gene coding for RELMy. We also found that the human biological homolog “RETN,” the genecoding for Resistin, was higher expressed in human infarcted myocardial tissue compared to non-infarcted tissue, similar to mice.

We saw that deleting the gene from bone marrow derived cells (such as neutrophils) and deleting the gene from neutrophils specifically significantly reduced incidents of ventricular arrhythmia in the mouse models.

Q: What are the implications?

The implications are that immune cells play a crucial role in sudden death and arrhythmia.

We should think about treating both the myocardial infarction both by quick recanalization of the vessel to restore oxygenated blood supply and also by targeting immune cells to mitigate the arrhythmic effects of the injury.

When we understand the underlying mechanisms better, we can pursue therapeutic targets that go beyond the broad immune suppression that is used today.

If we can treat targets more specifically, we can reduce unwanted side effects and unravel the full potential of immune modulation in cardiovascular disease.

Q: What are the next steps?

The next steps are to find a way to neutralize the harmful protein and test if this can reduce VT burden and infarct size. First in the mouse models, but, we hope, eventually also in humans.

We should gather more evidence about the significance of this protein in human disease. It is also interesting to see these findings have implications for other diseases with neutrophil recruitment and activation.

Authorship: In addition to Nina Kumowski and Matthias Nahrendorf, Mass General Brigham authors include Steffen Pabel, Jana Grune, Noor Momin, Kyle I. Mentkowski, Yoshiko Iwamoto, Yi Zheng, I-Hsiu Lee, Fadi E. Pulous, Hana Seung, Alexandre Paccalet, Charlotte G. Muse, Kenneth K. Y. Ting, Paul Delgado, Andrew J. M. Lewis, Vaishali Kaushal, Antonia Kreso, Dennis Brown, Kamila Naxerova, Michael A. Moskowitz, and Maarten Hulsmans.

Funding: This work was supported by grants from the Leducq Foundation, the National Institutes of Health (NIH grants HL155097, HL149647, HL142494, HL176359, NS136068, DP2AR075321); the Deutsche Forschungsgemeinschaft (DFG) Walter Benjamin Programm (491497342 and 530157297); the British Heart Foundation (FS/ICRF/24/26111 and RE/18/3/342140), and the NIHR Oxford Biomedical Research Centre.

Disclosures: Nahrendorf has received funds or material research support from Alnylam, Biotronik, CSL Behring, GlycoMimetics, GSK, Medtronic, Novartis, and Pfizer, and has received consulting fees from Biogen, Gimv, IFM Therapeutics, Molecular Imaging, Sigilon, Verseau Therapeutics and Bitterroot. Matthias and Wirth are employees of the company Abberior Instruments America, which commercializes the MINFLUX technology. Lewis is on the advisory board of Abbott, AstraZeneca, and Novartis. Pabel is employed by the Novartis Institute of Biomedical Research. Hayat is a cofounder and shareholder of Sequantrix GmbH and has received research funding from Novo Nordisk and AskBio. The remaining authors declare no competing interests.

For more than two decades, finasteride has been prescribed to millions of men seeking to slow or reverse hair loss. Behind its cosmetic appeal, however, evidence has continued to emerge suggesting serious mental health consequences, including depression, anxiety, and in some cases, suicide.

Prof. Mayer Brezis of the Hebrew University of Jerusalem argues that both the medical community and regulators have repeatedly failed to protect the public by overlooking signs of psychiatric harm associated with the drug.

His review analyzed data from eight large studies published between 2017 and 2023. The findings show a clear trend: people who used finasteride were far more likely to experience mood disorders and suicidal thoughts than those who did not. This pattern appeared consistently across various national databases, including the FDA’s adverse event system and healthcare records from Sweden, Canada, and Israel.

“The evidence is no longer anecdotal,” said Prof. Brezis, a professor emeritus of medicine and public health. “We now see consistent patterns across diverse populations. And the consequences may have been tragic.”

The report estimates that hundreds of thousands of users may have suffered from finasteride-related depression, and that hundreds — possibly more — may have died by suicide. Originally approved by the FDA in 1997 for male pattern baldness, the drug has remained popular for its perceived safety and effectiveness, particularly among younger men. Critics say, however, that its risks were downplayed or ignored.

A Delayed Response, With a High Cost

Although the FDA recognized depression as a possible side effect in 2011 and added suicidal thoughts to the label in 2022, researchers had been warning of potential dangers as early as 2002. Internal FDA files from 2010, cited in Brezis’ review, contained entire sections redacted as “confidential,” including estimates of how many people might have been affected.

By 2011, only 18 suicides linked to finasteride had been reported to the FDA. Based on worldwide usage, Brezis concluded the actual number should have been in the thousands. “It wasn’t just underreporting,” Dr. Brezis wrote. “It was a systemic failure of pharmacovigilance.”

Unlike drugs used to treat obesity or psychiatric disorders, which are often closely monitored after approval, finasteride’s classification as a cosmetic treatment may have shielded it from deeper scrutiny. None of the data-mining studies referenced in the review were initiated by Merck, the company that developed the drug, nor were they commissioned by regulatory authorities.

A Cosmetic Drug With Life-Altering Risks

Brezis argues the drug’s classification as a non-essential, appearance-enhancing medication changes the risk calculus. “This wasn’t about life or death medical necessity,” he said. “This was about hair.”

The biological rationale is clear. Finasteride works by blocking the conversion of testosterone into dihydrotestosterone (DHT), but in doing so, it may also disrupt neurosteroids like allopregnanolone — linked to mood regulation in the brain. Animal studies have shown long-term effects on neuroinflammation and even changes in hippocampal structure.

For some patients, the consequences don’t end when the pills do. Reports of lingering symptoms — dubbed “post-finasteride syndrome” — include insomnia, panic attacks, cognitive dysfunction, and suicidal thoughts that persist months or even years after stopping treatment.

Regulatory Gaps, Corporate Silence

The report is especially scathing toward the FDA and Merck. Despite having access to millions of patient records and robust pharmacovigilance tools, neither party acted in time, Brezis argues. The industry’s silence was strategic, he suggests, driven by market pressures and legal liability — echoing past controversies like Merck’s handling of Vioxx.

“Nothing is more important to Organon than the safety of our medicines,” the company recently claimed in a public statement. Yet none of the safety studies cited were initiated by the manufacturer.

The FDA, meanwhile, took five years to respond to a citizen petition calling for a black-box warning. Its final decision? To add suicidal ideation to the label — but not as a formal warning.

What Now?

Brezis is calling for immediate changes in how drugs like finasteride are approved, monitored, and prescribed. His recommendations include suspending marketing of the drug for cosmetic purposes until safety is re-established, mandatory post-approval studies with strict enforcement, and systematic recording of drug histories in suicide investigations.

“For many, those changes come too late. The paper is dedicated to one such individual — a previously healthy man who took finasteride “just” to improve his hair. Within days, he spiraled into severe psychiatric distress. He never recovered. Months later, he took his own life.”