Israeli scientists identify two types of heart scars, paving the way for targeted therapies

The practical applications of this discovery could significantly impact cardiology and fibrosis treatment across various medical fields.

By Pesach Benson, TPS

Challenging conventional medical wisdom, Israeli scientists found that scar tissue formation in the heart occurs through two distinct mechanisms — a discovery that could lead to new and more targeted therapeutic approaches for heart disease.

The findings of what the Weizmann Institute researchers describe as “hot fibrosis” and “cold fibrosis” were recently published in the peer-reviewed journal, Cell Systems.

The research began as an unexpected collaboration between two scientists at the Weizmann Institute. Prof. Eldad Tzahor, an expert in heart disease, learned about a mathematical model developed by his neighbor, Prof. Uri Alon.

That model, initially designed to classify scar tissue in various organs, suggested that fibrosis could be categorized based on interactions between just two cell types: fibroblasts, which produce collagen and provide tissue structure, and macrophages, immune cells involved in tissue repair and inflammation.

“At first, it sounded too simplistic to me,” admitted Tzahor. “Biological systems are incredibly complex, but the idea intrigued me. It was a great opportunity to collaborate with Uri, so I proposed we test the model on heart disease.”

Scar tissue forms in the heart when muscle cells are damaged, often due to heart attacks. While this scar tissue helps maintain the organ’s structural integrity, it does not contract effectively, leading to impaired heart function over time.

Since there is currently no effective treatment to eliminate or reverse heart fibrosis, medical efforts focus on prevention and minimizing scar formation.

The first mechanism, “hot fibrosis,” involves active interactions between myofibroblasts and macrophages. Because macrophages are immune system cells often linked to inflammation and fever, this type of fibrosis was named “hot.”

The second mechanism, “cold fibrosis,” is independent of macrophages; instead, myofibroblasts sustain the fibrosis process autonomously by secreting molecules that perpetuate scar formation.

“In medical textbooks, microscopic images of heart scars appear uniform, leading to the assumption that all fibrosis in the heart follows the same biological pathway,” explained Shoval Miyara, a joint doctoral student of Professors Tzahor and Alon and one of the research leaders.

“Our findings challenge that notion and show that these are, actually, two different diseases requiring different treatments,” she added.

Using real human heart tissue samples, the research team confirmed the model’s predictions.

The findings are particularly significant given the staggering number of heart cells affected by fibrosis. The left ventricle of the human heart contains roughly four billion muscle cells.

During a heart attack around one billion — or 25 percent — die. Understanding how scars form and how they can be treated more precisely may improve long-term survival and quality of life for millions of patients worldwide.

“If we can identify whether a patient has hot or cold fibrosis, we could tailor treatments to target the specific process involved,” said Tzahor. “This could lead to more effective therapies and better outcomes for people with heart disease.”

The practical applications of this discovery could significantly impact cardiology and fibrosis treatment across various medical fields.

Understanding whether a patient has “hot fibrosis” or “cold fibrosis” could allow doctors to prescribe tailored treatments that specifically address the underlying biological mechanism.

For example, drug companies may one day develop anti-inflammatory or immune-modulating therapies for hot fibrosis and drugs that block fibroblast self-sustaining signals for cold fibrosis.

The research could open new avenues for diagnostic tools that differentiate between the two fibrosis types.

Since fibrosis is a major factor in lung (pulmonary fibrosis), kidney, and liver diseases (cirrhosis), researchers may examine whether these organs also develop hot and cold fibrosis.

The study hinted that a similar classification could apply to scars that form after a stroke or in cancerous tissues.

“This collaboration changed my perspective on the biology of the heart,” said Alon. “Our combination of mathematical models, fundamental biology, and medical research has revealed something new. Now, future studies can explore whether this hot-cold fibrosis distinction applies to scarring in other organs.”