In Progress: Striving for Success Against Heart Failure

Einstein’s Gaetano Santulli, M.D., Ph.D., is developing drugs to prevent heart failure following heart attacks

Heart disease remains the country’s leading cause of death—responsible for 655,000 deaths each year, according to the U.S. Centers for Disease Control and Prevention (CDC). About 40,000 of those fatalities are classified as heart-attack deaths, occurring shortly after (within 30 days of) the attack. Many more heart-disease deaths, however, result from nonfatal heart attacks: Patients survive the attack, but the resulting heart-muscle damage eventually leads to heart failure—the progressive weakening of the heart's pumping ability. The CDC estimates that heart failure contributes to more than 300,000 deaths each year.

Gaetano Santulli, M.D., Ph.D.

Gaetano Santulli, M.D., Ph.D.

Gaetano Santulli, M.D., Ph.D., assistant professor of medicine and of molecular pharmacology at Einstein, is pursuing a novel therapy to prevent or even cure heart failure by minimizing the heart-muscle damage from heart attacks.

The Heart in Repair Mode

The heart is basically a pumping muscle. Cardiomyocytes—the cells responsible for the contraction of the heart—make up only about 35% of heart muscle. A significant number of the heart muscle’s other cells are fibroblasts.

Fibroblasts play a major role in repairing heart muscle and other tissues. They synthesize and secrete extracellular matrix (ECM)—the fibrous, non-cellular material that provides support for cells throughout the body.

Immediately after a heart attack, fibroblasts begin producing ECM at the site where heart muscle was damaged and cardiomyocytes have died. In this wound-healing process, ECM laid down by fibroblasts forms scars that replace dead cells and helps restore normal heart function. But in many heart-attack victims, the heart’s fibroblasts churn out ECM not only at the wound site but excessively and continuously in distant heart regions as well—the pathological process known as cardiac fibrosis.

The overabundant ECM deposits from cardiac fibrosis cause inflammation and scarring throughout the heart. Over time, scarring from cardiac fibrosis leaves heart muscle stiff and unable to pump enough blood to meet the body’s needs, thickens heart valves, interferes with normal electrical signaling, and all too often results in heart failure and cardiac arrhythmias. For Dr. Santulli, preventing heart failure by suppressing detrimental post-heart-attack fibrosis has long been a goal, but one that has proven highly elusive.

“No one has yet succeeded in preventing cardiac fibrosis, because targeting previously known fibrosis components would also stop fibrosis where it’s beneficial—at the site of the heart attack,” Dr. Santulli explains. “A treatment to prevent cardiac fibrosis needs to somehow retain fibrotic activity at the site of the heart attack, because otherwise the area would remain weakened and a rupture could occur there.”

A Key Fibroblast Difference

How Heart Attacks Affect the IP3 Pathway in Heart Fibroblasts
Click to enlarge

Recently, while studying the immediate consequences of heart attack in a mouse model, Dr. Santulli and his colleagues made a striking discovery that could lead to the therapy he’s seeking. The finding concerned intracellular calcium channels called IP3 receptors (IP3Rs), which are found in virtually all of the body’s cells.

When stimulated, IP3Rs allow calcium ions to flow into the cytoplasm and to activate key cellular functions. One effect of heart attacks is to stimulate IP3Rs in cardiac fibroblasts; this stimulation opens the IP3R floodgates, and the resulting calcium surge triggers fibroblasts to secrete ECM—helpful at the injury site but responsible for cardiac fibrosis when cardiac fibroblasts distant from the heart attack secrete excessive amounts. (See accompanying illustration of the IP3 signaling pathway.)

After inducing heart attacks in their mouse model, the researchers noticed that fibroblasts in distant heart regions expressed much higher levels of IP3R compared with fibroblasts directly involved in healing the heart-attack damage. To Dr. Santulli, this sharp contrast in IP3R expression in “bad” and “good” fibroblasts suggested a strategy for preventing heart failure: following a heart attack, administering an IP3R-inhibiting drug could possibly inactivate distant, cardiac-fibrosis-causing fibroblasts while leaving healing fibroblasts unscathed.

Promising Pre-Clinical Findings

To test this theory, researchers in Dr. Santulli’s lab induced heart attacks in mice genetically engineered so that cardiac fibroblasts activated by a heart attack did not express IP3. Sure enough, interfering with IP3 expression in heart fibroblasts prevented cardiac fibrosis but did not interfere with the vital repair of heart-attack damage.

Dr. Santulli’s lab is now developing drugs to prevent cardiac fibrosis by specifically targeting IP3Rs on fibroblasts distant from heart-attack sites. Currently, there are no drugs capable of targeting fibrosis at all, let alone drugs that can target the process in certain regions of the heart. “If we can develop a drug that will specifically prevent fibrosis in areas of the heart where it is detrimental, that would be exciting,” says Dr. Santulli, while acknowledging the challenges ahead.

Some members of the Santulli lab, from left: Fahimeh Varzideh, Ph.D., Urna Kansakar, Ph.D., Dr. Santulli, Jessica Gambardella, Ph.D., Stanislovas Jankauskas, Ph.D., Xujun Wang, M.D.
Some members of the Santulli lab, from left: Fahimeh Varzideh, Ph.D., Urna Kansakar, Ph.D., Dr. Santulli, Jessica Gambardella, Ph.D., Stanislovas Jankauskas, Ph.D., Xujun Wang, M.D.

The drug needs to target IP3R without affecting the ryanodine receptor—a very similar and important calcium channel.  Another problem: IP3Rs exists as three different subtypes that can compensate for each other if one is missing—so an anti-IP3R drug must be able to inactivate all three subtypes. In addition, IP3R is notoriously difficult to study: Extracting it from cells and identifying it using molecular techniques poses challenges even for seasoned biologists—one of the main reasons so few scientists study the IP3 receptor, according to Dr. Santulli.

In a related development, Dr. Santulli’s team recently identified novel molecular markers of cardiac fibroblast activation. These molecules, known as microRNAs, may help in identifying post-heart attack patients in whom cardiac scarring and inflammation is occurring. (MicroRNAs are small RNA molecules that help modulate gene expression). This finding is preliminary, Dr. Santulli says, but with additional lab testing “it could lead to other potential interventions for heart failure.”

Although research is now his focus, Dr. Santulli is a cardiologist and clinician who has treated heart patients—who are never far from his thoughts. “As we work to understand the molecular mechanisms occurring within cells, our ultimate goal is always to prevent morbidity and save lives,” he says.

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The members of Dr. Santulli’s lab are:

Postdoctoral Fellows: Jessica Gambardella, Ph.D.; Stanislovas Jankauskas, Ph.D.; Urna Kansakar, Ph.D.; Fahimeh Varzideh, Ph.D.; and Xujun Wang, M.D.

Medical students: Ayobami Adebayo; Kwame Donkor; Michael Eacobacci; and Scott Wilson

Undergraduate student: John Ferrara

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