The findings, published this month in Nature Cardiovascular Research, reveal a previously unknown link between immune dysfunction and the metabolic deterioration seen in diabetic hearts - and point toward an entirely new class of cardiac treatment.
Diabetic cardiomyopathy is one of the most serious and least-discussed complications of type 2 diabetes. It develops independently of blocked coronary arteries, instead arising from a combination of chronic inflammation, metabolic dysfunction, and structural damage, which progressively stiffens and weakens the heart muscle. Patients develop diastolic dysfunction - meaning the heart struggles to relax and fill properly - leaving them increasingly vulnerable to heart failure and far more likely to suffer severe damage if they have a heart attack.
Despite its prevalence, no approved therapies specifically target metabolism of diabetic hearts. Standard diabetes treatments regulate blood sugar levels, but largely leave the heart's underlying deterioration untouched.
The drug AZD1656 was originally developed by Astra Zeneca to improve blood sugar control in people with type 2 diabetes, but didn't work well for that purpose. Rather than targeting blood sugar, subsequent research revealed that the drug can rebalance the immune system by helping regulatory T (Treg) cells (a type of protective immune cell) move around the body more effectively. This discovery prompted an international team of researchers, led by Professor Dunja Aksentijevic of the William Harvey Research Institute at Queen Mary University of London, to investigate whether AZD1656's immune effects could be used to advantage in the diabetic heart.
The team found that AZD1656 corrects the Treg cell imbalance and can reverse serious heart damage in diabetic patients, a completely different mechanism than any described to date. They show that AZD1656 boosts the ability of protective immune Treg cells to travel into the heart, where they calm inflammation, reduce post-infarct scarring, and - remarkably - allow the heart's disrupted energy systems to recover almost to normal.
The study also showed that treatment dramatically improved heart function, cut heart attack damage, and restored the heart's metabolic profile to near-healthy levels. Crucially, none of this was explained by changes in blood sugar, body weight, liver, fat or muscle metabolism.
Dunja Aksentijevic, Professor of Cardiovascular Physiology and Metabolism at Queen Mary University of London and a Wellcome Trust Research Fellow, said: "This work stems directly from my Wellcome Career Re-Entry Fellowship and establishes aberrant immunometabolic signalling as a promoter of cardiac remodelling in type 2 diabetes. Targeting this axis by enhancing the migratory capacity of regulatory T cells improved diabetic cardiomyopathy thus opening a new therapeutic direction for the treatment of hundreds of millions of people worldwide living with type 2 diabetes."
This research was made possible by a Wellcome Career Re-Entry Fellowship awarded to Professor Aksentijevic. The Wellcome Career Re-Entry Fellowship provides grants to researchers to help them re-establish their research after taking a career break. Professor Aksentijevic was the only recipient of the Fellowship in 2020.
