The results of a new study published in Circulation suggest a link between a high-fat diet, the inflammatory activation of cardiac macrophages, and a reduction in the heart’s diastolic function

In diastolic heart failure, which accounts for half of all heart failure cases, the heart muscle is able to contract normally, but struggles to relax after contraction, thus reducing the volume of blood the heart can pump with each beat.

A new study, published in the journal Circulation, demonstrates the role of a high-fat diet and the subsequent cardiac inflammation in the genesis of the disease, paving the way for a more targeted use of available therapies, especially SGLT2 inhibitors, developed for the treatment of type 2 diabetes.

The research is the result of a collaboration between Gianluigi Condorelli, full professor at Humanitas University and director of the Humanitas Cardiovascular Research Program, and Carolina Greco, assistant professor at Humanitas University and head of the Humanitas Circadian Metabolism Laboratory, where she studies molecular clocks and their role in the onset of metabolic and cardiovascular diseases.

The work was funded by the European WINTHER project, part of the Horizon2020 framework program, in which Humanitas University is a partner.

Diastolic heart failure: an inflammatory disease?

Approximately 64 million people worldwide live with heart failure. The numbers are growing, and it is estimated that by 2030, in industrialized countries, heart failure will affect 3 out of every 100 adults. As of today, more than half of the patients with heart failure have the diastolic form, and the number is expected to grow due to both improved diagnostic capabilities and rising risk factors in the population.

Although the origin of the heart’s difficulty to relax after contraction is still poorly understood, chronic inflammation is undoubtedly associated with the disfunction, though the mechanisms are yet to be investigated. In fact, patients with the disease often exhibit high levels of inflammatory cytokines, and at the same time, health conditions associated with systemic inflammation – such as advanced age and obesity – are disease risk factors.

The discovery: a high-fat diet activates heart macrophages

Leveraging advanced techniques for analyzing gene expression, the research group led by Gianluigi Condorelli and Carolina Greco studied the impact of a high-fat diet on the behavior of macrophages residing in cardiac tissues. They used an experimental model of chronic metabolic disease characterized by high cholesterol levels.

“We discovered that a high-fat diet alters the local behavior of macrophages, pushing them towards an inflammatory profile. The activation of this inflammatory profile in macrophages leads to the release of cytokines and the recruitment of other immune cell populations to the heart,” explains Cristina Panico, first author of the work along with Arianna Felicetta and Paolo Kunderfranco. “It had never been observed before that the excessive presence of fat molecules in the heart can activate local inflammatory processes. Even more: according to our data, this is enough to cause a reduction in the muscle’s diastolic function, at least in our preclinical model.”

The researchers also studied the mechanism of action of a new class of drugs for the treatment of type 2 diabetes – SGLT2 inhibitors. Several clinical trials have confirmed their effectiveness in treating diastolic heart failure, and although these drugs were introduced to the market due to their ability to reduce blood glucose levels, the experiments showed that they also reduce inflammation: following the administration of the drug, the number of macrophages in the cardiac tissue decreased and their expression profile changed towards less marked inflammatory behaviors.

“Further studies will be necessary to understand if, and how much, the effectiveness of SGLT2 inhibitors in treating heart failure is due to their anti-inflammatory activity, but the results are nonetheless surprising and demonstrate that the drug, even if metabolic in nature, has a marked effect on the immune system,” explains Carolina Greco. “If further confirmed, these findings suggest that SGLT2 inhibitors could be more effective in patients with a pronounced metabolic and inflammatory stress profile.”