Untangling Heart Failure Complexity

Protein analysis identifies heart failure subtypes that could guide future care.

Image Caption: Determining the molecular changes that underlie the varying causes and symptoms of heart failure could help predict treatment response and identify new drug targets.

Despite medical advances, heart failure (HF) remains a leading cause of death and burden on health care systems around the world. A new study from UHN’s Peter Munk Cardiac Centre and the University of Toronto has identified important molecular differences between patients with HF that may explain differing responses to treatment.

The underlying cause of HF can vary from person to person, and multiple factors may contribute to its development, including inherited heart conditions, previous heart attacks, inflammation of the heart muscle, and damage caused by certain cancer treatments. The multifaceted nature of its development has made understanding the molecular changes associated with HF a challenge.

Despite diverse causes, patients are often treated using similar approaches. As a result, current standards of treatment are not equally as effective for everyone. Understanding differences between patients could help explain why some people respond better to treatment than others and may help pave the way for more personalized treatments.

Proteins influence gene activity and affect signalling pathways that regulate heart function. Due to small sample sizes and difficulty in representing the different types of HF, previous attempts at analyzing the protein profiles of patients with HF have been challenging.

To address these limitations, the research team performed a large-scale analysis of the proteins in heart tissue samples from 149 patients with advanced HF caused by nine different underlying conditions.

The team found that although patients had different clinical symptoms and causes of HF, their heart samples shared many similar molecular changes at end-stage disease. However, further analysis revealed that the samples could be divided into two distinct subgroups based on the expression of proteins linked to fibrosis (scarring) and inflammation during the process of cardiac remodelling—changes to the heart’s size, shape, and function in response to cardiac disease.

The results of an analysis of protein phosphorylation—a type of protein modification that can indicate which signalling proteins are active—supported the subgroup division. This analysis also identified specific signalling molecules associated with a defined subgroup of patients that could be potential drug targets.

In addition, by comparing the pattern of proteins (protein signatures) associated with each subgroup to an independent dataset, researchers found that the subgroups also applied to earlier stages of HF. They found that these protein signatures could be detected in the blood, supporting their potential use as blood-based markers of HF. The protein signatures were also associated with different survival outcomes, providing evidence that they could be used to assess HF prognosis and other characteristics.

Overall, this research provides new insight into the biological differences that underlie HF and may help pave the way for more personalized treatment approaches. Future studies are needed to determine whether the newly identified protein signatures could be targeted to create new treatments and improve patient outcomes.

Dr. Gramolini (left) and Dr. Filio Billia (right); (photo: Ted Rogers Centre for Heart Research)

Dr. Omar Hamed, Postdoctoral Researcher at the University of Toronto, is the first author of this study.

Dr. Anthony Gramolini, Professor in the Department of Physiology at the University of Toronto, is the co-corresponding author of the study.

Dr. Filio Billia, Senior Scientist at UHN’s Peter Munk Cardiac Centre and Ajmera Transplant Centre, and Associate Professor in the Department of Medicine at the University of Toronto, is the co-corresponding author of the study.

This work was supported by the Ted Rogers Centre for Heart Research, the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, and UHN Foundation.

Dr. Anthony Gramolini is the Ted Rogers Chair in Cardiovascular Systems Biology.

Dr. Filio Billia is the Ted Rogers and Family Chair in Heart Function

Hamed O, Reitz CJ, Kuzmanov U, Gramolini S, Hu M, Halpern J, Billia F, Gramolini AO. Cardiac proteomic and phosphoproteomic profiling defines clinically relevant molecular subgroups in human heart failure. Nat Cardiovasc Res. 2026 Oct;5(10):1016-1033. doi: 10.1038/s44161-026-00880-w. Epub 2026 Sep 25.

UHN Welcomes Inaugural Porter Chair

Global innovation leader Dr. Eyal Zimlichman joins UHN to accelerate health care innovation.

Image Caption: Dr. Eyal Zimlichman is the inaugural Porter Family Chair in Healthcare Innovation, established to bring world-leading expertise to UHN and accelerate transformative ideas with the potential to improve patient care.

Easing Pressures on Emergency Care

A community diversion program could help reduce demand on emergency departments.

Image Caption: Community-based diversion programs could help reduce pressures on emergency services by providing an alternative care setting for people who do not require emergency medical treatment.

Brain Plasticity and Chronic Pain

Researchers identify brain changes associated with pain relief after TN treatment.

Image Caption: Up to 25% of the world is affected by chronic pain conditions such as trigeminal neuralgia (TN)—a form of chronic nerve pain affecting the face and mouth. For those who fail to get relief from standard treatments, understanding why is an essential first step to improving care. (Image: Getty)

A new study from a team at UHN's Krembil Brain Institute (KBI), led by Senior Scientist Dr. Mojgan Hodaie, is shedding light on how specific structural changes in the brain, a form of brain (or neuro) plasticity, are associated with pain relief in trigeminal neuralgia (TN) following surgical treatment. For individuals living with TN—severe chronic neuropathic (nerve) facial pain—these findings may help advance personalized treatment planning and improve understanding of the brain's response to pain relief.

For many patients, trigeminal neuralgia (TN) can be effectively managed with surgery. However, about 25% of individuals do not respond well to surgery. Understanding why remains a challenge in helping more patients achieve effective pain relief.

Prior research from Hodaie's team revealed changes in the anatomy of 13 brain regions among people with TN that could help predict whether a patient was likely to respond to surgery. These regions showed reduced grey matter volume and reduced thickness of the cortex—the outermost layer of the brain. "We wanted to better understand what happens to these regions after treatment, and whether there is a correlation with pain relief," says Dr. Hodaie.

To explore the connection between brain changes and TN symptoms, KBI researchers evaluated MRI scans and pain relief scores from 115 patients with TN before and after surgical treatment.

Comparing imaging before and after surgery, the team observed changes in several brain structures. They identified eight key brain regions where increased thickness of the cortex after surgery was related to improvements in TN symptoms. In general, they found that in these regions, greater thickening between pre- and post-surgery was associated with greater pain relief. One region, the fusiform gyrus—an area of the brain linked to pain-memory—showed the strongest correlation, with post-surgical thickening of the cortex directly linked to pain relief achieved.

These findings give health care providers new insights into the biological processes underlying pain relief in TN. Moreover, they offer evidence that the brain's ability to change and adapt in response to experiences and conditions, a process known as neuroplasticity, may play a key role in the brain's response to chronic pain. For people with TN, this work lays the groundwork for the development of more personalized approaches to treatment in the future. Additional studies will further investigate the role of the fusiform gyrus and explore pain relief from a more multifaceted lens.

Emili Adhamidhis is the first author of this study. She is a medical student at McMaster University's Michael G. DeGroote School of Medicine and a former research trainee who obtained her MSc at UHN's Krembil Brain Institute. 

Dr. Mojgan Hodaie, the senior author of this study, is a Senior Scientist at UHN's Krembil Brain Institute, Affiliate Scientist at UHN's KITE Research Institute, and Professor of Surgery (Neurosurgery) at the University of Toronto's Temerty Faculty of Medicine.

This work was supported by the Institute of Medical Science and Temerty Faculty of Medicine at the University of Toronto, and UHN Foundation.

Adhamidhis E, Srisaikaew P, Li J, Latypov TH, Noorani A, Hodaie M. Brain Regional Predictors of Surgical Response Are Dynamically Associated with Post-Surgical Pain Relief in Trigeminal Neuralgia. Brain Sci. 2026 Sep 13;16(9):966.

Bold by Design

The 2025–2026 UHN Research Report highlights how discovery is designed to deliver impact.

Image Caption: The 2025–2026 UHN Research Report features stories of scientists, clinicians, trainees, staff, patients, and partners working together to move discovery into impact.

NEURONTO Symposium 2026

Toronto neuroscience and mental health research community comes together for joint symposium.

Image Caption: The NEURONTO research symposium was co-hosted by UHN’s Krembil Brain Institute, featuring talks and poster presentations on advancements in neuroscience and mental health research.

On October 8, 2026, UHN’s Krembil Brain Institute (KBI) and The Hospital for Sick Children’s (SickKids) Neurosciences & Mental Health Program (NMH) held the third annual NEURONTO Research Symposium.

With more than 300 registrants, 12 talks, and 100 poster presentations, the event showcased the innovation and collaborative spirit of Toronto’s neuroscience and mental health research community.

Researchers, trainees, and clinicians from KBI, SickKids’ NMH, and the Centre for Addiction and Mental Health came together to exchange ideas, foster new connections, and highlight cutting-edge research taking place across our institutions.

Throughout the day, attendees explored diverse topics, from neuro-immune interactions and dopamine-guided learning to advances in brain imaging and mental health research. Presentations centred on the symposium’s four core themes: glia in health and disease, neural circuits and systems, mental health, and brain imaging and computation.

Thank you to all the speakers, poster presenters, staff, and attendees whose contributions made the symposium such a success. The thoughtful questions and discussions were a reminder of why NEURONTO exists and the impact of collaboration in neuroscience and mental health research.

A New Immunotherapy Approach

Early trial shows that new drug has anti-tumour activity in patients with advanced cancer.

Image Caption: Despite the impact immunotherapy has had on cancer treatment, there is a need for new immunotherapies that have longer lasting effects with fewer side effects. The investigational drug, invikafusp alfa, uses a new and unique mechanism of action to treat cancer, targeting specific subsets of T cells to improve specificity.

A study published in Nature Medicine from UHN’s Princess Margaret Cancer Centre and collaborators found that a first-of-its-kind, investigational immunotherapy drug, invikafusp alfa (invika), showed early signs of anti-tumour activity in people with various types of advanced and treatment-resistant forms of cancer.

Cancer immunotherapy, which helps the immune system recognize and attack cancer cells, has transformed cancer treatment by improving outcomes for many types of cancer. One type of therapy, called immune checkpoint blockade (ICB), blocks checkpoint proteins that normally act as “brakes” on the immune system and prevent immune responses from becoming too strong. Some cancers exploit these checkpoint proteins to switch off cancer-fighting immune cells known as T cells. Blocking the checkpoints can help T cells remain active and attack the cancer.

Despite immense research in this area, only some patients achieve long-term benefits from ICB and there is a high likelihood of developing drug resistance. In addition, these treatments can trigger non-specific components of the immune system, which can lead to serious side effects.

There is a need for new immunotherapies that can generate strong and durable responses. As a result, a new generation of immunotherapies is being designed to be more selective. One such medication is invika, developed to both selectively bind to and activate Vβ6/Vβ10 T cell subsets—T cells that carry specific receptors on their surface. This specificity aims to enhance the tumour-specific immune response and improve safety.

In an early-phase clinical trial, the first trial of this drug in patients, participants with advanced solid tumours that had resistance to other therapies, including ICB, were treated with invika. The trial was designed to evaluate the safety of invika and identify a dose for further study (the recommended phase 2 dose), as well as measure preliminary anti-tumour activity. The study included 58 participants at hospitals around the world, including UHN’s Princess Margaret Cancer Centre.

Results showed that the drug was well-tolerated with an acceptable safety profile. Among the 27 participants treated at the recommended phase 2 dose, 14.8 % showed a response where tumours shrank enough to meet established clinical criteria. There was also some degree of tumour shrinkage in 44% of patients, even when the reduction was not large enough to meet the official criteria. These responses were observed in many tumour types such as cervical cancer, pancreatic cancer, melanoma, and more.

In 18 participants who had cancers that had stopped responding to earlier immunotherapy, and received invika at the recommended phase 2 dose, 66.7% achieved disease control, meaning their cancer either shrank or remained stable. Researchers also observed expansion of targeted T cells both in the bloodstream and inside tumours, providing early evidence that the therapy acted as intended.

Overall, these findings provide preliminary evidence of anti-tumour activity and support further study of invika in people with advanced cancers. Larger trials are needed to determine how well the drug works, which patients are most likely to benefit and how its risks compare with its potential benefits.

Dr. Ryan Sullivan from Mass General Research Institute and Harvard Medical School; Nicholas Tschernia, from the National Cancer Institute; and Claire Friedman from Memorial Sloan Kettering Cancer Center, at the time of this research, are co-first authors of the study.

Dr. Ke Liu from Marengo Therapeutics and Dr. James Gulley from the National Cancer Institute are co-corresponding authors of the study.

Dr. Lillian Siu, Senior Scientist and Medical Oncologist at UHN’s Princess Margaret Cancer Centre and Professor in the Department of Medicine at the University of Toronto, is the Co-Corresponding author of the study.

The START-001 phase 1/2 trial was supported by Marengo Therapeutics. This work was supported in part by the Center for Cancer Research, NCI, NIH and The Princess Margaret Cancer Foundation.

Dr. Lillian Siu is a consultant/advisory board member for Merck, Roche, Voronoi, GSK, Bayer, Pfizer, Arvinas, Daiichi Sankyo, Amgen, Pangea, Tubulis, LTZ Therapeutics, Marengo, AstraZeneca, Incyte, Gilead, Bristol-Myers Squibb, Systinn, Systimmune, EMD Serono, and MBrace. She reports other competing interests that can be found in the manuscript.

For a full list of competing interests, see the manuscript.

Sullivan RJ, Tschernia NP, Friedman CF, Herrera M, Sonpavde GP, He K, Italiano A, Marabelle A, Roulleaux-Dugage M, Danlos FX, Cabanas EG, Hernando-Calvo A, Pedregal M, Parikh A, Iyer G, Zakari A, Wherry EJ, Schlom J, Donahue RN, McCue S, Cross S, Srinivasan K, Benincosa L, Katragadda M, Shun Z, Chin K, Su Z, Liu K, Siu LL, Gulley JL. Bispecific dual T cell agonist invikafusp alfa in solid tumors: the phase 1/2 START-001 trial. Nat Med. 2026 Oct 23. doi: 10.1038/s41591-026-04711-0. Epub ahead of print.