A detailed molecular analysis of human heart tissue suggested that diabetes may play a more direct role in heart failure than previously recognized — partly by altering lipid metabolism — prompting renewed debate over whether diabetic cardiomyopathy represents a distinct clinical entity.

“This is one of the most detailed studies ever done on human diabetic heart failure tissue,” said senior author Sean Lal, MD, PhD, professor of clinical and molecular cardiology at the Precision Cardiovascular Laboratory, The University of Sydney, Sydney, Australia, of the study published in EMBO Molecular Medicine.

Investigators combined proteomic, lipidomic, and metabolomic analyses with RNA sequencing, advanced imaging, and sophisticated computer modelling using samples from the Sydney Heart Bank, one of the world’s largest human heart biobanks.

They analyzed left ventricular myocardium from 77 hearts: 30 from patients with ischemic cardiomyopathy, including 14 with type 2 diabetes (ICM-DM); 27 from patients with nonischemic cardiomyopathy, including nine with type 2 diabetes; and 20 healthy control participants.

Metabolic Differentiators

According to Lal, the study identified “major problems in mitochondria,” suggesting that diabetic hearts struggle even more to generate the energy needed for proper function than failing hearts without diabetes.

Several metabolites including oxaloacetate, acetylcholine, nicotinamide adenine dinucleotide phosphate, glycine, arginine, and cyclic adenosine monophosphate were differentially abundant in ICM-DM compared with other forms of heart failure.

Energy metabolism was disrupted, with key fat-burning pathways reduced. However, Lal noted that the heart “didn’t just stop handling fats. Instead, lipids appeared to be mismanaged or even exported out of the heart, challenging the prevailing belief that diabetic hearts simply accumulate fat.”

Lipidomic analysis identified 20 downregulated lipids in ICM-DM, including 15 medium-, long-, and very-long-chain acylcarnitines, as well as diacylglycerols and phosphatidylglycerols.

The diabetic heart also appeared to shift toward less efficient energy sources such as glucose, although these pathways were also impaired due to the presence of diabetes. Structural changes were evident, including increased fibrosis, disrupted calcium metabolism, and disorganized muscle fibers.

“Together, these changes make the heart weaker and stiffer,” said Lal, who noted that the findings indicate diabetes “is not just an ‘add-on’ problem — it fundamentally changes the heart structure and function.”

“The molecular signature of heart failure with diabetes was clearly different from heart failure without diabetes,” he said, adding that the “combination of diabetes and blocked arteries caused deeper disruption than either condition alone.”

The Importance of Early Intervention

P. Christian Schulze, MD, PhD, chair in the Department of Medicine I (Cardiology, Angiology, and Intensive Medical Care) at the University Hospital Jena, Jena, Germany, who was not involved in the study, described the study’s wide-ranging metabolic profiling and RNA sequencing as innovative.

He noted that the downregulation of proteins associated with fatty acid transport and oxidation was particularly interesting, along with reductions in proteins linked to acylcarnitines, perilipin, and ketone body, amino acid, and glucose metabolism, suggesting that lipid metabolism is altered but not entirely impaired.

In patients with ICM-DM, Schulze explained, two processes typically intersect: ischemic injury leading to infarction and scarring, and diabetes-related metabolic abnormalities, including fatty acid overload and triglycerides accumulation. Diabetes increases the risk for ischemic heart disease, intertwining the two.

The current findings indicate, however, that the “ultimate phenotype is probably defined by the occurrence of a cardiomyopathy characterized by an abnormality of oxidative metabolism due to mitochondrial dysfunction in the fading myocardium, which leads to decreased capacity of the myocardium to oxidize fatty acids in glucose.”

Because diabetes often precedes ischemic heart disease, Schulze said, the findings underscore the potential importance of early intervention to prevent irreversible myocardial changes.

Lal agreed, noting that “once heart failure reaches an advanced stage, damage is widespread and harder to reverse. Blood sugar control, cholesterol management, blood pressure control, physical activity, and heart-protective diabetes medications are all important.”

Could Weight Loss Reverse Cardiac Damage?

Recent studies have suggested that significant weight loss could lead to reversal of type 2 diabetes, and Naveed Sattar, MD, PhD, professor of cardiometabolic medicine at the University of Glasgow, Glasgow, Scotland, noted that there is emerging evidence indicating the same could apply to heart failure.

“If you live with heart failure with preserved ejection fraction and lose about 10 kilograms, symptomatically you do improve,” he told Medscape Medical News. “Your ability to walk improves, and your C-reactive protein level also improves.”

Sattar, who was not involved in the current study, emphasized that it remains unclear whether such improvements translate to structural cardiac remodeling.

From a mechanistic perspective, weight loss rapidly lowers blood pressure and volume load, decreasing cardiac stress.

“You’re de-stressing the heart very rapidly,” said Sattar, potentially leading to structural improvements.

Still, Schulze cautioned that it remains unclear whether correcting metabolic abnormalities fully restores myocardial health. The findings raise the possibility of “diabetic memory,” in which persistent tissue changes leave the heart more vulnerable to ischemic changes even after metabolic control improves.

Does Diabetic Cardiomyopathy Exist?

The study has notable limitations, Lal acknowledged. It examined end-stage heart failure, making it unclear when metabolic changes first occur. The cohort was predominantly male, reflecting disease prevalence but limiting generalizability. Additionally, the sample sizes were modest.

“Human tissue is rare but complex,” Lal said. “While studying real human hearts is a huge strength, it also means smaller sample sizes.”

Sattar questioned whether study group differences were fully controlled.

“If you don’t control for the simple factors, or at least try and match them as best you can, you’re going to find potentially spurious findings which may or may not be true,” Sattar said.

He also challenged the concept of diabetic cardiomyopathy as a distinct disease entity. As a coauthor of a 2024 clinical consensus statement from the Heart Failure Association of the European Society of Cardiology, Sattar said the group concluded that the evidence for diabetic cardiomyopathy as a specific condition remains unconvincing.

“Diabetes is another risk factor that accelerates cardiovascular disease and ischemia, alongside obesity, hypertension, and dyslipidemia,” he said. What is often labelled diabetic cardiomyopathy may simply reflect the cumulative burden of cardiometabolic risk factors rather than a distinct diabetes-related disease.

“Is there a distinct pathogenesis called diabetic cardiomyopathy? It’s very difficult to parse out,” he said.

Treatment Implications

Despite differing views on disease classification, experts agreed that the findings reinforce the need for individualized therapy.

“One-size-fits-all heart failure therapies may miss important metabolic problems specific to diabetes,” Lal said, suggesting that future treatment may need to target mitochondrial dysfunction and metabolic pathways in patients with diabetes and heart failure.

“We need to explore how human heart cells make and use energy,” he said. “That may be just as important as improving blood flow or lowering blood pressure.”

The study was funded by the R.T. Hall Trust and philanthropic donations to the University of Sydney, with additional support from the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia.

Lal and Schulzere ported having no relevant financial relationships.

Sattar reported having relationships with Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceuticals, Menarini-Ricerche, Metsera, Novartis, Novo Nordisk, Pfizer, and Roche.

Liam Davenport, MA (Hons), is a UK-based medical journalist and writer with more than 20 years’ experience. He studied medical sciences and anthropology at Emmanuel College, Cambridge, England.