Preventing onset and development of heart failure with preserved ejection fraction

"HFpEF is a complex, multifactorial disease associated with metabolic stress. One of the factors involved is the toxic accumulation of lipids in heart cells," said co-author Dr. Tamer Mohamed, associate professor of surgery and director of the Laboratory for Cardiac Regeneration at Baylor. "This study was the result of a productive multidisciplinary collaboration. We worked with slices of human hearts affected by HFpEF, a method developed in my lab at Baylor, integrating the findings with the results from studies in mouse and rat models of the condition to better understand what drives this lipid overload."

The team began by assessing gene changes in hearts from people diagnosed with metabolic stress along with various cardiovascular complications and found alterations in the expression of 488 genes. "We found particularly relevant the simultaneous reduction of the expression of genes XBP1 and EDEM2 in human HFpEF hearts," Mohamed said.

The link between EDEM2 and other conditions has been studied, but its role in the heart remains unexplored.

"We discovered that the XBP1 protein regulates the Edem2 gene in animal models and that EDEM2 was downregulated in hearts from individuals with metabolic disorders and in mouse models," Mohamed said. "Further evidence supported the involvement of EDEM2 and XBP1 in cardiovascular diseases and lipid regulation."

To investigate whether XBP1 and EDEM2 were directly involved in lipid toxicity and HFpEF, the researchers removed the Xbp1 or the Edem2 gene in mice. Consequently, these mice became more vulnerable to metabolic stress-induced heart lipid toxicity and cardiac dysfunction. "It was exciting to see that restoring XBP1 or EDEM2 alleviated lipid overload in the heart and reversed HFpEF," Mohamed said.

This comprehensive study uncovered that XBP1 and EDEM2 work together to maintain a healthy lipid balance in heart cells. The findings provide molecular and functional evidence that deficiency of XBP1-EDEM2 leads to lipid toxicity in the heart, accelerating the onset and development of heart failure in metabolic disorders.

"Our findings support further study of the XBP1s and EDEM2 pathway as a promising therapeutic target for mitigating cardiac lipotoxicity and progression of HFpEF," Mohamed said.

For a complete list of the contributors to this work and their affiliations, see the publication.

This work was supported by the British Heart Foundation (FS/15/16/31477, FS/18/73/33973, FS/19/70/34650, PG/19/66/34600, FS/PhD/22/29307, PG/22/10904 and PG/22/11075), a BHF Accelerator award (AA/18/4/34221), and grants FS/18/4/33310 and PG/23/11662. Further support was provided by a professorship and grant (81Z0700201) from the German Centre for Cardiovascular Research and the German Research Foundation (SFB-1470-A02). Additional support included NIH grants (R01HL147921, P30GM127607 and F32HL149140), Department of Defense grant (W81XWH-20-1-0419), American Heart Association grant (16SDG29950012) and NIHR Manchester Biomedical Research Centre grant (NIHR203308).