When Blood Vessels Trigger Heart Failure: A New Mechanism Driving Inherited Cardiomyopathy

August 12, 2026

A New Perspective on LMNA Cardiomyopathy

LMNA-related dilated cardiomyopathy (LMNA-DCM) is one of the most aggressive inherited forms of heart failure. Patients often develop dangerous heart rhythm disturbances, progressive scarring of the heart (fibrosis), and ultimately heart failure, frequently requiring heart transplantation. While mutations in the LMNA gene have long been thought to damage the heart primarily by affecting cardiomyocytes, the cells responsible for contraction, the mechanisms driving progressive fibrosis have remained poorly understood.

The Endothelium: An Unexpected Driver of Cardiac Fibrosis

Researchers at the Stanford Cardiovascular Institute have identified an unexpected culprit: the endothelium, the thin layer of cells lining every blood vessel. Endothelial cells are essential for maintaining healthy blood vessels and supporting normal heart function. Rather than serving as passive bystanders, these cells actively communicate with surrounding heart muscle and help preserve the normal architecture of the heart. The new study demonstrates that endothelial cells undergo a dramatic identity change known as endothelial-to-mesenchymal transition (EndoMT). During this process, endothelial cells lose their normal characteristics and acquire properties that actively promote fibrosis, leading to progressive stiffening and dysfunction of the heart. “For many years, LMNA cardiomyopathy has largely been viewed through the lens of the cardiomyocyte,” said Nazish Sayed, MD, PhD, senior author of the study. “Our findings suggest that the endothelium is not simply a bystander. Endothelial cells undergo profound reprogramming that can actively contribute to fibrosis and cardiac dysfunction.”

RUNX1 Reprograms Blood Vessel Cells

The research team identified the transcription factor RUNX1 as a central molecular regulator (a protein that helps switch genes on and off) of this endothelial reprogramming. Normally tightly controlled, RUNX1 became activated in endothelial cells from patients with LMNA cardiomyopathy, triggering widespread changes in gene expression and chromatin accessibility that drove EndoMT and fibrotic remodeling, , the buildup of scar tissue that changes the heart’s structure. Importantly, the investigators demonstrated that both genetic deletion and pharmacological inhibition of RUNX1 restored normal endothelial identity, suppressed EndoMT, reduced fibrosis, and improved cardiac function. “What was particularly exciting was identifying RUNX1 as a molecular switch underlying this endothelial transformation,” Sayed said. “When we inhibited RUNX1, genetically or pharmacologically, we were able to restore endothelial identity, reduce fibrosis, and improve cardiac function across multiple experimental models.”

Building a Human Model of Inherited Heart Disease

Led by senior author Nazish Sayed, the research team combined multiple complementary technologies to investigate the disease across biological scales. The study integrated spatial transcriptomics and single-nucleus multiomics of explanted human hearts with patient-specific induced pluripotent stem cell-derived endothelial cells, engineered multicellular cardiac organoids (small, three-dimensional heart-like tissues grown in the laboratory), and genetically engineered mouse models of LMNA cardiomyopathy. This comprehensive approach allowed the investigators to directly connect molecular changes observed in human patients with functional abnormalities reproduced in laboratory models.

Toward Disease-Modifying Therapies

Current treatments for LMNA cardiomyopathy primarily address the consequences of heart failure and arrhythmias but do not directly prevent the progressive development of fibrosis.

This study identifies RUNX1-mediated endothelial dysfunction as a previously unrecognized disease mechanism and demonstrates that targeting this pathway can reduce fibrosis, preserve cardiac function, and decrease arrhythmic burden even after disease has already begun. “Patients with LMNA cardiomyopathy currently have therapies that manage heart failure and arrhythmias, but we do not yet have treatments that directly target the mechanisms driving progressive fibrosis,” Sayed said. “The fact that RUNX1 inhibition was beneficial even after disease was established raises the possibility that targeting endothelial reprogramming could eventually provide a disease-modifying strategy rather than simply treating the consequences of the disease.”

These findings suggest that therapies directed at the endothelium could complement existing heart failure treatments and potentially alter the natural history of this inherited disease. More broadly, the study highlights endothelial plasticity, the ability of endothelial cells to change their identity, as a potential therapeutic target in fibrotic cardiomyopathy. It also provides a framework for developing treatments that target the mechanisms driving cardiac remodeling rather than solely treating its consequences.

Other Stanford Cardiovascular Institute authors include David Wu, Dipti Tripathi, Amit Manhas, Chikage Noishiki, Lu Liu, Catherine Wu, Ravichandra Venkateshappa, Hao Zhang, Lu Ren, Dilip Thomas, Shriram Nallamsherry, Jack Boyd, Y. Joseph Woo, Karim Sallam, and Joseph Wu. Additional Stanford collaborators include Minas Nalbandian, Lasemahang Limbu, Claire DaValle, and Helen Blau. This study also included a collaboration with Dr. Danish Sayed at Rutgers New Jersey Medical School.