Engineered human cardiac tissue reveals how lupus autoantibodies damage the heart

Study: An engineered human cardiac tissue model reveals contributions of systemic lupus erythematosus autoantibodies to myocardial injury. Image Credit: Shit4Sell / Shutterstock.com

In a recent study published in the journal Nature Cardiovascular Research, researchers investigate the mechanisms of myocardial injury in systemic lupus erythematosus (SLE).

How does lupus affect the heart?

Myocardial involvement affects 25-50% of SLE patients and often leads to ventricular dysfunction, inflammation, and heart failure. T-cells and autoantibodies are primarily responsible for organ damage in SLE; however, the exact mechanisms by which autoantibodies contribute to myocardial injury remain unclear. Thus, further research is needed to fully understand the complex mechanisms by which different SLE autoantibodies contribute to myocardial injury and identify targeted therapeutic strategies.

About the study

Study participants were recruited from the Columbia University Lupus Center and provided informed consent, with approval from the Columbia University Institutional Review Board (IRB). The current study included both non-hospitalized patients with SLE without active cardiac symptoms and hospitalized patients with active cardiac symptoms.

Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging was employed to detect myocardial inflammation in all study participants. Eligible participants were 18 years or older, met the 1997 American College of Rheumatology (ACR) classification criteria for SLE, and, in cases of both myocardial inflammation and systolic dysfunction (SD), showed an acute decline in ejection fraction (EF) at enrollment. Clinical data such as disease duration, cardiovascular risk factors, and SLE disease activity were collected, while laboratory tests assessed various autoantibodies and other biomarkers.

Myocardial inflammation was evaluated using a Siemens Medical Systems MCT 64 PET/CT (MCT 64 PET/CT) scanner. Immunoglobulin G (IgG) antibodies were isolated from patient serum samples and used in experiments with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cultured under optimized conditions.

Flow cytometry, calcium imaging, immunostaining, metabolic analysis, and ribonucleic acid (RNA) sequencing were utilized to assess the effects of patient IgG on cardiac tissue function. Surface protein analysis involved using liquid chromatography-tandem mass spectrometry (LC-MS/MS), whereas phage immunoprecipitation sequencing (PhIP-seq) identified differences in autoantibody profiles between patient groups. Statistical analyses ensured the reproducibility of the results, with appropriate tests used to compare data across groups.

Study findings 

Study participants were classified as those with or without myocardial inflammation and were denoted as Myo+ and Myo-, respectively, with SUVmax values greater than or less than 1.5, respectively. Serum samples and echocardiograms were collected at the time of imaging to further categorize Myo+ patients as those with systolic dysfunction (Myo+SD+) or those with preserved systolic function (Myo+SD−), with EF values less than or greater than 50%, respectively.

None of the study participants had elevated serum troponin levels or a history of ischemic heart disease. Furthermore, no significant differences in cardiovascular risk factors were observed between the groups.

Human cardiac tissues were engineered using hiPSC-CMs and primary human cardiac fibroblasts in a 3:1 ratio. These cells were subsequently embedded in fibrin hydrogels and subjected to an electromechanical stimulation regimen on the milliPillar platform.

Tissues were cultured in a maturation medium to enhance their metabolic and functional properties, tissue compaction, α-actinin striations, and calcium handling. When subjected to stress, the tissues released elevated levels of lactate dehydrogenase (LDH).

IgG fractions were purified from each serum sample and added to the cultured cardiac tissues after 14 days. Tissues were further cultured under stress conditions for an additional 14 days.

IgG binding, determined through anti-human IgG staining, revealed significantly higher binding levels in tissues in patients with elevated myocardial inflammation than in Myo-patients. Linear regression analysis identified a strong positive correlation between IgG binding and myocardial inflammation (SUVmax). Thus, IgG from patients with high inflammation levels preferentially binds to stress-induced apoptotic cells within cardiac tissues.

Further studies indicated that IgG from Myo+SD+ patients exhibited significantly higher binding to the surfaces of live cardiomyocytes as compared to IgG from other patient groups. This binding correlated with reduced EF and impaired calcium handling in the tissues, as demonstrated by increased tau and full width at half maximum (FWHM) in calcium transients. RNA sequencing revealed that tissues treated with Myo+SD+ IgG exhibited distinct gene expression profiles, particularly involving pathways related to cardiomyopathies, oxidative stress, and mitochondrial function.

Four candidate pathogenic autoantibodies targeting disco-interacting protein 2 homolog A (DIP2A), LIM domain only 7 (LMO7), poliovirus receptor (PVR), and plasminogen activator, urokinase receptor (PLAUR) were identified, with LMO7 showing the strongest correlation with EF. 

Conclusions

IgG from patients with elevated myocardial inflammation increasingly binds to stressed cells, whereas IgG from those with myocardial inflammation and systolic dysfunction binds more tightly to live cardiomyocytes. This binding altered cellular function, respiration, and calcium handling, independent of immune cells.

Taken together, the study findings reveal the complex role of autoantibodies in SLE-related heart disease and suggest potential therapeutic targets.

Journal reference:
  • Fleischer, S., Nash, T. R., Tamargo, M. A., et al. (2024). An engineered human cardiac tissue model reveals contributions of systemic lupus erythematosus autoantibodies to myocardial injury. Nature Cardiovascular Research. doi:10.1038/s44161-024-00525-w 
Vijay Kumar Malesu

Written by

Vijay Kumar Malesu

Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.    

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