Biology subjects

Voors, A. A.

Publications and source records attributed to Voors, A. A..

4 recordsLinked to original sources

bioRxiv2026

Tricuspid valve regurgitation accelerates heart failure via a cardio-intestinal innate immune circuit

Activation of the immune system impacts the progression of heart failure (HF), but the underlying mechanisms remain incompletely understood. Here, we identify a cardio-intestinal innate immune axis that links systemic venous congestion to myocardial inflammation, fibrosis, and functional decline. Using single-cell and single-nucleus transcriptomic profiling in patients and mice with tricuspid regurgitation (TR), we demonstrate that TR disrupts intestinal barrier integrity and elicits expansion of circulating monocytes which in turn orchestrate pathological crosstalk between the right and left heart. Monocyte-derived Interleukin-6 (IL-6) emerged as a key mediator of TR-driven myocardial fibrosis and dysfunction. Blockade of IL-6 attenuated cardiac fibrosis and improved cardiac function. In patients, catheter-based repair of TR resulted in reduced IL-6 levels. Together, these findings establish cardio-intestinal innate immunity as a mechanism linking altered hemodynamics to left ventricular remodeling and nominate TR patients as a selective target population for IL-6-directed therapy in HF. One Sentence SummaryThis work mechanistically resolves the heart-gut axis in tricuspid valve regurgitation, and its impact on heart failure progression as mediated by Interleukin-6.

immunology↗

bioRxiv2025

NGAL drives cardiac dysfunction and fibrosis in rats with chronic kidney disease

BackgroundPatients with chronic kidney disease (CKD) are at high risk of cardiovascular (CV) complications. Neutrophil gelatinase-associated lipocalin (NGAL) is a well established marker of kidney injury, but recent evidence suggests that NGAL might also play an active in the progression of the cardiorenal syndrome. MethodsCKD was induced in rats via 5/6 nephrectomy in wild-type (WT) and Ngal-knockout (KO) rats. Cardiorenal functions were assessed three months after subtotal nephrectomy or sham operation. Cardiac fibroblasts (CFs) were incubated with or without recombinant Ngal and galectin-3 (Gal-3). ResultsCardiac function, including diastolic hemodynamics and perfusion, was less impaired in CKD Ngal KO than in CKD WT. Cardiac fibrosis was more severe in CKD WT than sham, but was blunted in CKD Ngal KO rats. Levels of Gal-3, collagen I, MCP-1 and IL-6 were elevated in cardiac fibroblasts incubated with recombinant Ngal. A similar pattern was observed in cells treated with recombinant Gal-3. Both Ngal and Gal-3 induced activation of the Tlr4-Myd88 pathway. Using Gal-3 or Tlr4 inhibitors, we showed that Gal-3 contributes to Ngal-induced cardiac fibrosis and inflammation by activating the Tlr4-Myd88 pathway. In patients with heart failure with preserved ejection fraction (HFpEF) (MEDIA-DHF and BIOSTAT-CHF cohorts), elevated levels of NGAL and Gal-3 were associated with pulmonary artery systolic pressure, a marker of advanced diastolic dysfunction and adverse clinical outcomes, particularly among patients with impaired renal function. ConclusionIn non-diabetic CKD rats, Ngal was involved in the progression of diastolic dysfunction via a Gal-3/Tlr4-dependent pathway increasing inflammation and fibrosis.

pathology↗

bioRxiv2022

GDF15 antagonism limits severe heart failure and prevents cardiac cachexia in mice

Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2 phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.

pathology↗

bioRxiv2021

Variation in Human Herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals

Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally- integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV- 6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.

genetics↗