Mohamed Adel Zayed

Background: Abdominal aortic aneurysms (AAA) are a complex degenerative vascular disease. The role of fibrosis in AAA progression is unclear. Our study evaluated the impact of fibroblast activation protein (FAP), collagen, and vimentin on AAA fibrosis and progression. We hypothesized that FAP may influence fibrosis and disease severity in AAA, with potential sex-specific differences. Study Design: Multi-centered transcriptomic analysis of aortic samples from 15 human AAA and 5 non-AAA was performed to evaluate cell-specific fibrosis gene expression profiles. Histopathological and molecular analysis of 26 male and female AAA samples (mAAA and fAAA) and 29 male and female normal abdominal aortas (mNAA and fNAA) was performed to assess whole-tissue fibrosis markers and signaling. Results: Single-cell RNA sequencing (scRNA-seq) analysis identified eight major cell clusters with distinct sex-based distributions. Although vascular smooth muscle cells (VSMCs) and fibroblast clusters had reduced counts in both male and female AAAs, they more highly expressed FAP and COL1A1 genes, particularly in females. Whole-tissue analysis demonstrated elevated extracellular matrix deposits with markedly increased collagen type 1 in both mAAA and fAAA. Alpha-smooth muscle actin (α-SMA)-positive VSMCs were also reduced in mAAA and fAAA, but FAP was notably elevated, and robustly in fAAA. FAP-positive fibroblasts in fAAA exhibited increased expression of fibrosis markers, suggesting a unique pro-fibrotic phenotype. Conclusion: Our study reveals a sex-based difference in AAA tissue, with elevated fibrosis markers and increased FAP levels in females, suggesting its significant role in disease progression. These findings underscore the potential of FAP as a unique tissue biomarker for AAAs and warrants further investigation into novel targeted therapies that aim to stabilize AAAs, particularly in female patients.

Fatty acid synthase (FAS), the rate-limiting enzyme of de novo lipogenesis, is now recognized as a multifunctional regulator of cardiovascular homeostasis; its roles extend beyond simple FA biosynthesis to encompass calcium signalling, cholesterol trafficking, and inflammatory modulation. This review synthesizes current understanding of FAS molecular biology, tissue-specific expression, and pathophysiological contributions to cardiovascular disease. Circulating FAS (cFAS) associates with lipoproteins and promotes macrophage foam cell formation independently of low-density lipoprotein cholesterol concentration, establishing a novel atherogenic mechanism. cFAS is primarily hepatic in origin and is released under conditions of enhanced de novo lipogenesis and insulin resistance. Adipose tissue may also contribute through extrusion of FAS. In macrophages, Fasn deletion enhances cholesterol efflux through liver X receptor alpha induction and ATP-binding cassette transporter A1 upregulation, reducing atherosclerosis by 20–40% in preclinical models without affecting serum lipids. Vascular smooth muscle cells up-regulate FAS during phenotypic switching, facilitating transformation into foam cells within plaques. Clinical studies have established cFAS as a diagnostic biomarker for peripheral arterial disease, with higher concentrations present in affected individuals; elevated cFAS may also discriminate more severe disease. Despite its pathogenic roles in atherosclerosis, cardiac FAS serves essential stress-adaptive functions through calcium/calmodulin-dependent protein kinase II regulation, as cardiac-specific Fasn knockout mice exhibit profound stress intolerance and accelerated aging-related cardiac dysfunction, demonstrating that FAS-mediated de novo lipogenesis is indispensable for myocardial stress responses. This observation necessitates tissue-specific therapeutic approaches. Pharmacological FAS inhibitors, including TVB-2640 (denifanstat), demonstrate acceptable safety profiles in clinical trials and reduce hepatic de novo lipogenesis by 50–70%, while platensimycin reduces atherosclerotic burden in preclinical models. These findings position FAS as both a mechanistic driver and promising therapeutic target for cardiovascular disease. However, the divergent consequences of FAS modulation across tissues underscore the need for targeted delivery strategies that suppress pathological lipogenesis while preserving essential cardiac functions.

Background: Preoperative risk assessment in vascular surgery relies on clinical scores and lipids that do not capture atherosclerotic disease activity. Circulating fatty acid synthase (cFAS) is a liver-derived enzyme whose concentration correlates with arterial plaque FAS content independent of LDL. The 5-item modified frailty index (mFI-5) is a validated predictor of postoperative mortality. Whether cFAS predicts outcomes after vascular surgery, and whether combining it with the mFI-5 improves risk discrimination, have not been examined. Methods: We studied 657 patients undergoing elective vascular surgery at a single center (2014 to 2023). cFAS was classified as non-detectable (n = 306) or, among detectable values, by tertiles (n = 117 each). Multivariable Cox models assessed associations with major adverse events (MAE), major adverse cardiovascular events (MACE), major adverse limb events (MALE), reintervention, and mortality, and Harrell’s C-statistic quantified the incremental discrimination gained by adding cFAS and the mFI-5 to standard clinical covariates. Results: High serum cFAS was independently associated with 5-year MAE (adjusted hazard ratio [aHR] 1.94; 95% CI 1.31-2.85), mortality (aHR 1.77; 1.05 to 3.00), MALE (aHR 4.53; 2.04 to 10.05), and reintervention (aHR 2.50; 1.37 to 4.57), but not MACE. Severe frailty (mFI-5 of 3 or higher) was associated with MACE (aHR 2.69; 1.29 to 5.58) and MAE (aHR 2.46; 1.30 to 4.65) but not limb endpoints at 1 year. Adding cFAS raised the 1-year MALE C-statistic from 0.649 to 0.764; the combined model yielded the highest discrimination. Conclusions: cFAS and mFI-5 were independently and additively associated with adverse outcomes after elective vascular surgery. cFAS was associated with limb events and mortality, the mFI-5 with cardiovascular events. Combining them improved discrimination over standard covariates. CLINICAL PERSPECTIVE: What Is New?: A single preoperative measurement of circulating fatty acid synthase (cFAS) independently predicted adverse outcomes after elective vascular surgery, establishing cFAS as a prognostic biomarker of atherosclerotic disease activity beyond its previously reported diagnostic role. cFAS and the 5-item modified frailty index (mFI-5) captured complementary and additive dimensions of postoperative risk: disease activity and physiologic reserve, respectively. Combining cFAS with the mFI-5 improved risk discrimination beyond standard clinical covariates for all endpoints examined. What Are the Clinical Implications?: cFAS may identify residual atherosclerotic risk not captured by standard lipid panels, offering a novel dimension of preoperative assessment in vascular surgery. Incorporating a routine frailty assessment (mFI-5) alongside a disease-activity biomarker (cFAS) could enhance preoperative risk stratification by addressing two distinct and additive determinants of surgical outcome. Prospective external validation is warranted before cFAS is adopted as an adjunct to established preoperative cardiovascular risk assessment in vascular surgery.

Background: Abdominal aortic aneurysm (AAA) rupture leads to high morbidity and mortality. Current rodent models struggle to reliably mimic infrarenal AAA rupture. Chemical treatments using pancreatic elastase (PE), papain (Pa), β-aminopropionitrile (BAPN), and angiotensin II (ANG II) are known to induce AAA in rodents. We hypothesized that combining these agents can synergistically lead to acute AAA rupture models, as well as chronic AAA models that closely resemble human pathology. Methods: AAAs were induced in 125 male C57BL/6 mice via peri-adventitial exposure for twenty minutes using a cotton ball with either PE, Pa, or a combination of both (PE+Pa), with or without BAPN and ANG II. Results: Two weeks post-induction, all groups exhibit significantly elevated aortic diameters, increased inflammation, elastin and collagen degradation, and matrix metallopeptidase (MMP) activity. The addition of BAPN results in large chronic AAAs (500% growth) and intraluminal thrombus (ILT) formation. Further addition of ANG II results in a 93% rupture rate in the PE+Pa group, significantly increased compared to PE and Pa alone. Compared to previous models, the PE+Pa, BAPN and ANG II combination demonstrates an increase in rupture events, inflammation, and MMP activation. Conclusions: This murine model, using a synergistic combination of pancreatic elastase and papain, effectively replicates AAA pathophysiology and is ideal for investigating underlying mechanisms and potential therapeutic interventions.

The CCR2/CCL2 molecular axis is a critical mediator of abdominal aortic aneurysm (AAA) pathogenesis. It has been demonstrated to drive chronic inflammation, extracellular matrix degradation, and vascular remodeling through the recruitment and activation of monocytes/macrophages and other immune cell types. Pre-clinical studies demonstrate that CCR2 inhibition reduces AAA formation, expansion, and progression in animal models. Emerging imaging techniques have validated CCR2 as a biomarker for AAA instability in humans. Although clinical trials targeting CCR2 are currently limited in number, ongoing translational studies highlight that CCR2 blockade is a promising therapeutic strategy to mitigate AAA expansion and the risk of rupture. This review underscores the potential of CCR2-targeting interventions to fill a critical unmet need to develop effective medical therapies for longitudinal clinical AAA management.