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Abdominal aortic aneurysms (AAAs) are prevelant with aging, and AAA rupture is associated with high mortality. There is currently no effective medical therapy for AAA rupture. Previous work demonstrated that the monocyte chemoattractant protein (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis critically regulates AAA inflammation, matrix-metalloproteinase (MMP) production, and extracellular matrix (ECM) stability. Here we similarly observed that Ccr2-/- mice have significantly reduced AAA expansion and rupture. We therefore hypothesized that a dietary modulation of the CCR2 axis may therapeutically impact AAA risk of rupture. Since ketone bodies (KBs) can trigger repair mechanisms in response to inflammation, we specifically evaluated whether systemic ketosis in vivo can reduce CCR2 and AAA progression. Male Sprague-Dawley rats underwent surgical AAA formation using porcine pancreatic elastase (PPE), and received daily β-aminopropionitrile (BAPN) to promote AAA rupture. Animals with AAAs received either a standard diet (SD), ketogenic diet (KD), or exogenous KBs (EKB). Animals recieving KD and EKB reached a state of ketosis, and had significant reduction in AAA expansion and incidence of rupture. Ketosis also led to significantly reduced aortic CCR2 content, improved MMP balance, and reduced ECM degradation. In summary, this study demonstrates that ketosis plays a crucial role in AAA pathobiology, and provides the impetus for future clinical studies investigating the potential benefit of ketosis for prevention of AAA expansion and rupture., Competing Interests: Disclosures The authors declare that they have no competing interests.

Abdominal aortic aneurysms (AAAs) are common in aging populations, and AAA rupture is associated with high morbidity and mortality. There is currently no effective medical preventative therapy for AAAs to avoid rupture. It is known that the monocyte chemoattractant protein (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis critically regulates AAA tissue inflammation, matrix-metalloproteinase (MMP) production, and in turn extracellular matrix (ECM) stability. However, therapeutic modulation of the CCR2 axis for AAA disease has so far not been accomplished. Since ketone bodies (KBs) are known to trigger repair mechanisms in response to vascular tissue inflammation, we evaluated whether systemic in vivo ketosis can impact CCR2 signaling, and therefore impact AAA expansion and rupture. To evaluate this, male Sprague-Dawley rats underwent surgical AAA formation using porcine pancreatic elastase (PPE), and received daily β-aminopropionitrile (BAPN) to promote AAA rupture. Animals with formed AAAs received either a standard diet (SD), ketogenic diet (KD), or exogenous KB supplements (EKB). Animals that received KD and EKB reached a state of ketosis, and had significantly reduced AAA expansion and incidence of rupture. Ketosis also led to significantly reduced CCR2, inflammatory cytokine content, and infiltrating macrophages in AAA tissue. Additionally, animals in ketosis had improved balance in aortic wall matrix-metalloproteinase (MMP), reduced extracellular matrix (ECM) degradation, and higher aortic media Collagen content. This study demonstrates that ketosis plays an important therapeutic role in AAA pathobiology, and provides the impetus for future studies investigating the role of ketosis as a preventative strategy for individuals with AAAs.