Objectives: Fluoroquinolone (FQ) antibiotics are associated with adverse aortic clinical events. We assessed human aortic myofibroblast-mediated extracellular matrix (ECM) dysregulation as a possible cellular mechanism underlying FQassociated aortopathy. Methods: Human aortic myofibroblasts were isolated from patients with aortopathy undergoing elective ascending aortic resection (N ¼ 9). The capacity for extracellular matrix degradation in cells exposed to FQ was assessed by multiplex analysis of secreted matrix metalloproteinases relative to tissue inhibitors of matrix metalloproteinases (TIMPs). Direct evaluation of extracellular matrix degradation was investigated in human aortic cells using a 3-dimensional gelatin-fluorescein isothiocyanate fluorescence microgel assay. Aortic cellular collagen-1 expression following FQ exposure was determined by immunoblotting and immunofluorescent staining. Cell apoptosis, necrosis, and metabolic viability was determined by annexin-V, propidium iodide staining, and water-soluble tetrazolium salt (WST1) assay. Results: FQ exposure significantly decreased aortic cell TIMP-1 (P ¼ .004) and TIMP-2 (P ¼ .0004) protein expression compared with vehicle control. The ratio of matrix metalloproteinase-9/TIMP-2 was increased suggesting an increased capacity for extracellular matrix degradation (P ¼ .01). In collagen gels, we show a trend toward increased aortic myofibroblast-mediated collagen fiber degradation with FQ exposure (P ¼ .09). Similarly, FQ exposure attenuated collagen-1 expression as assessed by immunoblotting (P ¼ .002) and immunofluorescence (P ¼ .02). Cell apoptosis, necrosis, and metabolic viability was not significantly influenced by FQ exposure. Conclusions: For the first time, we document a putative mechanism underlying FQ-associated aortopathy whereby decreased TIMP expression with impaired compensatory collagen-1 expression results in human aortic myofibroblastmediated extracellular matrix dysregulation. These novel data may provide a cellular and molecular mechanism to explain the established clinical association between FQ exposure and acute aortic events.

Bicuspid aortic valve (BAV) disease has significant gaps in its clinical management practices. To highlight the potential utility of advanced hemodynamic biomarkers in strengthening BAV assessment, we used 4-dimentional flow magnetic resonance imaging to investigate altered hemodynamics in the ascending aorta (AAo). A total of 32 healthy controls and 53 age-matched BAV patients underwent cardiac magnetic resonance imaging at 3T, with cine imaging and 4D-flow. Analysis planes were placed along 3D-segmented aortas at the left ventricular outflow tract (LVOT), sinuses of Valsalva, mid-ascending aorta (MAA), and proximal to the first aortic branch. Locations were analyzed for aortic diameter (normalized to body surface area), pressure drop (PD), viscous energy loss (EL), and wall shear stress (WSS) sub-vectors (axial wall shear stress, circumferential wall shear stress [WSS C ], magnitude wall shear stress). Student's t tests, or non-parametric equivalents, compared parameters between cohorts. Univariable and multivariable analyses explored the associations of AAo diameter with hemodynamics within the BAV cohort. Compared to control cohort, BAV patients showed significantly greater PD (MAA: 9.5 ± 8.0 vs 2.8 ± 2.4 mm Hg; P < .01), EL (from LVOT-AA1: 7.39 ± 4.57 mW vs 2.90 ± 1.07 mW; P < .01), and WSS C (MAA: 0.3 ± 0.1 vs 0.2 ± 0.06 Pa; P ≤ .01) throughout the AAo. Correlational analyses revealed an inverse association between AAo diameter and both magnitude wall shear stress and axial wall shear stress. BAV patients exhibited increased PD, EL, and WSS C in the AAo, and an inverse association between AAo diameter and WSS sub-vectors. This demonstrated the impact of PD, EL, and WSS in BAV disease and the importance of altered hemodynamics in aortic remodelling.

Objectives: Clinical management decisions surrounding ascending aorta (AAo) dilation in bicuspid aortic valve (BAV) disease benefit from personalized predictive tools. 4D-flow MRI may provide patient-specific markers reflective of BAV-associated aortopathy. This study aims to explore novel 4D-flow MRI parametric voxel-by-voxel forward flow, reverse flow, kinetic energy and stasis in BAV disease. We hypothesize that novel parametric voxel-by-voxel markers will be associated with aortic dilation and referral for surgery and can enhance our understanding of BAV hemodynamics beyond standard metrics.Methods: A total of 96 subjects (73 BAV patients, 23 healthy controls) underwent MRI scan. Healthy controls had no known cardiovascular disease. Patients were clinically referred for AAo dilation assessment. Indexed diameters were obtained by dividing the aortic diameter by the patient’s body surface area. Patients were followed for the occurrence of aortic surgery. 4D-flow analysis was performed by a single observer in five regions: left ventricular outflow tract (LVOT), AAo, arch, proximal descending aorta (PDAo), and distal descending aorta (DDAo). In each region peak velocity, kinetic energy (KE), forward flow (FF), reverse flow (RF), and stasis were measured on a voxel-by-voxel basis. T-tests (or non-parametric equivalent) compared flow parameters between cohorts. Univariate and multivariate analyses explored associations between diameter and parametric voxel-by-voxel parameters.Results: Compared to controls, BAV patients showed reduced stasis (p &lt; 0.01) and increased RF and FF (p &lt; 0.01) throughout the aorta, and KE remained similar. In the AAo, indexed diameter correlated with age (R = 0.326, p = 0.01), FF (R = −0.648, p &lt; 0.001), RF (R = −0.441, p &lt; 0.001), and stasis (R = −0.288, p &lt; 0.05). In multivariate analysis, FF showed a significant inverse association with AAo indexed diameter, independent of age. During a median 179 ± 180 days of follow-up, 23 patients (32%) required aortic surgery. Compared to patients not requiring surgery, they showed increased KE and peak velocity in the proximal aorta (p &lt; 0.01), accompanied by increased RF and reduced stasis throughout the entire aorta (p &lt; 0.01).Conclusion: Novel voxel-by-voxel reverse flow and stasis were altered in BAV patients and are associated with aortic dilation and surgical treatment.