Background: Thoracic aortic aneurysms (TAAs) occur because of abnormal remodeling of aortic extracellular matrix and are accompanied by the emergence of proteolytically active myofibroblasts. The microRNA miR‐133a regulates cellular phenotypes and is reduced in clinical TAA specimens. This study tested the hypothesis that miR‐133a modulates aortic fibroblast phenotype, and overexpression by lentivirus attenuates the development of TAA in a murine model. Methods and Results: TAA was induced in mice. Copy number of miR‐133a was reduced in TAA tissue and linear regression analysis confirmed an inverse correlation between aortic diameter and miR‐133a. Analyses of phenotypic markers revealed an mRNA expression profile consistent with myofibroblasts in TAA tissue. Fibroblasts were isolated from the thoracic aortae of mice with/without TAA. When compared with controls, miR‐133a was reduced, migration was increased, adhesion was reduced, and the ability to contract a collagen disk was increased. Overexpression/knockdown of miR‐133a controlled these phenotypes. After TAA induction in mice, a single tail‐vein injection of either miR‐133a overexpression or scrambled sequence (control) lentivirus was performed. Overexpression of miR‐133a attenuated TAA development. The pro‐protein convertase furin was confirmed to be a target of miR‐133a by luciferase reporter assay. Furin was elevated in this murine model of TAA and repressed by miR‐133a replacement in vivo resulting in reduced proteolytic activation. Conclusions: miR‐133a regulates aortic fibroblast phenotype and over‐expression prevented the development of TAA in a murine model. These findings suggest that stable alterations in aortic fibroblasts are associated with development of TAA and regulation by miR‐133a may lead to a novel therapeutic strategy.

The authors present a comprehensive protocol for quantifying plasma miRNAs using droplet digital PCR.

This review article presents an appraisal of pioneering technologies poised to revolutionize the diagnosis and management of aortic aneurysm disease, with a primary focus on the thoracic aorta while encompassing insights into abdominal manifestations. Our comprehensive analysis is rooted in an exhaustive survey of contemporary and historical research, delving into the realms of machine learning (ML) and computer-assisted diagnostics. This overview draws heavily upon relevant studies, including Siemens’ published field report and many peer-reviewed publications. At the core of our survey lies an in-depth examination of ML-driven diagnostic advancements, dissecting an array of algorithmic suites to unveil the foundational concepts anchoring computer-assisted diagnostics and medical image processing. Our review extends to a discussion of circulating biomarkers, synthesizing insights gleaned from our prior research endeavors alongside contemporary studies gathered from the PubMed Central database. We elucidate the prevalent challenges and envisage the potential fusion of AI-guided aortic measurements and sophisticated ML frameworks with the computational analyses of pertinent biomarkers. By framing current scientific insights, we contemplate the transformative prospect of translating fundamental research into practical diagnostic tools. This narrative not only illuminates present strides, but also forecasts promising trajectories in the clinical evaluation and therapeutic management of aortic aneurysm disease.

Background: Thoracic aortic aneurysms (TAAs) associated with Marfan syndrome (MFS) are unique in that extracellular matrix metalloproteinase inducer (EMMPRIN) levels do not behave the way they do in other cardiovascular pathologies. EMMPRIN is shed into the circulation through the secretion of extracellular vesicles. This has been demonstrated to be dependent upon the Membrane Type-1 MMP (MT1-MMP). We investigated this relationship in MFS TAA tissue and plasma to discern why unique profiles may exist. Methods: Protein targets were measured in aortic tissue and plasma from MFS patients with TAAs and were compared to healthy controls. The abundance and location of MT1-MMP was modified in aortic fibroblasts and secreted EMMPRIN was measured in conditioned culture media. Results: EMMPRIN levels were elevated in MFS TAA tissue but reduced in plasma, compared to the controls. Tissue EMMPRIN elevation did not induce MMP-3, MMP-8, or TIMP-1 expression, while MT1-MMP and TIMP-2 were elevated. MMP-2 and MMP-9 were reduced in TAA tissue but increased in plasma. In aortic fibroblasts, EMMPRIN secretion required the internalization of MT1-MMP. Conclusions: In MFS, impaired EMMPRIN secretion likely contributes to higher tissue levels, influenced by MT1-MMP cellular localization. Low EMMPRIN levels, in conjunction with other MMP analytes, distinguished MFS TAAs from controls, suggesting diagnostic potential.

Thoracic aortic aneurysm (TAA) results from dysregulated remodeling of the extracellular matrix mediated by matrix metalloproteinase (MMP) activity. Previous studies identified elevated membrane type-1 MMP (MT1-MMP) abundance and activity during TAA development and suggested aortic fibroblasts as a potential key source. Herein, we extended our understanding of the role of MT1-MMP during TAA development using various MT1-MMP transgenic mouse strains. MT1-MMP deficient (MT1-MMP^+/−) mice exhibited reduced MT1-MMP abundance, activity, and collagen volume fraction following TAA induction, concomitant with reduced aortic dilatation. TAA tissue from wild-type and MT1-MMP^+/− mice showed a similar reduction in thin collagen fibers, while the MT1-MMP^+/− mice displayed no change in thick collagen fibers. The role of fibroblast-derived MT1-MMP was examined using a conditional fibroblast-specific tamoxifen-inducible MT1-MMP knockout strain (FbMT1KO). TAA-induced changes in aortic diameter and MT1-MMP abundance were attenuated in FbMT1KO mice. Using aortic fibroblasts isolated from multiple mouse strains expressing different levels of MT1-MMP, a significant correlation between MT1-MMP abundance and TGF-β activation was observed. Importantly, treatment with MT1-MMP activity-neutralizing antibody or TGF-β neutralizing antibody resulted in the attenuation aortic dilatation. Together, these findings suggest that fibroblast-derived MT1-MMP is required for TAA development, in part through its ability to induce TGF-β signaling.

Mitral valve prolapse (MVP) affects 1–3% of the general population and is largely considered benign. However, a small subset of MVP patients develops complex ventricular arrhythmias (VAs) and sudden cardiac death, including patients with nonsignificant mitral regurgitation (MR). This subgroup of arrhythmic MVP (aMVP) is variably associated with features such as mitral annular disjunction, bileaflet myxomatous prolapse, and regional myocardial fibrosis, with arrhythmic risk disproportionate to hemodynamic burden. The EHRA defines aMVP as MVP with complex VAs (frequent premature ventricular contractions, non-sustained or sustained ventricular tachycardia, ventricular fibrillation, or aborted sudden cardiac arrest) in the absence of another defined arrhythmic substrate. This narrative review reframes aMVP as a regional, stretch-induced cardiomyopathy with a distinct fibro-inflammatory signature. We further characterize a two-hit pathogenesis in which abnormal valvular mechanics create regional myocardial stress, while patient-specific vulnerability shapes variable fibro-inflammatory, fibrotic, and electromechanical responses. This narrative review synthesizes contemporary evidence across multimodal cardiac imaging, electrophysiology, surgical outcomes, mechanotransduction biology, and pharmacology, emphasizing a modifiable fibro-inflammatory trajectory underlying the intermediate risk aMVP phenotype and supporting a clinical shift from device-based rescue to substrate-directed prevention. Expanding on this model, we evaluate substrate-modifying pharmacotherapies for mechanistic fit, human cardiac evidence, and trial feasibility. Among these, mineralocorticoid receptor antagonists (MRAs) and sodium–glucose cotransporter 2 (SGLT2) inhibitors demonstrate the strongest convergence of antifibrotic potential and trial readiness.