Compendium: Pharmacologic Management of Aneurysms

• Published in: Circulation research Vol. 124; no. 4; pp. 631 - 646
• Main Authors: Lindeman, Jan H., Matsumura, Jon S.
• Format: Journal Article
• Language: English
• Published: 15.02.2019
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.118.312439

Current management of aortic aneurysms relies exclusively on prophylactic operative repair of larger aneurysms. Great potential exists for successful medical therapy that halts or reduces aneurysm progression and hence alleviates or postpones the need for surgical repair. Preclinical studies in the context of abdominal aortic aneurysm (AAA) identified hundreds of candidate strategies for stabilization, and data from pre-operative clinical intervention studies show that interventions in the pathways of the activated inflammatory and proteolytic cascades in enlarging AAA are feasible. Similarly, extensive series of studies in the murine models of Marfan syndrome-related aortapathy inherited aortic root aneurysm support the concept of pharmaceutical aorta stabilization in Marfan syndrome. Although some clinical studies report successful medical stabilization of growing aortic aneurysms and aortic root stabilization in Marfan syndrome, these claims are not consistently confirmed in larger and controlled studies. Consequently, no medical therapy can be recommended for the stabilization of aortic aneurysms. The discrepancy between preclinical successes and clinical trial failures implies shortcomings in the available models of aneurysm disease, and perhaps incomplete understanding of the pathologic processes involved in later stages of aortic aneurysm progression. Preclinical models more reflective of human pathophysiology, identification of biomarkers to predict severity of disease progression, and improved design of clinical trials may more rapidly advance the opportunities in this important field. The inconsistent correlations of preclinical successes and clinical trial results provide impetus for major advances in research innovation of aortic aneurysm. There are several explanations for this translational gap, including inadequate animal models, incomplete understanding of late stage human pathogenesis, and poorly-designed, underpowered clinical trials. Development of humanized models, advancing beyond early chemically-provoked models to those consistently demonstrating sequential dilation and rupture, addressing dysfunctional repair mechanisms, clinical studies utilizing digitized pharmaceutical histories and extensive prior radiographic records of aneurysm size to explore relationships without the heavy expense of prospective trials, imaging and genetic biomarkers predicting stability or rapid progression of aneurysm enlargement, run-in periods ensuring populations with active aortic enlargement prior to randomization of subjects, greater attention to concomitant medical therapy of cardiovascular risk factors, and longer follow up with clinical endpoints in clinical trials are all areas of opportunity in this important field.