The Pathophysiologic Basis and Management of Calcific Aortic Valve Stenosis (JACC August 2025-2)-Article: The Pathophysiologic Basis and Management of Calcific Aortic Valve Stenosis

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Calcific aortic valve stenosis (CAVS) is the most common valve disorder in adults and its prevalence increases with age. Traditionally viewed as a passive degenerative process, current understanding recognizes CAVS progression as an active, multifactorial disease driven by oxidative stress, chronic inflammation, lipoprotein deposition, and osteogenic signaling that lead to valve leaflet calcification and dysfunction.<br /><br />CAVS begins with endothelial injury and inflammation (initiation phase), progressing to valve interstitial cell osteoblastic differentiation and self-propagating calcification (propagation phase), resulting in worsening valve obstruction. Risk factors include elevated low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) (Lp[a]), hypertension, smoking, and mitochondrial dysfunction. Unique phenotypes such as bicuspid valves, chronic kidney disease, and female sex affect progression differently. Progressive valve obstruction leads to impaired cardiac output, left ventricular hypertrophy, subendocardial ischemia, and symptoms like angina, syncope, and heart failure.<br /><br />Currently, no pharmacologic treatments effectively slow or prevent CAVS progression. Surgical or transcatheter aortic valve replacement (SAVR or TAVR) remains the definitive treatment for symptomatic severe AS. Trials of lipid-lowering therapies, such as statins and ezetimibe, have failed to halt progression, possibly because they do not address the distinct pathophysiologic mechanisms in CAVS. Emerging therapies targeting Lp(a), oxidative stress pathways (e.g., soluble guanylate cyclase activators like ataciguat), and inflammation (e.g., colchicine) show promise but require further study.<br /><br />Novel imaging markers, specifically aortic valve calcification (AVC) quantified by computed tomography, provide sensitive assessment of disease severity and progression, independently predicting morbidity and mortality. These markers may aid earlier intervention and monitoring of therapeutic efficacy. Additionally, sodium-glucose cotransporter 2 (SGLT2) inhibitors like dapagliflozin have demonstrated benefits in reducing heart failure events post-TAVR.<br /><br />In summary, CAVS is an active, progressive disease with high morbidity and mortality. Despite advances in understanding its pathophysiology, effective medical therapies remain elusive. Future treatments focusing on molecular drivers of calcification and inflammation, combined with improved imaging for early detection and risk stratification, hold potential to alter the natural history of CAVS and improve patient outcomes.

Meta Tag

Concept Calcified Aortic Stenosis

Concept Aortic Valve Surgery

Concept SAVR

Concept Transcatheter Aortic Valve Replacement

Concept Aortic Sclerosis

Keywords

Calcific aortic valve stenosis

CAVS

valve calcification

oxidative stress

lipoprotein(a)

bicuspid aortic valve

transcatheter aortic valve replacement

sodium-glucose cotransporter 2 inhibitors

aortic valve calcification imaging

inflammation in valve disease

Calcified Aortic Stenosis

Aortic Valve Surgery

SAVR

Transcatheter Aortic Valve Replacement

Aortic Sclerosis