The increasing interest in treating aortic stenosis, coupled with the growing number of cases in an aging Western population (3% of individuals over 75, 10% over 80), has led to studies aimed at expanding knowledge of its pathophysiology, which has implications for different treatment techniques—both surgical and interventional—and their clinical outcomes. This article delves into various concepts related to calcification patterns of bicuspid and tricuspid aortic valves, their pathophysiology, and their relationship with patient survival following intervention.

Cardiac valve structure, from a histological perspective, comprises two well-differentiated regions. One is the endocardium, which produces nitric oxide, like the rest of the vascular endothelium; the other is the extracellular matrix that forms the valve structure and is populated by mesenchymal cells. Pathophysiologically, both regions are affected differently. The endocardium’s function is primarily compromised by the process known as atherosclerosis, where various cardiovascular risk factors play a role. The loss of functional cells reduces nitric oxide production and the hydrophilic coating of its glycocalyx, increasing the risk of atheroembolic events and bacterial endocarditis. On the other hand, stress forces, though also responsible for endothelial dysfunction, predominantly impact the extracellular matrix, transforming mesenchymal cells into osteoblastic cells and initiating the formation of calcification nuclei that lead to aortic stenosis. The growth of these nuclei without adequate vascularization can lead to central necrosis, also providing a substrate for infectious endocarditis.

Differences in stress and shear forces between bicuspid and tricuspid aortic valves lead to notable differences in degeneration and calcification patterns. In all valves, the highest stress area during the cardiac cycle is at the commissures, which is particularly significant at the raphe in bicuspid valves. Additionally, cardiac ejection through the outflow tract flows more laminar over the left and right coronary leaflets, causing greater vibration on the non-coronary leaflet. In bicuspid valves, due to their dome-shaped opening, this vibration is more common over the free edge of the effective valvular area, with the annulus being more protected as the leaflets lack the same degree of mobility as in tricuspid valves. In the annular region, the endocardium’s proximity to the aortic endothelium also subjects it to atherosclerotic processes.

The authors assigned 101 patients with severe aortic stenosis to surgical and interventional treatments. Fifty patients had bicuspid aortic valves, and fifty-one had tricuspid valves. Calcification patterns were rigorously analyzed in all patients via angio-CT. There were no differences in preoperative variables. Survival outcomes were analyzed based on calcification patterns, comparing both types of valves. Although the surgical and interventional options were not separately reported, the therapeutic choice did not significantly impact postoperative results. Regarding calcification patterns, the non-coronary leaflet exhibited the highest calcification degree across all valve types. Bicuspid valves showed a higher calcification volume, more concentrated on the non-coronary leaflet and the free edge, compared to tricuspid valves. Tricuspid valves showed a greater degree of annular involvement. Five-year survival was similar for patients with bicuspid or tricuspid valves after treatment. However, patients with annular calcification above the median showed lower survival. Calcification levels above the median in the leaflet body or free edge involvement did not significantly affect survival.

COMMENTARY:

This is an original study that investigates the pathophysiology of aortic stenosis and its clinical implications. Little is still known about the mechanisms underlying degenerative valve disease. However, this study confirms the osteoblastic activity’s preference for areas of highest mechanical stress.

The calcification pattern’s implications for treating aortic stenosis are critical and often overlooked in treatment planning. While surgical technique involves a complete replacement, where the calcified leaflets are entirely removed, and the annulus is adapted to the prosthesis, TAVI involves an implant where the persistence of the valvular structure can interfere with the newly deployed prosthesis and the structures in the aortic root. This fact results in complications such as paravalvular leaks, more commonly occurring in the non-coronary leaflet region, as it has the highest degree of calcification. Severe degrees of annular calcification have also been associated with paravalvular leaks, especially when distributed asymmetrically, and they favor annular rupture in balloon-expandable prostheses. In bicuspid valves, calcification pattern variations in the free edge and raphe lead to poor implant adaptation, resulting in suboptimal stent positioning with paravalvular leaks in the commissures and greater stress on calcium deposits, which can cause embolism. Calcium masses are laterally displaced, occupying the Valsalva sinus space, altering its diastolic hemodynamics and potentially compromising coronary flow in specific aortic root configurations (coronary ostium height <10 mm, prominent calcium masses on the aortic face of coronary leaflets). Along these lines, different studies, with limited impact on current clinical guidelines, have associated adverse events during TAVI with the valve’s calcium score measured in Hounsfield units. In the future, various computational systems with individualized flow dynamics analysis, mechanical stress, augmented reality, and 3D technology will allow more accurate implant outcome predictions and not only patient assignment to the surgical or interventional option at equal predicted risk but also the most suitable device to use according to adaptability, radial strength, stent cell size, release mechanism, etc.

Finally, another relevant factor has been the association of extensive annular calcification with higher mortality during follow-up. Despite balanced group characteristics, including age and cardiovascular risk factors, patients with more annular calcification may likely have a higher atherosclerotic burden, another mechanism underlying degenerative valve disease. This increased morbidity has likely been responsible for differences in survival during follow-up, regardless of the treatment technique applied.

REFERENCE:

Gollmann-Tepeköylü C, Nägele F, Engler C, Stoessel L, Zellmer B, Graber M, et al. Different calcification patterns of tricuspid and bicuspid aortic valves and their clinical impact. Interact Cardiovasc Thorac Surg. 2022 Nov 8;35(6). doi: 10.1093/icvts/ivac274.