Calcific aortic stenosis

Abstract

Calcific aortic stenosis (AS) is the most prevalent heart valve disorder in developed countries. It is characterized by progressive fibro-calcific remodelling and thickening of the aortic valve leaflets that, over years, evolve to cause severe obstruction to cardiac outflow. In developed countries, AS is the third-most frequent cardiovascular disease after coronary artery disease and systemic arterial hypertension, with a prevalence of 0.4% in the general population and 1.7% in the population >65 years old. Congenital abnormality (bicuspid valve) and older age are powerful risk factors for calcific AS. Metabolic syndrome and an elevated plasma level of lipoprotein(a) have also been associated with increased risk of calcific AS. The pathobiology of calcific AS is complex and involves genetic factors, lipoprotein deposition and oxidation, chronic inflammation, osteoblastic transition of cardiac valve interstitial cells and active leaflet calcification. Although no pharmacotherapy has proved to be effective in reducing the progression of AS, promising therapeutic targets include lipoprotein(a), the renin-angiotensin system, receptor activator of NF-κB ligand (RANKL; also known as TNFSF11) and ectonucleotidases. Currently, aortic valve replacement (AVR) remains the only effective treatment for severe AS. The diagnosis and staging of AS are based on the assessment of stenosis severity and left ventricular systolic function by Doppler echocardiography, and the presence of symptoms. The introduction of transcatheter AVR in the past decade has been a transformative therapeutic innovation for patients at high or prohibitive risk for surgical valve replacement, and this new technology might extend to lower-risk patients in the near future.

Figure 1. The prevalence of aortic stenosis as a function of age

The prevalence of aortic stenosis (AS) according to age in the following population-based series from the USA or Europe: Lindroos et al. (Finland), in which AS was defined as an aortic valve area of < 1.2 cm²; Stewart et al. (Cardiovascular Health Study, USA), in which AS was defined as a peak aortic jet velocity of > 2.5 m per sec; Nkomo et al. (USA), in which AS was defined as an aortic valve area of < 1.5 cm²; Eveborn et al. (Tromsø Study, Norway), in which AS defined was as a mean gradient of ≥ 15 mmHg; Danielsen et al. (AGES-Reykjavik Study, Iceland), in which AS was defined as an indexed aortic valve area of ≤ 0.6 cm² per m².

Figure 2. Comparison of tricuspid and bicuspid aortic valve structures

Schematic representation of A) a normal — tricuspid — aortic valve with the 3 cusps, B) a bicuspid valve with right-left coronary cusp fusion and one raphe (the line of union between the fused cups), C) a bicuspid valve with fusion of the right-left coronary cusps and no raphe, D) a bicuspid valve with right-non coronary cusp fusion and one raphe and E) a bicuspid valve with fusion of the left-non coronary cups and one raphe. LC, left coronary; LCA, left coronary artery; NC, non-coronary; RC, right coronary; RCA, right coronary artery.

Figure 3. Macroscopic and histopathologic appearance of normal and abnormal aortic valves

Photographs of A) a normal aortic valve and B) an aortic valve with severe calcific aortic stenosis (AS). C) Histopathologic section of normal aortic valve with hematoxylin staining showing the trilaminar structure of the valve from top to bottom. D) Histopathologic section of a valve with severe calcific AS with hematoxylin staining showing the presence of fibrotic material (pink) and calcified nodule. The tissue is thickened by the excess of fibrotic material and the calcified nodule, located in the fibrosa, contributes to alter the normal architecture of the leaflet.

Figure 4. Pathogenesis of calcific aortic stenosis

Endothelial damage allows infiltration of lipids, specifically low density lipoprotein (LDL) and lipoprotein(a) (Lp(a)) into the fibrosa and triggers the recruitment of inflammatory cells into the aortic valve. Endothelial injury can be triggered by several factors including lipid-derived species, cytokines, mechanical stress and radiation injury. The production of reactive oxygen species (ROS) is promoted by the uncoupling of nitric oxide synthase (NOS), which increases the oxidation of lipids and further intensifies the secretion of cytokines. Enzymes transported in the aortic valve by lipoproteins (LDL and LP(a)) such as Lp-PLA2 and autotaxin (ATX) produce lysophospholipid derivatives. ATX, which is also secreted by valve interstitial cells (VICs), transforms lysophosphatidylcholine (LysoPC) into lysophosphatidic acid (LysoPA). Several factors including LysoPA, the receptor activator of nuclear factor kappa-B ligand (RANKL) and Wnt3a promote the osteogenic transition of VICs. Arachidonic acid (AA) generated by cytosolic PLA2 promotes the production of eicosanoids (prostaglandins and leukotrienes) through the cyclooxygenase 2 (COX2) and 5-lipoxygenase (5-LO) pathways respectively. In turn, eicosanoids promote inflammation and mineralization. Chymase and angiotensin converting enzyme (ACE) promote the production of angiotensin II, which increases the synthesis and secretion of collagen by VICs. Owing to increased production of matrix metalloproteinases (MMPs) and decreased synthesis of tissue inhibitors of metalloproteinases (TIMPs), disorganized fibrous tissue accumulates within the aortic valve. Microcalcification begins early in the disease, driven by microvesicles secreted by VICs and macrophages. In addition, overexpression of ecto-nucleotidases (NPP1, 5′-NT, ALP) promotes both apoptosis and osteogenic-mediated mineralization. Bone morphogenetic protein 2 (BMP2) entrains osteogenic transdifferentiation, which is associated with the expression of bone-related transcription factors (RUNX2 and MSX2). Osteoblast-like cells subsequently coordinate calcification of the aortic valve as part of a highly regulated process analogous to skeletal bone formation. Deposition of mineralized matrix is accompanied by fibrosis and neovascularization, which is abetted by vascular endothelial growth factor (VEGF). In turn, neovascularization increases the recruitment of inflammatory cells and bone marrow-derived osteoprogenitor cells. IL-1β, interleukin-1–β; Lp(a), lipoprotein (a); LDL, low-density lipoprotein; OxPL, oxidized phospholipid; TGF-β transforming growth factor beta; NPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; 5′-NT, 5′ nucleotidase; ALP, alkaline phosphatase.

Figure 5. Maladaptive remodelling and impaired function of the left ventricle in response to pressure overload from AS

The narrowing of the aortic valve orifice causes an acceleration of the blood flow velocity with a concomitant decrease in systolic blood pressure between the left ventricular (LV) outflow tract (LVOT) and the aorta. The increased LV pressure imposed by AS results in LV hypertrophy (augmentation of the LV myocardial mass), reduced coronary flow reserve, myocardial fibrosis, diastolic dysfunction and decreased longitudinal systolic shortening, although the ejection fraction remains normal in most patients. Left atrial enlargement is common owing to elevated LV filling pressures. The latter often leads to secondary pulmonary hypertension and right ventricular dysfunction in the more advanced stages of the disease.

Figure 6. Patterns of left ventricular remodelling

Four left ventricular (LV) remodelling patterns can be defined according to the left ventricular mass and the ratio of the LV mass to the LV cavity size: Normal pattern: both LV mass and mass/cavity ratio are normal; Concentric remodelling: the LV mass is normal but the mass/cavity ratio is increased (thick LV walls with small cavity); Concentric hypertrophy: both LV mass and mass/cavity ratio are increased; Eccentric remodelling: LV mass is increased but the mass/cavity ratio is normal (thickness of LV walls is normal or slightly increased and the LV cavity is enlarged). Reproduced with permission from

Figure 7. Assessment of aortic stenosis severity by Doppler-echocardiography

For each degree of disease severity including aortic valve sclerosis (A), mild aortic stenosis (AS) (B), moderate AS (C), and severe AS (D), this figure shows a 2D echocardiographic short-axis view of the aortic valve (top left), the transvalvular velocity by continuous-wave Doppler (right), and the multidetector computed tomography (MDCT) view of aortic valve calcification (bottom left). In the patient with aortic sclerosis (A), there are some small isolated spots of calcification (appears white on the MDCT images) in the aortic valve leaflets but there is no obstruction to blood flow (i.e. no stenosis). The peak aortic jet velocity (1.47 m/s), mean gradient (5 mmHg) and aortic valve area (AVA: 2.87 cm²) are normal. In the patient with mild AS (B), there is mild aortic valve calcification with mild obstruction to blood flow. The peak aortic jet velocity is 2.08 m/s, mean gradient: 9 mmHg, and AVA: 1.62 cm². In the patient with moderate AS (C), there is more extensive aortic valve calcification with moderate obstruction of blood flow: peak aortic jet velocity: 3.51 m/s, mean gradient: 28 mmHg, and AVA: 1.21 cm². In the patient with severe AS (D), there is severe aortic valve calcification and severe obstruction to blood flow: peak aortic jet velocity: 4.35 m/s, mean gradient: 48 mmHg, and AVA: 0.75 cm².

Figure 8. Assessment of aortic valve mineralization activity by positron emission tomography – computed tomography

Coaxial short axis views of the aortic valve from one patient with aortic sclerosis, one patient with mild aortic stenosis and one patient with moderate aortic stenosis. Left panels: baseline multi-detector computed tomography (MDCT) images of the aortic valve; regions of macrocalcification appear white. Middle panels: baseline fused MDCT and ¹⁸F-sodium fluoride (NaF) positron emission tomography (PET) images showing intense 18F-NaF uptake (red yellow areas) both overlying and adjacent to existing calcium deposits on the MDCT. Right panels: One-year follow-up (without intervention) MDCT images demonstrate increased calcium accumulation in much the same distribution as the baseline PET activity. Reproduced with permission from.

Figure 9. Assessment of flow patterns in the Aorta by 4D flow cardiac magnetic resonance according to aortic valve phenotype

(A) A normal valve systolic flow in a healthy control. (B) A tricuspid aortic valve (TAV) with severe aortic stenosis (AS) and altered systolic flow with helical patterns in the ascending aorta. (C) A bicuspid aortic valve (BAV) with right-left (RL) cusp fusion and severe AS. Altered blood flow with asymmetric helical flow patterns are observed in the proximity of the aortic valve. Courtesy of Julio Garcia, Alex Barker and Michael Markl, Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Figure 10. Assessment of myocardial fibrosis by cardiac magnetic resonance in patients with aortic stenosis

Top panel: colour maps of T1 values using shortened modified Look–Locker inversion in a mid-ventricular short-axis slice; bottom panel: the corresponding slice with late gadolinium enhancement (LGE) imaging. The left panel shows a normal volunteer. The middle panels show moderate aortic stenosis (AS) with moderate left ventricular hypertrophy. The right panel shows severe AS with severe LV hypertrophy. Regions with high T1 values (orange and red) within the LV wall correspond to myocardial fibrosis. Reproduced with permission from Bull et al..

Figure 11. Algorithm for the management of aortic stenosis

This figure presents the algorithm recommended by the 2014 ACC/AHA guidelines for the management of aortic stenosis. AS:, aortic stenosis; AVA, aortic valve area; AVAi, AVA indexed for body surface area; BP, blood pressure; AVR, aortic valve replacement; ETT, exercise treadmill test; LVEF, LV ejection fraction; SVi, stroke volume index; TAVR, tr anscatheter AVR; V_Peak, peak aortic jet velocity.

Figure 12. Different types of surgical aortic valve replacement

(A) Surgical aortic valve replacement with a bileaflet mechanical valve. (B) Surgical aortic valve replacement with a bioprosthetic valve.

Figure 13. Different types of transcatheter aortic valve replacement

(A) Transcatheter aortic valve replacement with a balloon expandable valve via the transfemoral, transapical or transaortic approach. (B) Transcatheter aortic valve replacement with a self-expanding valve via the transfemoral approach.