Acquired aortic valve disease and valvular calcification is highly prevalent in adult populations worldwide and is associated with significant cardiovascular morbidity and mortality. At present, there are no medical therapies that will prevent or regress aortic valve calcification or stenosis and surgical or transcatheter aortic valve replacement remain the only effective therapies for treating this disease. In the setting of valve injury as a result of exposure to biochemical mediators or hemodynamic forces, normal homeostatic processes are disrupted resulting in extracellular matrix degradation, aberrant matrix deposition and fibrosis, inflammatory cell infiltration, lipid accumulation, and neoangiogenesis of the valve tissue and, ultimately, calcification of the valve. Calcification of the aortic valve is now understood to be an active process that involves the coordinated actions of resident valve endothelial and interstitial cells, circulating inflammatory and immune cells, and bone marrow-derived cells. These cells may undergo a phenotype transition to become osteoblast-like cells and elaborate bone matrix, endothelial-to-mesenchymal transition, and form matrix vesicles that serve as a nidus for microcalcifications. Each of these mechanisms has been shown to contribute to aortic valve calcification suggesting that strategies that target these cellular events may lead to novel therapeutic interventions to halt the progression or reverse aortic valve calcification.

Cellular Mechanisms of Aortic Valve Calcification

The prevalence of calcific aortic valve disease (CAVD) is increasing as the global population ages. In the absence of a specific drug therapy, the only treatment for CAVD is valve replacement. In this Review, Hutcheson et al. discuss the mechanisms of CAVD and identify potential therapeutic targets that warrant further investigation.

Potential drug targets for calcific aortic valve disease

—The aim of the present study was to analyze if LDL particles trapped in stenotic aortic valve tissue undergo oxidative modification. Degenerative aortic stenosis affects >3% of the population >75 years of age in the Western world. Recent studies have revealed the presence of a chronic inflammatory process similar to what has been described in other degenerative diseases such as atherosclerosis. However, the underlying disease mechanisms of degenerative aortic stenosis still remain largely unknown. Six tricuspid stenotic valves, obtained at valve replacement, were compared with 3 control valves collected from hearts taken out during transplantation. The stenotic valves and the control valves were examined by immunohistochemistry, using antibodies against apoB, 4-hydroxynonenal-modified LDL, leukocytes, and HLA-DR. All valves were also stained with oil red O for neutral lipids. Extracellular neutral lipids were found in all stenotic valves, extending from the bases along the fibrosa layer. This lip...

Presence of Oxidized Low Density Lipoprotein in Nonrheumatic Stenotic Aortic Valves

The superfamily of tumor necrosis factor (TNF) receptors includes osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). The OPG/RANKL/RANK system plays an active role in pathological angiogenesis and inflammation as well as cell survival. It has been demonstrated that there is crosstalk between endothelial cells and osteoblasts during osteogenesis, thus establishing a connection between angiogenesis and osteogenesis. This OPG/RANKL/RANK/TRAIL system acts on specific cell surface receptors, which are then able to transmit their signals to other intracellular components and modify gene expression. Cytokine production and activation of their receptors induce mechanisms to recruit monocytes and neutrophils as well as endothelial cells. Data support the role of an increased OPG/RANKL ratio as a possible marker of progression of endothelial dysfunction in metabolic disorders in relationship with inflammatory marker levels. We review the role of the OPG/RANKL/RANK triad in vascular function as well as molecular mechanisms related to the etiology of vascular diseases. The potential therapeutic strategies may be very promising in the future.

https://www.mdpi.com/1422-0067/20/3/705/pdf

The Role of Osteoprotegerin and Its Ligands in Vascular Function.

In vitro models of aortic valve calcification: solidifying a system.

High-density lipoproteins (HDL) are present in stenotic aortic valves and may interfere with the mechanisms of valvular calcification

Dietary plant stanols or sterols neither accumulate in stenotic aortic valves nor influence their structure or inflammatory status

Purpose: The pathogenesis of aortic valve stenosis (AS) is characterized by accumulation of low-density lipoprotein (LDL) cholesterol and inflammatory cells in aortic valves, as well as by marked c...

Abstract 5865: High-density Lipoproteins (HDL) Are Present In Stenotic Aortic Valves And May Protect Them Against Calcification


 
 
 Type of funding sources: Public Institution(s). Main funding source(s): Aarne Koskelo foundation and Helsinki University Hospital EVO funding
 Introduction
 Atrial fibrillation (AF) is common among patients with aortic valve stenosis (AS) and can cause similar symptoms. AF may also contribute to diastolic dysfunction. Since AF may alter the echocardiographic profile and provoke symptoms independent of AS, it may complicate the evaluation of AS severity and decision of the time for valve intervention. The purpose of this study was to assess the effect of AF on symptoms and the echocardiographic evaluation of AS.
 Methods
 We followed 192 patients (46% female) with suspected severe symptomatic AS who were referred to our institution for intervention. Echocardiography and symptom questionnaires were performed at baseline and 3 months after the intervention. Aortic valve calcium score was measured using computed tomography in the 121 patients considered for transcatheter intervention (TAVR).
 Results
 52 of the 192 patients (27%) had AF. Patients with AF were older (median 81.5 [IQR 74.5-86.3] vs. 74 [64.0-81.3] years) and more often underwent TAVR (81% vs. 54%).
 In patients with AF the aortic valve mean pressure gradient was lower (39.5 [31.8-48.3] mmHg) than in patients without AF (46 [39.8-52.3] mmHg, p = 0.006, Fig.1A) and a low-gradient phenotype was more common (50% vs. 25% had mean gradient < 40 mmHg). There were no significant differences between groups in AVA, median EF or the proportion of patients with EF <50% (27% vs 17%). The aortic valve calcium score was similar in patients with or without AF (Fig.1B) and, based on the calcium score, 86% (AF) vs. 88% (no AF) of the patients were classified likely or very likely to have severe AS.
 AF patients had more advanced diastolic dysfunction as demonstrated by higher average E/e’ ratio (15.5 [12.9-20.2] vs. 12.4 [9.90-14.0], p <0.001), left atrial volume index (55.3 [42.0-62.7] vs. 36.7 [32.4-48.7] ml/m2, p <0.001) and tricuspid regurgitation gradient (35.0 [29.0-43.0 vs. 25.0 [23.0-29.0] mmHg, p <0.001).
 AF patients had worse functional class at baseline (49% vs. 27% with NYHA III or higher, p = 0.01, Fig.2A). There was significant improvement in both groups on follow-up (71% vs 72% improved at least one class), with no difference between groups. Dyspnoea, chest pain and exercise intolerance were equally frequent in patients with and without AF (Fig.2B). After intervention symptoms decreased significantly in both groups. Only exercise intolerance remained more common among AF patients (35% vs. 17%, p = 0.01).
 Conclusions
 AS patients with AF present more often with low-gradient phenotype and diastolic dysfunction, which may hamper the evaluation of AS severity. However, calcium score can serve as an alternative tool in the assessment of AS severity particularly in patients with AF and low gradient. Patients with AF are more symptomatic at baseline, but their symptoms improve significantly after intervention and nearly as well as in those without AF. Multiple imaging tools may be needed in decision-making in these patients. Abstract Figure 1  Abstract Figure 2


Jaakko I. Lommi

Papers

High-density lipoproteins (HDL) are present in stenotic aortic valves and may interfere with the mechanisms of valvular calcification

Dietary plant stanols or sterols neither accumulate in stenotic aortic valves nor influence their structure or inflammatory status

Abstract 5865: High-density Lipoproteins (HDL) Are Present In Stenotic Aortic Valves And May Protect Them Against Calcification

Impact of atrial fibrillation on the symptoms and echocardiographic evaluation of patients with aortic valve stenosis