Sex Differences in Factors Associated With Progression of Aortic Valve Calcification in the General Population

Background: Guidelines recommend measurement of the aortic valve calcification (AVC) score to help differentiate between severe and nonsevere aortic stenosis, but a paucity exists in data about AVC in the general population. The aim of this study was to describe the natural history of AVC progression in the general population and to identify potential sex differences in factors associated with this progression rate. Methods: Noncontrast cardiac computed tomography was performed in 1298 randomly selected women and men aged 65 to 74 years who participated in the DANCAVAS trial (Danish Cardiovascular Screening). Participants were invited to attend a reexamination after 4 years. The AVC score was measured at the computed tomography, and AVC progression (ΔAVC) was defined as the difference between AVC scores at baseline and follow-up. Multivariable regression analyses were performed to identify factors associated with ΔAVC. Results: Among the 1298 invited citizens, 823 accepted to participate in the follow-up examination. The mean age at follow-up was 73 years. Men had significantly higher AVC scores at baseline (median AVC score 13 Agatston Units [AU; interquartile range, 0–94 AU] versus 1 AU [interquartile range, 0–22 AU], P <0.001) and a higher ΔAVC (median 26 AU [interquartile range, 0–101 AU] versus 4 AU [interquartile range, 0–37 AU], P <0.001) than women. In the fully adjusted model, the most important factor associated with ΔAVC was the baseline AVC score. However, hypertension was associated with ΔAVC in women (incidence rate ratios, 1.58 [95% CI, 1.06–2.34], P =0.024) but not in men, whereas dyslipidemia was associated with ΔAVC in men (incidence rate ratio: 1.66 [95% CI, 1.18–2.34], P =0.004) but not in women. Conclusions: The magnitude of the AVC score was the most important marker of AVC progression. However, sex differences were significant; hence, dyslipidemia was associated with AVC progression only among men; hypertension with AVC progression only among women. REGISTRATION: URL: https://www.isrctn.com ; Unique identifier: ISRCTN12157806.

The Role of Neutrophil Elastase in Aortic Valve Calcification

Background: Calcific aortic valve disease (CAVD) is the most commonly valvular disease in the western countries initiated by inflammation and abnormal calcium deposition. Currently, there is no clinical drugs for CAVD. Neutrophil elastase(NE) plays a causal role in inflammation and participates actively in cardiovascular diseases. However, the effects of NE on valve calcification remains unclear. So we next explore whether it is involved in valve calcification and the molecular mechanisms involved.Methods: NE expression and activity in calcific aortic valve stenosis (CAVS) patients (n=58) and healthy patients (n=30) were measured by enzyme-linked immunosorbent assay (ELISA), western blot and immunohistochemistry (IHC). Porcine aortic valve interstitial cells (pVICs) were isolated and used in vitro expriments. The effects of NE on pVICs inflammation, apoptosis and calcification were detected by hochest 33258 staining, MTT assay, reverse transcription polymerase chain reaction (RT-PCR) and western blot. The effects of NE knockdown and NE activity inhibitor Alvelestat on pVICs inflammation, apoptosis and calcification under osteogenic medium induction were also detected by RT-PCR, western blot, alkaline phosphatase staining and alizarin red staining. Changes of Intracellular signaling pathways after NE treatment were measured by western blot.Results: The level and activity of NE were evaluated in patients with CAVS and calcified valve tissues. NE promoted inflammation, apoptosis and phenotype transition in pVICs in the presence or absence of osteogenic medium. Under osteogenic medium induction, NE silencing or NE inhibitor Alvelestat both suppressed the osteogenic differentiation of pVICs. Mechanically, NE played its role in promoting osteogenic differentiation of pVICs by activating the NF-κB and AKT signaling pathway.Conclusions: Collectively, NE is highly involved in the pathogenesis of valve calcification. Targeting NE such as Alvelestat may be a potential treatment for CAVD.

Assessment of Magnesium level Among Hemodialysis Patients and Its Relation to Vascular Stiffness

Background The pathogenesis of vascular calcification in Chronic kidney disease (CKD) patients is multifactorial and complicated. It has been proposed that Magnesium (Mg) may be implicated in the process of vascular calcification on various levels. Aim This study aims to assess the level of magnesium in hemodialysis patients and its relation to the vascular stiffness. Patients and methods 100 prevalent hemodialysis patients were included in the study and they were clinically stable with absence of cardiovascular complications, all patients underwent the following laboratory investigation including complete blood picture, median of magnesium level over 3 months, electrolytes, ipth, lipid profile and radiological investigations including transthoracic echocardiography and carotid duplex. Results The studied population was divided into two groups, group I included 68 patients with normal mg level and group II included 32 patients with low mg level. There was statistically significant difference between the two groups as regard hemoglobin level (pvalue=0.033), otherwise there was no statistically significant difference as regard other laboratory and radiological investigations. Then they were divided into another two groups according to the presence of mitral valve calcification (MVC), group III involved 85 patients without MVC and group IV involved 15 patients with MVC. There was statistically significant difference between 2 groups as regard aortic wave pulse velocity (aPWV) with (pvalue=0.002), presence of plaques with (pvalue &lt;0.001) and intimal media thickness with (pvalue&lt;0.001). Another group was divided according to presence of aortic valve calcification (AVC) into two groups, first group V included 39 patients without AVC and second group VI included 61 patients with AVC. There was statistically significant difference between two groups as regard age with (pvalue&lt;0.001), ipth with (pvalue=0.033), presence of plaques with (pvalue=0.048) and intimal media thickness with (pvalue&lt;0.001). Conclusion There was high prevalence of vascular calcification among hemodialysis patients which may be related to age and hyperparathyroidism but without statistically significant correlation to Mg level.

Correlation between Peri-Coronary Epicardial Adipose Tissue Volume, Cardiac Calcification and the Severity of Coronary Artery Disease by Multi Slice Computed Tomography

ABSTRACT The authors in that article addressed a very important and relevant issue. Background Epicardial adipose tissue (EAT) is a complex endocrine organ that plays an important role in the development of unfavorable metabolic and cardiovascular risk profile. EAT may express a variety of inflammatory mediators which may contribute to the pathogenesis of coronary artery disease (CAD). Aortic and mitral valve calcification may reflect generalized atherosclerosis in the elderly and may be a marker of high prevalence and severity of CAD. There is a direct correlation (extent, severity and the future CV events) between the coronary artery calcium and the CAD. Aim and Objectives To correlate peri-coronary epicardial adipose tissue and coronary artery calcification and valvular (aortic and mitral) calcification with the severity of the coronary artery disease. Patients and Methods The study recruited 200 patients with suspected coronary artery disease. The amount of EAT surrounding the left main and the three main coronary arteries was quantified in axial cuts with the most distinct layer of EAT. The amount of calcium in the aortic and mitral valve and the coronaries were quantified with multi-detector computed tomography MDCT using dedicated software for measuring calcium score that is based on Agatson score. Coronary artery disease severity was assessed in terms of number of vessels affected and the severity of coronary stenosis by multi-planner reformation technique. Results Based on the finding of the MDCT and according to the presence of calcification in the aortic or the mitral valves, and the significance of the coronary artery disease, patients were classified into two groups, group (I): 115 patients with normal coronaries or with non significant lesions in their coronaries, and group (II): 85 patients with significant coronary artery disease. The Mean ± SD (in millimeters) of EAT for the entire study cohort in various coronary artery locations were as follows: LM EAT 9.82 ± 2.67, proximal LAD EAT 10.06 ± 2.80, mid LAD EAT 9.15 ± 2.41, distal LAD EAT 6.46 ± 1.87, proximal LCX EAT 8.10 ± 1.90, distal LCX EAT 6.83 ± 1.79, proximal RCA EAT 10.23 ± 2.42, mid RCA EAT 9.26 ± 2.72, distal RCA EAT 7.25 ± 2.58. Statistically highly significant difference was observed between the two groups with regards to LM EAT, proximal, mid and distal LAD EAT, proximal and distal LCX EAT, proximal, mid and distal RCA EAT (8.38 ± 2.18 Vs 11.77 ± 1.94 P: 0.000, 8.49 ± 2.21 Vs 12.18 ± 2.00, 7.93 ± 1.77 Vs 10.81 ± 2.16, 5.45 ± 1.26 Vs 7.82 ± 1.68 P: 0.000, 7.08 ± 1.34 Vs 9.46 ± 1.67, 6.05 ± 1.50 Vs 7.89 ± 1.61 P: 0.000, 9.01 ± 1.94 Vs 11.88 ± 1.99, 8.07 ± 2.32 Vs 10.86 ± 2.39, 6.31 ± 2.26 Vs 8.51 ± 2.45 P: 0.000; respectively). Statistically highly significant difference was observed between the two groups with regards calcium score and the severity of CAD in the three major vessels (LAD, LCX and RCA) and the total calcium score in all vessels (35 (16 – 85.5) Vs 179.5 (59.5 – 243) P: 0.000, 20.5 (7 – 50.5) Vs 56 (33 – 95) P: 0.000, 31 (9 – 54) Vs 97 (54 – 199) P: 0.000, 12 (0 – 84) Vs 286 (106 – 511) P:0.000; respectively) while calcium score in the LM was not statistically significant with the severity of CAD (4 (3 – 26) Vs 12 (9 – 16) P: 0.360). As regards aortic valve calcification there was statistically highly significant difference between the two groups; P value 0.000, while mitral valve calcification was found to be not statistically significant between the two groups P: 0.272. Conclusion The present study demonstrated a significant correlation between the peri-coronary epicardial adipose tissue, coronary calcification and aortic valve calcification and the severity of the coronary artery disease.

Organ Culture Model of Aortic Valve Calcification

A significant amount of knowledge has been gained with the use of cell-based assays to elucidate the mechanisms that mediate heart valve calcification. However, cells used in these studies lack their association with the extra-cellular matrix or the influence of other cellular components of valve leaflets. We have developed a model of calcification using intact porcine valve leaflets, that relies upon a biological stimulus to drive the formation of calcified nodules within the valve leaflets. Alizarin Red positive regions were formed in response to lipopolysaccharide and inorganic phosphate, which could be quantified when viewed under polarized light. Point analysis and elemental mapping analysis of electron microscope images confirmed the presence of nodules containing calcium and phosphorus. Immunohistochemical staining showed that the development of these calcified regions corresponded with the expression of RUNX2, osteocalcin, NF-kB and the apoptosis marker caspase 3. The formation of calcified nodules and the expression of bone markers were both inhibited by adenosine in a concentration-dependent manner, illustrating that the model is amenable to pharmacological manipulation. This organ culture model offers an increased level of tissue complexity in which to study the mechanisms that are involved in heart valve calcification.