Valvular Calcification Research Articles

719 CIRCULATING SORTILIN LEVELS ARE INCREASED IN PATIENTS RECEIVING LONG-TERM WARFARIN AND ITS INHIBITION ATTENUATES WARFARIN-INDUCED VASCULAR CALCIFICATION

Abstract Long-term use of the vitamin K antagonist (VKA) warfarin, has been shown to accelerate vascular and valvular calcification both in rodents and in humans. Increasing evidence suggests that vascular endothelium contributes to calcification via endothelial-mesenchymal transition (EndMT). However, additional research is warranted to elucidate the signaling mechanisms involved. In the last decade, a prominent role for sortilin has been demonstrated in cardiovascular calcification. Moreover, we recently demonstrated that the increase of sortilin in the endothelium promotes endothelial dysfunction, a known initiator of EndMT. Thus, we aim to investigate a potential contribution of sortilin in vascular calcification induced by warfarin. For this purpose, human endothelial cells and aortic rings from wild type C57BL/6J mice were cultured in promineralization medium in the presence of therapeutic levels of warfarin. Plasma sortilin and calcium levels were measured in 19 patients under VKA therapy who were stratified into short-term (3-12 months) or long-term group (24-45 months) based on VKA treatment duration. Increased protein expression of sortilin was found both in the endothelial and in the medial smooth muscle layers of aortic rings. Sortilin immunostaining was found to co-localize with α-SMA in the endothelium of warfarin-treated aortic rings, a hallmark of EndMT. Interestingly, pharmacological inhibition of sortilin with AF38469 reduced calcification and prevented loss of expression of the endothelial marker von Willebrand Factor (vWF) induced by warfarin treatment in human endothelial cells and mouse aortas. Finally, along with elevated plasma calcium levels, patients receiving long-term VKA showed increased circulating sortilin levels when compared to short term VKA-treated patients. Our data provide evidence for a potential role for endothelial-derived sortilin in regulating vascular calcification promoted by warfarin, and suggest that targeting circulating sortilin may be beneficial for the prevention of warfarin-associated cardiovascular calcification.

Sex-specific correlates of valvular and arterial calcification burden in patients with moderate aortic stenosis

IntroductionThere are significant sex differences in the prevalence and severity of cardiac calcifying processes. Women harbour more severe mitral annular calcification (MAC), while men exhibit worse aortic valve (AVC) and...

Fetal Endocardial Valvular and Supravalvular Calcification as a Manifestation of Anti-Ro/SSA-La/SSB Antibody Mediated Cardiac Phenotype

Fetal Endocardial Valvular and Supravalvular Calcification as a Manifestation of Anti-Ro/SSA-La/SSB Antibody Mediated Cardiac Phenotype

Abdominal aortic calcification as prognostic marker in continuous ambulatory peritoneal dialysis.

Patients with chronic kidney disease (CKD) on dialysis are at high risk of cardiovascular complications and mortality. We investigated the prognostic role of presence and severity of abdominal aortic calcification (AAC) detected by a simple lateral lumbar X-ray as a risk marker in CAPD. A prospective study was undertaken in 45 patients on CAPD (continuous ambulatory peritoneal dialysis). Lateral lumbar films of consented patients were checked for the presence of AAC at the level of L1-L4 lumbar vertebrae. The severity of aortic calcification was graded as per Antero-Posterior Severity Score (APSS). These APSS grades were correlated with the patient's demographic, biochemical, and echocardiographic findings. The patients were followed up prospectively for one year. 45 patients formed the study group. Mean standard deviation (SD) age and body mass index (BMI) were 57.2 (11.9) years and 25.8 (4.7) kg/m2, respectively. Males constituted 62% of the cohort. Average duration of dialysis was 34.3 months. Diabetic kidney disease was seen in 75%. The prevalence of AAC was 47%. AAC was positively correlated with age of patient (r=0.378; p=0.01). No correlation with BMI, diabetes, hypertension, dialysis vintage, serum calcium, phosphorus, and PTH was seen; whereas a trend towards negative correlation with alkaline phosphatase was seen. Mitral valve calcification had a significant association with APSS severity. Patients with severe APSS (≥4) had poor survival, with an average survival of 37 months (Log-rank test p=0.026). ROC analysis showed that APSS 3 predicted 1-year mortality with a specificity of 89% and sensitivity of 62% (AUC=0.73) (p=0.007). Abdominal aortic calcification was present in 47% of our CAPD patients. A simple lateral pelvic skiagram can be utilized as a cost-effective tool in prediction of All-cause mortality and cardiac valvular calcification.

Comparison of CT acquired cardiac valvular calcification scores in hemodialysis and peritoneal dialysis patients undergoing open heart surgery

Study objectiveData is scarce regarding which dialysis modality portends more severe cardiac valvular calcification (CVC). Our aim was to compare the degree of CVC in hemodialysis (HD) and peritoneal dialysis (PD) patient cohorts prior to open heart surgery (OHS) using a CT calcium score. Design, setting, and participantsDialysis patients who underwent OHS at our institution from 2009 to 2019 and who had pre-surgical cardiac CT were included in our study. We obtained duration of dialysis modality prior to their surgical date. There were two study cohorts to evaluate outcomes of interest: mitral and aortic calcification. CVC was assessed using the Agatston score. Logistic regression was performed to test for the association of PD and HD cumulative dialysis duration with presence of CVC. ResultsA total of 214 and 166 patients met inclusion for the mitral and aortic strata, respectively. Age, female sex, and BMI were associated with higher odds of presence of mitral calcification. Age and BMI were associated with higher odds of presence of aortic calcification, while female sex was associated with lower odds in the aortic strata. Cumulative years on PD and cumulative years on HD were not significantly associated with presence of CVC in either cohort. ConclusionPresence of mitral and aortic calcification for patients undergoing OHS was not significantly associated with cumulative length of PD or HD after adjusting for age, gender, and BMI suggesting that there may be more factors at play in the progression of CVC in end stage renal disease patients than what was previously established.

Different calcification patterns of tricuspid and bicuspid aortic valves and their clinical impact.

Mechanical strain plays a major role in the development of aortic calcification. We hypothesized that (i) valvular calcifications are most pronounced at the localizations subjected to the highest mechanical strain and (ii) calcification patterns are different in patients with bicuspid and tricuspid aortic valves. Multislice computed tomography scans of 101 patients with severe aortic stenosis were analysed using a 3-dimensional post-processing software to quantify calcification of tricuspid aortic valves (n = 51) and bicuspid aortic valves (n = 50) after matching. Bicuspid aortic valves exhibited higher calcification volumes and increased calcification of the non-coronary cusp with significantly higher calcification of the free leaflet edge. The non-coronary cusp showed the highest calcium load compared to the other leaflets. Patients with annular calcification above the median had an impaired survival compared to patients with low annular calcification, whereas patients with calcification of the free leaflet edge above the median did not (P = 0.53). Calcification patterns are different in patients with aortic stenosis with bicuspid and tricuspid aortic valves. Patients with high annular calcification might have an impaired prognosis.

Abstract 14073: Hypercalcemia Induced Reversible LBBB

Background: Parathyroid hormone (PTH) and calcitriol are the two hormones responsible for calcium and phosphate homeostasis. PTH exerts its effect on the renal tubular calcium reabsorption and bone resorption. PTH secretion is modulated by calcium acting on the sensitive calcium-sensing receptor on the parathyroid cells. Primary hyperparathyroidism has been linked to hypertension and valvular calcification. Structural changes are also seen including elevated left ventricular mass, diastolic dysfunction and myocardial calcification. Case presentation: A 61-year old female with hyperlipidemia and osteoporosis presented with polyarticular joint pain and diffuse myalgia noted to have elevated PTH of 90 pg/ml and elevated Ca of 10.1 mg/dl. Her calcium levels has ranged from 10.1 to 11.2 mg/dl and her PTH ranged from 90 to 113 pg/ml. She had a negative sestamibi scan, and thyroid ultrasound showed fusiform lesion measuring 0.82 x 0.36 in the right posterior neck suspicious for a parathyroid adenoma with the plan made for resection. The diagnosis at this time was primary hyperparathyroidism induced hypercalcemia. She developed exertional dizziness and was found to have a new LBBB and reduced ejection fraction of 40-45% with a small fixed defect in the septal area which was attributed to the LBBB. She was initiated on metoprolol succinate 25 mg, irbesartan 75 mg, atorvastatin 40 mg and aspirin 81 mg because of the reduced systolic function. SPECT was negative for ischemia with a fixed decreased uptake of the septum. She underwent right lower parathyroid excision on 11/2021 with normalization of calcium to 9.4 mg/dl and PTH to 9 pg/ml with resolution of the LBBB and systolic function in 2/2021 improving to 48%. Discussion: Calcium plays a key role in cardiac excitation, depolarization, repolarization, and also coupling of these signals to mechanical contraction via calcium induced calcium release and myofibril cross linking. In this case, calcium was only mildly elevated to cause a partial conduction defect. Literature is lacking on whether there is a threshold level for calcium that predisposes to varying degrees of conduction disease. This case also highlights the temporal nature of symptom resolution following parathyroid surgery with resolution of the LBBB.

Abstract 11966: Dlk1 Derived Adiposity Stimulates Lipids Retention in Aortic Valve

Calcified aortic valve disease (CAVD) is the most prevalent valvular heart disease in western populations affecting nearly 2.5% of individuals over 65. Currently, there is no viable pharmacological treatment to stop the progression of the disease or to activate mineral regression. The only effective therapy to treat CAVD is surgical valve replacement or trans-catheterization. Obesity is the major common nutritional disorder worldwide and is one of the important risk factors for CAVD. It has been shown before that DLK1 -/- mice have increased abdominal adiposity. Indeed Dlk1 plays an essential role in regulating adipocytes differentiation and proliferation. Recently, it has been shown that there is an association between fat tissue accumulation and an increased risk of aortic stenosis. We hypothesize that dysregulation of DLK1 stimulates adiposity, increases circulating lipids, enhances valve lipids retention, and stimulates calcification. Herein, our objective is to examine the expression of DLK1 in calcified aortic valve and its impact on lipid retention. Method: We examined the effect of Dlk1 loss of function on lipid retention in aortic valve tissue in ApoE -/- Dlk1 -/- mice fed with a high-fat diet and in human explanted aortic valves using immuno-staining. Results: The complete deletion of DLK-1 in ApoE -/- mice were associated with an increased oxidized-LDL deposit in aortic valve tissue. In addition, circulating cholesterol (420 ± 8 mg/dl vs 250± 12 mg/dl, P=0.002) and triglyceride concentration (200 ± 3 mg/dl vs 50± 10 mg/dl, P<0.001) were higher in ApoE -/- DLK1 -/- compared to apoE -/- mice. An increased valvular calcification accompanied these changes, as shown by the over-expression of RUNX2 and the increased aortic jet velocity in ApoE -/- DLK1 -/- mice. Interestingly the overexpression of DLK1 in isolated human valve cells decreased calcification and lipid retention in vitro. Conclusion: This study showed the significant role of Dlk1-derived abdominal adiposity in valve-lipid retention and calcification.

Abstract 13173: Impact of Bicuspid Aortic Valve Morphology on Computed Tomography Valvular Calcification in Aortic Stenosis and Sex Differences

Introduction: Aortic valve calcification (AVC) is the key pathophysiology underlying aortic stenosis (AS). We aimed to assess computed tomography AVC in AS by valve morphology (bicuspid [BAV] vs. tricuspid aortic valve[TAV]) and sex. Methods: Retrospective study of patients with echocardiographic AS severity and AVC assessments within six months. Patients with > moderate aortic regurgitation, prosthetic aortic valve, or indeterminate aortic valve morphology were excluded. Severe AS with high mean gradient (MG) was defined as aortic valve area (AVA)≤1cm2 or indexed AVA≤0.6 cm2/m2 + MG≥40 mmHg. Results: Of 2647 patients, 361(65% men) had BAV and 2286(59% men) had TAV, age 65±11 vs. 80±9 years(p<0.001), AVA 1.07±0.42 vs. 0.90±0.25 cm2(p<0.001), MG 41±16 vs.42±14 mmHg(p=0.4) for BAV and TAV, respectively. For both BAV and TAV groups, age, MG, and severe AS frequency were similar between women and men(all p≥0.06). BAV morphology affected AVC-AS severity and AVC-sex associations (p for interactions <0.001): as AS severity increased, mean AVC difference became larger between BAV-men and TAV-men, but smaller between BAV-women and TAV-women. Similar patterns were observed in AVC density (AVCd, AVC divided by left ventricular outflow tract diameter)-AS severity and AVCd-sex associations (p for interactions < 0.001). In patients with concordant AS severity and MG levels, the best BAV AVC-cutoff for detecting severe AS + high MG by area-under-the-curve analysis was 924 AU for BAV-women and 2851 AU for BAV-men, different from guideline-recommended AVC-thresholds (1200 for women and 2000 for men). The best BAV AVCd cutoff was 289 for BAV-women and 476 for BAV-men, similar to the cutoffs for patients predominantly with TAV (292 for women and 476 for men from Clavel MA JACC 2013). The BAV-AVC threshold identified more patients with severe AS than guideline-recommended threshold in BAV-women (84% vs 74%, p<0.001), but not in BAV-men. Conclusions: Valvular calcium accretion in AS was different by valve morphology and sex. As compared to TAV, BAV-women exhibited the least calcification while BAV-men exhibited the highest. Such patterns may impact the sensitivity of guideline-recommended AVC thresholds for detecting severe AS in BAV patients.

Effects of Consistently Strict Phosphate Control on Vascular and Valvular Calcification in Incident Hemodialysis Patients

Effects of Consistently Strict Phosphate Control on Vascular and Valvular Calcification in Incident Hemodialysis Patients

Cellular Senescence, Aging and Non-Aging Processes in Calcified Aortic Valve Stenosis: From Bench-Side to Bedside.

Aortic valve stenosis (AS) is the most common valvular heart disease. The incidence of AS increases with age, however, a significant proportion of elderly people have no significant AS, indicating that both aging and nonaging pathways are involved in the pathomechanism of AS. Age-related and stress-induced cellular senescence accompanied by further active processes represent the key elements of AS pathomechanism. The early stage of aortic valve degeneration involves dysfunction and disruption of the valvular endothelium due to cellular senescence and mechanical stress on blood flow. These cells are replaced by circulating progenitor cells, but in an age-dependent decelerating manner. When endothelial denudation is no longer replaced by progenitor cells, the path opens for focal lipid deposition, initiating subsequent oxidation, inflammation and micromineralisation. Later stages of AS feature a complex active process with extracellular matrix remodeling, fibrosis and calcification. Echocardiography is the gold standard method for diagnosing aortic valve disease, although computed tomography and cardiac magnetic resonance are useful additional imaging methods. To date, no medical treatment has been proven to halt the progression of AS. Elucidation of differences and similarities between vascular and valvular calcification pathomechanisms may help to find effective medical therapy and reduce the increasing health burden of the disease.

Relationship of fibroblast growth factor 21 with the prevalence and progression of vascular and valvular calcification: Multi-ethnic study of atherosclerosis

BackgroundElevated circulating levels of fibroblast growth factor 21 (FGF21) are associated with cardiovascular disease (CVD). Therefore, we investigated the relationship of plasma FGF21 with calcification at different vascular and valvular sites. MethodsA total of 5786 participants, free of clinically apparent CVD at baseline and with valid data on plasma FGF21 and calcification (Agatston score, volume and density) at coronary arteries, thoracic arteries, mitral and aortic valves, and aortic valve ring, were included in the analysis. Vascular calcification was measured at 2–3 follow-up visits. ResultsAt baseline, higher FGF21 levels were associated with prevalent descending thoracic aortic calcification (DTAC) (prevalence ratio = 1.06 [95% CI 1.01–1.11] per SD increase in log-transformed unit, P = 0.016). Among participants without prevalent calcification, higher FGF21 levels were associated with incident DTAC (relative risk [RR] = 1.13 [95% CI 1.04–1.22], P = 0.002). Among all participants, higher FGF21 levels were also associated with the progression of DTAC score and volume (RR = 1.07 [95% CI 1.03–1.12] and 1.08 [95% CI 1.03–1.12] respectively, both P < 0.01). No significant association of FGF21 was found for prevalence (prevalence ratio = 0.89–1.05), incidence (RR = 0.97–1.16) and progression of calcification (RR = 0.94–1.14) at the other sites. ConclusionHigher FGF21 levels were associated with the presence, incidence and progression of DTAC. However, the magnitude of this association was similar to those of the non-significant associations of FGF21 levels with calcifications at other sites. Further research is needed to assess the potential of FGF21 as a biomarker for vascular calcification.

Significant associations between bone mineral density and vascular calcification in patients with different stages of chronic kidney disease

IntroductionChronic kidney disease—mineral and bone disorders (CKD-MBD) is characterised by generalised vascular calcification (VC) and impaired bone health. We aimed to investigate the relationship between VC and bone mineral density (BMD) in CKD patients.MethodsWe performed a cross-sectional study of patients with different stages of CKD. For assessment of VC of abdominal aorta lateral lumbar X-rays (Kauppila score), the ankle-brachial index (ABI) and echocardiography were used. Total body densitometry provided BMD.ResultsNinety patients (41% male, median age 64 years (range 29–87)) were included, of whom 41.1% had a Kauppila score > 1. Evidence of peripheral VC as measured by ABI was detected in 23.3% of cases. Lesions of the heart valves were found in 46.7% of patients. There was a significant association between high ABI and lesions of the heart valves. In the multivariate regression model to analyse the independent determinants of abdominal aorta calcification (AAC) and ABI, the BMD of the femoral neck was identified as significant for both (p = 0.001, p = 0.001). The total spine BMD was found to be significant for AAC (p = 0.001), and the BMD of spine L1-L4 and the ribs were found to be significant for ABI (p = 0.01, p = 0.002 respectively). In factorial regression analysis, where BMD was independent determinant, valvular calcification was significant for BMD of femur, femoral neck and total BMD. Age and tALP were inversely correlated with the BMD of femur and femoral neck.ConclusionsOur work highlighted clinically important relationships between VC and bone mineral density (BMD) in CKD patients. We detected inverse relationships between AAC, high ABI and BMD. Secondly, BMD at certain bone sites (femur, femoral neck) and total BMD were associated with important lesions of heart valves. Thirdly, a significant association between a high ABI and lesions of the heart valves. We believe that the results of our study will help in the planning of future research and in current clinical practice for the early diagnosis, further monitoring and management of CKD-MBD. Additionally, these results may have treatment implications on use of different CKD-MBD medications.

Non-vitamin K antagonist oral anticoagulants (NOACs) attenuate valvular calcification in patients with severe aortic stenosis

Abstract Background In vitro studies has demonstrated that non-vitamin K antagonist oral anticoagulants (NOACs) down-regulated the expression of proteins responsible for valve calcification and inflammation in valve interstitial cells (VICs) cultures. Aims Our goal was to evaluate whether long-term anticoagulation with NOACs, including dabigatran (thrombin inhibitor), rivaroxaban and apixaban (FXa inhibitors) can impair the valvular calcification and inflammation in patients with severe AS. Methods We enrolled 38 patients with severe AS aged 70±5.9 years (mean gradient - PGmean: 50mmHg, max gradient - PGmax: 80mmHg), including 18 individuals with AS and concomitant atrial fibrillation taking NOACs for at least 3 years (51±10 months) (AS-NOACs group). Stenotic aortic valves were obtained during valve replacement surgery. Valvular calcification was estimated ex vivo using micro-computed tomography (micro-CT). Total volume of each calcification (bone volume - BV), the distribution of clods sizes of calcification parts (trabecular thickness -Tbth) and the volume of the hardest / most calcified part (hard CT) of each valve were assessed. Valvular expression of bone morphogenetic protein 2 (BMP-2) and NFκB was evaluated by immunostaining. The fluorescence intensity (FI) was computed as the ratio (%) of positively and negatively stained areas. Results AS patients did not differ from AS-NOACs participants with regard to demographic or risk factors. Micro-CT analysis showed 65.5% lower BV in AS-NOACs valves compared to patients not taking NOACs (87±47 mm3 vs. 252±146 mm3, p=0.0017). Of note, in AS-NOACs patients Tbth showed strong association with transvalvular pressure gradients (PGmean: r=0.76, p=0.033; PGmax: r=0.77, p=0.01), as clinical measures of the AS severity. The duration of anticoagulation was associated with the lower Tbth (from 0.35 mm for 60 months to 0.51 mm for 36 months, p&amp;lt;0.01), which suggests that long NOACs treatment changed the pattern of valvular calcification, leading to formation of calcium deposits with reduced volume. Moreover, in AS-NOACs patients BV correlated with hard CT (r=−0.69, p=0.027), suggesting that the lesions increase their volume but do not ossify. Valvular expression of BMP-2 and NFκB was 44% and 33% decreased in AS-NOACs patients, compared to those without such treatment and the expression of both proteins was positively associated (r=0.34, p=0.001). Moreover, in AS-NOACs patients the expression of BMP-2 and NFκB was observed mainly in the fibrosa layer of the leaflets, but not in the deeper layers of tissue, as in AS patients without NOACs treatment. Conclusions NOACs can inhibit the increase of valvular calcium volume and its ossification via suppressed NFkB expression. Our study may suggest that long-term anticoagulation with NOACs could slow down the rate of AS progression, at least in patients with an indication for anticoagulant therapy. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Polish National Science Centre

Comparison of CT acquired valvular calcification scores in hemodialysis vs peritoneal dialysis patients undergoing open heart surgery

Abstract Background Several factors have been identified as independent risk factors for cardiac valvular calcification (CVC), including but not limited to age, inflammatory conditions, loss of calcification inhibitors, and dysregulated bone mineral metabolism. However, data is scarce regarding which dialysis modality portends more severe CVC. Purpose Our aim was to compare the degree of valvular calcification in hemodialysis (HD) and peritoneal dialysis (PD) patients prior to open heart surgery (OHS) using a computed CT calcium score. Methods Dialysis patients who underwent OHS at our institution from 2009–2019 who had a pre-surgical cardiac CT were grouped according to duration of dialysis modality prior to their surgical date. There were two study cohorts to evaluate outcomes of interest: mitral and aortic calcification. We included the first surgical record per patient for patients undergoing isolated CABG, or CABG+valve surgery (repair or replacement), or valve-only surgery (repair or replacement). To evaluate mitral calcification, we excluded any patients undergoing any mitral valve surgery (repair or replacement). We also excluded patients with a history of mitral valve repair/replacement. To evaluate aortic calcification, we excluded any patients undergoing any aortic valve surgery (repair or replacement). We also excluded patients with a history of aortic valve repair/replacement. Mitral annular and aortic valvular calcification were assessed using the Agatston score. Logistic regression was performed to test for the association of PD and HD cumulative dialysis duration with presence of valvular calcification. Results A total of 296 patients met inclusion criteria for at least one of the strata in our study. Of those, 214 met inclusion for the mitral strata, and 166 met criteria for the aortic strata (Table 1). In the logistic regression model for the mitral strata, age and female sex were associated with higher odds of presence of mitral calcification (Figure 1). Cumulative years on PD and cumulative years on HD were not significantly associated with presence of mitral calcification. In the logistic regression model for the aortic strata, age was associated with higher odds of presence of aortic calcification, while female sex was associated with lower odds (Figure 1). Cumulative years on PD and cumulative years on HD were not significantly associated with presence of aortic calcification. Conclusion Presence of mitral and aortic calcification for patients undergoing OHS was not significantly associated with cumulative length of PD or HD after adjusting for age and gender, suggesting that there may be more factors at play in the progression of valvular calcification in end stage renal disease patients than what was previously thought. Funding Acknowledgement Type of funding sources: None.

Significance and distribution of aortic valve calcium score before TAVI

Abstract Introduction Aortic valve calcium scoring by multislice computed tomography (MSCT) is an alternative load independent assessment of aortic stenosis severity. Recent studies have further demonstrated that aortic valve calcification load is related to adverse outcomes during and after transcatheter aortic valve implantation (TAVI), however reference values in this population are uncertain. This study aimed to assess aortic valve calcium in P referred for TAVI. Methods Retrospective analysis of consecutive patients (P) submitted to TAVI between 2014 and 2020 in a tertiary care centre. Clinical and echocardiographic characteristics, along with MSCT-derived aortic valve calcium score were collected. Results A total of 467 P were included, 57% female, median age 83 (9) years (minimum 45 and maximum 95 years-old). The prevalence of hypertension, dyslipidemia and diabetes was 83%, 69% and 36%, respectively. Chronic renal failure was present in 51%, atrial fibrillation in 34% and peripheral artery disease in 14%. Considering the 346 P with aortic valve calcification quantified by MSCT, median calcium score was 2161 (1761) AU. Age did not correlate with valvular calcification (r=0.043, p=0.422). Male gender showed significantly higher calcium score (2800 (2093) vs 1850 (1584), p&amp;lt;0.001) (Figs. 1 and 2). 11P had bicuspid aortic valve disease, with this population being younger (75 (16) vs 83 (8) years, p=0.001), nonetheless displaying higher aortic valve calcium load (2800 (2599) vs 2112 (1788), p=0.025). A weak but statistically significant correlation between calcium score and maximum (r=0.366, p&amp;lt;0.001) and mean gradients (r=0.387, p&amp;lt;0.001) and aortic valve area (r=−0.120, p=0.047) was demonstrated. Valvular calcification was not significantly different in P with reduced ejection fraction (&amp;lt;50%) (p=0.388). Conclusion There are significant differences in aortic valve calcium score between men and women referred for TAVI. Higher maximum and mean gradients were associated with increasing valvular calcification. Age and left ventricle ejection fraction were not related. P with bicuspid aortic valve have distinct calcification characteristics. As calcification burden may influence preprocedural planning, this parameter should be incorporated in the general work-up and reference values in this population should be known. Funding Acknowledgement Type of funding sources: None.

The influence of rivaroxaban compared to vitamin K antagonist treatment upon development of cardiovascular calcification the IRIVASC-trial

Abstract Vitamin K antagonists (VKA) such as warfarin or phenprocoumon are the mainstay of therapy for patients with several specific indications for long-term oral anticoagulant therapy (OAT). Due to interferences with Matrix-Gla protein, an important vitamin K-dependent local calcification inhibitor in cardiovascular structures, VKAs are theoretically linked to the development of increased cardiovascular calcification (CVC). The IRIVASC trial was a multi-center, prospective, controlled, open, randomized, interventional clinical trial and included 192 patients with atrial fibrillation or pulmonary embolism and an indication for oral anticoagulation &amp;gt;12 months. In short, patients with an indication for OAT were randomized to receive either Rivaroxaban (n=96) or VKA (n=96) and followed up over 12 months. MultiSlice CT (MSCT) was performed at baseline and after 12-month follow up. The primary endpoint of the study was the progression of coronary artery and aortic valve (AV) calcification, as determined by MSCT (volume score). Baseline demographic and laboratory values were comparable between the VKA and the Rivaroxaban groups (median age 72 vs 68, 73.6 vs 69.9 male). The main indication for anticoagulation was AF (95.4% vs 96.6%) After 12-month follow-up complete data sets were available for 164 patients (86%) for coronary calcification and 67 patients for valvular calcification (per protocol analysis). Overall, we found no differences in the primary endpoints. Development of coronary artery calcification was similar within the 2 groups as evidenced by similar developments of the coronary agatston score (804.8±1062.3 vs 946.7±1024.4, p=0.38), the coronary volume score (571.9±855.6 ml vs 791.7±820.1 ml, p=0.359) and the coronary mass score (143.2±195.9 mg vs. 172.2±190.8 mg, p=0.335) after 12 month. Similarly, there was no difference in the development of aortic valve calcification (AV) (AV Agatston score 441.6±711.9 vs. 352.6±751.2, p=0.621. AV volume score 388.2±589.0 ml vs 354.3±654.3, ml p=0.824 and AV Mass Score 75.7±135.1 mg vs 60.2±122.9, p=0.626 mg) (Table 1). To our knowledge this is the first multicenter prospective, randomized trial to ever investigate the effects of VKA vs rivaroxaban treatment regarding the development of coronary and valvular calcification. Our findings are clinically relevant as VKA will remain the mainstay of treatment for several conditions including mechanical valve replacement or antiphospholipid syndrome and hence include patients at cardiovascular risk. Our data point towards a comparable risk of overt CVC progression as detectable by CT-scans in patients irrespective of VKA or NOAK treatment. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): BAYER GmBH

Enrichment in procoagulant microparticles in calcified human aortic valve – role in valvular endothelium alterations and enhanced thrombogenicity

Abstract Background Aortic stenosis (AS) is characterized by endothelial dysfunction (ED), inflammatory cell infiltration, myofibroblastic and osteoblastic differentiation. Subclinical leaflet thrombosis was recently linked to higher rates of stroke and transient ischemic attack after transcatheter aortic valve implantation (TAVI). Procoagulant microparticles (MPs) are associated with ED, inflammation and clot formation. There is limited evidence regarding intra-valvular MPs content and their potential biological effects. This question is particularly relevant in TAVI in which the residing native valve could constitute a source of thrombotic activity enhancing leaflet thrombosis and valve dysfunction. Purpose Therefore, we hypothesized that MPs trapped within the native aortic valve contribute to valvular dysfunction including enhanced thrombogenicity. Methods Human valves were collected from patients undergoing surgical valve replacement for AS or aortic insufficiency (AI). Pro-thrombotic, pro-inflammatory, and ED markers were identified in the calcified vs non-calcified part of the valves by Western-blot. Calcium content was measured through colorimetric method. MPs were extracted from human pathological valves, and quantified through their prothrombinase activity. Primary cultures of porcine valvular endothelial cells (VEC) were treated with the MPs (10 nmol/L) or thrombin (1U/ml) for 24hrs. Phenotypic change was appreciated through gene expression pattern assessed by RT-qPCR. IL-8 secretion was measured by ELISA. Results The phenotype of the AS valve was characterized through increased expression of thrombogenic (tissue factor, thrombomodulin, PAI-1), adhesive (VCAM-1, ICAM-1) and inflammatory (COX-1, COX-2) molecules in the calcified part of the valve. Moreover, MPs content was increased in the calcified vs non-calcified part of the valve or AI valves. MPs levels was correlated with valvular calcium content (R=0.3862: p&amp;lt;0.001). Tissue factor was increased in MPs extracted from AS vs AI. The biological effect of MPs was tested on VEC in-vitro. Results showed dramatic increase in expression of inflammatory cytokines (CXCL10, CCL11, CXCL8, MCP1) adhesion molecules (VCAM-1, ICAM-1, SELP, SELE) and proangiogenic factors (VEGFR2, ANGPTL4) in VEC exposed to MPs (24h) from AS vs AI. Enhanced secretory phenotype was evidenced through IL-8 determination in the supernatant of VEC stimulated with MPs from AS valve. Conclusion Calcified aortic valve is a potent reservoir of MPs, acting as a pro-thrombogenic source per se and promoting a switch of VEC phenotype toward prothrombotic, proinflammatory and proangiogenic pattern. These data suggest that MPs released from the native valve constitute an important source of mediators involved in enhanced thrombogenicity and valvular remodeling. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): GERCA-Groupe Etudes Reali Commercia Avignon

Aortic valve calcium score: does it correlate with mean transaortic gradient?

Abstract Introduction Aortic valvular calcium score (AVCS) is useful in patients with aortic stenosis for whom echocardiography was not conclusive in grading its severity. Transcatheter aortic valve implantation (TAVI) is an established procedure of treatment in symptomatic severe AS. The burden of aortic valve calcification has been associated with some TAVI related complications (as perivalvular leaks), but at the same time it is well accepted that some degree of calcification is needed to ensure stable anchoring of the prosthesis to the aortic annulus. Purpose To assess if there is a correlation between aortic valve calcium score and mean transvalvular gradient 6 months after TAVI – is a higher AVCS correlated with lower mean transaortic gradient after TAVI? Methods We performed a single-center, retrospective cohort study including patients who underwent TAVI with a preoperative standardized contrast enhanced MSCT with AVCS available. Clinical and echocardiographic data were collected previously to TAVI (pre-TAVI) and at 6 months follow up (6M-FUP). Results A total of 187 patients were included, with 54% female and a mean age of 79.4±9.0 years old. Most patients had tricuspid aortic valve (95.7%); 5 patients had aortic bicuspidy and 3 had aortic valve bioprothesis. Concerning the valve type, 73.3% had new generation prosthesis and the main valve used was the CoreValve Evolut Pro (33.7%). Also, 38,5% needed balloon pre-dilation before TAVI. The mean pre-TAVI aortic transvalvular maximum and mean gradients were 76.5±23.2 mmHg and 48.3±15.5 mmHg, respectively; mean aortic valve area was 0.75±0.16 cm2. The mean AVCS was 2851±1524 AU (Agaston Units); 81.2% of women had AVCS&amp;gt;1300 AU and 74.4% men had AVCS &amp;gt;2000 AU. Comparing transvalvular aortic gradients previously and 6M-FUP after TAVI, there was an average differential of maximum gradient of 61±22 mmHg and of mean gradient of 40±15 mmHg. A negative and weak correlation was found between the AVCS and the maximum gradient (pearson coefficient of −0.181, p=0.02) and between mean gradient at 6M-FUP (pearson coefficient of −0.191, p=0.014). Discussion and conclusion AVCS is a significant predictor for death, stroke and perivalvular leaks after TAVI. On the other hand, high AVCS is associated with better seating in the native annulus during deployment. Nevertheless, high AVCS did not strongly correlated with mean transaortic gradient 6 months after TAVI. Funding Acknowledgement Type of funding sources: None.

Identifying fragile calcifications of the aortic valve in transcatheter aortic valve replacement: iodine concentration of aortic valvular calcification by spectral CT.

To demonstrate the relationship between spectral computed tomography (CT) measured iodine concentration and strength of aortic valvular calcification (AVC) in patients with aortic valve stenosis (AVS). A retrospective study was performed on patients who underwent transcatheter aortic valve replacement (TAVR) for symptomatic AVS and underwent both pre and postprocedural electrocardiogram gated CT scans using a spectral CT system. Preprocedural CT was used to evaluate the volume and iodine concentration (IC) in the AVC. Postprocedural CT data were used to calculate the volume reduction percentage (VRP) of AVC. Multiple linear regression analysis was used to identify the independent variables related to the VRP in AVCs. A total of 94 AVCs were selected from 22 patients. The mean volume and IC of the AVCs before TAVR were 0.37 mL ± 0.15 mL and 7 mg/mL ± 10.5 mg/mL, respectively. After TAVR, a median VRP of all 94 AVCs was 18.5%. Multiple linear regression analysis showed that the IC was independently associated with the VRP (coefficient = 1.64, p < 0.001). When an optimal IC cutoff point was set at 4 mg/mL in the assessment of a fragile AVC which showed the VRP was > 18.5%, the sensitivity was 63%; specificity, 91%; positive predictive value, 88%; and negative predictive value, 71%. When using spectral CT to prepare the TAVR, measuring the IC of the AVC may be useful to assess the probability of AVC deformity after TAVR. • A dual-layer detector-based spectral CT enables quantifying iodine of contrast media in the aortic valve calcification (AVC) on contrast-enhanced CT images. • The AVC including iodine of contrast media on contrast-enhanced CT image may have loose compositions, associated with the deformity of AVC after TAVR. • Measuring the iodine concentration in AVC may have the potential to assess the probability of AVC deformity, which may be associated with the outcome and complications after TAVR.2.