Aortic Valve Calcification In Patients Research Articles

Insulin resistance in patients suffering from severe AS

Abstract Background There are several cardiovascular risk factors known to promote the development of AS, one of them being type 2 diabetes (T2D). T2D is increasingly recognized as a heterogenous disease, leading to the latest concept of five diabetes clusters based on clinical parameters. Until now, the impact of the respective clusters, especially insulin resistance in prediabetes, on valvular cells and therefore the development of AS is not clear. Purpose We hypothesize that insulin resistance, which is frequently underrated, features a specific pattern of aortic valve calcification characterized by an elevated degree of calcification. Methods In order to analyze the impact of diabetes on AS we examined 200 patients with severe AS, scheduled for a transcatheter aortic valve implantation (TAVI). With the exemption of previously diagnosed diabetics, we performed an oral glucose tolerance test (OGTT), identifying patients with prediabetes and T2D. Additionally, blood was drawn from all included patients 2-5 days after TAVI, depicting their metabolic condition and thereby assigning them to a diabetes cluster. These findings were subsequently correlated with data from computertomography in all patients pertaining the severity of the stenosis, including the Agatston score, which illustrates the aortic valve calcium burden. Results Following the hypothesis that the extent of insulin resistance impacts the aortic valve calcification, we correlated the HOMA-IR with the Agatston score, resulting in a weak non-significant linear correlation (r=-0.129, p = 0.097, n = 166). Therefore, increased insulin resistance has not been shown to be associated with increased aortic valve calcification. Moreover, no differences in the extent of calcification between diabetic, prediabetic and non-diabetic patients could be demonstrated (F (2, 147) = 0.410, p = 0.665). However, it was clearly striking that the majority of the patients examined had already developed prediabetes or diabetes (Non-Diabetic = 7.1%, Prediabetic = 34.6%, Diabetic = 58.2%, n= 182). Conclusion Although we were able to observe an increased rate in prediabetic and diabetic patients in our AS cohort, there was no significantly elevated aortic valve calcification in patients with pronounced insulin resistance. This suggests that insulin resistance might not directly impact valvular calcification but upstream processes in valvular cells predisposing for AS since the majority of AS patients in our cohort is (pre)diabetic.

The impact of resting heart rate on adverse outcomes and haemodynamic progression of aortic stenosis

Abstract Introduction A high resting heart rate (RHR) is an established risk factor for cardiovascular disease, adverse cardiac events, accelerated calcification in coronary artery disease and carotid stenosis, and increased aortic valve calcification in patients with and without a confirmed diagnosis of aortic stenosis (AS). Aortic valve calcification is the most common precursor to AS and is associated with significantly faster disease progression. There are few studies exploring the effects of RHR on the progression of AS, the development of severe stenosis, and the risk of complications and death. Purpose We hypothesised that an elevated RHR would be associated with poorer outcomes and more rapid haemodynamic disease progression in patients with AS and tested this in a large cohort of patients without severe disease. Methods Using the National Echocardiography Database of Australia (NEDA) we undertook a retrospective observational study on patients without severe AS, a bicuspid aortic valve or prior aortic valve replacement. The association between baseline RHR and time to the composite primary endpoint of severe AS, aortic valve replacement or cardiovascular death was tested using Cox proportional hazards regression. In addition, the relationship between baseline RHR and the components of this composite was investigated. Subsequently, the relationship between annualised AS progression rate, defined as change in standard indices of AS severity (maximal jet velocity [Vmax], mean pressure gradient [MPG], and aortic valve area [AVA]), and RHR were analysed using general linear models. Results The initial study cohort comprised 55 585 individuals: 54% male, mean age 63 years and median baseline RHR 70 bpm. The composite primary endpoint, reached by 7 434 patients, was independently associated with RHR (hazard ratio [per 10bpm increase], 1.04; 95% CI, 1.02-1.05; p < 0.001). RHR was also independently associated with time to developing severe AS (hazard ratio [per 10bpm increase], 1.06; 95% CI, 1.01-1.12; p = 0.017) and cardiovascular death (hazard ratio [per 10bpm increase], 1.04; 95% CI, 1.02-1.06; p < 0.001). The event rate was significantly higher in patients with a RHR of at least 70 bpm (the median RHR) compared to those with an RHR less than 70 bpm. In addition, RHR was independently associated with rate of change of each individual measurement index of AS severity including Vmax (β = 0.65 cm/s/year [per 10 bpm increase]; p < 0.001), MPG (β = 0.05 mmHg/ year [per 10 bpm increase]; p<0.001), and AVA (β = -0.01 cm2/year [per 10 bpm increase]; p < 0.001). Conclusions RHR is independently associated with adverse clinical outcomes and haemodynamic progression of AS in patients without severe disease. Future randomised controlled trials should investigate the effect of lowering RHR on clinical endpoints and progression of AS.

Association of aortic valve size with the degree of aortic valve calcification in patients with severe aortic stenosis

Abstract Background The development and progression of aortic valve calcification (AVC) is a major contributor to the severity of aortic stenosis (AS). Currently, the 2021 ESC/EACTS Guidelines recommend the use of the Agatston AVC score to predict the likelihood of severe AS in patients with unclear echocardiographic AS severity. It has been shown that AS in women is associated with less AVC, thus lower AVC thresholds for the diagnosis of severe AS in women are recommended. It has furthermore been demonstrated that women generally have smaller hearts. However, whether small aortic valve (AV) size, independent from sex, is associated with less AVC in patients with severe AS has not been explored. Purpose The aim of this study was to assess the association of AV dimension and the degree of AVC in severe AS. Methods AVC was assessed on computed tomography using the Agatston score in consecutive patients with severe AS. AV diameter and indexed AV annulus area adjusted for body surface area were measured. To analyze the association with AVC, Spearman rank correlation as well as multivariate linear regression models adjusted for age, sex, left ventricular ejection fraction and cardiovascular risk factors were performed. Results In total 446 patients (mean age 81±6 years, 45% female) were included. Median Agatston Score was 2949 AU [2135-3986] in men and 1755 AU [1303-2571] in women. Mean AV diameter was 24±2mm and mean indexed annulus area was 248±43mm2. We observed a significant correlation between AV Agatston score and AV diameter (r=0.6; p<0.001 Figure 1 Panel A) as well as between AV Agatston score and indexed annulus area (r=0.5; p <0.001; Figure 1 Panel B). On multivariate analysis AV diameter (β=273; p<0.001), indexed annulus area (β=13; p<0.001) and sex (β=396; p<0.001) were independently associated with AVC by the Agatston score. In addition, separate regression analyses in men and women showed a significant association of AV diameter (β(men)=265; β(women)=275; both p<0.001) and indexed annulus area (β(men)=13; β(women)=11; both p<0.001) with the AV Agatston score. Hypertension, dyslipidemia, diabetes mellitus, smoking and chronic kidney disease showed no statistically significant association with the amount of AVC. Conclusion Our results indicate that patients with severe AS and larger AV dimensions present with more AVC on Agatston scoring, independent from sex. From surgical data, it is known that smaller aortic bioprostheses cause higher gradients, consequently we hypothesize here, that less calcification is required in small valves to cause significant narrowing. Thus, AVC cut-offs for the diagnosis of AS should be indexed for AV size rather than sex.

Coronary artery calcification and aortic valve calcification in patients with kidney failure: a sex-disaggregated study

BackgroundChronic kidney disease (CKD) is linked to an increased cardiovascular disease (CVD) burden. Albeit underappreciated, sex differences are evident in CKD with females being more prone to CKD development, but males progressing more rapidly to kidney failure (KF). Cardiovascular remodelling is a hallmark of CKD with increased arterial and valvular calcification contributing to CKD. However, little is known regarding sex differences in calcific cardiovascular remodelling in KF patients. Thus, we hypothesise that sex differences are present in coronary artery calcification (CAC) and aortic valve calcification (AVC) in patients with KF.MethodsKF patients, males (n = 214) and females (n = 107), that had undergone computer tomography (CT) assessment for CAC and AVC were selected from three CKD cohorts. All patients underwent non-contrast multi-detector cardiac CT scanning, with CAC and AVC scoring based on the Agatston method. Baseline biochemical measurements were retrieved from cohort databases, including plasma analyses for inflammation markers (IL-6, TNF, hsCRP) and oxidative stress by skin autofluorescence measuring advanced glycation end-products (AGE), amongst other variables.ResultsSex-disaggregated analyses revealed that CAC score was associated with age in both males and females (both p < 0.001). Age-adjusted analyses revealed that in males CAC was associated with diabetes mellitus (DM) (p = 0.018) and CVD (p = 0.011). Additionally, for females CAC associated with IL-6 (p = 0.005) and TNF (p = 0.004). In both females and males CAC associated with AGE (p = 0.042 and p = 0.05, respectively). CAC was associated with mortality for females (p = 0.015) independent of age. AVC in females was not reviewed due to low AVC-positive samples (n = 14). In males, in multivariable regression AVC was associated with age (p < 0.001) and inflammation, as measured by IL-6 (p = 0.010).ConclusionsIn female KF patients inflammatory burden and oxidative stress were associated with CAC. Whereas in male KF patients oxidative stress and inflammation were associated with CAC and AVC, respectively. Our findings suggest a sex-specific biomarker signature for cardiovascular calcification that may affect the development of cardiovascular complications in males and females with KF.

Sex-Specific Differences in Aortic Valve Calcification Between Bicuspid and Tricuspid Severe Aortic Stenosis

Sex-specific thresholds of aortic valve calcification (AVC) correlate with aortic stenosis (AS) and may complement echocardiography to determine AS severity. Importantly, current guideline-recommended thresholds of AVC scores derived by multislice computed tomography do not distinguish between bicuspid and tricuspid aortic valves. The objective of this study was to evaluate the sex-specific differences in the amount of AVC in patients with severe AS and tricuspid (TAV) versus bicuspid (BAV) aortic valve morphologies, retrospectively evaluated by 2 tertiary care institutions. The inclusion criteria comprised patients with severe AS and a left ventricular ejection fraction ≥50% and suitable imaging examinations. The study included 1,450 patients (723 men; 49.9%) with severe AS, including 1,335 patients with TAV (92.1%) and 115 with BAV (17.9%). The calculated Agatston score was higher in BAV patients (men: BAV 4,358 [2,644 to 6,005] AU vs TAV 2,643 [1,727 to 3,794] AU, p <0.01; women: BAV 2,174 [1,330 to 4,378] AU vs TAV 1,703 [964 to 2,534] AU, p <0.01), also when indexed for valve dimensions and body surface area (men: BAV 2,227 [321 to 3,105] AU/m2 vs TAV 1,333 [872 to 1,913] AU/m2, p <0.01; women: BAV 1,326 [782 to 2,148] AU/m2 vs TAV 930 [546 to 1,456] AU/m2, p <0.01). Differences between the BAV- and TAV-derived Agatston score was more prominent in concordant severe AS. In conclusion, sex-specific Agatston scores in severe AS were approximately 1/3 higher in patients with BAV than in patients with TAV for both women and men. Optimal AVC thresholds should be adjusted for BAV, also respecting considerable prognostic implications.

Lipoprotein (a) is a risk factor of aortic valve calcification in patients with a risk of atherosclerosis.

Aortic valve calcification (AVC), which causes aortic stenosis (AS), is more common in elderly persons. Controlling for conventional risk variables did not, however, reduce the incidence of AS. Thus, residual risk factors of AS should be identified. We enrolled 513 patients who underwent coronary angiography with computed tomography because of suspicion of coronary artery disease (CAD) or ruling out of CAD before aortic valve replacement. Calcium volume was calculated with a commercially available application. Conventional and lipid-related risk factors including serum levels of Lp(a) were evaluated for all patients. Calcium volume and Lp(a) levels were significantly higher in patients who underwent aortic valve replacement than in those who did not. A single regression analysis showed that the calcium volume was positively associated with age and the Lp(a) levels and negatively associated with the estimated glomerular filtration rate. No statistical significance was observed for other risk factors, including oxidized low-density lipoprotein, omega-3 fatty acids levels. The multiple regression analysis revealed that age (P<0.001), female sex (P<0.05), Lp(a) (P<0.01), and hemoglobin A1c (P<0.01) were determinants of the calcium volume. The area under the curve in receiver operating characteristic analysis of Lp(a) for implementation of AVR was 0.65 at an Lp(a) cut-off level of 16 mg/dL. In conclusion, the serum Lp(a) level is a potent risk factor of AVC in patients with high risk of atherosclerosis. J. Med. Invest. 70 : 450-456, August, 2023.

Abstract 14822: Lipoprotein (a) is a Residual Risk Factor of Aortic Valve Calcification in Patients With High Risk of Atherosclerotic Disease

Introduction: The number of patients with aortic valve stenosis which results from aortic valve calcification (AVC), has been increasing in the elderly population. The risk factors of AVC include diabetes, dyslipidemia, and hypertension. However, control of these risk factors has not resulted in a decreased incidence of AVC. Increased Lipoprotein (LP) (a) and oxidized low-density lipoprotein (LDL), or decreased omega 3-fatty acids, are the candidates for serum biomarkers of residual risk factors. However, the most contributable risk factors for AVC has not been identified. Methods: We enrolled a total of 618 patients who underwent coronary angiography by computed tomography because of suspicion of coronary artery disease (CAD). Calcium scores were calculated using imaging software (3mensio Medical Imaging) and existence of coronary stenosis was evaluated. Patients who were suspected of having significant coronary stenosis underwent coronary angiography to confirm the existence of ischemic heart disease. Patients were evaluated for residual risk factors including Lp(a), oxidized LDL, omega 3- and 6-fatty acids, and C-reactive protein in addition to markers of conventional risk factors. Result: The calcium score in patients who received aortic valve replacement was significantly higher than that in patients who did not undergo AVR. There were no difference between the calcium scores in patients with CAD and those without CAD. Univariate analysis showed that the calcium score was associated with levels of Lp(a) (P&lt;0.01) but not with omega 3- and 6-fatty acids, oxidative LDL, hemoglobin A1c, LDL- and HDL-cholesterol, triglycerides, and C-reactive protein. Multivariate analysis showed that increased Lp(a) and age were independently correlated with the calcium score (P&lt;0.01), but sex and the existence of other conventional risk factors including hypertension, dyslipidemia, and chronic kidney disease were not. Conclusion: Serum Lp(a) is a potent risk factor for AVC in patients with high risk of atherosclerosis. Lowering Lp(a) may be a potential strategy for prevention of AVC. Intervention studies involving methods of lowering Lp(a) are needed to confirm the results.

The nonlinear correlation between lipoprotein (a) and the prevalence of aortic valve calcification in patients with new-onset acute myocardial infarction

Background Growing studies show that lipoprotein (a) [Lp(a)] is related to calcified aortic valve diseases in general population, while the relationship between Lp(a) and aortic valve calcification (AVC) in patients with new-onset acute myocardial infarction (AMI) remains unclear. Therefore, this study was to evaluate the correlation between Lp(a) and AVC in patients with new-onset AMI. Methods This cross-sectional study included 410 patients with new-onset AMI who were hospitalised in Zhongda Hospital affiliated to Southeast University from January 1, 2020 to December 31, 2021. Multivariable logistic regression, subgroup analysis, generalised additive model, threshold and saturation effect and receiver operator characteristic (ROC) curve were used to explore the association between Lp(a) and AVC. Results Patients with AVC had higher levels of Lp(a) than those without AVC. Multivariable logistic regression analysis showed that higher Lp(a) was still associated with higher risk of AVC after adjusting for confounding factors, and this correlation was robust in most subgroups and sensitivity analyses (p < 0.05). Additionally, the generalised additive model showed that there was a nonlinear correlation between Lp(a) and AVC (P for nonlinearity = 0.037). Threshold and saturation effect analysis indicated that when Lp(a) < 840 mg/L, it was positively correlated with the prevalence of AVC (p < 0.05), but when Lp(a) ≥ 840 mg/L, this correlation no longer existed. Besides, ROC curve analysis demonstrated that Lp(a) had a good diagnostic performance for AVC. Conclusion Lp(a) was independently associated with the prevalence of AVC in patients with new-onset AMI.

PTP1B Inhibition Improves Mitochondrial Dynamics to Alleviate Calcific Aortic Valve Disease Via Regulating OPA1 Homeostasis

There are currently no pharmacological therapies for calcific aortic valve disease (CAVD). Here, we evaluated the role of protein tyrosine phosphatase 1B (PTP1B) inhibition in CAVD. Up-regulation of PTP1B was critically involved in calcified human aortic valve, and PTP1B inhibition had beneficial effects in preventing fibrocalcific response in valvular interstitial cells and LDLR-/- mice. In addition, we reported a novel function of PTP1B in regulating mitochondrial homeostasis by interacting with the OPA1 isoform transition in valvular interstitial cellosteogenesis. Thus, these findings have identified PTP1B as a potential target for preventing aortic valvecalcification in patients with CAVD.

Factors predicting the occurrence of aortic valve calcification in patients with coronary artery calcification in China

Objectives In patients with coronary artery calcification (CAC), a predictor of adverse cardiovascular events, coronary computed tomography angiography (CCTA) also shows valvular calcification. In this study, we evaluated common clinical indicators in CAC patients with aortic (AoVC) and mitral valve (MVC) calcification. Methods CAC and valvular calcification were quantified using the Agatston score in 636 hospitalised patients with CAC who underwent CCTA. Results Valvular calcification was found in 30.5% of patients, with 25.2% (160 patients) showing AoVC. Age was an independent predictor of AoVC in both men (odds ratio (OR), 1.086; 95% confidence interval (CI), [1.054–1.119]; p < 0.001) and women (OR, 1.109; CI, [1.066–1.154]; p < 0.001). In men, we also found that a history of cerebral infarction was an independent predictor of AoVC (OR, 2.402; CI, [1.177–4.902]; p < 0.05). The independent predictors of AoVC in the 60- to 69-years age group were BMI (OR, 1.181; CI, [1.061–1.316]; p < 0.01) and history of cerebral infarction (OR, 3.187; CI, [1.283–7.919]; p < 0.05). Conclusions Age is a key independent predictor of AoVC in CAC patients. History of cerebrovascular disease was also an independent predictor of AoVC, but only in men and patients aged 60–69 years. Our results indicate that a history of cerebral infarction may be used as a risk factor when identifying AoVC in patients with CAC.

Letter by Spiering et al Regarding Article, “Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial”

HomeCirculationVol. 144, No. 22Letter by Spiering et al Regarding Article, “Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBLetter by Spiering et al Regarding Article, “Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial” Wilko Spiering, MD, PhD, Willem P. Mali, MD, PhD and Pim A. de Jong, MD, PhD Wilko SpieringWilko Spiering https://orcid.org/0000-0002-2493-6407 Departments of Vascular Medicine (W.S.), University Medical Center Utrecht, The Netherlands. Search for more papers by this author , Willem P. MaliWillem P. Mali Radiology (W.P.M., P.A.d.J.), University Medical Center Utrecht, The Netherlands. Search for more papers by this author and Pim A. de JongPim A. de Jong Radiology (W.P.M., P.A.d.J.), University Medical Center Utrecht, The Netherlands. Search for more papers by this author Originally published29 Nov 2021https://doi.org/10.1161/CIRCULATIONAHA.121.055622Circulation. 2021;144:e334To the Editor:We read with interest the article by Pawade et al1 on the effects of denosumab or alendronate on the progression of aortic stenosis. The authors conclude from this randomized, controlled trial that both drugs did not affect progression of aortic valve calcification in patients with calcific aortic stenosis. They call for a search to find alternative pathways and mechanisms to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. We think that this trial does not justify abandoning bisphosphonate therapy as a potential treatment, but that it would have been better if the authors had chosen etidronate as the comparator instead of alendronate.Mineralization in soft tissues such as arteries and valves is controlled by endogenous inhibitors of hydroxyapatite formation, of which inorganic pyrophosphate is the most important. Bisphosphonates are nonhydrolyzable analogs of inorganic pyrophosphate, and cumulating evidence shows that they can inhibit vascular calcification. Nonnitrogenous bisphosphonates, like etidronate, are potent inhibitors of ectopic calcification, whereas nitrogenous bisphosphonates, like alendronate, have a high affinity for bone and are more potent inhibitors of osteoclasts. In an ex vivo model of calcification in intact aortic valves, it was shown that etidronate completely prevented aortic valve leaflet calcification at already very low concentrations.2Pseudoxanthoma elasticum is a heritable ectopic mineralization disorder with increased medial arterial calcification. In an animal model of pseudoxanthoma elasticum, etidronate, but not alendronate, significantly reduced calcification, indicating that the inhibiting effect on ectopic calcification of bisphosphonates is not just a class effect.3 In a double-blind, placebo-controlled, randomized, controlled trial in patients with pseudoxanthoma elasticum, we showed that etidronate reduced arterial calcification.4 However, in a randomized, controlled trial in patients with chronic kidney disease, alendronate did not decrease the progression of vascular calcification.5We think that the absence of any effect of alendronate on the progression of aortic stenosis seen in the study of Pawade et al is in line with earlier findings that alendronate with its low affinity for soft tissues is not the ideal bisphosphonate for inhibiting ectopic calcification.We would like to know why, with cumulating evidence that etidronate is very efficacious in inhibiting soft tissue calcification, the authors decided to choose alendronate and not etidronate in their clinical trial.Article InformationDisclosuresNone.FootnotesCirculation is available at www.ahajournals.org/journal/circ

SNF472: mechanism of action and results from clinical trials.

Vascular calcification (VC) is associated with increased cardiovascular event rates, particularly in patients with end-stage kidney disease (ESKD). Dysregulated mineral metabolism and inflammation have been shown to promote VC, however, treatment options targeting VC specifically are not available. This review outlines the pathophysiological mechanisms contributing to VC in ESKD and describes recent studies evaluating the effects of the first-in-class inhibitor of VC, SNF472. SNF472 directly inhibits calcium phosphate crystal formation and aggregation. SNF472 has completed early phase clinical trials with a favourable safety profile and Phase 2 clinical trial data have shown attenuation of coronary artery and aortic valve calcification in patients receiving hemodialysis. Therapeutic agents that directly target VC may prevent the multiple complications associated with dystrophic calcification in patients with ESKD.

Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial.

Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis. In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and 18F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score. A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s [2.93-3.82 m/s]; aortic valve calcium score, 1152 AU [655-2065 AU]) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18-0.33 µg/L] to 0.11 µg/L [0.08-0.17 µg/L]) and alendronic acid (0.20 [0.14-0.28 µg/L] to 0.09 µg/L [0.08-0.13 µg/L]) but was unchanged with placebo (0.23 [0.17-0.30 µg/L] to 0.26 µg/L [0.16-0.31 µg/L]). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198-804 AU] versus 354 AU [76-675 AU]; P=0.41) or alendronic acid and placebo (326 [138-813 AU] versus 354 AU [76-675 AU]; P=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-sodium fluoride aortic valve uptake. Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Association of aortic valve calcification with carotid artery lesions and peripheral artery disease in patients with chronic kidney disease: a cross-sectional study

BackgroundPatients with chronic kidney disease (CKD) reportedly have a high prevalence of aortic valve calcification (AVC). In population-based studies, AVC is considered a manifestation of systemic atherosclerosis. The association of AVC with atherosclerotic lesions has not been fully investigated in predialysis patients. The present study was performed to determine whether carotid artery lesions and peripheral artery disease (PAD) are associated with AVC in patients with CKD not on dialysis.MethodsIn total, 749 patients were included in this cross-sectional study. AVC was evaluated using echocardiography. Carotid artery lesions including carotid artery plaque (CAP) and PAD were simultaneously examined in each patient. A logistic regression analysis was applied to determine the factors associated with AVC.ResultsAVC, CAP, and PAD were found in 201, 583, and 123 patients, respectively. In the multivariable analyses adjusted for covariates including the estimated glomerular filtration rate and makers of mineral metabolism (serum calcium, serum phosphorus, parathyroid hormone, 1,25-dihydroxyvitamin D, and fibroblast growth factor 23), AVC was significantly associated with the presence of CAP [odds ratio (OR), 3.37; 95% confidence interval (CI), 1.43–7.95], the presence of PAD (OR, 1.76; 95% CI, 1.10–2.81), the CAP score (per 1.0-point increase) (OR, 1.06; 95% CI, 1.02–1.11), and the ankle-brachial blood pressure index (per 0.1-point increase) (OR, 0.83; 95% CI, 0.72–0.95).ConclusionsAVC was associated with atherosclerotic lesions independent of kidney function and mineral metabolism. We consider that this association between AVC and atherosclerosis might reflect the burden of shared atherosclerotic risk factors.

P2747Identification of microRNAs in aortic valve calcification patients with bicuspid aortic valve

Abstract Background An individual with bicuspid aortic valve (BAV) has a higher risk of developing aortic valve calcification (AVC) than people with tricuspid aortic valve. AVC in patients with BAV and TAV is known to be distinct in molecular level. But the epigenetic mechanism of AVC in patients with BAV is still undefined. Purpose To describe the role of microRNA (miRNA) in the AVC process of patients with BAV Methods We collected aortic valve samples of 5 patients with BAV, of which 2 have AVC and 3 of which have not. We performed RNA-seq technology on an Illumina Hiseq 2500/2000 platform to characterized all feathers of miRNAs in BAV. We used miRBase20.0 to look for known miRNA. Gene expression levels between groups of valves were compared with degeR to find out differential miRNAs. Then we predicated the target gene of miRNA by targetscan database. We performed the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for the target gene candidates of differential miRNAs to predict the potential function of AVC specific miRNAs. A value of P&lt;0.05 (2-sided) was considered to be statistically significant. Results Compared with noncalcified aortic valves. We found that 33 miRNAs were upregulated and 29 are significantly downregulated in calcified aortic valves. The analysis showed the total of 62 miRNAs to be significantly altered as shown in the heat map in Figure1. the target gene candidates of differential miRNAs were enriched in numerous Go terms including the following: binding, protein binding, ion binding, catalytic activity, localization. The significantly (P&lt;0.05) affected pathways identified by KEGG pathway analysis are presented in table 1. Table 1 Pathway term Gene number P valvue Lysosome 70 0.001945 Axon guidance 66 0.013212 Glycerophospholipid metabolism 50 0.016075 Calcium signaling pathway 84 0.037645 Synaptic vesicle cycle 34 0.043983 Pyrimidine metabolism 52 0.04501 Homologous recombination 18 0.0453 Other glycan degradation 13 0.048068 Pathway analysis based on the KEGG database. Figure 1 Conclusion The present study proved that miRNAs play an important role in AVC of patients with BAV. The result may improve understanding of the special molecular alterations in AVC with BAV and may provide potential targets for future clinical applications. Acknowledgement/Funding the National Natural Science Foundation of China (No.81370435; 91339103; 81700405)

TCT-694 Prognostic Impact of Aortic Valve Calcification in Patients With Low Flow Low Gradient Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement

Compared with high-gradient aortic stenosis (AS), patients with low-flow, low-gradient AS have less satisfactory outcome after transcatheter aortic valve replacement (TAVR). However, distinct outcome predictors in this patient subset are yet to be determined. The aim of this study was to evaluate

IMPACT OF VASCULAR BURDEN IN AORTIC STENOSIS SEVERITY ASSESSMENT OF NORMAL FLOW-LOW GRADIENT PATIENTS

Fifty percent of Normal-Flow (NF), Low-Gradient (LG) patients (i.e. low mean gradient [MG] and small aortic valve area [AVA]) have severe aortic valve calcification (AVC) as measured by computed tomography. However, NF/LG patients are considered as moderate aortic stenosis (AS) in current ACC/AHA guidelines. The objective of this study was to evaluate the effect of hypertension (HTN) and systemic arterial compliance (SAC) on MG measurements and its relationship with AVC in patients with NF.

Systolic hypertension and progression of aortic valve calcification in patients with aortic stenosis: results from the PROGRESSA study

Hypertension is highly prevalent in patients with aortic stenosis (AS) and is associated with worse outcomes. The current prospective study assessed the impact of systolic hypertension (SHPT) on the progression of aortic valve calcification (AVC) measured by multidetector computed tomography (MDCT) in patients with AS. The present analysis includes the first series of 101 patients with AS prospectively recruited in the PROGRESSA study. Patients underwent comprehensive Doppler echocardiography and MDCT exams at baseline and after 2-year follow-up. AVC and coronary artery calcification (CAC) were measured using the Agatston method. Patients with SHPT at baseline (i.e. systolic blood pressure ≥140 mmHg; n = 37, 37%) had faster 2-year AVC progression compared with those without SHPT (i.e. systolic blood pressure <140 mmHg) (AVC median [25th percentile-75th percentile]: +370 [126-824] vs. +157 [58-303] AU; P = 0.007, respectively). Similar results were obtained with the analysis of AVC progression divided by the cross-sectional area of the aortic annulus (AVCdensity: +96 [34-218] vs. +45 [14-82] AU/cm2, P = 0.01, respectively). In multivariable analysis, SHPT remained significantly associated with faster progression of AVC or AVCdensity (all P = 0.001). There was no significant difference between groups with respect to progression of CAC (+39 [3-199] vs. +41 [0-156] AU, P = 0.88). This prospective study shows for the first time that SHPT is associated with faster AVC progression but not with CAC progression in AS patients. These findings provide further support for the elaboration of randomized clinical trials to assess the efficacy of antihypertensive medication to slow the stenosis progression in patients with AS.

Association of the C-Reactive Protein Gene (CRP) rs1205 C>T Polymorphism with Aortic Valve Calcification in Patients with Aortic Stenosis.

Elevation in C-reactive protein (CRP) levels have been shown in patients with aortic valve stenosis (AS). Minor allele of the CRP gene (CRP) rs1205 C>T polymorphism has been associated with lower plasma CRP concentrations in cohorts of healthy and atherosclerotic patients. Considering the existing similarities between atherosclerosis and AS, we examined the effect of CRP rs1205 C>T polymorphism on the AS severity. Three hundred consecutive Caucasian patients diagnosed with AS were genotyped for the rs1205 C>T polymorphism using the TaqMan assay. Severity of the AS was assessed using transthoracic echocardiography. The degree of calcification was analyzed semi-quantitatively. Carriers of the rs1205 T allele were characterized by elevated serum CRP levels (2.53 (1.51–3.96) vs. 1.68 (0.98–2.90) mg/L, p < 0.001) and a higher proportion of the severe aortic valve calcification (70.4% vs. 55.1%, p = 0.01) compared with major homozygotes. The effect of CRP rs1205 polymorphism on CRP levels is opposite in AS-affected than in unaffected subjects, suggesting existence of a disease-specific molecular regulatory mechanism. Furthermore, rs1205 variant allele predisposes to larger aortic valve calcification, potentially being a novel genetic risk marker of disease progression.

Significance of Aortic Valve Calcification in Patients With Low‐Gradient Low‐Flow Aortic Stenosis

Assessment of patients with aortic stenosis (AS) and impaired left ventricular function remains challenging. Aortic valve calcium (AVC) scoring with computed tomography (CT) and fluoroscopy has been proposed as means of diagnosing and predicting outcomes in patients with severe AS. Severity of aortic valve calcification correlates with the diagnosis of true severe AS and outcomes in patients with low-gradient low-flow AS. Echocardiography and CT database records from January 1, 2000 to September 26, 2009 were reviewed. Patients with aortic valve area (AVA)<1.0 cm2 who had ejection fraction (EF)≤25% and mean valvular gradient≤25 mmHg with concurrent noncontrast CT scans were included. AVC was evaluated using CT and fluoroscopy. Mortality and aortic valve replacement (AVR) were established using the Social Security Death Index and medical records. The role of surgery in outcomes was evaluated. Fifty-one patients who met the above criteria were included. Mean age was 75.1±9.6 years, and 15 patients were female. Mean EF was 21%±4.6% with AVA of 0.7±0.1 cm2. The peak and mean gradients were 35.5±10.6 and 19.0±5.1 mmHg, respectively. Median aortic valve calcium score was 2027 Agatston units. Mean follow-up was 908 days. Patients with calcium scores above the median value were found to have increased mortality (P=0.02). The benefit of surgery on survival was more pronounced in patients with higher valvular scores (P=0.001). Fluoroscopy scoring led to similar findings, where increased AVC predicted worse outcomes (P=0.04). In patients with low-gradient low-flow AS, higher valvular calcium score predicts worse long-term mortality. AVR is associated with improved survival in patients with higher valve scores.