Progression Of Calcific Aortic Stenosis Research Articles

Numerical investigation of calcification effects on aortic valve motions and ambient flow characteristics

The pathogenesis and progression of calcific aortic stenosis pose a significant challenge in medical science due to the intricate nature of blood fluid dynamics. To better understand this crucial phenomenon, this study investigates the physiological behaviors of aortic valves with varying degrees of lesions and ambient flow conditions using an in-house CFD solver, CgLES-Y code. The code is validated by simulating two-dimensional valve opening and closure, followed by the extension to three-dimensional symmetrically simplified valve dynamics. The simulation results exhibit great agreement with other numerical, experimental and clinical data. Patient-specific models of the aortic root and inner valve geometries are developed based on CT images. Analysis of fluid dynamics traits, configuration properties and leaflet stress is performed for both normal and calcified aortic valves during the systolic and diastolic periods. The study further examines the impact of calcium deposition on abnormal flow fields and leaflet motion, which indicates that calcium deposition increases the tensional burden on healthy leaflets, therefore, the microcosmic increase in valve modulus leads to global damage extending from the root to the tip, whereas macroscopic calcification primarily induces damage in the vicinity of the calcium compound. Additionally, the generation of additional vortices on the valve surface and sinus lumen heightens the likelihood of calcium accumulation.

Diabetes mellitus and aortic stenosis head to head: toward personalized medicine in patients with both pathologies

Diabetes mellitus (DM) and calcific aortic stenosis (CAS) are common morbidities in the elderly, which are both chronic, progressive and often concomitant diseases. Several studies revealed that DM increases the risk of developing severe CAS, yet clear information about the relationship between both these diseases and the influence of DM on the progression of CAS is currently lacking. To evaluate the effect of DM on aortic valves and on the process of calcification, and to achieve better patient management in daily clinical practice, we analysed calcified and noncalcified valve tissue from patients with severe CAS, with or without DM. A proteomic strategy using isobaric tags was adopted and the plasma concentrations of nine proteins were studied using 3 orthogonal methods and in a separate cell model. The differentially expressed proteins identified are implicated in biological processes like endopeptidase activity, lipid metabolism, coagulation, and fibrinolysis. The results obtained provide evidence that DM provokes changes in the proteome of aortic valves, affecting valve calcification. This finding may help enhance our understanding of the pathogenesis of CAS and how DM affects the evolution of this condition, an important step in identifying targets to personalize the treatment of these patients.

Indoxyl-sulfate activation of the AhR- NF-κB pathway promotes interleukin-6 secretion and the subsequent osteogenic differentiation of human valvular interstitial cells from the aortic valve

Calcific aortic stenosis (CAS) is more prevalent, occurs earlier, progresses faster and has worse outcomes in patients with chronic kidney disease (CKD). The uremic toxin indoxyl sulfate (IS) is powerful predictor of cardiovascular mortality in these patients and a strong promoter of ectopic calcification whose role in CAS remains poorly studied. The objective of this study was to evaluate whether IS influences the mineralization of primary human valvular interstitial cells (hVICs) from the aortic valve. Primary hVICs were exposed to increasing concentrations of IS in osteogenic medium (OM). The hVICs' osteogenic transition was monitored by qRT-PCRs for BMP2 and RUNX2 mRNA. Cell mineralization was assayed using the o-cresolphthalein complexone method. Inflammation was assessed by monitoring NF-κB activation using Western blots as well as IL-1β, IL-6 and TNF-α secretion by ELISAs. Small interfering RNA (siRNA) approaches enabled us to determine which signaling pathways were involved. Indoxyl-sulfate increased OM-induced hVICs osteogenic transition and calcification in a concentration-dependent manner. This effect was blocked by silencing the receptor for IS (the aryl hydrocarbon receptor, AhR). Exposure to IS promoted p65 phosphorylation, the blockade of which inhibited IS-induced mineralization. Exposure to IS promoted IL-6 secretion by hVICs, a phenomenon blocked by silencing AhR or p65. Incubation with an anti-IL-6 antibody neutralized IS's pro-calcific effects. IS promotes hVIC mineralization through AhR-dependent activation of the NF-κB pathway and the subsequent release of IL-6. Further research should seek to determine whether targeting inflammatory pathways can reduce the onset and progression of CKD-related CAS.

Lipoprotein(a): Insights for the Practicing Clinician.

Following the discovery of the Lipoprotein(a) (Lp(a)) molecule by Kare Berg in 1963, many physiological and pathological properties of this particle remain to be fully understood. Multiple population-based studies have demonstrated a correlation between elevated Lp(a) levels and the incidence of cardiovascular disease. Data extrapolated from the Copenhagen City Heart and ASTRONOMER studies also demonstrated the link between Lp(a) levels and the incidence and rate of progression of calcific aortic stenosis. Interest in Lp(a) has increased in recent years, partly due to new emerging therapies that can specifically reduce serum Lp(a) concentrations. Given the strong correlation between Lp(a) and CV disease from epidemiological studies, several international guidelines have also been updated to advocate Lp(a) testing in specific population groups. This review aims to highlight the importance of the role of Lp(a) in cardiovascular disease and discusses the potential of novel therapies in patients with elevated Lp(a) levels.

Thoracic Aortic 18F-Sodium Fluoride Activity and Ischemic Stroke in Patients With Established Cardiovascular Disease

BackgroundAortic atherosclerosis represents an important contributor to ischemic stroke risk. Identifying patients with high-risk aortic atheroma could improve preventative treatment strategies for future ischemic stroke. ObjectivesThe purpose of this study was to investigate whether thoracic 18F-sodium fluoride positron emission tomography (PET) could improve the identification of patients at the highest risk of ischemic stroke. MethodsIn a post hoc observational cohort study, we quantified thoracic aortic and coronary 18F-sodium fluoride activity in 461 patients with stable cardiovascular disease undergoing PET combined with computed tomography (CT). Progression of atherosclerosis was assessed by change in aortic and coronary CT calcium volume. Clinical outcomes were determined by the occurrence of ischemic stroke and myocardial infarction. We compared the prognostic utility of 18F-sodium fluoride activity for predicting stroke to clinical risk scores and CT calcium quantification using survival analysis and multivariable Cox regression. ResultsAfter 12.7 ± 2.7 months, progression of thoracic aortic calcium volume correlated with baseline thoracic aortic 18F-sodium fluoride activity (n = 140; r = 0.31; P = 0.00016). In 461 patients, 23 (5%) patients experienced an ischemic stroke and 32 (7%) a myocardial infarction after 6.1 ± 2.3 years of follow-up. High thoracic aortic 18F-sodium fluoride activity was strongly associated with ischemic stroke (HR: 10.3 [95% CI: 3.1-34.8]; P = 0.00017), but not myocardial infarction (P = 0.40). Conversely, high coronary 18F-sodium fluoride activity was associated with myocardial infarction (HR: 4.8 [95% CI: 1.9-12.2]; P = 0.00095) but not ischemic stroke (P = 0.39). In a multivariable Cox regression model including imaging and clinical risk factors, thoracic aortic 18F-sodium fluoride activity was the only variable associated with ischemic stroke (HR: 8.19 [95% CI: 2.33-28.7], P = 0.0010). ConclusionsIn patients with established cardiovascular disease, thoracic aortic 18F-sodium fluoride activity is associated with the progression of atherosclerosis and future ischemic stroke. Arterial 18F-sodium fluoride activity identifies localized areas of atherosclerotic disease activity that are directly linked to disease progression and downstream regional clinical atherothrombotic events. (DIAMOND–Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND], NCT02110303; Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis [SALTIRE II], NCT02132026; Novel Imaging Approaches To Identify Unstable Coronary Plaques, NCT01749254; and Role of Active Valvular Calcification and Inflammation in Patients With Aortic Stenosis, NCT01358513)

Dipeptidyl peptidase-4 inhibition to prevent progression of calcific aortic stenosis

ObjectiveTo evaluate whether the use of dipeptidyl peptidase-4 (DPP-4) inhibitors and their cardiac tissue distribution profile and anticalcification abilities are associated with risk of aortic stenosis (AS) progression.MethodsOut of the...

Progression of Calcific Aortic Stenosis and Its Association with Clinical Risk Factors

Aim: Haemodynamic progression of Aortic stenosis (AS) from mild to severe obstruction usually occurs over 5-10 years or more. This study aimed to evaluate the rate of progression and contributing clinical factors in a cohort of patients from a small suburban Hospital in Queensland. Methods: Retrospective review of patients for the period 2006-2015. Patients with clinical and echocardiographic evidence of aortic sclerosis and AS were included. Clinical risk factors and echocardiographic haemodynamic data were recorded. Results: Of the 53 patients 22 were female. Age (years) ranged from 57 to 95, median at presentation being 79. Five patients (9%) had bicuspid aortic valve. Hypertension was the most common comorbidity (79%) followed by hypercholesterolaemia (40%) and diabetes (30%). Eight patients (15%) had sclerosis. During the follow-up 45% progressed to severe AS; 9 of them (17%) had mild AS initially.42% developed heart failure. Although more females tended to have severe AS (50% versus 42% male) in this study, males had a higher intervention rate (19% versus 14% female). Eight patients (15%) died, including a sudden death and another from complications of endocarditis, others causes were mostly attributed to co-morbid conditions. Conclusion: Though increasing age is the most common association in calcific aortic stenosis, presence of modifiable clinical factors like hypertension and hypercholesterolaemia may contribute to onset and progression of disease and adequate management of these may delay onset or progression. Mortality remains high even in less severe disease, due mostly to complicating co-morbidities of old age.

IMPACT OF AGE, GENDER, AND METABOLIC SYNDROME COMPONENTS ON THE RATE OF PROGRESSION OF MILD CALCIFIC AORTIC VALVE DISEASE

Demographic and metabolic factors which promote progression of calcific aortic stenosis in its early phase are poorly understood. We identified patients with an initial aortic valve peak velocity of ≥ 1.8 but < 3.0 m/s by echo, and examined the effects of age, gender, and components of the

077 Osteoporosis and bisphosphonate's use associated with reduced progression of calcific aortic stenosis: retrospective observational single centre study

PurposeProgression of Aortic Stenosis (AS) has been subject of much debate in the recent past with studies evaluating effects of statin therapy. Little is known about the factors that affect...

Hypoadiponectinemia Is Associated with Valvular Inflammation and Faster Disease Progression in Patients with Aortic Stenosis

Objectives: Adiponectin is a protein secreted by adipocytes which has anti-inflammatory properties. The objective of this study was to examine the relationship between adiponectinemia and the hemodynamic progression of aortic stenosis (AS) as well as the degree of inflammation in the valve explanted at the time of aortic valve replacement (AVR). Methods: The plasma level of adiponectin was measured in 122 patients undergoing AVR. The explanted aortic valves were analyzed and the density of leukocytes (CD45+), T cells (CD3+) and blood vessels (von Willebrand factor positive; vWF+) was documented. Also, a subset of patients (n = 67) had ≧2 echocardiographic studies separated by at least 6 months, thereby allowing assessment of the rate of progression of stenosis during the preoperative period. Results: Patients with lower plasma levels of adiponectin (<5.4 µg/ml) had a faster progression rate of the mean transvalvular gradient before surgery than those with higher levels (9 ± 1 vs. 4 ±1 mm Hg/year; p = 0.008). Moreover, these patients with hypoadiponectinemia had significantly more leukocytes (CD45+), T cells and blood vessels (vWF+) in their explanted valves compared to those with higher adiponectin levels. Conclusion: These findings support the concept that adiponectin may play a protective role against the inflammatory process and progression of calcific AS.

Effects of Rosuvastatin on Progression of Stenosis in Adult Patients With Congenital Aortic Stenosis (PROCAS Trial)

Recent trials have failed to show that statin therapy halts the progression of calcific aortic stenosis (AS). We hypothesized that statin therapy in younger patients with congenital AS would be more beneficial, because the valve is less calcified. In the present double-blind, placebo-controlled trial, 63 patients with congenital AS (age 18 to 45 years) were randomly assigned to receive either 10 mg of rosuvastatin daily (n = 30) or matched placebo (n = 33). The primary end point was the progression of peak aortic valve velocity. The secondary end points were temporal changes in the left ventricular mass, ascending aortic diameter, and N-terminal pro-brain natriuretic peptide (NT-proBNP). The median follow-up was 2.4 years (interquartile range 1.9 to 3.0). The mean increase in peak velocity was 0.05 ± 0.21 m/s annually in the rosuvastatin group and 0.09 ± 0.24 m/s annually in the placebo group (p = 0.435). The annualized change in the ascending aorta diameter (0.4 ± 1.7 mm with rosuvastatin vs 0.5 ± 1.6 mm with placebo; p = 0.826) and left ventricular mass (1.1 ± 15.8 g with rosuvastatin vs -3.7 ± 30.9 g with placebo; p = 0.476) were not significantly different between the 2 groups. Within the statin group, the NT-proBNP level was 50 pg/ml (range 19 to 98) at baseline and 21 pg/ml (interquartile range 12 to 65) at follow-up (p = 0.638). NT-proBNP increased from 40 pg/ml (interquartile range 20 to 92) to 56 pg/ml (range 26 to 130) within the placebo group (p = 0.008). In conclusion, lipid-lowering therapy with rosuvastatin 10 mg did not reduce the progression of congenital AS in asymptomatic young adult patients. Interestingly, statins halted the increase in NT-proBNP, suggesting a potential positive effect of statins on cardiac function in young patients with congenital AS.

Risk factors for progression of calcific aortic stenosis and potential therapeutic targets

Current thought regarding the progression of calcific aortic stenosis (AS) is presented. After summarizing contemporary ideas about AS pathogenesis, the present article examines the factors that may affect disease progression. Data indicate that this process may be accelerated by aortic valve structure, degree of valvular calcification, chronic renal insufficiency and cardiovascular risk factors such as diabetes and dyslipidemia. Finally, the present review discusses potential therapeutic targets to slow AS progression.

Bisphosphonates in Calcific Aortic Stenosis: Association with Slower Progression in Mild Disease – A Pilot Retrospective Study

Objectives: An association between aortic valve calcification and osteoporosis has been observed. The aim of this study was to assess the association between bisphosphonate treatment for osteoporosis and the progression of calcific aortic stenosis (AS). Methods: A retrospective study of patients with AS (mean gradient ≧10 mm Hg), preserved renal function and two echocardiographies >8 months apart was performed. The patients were divided into those treated with bisphosphonates for osteoporosis and those not treated and then subdivided into mild (mean gradient <30 mm Hg) and moderate-to-severe AS groups. We compared the annualized gradient change between the groups and identified predictors of AS progression. Results: We analyzed the outcomes of 103 patients (51% females, age 68 ± 10 years, follow-up 29 ± 13 months), of whom 57 had mild and 46 moderate-to-severe AS. Bisphosphonates were taken by 28 patients, of whom 22 had mild and 6 moderate-to-severe AS. In the patients with mild AS, the annualized mean gradient change was lower in the bisphosphonate-treated than in the untreated patients (0.1 ± 3.3 vs. 2.8 ± 3.3 mm Hg/year; p = 0.002) and was negatively associated with bisphosphonate treatment (β coefficient –2.36%, 95% confidence interval –4.47 to –0.26; p = 0.028) independent of age, gender and baseline gradient. Conclusion: Bisphosphonate treatment was independently associated with slower progression of mild AS in patients with preserved renal function.

Hemodynamic Environments from Opposing Sides of Human Aortic Valve Leaflets Evoke Distinct Endothelial Phenotypes In Vitro

The regulation of valvular endothelial phenotypes by the hemodynamic environments of the human aortic valve is poorly understood. The nodular lesions of calcific aortic stenosis (CAS) develop predominantly beneath the aortic surface of the valve leaflets in the valvular fibrosa layer. However, the mechanisms of this regional localization remain poorly characterized. In this study, we combine numerical simulation with in vitro experimentation to investigate the hypothesis that the previously documented differences between valve endothelial phenotypes are linked to distinct hemodynamic environments characteristic of these individual anatomical locations. A finite-element model of the aortic valve was created, describing the dynamic motion of the valve cusps and blood in the valve throughout the cardiac cycle. A fluid mesh with high resolution on the fluid boundary was used to allow accurate computation of the wall shear stresses. This model was used to compute two distinct shear stress waveforms, one for the ventricular surface and one for the aortic surface. These waveforms were then applied experimentally to cultured human endothelial cells and the expression of several pathophysiological relevant genes was assessed. Compared to endothelial cells subjected to shear stress waveforms representative of the aortic face, the endothelial cells subjected to the ventricular waveform showed significantly increased expression of the “atheroprotective” transcription factor Kruppel-like factor 2 (KLF2) and the matricellular protein Nephroblastoma overexpressed (NOV), and suppressed expression of chemokine Monocyte-chemotactic protein-1 (MCP-1). Our observations suggest that the difference in shear stress waveforms between the two sides of the aortic valve leaflet may contribute to the documented differential side-specific gene expression, and may be relevant for the development and progression of CAS and the potential role of endothelial mechanotransduction in this disease.

Do Statins Slow Progression of Rheumatic Mitral Stenosis

The pleiotropic anti-inflammatory properties of statins are believed to bring about the slowing in progression of calcific aortic stenosis seen in some previous studies (but not in all; see JW Cardiol Jul 15 2005). In this observational study, investigators examined the effect of …

Does diabetes accelerate progression of calcific aortic stenosis?

Calcific aortic valve stenosis (CAS) is an active disease like atherosclerosis. Effect of diabetes (D) on severity of CAS is not well documented. We retrospectively analysed 166 consecutive patients with CAS and multiple echocardiograms from January 1997 to March 2005. Aortic valve area (AVA) was measured using the continuity equation. CAS severity was categorized using AVA. D and non-D patients were compared for differences in sex, hypertension, smoking, statin use using chi(2) tests. Comparisons between D and non-D for changes in AVA per year were performed using ANOVA. Study cohort included 166 males with age 70 +/- 9 years, of which 72 (43%) had D. Baseline CAS was mild in 66 subjects, moderate in 75, and severe in 25. D subjects smoked less (P = 0.02), but all other variables were similar (P > 0.05). The interaction between D and baseline CAS severity was significant (P = 0.0191), indicating comparisons should be viewed by baseline CAS severity. D had significantly larger change in AVA than non-D (P = 0.0016) for those with moderate CAS at baseline only. Adjusting for statin use did not alter the results. CAS severity progresses faster in D than in non-D in subjects with moderate CAS at baseline. Statins do not affect progression of CAS.

Nonrheumatic calcific aortic stenosis: an overview from basic science to pharmacological prevention☆

Calcific aortic stenosis is a frequent degenerative disease, which represents the most common indication for adult heart valve surgery, and carries substantial morbidity and mortality. Due to ageing populations in western countries, its prevalence is expected to increase in the coming years. Basic science studies suggest that the progression of aortic valve stenosis involves an active biological process, and that the molecular mechanisms promoting this development resemble those of atherosclerosis, as stenotic aortic valves are characterized by complex histological lesions, consisting of activated inflammatory cells, lipid deposits, extracellular matrix remodeling, calcific nodules, and bone tissue. This has led to the hypothesis that drugs effective in delaying atherosclerosis progression (e.g. statins) might also be able to prevent the progression of calcific aortic valve stenosis. The potential benefit of statin therapy, however, is controversial and widely debated, as recent randomized studies done in patients with moderate to severe degrees of aortic stenosis failed to consistently show substantial benefits of this class of drugs. This review focuses on various aspects of molecular mechanisms underlying calcific aortic valve stenosis and discusses recent experimental and clinical studies that address the potential benefit of targeted drug therapies. Taken together, current evidence suggests that the progression of calcific aortic stenosis is a multi-factorial process; the multitude of the mechanisms potentially involved in aortic valve stenosis indicates that drug therapy aimed at reducing its progression is necessarily multi-factorial and should address the earliest stages of the disease, as it is now evident that pharmacological treatment administered in more advanced stages of the disease may be ineffective or, at best, much less effective.

Abstract 3445: Notch1 Represses Bmp-Dependent Aortic Valve Calcification in a Cell-Autonomous Manner

Calcific aortic stenosis is the third leading cause of adult heart disease and the most common form of acquired valvular disease in developed countries. However, the molecular pathways leading to calcification are poorly understood. We recently reported two families in which heterozygous mutations in NOTCH1 that resulted in premature stop codons caused bicuspid aortic valve and severe calcification of the aortic valve. Notch1 is a part of a highly conserved signaling pathway involved in cell fate decisions, cell differentiation, and cardiac valve formation. We found that mice heterozygous-null for Notch1 had over four-fold more aortic valve calcification compared to age and sex matched littermates (p&lt;0.03). To determine what cell type is involved in the Notch1 related calcification, Notch1+/− bone-marrow was transplanted into wild-type mice. Six months after transplant, there was no difference in the amount of aortic valve calcification between the recipients of Notch1+/− bone-marrow versus recipients of control bone-marrow. In contrast, cultured sheep aortic valve interstitial cells (AVICs) treated with a chemical inhibitor of Notch signaling developed over five-fold more calcification (p&lt;0.03). We found that expression of Bmp2, which has been implicated in human aortic valve disease, was 3-fold higher in aortic valve leaflets of Notch1+/− mice compared to wild type littermates (p&lt;0.02). Furthermore, AVICs treated with the Notch inhibitor had increased Bmp2 protein levels and siRNA-mediated knock-down of Bmp2 expression in the AVICs blocked the calcification process induced by Notch inhibition. These findings suggest that Notch1 signaling within aortic valve cells is required for repression of Bmp2-dependent calcification pathways and may provide novel approaches to inhibit the progression of calcific aortic stenosis.

Overview of clinical trials on calcific aortic stenosis

Lipid-lowering therapy may slow the progression of calcific aortic stenosis (AS). Three completed studies on the effect of statin therapy on AS, as well as two ongoing trials, are summarised. Evidence that lipid-lowering therapy slows the progression of AS relative to non-statin therapy has been suggested by several retrospective studies. Further evidence that statin treatment can slow the progression of AS derives from the prospective (non-randomised), open-label Rosuvastatin Affecting Aortic Valve Endothelium (RAAVE) study, which was potentially subject to bias, but not by the randomised, double-blind, placebo-controlled Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) study, which enrolled 155 patients and had a follow-up period of 2.1 years. At present, two larger randomised clinical trials in AS are ongoing with a longer duration than the SALTIRE study. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study with 1873 patients has the longest planned treatment duration (4–7 years), while the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial includes 272 patients with AS who are receiving rosuvastatin 40 mg/day or placebo for 3–5 years and is designed to study progression of the disease. These and other ongoing studies are intended to evaluate the effects of lipid-lowering therapy on AS progression and aortic valve degradation, as well as the need for surgical valve replacement and mortality and morbidity, in patients with AS. Findings from recent clinical studies on lipid-lowering therapy for the management of AS (e.g. SALTIRE and RAAVE trials) are somewhat contradictory. The ongoing clinical trials—the SEAS study and the ASTRONOMER study—will probably resolve the question of the benefit of intensive lipid-lowering treatment in AS.

Do statins slow the progression of aortic valve stenosis?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether therapy with statins significantly slows the progression of aortic valve stenosis. Altogether 226 papers were found using the reported search, of which twelve represented the best evidence to answer the clinical question. The authors, journal, date, country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The results of the reported studies provided conflicting results. There are twelve studies. Ten retrospective studies and one prospective had been promising with a slower rate of hemodynamic progression in patients taking statins. One retrospective and one randomized controlled trial did not halt the progression of calcific aortic stenosis or induce its regression. The data are discrepant as to whether this effect is related to serum lipid levels or to other effects of statins. While the data are not yet strong enough to change clinical practice, two large randomized controlled trials (ASTRONOMER and SEAS) which have recruited 272 and 1873 patients, respectively, will provide important new evidence in this area in the near future.