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Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease.
Yutzey KE, Demer LL, Body SC, Huggins GS, Towler DA, Giachelli CM, Hofmann-Bowman MA, Mortlock DP, Rogers MB, Sadeghi MM, Aikawa E
(2014) Arterioscler Thromb Vasc Biol 34: 2387-93
MeSH Terms: Aortic Valve, Aortic Valve Stenosis, Biomedical Research, Calcinosis, Cardiac Surgical Procedures, Heart Defects, Congenital, Heart Valve Diseases, Heart Valve Prosthesis Implantation, Hemodynamics, Humans, Signal Transduction
Show Abstract · Added January 20, 2015
Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In 2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.
© 2014 American Heart Association, Inc.
1 Communities
1 Members
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11 MeSH Terms
Potential drug targets for calcific aortic valve disease.
Hutcheson JD, Aikawa E, Merryman WD
(2014) Nat Rev Cardiol 11: 218-31
MeSH Terms: Aortic Valve, Calcinosis, Heart Defects, Congenital, Heart Valve Diseases, Humans, Prognosis
Show Abstract · Added February 12, 2015
Calcific aortic valve disease (CAVD) is a major contributor to cardiovascular morbidity and mortality and, given its association with age, the prevalence of CAVD is expected to continue to rise as global life expectancy increases. No drug strategies currently exist to prevent or treat CAVD. Given that valve replacement is the only available clinical option, patients often cope with a deteriorating quality of life until diminished valve function demands intervention. The recognition that CAVD results from active cellular mechanisms suggests that the underlying pathways might be targeted to treat the condition. However, no such therapeutic strategy has been successfully developed to date. One hope was that drugs already used to treat vascular complications might also improve CAVD outcomes, but the mechanisms of CAVD progression and the desired therapeutic outcomes are often different from those of vascular diseases. Therefore, we discuss the benchmarks that must be met by a CAVD treatment approach, and highlight advances in the understanding of CAVD mechanisms to identify potential novel therapeutic targets.
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6 MeSH Terms
Computed tomography-derived cardiovascular risk markers, incident cardiovascular events, and all-cause mortality in nondiabetics: the Multi-Ethnic Study of Atherosclerosis.
Yeboah J, Carr JJ, Terry JG, Ding J, Zeb I, Liu S, Nasir K, Post W, Blumenthal RS, Budoff MJ
(2014) Eur J Prev Cardiol 21: 1233-41
MeSH Terms: Aged, Aged, 80 and over, Aorta, Thoracic, Aortic Diseases, Aortic Valve, Aortography, Area Under Curve, Cardiovascular Diseases, Cause of Death, Chi-Square Distribution, Coronary Angiography, Coronary Artery Disease, Coronary Vessels, Discriminant Analysis, Female, Health Status, Heart Valve Diseases, Humans, Incidence, Male, Middle Aged, Mitral Valve, Multidetector Computed Tomography, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, ROC Curve, Risk Assessment, Risk Factors, Time Factors, United States, Vascular Calcification
Show Abstract · Added February 24, 2014
AIM - We assess the improvement in discrimination afforded by the addition of the computed tomography risk markers thoracic aorta calcium (TAC), aortic valve calcification (AVC), mitral annular calcification (MAC), pericardial adipose tissue volume (PAT), and liver attenuation (LA) to the Framingham risk score (FRS) + coronary artery calcium (CAC) for incident coronary heart disease (CHD) and incident cerebrovascular disease (CVD) in a multiethnic cohort.
METHODS AND RESULTS - A total of 5745 participants were enrolled, with 2710 at intermediate Framingham risk, 210 CVD events, and 155 CHD events). Over 9 years of follow up, 251 had adjudicated CHD, 346 had CVD events, and 321 died. The data were analysed using Cox proportional hazard, receiver operator curve (ROC), and net reclassification improvement (NRI) analyses. In the whole cohort and also when the analysis was restricted to only the intermediate-risk participants, CAC, TAC, AVC, and MAC were all significantly associated with incident CVD, incident CHD, and mortality, and CAC had the strongest association. When added to the FRS, CAC had the highest area under the curve (AUC) for the prediction of incident CVD and incident CHD; LA had the least. The addition of TAC, AVC, MAC, PAT, and LA to FRS + CAC all resulted in a significant reduction in AUC for incident CHD (0.712 vs. 0.646, 0.655, 0.652, 0.648, and 0.569; all p < 0.01, respectively) in participants with intermediate FRS. The addition of CAC to FRS resulted in an NRI of 0.547 for incident CHD in the intermediate-risk group. The NRI when TAC, AVC, MAC, PAT, and LA were added to FRS + CAC were 0.024, 0.026, 0.019, 0.012, and 0.012, respectively, for incident CHD in the intermediate-risk group. Similar results were obtained for incident CVD in the intermediate-risk group and also when the whole cohort was used instead of the intermediate FRS group.
CONCLUSIONS - The addition of CAC to the FRS provides superior discrimination especially in intermediate-risk individuals compared with the addition of TAC, AVC, MAC, PAT, or LA for incident CVD and incident CHD. Compared with FRS + CAC, the addition of TAC, AVC, MAC, PAT, or LA individually to FRS + CAC worsens the discrimination for incident CVD and incident CHD. These risk markers are unlikely to be useful for improving cardiovascular risk prediction.
© The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
0 Communities
2 Members
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32 MeSH Terms
Mechanisms of calcification in aortic valve disease: role of mechanokinetics and mechanodynamics.
Merryman WD, Schoen FJ
(2013) Curr Cardiol Rep 15: 355
MeSH Terms: Aortic Valve, Biomechanical Phenomena, Calcinosis, Heart Defects, Congenital, Heart Valve Diseases, Humans, Mechanotransduction, Cellular
Show Abstract · Added February 12, 2015
The aortic valve is highly responsive to cyclical and continuous mechanical forces, at the macroscopic and cellular levels. In this report, we delineate mechanokinetics (effects of mechanical inputs on the cells) and mechanodynamics (effects of cells and pathologic processes on the mechanics) of the aortic valve, with a particular focus on how mechanical inputs synergize with the inflammatory cytokine and other biomolecular signaling to contribute to the process of aortic valve calcification.
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7 MeSH Terms
Cadherin-11 regulates cell-cell tension necessary for calcific nodule formation by valvular myofibroblasts.
Hutcheson JD, Chen J, Sewell-Loftin MK, Ryzhova LM, Fisher CI, Su YR, Merryman WD
(2013) Arterioscler Thromb Vasc Biol 33: 114-20
MeSH Terms: Actins, Animals, Aortic Valve, Cadherins, Calcinosis, Cell Communication, Cells, Cultured, Female, Heart Valve Diseases, Humans, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Male, Middle Aged, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Morphogenesis, Myofibroblasts, Phosphorylation, Protein Kinase Inhibitors, RNA Interference, Signal Transduction, Stress, Mechanical, Swine, Transfection, Transforming Growth Factor beta1
Show Abstract · Added December 10, 2013
OBJECTIVE - Dystrophic calcific nodule formation in vitro involves differentiation of aortic valve interstitial cells (AVICs) into a myofibroblast phenotype. Interestingly, inhibition of the kinase MAPK Erk kinase (MEK)1/2 prevents calcific nodule formation despite leading to myofibroblast activation of AVICs, indicating the presence of an additional mechanotransductive component required for calcific nodule morphogenesis. In this study, we assess the role of transforming growth factor β1-induced cadherin-11 expression in calcific nodule formation.
METHODS AND RESULTS - As shown previously, porcine AVICs treated with transforming growth factor β1 before cyclic strain exhibit increased myofibroblast activation and significant calcific nodule formation. In addition to an increase in contractile myofibroblast markers, transforming growth factor β1-treated AVICs exhibit significantly increased expression of cadherin-11. This expression is inhibited by the addition of U0126, a specific MEK1/2 inhibitor. The role of increased cadherin-11 is revealed through a wound assay, which demonstrates increased intercellular tension in transforming growth factor β1-treated AVICs possessing cadherin-11. Furthermore, when small interfering RNA is used to knockdown cadherin-11, calcific nodule formation is abrogated, indicating that robust cell-cell connections are necessary in generating tension for calcific nodule morphogenesis. Finally, we demonstrate enrichment of cadherin-11 in human calcified leaflets.
CONCLUSIONS - These results indicate the necessity of cadherin-11 for dystrophic calcific nodule formation, which proceeds through an Erk1/2-dependent pathway.
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26 MeSH Terms
Imaging of infective endocarditis with cardiac CT angiography.
Entrikin DW, Gupta P, Kon ND, Carr JJ
(2012) J Cardiovasc Comput Tomogr 6: 399-405
MeSH Terms: Cardiac-Gated Imaging Techniques, Coronary Angiography, Endocarditis, Female, Heart Valve Diseases, Humans, Male, Tomography, X-Ray Computed
Show Abstract · Added February 15, 2014
Infective endocarditis (IE) is a disease characterized by high rates of morbidity and mortality that can present with a spectrum of clinical and imaging findings. Cardiac-gated computed tomographic angiography (CTA) has been shown to be highly accurate in evaluation of both coronary artery disease and structural heart disease and is now considered an appropriate preoperative imaging modality in patients undergoing noncoronary cardiac surgery. This review discusses the use of cardiac-gated CTA in preoperative evaluation of patients with IE, with emphasis on imaging findings of valvular and perivalvular complications. Topics include technique tips specific to valve imaging with cardiac-gated CTA, potential benefits of cardiac-gated CTA compared with other imaging modalities such as echocardiography, limitations of imaging patients with IE with cardiac-gated CTA, and an overview of potential findings in patients with IE, including vegetations, valve perforations, perivalvular abscesses, perivalvular pseudoaneurysms, and fistulas. Throughout this review, cardiac-gated CTA findings of IE are presented with echocardiographic and operative correlation to emphasize that cardiac-gated CTA may in select cases provide incremental benefit in the preoperative assessment of patients with IE.
Copyright © 2012 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.
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8 MeSH Terms
The once and future state of percutaneous mitral valve repair.
Boronyak SM, Merryman WD
(2012) Future Cardiol 8: 779-93
MeSH Terms: Catheter Ablation, Heart Valve Diseases, Humans, Mitral Valve, Mitral Valve Annuloplasty, Percutaneous Coronary Intervention
Show Abstract · Added February 12, 2015
There has been a great deal of interest in percutaneous mitral valve repair techniques in recent years, with several devices undergoing animal testing and clinical trials. Percutaneous annuloplasty and leaflet repair devices are currently in development, and while safety rates have generally been equal or superior to conventional surgical techniques, efficacy has been suboptimal. Most current percutaneous mitral valve repair devices can only reduce regurgitant volumes by approximately 20-40%, but these reductions may be enough to treat high-risk patients, including the elderly and those with comorbidities, who are otherwise ineligible for surgery. An analysis of how these devices alter the geometry and mechanics of the mitral valve apparatus can provide insight into long-term efficacy and durability and may lead to improvements in the reduction of mitral regurgitation. In the future, multiple percutaneous techniques may be utilized in combination to increase overall efficacy. In this article, we report on percutaneous mitral valve repair techniques with published clinical or animal data.
0 Communities
1 Members
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6 MeSH Terms
Aortic valve calcium independently predicts coronary and cardiovascular events in a primary prevention population.
Owens DS, Budoff MJ, Katz R, Takasu J, Shavelle DM, Carr JJ, Heckbert SR, Otto CM, Probstfield JL, Kronmal RA, O'Brien KD
(2012) JACC Cardiovasc Imaging 5: 619-25
MeSH Terms: Aged, Aged, 80 and over, Aortic Valve, Calcinosis, Cardiovascular Diseases, Chi-Square Distribution, Coronary Artery Disease, Female, Heart Valve Diseases, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Multidetector Computed Tomography, Predictive Value of Tests, Primary Prevention, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Sclerosis, Time Factors, United States
Show Abstract · Added February 15, 2014
OBJECTIVES - This study sought to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population.
BACKGROUND - Aortic sclerosis is associated with increased cardiovascular morbidity and mortality among the elderly, but the mechanisms underlying this association remain controversial. Also, it is unknown whether this association extends to younger individuals.
METHODS - We performed a prospective analysis of 6,685 participants in MESA (Multi-Ethnic Study of Atherosclerosis). All subjects, ages 45 to 84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and nonfatal strokes, resuscitated cardiac arrest, and cardiovascular death, whereas a secondary combined endpoint of coronary events excluded strokes. The association between AVC and clinical events was assessed using Cox proportional hazards regression with incremental adjustments for demographics, cardiovascular risk factors, inflammatory biomarkers, and subclinical coronary atherosclerosis.
RESULTS - Over a median follow-up of 5.8 years (interquartile range: 5.6 to 5.9 years), adjusting for demographics and cardiovascular risk factors, subjects with AVC (n = 894, 13.4%) had higher risks of cardiovascular (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 1.10 to 2.03) and coronary (HR: 1.72; 95% CI: 1.19 to 2.49) events compared with those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for coronary artery calcium substantially attenuated both cardiovascular (HR: 1.32; 95% CI: 0.98 to 1.78) and coronary (HR: 1.41; 95% CI: 0.98 to 2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR: 2.51; 95% CI: 1.22 to 5.21).
CONCLUSIONS - In this MESA cohort, free of clinical cardiovascular disease, AVC predicts cardiovascular and coronary event risk independent of traditional risk factors and inflammatory biomarkers, likely due to the strong correlation between AVC and subclinical atherosclerosis. The association of AVC with excess cardiovascular mortality beyond coronary atherosclerosis risk merits further investigation. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).
Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Intracellular Ca(2+) accumulation is strain-dependent and correlates with apoptosis in aortic valve fibroblasts.
Hutcheson JD, Venkataraman R, Baudenbacher FJ, Merryman WD
(2012) J Biomech 45: 888-94
MeSH Terms: Animals, Aortic Valve, Apoptosis, Biomechanical Phenomena, Calcium, Calcium Channels, Calcium Phosphates, Cell Differentiation, Cells, Cultured, Fibroblasts, Heart Valve Diseases, Mechanotransduction, Cellular, Osteogenesis, Stress, Mechanical, Swine, Vascular Calcification
Show Abstract · Added May 27, 2014
Aortic valve (AV) disease is often characterized by the formation of calcific nodules within AV leaflets that alter functional biomechanics. In vitro, formation of these nodules is associated with osteogenic differentiation and/or increased contraction and apoptosis of AV interstitial cells (AVICs), leading to growth of calcium phosphate crystal structures. In several other cell types, increased intracellular Ca(2+) has been shown to be an important part in activation of osteogenic differentiability. However, elevated intracellular Ca(2+) is known to mediate cell contraction, and has also been shown to lead to apoptosis in many cell types. Therefore, a rise in intracellular Ca(2+) may precede cellular changes that lead to calcification, and fibroblasts similar to AVICs have been shown to exhibit increases in intracellular Ca(2+) in response to mechanical strain. In this study, we hypothesized that strain induces intracellular Ca(2+) accumulation through stretch-activated calcium channels. We were also interested in assessing possible correlations between intracellular Ca(2+) increases and apoptosis in AVICs. To test our hypothesis, cultured porcine AVICs were used to assess correlates between strain, intracellular Ca(2+), and apoptosis. Ca(2+) sensitive fluorescent dyes were utilized to measure real-time intracellular Ca(2+) changes in strained AVICs. Ca(2+) changes were then correlated with AVIC apoptosis using flow cytometric Annexin V apoptosis assays. These data indicate that strain-dependent accumulation of intracellular Ca(2+) is correlated with apoptosis in AVICs. We believe that these findings indicate early mechanotransductive events that may initiate AV calcification pathways.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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1 Members
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16 MeSH Terms
Serotonin receptors and heart valve disease--it was meant 2B.
Hutcheson JD, Setola V, Roth BL, Merryman WD
(2011) Pharmacol Ther 132: 146-57
MeSH Terms: Animals, Carcinoid Heart Disease, Heart Valve Diseases, Humans, Receptor, Serotonin, 5-HT2B, Serotonin Agents
Show Abstract · Added February 12, 2015
Carcinoid heart disease was one of the first valvular pathologies studied in molecular detail, and early research identified serotonin produced by oncogenic enterochromaffin cells as the likely culprit in causing changes in heart valve tissue. Researchers and physicians in the mid-1960s noted a connection between the use of several ergot-derived medications with structures similar to serotonin and the development of heart valve pathologies similar to those observed in carcinoid patients. The exact serotonergic target that mediated valvular pathogenesis remained a mystery for many years until similar cases were reported in patients using the popular diet drug Fen-Phen in the late 1990s. The Fen-Phen episode sparked renewed interest in serotonin-mediated valve disease, and studies led to the identification of the 5-HT(2B) receptor as the likely molecular target leading to heart valve tissue fibrosis. Subsequent studies have identified numerous other activators of the 5-HT(2B) receptor, and consequently, the use of many of these molecules has been linked to heart valve disease. Herein, we: review the molecular properties of the 5-HT(2B) receptor including factors that differentiate the 5-HT(2B) receptor from other 5-HT receptor subtypes, discuss the studies that led to the identification of the 5-HT(2B) receptor as the mediator of heart valve disease, present current efforts to identify potential valvulopathogens by screening for 5-HT(2B) receptor activity, and speculate on potential therapeutic benefits of 5-HT(2B) receptor targeting.
Copyright © 2011. Published by Elsevier Inc.
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6 MeSH Terms