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Cited by 982Cardiac Valve Diseases and TreatmentsAortic Disease and Treatment ApproachesCardiac Imaging and Diagnostics

Calcific aortic stenosis

Open access
Lindman, Brian R., Clavel, Marie-Annick, Mathieu, Patrick, Iung, Bernard, Lancellotti, Patrizio, Otto, Catherine M., Pibarot, Philippe·2016·Nature Reviews Disease Primers
DOI 10.1038/nrdp.2016.6PMC PMC5127286
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Abstract

Calcific aortic stenosis (AS) is the most prevalent heart valve disorder in developed countries. It is characterized by progressive fibro-calcific remodelling and thickening of the aortic valve leaflets that, over years, evolve to cause severe obstruction to cardiac outflow. In developed countries, AS is the third-most frequent cardiovascular disease after coronary artery disease and systemic arterial hypertension, with a prevalence of 0.4% in the general population and 1.7% in the population >65 years old. Congenital abnormality (bicuspid valve) and older age are powerful risk factors for calcific AS. Metabolic syndrome and an elevated plasma level of lipoprotein(a) have also been associated with increased risk of calcific AS. The pathobiology of calcific AS is complex and involves genetic factors, lipoprotein deposition and oxidation, chronic inflammation, osteoblastic transition of cardiac valve interstitial cells and active leaflet calcification. Although no pharmacotherapy has proved to be effective in reducing the progression of AS, promising therapeutic targets include lipoprotein(a), the renin-angiotensin system, receptor activator of NF-κB ligand (RANKL; also known as TNFSF11) and ectonucleotidases. Currently, aortic valve replacement (AVR) remains the only effective treatment for severe AS. The diagnosis and staging of AS are based on the assessment of stenosis severity and left ventricular systolic function by Doppler echocardiography, and the presence of symptoms. The introduction of transcatheter AVR in the past decade has been a transformative therapeutic innovation for patients at high or prohibitive risk for surgical valve replacement, and this new technology might extend to lower-risk patients in the near future.

Integrity signals

Registry

Crossref · 10.1038/nrdp.2016.6

Cites

286 of 286 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

175 of 310 cited sources checked · 72 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    The added value of these emerging blood biomarkers beyond established clinical, echocardiographic, tomographic and blood biomarkers has not yet been shown.

    “but their incremental value beyond already established clinical, echocardiographic, tomographic and blood biomarkers is yet to be demonstrated.”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [194] Chin, C. W. et al. High-sensitivity troponin I concentrations are a marker of an advanced hypertrophic response and adverse outcomes in patients with aortic stenosis. Eur. Heart J. 35, 2312–2321 (2014). source

      The Discussion (page unavailable) says large-scale prospective studies are needed to establish how troponin and CMR biomarkers should be used in risk stratification, supporting uncertainty about their clinical value. But the Results report that troponin’s association with adverse outcomes persisted after adjustment for several clinical, echocardiographic and CT measures. The paper does not establish the broader claim about all emerging blood biomarkers beyond all established markers considered together. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [195] Rosjo, H., Andreassen, J., Edvardsen, T. & Omland, T. Prognostic usefulness of circulating high-sensitivity troponin T in aortic stenosis and relation to echocardiographic indexes of cardiac function and anatomy. Am. J. Cardiol. 108, 88–91 (2011). source
    • cites [196] Chen, Z. et al. Circulating level of miR-378 predicts left ventricular hypertrophy in patients with aortic stenosis. PLoS ONE 9, e105702 (2014). source

      The Results section reports that miR-378 predicted left ventricular hypertrophy after adjustment for age, sex and trans-aortic pressure gradient (page unavailable). Our copy does not assess its incremental value beyond the full set of established clinical, echocardiographic, tomographic and blood biomarkers, or state that such value remains undemonstrated. Searches for incremental value and comparisons with existing biomarkers found no passage settling that broader claim. (LLM, conf=0.70)

      Experimental — accuracy not yet measured
    • cites [197] Rosjo, H. et al. Prognostic value of circulating microRNA-210 levels in patients with moderate to severe aortic stenosis. PLoS ONE 9, e91812 (2014). source

      The Discussion (page unavailable) explicitly says miR-210 provided incremental prognostic information beyond established risk indices in patients with aortic stenosis. The Results report an association with mortality after adjustment for clinical factors, echocardiographic relative wall thickness, and the blood biomarker NT-proBNP. The paper does not establish added value beyond tomographic biomarkers, but its demonstrated incremental value contradicts the claim that such value has yet to be shown. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [198] Lindman, B. R. et al. Prognostic utility of novel biomarkers of cardiovascular stress in patients with aortic stenosis undergoing valve replacement. Heart 101, 1382–1388 (2015). source

      The Results section ('Added prognostic utility of multiple biomarkers'; page unavailable) demonstrates improved risk reclassification when the biomarkers were added to the STS score or a clinical model, so their incremental value beyond clinical measures had been shown. The paper does not demonstrate incremental value beyond the full combination of clinical, echocardiographic, tomographic and established blood biomarkers claimed here. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    Some studies suggest that the adverse association between paravalvular aortic regurgitation and mortality extends to mild regurgitation.

    “with some studies even suggesting that this adverse association extends to mild regurgitation235;237;238.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [235] Genereux, P. et al. Paravalvular leak after transcatheter aortic valve replacement: the new Achilles’ heel? A comprehensive review of the literature. J. Am. Coll. Cardiol. 61, 1125–1136 (2013). source
    • cites [237] Kodali, S. et al. Paravalvular regurgitation after transcatheter aortic valve replacement with the Edwards sapien valve in the PARTNER trial: characterizing patients and impact on outcomes. Eur. Heart J. 36, 449–456 (2015). source
    • cites [238] Van Belle, E. et al. Postprocedural aortic regurgitation in balloon-expandable and self-expandable TAVR procedures: analysis of predictors and impact on long-term mortality: insights from the FRANCE2 registry. Circulation 129, 1415–1427 (2014). source

      In “Impact of AR on Mortality” (page unavailable), this study reports no association between mild (grade 1) postprocedural regurgitation and total or cardiovascular mortality. The “Incidence and Predictive Value of AR on One-Year Mortality” section acknowledges that the PARTNER study and a prior meta-analysis differed, but this paper’s own finding is contrary to the claim for which it is cited. (LLM, conf=0.89)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Surgical or transcatheter aortic valve replacement is the only effective treatment for severe aortic stenosis.

    “Currently, aortic valve replacement (AVR) remains the only effective treatment for severe AS.”
    • Also stated in: § Introduction · plain
      “Hence, surgical or transcatheter AVR are the only effective treatment options for severe AS3;4.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source
  • Premisecitation

    Circulating lipoprotein(a) and oxidized phospholipid levels are independently associated with faster progression of calcific aortic stenosis.

    “In addition, Capoulade and colleagues showed that circulating Lp(a) and Ox-PL levels were independently associated with faster progression of calcific AS51.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [51] Capoulade, R. et al. Oxidized phospholipids, lipoprotein(a) and progression of aortic valve stenosis. J. Am. Coll. Cardiol. 66, 1236–1246 (2015). source
  • Premisecitation

    Transforming growth factor β-1, which is activated in calcific aortic stenosis, promotes elongation of glycosaminoglycan chains.

    “Moreover, transforming growth factor β-1 (TGF-β1), which is activated in calcific AS, has been shown to promote the elongation of glycosaminoglycan (GAG) chains55.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [55] Osman, N. et al. Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans. Cardiovasc. Pathol. 22, 146–155 (2013). source
  • May combine two claims. 84
  • Classified as probably not a substantial claim. 35

  • May combine two claims.

    Interpretationcitation

    The geographic distribution of calcific aortic stenosis is heterogeneous and shows clustering that is probably due to genetic factors.

    “The geographical distribution of calcific AS is heterogeneous and displays a clustering effect which is probably the consequence of genetic factors17.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] Probst, V. et al. Familial aggregation of calcific aortic valve stenosis in the western part of France. Circulation 113, 856–860 (2006). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Among people with aortic sclerosis, progression to aortic stenosis occurs at a rate of 1.8-1.9% of patients per year.

    “According to a recent meta-analysis, the rate of progression to AS in individuals with aortic sclerosis is 1.8–1.9% of patients per year11.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Coffey, S., Cox, B. & Williams, M. J. The prevalence, incidence, progression, and risks of aortic valve sclerosis: a systematic review and meta-analysis. J. Am. Coll. Cardiol. 63, 2852–2861 (2014). source

  • May combine two claims.

    Premisecitation

    Proteoglycans biglycan and decorin are overexpressed in aortic valves during calcific aortic stenosis and might participate in lipid retention and modification.

    “Proteoglycans such as biglycan and decorin are overexpressed in aortic valves during calcific AS and might actively participate in lipid retention and modification (Figure 4)52–54.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [52] Derbali, H. et al. Increased biglycan in aortic valve stenosis leads to the overexpression of phospholipid transfer protein via Toll-like receptor 2. Am. J. Pathol. 176, 2638–2645 (2010). source
    • cites [53] Song, R. et al. Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via Toll-like receptor-2. Arterioscler. Thromb. Vasc. Biol. 32, 2711–2720 (2012). source

      The Discussion reports biglycan accumulation in calcific, stenotic valve areas, and the Conclusion states that interstitial cells from stenotic valves express more biglycan. The paper does not report decorin overexpression in aortic valves or show that either proteoglycan retains or modifies lipids; it instead finds that oxidized LDL promotes biglycan expression. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [54] Mahmut, A. et al. Lipoprotein lipase in aortic valve stenosis is associated with lipid retention and remodelling. Eur. J. Clin. Invest. 43, 570–578 (2013). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    In developed countries, the number of patients with calcific aortic stenosis older than 70 or 75 years is predicted to increase twofold to threefold over the next 50 years.

    “Estimates based on current prevalence rates and demographic forecasts predict that the number of patients with calcific AS >70 or >75 years of age will increase twofold to threefold over the next 50 years in developed countries15;16;19.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [15] Danielsen, R., Aspelund, T., Harris, T. B. & Gudnason, V. The prevalence of aortic stenosis in the elderly in Iceland and predictions for the coming decades: the AGES-Reykjavik study. Int. J. Cardiol. 176, 916–922 (2014). source

      The Results (‘Predicting the future’; page unavailable) project a 2.4-fold increase in Icelanders aged ≥70 with severe aortic stenosis by 2040 and a more-than-threefold increase by 2060. The Conclusions foresee a similar trend in other western countries, but the paper does not provide a twofold-to-threefold estimate for developed countries as a whole or for an over-75 age group. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [16] Osnabrugge, R. L. et al. Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J. Am. Coll. Cardiol. 62, 1002–1012 (2013). source

      The Results project that symptomatic severe aortic stenosis in people aged 75 or older will rise from 1.0 to 2.1 million in the studied European countries and from 540,000 to 1.4 million in North America by 2050—roughly a twofold to threefold increase. The paper does not give that projection specifically for calcific stenosis, people over 70, or a 50-year period. The indexed Results passage has no page number. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [19] Iung, B. & Vahanian, A. Degenerative calcific aortic stenosis: a natural history. Heart 98 (Suppl. 4), iv7–iv13 (2012). source

  • May combine two claims.

    Premisecitation

    Oxidative stress is increased in aortic stenosis valves and is related, at least in part, to uncoupling of the nitric oxide synthase pathway.

    “Oxidative stress is increased in AS valves and is related, at least in part, to the uncoupling of the nitric oxide synthase (NOS) pathway43.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [43] Miller, J. D. et al. Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J. Am. Coll. Cardiol. 52, 843–850 (2008). source

  • May combine two claims.

    Premisecitation

    Bicuspid aortic valve is associated with increased risk of aortopathy, in which genetic, haemodynamic, and mechanical factors may participate in aortic valve mineralization.

    “Bicuspid aortic valve is associated with an increased risk of aortopathy, in which genetic, haemodynamic and mechanical factors might participate in the mineralization of aortic valve132.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [132] Mathieu, P. et al. The pathology and pathobiology of bicuspid aortic valves: state of the art and novel research perspective. J. Pathol. Clin. Res. 1, 195–206 (2015). source

  • May combine two claims.

    Premisecitation

    For the same degree of AS, women tend to develop predominantly concentric remodelling/hypertrophy, whereas men are more prone to eccentric hypertrophy.

    “For the same degree of AS, women tend to predominantly develop concentric remodelling/hypertrophy, whereas men are more prone to developing eccentric hypertrophy116.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [116] Carroll, J. D. et al. Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation 86, 1099–1107 (1992). source

      The Abstract and Results report similar severity of aortic stenosis in the elderly women and men studied, with women more often having small, thick-walled ventricles and men more often having larger, more dilated ventricles. The Results do not establish that men generally had eccentric hypertrophy: the overall sex difference in end-diastolic chamber radius-to-wall-thickness ratio was not significant. The claim captures the tendency in chamber appearance but states the men's hypertrophy pattern more definitively than the paper supports. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Clinical factors associated with faster stenosis progression include older age, female sex, severity of stenosis, degree of aortic valve calcification at diagnosis, smoking, hypertension, obesity, metabolic syndrome, secondary hyperparathyroidism, renal failure, elevated circulating Lp(a), and increased Lp-PLA2 activity.

    “The clinical factors associated with faster stenosis progression include older age, female sex, severity of the stenosis and degree of aortic valve calcification at diagnosis, smoking, hypertension, obesity, metabolic syndrome, secondary hyperparathyroidism, renal failure elevated circulating levels of Lp(a), and increased activity of Lp-PLA2 (also called lipoprotein–associated phospholipase A2)51”
    Quote in the paperNot a substantial claim2 of 9 sources checked
    • cites [51] Capoulade, R. et al. Oxidized phospholipids, lipoprotein(a) and progression of aortic valve stenosis. J. Am. Coll. Cardiol. 66, 1236–1246 (2015). source

      The Conclusions (page not supplied) report that elevated Lp(a) is associated with faster aortic stenosis progression, and the passage on Lp-PLA2 (indexed under Abstract; page not supplied) reports an association between its plasma level and faster progression in patients with mild stenosis. The paper does not establish the full list as factors associated with faster progression: it uses age, sex, hypertension, smoking, metabolic syndrome, baseline severity, calcification and creatinine as adjustment variables, rather than reporting each as a predictor. It also does not establish increased Lp-PLA2 activity specifically as a predictor. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [59] Capoulade, R. et al. Impact of plasma Lp-PLA2 activity on the progression of aortic stenosis. JACC Cardiovasc. Imaging 8, 26–33 (2015). source

      The Abstract and Conclusions report that increased Lp-PLA2 activity was associated with faster stenosis progression in patients with mild aortic stenosis, but not significantly in the whole cohort. The paper does not establish the full list of clinical factors as predictors of faster progression; several appear only in references to other studies. The claim also omits the mild-stenosis qualifier on the Lp-PLA2 finding. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [94] Capoulade, R. et al. Impact of hypertension and renin–angiotensin system inhibitors in aortic stenosis. Eur. J. Clin. Invest. 43, 1262–1272 (2013). source
    • cites [137] Otto, C. M. et al. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 95, 2262–2270 (1997). This is one of the first prospective studies to describe the clinical and echocardiographic predictors of the progression and outcomes of calcific AS. source
    • cites [138] Livanainen, A. M., Lindroos, M., Tilvis, R., Heikkila, J. & Kupari, M. Natural history of aortic valve stenosis of varying severity in the elderly. Am. J. Cardiol. 78, 97–101 (1996). source
    • cites [139] Palta, S., Pai, A. M., Gill, K. S. & Pai, R. G. New insights into the progression of aortic stenosis: implications for secondary prevention. Circulation 101, 2497–2502 (2000). source
    • cites [140] Ngo, M. V., Gottdiener, J. S., Fletcher, R. D., Fernicola, D. J. & Gersh, B. J. Smoking and obesity are associated with the progression of aortic stenosis. Am. J. Geriatr. Cardiol. 10, 86–90 (2001). source
    • cites [141] Capoulade, R. et al. Impact of metabolic syndrome on progression of aortic stenosis: influence of age and statin therapy. J. Am. Coll. Cardiol. 60, 216–223 (2012). This is a post hoc analysis of the ASTRONOMER study showing that metabolic syndrome is associated with faster progression of AS and that statins may accelerate the stenosis progression in these patients. source
    • cites [142] Hekimian, G. et al. Progression of aortic valve stenosis is associated with bone remodelling and secondary hyperparathyroidism in elderly patients — the COFRASA study. Eur. Heart J. 34, 1915–1922 (2013). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Bicuspid aortic valves have two functional leaflets often of unequal size and result from incomplete separation of commissures during embryonic development.

    “Bicuspid aortic valves have two functional leaflets often of unequal size. This abnormality results from incomplete separation of commissures during embryonic development8.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] Michelena, H. I. et al. Bicuspid aortic valve: dentifying knowledge gaps and rising to the challenge from the international bicuspid aortic valve consortium (BAVCon). Circulation 129, 2691–2704 (2014). A review of the diagnosis, complications and management of bicuspid aortic valve syndrome. source

      The section “A Valvuloaortopathy With Varied Phenotypes and Unpredictable Outcomes” describes two aortic cusps that are usually asymmetrical, supporting the description of the leaflets. The “Pathobiology” section discusses embryological development but does not say that incomplete separation of commissures causes bicuspid aortic valves; that causal explanation, to which the citation is attached, is not supported by our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A genome-wide association study identified variants in RUNX2 and CACNA1C associated with calcific AS and found they upregulate their respective mRNA levels.

    “Recently, a study has identified in a genome wide association study that variants located in RUNX2 and CACNA1C, which encodes for an osteogenic transcription factor and a voltage-dependent calcium channel subunit respectively, were associated with calcific AS and were found to upregulate their respective mRNA levels.150”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [150] Guauque-Olarte, S. et al. Calcium signalings pathway genes RUNX2 and CACNA1C are associated with calcific aortic valve disease. Circ. Cardiovasc. Genet. 8, 812–822 (2015). source

      The Results (GWAS Results and Integration With Valve eQTL Mapping; page unavailable) report variants moderately associated with aortic stenosis in both genes, but none reached genome-wide significance. A CACNA1C risk allele was associated with higher CACNA1C mRNA; the AS-associated RUNX2 variants were not evaluated for an expression effect, and separate RUNX2 expression-associated variants were independent of them. The claim therefore overstates both the strength of the GWAS findings and the evidence that the RUNX2 risk variants upregulate mRNA. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Myocardial fibrosis is often not reversible (or only partially reversible) and is associated with increased risk of cardiovascular events and mortality during follow-up, as well as persistence of LV dysfunction and symptoms after AVR.

    “Myocardial fibrosis is often not reversible (or only partially reversible) and is associated with increased risk of cardiovascular events and mortality during follow-up as well as persistence of LV dysfunction and symptoms following AVR188–190;192;193.”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [188] Weidemann, F. et al. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation 120, 577–584 (2009). source
    • cites [189] Azevedo, C. F. et al. Prognostic significance of myocardial fibrosis quantification by histopathology and magnetic resonance imaging in patients with severe aortic valve disease. J. Am. Coll. Cardiol. 56, 278–287 (2010). This is one of the first studies to show the prognostic value of myocardial fibrosis measured by CMR in patients with calcific AS. source

      The Results report that greater fibrosis was associated with less improvement in LV function after aortic valve replacement, and the Abstract reports an association with worse long-term survival. The Results also show a reduction in total fibrous content after surgery, while fibrosis as a percentage of LV mass did not significantly change, consistent with partial rather than absent reversibility. The paper does not establish an association with cardiovascular events beyond mortality or directly link fibrosis to persistent symptoms after surgery. Page numbers were not provided in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [190] Dweck, M. R. et al. Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis. J. Am. Coll. Cardiol. 58, 1271–1279 (2011). source

      The Discussion (p. 7) says established midwall fibrosis appeared not to reverse after AVR and that its adverse mortality prognosis persisted to a degree; the mortality results (p. 5) also link it to higher cardiac mortality during follow-up. The paper does not demonstrate that LV dysfunction or symptoms persist after AVR, and its findings on events beyond mortality are limited. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [192] Herrmann, S. et al. Low-gradient aortic valve stenosis: myocardial fibrosis and its influence on function and outcome. J. Am. Coll. Cardiol. 58, 402–412 (2011). source
    • cites [193] Nazarian, S. Is ventricular arrhythmia a possible mediator of the association between aortic stenosis-related midwall fibrosis and mortality? J. Am. Coll. Cardiol. 58, 1280–1282 (2011). source

  • May combine two claims.

    Premisecitation

    Older patients over 80 years and sicker patients who were previously not candidates for definitive therapy are now being treated.

    “In addition, older (> 80 years) and sicker patients who previously were not candidates for definitive therapy are being treated200;201.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [200] Iung, B. et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur. Heart J. 26, 2714–2720 (2005). source
    • cites [201] Leon, M. B. et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Eng. J. Med. 363, 1597–1607 (2010). This randomized clinical trial shows the major superiority of TAVR compared with conservative management in patients who cannot undergo surgical AVR. source

  • May combine two claims.

    Premisecitation

    Patients with severe AS (peak aortic jet velocity ≥4 m/s, mean gradient ≥40 mmHg, AVA ≤1 cm2) may or may not have symptoms and require closer follow-up than mild or moderate AS.

    “Patients with severe AS (typically, those who have a peak aortic jet velocity of ≥ 4m/s, a mean gradient of ≥ 40mmHg and an AVA of ≤1cm2; Tables 1 and 2) may or may not have symptoms and require a closer clinical and Doppler-echocardiographic follow-up than those with mild or moderate forms of the disaese3.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source

      Section 3.2 defines severe AS using a velocity ≥4.0 m/s or mean gradient ≥40 mm Hg and says most such patients have a valve area ≤1.0 cm². Its Routine Follow-Up subsection recommends more frequent clinical monitoring and echocardiography for asymptomatic severe AS than for milder AS. The claim extends that follow-up recommendation to symptomatic patients, for whom the guideline instead discusses valve replacement. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Aortic valve replacement is reasonable in symptomatic patients with paradoxical low-flow, low-gradient aortic stenosis and preserved LVEF of at least 50% if clinical, haemodynamic and anatomic evidence indicates severe obstruction is the most likely cause of symptoms.

    “It is also reasonable to perform AVR in symptomatic patients with paradoxical low-flow, a low-gradient and preserved LVEF (≥50%) (Class IIa indication) provided there is clinical, haemodynamic and anatomic evidence that the obstruction is severe and the most likely cause of symptoms3;4;168.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [168] Clavel, M. A. et al. Stress echocardiography to assess stenosis severity and predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis and preserved LVEF. JACC Cardiovasc. Imaging 6, 175–183 (2013). source

  • May combine two claims.

    Premisecitation

    Aortic valve replacement may be considered in patients with classical low-flow, low-gradient aortic stenosis and no flow reserve at dobutamine stress echocardiography, but operative risk is higher.

    “AVR may be considered in patients with classical low-flow, low-gradient AS having no flow reserve at dobutamine stress echocardiography, but the operative risk is higher4;163;167;206.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source

      The AVR indications table (page unavailable) says AVR may be considered for symptomatic patients with severe low-flow, low-gradient AS and LV dysfunction without flow reserve. Section 5.4.1 (page unavailable) reports higher operative mortality in patients without flow reserve. The claim omits the guideline’s symptomatic-patient qualification. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [163] Monin, J. L. et al. Low-gradient aortic stenosis: operative risk stratification and predictors for long-term outcome: a multicenter study using dobutamine stress hemodynamics. Circulation 108, 319–324 (2003). source
    • cites [167] Tribouilloy, C. et al. Outcome after aortic valve replacement for low-flow/low-gradient aortic stenosis without contractile reserve on dobutamine stress echocardiography. J. Am. Coll. Cardiol. 53, 1865–1873 (2009). source
    • cites [206] Levy, F. et al. Aortic valve replacement for low-flow/low-gradient aortic stenosis: operative risk stratification and long-term outcome: a European multicenter study. J. Am. Coll. Cardiol. 51, 1466–1472 (2008). source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Patients with severe aortic stenosis who are asymptomatic by history but have reduced LVEF below 50% or are undergoing another cardiac surgical procedure should have their valve replaced as a Class I indication.

    “Patients with severe AS who are asymptomatic by history but who have a reduced LVEF (<50%) (Table 1) or are undergoing another cardiac surgical procedure should have their valve replaced (Class I indication)”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source

      Section 5.4.1 (page unavailable) says early surgery is indicated for rare asymptomatic patients with severe AS whose depressed LV function is not due to other causes. The retrieved AS passage does not specify an LVEF threshold of <50%. Section 5.7 discusses concomitant valve replacement with CABG, but does not establish the claim that undergoing another cardiac procedure is, in general, a Class I indication. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A transfemoral approach is associated with lower mortality and quicker recovery than alternative access approaches.

    “A transfemoral approach is associated with lower mortality and quicker recovery compared to alternative access approaches227–229.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [227] Ludman, P. F. et al. Transcatheter aortic valve implantation in the United Kingdom: temporal trends, predictors of outcome, and 6-year follow-up: a report from the UK Transcatheter Aortic Valve Implantation (TAVI) registry, 2007 to 2012. Circulation 131, 1181–1190 (2015). source
    • cites [228] Holmes, D. R. et al. Clinical outcomes at 1 year following transcatheter aortic valve replacement. JAMA 313, 1019–1028 (2015). source
    • cites [229] Blackstone, E. H. et al. Propensity-matched comparisons of clinical outcomes after transapical or transfemoral TAVR: a PARTNER-I trial substudy. Circulation 131, 1989–2000 (2015). source

      The Conclusions report greater early mortality and prolonged recovery after transapical than transfemoral TAVR in matched high-risk or inoperable patients, nearly all with peripheral arterial disease. The claim broadens this finding to alternative access approaches generally; the same section says whether transaortic or subclavian access has lower risk remains to be studied. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Symptomatic patients with classical low-flow, low-gradient aortic stenosis and reduced LVEF below 50% are reasonable candidates for aortic valve replacement if anatomic or haemodynamic evidence shows the stenosis is truly severe.

    “Symptomatic patients with classical low-flow, low-gradient and reduced LVEF (<50%) are reasonable candidates for AVR (Class IIa indication, Box 1) provided there is anatomic evidence (MDCT calcium score) or haemodynamic evidence (peak aortic jet velocity ≥4 m per sec or mean gradient ≥40 mmHg with dobutamine stress echocardiography) that the AS is truly severe3;4;170.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source

      Section 3.2 (page unavailable) gives a Class IIa recommendation for AVR in symptomatic patients with low-flow/low-gradient severe aortic stenosis and LVEF below 50% when low-dose dobutamine testing reaches the stated velocity or gradient threshold while valve area remains ≤1.0 cm². The guideline also requires a calcified valve with reduced opening; the passages do not support an MDCT calcium score as an alternative to the dobutamine criterion. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source

      Section 5.4.1 advises surgery for low-gradient AS when flow reserve is present, and §5.1 describes dobutamine echocardiography as a way to distinguish truly severe from pseudosevere AS. But the guidelines describe classical low-flow, low-gradient AS with EF below 40%, not the claimed below-50% threshold; they also do not give the cited peak-velocity threshold as a criterion in this setting. Section 5.1 says CT assessment of calcification may be helpful, rather than making a CT calcium score a stated condition for AVR (page numbers unavailable in our copy). (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [170] Clavel, M. A. et al. Impact of aortic valve calcification, as measured by MDCT, on survival in patients with aortic stenosis: results of an international registry study. J. Am. Coll. Cardiol. 64, 1202–1213 (2014). source

      The Discussion (‘AVC and AS Management’; page not provided) says dobutamine echocardiography helps distinguish pseudosevere stenosis in patients with low ejection fraction and that MDCT-measured valve calcification can inform decisions about valve implantation. The paper also says implantation is indicated for severe symptomatic stenosis. It does not establish the specific Class IIa recommendation, LVEF cutoff below 50%, or dobutamine velocity and gradient thresholds in the citing sentence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The survival benefit of TAVR was accompanied by symptom relief and improved functional capacity in many patients.

    “This survival benefit was accompanied by relief of symptoms and improvement in functional capacity in many patients201;225.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [201] Leon, M. B. et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Eng. J. Med. 363, 1597–1607 (2010). This randomized clinical trial shows the major superiority of TAVR compared with conservative management in patients who cannot undergo surgical AVR. source
    • cites [225] Biere, L. et al. Influence of sex on mortality and perioperative outcomes in patients undergoing TAVR: insights from the FRANCE 2 registry. J. Am. Coll. Cardiol. 65, 755–757 (2015). source

      In the results (pp. 755–757), the paper reports changes in New York Heart Association functional class after TAVR and lower one-year mortality in women than men. It does not specify that those functional-class changes were improvements or report symptom relief in many patients; its mortality comparison is between sexes, not a survival benefit of TAVR against another treatment. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Aortic valve replacement is reasonable in asymptomatic patients with findings suggesting rapid progression, such as severe valve calcification or an increase in peak aortic jet velocity of at least 0.3 m/s per year.

    “or findings suggestive of rapid progression (severe valve calcification or increase in peak aortic jet velocity of ≥0.3 m per sec per year)3;4.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source

      Section 3.2 identifies severe valve calcification and faster hemodynamic progression as predictors of rapid progression. Its Class IIb recommendation says AVR *may be considered* when serial testing shows a velocity increase of at least 0.3 m/s per year, but only for asymptomatic patients with severe aortic stenosis who are at low surgical risk. It does not say that severe calcification alone makes AVR reasonable. Page numbers are unavailable in our copy. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source

      Section 5.4.1 says surgery should be considered for asymptomatic patients at low operative risk with normal exercise performance when severe valve calcification is combined with a velocity increase of at least 0.3 m/s per year. The claim presents calcification and velocity increase as alternatives and omits those patient qualifications. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Aortic valve replacement is reasonable in asymptomatic patients at low surgical risk with very severe aortic stenosis, defined by peak aortic jet velocity above 5 m/s or 5.5 m/s depending on the guidelines.

    “and in those at low surgical risk with very severe AS (peak aortic jet velocity >5 m/sec or 5.5 m/s, depending on the guidelines,)”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source

      Section 5.4.1 says surgery should be considered for asymptomatic patients at low operative risk with very severe aortic stenosis, defined here by peak velocity >5.5 m/s. It also requires normal exercise performance, which the citing sentence omits. This paper does not give >5 m/s as its threshold; the sentence attributes that alternative to other guidelines. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the PARTNER Trial, TAVR compared with standard therapy produced a 20% absolute reduction in 1-year mortality, with an HR of 0.55 and 95% CI 0.40-0.74, and mortality rates of 30.7% versus 50.7%.

    “In the PARTNER Trial, there was a 20% absolute reduction in 1-year mortality (HR 0.55; 95% CI 0.40 to 0.74) with TAVR compared to standard therapy (30.7% versus 50.7%)201.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [201] Leon, M. B. et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Eng. J. Med. 363, 1597–1607 (2010). This randomized clinical trial shows the major superiority of TAVR compared with conservative management in patients who cannot undergo surgical AVR. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Aortic valve replacement is reasonable as a Class IIa indication in asymptomatic patients with severe aortic stenosis and decreased exercise tolerance or a drop in blood pressure with exercise.

    “It also is reasonable to perform AVR (Class IIa indication) in asymptomatic patients with severe AS and decreased exercise tolerance or a drop in blood pressure with exercise”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source

      In §3.2 (Aortic Stenosis), the guideline gives a Class IIa recommendation for AVR in apparently asymptomatic patients with severe AS whose exercise test shows decreased tolerance or a fall in systolic blood pressure. The recommendation also requires a calcified aortic valve and a specified velocity or pressure-gradient range, which the citing sentence omits. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source

      Section 5.4.1 recommends considering AVR for an asymptomatic patient with severe aortic stenosis whose blood pressure falls below baseline during exercise. It describes early surgery as indicated for an abnormal exercise test, particularly when symptoms develop, rather than assigning a single Class IIa recommendation to both decreased exercise tolerance and a blood-pressure drop. No page number is provided in our copy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The prevalence of considerable coronary disease in severe aortic stenosis increases with age and was as high as 75% in recent trials composed mostly of very elderly patients.

    “The prevalence of considerable coronary disease in the setting of severe AS increases with age and was as high as 75% in recent trials comprised mostly of very elderly patients201;220.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [201] Leon, M. B. et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Eng. J. Med. 363, 1597–1607 (2010). This randomized clinical trial shows the major superiority of TAVR compared with conservative management in patients who cannot undergo surgical AVR. source

      The baseline-characteristics table (p. 5) reports coronary artery disease in 74.3% of standard-therapy patients, whose mean age was 83.2 years, supporting the approximately 75% figure in a very elderly trial group. It does not show that coronary disease prevalence increases with age, and it does not define the reported disease as “considerable.” (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [220] Smith, C. R. et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N. Engl. J. Med. 364, 2187–2198 (2011). source

      Table 1 (labeled Discussion in our copy; page not supplied) reports coronary artery disease in 74.9% and 76.9% of the two groups, whose mean ages were 83.6 and 84.5 years. It does not show that prevalence increases with age or specify that the recorded coronary disease was “considerable.” (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Patients may be at prohibitive surgical risk because of technical factors such as porcelain aorta or clinical reasons such as multiple comorbidities or frailty.

    “Patients may be at prohibitive risk for surgery owing to technical factors (such as porcelain aorta) or for clinical reasons (such as multiple comorbidities or frailty)3;241.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source
    • cites [241] Makkar, R. R. et al. Stratification of outcomes after transcatheter aortic valve replacement according to surgical inoperability for technical versus clinical reasons. J. Am. Coll. Cardiol. 63, 901–911 (2014). source

  • May combine two claims.

    Premisecitation

    Among inoperable patients treated with TAVR in PARTNER I Cohort B, at 1 year approximately 31% were dead and 18% had less than moderate improvement in quality of life or NYHA functional class.

    “among inoperable patients treated with TAVR in the PARTNER I Cohort B trial (Table 4), at 1 year after the procedure approximately 31% were dead and 18 % had less than a moderate improvement in their quality of life or New York Heart Association functional class201;244”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [201] Leon, M. B. et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Eng. J. Med. 363, 1597–1607 (2010). This randomized clinical trial shows the major superiority of TAVR compared with conservative management in patients who cannot undergo surgical AVR. source

      The Results (p. 1) report 30.7% mortality at one year in the TAVI group, supporting the approximately 31% figure. Other Clinical Outcomes (p. 6) report that 74.8% of surviving TAVI patients were in NYHA class I or II, but do not report that 18% had less than moderate improvement in quality of life or NYHA class. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [244] Reynolds, M. R. et al. Health-related quality of life after transcatheter aortic valve replacement in inoperable patients with severe aortic stenosis. Circulation 124, 1964–1972 (2011). source

  • May combine two claims.

    Interpretationcitation

    A sizable subgroup dies soon after TAVR or does not experience improved quality of life, suggesting potential futility of TAVR in some patients.

    “there is a sizable sub-group that dies soon after TAVR or does not experience an improvement in quality of life, suggesting potential futility of TAVR in some patients201;202;220;244;245.”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [201] Leon, M. B. et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Eng. J. Med. 363, 1597–1607 (2010). This randomized clinical trial shows the major superiority of TAVR compared with conservative management in patients who cannot undergo surgical AVR. source

      Procedural Outcomes (p. 4) reports that 11 of 173 patients who underwent TAVI (6.4%) died within 30 days; Results (p. 1) reports 30.7% mortality at one year. Other Clinical Outcomes (p. 6) reports improved symptoms overall, but does not establish a subgroup whose quality of life failed to improve. The paper does not assess futility in such a subgroup. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [202] Lindman, B. R., Alexander, K. P., O'Gara, P. T. & Afilalo, J. Futility, benefit, and transcatheter aortic valve replacement. JACC Cardiovasc. Interv. 7, 707–716 (2014). This review describes the challenges and strategies for decision-making in patients with severe calcific AS who are potential candidates for TAVR. source
    • cites [220] Smith, C. R. et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N. Engl. J. Med. 364, 2187–2198 (2011). source

      The Mortality and Stroke section reports deaths after TAVR: 3.4% by 30 days and 24.2% by one year in the intention-to-treat group. The Other Clinical Outcomes section reports overall improvement in symptoms and walking distance, but does not identify a sizable subgroup without quality-of-life improvement or assess whether TAVR was futile for them. Page numbers are not available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [244] Reynolds, M. R. et al. Health-related quality of life after transcatheter aortic valve replacement in inoperable patients with severe aortic stenosis. Circulation 124, 1964–1972 (2011). source
    • cites [245] Reynolds, M. R. et al. Health-related quality of life after transcatheter or surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results from the PARTNER (Placement of AoRTic TraNscathetER Valve) trial (cohort A). J. Am. Coll. Cardiol. 60, 548–558 (2012). source

      The categorical results report that 68.3% of transfemoral TAVR patients had at least a small quality-of-life improvement at one month, supporting the point that a substantial proportion did not. The paper does not establish that a sizable subgroup died soon after TAVR, and its finding of no transapical TAVR advantage over surgery should not be read as no improvement from baseline. The suggested futility is therefore not established by this source alone. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Aortic valve replacement is indicated in patients with severe symptomatic aortic stenosis both to increase life expectancy and to improve symptoms and quality of life.

    “AVR is indicated in patients with severe symptomatic AS both to increase life expectancy and improve symptoms and quality of life3;4;199;202;252;253.”
    Quote in the paperSubstantial claim4 of 6 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source
      Experimental — accuracy not yet measured
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source
      Experimental — accuracy not yet measured
    • cites [199] Lindman, B. R., Bonow, R. O. & Otto, C. M. Current management of calcific aortic stenosis. Circ. Res. 113, 223–237 (2013). source
      Experimental — accuracy not yet measured
    • cites [202] Lindman, B. R., Alexander, K. P., O'Gara, P. T. & Afilalo, J. Futility, benefit, and transcatheter aortic valve replacement. JACC Cardiovasc. Interv. 7, 707–716 (2014). This review describes the challenges and strategies for decision-making in patients with severe calcific AS who are potential candidates for TAVR. source
    • cites [252] Otto, C. M. & Prendergast, B. Aortic-valve stenosis — from patients at risk to severe valve obstruction. N. Engl. J. Med. 371, 744–756 (2014). source
    • cites [253] Schwarz, F. et al. The effect of aortic valve replacement on survival. Circulation 66, 1105–1110 (1982). source

  • May combine two claims.

    Premisecitation

    Currently, surgical aortic valve replacement is indicated for patients with low to moderate surgical risk, while TAVR is indicated for patients at prohibitive risk for surgery.

    “Currently, surgical AVR is indicated for patients with low to moderate surgical risk and TAVR is indicated for patients at prohibitive risk for surgery (Figure 11, Table 3)3;4.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source

  • May combine two claims.

    Premisecitation

    For high-risk patients who were previously not treated with aortic valve replacement, TAVR has improved survival and quality of life.

    “For patients who are at high-risk for surgical interventions were previously not treated with AVR, TAVR has been a transformative innovation that has improved survival and quality of life200;201.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [200] Iung, B. et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur. Heart J. 26, 2714–2720 (2005). source
    • cites [201] Leon, M. B. et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Eng. J. Med. 363, 1597–1607 (2010). This randomized clinical trial shows the major superiority of TAVR compared with conservative management in patients who cannot undergo surgical AVR. source

      The Results (p. 1) show better one-year survival with TAVI than with standard therapy in patients unsuitable for surgery. Other Clinical Outcomes (p. 6) report fewer symptoms and improved six-minute walk performance, but the paper does not directly report a quality-of-life measure; that part of the claim goes beyond its findings. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The LV response to chronic pressure overload from aortic stenosis is characterized by hypertrophic remodelling with myocyte hypertrophy and fibrosis, and by diastolic and systolic dysfunction.

    “The LV response to chronic pressure overload from AS is characterized by hypertrophic remodelling (myocyte hypertrophy and fibrosis) and diastolic and systolic dysfunction.”
    Quote in the paperSubstantial claim5 of 5 sources checked
    • cites [199] Lindman, B. R., Bonow, R. O. & Otto, C. M. Current management of calcific aortic stenosis. Circ. Res. 113, 223–237 (2013). source
    • cites [257] Mihaljevic, T. et al. Survival after valve replacement for aortic stenosis: implications for decision making. J. Thorac Cardiovasc. Surg. 135, 1270–1278 (2008). source

      The “Severity of Aortic Stenosis” section (page unavailable) says chronic pressure overload causes concentric LV hypertrophy and associates severe hypertrophy with fibrosis and possible systolic or diastolic dysfunction. It does not specifically identify myocyte hypertrophy, and it presents dysfunction as a possible consequence of severe hypertrophy rather than a general feature of the LV response. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [258] Kupari, M., Turto, H. & Lommi, J. Left ventricular hypertrophy in aortic valve stenosis: preventive or promotive of systolic dysfunction and heart failure? Eur. Heart J. 26, 1790–1796 (2005). source

      The Introduction (page unavailable) describes increased LV wall thickness and mass in aortic stenosis, notes possible impairment of diastolic function, and reports an association between increased LV mass and systolic dysfunction. It does not describe fibrosis or establish that diastolic and systolic dysfunction characterize every LV response to aortic stenosis; it notes preserved systolic function in some patients with critical stenosis. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [259] Dweck, M. R., Boon, N. A. & Newby, D. E. Calcific aortic stenosis: a disease of the valve and the myocardium. J. Am. Coll. Cardiol. 60, 1854–1863 (2012). source
    • cites [260] Biner, S. et al. Prognostic value of E/E' ratio in patients with unoperated severe aortic stenosis. JACC Cardiovasc. Imaging 3, 899–907 (2010). source

      The Discussion (page not provided) says severe aortic stenosis causes systolic pressure overload and LV wall hypertrophy, and describes diastolic dysfunction alongside cases of depressed systolic function. It does not specify myocyte hypertrophy or fibrosis as components of that remodelling, so those details are unsupported by our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Natriuretic peptides such as BNP are somewhat of an exception, but their role in management decisions has not been clearly defined.

    “Natriuretic peptides, such as BNP, are somewhat of an exception, but their role in management decisions has not been clearly defined3;4.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [3] Nishimura, R. A. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, e57–e185 (2014). The most recent version of the clinical guidelines for the management of valvular heart disease, including AS. source
    • cites [4] Vahanian, A. et al. Guidelines on the management of valvular heart disease Joint Task Force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 33, 2451–2496 (2012). source

  • May combine two claims.

    Premisecitation

    Compared with inoperable patients treated conservatively, patients treated with TAVR had less severe heart failure symptoms and better disease-specific and generic health status over the year after randomization.

    “Compared with inoperable patients treated with conservative management, patients treated with TAVR had less severe heart failure symptoms and better disease-specific and generic health status over the year after randomization201;244.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [201] Leon, M. B. et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Eng. J. Med. 363, 1597–1607 (2010). This randomized clinical trial shows the major superiority of TAVR compared with conservative management in patients who cannot undergo surgical AVR. source

      Other Clinical Outcomes (p. 6) reports significantly less severe NYHA symptoms with TAVI than with standard therapy at 30 days, 6 months, and 1 year. The paper does not report the claimed improvements in disease-specific or generic health status; Study End Points (p. 3) lists NYHA class and the 6-minute walk test, but not those health-status measures. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [244] Reynolds, M. R. et al. Health-related quality of life after transcatheter aortic valve replacement in inoperable patients with severe aortic stenosis. Circulation 124, 1964–1972 (2011). source

  • Classified as probably not a substantial claim.

    Premisenone given

    Transcatheter aortic valve replacement has been a transformative innovation for patients at high or extreme-high risk for surgical aortic valve replacement.

    “The introduction of transcatheter AVR in the past decade has been a transformative innovation for patients at high or extreme-high risk for surgical AVR and this new technology might extend to lower-risk patients in the near future.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A congenitally bicuspid aortic valve and older age are strong risk factors for calcific aortic stenosis.

    “Congenital abnormality (bicuspid valve) and older age are powerful risk factors for calcific AS.”
    • Also stated in: § Epidemiology · plain
      “Although the prevalence of bicuspid aortic valve is only 0.5–1% in children, it accounts for nearly half of aortic valves that are surgically removed due to calcific AS5.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Roberts, W. C. & Ko, J. M. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation 111, 920–925 (2005). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In the developing world, aortic stenosis can also be caused by rheumatic heart disease.

    “In the developing world, AS may also be caused by rheumatic heart disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Aortic stenosis has a greater clinical impact than mitral valve regurgitation despite being less prevalent in population-based studies.

    “Although mitral valve regurgitation has a higher prevalence than AS in population-based studies, AS has a more important clinical impact18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Iung, B. et al. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on valvular heart disease. Eur. Heart J. 24, 1231–1243 (2003). A large European survey describing the clinical management of valvular heart disease and adherence to guidelines in real-life clinical practice. source

  • May combine two claims.

    Premisecitation

    Calcific aortic stenosis accounted for 34% of native valve diseases versus 25% for mitral regurgitation, and for 47% of patients operated for valvular disease versus 14% for mitral regurgitation.

    “Furthermore, calcific AS accounted for 34% of all native (non-prosthetic) valve diseases, as compared with 25% for mitral regurgitation, and 47% of patients operated for valvular disease, as compared with 14% for mitral regurgitation among patients operated for valvular disease18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Iung, B. et al. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on valvular heart disease. Eur. Heart J. 24, 1231–1243 (2003). A large European survey describing the clinical management of valvular heart disease and adherence to guidelines in real-life clinical practice. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In developed countries, aortic stenosis ranks second among cardiovascular diseases, after coronary artery disease and systemic arterial hypertension.

    “In developed countries, AS is the second-most frequent cardiovascular disease after coronary artery disease and systemic arterial hypertension”
    • Also stated in: § Introduction · plain
      “In developed countries, AS is one of the third most common cardiovascular diseases after coronary artery disease and systemic arterial hypertension2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Go, A. S. et al. Executive summary: heart disease and stroke statistics — 2013 update: a report from the American Heart Association. Circulation 127, 143–152 (2013). source

  • May combine two claims.

    Premisenone given

    Metabolic syndrome and high plasma lipoprotein(a) levels are associated with a higher risk of calcific aortic stenosis.

    “Metabolic syndrome and an elevated plasma level of lipoprotein(a) have also been associated with increased risk of calcific AS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The pathobiology of calcific aortic stenosis is complex and includes genetic factors, lipoprotein deposition and oxidation, chronic inflammation, osteoblastic transition of valve interstitial cells, and active leaflet calcification.

    “The pathobiology of calcific AS is complex and involves genetic factors, lipoprotein deposition and oxidation, chronic inflammation, osteoblastic transition of cardiac valve interstitial cells and active leaflet calcification”
    • Also stated in: § Mechanisms/pathophysiology · hedged
      “Now, there is compelling histopathologic and clinical data suggesting that calcific valve disease is, in fact, an active and multifaceted condition involving lipoprotein deposition, chronic inflammation, osteoblastic transition of valve interstitial cells and active leaflet calcification2223.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Freeman, R. V. & Otto, C. M. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation 111, 3316–3326 (2005). source
    • cites [23] Rajamannan, N. M., Bonow, R. O. & Rahimtoola, S. H. Calcific aortic stenosis: an update. Nat. Clin. Pract. Cardiovasc. Med. 4, 254–262 (2007). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Rheumatic fever and rheumatic heart disease can damage heart valves and lead to stenosis and regurgitation, especially of the mitral and aortic valves.

    “Both rheumatic fever and rheumatic heart disease may cause damage to the heart valves and can result in stenosis and regurgitation, in particular of the mitral and aortic valves.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Rheumatic heart disease is a chronic condition that results from acute rheumatic fever, which is caused by an untreated throat infection with group A Streptococcus.

    “Rheumatic heart disease is a chronic condition resulting from acute rheumatic fever, which in turn is caused by an untreated throat infection with group A Streptococcus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Calcific valve disease is an active and multifaceted condition involving lipoprotein deposition, chronic inflammation, osteoblastic transition of valve interstitial cells, and active leaflet calcification.

    “Now, there is compelling histopathologic and clinical data suggesting that calcific valve disease is, in fact, an active and multifaceted condition involving lipoprotein deposition, chronic inflammation, osteoblastic transition of valve interstitial cells and active leaflet calcification2223.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Freeman, R. V. & Otto, C. M. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation 111, 3316–3326 (2005). source
    • cites [23] Rajamannan, N. M., Bonow, R. O. & Rahimtoola, S. H. Calcific aortic stenosis: an update. Nat. Clin. Pract. Cardiovasc. Med. 4, 254–262 (2007). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The overall burden of calcific aortic stenosis is expected to increase in developing regions because life expectancy is rising.

    “In addition, the overall burden of calcific AS is expected to increase owing to the increasing in life expectancy in these regions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Each aortic valve leaflet has a trilaminar structure that determines the valve's biomechanical properties.

    “Each leaflet has a trilaminar structure that determines the biomechanical properties of the aortic valve24.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Chen, J. H. & Simmons, C. A. Cell–matrix interactions in the pathobiology of calcific aortic valve disease: critical roles for matricellular, matricrine, and matrix mechanics cues. Circ. Res. 108, 1510–1524 (2011). source

  • May combine two claims.

    Premisecitation

    Rheumatic heart disease rarely affects the aortic valve alone, in less than 10% of cases in countries where rheumatic fever remains endemic, and most often involves the mitral valve.

    “Rheumatic heart disease rarely affects the aortic valve alone (less than 10% in countries where rheumatic fever remains endemic) and most often involves the mitral valve.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Valvular remodelling differs markedly between rheumatic heart disease and calcific aortic stenosis.

    “Valvular remodelling markedly differs between rheumatic heart disease and calcific AS.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Valve interstitial cells are the predominant cell population in the aortic valve, whereas smooth muscle cells reside at the base of the ventricularis.

    “VICs is the predominant population of cells in the aortic valve, whereas SMCs reside at the base of the ventricularis27.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Latif, N., Sarathchandra, P., Chester, A. H. & Yacoub, M. H. Expression of smooth muscle cell markers and co-activators in calcified aortic valves. Eur. Heart J. 36, 1335–1345 (2015). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The fibrosa is rich in circumferentially oriented collagen type I and III fibers, while the ventricularis contains predominantly radially oriented elastic fibers.

    “The fibrosa is rich in circumferentially oriented collagen type I and III fibers25, whereas in the ventricularis, radially oriented elastic fibers predominate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Schoen, F. J. Evolving concepts of cardiac valve dynamics: the continuum of development, functional structure, pathobiology, and tissue engineering. Circulation 118, 1864–1880 (2008). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Endothelial cells cover the aortic and ventricular surfaces and provide an interface between the blood and the aortic valve.

    “The endothelial cells cover the aortic and ventricular surface and therefore provide an interface between the blood and the aortic valve26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Taylor, P. M., Allen, S. P. & Yacoub, M. H. Phenotypic and functional characterization of interstitial cells from human heart valves, pericardium and skin. J. Heart Valve Dis. 9, 150–158 (2000).

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    The composition of the ventricularis provides compliance and allows apposition of the free edge regions of the leaflets, preventing backward blood flow into the left ventricle during diastole.

    “The ventricularis composition provides more compliance (the ability to expand under pressure) and allows the apposition of free edge regions of leaflets, thus preventing the backward flow of blood into the LV during diastole.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Fusion of aortic leaflets at the commissures is a hallmark and distinctive feature of rheumatic heart disease.

    “Fusion of aortic leaflets at commissures is one hallmark and distinctive feature of rheumatic heart disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Fibrosis increases the stiffness of the aortic valve and might promote mineralization.

    “Fibrosis increases the stiffness of the aortic valve and might play a considerable part in promoting mineralization.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The fibrosa and ventricularis are the outermost leaflet layers, facing the aorta and the left ventricular outflow tract, respectively.

    “The outermost layers of the leaflet are formed by the fibrosa and ventricularis, which face the aorta and the LV outflow tract, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The cellular population of the aortic valve layers includes valve interstitial cells, smooth muscle cells, which make up less than 5%, and endothelial cells.

    “The cellular population of these aortic valve layers includes valve interstitial cells (VICs), smooth muscle cells (SMCs) (<5% of the population) and endothelial cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Expression of NAD(P)H oxidase is increased in surgically explanted calcific aortic stenosis valves and contributes to reactive oxygen species production.

    “Also, the expression NAD(P)H oxidase is increased in surgically explanted calcific AS valves and contributes to the production of reactive oxygen species (ROS)44.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Liberman, M. et al. Oxidant generation predominates around calcifying foci and enhances progression of aortic valve calcification. Arterioscler. Thromb. Vasc. Biol. 28, 463–470 (2008). source

  • May combine two claims.

    Interpretationreasoning

    High circulating lipoprotein(a) levels might promote accumulation of oxidized phospholipids in the aortic valve, which could trigger an osteogenic response.

    “Together, these studies suggest that high circulating levels of Lp(a) might promote the accumulation of Ox-PLs in the aortic valve, which could, in turn, trigger an osteogenic response (Figure 4).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The aortic valve normally has three leaflets named according to their relation to the coronary arteries: left coronary, right coronary, and non-coronary.

    “The aortic valve is typically composed of three leaflets that are named according to their location with respect to the coronary artery, specifically the left coronary, right coronary and non-coronary leaflets (Figure 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The spongiosa has a high proteoglycan content and lies between the fibrosa and ventricularis.

    “The spongiosa, which has a high proteoglycan content, is located between the fibrosa and ventricularis (Figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ALP, E-NPP1, and 5′-nucleotidase/CD73 are overexpressed in human stenotic aortic valves.

    “several ectonucleotidases such as ALP, ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (E-NPP 1) and 5′-nucleotidase (5′-NT, also called CD73) are overexpressed in human stenotic aortic valves”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [110] Cote, N. et al. ATP acts as a survival signal and prevents the mineralization of aortic valve. J. Mol. Cell. Cardiol. 52, 1191–1202 (2012). source
    • cites [111] Mahmut, A., Boulanger, M. C., Bouchareb, R., Hadji, F. & Mathieu, P. Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor. Cardiovasc. Res. 106, 109–120 (2015). source
    • cites [112] Mathieu, P. et al. Calcification of human valve interstitial cells is dependent on alkaline phosphatase activity. J. Heart Valve Dis. 14, 353–357 (2005).

  • May combine two claims.

    Premisenone given

    Mineralization begins in the fibrosa layer and is often near lipid deposits.

    “Mineralization starts in the fibrosa layer and it is often in the vicinity of lipid deposits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    E-NPP1 hydrolyzes ATP into AMP and pyrophosphate, and pyrophosphate strongly inhibits mineralization.

    “E-NPP 1 hydrolyzes ATP into AMP and pyrophosphate (PPi), a strong inhibitor of mineralization.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Mathieu, P. et al. Calcification of human valve interstitial cells is dependent on alkaline phosphatase activity. J. Heart Valve Dis. 14, 353–357 (2005).

  • May combine two claims.

    Premisecitation

    Recent studies suggest hypertension accelerates AS progression, potentially through increased mechanical stress on valve leaflets and activation of the renin-angiotensin system.

    “Recent studies suggest that hypertension accelerates the progression of AS, potentially owing to increased mechanical stress on the valve leaflets and activation of renin-angiotensin system (as discussed above)94.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Capoulade, R. et al. Impact of hypertension and renin–angiotensin system inhibitors in aortic stenosis. Eur. J. Clin. Invest. 43, 1262–1272 (2013). source

  • May combine two claims.

    Premisereasoning

    Increased cardiac mass in AS is due to hypertrophy of existing myocytes rather than hyperplasia, because cardiomyocytes become terminally differentiated soon after birth.

    “This increase in cardiac mass is due to the hypertrophy of existing myocytes rather than hyperplasia, because cardiomyocytes become terminally differentiated soon after birth.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    AS increases LV systolic pressure, which leads to cardiomyocyte hypertrophy and interstitial fibrosis.

    “AS results in increased LV systolic pressure that leads to hypertrophy of the cardiomyocytes and interstitial fibrosis (Figure 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    LV diastolic dysfunction occurs early in AS and worsens with stenosis severity and myocardial fibrosis.

    “LV diastolic dysfunction occurs early in the disease course and worsens with progression of stenosis severity and myocardial fibrosis (Figure 5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Concurrent addition of sarcomeres increases myocyte width, which increases wall thickness and helps normalize LV wall stress and maintain ejection performance despite elevated systolic pressure.

    “The concurrent addition of sarcomeres (force-generating units) causes an increase in myocyte width, which in turn increases wall thickness and therefore contributes to normalize LV wall stress and maintain LV ejection performance despite elevated systolic pressure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ALP acts on many substrates, including the mineralization inhibitor pyrophosphate, and produces phosphate with strong pro-mineralizing activity.

    “ALP has a broad spectrum of substrates including the mineralization inhibitor PPi from which it produces phosphate with strong pro-mineralizing activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Mathieu, P. et al. Calcification of human valve interstitial cells is dependent on alkaline phosphatase activity. J. Heart Valve Dis. 14, 353–357 (2005).

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Calcific AS shares several risk factors with coronary artery disease but also has important distinctive features.

    “Calcific AS shares several risk factors with coronary artery disease but it also presents some important distinctive features.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Although some clinical and genetic risk factors are associated with onset and progression of calcific AS, no strategy has been proven efficient for primary or secondary prevention.

    “Although some clinical and genetic risk factors have been associated with the onset and progression of calcific AS, no strategy has been yet proven to be efficient for primary or secondary prevention of this disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The most common bicuspid aortic valve form is fusion of the right and left coronary leaflets (~60%), followed by right and non-coronary fusion (~35%), then left and non-coronary fusion (~5%).

    “the most common form consists of a fusion of the right and left coronary leaflets (~60% of patients) followed by fusion between the right and non-coronary leaflets (~35% of patients) and then fusion between left and non-coronary cusp (~5% of patients) (Figure 2)131.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Fernandez, B. et al. Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiological entities. J. Am. Coll. Cardiol. 54, 2312–2318 (2009). source

  • May combine two claims.

    Premisecitation

    CA12 in VICs is normally expressed at the cell membrane after P2Y2 activation and promotes extracellular acidification, leading to resorption of mineral deposits.

    “CA12 in VICs is normally expressed at the cell membrane following activation of P2Y2 and promotes the acidification of the extracellular space leading to resorption of mineral deposits113.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Bouchareb, R. et al. Carbonic anhydrase XII in valve interstitial cells promotes the regression of calcific aortic valve stenosis. J. Mol. Cell. Cardiol. 82, 104–115 (2015). source

  • May combine two claims.

    Premisecitation

    In VICs, P2Y2 prevents mineralization by interfering with apoptosis and by promoting activation of carbonic anhydrase 12.

    “In VICs, P2Y2 prevents the mineralization of cells by interfering with apoptosis and also by promoting the activation of carbonic anhydrase 12 (CA12).110;113”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] Cote, N. et al. ATP acts as a survival signal and prevents the mineralization of aortic valve. J. Mol. Cell. Cardiol. 52, 1191–1202 (2012). source
    • cites [113] Bouchareb, R. et al. Carbonic anhydrase XII in valve interstitial cells promotes the regression of calcific aortic valve stenosis. J. Mol. Cell. Cardiol. 82, 104–115 (2015). source

  • May combine two claims.

    Premisenone given

    Reduced LVEF or cardiac output occurs only in end-stage AS and is usually preceded by clinical symptoms.

    “Reduced LVEF or cardiac output occurs only in end-stage disease and is usually preceded by clinical symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Reduced coronary flow reserve limits the coronary circulation's ability to match flow to myocardial oxygen demand, especially during exercise, and is a key factor in myocardial ischaemia and symptoms.

    “The reduction of coronary flow reserve limits the ability of coronary circulation to increase flow to match myocardial oxygen demand, especially during exercise, and it is therefore a key factor in the development of myocardial ischaemia and the occurrence of symptoms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Activation of multiple interacting pathways disrupts normal aortic valve biology and promotes fibro-calcific remodelling.

    “The activation of several pathways with multiple points of crosstalk disrupts the normal biology of the aortic valve and promotes fibro-calcific remodelling.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The lifetime risk of AVR is around 50% in individuals with a bicuspid valve.

    “For instance, the lifetime risk of AVR is around 50% in individuals with a bicuspid valve.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LV hypertrophy reduces coronary arteriolar vessel density, and increased LV transmural pressures raise coronary vascular resistance, together reducing coronary flow reserve in AS patients.

    “The LV hypertrophy, leading to a reduced density of coronary arteriolar vessels, and increased LV transmural pressures, leading to increased coronary vascular resistance, result in the reduction of coronary flow reserve in patients with AS123;124”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [123] Rajappan, K. et al. Mechanisms of coronary microcirculatory dysfunction in patients with aortic stenosis and angiographically normal coronary arteries. Circulation 105, 470–476 (2002). source
    • cites [124] Rajappan, K. et al. Functional changes in coronary microcirculation after valve replacement in patients with aortic stenosis. Circulation 107, 3170–3175 (2003). source

  • May combine two claims.

    Premisereasoning

    Congenital leaflet abnormality and older age are both powerful risk factors for developing calcific AS.

    “Congenital leaflet abnormality and older age are both powerful risk factors for developing calcific AS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Impaired coronary flow reserve may explain why patients with severe AS can have angina despite angiographically normal coronary arteries and why symptoms may regress immediately after AVR.

    “The impairment of coronary flow reserve might also explain why patients with severe AS can present with angina symptoms despite having angiographically normal coronary arteries and why these symptoms might regress immediately after AVR125.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Julius, B. K. et al. Angina pectoris in patients with aortic stenosis and normal coronary arteries. Mechanisms and pathophysiological concepts. Circulation 95, 892–898 (1997). source

  • May combine two claims.

    Premisereasoning

    Replacement myocardial fibrosis occurs predominantly in subendocardial and mid-wall layers and is generally not reversible after AVR relieves LV pressure overload.

    “This type of fibrosis occurs predominantly in the subendocardial and mid-wall layers of the LV wall and is generally not reversible following relief of LV pressure overload by AVR.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Overactivity of E-NPP1 and 5′-NT in human stenotic aortic valves depletes extracellular ATP and produces adenosine.

    “the over activity of E-NPP 1 and 5′-NT in human stenotic aortic valves depletes extracellular ATP and produces adenosine111.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Mahmut, A., Boulanger, M. C., Bouchareb, R., Hadji, F. & Mathieu, P. Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor. Cardiovasc. Res. 106, 109–120 (2015). source

  • May combine two claims.

    Premisecitation

    There are two main subtypes of low-flow, low-gradient AS: classical (stroke volume index <35 ml/m2, mean gradient <40 mmHg, reduced LVEF <50%) and paradoxical (stroke volume index <35 ml/m2, mean gradient <40 mmHg, preserved LVEF ≥50%).

    “There are two main subtypes of low-flow, low-gradient AS (Tables 1 and 2): ‘classical’ low-flow (stroke volume index <35 ml per m2), low-gradient (mean gradient <40 mmHg) AS with reduced LVEF (<50%)163; and ’paradoxical’ low-flow (stroke volume index <35 ml per m2), low-gradient (mean gradient <40 mmHg) AS with preserved LVEF (≥50%)164.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] Monin, J. L. et al. Low-gradient aortic stenosis: operative risk stratification and predictors for long-term outcome: a multicenter study using dobutamine stress hemodynamics. Circulation 108, 319–324 (2003). source
    • cites [164] Hachicha, Z., Dumesnil, J. G., Bogaty, P. & Pibarot, P. Paradoxical low flow low gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival. Circulation 115, 2856–2864 (2007). source

  • May combine two claims.

    Premisenone given

    Metabolic syndrome, diabetes, hypertension, smoking and elevated plasma Lp(a) are additional risk factors for calcific aortic stenosis.

    “Other risk factors include metabolic syndrome, diabetes, hypertension, smoking and increased plasma Lp(a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Despite evidence of a strong inheritance pattern for some bicuspid aortic valve cases with incomplete penetrance, the genetic architecture of calcific AS remains poorly understood.

    “However, despite the evidence of a strong inheritance pattern for some cases of bicuspid aortic valve with an incomplete penetrance, the genetic architecture of calcific AS is still poorly understood145.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Cripe, L., Andelfinger, G., Martin, L. J., Shooner, K. & Benson, D. W. Bicuspid aortic valve is heritable. J. Am. Coll. Cardiol. 44, 138–143 (2004). source

  • May combine two claims.

    Interpretationnone given

    No preventive or pharmacological therapy has been proven to prevent the onset of calcific aortic stenosis or slow its progression.

    “There is currently no preventive or pharmaco-therapeutic approach that has proven effective to prevent the onset or slow the progression of calcific AS”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hypertension further increases the already elevated LV afterload in AS and contributes to risk of symptoms and adverse cardiac events.

    “Moreover, hypertension further increases the LV afterload (Box 1) that is already elevated in patients with AS and contributes to the risk of developing symptoms and adverse cardiac events94;144.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] Capoulade, R. et al. Impact of hypertension and renin–angiotensin system inhibitors in aortic stenosis. Eur. J. Clin. Invest. 43, 1262–1272 (2013). source
    • cites [144] Rieck, A. E. et al. Hypertension in aortic stenosis: implications for left ventricular structure and cardiovascular events. Hypertension 60, 90–97 (2012). source

  • May combine two claims.

    Premisecitation

    Diagnosis of AS is generally established using echocardiography, which provides information on valve anatomy and blood flow parameters.

    “Diagnosis of AS is generally established using an echocardiographic exam, which provides a wealth of information regarding heart valve anatomy and blood flow parameters (Figure 7)155.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Baumgartner, H. et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur. J. Echocardiogr. 10, 1–25 (2009). source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Doppler echocardiography is the preferred method for diagnosing aortic stenosis, assessing its severity and following progression over time.

    “Doppler-echocardiography is the method of choice to diagnose AS and assess its severity as well as to follow disease progression over time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Reduced longitudinal strain is useful to identify subclinical LV dysfunction and predict risk of cardiac events in patients with asymptomatic AS and preserved LVEF.

    “For example, reduced longitudinal strain is useful to identify subclinical LV dysfunction and predict risk of cardiac events in patients with asymptomatic AS and preserved LVEF181–186.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [181] Bartko, P. E. et al. Two-dimensional strain for the assessment of left ventricular function in low flow-low gradient aortic stenosis, relationship to hemodynamics and outcome: a substudy of the multicenter TOPAS study. Circ. Cardiovasc. Imaging 6, 268–276 (2012). source
    • cites [182] Dahou, A. et al. Usefulness of global left ventricular longitudinal strain for risk stratification in low ejection fraction, low-gradient aortic stenosis: results from the multicenter true or pseudo-severe aortic stenosis study. Circ. Cardiovasc. Imaging 8, e002117 (2015). source
    • cites [183] Lancellotti, P. et al. Impact of global left ventricular afterload on left ventricular function in asymptomatic severe aortic stenosis: a two-dimensional speckle-tracking study. Eur. J. Echocardiogr. 11, 537–543 (2010). source
    • cites [184] Dahl, J. S. et al. Effect of left ventricular ejection fraction on postoperative outcome in patients with severe aortic stenosis undergoing aortic valve replacement. Circ. Cardiovasc. Imaging 8, e002917 (2015). source
    • cites [185] Lancellotti, P. et al. Prognostic effect of long-axis left ventricular dysfunction and B-type natriuretic peptide levels in asymptomatic aortic stenosis. Am. J. Cardiol. 105, 383–388 (2010). source
    • cites [186] Ozkan, A., Kapadia, S., Tuzcu, M. & Marwick, T. H. Assessment of left ventricular function in aortic stenosis. Nat. Rev. Cardiol. 8, 494–501 (2011). source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Quantification of myocardial fibrosis by CMR could potentially be useful to recommend early AVR in asymptomatic severe AS before extensive fibrosis and irreversible myocardial dysfunction develop, or to improve operative risk stratification and assess utility versus futility of AVR in low-flow, low-gradient AS.

    “Therefore, the quantification of myocardial fibrosis by CMR (Figure 10) could potentially be useful to recommend early AVR in patients with asymptomatic severe AS before extensive fibrosis and ensuing irreversible myocardial dysfunction have developed or to improve operative risk stratification and assess potential utility versus futility of AVR in patients with low-flow, low-gradient AS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mini-sternotomy is a viable option for isolated aortic valve replacement and is associated with similar mortality but decreased morbidity and resource utilization compared with full sternotomy.

    “A mini-sternotomy, which is a minimally invasive way of performing cardiac surgery, is a viable option for isolated AVR and is associated with similar mortality, but decreased morbidity and resource utilization, compared to a full sternotomy215.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [215] Brown, M. L., McKellar, S. H., Sundt, T. M. & Schaff, H. V. Ministernotomy versus conventional sternotomy for aortic valve replacement: a systematic review and meta-analysis. J. Thorac Cardiovasc. Surg. 137, 670–679 (2009). source

  • May combine two claims.

    Premisecitation

    Operative mortality for aortic valve replacement varies with the skill and experience of the surgical team and with hospital volume.

    “Operative mortality for AVR varies according to the skill and experience of the surgical team as well as hospital volume216.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [216] Astor, B. C., Kaczmarek, R. G., Hefflin, B. & Daley, W. R. Mortality after aortic valve replacement: results from a nationally representative database. Ann. Thorac Surg. 70, 1939–1945 (2000). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Stentless bioprosthetic valves have better haemodynamics than stented valves, but their implantation is more complex and requires longer cardiopulmonary bypass time.

    “These valves have better hemodynamics compared to stented valves but their implantation is more complex and thus requires longer cardiopulmonary bypass time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In some circumstances, balloon aortic valvuloplasty may be used for palliative care because there is some evidence it might provide short-term improvement in survival, functional capacity and quality of life, but these benefits are not sustained.

    “In some circumstances, a BAV may be utilized for palliative care as there is some evidence that it might provide a short-term benefit in terms of improved survival, functional capacity and quality of life, but these benefits are not sustained251.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [251] Kapadia, S. et al. Outcomes of inoperable symptomatic aortic stenosis patients not undergoing aortic valve replacement: insight into the impact of balloon aortic valvuloplasty from the PARTNER trial (Placement of AoRtic TraNscathetER valve trial). JACC Cardiovasc. Interv. 8, 324–333 (2015). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is a growing movement away from general anaesthesia to conscious sedation that might decrease the morbidity of TAVR.

    “There is a growing movement away from general anesthesia to conscious sedation that might decrease the morbidity of the procedure239.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] Babaliaros, V. et al. Comparison of transfemoral transcatheter aortic valve replacement performed in the catheterization laboratory (minimalist approach) versus hybrid operating room (standard approach): outcomes and cost analysis. JACC Cardiovasc. Interv. 7, 898–904 (2014). source

  • May combine two claims.

    Premisecitation

    Other TAVR complications include major vascular injury, heart block requiring a permanent pacemaker and acute kidney injury; rarer complications include stroke, aortic rupture and coronary obstruction.

    “Other complications of TAVR have included major vascular injury, heart block requiring a permanent pacemaker and acute kidney injury; more rare complications include stroke, aortic rupture and coronary obstruction233.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Rodes-Cabau, J. Transcatheter aortic valve implantation: current and future approaches. Nat. Rev. Cardiol. 9, 15–29 (2012). source

  • May combine two claims.

    Premisenone given

    Some patients have residual heart failure symptoms after valve replacement because of persistent diastolic dysfunction, which may resemble heart failure with preserved LVEF.

    “Notably, however, some patients have residual heart failure symptoms (albeit not as severe) after valve replacement owing to persistent diastolic dysfunction; this may manifest similar to the common syndrome of heart failure with preserved LVEF.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The pathobiology of aortic stenosis is complex and likely involves genetic factors, multiple signalling pathways, ageing, sex hormones, haemodynamic factors and shear stress, and the systemic milieu.

    “The pathobiology of AS is complex and likely involves genetic factors, multiple signalling pathways, ageing, sex hormones, haemodynamic factors and shear stress, and the systemic milieu.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Disease initiation and progression are influenced by different factors.

    “Disease initiation and progression are influenced by different factors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    When a patient's diminished quality of life is clearly related to heart failure symptoms from severe aortic stenosis, valve replacement conveys a predictable and noticeable improvement in quality of life and extends life expectancy.

    “When a patient’s diminished quality of life is clearly related to heart failure symptoms from severe AS, valve replacement conveys a predictable and noticeable improvement in quality of life and extends life expectancy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Although the STS score and EuroSCORE have reasonable accuracy in predicting morbidity and mortality after TAVR, they were developed in younger patient cohorts with fewer comorbidities undergoing cardiac surgery.

    “Although the STS score and EuroSCORE have reasonable accuracy in predicting morbidity and mortality after TAVR, they were developed in younger patient cohorts with fewer comorbidities undergoing cardiac surgery261.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [261] Dewey, T. M. et al. Reliability of risk algorithms in predicting early and late operative outcomes in high-risk patients undergoing aortic valve replacement. J. Thorac Cardiovasc. Surg. 135, 180–187 (2008). source
103 of 103

  • The paper relies on this without support.

    Findings from animal models and in vitro cell cultures about calcific aortic stenosis mechanisms can be extrapolated to human disease.

    “In vitro, serum-induced mineralization of collagen is increased by a population of VICs harbouring a pro-calcifying phenotype with elevated alkaline phosphatase (ALP) expression33;34.”
    “To this effect, in a murine model, the administration of LysoPA increased the deposition of hydroxyapatite (a form of calcium apatite) in the aortic valve and accelerated the development of calcific AS.”

  • The paper relies on this without support.

    The cited observational and retrospective studies are not substantially confounded and can support causal inferences about risk factors and treatments for calcific aortic stenosis.

    “Retrospective non-randomized studies have reported that administration of ARBs, but not ACE inhibitors, are associated with less fibro-calcific remodelling of aortic valve leaflets and slower progression of valve stenosis93;94.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Early abstract says AS is most prevalent, later text says mitral regurgitation is more prevalent

    Minor

    The abstract describes calcific aortic stenosis as the most prevalent valve disorder, but the epidemiology section later states that mitral valve regurgitation has a higher prevalence than AS in population-based studies. These claims cannot both be true as written without qualification.

  • Aortic stenosis is assigned conflicting prevalence ranks

    Minor

    The abstract calls AS the second-most frequent cardiovascular disease, while the introduction places it after two other cardiovascular diseases, making it third.

  • Most-prevalent valve disorder claim conflicts with mitral regurgitation comparison

    Minor

    The abstract identifies calcific AS as the most prevalent heart valve disorder in developed countries, but the epidemiology section says mitral valve regurgitation has a higher prevalence than AS in population-based studies.

3 of 3

Cites

Flagged first, then by citations

1 of the 287 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Kodali, S. & The PARTNER 3 TAVR Investigators. Clinical and echocardiographic outcomes at 30 days with the SAPIEN 3 TAVR system in inoperable, high-risk and intermediate-risk AS patients. J. Am. Coll. Cardiol. Abstr. press release [online] (2015).

Cited by

Sorted by citations

Related

Authors
Lindman, B. R., Clavel, M.-A., Mathieu, P., Iung, B., Lancellotti, P., Otto, C. M., & Pibarot, P.
Affiliations
  • Washington University in St. Louis (US)
  • Institut universitaire de cardiologie et de pneumologie de Québec (CA)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Centre Hospitalier Universitaire de Liège (BE)
  • University of Washington (US)
ORCID
Venue
Nature Reviews Disease Primers
Publisher
Springer Science and Business Media LLC
Published
2016-03-03
Volume
2
Issue
1
Pages
16006-16006
ISSN
2056-676X (ISSN-L)
DOI
10.1038/nrdp.2016.6
PMC
PMC5127286
OpenAlex
W2326187533
Cited by
982
References
287
Citations by year
2026: 108 · 2025: 141 · 2024: 118 · 2023: 109 · 2022: 132 · 2021: 117 · 2020: 94 · 2019: 73 · 2018: 55 · 2017: 32 · 2016: 2
FWCI
9.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Disease Primers (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Corpus Université Laval (Université Laval) (submittedVersion)
  • Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
Funders
National Heart, Lung, and Blood Institute (K23HL116660)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic Disease and Treatment Approaches
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Cardiac Imaging and Diagnostics
Keywords
calcific aortic stenosis, aortic valve calcification, bicuspid aortic valve, risk factors, lipoprotein(a), metabolic syndrome, chronic inflammation, valvular interstitial cells, RANKL, renin-angiotensin system, ectonucleotidases, aortic valve replacement, transcatheter aortic valve implantation, Doppler echocardiography, stenosis severity, left ventricular systolic function
MeSH terms
Aortic Valve, Aortic Valve Stenosis, Calcinosis, Heart Valve Prosthesis, Humans, Hyperlipidemias, Rheumatic Fever, Risk Factors, Prevalence, Hypertrophy, Left Ventricular, Heart Valve Prosthesis Implantation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

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