Calcific aortic stenosis

In the paper

“The geographical distribution of calcific AS is heterogeneous and displays a clustering effect which is probably the consequence of genetic factors17.”

What the sources say

• Supported

  The Methods and Results (p. 1) report a highly heterogeneous distribution of operated calcific aortic valve stenosis in western France and identify clusters with affected families. The Discussion (p. 4) says a common ancestor links affected patients in one cluster, suggesting a major genetic trait. (LLM, conf=0.91)

  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

In the paper

“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.”

What the sources say

• Supported

  The Systematic review, Progression section states that 1.8% to 1.9% of subjects with aortic sclerosis progressed to clinical aortic stenosis per year. This directly supports the cited rate; the copy does not provide a page number for the passage. (LLM, conf=0.95)

  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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [19] Iung, B. & Vahanian, A. Degenerative calcific aortic stenosis: a natural history. Heart 98 (Suppl. 4), iv7–iv13 (2012). source

In the paper

“Oxidative stress is increased in AS valves and is related, at least in part, to the uncoupling of the nitric oxide synthase (NOS) pathway43.”

What the sources say

• Supported

  The Discussion reports increased oxidative stress in stenotic aortic valves and says superoxide production in calcified regions seems related, at least in part, to NOS uncoupling. The claim preserves that qualified relationship, though the observed increase was concentrated near calcified regions. (LLM, conf=0.94)

  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

In the paper

“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.”

What the sources say

• Supported

  The “Aortopathy and BAV” section says aortic-wall abnormalities commonly accompany bicuspid aortic valve and can contribute to aortic dilatation. The “Contribution of mechanical factors to the mineralisation of BAV” section identifies altered blood flow, increased mechanical stress, and possible genetic contributions to valve mineralisation. Page numbers were not available in our copy. (LLM, conf=0.90)

  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

In the paper

“For the same degree of AS, women tend to predominantly develop concentric remodelling/hypertrophy, whereas men are more prone to developing eccentric hypertrophy116.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [51] Capoulade, R. et al. Oxidized phospholipids, lipoprotein(a) and progression of aortic valve stenosis. J. Am. Coll. Cardiol. 66, 1236–1246 (2015). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Bicuspid aortic valves have two functional leaflets often of unequal size. This abnormality results from incomplete separation of commissures during embryonic development8.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [188] Weidemann, F. et al. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation 120, 577–584 (2009). source
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“In addition, older (> 80 years) and sicker patients who previously were not candidates for definitive therapy are being treated200;201.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  Patient Selection (p. 2) says the trial studied patients with severe aortic stenosis who were not suitable candidates for surgery. Patients and Enrollment (p. 4) reports that 179 received TAVI, and the baseline table (p. 5) gives their mean age as 83.1 years. Together, these passages support the claim that older, medically high-risk patients previously unable to undergo surgical valve replacement were being treated. (LLM, conf=0.91)

  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

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

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

  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
• Partly supported

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

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• Supported

  The Abstract concludes that surgery should not be withheld solely because patients with low-flow/low-gradient aortic stenosis lack contractile reserve on dobutamine stress echocardiography. It also reports 22% operative mortality; the Discussion describes operative risk in this group as high. (LLM, conf=0.94)

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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)”

What the sources say

• Supported

  Section 3.2 (Aortic Stenosis; page unavailable) gives Class I recommendations for aortic valve replacement in asymptomatic patients with severe AS and LVEF below 50%, and in patients with severe AS undergoing cardiac surgery for another indication. The guideline specifies additional valve and hemodynamic criteria for these recommendations, which the citing sentence omits. (LLM, conf=0.91)

  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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“A transfemoral approach is associated with lower mortality and quicker recovery compared to alternative access approaches227–229.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [228] Holmes, D. R. et al. Clinical outcomes at 1 year following transcatheter aortic valve replacement. JAMA 313, 1019–1028 (2015). source
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“This survival benefit was accompanied by relief of symptoms and improvement in functional capacity in many patients201;225.”

What the sources say

• Supported

  The Results (p. 1) report lower one-year mortality with TAVI than with standard therapy. Other Clinical Outcomes (p. 6) report significantly reduced symptoms and improved six-minute walk distance after TAVI; the walk-test analysis was limited to a subgroup. (LLM, conf=0.94)

  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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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,)”

What the sources say

• Supported

  Section 3.2 (Aortic Stenosis), Class IIa, says AVR is reasonable for asymptomatic patients with very severe AS, low surgical risk, and an aortic velocity of at least 5.0 m/s. That supports the threshold attributable to this guideline; the citing sentence presents 5.5 m/s as an alternative depending on the guideline. (LLM, conf=0.90)

  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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Rates of Death, Repeat Hospitalization, and Stroke section (p. 6) reports 1-year mortality of 30.7% with TAVI versus 50.7% with standard therapy, with a hazard ratio of 0.55 (95% CI, 0.40–0.74). The Discussion (p. 10) explicitly describes the difference as 20 percentage points. (LLM, conf=0.95)

  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

In the paper

“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”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  Section 3.2 identifies a porcelain aorta and disease affecting three or more major organ systems as reasons a patient may have prohibitive surgical risk. It also describes frailty as a common reason for inoperability; Section 2.5 says comorbidities and frailty must be considered in surgical-risk assessment. (LLM, conf=0.92)

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Supported

  The Abstract says a sizable group dies or lacks quality-of-life improvement soon after TAVR and explicitly raises the possibility of futility in some patients. The Introduction likewise describes early deaths and limited quality-of-life improvement. (LLM, conf=0.95)

  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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Aortic Stenosis section (3.2; page unavailable) says surgical or transcatheter AVR improves survival, reduces symptoms, and improves exercise capacity in patients with severe symptomatic AS. It recommends prompt AVR for virtually all such patients, provided serious comorbidities do not limit life expectancy or quality of life. The General Principles section (2.5; page unavailable) also identifies improved quality of life as a potential benefit of valve intervention. (LLM, conf=0.91)

  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. sourceExperimental — accuracy not yet measured
• Supported

  Section 5.4.1 recommends early AVR for patients with symptomatic severe aortic stenosis who are candidates for surgery. Section 5.3 reports improved survival compared with conservative treatment, along with substantial improvements in symptoms and quality of life after successful AVR. (LLM, conf=0.90)

  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). sourceExperimental — accuracy not yet measured
• Supported

  The Aortic Valve Replacement section states that AVR is indicated for severe symptomatic aortic stenosis and improves symptoms and life expectancy. The Risk Stratification section treats quality-of-life improvement as a potential benefit, while noting that patients with very advanced disease or extensive comorbidities may not benefit. (LLM, conf=0.92)

  cites [199] Lindman, B. R., Bonow, R. O. & Otto, C. M. Current management of calcific aortic stenosis. Circ. Res. 113, 223–237 (2013). sourceExperimental — accuracy not yet measured
• Supported

  The Introduction states that valve replacement is the only treatment that improves survival and quality of life in patients with severe symptomatic aortic stenosis. The Anticipated Benefit of TAVR section also describes longer survival and improved symptoms as benefits of valve replacement. The supplied passages do not provide page numbers. (LLM, conf=0.92)

  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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [253] Schwarz, F. et al. The effect of aortic valve replacement on survival. Circulation 66, 1105–1110 (1982). source

In the paper

“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.”

What the sources say

• Supported

  Section 3.2.4, Choice of Intervention (page not available in our copy), recommends surgical AVR for patients who meet an indication for AVR and have low or intermediate surgical risk. The same section recommends TAVR for patients who meet an indication for AVR, have prohibitive surgical risk, and are predicted to survive more than 12 months after TAVR. The claim summarizes those recommendations, though it omits their eligibility conditions. (LLM, conf=0.92)

  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
• Supported

  Section 5.4.3 and its treatment algorithm direct patients with low or intermediate surgical risk toward AVR and those with a contraindication to AVR toward TAVI. The same section recommends TAVI for patients with severe symptomatic aortic stenosis whom the heart team considers unsuitable for conventional surgery because of severe comorbidities. The claim is a broad paraphrase of that risk-based distinction. (LLM, conf=0.88)

  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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“The LV response to chronic pressure overload from AS is characterized by hypertrophic remodelling (myocyte hypertrophy and fibrosis) and diastolic and systolic dysfunction.”

What the sources say

• Supported

  The Diagnosis section (“LV response to chronic pressure overload”) states that AS increases LV pressure, myocardial cell mass, and interstitial fibrosis. It also says diastolic dysfunction occurs earlier, while reduced ejection fraction or cardiac output generally occurs in end-stage disease; the Risk Stratification section notes that more sensitive measures can detect systolic dysfunction despite a normal ejection fraction. (LLM, conf=0.92)

  cites [199] Lindman, B. R., Bonow, R. O. & Otto, C. M. Current management of calcific aortic stenosis. Circ. Res. 113, 223–237 (2013). source
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Supported

  The Left Ventricular Hypertrophy section says aortic stenosis increases LV pressure afterload, stimulating hypertrophy in which myocytes enlarge. Figure 3 describes a subsequent fibrotic response and says increasing myocardial fibrosis leads to progressive systolic and diastolic impairment. (LLM, conf=0.93)

  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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“Natriuretic peptides, such as BNP, are somewhat of an exception, but their role in management decisions has not been clearly defined3;4.”

What the sources say

• Supported

  In §4.3 (Chronic Aortic Regurgitation; page unavailable), the guideline identifies brain natriuretic peptide as a marker under investigation and says more outcome evidence is needed before firm recommendations can be made. In §7.3 (Chronic Primary Mitral Regurgitation; page unavailable), it says BNP might help guide the timing of surgery, but calls the data preliminary. Together, these passages support the claim that BNP has potential clinical value while its role in management decisions remains unclear. (LLM, conf=0.90)

  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
• Supported

  Section 3.1.3.6 says BNP is related to functional class and prognosis, particularly in aortic stenosis and mitral regurgitation, but that evidence for its added value in risk stratification remains limited. This supports the claim that natriuretic peptides show promise while their role in management decisions is not clearly established. (LLM, conf=0.88)

  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

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“In the developing world, AS may also be caused by rheumatic heart disease.”

In the paper

“Although mitral valve regurgitation has a higher prevalence than AS in population-based studies, AS has a more important clinical impact18.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“Each leaflet has a trilaminar structure that determines the biomechanical properties of the aortic valve24.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“Valvular remodelling markedly differs between rheumatic heart disease and calcific AS.”

In the paper

“VICs is the predominant population of cells in the aortic valve, whereas SMCs reside at the base of the ventricularis27.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“The fibrosa is rich in circumferentially oriented collagen type I and III fibers25, whereas in the ventricularis, radially oriented elastic fibers predominate.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“The endothelial cells cover the aortic and ventricular surface and therefore provide an interface between the blood and the aortic valve26.”

What the sources say

• ?Not checked — no full text of the sourcecites [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).

In the paper

“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.”

In the paper

“Fusion of aortic leaflets at commissures is one hallmark and distinctive feature of rheumatic heart disease.”

In the paper

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

In the paper

“The outermost layers of the leaflet are formed by the fibrosa and ventricularis, which face the aorta and the LV outflow tract, respectively.”

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

In the paper

“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).”

In the paper

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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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).

In the paper

“Mineralization starts in the fibrosa layer and it is often in the vicinity of lipid deposits.”

In the paper

“E-NPP 1 hydrolyzes ATP into AMP and pyrophosphate (PPi), a strong inhibitor of mineralization.”

What the sources say

• ?Not checked — no full text of the sourcecites [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).

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“ALP has a broad spectrum of substrates including the mineralization inhibitor PPi from which it produces phosphate with strong pro-mineralizing activity.”

What the sources say

• ?Not checked — no full text of the sourcecites [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).

In the paper

“Calcific AS shares several risk factors with coronary artery disease but it also presents some important distinctive features.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [124] Rajappan, K. et al. Functional changes in coronary microcirculation after valve replacement in patients with aortic stenosis. Circulation 107, 3170–3175 (2003). source

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“the over activity of E-NPP 1 and 5′-NT in human stenotic aortic valves depletes extracellular ATP and produces adenosine111.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Other risk factors include metabolic syndrome, diabetes, hypertension, smoking and increased plasma Lp(a).”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [144] Rieck, A. E. et al. Hypertension in aortic stenosis: implications for left ventricular structure and cardiovascular events. Hypertension 60, 90–97 (2012). source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [155] Baumgartner, H. et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur. J. Echocardiogr. 10, 1–25 (2009). source

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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