Calcific aortic stenosis

In the paper

“but their incremental value beyond already established clinical, echocardiographic, tomographic and blood biomarkers is yet to be demonstrated.”

What the sources say

• Partly supported

  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)

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

  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)

  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). sourceExperimental — accuracy not yet measured
• Disputed

  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.

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“with some studies even suggesting that this adverse association extends to mild regurgitation235;237;238.”

What the sources say

• Supported

  The Impact on Clinical Outcomes section reports that the PARTNER trial’s two-year results associated even mild paravalvular leak with significant mortality. It also cautions that a causal relationship remains unproven and calls the observation hypothesis-generating, consistent with the citing sentence’s hedged wording. No page number is provided in our copy. (LLM, conf=0.93)

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

  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.

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Aortic Stenosis section (§3.2.3–3.2.4; page unavailable) recommends AVR for symptomatic severe AS and says its intervention recommendations cover both surgical and transcatheter AVR. It also states that balloon dilation is not a substitute for AVR because its benefits are limited and deterioration commonly follows. (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 5.3 calls aortic valve replacement the definitive therapy for severe aortic stenosis and discusses both surgical replacement and TAVI. Section 5.5 says no medical therapy improves outcomes compared with the natural history; section 5.3 describes balloon valvuloplasty alone as having very limited efficacy in adults. (LLM, conf=0.93)

  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

“In addition, Capoulade and colleagues showed that circulating Lp(a) and Ox-PL levels were independently associated with faster progression of calcific AS51.”

What the sources say

• Supported

  The paper’s Conclusions state that elevated plasma Lp(a) and OxPL-apoB are associated with faster aortic stenosis progression. The reported multivariable analyses also identify elevated levels of either marker as independent predictors after adjustment for other factors. (LLM, conf=0.94)

  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

In the paper

“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.”

What the sources say

• Supported

  The Results section on human valve leaflets reports staining indicative of an activated TGF-β1 receptor–Smad2/3 pathway in calcific aortic valve disease. The Discussion reports that TGF-β1 strongly stimulated GAG-chain elongation in porcine aortic valve interstitial cells. No page numbers are available in our copy. (LLM, conf=0.91)

  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

In the paper

“In addition, the increased production of several components of the extracellular matrix, including periostin, tenascin (also called tenascin-c) and proteoglycans contributes to the remodelling of the aortic valve during AS35;36.”

What the sources say

• ?Not checked — no full text of the sourcecites [35] Hinton, R. B. et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ. Res. 98, 1431–1438 (2006). source
• Partly supported

  The Immunohistochemistry of TN-C and cellular composition section (page not specified in our copy) reports increased tenascin-C mRNA expression in stenotic valves, supporting the tenascin-C part of the claim. The paper does not establish increased periostin or proteoglycan production, and its discussion proposes rather than demonstrates that tenascin-C contributes to valve changes. (LLM, conf=0.88)

  cites [36] Satta, J. et al. Progression of human aortic valve stenosis is associated with tenascin-C expression. J. Am. Coll. Cardiol. 39, 96–101 (2002). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Could not verify

  The Discussion and prosthetic-valve hemodynamics sections address patient–prosthesis mismatch and outcomes after aortic valve replacement, not cell-culture mineralization. Searches for serum-induced collagen mineralization, valve interstitial cells, and alkaline phosphatase found no passage addressing the attributed claim; page numbers were not provided in our copy. (LLM, conf=0.77)

  cites [33] Price, J. et al. Prosthesis–patient mismatch is less frequent and more clinically indolent in patients operated for aortic insufficiency. J. Thorac Cardiovasc. Surg. 138, 639–645 (2009). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [34] Rattazzi, M. et al. Extracellular pyrophosphate is reduced in aortic interstitial valve cells acquiring a calcifying profile: implications for aortic valve calcification. Atherosclerosis 237, 568–576 (2014). source

In the paper

“Recent studies that used a Mendelian randomization design showed that the gene encoding apo(a) (LPA) is potentially causally related to calcific aortic valve disease48–50.”

What the sources say

• Supported

  The Statistical Analysis section describes a Mendelian randomization analysis using an LPA variant. The Discussion reports a causal association between genetically determined Lp(a) levels and aortic-valve calcification and implicates variation at the LPA locus in calcific aortic-valve disease. (LLM, conf=0.93)

  cites [48] Thanassoulis, G. et al. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 368, 503–512 (2013). This is the first large genetic study to show an association between the LPA gene and incident AS. source
• Supported

  The Abstract (page unavailable) identifies LPA as the gene coding for apolipoprotein(a) and says the authors used LPA variants in a Mendelian randomization study of aortic valve stenosis. The Mechanism of action section (page unavailable) reports increased stenosis risk with genetically elevated Lp(a) and argues that reverse causality cannot explain the association between LPA genotype and stenosis. (LLM, conf=0.91)

  cites [49] Kamstrup, P. R., Tybjaerg-Hansen, A. & Nordestgaard, B. G. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J. Am. Coll. Cardiol. 63, 470–477 (2014). source
• ?Not checked — no full text of the sourcecites [50] Arsenault, B. J. et al. Lipoprotein(a) levels, genotype and incident aortic valve stenosis: a prospective Mendelian randomization study and replication in a case–control cohort. Circ. Cardiovasc. Genet. 7, 304–310 (2014). source

In the paper

“Work conducted in vitro has shown that Ox-LDL and several oxidized phospholipid (Ox-PL) species promote the calcification of isolated vascular cells45.”

What the sources say

• Partly supported

  The ‘Effect of MM-LDL on CVC Morphology and Nodules’ section reports larger areas of calcifying condensations in cultured vascular cells treated with minimally oxidized LDL. The ‘Effect of Ox-PAPC and Iso-PGE2 on Alkaline Phosphatase Activity’ section reports that ox-PAPC increased a marker of osteoblastic differentiation, but it does not show calcification promoted by several distinct oxidized phospholipid species. The available passages have no page numbers. (LLM, conf=0.87)

  cites [45] Parhami, F. et al. Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler. Thromb. Vasc. Biol. 17, 680–687 (1997). sourceExperimental — accuracy not yet measured

In the paper

“Therefore, the production of peroxide and superoxide anions, in the vicinity of calcified areas might participate in the production of oxidatively-modified lipid species with osteogenic properties43.”

What the sources say

• Partly supported

  The Discussion section “Reactive oxygen species are increased in calcified regions of stenotic valves” (page unavailable) reports elevated superoxide and hydrogen peroxide near calcified valve regions. It speculates that oxidative stress may contribute to calcification, but does not say these species produce oxidatively modified lipids with osteogenic properties. (LLM, conf=0.85)

  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). sourceExperimental — accuracy not yet measured

In the paper

“The burden of calcific AS in the community is expected to increase over the next decades owing to population aging and the lack of a prevention strategy aimed at reducing disease progression.”

What the sources say

• Supported

  The Introduction predicts that population aging will substantially increase the number of people with aortic stenosis. The Discussion and Conclusions also state that no medical treatment currently prevents valve calcification or effectively slows the development of aortic stenosis. (LLM, conf=0.93)

  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 introductory passage following Conclusions (pp. 1002–12) expects the public-health impact of aortic stenosis to increase as populations age. The Results also projects more elderly patients with symptomatic severe aortic stenosis in 2025 and 2050. Our copy does not identify the absence of a prevention strategy that slows progression as a reason for that increase. (LLM, conf=0.88)

  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

“To support the increased biomechanical load, the myocyte growth must be accompanied by coordinated increases in the surrounding architecture of connective tissue as well as the capillary and nerve networks114.”

What the sources say

• Supported

  The “Hypertrophy and Connective Tissue” section states that supporting an increased biomechanical load requires coordinated increases in connective tissue architecture and capillary and nerve networks. The paper also identifies aortic stenosis as a pressure-overload condition in which myocytes hypertrophy. (LLM, conf=0.95)

  cites [114] Lorell, B. H. & Carabello, B. A. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 102, 470–479 (2000). source

In the paper

“Additionally, hypertension, and particularly systolic hypertension, is highly prevalent in these patients, affecting 30–70% of those with AS94;143;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
• Supported

  Table 1 (p. 294) reports hypertension in 141 of 208 patients with moderate or severe aortic stenosis (about 68%) and systolic pressure above 140 mm Hg in 101 (about 49%). Both fall within the cited 30–70% range. The paper also describes hypertension as a frequent association of degenerative aortic stenosis in its Patients section. (LLM, conf=0.90)

  cites [143] Briand, M. et al. Reduced systemic arterial compliance impacts significantly on left ventricular afterload and function in aortic stenosis: implications for diagnosis and treatment. J. Am. Coll. Cardiol. 46, 291–298 (2005). 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

“In particular, the presence of elevated plasma Lp(a) (>50 mg per dL; the upper normal limit is <30 mg per dL)) is associated with a twofold faster stenosis progression51.”

What the sources say

• Partly supported

  The progression results (page unavailable) associate the top Lp(a) tertile (>58.5 mg/dL) with faster stenosis progression, but the measured rates were 0.26 versus 0.17 m/s/year—not twofold faster. The paper’s approximately twofold figure refers instead to the odds of being a rapid progressor. Our copy does not establish <30 mg/dL as an upper normal limit. (LLM, conf=0.91)

  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

In the paper

“In the more advanced stages of the disease, the increased LV filling pressures lead to secondary pulmonary hypertension and dyspnoea symptoms126;127.”

What the sources say

• ?Not checked — no full text of the sourcecites [126] Mutlak, D. et al. Frequency determinants and outcome of pulmonary hypertension in patients with aortic valve stenosis. Am. J. Med. Sci. 343, 397–401 (2012). source
• Partly supported

  The “Exercise PHT in AS” section (p. 9) explains that increased LV filling pressure can be transmitted to the pulmonary circulation and trigger exercise pulmonary hypertension. The study concerns asymptomatic patients and does not establish that this mechanism causes dyspnoea symptoms in advanced AS. (LLM, conf=0.86)

  cites [127] Lancellotti, P. et al. Determinants and prognostic significance of exercise pulmonary hypertension in asymptomatic severe aortic stenosis. Circulation 126, 851–859 (2012). sourceExperimental — accuracy not yet measured

In the paper

“In both individuals with a bicuspid valve and those with a tricuspid valve, age is a powerful risk factor for AS9;133.”

What the sources say

• Partly supported

  The Abstract reports that age was associated with degenerative aortic valve disease, with roughly twice the risk per decade. But the Results state that people with bicuspid aortic valves were excluded, so this paper does not support the claim for both bicuspid and tricuspid valves. Its analyzed outcome also combined aortic sclerosis and stenosis rather than stenosis alone. (LLM, conf=0.89)

  cites [9] Stewart, B. F. et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J. Am. Coll. Cardiol. 29, 630–634 (1997). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [133] Mohty, D. et al. Age-related differences in the pathogenesis of calcific aortic stenosis: the potential role of resistin. Int. J. Cardiol. 142, 126–132 (2010). source

In the paper

“The pattern and magnitude of LV hypertrophic remodelling is influenced not only by AS severity but also by several other factors including age, sex, genetic factors, metabolic factors and the coexistence of coronary artery disease or hypertension116–119.”

What the sources say

• Partly supported

  The Summary reports that sex affects the pattern of left ventricular hypertrophy in aortic stenosis, and the ‘Response of the Left Ventricle to Aortic Stenosis’ section links valve obstruction to hypertrophy. The paper studies patients aged 60 or older but says an age-related contribution is only possible; it does not establish effects of genetic or metabolic factors, coexisting coronary artery disease, or coexisting hypertension on remodelling in these patients. Page numbers are not provided for these passages in our copy. (LLM, conf=0.89)

  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
• ?Not checked — no full text of the sourcecites [117] Pagé, A. et al. Metabolic syndrome is associated with more pronounced impairment of LV geometry and function in patients with calcific aortic stenosis: a substudy of the ASTRONOMER trial (Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin). J. Am. Coll. Cardiol. 55, 1867–1874 (2010). source
• ?Not checked — no full text of the sourcecites [118] Lund, B. P. et al. Effect of obesity on left ventricular mass and systolic function in patients with asymptomatic aortic stenosis (a Simvastatin Ezetimibe in Aortic Stenosis [SEAS] substudy). Am. J. Cardiol. 105, 1456–1460 (2010). source
• Partly supported

  The Introduction (page not available in our copy) identifies AS-related pressure overload, blood pressure, and sex as influences on LV remodelling. The Discussion and Conclusion report an additional association with diabetes, a metabolic factor. The paper does not establish genetic factors, age, or coexisting coronary artery disease as influences on the pattern or magnitude of remodelling; it adjusts for age and coronary disease instead. (LLM, conf=0.86)

  cites [119] Lindman, B. R. et al. The adverse impact of diabetes mellitus on left ventricular remodeling and function in patients with severe aortic stenosis. Circ. Heart Fail 4, 286–292 (2011). sourceExperimental — accuracy not yet measured

In the paper

“In pressure overload cardiomyopathies, there is an early and selective alteration of the shortening of myocardial fibers within the subendocardial layer where ischaemia and fibrosis are generally more pronounced (Figure 5)128–130.”

What the sources say

• ?Not checked — no full text of the sourcecites [128] Dumesnil, J. G., Shoucri, R. M., Laurenceau, J. L. & Turcot, J. A mathematical model of the dynamic geometry of the intact left ventricle and its application to clinical data. Circulation 59, 1024–1034 (1979). source
• ?Not checked — no full text of the sourcecites [129] Lancellotti, P. et al. Risk stratification in asymptomatic moderate to severe aortic stenosis: the importance of the valvular, arterial and ventricular interplay. Heart 96, 1364–1371 (2010). This is a prospective study that shows the prognostic value of valve stenosis severity, valvulo-arterial impedance, left ventricular longitudinal function and left atrial dilation in patients with calcific aortic stenosis. source
• Partly supported

  The Discussion (page not provided) says that longitudinal strain can reveal subtle myocardial abnormalities in aortic stenosis before conventional measures do, and reports an association between strain and fibrosis. It does not establish selective early impairment of subendocardial fiber shortening or say that ischemia and fibrosis are more pronounced in that layer; its evidence is also specific to aortic stenosis rather than pressure-overload cardiomyopathies generally. (LLM, conf=0.83)

  cites [130] Kusunose, K. et al. Incremental prognostic value of left ventricular global longitudinal strain in patients with aortic stenosis and preserved ejection fraction. Circ. Cardiovasc. Imaging 7, 938–945 (2014). sourceExperimental — accuracy not yet measured

In the paper

“The mechanical signal generated by increased LV systolic pressure initiates a cascade of biological events, including re-expression of immature fetal genes, which lead to coordinated cardiac growth in patients with AS114.”

What the sources say

• Partly supported

  In “Pathogenesis of Load-Induced Hypertrophy” (page not provided), the review says a mechanical signal is generally believed to initiate a cascade leading to cardiac growth, and it describes fetal-gene re-expression in hypertrophy, including in aortic stenosis. The citing sentence presents that proposed mechanism as established and specifically attributes its initiation to increased LV systolic pressure in AS patients; the passage does not establish that specific causal sequence. (LLM, conf=0.84)

  cites [114] Lorell, B. H. & Carabello, B. A. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 102, 470–479 (2000). sourceExperimental — accuracy not yet measured

In the paper

“In patients with calcific AS, LV concentric remodelling or hypertrophy has been linked to worse myocardial function and increased risk of cardiac events and mortality compared to patients with normal LV geometry or with LV eccentric hypertrophy120–122.”

What the sources say

• ?Not checked — no full text of the sourcecites [120] Cramariuc, D. et al. Low-flow aortic stenosis in asymptomatic patients: valvular arterial impedance and systolic function from the SEAS substudy. JACC Cardiovasc. Imaging 2, 390–399 (2009). source
• ?Not checked — no full text of the sourcecites [121] Cioffi, G. et al. Prognostic value of inappropriately high left ventricular mass in asymptomatic severe aortic stenosis. Heart 97, 301–307 (2011). source
• Partly supported

  The Outcomes: Propensity-Matched Patients section (page unavailable) reports higher early postoperative mortality and cardiac morbidity with concentric than nonconcentric geometry, including higher mortality than with eccentric hypertrophy. The study did not isolate patients with calcific aortic stenosis, and comparisons with normal geometry were not statistically significant. Its baseline description says patients with concentric geometry had better-preserved LV function, although the Comment discusses possible diastolic dysfunction; it therefore does not establish worse myocardial function as claimed. (LLM, conf=0.88)

  cites [122] Duncan, A. I. et al. Influence of concentric left ventricular remodeling on early mortality after aortic valve replacement. Ann. Thorac Surg. 85, 2030–2039 (2008). sourceExperimental — accuracy not yet measured

In the paper

“Several studies suggest that a genetic component is involved in promoting calcific AS associated with bicuspid or tricuspid aortic valves6;17;48;145.”

What the sources say

• Supported

  The Genetic epidemiology section reports strong evidence that bicuspid aortic valves are heritable. It also describes geographic clustering and familial aggregation of aortic valve stenosis in studies that included patients without bicuspid valves. The authors caution that shared genes have not been distinguished from shared environmental factors, consistent with the claim’s tentative wording. (LLM, conf=0.86)

  cites [6] Bosse, Y., Mathieu, P. & Pibarot, P. Genomics: the next step to elucidate the etiology of calcific aortic valve stenosis. J. Am. Coll. Cardiol. 51, 1327–1336 (2008). source
• Supported

  The Discussion (p. 4) describes familial clustering of calcific aortic valve stenosis in patients with tricuspid valves and says it suggests a major genetic trait. The Clinical Perspective (p. 5) also notes demonstrated familial inheritance of bicuspid valve disease. Together, these support the citing sentence’s hedged claim of a genetic component. (LLM, conf=0.89)

  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
• Partly supported

  The Discussion (page not provided) reports familial clustering of calcific valvular disease and genetic findings involving bicuspid aortic valves. The Conclusions (page not provided) associate variation at the LPA locus with aortic-valve calcification and incident clinical aortic stenosis. Our copy does not establish the claim specifically for calcific stenosis of tricuspid aortic valves. (LLM, conf=0.84)

  cites [48] Thanassoulis, G. et al. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 368, 503–512 (2013). This is the first large genetic study to show an association between the LPA gene and incident AS. sourceExperimental — accuracy not yet measured
• ?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

“A BNP ratio of >1 was found to be a powerful independent predictor of mortality in AS, even in patients with asymptomatic AS187.”

What the sources say

• Supported

  The Conclusions (article pp. 2016–2025) define BNP clinical activation as a level above the individual upper limit of normal and call it a powerful, independent predictor of long-term mortality. The same passage says its predictive value was particularly evident in asymptomatic patients with normal ejection fraction and no history of myocardial infarction. (LLM, conf=0.94)

  cites [187] Clavel, M. A. et al. B-type natriuretic peptide clinical activation in aortic stenosis: impact on long-term survival. J. Am. Coll. Cardiol. 63, 2016–2025 (2014). This study shows the prognostic value of plasma BNP in patients with calcific AS. It also shows the importance of standardizing the measured level of BNP against the normal reference value for the patient's age and sex. source

In the paper

“several randomized trials showed no effect of statins on haemodynamic progression or AS-related clinical events152–154.”

What the sources say

• Partly supported

  The disease-progression results report no effect of atorvastatin on aortic-jet velocity, supporting the haemodynamic part of the claim. The adverse-events discussion says there was no demonstrable effect on clinical endpoints, but the trial was not powered to assess them and could not rule out a significant reduction; stating that it showed no effect on AS-related clinical events is too definitive. This paper reports one trial, not the results of the several trials cited in the sentence. (LLM, conf=0.87)

  cites [152] Cowell, S. J. et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N. Engl. J. Med. 352, 2389–2397 (2005). sourceExperimental — accuracy not yet measured
• Supported

  In Effect on Progression (page not provided), the simvastatin–ezetimibe and placebo groups had similar changes in peak aortic-jet velocity, a measure of haemodynamic progression. Outcome Measures (page not provided) reports no significant difference in aortic-valve-related events. This paper supports the claim as one of the cited randomized trials, though it tested simvastatin combined with ezetimibe rather than a statin alone. (LLM, conf=0.91)

  cites [153] Rossebo, A. B. et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N. Engl. J. Med. 359, 1343–1356 (2008). This is a randomized clinical trial that reports no effect of statins on the progression and the outcomes of calcific AS. source
• ?Not checked — no full text of the sourcecites [154] Chan, K. L., Teo, K., Dumesnil, J. G., Ni, A. & Tam, J. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 121, 306–314 (2010). source

In the paper

“Emerging blood biomarkers, such high-sensitivity cardiac troponin194;195, growth/differentiation factor 15, soluble interleukin-1 receptor-like 1 (also called protein ST2) and micro RNAs196–198, might be helpful to detect subclinical and/or irreversible myocardial dysfunction”

What the sources say

• Supported

  The citation to this paper is attached to high-sensitivity cardiac troponin, not the other biomarkers in the sentence. The Discussion (page unavailable) describes high-sensitivity troponin I as a potential early marker of left-ventricular decompensation in patients with aortic stenosis and reports its association with replacement myocardial fibrosis. That supports the citing sentence’s cautious claim that it might help detect subclinical or irreversible myocardial dysfunction. (LLM, conf=0.90)

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

  The Introduction and Discussion (page numbers unavailable) describe circulating microRNAs as potential blood biomarkers for left ventricular hypertrophy in patients with aortic stenosis, and report an association between miR-378 and left ventricular mass. They do not establish that microRNAs detect subclinical or irreversible myocardial dysfunction. This paper also does not address the other biomarkers in the sentence, which are cited separately. (LLM, conf=0.82)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) says irreversible myocardial damage may precede symptoms in aortic stenosis and presents circulating microRNAs as potential cardiovascular biomarkers. The Discussion (page unavailable) reports that miR-210 adds prognostic information, but the paper does not show that it detects subclinical or irreversible myocardial dysfunction. This citation is attached to microRNAs, not to the other biomarkers listed in the sentence. (LLM, conf=0.82)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction identifies GDF15, soluble ST2 and high-sensitivity troponin as biomarkers of cardiovascular stress, and the Results (Biomarkers and tissue fibrosis and inflammation; page unavailable) link some of them to myocardial fibrosis or inflammation. The paper does not assess microRNAs or establish that these biomarkers detect subclinical or irreversible myocardial dysfunction; its study concerns patients with aortic stenosis undergoing valve replacement. (LLM, conf=0.84)

  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). sourceExperimental — accuracy not yet measured

In the paper

“there is no pharmacotherapy specifically targeting AS to prevent progressive leaflet calcification or to delay time to valve replacement3;199.”

What the sources say

• Partly supported

  Section 3.2 (Aortic Stenosis; page not provided) says three large trials found no benefit from statins for progression of calcific aortic stenosis and recommends against statins for that purpose. It does not establish the broader claim that no pharmacotherapy can prevent leaflet calcification or delay valve replacement. (LLM, conf=0.83)

  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

  The Medical Therapy section (page unavailable) states that no medical therapies currently delay progression of calcific aortic stenosis. Its valve-focused subsection describes leaflet calcification and reports that statins do not slow disease progression or reduce aortic valve events, supporting the claim that pharmacotherapy does not prevent progression or delay the need for replacement. (LLM, conf=0.90)

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

In the paper

“A large study using a Mendelian randomization design identified the single nucleotide polymorphism (SNP) rs10455872 in the LPA gene as the only genome-wide significant SNP associated with the presence of aortic valve calcification and clinical calcific AS48.”

What the sources say

• Supported

  The Results (SNPs Associated with Aortic-Valve Calcification; page not provided) identify rs10455872 in LPA as the one SNP reaching genome-wide significance for aortic-valve calcification. The Discussion reports its association with clinical aortic stenosis in two prospective cohorts and describes the Mendelian randomization analysis. (LLM, conf=0.90)

  cites [48] Thanassoulis, G. et al. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 368, 503–512 (2013). This is the first large genetic study to show an association between the LPA gene and incident AS. source

In the paper

“So far, variants of NOTCH1 and GATA binding protein 5 (GATA5) have been associated with bicuspid aortic valves in humans97;146;147.”

What the sources say

• ?Not checked — no full text of the sourcecites [97] Garg, V. et al. Mutations in NOTCH1 cause aortic valve disease. Nature 437, 270–274 (2005). This is the first study to report that mutations in NOTCH1 cause both development of bicuspid aortic valve and calcification of aortic valve. source
• Partly supported

  The Introduction states that NOTCH1 mutations had been linked to bicuspid aortic valve in humans, but says NOTCH1 was the only gene linked at the time. The Abstract reports that Gata5 deletion caused bicuspid aortic valve in mice and identifies GATA5 only as a potential human disease gene; it does not establish an association between GATA5 variants and human bicuspid aortic valve. (LLM, conf=0.89)

  cites [146] Laforest, B., Andelfinger, G. & Nemer, M. Loss of Gata5 in mice leads to bicuspid aortic valve. J. Clin. Invest. 121, 2876–2887 (2011). sourceExperimental — accuracy not yet measured
• Supported

  The paper’s introductory passage reports NOTCH1 mutations associated with BAV, and the Abstract reports GATA5 mutations identified in two families with BAV. Both support the claimed association in humans. (LLM, conf=0.93)

  cites [147] Shi, L. M. et al. GATA5 loss-of-function mutations associated with congenital bicuspid aortic valve. Int. J. Mol. Med. 33, 1219–1226 (2014). source

In the paper

“Studies have shown that different cut-off values of aortic valve calcium score (AU) should be used in women (>1200 AU) compared with men (>2000 AU) to identify haemodynamically severe stenosis169;170.”

What the sources say

• Partly supported

  The AS grading results and Table 4 report sex-specific aortic valve calcium thresholds for identifying severe stenosis. They give best cutoffs of approximately 1,275 AU for women and 2,065 AU for men, rather than the cited >1,200 and >2,000 AU; those figures are close but not the thresholds this paper reports. (LLM, conf=0.86)

  cites [169] Clavel, M. A. et al. The complex nature of discordant severe calcified aortic valve disease grading: new insights from combined doppler-echocardiographic and computed tomographic study. J. Am. Coll. Cardiol. 62, 2329–2338 (2013). This is a multicentre study showing the usefulness of aortic valve calcium scoring by MDCT to corroborate the stenosis severity in patients with discordant findings at echocardiography. sourceExperimental — accuracy not yet measured
• Partly supported

  The Methods (MDCT Measurements; page unavailable) and Discussion (AVC in AS; page unavailable) support sex-specific calcium thresholds for identifying severe haemodynamic aortic stenosis. They give ≥1,274 AU for women and ≥2,065 AU for men, however, not the cited >1,200 and >2,000 AU cut-offs. (LLM, conf=0.87)

  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

“However, three randomized clinical trials (RCTs) failed to demonstrate any significant benefit of LDL lowering with statins on the progression of AS152–154.”

What the sources say

• Supported

  The Discussion passage labeled “adverse events” reports that this randomized, placebo-controlled trial substantially lowered LDL cholesterol with atorvastatin but did not halt or reverse aortic-stenosis progression. This source supports one of the three trials cited in the sentence; it need not establish the results of the other two. (LLM, conf=0.93)

  cites [152] Cowell, S. J. et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N. Engl. J. Med. 352, 2389–2397 (2005). source
• Supported

  The Discussion reports that the randomized SEAS trial substantially lowered LDL cholesterol with simvastatin plus ezetimibe but found no effect on aortic-stenosis progression. This paper supports the claim as one of the three trials cited, not as evidence that it itself reports three such trials. (LLM, conf=0.93)

  cites [153] Rossebo, A. B. et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N. Engl. J. Med. 359, 1343–1356 (2008). This is a randomized clinical trial that reports no effect of statins on the progression and the outcomes of calcific AS. source
• ?Not checked — no full text of the sourcecites [154] Chan, K. L., Teo, K., Dumesnil, J. G., Ni, A. & Tam, J. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 121, 306–314 (2010). source

In the paper

“NOTCH1 mutations explain approximately 4% of sporadic cases of AS that occurs in the context of a bicuspid aortic valve148;149.”

What the sources say

• Partly supported

  The Discussion reports NOTCH1 mutations in approximately 4% of sporadic bicuspid aortic valve (BAV) cases. It does not establish that 4% figure specifically for sporadic aortic stenosis (AS) occurring with BAV; the paper's Methods distinguish AS from other BAV presentations. (LLM, conf=0.88)

  cites [148] Foffa, I. et al. Sequencing of NOTCH1, GATA5, TGFBR1 and TGFBR2 genes in familial cases of bicuspid aortic valve. BMC Med. Genet. 14, 44 (2013). sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports NOTCH1 mutations in two sporadic cases of bicuspid aortic valve disease. It does not say that mutations explain approximately 4% of sporadic AS cases with a bicuspid valve; this study examined patients with tricuspid AS. Page numbers are not provided in our copy. (LLM, conf=0.85)

  cites [149] Ducharme, V., Guauque-Olarte, S., Pibarot, P., Mathieu, P. & Bossé, Y. NOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis. J. Heart Valve Dis. 22, 142–149 (2013).Experimental — accuracy not yet measured

In the paper

“However, the combination of simvastatin (drug that lowers plasma LDL cholesterol levels) and ezetimibe (drug that decreases cholesterol absorption in the small intestine) did reduce ischaemic cardiovascular events in patients with mild to moderate AS153.”

What the sources say

• Supported

  The Outcome Measures section reports significantly fewer ischemic cardiovascular events with simvastatin–ezetimibe than with placebo (15.7% versus 20.1%; P=0.02). The Patient Population section specifies asymptomatic, mild-to-moderate aortic-valve stenosis. Page numbers were not supplied. (LLM, conf=0.94)

  cites [153] Rossebo, A. B. et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N. Engl. J. Med. 359, 1343–1356 (2008). This is a randomized clinical trial that reports no effect of statins on the progression and the outcomes of calcific AS. source

In the paper

“those with severe AS who present with symptoms and/or LV systolic dysfunction (defined as a LVEF of <50%) have a firm (Class I, Box 1) indication for AVR”

What the sources say

• Partly supported

  Section 3.2.3 (page not provided) gives Class I AVR recommendations for symptomatic severe AS (stage D1) and for asymptomatic severe AS (stage C2) with LVEF below 50%, subject to specified valve and hemodynamic criteria. The claim is too broad: the same section classifies AVR for symptomatic low-flow/low-gradient severe AS with reduced LVEF (stage D2) as Class IIa, not Class I. (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. sourceExperimental — accuracy not yet measured
• Partly supported

  Section 5.4.1 strongly recommends early valve replacement for symptomatic patients with severe aortic stenosis who are candidates for surgery. It also says surgery is indicated for asymptomatic patients with depressed LV function, but only when the dysfunction is not due to another cause; Figure 2 uses LVEF <50% in its management pathway. The claim omits those qualifications and therefore states the indication more broadly than the guideline does. (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

“Balloon-expandable and self-expanding transcatheter valves have been the most rigorously studied to date, specifically the CoreValve (Medtronic, Dublin, Ireland) and SAPIEN (Edwards, Irvine CA, USA) valves”

What the sources say

• Partly supported

  The Study Device and Procedure section (p. 3) identifies SAPIEN as balloon-expandable, and the paper reports a randomized trial using it. The References (p. 11) identify CoreValve as self-expanding, but the paper does not establish that CoreValve and SAPIEN were the most rigorously studied valves. (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
• Partly supported

  The Methods and Study Device and Procedure sections describe a randomized trial of the balloon-expandable Edwards SAPIEN valve. The References list studies of the self-expanding CoreValve, but this paper neither studies CoreValve nor says that CoreValve and SAPIEN were the most rigorously studied valves. The comparative claim is therefore unsupported by this source. (LLM, conf=0.84)

  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
• Partly supported

  The Study Procedures section identifies CoreValve as the self-expanding prosthesis tested in this trial, and the Conclusions passage discusses prior studies of balloon-expandable valves. The copy does not name SAPIEN or say that CoreValve and SAPIEN were the most rigorously studied valves. Page numbers are not provided in the indexed passages. (LLM, conf=0.85)

  cites [221] Adams, D. H. et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N. Engl. J. Med. 370, 1790–1798 (2014). This randomized clinical trial shows the superiority of TAVR compared with surgical AVR in patients with intermediate or high surgical risk. sourceExperimental — accuracy not yet measured
• Partly supported

  The Study device and Study design sections identify CoreValve as a self-expanding valve evaluated in a multicenter trial. The Discussion also compares its results with studies of SAPIEN. The paper does not establish that CoreValve and SAPIEN were the most rigorously studied transcatheter valves; pages are not specified in our copy. (LLM, conf=0.82)

  cites [224] Popma, J. J. et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J. Am. Coll. Cardiol. 63, 1972–1981 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  The Patients and Study Devices and Procedures sections identify SAPIEN as balloon-expandable and CoreValve as self-expanding; the Results section reports their use in 3,195 registry patients. The paper does not establish that these were the most rigorously studied transcatheter valves relative to other devices. (LLM, conf=0.85)

  cites [226] Gilard, M. et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N. Eng. J. Med. 366, 1705–1715 (2012). sourceExperimental — accuracy not yet measured
• Supported

  The Abstract (page not provided) identifies SAPIEN as balloon-expandable and CoreValve as self-expanding, describes them as the two devices under post-marketing surveillance in Europe, and notes a substantial body of TAVI outcome data. The Methods and Results (pages not provided) study both devices in a large registry, supporting the broad description of them as the most studied valves. (LLM, conf=0.83)

  cites [231] Moat, N. E. et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis the U. K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) registry. J. Am. Coll. Cardiol. 58, 2130–2138 (2011). source
• ?Not checked — no full text of the sourcecites [232] Walther, T. et al. Perioperative results and complications in 15,964 transcatheter aortic valve replacements: prospective data from the GARY registry. J. Am. Coll. Cardiol. 65, 2173–2180 (2015). source

In the paper

“Despite increasing age and comorbidities, the mortality associated with AVR has decreased dramatically during the past two decades208;209.”

What the sources say

• Partly supported

  The Trends in Mortality section and Table 2 report that mortality for isolated aortic valve surgery fell from 5.6% to 4.4%, while Trends in Patient Demographics reports increasing age and several worsening risk factors. The study covers 1993–2007, however, so it supports a decline over 15 years, not the claimed two decades. (LLM, conf=0.86)

  cites [208] Lee, R. et al. Fifteen-year outcome trends for valve surgery in North America. Ann. Thorac Surg. 91, 677–684 (2011). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and Discussion report that mortality after isolated AVR fell despite increasing age, comorbidities, and predicted risk. But this study covers 1997–2006, a 10-year period, not the two decades claimed. (LLM, conf=0.88)

  cites [209] Brown, J. M. et al. Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database. J. Thorac Cardiovasc. Surg. 137, 82–90 (2009). sourceExperimental — accuracy not yet measured

In the paper

“For an isolated AVR, the overall 30-day mortality rate is currently under 3% as reported in the Society of Thoracic Surgeons (STS) database and German Aortic Valve Registry (GARY)209;210.”

What the sources say

• Partly supported

  Table 4 reports 2.6% observed mortality for isolated AVR in the STS database in 2006, supporting the under-3% figure. But the End Points section specifies that this study measured in-hospital mortality and did not analyze postdischarge 30-day mortality, so it does not establish the claimed 30-day rate. The German registry is associated with a separate citation and is not assessed here. (LLM, conf=0.90)

  cites [209] Brown, J. M. et al. Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database. J. Thorac Cardiovasc. Surg. 137, 82–90 (2009). sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract (Methods and results) and Results (Peri-operative outcome, Table 4; page unavailable) report 2.1% mortality for conventional AVR without concomitant bypass surgery, which is under 3%. They identify this as in-hospital mortality, not 30-day mortality, so GARY does not establish the claimed 30-day rate. (LLM, conf=0.88)

  cites [210] Hamm, C. W. et al. The German Aortic Valve registry (GARY): in-hospital outcome. Eur. Heart J. 35, 1588–1598 (2014). sourceExperimental — accuracy not yet measured

In the paper

“Increasing age and comorbidities substantially increase both operative and long-term mortality after AVR217;218.”

What the sources say

• Partly supported

  The Discussion identifies age, renal failure, diabetes, hypertension, and other conditions as predictors of in-hospital mortality after aortic and/or mitral valve surgery. The Patients section defines the outcome as death before discharge; the paper does not assess long-term mortality. Its population also includes valve repair and mitral surgery, not only aortic valve replacement. (LLM, conf=0.90)

  cites [217] Ambler, G. et al. Generic, simple risk stratification model for heart valve surgery. Circulation 112, 224–231 (2005). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [218] Ashikhmina, E. A. et al. Aortic valve replacement in the elderly: determinants of late outcome. Circulation 124, 1070–1078 (2011). source

In the paper

“There has been a shift away from mechanical valves toward greater use of bioprosthetic valves, particularly in patients >65 years of age (Figure 12)209.”

What the sources say

• Partly supported

  The Results (page not provided) report that bioprosthetic valve use rose to 78.4% while mechanical valve use fell to 20.5%, supporting the overall shift. The Discussion links valve choice to an aging patient population, but our copy does not establish that the shift was particularly pronounced among patients over 65. (LLM, conf=0.85)

  cites [209] Brown, J. M. et al. Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database. J. Thorac Cardiovasc. Surg. 137, 82–90 (2009). sourceExperimental — accuracy not yet measured

In the paper

“Approximately two-thirds (56–75%) of TAVR procedures are performed via a transfemoral approach226–229.”

What the sources say

• Supported

  The Procedural Characteristics section reports that 74.6% of patients in this registry underwent TAVI via a transfemoral approach. That figure falls within the cited 56–75% range and supports the claim that the approach accounted for approximately two-thirds of procedures. (LLM, conf=0.93)

  cites [226] Gilard, M. et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N. Eng. J. Med. 366, 1705–1715 (2012). source
• ?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 Abstract (page unavailable) reports 1,521 transfemoral procedures among 2,621 PARTNER-I TAVR patients, or about 58%, which falls within the claimed range. It does not establish the full 56–75% range or show that this proportion applies to TAVR procedures generally. (LLM, conf=0.86)

  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

“The most notable has been paravalvular aortic regurgitation234–236.”

What the sources say

• Partly supported

  The Background calls aortic regurgitation an important limitation of TAVR, and the Conclusions describe it as a frequent complication with adverse prognostic implications. The paper discusses paravalvular leak, but does not establish that it is the most notable TAVR complication; its study limitations also say that paravalvular and valvular regurgitation were not precisely distinguished. (LLM, conf=0.83)

  cites [234] Athappan, G. et al. Incidence, predictors, and outcomes of aortic regurgitation after transcatheter aortic valve replacement: meta-analysis and systematic review of literature. J. Am. Coll. Cardiol. 61, 1585–1595 (2013). sourceExperimental — accuracy not yet measured
• Supported

  The Conclusions (page not available in our copy) call paravalvular leak the new “Achilles’ heel” of TAVR because of its association with mortality. This supports describing paravalvular aortic regurgitation as a particularly notable TAVR complication. (LLM, conf=0.90)

  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
• Partly supported

  The Abstract describes paravalvular regurgitation as a frequent, important complication of TAVR associated with increased mortality. It does not establish that it is the most notable complication relative to others. (LLM, conf=0.83)

  cites [236] Pibarot, P., Hahn, R. T., Weissman, N. J. & Monaghan, M. J. Assessment of paravalvular regurgitation following TAVR: a proposal of unifying grading scheme. JACC Cardiovasc. Imaging 8, 340–360 (2015). sourceExperimental — accuracy not yet measured

In the paper

“For patients at high or prohibitive risk of operative mortality, with surgical AVR, TAVR has been a transformative innovation, providing a life-saving treatment for patients who were previously not candidates for AVR”

What the sources say

• Partly supported

  The Results (p. 1) show that TAVI reduced one-year mortality compared with standard therapy among patients who were not suitable candidates for surgery, supporting the life-saving characterization for that group. The Discussion (p. 10) explicitly says these results cannot be extrapolated to other patients and calls for trials in high-risk patients for whom surgery remains a viable option; this paper therefore does not establish the claim for that broader group. (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
• Supported

  The Background (page not available) states that TAVR reduces mortality in high-risk patients who are not candidates for surgical replacement. The Results (page not available) report improved one-year survival in that group, while this paper’s Abstract reports similar one-year survival with TAVR and surgery among high-risk patients who remained surgical candidates. (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). source
• Supported

  The Conclusions section says many patients are unsuitable for surgical replacement because of operative risk and reports that TAVR improves survival versus medical therapy in patients who cannot undergo surgery. The Results also show lower one-year mortality with TAVR than with surgery in patients at increased surgical risk. Together, these support the citing sentence's substantive claim; “transformative” is the citing authors’ characterization. (LLM, conf=0.86)

  cites [221] Adams, D. H. et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N. Engl. J. Med. 370, 1790–1798 (2014). This randomized clinical trial shows the superiority of TAVR compared with surgical AVR in patients with intermediate or high surgical risk. source
• ?Not checked — no full text of the sourcecites [222] Kapadia, S. R. et al. 5-year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 385, 2485–2491 (2015). source
• ?Not checked — no full text of the sourcecites [223] Mack, M. J. et al. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 385, 2477–2484 (2015). source
• Partly supported

  The Abstract says that some patients are not candidates for surgical valve replacement and reports that TAVR reduced 12-month mortality versus medical therapy in patients unsuitable for surgery. The Discussion reports favorable outcomes for this study’s extreme-risk patients. The paper does not establish the life-saving claim for the broader group of high-risk patients included in the citing sentence. (LLM, conf=0.82)

  cites [224] Popma, J. J. et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J. Am. Coll. Cardiol. 63, 1972–1981 (2014). sourceExperimental — accuracy not yet measured

In the paper

“a recent meta-analysis confirms that these patients have worse outcomes compared to moderate or high-gradient severe AS”

What the sources say

• Supported

  The Overall Mortality section reports that patients with low-flow, low-gradient aortic stenosis had higher mortality than patients with moderate AS (HR 1.68) or high-gradient AS (HR 1.67). The Discussion identifies the pooled analysis as a meta-analysis and concludes that paradoxical low-flow, low-gradient AS is associated with increased mortality compared with other AS subtypes with preserved LVEF. Page numbers were not available in our copy. (LLM, conf=0.94)

  cites [174] Dayan, V. et al. Outcome and impact of aortic valve replacement in patients with preserved LVEF and low-gradient aortic stenosis. J. Am. Coll. Cardiol. 66, 2594–2603 (2015). source

In the paper

“Randomized trials of balloon-expandable and self-expanding valves have also demonstrated that TAVR is a viable alternative to surgery in patients at high risk for AVR (Table 4)220;221.”

What the sources say

• Supported

  The Methods describe a randomized comparison of a balloon-expandable transcatheter valve with surgery in high-risk patients. The Discussion concludes that transcatheter replacement is an alternative to surgery in a well-chosen high-risk subgroup. This source supports the balloon-expandable trial portion of the sentence; the separate self-expanding trial is not attributed to it. (LLM, conf=0.92)

  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
• Supported

  The Methods and Results describe a randomized comparison of self-expanding TAVR with surgery in patients at increased surgical risk, with lower one-year mortality in the TAVR group. The Conclusions also report similar one-year survival with balloon-expandable TAVR and surgery in high-risk patients. Together, these passages support the claim that both types were viable alternatives to surgery. (LLM, conf=0.91)

  cites [221] Adams, D. H. et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N. Engl. J. Med. 370, 1790–1798 (2014). This randomized clinical trial shows the superiority of TAVR compared with surgical AVR in patients with intermediate or high surgical risk. source

In the paper

“and that their survival is markedly improved by AVR174.”

What the sources say

• Supported

  The SURVIVAL BENEFIT WITH AVR section reports 56% lower mortality among patients with low-flow, low-gradient aortic stenosis who underwent AVR (HR 0.44; 95% CI 0.25–0.77). The Discussion explicitly calls this a major survival benefit in patients with paradoxical low-flow, low-gradient aortic stenosis. No page number is available in our copy. (LLM, conf=0.94)

  cites [174] Dayan, V. et al. Outcome and impact of aortic valve replacement in patients with preserved LVEF and low-gradient aortic stenosis. J. Am. Coll. Cardiol. 66, 2594–2603 (2015). source

In the paper

“In patients with considerable associated mitral or tricuspid regurgitation, it is unclear whether concomitant surgical repair of the mitral or tricuspid valve at the time of AVR would improve clinical outcomes242;243.”

What the sources say

• Partly supported

  The Survival section (p. 2073) reports increased postoperative morbidity and mortality with combined mitral and aortic valve surgery, and conflicting findings about the effects of leaving moderate mitral regurgitation untreated during surgical aortic valve replacement. This supports uncertainty about the clinical benefit of concomitant mitral repair, but the paper does not address concomitant tricuspid repair. (LLM, conf=0.82)

  cites [242] Toggweiler, S. et al. Transcatheter aortic valve replacement: outcomes of patients with moderate or severe mitral regurgitation. J. Am. Coll. Cardiol. 59, 2068–2074 (2012). sourceExperimental — accuracy not yet measured
• Supported

  The Discussion’s Clinical Implications section says that how best to treat patients with concomitant mitral or tricuspid regurgitation requires further investigation. It specifically raises the possibility that adding tricuspid repair to surgical aortic valve replacement could improve outcomes and says further studies are needed to guide treatment of patients with significant TR or MR. (LLM, conf=0.88)

  cites [243] Lindman, B. R. et al. Effect of tricuspid regurgitation and the right heart on survival after transcatheter aortic valve replacement: insights from the placement of aortic transcatheter valves II inoperable cohort. Circ. Cardiovasc. Interv. 8, e002073 (2015). source

In the paper

“When there is uncertainty whether a patient will benefit clinically from valve replacement owing to markedly depressed LV function or concomitant oxygen dependent lung disease or other factors, a BAV may have diagnostic utility to determine whether valve replacement is appropriate202.”

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 [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

In the paper

“Moreover, when cause of death was difficult to categorize, it often occurred in frail patients who were failing to thrive246.”

What the sources say

• Supported

  In “Subcategories of Noncardiovascular Death,” the paper says that uncategorizable deaths among PARTNER-B patients were associated with old age, frailty, or failure to thrive. This supports the citing sentence’s account of deaths whose causes were difficult to categorize. (LLM, conf=0.90)

  cites [246] Svensson, L. G. et al. Comprehensive analysis of mortality among patients undergoing TAVR: results of the PARTNER trial. J. Am. Coll. Cardiol. 64, 158–168 (2014). source

In the paper

“In patients with severe AS undergoing non-cardiac surgery, a BAV is generally not warranted unless the patient is symptomatic or hemodynamically unstable and needs to undergo non-cardiac surgery before aortic valve replacement can be performed3.”

What the sources say

• Partly supported

  Section 3.2 (page unavailable) says balloon dilation is not recommended for most asymptomatic patients with severe aortic stenosis who need urgent noncardiac surgery. It also allows consideration of dilation as a bridge to valve replacement in severe symptomatic aortic stenosis, including patients with cardiogenic shock. Our copy does not specifically recommend it for symptomatic or unstable patients who need noncardiac surgery before valve replacement. (LLM, conf=0.82)

  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

“Among patients treated in the high-risk Cohort A of the PARTNER I trial with TAVR or surgical AVR (Table 4), death from non-cardiovascular causes was more common than death from cardiovascular causes48.”

What the sources say

• ?Could not verify

  The Methods (page unavailable) describe population-based genetic and CT studies, while the Results section on incident aortic stenosis (page unavailable) reports valve-replacement outcomes in the MDCS, not the PARTNER I trial. Searches for PARTNER I Cohort A and for cardiovascular versus non-cardiovascular deaths found no passage comparing causes of death after TAVR or surgical replacement. (LLM, conf=0.78)

  cites [48] Thanassoulis, G. et al. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 368, 503–512 (2013). This is the first large genetic study to show an association between the LPA gene and incident AS. sourceExperimental — accuracy not yet measured

In the paper

“Therefore, when lifespan or quality of life is profoundly limited by frailty, noncardiac disease, mental or physical disability, the potential benefit of AVR may be low11.”

What the sources say

• ?Could not verify

  The Significance of Aortic Valve Sclerosis section discusses cardiovascular risk and treatment of other risk factors in people with at least five years’ life expectancy, not the benefit of aortic valve replacement. Searches for frailty, disability, quality of life, and valve replacement found no passage addressing the claimed circumstances in which AVR may offer little benefit. The indexed passages provide no page numbers. (LLM, conf=0.76)

  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). sourceExperimental — accuracy not yet measured

In the paper

“Surgical AVR has excellent results with low mortality in low risk populations209.”

What the sources say

• Supported

  The Discussion (page unavailable) reports mortality below 1% in patients younger than 60 and 1.3% in those younger than 70 after isolated surgical AVR in 2006. The Results identify older age and several comorbidities as associated with higher mortality, supporting the claim that mortality is low in lower-risk populations. (LLM, conf=0.88)

  cites [209] Brown, J. M. et al. Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database. J. Thorac Cardiovasc. Surg. 137, 82–90 (2009). source

In the paper

“In older patients at high or extreme surgical risk undergoing TAVR, disease-specific and generic health status are often extremely poor221;224;244;245.”

What the sources say

• Partly supported

  Table 1 shows that the TAVR patients were older and that most had NYHA class III or IV symptoms; Study End Points says the paper assessed disease-specific and generic quality of life. But the passages do not establish that both health-status measures were often extremely poor, and Patient Selection describes increased surgical risk rather than an extreme-risk group. (LLM, conf=0.84)

  cites [221] Adams, D. H. et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N. Engl. J. Med. 370, 1790–1798 (2014). This randomized clinical trial shows the superiority of TAVR compared with surgical AVR in patients with intermediate or high surgical risk. sourceExperimental — accuracy not yet measured
• Partly supported

  Table 1 reports a mean age of 83.2 years, and the Patient enrollment results say 91.3% of these extreme-risk TAVR patients were in NYHA class III or IV at baseline, supporting poor baseline symptom status. The paper does not report disease-specific and generic health-status measures, so it does not establish that both were extremely poor; its cohort also does not establish the claim for high-risk patients generally. (LLM, conf=0.82)

  cites [224] Popma, J. J. et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J. Am. Coll. Cardiol. 63, 1972–1981 (2014). 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 baseline health-status table (p. 551) shows poor disease-specific KCCQ scores and generic physical-health scores in elderly, high-surgical-risk patients assigned to TAVR. The paper does not study an extreme-risk cohort, and its generic mental-health scores are near the population norm, so it does not support describing all generic health status as extremely poor. (LLM, conf=0.86)

  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

“Severe AS primarily impairs quality of life by causing heart failure symptoms including shortness of breath, fatigue and diminished functional capacity199;252.”

What the sources say

• Partly supported

  The 'Symptom onset' section identifies exertional dyspnea as the most common early symptom and describes declining exercise tolerance and functional capacity in adults with severe AS. The 'Heart failure' section also discusses heart failure symptoms in severe AS. Our copy does not identify fatigue or establish that these symptoms are the primary way severe AS impairs quality of life. (LLM, conf=0.85)

  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
• ?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

In the paper

“Balloon aortic valvuloplasty (BAV), which uses the pressure of an inflated balloon to widen the opening of the stenotic valve, is not a definitive therapy for AS3.”

What the sources say

• Supported

  Section 3.2 (Aortic Stenosis; page not provided) states that balloon dilation is not a substitute for aortic valve replacement in patients with AS. It describes its effects as modest and notes that restenosis and clinical deterioration occur within 6 to 12 months in most older patients, supporting the claim that it is not definitive therapy. (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

In the paper

“In particularly ill patients, BAV may be used as a ‘bridge’ to stabilize the patient prior to definitive therapy with valve replacement3.”

What the sources say

• Supported

  Section 3.2 (Aortic Stenosis) says patients with severe aortic stenosis and refractory pulmonary edema or cardiogenic shock might benefit from balloon dilation as a bridge to aortic valve replacement. It explains that improved hemodynamics may reduce the risks of subsequent valve replacement, matching the claim's qualified wording. (LLM, conf=0.93)

  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 the paper

“Given the high prevalence of frailty and disability in this patient population, the relationship between valvular stenosis and overall quality of life is also complex and variable.202”

What the sources say

• Supported

  The Geriatric Risk Stratification section describes frailty and disability as prevalent among TAVR patients and says substantial disability can limit quality-of-life gains even after technically successful valve replacement. The Anticipated Benefit of TAVR section explains that, in patients with other conditions and poor functional status, determining how much aortic stenosis contributes to symptoms and predicting benefit from treatment are difficult. Page numbers were not available in our copy. (LLM, conf=0.89)

  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. sourceExperimental — accuracy not yet measured

In the paper

“However, because patients who develop severe AS are usually older adults, these symptoms may also result, in part, from normal aging, numerous comorbidities or frailty202.”

What the sources say

• Partly supported

  The Introduction’s “Anticipated Benefit of TAVR” section distinguishes patients whose main medical problem can be ascribed to severe AS, and “Geriatric Risk Stratification” describes comorbidities and frailty as prevalent in TAVR patients. These passages support the possibility that problems other than AS contribute to patients’ condition, but they do not specifically attribute the symptoms to normal aging or establish that frailty causes those symptoms. (LLM, conf=0.80)

  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. sourceExperimental — accuracy not yet measured

In the paper

“The way in which coronary disease should influence decisions between valve replacement with TAVR versus surgical valve replacement is also unclear in some scenarios.”

What the sources say

• Supported

  The review’s discussion of CAD and valve-replacement outcomes (JACC 62:1–10) says data directly comparing TAVR and surgical valve replacement, including their coronary-disease management strategies, are limited. Its Future Directions section describes ongoing trials comparing the two approaches, supporting the claim that the choice remains unclear in some scenarios. (LLM, conf=0.92)

  cites [247] Goel, S. S. et al. Severe aortic stenosis and coronary artery disease — implications for management in the transcatheter aortic valve replacement era: a comprehensive review. J. Am. Coll. Cardiol. 62, 1–10 (2013). source
• Partly supported

  The Discussion (page unavailable) says it is debated whether the extent and complexity of coronary artery disease affect outcomes after TAVI, and contrasts TAVI patients with those undergoing surgical replacement. It does not directly address how coronary disease should determine the choice between TAVI and surgery; its stated uncertainty concerns outcomes and revascularization strategy among TAVI patients. (LLM, conf=0.83)

  cites [248] Stefanini, G. G. et al. Coronary artery disease severity and aortic stenosis: clinical outcomes according to SYNTAX score in patients undergoing transcatheter aortic valve implantation. Eur. Heart J. 35, 2530–2540 (2014). sourceExperimental — accuracy not yet measured

In the paper

“The association between moderate or severe paravalvular aortic regurgitation and increased mortality has been clearly established”

What the sources say

• Supported

  The Impact on Clinical Outcomes section reports that several studies identified moderate-or-worse aortic regurgitation as a predictor of mortality, and a registry found higher late mortality with moderate-or-worse paravalvular leak. The Conclusions section also describes moderate-to-severe paravalvular leak as a predictor of worse outcomes. The paper questions whether the relationship is causal, but the claim concerns association, not causation; page numbers were not provided. (LLM, conf=0.90)

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

  The Discussion reports that postprocedural paravalvular AR of grade ≥2 was the strongest predictor of one-year mortality after TAVR. The Impact of AR on Mortality section also reports higher mortality among patients with grade ≥2 AR than among those without AR. (LLM, conf=0.94)

  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 the paper

“Finally, valve-in-valve procedures for failed bioprostheses are becoming more common as an alternative to re-doing surgical AVR240.”

What the sources say

• Supported

  The introduction (p. 2) describes repeat surgery as the standard treatment for failed bioprostheses but notes its risks. “Implications for Cardiac Surgery” (p. 8) describes increasing global valve-in-valve experience and presents the procedure as a less invasive treatment for failed surgical bioprostheses, supporting the paraphrase. (LLM, conf=0.88)

  cites [240] Dvir, D. et al. Transcatheter aortic valve implantation in failed bioprosthetic surgical valves. JAMA 312, 162–170 (2014). source

In the paper

“Although, in general, TAVR is associated with a survival advantage compared to conservative (no AVR) management”

What the sources say

• Partly supported

  The Rates of Death section (p. 6) reports lower one-year mortality with TAVI than with standard therapy in patients unsuitable for surgery (30.7% versus 50.7%). The Discussion (p. 10) explicitly says these results cannot be extrapolated to other patients with aortic stenosis, so the source does not support the claim's unqualified “in general” framing. (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
• Supported

  The Introduction states that TAVR provides a substantial survival advantage for many patients compared with no valve replacement. It also reports randomized-trial evidence that TAVR is superior to medical therapy in patients at prohibitive surgical risk, while noting that some patients do not benefit. (LLM, conf=0.94)

  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 Results introduction (page unavailable) reports a 20% improvement in 1-year survival with transfemoral TAVR in a PARTNER subgroup who were not candidates for surgery. That supports a survival advantage in that specific group, but not the claim’s unqualified “in general” comparison with conservative management. This paper’s own trial compared TAVR with surgical replacement, not no replacement. (LLM, conf=0.83)

  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 introductory passage labeled Abstract reports that TAVR greatly improved survival compared with standard therapy, but specifies that this was in patients who were not candidates for surgery. The claim presents the survival advantage as general; this paper’s own Cohort A comparison was TAVR versus surgical AVR, not conservative management. (LLM, conf=0.85)

  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

“With the emergence of TAVR, decisions regarding the treatment of coronary disease have become more complex, including which coronary lesions to treat versus leave alone, how to treat them (percutaneous versus bypass) and when to treat them (before, during, or after valve replacement)247.”

What the sources say

• Supported

  The “Management Options for CAD in Patients With Severe AS Being Considered for TAVR” section (page not specified in the supplied passages) explicitly lists the need for revascularization, PCI versus surgery, and timing relative to TAVR as considerations. It also discusses PCI before, during, or after TAVR. (LLM, conf=0.94)

  cites [247] Goel, S. S. et al. Severe aortic stenosis and coronary artery disease — implications for management in the transcatheter aortic valve replacement era: a comprehensive review. J. Am. Coll. Cardiol. 62, 1–10 (2013). source

In the paper

“Although long considered to be a passive and degenerative process, it is now clear that calcific AS results from an active biology that promotes fibrosis and calcification of the valve leaflets1.”

What the sources say

• Supported

  The Introduction (page unavailable) describes leaflet thickening and calcium-nodule formation, and says calcific aortic valve disease is actively regulated rather than simply passive or degenerative. The Pathobiology section links cellular activity to valve calcification, supporting the claim’s account of active disease biology. (LLM, conf=0.90)

  cites [1] Rajamannan, N. M. et al. Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the national heart and lung and blood institute aortic stenosis working group executive summary: calcific aortic valve disease — 2011 update. Circulation 124, 1783–1791 (2011). A good review of the state of knowledge and future research directions for calcific aortic valve disease (in 2011). source

In the paper

“In many ways, this LV response considerably influences the morbidity and mortality of the disease199;257–260.”

What the sources say

• Supported

  The Medical Therapy section states that hypertrophic LV remodeling and dysfunction in response to pressure overload drive much of the morbidity and mortality of aortic stenosis. This directly supports the citing sentence’s paraphrase about the importance of the LV response. (LLM, conf=0.94)

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

  The “Severity of Aortic Stenosis” section describes LV hypertrophy as a response to chronic pressure overload and links severe hypertrophy to LV dysfunction and decreased long-term survival. The “Left ventricular hypertrophy” section also reports higher late mortality and more advanced symptoms among patients with severe hypertrophy. The supplied passages do not give page numbers. (LLM, conf=0.90)

  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
• Partly supported

  In “Predictors of HF and ejection fraction” (page unavailable), higher LV mass is independently associated with heart failure and lower ejection fraction in patients with aortic stenosis, supporting the morbidity aspect. The paper does not establish that the LV response influences mortality; its mortality discussion in “Methodological considerations” (page unavailable) does not test that relationship. The claim also states an influence more strongly than the study’s observational associations establish. (LLM, conf=0.85)

  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 (page not available in our copy) reports that variation in the LV hypertrophic response has important clinical consequences: greater LV mass was associated with increased mortality, while decompensation heralds symptoms, adverse events, and poor prognosis. This supports the claim that the LV response substantially influences morbidity and mortality in aortic stenosis. (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) describes LV hypertrophy and diastolic dysfunction in severe aortic stenosis and reports that an elevated E/E′ ratio marks patients at high risk of one-year mortality. This supports a link between the LV response and mortality, but the paper does not establish that the response causes worse outcomes or assess its effect on morbidity. (LLM, conf=0.84)

  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

“Results from some recent studies suggest that TAVR might be preferable to surgical AVR in patients with diabetes, chronic obstructive pulmonary disease, pulmonary hypertension, small aortic annulus and low-flow, low-gradient AS262–266.”

What the sources say

• Partly supported

  The Conclusion supports the diabetes portion of the claim: TAVR may be preferred over surgery for patients with aortic stenosis and diabetes. That finding comes from high-surgical-risk patients, a restriction the citing sentence omits. The other listed conditions are not attributed to this source alone within the citation range. (LLM, conf=0.85)

  cites [262] Lindman, B. R. et al. Transcatheter versus surgical aortic valve replacement in patients with diabetes and severe aortic stenosis at high risk for surgery: an analysis of the PARTNER trial (placement of aortic transcatheter valve). J. Am. Coll. Cardiol. 63, 1090–1099 (2014). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [263] Herrmann, H. C. et al. Predictors of mortality and outcomes of therapy in low flow severe aortic stenosis: a PARTNER trial analysis. Circulation 127, 2316–2326 (2013). source
• Partly supported

  The TAVR VERSUS SAVR section (page not provided) reports fewer major bleeding events with TAVR and a nonsignificant six-month trend favoring transfemoral TAVR in patients with chronic lung disease. But it finds no significant long-term survival difference, and the Conclusions say TAVR was similar to SAVR—not preferable. This paper addresses chronic lung disease rather than separately establishing a preference for TAVR in the other listed subgroups. (LLM, conf=0.87)

  cites [264] Dvir, D. et al. Outcomes of patients with chronic lung disease and severe aortic stenosis treated with transcatheter versus surgical aortic valve replacement or standard therapy: insights for the PARTNER trial. J. Am. Coll. Cardiol. 63, 269–279 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page not available in our copy) describes TAVI as an alternative to surgical AVR for patients who are inoperable or at very high surgical risk, and identifies COPD as a common reason for inoperability. That supports considering TAVI for some patients with COPD, but the study followed TAVI recipients without a surgical comparison group; it does not establish that TAVI is preferable to surgery for patients with COPD generally. The other conditions in the sentence are not attributed specifically to this citation. (LLM, conf=0.83)

  cites [265] Mok, M. et al. Chronic obstructive pulmonary disease in patients undergoing transcatheter aortic valve implantation: insights on clinical outcomes, prognostic markers, and functional status changes. JACC Cardiovasc. Interv. 6, 1072–1084 (2013). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [266] Rodes-Cabau, J. et al. Impact of aortic annulus size on valve hemodynamics and clinical outcomes after transcatheter and surgical aortic valve replacement: insights from the PARTNER Trial. Circ. Cardiovasc. Interv 7, 701–711 (2014). source

In the paper

“When poor health status is principally due to comorbidities and geriatric conditions, valve replacement might lead to an unsatisfactory result both in terms decreased survival and a decline or lack of improvement in quality of life253–256.”

What the sources say

• ?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
• Partly supported

  The Results (Long-term survival; page unavailable) associate greater frailty with increased mortality after TAVR, supporting the survival concern for a geriatric condition. The paper did not assess quality-of-life decline or lack of improvement, and its comorbidity score was not associated with long-term mortality. It therefore does not support the full claim about poor health principally due to comorbidities and geriatric conditions. (LLM, conf=0.88)

  cites [254] Green, P. et al. The impact of frailty status on survival after transcatheter aortic valve replacement in older adults with severe aortic stenosis: a single-center experience. JACC Cardiovasc. Interv. 5, 974–981 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) reports that frailty before TAVI predicts functional decline and that a previous analysis of the same cohort linked the frailty index to mortality. The paper treats functional status as a component of quality of life, but it does not establish that poor health is principally due to comorbidities or geriatric conditions, or directly measure a decline or lack of improvement in quality of life after TAVI. (LLM, conf=0.84)

  cites [255] Schoenenberger, A. W. et al. Predictors of functional decline in elderly patients undergoing transcatheter aortic valve implantation (TAVI). Eur. Heart J. 34, 692 (2013). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports that several geriatric-assessment measures were associated with mortality after transcatheter aortic valve implantation, supporting the decreased-survival concern. The study did not assess quality of life or establish that poor health was principally due to comorbidities and geriatric conditions, so those parts of the claim are not supported by this paper. (LLM, conf=0.88)

  cites [256] Stortecky, S. et al. Evaluation of multidimensional geriatric assessment as a predictor of mortality and cardiovascular events after transcatheter aortic valve implantation. JACC Cardiovasc. Interv. 5, 489–496 (2012). sourceExperimental — accuracy not yet measured

In the paper

“Several intervention studies have been performed to test the hypothesis that lipid lowering with statin medications would slow the progression of AS, however the results were generally disappointing152–154.”

What the sources say

• Supported

  The Abstract identifies this as a trial testing whether intensive statin-based lipid lowering would slow calcific aortic stenosis and concludes that it did not halt progression or induce regression. The discussion passage under “adverse events” likewise reports progression despite substantial LDL reduction. This paper supports the sentence as one of the intervention studies cited, though it does not itself establish the results of the other studies. (LLM, conf=0.91)

  cites [152] Cowell, S. J. et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N. Engl. J. Med. 352, 2389–2397 (2005). source
• Supported

  The Discussion reports that this trial found no effect on aortic-stenosis progression despite substantial LDL lowering, consistent with the smaller SALTIRE trial. It also notes a favorable result in the nonrandomized, open-label RAAVE study, so the claim’s qualification that results were generally—not uniformly—disappointing is apt. (LLM, conf=0.90)

  cites [153] Rossebo, A. B. et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N. Engl. J. Med. 359, 1343–1356 (2008). This is a randomized clinical trial that reports no effect of statins on the progression and the outcomes of calcific AS. source
• ?Not checked — no full text of the sourcecites [154] Chan, K. L., Teo, K., Dumesnil, J. G., Ni, A. & Tam, J. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 121, 306–314 (2010). source

In the paper

“Although no pharmacotherapy has proven to be effective in reducing the progression of AS, promising therapeutic targets include lipoprotein(a), the renin-angiotensin system, tumor necrosis factor ligand superfamily member 11 (also called receptor activator of NF-κB ligand (RANKL)) and ectonucleotidases.”

• Also stated in: § Introduction · plain

  “However, no pharmacotherapy has proved to reduce either the progression of valve stenosis or the resulting adverse effects on left ventricular (LV) function and patient outcomes.”

In the paper

“and that there is an association between the level of Ox-LDL and the degree of inflammation and fibro-calcific remodelling in surgically removed AS valves40;42.”

What the sources say

• ?Not checked — no full text of the sourcecites [40] Mohty, D. et al. Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler. Thromb. Vasc. Biol. 28, 187–193 (2008). source
• ?Not checked — no full text of the sourcecites [42] Cote, C. et al. Association between circulating oxidised low-density lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis. Heart 94, 1175–1180 (2008). source

In the paper

“To this effect, the collagen produced by VICs serves as a scaffold on which the nucleation of calcium and phosphorus can start32.”

What the sources say

• ?Not checked — no full text of the sourcecites [32] Price, P. A., Toroian, D. & Chan, W. S. Tissue-nonspecific alkaline phosphatase is required for the calcification of collagen in serum: a possible mechanism for biomineralization. J. Biol. Chem. 284, 4594–4604 (2009). source

In the paper

“The proportion of AS caused by calcific AS is expected to increase in industrially developing countries owing to the decreasing incidence of rheumatic fever.”

In the paper

“In vivo, circulating Ox-PLs are mostly carried by the lipoprotein(a) (Lp(a)) fraction,46”

What the sources say

• ?Not checked — no full text of the sourcecites [46] Tsimikas, S. & Witztum, J. L. The role of oxidized phospholipids in mediating lipoprotein (a) atherogenicity. Curr. Opin. Lipidol. 19, 369–377 (2008). source

In the paper

“Increasing evidence suggests that infiltration of the aortic valve by lipoproteins has a central role in promoting inflammation, which precedes the pathologic mineralization that is characteristic of calcific AS38.”

What the sources say

• ?Not checked — no full text of the sourcecites [38] Abdelbaky, A. et al. Early aortic valve inflammation precedes calcification: a longitudinal FDG-PET/CT study. Atherosclerosis 238, 165–172 (2015). source

In the paper

“Calcified valves often contain dense inflammatory infiltrates, which consist mostly of macrophages29;30.”

What the sources say

• ?Not checked — no full text of the sourcecites [29] Cote, N. et al. Inflammation is associated with the remodeling of calcific aortic valve disease. Inflammation 36, 573–581 (2013). source
• ?Not checked — no full text of the sourcecites [30] Helske, S. et al. Possible role for mast cell-derived cathepsin G in the adverse remodelling of stenotic aortic valves. Eur. Heart J. 27, 1495–1504 (2006). source

In the paper

“In this regard, histological studies have demonstrated that several apolipoproteins (apos) such as apoB, apoE, apoA1 and apo(a) are present in surgically removed stenotic aortic valves39.”

What the sources say

• ?Not checked — no full text of the sourcecites [39] O'Brien, K. D. et al. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis. Arterioscler. Thromb. Vasc. Biol. 16, 523–532 (1996). source

In the paper

“Therefore, the retention of lipids promotes a chronic low-grade inflammatory process, which, in turn, might induce an osteogenic program in aortic valves.”

In the paper

“In addition, excess production and disorganization of collagen fibers is an important feature of calcific AS.”

In the paper

“Oxidative stress has also been implicated in calcific AS.”

In the paper

“A small proportion (10–15%) of calcific AS valves show advanced osteogenic metaplasia with the presence of osteoblast-like cells, chondrocytes and bone marrow28.”

What the sources say

• ?Not checked — no full text of the sourcecites [28] Steiner, I., Kasparova, P., Kohout, A. & Dominik, J. Bone formation in cardiac valves: a histopathological study of 128 cases. Virchows Arch. 450, 653–657 (2007). source

In the paper

“For instance, immunostaining has demonstrated that apoB co-localizes with oxidized low-density lipoproteins (Ox-LDLs) in valves from patients with calcific AS,40;41”

What the sources say

• ?Not checked — no full text of the sourcecites [40] Mohty, D. et al. Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler. Thromb. Vasc. Biol. 28, 187–193 (2008). source
• ?Not checked — no full text of the sourcecites [41] Olsson, M., Thyberg, J. & Nilsson, J. Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves. Arterioscler. Thromb. Vasc. Biol. 19, 1218–1222 (1999). source

In the paper

“Inspection of surgically explanted valves with calcific AS reveals two features, fibrosis and calcification (Figure 3), which substantially alter the biomechanical properties of the aortic valve leaflets.”

In the paper

“Together, these observations suggest that the fibro-calcific process in the aortic valve is a response to injury, which might be triggered by lipid-derived species and inflammation (Figure 4)31.”

What the sources say

• ?Not checked — no full text of the sourcecites [31] Mathieu, P. & Boulanger, M. C. Basic mechanisms of calcific aortic valve disease. Can. J. Cardiol. 30, 982–993 (2014). source

In the paper

“When the aortic valve is affected, the dysfunction is often mixed: aortic stenosis combined with some degree of aortic regurgitation20;21.”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Demirbag, R., Sade, L. E., Aydin, M., Bozkurt, A. & Acarturk, E. The Turkish registry of heart valve disease. Turk Kardiyol. Dern. Ars. 41, 1–10 (2013). source
• ?Not checked — no full text of the sourcecites [21] Sliwa, K. et al. Incidence and characteristics of newly diagnosed rheumatic heart disease in urban African adults: insights from the heart of Soweto study. Eur. Heart J. 31, 719–727 (2010). source

In the paper

“a LDL-like particle in which the apoB protein is linked by a disulfide bridge to apo(a)47.”

What the sources say

• ?Not checked — no full text of the sourcecites [47] Dube, J. B., Boffa, M. B., Hegele, R. A. & Koschinsky, M.L. Lipoprotein (a): more interesting than ever after 50 years. Curr. Opin. Lipidol. 23, 133–140 (2012). source

In the paper

“The epidemiology of AS in developing countries and resource poor settings differs in some respects to that seen in developed countries, in part due to higher rates of rheumatic fever and rheumatic heart disease in poorer communities.”

In the paper

“These membrane-bound enzymes use nucleotides and nucleosides secreted by cells as substrates and produce phosphate-derived products that promote mineralization112.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be 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).

In the paper

“The other clinical risk factors associated with AS are similar to those associated with atherosclerosis and include male sex, smoking, hypertension, hypercholesterolaemia, obesity, metabolic syndrome, diabetes and elevated Lp(a)9;13448;135;136.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites 9;13448;135;136

In the paper

“Hence, a considerable proportion of patients with AS may have subclinical LV systolic dysfunction despite preserved LVEF and the absence of symptoms.”

In the paper

“The global LV systolic function, which is measured using the LV ejection fraction (LVEF), and cardiac output are generally well preserved even in the presence of severe AS because the increase in LV wall thickness allows wall stress to remain relatively normal.”

In the paper

“However, a large proportion of patients with preserved LVEF have subtle LV systolic dysfunction that is characterized by impaired LV longitudinal function with relatively well preserved radial and circumferential function (Box 1)”

In the paper

“As such, purinergic signalling, which is under the control of ectonucleotidases, plays a central part in controlling the mineralization of the aortic valve.”

In the paper

“The pattern of the LV adaptive response to pressure overload in AS is highly heterogeneous and includes concentric remodelling, concentric hypertrophy and eccentric hypertrophy (Figure 6)”

In the paper

“Obesity, metabolic syndrome and diabetes also predispose to the development of more concentric hypertrophy in the presence of AS117;118.”

What the sources say

• ?Not checked — no full text of the sourcecites [117] Pagé, A. et al. Metabolic syndrome is associated with more pronounced impairment of LV geometry and function in patients with calcific aortic stenosis: a substudy of the ASTRONOMER trial (Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin). J. Am. Coll. Cardiol. 55, 1867–1874 (2010). source
• ?Not checked — no full text of the sourcecites [118] Lund, B. P. et al. Effect of obesity on left ventricular mass and systolic function in patients with asymptomatic aortic stenosis (a Simvastatin Ezetimibe in Aortic Stenosis [SEAS] substudy). Am. J. Cardiol. 105, 1456–1460 (2010). source

In the paper

“A decrease in the level of extracellular ATP also diminishes purinergic signalling through the P2Y purinoreceptor 2 (P2Y2).”

In the paper

“The symptoms in AS are essentially due to an imbalance between the increase in LV haemodynamic load caused by valvular obstruction, on the one hand, and the capacity of the LV to overcome this increase in load both at rest and during exercise, on the other hand.”

In the paper

“Repetitive myocardial ischaemia related to the exhaustion of coronary flow reserve leads to apoptosis of myocytes and development of ‘replacement’ myocardial fibrosis.”