***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background — Diffuse myocardial fibrosis is a final end point in most cardiac diseases . It is missed by the cardiovascular magnetic resonance ( CMR ) late gadolinium enhancement technique . Currently , quantifying diffuse myocardial fibrosis requires invasive biopsy , with inherent risk and sampling error . We have developed a robust and noninvasive technique , equilibrium contrast CMR ( EQ – CMR ) to quantify diffuse fibrosis and have vali date d it against the current gold st and ard of surgical myocardial biopsy . Methods and Results — The 3 principles of EQ – CMR are a bolus of extracellular gadolinium contrast followed by continuous infusion to achieve equilibrium ; a blood sample to measure blood volume of distribution ( 1−hematocrit ) ; and CMR to measure pre- and postequilibrium T1 ( with heart rate correction ) . The myocardial volume of distribution is calculated , reflecting diffuse myocardial fibrosis . Clinical validation occurred in patients undergoing aortic valve replacement for aortic stenosis or myectomy in hypertrophic cardiomyopathy ( n=18 and n=8 , respectively ) . Surgical biopsies were analyzed for picrosirius red fibrosis quantification on histology . The mean histological fibrosis was 20.5±11 % in aortic stenosis and 17.1±7.4 % in hypertrophic cardiomyopathy . EQ – CMR correlated strongly with biopsy histological fibrosis : aortic stenosis , r2=0.86 , Kendall Tau coefficient (T)=0.71 , P<0.001 ; hypertrophic cardiomyopathy , r2=0.62 , T=0.52 , P=0.08 ; combined r2=0.80 , T=0.67 , P<0.001 . Conclusions — We have developed and vali date d a new technique , EQ – CMR , to measure diffuse myocardial fibrosis as an add-on to a st and ard CMR scan , which allows for the noninvasive quantification of the diffuse fibrosis burden in myocardial diseases Background — The pathophysiology of aortic stenosis is incompletely understood , and the relative contributions of valvular calcification and inflammation to disease progression are unknown . Methods and Results — Patients with aortic sclerosis and mild , moderate , and severe stenosis were compared prospect ively with age- and sex-matched control subjects . Aortic valve severity was determined by echocardiography . Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride ( 18F-NaF ) and 18F-fluorodeoxyglucose ( 18F-FDG ) uptake with the use of positron emission tomography .  One hundred twenty-one subjects ( 20 controls ; 20 aortic sclerosis ; 25 mild , 33 moderate , and 23 severe aortic stenosis ) were administered both 18F-NaF and 18F-FDG . Quantification of tracer uptake within the valve demonstrated excellent interobserver repeatability with no fixed or proportional biases and limits of agreement of ±0.21 ( 18F-NaF ) and ±0.13 ( 18F-FDG ) for maximum tissue-to- background ratios . Activity of both tracers was higher in patients with aortic stenosis than in control subjects ( 18F-NaF : 2.87±0.82 versus 1.55±0.17 ; 18F-FDG : 1.58±0.21 versus 1.30±0.13 ; both P<0.001 ) . 18F-NaF uptake displayed a progressive rise with valve severity ( r2=0.540 , P<0.001 ) , with a more modest increase observed for 18F-FDG ( r2=0.218 , P<0.001 ) . Among patients with aortic stenosis , 91 % had increased 18F-NaF uptake ( > 1.97 ) , and 35 % had increased 18F-FDG uptake ( > 1.63 ) . A weak correlation between the activities of these tracers was observed ( r2=0.174 , P<0.001 ) . Conclusions — Positron emission tomography is a novel , feasible , and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis . The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF. Clinical Trial Registration — http://www . clinical trials.gov . Unique identifier : NCT01358513 Background —Aortic valve calcification ( AVC ) is the intrinsic mechanism of valvular obstruction leading to aortic stenosis ( AS ) and is measurable by multidetector computed tomography . The link between sex and AS is controversial and that with AVC is unknown . Methods and Results —We prospect ively performed multidetector computed tomography in 665 patients with AS ( aortic valve area , 1.05±0.35 cm2 ; mean gradient , 39±19 mm Hg ) to measure AVC and to assess the impact of sex on the AVC – AS severity link in men and women . AS severity was comparable between women and men ( peak aortic jet velocity : 4.05±0.99 versus 3.93±0.91 m/s , P=0.11 ; aortic valve area index : 0.55±0.20 versus 0.56±0.18 cm2/m2 ; P=0.46 ) . Conversely , AVC load was lower in women versus men ( 1703±1321 versus 2694±1628 arbitrary units ; P<0.0001 ) even after adjustment for their smaller body surface area or aortic annular area ( both P<0.0001 ) . Thus , odds of high-AVC load were much greater in men than in women ( odds ratio , 5.07 ; P<0.0001 ) . Although AVC showed good associations with hemodynamic AS severity in men and women ( all r>0.67 ; P<0.0001 ) , for any level of AS severity measured by peak aortic jet velocity or aortic valve area index , AVC load , absolute or indexed , was higher in men versus women ( all P⩽0.01 ) . Conclusions —In this large AS population , women incurred similar AS severity than men for lower AVC loads , even after indexing for their smaller body size . Hence , the relationship between valvular calcification process and AS severity differs in women and men , warranting further pathophysiological inquiry . For AS severity diagnostic purpose s , interpretation of AVC load should be different in men and in women Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background Aortic valve stenosis ( AS ) is a progressive disease , but the impact of baseline AS haemodynamic or anatomic severity on AS progression remains unclear . Methods In 149 patients ( 104 mild AS , 36 moderate AS and 9 severe AS ) enrolled in 2 ongoing prospect i ve cohorts ( COFRASA/GENERAC ) , we evaluated AS haemodynamic severity at baseline and yearly , thereafter , using echocardiography ( mean pressure gradient ( MPG ) ) and AS anatomic severity using CT ( degree of aortic valve calcification ( AVC ) ) . Results After a mean follow-up of 2.9±1.0 years , mean MGP increased from 22±11 to 30±16 mm Hg ( + 3±3 mm Hg/year ) , and mean AVC from 1108±891 to 1640±1251 AU ( arbitrary units ) ( + 188±176 AU/year ) . Progression of AS was strongly related to baseline haemodynamic severity ( + 2±3 mm Hg/year in mild AS , + 4±3 mm Hg/year in moderate AS and + 5±5 mm Hg/year in severe AS ( p=0.01 ) ) , and baseline haemodynamic severity was an independent predictor of haemodynamic progression ( p=0.0003 ) . Annualised haemodynamic and anatomic progression rates were significantly correlated ( r=0.55 , p<0.0001 ) , but AVC progression rate was also significantly associated with baseline haemodynamic severity ( + 141±133 AU/year in mild AS , + 279±189 AU/year in moderate AS and + 361±293 AU/year in severe AS , p<0.0001 ) , and both baseline MPG and baseline AVC were independent determinants of AVC progression ( p<0.0001 ) . Conclusions AS progressed faster with increasing haemodynamic or anatomic severity . Our results suggest that a medical strategy aim ed at preventing AVC progression may be useful in all subsets of patients with AS including those with severe AS and support the recommended closer follow-up of patients with AS as AS severity increases . Clinical trial registration COFRASA ( clinical Trial.gov number NCT 00338676 ) and GENERAC ( clinical Trial.gov number NCT00647088 ) Background — In this prospect i ve follow-up study , the effect of myocardial fibrosis on myocardial performance in symptomatic severe aortic stenosis was investigated , and the impact of fibrosis on clinical outcome after aortic valve replacement ( AVR ) was estimated . Methods and Results — Fifty-eight consecutive patients with isolated symptomatic severe aortic stenosis underwent extensive baseline characterization before AVR . St and ard and tissue Doppler echocardiography and cardiac magnetic resonance imaging ( late-enhancement imaging for replacement fibrosis ) were performed at baseline and 9 months after AVR . Endomyocardial biopsies were obtained intraoperatively to determine the degree of myocardial fibrosis . Patients were analyzed according to the severity of interstitial fibrosis in cardiac biopsies ( severe , n=21 ; mild , n=15 ; none , n=22 ) . The extent of histologically determined cardiac fibrosis at baseline correlated closely with New York Heart Association functional class and markers of longitudinal systolic function ( all P<0.001 ) but not global ejection fraction or aortic valve area . Nine months after AVR , the degree of late enhancement remained unchanged , implying that AVR failed to reduce the degree of replacement fibrosis . Patients with no fibrosis experienced a marked improvement in New York Heart Association class from 2.8±0.4 to 1.4±0.5 ( P<0.001 ) . Only parameters of longitudinal systolic function predicted this functional improvement . Four patients with severe fibrosis died during follow-up , but no patient from the other groups died . Conclusions — Myocardial fibrosis is an important morphological substrate of postoperative clinical outcome in patients with severe aortic stenosis and was not reversible after AVR over the 9 months of follow-up examined in this study . Because markers of longitudinal systolic function appear to indicate sensitively both the severity of myocardial fibrosis and the clinical outcome , they may prove valuable for preoperative risk assessment in patients with aortic stenosis Objectives Cardiac magnetic resonance ( CMR ) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis , as well as their association with other measures of left ventricular decompensation and mortality . Background Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis . Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping , whereas late gadolinium enhancement ( LGE ) detects replacement fibrosis . Methods In a prospect i ve observational cohort study , 203 subjects ( 166 with aortic stenosis [ 69 years ; 69 % male ] ; 37 healthy volunteers [ 68 years ; 65 % male ] ) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation . On CMR , we quantified the total extracellular volume of the myocardium indexed to body surface area ( iECV ) . The iECV upper limit of normal from the control group ( 22.5 ml/m2 ) was used to define extracellular compartment expansion . Areas of replacement mid-wall LGE were also identified . All-cause mortality was determined during 2.9 ± 0.8 years of follow up . Results iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies ( r = 0.87 ; p < 0.001 ; n = 11 ) and was increased in patients with aortic stenosis ( 23.6 ± 7.2 ml/m2 vs. 16.1 ± 3.2 ml/m2 in control subjects ; p < 0.001 ) . iECV was used together with LGE to categorize patients with normal myocardium ( iECV < 22.5 ml/m2 ; 51 % of patients ) , extracellular expansion ( iECV ≥22.5 ml/m2 ; 22 % ) , and replacement fibrosis ( presence of mid-wall LGE , 27 % ) . There was evidence of increasing hypertrophy , myocardial injury , diastolic 
    Output:
    
Conclusion : AVC and myocardial fibrosis imaging biomarkers predict the outcomes in AS , and help underst and ing AS pathophysiology and setting therapeutic targets