Hemodynamic Progression of Asymptomatic Aortic
Stenosis and Outcome in Primary Care
Stefano Nistri MD*, Pompilio Faggiano MD†, Iacopo Olivotto MD‡,
Barbara Papesso MD*, Tania Bordonali MD †, Giorgio Vescovo MD§,
Livio Dei Cas†, Franco Cecchi MD‡ and Robert O. Bonow MD‖
*CMSR Veneto Medica, Altavilla Vicentina (VI) , Italy; †Cardiology Division, Spedali Civili and University of Brescia, Italy; ‡Referral Centre for Cardiomyopathies, Azienda Ospedaliera
Universitaria Careggi, Firenze, Italy; §Dpmt. of Medicine, Ospedale di Vicenza, Italy;
‖Northwestern University, Chicago (IL)USA
Brief title: Aortic Stenosis in Primary Care
Key words: Aortic stenosis; Echocardiography; Prognosis.
Word count: 2,894 Excluding abstract, table, references and figures legends.
Address for Correspondence: Stefano Nistri, MD
CMSR Veneto Medica Via Vicenza 204
36077, Altavilla Vicentina (VI) - Italy Tel. +390444225111
Fax. +390444225199 E-mail: snistr@tin.it
Abstract
Objective: To describe and assess prognostic relevance of the rate of hemodynamic progression of aortic stenosis (AS).
Setting: Non referral primary-care ambulatory centre
Design: Retrospective evaluation of asymptomatic AS patients with left ventricular ejection fraction ≥50%. The severity of AS was graded by peak aortic velocity (Vmax) and progression classified as slow or fast according to a cutoff value of 0.3 m/s/y.
Patients: 153 patients (77±9 years; 65% men) with ≥2 echocardiograms (mean time interval: 32 ±23 months); 135 (88%) had mild-to-moderate and 18 (12%) had severe AS.
Main Outcome Measures: endpoints were all-cause mortality and a composite of all-cause mortality and aortic valve replacement (AVR).
Results: Fast progression was observed in 49 (32%) patients. Among 144 (94%) subjects with clinical follow-up data (mean duration: 2.36 ±1.9 years), 40 died and 48 underwent AVR. The mortality rate was higher than that of the general population (p <0.001). By multivariate analysis, independent predictors of mortality were yearly change in Vmax (HR 13.352, 95% confidence interval (CI) 5.136-34.713, p<0.001) and age (HR 1.122, 95%CI 1.0728-1,735, p<0.001). Predictors of the composite end-point of death and AVR were yearly change in Vmax (HR 12.307, 95% CI 6.024-25.140, p <0.001) and Vmax (HR 2.684, 95%CI 1.921-3.750, p<0.001).
Conclusion: In a primary care setting asymptomatic AS patients frequently develop rapid hemodynamic progression, which is an independent predictor not only of AVR but also overall mortality. These findings underscore the need for stricter echocardiographic surveillance of asymptomatic older patients with mild-to-moderate AS.
Aortic valve stenosis (AS) is a common progressive disorder which is most frequently caused by calcification of a normal trileaflet or a congenital bicuspid aortic valve. The prevalence of AS increases sharply with age, and management decisions in the elderly are often difficult.[1-4] The natural history of AS in the adult is characterized by marked individual variability in the rate of hemodynamic progression, which may be particularly fast in subjects with degenerative calcification of the valve. In particular, the combination of a severely calcified valve with a rapid increase in aortic valve jet velocity has been shown to identify patients likely to require aortic valve replacement (AVR) because of onset of symptoms or left ventricular dysfunction.[1,2]
However, the majority of available data assessing the hemodynamic progression of AS have been reported from tertiary referral centres, and the prognostic implications of rapid progression of AS in terms of survival remain uncertain.[5-12] Thus, we decided to evaluate persistently asymptomatic patients with AS who underwent multiple echocardiographic evaluations performed in a primary-care ambulatory centre, in order to assess characteristics, predictors and prognostic relevance of the rate of hemodynamic progression of AS in a non referral outpatient facility.
METHODS
Patient Population. Subjects aged ≥21 years, with any degree of AS, referred to the echocardiographic laboratory of an outpatient facility (CMSR Veneto Medica) from January 1997 to December 2008 by their primary care physician were retrospectively identified. Patients who had ≥2 echocardiograms ≥4 months apart and without any symptom attributable to AS at each echocardiographic examination were included in this study. Exclusion criteria were 1) left ventricular (LV) ejection fraction <50%; 2) the presence of any other valvular disease greater than mild in severity; 3) the presence of a congenital heart condition other than bicuspid aortic valve; and 5) previous valvular or aortic surgery. The study protocol was approved by an Internal Review Board.
Echocardiographic and Doppler Measurements. All patients underwent comprehensive Doppler-echocardiography, according to American Society of Echocardiography recommendations, by experienced echocardiographers.[13,14] LV volumes and ejection fraction were measured using Simpson’s biplane rule method. LV mass (in g) was calculated using the Devereux formula and indexed for height to the power of 2.7. Relative wall thickness was computed as posterior wall thickness/LV radius at end-diastole.
AS was assessed as previously reported.[5] The maximal instantaneous and mean pressure gradients across the aortic valve were calculated using a modified Bernoulli equation and the aortic valve area (AVA) was calculated from the continuity equation. AS was graded as mild, moderate or severe according to peak aortic velocity (Vmax) <3, 3 to 4 and >4 m/s, respectively. Mean progression of aortic jet velocity (expressed as m/s/y) was calculated by dividing the difference between the last and first echocardiographic examination by the time between examinations and was graded as slow or fast according to a cut-off value of 0.3 m/s/y. [10] In our laboratory, the interobserver coefficient of reproducibility by Bland-Altman method, for both recording and measuring peak aortic velocity, assessed in 50 patients was 0.2 m/s. Calcification of the aortic valve was assessed qualitatively as previously suggested. [10] Arterial blood pressure was measured using a properly sized cuff sphygmomanometer.
Follow-up. The follow-up information was obtained from direct interviews with the patients or their general practitioner. The endpoints were all-cause mortality and a composite end-point constituted by all-cause mortality and aortic valve replacement (AVR). Particular care was taken to obtain information regarding indications for AVR and cause of death, including the review of reports from in-hospital stay and death certifications. The primary indications for AVR were classified as (a) development of AS-related symptoms, (b) patients with severe AS who developed LV ejection fraction <50%; (c) patients with moderate-to-severe AS undergoing coronary artery bypass graft surgery; and (d) patients with moderate-to-severe AS undergoing surgery on the aorta
or other heart valves. As the physicians caring for the patients were not part of the study, with the exception of 7 patients, we could not stipulate that patients not undergo AVR for other reasons, such as severe AS, moderate-to-severe calcification of the aortic valve or rapid hemodynamic progression of valve stenosis.
Statistical analysis. Continuous variables are expressed as mean ± standard deviation unless otherwise specified. For the comparison of normally distributed data, Student’s t-test (followed by Bonferroni’s post-hoc test) was employed, as appropriate. Chi-square or Fisher’s exact tests were utilized to compare non-continuous variables expressed as proportions. The survival curve was constructed according to the Kaplan-Meier method. The effects of clinical and echocardiographic factors (age, gender, hypercholesterolemia, diabetes mellitus, arterial hypertension, coronary artery disease, LV ejection fraction, LV mass index, aortic valve jet velocity at study entry, and yearly change in aortic jet velocity) on survival were assessed by simple and multiple Cox models. Overall survival from study entry was also quantified and related to the survival of age- and gender-matched “control subjects”, obtained by the data base of the general population of the Veneto Region reported by the Servizio Epidemiologico della Regione Veneto (available at http://www.ser-veneto.it/). All p-values are two-sided and considered significant when <0.05. Calculations were performed with SPSS 12.0 software (Chicago, IL).
RESULTS
During the study period 153 individuals with AS, without exclusion criteria and ≥2 echocardiograms (range 2-7 per patient) were evaluated in our echocardiographic laboratory, and constitute the study population (Table). All patients were free from AS-related symptoms at the time of each echocardiogram. Echocardiographers were not involved in any aspect of patient care, except for 7 of the AS patients. At baseline examination, 64 patients (42%) had mild, 71 (46%) moderate and 18 (12%) severe AS; the aortic valve was moderately to heavily calcified in all but 6 patients with mild aortic calcification.
Table: Clinical and echocardiographic data at baseline in the overall study group and according to different rates of hemodynamic progression.
Overall (n=153) Slow progressors (n=104) Fast progressors (n=49) P-value Males (%) 85 (65) 64 (62) 21 (43) 0.16 Age (years) 77±1.9 76±9 77±9 0.5 Height (cm) 168±0.1 168±0.1 167±0.1 0.4 Weight (Kg) 75.2±12.6 74.8±12.8 75.9±12.4 0.6
Body Surface area (m2) 1.85±0.19 1.84±0.16 1.84±0.2 0.7
Body Mass Index (Kg/m2) 26.7±3.8 26.4±3.8 27.1±4.0 0.3
Hypertension (%) 73 75 73 0.8
Hypercholesterolemia (%) 36 34 41 0.4
Diabetes (%) 22 19 26 0.4
Coronary artery disease (%) 24 25 24 0.9
Current smoking (%) 7 8 5 0.6
SBP *(mmHg) 142.4±15.2 143.1±15.6 141.0±14.1 0.4
DBP †(mmHg) 82.2±9.2 82.5±9.2 81.5±9.1 0.6
LVEDD ‡(mm) 51.0±5.1 51.6±4.7 49.6±5.5 0.02
LVMI § (g/m2.7) 58.8±13.6 59.4±12.2 57.5±16.1 0.4
Relative wall thickness 0.45±0.06 0.44±0.06 0.46±0.07 0.10
LVEDVI‖ (ml/m2) 60.4±13.0 61.6±13.0 57.7±12.8 0.08
Ejection fraction (%) 62.1±5.2 62.0±5.5 62.2±4.5 0.8
Aortic valve jet velocity (m/sec) 3.2±0.6 3.2±0.7 3.3±0.6 0.3
Mean aortic gradient (mmHg) 26±12.4 25±13.4 26.8±10 0.4
Aortic valve area (cm2) 1.2±0.3 1.3±0.3 1.2±0.3 0.1
Abbreviation: DBP: diastolic blood pressure; LVEDD: Left ventricular end-diastolic diameter; LVEDVI: left ventricular end-diastolic volume index; LVMI: left ventricular mass index; SBP: systolic blood pressure
Hemodynamic Progression. For the entire patient group, the mean time interval between the first and the last echocardiographic examinations was 32±23 months (range 4-108) and was <12 months (range 4-11) for only 16 (10.5%) patients (mean age: 78.9±7 years). The average increase in aortic peak jet velocity was 0.3±0.3 m/s/y, with a great individual variability in hemodynamic progression (Figure 1). In patients with >2 echocardiograms the rate of change in stenosis severity over the first year of follow-up was no different than the overall annual rate. A faster pattern of hemodynamic progression (>0.3m/s/y) was detected in 49 (32%) patients (0.61 ±0.32 m/s/y), while 104 (68%) displayed a slow progression pattern (0.10 ±0.16 m/s/y, p <0.001) (Figure 2, Table). Only LV end-diastolic diameter was different in patients with more rapid than in patients with slower progression pattern. No difference in clinical variables was observed between patients with different rates of hemodynamic progression (Table).
At last echocardiographic evaluation, patients with rapid progression had higher Vmax compared with those with slow progression (4.3 ±0.6 vs. 3.6 ±0.7 m/s, respectively, p <0.001) (figure 2) and smaller AVA (0.92 ±0.21 cm2 vs. 1.07 ±0.28 cm2, respectively, p =0.001). A progression to severe valve stenosis (Vmax >4 m/s) was observed in 43 patients out of the 135 patients with initially mild-to-moderate AS (32%). At last echocardiographic examination the mean AVA in these 43 patients was 0.85 ±0.14 cm2, and was ≤ 1 cm2 in 38.
Aortic Valve Replacement and Death. Follow-up data were available for 144 (94%) patients. During a mean follow-up of 4.9±2.7 years after the first echocardiographic examination, the actuarial probability of survival was significantly worse than that predicted for age- and gender-matched control subjects (P<.001) (Figure 3). At the baseline evaluation, patients who experienced combined events, compared with those without events, had higher Vmax (3.4 ±0.7 m/s vs. 3.0 ±0.5 m/s, p =0.001) and smaller AVA (1.2 ±0.3 cm2 vs. 1.4 ±0.3 cm2; p =0.001). However, baseline Vmax and AVA were not associated with mortality alone.
During a mean follow-up of 2.36 ±1.9 years after the last echocardiographic examination, 88 end-points (61%) were observed, including 40 deaths and 48 valve replacements. The reason for AVR (n=48) was development of symptoms attributable to AS in 38, decrease in LV ejection fraction to <50% in 4, and coexistent need for coronary artery revascularization in presence of moderate-to-severe AS in 3. Only 3 patients were referred for AVR by their primary physician because of a rapid increase in Vmax in severe AS. The cause of death was definitely of cardiovascular origin in 30 (75%) (including 2 patients whose death was related to an ischemic stroke), of non-cardiac origin in 5 (including one with perioperative mortality at non-cardiac surgery), and not determined in the remaining 5.
The rate of increase in Vmax was significantly greater in patients with an event (0.33±0.36 m/s/y) than in those without (0.15±0.22 m/s/y, p =0.001). The event rate in patients with rapid progression (80%) was significantly higher than that in patients with slow progression (52%,
p=0.001). Furthermore, the overall and event-free survival were significantly worse in AS patients
with rapid hemodynamic progression compared to that of patients with slow progression of hemodynamic severity (p=0.008 and p = 0.0003, respectively)(Figure 4).
At first echocardiographic examination patients who subsequently died compared with those who incurred in AVR were older (83±7 years vs. 73 ±10 years, respectively, p <0.01), had smaller mean body surface area (1.78±0.19 m2 vs. 1.87±0.17 m2, respectively, p =0.03) and mean body mass index (25.6±3.9 kg/m2 vs. 27.3±3.9 kg/m2, respectively, p=0.02). No difference was observed in all the other clinical and echocardiographic parameters (data not shown).
The yearly increase in Vmax was comparable between patients who died and in those who had AVR (0.31 ±0.36 m/s/y vs. 0.33 ±0.36 m/s/y, respectively, p=0.84). Nonetheless, at the last echocardiographic examination, patients who died during follow-up had lower Vmax compared to those who had AVR (3.78 ±0.66 m/s vs. 4.24 ±0.65 m/s, respectively, p =0.002), with relatively larger AVA (0.98 ±0.22 cm2 vs. 0.88 ±0.2 cm2, respectively, p =0.03), but similar LV ejection fraction (60.3 ±7.4 % vs. 61.8 ±6.6 %, respectively).
By multivariate analysis, independent predictors of mortality were yearly change in Vmax (HR 13.352, 95% confidence interval (CI) 5.136-34.713, p<0.001) and age (HR 1.122, 95%CI 1.0728-1,735, p<0.001). Predictors of the composite end-point of death and AVR were yearly change in Vmax (HR 12.307, 95% CI 6.024-25.140, p <0.001) and Vmax (HR 2.684, 95%CI 1.921-3.750, p<0.001).
DISCUSSION
This report represents the first study evaluating predictors and prognostic significance of hemodynamic progression of AS in asymptomatic patients with normal LV function detected in a primary-care echocardiographic laboratory, likely less conditioned by patient selection biases that may be substantial in cohorts reported from tertiary AS referral centres.[11] In this setting, the yearly rate of progression of AS is frequently very rapid, particularly among patients with only mild-to-moderate AS at baseline. Importantly, this progression is an independent predictor of overall mortality and of the combined end-point. Of note our patients at study entry are older than those reported in studies from the tertiary centres; nevertheless, the mortality rate of these patients with asymptomatic AS is higher than in the general population when matched to the age and gender demographics of our population.
The recognition that the mean age of the patients detected in a non referral facility is higher that of patients from referral centres is clinically relevant, since multiple age-related problems are evident in the management of AS patients commonly encountered in clinical practice.[3,4,15,16,17] A combination of comorbidities (resulting in progressive inactivity), added to the gradual reduction of daily activities to eventually mask the development of symptoms, and combined with the reluctancy of both patients and physician to utilize exercise stress testing, can lead to an underestimation of the presence and severity of symptoms.[1,2,15-20] In this regard, the incremental prognostic value of B-type natriuretic peptide (BNP) level over peak aortic jet velocity in asymptomatic AS [21] has also been reported, suggesting that a “watchful waiting” strategy might not be appropriate for every patient with AS. [22] Moreover, in elderly subjects with AS,
particularly if hypertension is present, the occurrence of reduced systemic arterial compliance contributes to increased afterload and decreased LV function often resulting in a paradoxical clustering of severe narrowing of the aortic valve and low transvalvular flow and gradients. This represents another potential source of underestimation of symptom and hemodynamic severity of AS and subsequent inappropriate delay in referral to AVR. [23-25] In this context, it has been recently shown that measurements integrating the ventricular, vascular and valvular components of moderate-to-severe AS may improve the risk stratification of asymptomatic patients and may help to identify patients who could benefit from early elective aortic valve surgery.[26] Altogether, these observations support the concept that a considerable subset of elderly AS patients, who are scarcely represented in most studies from referral centres but are commonly encountered in clinical practice, might be misclassified both from the hemodynamic and clinical point of view, and demonstrate the pressing need for future prospective studies in AS patients aged >75. Such studies should include a more comprehensive evaluation of the stenosis (implementing newer indexes of AS severity), possibly integrated with the evaluation of BNP or other biomarkers during a prolonged follow-up.
Hemodynamic progression. Despite substantial individual variability, progression of moderate or even mild stenosis to severe AS occurred in one-third of subjects over the course of approximately 3 years. Of interest, patients with more rapid hemodynamic progression could not be readily identified based on baseline clinical and echocardiographic characteristics. [1,2] In fact, although LV end-diastolic diameter was different between patients with diverse progression in hemodynamic severity, it had a very poor positive predictive accuracy due to substantial overlap between groups. Thus, our findings indicate that patients with mild-to-moderate AS should be viewed with more caution [11] than recommended by current guidelines. [1,2] It is conceivable that one first yearly re-evaluation of an individual patient with mild and moderate AS should be performed for tailoring subsequent decisions based on the hemodynamic progression of the disease. This could particularly hold true for asymptomatic patients with adjunctive predictors of worse
outcome such as moderate-to-severe aortic valve calcification and more advanced age, as those reported in the present study.
Outcome. The majority of our patients died or underwent AVR during a substantial follow-up period. The mortality rate of our patients was significantly worse than that of the control population. This is thus unlikely simply related to comorbid conditions and/or shorter life expectancy, and appears related to the significant rate of calcific aortic valve degeneration of our study subjects.[27] This finding is in accordance with previous findings in elderly patients with asymptomatic but severe AS,[28] and in younger patients with mild-to-moderate AS.[11] Noteworthy, in the latter study[11] mortality alone was not reported in relation to rate of progression and half of mortality was non cardiac in origin, possibly reflecting the higher comorbidity attributable to the patient selection of a referral centre. Importantly, unlike most previous studies, [5-12] rapid progression was an independent predictor of all cause mortality, together with age, in our patients. Moreover, the yearly rate of progression was also a predictor for the combined end-point together with peak aortic velocity at baseline. Finally, although advanced age has been described as a risk factor and clinical marker for poor outcome, it is also a known (and debated) reason why surgery is denied in symptomatic patients with severe AS.[15-20] Contemporary results show that AVR for AS can be performed with low operative mortality and morbidity, supporting the argument that asymptomatic patients who have a high likelihood of progression of AS may be considered for earlier surgical referral. [29,30] It is thus noteworthy that, in our study, the patients who subsequently died were older at baseline compared with patients who underwent AVR.
Study limitations. We acknowledge the retrospective design of the present study, and that only patients with multiple echocardiograms were included. However, as all patients in this study remained asymptomatic during echocardiographic follow-up, the referral for serial echocardiograms was not biased by AS-related symptoms. Although we identified the primary indication for AVR, we do not have similar information on the remaining subjects who survived without AVR. In
particular, our data do not reveal the proportion of patients in whom severe symptomatic AS eventually developed but were not referred to AVR. We also cannot determine if surgery was recommended but refused in some patients. We believe, however, that all these limitations are overcome by the utilization of overall mortality as end-point (alone or in combination with AVR) and, most importantly, by the demonstration that the all-cause mortality rate of our AS patients after the first echocardiogram was higher than that observed in the general age- and sex-matched population. Finally, 3 asymptomatic patients were referred for AVR on the basis of rapid progression of AS severity, thus influencing the combined endpoint. However, this represents a small minority of surgical referrals, does not adversely influence the mortality results, and is thus unlikely to importantly influence our conclusions.
Conclusions. In primary care, asymptomatic patients with AS and normal LV function are substantially older that those described in most studies from referral centres. One-third of patients with mild-to-moderate AS manifested rapid hemodynamic progression and developed severe AS within 3 years. A rapid rate of hemodynamic progression was independently related both to all-cause mortality and to the combined endpoint of death plus AVR during the follow-up, These data emphasize that even mild-to-moderate calcific AS, particularly in the elderly patients commonly encountered in every-day clinical practice, should be viewed with more caution than currently recommended, suggesting the need for stricter echocardiographic (as well as clinical) surveillance in asymptomatic patients with less than severe calcific AS in the primary care setting.
FIGURE LEGENDS
Figure 1. Individual variability in hemodynamic AS progression. The scatterplot reports, for each patient, the yearly rate of change in peak aortic valve jet velocity (on the ordinate) as a function of the baseline severity of aortic stenosis (on the abscissa).
Figure 2. Hemodynamic variability according to different rates of progression. Aortic valve jet velocity measured at first and at last echocardiographic (Echo) examination is reported for individual patients, grouped according to patterns of slow and rapid hemodynamic progression.
Figure 3. Overall survival. Kaplan-Meier analysis of overall survival of AS patients compared with that of age- and gender-matched control subjects.
Figure 4. Event-free and overall survival according to hemodynamic progression. Panel A Kaplan-Meier analysis of overall survival in patients with AS and rapid hemodynamic progression (red) was significantly worse than AS patients with slower pattern of hemodynamic progression (black) (p=0.008). Panel B. Event-free survival (survival from from aortic valve replacement (AVR) in AS patients with rapid hemodynamic progression (red) was significantly worse compared with AS patients with slow pattern of hemodynamic progression (black) (p=0.0003).
AKNOWLEDGMENT
There are no potential relationships with industry to disclose, other than Dr. Bonow, who has a consulting relationship with Edwards Life Sciences. This consultanship focuses on percutaneous aortic valve implantation technology and not on surgical aortic valve replacement per se
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