Article Text
PDF
Abstract
Objective We aimed to describe the progression rate into manifest aortic stenosis (AS) in subjects with normal aortic valves or in an early phase of calcific aortic valve disease.
Methods Participants were recruited from the Tromsø Study, a population-based health survey. In our prospective cohort study, we performed two echocardiographical examinations (2001 and 2008) of a random sample of 1884 participants. AS was defined as a mean aortic valve gradient ≥15 mm Hg or a peak flow exceeding 2.6 m/s. Those with lesser values were stratified into three groups based on mean gradients (cut-off 5 and 10 mm Hg) and peak aortic flow (cut-off 1.5 and 2 m/s).
Results At baseline, 71 participants had gradients from 10 to 14.9 mm Hg, of whom 32.4% developed AS during follow-up. AS developed in only 3.6% of those with a baseline gradient of 5–9.9 mm Hg and in 0.3% of those with a gradient <5 mm Hg. Almost identical separations were obtained among the three flow velocity groups. Of the 45 subjects who developed incident AS, 56% acquired mild, 33% moderate and 11% severe AS. Their mean gradient progression rate was 2.7 mm Hg/year.
Conclusions The results support that subjects with a mean aortic valve gradient of 10–15 mm Hg or aortic flow >2.0 m/s should be followed routinely. This group identifies about half of those who develop AS in the following 7 years.
Statistics from Altmetric.com
Introduction
Subclinical degenerative aortic valve disease is a common condition, often detected either by a systolic ejection murmur on physical examination or incidentally by echocardiography. However, estimates both on prevalence and prognosis of the condition varies widely.1–6 Guidelines of today do not tell whether follow-up of gradients/flows in the upper normal range is necessary.7 ,8 Previously, we reported longitudinal population-based prospective data on prevalence, incidence and progression rate of aortic stenosis (AS).9 These data also gave an opportunity to study the progression rate in the early phase of the disease. We, therefore, aimed to describe the progression into manifest valvular AS in a population cohort consisting of participants with normal valves or minor aortic valve disease.
Methods
Study population
The Tromsø Study was initiated in 1974 and is an ongoing population-based cohort study in the municipality of Tromsø, a city in Northern Norway with 70 000 inhabitants. The cohort consists of complete birth cohorts and random population samples examined in 1974, 1979, 1986, 1994, 2001 and 2008.10 A total of 40 051 citizens participated in at least one of the surveys, attendance rates being >75% in the first five surveys and 66% in 2008. Details on the study design and rationale have been published previously.9–11
At baseline, 66 subjects had prevalent AS and were excluded. The remaining 1884 participants had an echocardiographical examination performed in 2001 and constitute the baseline population of this study (figure 1). After 7 years, a total of 227 subjects had died, 66 had moved out of the region and 485 were non-attendees in 2008, leaving 1106 for follow-up by second screening.
Flowchart of the study. Hospital data: participants who did not attend the follow-up screening or died during the survey were followed through hospital records. AS, aortic stenosis.
In addition, we retrospectively integrated data from the only hospital serving the study population. We retrieved inhospital and outpatient records from all except those who had moved. We searched for both International Classification of Diseases (ICD) 9 (424.1, n=115) and ICD 10 (I 35.0 n=159, I 35.2 n=42) coding of the disease as well as AS-related surgery codes in The Nordic Medico-Statistical Committee (NOMESCO) Classification of surgical procedures. Reading through all retrieved patient journals, we avoided registration of patients with isolated aortic regurgitation (AR) or only aortic sclerosis (Asc). Among data registered were hospital diagnosis of AS, the first and last measured aortic mean gradient and examination dates.
Due to the scattered arctic population, the distance to the closest hospital treating AS exceeds 1000 km. Further, there are no private practising cardiologists in the region, murmurs detected by general practitioners are generally referred with a low threshold, making it reasonable to assume that the database included almost all clinically detected cases. Through this combined use of screening and hospital data, we were able to follow 1818 subjects (attendees, non-attendees and dead).
Echocardiography
Comprehensive transthoracic echocardiography was performed in all subjects using an Acuson Sequoia C256 or C512 with a combined 3.5 MHz second harmonic ultrasound and 2.5 MHz Doppler probe (Acuson, Mountain View, California, USA). M-mode and 2D echocardiograms with Doppler analysis were obtained for all participants.
As our primary baseline observation we used two simple Doppler measurements of aortic valve obstruction, mean aortic valve gradient and peak aortic flow. These were measured by continuous-wave Doppler recordings from the apical four-chamber view. Mean pressure gradients across the valve were calculated with the modified Bernoulli equation. AR was defined and staged by measuring the vena contracta. LV diameters were measured from 2D-guided M-mode echocardiography. A morphological evaluation of the aortic valve was not part of the protocol. Regarding further details on the echocardiographical examination, we refer to our recently published article.9
AS was defined to be present either if the transvalvular mean gradient was ≥15 mm Hg or, as defined by American Society of Echocardiography (ASE)/European Association of Echocardiography (EAE), if the aortic jet velocity was >2.6 m/s. Observational studies have shown that a mean aortic valve gradient of 20 mm Hg corresponds to a peak aortic jet velocity of 3 m/s.12 Also, in native AS the mean transaortic pressure gradient correlates closely and linearly with the maximum gradient, accordingly the mean gradient can be approximated from the published regression equation as ΔP=2.4 (Vmax)².13 AS was graded as follows: mild AS ≥15–25 mm Hg, moderate AS ≥25–40 mm Hg and severe AS ≥40 mm Hg.12
Participants with baseline values below the limits for AS were stratified into three groups: mean gradients <5 mm Hg, 5–9.9 mm Hg and 10–14.9 mm Hg or flow rates of ≤1.5 m/s, >1.5–2.0 m/s and >2.0–2.6 m/s.
The Bland Altman test of 42 participants showed mean interobserver differences (95% limits of agreement) in the mean aortic gradient of −0.06 mm Hg (−3.06 to 3.18). Intraobserver analysis gave a mean difference of −0.04 mm Hg (−1.86 to 1.78) and 0.30 mm Hg (−3.96 to 4.56).
Statistics
We observed the incidence of AS according to their mean aortic valve gradient and maximal aortic jet velocity at baseline. Data comparisons were performed according to the presence or absence of incident AS using the Student's unpaired t test or χ2 test as appropriate. We used simple and multivariate logistic regression to analyse predictors of progression to AS (age, sex, peak aortic jet velocity, mean aortic valve gradient, aortic cusp separation and aortic diameter). In the multivariate analysis, aortic jet velocity was excluded due to colinearity with the mean aortic gradient. Participants with missing data on aortic cusp separation (n=82) and aortic diameter (n=62) were excluded from the multivariable analysis. Survival analysis was performed using Cox proportional hazards regression. Values of p<0.05 were considered significant. All statistical analyses were performed using SPSS, V.19.0.
Ethics
The study was approved by the regional ethical committee. All participants gave written consent to scientific use of the health survey data and linkage to death and health registries. Our study complies with the Declaration of Helsinki.
Results
Baseline characteristics of the 1884 study subjects are shown in table 1. When stratified by their mean aortic valve gradient, the three groups from 0 to 5, 5 to 9.9 and 10 to 14.9 mm Hg had a prevalence of 66.8%, 29.3% and 3.9%, respectively. Based on peak flow rate, the corresponding prevalences were 68.1%, 26.7% and 5.2%.
Baseline data
During the second screening, 26 new cases of AS were detected. In addition, 19 subjects not attending the second screening were diagnosed with AS at the hospital, thus increasing the total number of incident AS to 45 (figure 1). Those developing AS during follow-up had a 5.5 years higher mean age than the remaining study group (p=0.001) and a smaller cusp separation at baseline (p<0.001). Within the AS group, we found an increasing mean aortic gradient at baseline associated with a decreasing cusp separation. Mild AR was present in 11 (24.4%) of the 45 subjects who developed AS. In those without AS during follow-up, the presence of AR was 14.7%.
Only one subject in the AS group had a reduced LV function at baseline, developing a mild AS during follow-up.
Figure 2 displays the number of participants that developed mild (56%), moderate (33%) and severe AS (11%), stratified by their baseline mean aortic gradient.
Aortic stenosis (AS) stage in 2008. The left y-axis and bar graph show the numbers and stage of AS in participants stratified by the mean aortic valve gradient at baseline. The right y-axis and line graph show the percentage of AS development in the three groups stratified by mean gradient.
In the group with an initial mean aortic valve gradient of 0–4.9 mm Hg, only 0.3% (3/1215) progressed to manifest AS (table 2). In those with a baseline gradient of 5–9.9 mm Hg, 3.6% (19/532) developed AS. In contrast as many as 32.4% (23/71) progressed to AS in the group with a baseline mean gradient of 10–14.9 mm Hg. Thus, there was an exponential 10-fold increase in the risk of developing AS going from one mean gradient group to the next. Nineteen participants with mean aortic gradients at baseline of 10–14.9 mm Hg (n=71) had mild AR in 2001, two were graded as moderate and one as severe. AS developed only in those with mild AR.
Study participants stratified by aortic valve mean gradient
When using the maximal aortic velocity as the stratifying parameter, five participants were excluded due to baseline velocities above the cut-off at 2.6 m/s, thus already fulfilling the criterion for AS. The incident number of AS was reduced to 42, which modified, but did not change the main result of the study, as the group with peak flow from >2.0 to 2.6 m/s still had 25.3% incident cases of AS (table 3).
Progression to aortic stenosis
Exclusion of subjects with hospital identified AS from the calculations did not alter the estimates of progression to AS, as shown in table 3.
We evaluated those with a progression of the mean aortic gradient >5 mm Hg among those (1106) attending the follow-up in 2008. This was present in all patients with incident AS. Sixteen participants without AS also had a progression >5 mm Hg. A 7-year progression >5 mm Hg was found to be a significant predictor of incident AS (p<0.001).
Simple logistic regression analyses identified mean aortic valve gradient, aortic cusp separation, aortic jet velocity and age as significant predictors of developing AS. In multivariate analyses, the mean aortic gradient and aortic cusp separation were significant predictors. Comparing the 10–15 mm Hg and the 5–10 mm Hg groups gave an OR for developing AS of 8.52, 95% CI 4.0 to 18.0. The OR for incident AS for a cusp separation <1.6 cm was 2.70 (95% CI 1.19 to 6.25).
Using an age-adjusted Cox regression analysis, we did not find a significant difference in death rate (p=0.239) for the group with mean gradients of 10–14.9 mm Hg compared with those with gradients of <10 mm Hg at baseline.
The progression rate during the 7-year follow-up among those developing AS shows a wide range from 0.7 to 12.6 mm Hg/year (figure 3). The mean progression rate was 2.7 mm Hg/year (SD 1.6). It is in accordance with our previous progression analysis indicating a non-linear development of the disease, being more rapid with increasing mean gradient.9 Regardless of the initial gradient, participants did, however, show a large interindividual variability in progression.
Progression of small aortic gradients to aortic stenosis. The figure delineates the progression of the mean aortic valve gradient in subjects developing aortic stenosis during follow-up.
Discussion
Small increases in aortic gradients and flow as risk factors of AS
Our main result was that of a 10-fold increase in risk of developing AS for each step in mean gradient or flow velocity. In about one-third of the subjects with the highest gradients or flows at baseline, AS developed over the subsequent 7 years, constituting only about 4%–5% of the population, but contributing about half the number of subjects developing AS over the period. The mean gradient provided a slightly but not significantly better index for prognostication than peak aortic flow, with predictive values of 32% and 25%, respectively.
If the mean aortic gradient was 10–15 mm Hg and/or the aortic cusp separation was <1.6 cm, we would detect 67.5% of those developing AS 7 years later. However, this group constitutes 9.4% of the population, and would indicate a screening sensitivity of only 18%.
Methods and definitions
Doppler measurements are probably less subjective and more reproducible than morphological observations of the valve, either by echocardiography or by radiology. The clear stepwise increase in risk of developing AS with increasing mean gradient and flow may be said to substantiate our choice of measurement.
We applied a strict physiological Doppler-based grading of valve lesions both for those with ‘normal and slightly elevated’ gradients and for manifest AS. In our previous studies, we have defined AS as a mean gradient >15 mm Hg; it is, therefore, consistent to keep this definition in further studies. It is also reasonable to apply the same method for subjects in the border-zone between normality and AS. In addition, we have provided data on peak aortic flow. Both mean valve gradient and peak flow are primary haemodynamic parameters recommended for clinical evaluation of AS severity.12 The mean gradient is slightly more reproducible than the peak gradient, corresponds best with invasive measurements and is less influenced by accompanying AR.14
Asc versus Doppler estimates
Asc is conventionally defined anatomically by irregular leaflet thickening and focal subendothelial plaque-like lesions on the aortic side of the leaflet without a haemodynamically significant obstruction of blood flow.15 Thus, defined Asc is a highly prevalent condition, being present in 21%–26% of subjects >65 years of age and with an increasing prevalence with age.1–3
Three previous studies regarding progression of Asc to AS have been reported.4–6 Two studies are retrospective, based on an echo database population and therefore vulnerable to selection bias. They reported progression to AS in 33% and 16% of patients after 44 months and 7.4 years, respectively.4 ,5 One prospective population-based study by Novaro et al6 observed a rate of progression to AS of 9% over a mean follow-up of 5 years. Thus, the progression estimates vary widely, maybe partly due to subjective evaluation of morphology in these studies. These studies do not give hope of a sufficient sensitivity for selecting subjects for a regular follow-up.
Screening by stethoscopy might provide an alternative to echocardiographical imaging or Doppler. Recently, a Norwegian study showed that healthy men aged 40–59 years with a low-grade or moderate-grade systolic murmur after 35 years of follow-up had a 4.7-fold and 89-fold increased risk of having aortic valve replacement, respectively, compared with the population without a murmur.16 Today, most of these subjects will sooner or later be referred to echocardiography.
Follow-up
Recommendations regarding follow-up of small or moderate risk factors for developing disease should always be made with caution. The follow-up programme should depend on the resources in the healthcare system and in particular the availability of modern echocardiography. The level of the control system should also be dependent on other clinical and echocardiographical observations, for instance, the presence of AR and aortic root dilatation. It should also be remembered that disease progression may be picked up by a number of other clinical methods, for instance, cardiac auscultation. With these reservations, however, we would, based on the present data, recommend that subjects with aortic gradients or flow rates in the upper stratum should be followed routinely by echocardiography at about 5 years intervals. Those who regress to lower strata may be dropped from follow-up. Subjects with lower gradients or flow should probably be followed on clinical indications only. The large interindividual variability in progression rate should always be remembered.
Today, a large number of individuals with some evidence of imminent aortic valve disease are subjected to regular control systems. If the suggested rules are followed, a number of unnecessary controls of subclinical aortic valve disease may probably be avoided.
Limitations
In this study, we have used two simple and highly correlated Doppler measurements as a basis for follow-up of this population. Both measurements have their limitations, primarily because the subvalvular aortic flow was not taken into account. However, we found that this was the only possible approach for a prospective longitudinal study. The results may be said to corroborate this view.
The assumptions behind the modified Bernoulli equation may not be entirely valid in low-flow conditions. Nevertheless, we found the mean gradient to be a slightly better predictor of progression than peak flow.
The overall prevalence of AR (14.9%) is comparable with a previous population study.17 AR was present in 19 of 71 subjects in the high risk group. This could have contributed to a ‘falsely high’ mean aortic valve gradient/jet velocity, and thus represent an inclusion bias. We believe that the chances of such misclassification of AS are scarce since all regurgitations in participants developing AS were mild. However, also regurgitation as such might warrant follow-up.
Among those followed only through hospital data, cases of AS may have been missed. However, the incidence of AS was somewhat higher in this group (2.7%/7 years) than in those attending the second screening (2.4%/7 years). The underestimation of risk due to this limitation is therefore probably small. None of the factors influencing the development of AS were differently distributed between the rescreened group and the hospital group. In particular, there were no differences in baseline gradient/flow, which is by far the factor that mostly influences the development of AS.11
Conclusions
When mild aortic valve obstruction is present, the mean aortic gradient and aortic jet velocity are major factors predicting progression to AS. These measurements alone make it possible to define a small proportion of subjects in need of follow-up.
With reservations discussed above, we will make the following recommendations for echocardiographical and clinical follow-up of subjects in whom mild aortic valve disease is suspected:
Subjects with a mean aortic gradient in the range of 10–15 mm Hg or a maximal aortic jet velocity from 2.0 to 2.6 m/s should be followed routinely at approximately 5 years intervals.
Subjects with a gradient in the 5–10 mm Hg range or a jet velocity of >1.5–2.0 m/s should be informed and be controlled when clinically indicated.
Subjects with smaller gradients or jet velocities do not need any specific follow-up.
Key messages
What is already known on this subject?
We know that calcific degenerative aortic valve disease is a prevalent condition in the elderly population and that the progression rate varies widely. Also, a large number of subjects with clinical or morphological evidence of early aortic valve disease, often termed as aortic sclerosis, are followed by the healthcare system. However, guidelines of today do not tell whether follow-up of subclinical gradients or flow rates is necessary.
What might this study add?
The main finding was that about one-third of the participants with a baseline mean aortic gradient of 10–14.9 mm Hg and/or an aortic jet velocity >2 m/s developed aortic stenosis (AS) during 7 years, in contrast to only 3.7% in those with a mean gradient of 5–9.9 mm Hg and 0.3% when the gradient was <5 mm Hg.
How might this impact on clinical practice?
Our study defines a small fraction, about 4% of the population, with a substantial risk of developing valvular AS. We recommend regular echocardiographical follow-up at about 5 years’ interval of the group with mean aortic gradients of 10–14.9 mm Hg and/or an aortic jet velocity >2 m/s. Simultaneously, the study indicates that a large number of subjects with evidence of none or only minor aortic valve pathology have a low risk of developing the disease.
References
Footnotes
Contributors All authors have read and approved the manuscript. They have also sufficiently contributed to the conception and design of the study, analysis and interpretation of the data, drafting of the manuscript or revising it to justify authorship.
Funding This study was supported by the Northern Norway Regional Health Authorities (PhD grant number SFP-727–08).
Competing interests None declared.
Ethics approval by REK nord (the Regional Ethical Committee in North Norway).
Provenance and peer review Not commissioned; externally peer reviewed.