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J Am Coll Cardiol, 2002; 40:1723-1730 © 2002 by the American College of Cardiology Foundation |
* Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Manuscript received March 20, 2002; revised manuscript received August 1, 2002, accepted August 26, 2002.
* Reprint requests and correspondence: Dr. Maurice Enriquez-Sarano, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
Sarano.Maurice{at}mayo.edu
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Abstract |
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BACKGROUND: Aortic stenosis is a progressive disease for which there is no known medical treatment to prevent or slow progression. Despite plausible pathologic mechanisms linking hypercholesterolemia to AS progression, clinical studies have been inconsistent and affected by referral bias, and the role of lipid-lowering therapy is uncertain.
METHODS: We determined the association between blood cholesterol levels and progression of native AS (assessed by Doppler echocardiography at baseline and at least six months later; mean interval, 3.7 ± 2.3 years) in a community-based study of 156 patients (age 77 ± 12 years; 90 men). Thirty-eight patients received statin treatment during follow-up.
RESULTS: In untreated subjects, mean gradient increased from 22 ± 12 mm Hg to 39 ± 19 mm Hg, and aortic valve area (AVA) decreased from 1.20 ± 0.35 cm2 to 0.91 ± 0.33 cm2 (both p < 0.001). The annualized change in AVA was –0.09 ± 0.17 cm2/year (–7% ± 13%/year). Neither total cholesterol (r = –0.01, p = 0.92) nor low-density lipoprotein cholesterol (r = 0.01; p = 0.88) showed a significant correlation to AS progression. Nevertheless, progression of AS was slower in patients receiving statins compared with untreated patients (decrease in AVA –3 ± 10% vs. –7 ± 13% per year, respectively; p = 0.04), even when adjusted for age, gender, cholesterol, and baseline valve area (p = 0.04). The association of statin treatment with slower progression was confirmed when analysis was restricted to patients coming for a systematic follow-up (p=0.02). The odds ratio of AS progression with statin treatment was 0.46 (95% confidence interval, 0.21 to 0.96).
CONCLUSIONS: In the community, progression of AS shows no trend of association with cholesterol levels. Statin treatment, however, is associated with slower progression, suggesting that the effects of statin treatment on progression of AS should be pursued with appropriate clinical trials.
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However, human studies of the association of AS and hyperlipidemia have been inconsistent. Some have shown a positive association (6–11), but were balanced by others demonstrating only a weak or absent association (12–16). This inconsistency may be due to design issues; positive association of cholesterol levels with AS severity was observed in studies using single rather than sequential examinations to determine progression (7–9), or in which patients with renal failure may have skewed results (10). These limitations, and the referral bias to which all referral center studies were subject, also influence evaluation of treatment effect (6,17). There are concerns that those patients with hyperlipidemia and progressive AS may be overrepresented in studies, and that reasons for follow-up (progression of AS symptoms vs. hyperlipidemia) may lead to spurious associations of lipid levels with AS progression. Therefore, further human studies are needed, not only to ascertain AS progression and its association with lipid levels, but also to assess treatments taken and reasons for follow-up, which can be best defined in community-based studies. Association between elevated cholesterol and AS progression would support conduct of a randomized clinical trial of lipid-lowering drugs, particularly statins, which have proven clinical benefits (18).
The Rochester Epidemiology Project, based in Olmsted County, Minnesota (19), is a population-based data resource allowing identification of all patients with AS who have undergone assessment by a single-core echocardiographic laboratory and where reasons for evaluation and drug treatments are consistently recorded. We performed this community-based study to answer two specific questions: First, is AS progression in the community correlated with cholesterol levels or other risk factors? Second, is AS progression slower in subjects receiving lipid-lowering treatment, particularly statins?
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Methods |
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18 years) with AS in Olmsted County, Minnesota, from January 1987 to March 2000. Clinical, laboratory, and echocardiographic data were utilized, unaltered via electronic transfer.
Eligibility criteria
Inclusion criteria were as follows: evaluation of native AS with Doppler aortic mean gradient (MG) 10 mm Hg and aortic valve area (AVA) 
2.0 cm2, coinciding with cholesterol level measurement, consent to research, and a second echocardiographic assessment of AS separated by 6 months. The follow-up echocardiogram was the latest performed or the last before valve surgery.
Exclusion criteria were presence of congenital heart disease (other than bicuspid aortic valve), overt history and echocardiographic features of rheumatic heart disease, creatinine 2.0 mg/dl, lipid-lowering treatment without statin, subaortic obstruction precluding measurement of AVA, aortic regurgitation >mild, and previous aortic valve surgery, repair, or decalcification.
Clinical data
Clinical data prospectively collected by attending physicians included age, gender, etiology of valvular stenosis, smoking history, and documented diagnoses of hypertension, diabetes, and coronary disease (history of myocardial infarction or coronary obstruction on coronary angiography). At baseline and follow-up, symptoms, heart rhythm, and blood pressure were recorded with prospectively obtained laboratory results for serum total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), calculated low-density lipoprotein cholesterol (LDL-C), calcium, phosphate, and creatinine. The last follow-up visit was classified as motivated by new symptoms for patients with symptomatic progression or as a systematic follow-up for patients followed routinely without symptomatic progression. Complete drug treatment received could be defined from all Olmsted County health care providers.
Echocardiographic methods
Comprehensive transthoracic echocardiograms were performed within a single echocardiographic laboratory, with stable guidelines for Doppler echocardiography whether patients had symptoms or not. Immediate physician review (level III) allowed re-imaging for quality control. Doppler of left ventricular outflow tract and of aortic valve from multiple windows to obtain the maximum velocity were recorded (20,21). This approach provides accurate peak velocity, MG, and AVA using continuity equation (21). All data were used as originally reported.
Statistical analysis
Data are presented as mean ± SD. Group comparisons used t test, chi-square as appropriate. Comparisons of baseline and follow-up data used paired t test. Changes in MG, aortic peak velocity, dimensionless index, and AVA were major end points for analysis. The dimensionless index was the ratio of left ventricular outflow tract velocity to aortic peak velocity. Changes in AS severity were expressed as difference between baseline and follow-up data, annualized rate of change, and percent annualized change (proportion of baseline). Stepwise multiple linear regression defined independent determinants of AS progression, and logistic regression defined odds ratios of progression to specific thresholds. The association of statin treatment with AS progression was adjusted for baseline AVA and for age, gender, and other predictors of faster progression. A value of p < 0.05 was considered statistically significant.
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Results |
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Untreated subjects. In 118 untreated subjects, age was 78 ± 12 years with 51% men. Most were asymptomatic; dyspnea or chest pain was noted in only 3% and 7%, respectively, but these symptoms were considered unrelated to AS. Baseline characteristics are presented in the left column of Table 1. Aortic stenosis was on average moderate at baseline, with MG of 22 ± 12 mm Hg and AVA of 1.20 ± 0.35 cm2. Atherosclerotic risk factors were highly prevalent, and TC level (214 ± 45 mg/dl) showed a wide range (122 to 391 mg/dl).
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Mean interval between echocardiograms was 3.7 ± 2.3 years. Aortic MG increased from 22 ± 12 mm Hg to 39 ± 19 mm Hg and AVA decreased from 1.20 ± 0.35 cm2 to 0.92 ± 0.33 cm2 (both p < 0.01) (Table 2). Annualized decrease in AVA was –0.09 ± 0.17 cm2 per year or –7 ± 13% per year. Aortic stenosis progression was similar in 17 subjects with bicuspid valves and 101 subjects with degenerative valves: MG increased from 20 ± 10 mm Hg to 41 ± 21 mm Hg for bicuspid valves versus 22 ± 13 mm Hg to 39 ± 19 mm Hg for degenerative valves (p = 0.28), and AVA decreased from 1.33 ± 0.35 cm2 to 1.05 ± 0.35 cm2 (change = –0.28 ± 0.34 cm2) versus 1.17 ± 0.35 cm2 to 0.89 ± 0.33 cm2 (change = –0.28 ± 0.29 cm2), respectively (p = 0.97). Follow-up duration (3.8 ± 1.9 years vs. 3.7 ± 2.4 years, p = 0.85) and annualized change in AVA (–0.07 ± 0.09 cm2 vs. –0.09 ± 0.18 cm2/year; p = 0.56), even adjusted for body surface area (p = 0.40), were also similar.
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Association of cholesterol levels with progression of AS
Neither the direct difference in AVA between baseline and follow-up (r = 0.01, p = 0.26) nor the annualized change in AVA (r = 0.01, p = 0.88) correlated with TC levels. Similarly, no correlation was observed for progression of AS and LDL-C (direct difference, r = 0.07, p = 0.50; annualized change, r = 0.01, p = 0.94). There was no correlation of cholesterol level with other measures of AS progression (MG, peak velocity, and dimensionless index), even excluding bicuspid valves (all p > 0.42).
There was no difference in annualized change in AVA (–0.09 ± 0.19 cm2/year vs. –0.09 ± 0.12 cm2/year, respectively; p = 0.40) according to TC level or <200 mg/dl or according to LDL-C level or <120 mg/dl (p = 0.29). Untreated subjects were also divided according to quartiles of TC concentration (<183, 183 to <207, 207 to 237, and >237 mg/dl). There was no relationship between TC quartiles and annualized changes in MG, peak velocity, or AVA unadjusted or adjusted for body surface area (Fig. 1). In fast-stenosis progressors (annualized AVA decrease median or –0.07 cm2/year), neither TC (207 ± 45 mg/dl vs. 221 ± 43 mg/dl, p = 0.11) nor LDL-C (134 ± 43 mg/dl vs. 142 ± 43 mg/dl, p = 0.45) differed from slower progressors. Finally, there was no correlation between follow-up (or difference baseline-follow-up) TC or LDL-C and any measure of AS progression (all p > 0.40).
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Subjects treated with statins
Treated subjects were slightly younger than those untreated, but they had more prevalent risk factors and clinical coronary disease and higher triglycerides, TC, and LDL-C (Table 1) as part of the indication for statin treatment. Baseline AVA was also slightly larger (p = 0.04) in treated patients, a factor associated with faster progression.
Follow-up was 3.7 ± 2.1 years, identical to untreated subjects (p = 0.94), and the duration of statin treatment was 2.9 ± 1.7 years (78%). The drugs used were mostly simvastatin (n = 13) or lovastatin (n = 13). During follow-up, TC and LDL-C decreased (both p < 0.01, Table 2). Comparing statin-treated with untreated patients, follow-up TC (p=0.30) and LDL-C (p = 0.78) were not different, whereas triglycerides remained borderline higher (160 ± 66 mg/dl vs. 135 ± 69 mg/dl, p = 0.08).
Progression of AS in statin-treated subjects
New symptoms occurred in 7 patients (18%) (dyspnea in 4, chest pain in 2, both in 1) and systematic follow-up was obtained in 31 subjects (82%) with unchanged clinical status.
There was AS progression with MG increasing (18 ± 7 mm Hg to 27 ± 12 mm Hg), peak velocity increasing (2.8 ± 0.5 m/s to 3.4 ± 0.7 m/s), and AVA decreasing (1.32 ± 0.29 cm2 to 1.13 ± 0.35 cm2, all p < 0.01). Annualized AVA decrease was –0.04 ± 0.15 cm2/year or –3 ±10%/year. Compared with untreated subjects and adjusting for baseline AVA differences, statin-treated subjects had markedly smaller annualized increase in peak velocity, decrease in dimensionless index, and decrease in AVA (Table 3).
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–5%/year (group median), the odds ratio (Fig. 2, Table 3) of progression with statin treatment was 0.46 (95% confidence interval [CI], 0.21 to 0.96) and remained unchanged even after adjustment for age, gender, and baseline AVA (odds ratio, 0.46; 95% CI, 0.21 to 0.98).
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5 mg/dl versus <5 mg/dl, there was no difference in annualized AVA decrease (–0.08 ± 0.15 vs. cm2/year –0.07 ± 0.10 cm2/year, p = 0.77). This result was similar stratifying for a decrease in LDL-C of 5 versus <5 mg/dl (p = 0.70). Also, there was no difference between rapid (AVA decrease –5%/year) and slow progressors regarding follow-up triglycerides, TC, HDL-C, and LDL-C levels (all p > 0.60).
Statin treatment and AS progression in patients with systematic follow-up
Patients with symptom increase warranting follow-up examination presented with lower AVA at baseline (1.1 ± 0.36 cm2 vs. 1.28 ± 0.32 cm2, p = 0.006) and follow-up (0.82 ± 0.35 cm2 vs. 1.04 ± 33 cm2, p < 0.001) and with larger MG increase (+19 ± 17 mm Hg vs. +13 ± 14 mm Hg, p = 0.035) than patients examined systematically. As increased symptoms were more frequent in untreated patients (35% vs.18%, p < 0.05), we examined statin treatment effect in the 108 patients coming for systematic follow-up.
In patients with systematic follow-up (n = 108), statin-treated (n = 31) compared with untreated (n = 77) patients had an identical follow-up (p = 0.98) and baseline AVA (1.33 ± 0.28 cm2 vs. 1.26 ± 0.34 cm2, p = 0.29) but less AS progression. Mean gradient increase (+8 ± 9 mm Hg vs. +15 ± 15 mm Hg, p = 0.01) and AVA decrease (–0.01 ± 015 cm2/year vs. –0.09 ± 0.19 cm2/year, p = 0.04) were slower in statin-treated patients. Odds ratio of AVA progression –5%/year in statin-treated patients was 0.34 (95% CI, 0.13 to 0.82; p = 0.02) unadjusted (Fig. 2) and 0.31 (95% CI, 0.11 to 0.81; p < 0.03) after adjustment for age, gender, baseline cholesterol level, and AVA.
Subjects eligibility
As eligibility criteria may affect results, we examined all patients with AS in Olmsted County. First, patients without follow-up echocardiogram (n = 583) did not allow assessment of AS progression but had identical baseline characteristics (age 75 ± 13 years, MG 22 ± 15 mm Hg, AVA 1.26 ± 0.40 cm2, and cholesterol 204 ± 45 mg/dl), showing that our study population is representative of all patients with AS. Second, a baseline cholesterol level measurement is indispensable to assess cholesterol’s relation to AS progression. Aortic stenosis progression was similar in subjects without baseline cholesterol (n = 47, –0.08 ± 0.17 cm2/year) and study patients. Third, lipid-lowering treatment without statin was rarely taken (n = 11) and involved fibrate in seven patients, niacin in three, and cholestyramine in one. In these subjects, changes in MG (+21 ± 18 mm Hg), AVA (–0.36 ± 0.33 cm2), and annualized AVA decline (–0.13 ± 0.05 cm2/year) were similar to untreated patients (all p > 0.40) despite a notable LDL-C decrease (–30 ± 23 mg/dl, p = 0.69 vs. statin treatment).
To examine if limited power caused the lack of correlation between TC and AS progression, we analyzed 729 patients with AS (without intervening AVR or endocarditis) not from Olmsted County. Baseline AVA, MG, and cholesterol (1.26 ± 0.34 cm2, 22 ± 11 mm Hg, 213 ± 46 mg/dl, respectively) were similar to our study group, and decline of AVA (–0.08 ± 0.19 cm2/year) was unrelated to cholesterol level (r < 0.01, p = 0.81). Hence, increased power does not affect results.
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Discussion |
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The cholesterol hypothesis of AS progression. Degenerative AS lesions involve calcifications of leaflets, which become rigid and obstruct blood flow, and these lesions differ from rheumatic ones (commissural fusion). The initial lesion, valve sclerosis, is a deposition of lipids (22), which are oxidized similarly to atherosclerosis (4). Also similar to atherosclerosis, lipoproteins are present (3), with co-localization of calcifications (22), which are actively regulated (23). Not surprisingly, atherosclerotic risk factors are frequent in patients with aortic sclerosis defined by echocardiography (7) or by computed tomography (24). These observations have been the basis for the cholesterol hypothesis of AS and for the interest raised by the possibility for medical treatment of a condition that has none.
However, AS and sclerosis are different: AS has overgrowth of calcium, which may have its own determinants independent of cholesterol levels (25). Therefore, it is important to analyze hyperlipidemia, not for its case-control association with presence of valve sclerosis (7–9,12), but for its temporal association with AS progression. Indeed, AS progression is consistently observed (26), but at a variable rate (27), and fast progression leads to poor outcome (15). Studies linking AS progression and hyperlipidemia have been unconvincing and contradictory (10,11,15). All were limited by major referral bias. The largest "positive" study found faster progression with cholesterol 200 mg/dl, but overall showed strictly no correlation between cholesterol and AS progression (10). In our community-based study, with the longest available follow-up, we found that in untreated subjects neither TC nor LDL-C levels predicted AS progression. This lack of correlation between lipid levels and AS progression was also confirmed using all possible statistical approaches. Similarly, other atherosclerotic risk factors were not associated with AS progression.
Thus, although AS starts as an atherosclerotic process, as shown in our community by the association of aortic sclerosis and atherosclerosis (28), severity of atherosclerotic risk factors, particularly cholesterol level, does not affect AS progression measurably (10). However, this observation should not be taken to suggest that mechanistic anti-atherosclerotic treatment of AS should not be tested. Indeed, in vascular atherosclerosis cholesterol levels correlate poorly to anatomic progression of disease (29,30). Nevertheless, statin treatment improves anatomic atherosclerotic lesions (31) and considerably improves clinical outcome even in patients without hyperlipidemia. Using that similarity, it is crucial to analyze the statin treatment effect on AS progression.
Pleiotropic effects of statins
The suggested effect of statins in reducing AS progression (6,17) stems from the mechanistic similarities between atherosclerosis and AS. However, this effect may be overestimated because of confounding association with renal failure. Importantly, referral bias in general, and particularly related to hyperlipidemia and frequent coronary disease in patients treated with statins, may lead to spurious effects. Repeated examination, indispensable for assessment of AS progression, may be misleading, as patients returning for systematic evaluation of hyperlipidemia have a less severe and less progressive AS than patients returning for symptomatic AS progression. This raises concerns that stated statin effects may be overestimated (6,17). Therefore, focusing on community patients rather than on those distantly referred to major centers, prospectively recording therapies, and confirming observations among patients systematically evaluated are essential steps in linking statins to reduced AS progression. Indeed, despite unassociated cholesterol levels and AS progression, statin-treated patients demonstrate much slower AS progression, with odds ratio of progression between 0.38 and 0.48. No other treatment showed a trend for such a preventive effect. This observation does not replace randomized clinical trials in establishing therapeutic effects of statins in AS, but is a seminal and strong suggestion that a trial is warranted in patients with and without hyperlipidemia, as AS progresses equally fast in both groups. The observation that AS progression is unrelated to cholesterol levels but is markedly slowed by cholesterol-lowering treatment is challenging and raises questions about potential mechanisms of this effect.
Aortic stenosis formation and progression is complex and, although called "degenerative," is active. Lipoprotein deposition, aortic valvular inflammation (22), and simultaneous calcification and ossification (23,32,33) are involved. Indeed, AS is an inflammatory disease where excess tissue valvular adhesion molecules (34), metalloproteinase (35), and tenascin (36) link local inflammatory process and development of the hemodynamic valvular lesion. Furthermore, elevated blood levels of E-selectin (34), C-reactive protein (37), and tumor necrosis factor (38) demonstrate systemic inflammation in AS. In turn, active inflammation, even without overt hyperlipidemia, may be associated with increased disease risk, similar to atherosclerosis (39).
Statins have pleiotropic effects, including anti-inflammatory effects (40), with reduction of C-reactive protein independent of lipid changes (41). Statins depress leukocyte cell surface molecules required for monocyte adhesion and initiation of inflammation (42). Statins retard extra-osseous calcifications, as for coronary vessels (43), while they improve osseous calcifications, protect against bone fracture (44), stimulate bone morphogenetic protein production and increase bone formation (45). More research is needed, but one can propose that statins’ benefit may be related in part to their particular pleiotropic effects, anti-inflammatory together with stabilization of the early aortic valve lesion, retarding ossification and calcification.
Potential limitations
Echocardiographic assessment may have limitations but has been proven to be reliable and reproducible in our institution (20,21), and is now the main method on which surgical decisions are based in AS. Furthermore, dimensionless index, independent of annulus diameter, provided similar results to those obtained with AVA.
The degree of obstruction qualifying as AS is not well defined (2). However, patients with mildest baseline obstruction (MG 10 mm Hg to <20 mm Hg) progressed markedly (MG 14 ± 3 mm Hg to 30 ± 15 mm Hg, p < 0.001; AVA changed by –0.32 ± 0.04 cm2 vs. –0.22 ± 0.04 cm2 in patients with more severe AS, p = 0.10), showing that AS progression in these patients may lead to severe stenosis and should be prevented.
Our community study was powered to detect a correlation coefficient of r = 0.22. Lack of association between cholesterol and AS progression was supported by trends for greater progression with lowest cholesterol (Fig. 1) and by results in noncommunity patients, showing that with increased power, results are unchanged.
Conclusions
In our community, AS progression is unaffected by hyperlipidemia, cholesterol levels, or other atherosclerosis risk factors. Statin treatment, however, is associated with slower progression, suggesting an independent beneficial effect. This seminal observation supports the proposal for a clinical trial of statins in degenerative AS across the range of cholesterol concentrations.
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Acknowledgments |
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R. O. Bonow, B. A. Carabello, K. Chatterjee, A. C. de Leon Jr, D. P. Faxon, M. D. Freed, W. H. Gaasch, B. W. Lytle, R. A. Nishimura, P. T. O'Gara, et al. ACC/AHA 2006 Guidelines 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 (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease) Developed in Collaboration With the Society of Cardiovascular Anesthesiologists Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons J. Am. Coll. Cardiol., August 1, 2006; 48(3): e1 - e148. [Full Text] [PDF]
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