Author + information
- Received January 24, 2012
- Revision received March 1, 2012
- Accepted March 5, 2012
- Published online July 17, 2012.
- Romain Capoulade, MSc⁎,
- Marie-Annick Clavel, DVM, MSc⁎,
- Jean G. Dumesnil, MD⁎,
- Kwan L. Chan, MD†,
- Koon K. Teo, MBBcH, PhD‡,
- James W. Tam, MD§,
- Nancy Côté, MSc⁎,
- Patrick Mathieu, MD⁎,
- Jean-Pierre Després, PhD⁎,
- Philippe Pibarot, DVM, PhD⁎,⁎ (, )
- ASTRONOMER Investigators
- ↵⁎Reprints requests and correspondence:
Dr. Philippe Pibarot, Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec City, Québec G1V 4G5, Canada
Objectives The aims of this study were to examine prospectively the relationship between metabolic syndrome (MetS) and aortic stenosis (AS) progression and to evaluate the effect of age and statin therapy on AS progression in patients with or without MetS.
Background Despite the clear benefits of statin therapy in primary and secondary coronary heart disease prevention, several recent randomized trials have failed to demonstrate any significant effect of this class of drugs on the progression of AS. Previous retrospective studies have reported an association between MetS and faster AS progression.
Methods This predefined substudy included 243 of the 269 patients enrolled in the ASTRONOMER (AS Progression Observation: Measuring Effects of Rosuvastatin) trial. Follow-up was 3.4 ± 1.3 years. AS progression rate was measured by calculating the annualized increase in peak aortic jet velocity measured by Doppler echocardiography.
Results Patients with MetS (27%) had faster stenosis progression (+0.25 ± 0.21 m/s/year vs. +0.19 ± 0.19 m/s/year, p = 0.03). Predictors of faster AS progression in multivariate analysis were older age (p = 0.01), higher degree of valve calcification (p = 0.01), higher peak aortic jet velocity at baseline (p = 0.007), and MetS (p = 0.005). Impact of MetS on AS progression was most significant in younger (< 57 years) patients (MetS: +0.24 ± 0.19 m/s/year vs. no MetS: +0.13 ± 0.18 m/s/year, p = 0.008) and among patients receiving statin therapy (+0.27 ± 0.23 m/s/year vs. +0.19 ± 0.18 m/s/year, p = 0.045). In multivariate analysis, the MetS-age interaction was significant (p = 0.01), but the MetS-statin use interaction was not.
Conclusions MetS was found to be a powerful and independent predictor of faster AS progression, with more pronounced impact in younger patients. These findings emphasize the importance of routinely identifying and treating MetS in AS patients. The apparent faster stenosis progression in the subset of normocholesterolemic patients with MetS receiving the statin will need to be confirmed by future studies.
Recent studies suggest that calcific aortic stenosis (AS) is not a passive degenerative disease resulting from decades of repetitive mechanical stress, but rather an active disease that involves the interaction of several pathways, including lipid infiltration and retention, chronic inflammation, osteoblastic activation, and active mineralization within the aortic valve (1). This paradigm shift from a passive, purely degenerative disease to an active, atherosclerosis-like disease has opened the new and revolutionary perspective that AS may be a modifiable disease. Experimental animal studies as well as several retrospective clinical studies initially reported that low-density lipoprotein (LDL)-lowering therapy with statins may reduce stenosis progression (2–4). One open-label prospective study also reported that hypercholesterolemic patients treated with statins had significantly slower AS progression compared with normocholesterolemic patients with a similar degree of AS but who were left untreated (5). However, 3 subsequent randomized trials performed in normocholesterolemic patients (SALTIRE [Scottish Aortic Stenosis and Lipid Lowering Trial], SEAS [Simvastatin and Ezetimibe in Aortic Stenosis] trial, and the ASTRONOMER [AS Progression Observation: Measuring Effects of Rosuvastatin] trial) failed to demonstrate any significant effect of statins on either stenosis progression or occurrence of valve-related events (6–8).
In a single-center retrospective study of 105 patients with AS, we previously reported that MetS was associated with faster AS progression and with a higher rate of adverse events (i.e., aortic valve replacement [AVR], death, or both) (9). Other retrospective or cross-sectional studies also revealed independent associations between MetS and increased prevalence of aortic valve calcification (10) or faster degeneration of bioprosthetic aortic valves (11). These findings lend support to the hypothesis that MetS could be associated with faster AS progression independently of the traditional risk factors, and in particular LDL cholesterol level. The objectives of this predefined substudy of the ASTRONOMER trial (ISRCTN32424163) were: 1) to examine the relationship between the MetS and the progression of AS; and 2) to assess the effect of age and statin therapy on AS progression in the patients with or without MetS.
The design and core results of the ASTRONOMER trial have been reported previously (8,12). The design and protocol of the present substudy were established before the conduct of the main study.
The ASTRONOMER trial included 269 patients (age range: 18 to 82 years) with mild to moderate AS (peak aortic jet velocity [Vpeak]: 2.5 to 4.0 m/s) recruited in 23 Canadian sites between 2002 and 2005. Exclusion criteria were severe or symptomatic AS, severe aortic regurgitation, mitral valve disease (mitral stenosis or severe mitral regurgitation), symptomatic coronary artery disease, congestive heart failure, diabetes, or need for cholesterol-lowering treatment. Patients were randomized to rosuvastatin 20 mg versus placebo. Twenty-six patients (10%) were excluded from this substudy because waist circumference data, Doppler echocardiographic follow-up data, or both were not available. Hence, we analyzed the clinical, laboratory, and Doppler echocardiographic data of the 243 remaining patients (90%).
Clinical data included age, gender, history of smoking, documented diagnosis of hypertension (patients taking antihypertensive medications or with known but untreated hypertension: blood pressure ≥ 130/85 mm Hg) and randomization group (statin or placebo).
Weight, height, body mass index, and waist circumference were determined following the standard procedures (13).
Fasting blood samples were collected at baseline, 1 year, and last follow-up to obtain plasma levels of glucose, insulin, and creatinine and complete lipid profile, which included total cholesterol, triglycerides, LDL cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B using automated techniques standardized with the Canadian reference laboratory. After centrifugation, plasma samples were stored at −80°C until measurement of LDL particle size, as previously described (14). To assess insulin resistance, we calculated the homeostatic assessment model (HOMA) index using the formula: insulin (μU/ml)·[glucose (mmol/l)/22.5] (15).
Identification of Patients With Metabolic Syndrome
The clinical identification of patients with the features of MetS was based on the modified criteria proposed by the National Cholesterol Education Program–Adult Treatment Panel III (16).
Doppler echocardiographic data
The echocardiographers at each site received training in the acquisition and interpretation of the echocardiograms before the beginning of the study. Randomly selected studies that contributed 10% of the total number of echocardiograms were reviewed to ensure that the studies and measurements were performed in accordance with the protocol.
Aortic Valve Configuration and Function
The Doppler echocardiographic indices of AS severity included Vpeak, peak and mean transvalvular pressure gradients obtained with the use of the modified Bernoulli equation, and the aortic valve area (AVA) calculated by the standard continuity equation. The AVA could not be determined in 19% (n = 45) of the patients because of subvalvular flow acceleration or inadequate measure of left ventricle (LV) outflow tract diameter. The Doppler velocity index (DVI) was computed by dividing the flow velocity time integral in the LV outflow tract by the aortic jet velocity time integral. The degree of aortic valve calcification was scored (1: none; 2: mild; 3: moderate; 4: severe) according to the criteria proposed by Rosenhek et al. (17).
LV Geometry and Function
The relative wall thickness ratio was calculated by dividing the sum of the LV posterior wall and interventricular septal thicknesses by the LV internal dimension (18). LV mass was calculated with the corrected formula of the American Society of Echocardiography and was indexed to a 2.7 power of height (19). As a measure of global LV hemodynamic load, we calculated the valvuloarterial impedance (20): Zva = (SBP + ΔPmean)/SVi where SBP is the systolic blood pressure, ΔPmean is the mean transvalvular gradient, and SVi is the stroke volume indexed to a 2.04 power of height (19).
The primary outcome for this study was the progression rate of valve stenosis measured by Doppler echocardiography. To account for different follow-up lengths, annualized changes in peak aortic jet velocity, AVA, and DVI were calculated by dividing the total change by length of follow-up. The secondary outcome was the composite of AVR or cardiac death.
Continuous data were expressed as mean ± SD. The continuous variables were tested for normality of distribution and homogeneity of variances with the Shapiro-Wilk and Levene tests, respectively. These variables then were compared between patients with and without MetS using the unpaired Student t test. Categorical data were expressed as a percentage and were compared with the chi-square test. Multivariate linear regression analysis was performed to identify the independent predictors of faster AS progression (i.e., annualized progression rates of peak aortic jet velocity, AVA, and DVI). We entered in the multivariate model: 1) the variables with p value <0.10 in individual analysis; 2) the traditional cardiovascular risk factors (age, male gender, history of hypertension, LDL cholesterol, and history of smoking); 3) the aortic valve phenotype (bicuspid vs. tricuspid); and 4) the randomization status (statin vs. placebo). A second multivariate model was obtained by including the interaction terms: MetS·age and MetS·statin use. A 1-way analysis of variance followed by a Tukey post-hoc test was used to evaluate the effect of MetS and age (dichotomized according to the median value: 57 years of age) or statin therapy on stenosis progression. Kaplan-Meier curves and log-rank tests of the time-to-event data were used to assess the effect of MetS on the composite of AVR or cardiac death. The predictors of event-free survival were assessed with the use of individual and multivariate Cox proportional hazard analyses. Two- or 3-way analyses of variance for repeated measures followed by a Tukey post hoc test were used to determine the effect of treatment (statin vs. placebo), group (MetS vs. no MetS), and time (baseline vs. 1-year follow-up) on blood metabolic markers. A p value of <0.05 was considered statistically significant.
Baseline characteristics of the study population
Among the 243 patients included in this study (mean follow-up: 3.4 ± 1.3 years), 30% had systemic arterial hypertension, 46% had a history of smoking, and 27% had MetS according to the National Cholesterol Education Program–Adult Treatment Panel III criteria (Table 1). Baseline Doppler echocardiographic data showed significantly higher relative wall thickness ratio and LV mass index and a nonsignificant trend for lower prevalence of bicuspid aortic valve in the patients with MetS, whereas the degree of aortic valve calcification, Vpeak, transvalvular pressure gradients, AVA, DVI, and LV ejection fraction were similar in both groups (Table 1).
Impact of MetS on AS progression and interaction with age
AS progression rate was significantly higher in patients with MetS compared with those without MetS: annualized progression rate of Vpeak: +0.25 ± 0.21 m/s/year vs. +0.19 ± 0.19 m/s/year, p = 0.03 (Fig. 1A); annualized progression rate of AVA: −0.10 ± 0.06 cm2/year vs. −0.07 ± 0.07 cm2/year, p = 0.005; annualized progression rate of DVI: −0.025 ± 0.018 vs. −0.016 ± 0.019, p = 0.004. Baseline variables independently predicting Vpeak progression rate in multivariate analysis were older age (p = 0.01), higher degree of aortic valve calcification (p = 0.01), higher Vpeak at baseline (p = 0.007), and MetS (p = 0.005) (Online Table 1). MetS also was found to be an independent predictor of AVA (p = 0.03) or DVI (p = 0.02) progression rates.
The impact of the MetS on AS progression differed depending on patient's age (MetS·age interaction: p = 0.01) (Online Table 1). In patients 57 years of age or younger (median age for the entire cohort), the AS progression rate was 2-fold faster in subjects with MetS versus those without MetS (Vpeak annualized change: +0.24 ± 0.19 m/s/year vs. +0.13 ± 0.18 m/s/year, p = 0.008; AVA annualized change: −0.10 ± 0.06 cm2/year vs. −0.05 ± 0.07 cm2/year, p = 0.004; DVI annualized change: −0.024 ± 0.017 vs. −0.010 ± 0.017, p = 0.002), whereas AS progression was unchanged in the older patients (age >57 years) with or without MetS (Vpeak annualized change: +0.26 ± 0.24 m/s/year vs. +0.25 ± 0.19 m/s/year, p = not significant [p = NS]; AVA annualized change: −0.10 ± 0.06 cm2/year vs. −0.08 ± 0.08 cm2/year, p = NS; DVI annualized change: −0.027 ± 0.019 vs. −0.021 ± 0.020, p = NS) (Fig. 1B). In the subset of patients 57 years of age or younger, multivariate analysis showed that the only significant predictors of faster Vpeak progression were MetS (p = 0.0009) and moderate or severe aortic valve calcification score of 3 or more (p = 0.01). MetS also was an independent predictor of faster AVA (p = 0.009) or DVI (p = 0.006) decrease in these younger patients.
Impact of MetS on clinical outcomes
During follow-up, there were 53 AS-related events, of which 51 were AVRs and 2 were cardiac deaths. The 4-year event-free survival in patients with MetS versus no MetS was 63 ± 10% versus 80 ± 5% (p = 0.18) in the entire cohort (Online Fig. 1A), 51 ± 15% versus 90 ± 5% (p = 0.0006) in the subset of patients 57 years of age or younger (Online Fig. 1B), and 75 ± 15% vs. 68 ± 8% (p = 0.30) in the subset of patients older than 57 years (Online Fig. 1C). In patients 57 years of age or younger, MetS was a predictor of events in individual analysis (hazard ratio: 4.04, 95% confidence interval: 1.69 to 9.75, p = 0.002) and remained a powerful predictor after adjusting for age, peak aortic jet velocity, and degree of valve calcification (hazard ratio: 3.86, 95% confidence interval: 1.57 to 9.61, p = 0.004).
Effect of statin therapy
As previously reported for the main ASTRONOMER trial (8), statin therapy had no effect on AS progression in the entire cohort (Online Table 1). A subanalysis with respect to the presence or absence of MetS and treatment assignment, however, revealed that rosuvastatin treatment was associated with faster AS progression in patients with MetS than in those with no MetS (Vpeak annualized change: +0.27 ± 0.23 m/s/year vs. +0.19 ± 0.18 m/s/year, p = 0.045) (Fig. 1C) (AVA annualized change: −0.10 ± 0.06 vs. cm2/year −0.06 ± 0.06 cm2/year, p = 0.02, DVI annualized change: −0.024 ± 0.018 vs. −0.014 ± 0.016, p = 0.02). In patients who received placebo, the AS progression rate was not different between patients with or without MetS (Vpeak: +0.23 ± 0.19 m/s/year vs. +0.19 ± 0.21 m/s/year, p = NS, AVA: −0.09 ± 0.06 cm2/year vs. −0.07 ± 0.09 cm2/year, p = NS, DVI annualized change: −0.026 ± 0.018 vs. −0.017 ± 0.023, p = NS). In the multivariate model (Online Table 1), the MetS·statin use interaction term was not statistically significant.
As expected, LDL cholesterol level decreased markedly from baseline to the 1-year follow-up in the patients treated with statin, whereas there was a minimal reduction in the patients who received placebo (absolute change: −1.86 ± 0.77 mmol/l vs. −0.24 ± 0.68 mmol/l, p < 0.001) (Online Table 2). However, the LDL peak particle size decreased significantly in the statin group (absolute change: −1.1 ± 5.0 Å vs. +0.7 ± 4.7 Å, p = 0.01) and became significantly different from that of the placebo group at the 1-year follow-up (Online Table 2). The HOMA index increased significantly in the patients treated with statin, whereas it remained stable in those who received placebo (+0.41 ± 1.15 vs. −0.01 ± 0.88, p = 0.004), and this was observed in the entire cohort as well as in the patients with or without MetS (Online Table 2), but the 1-year change in HOMA index associated with statin therapy was greater (p = 0.03) in the patients with MetS (+0.78 ± 1.74) compared with those with no MetS (+0.28 ± 0.81) (Online Table 2). Moreover, the annualized change (from baseline to last follow-up) in the HOMA index was more important (p = 0.02) in patients with MetS (+0.45 ± 1.25 U/year) compared with those without MetS (+0.16 ± 0.41 U/year), and the patients with MetS who were receiving rosuvastatin treatment by far had the largest increase in HOMA index (0.61 ± 1.41 U/year) during follow-up (Fig. 2).
When adding the annualized changes in blood metabolic markers into the multivariate model, the independent determinants of AS progression in the entire cohort were older age (p = 0.038), higher degree of aortic valve calcification (p = 0.039), higher Vpeak (p = 0.048), MetS (p = 0.017), and annualized change in HOMA index (p = 0.027). The baseline values of LDL or high-density lipoprotein cholesterol levels and their annualized changes were not associated significantly with AS progression.
The main findings of the present study are as follows: 1) this is the first prospective study to demonstrate that MetS is associated with faster stenosis progression and poorer prognosis in patients with AS; 2) this detrimental impact of MetS on AS progression and prognosis is significant only in younger patients, that is, those 57 years of age and younger, and not in older ones; 3) statin therapy was associated with a deterioration of patients' insulin resistance and the induction of the small LDL phenotype in this cohort of patients with normal LDL cholesterol levels, and theses effects were more pronounced in those patients with a clinical diagnosis of the MetS; 4) in this latter subset of patients, we also observed that statin therapy was associated with faster progression of AS, but multivariate analysis revealed no significant independent effect of statin and no significant interaction between MetS and statin use.
Interaction between MetS and age
The findings of this study suggest that the pathophysiological mechanisms leading to the development and progression of AS may be, at least in part, different between the older population and the younger middle-aged population. These findings are consistent with our previous study of explanted AS valves in which the small, dense LDL phenotype was associated with aortic valve inflammatory and calcifying processes in middle-aged but not in elderly patients (21). Hence, the insulin-resistant state and atherogenic dyslipidemia linked to visceral obesity may have a predominant role in the development of aortic valve inflammation and calcification in the younger population, whereas other mechanisms may be involved to a greater degree in the older population, including dysregulation in the mineral metabolism, postmenopausal deficiency in estrogen, and age-related modification in the adipokine system (21–23).
Statin therapy in normocholesterolemic patients with both AS and MetS
In this study, statin therapy with rosuvastatin was found to be associated with worsening metabolic abnormalities (insulin resistance and small LDL peak particle size), which often are present in patients with MetS. In particular, the HOMA index, which reflects insulin resistance, deteriorated significantly only in patients receiving statin therapy and to a much greater extent in patients with MetS (Fig. 2, Online Table 2). These results are consistent with several recent reports. A randomized study by Koh et al. (24) showed that atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. Moreover, several large-scale clinical trials have demonstrated that lipophilic statins such as atorvastatin, simvastatin, and rosuvastatin may be associated with an increased risk of new-onset type II diabetes (25–27). In a recent meta-analysis of 3 large randomized trials, treatment with high-dose atorvastatin increased the risk of new-onset diabetes to a larger extent in the patients with MetS compared with those with no MetS (28). In this context, it thus is not surprising that the deleterious effects of MetS on AS progression and metabolic profile were more pronounced in the patients treated with rosuvastatin, because both MetS and statin treatment seemed to be acting in synergy to increase insulin resistance and to decrease LDL peak particle size. A tendency toward a synergy between MetS and statin therapy with faster AS progression or accelerated aortic valve bioprosthesis degeneration also has been observed in 2 retrospective studies from our group (9,11).
We propose that this study has important clinical implications. The role of MetS as an independent predictor of faster AS progression is confirmed, and importantly, this detrimental effect is observed even if total or LDL cholesterol levels are normal. Hence, newer therapeutic targets in AS logically should be aimed at treating the risk factors associated with MetS when present and should include aggressive lifestyle changes such as increased physical activity and dietary changes aimed at weight loss, particularly at the loss of visceral or ectopic fat, which is so closely related to the presence of the MetS (29). Unfortunately long-term patient compliance with lifestyle changes is difficult to achieve, and specific pharmacological therapies directed toward visceral obesity are not yet available. Nonetheless, the findings of the present study provide additional evidence for motivating patients to achieve better long-term compliance regarding these lifestyle changes.
The SALTIRE, SEAS, and ASTRONOMER trials have provided compelling evidence that statins are not helpful in the treatment of AS (6–8). Nonetheless, in light of earlier studies that largely were retrospective and reported positive results, the perception of a possible benefit has lingered to the extent that many patients with AS, and yet with no indication for statins, probably are still receiving statin treatment based on the adage that it cannot harm and may help. The wisdom of such an approach, however, is challenged by the present observation of a marked worsening of insulin resistance and a faster stenosis progression in the subset of patients with MetS and normal cholesterol levels. Because of the small number of patients in this analysis and the lack of significant interaction between MetS and statin therapy in the entire cohort, these results should be considered hypothesis generating and must be evaluated in future trials. Furthermore in the SEAS trial, it has been reported that the combination of simvastatin and ezetimibe reduced the risk of ischemic events, especially the need for coronary artery bypass graft (7). Hence, considering the very significant benefits associated with statin use in patients at increased risk of coronary heart disease, including those with the MetS (27,30), the dilemma of the tradeoff between reducing coronary heart disease risk and potentially accelerating AS progression with statin use in normocholesterolemic patients with MetS will have to be addressed and debated.
The AVA data were not available in 19% of the patients included in this cohort. However, the results of the annualized changes in AVA were highly consistent with those of peak aortic jet velocity. Furthermore, the ASTRONOMER trial was not powered to assess valve-related events, which limited our ability to perform multivariable analyses for this outcome.
In view of the relatively small number (n = 33) of patients with MetS who were being treated with statins, the subanalysis with respect to the effect of statin therapy on AS progression in patients with MetS is at risk of a type I error. Furthermore, the MetS·statin use interaction was not statistically significant in the multivariate analysis of the entire cohort. A larger study thus is needed to confirm the effect of statin therapy on AS progression in the subset of patients with MetS and normal LDL cholesterol levels. Nonetheless, the marked deterioration of the metabolic profile associated with statin therapy in normocholesterolemic patients with MetS provides some support to the hypothesis of an unwanted side effect of statin therapy on AS progression in this subset of patients. Given that the need for statin therapy was a prespecified exclusion criteria in the ASTRONOMER trial, the results and conclusions of this substudy can be applied only to patients with no hypercholesterolemia.
In the ASTRONOMER trial, MetS was found to be a powerful and independent predictor of faster AS progression with more pronounced impact in younger patients. Treatment with rosuvastatin worsened insulin resistance state and LDL particle phenotype, particularly in patients with MetS. These findings emphasize the importance of systematically identifying and treating MetS in AS patients. The apparent faster stenosis progression in the subset of normocholesterolemic patients with MetS receiving the statin will need to be confirmed by future studies.
The authors thank all the investigators of the ASTRONOMER trial (Online Appendix). They also thank Isabelle Gaboury, Lynda Hoey, Judy Keys, and Isabelle Laforest for their help in data collection and management.
For supplementary tables and figure, please see the online version of this article.
Impact of Metabolic Syndrome on Progression of Aortic Stenosis: Influence of Age and Statin Therapy
The ASTRONOMER trial is funded by AstraZeneca and the Canadian Institutes of Health Research (CIHR), Ottawa, Canada. This substudy was also funded in part by a CIHR grant no. MOP-114997. Dr. Pibarot holds the Canada Research Chair in Valvular Heart Diseases supported by CIHR. Dr. Clavel holds a Vanier Canada Graduate Scholarship, Canadian Institutes of Health Research, Ottawa, Ontario, Canada. Dr. Mathieu is a research scholar from the Fonds de Recherches en Santé du Québec, Montreal, Canada. Dr. Després is the scientific director of the International Chair on Cardiometabolic Risk at Université Laval, which is supported by an unrestricted grant from Sanofi-Aventis awarded to Université Laval; has served as a speaker for Abbott Laboratories, AstraZeneca, Solvay Pharma, GlaxoSmithKline, and Pfizer Canada, Inc.; has received research funding from Eli Lilly Canada; and has served on the advisory boards of Novartis, Theratechnologies, Torrent Pharmaceuticals Ltd., and Sanofi-Aventis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- aortic stenosis
- aortic valve area
- aortic valve replacement
- Doppler velocity index
- homeostatic assessment model
- low-density lipoprotein
- left ventricle
- metabolic syndrome
- not significant
- peak aortic jet velocity
- Received January 24, 2012.
- Revision received March 1, 2012.
- Accepted March 5, 2012.
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