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J Am Coll Cardiol, 2006; 47:2229-2236, doi:10.1016/j.jacc.2005.12.073 (Published online 12 May 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: VALVULAR HEART DISEASE

Metabolic Syndrome Negatively Influences Disease Progression and Prognosis in Aortic Stenosis

Martin Briand, MS*,1, Isabelle Lemieux, PhD*, Jean G. Dumesnil, MD, FACC*, Patrick Mathieu, MD*, Amélie Cartier, MS*, Jean-Pierre Després, PhD, FAHA*,{dagger},3, Marie Arsenault, MD*,4, Jacques Couet, PhD*,4 and Philippe Pibarot, DVM, PhD, FACC*,2,*

* Laval Hospital Research Center/Québec Heart Institute, Department of Medicine, Laval University, Québec, Canada
{dagger} Division of Kinesiology, Department of Social and Preventive Medicine, Laval University, Québec, Canada

Manuscript received September 7, 2005; revised manuscript received December 19, 2005, accepted December 30, 2005.

* Reprint requests and correspondence: Dr. Philippe Pibarot, Laval Hospital Research Center, 2725 Chemin Sainte-Foy, Sainte-Foy, Quebec, Canada, G1V-4G5. (Email: philippe.pibarot{at}med.ulaval.ca).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: This study sought to examine the association between the metabolic syndrome (MS) and the progression of aortic stenosis (AS).

BACKGROUND: It has been suggested that aortic valve sclerosis and its progression to AS are caused by an atherosclerotic process. Metabolic syndrome is associated with a higher risk of vascular atherosclerosis. Thus, we hypothesized that the atherogenic features of MS could negatively influence disease progression and prognosis in patients with AS.

METHODS: We retrospectively analyzed the data of 105 consecutive patients (age 69 ± 12 years, 64 men) with at least moderate AS. Of these patients, 40 (38%) had MS identified according to the modified clinical criteria proposed by the National Cholesterol Education Program-Adult Treatment Panel III. The hemodynamic progression of AS was assessed by the measurement of the annualized decrease in valve area during the follow-up period of the study, which averaged 28 ± 13 months. Event-free survival was defined as the absence of death or aortic valve replacement during follow-up.

RESULTS: The hemodynamic progression of the stenosis was twice as fast (–0.14 ± 0.13 cm2/year vs. –0.08 ± 0.08 cm2/year, p = 0.008) and the three-year event-free survival was markedly lower (44 ± 8% vs. 69 ± 6%, p = 0.002) among patients with MS. In multivariate analysis, MS was found to be a strong independent predictor of both stenosis progression (p = 0.006) and event-free survival (odds ratio 3.85, 95% CI 1.96 to 7.58, p < 0.001).

CONCLUSIONS: The present study is the first to report that MS is associated with a faster disease progression and worse outcome in patients with AS. Such findings open new avenues of research and provide a strong impetus for the elaboration of additional prospective studies focusing on this association.

Abbreviations and Acronyms
  ACE = angiotensin-converting enzyme
  AS = aortic stenosis
  AVA = aortic valve area
  AVR = aortic valve replacement
  CRP = C-reactive protein
  HDL = high-density lipoprotein
  LDL = low-density lipoprotein
  MS = metabolic syndrome
  NCEP-ATPIII = National Cholesterol Education Program-Adult Treatment Panel III

Calcific aortic valve stenosis (AS) has become the most common cardiovascular disease in developed countries after coronary artery disease and hypertension (1). Historically, calcific AS has been considered degenerative because it was thought to be the result from aging and wear and tear of the aortic valve. However, this perception has changed over the years with the publication of several studies showing that the calcific AS lesions shares many histologic similarities with atherosclerosis (1–5). Furthermore, the development and progression of AS are linked to various traditional risk factors for coronary artery disease (6–15). Hence these findings suggest that calcific AS is not a degenerative disease resulting from decades of repetitive mechanical stress, but rather an active disease related to atherosclerosis.

Previous studies evaluating the rate of hemodynamic progression in patients with AS have shown that the average rate of decrease in aortic valve effective orifice area (AVA) is approximately 0.1 cm2/year (5,16,17). However, the rate of stenosis progression may vary extensively from one patient to another. It is thus crucial to identify the independent clinical and metabolic factors that determine the progression of AS because this information would eventually contribute to developing new therapeutic approaches to delay or stop stenosis progression, thus avoiding the need for aortic valve replacement (AVR).

The metabolic syndrome (MS) is a cluster of metabolic perturbations largely resulting from an excess accumulation of abdominal fat. Metabolic syndrome components include proatherogenic dyslipidemia as well as proinflammatory and prothrombotic abnormalities linked to in vivo insulin resistance, such as fasting hyperinsulinemia, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, elevated apolipoprotein B, small low-density lipoprotein (LDL) particles, endothelial dysfunction, elevated cytokines and C-reactive protein (CRP) levels, and reduced adiponectin concentrations (18,19). The prevalence of MS is estimated to be approximately 25% in the Western world population (19,20). Previous studies have shown that the presence of features of MS is predictive of an increased risk of coronary artery disease, independent of traditional risk factors (21). We hypothesized that the proatherogenic and proinflammatory features of MS could accelerate the progression of AS and thus precipitate the occurrence of adverse outcomes. The objective of this retrospective study was thus to determine the impact of MS on hemodynamic progression and clinical outcomes of AS.


   Methods
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 Methods
Results
 Discussion
 References
 
Patient population.   All patients examined in our echocardiography laboratory between August 1999 and July 2004 who were found to have at least moderate AS defined by an AVA ≤1.5 cm2 and who had a minimum of two echocardiograms separated by at least six months were eligible for this study. Exclusion criteria were as follows: 1) presence of symptoms; 2) left ventricular ejection fraction ≤50%, 3) presence of congenital heart disease (other than bicuspid aortic valve); 4) at least mild aortic or mitral regurgitation; 5) subaortic obstruction precluding measurement of AVA; 6) history and echocardiographic features of rheumatic heart disease; and 7) previous aortic valve surgery. The occurrence of cardiac events during follow-up was recorded and documented. For the assessment of outcome, end points were defined as death or AVR (16,17).

Doppler echocardiography.   All patients underwent a comprehensive Doppler echocardiographic examination with commercially available ultrasound systems. Doppler echocardiographic measurements included the left ventricular stroke volume, the peak and mean transvalvular gradients using the modified Bernoulli equation, and the AVA using the standard continuity equation. Particular care was taken to record the maximum aortic jet velocity. For assessment of hemodynamic progression, echocardiographic studies separated by at least six months were used. When patients had two or more serial echocardiograms, hemodynamic progression between the first and last studies was calculated. Annualized changes in peak and mean gradients (mm Hg/year) and AVA (cm2/year) were calculated by dividing the difference between the first and last measurements by the time between examinations. The degree of calcification of the aortic valve was scored according to the criteria proposed by Rosenhek et al. (17): 1) no calcification; 2) mildly calcified (isolated, small spots); 3) moderately calcified (multiple larger spots); and 4) heavily calcified (extensive thickening/calcification of all cusps).

Clinical and laboratory data.   Clinical data included age, gender, etiology of valvular stenosis, history of smoking, and documented diagnoses of hypertension (patients receiving antihypertensive medications or having known but untreated, hypertension [blood pressure ≥140/90 mm Hg]), hypercholesterolemia (patients receiving cholesterol-lowering medication or, in the absence of such medication, having a total plasma cholesterol level >240 mg/dl), diabetes (fasting glucose ≥7 mmol/l), obesity (body mass index ≥30 kg/m2), and coronary heart disease (history of myocardial infarction or coronary artery stenosis on coronary angiography). Furthermore, a fasting plasma lipid profile (including total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels) and blood pressure were assessed in the resting state in all patients. Information on statin and angiotensin-converting enzyme (ACE) inhibitor treatment was also recorded. Among the 105 patients included in this study, 45 underwent an AVR during follow-up. In 20 of these 45 patients, plasma was collected at the time of operation and stored at –80°C. In these samples, insulin, apolipoprotein B, the size of LDL particles, CRP, and adiponectin were retrospectively measured using methods used on a routine basis in our laboratory (22,23).

Identification of patients with MS.   The clinical identification of patients with the features of MS was based on the modified criteria proposed by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) (24). Because waist circumference was not measured in this sample, body mass index was substituted for waist circumference as an index of obesity (25). Patients were considered to have MS when three of the five following criteria were present: 1) body mass index ≥30 kg/m2; 2) fasting glycemia ≥110 mg/dl; 3) triglycerides ≥150 mg/dl; 4) HDL cholesterol <40 mg/dl in men and <50 mg/dl in women; and 5) systolic/diastolic blood pressures ≥130/85 mm Hg.

Statistical analysis.   Continuous data were expressed as mean ± standard deviation and compared using the unpaired Student t test. Categorical data were expressed as a percentage and compared with the chi-square test. A logarithmic transformation was used when variables did not follow a normal distribution. A forward multiple linear regression analysis was used to identify the independent predictors of the hemodynamic progression of AS. Probabilities of event-free survival were obtained by Kaplan-Meier estimates for the levels of various risk factors. The effect of these factors on survival was assessed by means of simple and multiple Cox proportional hazards models.


   Results
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 Results
Discussion
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Patient characteristics.   Of the 105 subjects, 40 (38%) met the clinical criteria of MS. The baseline characteristics and the hemodynamic progression of AS in the different groups are shown in Table 1. The patients with MS had a higher prevalence of hypertension, diabetes, obesity, smoking, history of hypercholesterolemia, and therapy with statins or ACE inhibitors compared with patients without MS. Also, patients with MS tended to have a higher prevalence of concomitant coronary artery disease (70% vs. 51%, p = 0.08) compared with patients without MS. Moreover, as expected, patients with MS had significantly higher plasma levels of glucose and triglycerides and lower levels of HDL cholesterol. However, they had significantly lower total and LDL cholesterol. The more frequent use of statins in MS patients likely explains the lower plasma levels of LDL cholesterol in these patients. Despite the higher number of traditional cardiovascular risk factors such as age >70 years, male gender, hypertension, diabetes, hypercholesterolemia, smoking, and obesity in the MS group, the global Framingham risk score was slightly lower in this group, a result which was essentially related to the lower LDL levels in MS group compared with patients without MS.


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  		Table 1. Patient Characteristics
 
Predictors of AS progression.   The mean baseline AVA was 1.08 ± 0.24 cm2, and 40% of the patients had severe AS (valve AVA ≤1.0 cm2) at baseline. The mean time interval between the first and last echocardiographic examination was 28 ± 13 months. The rate of progression of peak transvalvular velocity, peak gradient, mean gradient, and AVA was +0.19 ± 0.27 ms–1/year, +6 ± 9 mm Hg/year, +4 ± 6 mm Hg/year, and –0.10 ± 0.11 cm2/year, respectively. In univariate analysis, only baseline severity of AS, male gender, and MS were significantly associated with hemodynamic progression of AS (Fig. 1). Patients with moderate AS at baseline had faster progression of AVA (–0.12 ± 0.11 cm2/year vs. –0.07 ± 0.10 cm2/year, p = 0.02), but this difference was no longer significant when examining relative changes (–10 ± 8% vs. –8 ± 11%, p = NS). Male patients had a significantly (p = 0.02) higher rate of progression of AVA. However, AVA was also higher at baseline (1.15 ± 0.23 cm2) in men than in women (0.96 ± 0.21 cm2, p < 0.001). No significant association was found between the hemodynamic progression of AS and age, hypertension, obesity, history of smoking, Framingham risk score, number of traditional cardiovascular risk factors, coronary artery disease, degree of aortic valve calcification, statin therapy, or ACE inhibitor therapy. There was a trend for more rapid progression of gradient in patients with a history of hypercholesterolemia (+6.5 ± 9.5 mm Hg/year vs. +3.6 ± 6.5 mm Hg/year, p = 0.09) as well as in patients with diabetes (+7.0 ± 9.5 mm Hg/year vs. +4.2 ± 6.5 mm Hg/year, p = 0.09); this trend was not observed for progression of AVA. The rate of stenosis progression was twice as high among patients with MS compared with those without MS (peak gradient progression +8.4 ± 10.5 mm Hg/year vs. +3.7 ± 6.7 mm Hg/year, p = 0.006; AVA progression –0.14 ± 0.13 cm2/year vs. –0.08 ± 0.08 cm2/year, p = 0.008). There was a weak correlation between the number of NCEP-ATPIII components of MS and progression rate of AVA (r = 0.24, p = 0.02).


Figure 1
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  		Figure 1 Rate of progression of aortic valve area (AVA) with presence (orange bars) or absence (blue bars) of age ≥70 years, male gender, hypertension (HPT), obesity, history of hypercholesterolemia (Hyperchol), history of smoking, diabetes, and metabolic syndrome (MS).

 
In the whole group (105 patients), there was a significant correlation between the annualized decrease in AVA and fasting glycemia (r = –0.32, p = 0.003). On the other hand, no significant correlation was found between rate of progression of AVA or gradients and total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride concentrations, and the total/HDL cholesterol ratio.

In the subgroup of 20 patients for whom plasma was available for measurement of additional markers of MS, patients with MS (11 of 20, 55%) had significantly smaller LDL particle size, higher fasting insulin, lower adiponectin, and higher CRP, although this difference did not reach statistical significance (Table 2). There were trends for the rate of progression of AVA to be associated with LDL particle size (r = 0.38, p = 0.11) and with insulin levels (r = –0.40, p = 0.09).


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  		Table 2. Metabolic Markers in the Subset of 20 Patients With Available Fasting Plasma
 
In multivariate analysis, MS (p = 0.006) and baseline AS severity (i.e., baseline AVA (p = 0.002) or peak gradient (p = 0.05) were the only independent predictors of the progression of AS (Table 3). The MS remained a strong independent predictor (standardized coefficient: –0.25 and p = 0.009 in the model predicting AVA progression rate; standardized coefficient: +0.33, p < 0.001 in the model predicting peak gradient progression rate) after adjusting for age, baseline AS severity, history of hypercholesterolemia, diabetes, and Framingham score. Nonetheless, the impact of MS on stenosis progression seemed to be more important among patients with a Framingham score ≥8 than in those with a lower score (Fig. 2).


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  		Table 3. Independent Determinants of the Hemodynamic Progression of Aortic Stenosis
 

Figure 2
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  		Figure 2 Rate of progression of aortic valve area (AVA) among the two groups separated according to the median value of the Framingham score in patients with metabolic syndrome (MS) (orange bars) and those without MS (blue bars). {dagger}Significant difference versus group 2 (p < 0.05).

 
Insulin resistance is an important feature of MS. However, among patients with diabetes, the patients with MS had a much faster progression of gradient compared with those with no MS (11 ± 13 mm Hg vs. 3 ± 7 mm Hg, p = 0.003). In addition, among the patients without MS, there was no significant difference between patients with diabetes (3 ± 7 mm Hg) versus those without diabetes (4 ± 7 mm Hg). Moreover, MS remained a strong independent predictor of stenosis progression after adjusting for diabetes. These findings support the notion that the effect of MS on stenosis progression is in large part independent of that of diabetes. Finally, statin therapy had no significant effect on the progression of the disease both in patients with MS and in those without MS (Fig. 3).


Figure 3
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  		Figure 3 Rate of progression of aortic valve area (AVA) among the two groups separated according to the presence or absence of statin therapy in patients with metabolic syndrome (MS) (orange bars) and those without MS (blue bars). *Significant difference versus group 1 (p < 0.05); {dagger}significant difference versus group 2 (p < 0.05).

 
Predictors of clinical outcomes.   During follow-up, 53 end points were observed, including 45 AVRs and 8 deaths: 5 cardiac and 3 noncardiac. Of the five cardiac deaths, there was one sudden death and four deaths related to acute myocardial infarction. The event-free survival in this series was 59 ± 5% at three years and 33 ± 9% at five years. The MS was the most powerful predictor of outcome (Fig. 4 and Table 4). Three-year event-free survival was 44 ± 8% in patients with MS versus 69 ± 6% in those without MS (p = 0.002) (Fig. 4). The other predictors of outcome were male gender (p = 0.005), a peak gradient ≥65 mm Hg (peak velocity ≥4 m/s) at baseline (p = 0.004), and diabetes (p = 0.05). There was also a trend for a lower event-free rate in patients with an aortic valve calcification score >3 (p = 0.065) as well as in patients with a history of smoking (p = 0.06). In multivariate analysis, male gender (p = 0.03), a baseline peak gradient ≥65 mm Hg (p = 0.001), and MS (p < 0.001) were the only independent predictors of outcome (Table 4). The risk of outcome was increased 3.85-fold (95% confidence interval 1.96 to 7.58) in patients with MS compared with patients without MS.


Figure 4
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  		Figure 4 Kaplan-Meier analysis of event-free survival in 40 patients with metabolic syndrome (MS) compared with 65 patients without MS.

 

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  		Table 4. Predictors of Outcome in Univariate and Multivariate Analysis
 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
The contribution of the present study is to provide, for the first time, evidence that MS is a strong independent predictor of stenosis progression and clinical outcome in patients with AS. These findings are clinically relevant given that MS is a frequent and modifiable condition largely resulting from overweight/obesity and a sedentary lifestyle. Previous studies have reported that the prevalence of MS was estimated to reach about 25% in the Western world population (19,20). In our sample of elderly patients with AS, the prevalence of MS was up to 38%.

Comparison with previous studies of AS progression.   Previous studies have identified several factors predictive of faster progression of AS, including the stenosis severity and the degree of aortic valve calcification at baseline, advanced age, smoking, obesity, hypercholesterolemia, high total/HDL cholesterol ratio, diabetes, coronary artery disease, and absence of statin treatment (5,8,12–17,26–34). In the present study, the baseline severity of AS was also found to be an independent risk factor for stenosis progression. Other factors also previously reported to be independent predictors of progression were not found to be as such in the present study. However, it should be pointed out that factors such as valve calcification and coronary artery disease are more likely surrogate markers rather than metabolic determinants of the disease. Moreover, the influence of MS was not taken into account in these previous studies.

The association between hypercholesterolemia and AS hemodynamic progression remains unclear. One study reported a modest correlation between the change in AVA and the change in plasma LDL cholesterol level during follow-up (30), whereas other studies reported no correlation between LDL cholesterol levels and stenosis progression (31,34). Accordingly, in the present study, there was no significant correlation between history of hypercholesterolemia or plasma LDL cholesterol level at baseline and stenosis progression.

Patients with MS are at higher global risk of cardiovascular diseases and thus require more aggressive therapy. Accordingly, in the present study the proportion of patients treated with statins and/or ACE inhibitors was markedly higher in the MS group. Nevertheless, this aggressive treatment was not able to slow the stenosis progression of patients with MS (Fig. 3). Indeed, although lipid-lowering therapy was successful in achieving the recommended goal of the NCEP-ATPIII, i.e., an LDL cholesterol level of <100 mg/dl, in all patients with MS, the average rate of progression of their stenosis was nonetheless twice as fast compared with patients without MS.

Another major finding of this study is that MS is independently associated with a worse outcome in patients with AS. This result is consistent with the much faster hemodynamic progression measured by Doppler echocardiography in the MS group. The strong agreement between the results of hemodynamic progression and those of clinical outcome gives further robustness to the conclusion that MS is a powerful independent predictor of the progression of calcific AS. The other factors previously reported as independent predictors of clinical outcome in AS were patient’s age and functional status, baseline severity of AS, and degree of aortic valve calcification (16,17,33,35). However, as mentioned above, most of these factors can be viewed as markers rather than determinants of the disease. Hence, although these factors may be particularly useful for risk stratification of AS patients (16,17,33), they cannot be used to identify new therapeutic targets for this disease.

Potential mechanisms responsible for the association between MS and AS progression.   The NCEP-ATPIII has recognized that MS represents a cluster of atherogenic, atherothrombotic, and inflammatory abnormalities (24). Indeed, there are several features of MS that could be involved in the progression of aortic valve disease, including the following:

1 The presence of small, dense LDL particles may enhance the infiltration of LDL into the aortic valve leaflets. Moreover, these small, dense particles have an increased susceptibility to oxidation. Small LDL particles may also carry other proatherogenic factors, such as ACE and CRP, into the aortic valve lesions (36,37). The proinflammatory and proatherogenic effects of angiotensin II, the enzymatic product of ACE, are well established and recent reports suggest that CRP is not only a marker of inflammation but that it may also participate in the disease process (38,39).
2 It is well known that HDL cholesterol has antioxidant and antithrombogenic effects (40). Hence, the reduction of HDL cholesterol as well as the presence of small, dense LDL particles associated with MS could predispose to the production of oxidized LDL and thus promote inflammation and calcification within aortic valve leaflets (3,41–43).
3 It is now well accepted that atherosclerosis has an inflammatory component and that its related markers predict acute coronary events. Several studies also showed that inflammation is involved in the pathogenesis of nonrheumatic AS (37,43–45). The expanded abdominal adipose depot in patients with MS could represent an important source of cytokine (e.g., interleukin-6, tumor necrosis factor-alpha) production (46–49). Interleukin-6 has a proinflammatory and proatherogenic effects, and it stimulates hepatic production of CRP (38,46,47). Hence, the presence of abdominal obesity in patients with MS could exacerbate the inflammatory response to various environmental stimuli.
4 Adiponectin is an adipocyte-specific protein with an insulin-enhancing activity as well as antiinflammatory and antiatherogenic properties, which has been shown to have a protective effect on the initiation and progression of atherosclerosis (50). It is well known that plasma adiponectin levels are reduced in the presence of obesity and/or MS (22). Hence, it is possible that hypoadiponectinemia associated with MS would play a role in the progression of calcific AS. Additional studies will now be needed to identify which feature(s) of MS are responsible for the faster progression of AS. This knowledge could lead to the development of new potentially important therapeutic targets.

Clinical implications.   The results of this study have important clinical implications. Indeed, MS is a potentially preventable and modifiable condition that often goes undiagnosed and untreated. Hence, in light of our results, patients diagnosed with AS should be systematically screened for the presence of MS, and if found, patients should probably be followed up more closely with regard to the evolution of their disease and the appearance of symptoms. Moreover, many of the features of MS are not reversed by the pharmacologic treatment of traditional risk factors. To this effect, it should be pointed out that the two pharmacological agents (i.e., statins and ACE inhibitors) that are currently under the most scrutiny for potentially delaying AS progression (1,30,31,34,51–53) have no or little effect on the metabolic perturbations associated with MS (54,55). The treatment of the features of MS requires aggressive changes in lifestyle habits, such as increasing physical activity and implementing dietary changes leading to weight reduction. The main challenge with regard to the latter is patient compliance, and the findings of the present study should provide added motivation for patients with the combination of AS and MS to undergo such changes. Newer pharmacologic approaches that specifically target some of the key causal mechanisms of MS might also be considered as becoming part of the treatment of these patients (19,56). Additional prospective studies will, of course, be necessary to determine whether the evolution of AS can actually be slowed by a more aggressive treatment of MS.

Study limitations.   The study was retrospective in nature. Patients with MS might therefore be more likely to have repeated echocardiographic studies, thus biasing the results to show more rapid progression in that group. This study also included a relatively small number of patients. Hence, the apparent lack of significant association between stenosis progression and some clinical factors, including history of hypercholesterolemia, diabetes, and statin therapy, may be a type II error because of the small sample size. Nonetheless, this limitation does not affect the validity of the main result of this study, which is the demonstration of a strong association between MS and AS progression.

Plasma was not available in the vast majority of the patients. It was thus not possible to investigate the potential mechanisms responsible for the more rapid progression of the aortic valve lesions in the presence of MS.

The waist circumference was not measured in this study. Alternatively, to identify patients likely to have MS, we used a body mass index ≥30 kg/m2, which has been shown to correspond to the NCEP-ATPIII cutoff values of 102 cm in men and 88 cm in women for waist circumference (57). Body mass index alone is not necessarily a good marker of abdominal obesity and of MS. Nonetheless, when combined with the other metabolic criteria of the NCEP-ATPIII guidelines, it is useful for identifying individuals with MS (18,19,39). In fact, its use in this circumstance seems to be highly specific, but its sensitivity is probably lower than waist circumference (58). Hence, the prevalence of MS in this study might actually have been higher had waist circumference been used as a criteria for its detection, whereas the likelihood of false positives is probably very low.

In conclusion, this is the first study to report that MS is highly prevalent in patients with AS and that it is a strong and independent predictor of disease progression and occurrence of adverse outcomes. Such findings open new avenues of research and provide a strong impetus for the elaboration of prospective studies focusing on the aggressive treatment of the features of MS in patients with AS.


   Acknowledgments
 
The authors thank Dominique Labrèche, PhD, Martin Gaudreau, MS, Isabelle Laforest, MS, and Serge Simard, MS, for their technical assistance.


   Footnotes
 
This work was supported by the Canadian Institutes of Health Research (Grant MOP 79342), the Foundation of the Quebec Heart Institute, and the Canadian Foundation for Innovation.

1 Mr. Briand is the recipient of a PhD student scholarship from the Fonds de Recherche en Santé du Québec, Montreal, Quebec, Canada. Back

2 Dr. Pibarot holds the Canada Research Chair in Valvular Heart Diseases, Canadian Institutes of Health Research, Ottawa, Ontario, Canada. Back

3 Dr Després holds the Laval University Chair in nutrition, lipidology, and prevention of cardiovascular diseases, which is supported by Pfizer, Provigo, and the Foundation of the Québec Heart Institute. Back

4 Drs. Arsenault and Couet are research scholars from the Fonds de Recherche en Santé du Québec, Montreal, Canada. Back


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