Kwan L. Chan

Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis

BACKGROUND Elevated lipoprotein(a) (Lp[a]) is associated with aortic stenosis (AS). Oxidized phospholipids (OxPL) are key mediators of calcification in valvular cells and are carried by Lp(a). OBJECTIVES This study sought to determine whether Lp(a) and OxPL are associated with hemodynamic progression of AS and AS-related events. METHODS OxPL on apolipoprotein B-100 (OxPL-apoB), which reflects the biological activity of Lp(a), and Lp(a) levels were measured in 220 patients with mild-to-moderate AS. The primary endpoint was the progression rate of AS, measured by the annualized increase in peak aortic jet velocity in m/s/year by Doppler echocardiography; the secondary endpoint was need for aortic valve replacement and cardiac death during 3.5 ± 1.2 years of follow-up. RESULTS AS progression was faster in patients in the top tertiles of Lp(a) (peak aortic jet velocity: +0.26 ± 0.26 vs. +0.17 ± 0.21 m/s/year; p = 0.005) and OxPL-apoB (+0.26 ± 0.26 m/s/year vs. +0.17 ± 0.21 m/s/year; p = 0.01). After multivariable adjustment, elevated Lp(a) or OxPL-apoB levels remained independent predictors of faster AS progression. After adjustment for age, sex, and baseline AS severity, patients in the top tertile of Lp(a) or OxPL-apoB had increased risk of aortic valve replacement and cardiac death. CONCLUSIONS Elevated Lp(a) and OxPL-apoB levels are associated with faster AS progression and need for aortic valve replacement. These findings support the hypothesis that Lp(a) mediates AS progression through its associated OxPL and provide a rationale for randomized trials of Lp(a)-lowering and OxPL-apoB-lowering therapies in AS. (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin [ASTRONOMER]; NCT00800800).

Impact of Metabolic Syndrome on Progression of Aortic Stenosis Influence of Age and Statin Therapy

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.

Lipid Lowering on Progression of Mild to Moderate Aortic Stenosis: Meta-analysis of the Randomized Placebo-Controlled Clinical Trials on 2344 Patients

BACKGROUND Aortic stenosis (AS) is believed to develop through an inflammatory similar to the atherosclerosis process. Based on findings from animal studies and uncontrolled clinical studies, lipid-lowering therapy with a statin is postulated to slow this process. Randomized trials, however, reported neutral results. This meta-analysis of randomized lipid trials on patients with AS examined the effects of treatment on AS progression and clinical outcomes. METHODS Echocardiographic measures of AS (aortic valve jet velocity, peak and mean valve gradients, and aortic valve area) were pooled and clinical outcomes were evaluated in 4 randomized placebo controlled trials (N=2344). RESULTS Although active treatment with statin therapy was associated with highly significant 50% reduction in low-density lipoprotein cholesterol levels, there were no statistical differences between active and placebo groups in any of the echocardiographic indicators of AS severity: annual increase in AS velocity was 0.16±0.28 m/sec, and mean gradient was 2.8±3.0 mm Hg. Each trial reported no differences in clinical outcomes between the 2 treatment groups. Substantial events rates (6.6% aortic valve surgery and 1.2% cardiovascular deaths per year in SEAS with follow-up of 4.4 years and 5.8% aortic valve surgery and 0.7% cardiovascular deaths per year in ASTRONOMER over 3.5 years) were observed in these patients despite the relatively mild disease. CONCLUSION The current data do not support the hypothesis that statin therapy reduces AS progression. Patients with mild to moderate AS may require closer follow-up because despite the less severe disease in these trials, event rates remain substantial.

Clinical ResearchValve DiseaseImpact of Metabolic Syndrome on Progression of Aortic Stenosis: Influence of Age and Statin Therapy

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.

Arbutamine echocardiography: Efficacy and safety of a new pharmacologic stress agent to induce myocardial ischemia and detect coronary artery disease

OBJECTIVES This study sought to determine the efficacy and safety of arbutamine echocardiography in inducing myocardial ischemia and detecting coronary artery disease. BACKGROUND Exercise and pharmacologic stress echocardiography are clinically accepted techniques for detecting coronary artery disease. Arbutamine is a new synthetic beta-adrenoceptor agonist developed specifically as a stress agent. Arbutamine is delivered by a new computerized drug delivery device that adjusts the rate of drug infusion according to the patients heart rate response during stress testing. METHODS The sensitivity of arbutamine echocardiography was determined in 143 patients who had coronary artery disease documented by coronary angiography. A subset of these patients (n = 114) also underwent exercise echocardiography. The specificity, or normalcy, of arbutamine echocardiography was determined in 54 patients considered to have a low likelihood of coronary artery disease. RESULTS Among those patients who had both stress test results, the incidence of inducing myocardial ischemia (new or worsening wall motion abnormalities) was 79% (95% confidence interval [CI] 69% to 86%, n = 98) for arbutamine and 77% (95% CI 67% to 85%, n = 98) for exercise echocardiography. The sensitivity of detecting coronary artery disease (ischemia or rest wall motion abnormality) was 87% (95% CI 79% to 93%, n = 101) for arbutamine and 83% (95% CI 74% to 90%, n = 101) for exercise echocardiography. The specificity (normalcy) of arbutamine echocardiogrpahy was 96% (95% CI 87% to 100%, n = 52). Arbutamine was well tolerated, and there were no serious adverse events. CONCLUSIONS Arbutamine echocardiography is an effective and safe pharmacologic stress test technique for diagnosing or excluding the presence of coronary artery disease. The ability of arbutamine stress to induce myocardial ischemia, detectable by echocardiography, was comparable to that for exercise.

Dobutamine and dipyridamole stress echocardiography in patients with a low incidence of severe coronary artery disease.

The aim of this study was to determine the relative sensitivity, specificity, accuracy, and tolerance of dobutamine and dipyridamole stress echocardiography in patients with a lower likelihood of severe coronary artery disease. Previous comparative studies, which included patients with a history of myocardial infarction or a high incidence of coronary artery disease, showed both methods to have similar and acceptable diagnostic accuracy. To assess the role of these agents in evaluating patients with a lower likelihood of significant coronary artery disease, a lower-risk group was selected by excluding patients with known coronary artery disease, myocardial infarction, unstable angina, or strongly positive stress test results. Dobutamine and dipyridamole stress echocardiographic studies were performed in random order, before coronary angiography. Of the 46 patients enrolled (31 men and 15 women), 24 had atypical chest pain or none at all. Coronary angiography revealed no significant disease in 22 (48%), single-vessel disease in 11 (24%), and multivessel disease in only 13 patients (28%). Dobutamine and dipyridamole stress echocardiography were equally well tolerated, with identical accuracy (76%) that was maintained in patients with atypical symptoms. This confirms the usefulness of both dobutamine and dipyridamole stress echocardiography in evaluating patients with suspected coronary artery disease and extends this role to a lower-risk group for severe disease who often have atypical symptoms. The choice of which agent is used should reflect an institutions experience.

Association of mitral annular calcification and aortic valve morphology: a substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study

AIMS Mitral annular calcification (MAC) is characterized by calcium and lipid deposition in the annular fibrosa of the mitral valve. Although individuals with MAC are at increased risk of cardiovascular events, little is known about the significance of this finding in patients with concurrent aortic stenosis (AS). The aim of this study was to describe the association of baseline MAC and aortic valve morphology in asymptomatic patients enrolled in the ASTRONOMER study, a multicentre study to assess the effect of Rosuvastatin on the progression of AS. METHODS AND RESULTS At baseline, transthoracic echocardiography was performed with two-dimensional and Doppler imaging following a standardized protocol. Echo measurements including left ventricular (LV) dimensions and aortic root dimensions were obtained according to the ASE recommendations. MAC was identified by bright echoes at the base of the mitral leaflets or annulus on 2D imaging, and aortic valve calcification by visualization of bright echoes on the aortic valve leaflets. The degree of calcification was semi-quantitated from absent to severe. The study population included 219 patients (57 +/- 14 years; 129 males), divided into two pre-specified categories; bicuspid (n = 133) and tricuspid (n = 86) aortic valves. Baseline LV dimensions, aortic valve haemodynamics, and cholesterol profiles were similar between the two groups at baseline. Individuals with tricuspid aortic valves were older, more hypertensive, with higher degrees of MAC and AV calcification (P < 0.001). The higher degree of MAC persisted in patients with tricuspid AV after adjustment for age and systolic blood pressure (P = 0.004). CONCLUSION In patients with asymptomatic mild to moderate AS, MAC is more prevalent in those individuals with tricuspid AV, independent of age, and systolic blood pressure. Whether the degree of MAC may be a surrogate for atherosclerosis, and predict the subset of patients who will respond to statin therapy in preventing the progression of AS, remains to be determined.

Insulin Resistance and LVH Progression in Patients With Calcific Aortic Stenosis: A Substudy of the ASTRONOMER Trial

OBJECTIVES The objective of this substudy of the ASTRONOMER (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin) trial was to examine the association between insulin resistance and progression of left ventricular hypertrophy (LVH) in patients with aortic stenosis (AS). BACKGROUND In a recent cross-sectional study, the authors reported that the metabolic syndrome was associated with an increased prevalence of concentric LVH in patients with AS. As a central feature of the metabolic syndrome, insulin resistance could be an important mediator of this association. METHODS This substudy included 250 of 269 patients enrolled in ASTRONOMER. Follow-up was 3.4 ± 1.3 years. Insulin resistance was evaluated using the homeostatic assessment model (HOMA) index, and patients were dichotomized using the median HOMA index value (1.24). The rate of LVH progression was estimated by calculating the annualized change in LV mass index (LVMi), measured on echocardiography. The presence of LVH was defined as an LVMi >47 g/m(2.7) in women and >49 g/m(2.7) in men. RESULTS There was a significant progression of LVH among the patients without LVH at baseline (n = 134; p < 0.0001) but not in those with it (n = 116; p = NS). In those without LVH at baseline, the annualized progression rate of LVMi was significantly faster in the subset with HOMA >1.24 compared to that in the subset with HOMA <1.24 (2.49 ± 4.38 g/m(2.7)/year vs. -0.03 ± 3.90 g/m(2.7)/year; p = 0.001). During follow-up, LVH developed in 46% of patients with HOMA >1.24 compared to 11% of those with HOMA <1.24 (p = 0.0005). Independent predictors of faster LVH progression identified on multivariate analysis were history of hypertension (p = 0.048), degree of aortic valve calcification (p = 0.035), and HOMA index (p = 0.02). CONCLUSIONS In this ASTRONOMER substudy, insulin resistance was a powerful independent predictor of progression to LVH in patients with AS. Visceral obesity and ensuing insulin resistance may thus present novel therapeutic targets in AS patients.

Mobile ventricular thrombus arising from the mitral annulus in patients with dense mitral annular calcification

Mitral annular calcification (MAC) has been considered a risk factor for thrombo-embolic disease. Superimposed thrombus formation on MAC has not been well described as a possible underlying mechanism for this association. We report three patients with mobile left ventricular (LV) thrombus arising from the LV aspect of severe calcified mitral annulus in the setting of normal LV function, mitral valve function, and sinus rhythm.

Unusual Cause of an Ejection Murmur: Myxoma in the Left Ventricular Outflow Tract

We present the case of a healthy, asymptomatic 50-year-old woman with a systolic ejection murmur who was found to have an obstructive left ventricular outflow tract mass. Transthoracic echocardiography revealed a large mobile mass attached to the basal anterior septum of the left ventricle. Surgical resection was performed and a benign left ventricular outflow tract myxoma was diagnosed. The patients postoperative course was unremarkable. We describe the clinical presentation and role of 2- and 3-dimensional transthoracic and transesophageal echocardiography in surgical management.