Anne B. Rossebø

Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.

BACKGROUND Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results. METHODS We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events. RESULTS During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01). CONCLUSIONS Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. (ClinicalTrials.gov number, NCT00092677.)

Outcome of Patients With Low-Gradient “Severe” Aortic Stenosis and Preserved Ejection Fraction

Background— Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area <1.0 cm2 and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient “severe” stenosis (defined as aortic valve area <1.0 cm2 and mean gradient ⩽40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Methods and Results— Outcome in patients with low-gradient “severe” aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm2; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67±10 years; ejection fraction, ≥55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182±64 versus 212±68 g; P<0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P=0.37; major cardiovascular events, 50.9% versus 48.5%, P=0.58; cardiovascular death, 7.8% versus 4.9%, P=0.19). Low-gradient severe stenosis patients with reduced stroke volume index (⩽35 mL/m2; n=223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P=0.53). Conclusions— Patients with low-gradient “severe” aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

Outcome of Patients With Low-Gradient “Severe” Aortic Stenosis and Preserved Ejection Fraction The Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) Study

Background— Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area <1.0 cm2 and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient “severe” stenosis (defined as aortic valve area <1.0 cm2 and mean gradient ⩽40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Methods and Results— Outcome in patients with low-gradient “severe” aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm2; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67±10 years; ejection fraction, ≥55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182±64 versus 212±68 g; P<0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P=0.37; major cardiovascular events, 50.9% versus 48.5%, P=0.58; cardiovascular death, 7.8% versus 4.9%, P=0.19). Low-gradient severe stenosis patients with reduced stroke volume index (⩽35 mL/m2; n=223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P=0.53). Conclusions— Patients with low-gradient “severe” aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

Factors Influencing Left Ventricular Structure and Stress-Corrected Systolic Function in Men and Women With Asymptomatic Aortic Valve Stenosis (a SEAS Substudy)

To identify determinants of left ventricular (LV) structure and stress-corrected systolic function in men and women with asymptomatic aortic stenosis (AS), Doppler echocardiography was performed at baseline in 1,046 men and 674 women 28 to 86 years of age (mean 67 +/- 10) recruited in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study evaluating placebo-controlled combined simvastatin and ezetimibe treatment in AS. LV hypertrophy was less prevalent in women despite older age, higher systolic blood pressure, and smaller aortic valve area/body surface area (all p values <0.05). In logistic regression analyses, LV hypertrophy was independently associated with male gender, severity of AS, hypertension, higher systolic blood pressure, and lower stress-corrected midwall shortening (scMWS) or stress-corrected fractional shortening (scFS; all p values <0.01). In men aortic regurgitation also was a predictor of LV hypertrophy (p <0.05). Women had greater scFS and scMWS when corrected for LV size or geometry (all p values <0.001). In multivariate analyses, female gender predicted 11% greater scFS and 4% greater scMWS independent of age, body mass index, heart rate, aortic valve area, LV mass, relative wall thickness, aortic regurgitation, hypertension, and end-systolic stress (R(2) = 0.23 and 0.59, respectively, p <0.001). In conclusion, the major determinants of LV hypertrophy in patients with asymptomatic AS are male gender, severity of AS, and concomitant hypertension. Women have higher stress-corrected indexes of systolic function independent of LV geometry or size, wall stress, older age, or more concomitant hypertension.

Hypertension in Aortic Stenosis Implications for Left Ventricular Structure and Cardiovascular Events

The impact of hypertension on left ventricular structure and outcome during progression of aortic valve stenosis has not been reported from a large prospective study. Data from 1616 patients with asymptomatic aortic stenosis randomized to placebo-controlled treatment with combined simvastatin and ezetimibe in the Simvastatin Ezetimibe in Aortic Stenosis Study were used. The primary study end point included combined cardiovascular death, aortic valve events, and ischemic cardiovascular events. Hypertension was defined as history of hypertension or elevated baseline blood pressure. Left ventricular hypertrophy was defined as left ventricular mass/height2.7 ≥46.7 g/m2.7 in women and ≥49.2 g/m2.7 in men and concentric geometry as relative wall thickness ≥0.43. Baseline peak aortic jet velocity and aortic stenosis progression rate did not differ between hypertensive (n=1340) and normotensive (n=276) patients. During 4.3 years of follow-up, the prevalence of concentric left ventricular hypertrophy increased 3 times in both groups. Hypertension predicted 51% higher incidence of abnormal LV geometry at final study visit independent of other confounders (P<0.01). In time-varying Cox regression, hypertension did not predict increased rate of the primary study end point. However, hypertension was associated with a 56% higher rate of ischemic cardiovascular events and a 2-fold increased mortality (both P<0.01), independent of aortic stenosis severity, abnormal left ventricular geometry, in-treatment systolic blood pressure, and randomized study treatment. No impact on aortic valve replacement was found. In conclusion, among patients with initial asymptomatic mild-to-moderate aortic stenosis, hypertension was associated with more abnormal left ventricular structure and increased cardiovascular morbidity and mortality.The impact of hypertension on left ventricular structure and outcome during progression of aortic valve stenosis has not been reported from a large prospective study. Data from 1616 patients with asymptomatic aortic stenosis randomized to placebo-controlled treatment with combined simvastatin and ezetimibe in the Simvastatin Ezetimibe in Aortic Stenosis Study were used. The primary study end point included combined cardiovascular death, aortic valve events, and ischemic cardiovascular events. Hypertension was defined as history of hypertension or elevated baseline blood pressure. Left ventricular hypertrophy was defined as left ventricular mass/height2.7 ≥46.7 g/m2.7 in women and ≥49.2 g/m2.7 in men and concentric geometry as relative wall thickness ≥0.43. Baseline peak aortic jet velocity and aortic stenosis progression rate did not differ between hypertensive (n=1340) and normotensive (n=276) patients. During 4.3 years of follow-up, the prevalence of concentric left ventricular hypertrophy increased 3 times in both groups. Hypertension predicted 51% higher incidence of abnormal LV geometry at final study visit independent of other confounders ( P <0.01). In time-varying Cox regression, hypertension did not predict increased rate of the primary study end point. However, hypertension was associated with a 56% higher rate of ischemic cardiovascular events and a 2-fold increased mortality (both P <0.01), independent of aortic stenosis severity, abnormal left ventricular geometry, in-treatment systolic blood pressure, and randomized study treatment. No impact on aortic valve replacement was found. In conclusion, among patients with initial asymptomatic mild-to-moderate aortic stenosis, hypertension was associated with more abnormal left ventricular structure and increased cardiovascular morbidity and mortality. # Novelty and Significance {#article-title-41}

Impact of hypertension on left ventricular structure in patients with asymptomatic aortic valve stenosis (a SEAS substudy).

Objective Both hypertension and aortic valve stenosis induce left ventricular hypertrophy. However, less is known about the influence of concomitant hypertension on left ventricular structure in patients with aortic valve stenosis. Methods Baseline Doppler echocardiography was performed in 1720 patients with asymptomatic aortic valve stenosis (peak transaortic velocity ≥2.5 m/s and ≤4.0 m/s) recruited in the Simvastatin and Ezetimibe in Aortic Stenosis study at 173 centers in seven European countries. Patients were grouped as normotensive (n = 482) or hypertensive (n = 1238) according to history of hypertension or clinic blood pressure greater than 140 mmHg systolic or greater than 90 mmHg diastolic at baseline visits. Results Hypertensive patients were older, more obese, and included more women (all P < 0.05). Furthermore, the hypertensive group had higher wall thicknesses and left ventricular mass and higher prevalence of left ventricular hypertrophy (40 vs. 25%) and increased relative wall thickness (21 vs. 14%, both P < 0.01). On the basis of aortic valve area and energy loss the degree of aortic valve stenosis did not differ between the groups. In multivariate analysis, hypertension predicted higher left ventricular mass independent of other well known confounders including male sex, circumferential end-systolic stress, body mass index, aortic regurgitation, left ventricular ejection fraction and severity of aortic stenosis (multiple R2 = 0.30, P < 0.001). Conclusion In patients with asymptomatic aortic stenosis, concomitant hypertension significantly influences left ventricular geometry and is associated with higher left ventricular mass, relative wall thickness and higher prevalence of left ventricular hypertrophy.

Clinical Implications of Electrocardiographic Left Ventricular Strain and Hypertrophy in Asymptomatic Patients with Aortic Stenosis: The Simvastatin and Ezetimibe in Aortic Stenosis Study

Background— The prognostic impact of ECG left ventricular strain and left ventricular hypertrophy (LVH) in asymptomatic aortic stenosis is not well described. Methods and Results— Data were obtained in asymptomatic patients randomized to simvastatin/ezetimibe combination versus placebo in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Primary end point was the first of myocardial infarction, nonhemorrhagic stroke, heart failure, aortic valve replacement, or cardiovascular death. The predictive value of ECG left ventricular strain (defined as T-wave inversion in leads V4 through V6) and LVH, assessed by Sokolow-Lyon voltage criteria (RV5–6+SV1 ≥35 mV) and Cornell voltage-duration criteria {[RaVL+SV3+(6 mV in women)]×QRS duration ≥2440 mV · ms}, was evaluated by adjustment for other prognostic covariates. A total of 1533 patients were followed for 4.3±0.8 years (6592 patient-years of follow-up), and 627 cardiovascular events occurred. ECG strain was present in 340 patients (23.6%), with LVH by Sokolow-Lyon voltage in 260 (17.1%) and by Cornell voltage-duration product in 220 (14.6%). In multivariable analyses, ECG left ventricular strain was associated with 3.1-fold higher risk of in-study myocardial infarction (95% confidence interval, 1.4–6.8; P=0.004). Similarly, ECG LVH by both criteria predicted, compared with no ECG LVH, 5.8-fold higher risk of heart failure (95% confidence interval, 2.0–16.8), 2.0-fold higher risk of aortic valve replacement (95% confidence interval, 1.3–3.1; both P=0.001), and 2.5-fold higher risk of a combined end point of myocardial infarction, heart failure, or cardiovascular death (95% confidence interval, 1.3–4.9; P=0.008). Conclusions— ECG left ventricular strain and LVH were independently predictive of poor prognosis in patients with asymptomatic aortic stenosis. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Impact of Baseline Severity of Aortic Valve Stenosis on Effect of Intensive Lipid Lowering Therapy (from the SEAS Study)

Retrospective studies have suggested a beneficial effect of lipid-lowering treatment on the progression of aortic stenosis (AS) in milder stages of the disease. In the randomized, placebo-controlled Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, 4.3 years of combined treatment with simvastatin 40 mg and ezetimibe 10 mg did not reduce aortic valve events (AVEs), while ischemic cardiovascular events (ICEs) were significantly reduced in the overall study population. However, the impact of baseline AS severity on treatment effect has not been reported. Baseline and outcomes data in 1,763 SEAS patients (mean age 67 years, 39% women) were used. The study population was divided into tertiles of baseline peak aortic jet velocity (tertile 1: ≤ 2.8 m/s; tertile 2: > 2.8 to 3.3 m/s; tertile 3: > 3.3 m/s). Treatment effect and interaction were tested in Cox regression analyses. The rates of AVEs and ICEs increased with increasing baseline severity of AS. In Cox regression analyses, higher baseline peak aortic jet velocity predicted higher rates of AVEs and ICEs in all tertiles (all p values < 0.05) and in the total study population (p < 0.001). Simvastatin-ezetimibe treatment was not associated with a statistically significant reduction in AVEs in any individual tertile. A significant quantitative interaction between the severity of AS and simvastatin-ezetimibe treatment effect was demonstrated for ICEs (p < 0.05) but not for AVEs (p = 0.10). In conclusion, the SEAS study results demonstrate a strong relation between baseline the severity of AS and the rate of cardiovascular events but no significant effect of lipid-lowering treatment on AVEs, even in the group with the mildest AS.

Left Ventricular Systolic and Diastolic Function in Asymptomatic Patients With Moderate Aortic Stenosis

Tissue Doppler imaging (TDI) has improved the ability to detect subclinical changes in left ventricular (LV) function. The aim of this study was to investigate if asymptomatic patients with moderate aortic stenosis (AS) had impaired LV systolic and diastolic function. Fifty patients (mean age 65 +/- 12 years) recruited into the multicenter Simvastatin + Ezetimibe in Aortic Stenosis (SEAS) study with aortic peak velocities of 2.5 and 4.0 m/s were compared with 26 healthy subjects (mean age 64 +/- 12 years) (p = NS). Peak systolic tissue velocities and strain were measured at 8 LV locations and averaged. Early diastolic tissue velocity from the septal mitral annulus (Esep) was measured as an index of LV relaxation. The ratio of early diastolic transmitral pulsed Doppler (E) to Esep (E/Esep) was calculated as an index of LV filling pressure. Peak systolic tissue velocity (4.1 +/- 1.0 vs 4.8 +/- 1.1 cm/s, p <0.01) and strain (-16.6 +/- 2.7% vs -17.9 +/- 2.0%, p <0.05) were decreased in patients with AS compared with controls. Esep was decreased (4.9 +/- 1.0 vs 5.8 +/- 1.3 cm/s, p <0.01) and E/Esep was increased (17.4 +/- 9.7 vs 11.7 +/- 3.8, p <0.01) in the AS group compared with the control group. In conclusion, asymptomatic patients with moderate AS have impaired LV systolic function as measured by reduced peak systolic tissue velocity and strain. Augmented LV filling pressure measured by E/Esep and impaired LV relaxation measured by reduced Esep also indicate diastolic dysfunction in these patients.

Hyperlipidaemia and aortic valve disease.

Purpose of review Degenerative aortic valve stenosis is a common disease in the elderly, and traditional risk factors for atherosclerotic disease including hyperlipidaemia have been associated with the condition in several studies. This review addresses the role of the various risk factors and the potential for intervention. Recent findings The association of lipid abnormalities such as high lipoprotein(a) levels and the presence of the apolipoprotein E4 allele with aortic stenosis, as well as the presence of several inflammatory markers both in plasma and in surgically excised valves, suggest that the stenotic process is driven by many of the same factors behind atherosclerosis. The aortic valves of animals fed a cholesterol-rich diet exhibit many characteristics in common with the early stages of aortic stenosis. This opens up the potential of retarding the process through intervention strategies. Summary Hyperlipidaemia is associated with degenerative aortic valve stenosis, and the disease resembles the inflammatory process of atherosclerosis. Randomized controlled clinical trials will be needed to demonstrate the role of lipid intervention in patients with this condition.